Deuterated domperidone for treating gastroparesis

Abstract

The present disclosure relates to methods of increasing gastric emptying in humans with gastroparesis.

Description

[0001] CROSS REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 333,042, filed on April 20, 2022, and U.S. Provisional Patent Application No. 63 / 333,034, filed on April 20, 2022, the disclosures of which are incorporated herein by reference. Technical Field

[0003] The present disclosure relates to methods of increasing gastric emptying in a human suffering from gastroparesis. Background Art

[0004] 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 affects the nutritional status of patients, especially in patients with diabetes, and severe symptoms of gastroparesis can lead to other complications such as malnutrition, esophagitis, and esophageal cardia mucosal lacerations. Gastroparesis has a negative impact on the patient's quality of life, resulting in reduced social interaction, poor work function, and the development of anxiety or depression.

[0005] First-line treatment for gastroparesis includes nutritional management and support, including fluid and electrolyte replacement. Currently, metoclopramide, a dopamine D2 receptor antagonist, is the only agent approved by the United States Food and Drug Administration for the treatment of gastroparesis. Unfortunately, this agent readily crosses the blood-brain barrier, causing central nervous system (CNS) side effects in up to 40% of patients.

[0006] Safe and effective treatments for gastroparesis are needed. Summary of the invention

[0007] In some aspects, the disclosure provides a method of increasing gastric emptying in a human suffering from gastroparesis, the method comprising orally administering to the human 5 mg to 120 mg of deuterated domperidone per day.

[0008] Other aspects and embodiments of the present invention will become apparent from the following detailed description of the invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Figure 1 Schematic diagram of the study of Example 2. In this figure, * expected dose level; ** for each cohort, subjects were randomly assigned to CIN-102 or placebo. Randomization was performed on the morning of Day 1; *** subjects participating in the dense PK subgroup were observed in the clinic on Days 15 and 16 (+1 day). Subjects participating in the sparse PK subgroup were observed on Days 15 or 16 (+1 day).

[0010] Figure 2A and 2B is a linear scale plot of the mean (± standard deviation) of plasma deuterated domperidone concentrations following treatment of the pharmacokinetic population with deuterated domperidone in the mornings of Days 1 and 14. Figure 2A is Cohort 3 (5 mg deuterated domperidone BID), and Figure 2B is Cohort 1 (10 mg deuterated domperidone BID). In this figure, the LLOQ of deuterated domperidone = 0.01 ng / mL. This figure excludes concentrations outside the analytical collection window at the corresponding time points.

[0011] Figure 3 is a linear and semi-logarithmic scale graph of the mean (± standard deviation) of plasma deuterated domperidone concentrations after treatment for the pharmacokinetic population by day 1 and day 14 - Cohort 2: CIN-102 20 mg QD. For this figure, the LLOQ of deuterated domperidone = 0.01 ng / mL. This figure excludes concentrations outside the analytical collection window at the corresponding time point. No 24 hour time point was collected on day 1.

[0012] Figure 4 It is a line graph of the change (ΔHR) of HR compared to baseline across time points (QT / QTc population). In this figure, the LS mean and 90% CI based on the linear mixed effects model for the active drug and placebo treatment groups: ΔHR=time+treatment+time×treatment+baseline HR+cycle+order. An unstructured covariance structure is used to specify repeated measurements of subjects at time points after dosing within the treatment cycle. The model also includes subject-specific random effects.

[0013] Figure 5 It is a line graph (QT / QTc population) of the change (ΔQTcF) of QTcF compared to baseline across time points. In this figure, the LS means and 90% CI of the active drug and placebo treatment groups based on the linear mixed effects model: ΔQTcF=time+treatment+time×treatment+baseline QTcF+cycle+order. An unstructured covariance structure is used to specify repeated measurements of time points after dosing of subjects within the treatment cycle. The model also includes subject-specific random effects.

[0014] Figure 6It is a scatter plot of observed M3 plasma concentrations and estimated placebo-adjusted ΔQTcF (PK / QTc population). In this figure, the solid red line and the dashed red line represent the model-predicted mean ΔΔQTcF with 90% CI, which is calculated from the equation ΔΔQTcF=0.3678 (ms)+0.1439 (ms per ng / mL)×M3 concentration (ng / mL). The plotted points represent the paired observed drug plasma concentrations and estimated placebo-adjusted ΔQTcF (ΔΔQTcF) for subjects in each active drug treatment group and placebo group. The individually estimated placebo-adjusted ΔQTcFi, k (ΔΔQTcFi, k) is equal to the individual ΔQTcFi, k of subject i administered active drug or placebo at time point k minus the estimated value of the time effect at time point k.

[0015] Figure 7 is a graph of model-predicted ΔΔQTcF (mean and 90% CI) and estimated placebo-adjusted ΔQTcF (mean and 90% CI) across deciles of M3 plasma concentration (PK / QTc population). In this figure, the black solid line with a gray shaded area represents the model-predicted mean ΔΔQTcF with 90% CI, which is calculated from the equation ΔΔQTcF=0.3678 (ms)+0.1439 (ms per ng / mL)×M3 concentration (ng / mL). The red solid circles with vertical bars represent the estimated mean and 90% CI of the placebo-adjusted ΔQTcF (ΔΔQTcF), which are displayed at the relevant median plasma concentration within each deciles of M3 concentration, where the individually estimated placebo-adjusted ΔQTcFi,k (ΔΔQTcFi,k) is equal to the individual ΔQTcFi,k of subject i administered M3 at time point k minus the estimated value of the time effect at time point k. The black circles with vertical bars indicate the mean and 90% CI of the placebo-adjusted ΔQTcF at placebo concentration 0. The horizontal red lines with notches show the range of concentrations that divide the M3 concentrations into deciles. The area between each decile indicates the point where 10% of the data lie; the first to second notches indicate the first 10% of the data, the second to third notches indicate 10-20% of the data, and so on.

[0016] Figure 8: is a graph of the model-predicted ΔΔQTcF intervals (PK / QTc population) within the observed range of deuterated domperidone plasma concentrations and at the geometric mean of peak deuterated domperidone concentrations after administration of 30 mg and 100 mg CIN-102. In this figure, the solid black line with the gray shaded area represents the model-predicted mean (90% CI) ΔΔQTcF, which is calculated from the equation ΔΔQTcF=-0.02844 (ms)+0.7918 (ms per ng / mL)×deuterated domperidone concentration (ng / mL). The vertical blue and red lines represent the estimated mean (90% CI) of ΔΔQTcF, and the plotted points are located at the geometric mean C of deuterated domperidone. max Place.

[0017] Fig. 9 It is a plot of the change (ΔΔHR) of the placebo-corrected HR from baseline across time points (QT / QTc population). LS means and 90% CIs for the active and placebo treatment groups based on a linear mixed effects model: ΔHR=time+treatment+time×treatment+baseline HR+cycle+order. An unstructured covariance structure was used to specify repeated measurements of subjects at time points after dosing within the treatment cycle. The model also included subject-specific random effects.

[0018] Fig.10 Is a scatter plot of observed deuterated domperidone plasma concentrations and ΔQTcF with a simple linear regression line and LOESS regression (PK / QTc population). In this figure, the red line with a blue shaded area represents the LOESS regression and 90% confidence limits. The black solid line represents the simple linear regression line. The plotted points represent paired observed deuterated domperidone plasma concentrations and ΔQTcF.

[0019] Fig.11 It is a plot of the change from baseline (ΔΔQTcF) of placebo-corrected QTcF across time points (QT / QTc population). LS means and 90% CIs for active and placebo treatment groups based on a linear mixed effects model: ΔQTcF=time+treatment+time×treatment+baseline QTcF+cycle+order. An unstructured covariance structure was used to specify repeated measurements of subjects at time points after dosing within the treatment cycle. The model also included subject-specific random effects.

[0020] Fig.12 is a plot of mean plasma concentrations of deuterated domperidone over time by dose group (PK / QTc population). The plot shows the mean ± SD for descriptive statistics. If the mean–SD is less than 0, it is replaced by 0 because concentrations below 0 are biologically implausible.

[0021] Fig.13is a plot of mean CIN-102M3 plasma concentrations over time by dose group (PK / QTc population). The plot shows the mean ± SD for descriptive statistics. If the mean–SD is less than 0, it is replaced by 0 because concentrations below 0 are biologically implausible.

[0022] Fig.14 : is a scatter plot of observed CIN-102M3 plasma concentrations and ΔQTcF with a simple 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 black solid line represents the simple linear regression line. The plotted points represent paired observed CIN-102M3 plasma concentrations and ΔQTcF.

[0023] Fig.15 It is a scatter plot of observed deuterated domperidone plasma concentrations and estimated placebo-adjusted ΔQTcF (PK / QTc population). The solid red line and the dashed red line represent the model-predicted mean ΔΔQTcF with 90% CI, which is calculated from the equation ΔΔQTcF=-0.02844 (ms)+0.7918 (ms per ng / mL)×deuterated domperidone concentration (ng / mL). The plotted points represent the paired observed drug plasma concentrations and estimated placebo-adjusted ΔQTcF (ΔΔQTcF) for subjects in each active drug group and placebo group. The individually estimated placebo-adjusted ΔQTcFi, k (ΔΔQTcFi, k) is equal to the individual ΔQTcFi, k of subject i administered active drug or placebo at time point k minus the estimated value of the time effect at time point k.

[0024] Fig.16is a plot of model-predicted ΔΔQTcF (mean and 90% CI) and estimated placebo-adjusted ΔQTcF (mean and 90% CI) across deuterated domperidone plasma concentration deciles (PK / QTc population). In this figure, the solid black line with the grey shaded area represents the model-predicted mean ΔΔQTcF with 90% CI, which is calculated from the equation ΔΔQTcF=-0.02844 (ms)+0.7918 (ms per ng / mL)×deuterated domperidone concentration (ng / mL). The solid red circles with vertical bars represent the estimated mean and 90% CI of the placebo-adjusted ΔQTcF (ΔΔQTcF), which are displayed at the relevant median plasma concentration within each decile of deuterated domperidone concentration, where the individual estimated placebo-adjusted ΔQTcFi,k (ΔΔQTcFi,k) is equal to the individual ΔQTcFi,k for subject i administered deuterated domperidone at time point k minus the estimate of the time effect at time point k. The black circles with vertical bars represent the mean and 90% CI of the placebo-adjusted ΔQTcF at a placebo concentration of 0. The horizontal red lines with notches show the range of concentrations that divide deuterated domperidone concentrations into deciles. The area between each decile represents the point where 10% of the data are located; the first notch to the second notch represent the first 10% of the data, the second notch to the third notch represent 10-20% of the data, and so on.

[0025] Fig.17 It is a graph of the change (ΔPR) of PR from baseline across time points (QT / QTc population). LS means and 90% CI based on a linear mixed effects model for active and placebo treatment groups: APR = time + treatment + time × treatment + baseline PR + cycle + sequence. An unstructured covariance structure is used to specify repeated measurements of subjects at time points after dosing within the treatment cycle. The model also includes subject-specific random effects.

[0026] Fig.18 It is a plot of the change (ΔΔPR) of the placebo-corrected PR from baseline across time points (QT / QTc population). LS means and 90% CI based on a linear mixed effects model for active and placebo treatment groups: APR = time + treatment + time × treatment + baseline PR + cycle + sequence. An unstructured covariance structure was used to specify repeated measurements of subjects at time points after dosing within the treatment cycle. The model also included subject-specific random effects.

[0027] Fig.19It is a graph of the change (ΔQRS) of QRS compared to baseline across time points (QT / QTc population). LS mean and 90% CI based on a linear mixed effects model for active and placebo treatment groups: AQRS=time+treatment+time×treatment+baseline QRS+cycle+order. An unstructured covariance structure is used to specify repeated measurements of time points after administration of the subject within the treatment cycle. The model also includes subject-specific random effects.

[0028] Fig. 20 It is a plot of the change (ΔΔQRS) of the placebo-corrected QRS compared to baseline across time points (QT / QTc population). LS means and 90% CI based on a linear mixed effects model for active and placebo treatment groups: AQRS=time+treatment+time×treatment+baseline QRS+cycle+order. An unstructured covariance structure is used to specify repeated measurements of subjects at time points after dosing within the treatment cycle. The model also includes subject-specific random effects.

[0029] Fig.21 Plot of model-predicted ΔΔQTcF intervals at geometric mean peak CIN-102M3 concentrations (PK / QTc population). In this figure, the solid black line with the gray shaded area represents the model-predicted mean (90% CI) ΔΔQTcF, which is calculated from the equation ΔΔQTcF=0.3678 (ms)+0.1439 (ms per ng / mL)×CIN-102M3 concentration (ng / mL). The non-gray shaded area represents the estimated mean (90% CI) of ΔΔQTcF, and the plotted points are located at the geometric mean CIN-102M3 max Place. DETAILED DESCRIPTION

[0030] In the present disclosure, references to no specific number include plural referents, and references to a particular value include at least that particular value unless the context clearly dictates otherwise. Thus, for example, a 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.

[0031] When the descriptor "about" is used to express a value as an approximation, it should be understood that the specific value forms another embodiment. In general, the use of the term "about" represents an approximation, which may vary with the desired properties attempted to be obtained by the disclosed subject matter, and should be interpreted according to its function in the specific context in which it is used. Those skilled in the art will be able to interpret this as a routine matter. In some cases, the number of significant figures used for a particular value may be a non-limiting method for determining the scope of the term "about". In other cases, the gradation used in a series of values ​​can be used to determine the available expected range of the term "about" for each value. Where present, all ranges are inclusive and combinable. That is, the reference to the value stated in a range includes each value within the range.

[0032] When a list is presented, it should be understood that each individual element of the list and each combination of the list should be interpreted as a separate embodiment unless otherwise specified. For example, a list of embodiments presented as "A, B, or C" should be interpreted to include embodiments "A", "B", "C", "A or B", "A or C", "B or C", or "A, B, or C".

[0033] It should be understood that certain features of the invention described herein in the context of separate embodiments for the sake of clarity may also be provided in combination in a single embodiment. That is, unless clearly incompatible or exclusive, each individual embodiment is deemed to be combinable with any other embodiment, and such combination is considered to be another embodiment. Conversely, the various features of the invention described in the context of a single embodiment for the sake of brevity may also be provided individually or in any sub-combination. It should also be noted that the claims may be drafted to exclude optional elements. Therefore, this statement is intended to serve as an antecedent basis for the use of exclusive terms such as "only", "only", etc., or the use of "negative" limitations in association with the recitation of claim elements. Finally, although an embodiment may be described as part of a series of steps or part of a more general structure, each of the steps may also be considered an independent embodiment in itself.

[0034] The terms "subject" and "patient" are used interchangeably and generally 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., less than 18 years of age.

[0035] "Treatment" or variations thereof refers to eliminating or reducing at least one physical parameter of a disease or disorder. In other embodiments, "treating" refers to regulating a disease or disorder physically (e.g., by stabilizing a discernible symptom), physiologically (e.g., stabilizing a physical parameter), or both. In other embodiments, "treating" refers to delaying the onset of a disease or disorder.

[0036] "Deuterated domperidone", "d4-domperidone" or "CIN-102" as referred to herein are interchangeable and refer 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, which has the following structure:

[0037]

[0038] Where indicated, any reference to deuterated domperidone may also include pharmaceutically acceptable salts, esters, hydrates, solvates, prodrug forms and derivatives thereof, which are broadly defined as modified or partially substituted deuterated domperidone compounds.

[0039] "Pharmaceutically acceptable" refers to properties and / or materials that are acceptable to patients from a pharmacological / toxicological point of view, as well as to manufacturing medicinal chemists from a physical / chemical point of view with respect to composition, formulation, stability, patient acceptance and bioavailability.

[0040] Pharmaceutically acceptable salts include salts formed with pharmaceutically acceptable acids or bases. In some embodiments, the pharmaceutically acceptable salt is a salt formed with an acid such as an inorganic acid. 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 salt is a salt formed with an organic acid. 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, cyclohexylaminosulfonic acid (cyclamic acid) or p-toluenesulfonic acid. In other embodiments, the pharmaceutically acceptable salt is a salt formed with a base such as an alkali metal. Examples of alkali metals include sodium or potassium. In other embodiments, the pharmaceutically acceptable salt is a salt formed with a base such as an alkaline earth metal. Examples of alkaline earth metals include hydroxides of calcium or magnesium. In other embodiments, the pharmaceutically acceptable salt is a salt formed with an organic base. Examples of the organic base include alkylamines, aralkylamines and heterocyclic amines.

[0041] The abbreviation "D" as used herein refers to the stable isotope of hydrogen, deuterium (heavy hydrogen or 2H). Such instances of "D" include amounts of deuterium that are greater than the naturally occurring deuterium distribution. In some embodiments, D has a deuterium enrichment of not less than about 1%. In other embodiments, D has a deuterium enrichment of not less than about 5%. In other embodiments, D has a deuterium enrichment of not less than about 10%. In other embodiments, D has a deuterium enrichment of not less than about 20%. In other embodiments, D has a deuterium enrichment of not less than about 30%. In other embodiments, D has a deuterium enrichment of not less than about 40%. In other embodiments, D has a deuterium enrichment of not less than about 50%. In other embodiments, D has a deuterium enrichment of not less than about 60%. In other embodiments, D has a deuterium enrichment of not less than about 70%. In other embodiments, D has a deuterium enrichment of not less than about 80%. In other embodiments, D has a deuterium enrichment of not less than about 90%. In other embodiments, D has a deuterium enrichment of not less than about 98% deuterium. In other embodiments, D has a deuterium enrichment of not less than about 99% deuterium. In other embodiments, D has a deuterium enrichment of at least 99% deuterium.

[0042] The present disclosure provides methods of increasing gastric emptying, particularly in humans suffering from gastroparesis. As used herein, the term "gastroparesis" refers to a disorder involving delayed gastric emptying in the absence of physical gastric outlet obstruction. In some embodiments, the gastroparesis is idiopathic gastroparesis. In other embodiments, the gastroparesis is diabetic gastroparesis.

[0043] Prior to administration of deuterated domperidone, the human may be experiencing upper gastrointestinal symptoms. In some embodiments, the upper gastrointestinal symptom is nausea, vomiting, postprandial fullness, early satiety, abdominal distension, upper abdominal pain, abdominal pain, or a combination thereof. In other embodiments, the upper gastrointestinal symptom is nausea. In other embodiments, the upper gastrointestinal symptom is vomiting. In other embodiments, the gastrointestinal symptom is postprandial fullness. In other embodiments, the gastrointestinal symptom is early satiety. In other embodiments, the gastrointestinal symptom is abdominal distension. In other embodiments, the gastrointestinal symptom is upper abdominal pain. In other embodiments, the gastrointestinal symptom is abdominal pain.

[0044] The method comprises orally administering 5 mg to 120 mg of deuterated domperidone to the human per day. For example, the free base of deuterated domperidone is administered to the human. In some embodiments, the daily dose of deuterated domperidone 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 deuterated domperidone is from 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 ... 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 0 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 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 In some embodiments, the daily dose of deuterated domperidone is about 5 mg. In other embodiments, the daily dose of deuterated domperidone is about 10 mg. In other embodiments, the daily dose of deuterated domperidone is about 20 mg. In other embodiments, the daily dose of deuterated domperidone is about 30 mg. In other embodiments, the daily dose of deuterated domperidone is about 40 mg. In other embodiments, the daily dose of deuterated domperidone is about 60 mg. In other embodiments, the daily dose of deuterated domperidone is about 90 mg.In other embodiments, the daily dose of deuterated domperidone is about 120 mg.

[0045] Deuterated domperidone can be used as needed to reach the required daily dose. For example, deuterated domperidone can be used in divided doses. In some aspects, deuterated domperidone is used in one dose. In other aspects, deuterated domperidone is used in two doses. In other aspects, deuterated domperidone is used in three doses. In other aspects, deuterated domperidone is used in four doses. In some embodiments, deuterated domperidone is used once a day (QD). In other embodiments, deuterated domperidone is used twice a day (BID). In other embodiments, deuterated domperidone is used three times a day (TID). In other embodiments, deuterated domperidone is used four times a day (QID). In some aspects, the deuterated domperidone of a daily dose of 10 mg is used with 10 mg QD. In other aspects, the deuterated domperidone of a daily dose of 10 mg is used with 5 mg BID. In other aspects, the deuterated domperidone of 20mg daily dose is applied with 20mg QD. In other aspects, the deuterated domperidone of 20mg daily dose is applied with 10mg BID. In other aspects, the deuterated domperidone of 20mg daily dose is applied with 5mg QID. In other aspects, the deuterated domperidone of 60mg daily dose is applied with 30mg BID. In other aspects, the deuterated domperidone of 120mg daily dose is applied with 60mg BID. In other aspects, the deuterated domperidone of 30mg daily dose is applied with 10mg TID. In other aspects, the deuterated domperidone of 30mg daily dose is a dose of 15mg BID, which is provided as a combination of 10mg deuterated domperidone and 5mg deuterated domperidone.

[0046] Prior to administration of the first dose of deuterated domperidone, the human has delayed gastric emptying. Gastric emptying can be measured by a gastric emptying breath test (GEBT). The GEBT is known in the art. Briefly, the GEBT is a non-radioactive stable isotope breath test used in the art to diagnose or monitor gastroparesis. In this test, a patient ingests a standardized, 1:1% td-rich gastroparesis solution. 13 After C's meal, use the exhaled 13 CO2 / 12 In some embodiments, the gastric emptying rate is determined by the ratio of CO2 to 13 C's meal is 13 C-Spirulina platensis. In some embodiments, the test comprises ingesting a standardized 13C. See, e.g., Cairn Gastric Emptying Breath Test (GEBT) Management Guide, available at https: / / cairndiagnostics.com / wp-content / uploads / 2019 / 05 / Cairn-GEBT-How-To-Guide-updated-07May2019.pdf, which is incorporated herein by reference. 13 One or more breath samples are obtained before the meal of C, and then one or more breath samples are obtained after the meal is ingested. The breath samples are then measured using, for example, a gas isotope ratio mass spectrometer. 13 C levels indicate delayed gastric emptying, i.e., the stomach does not metabolize the 13 C's meals. Lower 13 C levels indicate normal gastric emptying. In some embodiments, gastric emptying is measured at least about 10 days prior to administering the first dose of deuterated domperidone. In other embodiments, gastric emptying is measured 10 days prior to administering the first dose of deuterated domperidone. In other embodiments, gastric emptying is measured from about 1 to about 10 days prior to administering the first dose of deuterated domperidone.

[0047] The human may also have a best fit exponential emptying rate (T1 / 2) of greater than about 80 minutes prior to administration of deuterated domperidone, as determined by using 13 In some embodiments, prior to administration of deuterated domperidone, the human has a T of greater than about 100 minutes. 1 / 2 , as by using 13 In other embodiments, prior to administration of deuterated domperidone, the human has a T greater than about 120 minutes. 1 / 2 , as by using 13 In other embodiments, prior to administration of deuterated domperidone, the human has a T greater than about 140 minutes. 1 / 2 , as by using 13 In other embodiments, prior to administration of deuterated domperidone, the human has a T greater than about 160 minutes. 1 / 2 , as by using 13 In other embodiments, prior to administration of deuterated domperidone, the human has a T greater than about 180 minutes. 1 / 2 , as by using 13 In other embodiments, prior to administration of deuterated domperidone, the human has a T of greater than about 200 minutes. 1 / 2, as by using 13 C- measured by GEBT of Spirulina platensis.

[0048] Prior to administration of deuterated domperidone, the patient may have an average composite score of the American Society of Neurogastroenterology and Motility Gastroparesis Major Symptom Index Daily Diary (ANMS GCSI-DD) of 2 or more months. As known in the art, the ANMS GCSI-DD covers 5 core-related symptoms of gastroparesis: nausea, early satiety, postprandial fullness, epigastric pain and vomiting. Abdominal distension is included as an exploratory symptom. The symptoms are scored from 0 (none) to 4 (very severe) on a severity numeric response scale. Vomiting is captured on a frequency response scale and scored as follows: 0 for no episodes, 1 for one episode, 2 for two episodes, 3 for three episodes, and 4 for four or more episodes. In some embodiments, the subject recalls symptoms over the past 24 hours and completes a symptom questionnaire reported by the ANMS GCSI-DD patient. In certain embodiments, the total ANMS GCSI-DD score is calculated as the average of the 3 subscale scores of severity of nausea / vomiting, postprandial fullness / early satiety and bloating. See, e.g., "ANMS GCSI-DD Manual for Use," American Society of Neurogastroenterology and Motility Gastroparesis Primary Symptom Index Daily Diary, 2018; https: / / www.fda.gov / media / 125038 / download. In other embodiments, the ANMS GCSI-DD total score is calculated using a "manual" scoring method. The ANMS GCSI-DD manual scoring method is generated by adding the scores for each of the five symptom items (nausea, early satiety, postprandial fullness, epigastric pain, and number of vomiting episodes) and then dividing by 5 (i.e., the number of items in the gastroparesis-related symptom score). Therefore, the maximum total symptom score can be (5 symptoms * maximum score 4 divided by 5); therefore, the highest score is 20 / 5=4. The ANMS GCSI-DD gastroparesis symptom daily score can range from 0 to 4. A high score on the ANMS GCSI-DD reflects a higher symptom severity. See, e.g., "ANMS GCSI-DD User Manual," Federal Drug Administration, https: / / www.fda.gov / media / 125038 / download, which is incorporated herein by reference. In some embodiments, prior to administration of deuterated domperidone, the ANMS GCSI-DD average composite score is 2. In other embodiments, prior to administration of deuterated domperidone, the ANMS GCSI-DD average composite score is 3. In other embodiments, prior to administration of deuterated domperidone, the ANMS GCSI-DD average composite score is 4.

[0049] Prior to the administration of deuterated domperidone, the patient may further have an ANMS GCSI-DD subscale score of 2 or higher. In some embodiments, prior to the administration of deuterated domperidone, the patient has an ANMS GCSI-DD nausea subscale score of 2 or higher. In other embodiments, prior to the administration of deuterated domperidone, the patient has an ANMS GCSI-DD nausea subscale score of 2 or higher for at least about 4 days. In other embodiments, prior to the administration of deuterated domperidone, the patient has an ANMS GCSI-DD early satiety / fullness subscale score of 2 or higher. In other embodiments, prior to the administration of deuterated domperidone, the patient has an ANMS GCSI-DD bloating subscale score of 2 or higher.

[0050] Ideally, the method results in increased gastric emptying in the patient. In some embodiments, after administration of deuterated domperidone, by using 13 C-GEBT of Spirulina platensis measures an increase in gastric emptying. In some embodiments, at least one day after administration of deuterated domperidone, by using 13 C- GEBT of Spirulina platensis measures an increase in gastric emptying. In other embodiments, the increase in gastric emptying is measured by GEBT at baseline and at the end of the study. In other embodiments, the increase in gastric emptying is measured by GEBT 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 deuterated domperidone. 13C-GEBT of Spirulina platensis measures an increase in gastric emptying. In other embodiments, the GEBT of Spirulina platensis measures an increase in gastric emptying from about 2 to about 15, about 2 to about 14, about 2 to about 13, about 2 to about 12, about 2 to about 11, about 2 to about 10, about 2 to about 9, about 2 to about 8, about 2 to about 7, about 2 to about 6, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 3 to about 16, about 3 to about 15, about 3 to about 14, about 3 to about 13, about 3 to about 12, about 3 to about 11, about 3 to about 10, about 3 to about 9, about 3 to about 8, about 3 to about 7, about 3 to about 6, about 3 ... from about 3 to about 4, from about 4 to about 16, from about 4 to about 15, from about 4 to about 14, from about 4 to about 13, from about 4 to about 12, from about 4 to about 11, from about 4 to about 10, from about 4 to about 9, from about 4 to about 8, from about 4 to about 7, from about 4 to about 6, from about 4 to about 5, from about 5 to about 16, from about 5 to about 15, from about 5 to about 14, from about 5 to about 13, from about 5 to about 12, from about 5 to about 11, from about 5 to about 10, from about 5 to about 9, from about 5 to about 8, from about 5 to about 7, from about 5 to about 6, from about 6 to about 16, from about 6 to about 15, from about 6 to about 12, from 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 to 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 by using 13 C- GEBT of Spirulina platensis measures an increase in gastric emptying. In other embodiments, about 12 to about 14 days after administration of deuterated domperidone, by using 13 C-Enhancement of gastric emptying measured by the GEBT of Spirulina platensis.

[0051] Advantageously, after treatment with deuterated domperidone, for example, about 6 to about 12 weeks after administration, administration of deuterated domperidone results in clinically significant improvement in nausea (e.g., postprandial nausea), early satiety, postprandial fullness, epigastric pain, vomiting, abdominal distension, or a combination thereof, as measured by the ANMS GCSI-DD score. In certain aspects, administration of deuterated domperidone results in clinically significant improvement in postprandial nausea, early satiety, postprandial fullness, epigastric pain, vomiting, and abdominal distension, as measured by the ANMS GSI-DD score, at about 6, about 7, about 8, about 9, about 10, about 11, or about 12 weeks after administration. In other aspects, administration of deuterated domperidone results in clinically significant improvement in postprandial nausea, early satiety, postprandial fullness, epigastric pain, vomiting, and abdominal distension as measured by the ANMS GSI-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 deuterated domperidone results in clinically significant improvement in nausea as measured by the ANMS GCSI-DD score following treatment with deuterated domperidone. In other embodiments, after treatment with deuterated domperidone, the administration of deuterated domperidone results in a clinically significant improvement in early satiety, as measured by the ANMS GCSI-DD score. In other embodiments, after treatment with deuterated domperidone, the administration of deuterated domperidone results in a clinically significant improvement in postprandial fullness, as measured by the ANMS GCSI-DD score. In other embodiments, after treatment with deuterated domperidone, the administration of deuterated domperidone results in a clinically significant improvement in upper abdominal pain, as measured by the ANMS GCSI-DD score. In other embodiments, after treatment with deuterated domperidone, the administration of deuterated domperidone results in a clinically significant improvement in vomiting, as measured by the ANMS GCSI-DD score. In other embodiments, administration of deuterated domperidone results in a clinically significant improvement in abdominal bloating as measured by the ANMS GCSI-DD score following treatment with deuterated domperidone.

[0052] Administration of deuterated domperidone also results in a clinically significant improvement in the mean composite score of the ANMS GCSI-DD score after treatment, e.g., about 6 to about 12 weeks after administration. In certain aspects, administration of deuterated domperidone may result in a clinically significant improvement in the mean composite score of the ANMS GCSI-DD score at about 6, about 7, about 8, about 9, about 10, about 11, or about 12 weeks after administration. In other aspects, administration of deuterated domperidone may result in a clinically significant improvement in the mean composite 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. In some embodiments, after administration of deuterated domperidone, 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. In other embodiments, after administration of deuterated domperidone, the ANMS GCSI-DD average composite score is reduced by 1 point. In other embodiments, after administration of deuterated domperidone, the ANMS GCSI-DD average composite score is reduced by 2 points. In other embodiments, after administration of deuterated domperidone, the ANMS GCSI-DD average composite score is reduced by 3 points. In other embodiments, the ANMS GCSI-DD mean composite score decreases by 4 points following administration of deuterated domperidone.

[0053] Administration of deuterated domperidone further results in a clinically significant improvement in the ANMS GCSI-DD nausea subscale score after treatment, e.g., about 6 to about 12 weeks after administration. In certain aspects, administration of deuterated domperidone may result in a clinically significant improvement in the nausea 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 of administration. In other aspects, administration of deuterated domperidone may result in a clinically significant 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 of 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 other embodiments, the ANMS GCSI-DD nausea subscale score is reduced by 1 point after administration of deuterated domperidone. In other embodiments, the ANMS GCSI-DD nausea subscale score is reduced by 2 points after administration of deuterated domperidone. In other embodiments, the ANMS GCSI-DD nausea subscale score is reduced by 3 points after administration of deuterated domperidone. In other embodiments, the mean composite score decreases by 4 points following administration of deuterated domperidone.

[0054] After about 12 to about 16 days after treatment with deuterated domperidone, the administration of deuterated domperidone further results in a clinically significant improvement in gastric emptying, as measured by GEBT. In some embodiments, after about 12, about 13, about 14, about 15, or about 16 days after treatment with deuterated domperidone, the administration of deuterated domperidone further results in a clinically significant improvement in gastric emptying, as measured by GEBT. In other embodiments, after 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 deuterated domperidone, the administration of deuterated domperidone further results in a clinically significant improvement in gastric emptying, as measured by GEBT. In other embodiments, after about 12 days of treatment with deuterated domperidone, the administration of deuterated domperidone further results in a clinically significant improvement in gastric emptying, as measured by GEBT. In other embodiments, after about 13 days of treatment with deuterated domperidone, the administration of deuterated domperidone further results in a clinically significant improvement in gastric emptying, as measured by GEBT. In other embodiments, after about 14 days of treatment with deuterated domperidone, the administration of deuterated domperidone further results in a clinically significant improvement in gastric emptying, as measured by GEBT. In other embodiments, after about 15 days of treatment with deuterated domperidone, the administration of deuterated domperidone further results in a clinically significant improvement in gastric emptying, as measured by GEBT. In other embodiments, after about 16 days of treatment with deuterated domperidone, the administration of deuterated domperidone further results in a clinically significant improvement in gastric emptying, as measured by GEBT.

[0055] Administration of deuterated domperidone also resulted in clinically significant improvements in gastric emptying (as measured by the GEBT) and symptoms (as measured by the ANMS GCSI-DD total score) following treatment.

[0056] Following treatment, administration of deuterated domperidone further resulted in a clinically significant improvement in gastric emptying as measured by the GEBT.

[0057] In other embodiments, administration of deuterated domperidone may result in a clinically significant improvement in the vomiting subscale score of the ANMS GCSI-DD score after administration, for example, about 6 to about 12 weeks after administration. In certain aspects, administration of deuterated domperidone may result in a clinically significant improvement in the vomiting 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 of administration. In other aspects, administration of deuterated domperidone may result in a clinically significant improvement in the vomiting 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.

[0058] In other embodiments, administration of deuterated domperidone may result in a clinically significant improvement in the total score of the ANMS GCSI-DD score after administration, e.g., about 6 to about 12 weeks after administration. In certain aspects, administration of deuterated domperidone may result in a clinically significant 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 of administration. In other aspects, administration of deuterated domperidone may result in a clinically significant improvement in the total 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.

[0059] In other embodiments, administration of deuterated domperidone may result in a clinically significant 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 certain aspects, administration of deuterated domperidone may result in a clinically significant 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 of administration. In other aspects, administration of deuterated domperidone may result in a clinically significant improvement in the score on the early satiety subscale 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.

[0060] In other embodiments, administration of deuterated domperidone may result in a clinically significant improvement in the postprandial fullness subscale score of the ANMS GCSI-DD score after administration, for example, about 6 to about 12 weeks after administration. In certain aspects, administration of deuterated domperidone may result in a clinically significant improvement in the postprandial fullness 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 of administration. In other aspects, administration of deuterated domperidone may result in a clinically significant improvement in the postprandial fullness 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.

[0061] In other embodiments, administration of deuterated domperidone may result in a clinically significant 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 certain aspects, administration of deuterated domperidone may result in a clinically significant 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 of administration. In other aspects, administration of deuterated domperidone may result in a clinically significant improvement in the upper abdominal pain 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.

[0062] In other embodiments, administration of deuterated domperidone may result in a clinically significant improvement in gastric emptying as measured by the ANMS GCSI-DD subscale score after administration, e.g., about 6 to about 12 weeks after administration. In certain aspects, administration of deuterated domperidone may result in a clinically significant 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 of administration. In other aspects, administration of deuterated domperidone may result in a clinically significant improvement in gastric emptying as measured by the ANMS GCSI-DD subscale 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.

[0063] In other embodiments, administration of deuterated domperidone may result in a clinically significant improvement in gastric emptying as measured by the ANMS GCSI-DD total score after administration, e.g., about 6 to about 12 weeks after administration. In certain aspects, administration of deuterated domperidone may result in a clinically significant 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 of administration. In other aspects, administration of deuterated domperidone may result in a clinically significant improvement in gastric emptying as measured by the ANMS GCSI-DD total 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.

[0064] The deuterated domperidone formulations described herein can be used in various treatment methods, including but not limited to methods for treating disorders of gastroparesis, nausea other than gastroparesis, vomiting other than gastroparesis, nausea associated with gastroparesis, vomiting associated with gastroparesis, gastroesophageal reflux disease, inadequate lactation, nausea and / or vomiting associated with chemotherapy, or a combination thereof. The method comprises administering to the patient a pharmaceutical formulation described herein. In some embodiments, the method can be used to treat gastroparesis. In other embodiments, the method can be used to treat nausea other than gastroparesis. In other embodiments, the method can be used to treat vomiting other than gastroparesis. In other embodiments, the method can be used to treat nausea associated with gastroparesis. In other embodiments, the method can be used to treat vomiting associated with gastroparesis. In other embodiments, the method can be used to treat gastroesophageal reflux disease. In other embodiments, the method can be used to treat inadequate lactation. In other embodiments, the method can be used to treat nausea and / or vomiting associated with chemotherapy.

[0065] The pharmaceutical preparation can be administered by any route acceptable to humans. In some embodiments, the administration of the pharmaceutical preparation is oral, transdermal, parenteral or a combination thereof. In other embodiments, the administration is oral.

[0066] The pharmaceutical preparation can be formulated into a solid or liquid form for administration. In some embodiments, the pharmaceutical preparation is formulated in the form of a tablet, a caplet, a capsule, a powder, a soft gel, a suspension or a liquid or a combination thereof. In other embodiments, the pharmaceutical preparation is formulated in the form of a tablet. In other embodiments, the pharmaceutical preparation is formulated in the form of a caplet. In other embodiments, the pharmaceutical preparation is formulated in the form of a capsule. In other embodiments, the pharmaceutical preparation is formulated in the form of a powder. In other embodiments, the pharmaceutical preparation is formulated in the form of a soft gel. In other embodiments, the pharmaceutical preparation is formulated in the form of a suspension. In other embodiments, the pharmaceutical preparation is formulated in the form of a liquid.

[0067] Administration of deuterated domperidone according to the present disclosure does not cause or result in clinically significant QT interval prolongation. For example, after administration of deuterated domperidone according to the present disclosure, the patient's ΔΔQTcF is 10 ms or less than about 10 ms (e.g., 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or 0 ms). In some aspects, after administration of deuterated domperidone according to the present disclosure, the patient's ΔΔQTcF 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, after administration of about 30 mg, or about 20 mg, or about 10 mg of deuterated domperidone according to the present disclosure, the patient's ΔΔQTcF 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 patient's ΔΔQTcF 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, 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 deuterated domperidone in accordance with the present disclosure.

[0068] In addition, the use of deuterated domperidone according to the present disclosure does not cause or result in a clinically significant change in the patient's heart rate. In other aspects, the use of deuterated domperidone according to the present disclosure does not cause or result in a clinically significant change in the patient's cardiac conduction. In other aspects, after the use of deuterated domperidone according to the disclosed method, the patient's pulse rate (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). In some aspects, after the use of deuterated domperidone, the patient's QRS interval is about 0.08 and 0.10 seconds (e.g., 0.08, 0.09, 0.10 seconds).

[0069] The following examples are provided to illustrate some of the concepts described in this disclosure.While the examples are considered to provide specific individual embodiments of formulations, methods of preparation, and uses, it should be considered limiting of the more general embodiments described herein.

[0070] In the following examples, efforts have been made to ensure accuracy with respect to numbers used (eg, amounts, temperature, etc.) but some experimental errors and deviations should be accounted for.

[0071]

[0072]

[0073]

[0074]

[0075] Example 1

[0076] This is a randomized, double-blind, placebo-controlled, Phase 2A study to evaluate the safety, efficacy, PK, and dose response of oral deuterated domperidone in adults with idiopathic or diabetic gastroparesis.

[0077] The study begins by randomizing subjects in Cohort 1 to deuterated domperidone 10 mg BID or placebo BID, with a ratio of 15 subjects receiving deuterated domperidone and 5 subjects receiving placebo. Subjects will choose to be included in the sparse pharmacokinetic sampling subgroup or the dense PK sampling subgroup. The study will be stratified by idiopathic gastroparesis and diabetic gastroparesis at randomization. The dose levels for Cohorts 2 and 3 are 20 mg QD and 5 mg BID, respectively, with 15 subjects in each cohort receiving study drug and 5 subjects receiving placebo. The highest dose will not exceed 60 mg BID.

[0078] Subjects will be evaluated as follows:

[0079] ● Days -28 to -11: Screening procedures will be performed. Complete the ANMS GCSI-DD questionnaire daily for at least 14 days prior to randomization.

[0080] Days -10 to -3: Complete the ANMS GCSI-DD questionnaire daily. The GEBT is performed on a day within this window using a standardized, high-calorie diet after an 8-hour fast. 13 Breath samples will be obtained twice before the meal of C and then at 45, 90, 120, 150, 180, and 240 minutes after ingestion of the meal. A baseline PAGI-SYM will be completed prior to the start of the GEBT.

[0081] ●Day -3 to Day -1: A pre-randomization visit will be completed for safety assessments and to allow adequate turnaround time for laboratory results before Day 1 (randomization).

[0082] ● Day 1 to Day 14: Study drug (deuterated domperidone) or placebo will be administered BID for 14 days (±2 days) and safety assessments will be performed; ANMS GCSI-DD questionnaires will be completed daily and PK blood sampling will be completed at designated time points. On Day 14 (±2 days), the PAGI-SYM and Clinical Grade Assessment Questionnaires will be completed before the last dose of study drug.

[0083] ● Day 14 (± 2 days): GEBT was performed 30 minutes after study drug administration on Day 14 (± 2 days). 13 Breath samples were obtained twice before C's meal and then at 45, 90, 120, 150, 180, and 240 minutes after meal ingestion.

[0084] At randomization, participants will be stratified according to the etiology of their gastroparesis (ie, diabetic gastroparesis versus idiopathic gastroparesis).

[0085] On the day of the GEBT, subjects will arrive at the clinic after an overnight fast and should take their regular medications, including any diabetes treatments, with the exception of any prohibited concomitant medications. Subjects will self-administer their usual morning insulin injection based on their fasting state. Subjects are instructed to bring their study medication and additional insulin to the clinic as needed. Assess fasting blood glucose prior to study drug administration and gastric emptying assessment to ensure blood glucose ≤275 mg / dL. Prior to the gastric emptying procedure, additional insulin (prorated based on the caloric content of the meal) may be administered to ensure blood glucose ≤275 mg / dL.

[0086] Subjects will be followed up 1 to 3 days after the last dose of study drug to assess adverse events, changes in concomitant medications (including use of rescue medications), vital signs, and for PK sampling. Subjects participating in the intensive PK subgroup will be observed in the clinic on Day 3 (±1 day), Day 7 (±1 day), Day 10 (±1 day), Day 14 (±2 days), Day 15 (±1 day), and Day 16 (+1 day). Subjects participating in the sparse PK subgroup will choose to complete either the Day 15 visit or the Day 16 (+1 day) visit.

[0087] A. Research Objectives (i) Objectives

[0088] The objectives of this study are as follows:

[0089] To evaluate the safety and tolerability of multiple doses of deuterated domperidone in subjects with idiopathic or diabetic gastroparesis

[0090] To evaluate the effects of multiple doses of deuterated domperidone on gastric emptying as measured by GEBT in subjects with idiopathic or diabetic gastroparesis

[0091] ● Characterizing the PK of multiple doses of deuterated domperidone in subjects with idiopathic or diabetic gastroparesis

[0092] (ii) Exploratory objectives

[0093] The exploratory objectives of this study include the following:

[0094] ● To evaluate the effects of multiple doses of deuterated domperidone on nausea associated with gastroparesis based on nausea scores on the ANMS GCSI-DD

[0095] To evaluate the effects of multiple doses of deuterated domperidone on ANMSGCSI-DD scores (total and subscale scores) in subjects with idiopathic or diabetic gastroparesis

[0096] ● Evaluate the effects of multiple doses of deuterated domperidone on various patient-reported outcomes

[0097] ● Characterization of exposure-response relationships for deuterated domperidone

[0098] B. Inclusion Criteria

[0099] Patients who meet all of the following criteria will be eligible to participate in this study:

[0100] 1. Male and female patients aged 18 to 70 years.

[0101] 2. Current diagnosis of idiopathic or diabetic gastroparesis, as defined by:

[0102] ●Perceived gastrointestinal symptoms consistent with gastroparesis (eg, postprandial nausea / vomiting, postprandial fullness, early satiety, bloating, and / or epigastric / abdominal pain) within six months prior to screening; or

[0103] ● Documented DGE confirmed by GEBT or scintigraphy within the past 3 years. Other modalities (eg, SmartPill TM Patients with documented DGE (by CT, manometry) or abnormal GEBT or scintigraphy > 3 years ago.

[0104] 3. BMI between 18 and 40 kg / m 2 (inclusive) between.

[0105] 4. Glycated hemoglobin level ≤11% at screening.

[0106] 5. Male patients with female partners of reproductive potential must agree to use two medically recognized highly effective birth control methods from day 1 to 60 days after the last dose of study drug. For male patients with female partners of reproductive potential, medically recognized highly effective birth control methods include: latex condoms containing spermicide, diaphragms containing intravaginal spermicide, cervical caps containing spermicide, indwelling intrauterine devices (hormonal or non-hormonal), implantable contraceptives, and oral contraceptives.

[0107] 6. Male patients must agree to give up sperm donation from day 1 to 60 days after the last dose of study drug.

[0108] 7. Female patients with male partners must be surgically sterilized (hysterectomy and / or bilateral oophorectomy), at least 1 year postmenopausal (FSH confirmed to be within the postmenopausal range at the screening visit) or agree to use 2 medically recognized highly effective birth control methods from day -14 to 60 days after the last dose of study drug. For female patients with male partners, medically recognized highly effective birth control methods include: latex condoms containing spermicide, diaphragms containing intravaginal spermicide, cervical caps containing spermicide, and non-hormonal indwelling intrauterine devices.

[0109] 8. Negative breath alcohol and urine drug screen (including THC) at the screening visit and randomization.

[0110] 9. Willing to give up eating grapefruit, grapefruit products, star fruit, star fruit products and lime from 48 hours before randomization to the end of the study.

[0111] 10. Willing to give up the use of long-acting GLP-1 agonists, SGLT-2 inhibitors or pramlintide.

[0112] C. Exclusion criteria

[0113] Patients who meet any of the following criteria will be excluded from this study:

[0114] 1. History or current clinically significant arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsade de pointes. Patients with milder forms of ectopic beats (e.g., premature atrial beats) are not necessarily excluded.

[0115] 2. Have clinically significant bradycardia, resting heart rate less than 50 beats per minute, sinus node dysfunction or heart block.

[0116] 3. Prolonged heart rate corrected QTcF (QTcF>450 msec in males or QTcF>470 msec in females) based on the average of three ECGs.

[0117] 4. Personal or family history of long QT syndrome, torsades de pointes, or other complex ventricular arrhythmias, or family history of sudden death.

[0118] 5. Evidence (based on screening or baseline assessment) or history of the following diseases: clinically significant immune, hematological, renal, endocrine, pulmonary, GI, cardiovascular, hepatic, psychiatric, neurological, or allergic diseases (including drug allergies); surgical conditions; cancer (except basal or squamous cell carcinoma of the skin and cancer that has been resolved or in remission for more than 5 years before the screening visit); or any condition that may significantly interfere with the absorption, distribution, metabolism, or excretion of the study drug.

[0119] 6. Have a history of prolactin-releasing pituitary tumor (i.e. prolactinoma).

[0120] 7. Elevated serum prolactin.

[0121] 8. Patients with 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.

[0122] 9. Helicobacter pylori injection within 6 months of screening and / or during the study.

[0123] 10. Bilirubin, alkaline phosphatase, AST, or ALT levels are higher than 2 times the upper limit of normal, or the Child-Pugh classification grade is B or C.

[0124] 11. Screening serum creatinine level higher than 1.5 times the upper limit of normal, or eGFR < 30 mL / min / 1.73 m using the CKD-EPI equation 2 .

[0125] 12. Hemoglobin level <10g / dL at screening.

[0126] 13. Abnormal TSH level during screening.

[0127] 14. Unable to conduct a breath test.

[0128] 15. Known allergy to eggs or spirulina.

[0129] 16. Use of the following investigational, prescription or over-the-counter drugs:

[0130] ● Actively participate in experimental therapy research; receive experimental therapy using small molecules within 30 days or 5 half-lives of randomization (whichever is longer); or receive experimental therapy using large molecules within 90 days or 5 half-lives of randomization (whichever is longer).

[0131] ●Use of concomitant CYP3A4 inhibitors (whether medications, herbal supplements, dietary supplements, or nutraceuticals) within 14 days or 5 half-lives (whichever is longer) of the first dose of study drug until the end of the study.

[0132] ●Use of concomitant CYP3A4 inducers (whether medications, herbal supplements, dietary supplements, or nutraceuticals) within 28 days or 5 half-lives (whichever is longer) of the first dose of study drug or inducer until the end of the study.

[0133] ●Use of any medication, herbal supplement, dietary supplement, or nutraceutical that may prolong QT within 28 days before the first dose of study drug until the end of the study.

[0134] ● Use of gastric motility agents (including but not limited to metoclopramide, domperidone, erythromycin, etc.), other drugs that may affect gastric emptying (such as opioids, marijuana, and anticholinergic drugs), and antiemetics (except rescue antiemetics specified in the protocol) within 14 days before baseline GEBT until the end of the study. Gastric pacemakers should be turned off within 14 days before baseline GEBT and remain turned off until the end of the study.

[0135] 17. History of alcohol or drug abuse as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th edition within 2 years prior to medication.

[0136] 18. Typical consumption of ≥14 alcoholic drinks per week.

[0137] 19. Evidence of continued illegal drug use.

[0138] 20. HIV antibody, HCV RNA or HBsAg positive at the screening visit.

[0139] 21. Donated blood or blood products within 30 days before administration.

[0140] 22. Currently receiving weight loss medication or previously underwent weight loss surgery (e.g., gastric bypass surgery).

[0141] 23. Pregnancy, breastfeeding, or planning to become pregnant during the study.

[0142] 24. Inability to swallow medication.

[0143] 25. Currently receiving parenteral feeding or having a nasogastric or other enteral tube (e.g., PEG tube) for feeding or pressure relief.

[0144] 26. Known or suspected gastric outlet obstruction (e.g., gastrointestinal stenosis) or other GI mechanical obstruction documented by upper gastrointestinal endoscopy or upper gastrointestinal radiology series within the past 3 years.

[0145] 27. Known history or current diagnosis of intestinal malabsorption or exocrine pancreatic disease.

[0146] 28. History of gastric surgery, such as fundoplication, gastrectomy, vagotomy, pyloroplasty, or bariatric surgery.

[0147] 29. History or presence of any medical condition or psychiatric illness that might interfere with the conduct of the study or expose the patient to unacceptable risk.

[0148] 30. Previous lack of response to domperidone, or known allergy or intolerance to domperidone or any excipient in the deuterated domperidone formulation.

[0149] Subjects must also meet the following criteria at the time of randomization:

[0150] ●Having stopped all gastric motility agents and antiemetics for at least 14 days and being willing to continue to stop such medications during the study (except for antiemetic rescue medications specified in the protocol).

[0151] ●Confirmed diagnosis of idiopathic or diabetic gastroparesis, as defined by:

[0152] ○ Current upper gastrointestinal symptoms (e.g., nausea / vomiting, postprandial fullness, early satiety, bloating, and / or epigastric / abdominal pain).

[0153] ○ Within 10 days before the first dose of study drug, based on the use of 13 C-GEBT of Spirulina platensis demonstrated T1 / 2>80 minutes, and DGE was recorded. Subjects with T1 / 2>200 minutes can be considered.

[0154] ANMS GCSI-DD score that meets the following requirements:

[0155] ○ Mean composite score ≥ 2 (using a Likert scale from 0 [none] to 4 [very severe]) during the last 10 days before randomization. The main symptom experienced should not be abdominal pain.

[0156] ○ Nausea subscale score (including nausea, retching, and vomiting) ≥ 2 or at least 1 episode of vomiting on at least 4 of 7 days during the portion of the screening period in which the subject has not taken a prokinetic agent or antiemetic (other than protocol-specified rescue medication).

[0157] D. Study Treatment (i) Treatment Group

[0158] This study is planned to include 4 treatment groups, with 15 subjects in each group.

[0159] At randomization, subjects who meet all eligibility criteria (based on inclusion / exclusion and randomization criteria) will be randomly assigned to deuterated domperidone 10 mg BID or placebo BID in a ratio of 3: 1. The study begins with randomization of subjects in cohort 1 to deuterated domperidone 10 mg BID or placebo BID, so that 15 subjects receive deuterated domperidone and 5 subjects receive placebo. The current planned dose levels for cohorts 2 and 3 are 20 mg QD and 5 mg BID, respectively, with 15 subjects receiving study drugs and 5 subjects receiving placebo in each cohort.

[0160] The duration of the double-blind treatment period of study drug was 14 days (± 2 days).

[0161] (ii) Drug Supply

[0162] Deuterated domperidone capsules consist of deuterated domperidone drug product in 2C size, oval, blue soft gel capsules. Each deuterated domperidone capsule will contain 5 or 10 mg of active deuterated domperidone API. The deuterated domperidone capsules also contain inactive ingredients.

[0163] A matching placebo softgel containing the same inactive ingredients but without the deuterated domperidone drug substance will also be provided.

[0164] (iii) Study drug administration

[0165] All subjects took a dose of blinded study medication (deuterated domperidone or placebo capsule) with approximately 240 mL of water at 8:00 AM (± 2 hours) and 8:00 PM (± 2 hours). For a given individual, a 12-hour interval will be maintained between each dose. All subjects should try to fast for at least 8 hours before dosing on the morning of Day 1. However, if the subject should eat (i.e., due to low blood glucose levels or hypoglycemic symptoms), they can eat before the morning dose of study medication. >Subjects providing sparse PK samples should continue to fast for at least 2 hours after the morning dose on Day 1, and subjects providing more intensive PK samples should continue to fast for at least 4 hours. However, if food should be consumed, breaks from the prescribed fast are permitted to ensure subject safety. On Day 14 [±2 days], all subjects fasted for at least 8 hours before the morning dose of study drug and for 4 hours after completing the GEBT meal. Subjects were required to fast 2 hours before and 1 hour after all other doses.

[0166] E. Excluded Drugs, Foods, and / or Procedures

[0167] The following investigational, prescription, or over-the-counter medications were not permitted during the study:

[0168] Pramlintide

[0169] ●SGLT2 inhibitors or GLP-1 agonists with long half-lives [e.g. (Exenatide sustained release), (liraglutide), Tanzeum TM (albiglutide) or (dulaglutide)].

[0170] ●Use of small molecule experimental therapy within 30 days or 5 half-lives (whichever is longer) before randomization; or use of large molecule experimental therapy within 90 days or 5 half-lives (whichever is longer) before randomization.

[0171] ●CYP3A4 inhibitors (whether drugs, herbal supplements, dietary supplements, nutraceuticals, or foods) within 14 days or 5 half-lives (whichever is longer) of the first dose of study drug or inducer until the end of the study.

[0172] ●CYP3A4 inducers (whether drugs, herbal supplements, dietary supplements, nutraceuticals, or foods) within 28 days or 5 half-lives (whichever is longer) of the first dose of study drug until the end of the study.

[0173] ● Any medications, herbal supplements, dietary supplements, or nutraceuticals that may prolong QT within 28 days before the first dose of study drug until the end of the study.

[0174] ●In the 14 days before the baseline GEBT until the end of the study, gastric prokinetic agents (including but not limited to metoclopramide, domperidone, erythromycin, etc.), other drugs that may affect gastric emptying (such as opioids, marijuana and anticholinergic drugs), and antiemetics (except rescue antiemetics specified in the protocol). Gastric pacemakers should be turned off within 14 days before the baseline GEBT and remain turned off until the end of the study.

[0175] ●Hylophore injection within 6 months after screening and during the study.

[0176] ●Weight-loss medications or previous weight-loss surgery (such as gastric bypass surgery).

[0177] ●Parenteral feeding or the presence of a nasogastric or other enteral tube (eg, PEG tube) for feeding or pressure relief.

[0178] F. Procedure

[0179] The baseline GEBT will be performed between days -10 and -3 after at least 14 days of washout of gastric motility agents.

[0180] The following procedures were performed at the baseline GEBT visit (Days -10 to -3):

[0181] ●Assess fasting blood glucose prior to assessment of gastric emptying to ensure blood glucose ≤275 mg / dL.

[0182] ● Complete the PAGI-SYM questionnaire on site before starting the GEBT.

[0183] ● After fasting for 8 hours, take a standardized diet rich in 13 C's meal twice and then 45, 90, 120, 150, 180, and 240 minutes after meal ingestion.

[0184] ●Record previous medication use.

[0185] ●Obtain vital signs (including heart rate, blood pressure, respiratory rate, and temperature) after the subject has been seated and resting for at least 5 minutes.

[0186] ●Complete the ANMS GCSI-DD questionnaire every evening.

[0187] G. Efficacy Evaluation (i) Primary Efficacy Evaluation

[0188] The primary efficacy variable was the change in gastric emptying measured by GEBT at Day 14 (±2 days) compared with baseline (collected on Days -10 to -3).

[0189] The GEBT is a non-radioactive stable isotope breath test in which a standardized 13 C uses exhaled air after meals 13 CO2 / 12 The gastric emptying rate is determined by the ratio of CO2 to CO2. Subjects will ingest a standardized rich 13C. On days -10 to -3 and 14 (±2 days), a standardized diet rich in 13 Breath samples were obtained twice before meals on Day 14 (± 2 days) and then at 45, 90, 120, 150, 180, and 240 minutes after meal ingestion, and 30 minutes after study drug administration on Day 14 (± 2 days).

[0190] (ii) Secondary efficacy assessments

[0191] Secondary efficacy variables were as follows:

[0192] ● On day 14 (±2 days) through GEBT T 1 / 2 (BT T 1 / 2 ) measured by change from baseline in gastric emptying

[0193] Change from baseline in ANMS GCSI-DD total score

[0194] Change from baseline in ANMS GCSI-DD subscale scores

[0195] The ANMS GCSI-DD covers 5 core-related symptoms of gastroparesis: nausea, early satiety, postprandial fullness, epigastric pain, and vomiting. Abdominal distension was included as an exploratory symptom. Symptoms were scored from 0 (none) to 4 (very severe) on a severity numeric response scale. Vomiting was recorded on a frequency response scale and scored as follows: 0 for no episodes, 1 for one episode, 2 for two episodes, 3 for three episodes, and 4 for four or more episodes. Subjects were asked to recall symptoms over the past 24 hours and complete the ANMS GCSI-DD patient-reported symptom questionnaire at least 14 days before randomization, on the day of randomization, and daily from day 1 to day 14 (±2 days). The total ANMS GCSI-DD score was calculated as the average of the 3 subscale scores for severity of nausea / vomiting, postprandial fullness / early satiety, and bloating. ANMS GCSI-DD subscale scores were assessed separately. The baseline for ANMS GCSI-DD analysis was based on the average score over the 3 days before randomization. Both ANMS GCSI-DD total and subscale scores were analyzed to compare symptom scores between treatment groups for descriptive purposes only.

[0196] (iii) Efficacy evaluation

[0197] The efficacy variable was the change from baseline in gastroparesis symptoms measured by the PAGI-SYM questionnaire score.

[0198] The PAGI-SYM includes 6 subscales: heartburn / reflux, fullness / early satiety, nausea / vomiting, bloating, upper abdominal pain, and lower abdominal pain. Both the PAGI-SYM total score and the subscale scores were used to compare symptom scores between treatment groups for descriptive purposes only.

[0199] The Clinical Rating Assessment Scale was also included as an exploratory efficacy variable. To assess overall clinical response, the following question was used: "Looking back over the past two weeks, how do you think your stomach / gastroparesis-related problems / symptoms compare to the period before you started this study treatment?" Responses will be: improved, no change, or worse. Subjects were asked to quantify their treatment response using the CPGAS. Subjects will pick a number within a range that best answers the question (+7 = completely better; 0 = no change; -7 = a lot worse). Responders were defined as CPGAS scores > 0 and non-responders as ≤ 0. Comparisons of Clinical Rating Assessment Scale scores between the deuterated domperidone treatment group and the placebo group were used for descriptive purposes only.

[0200] (iv) Pharmacokinetics

[0201] For all subjects, blood samples for PK analysis were collected at the following visits and time points:

[0202] Day 1: Within 60 minutes before and 1 and 2 hours after morning dose

[0203] Days 3 [±1 day], 7 [±2 days], and 10 [±3 days]: within 5 minutes before morning dosing

[0204] Day 14 [±2 days]: Approximately 5 minutes before morning dose and 1, 2, 3, and 4 hours after morning dose

[0205] Day 15 or 16 (+1 day)

[0206] Subjects may agree to participate in a more intensive PK subgroup in which PK samples are also collected at the following time points:

[0207] Day 1: 3, 4, 6, 8, and 12 hours after morning dose

[0208] Day 14 (±2 days): 6, 8, and 12 hours after morning dose

[0209] Day 15

[0210] ●Day 16 (+1 day)

[0211] Collection of PK samples allowed the following windows: ±2 minutes for samples collected ≤2 hours post-dose and ±5 minutes for samples collected >2 hours post-dose.

[0212] If data permit, the following PK parameters for deuterated domperidone (and any measured metabolites) will be calculated using plasma concentrations measured after dosing with deuterated domperidone on Day 1:

[0213] ●C max

[0214] ●Time to maximum plasma concentration

[0215] AUC 0-12 hours

[0216] If data permit, the following PK parameters for deuterated domperidone (and any measured metabolites) will be calculated using plasma concentrations measured after the last dose of deuterated domperidone:

[0217] ●C max

[0218] ●Time to maximum plasma concentration

[0219] AUC within the dosing interval

[0220] ● AUC from time 0 to the time of the last quantifiable plasma concentration

[0221] ●AUC from time 0 to infinity

[0222] ●Percentage of extrapolated AUC

[0223] T1 / 2

[0224] Apparent plasma clearance

[0225] Apparent volume of distribution

[0226] Trough concentrations collected throughout the study were used to confirm compliance and achievement of steady state. A timeline of procedures is provided in Table 1.

[0227]

[0228]

[0229] Example 2

[0230] This is a randomized, double-blind, placebo-controlled, Phase 2a study to evaluate the safety, efficacy, PK, and dose response of oral deuterated domperidone in adults with idiopathic or diabetic gastroparesis.

[0231] The study began by randomizing subjects in Cohort 1 to deuterated domperidone 10 mg BID or placebo BID in a ratio of 15 subjects to deuterated domperidone and 5 subjects to placebo. Subjects chose to be included in the sparse PK sampling subgroup or the dense PK sampling subgroup. Cohort 1 was stratified by idiopathic gastroparesis and 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) vs. baseline GEBT T1 / 2 <110 minutes (less severe gastroparesis). Efforts were made to ensure the inclusion of adequate numbers of subjects with idiopathic and diabetic gastroparesis.

[0232] After 16 subjects in Cohort 1 completed the study, an independent DRC met to review data from Cohort 1. The DRC reviewed emerging safety, PK, and / or efficacy data throughout the study to determine whether it was safe and appropriate to continue the study using the planned dose levels for Cohorts 2 and 3, or whether further refinement of the proposed dose levels was necessary. The highest dose was not to exceed 60 mg BID, and no more than 40 additional subjects were to be added without modifying the protocol. The DRC also decided to advance the cohorts serially.

[0233] The planned dose levels for Cohorts 2 and 3 were initially 30 mg BID and 60 mg BID, respectively, with 15 subjects in each cohort receiving active study drug and 5 subjects receiving placebo. Based on new information from the current study and other ongoing studies, the DRC has modified the planned dose levels and cohort sizes for the studies as follows:

[0234] ● Cohort 1 was expanded to a total of 41 randomized subjects, and a 5 mg BID cohort (Cohort 3) was planned;

[0235] The dose level for Cohort 2 was changed to 20 mg once daily (QD), administered as one deuterated domperidone 20 mg capsule in the morning and one matching placebo capsule in the evening to maintain the blinding of the study so that each dose could have either active study drug or placebo involved; and

[0236] ●An expansion of the 15 mg BID cohort (Cohort 2 expansion) and expansion of Cohort 3 were planned; however, only Cohort 3 was enrolled.

[0237] At the screening visit, all subjects signed informed consent before any study procedures were performed. Subjects had to meet all inclusion criteria and not meet any exclusion criteria to be eligible for the study.

[0238] Subjects were evaluated as follows:

[0239] ● Days -28 to -11: Screening procedures were performed. ANMSGCSI-DD questionnaires were completed daily for at least 14 days before randomization (Day 1).

[0240] Days -10 to -3: Complete the ANMS GCSI-DD questionnaire daily. The GEBT is performed on a day within this window using a standardized carbon-13-rich ( 13 C) twice before the meal and then 45, 90, 120, 150, 180 and 240 minutes after meal ingestion.Before the start of the GEBT, a baseline Patient Assessment of Gastrointestinal Symptom Severity Index (PAGI-SYM) will be completed.

[0241] Day -3 to Day -1: Complete the pre-randomization visit for safety assessments and allow adequate turnaround time for laboratory results before randomization (Day 1); and

[0242] ● Day 1 to Day 14: Administer study drug (deuterated domperidone) or placebo BID for 14 days (±2 days) and conduct safety assessments; complete the ANMS GCSI-DD questionnaire daily and complete PK blood sampling at designated time points. On Day 14 (±2 days), complete the PAGI-SYM and Clinical Grade Assessment Questionnaires before the last dose of study drug.

[0243] ● Day 14 (± 2 days): GEBT was performed 30 minutes after study drug administration on Day 14 (± 2 days). 13 Breath samples were obtained twice before the meal of 14 days and then at 45, 90, 120, 150, 180, and 240 minutes after meal ingestion. If a subject withdrew from the study before the GEBT on Day 14 (±2 days), a GEBT should be attempted on the last day of study drug administration. A clinical rating scale was also performed.

[0244] At randomization, participants were stratified according to the etiology of their gastroparesis (ie, diabetic gastroparesis versus idiopathic gastroparesis) or, starting in cohort 2, according to the severity of their gastroparesis using GEBT T1 / 2 (ie, more severe gastroparesis [baseline GEBT T1 / 2 ≥ 110 minutes] versus less severe gastroparesis [baseline GEBT T1 / 2 < 110 minutes]).

[0245] On the day of the GEBT, subjects arrive at the clinic after an overnight fast and should take their usual medications, including any diabetes treatments, with the exception of any prohibited concomitant medications. Subjects self-administer their usual morning insulin injection based on their fasting state. Subjects are instructed to bring their study medication and additional insulin to the clinic as needed. Fasting blood glucose is assessed prior to study drug administration and gastric emptying assessment to ensure blood glucose is ≤275 mg / dL. Prior to the gastric emptying procedure, additional insulin may be administered (prorated based on the caloric content of the meal) to ensure blood glucose is ≤275 mg / dL prior to the gastric emptying procedure. Similarly, investigators should manage hypoglycemia (low blood sugar; <60 mg / dL) at their discretion.

[0246] Safety was assessed by evaluating AEs, vital signs, physical examination, clinical laboratory evaluations (including prolactin), and ECG findings. In addition, an optional PGx blood sample could be collected at any time during the subject's participation in the study.

[0247] Subjects were followed up 1 to 3 days after the last dose of study drug to assess AEs, changes in concomitant medications (including use of rescue medications), vital signs, and for PK sampling. Subjects participating in the intensive PK subgroup visited the clinic for observation on Day 15 and Day 16 (+1 Day). Subjects participating in the sparse PK subgroup chose to complete either the Day 15 visit or the Day 16 (+1 Day) visit. Unplanned visits and / or additional follow-up may be required. For example, subjects with clinically significant abnormal laboratory findings, unresolved TEAEs, SAEs requiring subsequent laboratory follow-up and review, or clinically significant AEs may require further evaluation.

[0248] Figure 1 A schematic diagram of the planned study is presented.

[0249] A. Research Objectives

[0250] Target

[0251] The objectives of this study are as follows:

[0252] To evaluate the safety and tolerability of multiple doses of deuterated domperidone in subjects with idiopathic or diabetic gastroparesis

[0253] To evaluate the effects of multiple doses of deuterated domperidone on gastric emptying as measured by GEBT in subjects with idiopathic or diabetic gastroparesis

[0254] ● Characterizing the PK of multiple doses of deuterated domperidone in subjects with idiopathic or diabetic gastroparesis

[0255] (ii) Exploratory objectives

[0256] The exploratory objectives of this study include the following:

[0257] ● To evaluate the effects of multiple doses of deuterated domperidone on nausea associated with gastroparesis based on nausea scores on the ANMS GCSI-DD

[0258] To evaluate the effects of multiple doses of deuterated domperidone on ANMSGCSI-DD scores (total and subscale scores) in subjects with idiopathic or diabetic gastroparesis

[0259] ● Evaluate the effects of multiple doses of deuterated domperidone on various PROs; and

[0260] ● Characterize the exposure-response relationship of deuterated domperidone.

[0261] B. Selection of Study Population

[0262] Inclusion criteria

[0263] Patients who meet all of the following criteria will be eligible to participate in this study:

[0264] Male and female patients aged 18 to 70 years;

[0265] A current diagnosis of idiopathic or diabetic gastroparesis, which is defined as follows:

[0266] ○ Perceived gastrointestinal symptoms consistent with gastroparesis (e.g., postprandial nausea / vomiting, postprandial fullness, early satiety, bloating, and / or epigastric / abdominal pain) within 6 months prior to screening; or

[0267] ○ Documented DGE confirmed by GEBT or scintigraphy within the past 3 years. Other modalities (e.g., SmartPill) may be considered with sponsor approval. TM Patients with documented DGE (by CT, manometry) or abnormal GEBT or scintigraphy > 3 years ago.

[0268] BMI 18 to 40 kg / m 2 (inclusive) between;

[0269] ●Glycated hemoglobin level ≤11 percent at screening;

[0270] Male patients with female partners of reproductive potential must agree to use 2 medically recognized highly effective methods of birth control from day 1 to 60 days after the last dose of study drug;

[0271] ●For male patients with female partners of reproductive potential, medically recognized and highly effective birth control methods include: latex condoms with spermicide, diaphragms with intravaginal spermicide, cervical caps with spermicide, intrauterine devices (hormonal or non-hormonal), implantable contraceptives, and oral contraceptives.

[0272] Male patients must agree to forgo sperm donation from day 1 to 60 days after the last dose of study drug;

[0273] ●Female patients with male partners must be surgically sterilized (hysterectomy and / or bilateral oophorectomy), at least 1 year postmenopausal (FSH confirmed in the postmenopausal range at the screening visit), or agree to use 2 medically accepted highly effective methods of birth control from Day -14 to 60 days after the last dose of study drug - for female patients with male partners, medically accepted highly effective methods of birth control include: latex condoms with spermicide, diaphragms with intravaginal spermicide, cervical caps with spermicide, and non-hormonal indwelling intrauterine devices.

[0274] Negative breath alcohol and urine drug screens (including THC) at the screening visit and randomization.

[0275] ● Willing to abstain from consuming grapefruit, grapefruit products, star fruit, star fruit products, and limes from 48 hours before randomization until the end of the study.

[0276] ●Participants who are willing to forgo long-acting GLP-1 agonists, sodium-glucose transporter-2 (SGLT-2) inhibitors, or pramlintide and are currently taking SGLT-2 inhibitors or GLP-1 agonists other than Bydureon (exenatide extended-release), Tanzeum (albiglutide), or Trulicity (dulaglutide) may be considered for inclusion in the study if they are willing to stop medication for 3 days prior to each GEBT visit (Days -10 to -3 and Day 14 [±2 days]).

[0277] ●Able to understand and be willing to comply with all study visits, procedures, restrictions, and discontinuations, including medications for gastroparesis, and provide written informed consent in accordance with institutional and regulatory guidelines.

[0278] Exclusion criteria

[0279] Patients who meet any of the following criteria will be excluded from this study:

[0280] 1. History or current clinically significant arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsade de pointes. Patients with milder forms of ectopic beats (e.g., premature atrial beats) are not necessarily excluded.

[0281] 2. Have clinically significant bradycardia, resting heart rate less than 50 beats per minute, sinus node dysfunction or heart block.

[0282] 3. Prolonged QTcF (QTcF>450 msec for males or QTcF>470 msec for females) based on the average of three ECGs.

[0283] 4. Personal or family history of long QT syndrome, torsades de pointes, or other complex ventricular arrhythmias, or family history of sudden death.

[0284] 5. Have evidence (based on screening or baseline assessment) or history of the following diseases: clinically significant immune, blood, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological or allergic diseases (including drug allergy); surgical conditions; cancer (except basal or squamous cell carcinoma of the skin and cancer that has been regressed or in remission for more than 5 years before the screening visit); or any condition that may significantly interfere with the absorption, distribution, metabolism or excretion of the study drug. Cholecystectomy and appendectomy are allowed.

[0285] 6. A history of prolactin-releasing pituitary tumor (i.e., prolactinoma);

[0286] 7. Elevated serum prolactin - Patients who are taking medications known to elevate prolactin (e.g., domperidone, metoclopramide, phenothiazines, selective serotonin reuptake inhibitors, verapamil, etc.) and have elevated prolactin at the time of screening may be considered for this study.

[0287] 8. Patients with known or suspected hypogonadism, current clinically significant menstrual abnormalities (such as oligomenorrhea or amenorrhea), gynecomastia, galactorrhea, or other clinical features that may be consistent with hyperprolactinemia;

[0288] 9. Helicobacter pylori injection within 6 months of screening and / or during the study;

[0289] 10. Bilirubin, alkaline phosphatase, AST or ALT levels greater than 2×ULN, or Child-Pugh classification grade B or C;

[0290] 11. Serum creatinine level greater than 1.5×ULN at screening, or eGFR <30 mL / min / 1.73 m using the CKD-EPI equation 2 ;

[0291] 12. Hemoglobin level <10g / dL at screening;

[0292] 13. Abnormal thyroid stimulating hormone level during screening;

[0293] 14. Unable to conduct a breath test;

[0294] 15. Known allergy to eggs or spirulina;

[0295] 16. Use of the following investigational, prescription or over-the-counter drugs:

[0296] ● Actively participate in experimental therapy research; receive experimental therapy using small molecules within 30 days of randomization or 5 half-lives (whichever is longer); or receive experimental therapy using large molecules within 90 days of randomization or 5 half-lives (whichever is longer);

[0297] ● Use of concomitant CYP3A4 inhibitors (whether medications, herbal supplements, dietary supplements, or nutraceuticals) within 14 days or 5 half-lives (whichever is longer) of the first dose of study drug until the end of the study;

[0298] ● Use of concomitant CYP3A4 inducers (whether medications, herbal supplements, dietary supplements, or nutraceuticals) within 28 days or 5 half-lives (whichever is longer) of the first dose of study drug or inducer until the end of the study;

[0299] ● Use of any medication, herbal supplement, dietary supplement, or nutraceutical that may prolong QT within 28 days before the first dose of study drug until the end of the study; or

[0300] ● Use of gastric motility agents (including but not limited to metoclopramide, domperidone, erythromycin, etc.), other drugs that may affect gastric emptying (such as opioids, marijuana, and anticholinergic drugs), and antiemetics (except rescue antiemetics specified in the protocol) within 14 days before baseline GEBT until the end of the study. Gastric pacemakers should be turned off within 14 days before baseline GEBT and remain turned off until the end of the study.

[0301] 17. A history of alcoholism or drug abuse as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th edition within 2 years before medication;

[0302] 18. Typical consumption of ≥14 alcoholic drinks per week;

[0303] 19. Evidence of continued use of illegal drugs;

[0304] 20. HIV antibody, HCV RNA or HBsAg positive at the screening visit;

[0305] 21. Donated blood or blood products within 30 days before administration;

[0306] 22. Currently receiving weight loss medication or previous weight loss surgery (e.g., gastric bypass surgery);

[0307] 23. Pregnancy, breastfeeding or planning to become pregnant during the study period;

[0308] 24. Unable to swallow medication;

[0309] 25. Currently receiving parenteral feeding or having a nasogastric tube or other intestinal tube (e.g., PEG tube) for feeding or decompression;

[0310] 26. Known or suspected gastric outlet obstruction (e.g., gastrointestinal stenosis) or other gastrointestinal mechanical obstruction documented by upper gastrointestinal endoscopy or upper gastrointestinal radiology series within the past 3 years;

[0311] 27. Known history or current diagnosis of intestinal malabsorption or exocrine pancreatic disease;

[0312] 28. History of gastric surgery, such as fundoplication, gastrectomy, vagotomy, pyloroplasty, or bariatric surgery; patients with a gastric pacemaker may be considered for inclusion in this study if the pacemaker can be turned off at least 14 days before baseline GEBT and throughout the remainder of the study period. History of diagnostic endoscopy is not excluded. Cholecystectomy and appendectomy are allowed.

[0313] 29. Any history or presence of any medical condition or psychiatric illness that may interfere with the conduct of the study or expose the patient to unacceptable risk;

[0314] 30. Previous lack of response to domperidone, or known allergy or intolerance to domperidone or any excipient in the deuterated domperidone formulation;

[0315] 31. Unsuitable for any other reason that may expose the patient to increased risk during participation or interfere with the interpretation of the study results.

[0316] C. Randomization criteria

[0317] In addition to the general criteria, in order to be randomized into the study, subjects must meet the following criteria at the time of randomization:

[0318] 1. Continue to meet all inclusion / exclusion criteria;

[0319] 2. All gastrokinetic agents and antiemetics have been discontinued for at least 14 days, and the patient is willing to continue to discontinue such drugs during the study (except for rescue antiemetic drugs specified in the protocol);

[0320] 3. A confirmed diagnosis of idiopathic or diabetic gastroparesis is established, as defined below:

[0321] ○ Current upper gastrointestinal symptoms (e.g., nausea / vomiting, postprandial fullness, early satiety, bloating, and / or epigastric / abdominal pain); or

[0322] ○ Within 10 days before the first dose of study drug, based on the use of 13 C-Spirulina platensis demonstrated T1 / 2>80 minutes with DGE recorded. Subjects with T1 / 2>200 minutes may be considered for inclusion in this study with sponsor approval.

[0323] 4. The ANMS GCSI-DD score meets the following requirements:

[0324] ○ Mean composite score ≥ 2 (using a Likert scale from 0 [none] to 4 [very severe]) in the last 10 days prior to randomization or sponsor approval. The main symptom experienced should not be abdominal pain; and

[0325] ○ Nausea subscale score (including nausea, retching, and vomiting) ≥ 2 or at least 1 episode of vomiting on at least 4 of 7 days during the portion of the screening period in which the subject has not taken a prokinetic agent or antiemetic (other than protocol-specified rescue medication).

[0326] 5. Compliance with the ANMS GCSI-DD during screening, defined as compliance ≥75% or approved by the sponsor; and

[0327] 6. Have continuous required results of initial safety laboratory tests performed at screening.

[0328] Removal of Subjects from Treatment or Evaluation

[0329] Subjects may stop participating in this clinical study due to any of the following reasons:

[0330] ●The subject withdraws consent or requests termination of the study for any reason;

[0331] ● The occurrence of any medical condition or circumstance that exposes the subject to substantial risk and / or does not allow the subject to comply with the requirements of the study protocol;

[0332] Any SAE, clinically significant AE, serious laboratory abnormality, clinically significant change in ECG from baseline (e.g., QTcF>500msec, change in QTcF from baseline>60msec [confirmed by repeat ECG with central interpretation], etc.), new ECG abnormality deemed clinically significant, concurrent illness, or other medical condition indicating that continued participation is not in the best interest of the subject;

[0333] ●Pregnancy;

[0334] ●Need to take prohibited concomitant medications;

[0335] ● The subject fails to comply with the study protocol requirements or study-related procedures; or

[0336] ●The study is terminated by the sponsor or regulatory agency.

[0337] If a subject withdraws from the study prematurely due to the above criteria or for any other reason, the investigator should make every effort to complete the full assessment panel for the premature termination visit. The reason for the subject's withdrawal must be documented.

[0338] Study recruitment will continue until 60 subjects (15 subjects in each treatment group: deuterated domperidone 10 mg BID, deuterated domperidone 20 mg QD, deuterated domperidone 5 mg BID and placebo) complete the treatment cycle. The DRC may expand study recruitment, but without modifying the protocol, it can only add no more than 40 additional subjects. Subjects who withdraw will not be replaced.

[0339] D. Treatment (i) Treatment administered

[0340] The subjects were orally administered deuterated domperidone or placebo capsules. The subjects were randomized in a 3:1 ratio to deuterated domperidone or placebo.

[0341] The deuterated domperidone dosage applied to queues 1 to 3 was 10mg BID, 20mg QD and 5mg BID. DRC approved the expansion of queue 2 at a dosage level of 15mg BID, but no subjects were recruited. All subjects took a blinded study drug (deuterated domperidone or placebo capsule) orally at 8:00AM (± 2 hours) and 8:00PM (± 2 hours) with about 240mL of water. For a given individual, a 12-hour interval was maintained between each administration. All subjects should try to fast for at least 8 hours before administration in the morning of the first day.

[0342] The duration of the double-blind treatment period was 14 (± 2) days of study drug administration.

[0343] (ii) Product Labeling

[0344] Deuterated domperidone consists of deuterated domperidone drug product in 2C size, oval, blue soft capsules. Each deuterated domperidone capsule contains 5, 10 or 20 mg of active deuterated domperidone API (deuterated domperidone). The deuterated domperidone capsule contains the ingredients presented in Table 1.

[0345]

[0346] A matching placebo softgel capsule containing all the ingredients in Table 1 except the deuterated domperidone API was also provided. The softgel capsules (deuterated domperidone and placebo) were packaged in high-density polyethylene bottles with child-resistant screw caps or blister packs. Table 3 lists the batch numbers of the study drugs used in this study.

[0347]

[0348]

[0349] Study medication (deuterated domperidone and placebo) was stored at ambient room temperature (15 to 25°C [59 to 77°F]) protected from moisture and light.

[0350] (iii) Methods for assigning subjects to treatment groups

[0351] The study was planned to include 3 treatment groups of 20 subjects in each group. The study began with randomization of subjects in Cohort 1 to deuterated domperidone 10 mg BID or placebo BID, with 15 subjects receiving deuterated domperidone and 5 subjects receiving placebo. An independent DRC reviewed emerging safety, PK, and / or efficacy data throughout the study to determine whether it was safe and appropriate to continue the study using the planned dose levels for Cohorts 2 and 3, or whether further refinement of the proposed dose levels was necessary. The planned dose levels for Cohorts 2 and 3 were initially 30 mg BID and 60 mg BID, respectively, with 15 subjects in each cohort receiving study drug and 5 subjects receiving placebo. Based on emerging information from the current study and other ongoing studies, the planned dose levels and cohort sizes for the study were modified as follows:

[0352] ● Cohort 1 was expanded to a total of 41 randomized subjects, and a 5 mg BID cohort (Cohort 3) was planned;

[0353] The dose level for Cohort 2 was changed to 20 mg QD, administered as one deuterated domperidone 20 mg capsule in the morning and one matching placebo capsule in the evening to maintain the blinding of the study so that each dose could have either active study drug or placebo involved; and

[0354] ● Cohort 2 was planned to be expanded to 18 subjects at the 15 mg BID dose level, consisting of 10 mg and 5 mg capsules taken as a single agent. Due to a change in the manufacturing process for the 10 mg capsules, the sponsor chose not to proceed with the 15 mg BID dose level to avoid introducing potential variability between batches and thus confounding data analysis. The 5 mg BID (Cohort 3) was expanded to a total of 18 subjects, but only 12 subjects were randomized.

[0355] Subjects who completed the screening visit and met all inclusion criteria, did not meet any exclusion criteria, and met all additional criteria based on the randomization procedure (including safety laboratory testing) were randomized to the study. Subjects were randomized in a 3:1 ratio to deuterated domperidone BID or placebo BID. Randomization occurred on Day 1.

[0356] (iv) Dose selection and scheduling for each subject

[0357] All subjects took a dose of blinded study drug (deuterated domperidone or placebo capsule) orally with about 240mL of water at 8:00AM (±2 hours) and 8:00PM (±2 hours). For a given individual, a 12-hour interval will be maintained between each administration. All subjects should try to fast for at least 8 hours before administration on the morning of the first day. However, if it is determined that the subject should eat (i.e., due to low blood sugar levels or hypoglycemia symptoms), a light meal can be eaten >2 hours before the morning administration of the study drug. Subjects who provide sparse PK samples should continue to fast for at least 2 hours after administration on the morning of the first day, and subjects who provide more intensive PK samples should continue to fast for at least 4 hours. However, if it is determined that food should be taken, breaking the prescribed fast is allowed to ensure the safety of the subject. On Day 14 [±2 days], all subjects fasted for at least 8 hours before the morning administration of the study drug and fasted for 4 hours after completing the GEBT meal. Subjects need to fast for 2 hours before and 1 hour after all other administrations. Subjects were provided with study medication for self-administration of medication not administered on site.

[0358] In the event that a subject misses their scheduled dose and realizes the missed dose within 2 hours of their scheduled dosing time, the subject is instructed to take their assigned dose of study medication when they realize the missed dose. If a subject realizes the missed dose more than 2 hours after their scheduled dosing time, the subject is instructed to skip that dose of study medication and resume the assigned dose of study medication at the next scheduled time.

[0359] In the event that a subject vomits after taking their scheduled dose of study drug, instruct the subject to record the time of study drug administration and the time of vomiting and to resume their assigned dose of study drug at the next scheduled time. During the treatment period, subjects should attempt to record the time of vomiting in relation to the time of study drug administration and report this to site staff during scheduled clinic visits.

[0360] (v) Blindness

[0361] After randomization, study medication was dispensed in a double-blind fashion on Day 1. The sponsor and all clinical staff were masked to each subject's treatment group. Subjects were also masked to the treatment they received.

[0362] At randomization, participants were stratified according to the etiology of their gastroparesis (ie, diabetic gastroparesis versus idiopathic gastroparesis) or, starting in cohort 2, according to the severity of their gastroparesis using GEBT T1 / 2 (ie, more severe gastroparesis [baseline GEBT T1 / 2 ≥ 110 minutes] versus less severe gastroparesis [baseline GEBT T1 / 2 < 110 minutes]).

[0363] Due to the nature of the sample analysis results, bioanalysts involved in PK sample analysis were not blinded to treatment. PK data were de-identified to maintain blinding before being provided to any other individuals, including those involved in calculating PK parameters and related descriptive statistics, performing any modeling or simulations, and / or plotting PK data.

[0364] (vi) Previous and concomitant therapy

[0365] Excluded medications, foods, and / or procedures

[0366] The following investigational, prescription, or over-the-counter medications were not permitted during the study:

[0367] Pramlintide;

[0368] ●SGLT2 inhibitors or GLP-1 agonists with a long half-life [such as Bydureon (exenatide extended release), Tanzeum (albiglutide), or Trulicity (dulaglutide)];

[0369] ● Use of small molecule experimental therapy within 30 days or 5 half-lives (whichever is longer) before randomization; or use of large molecule experimental therapy within 90 days or 5 half-lives (whichever is longer) before randomization;

[0370] ●CYP3A4 inhibitors (whether drugs, herbal supplements, dietary supplements, nutraceuticals, or foods) within 14 days or 5 half-lives (whichever is longer) of the first dose of study drug or inducer until the end of the study;

[0371] CYP3A4 inducers (whether drugs, herbal supplements, dietary supplements, nutraceuticals, or foods) within 28 days or 5 half-lives (whichever is longer) of the first dose of study drug until the end of the study;

[0372] Any medication, herbal supplement, dietary supplement, or nutraceutical that may prolong QT within 28 days before the first dose of study drug until the end of the study;

[0373] ●In the 14 days before the baseline GEBT until the end of the study, gastric prokinetic agents (including but not limited to metoclopramide, domperidone, erythromycin, etc.), other drugs that may affect gastric emptying (such as opioids, marijuana and anticholinergic drugs), and antiemetics (except rescue antiemetics specified in the protocol). Gastric pacemakers should be turned off within 14 days before the baseline GEBT and remain turned off until the end of the study.

[0374] ● Botulinum toxin injection to Pylori within 6 months after screening and during the study;

[0375] Weight loss medications or previous weight loss surgery (such as gastric bypass surgery); and

[0376] ●Parenteral feeding or the presence of a nasogastric or other enteral tube (eg, PEG tube) for feeding or pressure relief.

[0377] Rescue Medication: Subjects experiencing severe symptoms of gastroparesis may have received a daily dose of promethazine hydrochloride However, such treatments should be avoided if possible on days when GEBT is being performed. Subjects who required further treatment with the prohibited medication may have discontinued study treatment and undergone follow-up study procedures.

[0378] Allowed medications and / or procedures: The use of additional medications not specifically excluded previously (e.g., rescue medications) is allowed.

[0379] Record of Previous and Concomitant Medication Use: Any medications administered within 28 days prior to the first dose of study drug and / or during the study must be recorded.

[0380] E. Efficacy and Safety Variables (i) Efficacy and safety measurements and flow chart for evaluation

[0381] Tables 4A and 4B provide a procedural timeline for the study.

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392] (ii) Appropriateness of measurement methods

[0393] The GEBT and ANMS GCSI-DD were used as efficacy measures. The GEBT is an FDA-approved measure of gastric emptying and is an appropriate endpoint for the 2-week treatment period used in this study. The use of the ANMS GCSI-DD is standard for this type of study and assesses core signs and symptoms as endpoints as recommended in FDA guidance. The PK and safety measures in this study are widely used and are recognized to be reliable, accurate, and relevant.

[0394] (iii) Efficacy variables

[0395] Main efficacy variables

[0396] The primary efficacy variable was the change from baseline in gastric emptying measured by GEBT at Day 14.

[0397] Secondary efficacy variables

[0398] The secondary efficacy variables were as follows:

[0399] Change from baseline in gastric emptying measured by GEBT T1 / 2 at day 14;

[0400] Change from baseline in the ANMS GCSI-DD total score; and

[0401] Change from baseline in the ANMS GCSI-DD subscale score.

[0402] (iv) American College of Neurogastroenterology and Motility Medicine Gastroparesis Primary Symptom Index Daily Diary:

[0403] Scoring method specified in the scheme

[0404] The ANMS GCSI-DD covers the 5 core symptoms associated with gastroparesis: nausea, early satiety, postprandial fullness, epigastric pain, and vomiting. Abdominal distension was included as an exploratory symptom. Symptoms were scored on a severity numeric response scale from 0 (none) to 4 (very severe). Vomiting was recorded on a frequency response scale and scored as follows: 0 for no episodes, 1 for 1 episode, 2 for 2 episodes, 3 for 3 episodes, and 4 for 4 or more episodes. Participants were asked to recall their symptoms over the past 24 hours and to complete the ANMS GCSI-DD patient-reported symptom questionnaire for at least 14 days before randomization, on the day of randomization, and daily from day 1 to day 14 (±2 days).

[0405] Manual scoring method of the American Society of Neurogastroenterology and Motility

[0406] The severity of the four gastroparesis-related symptoms (nausea, early satiety, postprandial fullness, and epigastric pain) was scored on a scale ranging from 0 (none) to 4 (very severe). The vomiting score assessed the number of vomiting episodes in a day, capped at a maximum of 4; thus, the vomiting score ranged from 0 (no vomiting episodes) to 4 (4 or more vomiting episodes). The frequency of vomiting was scored as 0 episodes, 1 episode, 2 episodes, 3 episodes, or 4 or more episodes (capped at 4).

[0407] (vi) Exploratory efficacy variables

[0408] The exploratory efficacy variables were as follows:

[0409] ●Change from baseline in gastroparesis symptoms as measured by the PAGI-SYM questionnaire score; and

[0410] ●Clinical grading assessment scale on day 14.

[0411] Patient Assessment of the Gastrointestinal Disorders Symptom Severity Index:

[0412] The PAGI-SYM includes 6 subscales: heartburn / regurgitation, fullness / early satiety, nausea / vomiting, bloating, upper abdominal pain, and lower abdominal pain.

[0413] Clinical Grading Assessment Scale:

[0414] To assess overall clinical response, the following question was used on Day 14: "Looking back over the past two weeks, how do you think your stomach / gastroparesis related problems / symptoms compare to the period before you started this study treatment?" Responses were as follows: improved, no change, or worse. Subjects were asked to quantify their treatment response using a clinical patient rating scale. Subjects were to select a number within a range (+7 = definitely better; 0 = no change; -7 = much worse) that best answered the question.

[0415] (vii) Drug concentrations and other pharmacokinetic variables

[0416] PK variables were the concentrations of deuterated domperidone and derived PK parameters after multiple doses of deuterated domperidone. If data permitted, the following PK parameters of deuterated domperidone were calculated from plasma concentrations (Day 1) using non-compartmental methods:

[0417] ● C determined directly from the concentration-time curve max If the maximum value occurs at more than one time point, then C max is defined as the first maximum value;

[0418] ●T max ; If the maximum value occurs at more than one time point, then T max is defined as the first time point with that value; and

[0419] AUC 0-12 .

[0420] If data permitted, the following PK parameters for deuterated domperidone were calculated using measured plasma concentrations after the last dose of deuterated domperidone (morning of day 14):

[0421] ● C determined directly from the concentration-time curve max If the maximum value occurs at more than one time point, then C max is defined as the first maximum value;

[0422] ●T max ; If the maximum value occurs at more than one time point, then T max is defined as the first time point with that value;

[0423] ●AUC calculated using the trapezoidal method tau ;

[0424] AUC 0-t ;

[0425] AUC 0-∞ ; calculated as (AUC 0-t +C last / λz);

[0426] AUC ％extrap ; is expressed as (1-AUC 0-t / AUC 0-∞ )×100;

[0427] λz calculated from a semi-log plot of the plasma concentration versus time curve. The parameter was calculated by linear least squares regression analysis using points in the terminal log-linear phase;

[0428] ●T1 / 2, calculated as the natural logarithm (2) / λz;

[0429] CL / F, calculated as dose / AUC 0-∞ ;

[0430] Vz / F, calculated as dose / (λz × AUC 0-∞ );

[0431] ●R Cmax , calculated as C on day 14 max / Day 1 C max ;and

[0432] ●R AUC , was calculated as the AUC on day 14 tau / AUC on day 1 tau .

[0433] (viii) Security variables

[0434] Safety variables included AEs, clinical laboratory results (including prolactin), vital signs, ECG, and physical examination results.

[0435] F. Study Subjects (i) Disposition of Subjects

[0436] Based on new information from the current study and other ongoing studies, the planned dose levels and cohort sizes for the studies have been modified as follows:

[0437] ● Cohort 1 was expanded to a total of 41 randomized subjects, and a 5 mg BID cohort (Cohort 3) was planned;

[0438] The dose level for Cohort 2 was changed to 20 mg QD, administered as one deuterated domperidone 20 mg capsule in the morning and one matching placebo capsule in the evening to maintain the blinding of the study so that each dose could have either active study drug or placebo involved; and

[0439] ● Cohort 2 was planned to be expanded to 18 subjects at the 15 mg BID dose level, consisting of 10 mg and 5 mg capsules taken as a single agent. Due to a change in the manufacturing process for the 10 mg capsules, the sponsor chose not to proceed with the 15 mg BID dose level to avoid introducing potential variability between batches and thus confounding data analysis. The 5 mg BID (Cohort 3) was expanded to a total of 18 subjects, but only 12 subjects were randomized.

[0440] Table 5 summarizes the subject disposition for the ITT population.

[0441] A total of 72 subjects were recruited into one of the three cohorts. Fifty-four subjects were randomized to one of the following deuterated domperidone treatment groups:

[0442] 10 mg BID deuterated domperidone (30 randomized subjects);

[0443] 20 mg QD domperidone-d (15 randomized subjects); or

[0444] 5 mg BID deuterated domperidone (9 randomized subjects).

[0445] Eighteen subjects were randomized to receive a placebo.

[0446] Of the randomized subjects, 29 (96.7%) subjects in the 10 mg BID deuterated domperidone treatment group, 15 (100.0%) subjects in the 20 mg QD deuterated domperidone treatment group, 9 (100.0%) subjects in the 5 mg BID deuterated domperidone treatment group, and 18 (100.0%) subjects in the combined placebo treatment group completed the study. One subject (1.4%) withdrew from the study early. The subject (subject 113-010) received 10 mg BID deuterated domperidone and was discontinued.

[0447]

[0448] (ii) Analyzed datasets

[0449] Table 6 describes the analysis populations used for the study.

[0450] The ITT population included 72 subjects (30 subjects in the 10 mg BID domperidone-d60 group, 15 subjects in the 20 mg QD domperidone-d60 group, 9 subjects in the 5 mg BID domperidone-d60 group, and 18 subjects in the combined placebo groups) and was identical to the MITT population, PD-evaluable population, and safety population.

[0451] The PP population included 69 subjects (29 subjects in the 10 mg BID deuterated domperidone treatment group, 14 subjects in the 20 mg QD deuterated domperidone treatment group, 8 subjects in the 5 mg BID deuterated domperidone treatment group, and 18 subjects in the combined placebo treatment groups).

[0452] The PK population included 54 subjects (30 subjects in the 10 mg BID deuterated domperidone treatment group, 15 subjects in the 20 mg QD deuterated domperidone treatment group, and 9 subjects in the 5 mg BID deuterated domperidone treatment group), which was the same as the PK evaluable population.

[0453]

[0454] (iii) Demographic and other baseline characteristics

[0455] Table 7 summarizes the demographic and baseline characteristics of 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 2range. The majority of subjects were female. Overall, 83.3% of subjects were white and 15.3% 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 etiology for gastroparesis. Among subjects with diabetic gastroparesis, the number of subjects with and without neuropathy was similar, with the exception of Cohort 2, in which the majority of subjects had neuropathy. There were more subjects with baseline GEBT ≥ 110 kPCD than with < 100 kPCD. These observed differences in demographic and baseline characteristics are considered unlikely to impact data interpretation and conclusions.

[0456]

[0457]

[0458] (vi) Previous and concomitant medications

[0459] Overall, 70 (97.2%) subjects took protocol-permitted concomitant medications, and 70 (97.2%) subjects took any prior medications.

[0460] In this study, a total of 20 subjects (27.8%) took rescue medication as permitted by the protocol, as reported by the subjects in their subject diaries.

[0461] Results were not confounded by any medication use.

[0462] G. Efficacy, Pharmacodynamics, and Pharmacokinetic Results

[0463] (i) Efficacy results and individual subject data tables

[0464] Gastric emptying time

[0465] Table 8 presents gastric emptying time at baseline and day 14 for the ITT population, as well as the change and percentage change in gastric emptying time from baseline to day 14, as measured by GEBT T1 / 2. For the 10 mg BID deuterated domperidone group, the deuterated domperidone and placebo treatment groups had shorter gastric emptying times than baseline, and the change and percentage change in gastric emptying measured by GEBT T1 / 2 by day 14 (± 2 days) compared to baseline (collected on days -10 to -3) were greater than the placebo group, indicating faster gastric emptying after administration of deuterated domperidone.

[0466]

[0467]

[0468] Table 9 presents gastric emptying time at baseline and day 14 for the ITT population, as well as the change in gastric emptying time from baseline to day 14 as measured by GEBT by time point. All pre-meal results were 0 and therefore excluded from the analysis.

[0469]

[0470]

[0471]

[0472]

[0473] American Society of Neurogastroenterology and Motility Medicine Gastroparesis Major Symptom Index Daily Diary

[0474] Table 10 presents the ANMS GCSI-DD total and subscale scores for the ITT population and the changes and percentage changes from baseline using the protocol-specified scoring method. For all deuterated domperidone treatment groups, the ANMS GCSI-DD total 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 and subscale scores.

[0475]

[0476]

[0477]

[0478]

[0479] Table 11 presents the ANMS GCS6-DD total and subscale scores of the ITT population using the ANMS GCSI-DD manual scoring method and the changes and percentage changes compared to baseline. For all deuterated domperidone treatment groups, the ANMS GCSI-DD total and all subscale scores decreased compared to baseline on Day 14 / EOT. Subjects receiving placebo also experienced a decrease in the ANMS GCSI-DD total and subscale scores.

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486] Patient Assessment of the Gastrointestinal Disorders Symptom Severity Index

[0487] Table 12 presents the PAGI-SYM total and subscale scores for the safety population and the change and percent change from baseline to Day 14. For all deuterated domperidone treatment groups, the PAGI-SYM total and subscale scores decreased from baseline on Day 14. Subjects receiving placebo also experienced a decrease in the PAGI-SYM total and subscale scores.

[0488]

[0489]

[0490]

[0491]

[0492]

[0493] Clinical Grading Assessment Scale

[0494] The Clinical Rating Assessment Scale responses for the ITT population are presented in Table 13. Improvements were noted for the majority of subjects in all treatment groups.

[0495]

[0496] (ii) Pharmacodynamic evaluation

[0497] Prolactin concentrations and changes from baseline by planned time point and treatment for the safety population are summarized in Table 14. Prolactin concentrations generally increased with increasing doses and increased during treatment, confirming target engagement.

[0498]

[0499]

[0500] Figure 2A and Figure 2B Shown are the mean (± SD) plasma deuterated domperidone concentrations versus time for the BID deuterated domperidone treatment groups in the PK population within a single dosing interval following administration of deuterated domperidone on the morning of Day 1 and the morning of Day 14 on a linear scale.

[0501] As expected, the exposure of deuterated domperidone generally increased with increasing doses. After administration of deuterated domperidone, the plasma concentration of deuterated domperidone generally reached or approached the peak level rapidly, with the median T of each dose group being max Values ​​ranged from 2.0 to 2.5 hours. Plasma concentrations of deuterated domperidone generally declined slowly from the peak. Table 15 summarizes the single dose (Day 1) and steady state (Day 14) plasma PK parameters of deuterated domperidone by treatment for the PK evaluable population.

[0502]

[0503]

[0504] At steady state, the exposure (based on C max The variability at steady state was moderate to high, with C max and AUC (AUC tau , AUC 0-t and AUC 0-∞ ) values ​​ranged from approximately 43.9% to 136.5%. This may be due in part to the more truncated and / or variable sampling schedule in the current study.

[0505] Of note, two subjects had plasma concentration values ​​on Day 14 that were inconsistent with those expected based on their assigned dosing regimen, suggesting a possible lack of compliance. PK parameters were similar with and without these subjects, suggesting that their presence in the data set had no noteworthy impact on the overall conclusions.

[0506] (iii) Efficacy, pharmacodynamics and pharmacokinetic conclusions

[0507] Subjects with idiopathic or diabetic gastroparesis treated with deuterated domperidone over a range of doses and those treated with placebo experienced a decrease in gastric emptying time from baseline.

[0508] Subjects receiving deuterated domperidone as well as placebo demonstrated improvement in gastroparesis symptoms as indicated by lower scores on the ANMSGCSI-DD (protocol-specified and manual scoring methods), lower scores on the PAGI-SYM, and improvement on the Clinical Rating Assessment Scale for most subjects.

[0509] Prolactin concentrations generally increase with increasing dose and remain elevated during treatment, confirming target engagement.

[0510] The PK properties of deuterated domperidone were characterized by Cmax Relatively fast and with a long T1 / 2. Steady-state accumulation ranges from about 2.0 to 2.5 times higher than after a single dose after BID dosing and about 1.5 to 2.0 times higher than after a single dose after QD dosing.

[0511] H. Safety Outcomes (iii) Exposure

[0512] A total of 72 subjects were randomized to one of three cohorts. Fifty-four subjects were randomized to receive multiple doses of deuterated domperidone 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 average exposure to study drug was 14 days.

[0513] (ii) Adverse events

[0514] Overview of adverse events

[0515] Table 16 provides a summary of AEs by treatment group at onset for the safety population.

[0516] There were no deaths, serious TEAEs, or discontinuations due to TEAEs. A total of 15 (20.8%) subjects experienced 23 TEAEs: 6 (20.0%) subjects in the 10 mg BID deuterated domperidone treatment group (11 TEAEs reported), 6 (40.0%) subjects in the 20 mg QD deuterated domperidone treatment group (8 TEAEs reported), 1 (11.1%) subject in the 5 mg BID deuterated domperidone treatment group (1 TEAE reported), and 2 (11.10%) subjects in the combined placebo treatment groups (3 TEAEs reported). Most TEAEs were mild in severity.

[0517] Overall, 9 (12.5%) subjects experienced TEAEs that were considered by the investigator to be related to study drug: 4 (13.3%) subjects in the 10 mg BID domperidone-d60 group, 4 (26.7%) subjects in the 20 mg QD domperidone-d60 group, 1 (11.1%) subject in the 5 mg BID domperidone-d60 group, and 0 (0.0%) subjects in the combined placebo groups.

[0518]

[0519]

[0520] Adverse event analysis

[0521] Table 17 summarizes the TEAEs grouped by treatment and SOC and PT in the safety population at the time of onset. Overall, 15 subjects (20.8%) experienced a total of 23 TEAEs: 6 (20.0%) subjects receiving 10 mg BID deuterated domperidone (reported 11 TEAEs), 6 (40.0%) subjects receiving 20 mg QD deuterated domperidone (reported 8 TEAEs), and 1 (11.1%) subject receiving 5 mg BID deuterated domperidone (reported 1 TEAE). In the combined placebo treatment group, 2 (11.1%) subjects experienced a total of 3 TEAEs.

[0522] The most common SOC of TEAE is gastrointestinal disorder. In the deuterated domperidone treatment group, 3 (10.0%) subjects receiving 10mg BID deuterated domperidone and 1 (6.7%) subject receiving 20mg QD deuterated domperidone experienced diarrhea. The second most common SOC of TEAE is investigation and metabolic and nutritional disorders. In the deuterated domperidone treatment group, 1 (3.3%) subject receiving 10mg BID deuterated domperidone and 2 (13.3%) subjects receiving 20mg QD deuterated domperidone experienced electrocardiogram QT interval prolongation, and 1 (3.3%) subject receiving 10mg BID deuterated domperidone and 1 (6.7%) subject receiving 20mg QD deuterated domperidone experienced hypoglycemia. All other TEAEs in the deuterated domperidone treatment groups were experienced by one subject each: nausea, vomiting, increased blood creatine phosphokinase, decreased appetite, palpitations, and tinnitus (10 mg BID deuterated domperidone treatment group); constipation, dyspepsia, sinusitis, and headache (20 mg QD deuterated domperidone treatment group); lower abdominal pain (5 mg BID deuterated domperidone treatment group).

[0523] In the combined placebo-treated groups, nausea, arthralgia, and back pain were experienced by 1 subject each (5.6%).

[0524]

[0525]

[0526] Drug-related adverse events

[0527] Table 18 summarizes the TEAEs related to the study drug in the safety population by treatment and by SOC and PT grouping at the time of onset. Overall, 9 subjects (12.5%) experienced a total of 11 TEAEs related to the study drug: 4 (13.3%) subjects receiving 10 mg BID deuterated domperidone (reported 6 TEAEs), 4 (26.7%) subjects receiving 20 mg QD deuterated domperidone (reported 4 TEAEs), and 1 (11.1%) subject receiving 5 mg BID deuterated domperidone (reported 1 TEAE). No subject in the combined placebo treatment group experienced TEAEs related to the study drug.

[0528] The most common SOC of TEAEs related to the study drug is gastrointestinal disorders. In the deuterated domperidone treatment group, 2 (6.7%) subjects receiving 10mg BID deuterated domperidone and 1 (6.7%) subject receiving 20mg QD deuterated domperidone experienced diarrhea. The second most common SOC of TEAEs related to the study drug is investigation. In the deuterated domperidone treatment group, 2 (13.3%) subjects receiving 20mg QD deuterated domperidone experienced electrocardiogram QT interval prolongation. All other study drug-related TEAEs in the deuterated domperidone treatment group were experienced by 1 subject each: nausea, elevated blood creatine phosphokinase, palpitations and tinnitus (10mg BID deuterated domperidone treatment group); headache (20mg QD deuterated domperidone treatment group); and lower abdominal pain (5mg BID deuterated domperidone treatment group).

[0529]

[0530]

[0531] Adverse events by severity

[0532] Most TEAEs were mild in severity. Overall, 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.

[0533] There were no deaths, SAEs, or other major AEs during the study period.

[0534] (iii) Clinical laboratory evaluation

[0535] Evaluation of laboratory parameters

[0536] Changes in Laboratory Values ​​Over Time: There were no meaningful changes in laboratory parameters from baseline. Prolactin concentrations generally increased with increasing doses and increased during treatment, confirming target engagement.

[0537] Individual Subject Changes: There were no clinically meaningful changes from baseline in any laboratory parameter. There were no clinically meaningful changes from baseline in prolactin concentrations.

[0538] Individual Clinically Significant Abnormalities: No laboratory abnormalities were considered SAEs or led to discontinuation of the study or study drug.

[0539] (iv) Vital signs, physical examination results, and other safety-related observations

[0540] There were no clinically meaningful changes in vital signs from baseline. There were no clinically meaningful changes in physical examination findings.

[0541] There was no clinically significant prolongation of the QTcF interval; however, some subjects met the protocol-specified QTcF alert criteria. Two (13.3%) subjects in the 20 mg QD deuterated domperidone treatment group experienced a change in QTcF of ≥6% from baseline on Days 3 and 7. Four hours after dosing on Day 14, one (3.6%) subject in the 10 mg BID deuterated domperidone treatment group, three (20.0%) subjects in the 20 mg QD deuterated domperidone treatment group, and one (6.3%) subject in the combined placebo treatment group experienced a change in QTcF of ≥6% from baseline. At 6 hours post-dose on Day 14, 1 (4.3%) subject in the 10 mg BID deuterated domperidone treatment group, 2 (16.7%) subjects in the 20 mg QD deuterated domperidone treatment group, and 1 (7.1%) subject in the combined placebo treatment group experienced a change in QTcF of ≥6% from baseline. 1 (6.7%) female subject in the 20 mg QD deuterated domperidone treatment group experienced a QTcF of ≥470 msec. Two subjects were assessed as having a study drug-related TEAE with prolonged electrocardiographic QT interval.

[0542] Safety Conclusion

[0543] No subject died, experienced a severe TEAE, or discontinued the study due to a TEAE during the study. Overall, 15 subjects (20.8%) experienced a TEAE and 9 subjects (12.5%) experienced a TEAE that was considered by the investigator to be generally related to the study drug; all of these subjects received deuterated domperidone. All study drug-related TEAEs were mild in severity. The most common SOC for study drug-related TEAEs was gastrointestinal disorders.

[0544] There were no clinically meaningful changes from baseline in laboratory parameters during the study, and no clinically meaningful changes in vital signs or physical examination findings during the study. There was no clinically meaningful prolongation of the QTcF interval; however, 2 subjects met the protocol-specified QTcF alarm criteria. For 1 subject, the alarm was an increase of ≥6% from baseline in QTcF at 4 and 6 hours post-dose on Day 14; notably, QTcF never increased above 426 msec. For the second subject, the alarm for an increase of ≥6% from baseline in QTcF occurred on Day 7 with a value of 474 msec (baseline QTcF mean of 430 msec); the subject continued to take study medication for the remainder of the study, and QTcF remained at or below baseline.

[0545] I. Discussion and Overall Conclusions

[0546] A total of 72 subjects were randomized to one of 3 cohorts: 54 subjects were randomized to receive multiple doses of deuterated domperidone at 10 mg BID, 20 mg QD, or 5 mg BID, and the combined 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 etiology for gastroparesis, and the number of diabetic subjects with and without neuropathy was similar, with the exception of cohort 2, in which the majority of subjects had neuropathy. The observed differences in demographic and baseline characteristics were considered unlikely to affect data interpretation and conclusions. There were no issues with administration of study medication, and the mean percentage of adherence based on medication accountability did not differ between treatment groups.

[0547] Subjects receiving deuterated domperidone and placebo showed improvement in gastroparesis symptoms, as indicated by lower ANMSGCSI-DD (protocol-specified and manual scoring methods), lower PAGI-SYM scores, and improvement on the Clinical Rating Assessment Scale for most subjects. A separate meta-analysis demonstrated a positive correlation between faster gastric emptying and improvement in upper gastrointestinal symptoms.

[0548] However, for a given dose level of deuterated domperidone, the exposure of deuterated domperidone in patients with gastroparesis (based on C max The exposures in healthy subjects (assessed by C and AUC) were approximately 2-fold higher than expected based on PK data in healthy subjects, although accumulation was similar in both populations. Specifically, data in healthy subjects suggest that a 10 mg BID dosing regimen of deuterated domperidone is expected to produce a mean C of approximately 7 to 11 ng / mL. maxHowever, in patients with gastroparesis, C max The AUC was approximately 18 ng / mL. Similarly, an approximately 2-fold higher AUC was observed in patients with gastroparesis compared to the expected value in healthy subjects. The PK differences were most significant in patients with more severe gastroparesis.

[0549] Prolactin concentrations generally increase with increasing dose and remain elevated during treatment, confirming target engagement.

[0550] Characterization of the safety of deuterated domperidone after multiple doses was also a study objective. Subjects with idiopathic or diabetic gastroparesis who participated in this study generally tolerated multiple doses of deuterated domperidone well. During the study, no subject died, experienced a serious TEAE, or discontinued the study due to a TEAE. A total of 15 (20.8%) subjects experienced 23 TEAEs: 6 (20.0%) subjects in the 10 mg BID deuterated domperidone treatment group (11 TEAEs reported), 6 (40.0%) subjects in the 20 mg QD deuterated domperidone treatment group (8 TEAEs reported), 1 (11.1%) subject in the 5 mg BID deuterated domperidone treatment group (1 TEAE reported), and 2 (11.1%) subjects in the combined placebo treatment group (3 TEAEs reported). Most TEAEs were mild in severity. Overall, 9 (12.5%) subjects experienced TEAEs that were considered by the investigator to be related to study drug: 4 (13.3%) subjects in the 10 mg BID domperidone deuteride group, 4 (26.7%) subjects in the 20 mg QD domperidone deuteride group, 1 (11.1%) subject in the 5 mg BID domperidone deuteride group, and 0 (0.0%) subjects in the combined placebo groups. In the domperidone deuteride groups, 2 (6.7%) subjects receiving 10 mg BID domperidone deuteride and 1 (6.7%) subject receiving 20 mg QD domperidone deuteride experienced diarrhea, and 2 (13.3%) subjects receiving 20 mg QD domperidone deuteride experienced electrocardiogram QT interval prolongation. All other study drug-related TEAEs in the deuterated domperidone treatment group were experienced by 1 subject each: nausea, elevated blood creatine phosphokinase, palpitations, and tinnitus (10 mg BID deuterated domperidone treatment group); headache (20 mg QD deuterated domperidone treatment group); and lower abdominal pain (5 mg BID deuterated domperidone treatment group). All TEAEs related to study drug were mild in severity. No subject in the combined placebo treatment group experienced TEAEs related to study drug.

[0551] There were no clinically meaningful changes from baseline in laboratory parameters during the study, and no clinically meaningful changes in vital signs or physical examination findings during the study. There was no clinically meaningful prolongation of the QTcF interval; however, 2 subjects met protocol-specified QTcF alert criteria. These subjects experienced a TEAE of electrocardiographic QT interval prolongation, which was considered related to study drug and did occur during the T max After that. For 1 subject, the alert for a QTcF increase of ≥6% from baseline was at 4 and 6 hours post-dose on Day 14; notably, the QTcF never increased above 426 msec. For the second subject, the alert for a QTcF increase of ≥6% from baseline was on Day 7 at 474 msec (baseline QTcF mean 430 msec); this subject continued to take study drug for the remainder of the study, and the QTcF remained at or below baseline.

[0552] Overall conclusion

[0553] In this study, adults with idiopathic or diabetic gastroparesis generally tolerated multiple oral doses of 10 mg BID, 20 mg BID, and 5 mg BID of deuterated domperidone well. There were no deaths, serious TEAEs, or discontinuations due to TEAEs. Most TEAEs were mild in severity.

[0554] For subjects with idiopathic or diabetic gastroparesis treated with deuterated domperidone over a range of doses and for subjects treated with placebo, a reduction in gastric emptying time and improvement in gastroparetic symptoms from baseline were observed.

[0555] The PK properties of deuterated domperidone were characterized by C max Relatively fast and with a long T1 / 2. Steady-state accumulation ranges from about 2.0 to 2.5 times higher after a single dose after BID dosing and about 1.5 to 2.0 times higher after a single dose after QD dosing. After administration of a given dose level of deuterated domperidone, the exposure in gastroparesis patients (based on C max Exposures (assessed by RT-PCR and AUC) were approximately 2-fold higher than expected based on PK data in healthy subjects.

[0556] Example 3: Components and Composition

[0557] Table 19 shows the composition of CIN-102 5 mg, 10 mg, and 20 mg soft gel capsules. CIN 102DP is formulated with 5 mg, 10 mg, or 20 mg of CIN-102 drug substance (as free base) and excipients to produce a lower C maxBased on the lipophilic nature of the fill formulation, a 2A gelatin shell formulation was used for encapsulation.

[0558]

[0559] The placebo soft gel capsule contained all of the ingredients listed in Table 19 except CIN-102.

[0560] Example 4: Comprehensive QT Study

[0561] This example details the results of the cardiodynamic assessment of CIN-102, where a single dose of CIN-102 was administered to healthy adult subjects (producing therapeutic and supratherapeutic exposures). The primary objective of this study was to evaluate the effect of CIN-102 on cardiac repolarization based on baseline and placebo-corrected corrected QT interval changes using the Fridericia formula (QTcF) in healthy subjects using a concentration-QTc analysis (primary analysis). Serial ECGs were extracted from continuous ECG recordings at predetermined time points beginning at least one hour before dosing and ending approximately 48 hours after dosing in each time period.

[0562] In healthy subjects, a 10 mg dose of deuterated domperidone drug product produced C max Approximately 50% lower than the same oral dose of domperidone. Within the dose range studied, the mean half-life values ​​after a single dose of the deuterated domperidone drug product ranged from approximately 18 to 29 hours. In order to evaluate the effect of the deuterated domperidone drug product on the QT interval, a definitive TQT study was conducted. The primary analysis was based on concentration-QTc modeling of the relationship between plasma drug concentration and the change in QTcF from baseline (ΔQTcF), designed to exclude the effect of placebo-corrected ΔQTcF (ΔΔQTcF) > 10 milliseconds (ms) at clinically relevant plasma levels.

[0563] 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 received a single dose of each of the following drugs in a randomized manner (1 treatment per study period) in a separate period (≥10 days between doses), as shown in Table 20:

[0564] 30 mg deuterated domperidone formulation (represents the approximate steady-state therapeutic exposure in patients);

[0565] 100 mg deuterated domperidone formulation (representing potential steady-state supratherapeutic exposure in patients);

[0566] 400 mg of moxifloxacin; and

[0567] ●Placebo.

[0568] Table 20: Sequence of treatments that can be randomly assigned to subjects

[0569]

[0570]

[0571] For treatments A, B, and D, subjects ingested a total of 10 capsules of CIN-102 and / or matching placebo. For treatment C, subjects ingested one 400 mg moxifloxacin tablet.

[0572] Subjects fasted for at least 8 hours before and 4 hours after each treatment. There was a washout period of at least 10 days between treatments.

[0573] Research objectives

[0574] The primary objective of this study was to evaluate the effect of CIN-102 on cardiac repolarization based on the change in QT interval corrected from baseline and placebo-corrected using the Fridericia formula (QTcF).

[0575] The secondary objectives of this study are to:

[0576] ●Evaluate the effect of CIN-102 on other ECG parameters (heart rate [HR], PR and QRS intervals, and changes in T wave morphology that occur with treatment)

[0577] ● Characterize the safety of a single dose of CIN-102 when administered to healthy adult subjects

[0578] ● Characterize the pharmacokinetics (PK) of a single dose of CIN-102 when administered to healthy adult subjects

[0579] Primary End Point

[0580] The primary endpoint was the placebo-corrected change from baseline in QTcF (ΔΔQTcF).

[0581] Secondary endpoints were:

[0582] Change from baseline in QTcF, HR, PR, and QRS interval (ΔQTcF, ΔHR, ΔPR, and ΔQRS)

[0583] ●Placebo-corrected change from baseline in HR, PR, and QRS intervals (ΔΔHR, ΔΔPR, ΔΔQRS)

[0584] Categorical abnormal values ​​for QTcF, HR, PR, and QRS

[0585] ● Changes in T wave morphology and frequency of U waves during treatment ECG and pharmacokinetic sample collection

[0586] During each treatment period, continuous 12-lead ECG was recorded from at least one hour before administration to about 48 hours after administration. At the following time points in each period, 12-lead ECG was extracted in up to 10 parallel determinations in a central ECG laboratory (ERT, Philadelphia, PA): 3 time points (-45, -30 and -15 minutes) within one hour before administration and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 36 and 48 hours after each administration. The subject rested in supine position for at least 10 minutes and 5 minutes before and after each time point. When ECG extraction meets safety, ECG, vital signs assessment and blood drawing procedures are performed in the order described. No PK or other laboratory blood draws were performed, and at least 5 minutes after the 5-minute window of 12-lead ECG extraction for QT analysis, the subject was approached.

[0587] Blood samples for PK determination were drawn at the same time points immediately after ECG extraction.

[0588] The core laboratory measured ECG intervals in a blinded manner using the Early Precision QT technique (EPQT). The ECG database was locked before any statistical analysis was performed.

[0589] TQT Plus ECG Extraction Technology

[0590] Up to 10 non-overlapping 14-second digital 12-lead ECG tracings were extracted from continuous recordings during the protocol-specified ECG extraction window. The TQT Plus method enabled the extraction of high-quality datasets by identifying recording periods with the lowest available HR variability and noise.

[0591] ECG is extracted according to the following principles:

[0592] • Site personnel communicate actual times of dosing, extraction windows, and PK sampling to the central ECG laboratory.

[0593] The TQT Plus process identified periods of stable HR on continuous 12-lead ECG tracings within a 5-minute extraction window. Stability was defined as beat-to-beat variations in heart rate and other ECG parameters below pre-defined thresholds. If the TQT Plus method resulted in a low number of continuous, readable cardiac cycles within the 5-minute window, time points were fully reviewed manually.

[0594] ●Continuously extract repeated, non-overlapping ECGs within each extraction window.

[0595] Early Precision QT Analysis

[0596] At each nominal time point specified in the protocol, up to 10 ECG replicates were extracted using the TQT Plus method. All readable cardiac cycles from these ECG replicates were evaluated for multiple quality metrics, including beat-to-beat stability, HR variation, noise, and other parameters, and classified into high-confidence and low-confidence levels. All low-confidence beats were fully reviewed and manually adjudicated by ECG technicians using pass-fail criteria. Beats found acceptable by manual review were included in the analysis.

[0597] The primary analysis lead is Lead II. If Lead II is not analyzable, the primary analysis lead for the subject's entire data set is changed to V5. If Lead V5 is not analyzable, Lead V2 is used for the subject's entire data set. If neither of the two optional leads can be used, the ERT cardiologist may choose to treat the data as not analyzable, or may decide to use the most appropriate lead for the subject's entire data set. The leads used for analysis are listed in the data list transmitted from the ERT.

[0598] In 3 of the 10 ECG replicates at each time point, categorical T-wave morphology analysis and measurement of PR and QRS intervals were performed completely manually using a semi-automated process. Final quality control and diagnostic interpretation were performed by the study cardiologist. When the results for each time point were compiled in the final raw data set, the mean QTcF from the 3 manually reviewed ECGs was compared to the mean QTcF from the TQT Plus ECG replicates (up to 10) for quality control purposes.

[0599] A total of 62 subjects were enrolled in the TQT study. At baseline, data were available for all 55 subjects in the placebo treatment period, then for 52 subjects in the deuterated domperidone formulation (30 mg) and supratherapeutic (100 mg) treatment periods, and for 51 subjects in the moxifloxacin treatment period. The mean (standard deviation) age of the subjects was 38.5 (9.20) years, and the mean (standard deviation) BMI was 26.3 (2.48) kg / m 2 61% of the subjects were male and 39% were female. Baseline ECG parameters were within the expected range for a healthy subject population.

[0600] (i) PK data from the study indicated that 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.

[0601] The highest mean plasma concentrations of M3 (the major metabolite) were observed at 2 hours post-dose for each of the 30 mg and 100 mg treatment groups.

[0602] ● The LS mean placebo-corrected change from baseline in QTcF (ΔΔQTcF) within the first 4 hours after deuterated domperidone formulation ranged from -0.3 to 1.8 ms at 0.5 and 2 hours post-dose in the 30 mg treatment group and from -0.1 to 3.7 ms at 0.5 and 3 hours post-dose in the 100 mg treatment group. Figure 7 LS means and 90% CIs for active and placebo treatment groups are based on linear mixed-effects models:

[0603] ●ΔQTcF = time + treatment + time × treatment + baseline QTcF + cycle + sequence.

[0604] • An unstructured covariance structure was used to specify repeated measures of subjects at post-dose time points within the treatment period. The model also included subject-specific random effects.

[0605] exist Figure 5 In the data, the upper limit of the 90% CI for ΔΔQTcF was <10 ms for both deuterated domperidone doses at all time points, indicating that an effect on ΔΔQTcF exceeding 10 ms could be excluded at both deuterated domperidone doses. Moxifloxacin caused significant QTc interval prolongation.

[0606] (ii) An analysis was also performed to understand the time-independent relationship between deuterated domperidone plasma concentration and ΔΔQTcF. Based on this concentration-QTc analysis, an effect on ΔΔQTcF exceeding 10 ms could be excluded at deuterated domperidone plasma concentrations up to ∼92 ng / mL, which is approximately 5 times the therapeutic steady-state concentration ( Figure 8 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.

[0607] exist Figure 8 In the figure, the solid black line with the gray shaded area represents the model-predicted mean ΔΔQTcF (90% CI), which is calculated from the equation ΔΔQTcF = -0.02844 (ms) + 0.7918 (ms per ng / mL) × deuterated domperidone concentration (ng / mL). The vertical blue line (far left) and red line (far right) represent the estimated mean ΔΔQTcF (90% CI), and the plotted points are located at the geometric mean C of deuterated domperidone max Place.

[0608] The same linear model was used for moxifloxacin. The slope of the relationship was positive and statistically significant. The lower limit of the two-sided CI predicting the QT effect at the geometric mean peak concentration of moxifloxacin was >5 ms, indicating the sensitivity of the assay.

[0609] (iii) A similar analysis was also performed to understand the relationship between the plasma concentration of the major metabolite (M3) and ΔΔQTcF. The results of this analysis showed that at M3 plasma concentrations up to 480 ng / mL, an effect of more than 10 ms on ΔΔQTcF could be excluded. For the 30 mg and 100 mg treatment groups, 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), respectively.

[0610] exist Figure 7 In the figure, the solid black line with the gray shaded area represents the model-predicted mean ΔΔQTcF (90% CI), which is calculated from the equation ΔΔQTcF = 0.3678 (ms) + 0.1439 (ms per ng / mL) × M3 concentration (ng / mL). Therefore, the estimated population slope of the concentration-QTc relationship is very shallow: 0.14 ms per ng / mL (90% CI: 0.08 to 0.20), and the treatment effect-specific intercept is small, 0.37 ms (90% CI: -0.16 to 0.89) ( Figure 6 and Figure 7 ).

[0611] The vertical blue (far left) and red (far right) lines represent the estimated mean ΔΔQTcF (90% CI), with the plotted points located at the geometric mean C of M3. max Place.

[0612] (iv) Effect of the doses of deuterated domperidone studied on heart rate ( Figure 8 There were no clinically relevant effects on cardiac conduction (i.e., PR and QRS intervals).

[0613] Baseline ECG parameters were within the expected range for a healthy population across treatment groups, with mean HR ranging from 59.9 to 61.0 bpm, mean QTcF ranging from 404.0 to 406.1 ms, mean PR ranging from 152.3 to 153.7 ms, and mean QRS ranging from 103.0 to 103.7 ms.

[0614] The LS mean HR change from baseline (ΔHR) for CIN-102 closely followed the pattern observed for placebo ( Figure 4During CIN-102 treatment, the LS mean placebo-corrected ΔHR (ΔΔHR) at post-dose time points ranged from ±1.4 bpm, from -1.4 to 1.1 bpm (at 3 and 24 hours post-dose, respectively, both in the 30 mg treatment group) ( Fig. 9 and Table 21). There was 1 case of bradycardia during the treatment period (5 time points in the 30 mg treatment group) and no abnormal values ​​for tachycardia.

[0615] Table 21: Placebo-corrected HR change from baseline (ΔΔHR) at each time point (QT / QTc population)

[0616]

[0617]

[0618]

[0619] Linear mixed effects model based on active drug and placebo treatment groups: ΔHR = time + treatment + time × treatment + baseline HR + period + sequence. An unstructured covariance structure was used to specify repeated measurements of subjects at post-dose time points within the treatment period. The model also included subject-specific random effects.

[0620] Treatment A: 30 mg CIN-102 [representing the approximate steady-state therapeutic exposure in the subject population]; Treatment B: 100 mg CIN-1002 [representing the potential steady-state supratherapeutic exposure in the subject population); Treatment C: 400 mg open-label moxifloxacin

[0621] The same linear model with treatment effect-specific intercept as in the concentration-QTc analysis was used in the assay sensitivity analysis for moxifloxacin. The slope of the relationship was positive and statistically significant: 0.07 ms per ng / mL (90% CI: 0.06 to 0.09), and the lower limit of the two-sided CI predicting QT effect (12.98 ms [90% CI: 11.43 to 14.52]) was above 5 ms at the geometric mean peak concentration of moxifloxacin (1552.6 ng / mL), demonstrating the sensitivity of the assay.

[0622] Effects on cardiac repolarization: QT interval (a) Results by time point (central tendency) and category

[0623] The LS mean QTcF change from baseline (ΔQTcF) for CIN-102 followed the pattern of placebo at postdose time points, with a slightly greater effect in the highest treatment group (100 mg CIN-102) between 3 and 6 hours postdose ( Figure 5LS mean placebo-corrected ΔQTcF (ΔΔQTcF) within the first 4 hours after CIN-102 ranged from -0.3 to 1.8 ms at 0.5 and 2 hours post-dose in the 30 mg treatment group and from -0.1 to 3.7 ms at 0.5 and 3 hours post-dose in the 100 mg treatment group ( Fig.11 and Table 22). The upper limit of the 90% CI for ΔΔQTcF was below 10 ms at both CIN-102 doses at all time points.

[0624] Following administration of 400 mg oral moxifloxacin, a significant increase in LS mean ΔΔQTcF was observed, peaking at 13.3 ms (90% CI: 11.52 to 15.00) at 3 hours post-dose.

[0625] No subject had a QTcF>480 ms or a ΔQTcF>30 ms (Tables 23 and 24). During moxifloxacin and placebo treatment, 6 and 1 subjects in the treatment groups (at 19 and 1 time points), respectively, had a QTcF>450 and ≤480 ms. The following changes in T-wave morphology were observed during treatment: 2 subjects (at 2 time points) had a flat T wave during the 100 mg treatment period; 1 to 2 subjects (at 1 to 7 time points) had a biphasic T wave during all treatment periods; and 1 subject each (at 10 and 1 time points) had an inverted T wave during the 30 mg and moxifloxacin treatment periods. No U waves occurred during treatment.

[0626] Table 22: Placebo-corrected change from baseline in QTcF (ΔΔQTcF) at each time point (QT / QTc population)

[0627]

[0628]

[0629] Linear mixed effects model based on active and placebo treatment groups: ΔQTcF = time + treatment + time × treatment + baseline QTcF + cycle + sequence. An unstructured covariance structure was used to specify repeated measurements of subjects at post-dose time points within the treatment cycle. The model also included subject-specific random effects. Treatment A: 30 mg CIN-102 [representing the approximate steady-state therapeutic exposure in the subject population]; Treatment B: 100 mg CIN-1002 [representing the potential steady-state supratherapeutic exposure in the subject); Treatment C: 400 mg open-label moxifloxacin.

[0630] Table 23: QTcF outliers by absolute category (QT / QTc population)

[0631]

[0632] Treatment A: 30 mg CIN-102 [representing the approximate steady-state therapeutic exposure in the subject population]; Treatment B: 100 mg CIN-1002 [representing the potential steady-state supratherapeutic exposure in the subject); Treatment C: 400 mg open-label moxifloxacin; Treatment D: CIN-102 placebo. Subjects may appear in more than 1 category. The denominator (total) is defined as the number of subjects or time points in the QT / QTc population for each treatment.

[0633] Table 24: QTcF Outliers by Category Change from Baseline (QT / QTc Population)

[0634]

[0635]

[0636] Treatment A: 30 mg CIN-102 [representing the approximate steady-state therapeutic exposure in the subject population]; Treatment B: 100 mg CIN-1002 [representing the potential steady-state supratherapeutic exposure in the subject); Treatment C: 400 mg open-label moxifloxacin; Treatment D: CIN-102 placebo. Subjects may appear in more than 1 category. The denominator (total) is defined as the number of subjects or time points in the QT / QTc population for each treatment.

[0637] (b) Concentration-QTc results

[0638] Pharmacokinetic properties

[0639] The time course of plasma concentrations of deuterated domperidone and its metabolite M3 is shown in Fig.12 and Fig.13 For the 30 and 100 mg treatment groups, the highest mean plasma concentrations of deuterated domperidone were observed at 1.5 and 2 hours after dosing, respectively. For the 30 and 100 mg treatment groups, the highest mean plasma concentrations of M3 were observed at 2 hours after dosing, respectively.

[0640] Evaluation of the model independence assumption

[0641] The following model independence checks of the assumptions were performed using exploration plots.

[0642] Heart rate impact

[0643] In the time-point analysis, the mean ΔΔHR was below 10 bpm at both CIN-102 dose levels at all post-dose time points ( Fig. 9 and Table 21), thus demonstrating that CIN-102 had no relevant effect on HR.

[0644] Linear concentration-QTc relationship

[0645] exist Fig.14 and Fig.10 A scatter plot of deuterated domperidone and M3 concentration versus ΔQTcF with linear regression lines and LOESS regression lines (90% CI) is given in Figure . For deuterated domperidone, the linear regression line and LOESS regression line are close in all observed concentration ranges, with a slight deviation at high concentrations. This indicates that the linear model of the concentration-QTc relationship can appropriately capture the observed data.

[0646] Table 25 and Fig.21 The effects of ΔΔQTcF predicted using Model C at geometric mean concentrations of M3 are shown in . At plasma concentrations of M3 up to -480 ng / mL, effects on ΔΔQTcF exceeding 10 ms could be excluded.

[0647] Table 25: ΔΔQTcF intervals predicted by Model C at geometric mean peak CIN-102M3 (ng / mL) concentrations (PK / QTc population)

[0648]

[0649] Based on a linear mixed effects model, ΔQTcF was used as the dependent variable, time-matched deuterated domperidone plasma concentrations as the explanatory variable, central baseline QTcF as an additional covariate, treatment (active drug = 1 or placebo = 0) and time as fixed effects, and a random intercept and slope for each subject.

[0650] Concentration-QTc model for Model B (Domperidone-deuterated)

[0651] Fig.15 The relationship between the individually observed plasma concentrations of deuterated domperidone and the estimated placebo-adjusted ΔQTcF (ie, ΔΔQTcF) is shown in FIG.

[0652] Table 26 and Figure 8 The predicted effects of ΔΔQTcF using Model B at deuterated domperidone geometric mean concentrations are shown in . At deuterated domperidone plasma concentrations up to -92 ng / mL, effects on ΔΔQTcF exceeding 10 ms could be excluded.

[0653] Table 26: ΔΔQTcF intervals predicted by model B at geometric mean peak deuterated domperidone concentrations (PK / QTc population)

[0654]

[0655]

[0656] Based on a linear mixed effects model, ΔQTcF was used as the dependent variable, time-matched deuterated domperidone plasma concentrations as the explanatory variable, central baseline QTcF as an additional covariate, treatment (active drug = 1 or placebo = 0) and time as fixed effects, and a random intercept and slope for each subject.

[0657] Effects on cardiac conduction: PR and QRS intervals

[0658] CIN-102 had no clinically relevant effects on cardiac conduction (i.e., PR and QRS intervals) at the doses studied. The change from baseline in LS mean PR (ΔPR) on CIN-102 closely followed the pattern observed in placebo subjects ( Fig.17 During the 30 mg and 100 mg treatment periods, the LS mean placebo-corrected ΔPR (ΔΔPR) on CIN-102 varied between ±2.3 ms and -2.3 to 1.3 (24 and 8 hours after dosing, respectively). Fig.18 and Table 27). The LS mean QRS change from baseline (ΔQRS) was small ( Fig.19 ), and at all post-dose time points, the LS mean placebo-corrected ΔQRS (△△QRS) was within ±1.1 ms ( Fig. 20 and Table 28). There were no abnormal PR or QRS values.

[0659] Table 27: Placebo-corrected change from baseline in PR at each time point (ΔΔPR) (QT / QTc population)

[0660]

[0661]

[0662]

[0663] Linear mixed effects model based on active and placebo treatment groups: ΔPR = time + treatment + time × treatment + baseline PR + period + order. An unstructured covariance structure was used to specify repeated measurements of subjects at post-dose time points within the treatment period. The model also included subject-specific random effects. Treatment A: 30 mg CIN-102 [representing the approximate steady-state therapeutic exposure in the subject population]; Treatment B: 100 mg CIN-1002 [representing the potential steady-state supratherapeutic exposure in the subject); Treatment C: 400 mg open-label moxifloxacin.

[0664] Table 28: Placebo-corrected change from baseline in ΔQRS at each time point (ΔΔQRS) (QT / QTc population)

[0665]

[0666]

[0667] Linear mixed effects model based on active and placebo treatment groups: ΔQRS = time + treatment + time × treatment + baseline QRS + cycle + sequence. An unstructured covariance structure was used to specify repeated measurements of subjects at post-dose time points within the treatment period. The model also included subject-specific random effects. Treatment A: 30 mg CIN-102 [representing the approximate steady-state therapeutic exposure in the subject population]; Treatment B: 100 mg CIN-1002 [representing the potential steady-state supratherapeutic exposure in the subject); Treatment C: 400 mg open-label moxifloxacin.

[0668] Discussion and Conclusion

[0669] This is 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 this study is to evaluate the effect of CIN-102 on cardiac repolarization based on baseline and placebo-corrected change in QTcF. In each cycle, 12-lead ECGs paired with PK sampling were extracted at 3 time points before and after dosing.

[0670] At baseline, data were available from all 55 subjects in the placebo treatment period, then data were available from 52 subjects in the CIN-102 treatment (30 mg) and supratherapeutic (100 mg) treatment periods, and data were available from 51 subjects in the moxifloxacin treatment period.

[0671] CIN-102 had no clinically relevant effects on heart rate or cardiac conduction (ie, PR and QRS intervals) at the doses studied.

[0672] The highest mean plasma concentrations of deuterated domperidone were observed at 1.5 hours and 2 hours post-dose for the 30 mg 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.

[0673] The LS mean ΔΔQTcF was small at both CIN-102 doses and varied within a narrow range during the first 4 h after dosing: between -0.3 and 1.8 ms at 0.5 and 2 h after dosing in the 30 mg treatment group, and between -0.1 and 3.7 ms at 0.5 and 3 h after dosing in the 100 mg treatment group. Of note, the upper limit of the 90% CI for ΔΔQTcF was below 10 ms at both CIN-102 doses at all time points, indicating that an effect on ΔΔQTcF exceeding 10 ms could be excluded at both CIN-1002 doses.

[0674] In the concentration-QTc analysis, a complete model including deuterated domperidone and its metabolite M3 was first fitted and a model selection procedure was performed. Due to the smallest AIC value, the model using only M3 (Model C) was selected as the primary model and represented the data in an acceptable manner. The estimated slope of the M3 plasma concentration in the concentration-QTc relationship was positive and statistically significant (0.14ms per ng / mL [90% CI: 0.08 to 0.20]), and the treatment effect-specific intercept was small and statistically insignificant at 0.37ms. For the 30mg and 100mg treatment groups, the effects on ΔΔQTcF were predicted to be 1.43ms (90% CI: 0.90 to 1.96) and 3.58ms (90% CI: 2.34 to 4.83), respectively.

[0675] The results of the QTc model using deuterated domperidone alone (Model B) were similar to those of the primary model. The estimated slope of the deuterated domperidone plasma concentration in the concentration-QTc relationship was positive and statistically significant (0.79 ms per ng / mL [90% CI: 0.47 to 1.11]), and the treatment effect-specific intercept was small and statistically insignificant at -0.03 ms. For the 30 mg and 100 mg treatment groups, the effects on ΔΔQTcF were predicted to be 1.10 ms (90% CI: 0.58 to 1.61) and 3.50 ms (90% CI: 2.18 to 4.82), respectively.

[0676] Based on this concentration-QTc analysis, a QTcF effect exceeding 10 ms (ΔΔQTcF) could be excluded when deuterated domperidone and M3 plasma concentrations were as high as ∼92 and 480 ng / mL, respectively.

[0677] The same linear model with treatment effect-specific intercept as in the concentration-QTc analysis was used in the assay sensitivity analysis for moxifloxacin. The slope of the relationship was positive and statistically significant: 0.07 ms per ng / mL (90% CI: 0.06 to 0.09), and the lower limit of the two-sided CI predicting QT effect (12.98 ms [90% CI: 11.43 to 14.52]) was above 5 ms at the geometric mean peak concentration of moxifloxacin (1552.6 ng / mL), demonstrating the sensitivity of the assay.

[0678] In conclusion, the doses of CIN-102 studied had no clinically relevant effects on the ECG parameters studied. Based on the concentration-QTc analysis, an effect on ΔΔQTcF exceeding 10 ms could be excluded when deuterated domperidone and M3 plasma concentrations were as high as ∼92 and 480 ng / mL, respectively.

[0679] In conclusion, the results of this negative TQT study suggest that when deuterated domperidone and M3 are administered at concentrations higher than those produced by the highest current therapeutic dose (10 mg BID) in patients with gastroparesis, which has a mean C of deuterated domperidone of approximately 18.2 ng / mL, the max Small QT effects can be excluded when the dose is approximately 5-fold higher than the baseline dose. CIN-102 had no clinically relevant effects on heart rate or cardiac conduction. No deaths or serious adverse events occurred during the study. Therapeutic and supratherapeutic doses of deuterated domperidone had no clinically meaningful effects on ECG parameters, including the QT interval.

[0680] It should be understood that, although the present invention has been described in conjunction with the preferred specific embodiments of the present invention, the above description and embodiments are intended to illustrate rather than limit the scope of the present invention. It will be appreciated by those skilled in the art that, without departing from the scope of the present invention, various changes may be made and may be replaced with equivalents, and in addition, other aspects, advantages and modifications will be apparent to those skilled in the art to which the present invention belongs. In addition to the embodiments described herein, the present invention also contemplates and claims those inventions produced by the combination of the features of the present invention cited herein and the features of the prior art references cited to supplement the features of the present invention. Similarly, it should be understood that any described material, feature or article may be used in combination with any other material, feature or article, and such combinations are considered to be within the scope of the present invention.

[0681] The disclosures of each patent, patent application, and publication cited or described in this document are incorporated herein by reference in their entirety for all purposes.

Claims

1. A method of increasing gastric emptying in a human suffering from gastroparesis, the method comprising orally administering to the human 10 mg to 120 mg of deuterated domperidone per day.

2. The method of claim 1, wherein the gastroparesis is idiopathic gastroparesis or diabetic gastroparesis.

3. The method of claim 1 or 2, wherein the human is experiencing upper gastrointestinal symptoms prior to said administering.

4. The method of claim 3, wherein the upper gastrointestinal symptom is postprandial nausea, postprandial vomiting, postprandial fullness, early satiety, abdominal distension, upper abdominal pain, abdominal pain, or a combination thereof.

5. The method of claim 3, wherein the upper gastrointestinal symptom is nausea, vomiting, postprandial fullness, early satiety, abdominal distension, upper abdominal pain, abdominal pain, or a combination thereof.

6. The method of any of the preceding claims, wherein the increase in gastric emptying is measured by a gastric emptying breath test (GEBT) about 12 to about 14 days after administration of the deuterated domperidone, as measured by using 13 C- measured by gastric emptying breath test (GEBT) of Spirulina platensis.

7. The method of any one of the preceding claims, wherein the human has delayed gastric emptying for about 10 days prior to the first dose of deuterated domperidone, as determined by administration of 13 C- measured by gastric emptying breath test (GEBT) of Spirulina platensis.

8. The method of any one of the preceding claims, wherein prior to administration of the deuterated domperidone, the human has a T of greater than about 80 minutes, or such as greater than about 200 minutes. 1 / 2, this is done by using 13 C- measured by gastric emptying breath test (GEBT) of Spirulina platensis.

9. The method of any one of the preceding claims, wherein prior to administration of the deuterated domperidone, the human has an American Neurogastroenterology and Motor Society Gastroparesis Cardinal Symptom Index Daily Diary (ANMSGCSI-DD) mean composite score of 2 or greater.

10. The method of any one of the preceding claims, wherein the human has an ANMS GCSI-DD nausea subscale score of about 2 or greater for at least about 4 days prior to administration of the deuterated domperidone.

11. The method of any one of the preceding claims, wherein about 10 mg, or about 20 mg, or about 30 mg, or about 60 mg, or about 120 mg of deuterated domperidone is administered to the human.

12. A method according to any one of the preceding claims, wherein the deuterated domperidone is administered in divided doses, such as two doses.

13. The method according to any one of the preceding claims, wherein the human is an adult.

14. The method of any one of the preceding claims, wherein the administration results in clinically significant improvement in nausea, early satiety, postprandial fullness, epigastric pain, vomiting, and abdominal distension as measured by post-treatment ANMS GCSI-DD scores.

15. The method of any one of the preceding claims, wherein the administration results in a clinically significant improvement in the mean composite score of the ANMS GCSI-DD score after treatment.

16. The method according to any one of the preceding claims, wherein the administration results in a clinically significant improvement in the nausea subscale score of the ANMS GCSI-DD score after treatment.

17. The method of any one of the preceding claims, wherein the administration results in a clinically significant improvement in gastric emptying as measured by GEBT after about 12 days to about 16 days following treatment.

18. The method of any one of the preceding claims, wherein the administration results in a clinically significant improvement in gastric emptying as measured by the post-treatment ANMS GCSI-DD total score.

19. The method of any one of the preceding claims, wherein the administration results in a clinically significant improvement in gastric emptying as measured by post-treatment ANMS GCSI-DD subscale score.

20. The method of any one of the preceding claims, wherein the human suffers from diabetic neuropathy.

21. The method of any one of the preceding claims, wherein prior to administration of the deuterated domperidone, the human has a T of greater than about 110 minutes. 1 / 2.

22. The method of any one of the preceding claims, wherein prior to administration of the deuterated domperidone, the human has a T of less than about 110 minutes. 1 / 2.

23. The method of any one of the preceding claims, wherein administration of the deuterated domperidone does not result in clinically significant QT interval prolongation.

24. The method of any of the preceding claims, wherein the administration does not result in a clinically significant change in the patient's heart rate.

25. The method of any of the preceding claims, wherein the administration does not result in clinically significant changes in cardiac conduction in the patient.

26. The method of any one of the preceding claims, wherein following administration of the deuterated domperidone, the patient's pulse rate (PR) interval is from about 0.12 seconds to about 0.2 seconds.

27. The method of any one of the preceding claims, wherein following administration of the deuterated domperidone, the patient's QRS interval is between about 0.08 seconds and 0.10 seconds.

28. The method of any one of the preceding claims, wherein the administration results in a ΔΔQTcF of less than about 10 ms.

29. The method of claim 28, wherein the amount of deuterated domperidone is about 30 mg and the administering results in a ΔΔQTcF of about 1.1 ms or less.

30. The method of claim 29, wherein the amount of deuterated domperidone is about 100 mg and the administering results in a ΔΔQTcF of about 3.5 ms or less.

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