Deuterated domperidone for treating gastroparesis - Patent Application 20070229933

Abstract

The present disclosure relates to methods for increasing gastric emptying in humans with gastroparesis. TIFF2025514817000044.tif44158

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 333,042, filed April 20, 2022, and No. 63 / 333,034, filed April 20, 2022, the disclosures of which are incorporated herein by reference.

[0002] Technical Field The present application relates to methods for increasing gastric emptying in humans with gastroparesis. [Background technology]

[0003] background Gastroparesis is defined as impaired gastric emptying in the absence of physical gastric outlet obstruction. Symptoms include early satiety, postprandial fullness, nausea, vomiting, and abdominal pain. Gastroparesis, especially of diabetic origin, affects the nutritional status of the patient, and severe symptoms of gastroparesis can lead to other complications such as malnutrition, esophagitis, and Mallory-Weiss tears. Gastroparesis negatively impacts the patient's quality of life, causing reduced social interaction, poor occupational functioning, and the development of anxiety or depression.

[0004] First-line treatment for gastroparesis involves nutritional management and support, including fluid and electrolyte replacement. Currently, metoclopramide, a dopamine D2 receptor antagonist, is the only agent approved by the U.S. Food and Drug Administration for the treatment of gastroparesis. Unfortunately, this agent readily crosses the blood-brain barrier, resulting in central nervous system (CNS) side effects in up to 40% of patients.

[0005] There is a need for a safe and effective treatment for gastroparesis. Summary of the Invention

[0006] overview In some aspects, the disclosure provides a method for increasing gastric emptying in a human with gastroparesis, the method comprising orally administering to the human between 5 mg and 120 mg of deuterium peridone daily.

[0007] Other aspects and embodiments of the present invention will become readily apparent from the following detailed description of the invention. [Brief description of the drawings]

[0008] [Figure 1] Figure 2 is a study summary for Example 2. In this figure, *expected dose level; **subjects were randomized to CIN-102 or placebo by cohort. Randomization occurred on the morning of day 1; ***subjects participating in the intensive PK subgroup visited the clinic on days 15 and 16 (day +1). Subjects participating in the sparse PK subgroup visited on days 15 or 16 (day +1). [Figure 2A] Figures 2A and 2B are linear scale plots of mean (± standard deviation) plasma diuodosperidone concentrations by treatment following morning dosing of diuodosperidone on days 1 and 14 for the pharmacokinetic population. Figure 2A is for cohort 3 (diuodosperidone 5 mg BID) and Figure 2B is for cohort 1 (diuodosperidone 10 mg BID). In this figure, the LLOQ for deuterated diuodosperidone = 0.01 ng / mL. Concentrations outside the analytical collection period for each time point were excluded from this plot. [Figure 2B] See legend to Figure 2A. [Figure 3A] Figure 3 is a linear and semi-logarithmic plot of mean (± standard deviation) plasma deuterated domperidone concentrations by treatment for Pharmacokinetic Population - Cohort 2: CIN-102 20 mg QD on days 1 and 14. For this figure, the LLOQ for deuterated domperidone=0.01 ng / mL. Concentrations outside the analytical collection period for each time point were excluded from this plot. No 24 hour time points were collected on day 1. [Figure 3B]See legend to Figure 3A. [Figure 4] Line graph of change from baseline HR (ΔHR) across time points (QT / QTc population). In this figure, LS means and 90% CI based on the linear mixed-effects model for active and placebo treatment groups: ΔHR=time+treatment+time×treatment+baseline HR+period+sequence. An unstructured covariance structure was used to specify repeated measures at post-dose time points for subjects within the treatment period. The model also included subject-specific random effects. [Diagram 5] Line graph of change from baseline QTcF (ΔQTcF) across time points (QT / QTc population). In this figure, LS means and 90% CI based on the linear mixed-effects model for active and placebo treatment groups: ΔQTcF=time+treatment+time×treatment+baseline QTcF+period+sequence. An unstructured covariance structure was used to specify repeated measures at post-dose time points for subjects within the treatment period. The model also included subject-specific random effects. [Figure 6] Scatter plot of observed M3 plasma concentrations versus estimated placebo-adjusted ΔQTcF (PK / QTc population). In this figure, the solid red line with dashed red line represents the model-predicted mean ΔΔQTcF with 90% CI calculated from the equation ΔΔQTcF=0.3678(ms)+0.1439(ms per ng / mL)×M3 concentration (ng / mL). Plotted points represent pairs of observed drug plasma concentrations and estimated placebo-adjusted ΔQTcF (ΔΔQTcF) per subject for each of the active treatment and placebo groups. The individually estimated placebo-adjusted ΔQTcFi,k (ΔΔQTcFi,k) is equal to the individual ΔQTcFi,k at time point k for subject i receiving active or placebo minus the estimate of the time effect at time point k. [Figure 7]Graph of model-predicted ΔΔQTcF (mean and 90% CI) and estimated placebo-adjusted ΔQTcF (mean and 90% CI) across deciles of M3 plasma concentrations (PK / QTc population). In this figure, the solid black line with grey shaded area represents the model-predicted mean ΔΔQTcF with 90% CI calculated from the formula ΔΔQTcF=0.3678(ms)+0.1439(ms per ng / mL)×M3 concentration (ng / mL). The vertical bars represent the estimated mean placebo-adjusted ΔQTcF (ΔΔQTcF) with 90% CI at the relevant median plasma concentration within each decile for M3 concentrations, where the individually estimated placebo-adjusted ΔQTcFi,k (ΔΔQTcFi,k) is equal to the individual ΔQTcFi,k for subject i who received M3 at time point k minus the estimate of the time effect at time point k. The vertical bars represent the mean placebo-adjusted ΔQTcF with 90% CI for placebo at concentration 0. The notched red horizontal lines indicate the concentration ranges divided into deciles for M3 concentrations. The area between each decile represents the point where 10% of the data lie; the first to second notch represents the first 10% of the data, the second to third notch represents 10-20% of the data, etc. [Figure 8] Graph of model predicted ΔΔQTcF intervals over the range of observed diuodosperidone plasma concentrations following administration of 30 mg and 100 mg CIN-102, and at the geometric mean peak diuodosperidone concentration (PK / QTc population). In this figure, the solid black line with grey shaded area represents the model predicted mean (90% CI) ΔΔQTcF calculated from the formula ΔΔQTcF=-0.02844(ms)+0.7918(ms per ng / mL)×diuodosperidone concentration (ng / mL). The blue and red vertical lines represent the estimated mean (90% CI) ΔΔQTcF with the points plotted at the geometric mean Cmax of diuodosperidone. [Figure 9]Graph of placebo-corrected change from baseline HR (ΔΔHR) across time points (QT / QTc population). LS means and 90% CI based on linear mixed-effects model for active and placebo treatment groups: ΔHR=time+treatment+time×treatment+baseline HR+period+sequence. Unstructured covariance structures were used to specify repeated measures at post-dose time points for subjects within the treatment period. The model also included subject-specific random effects. [Figure 10] Scatter plot of observed deuterated domperidone plasma concentrations vs. ΔQTcF with linear regression line and LOESS regression (PK / QTc population). In this figure, the red line with blue shaded area represents the LOESS regression and 90% confidence limits. The solid black line represents the linear regression line. The plotted points represent observed deuterated domperidone plasma concentration vs. ΔQTcF pairs. [Figure 11] Graph of placebo-corrected change from baseline QTcF (ΔΔQTcF) across time points (QT / QTc population). Linear mixed-effects model for active and placebo treatment groups: ΔQTcF=time+treatment+time×treatment+baseline QTcF+period+sequence, with LS means and 90% CI. Unstructured covariance structures were used to specify repeated measures at post-dose time points for subjects within the treatment period. The model also included subject-specific random effects. [Figure 12] Graph of mean deuterated domperidone plasma concentrations over time by dose (PK / QTc population). The figure shows the mean ± SD from descriptive statistics. When the mean-SD was below 0, 0 was used instead since concentrations below 0 are biologically impossible. [Figure 13] Graph of mean CIN-102 M3 plasma concentrations over time by dose (PK / QTc population). The figure shows the mean ± SD from descriptive statistics. When the mean-SD was below 0, 0 was used instead since concentrations below 0 are biologically impossible. [Figure 14]Scatter plot of observed CIN-102 M3 plasma concentrations vs. ΔQTcF with linear regression line and LOESS regression (PK / QTc population). The red line with blue shaded area represents the LOESS regression and 90% confidence limits. The solid black line represents the linear regression line. The plotted points represent observed CIN-102 M3 plasma concentration vs. ΔQTcF pairs. [Figure 15] Scatter plot of observed deuterated domperidone plasma concentrations and estimated placebo-adjusted ΔQTcF (PK / QTc population). The solid red line with dashed red line represents the model-predicted mean ΔΔQTcF with 90% CI calculated from the equation ΔΔQTcF=-0.02844(ms)+0.7918(ms per ng / mL)×deuterated domperidone concentration (ng / mL). Plotted points represent pairs of observed drug plasma concentration and estimated placebo-adjusted ΔQTcF (ΔΔQTcF) per subject for each of the active and placebo groups. The individually estimated placebo-adjusted ΔQTcFi,k (ΔΔQTcFi,k) is equal to the individual ΔQTcFi,k for subject i receiving active or placebo at time point k minus the estimate of the time effect at time point k. [Figure 16]Graph of model-predicted ΔΔQTcF (mean and 90% CI) and estimated placebo-adjusted ΔQTcF (mean and 90% CI) across deciles of deuterated domperidone plasma concentrations (PK / QTc population). The solid black line with grey shaded area represents the model-predicted mean ΔΔQTcF with 90% CI calculated from the equation ΔΔQTcF=-0.02844(ms)+0.7918(ms per ng / mL)×deuterated domperidone concentration (ng / mL). The vertical bars represent the estimated mean placebo-adjusted ΔQTcF (ΔΔQTcF) with 90% CI at the relevant median plasma concentration within each decile for deuterated domperidone concentrations, where the individually estimated placebo-adjusted ΔQTcFi,k (ΔΔQTcFi,k) is equal to the individual ΔQTcFi,k for subject i who received deuterated domperidone at time point k minus the time effect estimate at time point k. The vertical bars represent the mean placebo-adjusted ΔQTcF for placebo at concentration 0 with 90% CI. The notched red horizontal lines indicate the concentration ranges divided into deciles for deuterated domperidone concentrations. The area between each decile represents the point where 10% of the data lies; the first notch to the second notch represents the first 10% of the data, the second notch to the third notch represents 10-20% of the data, etc. [Figure 17] Graph of change from baseline PR (ΔPR) across time points (QT / QTc population). LS means and 90% CI based on linear mixed-effects model for active and placebo treatment groups: ΔPR=time+treatment+time×treatment+baseline PR+duration+sequence. Unstructured covariance structures were used to specify repeated measures at post-dose time points for subjects within the treatment period. The model also included subject-specific random effects. [Figure 18]Graph of placebo-corrected change from baseline PR (ΔΔPR) across time points (QT / QTc population). LS means and 90% CI based on linear mixed-effects model for active and placebo treatment groups: ΔPR=time+treatment+time×treatment+baseline PR+duration+sequence. Unstructured covariance structures were used to specify repeated measures at post-dose time points for subjects within the treatment period. The model also included subject-specific random effects. [Figure 19] Graph of change from baseline QRS (ΔQRS) across time points (QT / QTc population). LS means and 90% CI based on linear mixed-effects model for active and placebo treatment groups: ΔQRS=time+treatment+time×treatment+baseline QRS+duration+sequence. Unstructured covariance structures were used to specify repeated measures at post-dose time points for subjects within the treatment period. The model also included subject-specific random effects. [Figure 20] Graph of placebo-corrected change from baseline QRS (ΔΔQRS) across time points (QT / QTc population). LS means and 90% CI based on linear mixed-effects model for active and placebo treatment groups: ΔQRS=time+treatment+time×treatment+baseline QRS+duration+sequence. Unstructured covariance structures were used to specify repeated measures at post-dose time points for subjects within the treatment period. The model also included subject-specific random effects. [Figure 21] Graph of model predicted ΔΔQTcF interval at geometric mean peak CIN-102 M3 concentration (PK / QTc population). In this figure, the solid black line with grey shaded area represents the model predicted mean (90% CI) ΔΔQTcF, which is calculated from the formula ΔΔQTcF=0.3678(ms)+0.1439(ms per ng / mL)×CIN-102 M3 concentration (ng / mL). The grey unshaded area represents the estimated mean (90% CI) ΔΔQTcF with the points plotted at the geometric mean Cmax of CIN-102 M3. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS In this disclosure, the singular forms "a," "an," and "the" include plural referents and reference to a particular numerical value includes at least that particular value unless the context clearly dictates otherwise. Thus, for example, reference to "a material" is a reference to at least one of such material and equivalents thereof known to those skilled in the art, and so forth.

[0010] When values ​​are expressed as approximations by using the descriptor "about", it is understood that the particular value forms another aspect. In general, the use of the term "about" means an approximation that can vary depending on the desired properties to be obtained by the disclosed subject matter and should be interpreted in the specific context in which it is used based on its function. Those skilled in the art can interpret this as a given. In some cases, the number of significant figures used for a particular value can be one non-limiting way to determine the extent of the phrase "about". In other cases, the scale used for a series of values ​​can be used to determine the intended range available for the term "about" for each value. When present, all ranges are inclusive and combinable. That is, reference to values ​​stated in the form of a range includes every value within that range.

[0011] When lists are presented, it is to be understood that each individual member of that list and any combination of that list is to be construed as a separate embodiment unless otherwise stated. For example, a list of embodiments presented as "A, B, or C" should be construed as including the embodiments "A," "B," "C," "A or B," "A or C," "B or C," or "A, B, or C."

[0012] For clarity, certain features of the invention described herein in the context of separate embodiments should be construed as also being provided in combination in a single embodiment. That is, unless clearly incompatible or excluded, individual embodiments are considered combinable with any other embodiment, and such combinations are considered to be separate embodiments. Conversely, various features of the invention that are described in the context of a single embodiment for brevity may also be provided separately or in any subcombination. Furthermore, it should be noted that the claims may be drafted to exclude optional elements. As such, this statement is intended to serve as a predicate for the use of such exclusive language, such as "solely," "only," and the like, or the use of "negative" limitations in connection with the recitation of claim elements. Finally, while an embodiment may be described as part of a series of steps, or as part of a more general structure, each of said steps may also be considered an independent embodiment in itself.

[0013] The terms "subject" and "patient" are used interchangeably and typically refer to a human. In some embodiments, the human is an adult, i.e., 18 years of age or older. In other embodiments, the human is a child, i.e., under 18 years of age.

[0014] "Treating" or variations thereof refers to removing or reducing at least one physical parameter of a disease or disorder. In other embodiments, "treating" refers to modulating a disease or disorder, either physically (e.g., by stabilizing a discernible symptom), physiologically (e.g., stabilizing a physical parameter), or both. In further embodiments, "treating" refers to delaying the onset of a disease or disorder.

[0015] "Duodoperidone", "d4-domodoperidone", or "CIN-102" as referred to herein are interchangeable and have the following structure: refers to 1-{3-[4-(5-chloro-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidin-1yl]propyl}-2,3-dihydro(4,5,6,7-D4)-1H-1,3-benzodiazol-2-one with TIFF2025514817000002.tif31128.

[0016] Any reference to dewdonperidone, when stated, may also include pharma- ceutically acceptable salts, esters, hydrates, solvates, prodrug forms, and derivatives thereof, which are broadly defined as modified or partially substituted dewdonperidone compounds.

[0017] "Pharmaceutically acceptable" refers to properties and / or substances that are acceptable to a patient from a pharmacological / toxicological standpoint, and acceptable to a pharmaceutical chemist from a physical / chemical standpoint with respect to composition, formulation, stability, patient acceptance, and bioavailability.

[0018] Pharmaceutically acceptable salts include salts with pharmaceutically acceptable acids or bases. In some embodiments, the pharmaceutically acceptable salts are salts with acids such as inorganic acids. Examples of inorganic acids include hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid, hydroiodic acid and nitric acid. In other embodiments, the pharmaceutically acceptable salts are salts with organic acids. Examples of organic acids include citric acid, fumaric acid, maleic acid, malic acid, mandelic acid, ascorbic acid, oxalic acid, succinic acid, tartaric acid, benzoic acid, acetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, cyclohexylsulfamic acid (cyclamic acid) or p-toluenesulfonic acid. In further embodiments, the pharmaceutically acceptable salts are salts with bases such as alkali metals. Examples of alkali metals include sodium or potassium. In still other embodiments, the pharmaceutically acceptable salts are salts with bases such as alkaline earth metals. Examples of alkaline earth metals include calcium hydroxide or magnesium hydroxide. In yet a further aspect, the pharma- ceutically acceptable salt is a salt with an organic base. Examples of organic bases include alkylamines, arylalkylamines, and heterocyclic amines.

[0019] The abbreviation "D" as used herein means deuterium (heavy hydrogen or 2 "H" refers to a stable isotope of hydrogen that is hydrogen (H). Such instances of "D" contain an amount of deuterium above the natural distribution of deuterium. In some embodiments, D has a deuterium enrichment of about 1% or greater. In other embodiments, D has a deuterium enrichment of about 5% or greater. In further embodiments, D has a deuterium enrichment of about 10% or greater. In still other embodiments, D has a deuterium enrichment of about 20% or greater. In still other embodiments, D has a deuterium enrichment of about 30% or greater. In still other embodiments, D has a deuterium enrichment of about 40% or greater. In still further embodiments, D has a deuterium enrichment of about 50% or greater. In still other embodiments, D has a deuterium enrichment of about 60% or greater. In other embodiments, D has a deuterium enrichment of about 70% or greater. In further embodiments, D has a deuterium enrichment of about 80% or greater. In still other embodiments, D has a deuterium enrichment of about 90% or greater. In even further embodiments, D has a deuterium enrichment of about 98% or greater. In even further embodiments, D has a deuterium enrichment of about 99% or greater. In even further embodiments, D has a deuterium enrichment of at least 99%.

[0020] The present disclosure provides a method for increasing gastric emptying, particularly for increasing gastric emptying in humans with gastroparesis.The term "gastroparesis" as used herein refers to a disorder with delayed gastric emptying in the absence of physical gastric outlet obstruction.In some aspects, gastroparesis is idiopathic gastroparesis.In other aspects, gastroparesis is diabetic gastroparesis.

[0021] Before administration of dewdonperidone, the human may experience upper gastrointestinal symptoms. In some embodiments, the upper gastrointestinal symptoms are nausea, vomiting, postprandial fullness, early satiety, abdominal distension, epigastric pain, abdominal pain, or combinations thereof. In other embodiments, the upper gastrointestinal symptoms are nausea. In further embodiments, the upper gastrointestinal symptoms are vomiting. In still other embodiments, the gastrointestinal symptoms are postprandial fullness. In still further embodiments, the gastrointestinal symptoms are early satiety. In other embodiments, the gastrointestinal symptoms are abdominal distension. In still further embodiments, the gastrointestinal symptoms are epigastric pain. In still other embodiments, the gastrointestinal symptoms are abdominal pain.

[0022] The method includes orally administering 5 mg to 120 mg of diuodosperidone to a human daily. For example, the free base of diuodosperidone is administered to the human. In some embodiments, the daily dose of diuodosperidone is about 5, about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, or about 120 mg. In other embodiments, the daily dose of dudomeperidone is about 5 to about 120, about 5 to about 110, about 5 to about 100, about 5 to about 90, about 5 to about 80, about 5 to about 70, about 5 to about 60, about 5 to about 50, about 5 to about 40, about 5 to about 30, about 5 to about 20, about 5 to about 10, about 10 to about 120, about 10 to about 110, about 10 to about 100, about 10 to about 90, about 10 to about 80, about 10 to about 70, about 10 to about 60, about 10 to about 50, about 10 to about 40, about 10 to about 30, about 10 to about 20, about 20 to about 120, about 20 to about 110, about 20 to about 100, about 20 to about 90, about 20 to about 80, about 20 to about 70, about 20 to about 60, about 20 to about 50, about 20 to about 40, about 20 to about 30, about 30 to about 120, about 30 to about 110, about 30 to about 100, about 30 to about 90, about 30 to about 80, about 30 to about 70, about 30 to about 60, about 30 to about 50, about 30 to about 40, about 40 to about 120, about 40 to about 110, about 40 to about 100, about 40 to about 90, about 40 to about 80, about 40 to about 70, about 40 to about 60, about 40 to about 50, about 50 to about 120, about 50 to about 110, about 50 to about 100, about 50 to about 90, about 50 to about 80, about 50 to about 70, about 50 to about 60, about 60 to about 120, about 60 to about 110, about 60 to about 1 00, about 60 to about 90, about 60 to about 80, about 60 to about 70, about 70 to about 120, about 70 to about 110, about 70 to about 100, about 70 to about 90, about 70 to about 80, about 80 to about 120, about 80 to about 110, about 80 to about 100, about 80 to about 90, about 90 to about 120, about 90 to about 110, about 90 to about 100, about 100 to about 120, about 100 to about 110, or about 110 to about 120 mg. In a further embodiment, the daily dose of diuodosperidone is about 5 mg. In yet another embodiment, the daily dose of diuodosperidone is about 10 mg. In an even further embodiment, the daily dose of diuodosperidone is about 20 mg. In another embodiment, the daily dose of diuodosperidone is about 30 mg. In a further embodiment, the daily dosage of diudomeperidone is about 40 mg.In another embodiment, the daily dose of diudomesperidone is about 60 mg. In yet another embodiment, the daily dose of diudomesperidone is about 90 mg. In a further embodiment, the daily dose of diudomesperidone is about 120 mg.

[0023] Dieudonperidone can be administered as needed to achieve the desired daily dosage. For example, dieudonperidone can be administered in divided doses. In some aspects, dieudonperidone is administered in one dose. In other aspects, dieudonperidone is administered in two doses. In further aspects, dieudonperidone is administered in three doses. In still other aspects, dieudonperidone is administered in four doses. In some embodiments, dieudonperidone is administered once a day (QD). In other embodiments, dieudonperidone is administered twice a day (BID). In further embodiments, dieudonperidone is administered three times a day (TID). In still other embodiments, dieudonperidone is administered four times a day (QID). In some aspects, a 10 mg daily dose of dieudonperidone is administered 10 mg QD. In other aspects, a 10 mg daily dose of dieudonperidone is administered 5 mg BID. In a further aspect, the daily dose of 20mg of diudomperidone is administered 20mg QD. In yet another aspect, the daily dose of 20mg of diudomperidone is administered 10mg BID. In yet another aspect, the daily dose of 20mg of diudomperidone is administered 5mg QID. In another aspect, the daily dose of 60mg of diudomperidone is 30mg BID. In yet another aspect, the daily dose of 120mg of diudomperidone is 60mg BID. In yet another aspect, the daily dose of 30mg of diudomperidone is 10mg TID. In yet another aspect, the daily dose of 30mg of diudomperidone is 15mg BID dose, which is given as a combination of 10mg of diudomperidone and 5mg of diudomperidone.

[0024] Before the administration of the first dose of diudomeperidone, the human has delayed gastric emptying. Gastric emptying can be measured by gastric emptying breath test (GEBT). GEBT is known in the art. Briefly, GEBT is a non-radioactive stable isotope breath test used in the art to diagnose or monitor gastroparesis. In this test, breath 13 CO2 / 12 Normalized using CO2 ratio 13 The rate of gastric emptying after ingestion of a C-enriched meal is determined. 13 C enriched diet is 13 C - Spirulina platensis. In some cases, the test is standardized after an 8-hour fast. 13 C-enriched diet. https: / / cairndiagnostics Please see the Cairn Gastric Emptying Breath Test (GEBT) Administration Guide at: .com / wp-content / uploads / 2019 / 05 / Cairn-GEBT-How-To-Guide-updated-07May2019.pdf. Breath samples should be: 13 One or more breath samples are taken before and one or more after the ingestion of a C-enriched meal. The breath samples are then measured, for example, using gas isotope ratio mass spectrometry. Higher levels of 13 C is delayed gastric emptying, i.e., the stomach 13 C indicates that the enriched food is not metabolized. Lower levels 13 C indicates normal gastric emptying. In some embodiments, gastric emptying is measured at least about 10 days before administering the first dose of diuodosperidine. In other embodiments, gastric emptying is measured 10 days before administering the first dose of diuodosperidine. In further embodiments, gastric emptying is measured about 1 to about 10 days before administering the first dose of diuodosperidine.

[0025] Humans should also take the following medication before administering dewdropperidone: 13C-Spirulina platensis may have a best fit index elimination rate (T1 / 2) of greater than about 80 minutes as measured by GEBT using Spirulina platensis. In some embodiments, the human may be administered 10 mg of diazepam prior to administration of diazepam. 13 C - T longer than approximately 100 min as measured by GEBT using Spirulina platensis 1 / 2 In another embodiment, the human has, prior to administration of dewdonperidone: 13 C - T longer than approximately 120 min as measured by GEBT using Spirulina platensis 1 / 2 In a further aspect, the human has, prior to administration of dudomeperidone: 13 C - A T longer than approximately 140 min as measured by GEBT using Spirulina platensis 1 / 2 In yet another embodiment, the human has, prior to administration of dudomeperidone: 13 C - A T longer than approximately 160 min as measured by GEBT using Spirulina platensis 1 / 2 In an even further aspect, the human has, prior to administering dewdonperidone: 13 C - T longer than approximately 180 min as measured by GEBT using Spirulina platensis 1 / 2 In another embodiment, the human has, prior to administration of dewdonperidone: 13 C - T longer than approximately 200 min as measured by GEBT using Spirulina platensis 1 / 2 has.

[0026] Prior to administering dewdonperidone, the patient may have a mean composite score of about 2 or greater on the American Neurogastroenterology and Motility Society Gastroparesis Cardinal Symptom Index Daily Diary (ANMS GCSI-DD). As known in the art, the ANMS GCSI-DD covers five core related symptoms of gastroparesis: nausea, early satiety, postprandial fullness, epigastric pain, and vomiting. Abdominal bloating is included as an exploratory symptom. Symptoms are scored on a severity numerical response scale from 0 (none) to 4 (very severe). Vomiting is captured on a frequency response scale and scored as follows: 0 is no episodes, 1 is 1 episode, 2 is 2 episodes, 3 is 3 episodes, and 4 is 4 or more episodes. In some embodiments, the subject recalls symptoms from the past 24 hours and completes the ANMS GCSI-DD patient-reported symptoms questionnaire. In some embodiments, the total ANMS GCSI-DD score is calculated as the average of three subscale scores for nausea / vomiting, postprandial bloating / early satiety, and abdominal distension severity. See, e.g., "The Use Manual for the ANMS GCSI-DD," American Neurogastroenterology and Motility Society Gastroparesis Cardinal Symptom Index Daily Diary, 2018; https: / / wwwSee .fda.gov / media / 125038 / download. In other embodiments, the total ANMS GCSI-DD score is calculated using a "manual" scoring method. The ANMS GCSI-DD manual scoring method is generated by summing the scores for each of the five symptom items (nausea, early satiety, postprandial bloating, epigastric pain, and number of vomiting episodes) and then dividing by 5, the number of items in the Gastroparesis Related Symptom Score. Thus, the maximum total symptom score can be (5 symptoms x maximum score 4 ÷ 5); thus, the maximum score is 20 / 5 = 4. The ANMS GCSI-DD Gastroparesis Symptom Daily Score can range from 0 to 4. Higher scores on the ANMS GCSI-DD reflect greater symptom severity. For example, see the ANMS GCSI-DD Manual Scoring Method for Gastroparesis, incorporated herein by reference. https: / / www See "User Manuel for the ANMS GCSI-DD," Federal Drug Administration, at .fda.gov / media / 125038 / download. In some embodiments, the ANMS GCSI-DD average composite score is 2 before administering dewdonsperidone. In other embodiments, the ANMS GCSI-DD average composite score is 3 before administering dewdonsperidone. In further embodiments, the ANMS GCSI-DD average composite score is 4 before administering dewdonsperidone.

[0027] The patient may further have an ANMS GCSI-DD subscale score of 2 or more before administering diudomesperidone. In some embodiments, the patient has an ANMS GCSI-DD nausea subscale score of 2 or more before administering diudomesperidone. In other embodiments, the patient has an ANMS GCSI-DD nausea subscale score of 2 or more for at least about 4 days before administering diudomesperidone. In other embodiments, the patient has an ANMS GCSI-DD early satiety / bloating subscale score of 2 or more before administering diudomesperidone. In further embodiments, the patient has an ANMS GCSI-DD abdominal bloating subscale score of 2 or more before administering diudomesperidone.

[0028] Desirably, the method results in increased gastric emptying in the patient. In some embodiments, the increased gastric emptying occurs after administration of dewdonperidone. 13 In some embodiments, the increase in gastric emptying is measured by GEBT using C-Spirulina platensis. In some embodiments, the increase in gastric emptying is measured at least one day after administration of deuterium peridon. 13 In a further embodiment, the increase in gastric emptying is measured by GEBT using C-Spirulina platensis. In a further embodiment, the increase in gastric emptying is measured by GEBT at baseline and at the end of the study. In another embodiment, the increase in gastric emptying is measured at about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, or about 16 days after administration of dewdonperidone. 13In another embodiment, the increase in gastric emptying is measured by GEBT using C-Spirulina platensis. , about 3 to about 5, about 3 to about 4, about 4 to about 16, about 4 to about 15, about 4 to about 14, about 4 to about 13, about 4 to about 12, about 4 to about 11, about 4 to about 10, about 4 to about 9, about 4 to about 8, about 4 to about 7, about 4 to about 6, about 4 to about 5, about 5 to about 16, about 5 to about 15, about 5 to about 14, about 5 to about 13, about 5 to about 12, about 5 to about 11, about 5 to about 10, about 5 to about 9, about 5 to about 8, about 5 to about 7, about 5 to about 6, about 6 to about 16, about 6 to about 15, about 6 to about 12, about 6 to about 11, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 16, about 7 to about 15, about 7 to about 14, about 7 to about 13, about 7 to about 12, about 7 to about 11, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 16, about 8 to about 15, about 8 to about 14, about 8 to about 13, about 8 to about 12, about 8 to about 11, about 8 to about 10, about 8 to about 9, about 9 to about 16, about 9 to about 15, about 9 to about 14, about 9 to about 13, about 9 to about 12, about 9 about 11, about 9 to about 10, about 10 to about 16, about 10 to about 16, about 10 to about 14, about 10 to about 13, about 10 to about 12, about 10 to about 11, about 11 to about 16, about 11 to about 15, about 11 to about 14, about 11 to about 13, about 11 to about 12, about 12 to about 16, about 12 to about 15, about 12 to about 14, about 12 to about 13, about 13 to about 16, about 13 to about 15, about 13 to about 14, about 14 to about 16, about 14 to about 15, or about 15 to about 16 days later, 13 In a further aspect, the increase in gastric emptying is measured by GEBT using C-Spirulina platensis. 13 C-Measured by GEBT using Spirulina platensis.

[0029] Advantageously, administration of dewdonperidone results in a clinically meaningful improvement in nausea (such as postprandial nausea), early satiety, postprandial fullness, epigastric pain, vomiting, abdominal distension, or a combination thereof, as measured by the ANMS GCSI-DD score, for example, about 6 to about 12 weeks after administration, following treatment with dewdonperidone. In one aspect, administration of dewdonperidone results in a clinically meaningful improvement in postprandial nausea, early satiety, postprandial fullness, epigastric pain, vomiting, and abdominal distension, as measured by the ANMS GCSI-DD score, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 weeks after administration. In other aspects, administration of dewdonosperidone results in clinically meaningful improvements in postprandial nausea, early satiety, postprandial fullness, upper abdominal pain, vomiting, and abdominal bloating as measured by the ANMS GCSI-DD score at about 6 to about 11, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 12, about 7 to about 11, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 12, about 8 to about 11, about 8 to about 10, about 8 to about 9, about 9 to about 12, about 9 to about 11, about 9 to about 10, about 10 to about 12, about 10 to about 11, or about 11 to about 12 weeks after administration. In some embodiments, administration of diudomesperidone results in a clinically meaningful improvement in nausea as measured by ANMS GCSI-DD score after treatment with diudomesperidone.In other embodiments, administration of diudomesperidone results in a clinically meaningful improvement in early satiety as measured by ANMS GCSI-DD score after treatment with diudomesperidone.In further embodiments, administration of diudomesperidone results in a clinically meaningful improvement in postprandial fullness as measured by ANMS GCSI-DD score after treatment with diudomesperidone.In still other embodiments, administration of diudomesperidone results in a clinically meaningful improvement in upper abdominal pain as measured by ANMS GCSI-DD score after treatment with diudomesperidone.In yet another embodiment, administration of diudomestic periodon results in a clinically meaningful improvement in vomiting as measured by ANMS GCSI-DD score after treatment with diudomestic periodon.In another embodiment, administration of diudomestic periodon results in a clinically meaningful improvement in abdominal distension as measured by ANMS GCSI-DD score after treatment with diudomestic periodon.

[0030] Administration of dewdonperidone also results in a clinically meaningful improvement in the mean composite score of the ANMS GCSI-DD score after treatment, for example, about 6 to about 12 weeks after administration. In some aspects, administration of dewdonperidone can result in a clinically meaningful improvement in the mean composite score of the ANMS GCSI-DD score after about 6, about 7, about 8, about 9, about 10, about 11, or about 12 weeks after administration. In other aspects, administration of deudomperidone may result in a clinically meaningful improvement in the mean composite score on the ANMS GCSI-DD score at about 6 to about 11, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 12, about 7 to about 11, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 12, about 8 to about 11, about 8 to about 10, about 8 to about 9, about 9 to about 12, about 9 to about 11, about 9 to about 10, about 10 to about 12, about 10 to about 11, or about 11 to about 12 weeks after administration. In some embodiments, the ANMS GCSI-DD average composite score is reduced by 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4 points after administration of dewdonperidone. In other embodiments, the ANMS GCSI-DD average composite score is reduced by 1 point after administration of dewdonperidone. In other embodiments, the ANMS GCSI-DD average composite score is reduced by 2 points after administration of dewdonperidone. In further embodiments, the ANMS GCSI-DD average composite score is reduced by 3 points after administration of dewdonperidone. In yet other embodiments, the ANMS GCSI-DD mean composite score is reduced by 4 points following administration of deudomeperidone.

[0031] Administration of dewdonperidone further results in a clinically meaningful improvement in the ANMS GCSI-DD nausea subscale score after treatment, for example, about 6 to about 12 weeks after administration. In some aspects, administration of dewdonperidone can result in a clinically meaningful improvement in the nausea subscale score of the ANMS GCSI-DD score about 6, about 7, about 8, about 9, about 10, about 11, or about 12 weeks after administration. In other aspects, administration of deudomperidone may result in a clinically meaningful improvement in the nausea subscale score of the ANMS GCSI-DD score after about 6 to about 11, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 12, about 7 to about 11, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 12, about 8 to about 11, about 8 to about 10, about 8 to about 9, about 9 to about 12, about 9 to about 11, about 9 to about 10, about 10 to about 12, about 10 to about 11, or about 11 to about 12 weeks after administration. In some embodiments, the ANMS GCSI-DD nausea subscale score is reduced by 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4 points. In further embodiments, the ANMS GCSI-DD nausea subscale is reduced by 1 point after administration of dewdonperidone. In other embodiments, the ANMS GCSI-DD nausea subscale score is reduced by 2 points after administration of dewdonperidone. In further embodiments, the ANMS GCSI-DD nausea subscale score is reduced by 3 points after administration of dewdonperidone. In yet other embodiments, the mean composite score is reduced by 4 points following administration of deudomeperidone.

[0032] Administration of diuodosperidone further results in a clinically meaningful improvement in gastric emptying as measured by GEBT about 12 to about 16 days after treatment with diuodosperidone. In some embodiments, administration of diuodosperidone further results in a clinically meaningful improvement in gastric emptying as measured by GEBT about 12, about 13, about 14, about 15, or about 16 days after treatment with diuodosperidone. In other embodiments, administration of diuodosperidone further results in a clinically meaningful improvement in gastric emptying as measured by GEBT about 12 to about 16, about 12 to about 15, about 12 to about 14, about 12 to about 13, about 13 to about 16, about 13 to about 15, about 13 to about 14, about 14 to about 16, about 14 to about 15, or about 15 to 16 days after treatment with diuodosperidone. In a further embodiment, administration of diudomesperidone further results in a clinically meaningful improvement in gastric emptying as measured by GEBT about 12 days after treatment with diudomesperidone. In yet another embodiment, administration of diudomesperidone further results in a clinically meaningful improvement in gastric emptying as measured by GEBT about 13 days after treatment with diudomesperidone. In yet a further embodiment, administration of diudomesperidone further results in a clinically meaningful improvement in gastric emptying as measured by GEBT about 14 days after treatment with diudomesperidone. In another embodiment, administration of diudomesperidone further results in a clinically meaningful improvement in gastric emptying as measured by GEBT about 15 days after treatment with diudomesperidone. In a further embodiment, administration of diudomesperidone further results in a clinically meaningful improvement in gastric emptying as measured by GEBT about 16 days after treatment with diudomesperidone.

[0033] Administration of diudomeperidone also results in clinically meaningful improvements in gastric emptying as measured by GEBT and in symptoms as measured by ANMS GCSI-DD total score after treatment.

[0034] Administration of diudomeperidone further results in clinically meaningful improvements in gastric emptying as measured by GEBT following treatment.

[0035] In yet other embodiments, administration of diudomeperidone may result in a clinically meaningful improvement in the emesis subscale score of the ANMS GCSI-DD score after administration, for example, about 6 to about 12 weeks after administration. In some aspects, administration of diudomeperidone may result in a clinically meaningful improvement in the emesis subscale score of the ANMS GCSI-DD score after about 6, about 7, about 8, about 9, about 10, about 11, or about 12 weeks after administration. In other aspects, administration of deudomperidone may result in a clinically meaningful improvement in the emesis subscale score of the ANMS GCSI-DD score at about 6 to about 11, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 12, about 7 to about 11, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 12, about 8 to about 11, about 8 to about 10, about 8 to about 9, about 9 to about 12, about 9 to about 11, about 9 to about 10, about 10 to about 12, about 10 to about 11, or about 11 to about 12 weeks after administration.

[0036] In yet further embodiments, administration of dewdonperidone may result in a clinically meaningful improvement in the total score of the ANMS GCSI-DD score after administration, for example, about 6 to about 12 weeks after administration. In some aspects, administration of dewdonperidone may result in a clinically meaningful improvement in the total score of the ANMS GCSI-DD score after about 6, about 7, about 8, about 9, about 10, about 11, or about 12 weeks after administration. In other aspects, administration of deudomperidone may result in a clinically meaningful improvement in the total score of the ANMS GCSI-DD score at about 6 to about 11, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 12, about 7 to about 11, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 12, about 8 to about 11, about 8 to about 10, about 8 to about 9, about 9 to about 12, about 9 to about 11, about 9 to about 10, about 10 to about 12, about 10 to about 11, or about 11 to about 12 weeks after administration.

[0037] In other embodiments, administration of dewdonperidone may result in a clinically meaningful improvement in the early satiety subscale score of the ANMS GCSI-DD score after administration, for example, about 6 to about 12 weeks after administration. In some aspects, administration of dewdonperidone may result in a clinically meaningful improvement in the early satiety subscale score of the ANMS GCSI-DD score after about 6, about 7, about 8, about 9, about 10, about 11, or about 12 weeks after administration. In other aspects, administration of deudomperidone may result in a clinically meaningful improvement in the early satiety subscale score of the ANMS GCSI-DD score at about 6 to about 11, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 12, about 7 to about 11, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 12, about 8 to about 11, about 8 to about 10, about 8 to about 9, about 9 to about 12, about 9 to about 11, about 9 to about 10, about 10 to about 12, about 10 to about 11, or about 11 to about 12 weeks after administration.

[0038] In further embodiments, administration of dewdonperidone may result in a clinically meaningful improvement in the postprandial bloating subscale score of the ANMS GCSI-DD score after administration, for example, about 6 to about 12 weeks after administration. In some aspects, administration of dewdonperidone may result in a clinically meaningful improvement in the postprandial bloating subscale score of the ANMS GCSI-DD score after about 6, about 7, about 8, about 9, about 10, about 11, or about 12 weeks after administration. In other aspects, administration of deudomperidone may result in a clinically meaningful improvement in the postprandial bloating subscale score of the ANMS GCSI-DD score after about 6 to about 11, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 12, about 7 to about 11, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 12, about 8 to about 11, about 8 to about 10, about 8 to about 9, about 9 to about 12, about 9 to about 11, about 9 to about 10, about 10 to about 12, about 10 to about 11, or about 11 to about 12 weeks of administration.

[0039] In yet another embodiment, administration of dewdonperidone may result in a clinically meaningful improvement in the upper abdominal pain subscale score of the ANMS GCSI-DD score after administration, for example, about 6 to about 12 weeks after administration. In one aspect, administration of dewdonperidone may result in a clinically meaningful improvement in the upper abdominal pain subscale score of the ANMS GCSI-DD score after about 6, about 7, about 8, about 9, about 10, about 11, or about 12 weeks after administration. In other aspects, administration of deudomperidone may result in a clinically meaningful improvement in the upper abdominal pain subscale score of the ANMS GCSI-DD score at about 6 to about 11, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 12, about 7 to about 11, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 12, about 8 to about 11, about 8 to about 10, about 8 to about 9, about 9 to about 12, about 9 to about 11, about 9 to about 10, about 10 to about 12, about 10 to about 11, or about 11 to about 12 weeks after administration.

[0040] In other embodiments, administration of dewdonperidone may result in a clinically meaningful improvement in gastric emptying as measured by the ANMS GCSI-DD subscale score after administration, for example, about 6 to about 12 weeks after administration. In some aspects, administration of dewdonperidone may result in a clinically meaningful improvement in gastric emptying as measured by the ANMS GCSI-DD subscale score after about 6, about 7, about 8, about 9, about 10, about 11, or about 12 weeks after administration. In other aspects, administration of deudomperidone may result in a clinically meaningful improvement in gastric emptying as measured by the ANMS GCSI-DD subscale score at about 6 to about 11, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 12, about 7 to about 11, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 12, about 8 to about 11, about 8 to about 10, about 8 to about 9, about 9 to about 12, about 9 to about 11, about 9 to about 10, about 10 to about 12, about 10 to about 11, or about 11 to about 12 weeks after administration.

[0041] In yet other embodiments, administration of dewdonperidone may result in a clinically meaningful improvement in gastric emptying as measured by the ANMS GCSI-DD total score after administration, for example, about 6 to about 12 weeks after administration. In some aspects, administration of dewdonperidone may result in a clinically meaningful improvement in gastric emptying as measured by the ANMS GCSI-DD total score after about 6, about 7, about 8, about 9, about 10, about 11, or about 12 weeks after administration. In other aspects, administration of diudomeperidone may result in a clinically meaningful improvement in gastric emptying as measured by the ANMS GCSI-DD total score at about 6 to about 11, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 12, about 7 to about 11, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 12, about 8 to about 11, about 8 to about 10, about 8 to about 9, about 9 to about 12, about 9 to about 11, about 9 to about 10, about 10 to about 12, about 10 to about 11, or about 11 to about 12 weeks after administration.

[0042] The diudomeperidone formulations described herein are useful for a variety of treatment methods, including, but not limited to, methods for treating disorders that are gastroparesis, nausea other than gastroparesis, vomiting other than gastroparesis, nausea associated with gastroparesis, vomiting associated with gastroparesis, gastroesophageal reflux disease, lactation insufficiency, chemotherapy-associated nausea and / or vomiting, or combinations thereof. The methods include administering to a patient a pharmaceutical formulation described herein. In some embodiments, the methods are useful for treating gastroparesis. In other embodiments, the methods are useful for treating nausea other than gastroparesis. In further embodiments, the methods are useful for treating vomiting other than gastroparesis. In still other embodiments, the methods are useful for treating nausea associated with gastroparesis. In still further embodiments, the methods are useful for treating vomiting associated with gastroparesis. In other embodiments, the methods are useful for treating gastroesophageal reflux disease. In further embodiments, the methods are useful for treating lactation insufficiency. In yet other embodiments, the methods are useful for treating chemotherapy-associated nausea and / or vomiting.

[0043] The pharmaceutical preparation may be administered by any route acceptable to humans. In some aspects of the pharmaceutical preparation, administration is oral, transdermal, parenteral, or a combination thereof. In further aspects, administration is oral.

[0044] The pharmaceutical formulation may be formulated for administration in solid or liquid form. In some embodiments, the pharmaceutical formulation is formulated in the form of a tablet, caplet, capsule, powder, softgel, suspension or liquid, or a combination thereof. In other embodiments, the pharmaceutical formulation is formulated in the form of a tablet. In a further embodiment, the pharmaceutical formulation is formulated in the form of a caplet. In still other embodiments, the pharmaceutical formulation is formulated in the form of a capsule. In yet further embodiments, the pharmaceutical formulation is formulated in the form of a powder. In other embodiments, the pharmaceutical formulation is formulated in the form of a softgel. In a further embodiment, the pharmaceutical formulation is formulated in the form of a suspension. In still other embodiments, the pharmaceutical formulation is formulated in the form of a liquid.

[0045] The administration of Dudoneperidone according to the present disclosure does not cause or result in clinically significant QT prolongation.For example, the ΔΔQTcF of the patient after the administration of Dudoneperidone according to the present disclosure is 10ms or less than about 10ms (for example, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or 0ms).In some aspects, the ΔΔQTcF of the patient after the administration of Dudoneperidone according to the present disclosure is about 1.5ms or less, for example, 1.5, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1 or 0ms. In some aspects, the patient's ΔΔQTcF after administration of about 30 mg or about 20 mg or about 10 mg of dudomeperidone according to the present disclosure is about 1.5 ms or less, e.g., 1.5, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, or 0 ms. In some aspects, the ΔΔQTcF of a patient following administration of about 100 mg or about 90 mg or about 80 mg or about 70 mg or about 60 mg or about 50 mg or about 40 mg of dudomeperidone according to the present disclosure is about 3.5 ms or less, e.g., 3.5, 3.4, 3.3, 3.2, 3.1, 3, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1, 2, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, or 0 ms.

[0046] Moreover, administering diudone peridone according to the present disclosure does not cause or result in a clinically meaningful change in the patient's heart rate. In a further aspect, administering diudone peridone according to the present disclosure does not cause or result in a clinically meaningful change in the patient's cardiac conduction. In other aspects, the patient's pulse-to-pulse (PR) interval is about 0.12 to about 0.2 seconds (e.g., 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2 seconds) after administration of diudone peridone according to the disclosed methods. In some aspects, the patient's QRS interval is about 0.08 and 0.10 seconds (e.g., 0.08, 0.09, 0.10 seconds) after administration of diudone peridone.

[0047] The following examples are provided to illustrate some of the concepts described within this disclosure. The examples are believed to provide specific, individual aspects of the formulations, preparations and methods of use, but should be considered as limitations of the more general aspects described herein.

[0048] In the following examples, efforts have been made to ensure accuracy with respect to numbers used (eg, amounts, temperatures, etc.) but some experimental error and deviation should be accounted for. TIFF2025514817000003.tif214152TIFF2025514817000004.tif234152TIFF2025514817000005.tif27152 EXAMPLES

[0049] Example 1 This is a randomized, double-blind, placebo-controlled Phase 2A study to evaluate the safety, efficacy, PK, and dose-response of oral deuterated peridone in adults with idiopathic or diabetic gastroparesis.

[0050] The study will begin by randomizing subjects in cohort 1 to either dewdonperidone 10mg BID or placebo BID, with a ratio such that 15 subjects will receive dewdonperidone and 5 subjects will receive placebo. Subjects will be selected to enter either the minority pharmacokinetic sampling subgroup or the intensive PK sampling subgroup. At randomization, the study will be stratified by idiopathic gastroparesis and diabetic gastroparesis. The dose levels for cohorts 2 and 3 will be 20mg QD and 5mg BID, respectively, with 15 subjects receiving the study drug and 5 subjects receiving placebo in each cohort. The maximum dose will not exceed 60mg BID.

[0051] Subjects are evaluated as follows: Days -28 to -11: Screening procedures will be performed. The ANMS GCSI-DD questionnaire will be completed daily for at least 14 days prior to randomization. Days -10 to -3: Complete the ANMS GCSI-DD questionnaire daily. On one day during this period, perform the GEBT and standardize. 13 Breath samples will be obtained twice prior to ingestion of the C-enriched meal, and then at 45, 90, 120, 150, 180, and 240 minutes after ingestion of the meal following an 8-hour fast. Prior to the start of GEBT, a baseline PAGI-SYM will be completed. Days -3 to -1: Complete a pre-randomization visit to conduct safety assessments and allow sufficient time for laboratory test results prior to Day 1 (randomization). Days 1-14: Administer study medication (deuxoperidone or placebo BID for 14 (± 2 days) and conduct safety assessments; complete the ANMS GCSI-DD questionnaire daily and complete PK blood draws at specific time points. On day 14 (± 2 days), complete the PAGI-SYM and Clinical Grading Assessment questionnaires prior to the final dose of study medication. Day 14 (± 2 days): On day 14 (± 2 days), GEBT will be performed 30 minutes after administration of the study drug. 13 Breath samples are obtained twice before ingestion of the C-enriched meal and then at 45, 90, 120, 150, 180, and 240 min after ingestion of the meal after an 8-h fast.

[0052] Subjects are stratified at randomization based on the subject's etiology for gastroparesis (ie, diabetic vs. idiopathic gastroparesis).

[0053] On the day of GEBT, subjects will come to the clinic after an overnight fast but should be taking regular medications including any treatment for diabetes (excluding any prohibited concomitant medications). Subjects will self-administer their usual morning insulin injection taking into account their fasting status. Subjects will be instructed to bring their study medication and additional insulin if needed to the clinic. Fasting blood glucose will be assessed prior to administration of study medication and assessment of gastric emptying to ensure blood glucose is ≦275 mg / dL. Additional insulin (prorated based on meal caloric content) may be given to ensure blood glucose is ≦275 mg / dL prior to the gastric emptying procedure.

[0054] Subjects will have a follow-up visit 1-3 days after the last dose of study drug to assess adverse events, changes to concomitant medications (including rescue medication use), vital signs, and for PK specimen collection. Subjects participating in the intensive PK subgroup will visit the clinic on days 3 (± 1 day), 7 (± 1 day), 10 (± 1 day), 14 (± 2 days), 15 (± 1 day), and 16 (+1 day). Subjects participating in the paucity PK subgroup can choose to complete at either the day 15 visit or the day 16 (+1 day) visit.

[0055] A. Purpose of the Study (i) Purpose The objectives of this study are to: To evaluate the safety and tolerability of multiple doses of diudoseperidone in subjects with idiopathic or diabetic gastroparesis. To evaluate the effect of multiple doses of diudomeperidone on gastric emptying, as measured by GEBT, in subjects with idiopathic or diabetic gastroparesis. · To characterize the PK of multiple doses of deuteroperidone in subjects with idiopathic or diabetic gastroparesis.

[0056] (ii) exploratory purpose; Exploratory objectives of this study include: To evaluate the effect of multiple doses of dewdonoperidone on nausea associated with gastroparesis based on nausea score on the ANMS GCSI-DD. To evaluate the effect of multiple doses of deuterium peridone on ANMS GCSI-DD scores (total and subscales) in subjects with idiopathic or diabetic gastroparesis. To evaluate the effects of multiple doses of diuzonperidone on a variety of patient-reported outcomes. · Characterize the exposure-response relationship of deudomperidone.

[0057] B. Inclusion Criteria Patients who meet all of the following criteria are eligible to participate in this study: 1. Male and female patients aged 18-70 years. 2. Have a current diagnosis of idiopathic or diabetic gastroparesis as defined by: Have had GI symptoms within 6 months prior to screening that are felt to be consistent with gastroparesis (e.g., postprandial nausea / vomiting, postprandial fullness, early satiety, abdominal bloating, and / or epigastric / abdominal pain); or · Demonstrated DGE within the past 3 years as determined by GEBT or scintigraphy. Patients with demonstrated DGE by other modalities (e.g., SmartPill™, manometry, etc.) or who have had a GEBT or scintigraphic abnormality >3 years prior may be considered. 3. 18~40kg / m 2 Have a BMI of (inclusive). 4. Have a glycosylated hemoglobin level of ≦11% at screening. 5. Male patients with female partners of childbearing potential must agree to use two medically acceptable and highly effective methods of birth control from Day 1 to Day 60 after the last dose of study drug. Medically acceptable and highly effective methods of birth control for male patients with female partners of childbearing potential include: latex condoms with spermicide, intravaginal diaphragms with spermicide, cervical caps with spermicide, indwelling intrauterine devices (hormonal or non-hormonal), contraceptive implants, and oral contraceptives. 6. Male patients must agree not to donate sperm from 1 to 60 days after the last dose of study drug. 7. Female patients with male partners must be surgically sterilized (hysterectomy and / or bilateral oophorectomy), be postmenopausal for at least 1 year (FSH confirmed to be in the postmenopausal range at the screening visit), or agree to use two medically accepted and highly effective methods of birth control from day -14 to day 60 after the last dose of study drug. Medically accepted and highly effective methods of birth control for female patients with male partners include: latex condoms with spermicide, intravaginal diaphragms with spermicide, cervical caps with spermicide, non-hormonal indwelling intrauterine devices. 8. Negative breath alcohol and urine drug (including tetrahydrocannabinol) screens at the screening visit and randomization. 9. Willing to avoid grapefruit, grapefruit products, starfruit, starfruit products, and Seville oranges from 48 hours prior to randomization until the end of the study. 10. Willingness to avoid long-acting GLP-1 agonists, SGLT-2 inhibitors, or pramlintide.

[0058] C. Exclusion criteria Patients who meet any of the following criteria will be excluded from participating in the study: 1. Patients with a history or current clinically significant arrhythmia, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes. Patients with minimally symptomatic ectopic excitation (e.g., atrial premature beats) are not necessarily excluded. 2. Have clinically significant bradycardia with a resting heart rate of less than 50 beats per minute, sinus node dysfunction, or heart block. 3. Have a heart rate corrected QTcF prolongation (QTcF>450 msec for men or QTcF>470 msec for women) based on the average of three consecutive (triplicate) ECGs. 4. Personal or family history of long QT syndrome, torsades de pointes, or other complex ventricular arrhythmias, or family history of sudden death. 5. Has evidence (based on screening or baseline assessment) or history of any condition that may significantly interfere with the absorption, distribution, metabolism, or excretion of study drug. 6. History of prolactin-releasing pituitary tumor (i.e., prolactinoma). 7. Serum prolactin is elevated. 8. Have known or suspected hypogonadism, current clinically significant menstrual abnormalities (e.g., oligomenorrhea or amenorrhea), gynecomastia, galactorrhea, or other clinical features that may be consistent with hyperprolactinemia. 9. Received a botulinum toxin intrapyloric injection within 6 months of screening and / or during the course of the study. 10. Having bilirubin, alkaline phosphatase, AST, or ALT levels greater than 2× the upper limit of the reference range, or having a Child-Pugh grade of B or C. 11. Have a serum creatinine level greater than 1.5 × upper limit of reference range or <30 mL / min / 1.73 m using the CKD-EPI formula at screening 2 have an eGFR of 12. Have a hemoglobin level of <10 g / dL at screening. 13. Having abnormal TSH levels at screening. 14. Breath tests cannot be administered. 15. You have a known allergy to eggs or spirulina. 16. Use of investigational, prescription, or over-the-counter drugs, such as: Actively participating in an experimental treatment trial; received experimental treatment with a small molecule within 30 days or within 5 half-lives (whichever is longer) of randomization; or received experimental treatment with a large molecule within 90 days or within 5 half-lives (whichever is longer) of randomization. Use of a concomitant CYP3A4 inhibitor (whether a drug, herbal supplement, dietary supplement, or nutraceutical) within 14 days or 5 half-lives of the first dose of study drug (whichever is longer) through the end of the study. Use of concomitant CYP3A4 inducers (whether pharmaceuticals, herbal supplements, dietary supplements, or nutraceuticals) within 28 days or 5 half-lives (whichever is longer) of the first dose of the study drug or inducer through the end of the study. Use of any medication, herbal supplement, dietary supplement, or nutraceutical with the potential to prolong the QT interval within 28 days prior to the first dose of study drug through the end of the study. Use of motility agents (including but not limited to metoclopramide, domperidone, erythromycin, etc.), other medications that may affect gastric emptying (e.g., opiates, marijuana, and anticholinergics), and antiemetics (except protocol-specified rescue antiemetics) within 14 days prior to baseline GEBT and until the end of the study. Gastric pacemakers should be switched off within 14 days prior to baseline GEBT and remain off until the end of the study. 17. History of alcoholism or drug abuse as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, within 2 years prior to medication. 18. Typical intake of ≥ 14 alcoholic drinks per week. 19. Evidence of continuing illegal drug use. 20. HIV antibody, HCV RNA, or HbsAg positive at the screening visit. 21. Donation of blood or blood products within 30 days prior to administration of this medication. 22. Current weight loss medication treatment or previous weight loss surgery (e.g., gastric bypass surgery). 23. Pregnant, breastfeeding, or planning to become pregnant during the course of the study. 24. Unable to swallow medicine. 25. Current receipt of parenteral nutrition or presence of a nasogastric or other enteral tube for feeding or decompression (e.g., PEG tube). 26. Known or suspected gastric outlet obstruction (e.g., peptic stricture) or other GI mechanical obstruction if documented by upper GI endoscopy or upper GI x-ray series within the past 3 years. 27. Known history or current diagnosis of intestinal malabsorption or exocrine pancreatic disease. 28. History of gastric surgery, including fundoplication, gastrectomy, vagotomy, pyloroplasty, or weight loss procedure. 29. History or presence of any medical or psychiatric condition that may interfere with the conduct of the study or that would expose the patient to unacceptable risk. 30. Previous non-response to domperidone or known hypersensitivity or intolerance to domperidone or to the excipients in any deux domperidone formulation.

[0059] Subjects must also meet the following criteria at the time of randomization: Free from all prokinetic and antiemetic medications for at least 14 days and willing to avoid such medications (except protocol-specified rescue antiemetics) during the course of the study. Indicates a confirmed diagnosis of idiopathic or diabetic gastroparesis as defined by: o Current upper GI symptoms (e.g., nausea / vomiting, postprandial fullness, early satiety, abdominal bloating, and / or epigastric / abdominal pain). o 13 Based on the GEBT using C-Spirulina platensis, T 1 / 2 DGE was demonstrated to be >80 min. 1 / 2 Subjects with >200 minutes may be considered. Have an ANMS GCSI-DD score that meets the following: o Mean composite score of ≥ 2 (utilizing a Likert scale from 0 [none] to 4 [very severe]) during the last 10 days prior to randomization. The presenting symptom experienced should not be abdominal pain. o A nausea subscale score (including nausea, retching, and vomiting) of ≥ 2 on at least 4 out of 7 days, or at least one episode of vomiting during any portion of the screening period in which the subject did not take any prokinetic or antiemetic medications (excluding protocol-specified rescue medications).

[0060] D. Test Procedures (i) Treatment group The study is planned to include four treatment arms with 15 subjects each.

[0061] At randomization, subjects who meet all eligibility criteria (based on inclusion / exclusion and randomization criteria) will be randomized in a 3:1 ratio to either diuodosperidone 10 mg BID or placebo BID. The study will begin by randomizing subjects in cohort 1 to either diuodosperidone 10 mg BID or placebo BID, such that 15 subjects will receive diuodosperidone and 5 subjects will receive placebo. The currently planned dose levels for cohorts 2 and 3 are 20 mg QD and 5 mg BID, respectively, with 15 subjects receiving study drug and 5 subjects receiving placebo in each cohort.

[0062] The duration of the double-blind treatment period is 14 days (± 2 days) of study drug.

[0063] (ii) Supply of drugs Dieudonperidone capsules consist of a dieudonperidone formulation in a size 2C oval blue softgel capsule. Each dieudonperidone capsule contains either 5 or 10 mg of active dieudonperidone drug substance. Dieudonperidone capsules also contain inactive ingredients.

[0064] A matching placebo softgel capsule containing the same inactive ingredients and no dudomeperidone drug substance will also be provided.

[0065] (iii) Administration of test drugs All subjects will receive oral doses of blinded study medication (Dieudomperidone or placebo capsules) with approximately 240 mL of water at 8:00 AM (± 2 hours) and 8:00 PM (± 2 hours). A 12-hour interval will be maintained between each dose for a given individual. All subjects should strive to fast for a minimum of 8 hours prior to the morning dose on Day 1. However, if a subject should consume food (i.e., due to low blood glucose levels or symptoms of hypoglycemia), they may consume a light meal ≥ 2 hours prior to the morning dose of study medication. Subjects providing a small number of PK samples should continue to fast for a minimum of 2 hours, and subjects providing a more intensive PK sample should continue to fast for a minimum of 4 hours after the morning dose on Day 1. However, if food should be consumed, it is acceptable to break the specific fast to ensure the safety of the subject. On Day 14 [± 2 days], all subjects will fast for a minimum of 8 hours prior to the morning dose of study medication and 4 hours after completion of the GEBT meal. Subjects are asked to fast 2 hours before and 1 hour after all other doses.

[0066] E. Excluded Medications, Foods, and / or Procedures Use of the following investigational, prescription, or over-the-counter drugs is not permitted during the study: Pramlintide. An SGLT2 inhibitor or GLP-1 agonist with a long half-life (e.g., Bydureon® (exenatide extended-release), Victoza® (liraglutide), Tanzeum™ (albiglutide), or Trulicity® (dulaglutide)). · Experimental treatment with a small molecule within 30 days or 5 half-lives (whichever is longer) prior to randomization; or experimental treatment with a large molecule within 90 days or 5 half-lives (whichever is longer) prior to randomization. - CYP3A4 inhibitors (whether pharmaceuticals, herbal supplements, dietary supplements, nutraceuticals, or foods) within 14 days or 5 half-lives (whichever is longer) of the first dose of the study drug or inducer until the end of the study. Any CYP3A4 inducer (whether a drug, herbal supplement, dietary supplement, nutraceutical, or food) within 28 days or 5 half-lives (whichever is longer) of the first dose of study drug through the end of the study. - Any medication, herbal supplement, dietary supplement, or nutraceutical with the potential to prolong the QT interval within 28 days prior to the first dose of study drug through the end of the study. Prokinetic agents (including but not limited to metoclopramide, domperidone, erythromycin, etc.), other medications that may affect gastric emptying (e.g., opiates, marijuana, and anticholinergics), and antiemetics (except protocol-specified rescue antiemetics) within 14 days prior to baseline GEBT until study completion. Gastric pacemakers should be switched off within 14 days prior to baseline GEBT and remain off until study completion. · Transpyloric injection of botulinum toxin within 6 months of screening and over the course of the study. · Weight loss medications or previous weight loss surgery (e.g. gastric bypass surgery). · Parenteral nutrition, or the presence of a nasogastric or other enteral tube for feeding or decompression (e.g., PEG tube).

[0067] F. Procedure After a minimum of 14 days off prokinetic agents, baseline GEBT will be performed on days -10 to -3.

[0068] At the Baseline GEBT visit (Days -10 to -3) perform the following steps: · Assess fasting blood glucose to ensure blood glucose ≤275 mg / dL prior to gastric emptying assessment. Completion of the PAGI-SYM questionnaire at the study site prior to the start of GEBT. Standards according to test manual 13 Breath samples for GEBT are obtained twice before ingestion of the C-enriched meal, and then 45, 90, 120, 150, 180, and 240 min after ingestion of the meal after an 8-h fast. Record prior medications. · Obtain vital signs (including heart rate, blood pressure, respiratory rate, and temperature) while the subject is seated after a minimum of 5 minutes of rest. · Complete the ANMS GCSI-DD questionnaire each night.

[0069] G. Effectiveness Evaluation (i) Primary efficacy evaluation The primary efficacy variable was the change from baseline (collected on days -10 to -3) in gastric emptying as measured by GEBT on day 14 (±2 days).

[0070] GEBT is exhaled 13 CO2 / 12 Standard using CO2 ratio 13 This is a non-radioactive stable isotope breath test in which the rate of gastric emptying after ingestion of a C-enriched meal is determined. Subjects will consume the standard 13 The subjects consumed a C-enriched meal. The breath samples were 13 C-enriched meal, twice prior to ingestion, and then 45, 90, 120, 150, 180, and 240 min after meal ingestion on days -10 to -3 and 14 (± 2 days), and 30 min after administration of the study drug on day 14 (± 2 days).

[0071] (ii) Secondary Efficacy Assessments Secondary efficacy variables were: GEBT T on the 14th day (± 2 days) 1 / 2 (BT 1 / 2 ) Change from baseline in gastric emptying as measured by Change from baseline in ANMS GCSI-DD total score. Change from baseline in ANMS GCSI-DD subscale scores.

[0072] The ANMS GCSI-DD covers five core associated symptoms of gastroparesis: nausea, early satiety, postprandial fullness, epigastric pain and vomiting. Abdominal bloating is included as an exploratory symptom. Symptoms are scored on a severity numerical response scale ranging from 0 (none) to 4 (very severe). Vomiting is captured on a frequency response scale and scored as follows: 0 - no episodes, 1 - one episode, 2 - two episodes, 3 - three episodes, and 4 - four or more episodes. Subjects are asked to recall symptoms for the past 24 hours and to complete the ANMS GCSI-DD patient-reported symptoms questionnaire daily for at least 14 days prior to randomization, on the day of randomization, and on days 1-14 (± 2 days). A total ANMS GCSI-DD score is calculated as the mean of the three subscale scores for severity of nausea / vomiting, postprandial fullness / early fullness, and abdominal bloating. ANMS GCSI-DD subscale scores will be assessed separately. The baseline for analysis of ANMS GCSI-DD will be based on the average score for the 3 days prior to randomization. Both total ANMS GCSI-DD and subscale scores will be analyzed to compare symptom scores between treatment groups for descriptive purposes only.

[0073] (iii) Effectiveness evaluation The efficacy variable was the change from baseline in gastroparesis symptoms as measured by the PAGI-SYM questionnaire score.

[0074] The PAGI-SYM includes six subscales: heartburn / regurgitation, bloating / early satiety, nausea / vomiting, abdominal bloating, upper abdominal pain, and lower abdominal pain. Both the total and subscale PAGI-SYM scores are used to compare symptom scores between treatment groups for descriptive purposes only.

[0075] The Clinical Grading Scale is also included as an exploratory efficacy variable. For the assessment of the overall clinical response, the following question is utilized: "Considering the last 2 weeks, how have your stomach / gastroparesis related problems / symptoms been compared to the period before you started treatment in this study?" Responses are improved, unchanged, or worsened. Subjects are asked to quantify their treatment response using the CPGAS. Subjects select a number within the range (+7=no improvement; 0=no change; -7=very worse) that best answers the question. Responders are defined as CPGAS scores >0 and non-responders as ≦0. Clinical Grading Scale scores are compared between the deudomperidone treatment and placebo groups for illustrative purposes only.

[0076] (iv) Pharmacokinetics For all subjects, blood samples for PK analysis will be collected at the following visits and time points: Day 1: Within 60 minutes before and 1 and 2 hours after the morning dose Days 3 [± 1 day], 7 [± 1 day], and 10 [± 1 day]: Within 5 minutes before morning administration Day 14 [± 2 days]: Approximately 5 minutes before and 1, 2, 3, and 4 hours after the morning dose 15th or 16th day (+1 day)

[0077] Subjects may agree to participate in a more intensive PK subgroup in which PK samples will also be collected as follows: Day 1: 3, 4, 6, 8, and 12 hours after morning dose Day 14 (± 2 days): 6, 8, and 12 hours after morning dose Day 15 16th day (+1 day)

[0078] The following time periods are allowed for collection of PK samples: ±2 minutes for samples collected ≦2 hours post-dose, and ±5 minutes for samples collected >2 hours post-dose.

[0079] If data permits, the following PK parameters will be calculated for deuterated domperidone (and any measured metabolites) using plasma concentrations measured after deuterated domperidone administration on Day 1: C max · Time to reach maximum plasma concentration · AUC 0~12 hours

[0080] If data permits, the following PK parameters will be calculated for deuterated domperidone (and any measured metabolites) using the plasma concentrations measured after the last deuterated domperidone dose: C max · Time to reach maximum plasma concentration AUC over dosing interval AUC from time 0 to the last time of quantifiable plasma concentration AUC from time 0 to infinity Percentage of extrapolated AUC T 1 / 2 Apparent plasma clearance Apparent volume of distribution

[0081] Trough concentrations collected throughout the study will be used to verify compliance and attainment of steady state. See Table 1 for procedure schedule.

[0082] Table 1. Schedule of procedures TIFF2025514817000006.tif931621. On Day 1, blood samples for PK analysis are collected from all subjects within 60 minutes prior to administration of study drug and approximately 1 and 2 hours after administration on Day 1. For subjects in the intensive PK subgroup, PK samples are also collected 3, 4, 6, 8, and 12 hours after the morning dose on Day 1 (unless one or more of these time points are specifically excluded). On Day 14 (± 2 days), blood samples for PK analysis are collected from all subjects within approximately 5 minutes prior to administration of study drug and 1, 2, 3, and 4 hours after administration. For subjects in the intensive PK subgroup, PK samples are also collected 6, 8, and 12 hours after the morning dose on Day 14 (± 2 days) (unless one or more of these time points are specifically excluded). The following time periods are allowed for collection of PK samples: ± 2 minutes for samples collected ≦ 2 hours post-dose and ± 5 minutes for samples collected > 2 hours post-dose. 2. Blood samples for PK analysis are collected (within 5 minutes) prior to the morning dose of study drug on days 3 (± 1 day), 7 (± 1 day), and 10 (± 1 day). For subjects in the intensive PK subgroup, PK samples are collected on the day after the subject's last dose of study drug (day 15) and on day 16 (day +1). For subjects in the paucity PK subgroup, PK samples are collected on days 15 or 16 (day +1). 3. Subjects will complete the ANMS GCSI-DD questionnaire daily for at least 14 days prior to randomization. Questionnaires should be completed at approximately the same time each evening. PAGI-SYM questionnaires will be completed on days -10 to -3 prior to initiating GEBT and on day 14 [± 2 days] prior to the last dose of study medication. Clinical Grading Scales will be completed on days 14 [± 2 days] prior to initiating the last dose of study medication and initiating GEBT. 4. Sample collected pre-dose. If prolactin was obtained for the last 72 hour pre-randomization visit, there is no need to repeat the Day 1 prolactin sample. 5. For subjects participating in any PGx assessment, blood samples will be collected at any time while the subject is participating in the study. 6. For subjects participating in the intensive PK subgroup, PK samples will be collected on days 15 and 16 (day +1). For subjects in the minority PK subgroup, PK samples will be collected on days 15 or 16 (day +1). 7. For subjects participating in the minority PK subgroup who are only required to complete Day 15 or Day 16 (Day +1), if not performed on Day 15, perform these procedures on Day 16 (Day +1).

[0083] Example 2 This was a randomized, double-blind, placebo-controlled phase 2a study to evaluate the safety, efficacy, PK, and dose-response of oral deuterated peridone in adults with idiopathic or diabetic gastroparesis.

[0084] The study began by randomizing subjects in cohort 1 to either diudomeperidone 10 mg BID or placebo BID, with a ratio such that 15 subjects received diudomeperidone and 5 subjects received placebo. Subjects were selected to enter either the sparing PK sampling subgroup or the intensive PK sampling subgroup. Cohort 1 was stratified by idiopathic or diabetic gastroparesis at randomization. Cohorts 2 and 3 were stratified by severity of gastroparesis: baseline gastric emptying breath test half-life (GEBT T1 / 2) ≥ 110 minutes (more severe gastroparesis) or baseline GEBT T1 / 2 < 110 minutes (milder gastroparesis). Efforts were made to ensure that an adequate number of idiopathic and diabetic gastroparesis subjects were included.

[0085] An independent DRC met to review the data from Cohort 1 after 16 subjects in Cohort 1 completed the study. The DRC reviewed any new safety, PK, and / or efficacy data throughout the study to determine whether it was safe and appropriate to continue the study at the planned dose level for Cohorts 2 and 3, or whether further refinement of the proposed dose level was justified. The maximum dose was not to exceed 60 mg BID, and no more than 40 subjects were to be added without a protocol amendment. The DRC also decided to progress the cohorts sequentially.

[0086] The planned dose levels for cohorts 2 and 3 were originally 30 mg BID and 60 mg BID, respectively, with 15 subjects in each cohort receiving the active study drug and 5 subjects receiving placebo. Based on new information from this study as well as other ongoing studies, the planned dose levels and cohort sizes for the study were revised by the DRC as follows: Cohort 1 was expanded to a total of 41 randomized subjects, with a 5 mg BID cohort (cohort 3) planned; To maintain the blinding of the study so that each dose could contain the study active or placebo, the dose level in Cohort 2 was changed to 20 mg once daily (QD) administered as a morning dose of a deudomperidone 20 mg capsule and an evening dose of a matching placebo capsule; and An expanded 15 mg BID cohort (expansion of cohort 2) was planned and cohort 3 was expanded; however, only cohort 3 was enrolled.

[0087] At the screening visit, all subjects signed informed consent before undergoing any study procedures. To be eligible to participate in the study, subjects must meet all inclusion criteria and must not meet any exclusion criteria.

[0088] Subjects were assessed as follows: Days -28 to -11: Screening procedures were performed. The ANMS GCSI-DD questionnaire was completed daily for at least 14 days prior to randomization (Day 1); Days -10 to -3: The ANMS GCSI-DD questionnaire was completed daily. On one day during this period, GEBT was performed and standardized carbon-13 ( 13 C) Breath samples were obtained twice before ingestion of the enriched meal, and then 45, 90, 120, 150, 180, and 240 min after ingestion of the meal after an 8-h fast.A baseline Patient-Assessed Gastrointestinal Disorders Symptom Severity Index (PAGI-SYM) was completed prior to initiation of GEBT; Days -3 to -1: Completed a pre-randomization visit to conduct safety assessments and allow sufficient time for laboratory test results prior to randomization (Day 1); and Days 1-14: Study medication (deuxoperidone or placebo BID) was administered for 14 (± 2) days with safety assessments; ANMS GCSI-DD questionnaires were completed daily and PK blood draws were completed at specific time points. On day 14 (± 2 days), PAGI-SYM and Clinical Grading Assessment questionnaires were completed before the last dose of study medication. On day 14 (± 2 days), GEBT was performed 30 minutes after administration of the study drug. 13 Breath samples were obtained twice before ingestion of the C-enriched meal, and then 45, 90, 120, 150, 180, and 240 min after ingestion of the meal after an 8-h fast. If subjects discontinued the study before GEBT on day 14 (± 2 days), an attempt was to be made to perform GEBT on the last day of administration of study drug. Clinical grading scales were also performed.

[0089] Randomization was stratified based on subject etiology for gastroparesis (i.e., diabetic vs. idiopathic gastroparesis) or, starting in cohort 2, by severity of gastroparesis using GEBT T1 / 2 (i.e., more severe gastroparesis [baseline GEBT T1 / 2 ≥ 110 min] vs. milder gastroparesis [baseline GEBT T1 / 2 < 110 min]).

[0090] On the day of GEBT, subjects attended the clinic after an overnight fast but should have taken their regular medications, including any treatment for diabetes (excluding any prohibited concomitant medications). Subjects self-administered their usual morning insulin injection taking into account their fasting status. Subjects were instructed to bring their study medication and additional insulin, if necessary, to the clinic. Fasting blood glucose was assessed prior to administration of study medication and assessment of gastric emptying to ensure blood glucose was ≦275 mg / dL. Additional insulin (prorated based on meal caloric content) may have been given to ensure blood glucose was ≦275 mg / dL prior to the gastric emptying procedure. Similarly, investigators should have managed hypoglycemia (hypoglycemia; <60 mg / dL) at their discretion.

[0091] Safety was assessed by AEs, vital sign assessments, physical examination, clinical laboratory evaluations (including prolactin), and ECG findings. In addition, a single optional PGx blood sample may be collected at any time while subjects were participating in the study.

[0092] Subjects had a follow-up visit 1–3 days after the last dose of study drug to assess AEs, changes to concomitant medications (including rescue medication use), vital signs, and for PK specimen collection. Subjects participating in the intensive PK subgroup visited the clinic on days 15 and 16 (day +1). Subjects participating in the paucity PK subgroup could choose to complete either the day 15 visit or the day 16 (day +1) visit. Unscheduled visits and / or additional follow-up may have been necessary. For example, subjects with clinically significant abnormal laboratory findings, unresolved TEAEs, SAEs that required follow-up laboratory testing and review, or clinically significant AEs may have required further evaluation.

[0093] An outline of the planned study is shown in Figure 1.

[0094] A. Purpose of the Study the purpose The objectives of this study were to: · To evaluate the safety and tolerability of multiple doses of deuteroperidone in subjects with idiopathic or diabetic gastroparesis; To evaluate the effect of multiple doses of deuterium peridone on gastric emptying, as measured by GEBT, in subjects with idiopathic or diabetic gastroparesis; and · To characterize the PK of multiple doses of deuteroperidone in subjects with idiopathic or diabetic gastroparesis.

[0095] exploratory purpose The exploratory objectives of this study included: · To evaluate the effect of multiple doses of dewdonperidone on nausea associated with gastroparesis based on nausea scores on the ANMS GCSI-DD; · To evaluate the effect of multiple doses of deudomperidone on ANMS GCSI-DD scores (total and subscales) in subjects with idiopathic or diabetic gastroparesis; To evaluate the effects of multiple doses of deuterium peridone on various PROs; and · Characterize the exposure-response relationship of deudomperidone.

[0096] B. Selection of Study Population Inclusion criteria Subjects who met all of the following criteria were eligible to participate in the study: · Male and female patients aged 18-70 years; Had a current diagnosis of idiopathic or diabetic gastroparesis as defined by: o had gastrointestinal symptoms felt to be consistent with gastroparesis (e.g., postprandial nausea / vomiting, postprandial fullness, early satiety, abdominal distension, and / or epigastric / abdominal pain) within 6 months prior to screening; or o Demonstrated DGE within the past 3 years as determined by GEBT or scintigraphy. Patients with demonstrated DGE by other modalities (e.g., SmartPill, manometry, etc.) or who had a GEBT or scintigraphic abnormality >3 years prior may be considered with sponsor's approval. 18~40kg / m 2 had a BMI of (inclusive); · had a glycosylated hemoglobin level of ≤11% at screening; · Male patients with female partners of childbearing potential had to agree to use two medically acceptable and highly effective methods of birth control from day 1 to day 60 after the last dose of study drug; Medically accepted and highly effective birth control methods for male patients with female partners of childbearing potential included the following: latex condoms with spermicide, diaphragms with intravaginal spermicide, cervical caps with spermicide, indwelling intrauterine devices (hormonal or non-hormonal), contraceptive implants, and oral contraceptives. Male patients had to agree not to donate sperm between days 1 and 60 after the last dose of study drug; Female patients with male partners must have been surgically sterilized (hysterectomy and / or bilateral oophorectomy), been postmenopausal for at least 1 year (FSH confirmed to be in the postmenopausal range at the screening visit), or agreed to use two medically accepted and highly effective methods of birth control between days -14 and 60 after the last dose of study drug - Medically accepted and highly effective methods of birth control for female patients with male partners included: latex condoms with spermicide, intravaginal diaphragms with spermicide, cervical caps with spermicide, and non-hormonal indwelling intrauterine devices. · Negative breath alcohol and urine drug (including tetrahydrocannabinol) screens at the screening visit and randomization; · Willingness to avoid grapefruit, grapefruit products, starfruit, starfruit products, and Seville oranges from 48 hours before randomization until the end of the study; Willing to avoid long-acting GLP-1 agonists, sodium-glucose transporter-2 (SGLT-2) inhibitors, or pramlintide; and subjects who were taking SGLT-2 inhibitors or GLP-1 agonists other than Bydureon (exenatide extended release), Tanzeum (albiglutide), or Trulicity (dulaglutide) may have been considered for the study if they were willing to discontinue medication for 3 days before each GEBT visit (days -10 to -3 and day 14 [± 2 days]). Able to understand and willing to comply with all study visits, procedures, regulations, and withdrawals of medications, including those to treat gastroparesis, and was able to provide written informed consent per institutional and regulatory guidelines.

[0097] Exclusion criteria Subjects were excluded from participation in the study if they met any of the following criteria: 1. Patients had a history or current clinically significant arrhythmia, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes. Patients with minimally symptomatic ectopic excitation (e.g., atrial premature beats) were not necessarily excluded; 2. Had clinically significant bradycardia with a resting heart rate of less than 50 beats per minute, sinus node dysfunction, or heart block; 3. Had prolongation of QTcF (QTcF>450 msec for men or QTcF>470 msec for women) based on the average of three consecutive ECGs; 4. Had a personal or family history of long QT syndrome, torsades de pointes, or other complex ventricular arrhythmias or a family history of sudden death; 5. Had evidence (based on screening or baseline assessment) or history of any condition that could significantly interfere with the absorption, distribution, metabolism, or excretion of study drug; cholecystectomy and appendectomy were permitted. 6. Had a history of a prolactin-releasing pituitary tumor (i.e., prolactinoma); 7. Elevated serum prolactin - Patients with elevated prolactin at the time of screening and receiving medications known to increase prolactin (e.g., domperidone, metoclopramide, phenothiazines, selective serotonin reuptake inhibitors, verapamil, etc.) may have been considered for this study. 8. Had known or suspected hypogonadism, current clinically significant menstrual abnormalities (e.g., oligomenorrhea or amenorrhea), gynecomastia, galactorrhea, or other clinical features that may be consistent with hyperprolactinemia; 9. Received a botulinum toxin transpyloric injection within 6 months of screening and / or during the course of the study; 10. Had bilirubin, alkaline phosphatase, AST, or ALT levels higher than 2 × ULN or had a Child-Pugh classification grade of B or C; 11. Had a serum creatinine level greater than 1.5 × ULN or <30 mL / min / 1.73 m using the CKD-EPI equation at screening 2 had an eGFR of; 12. Had a hemoglobin level of <10 g / dL at screening; 13. Had abnormal thyroid-stimulating hormone levels at screening; 14. Failing to submit to a breath test; 15. Known allergy to eggs or spirulina; 16. Use of investigational, prescription, or over-the-counter drugs, including: Active participation in an experimental treatment trial; received experimental treatment with a small molecule within 30 days or within 5 half-lives (whichever is longer) of randomization; or received experimental treatment with a large molecule within 90 days or within 5 half-lives (whichever is longer) of randomization; Use of a concomitant CYP3A4 inhibitor (whether a drug, herbal supplement, dietary supplement, or nutraceutical) within 14 days or 5 half-lives of the first dose of study drug (whichever is longer) through the end of the study; Use of a concomitant CYP3A4 inducer (whether a drug, herbal supplement, dietary supplement, or nutraceutical) within 28 days or 5 half-lives (whichever is longer) of the first dose of the study drug or inducer through the end of the study; Use of any medication, herbal supplement, dietary supplement, or nutraceutical with the potential to prolong the QT interval within 28 days prior to the first dose of study drug through the end of the study; or Use of prokinetic agents (including but not limited to metoclopramide, domperidone, erythromycin, etc.), other medications that may affect gastric emptying (e.g., opiates, marijuana, and anticholinergics), and antiemetics (except protocol-specified rescue antiemetics) within 14 days prior to baseline GEBT and until the end of the study. Gastric pacemakers were to be switched off within 14 days prior to baseline GEBT and remained off until the end of the study. 17. History of alcoholism or drug abuse as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, within 2 years prior to medication initiation; 18. Typical intake of ≥14 alcoholic drinks per week; 19. Evidence of continuing illegal drug use; 20. HIV antibody, HCV RNA, or HbsAg positivity at the screening visit; 21. Donation of blood or blood products within 30 days prior to administration of the drug; 22. Currently undergoing treatment with weight loss medication or previously undergoing weight loss surgery (e.g., gastric bypass surgery); 23. Pregnant, breastfeeding, or planning to become pregnant during the course of the study; 24. Could not swallow medicines; 25. Current receipt of parenteral nutrition or presence of a nasogastric or other enteral tube (e.g., PEG tube) for feeding or decompression; 26. Known or suspected gastric outlet obstruction (e.g., peptic stricture) or other gastrointestinal mechanical obstruction if documented by upper gastrointestinal endoscopy or upper gastrointestinal x-ray series within the past 3 years; 27. Known history or current diagnosis of intestinal malabsorption or exocrine pancreatic disease; 28. History of gastric surgery, such as fundoplication, gastrectomy, vagotomy, pyloroplasty, or weight loss procedures; patients with a gastric pacemaker may have been considered for the study if they were able to switch off the pacemaker for at least 14 days before baseline GEBT and for the remainder of the study. Previous diagnostic endoscopy was not excluded. Cholecystectomy and appendectomy were permitted. 29. History or presence of any medical or psychiatric condition that could have interfered with the conduct of the study or that would have exposed the patient to unacceptable risk; 30. Previous non-response to domperidone or known hypersensitivity or intolerance to domperidone or to the excipients in any deux domperidone formulation; or 31. Unsuitable because it exposed patients to high risk during participation or for any other reason that may interfere with the interpretation of the study outcomes.

[0098] C. Randomization Criteria In addition to the general criteria, to be randomized into the study, subjects also had to meet the following criteria at the time of randomization: 1. continued to meet all inclusion / exclusion criteria; 2. Free from all prokinetic and antiemetic medications for at least 14 days and willing to avoid such medications (except protocol-specified rescue antiemetics) during the course of the study; 3. Demonstrated a confirmed diagnosis of idiopathic or diabetic gastroparesis as defined by: o Current upper gastrointestinal symptoms (e.g., nausea / vomiting, postprandial fullness, early satiety, abdominal bloating, and / or epigastric / abdominal pain); or o T1 / 2>80 min 13 C-Subjects with documented DGE within 10 days prior to the first dose of study medication based on GEBT using Spirulina platensis. Subjects with T1 / 2>200 min may be considered for the study with sponsor's approval. 4. Had an ANMS GCSI-DD score that met the following: o A mean composite score of ≥ 2 (utilizing a Likert scale ranging from 0 [none] to 4 [very severe]) during the last 10 days prior to randomization or as approved by the sponsor. The presenting symptom experienced could not have been abdominal pain; and o A nausea subscale score (including nausea, retching, and vomiting) of ≥ 2 on at least 4 out of 7 days, or at least 1 episode of vomiting during any portion of the screening period in which the subject did not take any prokinetic or antiemetic medications (excluding protocol-specified rescue medications). 5. Compliance with the ANMS GCSI-DD during the screening period defined as ≥75% compliance or as approved by the sponsor; and 6. Necessary results of initial safety laboratory tests performed at screening were continued.

[0099] Exclusion of subject from treatment or evaluation A subject's participation in this clinical trial may have been discontinued for any of the following reasons: · The subject withdraws consent or requests to discontinue the study for any reason; · The occurrence of any medical condition or circumstance that placed the subject at substantial risk and / or caused the subject to fail to comply with the requirements of the study protocol; Any SAE, clinically significant AE, serious laboratory abnormality, clinically significant change from baseline in ECG (e.g., QTcF >500 msec, change from baseline in QTcF >60 msec [confirmed by central interpretation with repeat ECG], etc.), new ECG abnormalities deemed clinically significant, intercurrent illness, or other medical condition that indicates continued participation would not be in the subject's best interest; Pregnancy; · Prohibited concomitant medication required; Failure to comply with any requirement of a study protocol or study-related procedure; or Termination of a trial by the sponsor or a regulatory authority.

[0100] If a subject discontinued the study early based on the above criteria or for any other reason, study staff should have made every effort to complete all scheduled evaluation panels at the early termination visit. The reason for the subject's discontinuation must be recorded.

[0101] Enrollment in the study was to continue until 60 subjects (15 subjects / treatment group: diudomestic 10 mg BID, diudomestic 20 mg QD, diudomestic 5 mg BID, and placebo) had completed the treatment period. The DRC was also free to expand study enrollment, but could add up to 40 additional subjects without a protocol amendment. Excluded subjects were not replaced.

[0102] D. Treatment (i) The action taken Subjects were orally administered either diudomestic or placebo capsules. Subjects were randomized in a 3:1 ratio to receive either diudomestic or placebo.

[0103] The doses of diuodosperidone administered to cohorts 1-3 were 10 mg BID, 20 mg QD, and 5 mg BID. An expansion to cohort 2 at a dose level of 15 mg BID was approved by the DRC but did not enroll any subjects. All subjects received blinded oral doses of study medication (diuodosperidone or placebo capsules) with approximately 240 mL of water at 8:00 AM (± 2 h) and 8:00 PM (± 2 h). The interval between each dose for a given individual was maintained at 12 h. All subjects should have endeavored to fast for a minimum of 8 h prior to the morning dose on Day 1.

[0104] The double-blind treatment period was 14 (± 2) days after administration of study drug.

[0105] (ii) Product identification information Dewdonperidone capsules consisted of a formulation of dewdonperidone in a size 2C, oval, blue softgel capsule. Each dewdonperidone capsule contained either 5, 10, or 20 mg of active dewdonperidone drug substance (deuterated dewdonperidone). Dewdonperidone capsules contained the ingredients shown in Table 1.

[0106] Table 2. Composition of Dieudonperidone Capsules TIFF2025514817000007.tif37149 1 The softgel capsule contained the following ingredients: Gelatin 150 LB, NF; Glycerin, USP; Gelatine Hydrolysate, NF; Purified Water, USP; Titanium Dioxide, USP; and FD&C Blue #1.

[0107] Matching placebo softgel capsules were also provided, containing all of the components in Table 1 except the diudomperidone drug substance. The softgel capsules (diudomperidone and placebo) were packaged in child-resistant screw-capped high-density polyethylene bottles or blister packs. The lot numbers of the study medications used in this study are listed in Table 3.

[0108] Table 3: Test drugs TIFF2025514817000008.tif27128

[0109] Study medications (deudomperidone and placebo) were stored at ambient room temperature (15-25°C [59-77°F]) away from moisture and light.

[0110] (iii) The method for assigning subjects to treatment groups The study was planned to include three treatment arms with 20 subjects each. The study began by randomizing subjects in cohort 1 to either dudomeperidone 10 mg BID or placebo BID in a ratio such that 15 subjects received dudomeperidone and 5 subjects received placebo. An independent DRC reviewed new safety, PK, and / or efficacy data throughout the study to determine whether it was safe and appropriate to continue the study at the planned dose levels for cohorts 2 and 3, or whether further refinement of the proposed dose levels was warranted. The planned dose levels for cohorts 2 and 3 were initially 30 mg BID and 60 mg BID, respectively, with 15 subjects receiving the study drug and 5 subjects receiving placebo in each cohort. Based on new information from this study as well as other ongoing studies, the planned dose levels and cohort sizes for the study were revised as follows: · Cohort 1 was expanded to a total of 41 randomized subjects, with a 5 mg BID cohort (Cohort 3) planned; To maintain the blinded nature of the study so that each dose could contain either the active study drug or placebo, the dose level in Cohort 2 was changed to 20 mg QD administered as a morning dose of a dudomeperidone 20 mg capsule and an evening dose of a matching capsule; and Expansion of Cohort 2 to 18 subjects was planned at the 15 mg BID dose level consisting of 10 mg and 5 mg capsules taken as a single dose. Due to changes in manufacturing methods for the 10 mg capsules, the sponsor elected not to proceed to the 15 mg BID dose level to avoid introducing potential lot-to-lot variability that would confound data analysis. 5 mg BID (Cohort 3) was expanded to a total of 18 subjects, but only 12 subjects were randomized.

[0111] Subjects who completed the screening visit, met all inclusion criteria, did not meet any exclusion criteria, and met all additional criteria based on the randomization procedure, including safety laboratory tests, were randomized into the study. Subjects were randomized in a 3:1 ratio to either diudomeperidone BID or placebo BID. Randomization occurred on day 1.

[0112] (iv) Selection and timing of doses for each subject All subjects received blinded oral doses of study medication (Dieudomperidone or placebo capsules) with approximately 240 mL of water at 8:00 AM (± 2 hours) and 8:00 PM (± 2 hours). The interval between each dose for a given individual was maintained at 12 hours. All subjects should strive to fast for a minimum of 8 hours prior to the morning dose on Day 1. However, if it was determined that a subject should consume food (i.e., due to low blood glucose levels or symptoms of hypoglycemia), they may consume a light meal >2 hours prior to the morning dose of study medication. Subjects providing a small number of PK samples should continue to fast for a minimum of 2 hours, and subjects providing a more intensive PK sample should continue to fast for a minimum of 4 hours after the morning dose on Day 1. However, if it was determined that food should be consumed, certain fasting was permitted to cease to ensure the safety of the subject. On Day 14 (± 2 days), all subjects fasted for a minimum of 8 hours prior to the morning dose of study medication and 4 hours after completion of the GEBT meal. Subjects were asked to fast 2 hours before and 1 hour after all other doses. Subjects were provided with study drug to self-administer for any doses not administered at the investigational site.

[0113] If a subject missed a scheduled dose and realized the missed dose within 2 hours of the scheduled dose time, the subject was instructed to take their assigned dose of study medication when they realized they had missed a dose.If a subject realized the missed dose more than 2 hours after the scheduled dose time, the subject was instructed to skip this dose of study medication and resume their assigned dose of study medication at the next scheduled time.

[0114] If a subject vomited after taking a scheduled dose of study medication, the subject was instructed to note the time of study medication administration and the time of vomiting, and to resume the assigned dose of study medication at the next scheduled time. During the treatment period, subjects should attempt to note the time of vomiting in relation to the time of study medication administration and report this to the investigational site staff during scheduled clinic visits.

[0115] (v) Blinding Study medication was distributed in a double-blind manner after randomization on Day 1. The sponsor and all medical personnel were blinded to the treatment group for each subject. Subjects were also blinded to the treatment they received.

[0116] Randomization was based on subject etiology for gastroparesis (i.e., diabetic vs. idiopathic gastroparesis) or, starting in cohort 2, subjects were stratified by severity of gastroparesis using GEBT T1 / 2 (i.e., more severe gastroparesis [baseline GEBT T1 / 2 ≥ 110 min] vs. milder gastroparesis [baseline GEBT T1 / 2 < 110 min]).

[0117] Bioanalytical staff involved in the analysis of the PK samples were unblinded to treatment due to the nature of the results of the sample analysis. The PK data were de-identified to maintain blinding before being provided to any other individuals, including those involved in calculating the PK parameters and related descriptive statistics, performing any modeling or simulations, and / or plotting the PK data.

[0118] (vi) Prior and concomitant treatments Excluded medicines, foods, and / or procedures Use of the following investigational, prescription, or over-the-counter medications was not permitted during the study: Pramlintide; · SGLT-2 inhibitors or GLP-1 agonists with long half-lives (e.g., Bydureon [exenatide extended-release], Tanzeum [albiglutide], or Trulicity [dulaglutide]); experimental treatment with a small molecule within 30 days or 5 half-lives (whichever is longer) prior to randomization; or experimental treatment with a large molecule within 90 days or 5 half-lives (whichever is longer) prior to randomization; - CYP3A4 inhibitors (whether pharmaceutical, herbal supplement, dietary supplement, nutraceutical, or food) within 14 days or 5 half-lives (whichever is longer) of the first dose of the study drug or inducer until the end of the study; - CYP3A4 inducers (whether pharmaceuticals, herbal supplements, dietary supplements, nutraceuticals, or foods) within 28 days or 5 half-lives of the first dose of study drug through the end of the study, whichever is longer; · Any medication, herbal supplement, dietary supplement, or nutraceutical with the potential to prolong the QT interval within 28 days prior to the first dose of study drug through the end of the study; Prokinetic agents (including but not limited to metoclopramide, domperidone, erythromycin, etc.), other medications that may affect gastric emptying (e.g., opiates, marijuana, and anticholinergics), and antiemetics (except protocol-specified rescue antiemetics) within 14 days prior to baseline GEBT until study completion; gastric pacemakers were to be switched off within 14 days prior to baseline GEBT and remained off until study completion. · Transpyloric injection of botulinum toxin within 6 months of screening and over the course of the study; Weight loss medications or previous weight loss surgery (e.g., gastric bypass surgery); and · Parenteral nutrition, or the presence of a nasogastric or other enteral tube for feeding or decompression (e.g., PEG tube).

[0119] Rescue Medications: Subjects who experienced severe symptoms of gastroparesis could receive a once-daily dose of promethazine hydrochloride (Phenergan®), but should avoid such treatment if possible on the day of GEBT. Subjects who required further treatment with prohibited medications could discontinue study treatment and undergo follow-up study procedures.

[0120] Allowed Medications and / or Procedures: Other medications (eg, rescue medications) that were not expressly and previously excluded were permitted.

[0121] Description of prior and concomitant medication use: Any medications administered within 28 days prior to the first dose of study drug and / or during the study period had to be recorded.

[0122] E. Efficacy and Safety Variables (i) Efficacy and safety measures evaluated and flow chart Tables 4A and 4B provide a schedule of procedures for the study.

[0123] Table 4A: Schedule of procedures TIFF2025514817000009.tif183155All days were reported as the next nominal day in consecutive order (i.e., if an outpatient visit on day 3 [± 1 day] occurred on a consecutive day 4, this was reported as day 4; all subsequent days were recorded similarly). 1. On Day 1, all subjects were confined to the clinic for a minimum of approximately 2 hours after the morning dose of study drug. Blood samples for PK analysis were collected from all subjects within 60 minutes before and approximately 1 and 2 hours after the administration of study drug on Day 1. Subjects in the intensive PK subgroup remained confined to the clinic and PK samples were also collected at 3, 4, 6, 8, and 12 hours after the morning dose on Day 1 (unless one or more of these time points were waived in writing by the sponsor prior to the scheduled time). On Day 14 (± 2 days), subjects were confined to the clinic for a minimum of approximately 4 hours after the morning dose of study drug. Blood samples for PK analysis were collected from all subjects within approximately 5 minutes before and 1, 2, 3, and 4 hours after the administration of study drug on Day 14 (± 2 days). Subjects in the intensive PK subgroup remained confined to the clinic, and PK samples were also collected at 6, 8, and 12 hours after the morning dose on day 14 (± 2 days) (unless one or more of these time points were waived prior to the scheduled time in writing by the sponsor). The following time periods were allowed for collection of PK samples: ± 2 minutes for samples collected ≤ 2 hours post-dose and ± 5 minutes for samples collected > 2 hours post-dose. 2. On days 3 (±1 day), 7 (±1 day), and 10 (±1 day), all subjects visited the clinic for outpatient visits. Blood samples for PK analysis were collected (within 5 minutes) before the morning administration of study drug. Subjects in the intensive PK subgroup visited the clinic on the day after the last dose of study drug (day 15) and on day 16 (day +1), and PK samples were collected at each visit. Subjects in the paucity PK subgroup could visit the clinic on either day 15 or day 16 (day +1), and PK samples were collected at this visit. 3. Written informed consent for the study was obtained from all subjects before any study procedures were performed. 4. Screening procedures, including vital signs assessment, may be repeated no more than twice for eligibility. 5. Any medications taken within 28 days prior to the first dose of study drug and during the study period must be recorded. Beginning on Day 1, subjects were to record concomitant medications prior to each dose and at each outpatient visit prior to each dose. 6. AEs were monitored and recorded at every outpatient visit from the time of first administration of study drug until completion of study participation. 7. A complete physical examination consisted of general appearance, skin, head, eyes, ears, mouth, oropharynx, neck, heart, lungs, abdomen, extremities, and neuromuscular system. A limited physical examination consisted of a minimum of general appearance, skin, heart, lungs, and abdomen. 8. Height was measured at the screening visit only. Height and weight collected at the screening visit were used to calculate BMI at the screening visit. At the time of randomization (Day 1), BMI was calculated using weight at randomization (Day 1) and height from the screening visit. 9. Vital signs included heart rate, blood pressure, respiratory rate, and temperature and were collected while the subject was seated after resting for a minimum of 5 minutes. 10. FSH was measured only in women who had been menopausal for at least 1 year and had not been surgically sterilized. 11. At the time of randomization (Day 1), POC drug testing was performed for use in assessing eligibility. Urine samples were also sent to a central laboratory for confirmatory testing. 12. Pregnancy testing was performed only in women who had not been surgically sterilized (or had been menopausal for at least 1 year [FSH confirmed to be within the menopausal range at the screening visit]). Serum pregnancy tests were performed by a central laboratory on days -28 to -11 and 14 (± 2 days). An initial POC pregnancy test was performed at visit -3 to -1 to be used to assess eligibility for randomization. 13. All 12-lead ECGs were taken in three consecutive sets, approximately 1 minute apart, after subjects had rested in the supine position for at least 10 minutes. 12-lead ECGs were printed and interpreted as soon as possible. Digital records of all ECGs from randomized subjects were submitted to the center's reviewer. ECGs were to be completed ±15 minutes from all specified time points. 14. On Days 1 and 14 (± 2 days), ECGs were to be obtained prior to the morning dose and at 2, 4, 6, and 12 hours (if applicable) after the morning dose and completed ± 15 minutes from the specified time point. For subjects participating in intensive PK, additional ECGs were obtained at 4, 6, and 12 hours (if applicable) after the morning dose. If collection of specific individual PK samples (including but not limited to 8 and / or 12 hour post-dose samples for intensive PK subgroups) was not required based on written sponsor approval, a final ECG for these visits had to be collected when the final PK sample was obtained. 15. Subjects performed a baseline GEBT on days -10 to -3 after a minimum of 14 days off prokinetic drugs, and 30 minutes after administration of study drug on day 14 (± 2 days). Subjects fasted for a minimum of 8 hours prior to the breath test. 13 Breath samples were obtained twice before ingestion of the C-enriched meal, then at 45, 90, 120, 150, 180, and 240 min postprandially after an 8-h fast on days -10 to -3, and at 45, 90, 120, 150, 180, and 240 min starting 30 min after administration of study drug on day 14 (±2 days). Fasting glucose was assessed before GEBT to ensure blood glucose levels of ≤275 mg / dL. 16. Subjects were instructed to complete the ANMS GCSI-DD questionnaire daily for at least 14 days prior to randomization (Day 1). Materials were distributed at the screening visit. Adherence to the ANMS GCSI-DD was assessed at the time of randomization (Day 1) and adherence had to be ≥ 75% to be eligible for the study. The questionnaire was to be completed at approximately the same time each evening. The PAGI-SYM questionnaire was completed at the study site prior to initiation of GEBT on Days -10 to -3 and prior to the last dose of study medication on Day 14 (± 2 days). The Clinical Grading Scale was completed prior to initiation of the last dose of study medication and initiation of GEBT on Day 14 (± 2 days). 17. Samples were collected pre-dose. If a prolactin sample was obtained for the previous 72 hour pre-randomization visit, there was no need to repeat the Day 1 prolactin sample. 18. Study medication was distributed according to treatment allocation on Day 1. 19. All subjects received blinded oral doses of study medication (Dieudomperidone or placebo capsules) with approximately 240 mL of water at 8:00 AM (± 2 hours) and 8:00 PM (± 2 hours). The interval between each dose for a given individual was maintained at 12 hours. Fasting requirement on Day 1: Subjects participating in the intensive PK subgroup should strive to fast for a minimum of 8 hours before the morning dose of study medication. However, if it was determined that food should be consumed (i.e., due to low blood glucose levels or symptoms of hypoglycemia), a light meal may be consumed >2 hours before the morning dose of study medication. Subjects should strive to fast for 4 hours after the morning dose of study medication; however, if it was determined that food should be consumed, certain fasting was permitted to be broken to ensure the safety of the subject. For the evening dose, subjects fasted >2 hours before and 1 hour after the study medication. Subjects self-administered the evening dose. Subjects participating in the paucity PK subgroup should have attempted to fast for a minimum of 8 hours prior to the morning dose of study drug. However, if it was determined that the subject should consume food (i.e., due to low blood glucose levels or symptoms of hypoglycemia), a light meal may be consumed >2 hours prior to the morning dose of study drug. Subjects should have fasted for >2 hours after the morning dose of study drug; however, if it was determined that food should be consumed, certain fasting was permitted to be broken to ensure the subject's safety. For the evening dose, subjects fasted for a minimum of 2 hours prior to and 1 hour after administration of study drug. The evening dose was self-administered by the subject. If the subject reported vomiting during the treatment period, the subject should have attempted to note the time of vomiting in relation to the time of administration of study drug and report this to the investigational site staff during the scheduled clinic visit. 20. Accountability for study drug occurred on days 3, 7, 10, and 14, or at early termination, if applicable. Unused study drug was collected only on day 14 (± 2 days) or at early termination, if applicable. 21. For subjects who provided written informed consent to participate in optional PGx evaluation, blood samples were collected at any time while the subject was participating in the study. 22. Subjects participating in the intensive PK subgroup reported to the clinic on days 15 and 16 (day +1) where PK samples were collected at each visit. Subjects in the minority PK subgroup may visit the clinic on either day 15 or day 16 (day +1) and had PK samples collected at selected visits. 23. For subjects who were participating in the minority PK subgroup and were only required to complete on either Day 15 or Day 16 (day +1), if these procedures were not performed on Day 15, they were performed on Day 16 (day +1).

[0124] Table 4B. Procedure Schedule TIFF2025514817000010.tif127156TIFF2025514817000011.tif244156All days were reported as the next nominal day in consecutive order (i.e., if an outpatient visit on day 3 [± 1 day] occurred on a consecutive day 4, this was reported as day 4; all subsequent days were recorded similarly). 1. On Day 1, all subjects were confined to the clinic for a minimum of approximately 2 hours after the morning dose of study drug. Blood samples for PK analysis were collected from all subjects within 60 minutes before and approximately 1 and 2 hours after the administration of study drug on Day 1. Subjects in the intensive PK subgroup remained confined to the clinic and PK samples were also collected at 3, 4, 6, 8, and 12 hours after the morning dose on Day 1 (unless one or more of these time points were waived in writing by the sponsor prior to the scheduled time). On Day 14 (± 2 days), subjects were confined to the clinic for a minimum of approximately 4 hours after the morning dose of study drug. Blood samples for PK analysis were collected from all subjects within approximately 5 minutes before and 1, 2, 3, and 4 hours after the administration of study drug on Day 14 (± 2 days). Subjects in the intensive PK subgroup remained confined to the clinic, and PK samples were also collected at 6, 8, and 12 hours after the morning dose on day 14 (± 2 days) (unless one or more of these time points were waived prior to the scheduled time in writing by the sponsor). The following time periods were allowed for collection of PK samples: ± 2 minutes for samples collected ≤ 2 hours post-dose and ± 5 minutes for samples collected > 2 hours post-dose. 2. On days 3 (±1 day), 7 (±1 day), and 10 (±1 day), all subjects visited the clinic for outpatient visits. Blood samples for PK analysis were collected (within 5 minutes) before the morning administration of study drug. Subjects in the intensive PK subgroup visited the clinic on the day after the last dose of study drug (day 15) and on day 16 (day +1), and PK samples were collected at each visit. Subjects in the paucity PK subgroup could visit the clinic on either day 15 or day 16 (day +1), and PK samples were collected at this visit. 3. Written informed consent for the study was obtained from all subjects before any study procedures were performed. 4. Screening procedures, including vital signs assessment, may be repeated no more than twice for eligibility. 5. Any medications taken within 28 days prior to the first dose of study drug and during the study period must be recorded. Beginning on Day 1, subjects were to record concomitant medications prior to each dose and at each outpatient visit prior to each dose. 6. AEs were monitored and recorded at every outpatient visit from the time of first administration of study drug until completion of study participation. 7. A complete physical examination consisted of general appearance, skin, head, eyes, ears, mouth, oropharynx, neck, heart, lungs, abdomen, extremities, and neuromuscular system. A limited physical examination consisted of a minimum of general appearance, skin, heart, lungs, and abdomen. 8. Height was measured at the screening visit only. Height and weight collected at the screening visit were used to calculate BMI at the screening visit. At the time of randomization (Day 1), BMI was calculated using weight at randomization (Day 1) and height from the screening visit. 9. Vital signs included heart rate, blood pressure, respiratory rate, and temperature and were collected while the subject was seated after resting for a minimum of 5 minutes. 10. FSH was measured only in women who had been menopausal for at least 1 year and had not been surgically sterilized. 11. At the time of randomization (Day 1), POC drug testing was performed for use in assessing eligibility. Urine samples were also sent to a central laboratory for confirmatory testing. 12. Pregnancy testing was performed only in women who had not been surgically sterilized (or had been menopausal for at least 1 year [FSH confirmed to be within the menopausal range at the screening visit]). Serum pregnancy tests were performed by a central laboratory on days -28 to -11 and 14 (± 2 days). An initial POC pregnancy test was performed at visit -3 to -1 to be used to assess eligibility for randomization. 13. All 12-lead ECGs were taken in three consecutive sets, approximately 1 minute apart, after subjects had rested in the supine position for at least 10 minutes. 12-lead ECGs were printed and interpreted as soon as possible. Digital records of all ECGs from randomized subjects were submitted to the center's reviewer. ECGs were to be completed ±15 minutes from all specified time points. 14. On Days 1 and 14 (± 2 days), ECGs were to be obtained prior to the morning dose and at 2, 4, 6, and 12 hours (if applicable) after the morning dose and were to be completed ± 15 minutes from the specified time point. For subjects participating in intensive PK, additional ECGs were obtained at 4, 6, and 12 hours (if applicable) after the morning dose. If collection of specific individual PK samples (including but not limited to samples at 8 and / or 12 hours post-dose for intensive PK subgroups) was not required based on written sponsor approval, a final ECG for these visits had to be collected when the final PK sample was obtained. 15. Subjects performed a baseline GEBT on days -10 to -3 after a minimum of 14 days off prokinetic drugs, and 30 minutes after administration of study drug on day 14 (± 2 days). Subjects fasted for a minimum of 8 hours prior to the breath test. 13 Breath samples were obtained twice before ingestion of the C-enriched meal, then at 45, 90, 120, 150, 180, and 240 min postprandially after an 8-h fast on days -10 to -3, and at 45, 90, 120, 150, 180, and 240 min starting 30 min after administration of study drug on day 14 (±2 days). Fasting glucose was assessed before GEBT to ensure blood glucose levels of ≤275 mg / dL. 16. Subjects were instructed to complete the ANMS GCSI-DD questionnaire daily for at least 14 days prior to randomization (Day 1). Materials were distributed at the screening visit. Adherence to the ANMS GCSI-DD was assessed at the time of randomization (Day 1) and adherence had to be ≥ 75% to be eligible for the study. The questionnaire was to be completed at approximately the same time each evening. The PAGI-SYM questionnaire was completed at the study site prior to initiation of GEBT on Days -10 to -3 and prior to the last dose of study medication on Day 14 (± 2 days). The Clinical Grading Scale was completed prior to initiation of the last dose of study medication and initiation of GEBT on Day 14 (± 2 days). 17. Samples were collected pre-dose. If a prolactin sample was obtained for the previous 72 hour pre-randomization visit, there was no need to repeat the Day 1 prolactin sample. 18. Study medication was distributed according to treatment allocation on Day 1. 19. All subjects received blinded oral doses of study medication (Dieudomperidone or placebo capsules) with approximately 240 mL of water at 8:00 AM (± 2 hours) and 8:00 PM (± 2 hours). The interval between each dose for a given individual was maintained at 12 hours. Fasting requirement on Day 1: Subjects participating in the intensive PK subgroup should strive to fast for a minimum of 8 hours before the morning dose of study medication. However, if it was determined that food should be consumed (i.e., due to low blood glucose levels or symptoms of hypoglycemia), a light meal may be consumed >2 hours before the morning dose of study medication. Subjects should strive to fast for 4 hours after the morning dose of study medication; however, if it was determined that food should be consumed, certain fasting was permitted to be broken to ensure the safety of the subject. For the evening dose, subjects fasted >2 hours before and 1 hour after the study medication. Subjects self-administered the evening dose. Subjects participating in the paucity PK subgroup should have attempted to fast for a minimum of 8 hours prior to the morning dose of study drug. However, if it was determined that the subject should consume food (i.e., due to low blood glucose levels or symptoms of hypoglycemia), a light meal may be consumed >2 hours prior to the morning dose of study drug. Subjects should have fasted for >2 hours after the morning dose of study drug; however, if it was determined that food should be consumed, certain fasting was permitted to be broken to ensure the subject's safety. For the evening dose, subjects fasted for a minimum of 2 hours prior to and 1 hour after administration of study drug. The evening dose was self-administered by the subject. If the subject reported vomiting during the treatment period, the subject should have attempted to note the time of vomiting in relation to the time of administration of study drug and report this to the investigational site staff during the scheduled clinic visit. 20. Accountability for study drug occurred on days 3, 7, 10, and 14, or at early termination, if applicable. Unused study drug was collected only on day 14 (± 2 days) or at early termination, if applicable. 21. For subjects who provided written informed consent to participate in optional PGx evaluation, blood samples were collected at any time while the subject was participating in the study. 22. Subjects participating in the intensive PK subgroup reported to the clinic on days 15 and 16 (day +1) where PK samples were collected at each visit. Subjects in the minority PK subgroup may visit the clinic on either day 15 or day 16 (day +1) and had PK samples collected at selected visits. 23. For subjects who were participating in the minority PK subgroup and were only required to complete on either Day 15 or Day 16 (day +1), if these procedures were not performed on Day 15, they were performed on Day 16 (day +1).

[0125] (ii) Measurement validity The GEBT and ANMS GCSI-DD were used as efficacy measures. The GEBT is an FDA-approved measure of gastric emptying and was an appropriate endpoint for the 2-week treatment period used in this study. The use of the ANMS GCSI-DD is standard for studies of this type, evaluating core signs and symptoms as endpoints as suggested by FDA guidance. The PK and safety measures in this study are widely used and recognized as reliable, accurate, and appropriate.

[0126] (iii) Efficacy variables Primary efficacy variables The primary efficacy variable was the change from baseline in gastric emptying as measured by GEBT on day 14.

[0127] Secondary efficacy variables Secondary efficacy variables were: · Change from baseline in gastric emptying as measured by GEBT T1 / 2 on day 14; Change from baseline in the ANMS GCSI-DD total score; and Change from baseline in ANMS GCSI-DD subscale scores.

[0128] (iv) American Gastrointestinal Motility Society Gastroparesis Main Symptom Index Diary: Protocol-specific scoring methods The ANMS GCSI-DD covers five core associated symptoms of gastroparesis: nausea, early satiety, postprandial fullness, epigastric pain and vomiting. Abdominal bloating is included as an exploratory symptom. Symptoms are scored on a severity numerical response scale ranging from 0 (none) to 4 (very severe). Vomiting is captured on a frequency response scale and scored as follows: 0 - no episodes, 1 - 1 episode, 2 - 2 episodes, 3 - 3 episodes and 4 - 4 or more episodes. Subjects were asked to recall symptoms in the past 24 hours and to complete the ANMS GCSI-DD patient-reported symptoms questionnaire for at least 14 days prior to randomization, on the day of randomization, and daily on days 1-14 (± 2 days).

[0129] American Gastrointestinal Motility Society Manual Scoring Method Severity scores for the four gastroparesis-related symptoms (nausea, early satiety, postprandial fullness, and epigastric pain) range from 0 (none) to 4 (very severe). The emesis score, capped at a maximum of 4, assesses the number of vomiting episodes during the day; thus, the score for vomiting ranges from 0 (no vomiting episodes) to 4 (4 or more vomiting episodes). The frequency of vomiting is scored as 0 episodes, 1 episode, 2 episodes, 3 episodes, or 4 or more episodes (capped at 4).

[0130] (vi) Exploratory efficacy variables Exploratory efficacy variables were: change from baseline in gastroparesis symptoms as measured by the PAGI-SYM questionnaire score; and Clinical grading scale at 14 days.

[0131] Patient-rated Gastrointestinal Symptom Severity Index: The PAGI-SYM includes six subscales: heartburn / regurgitation, bloating / early satiety, nausea / vomiting, abdominal bloating, upper abdominal pain, and lower abdominal pain.

[0132] Clinical Grading Scale: For the assessment of overall clinical response, the following question was utilized on Day 14: "Looking at the past 2 weeks, how have your stomach / gastroparesis related problems / symptoms been compared to the period before you started treatment on this study?" Responses were: improved, unchanged, or worse. Subjects were asked to quantify their treatment response using a Clinical Patient Grading Scale. Subjects chose a number from a range (+7=completely improved; 0=no change; -7=very worse) that best answered the question.

[0133] (vii) Drug concentrations and other pharmacokinetic variables PK variables were concentrations and derived PK parameters of deuterated domperidone following multiple doses of deuterated domperidone. When data permitted, the following PK parameters were calculated for deuterated domperidone from plasma concentrations (Day 1) using noncompartmental methods: Concentration-time profile C max was determined directly. If more than one maximum exists at any one time point, C max was defined as the first maximum; T max ;If the maximum value exists at more than one time point, T max was defined as the first time point with this value; and AUC 0-12 .

[0134] Where data permitted, the following PK parameters for deuterated domperidone were calculated using plasma concentrations measured after the final deuterated domperidone dose (Day 14 AM): Concentration-time profile C max was determined directly. If more than one maximum exists at any one time point, C max was defined as the first maximum; T max ;If the maximum value exists at more than one time point, T max was defined as the first time point with this value; AUC using trapezoidal method tau was calculated; AUC 0-t ; AUC 0-∞ ;(AUC 0-t +C last / λz); AUC %extrap ;(1-AUC 0-t / AUC 0-∞ ) × 100; λz was calculated from a semi-logarithmic plot of the plasma concentration curve versus time. This parameter was calculated by linear least-squares regression analysis using the points of the terminal log-linear phase; · T1 / 2 was calculated as the natural log(2) / λz; · Dose / AUC 0-∞ CL / F was calculated as; · Dose / (λz×AUC 0-∞ ) was calculated as Vz / F; · Day 14 C max / Day 1 C max As R Cmax was calculated; and AUC on day 14 tau / AUC on day 1 tau As R AUC was calculated.

[0135] (viii) Safety variables Safety variables included AEs, clinical laboratory results (including prolactin), vital signs, ECG, and physical examination findings.

[0136] F. Test Subjects (i) Subject predisposition Based on new information from this study as well as other ongoing studies, the planned dose levels and cohort sizes for the study have been revised as follows: · Cohort 1 was expanded to a total of 41 randomized subjects, with a 5 mg BID cohort (Cohort 3) planned; To maintain the blinded nature of the study so that each dose could contain the study active or placebo, the dose level in Cohort 2 was changed to 20 mg QD administered as a morning dose of a deudomperidone 20 mg capsule and an evening dose of a matching placebo capsule; and Expansion of Cohort 2 to 18 subjects was planned at the 15 mg BID dose level consisting of 10 mg and 5 mg capsules taken as a single dose. To avoid introducing potential variability between lots due to changes in the manufacturing process of the 10 mg capsules and therefore confounding data analysis, the sponsor elected not to proceed with the 15 mg BID dose level. 5 mg BID (Cohort 3) was expanded to a total of 18 subjects, but only 12 subjects were randomized.

[0137] Table 5 summarizes subject dispositions for the ITT population.

[0138] A total of 72 subjects were enrolled into one of three cohorts. Fifty-four subjects were randomized to one of the following diudomaperidone treatment groups: · 10mg BID deuterium peridone (30 subjects randomized); 20 mg QD deuterium peridone (15 subjects randomized); or · 5 mg BID deuterium peridone (9 subjects randomized).

[0139] Eighteen subjects were randomized to receive placebo.

[0140] Of the randomized subjects, 29 (96.7%) subjects in the 10 mg BID diudomestic treatment group, 15 (100.0%) subjects in the 20 mg QD diudomestic treatment group, 9 (100.0%) subjects in the 5 mg BID diudomestic treatment group, and 18 (100.0%) subjects in the pooled placebo treatment group completed the study. One (1.4%) subject prematurely discontinued the study. This subject (subject 113-010) received 10 mg BID diudomestic treatment and was discontinued.

[0141] Table 5. Subject Predisposition-Intention-to-Treat Population TIFF2025514817000012.tif111152% = 100 × n / N, where n = number of subjects meeting a particular criterion; N = number of subjects in a treatment group

[0142] (ii) Datasets analyzed Table 6 describes the analysis population for the study. The ITT population included 72 subjects (30 subjects in the 10 mg BID diudomestic treatment group, 15 subjects in the 20 mg QD diudomestic treatment group, 9 subjects in the 5 mg BID diudomestic treatment group, and 18 subjects in the pooled placebo treatment group) and was identical to the MITT population, the PD-evaluable population, and the safety analysis population. The PP population included 69 subjects (29 subjects in the 10 mg BID diudomestic treatment group, 14 subjects in the 20 mg QD diudomestic treatment group, 8 subjects in the 5 mg BID diudomestic treatment group, and 18 subjects in the pooled placebo treatment group).

[0143] The PK population included 54 subjects (30 subjects in the 10 mg BID diudomperidone treatment group, 15 subjects in the 20 mg QD diudomperidone treatment group, and 9 subjects in the 5 mg BID diudomperidone treatment group) and was identical to the PK evaluable population.

[0144] Table 6. Analysis population - intention-to-treat population TIFF2025514817000013.tif62152%=100×n / N. 1 The ITT population included all randomized subjects. 2 The MITT population included all randomized subjects who received at least one dose of study drug. 3 The PP population included all subjects in the MITT population who had no major protocol violations and did not meet any of the criteria specified in the statistical analysis plan. 4The PK population included all subjects who received at least one dose of diudomeperidone and had at least one quantifiable post-dose plasma diudomeperidone concentration. 5 The PK-evaluable population included subjects who received dudomeperidone and had sufficient plasma concentration data to characterize at least one PK parameter. 6 The PD-evaluable population included all subjects who received study drug and had at least one prolactin value after initiation of study drug. 7 The safety analysis population consisted of any randomized subject who received any study drug. Data from subjects who received placebo across all cohorts were pooled for safety analyses.

[0145] (iii) Demographic and other baseline characteristics Table 7 summarizes the demographic and baseline characteristics for the ITT population. The mean age of the subjects ranged from approximately 50.7 to 58.9 years, and the mean BMI ranged from approximately 28.89 to 32.00 kg / m 2 The ethnicity ranged from 0.01 to 0.05. The majority of subjects were female. In total, 83.3% of subjects were white and 15.3% of subjects were black or African American. The majority of subjects were Hispanic or Latino. For all treatment groups, the majority of subjects (51 [70.8%] subjects) had a diabetic gastroparesis etiology. Among subjects with diabetic gastroparesis, the number of subjects with and without neuropathy was similar except in cohort 2, where the majority of subjects had neuropathy. More subjects had a baseline GEBT of ≥110 kPCD than <100 kPCD. It is unlikely that these observed differences in demographics and baseline characteristics would have affected the interpretation and conclusions of the data.

[0146] Table 7. Demographic and baseline characteristics - intention-to-treat population TIFF2025514817000014.tif198152% = 100 × n / N. Baseline was defined as the last measurement before the first dose of study drug. 1 Percentages were calculated based on diabetic subjects.

[0147] (vi) Previous and concomitant medications Overall, 70 (97.2%) subjects were taking concomitant medications as permitted by the protocol, and 70 (97.2%) subjects were taking any prior medications.

[0148] In this study, 20 subjects (27.8%) overall were taking protocol-allowed rescue medications as reported by the subjects in their diaries.

[0149] There was no use of medications that could have potentially confounded the results.

[0150] G. Efficacy, Pharmacodynamic, and Pharmacokinetic Results (i) Tabulation of efficacy results and individual subject data gastric emptying time Table 8 shows gastric emptying times at baseline and day 14 as measured by GEBT T1 / 2 for the ITT population, and the change and percent change in gastric emptying times from baseline to day 14. For the 10 mg BID diudomperidone group, gastric emptying times decreased from baseline for the diudomperidone and placebo treatment groups, and the change and percent change in gastric emptying from baseline (collected on days -10 to -3) to day 14 (±2 days) as measured by GEBT T1 / 2 was greater compared to placebo, suggesting that gastric emptying is more rapid following administration of diudomperidone.

[0151] Table 8. Gastric emptying time - intention-to-treat population TIFF2025514817000015.tif83152Baseline was defined as the last GEBT initiated before the first dose of study drug. GEBT results were reported using kPCD. kPCD was the total amount of 13 The dose of C for a given subject at any measurement time t 13 The formula for the CO2 emission rate per minute is kPCD(t) = 1000 × [at time t] 13 Emitted as CO2 13 Percentage of C / min -1 )].

[0152] Table 9 presents gastric emptying at baseline and day 14 as measured by GEBT by time point for the ITT population, and the change in gastric emptying time from baseline to day 14. All pre-meal results were 0 and therefore excluded from the analysis.

[0153] Table 9. Gastric emptying time by time point - intention-to-treat population TIFF2025514817000016.tif149152TIFF2025514817000017.tif230152TIFF2025514817000018.tif67152All pre-ingestion results were 0 and therefore excluded from the analysis. Baseline was defined as the last GEBT that began before the first dose of study medication. GEBT results were reported using kPCD. kPCD was calculated based on the amount of glycemic control included in the test meal. 13 The dose of C for a given subject at any measurement time t 13 The formula for the CO2 emission rate per minute is kPCD(t) = 1000 × [at time t] 13 Emitted as CO2 13 Percentage of C / min -1 )].

[0154] American Gastrointestinal Motility Society Gastroparesis Main Symptom Index Diary Table 10 shows the ANMS GCSI-DD total score and subscale score and the change from baseline and percent change for the ITT population using protocol-specific scoring method.For all dewdonperidone treatment groups, the ANMS GCSI-DD total score and all subscale scores decreased from baseline at Day 14 / end of treatment.Subjects receiving placebo also experienced a decrease in the ANMS GCSI-DD total score and subscale scores.

[0155] Table 10. ANMS GCSI-DD Total and Subscale Scores (Protocol Specific Scoring Methods) - Intent-to-Treat Population TIFF2025514817000019.tif61152TIFF2025514817000020.tif223152TIFF2025514817000021.tif137152Baseline was defined as the average score for the 3 days preceding randomization. Day 14 / EOT was defined as the last score available before the last day of treatment. The ANMS GCSI-DD total score was the average of the three subscale scores for severity of nausea / vomiting, postprandial bloating / early satiety, and abdominal bloating.

[0156] Table 11 shows the ANMS GCSI-DD total score and subscale score, and the change from baseline and percent change for the ITT population using the ANMS GCSI-DD manual scoring method.For all dewdonperidone treatment groups, the ANMS GCSI-DD total score and all subscale scores decreased from baseline at Day 14 / EOT.Subjects receiving placebo also experienced a decrease in the ANMS GCSI-DD total score and subscale scores.

[0157] Table 11. ANMS GCSI-DD Total and Subscale Scores (ANMS GCSI-DD Manual Scoring Method) - Intent-to-Treat Population TIFF2025514817000022.tif223152TIFF2025514817000023.tif223152TIFF2025514817000024.tif152152Baseline was defined as the average score for the 3 days preceding randomization. Day 14 / EOT was defined as the last score available before the last day of treatment. The ANMS GCSI-DD total score was the average of the five subscale scores for severity of nausea, early satiety, postprandial fullness, epigastric pain, and vomiting.

[0158] Patient-rated Gastrointestinal Symptom Severity Index Table 12 shows the PAGI-SYM total and subscale scores, as well as the change and percent change from baseline to Day 14 for the safety analysis population. For all dewdonperidone treatment groups, PAGI-SYM total and subscale scores decreased from baseline on Day 14. Subjects receiving placebo also experienced a decrease in PAGI-SYM total and subscale scores.

[0159] Table 12. Patient-Assessed Gastrointestinal Symptom Severity Index Questionnaire Total Score and Subscale Scores - Safety Analysis Population TIFF2025514817000025.tif223152TIFF2025514817000026.tif223152TIFF2025514817000027.tif233152Baseline was defined as the last available assessment before the first dose of study drug.

[0160] Clinical Grading Scale Table 13 shows the responses on the clinical grading scale for the ITT population. Improvement was observed for the majority of subjects across all treatment groups.

[0161] Table 13. Clinical Grading Scale, Day 14 - Intent to Treat Population TIFF2025514817000028.tif113152N' = number of subjects with a response available on day 14. % = 100 x n / N'. For the assessment of overall clinical response, the following question was utilized on day 14: "Looking at the past 2 weeks, how have your stomach / gastroparesis related problems / symptoms been compared to the period before you started treatment in this study?" Responses were: improved, unchanged, or worsened. Subjects were asked to quantify their treatment response using the CPGAS. Subjects chose a number from a range (+7 = completely improved; 0 = unchanged; -7 = very worse) that best answered the question. Investigators completed the same assessment based on their judgment of the subject's response to treatment.

[0162] (ii) Pharmacodynamic evaluation Prolactin concentrations and changes from baseline at scheduled time points and by treatment for the safety analysis population are summarized in Table 14. Prolactin concentrations generally increased with dose and over the treatment period, confirming target engagement.

[0163] Table 14. Summary of prolactin concentrations - safety analysis population TIFF2025514817000029.tif195152Baseline was defined as the last measurement taken before the first dose of study drug.

[0164] Figures 2A and 2B show plots of mean (±SD) plasma concentrations of deuterated domperidone versus time after administration of deuterated domperidone on the morning of Day 1 and the morning of Day 14 for the BID deuterated domperidone treatment group on a linear scale for the PK populations over a single dosing interval.

[0165] As expected, exposure to deuterated domperidone generally increased with increasing dose. Plasma concentrations of deuterated domperidone generally reached or near peak levels rapidly after dosing with deuterated domperidone, and T maxMedian time to onset ranged from 2.0 to 2.5 hours across dose groups. Plasma concentrations of deuterated domperidone generally declined slowly from the peak. Table 15 summarizes single-dose (Day 1) and steady-state (Day 14) plasma PK parameters of deuterated domperidone by treatment for the PK-evaluable population.

[0166] Table 15. Summary of single-dose (Day 1) and steady-state (Day 14) pharmacokinetic parameters of deuterated domperidone - Pharmacokinetic evaluable population TIFF2025514817000030.tif240152 For small sample collection profiles, C max , T max , and R Cmax For profiles where a valid pretreatment sample was not collected (missing or collected posttreatment), only C max , T max , λz, T 1 / 2 , and R Cmax Only the geometric CV% was calculated. Geometric CV% = 100 × (exp(SD 2 )-1) 0.5 [where SD is the standard deviation of log-transformed data] Tau = 12 hours for BID dosing and 24 hours for QD dosing.

[0167] At steady state, exposure (C max and AUC) were approximately 2.0-2.5-fold higher after both a single dose following BID dosing and a single dose following QD dosing. Variability at steady state was moderate to high, with geometric CV% of C max and AUC(AUC tau , AUC 0-t , and AUC 0-∞ ) values ​​ranged from approximately 43.9% to 136.5%, which may be due in part to the more compressed and / or more variable sampling schedule in this study.

[0168] Of note, two subjects had plasma concentration values ​​on Day 14 that were not consistent with those expected based on the assigned dosing regimen, suggesting potential lack of adherence. PK parameters were similar with and without these subjects, indicating that their presence in the data set did not have a notable impact on the overall conclusions.

[0169] (iii) Efficacy, pharmacodynamic, and pharmacokinetic conclusions Gastric emptying times were reduced from baseline for subjects with idiopathic or diabetic gastroparesis treated with deudomeperidone across a range of doses, as well as for subjects treated with placebo.

[0170] Improvement in gastroparesis symptoms was demonstrated for subjects receiving diudoseperidone as well as placebo, as shown by lower scores on the ANMS GCSI-DD (protocol specific scoring and manual scoring), lower scores on the PAGI-SYM, and improvements observed for the majority of subjects on the Clinical Grading Scale.

[0171] Prolactin concentrations generally increased with dose and over the treatment period, confirming target capture.

[0172] The PK profile of deuterated domperidone following multiple administration of deuterated domperidone QD or BID to patients with gastroparesis showed a relatively rapid C max and characterized by a long T1 / 2. Steady-state accumulation ranged from approximately 2.0-2.5 fold higher after a single dose following BID dosing and approximately 1.5-2.0 fold higher after a single dose following QD dosing.

[0173] H. Safety Conclusions (iii) Extent of exposure A total of 72 subjects were randomized into one of three cohorts. Fifty-four subjects were randomized to receive multiple doses of deuterium peridon at one of the following dose levels: 10 mg BID, 20 mg QD, and 5 mg BID. The pooled placebo treatment group included 18 subjects. Overall, the mean exposure to study drug was 14 days.

[0174] (ii) Adverse events Summary of adverse events Table 16 provides an overview of treatment-specific AEs at baseline for the safety analysis population.

[0175] There were no deaths, serious TEAEs, or discontinuations due to TEAEs. Overall, 15 (20.8%) subjects experienced 23 TEAEs: 6 (20.0%) subjects in the 10 mg BID diudomestic treatment group (11 TEAEs reported), 6 (40.0%) subjects in the 20 mg QD diudomestic treatment group (8 TEAEs reported), 1 (11.1%) subject in the 5 mg BID diudomestic treatment group (1 TEAE reported), and 2 (11.1%) subjects in the pooled placebo treatment group (3 TEAEs reported). The majority of TEAEs were mild in severity.

[0176] Overall, 9 (12.5%) subjects experienced TEAEs considered by the investigator to be related to study drug: 4 (13.3%) subjects in the 10 mg BID diudomestic treatment group, 4 (26.7%) subjects in the 20 mg QD diudomestic treatment group, 1 (11.1%) subject in the 5 mg BID diudomestic treatment group, and 0 (0.0%) subjects in the pooled placebo treatment group.

[0177] Table 16. Summary of adverse events - Safety analysis set TIFF2025514817000031.tif133152% = 100 × n / N. TEAEs were defined as AEs that began after the first dose of study drug. Subjects reporting more than one AE were counted once using the most severe incident. AEs were coded using the Glossary of Regulatory Terms for Drugs and Medical Devices version 22.0.

[0178] Analysis of adverse events Table 17 summarizes TEAEs by treatment at onset and by SOC and PT for the safety analysis population. Overall, 15 (20.8%) subjects experienced a total of 23 TEAEs: 6 (20.0%) subjects receiving 10 mg BID diudomperidone (11 TEAEs reported), 6 (40.0%) subjects receiving 20 mg QD diudomperidone (8 TEAEs reported), and 1 (11.1%) subject receiving 5 mg BID diudomperidone (1 TEAE reported). There were 2 (11.1%) subjects in the pooled placebo treatment group who experienced a total of 3 TEAEs.

[0179] The most common SOC for TEAEs was gastrointestinal disorders. In the diudomperidone treatment group, three (10.0%) subjects receiving 10 mg BID diudomperidone and one (6.7%) subject receiving 20 mg QD diudomperidone experienced diarrhea. The second most common SOC for TEAEs was laboratory tests and metabolic and nutrition disorders. In the diudomperidone treatment group, one (3.3%) subject receiving 10 mg BID diudomperidone and two (13.3%) subjects receiving 20 mg QD diudomperidone experienced electrocardiogram QT prolongation, and one (3.3%) subject receiving 10 mg BID diudomperidone and one (6.7%) subject receiving 20 mg QD diudomperidone experienced hypoglycemia. All other TEAEs in the dewdonperidone treatment groups were experienced by one subject each: nausea, vomiting, elevated blood creatinine phosphokinase, decreased appetite, palpitations, and tinnitus (10 mg BID dewdonperidone treatment group); constipation, dyspepsia, sinusitis, and headache (20 mg QD dewdonperidone treatment group); and lower abdominal pain (5 mg BID dewdonperidone treatment group).

[0180] In the pooled placebo treatment group, one (5.6%) subject each experienced nausea, arthralgia, and back pain.

[0181] Table 17. Summary of treatment-emergent adverse events by system organ class and preferred term - Safety analysis set TIFF2025514817000032.tif173152%=100×n / N. TEAEs were defined as AEs that began after the first dose of study drug. Subjects reporting more than one AE for a given MedDRA Preferred Term were counted only once for that term. Subjects reporting more than one type of event within a SOC were counted only once for that SOC. AEs were coded using MedDRA version 22.0.

[0182] Drug-related adverse events Table 18 summarizes study drug-related TEAEs by treatment at onset and by SOC and PT for the safety analysis population. Overall, 9 (12.5%) subjects experienced a total of 11 study drug-related TEAEs: 4 (13.3%) subjects receiving 10 mg BID deudenperidone (6 TEAEs reported), 4 (26.7%) subjects receiving 20 mg QD deudenperidone (4 TEAEs reported), and 1 (11.1%) subject receiving 5 mg BID deudenperidone (1 TEAE reported). No subjects in the pooled placebo treatment group experienced study drug-related TEAEs.

[0183] The most common SOC for study drug-related TEAEs was gastrointestinal disorders. In the diudomperidone treatment group, two (6.7%) subjects receiving 10 mg BID diudomperidone and one (6.7%) subject receiving 20 mg QD diudomperidone experienced diarrhea. The second most common SOC for study drug-related TEAEs was laboratory tests. In the diudomperidone treatment group, two (13.3%) subjects receiving 20 mg QD diudomperidone experienced electrocardiogram QT prolongation. All other study drug-related TEAEs in the diudomperidone treatment group were experienced by one subject each: nausea, elevated blood creatinine phosphokinase, palpitations, and tinnitus (10 mg BID diudomperidone treatment group); headache (20 mg QD diudomperidone treatment group); and lower abdominal pain (5 mg BID diudomperidone treatment group).

[0184] Table 18. Summary of treatment-emergent, study drug-related adverse events by system organ class and preferred term - Safety analysis set TIFF2025514817000033.tif112152%=100×n / N. TEAEs were defined as AEs that began after the first dose of study drug. Subjects reporting more than one AE for a given MedDRA preferred term were counted only once for that term. Subjects reporting more than one type of event within a SOC were counted only once for that SOC. AEs were coded using MedDRA version 22.0.

[0185] Adverse events by severity The majority of TEAEs were mild in severity. In total, 11 (15.3%) subjects reported mild TEAEs, 3 (4.2%) subjects reported moderate TEAEs, and 1 (1.4%) subject reported severe TEAEs. All study drug-related TEAEs were mild in severity.

[0186] There were no deaths, SAEs, or other significant AEs during the study.

[0187] (iii) Clinical laboratory evaluation Evaluation of clinical laboratory parameters Laboratory Values ​​Over Time: There were no significant changes from baseline in laboratory parameters. Prolactin concentrations generally increased with dose and over the treatment period, confirming target capture.

[0188] Individual Subject Changes: There were no clinically meaningful changes from baseline in any clinical laboratory parameters. There were no clinically meaningful changes from baseline in prolactin concentrations.

[0189] Individual Clinically Significant Abnormalities: No laboratory abnormalities were considered SAEs or resulted in discontinuation from the study or study drug.

[0190] (iv) Vital signs, physical examination findings, and other observations related to safety There were no clinically meaningful changes from baseline in vital signs.There were no clinically meaningful changes in physical examination results.

[0191] There was no clinically meaningful prolongation of the QTcF interval; however, some subjects met protocol-specified precautionary criteria for QTcF. Two (13.3%) subjects in the 20 mg QD deuconperidone treatment group experienced a ≥ 6% change from baseline in QTcF on both Days 3 and 7. At 4 hours post-dose on Day 14, one (3.6%) subject in the 10 mg BID deuconperidone treatment group, three (20.0%) subjects in the 20 mg QD deuconperidone treatment group, and one (6.3%) subject in the pooled placebo treatment group experienced a ≥ 6% change from baseline in QTcF. At 6 hours post-dose on Day 14, one (4.3%) subject in the 10 mg BID diudomestic treatment group, two (16.7%) subjects in the 20 mg QD diudomestic treatment group, and one (7.1%) subject in the pooled placebo treatment group experienced a ≥ 6% change from baseline in QTcF. One (6.7%) female subject in the 20 mg QD diudomestic treatment group experienced a QTcF of ≥ 470 msec. Two subjects were assessed as having a study drug-related TEAE of electrocardiogram QT prolongation.

[0192] Safety Conclusion No subjects died during the study, experienced serious TEAEs, or were withdrawn from the study due to TEAEs. Overall, 15 (20.8%) subjects experienced TEAEs and 9 (12.5%) subjects experienced TEAEs that were considered by the investigator to be related to study drug; all of these subjects were receiving deudomeperidone. All study drug-related TEAEs were mild in severity. The SOC for the most common study drug-related TEAE was gastrointestinal disorders.

[0193] There were no clinically meaningful changes from baseline in clinical laboratory parameters during the study, and no clinically meaningful changes in vital signs or physical examination results during the study. There was no clinically meaningful prolongation of the QTcF interval; however, two subjects met the protocol-specified alert criteria for QTcF. For one subject, alerts for a QTcF increase of ≥ 6% from baseline were at 4 and 6 hours post-dose on Day 14; notably, QTcF never increased beyond 426 msec. For the second subject, alerts for a QTcF increase of ≥ 6% from baseline were at Day 7, with a value of 474 msec (mean baseline QTcF was 430 msec); this subject continued on study drug, and QTcF remained below baseline for the remainder of the study.

[0194] I. Discussion and General Conclusions A total of 72 subjects were randomized into one of three cohorts: 54 subjects were randomized to receive multiple doses of either 10 mg BID, 20 mg QD, or 5 mg BID of deuterium peridon; the pooled placebo treatment group included 18 subjects. Overall, the mean exposure to study drug was 14 days. For all treatment groups, the majority of subjects (51 [70.8%] subjects) had a diabetic gastroparesis etiology, and the numbers of diabetic subjects with and without neuropathy were similar except in cohort 2, where the majority of subjects had neuropathy. It is unlikely that the observed differences in demographics and baseline characteristics would have influenced the interpretation and conclusions of the data. There were no problems with administration of study drug, and there was no difference in the mean percent adherence based on drug accountability between treatment groups.

[0195] Improvement in gastroparesis symptoms was demonstrated for subjects receiving diudense peridon as well as placebo, as shown by lower scores on the ANMS GCSI-DD (protocol-specific scoring and manual scoring), lower scores on the PAGI-SYM, and improvements observed for the majority of subjects on clinical grading scales. A separate meta-analysis demonstrated a positive association between faster gastric emptying and improved upper gastrointestinal symptoms.

[0196] However, exposure to deuterated domperidone (C max and AUC) are approximately 2-fold higher than would be expected based on PK data in healthy subjects for a given dose level of deudomperidone, despite similar accumulation in both populations. Specifically, data in healthy subjects show that a BID dosing regimen of 10 mg deudomperidone results in mean C of approximately 7-11 ng / mL. max However, the C in patients with gastroparesis after BID administration of 10 mg deutzomaperidone max is approximately 18 ng / mL. Similarly, an approximately 2-fold higher AUC was observed in patients with gastroparesis compared to that expected in healthy subjects. The PK differences are most pronounced in patients with more severe gastroparesis.

[0197] Prolactin concentrations generally increased with dose and over the treatment period, confirming target capture.

[0198] The study also aimed to characterize the safety of diudomperidone after multiple dosing. Multiple dosing of diudomperidone was generally well tolerated by subjects with idiopathic or diabetic gastroparesis participating in the study. No subjects died during the study, experienced serious TEAEs, or were withdrawn from the study due to TEAEs. Overall, 15 (20.8%) subjects experienced 23 TEAEs: 6 (20.0%) subjects in the 10 mg BID diudomperidone treatment group (11 TEAEs reported), 6 (40.0%) subjects in the 20 mg QD diudomperidone treatment group (8 TEAEs reported), (11.1%) subjects in the 5 mg BID diudomperidone treatment group (1 TEAE reported), and (11.1%) subjects in the pooled placebo treatment group (3 TEAEs reported). The majority of TEAEs were mild in severity. Overall, 9 (12.5%) subjects experienced a TEAE considered by the investigator to be related to study drug: 4 (13.3%) subjects in the 10 mg BID diudomestic treatment group, 4 (26.7%) subjects in the 20 mg QD diudomestic treatment group, 1 (11.1%) subject in the 5 mg BID diudomestic treatment group, and 0 (0.0%) subjects in the pooled placebo treatment group. In the diudomestic treatment groups, 2 (6.7%) subjects receiving 10 mg BID diudomestic treatment and 1 (6.7%) subject receiving 20 mg QD diudomestic treatment experienced diarrhea, and 2 (13.3%) subjects receiving 20 mg QD diudomestic treatment experienced electrocardiogram QT prolongation. All other study drug-related TEAEs in the diudomperidone treatment groups were experienced by one subject each: nausea, elevated blood creatinine phosphokinase, palpitations, and tinnitus (10 mg BID diudomperidone treatment group); headache (20 mg QD diudomperidone treatment group); and lower abdominal pain (5 mg BID diudomperidone treatment group). All study drug-related TEAEs were mild in severity. No subjects in the pooled placebo treatment group experienced study drug-related TEAEs.

[0199] There were no clinically meaningful changes from baseline in clinical laboratory parameters during the study, and no clinically meaningful changes in vital signs or physical examination results during the study. There was no clinically meaningful prolongation of the QTcF interval; however, two subjects met protocol-specified precautionary criteria for QTcF. These subjects did not report any clinically meaningful changes from baseline in clinical laboratory parameters during the study, and there were no clinically meaningful changes in vital signs or physical examination results during the study. There was no clinically meaningful prolongation of the QTcF interval; however, two subjects met protocol-specified precautionary criteria for QTcF. These subjects did not report any clinically meaningful changes from baseline in clinical laboratory parameters during the study, which were considered to be related to the study drug. max One subject experienced a TEAE of electrocardiogram QT prolongation that occurred later in clear. For one subject, the alert for a QTcF increase of ≥ 6% from baseline was at 4 and 6 hours post-dose on Day 14; notably, QTcF never increased beyond 426 msec. For the second subject, the alert for a QTcF increase of ≥ 6% from baseline was at Day 7, with a value of 474 msec (mean baseline QTcF was 430 msec); this subject continued on study drug and QTcF remained at or below baseline for the remainder of the study.

[0200] General conclusions In this study, multiple oral doses of 10 mg BID, 20 mg BID, and 5 mg BID of diudomeperidone were generally well tolerated by adults with idiopathic or diabetic gastroparesis. There were no deaths, serious TEAEs, or discontinuations due to TEAEs. The majority of TEAEs were mild in severity.

[0201] A decrease in gastric emptying time from baseline and improvement in symptoms of gastroparesis was observed for subjects with idiopathic or diabetic gastroparesis treated with diudomeperidone across a range of doses and for subjects treated with placebo.

[0202] The PK profile of deuterated domperidone following multiple doses of deuterated domperidone QD or BID in patients with gastroparesis showed a relatively rapid C maxand characterized by a long T1 / 2. Steady-state accumulation ranged from approximately 2.0-2.5-fold higher following BID dosing than after a single dose, and approximately 1.5-2.0-fold higher following QD dosing than after a single dose. Exposure (C max and AUC) are approximately 2-fold higher than expected based on PK data in healthy subjects.

[0203] Example 3: Components and Composition Table 19 shows the composition of CIN-102 5 mg, 10 mg, and 20 mg softgel capsules. CIN-102 contains 5 mg, 10 mg, or 20 mg of CIN-102 drug substance (as free base) and lower C max Based on the lipophilicity of the fill formulation, a 2A gelatin shell formulation was used for encapsulation.

[0204] Table 19. Composition of 5 mg, 10 mg, and 20 mg softgel capsules of CIN-102 TIFF2025514817000034.tif37139 1 The softgel capsule contains the following ingredients: Gelatin 150 LB, NF; Glycerin, USP; Gelatine Hydrolysate, NF; Purified Water, USP; Titanium Dioxide, USP; and FD&C Blue #1.

[0205] The placebo softgel capsule contains all of the components listed in Table 19 except for CIN 102.

[0206] Example 4: Sara QT Study This example details the results of a cardiac dynamics evaluation of CIN-102 in which a single dose of CIN-102 (resulting in therapeutic and supratherapeutic exposures) was administered to healthy adult subjects. The primary objective of this study was to evaluate the effect of CIN-102 on cardiac repolarization based on baseline and placebo-corrected changes in corrected QT interval (QTcF) using Fridericia's formula in healthy subjects using concentration-QTc analysis (primary analysis). Serial ECGs were extracted from continuous ECG recordings at pre-specified time points beginning at least 1 hour prior to dosing and ending approximately 48 hours after dosing in each period.

[0207] The 10 mg dose of the deuxoperidone formulation had approximately 50% lower C than the same oral dose of domperidone in healthy subjects. max . Mean half-life values ​​after a single dose of diudomperidone formulations range from approximately 18 to 29 hours over the dose range tested. A definitive TQT study was performed to evaluate the effect of diudomperidone formulations on the QT interval. The primary analysis was based on concentration-QTc modeling of the relationship between plasma drug concentrations and the change from baseline QTcF (ΔQTcF) with the goal of excluding effects of placebo-corrected ΔQTcF (ΔΔQTcF) > 10 milliseconds (ms) at clinically meaningful plasma levels.

[0208] The study was a randomized, partially double-blind, active- and placebo-controlled, single-dose, four-period crossover study in healthy subjects aged 18-55 years. During the study, each subject was randomized to receive a single dose of each of the following (1 treatment / study period) in separate periods (≥10 days between doses) as shown in Table 20: · 30mg deudomperidone formulation (representing approximate steady-state therapeutic exposure in patients); · 100mg deudomperidone formulation (representing potential steady-state supratherapeutic exposure in patients); 400mg moxifloxacin; and Placebo.

[0209] Table 20. Treatment sequence in which subjects could be randomized TIFF2025514817000035.tif62152

[0210] For Treatments A, B, and D, subjects received a total of 10 CIN-102 and / or matching placebo capsules. For Treatment C, subjects received a single 400 mg tablet of moxifloxacin.

[0211] Subjects fasted for a minimum of 8 hours before and 4 hours after each treatment. There was a minimum of 10 days washout between treatments.

[0212] Purpose of the test The primary objective of this study was to evaluate the effect of CIN-102 on cardiac repolarization based on baseline and placebo-corrected changes in corrected QT interval (QTcF) using the Fridericia formula.

[0213] The secondary objectives of this study were: To evaluate the effect of CIN-102 on other ECG parameters (heart rate [HR], PR and QRS intervals, and treatment-emergent changes in T-wave morphology). · To characterize the safety of a single dose of CIN-102 when administered to healthy adult subjects. · To characterize the single-dose pharmacokinetics (PK) of CIN-102 when administered to healthy adult subjects.

[0214] Primary endpoint The primary outcome was placebo-corrected change from baseline QTcF (ΔΔQTcF).

[0215] Secondary outcomes were: Change from baseline QTcF, HR, PR, and QRS interval (ΔQTcF, ΔHR, ΔPR, and ΔQRS). Placebo-corrected change from baseline HR, PR, and QRS (ΔΔHR, ΔΔPR, ΔΔQRS). Categorical outliers for QTcF, HR, PR, and QRS. Frequency of treatment-emergent changes in T wave morphology and presence of U waves.

[0216] ECG and Pharmacokinetic Sample Collection In each treatment period, continuous 12-lead ECGs were recorded beginning at least 1 hour before dosing and ending approximately 48 hours after dosing. 12-lead ECGs were drawn in a central ECG laboratory (ERT, Philadelphia, PA) at the following time points in each period: 3 time points (-45, -30, and -15 minutes) within 1 hour before dosing and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 36, and 48 hours after each dose, with up to 10 repeats. Subjects were supine and at rest for at least 10 minutes before and 5 minutes after each time point. When ECG drawing was simultaneous with safety, ECG, vital sign assessments, and blood draws, procedures were performed in the order listed. No PK or other laboratory blood draws were performed and subjects were not approached until at least 5 minutes had elapsed after the 5 minutes for 12-lead ECG drawing for QT analysis.

[0217] Blood samples for PK determination were taken at the same time points immediately after ECG extraction.

[0218] ECG intervals were measured blindly in a core laboratory using Early Precision QT technology (EPQT).The ECG database was locked before any statistical analysis was performed.

[0219] TQT Plus ECG extraction technology Up to ten non-overlapping 14-second interval digital 12-lead ECG tracings were extracted from continuous recordings during the ECG extraction period specified in the protocol. The TQT Plus method enabled the extraction of high-quality data sets by identifying recording periods with the least available HR variability and noise.

[0220] The ECG was extracted according to the following principles: Study center personnel communicated actual times of dosing, extraction periods, and PK sample collection to the central ECG laboratory. The TQT Plus process identified periods of stable HR on consecutive 12-lead ECG tracings during a 5-minute sampling period. Stability was defined as fluctuations in HR and other ECG parameters below a predefined threshold from beat-to-beat interval. When the TQT Plus method resulted in few consecutive readable cardiac cycles within a 5-minute period, the time points were thoroughly reviewed manually. Repeated non-overlapping ECGs were sampled consecutively within each sampling period.

[0221] Early Precision QT Analysis At each nominal time point specified in the protocol, up to 10 ECG repeats were extracted with the TQT Plus method. All readable cardiac cycles from these ECG repeats were assessed for multiple quality criteria, including heart rate stability, HR variability, noise, and other parameters, and classified into high and low confidence ranks. All low confidence beats were thoroughly reviewed and manually adjudicated by an ECG technician using pass / fail criteria. Beats found to be acceptable by manual review were included in the analysis.

[0222] The primary analysis lead was lead II. If lead II was not analyzable, the primary analysis lead was changed to V5 for all data sets of interest. If lead V5 was not analyzable, lead V2 was used for all data sets of interest. If both alternative leads were not available, the ERT cardiologist had the option to consider the data as not analyzable or to decide to use the most appropriate lead for all data sets of interest. The leads used for analysis were listed in the data list transferred from the ERT.

[0223] Categorical T-wave morphology analysis and PR and QRS interval measurements were performed entirely manually using a semi-automated process on three of the ten ECG repeats at each time point. A study cardiologist performed final quality control and diagnostic interpretation. When results for each time point were compiled into a final raw data set, the mean QTcF from the three manually reviewed ECGs was compared to the mean QTcF from the TQT Plus ECG repeats (up to ten) for quality control purposes.

[0224] A total of 62 subjects were enrolled in the TQT study. At baseline, data were available from all 55 subjects during the placebo treatment period, from 52 subjects during the dudomeperidone formulation (30 mg) and supratherapeutic dose (100 mg) treatment periods, and from 51 subjects during the moxifloxacin treatment period. The subjects' mean (SD) age was 38.5 (9.20) years, and the subjects' mean (SD) BMI was 26.3 (2.48) kg / m2. 61% of the subjects were male and 39% were female. Baseline ECG parameters were within expected ranges for a healthy subject population.

[0225] (i) PK data from the study demonstrated that peak mean plasma concentrations of deuterated domperidone were observed at 1.5 and 2 hours post-dose for the 30 and 100 mg treatment groups, respectively.

[0226] The highest mean plasma concentrations of M3 (the major metabolite) were observed at 2 hours post-dose for the 30 and 100 mg treatment groups, respectively. LS mean placebo-corrected changes from baseline in QTcF (ΔΔQTcF) within the first 4 hours with diudoseperidone formulations ranged from -0.3 to 1.8 ms at 0.5 and 2 hours post-dose, respectively, in the 30 mg treatment group and -0.1 to 3.7 ms at 0.5 and 3 hours post-dose, respectively, in the 100 mg treatment group. See Figure 7. LS means and 90% CIs are based on linear mixed-effects models for active and placebo treatment groups. ΔQTcF=time + treatment + time × treatment + baseline QTcF + duration + sequence. An unstructured covariance structure was used to specify repeated measurements at post-dose time points for subjects within the treatment period. The model also included subject-specific random effects.

[0227] In Figure 5, the upper bound of the 90% CI for ΔΔQTcF was <10 ms for both diuodosinperidone formulation doses at all time points, demonstrating that effects on QTcF of >10 ms could be excluded for both diuodosinperidone formulation doses. Moxifloxacin caused a clear QTc prolongation.

[0228] (ii) An analysis was also performed to understand the relationship between diudomeperidone plasma concentrations and ΔΔQTcF independent of time. Based on this concentration-QTc analysis, we can exclude an effect on ΔΔQTcF of more than 10 ms with diudomeperidone plasma concentrations up to approximately 92 ng / mL, approximately 5 times the therapeutic steady-state concentration (Figure 8). We can predict the effect on ΔΔQTcF to be 1.10 ms (90% CI: 0.58-1.61) and 3.50 ms (90% CI: 2.18-4.82) for the 30 and 100 mg treatment groups, respectively.

[0229] In Figure 8, the solid black line with grey shaded area represents the model predicted mean (90% CI) ΔΔQTcF, which was calculated from the formula ΔΔQTcF = -0.02844 (ms) + 0.7918 (ms per ng / mL) × deuterated domperidone concentration (ng / mL). The vertical blue (left-most) and red (right-most) lines represent the geometric mean C of deuterated domperidone. max Points are plotted with to represent the estimated mean (90% CI) ΔΔQTcF.

[0230] The same linear model was used for moxifloxacin. The slope of the relationship was positive and statistically significant. The lower bound of the two-sided CI for the predicted QT effect at the geometric mean peak moxifloxacin concentration was >5 ms, demonstrating the sensitivity of the assay.

[0231] (iii) A similar analysis was also performed to understand the relationship between plasma concentrations of the major metabolite (M3) and ΔΔQTcF. The results of this analysis demonstrated that plasma M3 concentrations up to approximately 480 ng / mL could preclude an effect on ΔΔQTcF of more than 10 ms. The effect on ΔΔQTcF could be estimated to be 1.43 ms (90% CI: 0.90-1.96) and 3.58 ms (90% CI: 2.34-4.83) for the 30 and 100 mg treatment groups, respectively.

[0232] In Figure 7, the solid black line with grey shaded area represents the model-predicted mean (90% CI) ΔΔQTcF, which was calculated from the equation ΔΔQTcF = 0.3678 (ms) + 0.1439 (ms per ng / mL) × M3 concentration (ng / mL). Thus, the estimated population slope of the concentration-QTc relationship was very small at 0.14 ms per ng / mL (90% CI: 0.08 to 0.20), with a small treatment effect-specific intercept of 0.37 ms (90% CI: -0.16 to 0.89) (Figures 6 and 7).

[0233] The vertical blue (leftmost) and red (rightmost) lines are the geometric mean C of M3. max Points are plotted with to represent the estimated mean (90% CI) ΔΔQTcF.

[0234] (iv) Deuterated domperidone at the doses tested had no clinically meaningful effects on heart rate (FIG. 8) or cardiac conduction (ie, PR and QRS intervals).

[0235] Baseline ECG parameters were within expected ranges for the healthy population across treatment groups, with mean HR of 59.9-61.0 bpm, mean QTcF of 404.0-406.1 ms, mean PR of 152.3-153.7 ms, and mean QRS of 103.0-103.7 ms.

[0236] The LS mean change from baseline HR (ΔHR) for CIN-102 closely followed the pattern observed with placebo (Figure 4). LS mean placebo-corrected ΔHR (ΔΔHR) across post-dose time points during the CIN-102 treatment period ranged from -1.4 to 1.1 bpm (3 and 24 hours post-dose, respectively, both in the 30 mg treatment group) within ±1.4 bpm (Figure 9 and Table 21). There was one bradycardic outlier (5 time points in the 30 mg treatment group) and no tachycardic outliers across the treatment period.

[0237] Table 21: Placebo-adjusted change from baseline HR (ΔΔHR) at each time point (QT / QTc population) TIFF2025514817000036.tif252146 Linear mixed effects model for active and placebo treatment groups based on: ΔHR=time+treatment+time×treatment+baseline HR+period+sequence. Unstructured covariance structures were used to specify repeated measures at post-dose time points for subjects within the treatment period. The model also included subject-specific random effects. Treatment A: 30 mg CIN-102 [representing near steady-state therapeutic exposure in the subject population], Treatment B: 100 mg CIN-102 [representing potential steady-state supratherapeutic exposure in the subject], Treatment C: 400 mg open-label moxifloxacin.

[0238] The same linear model with treatment effect-specific intercepts as in the concentration-QTc analysis was used in the assay sensitivity analysis for moxifloxacin. The slope of the equation was positive and statistically significant: 0.07 ms (90% CI: 0.06 to 0.09) per ng / mL, and the lower bound of the two-sided CI of the predicted QT effect (12.98 ms [90% CI: 11.43 to 14.52]) at the geometric mean peak moxifloxacin concentration (1552.6 ng / mL) was greater than 5 ms, thereby demonstrating assay sensitivity.

[0239] Effects on cardiac repolarization: QT interval (a) Results of time-specific (central tendency) analysis and categorical analysis LS mean change from baseline QTcF (ΔQTcF) for CIN-102 followed a placebo pattern across post-dose time points, with a somewhat larger effect from 3 to 6 hours post-dose in the highest dose treatment group (100 mg CIN-102) (Figure 5). LS mean placebo-corrected ΔQTcF (ΔΔQTcF) within the first 4 hours for CIN-102 ranged from -0.3 to 1.8 ms at 0.5 and 2 hours post-dose, respectively, in the 30 mg treatment group and -0.1 to 3.7 ms at 0.5 and 3 hours post-dose, respectively, in the 100 mg treatment group (Figure 11 and Table 22). The upper bound of the 90% CI for ΔΔQTcF was below 10 ms at all time points for both CIN-102 doses.

[0240] Following dosing with 400 mg oral moxifloxacin, a clear increase in LS mean ΔΔQTcF was observed with a peak value of 13.3 ms (90% CI: 11.52–15.00) 3 hours after dosing.

[0241] No subjects had a QTcF >480 ms or ΔQTcF >30 ms (Tables 23 and 24). Across treatment groups, there were 6 and 1 subjects (19 and 1 time points) with QTcF >450 and ≦480 ms during the moxifloxacin and placebo treatment periods, respectively. The following treatment-emergent T-wave morphology changes were observed: 2 subjects (at 2 time points) had flattened T waves during the 100 mg treatment period; 1-2 subjects (at 1-7 time points) had biphasic T waves throughout all treatment periods; and 1 subject each (at 10 and 1 time point) had negative T waves during the 30 mg moxifloxacin treatment period, respectively. There were no treatment-emergent U waves.

[0242] Table 22: Placebo-corrected change from baseline QTcF (ΔΔQTcF) at each time point (QT / QTc population) TIFF2025514817000037.tif252146 Linear mixed effects model for active and placebo treatment groups: ΔQTcF=time+treatment+time×treatment+baseline QTcF+duration+sequence. Unstructured covariance structures were used to specify repeated measures at post-dose time points for subjects within the treatment period. The model also included subject-specific random effects. Treatment A: 30 mg CIN-102 [representing near steady-state therapeutic exposure in the subject population], Treatment B: 100 mg CIN-102 [representing potential steady-state supratherapeutic exposure in the subject], Treatment C: 400 mg open-label moxifloxacin.

[0243] Table 23. QTcF outliers by absolute category (QT / QTc population) TIFF2025514817000038.tif75154 Treatment A: 30 mg CIN-102 [representing near steady-state therapeutic exposure in the subject population]; Treatment B: 100 mg CIN-102 [representing potential steady-state supratherapeutic exposure in subjects]; Treatment C: 400 mg open-label moxifloxacin; Treatment D: CIN-102 placebo. Subjects may appear in more than one category. The denominator (sum) is defined as the number of subjects or time points in the QT / QTc population per treatment.

[0244] Table 24. QTcF outliers by change from baseline category (QT / QTc population) TIFF2025514817000039.tif59155 Treatment A: 30 mg CIN-102 [representing near steady-state therapeutic exposure in the subject population]; Treatment B: 100 mg CIN-102 [representing potential steady-state supratherapeutic exposure in subjects]; Treatment C: 400 mg open-label moxifloxacin; Treatment D: CIN-102 placebo. Subjects may appear in more than one category. The denominator (sum) is defined as the number of subjects or time points in the QT / QTc population for each treatment.

[0245] (b) Concentration-QTc results Pharmacokinetic profile The time courses of deuterated domperidone plasma concentrations and its metabolite, M3, are shown in Figures 12 and 13. The highest mean plasma concentrations of deuterated domperidone were observed at 1.5 and 2 hours post-dose for the 30 and 100 mg treatment groups, respectively. The highest mean plasma concentrations of M3 were observed at 2 hours post-dose for the 30 and 100 mg treatment groups, respectively.

[0246] Evaluating model-independent assumptions Exploratory plots were used to perform model-independent checks of the following assumptions:

[0247] Effect on heart rate In time-point analyses, mean ΔΔHR was below 10 bpm at both dose levels of CIN-102 across all post-dose time points (Figure 9 and Table 21), demonstrating that CIN-102 had no meaningful effect on HR.

[0248] Linear concentration-QTc relationship Scatter plots of concentration vs. ΔQTcF for deuterated domperidone and M3, along with linear and LOESS regression lines (90% CI), are shown in Figures 14 and 10. The linear and LOESS regression lines were close across the entire range of concentrations observed, with small deviations at higher concentrations for deuterated domperidone, indicating that a linear model for the concentration-QTc relationship can adequately capture the observed data.

[0249] The predicted ΔΔQTcF effects using Model C with the geometric mean concentrations for M3 are shown in Table 25 and Figure 21. Plasma M3 concentrations up to about 480 ng / mL can exclude effects on ΔΔQTcF of more than 10 ms.

[0250] Table 25. Predicted ΔΔQTcF Intervals by Geometric Mean Peak CIN-102 M3 (ng / mL) Concentration for Model C (PK / QTc Population) TIFF2025514817000040.tif31146Based on a linear mixed-effects model with ΔQTcF as the dependent variable, time-matched deuterated domperidone plasma concentrations as explanatory variables, centered baseline QTcF as an additional covariate, treatment (active = 1 or placebo = 0) and time as fixed effects, and a random intercept and slope for each subject.

[0251] Concentration-QTc model for Model B (deuterated domperidone) The relationship between the individual observed deuterated domperidone plasma concentrations and the estimated placebo-adjusted ΔQTcF (ie, ΔΔQTcF) is shown in FIG.

[0252] Using Model B at the geometric mean concentrations for deuterated domperidone, the predicted ΔΔQTcF effects are shown in Table 26 and Figure 8. Plasma deuterated domperidone concentrations up to approximately 92 ng / mL preclude effects on ΔΔQTcF of more than 10 ms.

[0253] Table 26. Predicted ΔΔQTcF Intervals by Geometric Mean Peak Deuterated Domperidone Concentration for Model B (PK / QTc Population) TIFF2025514817000041.tif26128Based on a linear mixed-effects model with ΔQTcF as the dependent variable, time-matched deuterated domperidone plasma concentrations as explanatory variables, centered baseline QTcF as additional covariates, treatment (active = 1 or placebo = 0) and time as fixed effects, and random intercept and slope by subject.

[0254] Effects on cardiac conduction: PR and QRS intervals CIN-102 at the doses tested had no clinically meaningful effects on cardiac conduction, i.e., PR and QRS intervals. LS mean change from baseline PR (ΔPR) for CIN-102 closely followed the pattern observed in placebo subjects (Figure 17). LS mean placebo-corrected ΔPR (ΔΔPR) for CIN-102 ranged from -2.3 to 1.3, between ±2.3 ms at 24 and 8 hours post-dose for the 30 and 100 mg treatment periods, respectively (Figure 18 and Table 27). LS mean change from baseline QRS (ΔQRS) was small (Figure 19), with LS mean placebo-corrected ΔQRS (ΔΔQRS) within ±1.1 ms at all post-dose time points (Figure 20 and Table 28). There were no PR or QRS outliers.

[0255] Table 27. Placebo-corrected change from baseline PR (ΔΔPR) at each time point (QT / QTc population) TIFF2025514817000042.tif254146 Linear mixed effects model for active and placebo treatment groups: ΔPR=time+treatment+time×treatment+baseline PR+period+sequence. Unstructured covariance structures were used to specify repeated measures at post-dose time points for subjects within the treatment period. The model also included subject-specific random effects. Treatment A: 30 mg CIN-102 [representing near steady-state therapeutic exposure in the subject population]; Treatment B: 100 mg CIN-102 [representing potential steady-state supratherapeutic exposure in the subject]; Treatment C: 400 mg open-label moxifloxacin.

[0256] Table 28: Placebo-corrected change from baseline QRS (ΔΔQRS) at each time point (QT / QTc population) TIFF2025514817000043.tif252146 Linear mixed effects model for active and placebo treatment groups based on: ΔQRS=time+treatment+time×treatment+baseline QRS+duration+sequence. Unstructured covariance structures were used to specify repeated measures at post-dose time points for subjects within the treatment period. The model also included subject-specific random effects. Treatment A: 30 mg CIN-102 [representing near steady-state therapeutic exposure in the subject population]; Treatment B: 100 mg CIN-102 [representing potential steady-state supratherapeutic exposure in subjects]; Treatment C: 400 mg open-label moxifloxacin.

[0257] Discussion and Conclusion This was a randomized, partially double-blind, placebo- and active-controlled, single-dose, four-period crossover study to evaluate the effect of CIN-102 on cardiac repolarization in healthy subjects. The primary objective of the study was to evaluate the effect of CIN-102 on cardiac repolarization based on baseline and placebo-corrected changes in QTcF. 12-lead ECGs paired with PK sampling pre- and post-dose in each period were drawn at three time points.

[0258] At baseline, data were available from a total of 55 subjects during the placebo treatment period, then from 52 subjects during the CIN-102 therapeutic (30 mg) and supratherapeutic (100 mg) treatment periods, and from 51 subjects during the moxifloxacin treatment period.

[0259] CIN-102 at the doses tested had no clinically meaningful effects on heart rate or cardiac conduction, i.e., PR and QRS intervals.

[0260] The highest mean plasma concentrations of deuterated domperidone were observed at 1.5 and 2 hours post-dose for the 30 and 100 mg treatment groups, respectively. The highest mean plasma concentrations of M3 were observed at 2 hours post-dose for the 30 and 100 mg treatment groups, respectively.

[0261] LS mean ΔΔQTcF was very small for both CIN-102 doses and varied within a narrow range during the first 4 h post-dose: −0.3 to 1.8 ms at 0.5 and 2 h, respectively, in the 30 mg treatment group, and −0.1 to 3.7 ms at 0.5 and 3 h, respectively, in the 100 mg treatment group. Of note, the upper bound of the 90% CI for ΔΔQTcF was below 10 ms for both CIN-102 doses across all time points, thereby demonstrating that effects on ΔΔQTcF of >10 ms could be excluded for both CIN-102 doses.

[0262] For the concentration-QTc analysis, a model selection procedure was performed by first fitting the full model including deuterated domperidone and its metabolite, M3. The model with M3 alone (Model C) was selected as the primary because it had the smallest AIC value and represented the data in an acceptable manner. The estimated slope of M3 plasma concentration in the concentration-QTc equation was positive and statistically significant (0.14 ms per ng / mL [90% CI: 0.08 to 0.20]), and the treatment effect specific intercept was small at 0.37 ms and not statistically significant. The effect on ΔΔQTcF could be predicted to be 1.43 ms (90% CI: 0.90 to 1.96) and 3.58 ms (90% CI: 2.34 to 4.83) for the 30 and 100 mg treatment groups, respectively.

[0263] Results from the concentration-QTc model using deuterated domperidone alone (Model B) were similar to those from the primary model. The estimated slope of the concentration-QTc equation for deuterated domperidone plasma concentrations was positive and statistically significant (0.79 ms per ng / mL [90% CI: 0.47 to 1.11]), with a small, statistically insignificant treatment effect intercept of -0.03 ms. The effect on ΔΔQTcF could be predicted to be 1.10 ms (90% CI: 0.58 to 1.61) and 3.50 ms (90% CI: 2.18 to 4.82) for the 30 and 100 mg treatment groups, respectively.

[0264] Based on this concentration-QTc analysis, deuterated domperidone and M3 concentrations up to approximately 92 and 480 ng / mL, respectively, can exclude a QTcF effect (ΔΔQTcF) of more than 10 ms.

[0265] The same linear model as the concentration-QTc analysis, with a treatment effect-specific intercept, was used for the assay sensitivity analysis for moxifloxacin. The slope of the equation was positive and statistically significant: 0.07 ms (90% CI: 0.06 to 0.09) per ng / mL, and the lower bound of the two-sided CI of the predicted QT effect (12.98 ms [90% CI: 11.43 to 14.52]) at the geometric mean peak moxifloxacin concentration (1552.6 ng / mL) was greater than 5 ms, thereby demonstrating assay sensitivity.

[0266] In summary, CIN-102 at the doses tested had no clinically meaningful effects on the ECG parameters tested. Based on concentration-QTc analysis, deuterated domperidone and M3 concentrations up to approximately 92 and 480 ng / mL, respectively, could exclude effects on ΔΔQTcF of more than 10 ms.

[0267] In conclusion, the results of this negative TQT study suggest that the mean C max These results indicate that even concentrations of deuterated domperidone and M3 approximately 5-fold higher than the QT interval (approximately 18.2 ng / mL) can eliminate minor QT effects. There were no clinically meaningful effects of CIN-102 on heart rate or cardiac conduction. No deaths or serious adverse events occurred during the study. Deuterated domperidone at therapeutic and supratherapeutic doses has no clinically meaningful effects on ECG parameters, including the QT interval.

[0268] Although the present invention has been described in connection with its preferred specific embodiments, it should be understood that the above description and the following examples are intended to illustrate the invention and not to limit its scope. Those skilled in the art will understand that various modifications may be made and equivalents may be substituted without departing from the scope of the invention, and further that other aspects, advantages, and modifications will be apparent to those skilled in the art to which the present invention pertains. In addition to the aspects described herein, the present invention contemplates and claims inventions resulting from combinations of features of the invention cited herein and features of the cited prior art references that are complementary to the features of the invention. Similarly, it is recognized that any described material, feature, or article may be combined with any other material, feature, or article, and such combinations are considered within the scope of the present invention.

[0269] The disclosures of each patent, patent application, and publication cited or described in this document are hereby incorporated by reference in their respective entireties for all purposes.

Claims

1. A pharmaceutical product comprising dudomperidone for use in a method for increasing gastric emptying in a subject with gastroparesis, wherein the method comprises the step of orally administering 10 mg to 120 mg of dudomperidone to the subject daily.

2. The pharmaceutical product according to claim 1, wherein the gastroparesis is idiopathic gastroparesis or diabetic gastroparesis.

3. The pharmacopoeia according to claim 1, wherein prior to the administration, the subject has experienced upper gastrointestinal symptoms, and optionally, the upper gastrointestinal symptoms are nausea, vomiting, postprandial bloating, early satiety, abdominal distension, epigastric pain, abdominal pain, or a combination thereof.

4. 13 The pharmaceutical product according to claim 1, wherein the increase in gastric emptying is measured by a gastric emptying breath test (GEBT) using C-spirulina platensis, approximately 12 to 14 days after administration of dudomperidone.

5. 13 The pharmacopoeia according to claim 1, wherein the subject has delayed gastric emptying approximately 10 days prior to the first dose of dudomperidone, as measured by a gastric emptying test (GEBT) using C-spirulina platensis.

6. Before administering the aforementioned dudonperidone, the subject, (i) 13 As measured by gastric emptying breath testing (GEBT) using C-spirulina platensis, having a T1 / 2 longer than approximately 80 minutes, or for example, longer than approximately 200 minutes, and / or (ii) Having an average composite score of approximately 2 or higher on the American Neurogastroenterology and Motility Society Gastroparesis Cardinal Symptom Index Daily Diary (ANMS GCSI-DD), and / or (iii) Having a nausea subscale score of approximately 2 or higher on the ANMS GCSI-DD for at least approximately 4 days, The pharmaceutical product according to claim 1.

7. In the method described above, approximately 10 mg, or approximately 20 mg, or approximately 30 mg, or approximately 60 mg, or approximately 120 mg of dudomperidone is administered to the subject, optionally, In the above method, the dudonperidone is administered in divided doses, such as two doses. The pharmaceutical product according to claim 1.

8. The aforementioned administration, (i) resulting in clinically significant improvement in nausea, early satiety, postprandial bloating, epigastric pain, vomiting, and abdominal distension as measured by the ANMS GCSI-DD score after the procedure, and / or (ii) resulting in a clinically significant improvement in the mean composite score of the ANMS GCSI-DD score after the procedure, and / or (iii) resulting in a clinically significant improvement in the nausea subscale score of the ANMS GCSI-DD score after treatment, (iv) resulting in a clinically significant improvement in gastric emptying as measured by GEBT approximately 12 to 16 days after the procedure, and / or (v) The treatment results in a clinically significant improvement in gastric emptying as measured by the ANMS GCSI-DD total score, and / or (vi) The procedure results in a clinically significant improvement in gastric emptying, as measured by the ANMS GCSI-DD subscale score. The pharmaceutical product according to claim 1.

9. The pharmaceutical product according to claim 1, wherein the subject has diabetic neuropathy.

10. The pharmacopoeia according to claim 1, wherein, prior to the administration of dudonperidone, the subject has a T1 / 2 longer than approximately 110 minutes.

11. The pharmaceutical product according to claim 1, wherein, prior to the administration of dudonperidone, the subject has a T1 / 2 of less than approximately 110 minutes.

12. The aforementioned administration of dudonperidone, (i) Does not cause clinically significant QT prolongation, and / or (ii) Not resulting in a clinically significant change in the heart rate of the subject, and / or (iii) Not resulting in clinically significant changes in cardiac conduction of the subject, The pharmaceutical product according to claim 1.

13. The pulse (PR) interval of the subject is approximately 0.12 to approximately 0.2 seconds after administration of dudomperidone, and / or The QRS intervals of the subject are approximately 0.08 and 0.10 seconds after the administration of dudonperidone. The pharmaceutical product according to claim 1.

14. The pharmacopoeia according to claim 1, wherein the administration results in a ΔΔQTcF of less than approximately 10 ms, less than or equal to approximately 1.1 ms, or less than or equal to approximately 3.5 ms.

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