Methods for treating diabetic gastroparesis

Abstract

The present disclosure provides methods for treating diabetic gastroparesis.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 491,823, filed on March 23, 2023, the disclosure of which is incorporated herein by reference. Technical Field

[0003] The present disclosure provides methods for treating diabetic gastroparesis. Background Art

[0004] Gastroparesis is defined as impaired gastric emptying in the absence of mechanical gastric outlet obstruction. Symptoms include early satiety, postprandial fullness, nausea, vomiting, and abdominal pain. The condition is often associated with diabetes and may occur after gastric surgery; it may also be idiopathic. Gastroparesis affects a patient's nutritional status, particularly in patients with diabetes, where severe symptoms can lead to other complications such as malnutrition, esophagitis, and Mallory-Weiss tears. Gastroparesis negatively impacts a patient's quality of life, leading to decreased social interaction, reduced work ability, and the development of anxiety or depression.

[0005] First-line treatment for gastroparesis includes nutritional management and support, including fluid and electrolyte replacement. Medical therapy aims to increase gastric emptying and accelerate intestinal transit time. Currently, metoclopramide, a dopamine D2 receptor antagonist, is the only drug approved by the US Food and Drug Administration (FDA) for the treatment of gastroparesis. Although effective, this drug readily crosses the blood-brain barrier, resulting in central nervous system (CNS) side effects in up to 40% of patients. Common CNS effects associated with metoclopramide treatment include irritability, somnolence, fatigue, and lethargy; however, the major safety concern with metoclopramide treatment is the development of tardive dyskinesia. Tardive dyskinesia is a condition characterized by involuntary movements of the face, tongue, or limbs that are generally irreversible. The risk of developing tardive dyskinesia increases with treatment duration; therefore, metoclopramide treatment is recommended to not exceed 12 weeks.

[0006] New approaches for treating diabetic gastroparesis are needed. Summary of the Invention

[0007] In some embodiments, the present disclosure provides methods of treating a human diagnosed with diabetic gastroparesis comprising administering a dosage form comprising 10 mg or 15 mg deuterated domperidone twice daily (BID), wherein the administration reduces the severity of gastroparesis-related symptoms in the human compared to baseline. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Figure 1The study protocol for Example 3. Pharmacokinetic (PK) Subgroup Analysis: Approximately 30 subjects in PK Subgroup A will be evaluated for emerging PK and safety data after Visit 5. Interim Analysis (IA): One unblinded IA will be conducted during the study once approximately 50% of the randomized subjects have completed the End of Treatment (EOT) visit or prematurely discontinue. DETAILED DESCRIPTION

[0009] In this disclosure, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a material" refers to at least one such material and equivalents thereof known to those skilled in the art, and so forth.

[0010] When a value is expressed as an approximation using the descriptor "about," it is understood that the particular value constitutes an additional embodiment. In general, the term "about" is used herein to describe approximations which can vary depending on the desired properties of the disclosed subject matter, and should be construed based on the function to be performed in the particular context of use. Those skilled in the art will be able to interpret this in the light of the general level of the art. In some cases, the number of significant digits used in a numerical value can be a non-limiting method of determining the range of values that the term "about" refers to. In other cases, the use of a gradient of values can be used to determine the range of values that the term "about" refers to for each value. Where present, all ranges include the end values and can be combined. That is, a recitation of a value range includes each value within the range.

[0011] When a list is presented, unless otherwise specified, each individual element of the list and every combination of the list should be construed as a separate embodiment. For example, a list of embodiments presented as "A, B, or C" should be construed as including the embodiments of "A," "B," "C," "A or B," "A or C," "B or C," or "A, B, or C."

[0012] The terms "subject" and "patient" are used interchangeably and generally refer to a mammal. In some embodiments, the patient or subject is a human. In other embodiments, the patient or subject is a veterinary animal or a farm animal, a livestock or a pet, or an animal used for conducting clinical studies.

[0013] "Treat," or variants thereof, means to alleviate or eliminate at least one physical parameter of a disease or condition.

[0014] As referred to herein, "deuterated pipamperone" and "d4-pipamperone" are interchangeable and refer to 1-{3-[4-(5-chloro-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidin-1-yl]propyl}-2,3-dihydro(4,5,6,7-D4)-1H-1,3-benzodiazol-2-one, which has the following structure:

[0015]

[0016] Any reference to deuterated pipamperone can also include (where noted) pharmaceutically acceptable salts, esters, hydrates, solvates, prodrug forms, and derivatives thereof, which are broadly defined as modified or partially substituted deuterated pipamperone compounds, examples including but not limited to addition of single atoms, addition of reactive groups, addition of functional groups, formation of dimers or multimers, conjugation to another molecule such as an antibody, and the like.

[0017] "Pharmaceutically acceptable" refers to properties / substances that are acceptable to the patient from a pharmacological / toxicological perspective, and properties / substances that are acceptable to a pharmaceutical chemist from a physical / chemical perspective in the manufacture, formulation, stability, patient acceptance, and bioavailability of the composition.

[0018] Pharmaceutically acceptable salts include salts formed with pharmaceutically acceptable acids or bases, for example, inorganic acids such as hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic, hydroiodic, and nitric acids; and organic acids such as citric, fumaric, maleic, malic, mandelic, ascorbic, oxalic, succinic, tartaric, benzoic, acetic, methanesulfonic, ethanesulfonic, benzenesulfonic, cyclohexylsulfamic (cyclamic) or p-toluenesulfonic acid. Pharmaceutically acceptable bases include hydroxides of alkali metals such as sodium or potassium and alkaline earth metals such as calcium or magnesium, and organic bases such as alkyl amines, aralkyl amines, and heterocyclic amines.

[0019] As used herein, the abbreviation "D" refers to the stable isotope of hydrogen, deuterium (heavy hydrogen or 2H). Such "D" examples include amounts of deuterium above the naturally occurring distribution of deuterium. In some embodiments, the deuterium enrichment of D is no less than about 1%. In other embodiments, the deuterium enrichment of D is no less than about 5%. In further embodiments, the deuterium enrichment of D is no less than about 10%. In other embodiments, the deuterium enrichment of D is no less than about 20%. In other embodiments, the deuterium enrichment of D is no less than about 30%. In other embodiments, the deuterium enrichment of D is no less than about 40%. In further embodiments, the deuterium enrichment of D is no less than about 50%. In other embodiments, the deuterium enrichment of D is no less than about 60%. In other embodiments, the deuterium enrichment of D is no less than about 70%. In further embodiments, the deuterium enrichment of D is no less than about 80%. In other embodiments, the deuterium enrichment of D is no less than about 90%. In further embodiments, the deuterium enrichment of D is no less than about 98%. In further embodiments, the deuterium enrichment of D is no less than about 99%. In further embodiments, the deuterium enrichment of D is at least 99%.

[0020] As used herein, "baseline" refers to the score or average score of a human on a particular measurement indicator as described herein prior to administration of any deuterated droperidol. The baseline can be established, for example, immediately prior to deuterated droperidol administration, or up to about 7 days or up to about 14 days prior to deuterated droperidol administration. For example, the baseline can be established about 30 minutes prior to first administration of deuterated droperidol. In other aspects, the baseline can be established 1 day prior to first administration of deuterated droperidol. In other aspects, the baseline can be established 2 days prior to first administration of deuterated droperidol. In other aspects, the baseline can be established 3 days prior to first administration of deuterated droperidol. In other aspects, the baseline can be established 4 days prior to first administration of deuterated droperidol. In other aspects, the baseline can be established 5 days prior to first administration of deuterated droperidol. In other aspects, the baseline can be established 6 days prior to first administration of deuterated droperidol. In other aspects, the baseline can be established 7 days prior to first administration of deuterated droperidol. In other aspects, the baseline can be established 8 days prior to first administration of deuterated droperidol. In other aspects, the baseline can be established 9 days prior to first administration of deuterated droperidol. In other aspects, the baseline can be established 10 days prior to first administration of deuterated droperidol. In other aspects, the baseline can be established 11 days prior to first administration of deuterated droperidol. In other aspects, the baseline can be established 12 days prior to first administration of deuterated droperidol. In other aspects, the baseline can be established 13 days prior to first administration of deuterated droperidol. In other aspects, the baseline can be established 14 days prior to first administration of deuterated droperidol.

[0021] The present disclosure provides methods of treating a human diagnosed with diabetic gastroparesis. As used herein, the term "diabetic gastroparesis" refers to a human having diabetes and gastroparesis. In some embodiments, the human has type 1 diabetes. In other embodiments, the human has type 2 diabetes. As used herein, the term "gastroparesis" refers to a condition in which delayed gastric emptying occurs without mechanical obstruction of the gastric outlet.

[0022] The methods include administering to the human a dosage form comprising 10 mg or 15 mg of deuterated domperidone twice daily. In some embodiments, 20 mg of deuterated domperidone is administered to the human. In other embodiments, 30 mg of deuterated domperidone is administered to the human. For example, deuterated domperidone free base is administered to the human.

[0023] Deuterated domperidone can be administered as needed to achieve a desired daily dose. For example, deuterated domperidone can be administered in divided doses. In some embodiments, deuterated domperidone is administered twice daily (BID). In further embodiments, a 20 mg dose of deuterated domperidone is administered as 10 mg twice daily. In other embodiments, a 30 mg dose of deuterated domperidone is administered as 15 mg twice daily. In further embodiments, a 20 mg dose of deuterated domperidone is administered as 20 mg twice daily, i.e., a single 10 mg deuterated domperidone capsule is taken twice daily. In other embodiments, a 30 mg dose of deuterated domperidone is administered as 15 mg twice daily, i.e., a single 10 mg capsule and a single 5 mg capsule are taken twice daily.

[0024] Deuterated domperidone can be formulated into a dosage form (e.g., a solid form) for administration. In some embodiments, the pharmaceutical formulation is formulated in the form of a tablet, a caplet, a capsule, a powder, a softgel, or a combination thereof. In other embodiments, the pharmaceutical formulation is formulated in the form of a tablet. In further embodiments, the pharmaceutical formulation is formulated in the form of a caplet. In other embodiments, the pharmaceutical formulation is formulated in the form of a capsule. In further embodiments, the pharmaceutical formulation is formulated in the form of a powder. In other embodiments, the pharmaceutical formulation is formulated in the form of a softgel. In further embodiments, the dosage form is a single capsule comprising 10 mg of deuterated domperidone. In other embodiments, the dosage form is a single capsule comprising 5 mg of deuterated domperidone and a single capsule comprising 10 mg of deuterated domperidone.

[0025] The dosage form (e.g., capsule) comprises one or more of the following ingredients: (i) medium chain triglyceride, (ii) glyceryl distearate, (iii) butylated hydroxyanisole, and (iv) butylated hydroxytoluene. In some embodiments, the dosage form comprises glyceryl distearate. As used herein, the term "glyceryl distearate" refers to a compound having a glyceryl group and two stearate components, as shown below, wherein the components are bound together to form a chemically stable molecule.

[0026]

[0027] In certain aspects, the glyceryl distearate is 1,3-glyceryl distearate. In further aspects, the capsule comprises 9.75 mg of glyceryl distearate.

[0028] In other embodiments, the dosage form (e.g., capsule) comprises a medium chain triglyceride. As used herein, the term "medium chain triglyceride" refers to a triglyceride having a fatty acid moiety with an aliphatic chain of about 6 to about 12 carbon atoms. In some aspects, the fatty acid moiety has an aliphatic chain of 6, 7, 8, 9, 10, 11, or 12 carbon atoms. In further aspects, the fatty acid aliphatic chains are the same. In other aspects, the fatty acid aliphatic chains are different. In further aspects, the fatty acid has an aliphatic chain of 6 carbon atoms, i.e., the medium chain triglyceride is caproic acid. In other aspects, the fatty acid has an aliphatic chain of about 8 carbon atoms, i.e., the medium chain triglyceride is caprylic acid. In other aspects, the fatty acid has an aliphatic chain of about 10 carbon atoms, i.e., the medium chain triglyceride is capric acid. In further aspects, the fatty acid has an aliphatic chain of about 12 carbon atoms, i.e., the medium chain triglyceride is lauric acid. In other aspects, the capsule comprises 85.1 mg of medium chain triglyceride. In further aspects, the capsule comprises 80.1 mg of medium chain triglyceride.

[0029] In further embodiments, the dosage form (e.g., capsule) comprises one or more antioxidants. In some aspects, the dosage form comprises butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), or a combination thereof. In other aspects, the antioxidant is BHA. In further embodiments, the antioxidant is BHT. In further aspects, the antioxidant is BHA and BHT. In further aspects, the capsule comprises 0.05 mg of butylated hydroxytoluene. In other aspects, the capsule comprises 0.10 mg of butylated hydroxyanisole. In further aspects, the capsule comprises 0.1 mg of butylated hydroxyanisole and 0.05 mg of butylated hydroxytoluene.

[0030] In certain embodiments, the capsule comprises one or more of the following ingredients: (i) 85.1 mg medium chain triglycerides, (ii) 9.75 mg glycerol distearate, (iii) 0.1 mg butylated hydroxyanisole, and (iv) 0.05 mg butylated hydroxytoluene. In other embodiments, the capsule comprises (i) 85.1 mg medium chain triglycerides, (ii) 9.75 mg glycerol distearate, (iii) 0.1 mg butylated hydroxyanisole, and (iv) 0.05 mg butylated hydroxytoluene. In further embodiments, the capsule comprises one or more of the following ingredients: (i) 80.1 mg medium chain triglycerides, (ii) 9.75 mg glycerol distearate, (iii) 0.1 mg butylated hydroxyanisole, and (iv) 0.05 mg butylated hydroxytoluene. In other embodiments, the capsule comprises (i) 80.1 mg medium chain triglycerides, (ii) 9.75 mg glycerol distearate, (iii) 0.1 mg butylated hydroxyanisole, and (iv) 0.05 mg butylated hydroxytoluene.

[0031] Prior to administration of the deuterated domperidone, the patient has an ANMS GCSI-DD weekly average score of >2 on the nausea subscale. In some embodiments, the patient has an ANMS GCSI-DD weekly average score of 2, 3, or 4 on the nausea subscale. In other embodiments, the patient has an ANMS GCSI-DD score of >2 on the nausea subscale for at least about 14 days prior to administration of the deuterated domperidone.

[0032] Prior to administration of the deuterated domperidone, the patient has an average of at least 1 episode of emesis per week. As used herein, the term “emesis” refers to the expulsion of gastrointestinal contents through the mouth due to contraction of the intestinal and chest abdominal wall muscles. In some embodiments, the patient has an average of at least 1 episode of emesis of any severity per week. In other embodiments, the patient has an average of at least 1, 2, 3, 4, or 5 episodes of emesis per week prior to administration of the deuterated domperidone.

[0033] A person skilled in the art will be able to calculate / determine the ANMS GCSI-DD score. See, e.g., ANMS GCSI-DD User Manual, American Neurogastroenterology and Motility Society Gastroparesis Cardinal Symptom Index-Daytime Version, 2018; https: / / www.fda.gov / media / 125038 / download. The ANMS GCSI-DD manual scoring method generates by summing the scores for the symptom items (e.g., nausea, early satiety, postprandial fullness, epigastric pain, and frequency of vomiting episodes), and then dividing by 5 (i.e., the number of items within the Gastroparesis-Related Symptom Score). Thus, the maximum total symptom score can be (5 symptoms x highest score of 4 / 5); thus, the maximum score is 20 / 5 = 4. A high score on the ANMS GCSI-DD reflects more severe symptoms. See, e.g., ANMS GCSI-DD User Manual, U.S. Food and Drug Administration, at https: / / www.fda.gov / media / 125038 / download, the contents of which are hereby incorporated by reference herein.

[0034] Ideally, the administration reduces the severity of the person’s gastroparesis-related symptoms compared to baseline. The gastroparesis-related symptoms include one or more of postprandial nausea, postprandial vomiting, postprandial fullness, early satiety, abdominal distension, epigastric pain, or abdominal pain. In some embodiments, the gastroparesis-related symptom is postprandial nausea. In other embodiments, the gastroparesis-related symptom is postprandial vomiting. In further embodiments, the gastroparesis-related symptom is postprandial fullness. In other embodiments, the gastroparesis-related symptom is early satiety. In further embodiments, the gastroparesis-related symptom is abdominal distension. In other embodiments, the gastroparesis-related symptom is epigastric pain. In further embodiments, the gastroparesis-related symptom is abdominal pain.

[0035] The reduction in severity is based on a composite value of the person's ANMS GCSI-DD nausea subscale and vomiting subscale mean scores. One of skill in the art will be able to calculate such subscales using the techniques described herein. In some embodiments, the person's ANMS GCSI-DD nausea subscale and vomiting score is reduced by at least 0.5 points from baseline. In other embodiments, the person's ANMS GCSI-DD nausea subscale and vomiting score is reduced by at least 0.5, 1, 1.5, 2, 2.5, 3, 3.5, or 4 points from baseline. In further embodiments, the person's ANMS GCSI-DD nausea subscale and vomiting score is reduced by at least 0.5 to 4 points, 0.5 to 3.5 points, 0.5 to 3 points, 0.5 to 2.5 points, 0.5 to 2 points, 0.5 to 1.5 points, 0.5 to 1 point, 1 to 4 points, 1 to 3.5 points, 1 to 3 points, 1 to 2.5 points, 1 to 2 points, 1 to 1.5 points, 1.5 to 4 points, 1.5 to 3.5 points, 1.5 to 3 points, 1.5 to 2.5 points, 1.5 to 2 points, 2 to 4 points, 2 to 3.5 points, 2 to 3 points, 2 to 2.5 points, 2.5 to 4 points, 2.5 to 3.5 points, 2.5 to 3 points, 3 to 4 points, 3 to 3.5 points, or 3.5 or 4 points from baseline.

[0036] In other embodiments, the person's ANMS GCSI-DD nausea subscale and vomiting score is reduced by at least 30% from baseline. In further embodiments, the person's ANMS GCSI-DD nausea subscale and vomiting score is reduced by at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% from baseline. In other embodiments, the person's ANMS GCSI-DD nausea subscale and vomiting score is reduced by 30% to 100%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 100%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 100%, 60% to 90%, 60% to 80%, 60% to 70%, 70% to 100%, 70% to 90%, 70% to 80%, 80% to 100%, 80% to 90%, or 90% to 100% from baseline.

[0037] In some embodiments, the percentage of days of gastroparesis-related symptoms in the person is increased compared to baseline after administration of deuterated domperidone. In other embodiments, the PAGI-QoL score in the person is improved compared to baseline. In further embodiments, the GERDQ score in the person is improved compared to baseline. In other embodiments, the PGIS score in the person is improved compared to baseline.

[0038] Aspects

[0039] Aspect 1 : A method of treating a person diagnosed with diabetic gastroparesis, comprising administering 10 mg or 15 mg of deuterated domperidone twice daily, wherein the administration reduces the severity of gastroparesis-related symptoms in the person.

[0040] Aspect 2: The method of aspect 1, wherein the reduction in severity is based on a composite of the ANMS GCSI-DD nausea subscale and vomiting subscale mean scores in the person.

[0041] Aspect 3: A method as substantially described herein.

[0042]

[0043]

[0044] Example 1

[0045] A. Study Description

[0046] (i) Overview of Study Design

[0047] This is a randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of deuterated domperidone in the treatment of adult subjects with diabetic gastroparesis after 12 weeks of treatment.

[0048] Safety of deuterated domperidone will be evaluated from the time of signing the informed consent until the end of the follow-up period. Efficacy and study drug adherence of subjects will be followed throughout the double-blind treatment period. Plasma concentrations of deuterated domperidone will also be measured at selected visits during the double-blind treatment period.

[0049] The total duration of a subject’s participation in the study will be approximately 18 weeks, including a <5-week screening and run-in period, a 12-week double-blind treatment period, and a maximum of 1 -week follow-up period. Throughout the participation, subjects will complete 8 visits (subjects with a documented history of delayed gastric emptying within 2 years prior to visit 1 can complete visit 2 by telephone).

[0050] Subjects who complete the Screening Period and Run-in Period and remain eligible will be randomly assigned in a 1 : 1 : 1 ratio to one of the following 3 treatment groups in parallel for 12 weeks:

[0051] • Deutetrabenazine 15 mg BID, administered as a single 10 mg capsule and a single 5 mg capsule;

[0052] • Deutetrabenazine 10 mg BID, administered as a single 10 mg deutetrabenazine capsule and a single placebo capsule; or

[0053] • Deutetrabenazine placebo BID, administered as 2 matching placebo capsules.

[0054] Approximately 400 subjects (about 133 per treatment group) will be randomized and it is expected that 363 subjects will complete the 12-week double-blind treatment phase. Subjects will be stratified according to birth gender (female, male) and a composite of baseline ANMS GCSI-DD Nausea and Vomiting subscale mean scores (< 2.6 vs > 2.6).

[0055] Figure 1

[0056] All subjects participating in the study will have a trough concentration PK sample collected within 60 minutes prior to study drug dosing at Visit 5 and Visit 7.

[0057] Subjects can opt to participate in the PK Subcohort study, in which post-dose PK samples will also be collected at Visit 5. These subjects will stay at the clinical research center for up to about 3 hours after taking the study drug in the morning. In addition to the PK blood samples collected within 60 minutes prior to study drug dosing, subjects in the PK Subcohort will also have blood samples collected at approximately 1 and 2 hours after dosing. If the subject is willing and able to stay at the clinical research center for a longer period of time, a PK sample will also be collected at approximately 3 hours after dosing. If the subject is willing to return to the research center, additional samples can be collected within the following post-dosing time windows on the same day: 4 to 8 hours and / or 8 to 12 hours. Subjects will be instructed to record the date and time of each dose within 2 days prior to Visit 5, and will also be instructed not to take the study drug at home on the day of Visit 5. Post-dose PK samples will be collected within nominal times ± 15 minutes.

[0058] After approximately 30 subjects in the PK Subcohort have completed Visit 5, the iDMC will evaluate the newly generated PK and safety data, without knowledge of the individual subject assignments, to determine the dose level(s) that will be advanced for the remainder of the study.

[0059] Once the initial data review is complete, post-dose samples will be collected within the following post-dose time windows at Visits 5, 6, and / or 7: 1 hour to 4 hours, 4 hours to 8 hours, or 8 hours to 12 hours, and this will be performed at least in the subset of subjects. For subjects selected to provide more than 1 sample, efforts will be made to collect each sample within a different time window. Subjects will be instructed to record the date and time of each dose within 2 days prior to the visit, and will also be instructed not to take study drug at home on the day of the visit.

[0060] If an SAE or AE occurs that results in withdrawal from the study, efforts will be made to collect a PK sample as soon as possible.

[0061] Pharmacokinetics

[0062] During the study, once approximately 70% of the randomized subjects have completed the EOT visit or prematurely discontinued, an interim analysis (IA) will be performed. The iDMC will meet to evaluate safety, early futility, and possible sample size re-estimation. The IA for the primary endpoint will be used only to assess early futility or to increase sample size. The study will not be terminated early for efficacy.

[0063] General Study Design and Procedures

[0064] Subjects must meet all inclusion criteria and not meet any exclusion criteria to be eligible for participation in the study. Subjects will be evaluated per the following flow:

[0065] • Screening Period (Visit 1, Days -35 to -22):

[0066] o Screening procedures will be performed and subjects will begin to wash out any applicable disqualifying medications. Subjects will be required to wash out all disqualifying medications for at least 14 days or 5 half-lives, whichever is longer, prior to starting the ANMS GCSI-DD Baseline Period (defined as 7 days or 14 days prior to randomization, depending on whether the subject meets randomization criteria 4a or 4b) and / or prior to Visit 2 GEBT; and

[0067] o From the evening of the screening visit, subjects will record ANMS GCSI-DD, PAGI-QoL, GERDQ, PGIS, and, if allowed, rescue medication use per Table 1A and Table 1B.

[0068] • Run-in Period (Visit 2, Days -21 to -1):

[0069] For subjects with documented delayed gastric emptying within the 2 years prior to Visit 1, this visit can be completed by telephone to assess diary adherence, concomitant medications, and AEs. If subjects require additional assessments requiring attendance at the clinical site, they can report to the clinical site to complete the additional procedures that are not part of the planned visit.

[0070] ○ Participants will be asked to continue completing the ANMS GCSI-DD questionnaire daily and to record daily use of permitted rescue medications;

[0071] ○ The average of the daily ANMS GCSI-DD measurements obtained during the 7 or 14 days prior to randomization will constitute the “baseline” measurement; and

[0072] ○ GEBT: For subjects with no documented delayed gastric emptying within the 2 years prior to Visit 1, a GEBT will be performed on a day between Days -21 and -12 (inclusive). The GEBT will be performed after washout of the drug discussed below for at least 14 days or 5 half-lives (whichever is longer). Subjects will fast for at least 8 hours before the GEBT. The GEBT will be performed after ingesting a standardized, high-dose 13 Two breath samples will be collected before the meal and then 45, 90, 120, 150, 180, and 240 minutes after the meal. Fasting blood glucose will be assessed before the gastric emptying test (GEBT) to ensure a blood glucose level of ≤275 mg / dL. If the subject's fasting blood glucose level is >275 mg / dL, the GEBT will not be performed. Subjects will be allowed to return to the study center within the next 1 to 3 days to complete the test or may be excluded from the study if they no longer meet the criteria for stable and well-controlled blood glucose. On the day of the GEBT, subjects should report to the clinical study center after an overnight fast and take their usual medications (including any diabetes medications), excluding any concomitant medications. Subjects requiring insulin will self-inject their regular morning insulin dose based on their fasting status. Subjects will be instructed to bring insulin to the clinical study center as needed. Fasting blood glucose will be assessed before the gastric emptying assessment to ensure a blood glucose level of ≤275 mg / dL. Additional insulin (adjusted based on the caloric content of the meal) may be administered to ensure a blood glucose level of ≤275 mg / dL before the gastric emptying procedure. Likewise, low blood sugar (hypoglycemia; blood glucose <60 mg / dL) requires management.

[0073] ○ Subjects will be required to wash out the following medications for 14 days or 5 half-lives (whichever is longer) before starting the American Society of Neurogastroenterology and Motility Gastroparesis Cardinal Symptom Index daily diary baseline period until the end of the study:

[0074] ■Metoclopramide;

[0075] ■ Domperidone;

[0076] ■erythromycin;

[0077] ■pyridostigmine;

[0078] ■opioid use for extended periods (if needed, subjects will be allowed to use opioid for < 72 hours once during the treatment period);

[0079] ■daily use of cannabis and / or tetrahydrocannabinol (subjects who test positive for tetrahydrocannabinol at Visit 1 can remain eligible to continue in the study if they have a prescription for the substance, have been using a stable dose for at least 6 months prior to screening, and agree to avoid daily use of tetrahydrocannabinol during the study period. Subjects with no documented delay in gastric emptying within 2 years prior to Visit 1 and who require completion of a gastric emptying breath test must agree to discontinue use of prescription cannabis and / or tetrahydrocannabinol for 2 weeks prior to the test);

[0080] ■anticholinergic medications; and

[0081] ■anti-emetics (except for rescue anti-emetics specified in the study protocol).

[0082] • 12-week double-blind treatment period (Visits 3 through 7, Days 1 through 84):

[0083] o Compliance with the ANMS GCSI-DD will be assessed at the time of randomization (Day 1) and must be > 75% to be eligible to participate in the study, or Sponsor approval must be obtained;

[0084] o Study drug (deuterated domperidone capsules and / or placebo capsules) will be administered for 84 (± 4) days, and safety assessments will be performed; the ANMS GCSI-DD questionnaire will be completed daily at approximately the same time in the evening;

[0085] o PAGI-QoL and GERDQ will be completed at the clinical research center at Visit 1, Visit 3 (prior to first study drug dosing), and Visits 4, 5, 6, and 7;

[0086] o All subjects participating in the study will have a trough concentration PK sample collected within 60 minutes prior to study drug dosing at Visit 5 and Visit 7. Subjects can opt to participate in the PK sub-study, in which post-dose PK samples will also be collected at Visit 5. These subjects will stay at the clinical research center for up to approximately 3 hours after taking the study drug in the morning. In addition to the PK blood samples collected within 60 minutes prior to study drug dosing, subjects in the PK sub-study will also have blood samples collected at approximately 1 and 2 hours post-dose. If the subject is willing and able to stay at the clinical research center for a longer period of time, a PK sample will also be collected at approximately 3 hours post-dose. If the subject is willing to return to the research center, additional samples can be collected within the following post-dose time windows on the same day: 4 to 8 hours and / or 8 to 12 hours. Subjects will be instructed to record the date and time of each dose within 2 days prior to Visit 5, and will also be instructed not to take the study drug at home on the day of Visit 5. Post-dose PK samples will be collected within nominal times ± 15 minutes.

[0087] o Safety will be assessed by evaluation of AEs, vital signs, physical examinations, clinical laboratory tests (biochemistry, hematology, coagulation, urinalysis, and prolactin), and 12-lead ECG results; and

[0088] o In addition, an optional PGx blood sample can be collected at any time during the treatment period.

[0089] • Follow-up period: (Visit 8, Day 91 [± 3 days]):

[0090] o Subjects will have a follow-up visit approximately 1 week (± 3 days) after the last study drug dose to assess AEs, changes in concomitant medications (including use of rescue medication), vital signs, 12-lead ECG, prolactin, biochemistry, hematology, and coagulation function.

[0091]

[0092]

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[0098]

[0099]

[0100] Unplanned visits and / or additional follow-up may be necessary. For example, subjects with clinically significant abnormal laboratory test results, unresolved TEAEs, SAEs requiring follow-up laboratory testing and review, or clinically significant AEs may require further evaluation.

[0101] Interim Analysis

[0102] Screening procedures (including vital signs assessments) may be repeated up to two times for eligibility purposes. Screened subjects who fail to meet the inclusion / exclusion criteria (even though they may have undergone repeated screening assessments, if relevant) may be considered for rescreening.

[0103] B. Screening and Withdrawal of Subjects

[0104] Subjects who meet all of the following criteria based on the screening assessment will be eligible to participate in this study:

[0105] 1. Male or female aged ≥18 years;

[0106] 2. Diagnosed with type 1 or type 2 diabetes according to the American Diabetes Association criteria;

[0107] 3. Current diagnosis of diabetic gastroparesis, defined as follows:

[0108] a. Gastrointestinal symptoms consistent with gastroparesis (e.g., postprandial nausea / vomiting, postprandial fullness, early satiety, abdominal distension, and / or epigastric / abdominal pain) within 6 months prior to screening; and

[0109] b. Record of symptoms of delayed gastric emptying confirmed by GEBT, scintigraphy, wireless motility capsule, or manometry within the past 2 years. Subjects who present with symptoms mentioned in inclusion criterion 3a but have no record of delayed gastric emptying within 2 years before Visit 1 may use the 13 C- Spirulina platensis completes GEBT. GEBT t ½ Must be ≥110 minutes to be eligible. GEBT t ½ Subjects with a time of <110 minutes could be considered for inclusion in the study;

[0110] 4. BMI between 18 kg / m2 at screening 2 and 45kg / m 2 Between (including end values);

[0111] 5. HbA1c level ≤ 10% at screening, and blood sugar is stable and well controlled;

[0112] 6. Male subjects with a female partner of childbearing potential must agree to use 2 medically accepted highly effective methods of contraception from Day 1 through 90 days after the last dose of study drug. Medically accepted highly effective methods of contraception for male subjects with a female partner of childbearing potential include the following: latex condoms with a spermicide, Fem-Choice® with intravaginal spermicide, cervical cap with spermicide, an intrauterine device (hormonal or non-hormonal), an implantable contraceptive, and oral contraceptives;

[0113] 7. Male subjects must agree to avoid donating sperm from Day 1 through 90 days after the last dose of study drug;

[0114] 8. Female subjects with a male partner must meet one of the following conditions: surgical sterilization (hysterectomy and / or bilateral oophorectomy), at least 1 year postmenopausal (follicle-stimulating hormone level confirmed to be in the postmenopausal range at the screening visit), or agree to use 1 medically accepted highly effective method of contraception from Day -14 through 30 days after the last dose of study drug. Medically accepted highly effective methods of contraception for female subjects with a male partner include the following: latex condoms with a spermicide, Fem-Choice® with intravaginal spermicide, cervical cap with spermicide, an intrauterine device (hormonal or non-hormonal), an implantable contraceptive, and oral contraceptives;

[0115] 9. Willing to avoid use of long-acting GLP-1 agonists, SGLT-2 inhibitors, or pramlintide from the screening period through the end of treatment. Subjects who are taking a GLP-1 agonist or SGLT-2 inhibitor can be considered for inclusion in the study if they are willing to discontinue 3 days prior to starting the ANMS GCSI-DD baseline period and agree to remain off throughout the study treatment period; and

[0116] 10. Able to understand and willing to comply with all study visits, procedures, restrictions, discontinuation requirements (including discontinuation of medications for treatment of gastroparesis).

[0117] (i) Inclusion Criteria

[0118] Subjects meeting any of the following criteria will be excluded from participation in the study:

[0119] 1. Presence of other known causes of gastroparesis other than diabetes mellitus (e.g., idiopathic gastroparesis, and / or gastroparesis attributed to surgery, viral infection, cancer, scleroderma, or other nervous system disease);

[0120] 1. Hospitalization for diabetic gastroparesis and / or diabetic ketoacidosis within 1 year prior to Visit 1;

[0121] 2. Presence of a history or current history of clinically significant cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes;

[0122] 3. Evidence (based on screening or baseline assessments) or history of clinically significant immune, hematologic, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disorders (including drug allergies); surgical procedures; cancer (except basal cell or squamous cell skin cancers, and except cancer that has been cured or is in remission for >5 years prior to the screening visit); or any condition that might significantly interfere with the absorption, distribution, metabolism, or excretion of study drug. Cholecystectomy and appendectomy are allowed if they occurred >6 months prior to screening;

[0123] 4. History of prolactin-secreting pituitary tumor (i.e., prolactinoma);

[0124] 5. Known or suspected hypogonadism, current presence of clinically significant menstrual abnormalities (e.g., oligo- or amenorrhea), gynecomastia, galactorrhea, or other clinical features that can be consistent with hyperprolactinemia;

[0125] 6. Received an intraduodenal injection of botulinum toxin within 6 months prior to screening and / or plans to receive such an injection during the study;

[0126] 7. History of pyloroplasty, pyloromyotomy, or per-oral endoscopic myotomy;

[0127] 8. Total bilirubin, alkaline phosphatase, AST, or ALT levels >2x ULN at screening, or Child-Pugh classification of B or C;

[0128] 9. Serum creatinine level >1.5x ULN at screening, or estimated glomerular filtration rate <30 mL / min / 1.73 m 2 ;

[0129] 10. Significantly abnormal thyroid-stimulating hormone level at screening;

[0130] 11. Inability to perform GEBT, or fasting blood glucose ≥275 mg / dL on the day of GEBT. This criterion applies only to subjects who have no documented history of delayed gastric emptying within 2 years prior to screening and who require completion of GEBT to confirm eligibility. If a subject’s fasting blood glucose level is ≥275 mg / dL, GEBT is not performed. The subject will be allowed to return to the study center within the next 1 to 3 days to complete the test, or the subject can be excluded from the study if the subject no longer meets the criteria for stable and well-controlled blood glucose;

[0131] 12. Known allergy to chicken eggs or spirulina. This criterion applies only to subjects who have no documented history of delayed gastric emptying within 2 years prior to screening and who require completion of GEBT to confirm eligibility;

[0132] 13. Use of research, prescription, or over-the-counter medications as follows:

[0133] a. Active participation in an experimental treatment study; received a small molecule experimental treatment within 30 days or 5 half-lives (whichever is longer) prior to randomization; or received a large molecule experimental treatment within 90 days or 5 half-lives (whichever is longer) prior to randomization;

[0134] b. Inhibitors and inducers of CYP3A4 (whether drugs, herbal supplements, dietary supplements, nutraceuticals, or foods):

[0135] ■For subjects selected to provide PK samples in addition to trough concentration samples at Visit 5 and Visit 7: All CYP3A4 inhibitors and / or inducers are prohibited from 14 days or 5 half-lives (whichever is longer) prior to first study drug dosing through the end of the study;

[0136] ■For all other subjects: Strong CYP3A4 inhibitors and / or inducers are prohibited from 14 days or 5 half-lives (whichever is longer) prior to first study drug dosing through the end of the study. Weak and moderate CYP3A4 inhibitors and inducers are permitted; and

[0137] ■For all subjects, grapefruit, grapefruit products, starfruit products, and Seville oranges are prohibited from 48 hours prior to randomization through the end of treatment.

[0138] c. Use of motility drugs (including but not limited to metoclopramide, domperidone, erythromycin, pyridostigmine, etc.), other drugs and therapies that can affect gastric emptying (e.g., all opioid medications used daily [if needed, subjects will be allowed to use an opioid medication for < 72 hours during the treatment period], cannabis and / or tetrahydrocannabinol products used daily [must be prescribed by a healthcare professional and, for non-daily use, the dose must be stably maintained for > 6 months], and all anticholinergic medications) and antiemetics (except for rescue antiemetics specified in the study protocol) from 14 days or 5 half-lives (whichever is longer) prior to the start of the ANMS GCSI-DD Baseline Period through the end of the study. For subjects who need to complete the GEBT to confirm eligibility, these medications must be discontinued for at least 14 days or 5 half-lives (whichever is longer) prior to the GEBT; and

[0139] d. Use of antipsychotic, antidepressant, anxiolytic, or prescription sleep medications, except for doses that have been stably used for > 6 months prior to screening.

[0140] 14. Positive results on drug or alcohol testing at screening with no medical explanation, or a history of alcohol or drug abuse within 2 years prior to screening as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, and / or a usual weekly alcohol consumption of > 14 drinks. One drink is equivalent to ½ pint of beer (285 mL), 1 shot of liquor (25 mL), or 1 glass of wine (125 mL). If a false positive is suspected, a confirmatory drug or alcohol test can be performed. Subjects with positive tetrahydrocannabinol (THC) testing at Visit 1 can still be eligible to continue in the study if they have a prescription for the substance, have been using a stable dose for at least 6 months prior to screening, and agree to avoid daily use of THC during the study. Subjects without a documented history of delayed gastric emptying within 2 years prior to Visit 1 and who require completion of the GEBT must agree to discontinue use of prescription cannabis and / or THC for 2 weeks prior to the trial;

[0141] 15. Evidence of current use of illegal drugs;

[0142] 16. Known history or presence of an eating disorder within 2 years prior to the screening visit;

[0143] 17. Positive test for human immunodeficiency virus antibody, hepatitis C virus antibody by RNA testing, or hepatitis B surface antigen at the screening visit;

[0144] 18. Currently receiving treatment with a weight loss medication or have had a weight loss surgery (e.g., gastric bypass surgery) in the past;

[0145] 19. Pregnant, breastfeeding, or planning to become pregnant or breastfeed during the study;

[0146] 20. Inability to swallow medication;

[0147] 21. Currently receiving parenteral nutrition or presence of a nasogastric or other enteral tube (e.g., PEG or PEJ tube) for feeding or decompression;

[0148] 22. Known or suspected presence of gastric outlet obstruction (e.g., peptic stricture) or other mechanical obstruction of the gastrointestinal tract documented by upper endoscopy or upper GI series within the last 2 years;

[0149] 23. Known history or current diagnosis of malabsorption of the small intestine or pancreatic exocrine disease;

[0150] 24. History of gastric surgery such as fundoplication, gastrectomy, vagotomy, pyloroplasty, or weight loss surgery. Subjects with a gastric pacemaker can be considered for inclusion in the study if the pacemaker can be turned off for > 14 days prior to the start of the ANMS GCSI-DD Baseline Period and remain off for the remainder of the study. History of diagnostic endoscopy does not constitute an exclusion;

[0151] 25. Any medical condition or history of psychiatric illness or current illness that might interfere with study conduct or would expose the subject to unacceptable risk;

[0152] 26. Prior exposure to deuterated droperidol;

[0153] 27. Prior demonstration of no response to droperidol, or known hypersensitivity or intolerance to droperidol or any excipient in the deuterated droperidol formulation; or

[0154] 28. In the judgment of the Investigator, is not suitable to participate for any other reason that might increase the risk to the subject of participation or interfere with interpretation of the study results.

[0155] (ii) Exclusion Criteria

[0156] Subjects who meet the following criteria will be randomized at Visit 3 (Day 1):

[0157] 1. Continue to meet all inclusion / exclusion criteria;

[0158] 2. Have discontinued a motility medication (including but not limited to metoclopramide, droperidol, erythromycin, pyridostigmine, etc.), other medications and therapies that can affect gastric emptying (e.g., all opioid medications [if needed, subjects will be allowed to use opioid medications for < 72 hours during the treatment period], daily use of cannabis and / or tetrahydrocannabinol products [must be prescribed by a healthcare professional and, for non-daily use, the dose must be stably maintained for > 6 months], and all anticholinergic medications], and antiemetics (except for rescue antiemetics specified in the study protocol) within 14 days or 5 half-lives (whichever is longer) prior to the start of the ANMS GCSI-DD Baseline Period and be willing to continue to discontinue such medications through the end of the study;

[0159] 3. Demonstrate a confirmed diagnosis of diabetic gastroparesis, defined as follows:

[0160] a. Presence of gastrointestinal symptoms consistent with gastroparesis (e.g., postprandial nausea / vomiting, postprandial fullness, early satiety, abdominal distension, and / or epigastric / abdominal pain) within 6 months prior to screening; and

[0161] b. Documentation of delayed gastric emptying symptoms by GEBT, scintigraphy, wireless motility capsule, or manometry within the past 2 years. Subjects who present with symptoms mentioned in inclusion criterion 3a but have no documentation of delayed gastric emptying within 2 years prior to Visit 1 can use 13 C- Spirulina platensis completed GEBT. GEBT t ½ Must be > 110 minutes to be eligible for participation. GEBT t ½<110 minutes of the subject can be considered for inclusion in the study;

[0162] 4. Meet one of the following criteria, "a" or "b":

[0163] a. During the 14 days prior to randomization (subject is not taking a prokinetic or antiemetic medication, with the exception of rescue medications as specified in the study protocol), the ANMS GCSI-DD scores meet the following:

[0164] ■Nausea subscale mean score of > 2 ("moderate" or worse) each week;

[0165] ■No day with a nausea subscale score of 0; and

[0166] ■At least 2 episodes of emesis per week.

[0167] b. Have diary records for at least 7 days and meet the following ANMS GCSI-DD scores and have received the maximum allowed rescue medication (i.e., 3 days per week of single dose of promethazine 25 mg, ondansetron 4 mg, or over-the-counter ginger) for the subject:

[0168] ■Nausea subscale score of > 3 ("severe") for at least 4 days of the 7 days;

[0169] ■No day with a nausea subscale score of 0; and

[0170] ■At least 2 episodes of emesis during the week.

[0171] Emesis is defined clinically as the expulsion of gastrointestinal contents through the mouth as a result of contraction of the intestinal and abdominal wall muscles; whereas, regurgitation is defined as the effortless return of stomach contents to the mouth. Subjects should be informed of the difference between emesis and regurgitation (regurgitation is defined as the act of bringing food down the throat back to the mouth) and record episodes of emesis accordingly.

[0172] 5. Be compliant with the ANMS GCSI-DD during the Baseline Period, defined as compliance > 75%, or approved by the Sponsor.

[0173] (iii) Randomization Criteria

[0174] C. Study Objectives

[0175] The primary objective of this study is to evaluate the ability of deuterated domperidone to significantly reduce the severity of gastroparesis-related symptoms compared to placebo, based on the combined value of the mean nausea and emesis subscale scores of the ANMS GCSI-DD during the last 2 weeks of the 12-week treatment period, compared to baseline, in adult subjects with diabetic gastroparesis.

[0176] (i) Primary Objective

[0177] The secondary objectives of this study were to assess the effect of deuterated

[0178] • Relationship between ANMS GCSI-DD nausea and vomiting subscale scores and PGIS and PGIC over the 12-week treatment period;

[0179] • Percentage of subjects showing clinical improvement in gastroparesis symptoms based on the composite of mean ANMS GCSI-DD nausea and vomiting subscale scores over the last 2 weeks of the 12-week treatment period in subjects with a history of non-response or intolerance to metoclopramide treatment or other prokinetic agents (such as erythromycin, neostigmine, or bethanechol) in subjects with a history of non-response or intolerance to metoclopramide treatment or other prokinetic agents (such as erythromycin, neostigmine, or bethanechol);

[0180] • Percentage of subjects with a decrease of >30% in ANMS GCSI-DD total and subscale scores from baseline over the last 2 weeks of the 12-week treatment period;

[0181] • Percentage of responders showing a mean decrease of >0.5 points in ANMS GCSI-DD nausea and vomiting subscale scores from baseline over the last 2 weeks of the 12-week treatment period;

[0182] • Effect of deuterated

[0183] • Percentage of symptom-free days in ANMS GCSI-DD total and subscale scores over the last 2 weeks of the 12-week treatment period;

[0184] • Effect of deuterated

[0185] • Percentage of subjects with a decrease of >30% in ANMS GCSI-DD total and subscale scores from baseline over the last 6 weeks of the 12-week treatment period;

[0186] • Effect of deuterated

[0187] • Percentage of symptom-free days in ANMS GCSI-DD total and subscale scores over the last 6 weeks of the 12-week treatment period;

[0188] • Change in PGIS from baseline; and

[0189] •Change from baseline in PGIC.

[0190] (ii) Secondary Objectives

[0191] The exploratory objectives of this study include evaluating the following in adult subjects with diabetic gastroparesis:

[0192] •PAGI-QoL scale investigates changes from baseline;

[0193] •Change from baseline in GERDQ;

[0194] • Changes in subjects' HbA1c, insulin requirements, and diabetes medications from baseline to Week 12;

[0195] • Characterize the absorption of deuterated domperidone and the concentrations of its major metabolites at steady state; and

[0196] • Characterization of the exposure-response relationship of deuterated domperidone with various efficacy and / or safety measures can also be performed.

[0197] (iii) Exploratory Objectives

[0198] Safety objectives included evaluating the safety of deuterated domperidone compared with placebo in adult subjects with diabetic gastroparesis.

[0199] (iv) Safety Objectives

[0200] D. Study Treatment

[0201] This study plans to include three treatment groups, with 133 subjects in each group. Subjects who have completed the screening and run-in periods and are still eligible will be randomly assigned in a 1:1:1 ratio to one of the following three treatment groups for 12 weeks:

[0202] • Deuterated domperidone 15 mg twice daily, administered as a single 10 mg capsule and a single 5 mg capsule;

[0203] • deuterated domperidone 10 mg twice daily, administered as a single 10 mg deuterated domperidone capsule and a single placebo capsule; or

[0204] • Deuterated domperidone placebo BID, administered as 2 matching placebo capsules.

[0205] (i) Treatment Groups

[0206] This is a randomized, double-blind study. Randomization of subjects will be managed by the IRT system. Subjects who complete the Screening Period and Run-in Period and remain eligible will be randomly assigned in a 1 : 1 : 1 ratio to one of the following 3 treatment groups in parallel for 12 weeks. Randomization will be performed at Visit 3 (Day 1). Subjects will be stratified according to birth gender (female, male) and a composite of baseline mean scores of the ANMS GCSI-DD Nausea and Vomiting subscales (< 2.6 vs > 2.6).

[0207] Blinding will be maintained at each dosing by administering 2 dose units. Thus, subjects randomized to the 10 mg dose level will take a single 10 mg capsule and a single placebo capsule at each dosing. Subjects randomized to the 15 mg dose level will take a single 10 mg capsule and a single 5 mg capsule at each dosing. Finally, subjects randomized to the placebo group will take 2 matching placebo capsules at each dosing.

[0208] Blinding of study drug will be maintained until database lock. Randomized subjects who prematurely discontinue the study will not be replaced.

[0209] (ii) Randomization and Blinding

[0210] The deuterated metoclopramide drug product capsules are 2C, oval, blue opaque soft capsules made from deuterated metoclopramide drug substance. Each deuterated metoclopramide soft capsule will contain 10 mg or 5 mg of active deuterated metoclopramide drug substance. The deuterated metoclopramide fill formulation composition contains the inactive ingredients in Table 2.

[0211]

[0212] Matching placebo soft capsules will also be provided with a formulation composition containing the same inactive ingredients (without deuterated metoclopramide drug substance). See Table 3.

[0213]

[0214] The soft capsules (capsules containing deuterated metoclopramide drug substance and placebo capsules) will be packaged in a blister pack to meet the dosing requirements of the study.

[0215] (iii) Drug Supply

[0216] All randomized subjects will orally take one dose of blinded study medication (deuterated paliperidone and / or placebo capsules) with approximately 240 mL of water. For a particular individual, an approximately 12-hour interval will be maintained between each dosing (e.g., 8:00 AM to 8:00 PM). Subjects will be required to fast for 2 hours prior to all dose administrations and for 1 hour after dose administration. Subjects in the PK subcohort who will provide postdose PK samples at Visit 5 will be required to fast for at least 8 hours prior to the morning dose of study medication. Subjects will be provided with study medication for doses that are not administered at the study center for self-administration.

[0217] If a subject misses a scheduled dose and realizes the missed dose within 2 hours of the scheduled dose, the subject will be instructed to take the assigned dose of study medication as soon as the missed dose is realized. If a subject realizes the missed dose more than 2 hours after the scheduled dose, the subject will be instructed to skip the missed dose of study medication and resume the assigned dose of study medication at the next scheduled time.

[0218] Prior and concomitant medications and / or procedures

[0219] (iv) Study Drug Administration

[0220] The following investigational drugs, prescription drugs, or over-the-counter drugs are not allowed during the study:

[0221] • antipsychotic, antidepressant, anxiolytic, or prescription sleep medication, except for doses that have been stable for > 6 months prior to screening;

[0222] • pramlintide;

[0223] • long half-life SGLT-2 inhibitors or GLP-1 agonists (e.g., Bydureon ® [exenatide extended-release], Victoza ® [lixisenatide], Tanzeum ® [albiglutide], or Trulicity ® [dulaglutide]);

[0224] • small molecule experimental treatments within 30 days or 5 half-lives (whichever is longer) prior to randomization; or large molecule experimental treatments within 90 days or 5 half-lives (whichever is longer) prior to randomization;

[0225] • inhibitors and inducers of CYP3A4 (whether drugs, herbal supplements, dietary supplements, nutraceuticals, or food):

[0226] o For subjects selected to provide PK samples in addition to glucose concentration samples at Visit 5 and Visit 7: All CYP3A4 inhibitors and / or inducers are prohibited from 14 days or 5 half-lives (whichever is longer) prior to first study drug dosing through the end of the study;

[0227] o For all other subjects: Strong CYP3A4 inhibitors and / or inducers are prohibited from 14 days or 5 half-lives (whichever is longer) prior to first study drug dosing through the end of the study. Weak and moderate CYP3A4 inhibitors and inducers are permitted; and

[0228] o For all subjects, grapefruit, grapefruit products, starfruit products, and Seville oranges are prohibited from 48 hours prior to randomization through the end of treatment.

[0229] • Drugs that can prolong the QT interval, herbal supplements, dietary supplements, or nutraceuticals from 28 days prior to first study drug dosing through the end of the study;

[0230] • Use of motility drugs (including but not limited to metoclopramide, domperidone, erythromycin, pyridostigmine, etc.), other drugs and therapies that can affect gastric emptying (e.g., all long-term opioid use [if needed, subjects will be allowed to use an opioid < 72 hours during the treatment period], daily cannabis and / or tetrahydrocannabinol product use [must be prescribed by a healthcare professional and, for non-daily use, the dose must be stably maintained > 6 months], and all anticholinergic drugs] and antiemetics (except for emergency antiemetics as specified in the study protocol) from 14 days or 5 half-lives (whichever is longer) prior to the start of the ANMS GCSI-DD Baseline Period through the end of the study. For subjects who require completion of the GEBT to confirm eligibility, these medications must be discontinued at least 14 days or 5 half-lives (whichever is longer) prior to the GEBT. Subjects who test positive for tetrahydrocannabinol at Visit 1 may still be eligible to continue in the study if they have a prescription for the substance, have been using a stable dose for at least 6 months prior to screening, and agree to avoid daily use of tetrahydrocannabinol during the study. Subjects who have no record of delayed gastric emptying within 2 years prior to Visit 1 and require completion of the GEBT must agree to discontinue prescription cannabis and / or tetrahydrocannabinol for 2 weeks prior to the test;

[0231] • Received a pyloric injection of botulinum toxin within 6 months prior to screening and during the study;

[0232] • Received a weight loss medication or have a history of weight loss surgery (e.g., gastric bypass surgery); and

[0233] • Received parenteral nutrition or have a nasogastric or other enteral tube (e.g., PEG or PEJ tube) for feeding or decompression.

[0234] Subjects who require continued treatment with a prohibited medication can be discontinued from study treatment and complete the follow-up procedures.

[0235] (v) Prohibited Medications, Foods, and / or Procedures

[0236] Subjects who experience severe gastroparesis symptoms can receive oral promethazine (Phenergan ® ) 25 mg or ondansetron (Zofran ® ) 4 mg.

[0237] (vi) Medications and / or Procedures to Limit Use

[0238] For subjects not participating in the PK subcohort, the use of weak and moderate CYP3A4 inhibitors and inducers is permitted.

[0239] If a subject has been stable on a dose of an antipsychotic, antidepressant, anxiolytic, or prescription sleep aid for > 6 months prior to screening, continuation of the medication is permitted.

[0240] If needed, subjects will be permitted to use an opioid medication for < 72 hours during the treatment period.

[0241] After approval, the use of other medications not previously explicitly excluded (e.g., rescue medications) is permitted.

[0242] (vii) Medications and / or Procedures to Allow Use

[0243] Subjects who experience severe gastroparesis symptoms during the study can receive oral promethazine (Phenergan) 25 mg or ondansetron (Zofran) 4 mg as described below.

[0244] Subjects should be encouraged to use over-the-counter ginger products (e.g., capsules, soft chewable tablets, gum, oil, or tea) prior to using promethazine or ondansetron, with a maximum daily dose of 1000 mg, once daily. Prior to taking any over-the-counter product, subjects should confirm that the specific product does not contain any ingredients that are prohibited by the study protocol.

[0245] During the washout period (Day -35 to Day -22), subjects can take rescue medications as needed.

[0246] However, during the 3-week run-in period (Day -21 to Day -1), subjects who experience severe gastroparesis symptoms can use promethazine 25 mg, ondansetron 4 mg, or over-the-counter ginger products for a single dose per day for only 3 days per week. During the baseline period of the ANMS GCSI-DD, subjects should be strongly encouraged to avoid the use of rescue medications if at all possible, and if necessary, to use them as sparingly as possible.

[0247] If the subject's gastroparesis symptoms are very severe, deemed to require rescue medication beyond the maximum permitted dose, and has completed 7 days of diary recording and meets randomization criteria, including randomization criterion 4b, then direct randomization is possible.

[0248] After randomization, the use of rescue medication will be limited to a maximum of 3 days per week, 1 dose per day, when the subject experiences CTCAE Grade 2 or higher nausea and / or vomiting. If a subject uses rescue medication 3 days per week, 1 dose per day, for two consecutive weeks, then they will be terminated from the study due to insufficient efficacy. Subjects who require continued treatment with prohibited medications can be terminated from study treatment and complete subsequent study procedures.

[0249] (viii) Emergency Medications

[0250] E. Efficacy Assessments

[0251] The primary efficacy endpoint of the study is to assess the effect of deutetrabenazine on the severity of gastroparesis-related symptoms in adult subjects with diabetic gastroparesis, based on the combined score of the ANMS GCSI-DD nausea subscale and vomiting subscale mean scores over the last 2 weeks of the 12-week treatment period, compared to placebo, compared to baseline.

[0252] (i) Primary Efficacy Endpoint

[0253] The secondary efficacy endpoints of the study include the following assessments of the difference in treatment effect of deutetrabenazine versus placebo in adult subjects with diabetic gastroparesis:

[0254] • Estimation based on the combined score of the ANMS GCSI-DD nausea subscale and vomiting subscale mean scores over the 12-week treatment period using PGIS and PGIC as anchors;

[0255] • Percentage of subjects showing >30% reduction from baseline in the combined score of the ANMS GCSI-DD nausea subscale and vomiting subscale mean scores over the last 2 weeks of the 12-week treatment period in subjects with a history of non-response or intolerance to metoclopramide treatment or other prokinetic agents (such as erythromycin, neostigmine, or bethanechol);

[0256] • Percentage of subjects identified as responders, where a responder is defined as having an average reduction of >0.5 points in their ANMS GCSI-DD nausea subscale and vomiting subscale scores from baseline over the last 2 weeks of the 12-week treatment period;

[0257] • Percentage of subjects with a composite score of the ANMS GCSI-DD Nausea subscale and Vomiting subscale average scores over the last 2 weeks of the 12-week treatment period that is reduced by >30% from baseline;

[0258] • Percentage of subjects with a score of the ANMS GCSI-DD Vomiting subscale average score over the last 2 weeks of the 12-week treatment period that is reduced by >30% from baseline;

[0259] • Effect of deutetrabenazine on reducing the severity of gastroparesis-related symptoms from baseline based on the ANMS GCSI-DD Nausea subscale average score over the last 2 weeks of the 12-week treatment period;

[0260] • Effect of deutetrabenazine on reducing the severity of gastroparesis-related symptoms from baseline based on the ANMS GCSI-DD Vomiting subscale average score over the last 2 weeks of the 12-week treatment period;

[0261] • Percentage of subjects with a score of the ANMS GCSI-DD Nausea subscale average score over the last 2 weeks of the 12-week treatment period that is reduced by >30% from baseline;

[0262] • Effect of deutetrabenazine on reducing the severity of gastroparesis-related symptoms from baseline based on the average ANMS GCSI-DD total score over the last 2 weeks of the 12-week treatment period;

[0263] • Percentage of subjects with a score of the average ANMS GCSI-DD total score over the last 2 weeks of the 12-week treatment period that is reduced by >30% from baseline;

[0264] • Effect of deutetrabenazine on reducing the severity of gastroparesis-related symptoms from baseline based on the ANMS GCSI-DD Early satiety subscale average score over the last 2 weeks of the 12-week treatment period;

[0265] • Effect of deutetrabenazine on reducing the severity of gastroparesis-related symptoms from baseline based on the ANMS GCSI-DD Postprandial fullness subscale average score over the last 2 weeks of the 12-week treatment period;

[0266] • Effect of deutetrabenazine on reducing the severity of gastroparesis-related symptoms from baseline based on the ANMS GCSI-DD Upper abdominal pain subscale average score over the last 2 weeks of the 12-week treatment period;

[0267] • Percentage of symptom-free days (defined as a score assessed as > mild [ANMS GCSI-DD score > 2]) in the total score of the ANMS GCSI-DD, the composite score of nausea and vomiting, the score of nausea, the score of vomiting, the score of early satiety, the score of postprandial fullness, and the score of epigastric pain after each dose of deuterated domperidone during the last 2 weeks of the 12-week treatment period;

[0268] • All of the above endpoints assessed during the last 2 weeks of the 12-week treatment period will also be assessed during the last 6 weeks of the 12-week treatment period;

[0269] • Change from baseline in PGIS at week 12 after each dose of deuterated domperidone; and

[0270] • Change from baseline in PGIC at week 12 after each dose of deuterated domperidone.

[0271] (ii) Secondary Efficacy Endpoints

[0272] Exploratory efficacy endpoints for this study include the assessment of the following in adult diabetic gastroparesis subjects:

[0273] • The effect of deuterated domperidone compared to placebo on the reduction of gastroparesis-related symptom severity compared to baseline gastroparesis based on the mean score of the ANMS GCSI-DD bloating subscale during the last 2 weeks of the 12-week treatment period;

[0274] • Change from baseline in PAGI-QoL after 12 weeks of treatment after each dose of deuterated domperidone compared to placebo;

[0275] • Change from baseline in GERDQ after 12 weeks of treatment after each dose of deuterated domperidone compared to placebo;

[0276] • Characterization of the absorption of deuterated domperidone and the concentration of its major metabolite at steady state; and

[0277] • Deuterated domperidone exposure-response relationships to various efficacy and / or safety measures can also be characterized.

[0278] (iii) Exploratory Efficacy Endpoints

[0279] The ANMS GCSI-DD questionnaire encompasses the 5 core gastroparesis-related symptoms: nausea, early satiety, postprandial fullness, epigastric pain, and vomiting. Bloating is included as an exploratory symptom. Symptoms are scored on a severity numerical rating scale, ranging from 0 (no symptoms) to 4 (very severe). Vomiting is recorded on a frequency rating scale, scored as follows: 0 (no episodes), 1 (1 episode), 2 (2 episodes), 3 (3 episodes), 4 (4 or more episodes).

[0280] Subjects will be instructed to complete the ANMS GCSI-DD questionnaire daily from the start of self-screening (for ANMS GCSI-DD Baseline Period assessment) and daily on the day of randomization and through Day 1 through Day 84 (±4 days). Materials will be distributed at the screening visit. Compliance with the ANMS GCSI-DD will be assessed at randomization (Day 1) and must be >75% to be eligible to participate in the study, or approval from the Sponsor must be obtained. The questionnaire should be completed daily at approximately the same time in the evening.

[0281] Subjects will be instructed to rate the severity of their symptoms and the occurrence of vomiting based on the most severe degree of symptoms in the past 24 hours prior to taking any rescue medication at the time the questionnaire is completed.

[0282] The ANMS GCSI-DD total score of gastroparesis symptoms will be calculated by adding the scores of the 5 symptom items and then dividing by 5; thus, the maximum total score of symptoms can be 4 points (5 symptoms x maximum score of 4 points = 20; 20 divided by 5 = 4). The baseline of the ANMS GCSI-DD total score and subscale scores will be based on the average weekly scores from 7 to 14 days prior to randomization. The ANMS GCSI-DD total score and subscale scores will be analyzed to compare symptom scores between treatment groups.

[0283] (iv) ANMS GCSI-DD Questionnaire

[0284] PGIS assessments will be performed once a week starting at Visit 1. At Visit 3, a PGIS assessment will be performed prior to the first study drug administration, which will constitute the baseline. The PGIS is a single measure completed by the subject at the clinical research center visit to assess the current overall severity over the past 7 days. The PGIS is assessed using a 5-point numerical rating scale. PGIC assessments will be performed at Visits 4, 5, 6, and 7. The PGIC is a single measure completed by the subject at the clinical research center visit to assess the change in gastroparesis symptoms since starting study drug. The PGIC is assessed using a 5-point numerical rating scale.

[0285] (v) PGIS and PGIC

[0286] The PAGI-QoL will be completed at the clinical research center at Visit 1, Visit 3 (prior to the first study drug administration), and Visits 4, 5, 6, and 7. The PAGI-QoL contains 30 questions that ask the subject how some gastrointestinal problems they can experience affect their overall quality of life and well-being.

[0287] (vi) PAGI-QoL Scale Surveys

[0288] The GERDQ will be completed at the clinical research center at Visit 1, Visit 3 (prior to first study drug dosing), and Visits 4, 5, 6, and 7. The GERDQ is the subject's assessment of their symptoms over the past week. The GERDQ score is the sum of the individual question scores, ranging from 0 to 18 points.

[0289] (vii) Gastroesophageal Reflux Disease Questionnaire

[0290] PK samples will be collected according to Table 1A and Table IB. Plasma concentrations of deuterated domperidone and its major metabolites will be measured and used to estimate the following parameters:

[0291] • Steady-state C based on samples collected post-dose at Visit 5 for the initial PK subpopulation max ; and

[0292] • Steady-state trough concentration based on samples collected pre-dose at Visit 5 and Visit 7.

[0293] (viii) Pharmacokinetics

[0294] For subjects participating in the optional PGx assessment, blood samples will be collected at any time during the treatment period.

[0295] PGx samples can be used for genetic research to explore potential reasons for variability and / or differences in response in PK, PD, and / or safety data following administration of deuterated domperidone. Subjects will be given the right to opt-in to the PGx assessment during the informed consent process for the study.

[0296] (ix) PGx Assessments

[0297] Safety of deuterated domperidone will be assessed from the time of signing the informed consent form until the end of the follow-up period. All safety endpoints will be summarized descriptively. Safety endpoints will include the following:

[0298] • Incidence of clinically significant changes in laboratory test parameters, physical examination findings, 12-lead ECG parameters, body weight measurements, and vital sign measurements;

[0299] • TEAEs;

[0300] • SAEs occurring during treatment;

[0301] • TEAEs leading to premature discontinuation of study drug; and

[0302] • Significant laboratory test abnormalities occurring during treatment.

[0303] F. Safety Assessments Example 2: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of Deuterated Domperidone in Adult Subjects with Diabetic Gastroparesis

[0304] Brief Abstract: The objective of this clinical trial is to assess whether the study drug deuterated domperidone can help reduce symptoms associated with diabetic gastroparesis in adult patients.

[0305] The main questions this study aims to answer include:

[0306] • Assess the efficacy of deuterated domperidone compared to placebo in the treatment of gastroparesis symptoms in patients with diabetic gastroparesis

[0307] • Assess the safety and tolerability of deuterated domperidone compared to placebo in patients with diabetic gastroparesis

[0308] Participants will follow the following schedule:

[0309] • Screening period (1-2 visits)

[0310] • Run-in period (1 visit)

[0311] o Daily diaries and other patient reported outcomes (PROs) will be completed as described in the study protocol to assess eligibility for continued participation in the study

[0312] • 12-week treatment period (5 visits)

[0313] o Study drug will be taken orally twice daily

[0314] o Daily diaries and other PROs will be completed as described in the study protocol

[0315] o 1-week follow-up period (1 visit)

[0316] The investigator will compare the therapeutic effects of:

[0317] • Drug = deuterated domperidone dose 1

[0318] • Drug = deuterated domperidone dose 2

[0319] • Drug = placebo

[0320] Study Design

[0321] Study type: Interventional

[0322] Estimated enrollment: 400 participants

[0323] Allocation: Randomized

[0324] Intervention model: Parallel group

[0325] Blinding: Quadruple-blinded (participant, care provider, investigator, outcome assessor)

[0326] Primary purpose: Therapeutic

[0327] Groups and Interventions

[0328]

[0329] Outcome Measures

[0330] Primary outcome measures:

[0331] 1. The effect of deuterated domperidone on the reduction of severity of gastroparesis-related symptoms compared to baseline based on the composite of the mean scores on the ANMS GCSI-DD nausea subscale and the vomiting subscale [time frame: last 2 weeks of the 12-week treatment period compared to baseline]

[0332] Secondary outcome measures:

[0333] 1. The safety of deuterated domperidone [time frame: duration of study participation]

[0334] • The incidence of clinically significant changes in laboratory test parameters, physical examination findings, 12-lead ECG parameters, body weight measurements, and vital sign measurements in the investigator assessments;

[0335] • TEAEs;

[0336] • SAEs occurring during treatment;

[0337] • TEAEs leading to premature discontinuation of study drug; and

[0338] • Significant laboratory abnormalities occurring during treatment.

[0339] 2. Estimate based on the composite of the mean scores on the ANMS GCSI-DD nausea subscale and the vomiting subscale using PGIS and PGIC as anchors [time frame: last 2 weeks of the 12-week treatment period]

[0340] 3. The percentage of subjects showing a reduction >30% in composite score in subjects with a history of non-response or intolerance to metoclopramide treatment or other prokinetic agents [time frame: last 2 weeks of the 12-week treatment period compared to baseline]

[0341] Composite of the mean scores on the ANMS GCSI-DD nausea subscale and the vomiting subscale

[0342] 4. The percentage of subjects identified as responders, where a responder is defined as having a mean reduction of >0.5 points in their ANMS GCSI-DD nausea subscale and vomiting subscale scores from baseline [time frame: last 2 weeks of the 12-week treatment period]

[0343] 5. Percentage of subjects with a composite of ANMS GCSI-DD Nausea subscale and Vomiting subscale mean scores that are reduced by >30% from baseline [Time Frame: Last 2 weeks of 12-week treatment period]

[0344] 6. Percentage of subjects with a reduction of >30% in ANMS GCSI-DD Vomiting subscale mean score from baseline [Time Frame: Last 2 weeks of 12-week treatment period]

[0345] 7. Effect of deutetrabenazine on significant reduction in severity of gastroparesis-related symptoms from baseline [Time Frame: Last 2 weeks of 12-week treatment period, compared to baseline]

[0346] Based on ANMS GCSI-DD Nausea subscale mean score

[0347] 8. Effect of deutetrabenazine on significant reduction in severity of gastroparesis-related symptoms from baseline [Time Frame: Last 2 weeks of 12-week treatment period, compared to baseline]

[0348] Based on ANMS GCSI-DD Vomiting subscale mean score

[0349] 9. Percentage of subjects with a reduction of >30% in ANMS GCSI-DD Nausea subscale mean score from baseline [Time Frame: Last 2 weeks of 12-week treatment period]

[0350] 10. Effect of deutetrabenazine on significant reduction in severity of gastroparesis-related symptoms [Time Frame: Last 2 weeks of 12-week treatment period, compared to baseline]

[0351] Based on mean ANMS GCSI-DD Total score

[0352] 11. Percentage of subjects with a reduction of >30% in mean ANMS GCSI-DD Total score from baseline [Time Frame: Last 2 weeks of 12-week treatment period, compared to baseline]

[0353] 12. Effect of deutetrabenazine on significant reduction in severity of gastroparesis-related symptoms [Time Frame: Last 2 weeks of 12-week treatment period, compared to baseline]

[0354] Based on ANMS GCSI-DD Early satiety subscale mean score

[0355] 13. Effect of deutetrabenazine on significant reduction in severity of gastroparesis-related symptoms [Time Frame: Last 2 weeks of 12-week treatment period, compared to baseline]

[0356] Based on ANMS GCSI-DD Postprandial fullness subscale mean score

[0357] 14. Effect of deutetrabenazine on the severity of gastroparesis-related symptoms [time frame: last 2 weeks of 12-week treatment period compared to baseline]

[0358] Based on mean score on the ANMS GCSI-DD abdominal pain subscale

[0359] 15. Percentage of symptom-free days for ANMS GCSI-DD total score, nausea and vomiting composite score, nausea score, vomiting score, early satiety score, postprandial fullness score, and epigastric pain score after each dose of deutetrabenazine [time frame: last 2 weeks of 12-week treatment period]

[0360] Symptom day defined as > mild (ANMS GCSI-DD score > 2)

[0361] 16. All of the above endpoints [time frame: last 6 weeks of 12-week treatment period]

[0362] 17. Change in PGIS after each dose of deutetrabenazine [time frame: from baseline to Week 12]

[0363] 18. Change in PGIC after each dose of deutetrabenazine [time frame: from baseline to Week 12]

[0364] Inclusion Criteria

[0365] Key Inclusion Criteria:

[0366] • Male or female, age > 18 years;

[0367] • Diagnosis of type 1 or type 2 diabetes mellitus according to American Diabetes Association criteria;

[0368] • Current diagnosis of diabetic gastroparesis defined as follows:

[0369] a. Presence of gastrointestinal symptoms consistent with gastroparesis within 6 months prior to screening; and

[0370] b. Documentation of delayed gastric emptying within the past 2 years or willingness to complete a gastric emptying breath test.

[0371] • Body mass index (BMI) between 18 kg / m 2 and 45 kg / m 2 , inclusive;

[0372] • Glycosylated hemoglobin (HbAlc) level < 10% at screening;

[0373] • Willingness to wash out current ongoing treatment for gastroparesis.

[0374] Key Exclusion Criteria:

[0375] • Presence of other known causes of gastroparesis other than diabetes (e.g., idiopathic gastroparesis, and / or gastroparesis due to surgery, viral infection, cancer, scleroderma, or other neurological disease);

[0376] • History or evidence of clinically significant cardiac arrhythmias;

[0377] • History of pyloroplasty, pyloromyotomy, per-oral endoscopic myotomy, fundoplication, gastrectomy, vagotomy, or bariatric surgery;

[0378] • Currently receiving parenteral nutrition, or presence of a nasogastric or other enteral tube for feeding or decompression;

[0379] • Received a pyloric injection of botulinum toxin within 6 months prior to screening;

[0380] • Positive drug abuse test;

[0381] • Female subjects who are pregnant, lactating, or planning to become pregnant or breastfeed during the study.

[0382] Example 3

[0383] A. Study Objectives

[0384] (i) Primary Objective

[0385] The primary efficacy objective of this study is to assess the ability of deutetrabenazine to significantly reduce gastroparesis-related symptoms in adult subjects with diabetic gastroparesis, as compared to placebo, based on the combined value of the ANMS GCSI-DD nausea subscale and mean scores of emesis over the last 2 weeks of the 12-week treatment period, as compared to baseline.

[0386] (ii) Secondary Objectives

[0387] The secondary efficacy objectives of this study are to assess the effect of deutetrabenazine relative to placebo on adult subjects with diabetic gastroparesis on the following parameters:

[0388] • Percentage of responders showing a mean reduction of >0.5 points in the ANMS GCSI-DD nausea subscale and emesis scores from baseline over the last 2 weeks of the 12-week treatment period;

[0389] • Percentage of subjects with a reduction of >30% in the ANMS GCSI-DD nausea subscale and emesis scores from baseline over the last 2 weeks of the 12-week treatment period;

[0390] • Percentage of subjects showing clinical improvement in gastroparesis symptoms based on the combined value of the mean ANMS GCSI-DD nausea subscale and vomiting subscale scores over the last 2 weeks of the 12-week treatment period in subjects with a history of non-response or intolerance to metoclopramide treatment or other prokinetic agents (such as erythromycin, neostigmine, or bethanechol);

[0391] • Relationship between the ANMS GCSI-DD nausea subscale and vomiting subscale scores and the patient global impression of severity (PGIS) and patient global impression of change (PGIC) over the 12-week treatment period;

[0392] • Percentage of subjects showing clinical improvement in gastroparesis symptoms based on the combined value of the mean ANMS GCSI-DD nausea subscale and vomiting subscale scores over the last 2 weeks of the 12-week treatment period in subjects with a history of non-response or intolerance to metoclopramide treatment or other prokinetic agents (such as erythromycin, neostigmine, or bethanechol);

[0393] • Effect of deutetrabenazine on the significant reduction of gastroparesis-related symptoms from baseline compared to placebo based on the mean ANMS GCSI-DD total score and subscale scores over the last 2 weeks of the 12-week treatment period;

[0394] • Change in the combined value of the mean ANMS GCSI-DD nausea subscale and vomiting subscale scores from baseline to the last 2 weeks of the 12-week treatment period in subjects receiving treatment with a glucagon-like peptide-1 receptor agonist (GLP-1 RA);

[0395] • Percentage of responders showing a mean reduction of >0.5 points in the ANMS GCSI-DD nausea subscale and vomiting subscale scores from baseline to the last 2 weeks of the 12-week treatment period in subjects receiving treatment with a GLP-1 RA;

[0396] • Percentage of subjects showing a reduction of >30% in the ANMS GCSI-DD nausea subscale and vomiting subscale scores from baseline to the last 2 weeks of the 12-week treatment period in subjects receiving treatment with a GLP-1 RA;

[0397] • Change in the ANMS GCSI-DD total score and the combined value of gastroparesis-related symptoms from baseline to the last 2 weeks of the 12-week treatment period in subjects receiving treatment with a GLP-1 RA;

[0398] • All of the above primary and secondary objectives assessed over the last 2 weeks of the 12-week treatment period will also be assessed over the last 6 weeks of the 12-week treatment period;

[0399] • Change in PGIS from baseline; and

[0400] • Change in PGIC from baseline.

[0401] The secondary safety objectives include the assessment of the safety of deuterated domperidone compared to placebo in adult subjects with diabetic gastroparesis.

[0402] (iii) Exploratory Objectives

[0403] The exploratory efficacy objectives of the study include the assessment of the effect of deuterated domperidone versus placebo on the following in adult subjects with diabetic gastroparesis:

[0404] • The percentage of subjects showing a mean decrease of >0.5 points in ANMS GCSI-DD total and subscale scores from baseline in the last 2 weeks of the 12-week treatment period and in the last 6 weeks of the 12-week treatment period;

[0405] • The percentage of subjects showing a decrease of >30% in ANMS GCSI-DD total and subscale scores from baseline in the last 2 weeks of the 12-week treatment period and in the last 6 weeks of the 12-week treatment period;

[0406] • The estimation based on the mean ANMS GCSI-DD total and subscale scores using PGIS and PGIC as anchors during the 12-week treatment period;

[0407] • The effect of deuterated domperidone on the significant reduction of gastroparesis-related symptoms based on the mean score of the ANMS GCSI-DD bloating subscale compared to baseline;

[0408] • Change from baseline in the Patient Assessment of Upper Gastrointestinal Disorders Quality of Life (PAGI-QoL) questionnaire;

[0409] • Change from baseline in the Gastroesophageal Reflux Disease Questionnaire (GERDQ);

[0410] • Change from baseline to Week 12 in subjects’ hemoglobin A1 c (HbA1 c), insulin requirements, and diabetes medications;

[0411] • Change from baseline to Week 12 in gastric emptying;

[0412] • Effect on the percentage of days and days of use of any rescue medication;

[0413] • Exploratory analysis of the severity of vomiting involving the assessment of the primary and secondary objectives of the ANMS GCSI-DD Vomiting Score will be performed;

[0414] • Characterization of the absorption of deuterated domperidone and the concentration of its main metabolite at steady state; and

[0415] • The deuterated domperidone exposure-response relationship can also be characterized with various efficacy and / or safety measures.

[0416] B. Study Description

[0417] (i) Overview of Study Design

[0418] This is a randomized, double-blind, placebo-controlled, multi-center study to evaluate the efficacy and safety of deutetrabenazine in the treatment of adult subjects with diabetic gastroparesis over 12 weeks. See Figure 1 .

[0419] Safety of deutetrabenazine will be assessed from the time of signing the informed consent form until the end of the follow-up period. Efficacy and study drug adherence will be tracked in subjects throughout the double-blind treatment period. Plasma concentrations of deutetrabenazine will also be measured at selected visits during the double-blind treatment period.

[0420] The total duration of subject participation in the study will be approximately 18 weeks, including a <5-week screening and run-in period, a 12-week double-blind treatment period, and a maximum 1-week follow-up period. Subjects will complete 8 visits throughout their participation.

[0421] Subjects who sign the informed consent form and complete the screening and run-in periods and remain eligible will be randomly assigned in a 1 : 1 : 1 ratio in parallel to one of the following 3 treatment groups for 12 weeks:

[0422] • Deutetrabenazine 15 mg BID, administered as a single 10 mg capsule and a single 5 mg capsule;

[0423] • Deutetrabenazine 10 mg BID, administered as a single 10 mg deutetrabenazine capsule and a single placebo capsule; or

[0424] • Deutetrabenazine placebo BID, administered as 2 matching placebo capsules.

[0425] Approximately 400 subjects (approximately 133 per treatment group) will be randomized and it is expected that 363 subjects will complete the 12-week double-blind treatment period. Subjects will be stratified by birth gender (female, male) and by the combined value of the baseline ANMS GCSI-DD nausea subscale and vomiting severity mean scores (<2.6 versus >2.6).

[0426] Pharmacokinetics

[0427] All subjects:

[0428] • All subjects participating in the study will have trough concentration PK samples collected at Visit 5 and Visit 7. Trough concentration samples should be collected within 60 minutes prior to study drug dosing (as applicable). Subjects participating in PK Subgroup B only will need to be dosed at Visit 7.

[0429] • The subject will be instructed to record the date and time of each dose within 2 days prior to Visit 5 and Visit 7, and will be instructed not to take study drug at home on these visit days.

[0430] • The exact date and time of the immediately preceding dose prior to each collection of these samples will be recorded, and the exact date and time of each PK sample collection will be recorded.

[0431] • If a serious adverse event (SAE) or AE occurs that results in withdrawal from the study, a PK sample will be attempted as soon as possible. The date and time of the last study drug dose prior to PK sample collection, and the date and time of PK sample collection will be recorded.

[0432] PK Subgroup A:

[0433] • Subjects can choose to participate in PK Subgroup A, in which only a post-dose PK sample will be collected at Visit 5.

[0434] • Subjects should fast for at least 8 hours at the time of this visit; however, if it is determined that the subject should eat (e.g., due to low blood glucose level or symptoms of hypoglycemia) to ensure the subject’s safety, a small meal can be eaten > 2 hours prior to the morning study drug dose and / or < 3 hours after the dose. The time of the subject’s last meal prior to dosing will also be recorded.

[0435] • A PK blood sample will be collected within 60 minutes prior to study drug dosing.

[0436] • Subjects will stay at the clinical research center for up to 3 hours after the morning study drug dose, and blood samples will be collected at approximately 1 and 2 hours after the dose. If the subject is willing and able to stay at the clinical research center for a longer period of time, a PK sample will also be collected at approximately 3 hours after the dose.

[0437] • If the subject is willing to stay at the research center or return to the research center, additional samples can be collected within the following time windows on the same day as the dose:

[0438] o 4 to 8 hours; and / or

[0439] o 8 to 12 hours.

[0440] • The subject will be instructed to record the date and time of each dose within 2 days prior to these visits, and will be instructed not to take study drug at home on these visit days. Post-dose PK samples will be collected within ± 15 minutes of the nominal time. The exact date and time of study drug dosing and each PK sample collection on the visit day will also be recorded.

[0441] • Approximately 30 subjects in PK Subgroup A will complete Visit 5, at which time emerging PK and safety data will be evaluated, along with unblinding of individual subjects, to determine the dose levels that will be advanced for the remainder of the study. Upon review, additional subjects can be enrolled in PK Subgroup A. Subjects can also elect to participate in PK Subgroup B, described below.

[0442] PK Subgroup B:

[0443] • Once the initial data review of PK Subgroup A is complete, new subject subgroup can elect to participate in PK Subgroup B, in which subjects will provide post-dose samples at Visit 5, 6, and / or 7, which samples will be collected.

[0444] • At Visit 5 and Visit 7, subjects should be fasted for at least 8 hours at the time of the visit; however, if it is determined that the subject should eat (e.g., due to low blood glucose level or symptoms of hypoglycemia) to ensure the subject's safety, a small meal can be eaten > 2 hours prior to the morning study drug and / or < 3 hours after dosing. At Visit 6, subjects can take their study drug at home. For each such visit, the time of the subject's last meal prior to dosing will also be recorded.

[0445] • PK blood samples will be collected within 60 minutes prior to study drug dosing (only at Visit 5 and Visit 7) and 1 sample will be collected at the following post-dose time windows at Visit 5, 6, or 7:

[0446] o 1 hour to 4 hours; and / or

[0447] o 4 hours to 8 hours; and / or

[0448] o 8 hours to 12 hours.

[0449] For subjects who are willing to provide post-dose samples at more than one of the specified visits (Visit 5, 6, 7), the post-dose samples should be within different time windows. For example, if a subject provides a post-dose sample at Visit 5 within the 1 hour to 4 hour time window, the subject should provide a sample at a subsequent visit (Visit 6 or Visit 7) within the 4 hour to 8 hour or 8 hour to 12 hour time window. If a subject elects to provide post-dose PK samples at all 3 visits, and the Visit 6 sample is taken between 8 hours and 12 hours after dosing, the Visit 7 sample should be taken between 4 hours and 8 hours after dosing.

[0450] • For subjects who elect to provide more than one post-dose sample, efforts will be made to collect each sample within a different time window. Subjects will be instructed to record the date and time of each dose within 2 days prior to the visit, and will also be instructed not to take study medication at home on the day of Visit 5 and / or Visit 7. Post-dose PK samples will be collected within the nominal time ± 15 minutes. The exact date and time of study medication dosing and each PK sample collection on the visit day will also be recorded.

[0451] Interim Analysis

[0452] After PK Subgroup A evaluation, a blinded sample size re-estimation can be performed. This analysis is intended to ensure that the common standard deviation of the primary efficacy endpoint has not deviated substantially from the original assumption used in the sample size and power calculations. This blinded analysis will not stop the study for futility or ineffectiveness. Since the analysis will be based on blinded data, the Type I error rate is tightly controlled, and the final significance level (a) will not need to be adjusted as a result of the blinded data review.

[0453] During the study, once approximately 50% of the randomized subjects have completed the End of Treatment (EOT) visit or have prematurely discontinued, 1 interim analysis (IA) will be performed.

[0454] General Study Design and Procedures

[0455] At the screening visit, all subjects will sign an informed consent form prior to any study procedures being performed. Subjects must meet all inclusion criteria and not meet any exclusion criteria to be eligible for participation in the study.

[0456] Except as noted for GEBT and subjects electing to join the PK Subgroup, subjects are not required to fast overnight.

[0457] Subjects will be evaluated according to the following schedule:

[0458] • Screening period (Visit 1, Days -35 to -22):

[0459] o Screening procedures will be performed and subjects will begin to wash out any applicable disallowed medications. Subjects will be required to wash out all disallowed medications for at least 14 days or 5 half-lives, whichever is longer, prior to the start of the ANMS GCSI-DD baseline period (defined as 14 days prior to randomization) and / or prior to Visit 2 GEBT; and

[0460] o From the screening visit, subjects will record ANMS GCSI-DD, PAGI-QoL, GERDQ, PGIS, and, if allowed, rescue medication use.

[0461] • Run-in period (Visit 2, Days -21 to -1):

[0462] In addition to the clinic site visits, telephone visits can be completed during this period to assess subject diary recording compliance, concomitant medications, and AEs. If a subject requires additional assessments that require an additional visit to the clinic site, the subject can be admitted to the clinic site to complete the additional procedures that are not part of the scheduled visit.

[0463] o Subjects will be required to continue to complete the ANMS GCSI-DD questionnaire daily and record use of rescue medication allowed daily;

[0464] o The mean of the daily measurements of the ANMS GCSI-DD obtained within 14 days prior to randomization will constitute the "baseline" measurement; and

[0465] o GEBT: The GEBT will be completed in a single day, ideally within days -21 to -12; however, it can be performed outside of this window if there is sufficient time to perform the GEBT analysis prior to randomization. The GEBT will be performed after at least 14 days or 5 half-lives of washout, whichever is longer. Subjects will fast for at least 8 hours prior to the GEBT and for 4 hours after completion of the GEBT test meal. Subjects who are actively using nicotine-containing products must refrain from using these products from the time they wake up on the morning of the GEBT day until the completion of the test. The GEBT will be performed after ingestion of a standardized, high-calorie 13C. Breath samples will be collected twice pre-meal, and then at 45, 90, 120, 150, 180, and 240 minutes post-meal. The meal should be consumed within 10 minutes. Fasting blood glucose will be assessed prior to GEBT to ensure blood glucose levels < 275 mg / dL. If a subject’s fasting blood glucose level is > 275 mg / dL despite the use of corrective insulin, the GEBT will not be performed. During the run-in period, subjects will be allowed to return to the study center to complete testing over the next 1 to 3 days, or can be excluded from the study if they no longer meet the criteria for stable and well-controlled blood glucose. On the day of the GEBT, subjects should report to the clinical research center after an overnight fast and should take their regular medications (including any diabetes treatment medications) with the exception of any prohibited concomitant medications. Subjects requiring insulin will self-inject their regular morning insulin according to their fasting status. Subjects will be instructed to bring insulin to the clinical research center as needed. Fasting blood glucose will be assessed prior to gastric emptying assessment to ensure blood glucose < 275 mg / dL. Additional insulin can be given (dose adjusted based on caloric content of the meal) to ensure blood glucose < 275 mg / dL prior to the gastric emptying procedure. Hypoglycemia (hypoglycemia; blood glucose < 60 mg / dL) should be managed. Baseline GEBT is preferred to be performed during the run-in period (Visit 2, Day -21 to Day -12), however, baseline GEBT can be performed outside of the specified Day -21 to Day -12 time window as long as the date of the trial is such that there is sufficient time to complete GEBT analysis prior to the intended randomization date. If the subject arrives at the clinical research center for Visit 1 without having taken any prohibited medications and meets all the required criteria specified in the protocol (e.g., fasted for at least 8 hours, blood glucose level < 275 mg / dL, etc.), the procedures for Visit 1 and Visit 2 can be performed on the same day.

[0466] • 12-week double-blind treatment period (Visits 3 through 7, Days 1 through 84):

[0467] o Compliance with the ANMS GCSI-DD will be assessed at randomization (Day 1) and must be > 75% to be eligible for participation in the study;

[0468] o Study drug (deuterated domperidone capsules and / or placebo capsules) will be administered for 84 (± 4) days and safety assessments will be performed;

[0469] o Use of permitted rescue medication will be recorded daily;

[0470] o The ANMS GCSI-DD questionnaire will be completed daily at approximately the same time in the evening;

[0471] o PAGI-QoL and GERDQ will be completed at the clinical research center at Visit 3 (prior to first study drug dosing) and Visits 4, 5, 6, and 7; and

[0472] o All subjects participating in the study will have trough concentration PK samples collected at Visit 5 and Visit 7. Trough concentration samples should be collected within 60 minutes prior to study drug dosing (as applicable). Subjects participating in PK Subgroup B only will need to be dosed at Visit 7. Subjects will be instructed to record the date and time of each dose within 2 days prior to Visit 5 and Visit 7, and will also be instructed not to take study drug at home on the day of these visits. The exact date and time of each dose immediately prior to the collection of these samples will be recorded, and the exact date and time of each PK sample collection will be recorded.

[0473] o PK Subgroup A:

[0474] Subjects can choose to participate in PK Subgroup A, in which only post-dose PK samples will be collected at Visit 5. A PK blood sample will be collected within 60 minutes prior to study drug dosing. Subjects will stay at the clinical research center for up to 3 hours after the morning dose of study drug, and blood samples will be collected at approximately 1 hour and 2 hours after dosing. If the subject is willing and able to stay at the clinical research center for a longer period of time, a PK sample will also be collected at approximately 3 hours after dosing. If the subject is willing to stay at the research center or return to the research center, additional samples can be collected within the following time windows on the same day as dosing: 4 hours to 8 hours; and / or 8 hours to 12 hours. Subjects will be instructed to record the date and time of each dose within 2 days prior to these visits, and will also be instructed not to take study drug at home on the day of these visits. Post-dose PK samples will be collected within the nominal time ± 15 minutes. The exact date and time of study drug dosing and each PK sample collection on the visit day will also be recorded. Subjects can continue to be enrolled in PK Subgroup A. Subjects can also choose to participate in PK Subgroup B, described below.

[0475] o PK Subgroup B:

[0476] Once the initial data review for PK Subgroup A is complete, a new subgroup of subjects can choose to participate in PK Subgroup B, in which subjects will provide additional post-dose samples at one or more of the following post-dose time windows at Visit 5, 6, and / or 7: 1 hour to 4 hours, 4 hours to 8 hours, 8 hours to 12 hours. For subjects willing to provide post-dose samples at more than one of the specified visits (Visit 5, 6, 7), the post-dose samples should be within different time windows. Subjects will be instructed to record the date and time of each dose within 2 days prior to Visit 5, Visit 6, and / or Visit 7, and will be instructed not to take study drug at home on the day of Visit 5 and / or Visit 7. Post-dose PK samples will be collected within the nominal time ± 15 minutes. The exact date and time of study drug dosing and each PK sample collection on the visit day will also be recorded;

[0477] o Subjects can elect to complete additional GEBT at Visit 7 (EOT) / ET, and will follow all requirements noted above for GEBT during the run-in period. If a subject’s fasting glucose level is >275 mg / dL despite the use of correction insulin, no GEBT will be performed at this or any future visit, and the remaining procedures will be performed to complete EOT;

[0478] o Safety will be assessed by evaluation of AEs, vital signs, physical examinations, clinical laboratory tests (biochemical, hematology, coagulation, urinalysis, and prolactin), and 12-lead electrocardiogram (ECG) results; and

[0479] o In addition, an optional pharmacogenomic (PGx) blood sample can be collected at any time during the treatment period.

[0480] • Follow-up period: (Visit 8, Day 91 [±3 days]):

[0481] o Subjects will have one follow-up visit approximately 1 week (±3 days) after the last study drug administration to assess AEs, changes in concomitant medications (including use of rescue medication), vital signs, 12-lead ECG, prolactin, biochemistry, hematology, and coagulation function.

[0482] Unscheduled visits and / or additional follow-up visits can be required. For example, subjects with the following can require further assessment: clinically significant laboratory test abnormal results, unresolved TEAEs, SAEs requiring follow-up laboratory tests and review, or clinically significant AEs.

[0483] C. Screening and Withdrawal of Subjects

[0484] (i) Inclusion Criteria

[0485] Subjects who meet all of the following criteria based on screening assessments will be eligible to participate in the study:

[0486] 1. Male or female who is >18 years of age;

[0487] 2. Diagnosed with type 1 or type 2 diabetes mellitus according to American Diabetes Association criteria;

[0488] 3. Currently diagnosed with diabetic gastroparesis, defined as follows:

[0489] a. Presence of persistent gastrointestinal symptoms consistent with gastroparesis (e.g., postprandial nausea / vomiting, postprandial fullness, early satiety, abdominal distension, and / or epigastric / abdominal pain) within 6 months prior to screening; and

[0490] b. Documented delayed gastric emptying as determined by GEBT, scintigraphy, or manometry. Although every effort should be made to obtain a previous gastric emptying record, if this information is not available, a GEBT completed during the run-in period can be used to fulfill this criterion.

[0491] 4. Body mass index (BMI) between 18kg / m2 at screening 2 and 45kg / m 2 Between (including end values);

[0492] 5. HbA1c level ≤ 10% at screening, and blood sugar is stable and well controlled;

[0493] 6. Patients currently receiving GLP-1RA therapy may be considered for inclusion in the study if all of the following criteria are met:

[0494] a. Have received stable doses of GLP-1RA for at least 3 months before screening and are expected to maintain the same dose during GEBT and the entire study;

[0495] b. GLP-1RA is well tolerated;

[0496] c. No qualifying signs / symptoms of gastroparesis (e.g., postprandial nausea / vomiting, postprandial fullness, early satiety, bloating, or epigastric / abdominal pain) are attributable solely to GLP-1RA use; and

[0497] d. Gastroparesis symptoms occurred before the start of GLP-1RA treatment.

[0498] 7. Male subjects with female partners of reproductive potential must agree to use two medically recognized effective contraceptive methods from day 1 to 90 days after the last dose of study drug. Medically recognized effective contraceptive methods for male subjects with female partners of reproductive potential include the following methods:

[0499] ○ Latex condoms containing spermicide;

[0500] A cervical cap containing an intravaginal spermicide;

[0501] ○ Cervical cap with spermicide;

[0502] ○ Indwelling intrauterine device (hormonal or non-hormonal);

[0503] ○ Implantable contraceptives;

[0504] ○ Oral contraceptives; and

[0505] ○ Vasectomy (if performed at least 6 months before study drug administration).

[0506] 8. Male subjects must agree to refrain from sperm donation from day 1 to 90 days after the last dose of study drug;

[0507] 9. Female subjects with a male partner must meet one of the following conditions: surgical sterilization (hysterectomy and / or bilateral oophorectomy), postmenopausal status (defined as age > 50 years, natural amenorrhea for at least 1 year, and follicle-stimulating hormone level in the postmenopausal range as defined by the laboratory at the time of screening visit), or agree to use 2 medically accepted effective methods of contraception from Day -14 to 60 days after the last study drug administration. Medically accepted effective methods of contraception for female subjects with a male partner include the following:

[0508] • Latex condoms with a spermicide;

[0509] • Cervical cap with intravaginal spermicide;

[0510] • Cervical cap with spermicide;

[0511] • Intrauterine device (hormonal and non-hormonal);

[0512] • Male partner has had a vasectomy (if performed at least 6 months prior to study drug administration); and

[0513] • Implantable or oral contraceptives.

[0514] 10. Willing and able to avoid the use of pramlintide from the Screening Period through EOT; and

[0515] 11. Able to understand and comply with all study visits, procedures, restrictions, washout requirements, including discontinuation of medications for treatment of gastroparesis (as specified in the study protocol), and to sign a written informed consent in accordance with institutional and regulatory guidelines.

[0516] (ii) Exclusion Criteria

[0517] Subjects meeting any of the following criteria will be excluded from participation in the study:

[0518] 1. Presence of other known primary causes of gastroparesis other than diabetes (e.g., idiopathic gastroparesis, gastroparesis attributed to surgery, viral infection, cancer, medications, scleroderma, or other neurological disorders);

[0519] 2. Hospitalization for diabetic gastroparesis and / or diabetic ketoacidosis within 1 year prior to Visit 1;

[0520] 3. Presence of a history or current history of clinically significant cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes;

[0521] 4. Evidence (based on screening or baseline assessments) or history of clinically significant immune, hematologic, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disorders (including drug allergies); surgical procedures; cancer (except basal cell or squamous cell skin cancers, and except cancers that have been cured or are in remission for >5 years prior to the screening visit); or any condition that might significantly interfere with the absorption, distribution, metabolism, or excretion of the study drug. Cholecystectomy and appendectomy are allowed if they occurred >6 months prior to screening;

[0522] 5. History of prolactin-secreting pituitary tumor (e.g., prolactinoma);

[0523] 6. Known or suspected hypogonadism, current presence of clinically significant menstrual abnormalities (e.g., oligo- or amenorrhea), gynecomastia, galactorrhea, or other clinical features that can be consistent with hyperprolactinemia;

[0524] 7. Received an intraduodenal injection of botulinum toxin within 6 months prior to screening and / or plans to receive such an injection during the study;

[0525] 8. History of pyloroplasty, pyloromyotomy, or per-oral endoscopic pyloromyotomy;

[0526] 9. Total bilirubin, alkaline phosphatase, AST, or ALT levels >2x ULN at screening, or Child-Pugh classification of B or C;

[0527] 10. Estimated glomerular filtration rate <30 mL / min / 1.73 m2 using the Chronic Kidney Disease Epidemiology Collaboration equation at screening; 2 ;

[0528] 11. Abnormal thyroid-stimulating hormone level at screening;

[0529] 12. Inability to perform GEBT, or fasting plasma glucose ≥275 mg / dL on the day of baseline GEBT (Visit 2). If a subject’s fasting plasma glucose level remains ≥275 mg / dL despite the use of corrective insulin, GEBT will not be performed. During the run-in period, subjects will be allowed to return to the study center within the next 1 to 3 days to complete the baseline GEBT test, or can be excluded from the study if the subject no longer meets the criteria for stable and well-controlled glycemia (Inclusion Criterion 5). Subjects who are actively using nicotine-containing products must refrain from using these products from the time they wake up on the morning of the day of GEBT until the completion of the test;

[0530] 13. Known allergy to eggs or spirulina;

[0531] 14. Use of investigational, prescription, or over-the-counter medications as follows:

[0532] a. is actively participating in an experimental treatment study; received a small molecule experimental treatment within 30 days or 5 half-lives (whichever is longer) prior to randomization; or received a large molecule experimental treatment within 90 days or 5 half-lives (whichever is longer) prior to randomization;

[0533] b. inhibitors and inducers of CYP3A4 (whether drugs, herbal supplements, dietary supplements, nutraceuticals, or foods):

[0534] ■For subjects selected to provide pharmacokinetic (PK) samples in addition to trough concentration samples at Visit 5 and Visit 7: all CYP3A4 inhibitors and / or inducers are prohibited from 14 days or 5 half-lives (whichever is longer) prior to first study drug dosing through the end of the study;

[0535] ■For all other subjects: strong CYP3A4 inhibitors and / or inducers are prohibited from 14 days or 5 half-lives (whichever is longer) prior to first study drug dosing through the end of the study. Weak and moderate CYP3A4 inhibitors and inducers are permitted; and

[0536] ■For all subjects, grapefruit, grapefruit products, starfruit products, and Seville oranges are prohibited from 48 hours prior to randomization through the end of the study.

[0537] c. Use of prokinetic drugs (including but not limited to metoclopramide, domperidone, erythromycin, pyridostigmine, etc.), other drugs and therapies that can affect gastric emptying (e.g., all anticholinergic drugs), and antiemetics (except for rescue antiemetics as specified in the study protocol) within 7 days or 5 half-lives (whichever is longer) prior to baseline GEBT (Visit 2) and / or start of ANMS GCSI-DD baseline period (defined as 14 days prior to randomization) and avoidance of use through the end of the study;

[0538] d. Participation in regular, scheduled use of opioid medications or anticipated need for regular use of opioid medications during the study. Prescription non-extended release opioid medications for up to a 72-hour course are permitted during the study treatment period. If any subject is using an opioid medication prior to GEBT, they must discontinue use at least 72 hours or 5 half-lives (whichever is longer) prior to the start of GEBT.

[0539] e. Daily use of cannabis and / or tetrahydrocannabinol (THC)-containing products. If a subject is not using THC daily and is using the product for medical reasons (as noted in exclusion criterion 15), they can still be considered for inclusion in the study;

[0540] f. Use of variable-dose antidepressants, anxiolytics, antipsychotics, or prescription sleep aids within 3 months prior to screening; and

[0541] g. Use of a medication known to prolong the QT interval, herbal supplement, dietary supplement, or nutraceutical from 28 days prior to first study drug administration through the end of the study.

[0542] 15. Positive drug or alcohol test result at screening with no medical explanation, or a history of alcohol or drug abuse within 2 years prior to screening as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4thEdition, and / or a usual weekly alcohol consumption of > 14 drinks. One drink is equivalent to ½ pint of beer (285 mL), 1 shot of liquor (25 mL), or 1 glass of wine (125 mL). If a false positive is suspected, a confirmatory drug or alcohol test can be performed using a different method. Cannabinoid testing is only performed at screening. Subjects with a positive THC test at Visit 1 can still be eligible to continue in the study if they have a prescription for the substance and agree to avoid daily use of THC-containing products during the study. Subjects receiving a stable, non-daily dosing regimen must agree to abstain from prescribed cannabis and / or THC-containing products for > 24 hours prior to the GEBT. The study site must have explicit understanding of the frequency of use and document in the source records. Cannabinoid test result non-exclusion factors, subjects with a positive test can still be eligible to continue in the study. Subjects who are actively using nicotine-containing products should maintain a generally stable frequency of use during the study, with the exception of the day of the GEBT, during which subjects must abstain from using these products from the time they wake up on the morning of the GEBT until the end of the test;

[0543] 16. Evidence of current use of illicit recreational drugs;

[0544] 17. Known history of or current eating disorder within 2 years prior to the screening visit;

[0545] 18. Positive test result for human immunodeficiency virus antibody, RNA-confirmed hepatitis C virus antibody, or hepatitis B surface antigen at the screening visit;

[0546] 19. Current treatment with a weight loss medication or prior receipt of a weight loss surgery (e.g., gastric bypass surgery);

[0547] 20. Pregnancy, lactation, or planning to become pregnant or breastfeed during the study;

[0548] 21. Inability to swallow medication;

[0549] 22. Current treatment with parenteral nutrition or presence of a nasogastric or other enteral tube for feeding or decompression (e.g., percutaneous endoscopic gastrostomy [PEG] tube or percutaneous endoscopic jejunostomy [PEJ] tube);

[0550] 23. Known or suspected presence of gastric outlet obstruction (e.g., peptic stricture) or other mechanical obstruction of the gastrointestinal tract, documented by upper endoscopy or upper GI series within the last 2 years;

[0551] 24. Known history or current diagnosis of intestinal malabsorption or pancreatic exocrine disease;

[0552] 25. History of severe constipation defined as meeting 2 of the following criteria over the past 3 months or longer: < 2 spontaneous bowel movements per week (e.g., without use of laxative induction); > 25% of stools are lumpy and / or hard; > 25% of bowel movements are incomplete; > 25% of bowel movements require straining; and / or reliance on (i.e., daily use of) osmotic or stimulant laxatives;

[0553] 26. History of gastric surgery such as fundoplication, gastrectomy, vagotomy, pyloroplasty, or bariatric surgery. Subjects with a gastric pacemaker can be considered for inclusion if the pacemaker can be turned off for > 14 days prior to the start of the ANMS GCSI-DD Baseline Period and remain off for the remainder of the study. History of diagnostic endoscopy does not constitute an exclusion;

[0554] 27. History of any medical condition or psychiatric illness that might interfere with study conduct or would subject the subject to unacceptable risk;

[0555] 28. Prior demonstrated lack of response to domperidone, or known hypersensitivity or intolerance to domperidone or any of the excipients in the deuterated domperidone formulation; or

[0556] 29. Inappropriate for participation for any other reason that might increase the subject’s risk of participation or interfere with interpretation of study results.

[0557] (iii) Randomization Criteria

[0558] Subjects meeting the following criteria will be randomized at Visit 3 (Day 1):

[0559] 1. Continue to meet all inclusion / exclusion criteria;

[0560] 2. Motility medications (including but not limited to metoclopramide, domperidone, erythromycin, pyridostigmine, etc.), other medications and therapies that may affect gastric emptying (e.g., all anticholinergics), and antiemetics (except for rescue antiemetics specified in the study protocol) must have been discontinued within 7 days or 5 half-lives (whichever is longer) prior to the baseline GEBT (Visit 2) and / or the start of the ANMS GCSI-DD baseline period (defined as 14 days prior to randomization), and their use must be avoided until the end of the study. Subjects who meet the criteria for GLP-1RA use (Inclusion Criteria 6) are not required to discontinue their GLP-1RA before the GEBT and should maintain their prescribed dose. Subjects who actively use nicotine-containing products must abstain from these products from the time they wake up on the morning of the GEBT until the completion of the test. Subjects must agree to abstain from opioid use for ≥72 hours or 5 half-lives (whichever is longer) prior to the GEBT. Subjects receiving a stable, non-daily dosing regimen were required to agree to abstain from prescription cannabis and / or THC-containing products for ≥24 hours prior to GEBT;

[0561] 3. Proof of a confirmed diagnosis of diabetic gastroparesis, as defined below:

[0562] a. Persistent 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; and

[0563] b. During the introduction period 13 C-Spirulina platensis GEBT confirms documentation of symptoms of delayed gastric emptying (GEBT is ideally performed between Days -21 and -12 but can be performed outside this time window if sufficient time is available for GEBT analysis before randomization). The GEBT must include kPCD values ​​within 240 minutes and should show peak excretion at 240 minutes (e.g., maximum kPCD at 240 minutes) and / or kPCD values ​​at 90 minutes, 120 minutes, or 150 minutes that are below the corresponding standard cutoff values.

[0564] 4. During the baseline period (i.e., 14 days before randomization) (subjects did not take motility drugs or antiemetics, except for rescue medications specified in the study protocol), the ANMS GCSI-DD score met the following conditions:

[0565] a. Weekly average nausea subscale score ≥ 2 (“moderate” or worse);

[0566] b. No day had a nausea subscale score of 0 ("none"); and

[0567] c. Mean >1 episode of vomiting (of any severity) per week. Emesis is defined clinically as the expulsion of gastrointestinal contents through the mouth as a result of contraction of the intestinal and abdominal wall muscles; whereas regurgitation is defined as the effortless return of stomach contents to the mouth. Subjects should be informed of the difference between vomiting and regurgitation (regurgitation is defined as the act of bringing food swallowed back up to the mouth), and episodes of vomiting should be recorded accordingly.

[0568] 5. Compliance with ANMS GCSI-DD during the Baseline Period, defined as >75% compliance.

[0569] D. Study Treatment

[0570] (i) Treatment Groups

[0571] The study is planned to enroll 3 treatment groups, with 133 subjects in each group.

[0572] Subjects who sign the informed consent form and remain eligible after completing the Screening and Run-in Periods will be randomly assigned in a 1:1:1 ratio to one of the following 3 treatment groups in parallel for 12 weeks:

[0573] • Deutetrabenazine 15 mg BID, administered as a single 10 mg capsule and a single 5 mg capsule;

[0574] • Deutetrabenazine 10 mg BID, administered as a single 10 mg deutetrabenazine capsule and a single placebo capsule; or

[0575] • Deutetrabenazine placebo BID, administered as 2 matching placebo capsules.

[0576] (ii) Drug Supply

[0577] (a) Formulations and Packaging

[0578] Deutetrabenazine drug product capsules are made from deutetrabenazine drug substance and are 2C, oval, blue, opaque soft gel capsules. Each deutetrabenazine soft gel capsule will contain 10 mg or 5 mg of active deutetrabenazine drug substance. The deutetrabenazine fill formulation composition contains the non-active ingredients in Table 4.

[0579]

[0580] Matching placebo soft gel capsules will also be provided (Table 5) with a formulation composition containing the same non-active ingredients (without deutetrabenazine drug substance).

[0581]

[0582] Soft gel capsules (capsules containing deuterated pipamperone drug substance and placebo capsules) will be packaged in a blister pack to meet the dose requirements of the study.

[0583] (b) Study Drug Administration

[0584] All randomized subjects will orally take one dose of blinded study drug (deuterated pipamperone and / or placebo capsules) with approximately 240 mL of water. For a particular individual, an approximately 12-hour interval will be maintained between each dose administration (e.g., 8:00 AM to 8:00 PM). Subjects will be required to fast for 2 hours prior to all dose administrations and for 1 hour after dose administration. Subjects participating in PK Subcohort B only will be required to dose at Visit 7. PK Subcohort subjects who will be provided with post-dose PK samples at Visits 5, 6, and / or 7 will be required to fast for at least 8 hours prior to the morning dose of study drug and for > 3 hours after study drug administration. However, if it is determined that the subject should eat (e.g., due to low blood glucose level or symptoms of hypoglycemia) to ensure the subject’s safety, a small meal can be consumed > 2 hours prior to the morning dose of study drug and / or > 3 hours after dose administration. Subjects who elect to complete the GEBT at Visit 7 will be required to fast for at least 8 hours prior to the start of the GEBT test meal (or fast prior to the morning dose of study drug, as applicable) and for 4 hours after completion of the GEBT test meal.

[0585] Subjects will be provided with study drug for self-administration of doses that are not administered at the study center.

[0586] If a subject misses a scheduled dose administration and realizes the missed dose within 2 hours of the scheduled dose administration, the subject will be instructed to take their assigned dose of study drug as soon as they realize the missed dose. If a subject realizes the missed dose more than 2 hours after the scheduled dose administration, the subject will be instructed to skip the missed dose of study drug and resume taking their assigned dose of study drug at the next scheduled time.

[0587] If a subject vomits after taking a scheduled dose of study drug, the subject will be instructed to record the time of study drug administration and the time of vomiting and resume taking their assigned dose of study drug at the next scheduled time. During the treatment period, subjects will be asked to record the time of vomiting in relation to the time of study drug administration as closely as possible and report to study center personnel during scheduled clinical study center visits. For subjects who elect to participate in the PK Subcohort, if vomiting occurs within the first 4 hours after dose administration and prior to completion of post-dose PK sampling for that visit, the PK sampling will be discontinued. However, samples collected prior to vomiting will be analyzed.

[0588] Subjects in the PK subcohort will be instructed to record the date and time of each dose within the applicable 2 days prior to Visit 5, Visit 6, and / or Visit 7, and will be instructed not to take study drug at home on the day of Visit 5 and / or Visit 7.

[0589] The exact date and time of study drug dosing and each PK sample collection on the visit day will also be recorded.

[0590] (ii) Prior and Concurrent Medications and / or Procedures

[0591] (a) Prohibited Medications, Foods, and / or Procedures

[0592] The following investigational drugs, prescription drugs, or nonprescription drugs are not allowed during the study period:

[0593] • Pramlintide, which is prohibited from the start of the Screening Period through the end of the study (EOT);

[0594] • Variable doses of GLP-1 RAs;

[0595] • Small molecule experimental treatments within 30 days or 5 half-lives (whichever is longer) prior to randomization; or large molecule experimental treatments within 90 days or 5 half-lives (whichever is longer) prior to randomization;

[0596] • Inhibitors and inducers of CYP3A4 (whether drugs, herbal supplements, dietary supplements, nutraceuticals, or food):

[0597] o For subjects selected to provide PK samples in addition to trough concentration samples at Visit 5 and Visit 7: All CYP3A4 inhibitors and / or inducers are prohibited from 14 days or 5 half-lives (whichever is longer) prior to the first study drug dose through the end of the study;

[0598] o For all other subjects: Strong CYP3A4 inhibitors and / or inducers are prohibited from 14 days or 5 half-lives (whichever is longer) prior to the first study drug dose through the end of the study. Weak and moderate CYP3A4 inhibitors and inducers are allowed; and

[0599] o For all subjects, the use of grapefruit, grapefruit products, starfruit products, and Seville oranges is prohibited from 48 hours prior to randomization through the end of the study.

[0600] • Use of drugs, herbal supplements, dietary supplements, or nutraceuticals known to prolong the QT interval from 28 days prior to the first study drug dose through the end of the study;

[0601] • Use of motility drugs (including but not limited to metoclopramide, domperidone, erythromycin, pyridostigmine, etc.), other drugs and therapies that may affect gastric emptying (e.g., all anticholinergic drugs), and antiemetics (except for rescue antiemetics specified in the study protocol) within 7 days or 5 half-lives (whichever is longer) before baseline GEBT (Visit 2) and / or the start of the ANMS GCSI-DD baseline period (defined as 14 days before randomization), and avoid their use until the end of the study;

[0602] • Regular opioid use or anticipated regular opioid use during the study period. Prescription non-extended-release opioids are permitted for up to 72 hours during the study treatment period. If any subject is using opioids prior to GEBT, they must be discontinued at least 72 hours or five half-lives (whichever is longer) before the start of GEBT.

[0603] • Daily use of cannabis and / or THC-containing products. Subjects who do not use THC daily and who use the products for medical reasons may still be considered for inclusion in the study. Subjects who test positive for THC at Visit 1 may remain eligible to continue in the study if they hold a prescription for the substance and agree to refrain from daily use of THC-containing products during their participation in the study. Subjects on a stable, non-daily dosing regimen must agree to abstain from prescription cannabis and / or THC-containing products for ≥24 hours prior to the GEBT. The frequency of use must be clearly understood by the study center and documented in the original records. Cotinine test results are not an exclusion factor; subjects who test positive remain eligible to continue in the study. Subjects who actively use nicotine-containing products should maintain a roughly stable frequency of use during the study, with the exception of the day of the GEBT, when subjects must abstain from these products from the time they wake up on the morning of the GEBT until the completion of the test;

[0604] •Variable doses of antidepressants, antianxiety medications, antipsychotics, or prescription sleep aids;

[0605] • Received a botulinum toxin injection into the pylori area within 6 months prior to screening and / or planned to receive such an injection during the study;

[0606] •Took weight loss medication or had previous weight loss surgery (e.g., gastric bypass surgery);

[0607] • Receiving parenteral nutrition, or having a nasogastric or other enteral tube (e.g., PEG or PEJ tube) for feeding or decompression;

[0608] • Dependence on (i.e., daily use of) osmotic or stimulant laxatives;

[0609] • Gastric pacemaker that cannot be turned off for > 14 days prior to the start of the ANMS GCSI-DD Baseline Period and remain off for the remainder of the study.

[0610] Subjects who require continued treatment with a prohibited medication can be discontinued from study treatment and complete the subsequent study procedures.

[0611] (b) Medications and / or Procedures to Limit Use

[0612] Subjects who develop symptoms of severe gastroparesis can receive promethazine (Phenergan ® ) 25 mg or ondansetron (Zofran ® ) 4 mg.

[0613] (c) Medications and / or Procedures to Allow Use

[0614] For subjects not participating in the PK subcohort, use of weak and moderate CYP3A4 inhibitors and inducers is permitted.

[0615] Permitted for subjects who meet the eligibility criteria to continue use of a stable dose of GLP-1 RA.

[0616] If a subject has been stable on a dose of an antidepressant, anxiolytic, or a prescription sleep aid for > 3 months prior to screening, they are permitted to continue use of the medication.

[0617] If needed, subjects will be permitted to use an opioid medication for severe pain relief only once during the treatment period (non-extended release formulation for a maximum of 72-hour course of therapy).

[0618] Use of other medications not previously explicitly excluded (e.g., rescue medications) is permitted.

[0619] Antacids, histamine-2 receptor antagonists, and proton pump inhibitors should only be used within ± 2 hours of study drug dosing. These medications can affect the oral bioavailability of deuterated domperidone.

[0620] (d) Emergency Medications

[0621] Subjects who develop symptoms of severe gastroparesis during the study can receive promethazine (Phenergan) 25 mg or ondansetron (Zofran) 4 mg orally as needed, as prescribed by the local site.

[0622] Subjects should be encouraged to use over-the-counter ginger products (e.g., capsules, soft chewable tablets, gum, oil, or tea) prior to using promethazine or ondansetron, with a maximum daily dose of 1000 mg once daily.

[0623] During the washout period (Day -35 to Day -22), subjects can take rescue medications as needed.

[0624] However, during the 3-week run-in period (Day -21 to Day -1), subjects who experience severe gastroparesis symptoms can use the rescue medication for only 3 days per week and only a single dose per day of either diphenhydramine 25 mg, ondansetron 4 mg, or over-the-counter ginger products.

[0625] During the ANMS GCSI-DD baseline period, subjects should be strongly encouraged to avoid the use of rescue medication as much as possible, and if it must be used, to use as little as possible. During the 14-day ANMS GCSI-DD baseline period, if a subject uses rescue medication for more than 3 days per week and / or exceeds the daily limit of rescue medication as noted above, the subject can be discontinued from the study after review.

[0626] After randomization, the use of rescue medication will be limited to a maximum of 3 days per week and 1 dose per day only when the subject experiences nausea and / or vomiting of Grade 2 or greater Common Terminology Criteria for Adverse Events (CTCAE). If a subject uses rescue medication for 3 days per week and 1 dose per day for two consecutive weeks, and is confirmed by the site staff, the subject will be discontinued from study drug for lack of efficacy, but will be encouraged to remain in the study to complete the remaining study procedures and assessments. These subjects will be required to complete the ET visit and then continue to complete the remaining study visits and procedures unless consent is withdrawn. The frequency of rescue medication use will be recorded from the screening period through the EOT / ET period; during the follow-up period, it will be recorded as concomitant medication, and the site staff will confirm these records. Subjects who require continued treatment with prohibited medication can be discontinued from study treatment and complete subsequent study procedures.

[0627] Subjects should enter the ANMS GCSI-DD daily to describe the most severe degree of each symptom over the past 24 hours. Thus, the ANMS GCSI-DD questionnaire score should reflect the most severe degree of each symptom score.

[0628] (e) General Requirements and Dietary Restrictions

[0629] During the study, subjects should maintain their regular diet and lifestyle at all times.

[0630] For all subjects, the use of grapefruit, grapefruit products, starfruit products, and Seville oranges is prohibited from 48 hours prior to randomization through the EOT period.

[0631] Subjects will be required to fast for 2 hours prior to all dose administrations and for 1 hour after dose administration.

[0632] Subjects will be required to fast for at least 8 hours prior to the scheduled GEBT and for 4 hours after completing the GEBT test meal.

[0633] PK Subgroup subjects who will provide post-dose PK samples at Visits 5, 6, and / or 7 will be required to fast for at least 8 hours prior to morning study drug administration and fast for > 3 hours after study drug administration.

[0634] E. Efficacy Assessments

[0635] (i) Efficacy Endpoints

[0636] (a) Primary Efficacy Endpoint

[0637] The primary efficacy endpoint of this study is to assess the effect of deutetrabenazine on significantly reducing gastroparesis-related symptoms in adult subjects with diabetic gastroparesis, as compared to placebo, based on the combined value of the ANMS GCSI-DD nausea subscale and vomiting mean scores over the last 2 weeks of the 12-week treatment period, as compared to baseline.

[0638] (b) Secondary Efficacy Endpoints

[0639] The secondary efficacy endpoints of this study include the following assessments of the treatment effect difference of deutetrabenazine versus placebo in adult subjects with diabetic gastroparesis:

[0640] • The percentage of subjects identified as responders, where a responder is defined as having a mean decrease of > 0.5 points in the combined value of the ANMS GCSI-DD nausea subscale and vomiting mean scores over the last 2 weeks of the 12-week treatment period, as compared to baseline;

[0641] • The percentage of subjects who have a > 30% decrease in the combined value of the ANMS GCSI-DD nausea subscale and vomiting mean scores over the last 2 weeks of the 12-week treatment period, as compared to baseline;

[0642] • The percentage of subjects who have a symptom-free day (defined as a score assessed as > mild [ANMS GCSI-DD score > 2]) in the combined value of the ANMS GCSI-DD total score, nausea subscale, and vomiting scores and in the subscale scores over the last 2 weeks of the 12-week treatment period;

[0643] • The estimate based on the combined value of the ANMS GCSI-DD nausea subscale and vomiting mean scores using PGIS and PGIC as anchors over the 12-week treatment period;

[0644] • The percentage of subjects who exhibit a > 30% decrease in the combined value of the ANMS GCSI-DD nausea subscale and vomiting mean scores over the last 2 weeks of the 12-week treatment period, as compared to baseline, in subjects who have a history of non-response to metoclopramide treatment or other prokinetic agents (such as erythromycin, neostigmine, or bethanechol) that they could not tolerate;

[0645] • Deuterated domperidone significantly reduced the effect of gastroparesis-related symptoms compared to baseline based on the mean ANMS GCSI-DD total and subscale scores over the last 2 weeks of the 12-week treatment period;

[0646] • Change in the combined values of the ANMS GCSI-DD nausea subscale and vomiting mean scores from baseline to the last 2 weeks of the 12-week treatment period in subjects receiving GLP-1 RA therapy;

[0647] • Percentage of responders showing a mean reduction of >0.5 points in the ANMS GCSI-DD nausea subscale and vomiting scores from baseline to the last 2 weeks of the 12-week treatment period in subjects receiving GLP-1 RA therapy;

[0648] • Percentage of subjects with a reduction of >30% in the ANMS GCSI-DD nausea subscale and vomiting scores from baseline to the last 2 weeks of the 12-week treatment period in subjects receiving GLP-1 RA therapy;

[0649] • Change in the ANMS GCSI-DD total score and the combined values of gastroparesis-related symptoms from baseline to the last 2 weeks of the 12-week treatment period in subjects receiving GLP-1 RA therapy;

[0650] • All of the above primary and secondary endpoints assessed over the last 2 weeks of the 12-week treatment period will also be assessed over the last 6 weeks of the 12-week treatment period;

[0651] • Change in PGIS from baseline to Week 12; and

[0652] • Change in PGIC from baseline to Week 12.

[0653] (c) Exploratory Efficacy Endpoints

[0654] Exploratory efficacy endpoints for this study include assessing the effect of deuterated domperidone versus placebo in adult subjects with diabetic gastroparesis on:

[0655] • Percentage of subjects identified as responders, where a responder is defined as having a mean reduction of >0.5 points in the ANMS GCSI-DD total and subscale scores from baseline to the last 2 weeks of the 12-week treatment period and to the last 6 weeks of the 12-week treatment period;

[0656] • Percentage of subjects with a reduction of >30% in the ANMS GCSI-DD total and subscale scores from baseline to the last 2 weeks of the 12-week treatment period and to the last 6 weeks of the 12-week treatment period;

[0657] ​​​​​​​​​​​​• Estimates based on mean ANMS GCSI-DD total and subscale scores during the 12-week treatment period, using PGIS and PGIC as anchors;

[0658] • Deuterated domperidone significantly reduced gastroparesis-related symptoms compared to baseline, based on the mean scores on the ANMS GCSI-DD bloating subscale during the last two weeks of the 12-week treatment period and the last six weeks of the 12-week treatment period;

[0659] • Change from baseline in PAGI-QoL after 12 weeks of treatment compared with placebo;

[0660] •Change from baseline in GERDQ after 12 weeks of treatment compared to placebo;

[0661] • Changes in subjects' HbA1c, insulin requirements, and diabetes medications from baseline to Week 12;

[0662] • Change from baseline to week 12 in gastric emptying as measured by GEBT;

[0663] •The effect on the percentage and number of days with any rescue medication use compared to placebo during the 12-week treatment period;

[0664] • The primary endpoint, which involves evaluating the ANMS GCSI-DD vomiting score, and the secondary endpoint, which will include exploratory analyses of vomiting severity;

[0665] • Characterize the absorption of deuterated domperidone and the concentrations of its major metabolites at steady state; and

[0666] • Characterization of the exposure-response relationship of deuterated domperidone with various efficacy and / or safety measures can also be performed.

[0667] (ii) ANMS GCSI-DD Questionnaire

[0668] The ANMS GCSI-DD questionnaire covers five core symptoms associated with gastroparesis: nausea, early satiety, postprandial fullness, epigastric pain, and vomiting. Abdominal distension was included as an exploratory symptom. Symptoms were rated on a numeric severity scale ranging from 0 (no symptoms) to 4 (very severe). Vomiting was recorded on a frequency rating scale with the following scores: 0 (no episode), 1 (one episode), 2 (two episodes), 3 (three episodes), and 4 (four or more episodes).

[0669] Participants will be instructed to complete the ANMS GCSI-DD questionnaire daily starting at screening (for ANMS GCSI-DD baseline assessment) and on the day of randomization and daily from Day 1 to Day 84 (±4 days). Materials will be distributed at the screening visit. Adherence to the ANMS GCSI-DD will be assessed at randomization (Day 1) and must be ≥75% to be eligible for study participation.

[0670] Participants will be instructed to complete a questionnaire regarding symptom severity and episodes of vomiting, rating the worst severity of the symptom in the past 24 hours and providing the number of vomiting episodes.

[0671] The total ANMS GCSI-DD daily gastroparesis symptom score will be calculated by adding the scores for the 5 symptom items and then dividing by 5; thus, the highest possible total symptom score is 4 (5 symptoms × maximum score of 4 = 20; 20 divided by 5 = 4).

[0672] Baseline analysis of the ANMS GCSI-DD total and subscale scores will be based on the average of daily measurements during the 14 days prior to randomization. Analyses of the ANMS GCSI-DD total and subscale scores will be performed to compare symptom scores between treatment groups. A minimum of 4 valid, non-missing days within a 7-day cycle will be required to obtain weekly averages for specific subscale scores.

[0673] The ANMS GCSI-DD questionnaire will be recorded.

[0674] (iii) PGIS and PGIC

[0675] PGIS assessments will be performed weekly beginning at Visit 1. At Visit 3, a PGIS assessment will be performed before the first dose of study drug and will constitute baseline.

[0676] The PGIS is a single-item measure completed by subjects at their clinical site visit that assesses the current global severity of symptoms over the past 7 days. The PGIS is assessed using a 5-point numeric rating scale. The PGIS will be recorded.

[0677] PGIC assessments will be performed at Visits 4, 5, 6, and 7.

[0678] The PGIC is a single measure completed by subjects at the clinical site visit to assess changes in gastroparesis symptoms since the start of study medication. The PGIC is assessed using a 5-point numeric rating scale. The PGIC will be recorded.

[0679] (iv) PAGI-QoL Scale Surveys

[0680] The PAGI-QoL will be completed at the clinical research center at Visit 1, Visit 3 (prior to first study drug dosing), and Visits 4, 5, 6, and 7.

[0681] The PAGI-QoL contains 30 questions that ask subjects how some gastrointestinal problems they can experience affect their overall quality of life and well-being.

[0682] (v) Gastroesophageal Reflux Disease Questionnaire

[0683] The GERDQ will be completed at the clinical research center at Visit 1, Visit 3 (prior to first study drug dosing), and Visits 4, 5, 6, and 7.

[0684] The GERDQ is a subject’s assessment of their symptoms over the past week. The GERDQ score is the sum of the individual question scores, ranging from 0 to 18 points.

[0685] (vi) Gastric Emptying Breath Test

[0686] Baseline gastric emptying measurements using stable isotope GEBT will be completed at the clinical research center. Baseline GEBT is preferred to be performed within the run-in period (Visit 2, Day -21 to Day -12), however, baseline GEBT can be performed outside of the specified Day -21 to Day -12 time window as long as the date of the trial’s conduct ensures sufficient time for GEBT analysis to be completed prior to the intended date of randomization. If the subject arrives at the clinical research center at Visit 1 without having taken any prohibited medications and meets all the required criteria specified in the study protocol (e.g., fasted at least 8 hours, blood glucose level <275 mg / dL, etc.), the procedures for Visit 1 and Visit 2 can be performed on the same day.

[0687] If a subject is rescreened after failing screening for reasons other than GEBT results, the GEBT does not need to be repeated as long as the trial is completed within 3 months of the rescreening and the results meet the eligibility criteria.

[0688] For subjects who elect to participate, GEBT will also be performed at Visit 7 (EOT) or ET.

[0689] Subjects who are actively using nicotine-containing products must refrain from using these products from the time they wake up on the morning of the GEBT day until the completion of the test. Subjects must agree to refrain from opioid medications for >72 hours or 5 half-lives (whichever is longer) prior to the GEBT. Subjects receiving stable, non-daily dosing regimens must agree to refrain from prescribed cannabis and / or THC-containing products for >24 hours prior to the GEBT. Subjects are not required to discontinue their GLP-1 RA prior to the GEBT and should maintain their prescribed dose.

[0690] GEBT includes the collection of 2 pre-prandial breath samples, ingestion of the GEBT test meal, and collection of breath samples at 6 time points post-prandial (45 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes, and 240 minutes). The GEBT test meal should be consumed within 10 minutes.

[0691] Eligibility will be determined based on the percentage of excreted dose at time point t post test meal (PCD):

[0692]

[0693] Where:

[0694] DOB = the measured difference in the ratio of [ 13 CO2 / 12 CO2] between the breath sample at any post-prandial time point (t minutes) and the baseline breath sample.

[0695] CO2PR = CO2 production rate (mmol CO2 / min) calculated using the Sheffield equation (26) which incorporates the subject's age, gender, height, and weight.

[0696] R s = the ratio of [ 13 CO2 / 12 CO2] in the reference standard used for these measurements (Pee Dee belemnite), R s = 0.0112372

[0697] 13 = atomic mass of carbon-13

[0698] 10 = constant factor used for unit conversion

[0699] dose = the weight of carbon-13 (mg) contained in the [ 13 C]-A. platensis dose given to the subject in the test meal. Since the [ 13 C]-A. platensis contains approximately 43% carbon-13, 100 mg of [ 13 C]-A. platensis dose is approximately equivalent to 43 mg of carbon-13.

[0700] A subject will be judged to have a delayed gastric emptying if the subject has a kPCD value at any of the 90 minute, 120 minute, or 150 minute time points that is below the corresponding cut-point, and / or if the subject's maximum kPCD value occurs at 240 minutes.

[0701] The delayed cut-point parameters for each time point are shown in Table 6 below.

[0702]

[0703] To confirm the presence of delayed gastric emptying based on established diagnostic criteria, all subjects will complete a baseline GEBT as indicated above at Visit 2. For subjects who opt in, a GEBT will be performed at Visit 7 (EOT) / ET.

[0704] (vii) Pharmacokinetic Assessments

[0705] PK samples will be collected according to the procedural schedule in Table 7.

[0706] Plasma concentrations of deuterated domperidone and its major metabolite will be measured and used to estimate the following parameters:

[0707] • Steady-state C based on samples collected post-dose at Visit 5 from the initial PK subgroup max ;as well as

[0708] •Based on steady-state trough concentrations from samples collected at Visits 5 and 7, before dosing.

[0709] (viii) Pharmacogenomic Assessments

[0710] For subjects who provide written informed consent for optional PGx assessment, blood samples will be collected at any time during the treatment period.

[0711] PGx samples can be used for genetic studies to explore potential causes of variability and / or differences in response to domperidone-d. Subjects will be given the option to participate in PGx assessments during the informed consent process for the study. Subjects may withdraw their consent for PGx assessments at any time during the study without withdrawing their consent to participate in the overall study.

[0712] F. Safety Assessments

[0713] The safety of deuterated domperidone will be assessed from the time of informed consent until the end of the follow-up period. All safety endpoints will be summarized descriptively. Safety endpoints will include the following:

[0714] • The incidence of clinically significant changes in laboratory parameters, physical examination results, 12-lead ECG parameters, weight measurements, and vital sign measurements;

[0715] •TEAEs;

[0716] •SAEs that occur during treatment;

[0717] •TEAEs leading to premature discontinuation of study drug; and

[0718] •Significant laboratory abnormalities occurring during treatment.

[0719]

[0720]

[0721]

[0722]

[0723]

[0724]

[0725]

[0726]

[0727]

[0728]

[0729]

Claims

1. A method of treating a human diagnosed with diabetic gastroparesis comprising administering a dosage form comprising 10 mg or 15 mg of deuterated domperidone twice daily, wherein said administration reduces the severity of gastroparesis-related symptoms in the human compared to baseline.

2. The method of claim 1, wherein the dosage form is a capsule.

3. The method of claim 2, wherein the capsule further comprises one or more of the following ingredients: (i) medium chain triglycerides, (ii) glyceryl distearate, (iii) butylated hydroxyanisole, and (iv) butylated hydroxytoluene.

4. The method of claim 2 or 3, wherein the capsule further comprises one or more of the following ingredients: (i) 85.1 mg medium chain triglycerides, (ii) 9.75 mg glyceryl distearate, (iii) 0.1 mg butylated hydroxyanisole, and (iv) 0.05 mg butylated hydroxytoluene.

5. The method of claim 2 or 3, wherein the capsule further comprises one or more of the following ingredients: (i) 80.1 mg medium chain triglycerides, (ii) 9.75 mg glyceryl distearate, (iii) 0.1 mg butylated hydroxyanisole, and (iv) 0.05 mg butylated hydroxytoluene.

6. The method according to any one of claims 1 to 3 and 5, wherein the dosage form is a single capsule comprising 10 mg of deuterated domperidone.

7. The method according to any one of claims 1 to 4, wherein the dosage form comprises a single capsule comprising 5 mg of deuterated domperidone and a single capsule comprising 10 mg of deuterated domperidone.

8. The method of any one of the preceding claims, wherein prior to administration of deuterated domperidone, the patient's average weekly nausea subscale score is ≥ 2.

9. The method of any preceding claim, wherein prior to administration of deuterated domperidone, the patient has an average of at least 1 emetic episode per week.

10. The method of any preceding claim, wherein the reduction in severity is based on a composite of the person's mean ANMS GCSI-DD nausea subscale and vomiting subscale scores.

11. The method according to claim 11, wherein the gastroparesis-related symptoms are one or more of postprandial nausea, postprandial vomiting, postprandial fullness, early satiety, abdominal distension, upper abdominal pain, or abdominal pain.

12. The method of any one of the preceding claims, wherein the human's ANMS GCSI-DD nausea subscale and vomiting scores are reduced by at least 0.5 points compared to baseline.

13. The method of any one of the preceding claims, wherein the human's ANMS GCSI-DD nausea subscale and vomiting scores are reduced by at least 30% compared to baseline.

14. The method of any one of the preceding claims, wherein the human's percentage of gastroparesis-related symptom-free days is increased compared to baseline.

15. The method of any one of the preceding claims, wherein the human's PAGI-QoL score improves compared to baseline.

16. The method of any one of the preceding claims, wherein the human's GERDQ score improves compared to baseline.

17. The method of any one of the preceding claims, wherein the human's PGIS score improves compared to baseline.

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