Methods for treating gastroesophagael symptoms in cystic fibrosis patients

Abstract

The disclosure provides methods for improving one or more gastrointestinal symptom in a human patient having cystic fibrosis and gastroparesis, comprising orally administering 10 mg to 120 mg of deudomperidone daily to the human patient.

Description

METHODS FOR TREATING GASTROESOPHAGAEL SYMPTOMS IN CYSTICFIBROSIS PATIENTSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of the priority of U.S. Provisional Patent Application No. 63 / 637,639, filed April 23, 2024, the disclosure of which is incorporated by reference herein.TECHNICAL FIELD

[0002] This disclosure relates to methods for improving gastroesophageal symptoms in human patients having cystic fibrosis and gastroparesis.BACKGROUND

[0003] Gastrointestinal (GI) disturbances are the most significant non-pulmonary manifestations of cystic fibrosis (CF) that contribute to reduced survival of patients. In particular, gastroparesis (GP), a syndrome characterized by delayed gastric emptying in the absence of mechanical obstruction and the presence of cardinal symptoms, including early satiety, postprandial fullness, nausea, vomiting, bloating, and abdominal pain, has been reported to affect up to about 38% of patients with CF. While highly dependent upon the diagnostic modality, some studies have shown the prevalence to be as high as 62% in some children and young adults with CF. GP has serious implications in CF as it can worsen the chronic malnutrition associated with the disease due to reduced oral caloric intake; reduce quality of life; interfere with oral medication delivery and absorption; and even worsen pulmonary function if associated with stomach contents coming back up into the airways.

[0004] Pharmacologic therapy for GP is directed at increasing gastric emptying and accelerating intestinal transit time. In the United States, only metoclopramide is approved for the pharmacotherapy of gastroparesis. Metoclopramide, a dopamine antagonist, is indicated for the relief of symptoms associated with acute and recurrent diabetic gastroparesis in adults only. While effective, this agent readily crosses the blood-brain barrier resulting in central nervous system (CNS) side effects in up to 40% of patients. Common CNS effects with metoclopramide treatment include restlessness, drowsiness, fatigue, and lassitude. The majorsafety concern with metoclopramide treatment is the development of tardive dyskinesia, which is often irreversible.

[0005] Safe and efficacious treatments for improving gastrointestinal symptoms in in patients with CF and GP are needed.SUMMARY

[0006] The disclosure provides methods for improving one or more gastrointestinal symptom in a human patient having cystic fibrosis and gastroparesis, comprising orally administering 5 mg to 120 mg of deudomperidone daily to the human patient.DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0007] In the disclosure, the singular forms “a,” “an,’’ and “the” include the plural reference, and reference to a particular numerical value includes at least that particular value, unless the context clearly indicates otherwise. Thus, for example, a reference to “a material” is a reference to at least one of such materials and equivalents thereof known to those skilled in the art, and so forth.

[0008] When a value is expressed as an approximation by use of the descriptor “about” it will be understood that the particular value forms another embodiment. In general, use of the term "about" indicates approximations that can vary depending on the desired properties sought to be obtained by the disclosed subject matter and is to be interpreted in the specific context in which it is used, based on its function. The person skilled in the art will be able to interpret this as a matter of routine. In some cases, the number of significant figures used for a particular value may be one non-limiting method of determining the extent of the word “about.” In other cases, the gradations used in a series of values may be used to determine the intended range available to the term “about” for each value. Where present, all ranges are inclusive and combinable. That is, references to values stated in ranges include every value within that range.

[0009] When a list is presented, unless stated otherwise, it is to be understood that each individual element of that list and every combination of that list is to be interpreted as a separate embodiment. For example, a list of embodiments presented as “A, B, or C” is to be interpreted as including the embodiments, “A,” “B,” “C,” “A or B,” “A or C,” “B or C,” or “A, B, or C.”

[0010] It is to be appreciated that certain features of the invention which are, for clarity', described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. That is. unless obviously incompatible or excluded, each individual embodiment is deemed to be combinable with any other embodiment(s) and such a combination is considered to be another embodiment. Conversely, various features of the invention that are, for brevity', described in the context of a single embodiment, may also be provided separately or in any sub-combination. It is further noted that the claims may be drafted to exclude an optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation. Finally, while an embodiment may be described as part of a series of steps or part of a more general structure, each said step may also be considered an independent embodiment in itself.

[0011] The terms “subject” and “patient” are used interchangeably and typically refer to a human. In some embodiments, the human is an adult, i.e., 18 years of age or older. In other embodiments, the human is a child, i.e., younger than 18 years of age.

[0012] “Treating” or variations thereof refers to eliminating or reducing at least one physical parameter of the disease or disorder. In other embodiments, “treating” refers to modulating the disease or disorder, either physically, (e.g., by stabilizing a discernible symptom), physiologically, (e.g., stabilizing a physical parameter), or both. In further embodiments, “treating” refers to delaying onset of the disease or disorder.

[0013] “Cystic fibrosis” or “CF” as used herein refers to a progressive, genetic disease that causes persistent lung infections and limits the ability to breathe over time. CF is classified into six types, i.e., class I: protein synthesis defect; class II: maturation defect; class III: gating defect; class IV: conductance defect; class V: reduced quantity; and class VI: reduced stability. Symptoms of CF may include, without limitation, respiratory and / or digestive symptoms. Examples of respiratory symptoms include, without limitation, thick and sticky mucus, cough such as persistent cough that produces thick mucus, wheezing, exercise intolerance, repeated lung infections, inflamed nasal passages or a stuffy nose, and / or recurrent sinusitis. Examples of digestive symptoms include, without limitation, gastroparesis, foul-smelling, greasy stools, poor weight gain / growth, intestinal blockage, and / or constipation.

[0014] “Deudomperidone,” “d4-domperidone,” “deuterated domperidone,” or “CIN- 102 drug substance” as referenced herein are interchangeable and refer to l-{3-[4-(5-chloro- 2-oxo-2,3-dihydro-lH-l,3-benzodiazol-l-yl)piperidin-lyl]propyl}-2.3-dihydro(4,5,6,7-D4)- lH-l,3-benzodiazol-2-one, which has the following structure:

[0015] Any reference to deudomperidone may also include, where noted, pharmaceutically acceptable salts, esters, hydrates, solvates, prodrug forms, and derivatives of these, which are broadly defined as deudomperidone compounds that are modified or partially substituted.

[0016] "‘Pharmaceutically acceptable" refers to properties and / or substances that are acceptable to the patient from a pharmacological / toxicological vantage, and to the manufacturing pharmaceutical chemist from a physical / chemical vantage regarding composition, formulation, stability , patient acceptance, and bioavailability7.

[0017] A pharmaceutically acceptable salt includes salts with a pharmaceutically acceptable acid or base. In some embodiments, the pharmaceutically acceptable salt is with an acid such as an inorganic acid. Examples of inorganic acids include hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic, hydroiodic and nitric acid. In other embodiments, the pharmaceutically acceptable salt is with an organic acid. Examples of organic acids include as citric, fumaric, maleic, malic, mandelic, ascorbic, oxalic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic, cyclohexylsulfamic (cyclamic) or p-toluenesulphonic acid. In further embodiments, the pharmaceutically acceptable salt is with a base such as an alkali metal. Examples of alkali metals include sodium or potassium. In yet other embodiments, the pharmaceutically acceptable salt is with a base such as an alkaline earth metal. Examples of alkaline earth metals include calcium or magnesium hydroxides. In still further embodiments, the pharmaceutically acceptable salt is with an organic base. Examples of organic bases include alkyl amines, arylalkyl amines and heterocyclic amines.

[0018] The abbreviation “D,” as used herein, refers to a stable isotope of hydrogen that is deuterium (heavy hydrogen or2H). Such instances of “D” include an amount ofdeuterium that is above the naturally occurring distribution of deuterium. In some embodiments, D has deuterium enrichment of no less than about 1%. In other embodiments,D has a deuterium enrichment of no less than about 5%. In further embodiments, D has a deuterium enrichment of no less than about 10%. In still other embodiments, D has a deuterium enrichment of no less than about 20%. In still other embodiments, D has a deuterium enrichment of no less than about 30%. In still other embodiments, D has a deuterium enrichment of no less than about 40%. In yet further embodiments, D has a deuterium enrichment of no less than about 50%. In still other embodiments, D has a deuterium enrichment of no less than about 60%. In other embodiments, D has a deuterium enrichment of no less than about 70%. In further embodiments, D has a deuterium enrichment of no less than about 80%. In yet other embodiments, D has a deuterium enrichment of no less than about 90%. In still further embodiments, D has a deuterium enrichment of no less than about 98% of deuterium. In still further embodiments, D has a deuterium enrichment of no less than about 99% of deuterium. In still further embodiments, D has a deuterium enrichment of at least 99% of deuterium.

[0019] The disclosure provides methods for improving one or more gastrointestinal symptom in a human patient having cystic fibrosis and gastroparesis. The term "gastroparesis" as used herein refers to a disorder involving delayed gastric emptying in the absence of physical gastric outlet obstruction. In some embodiments, the gastroparesis is acute gastroparesis. In other embodiments, the gastroparesis is recurrent gastroparesis. Thus, the methods may be useful in improving gastric emptying, as measured by a gastric emptying breath test (GEBT) using13C-spirulina platensis.

[0020] In some embodiments, prior to administration of deudomperidone, the human patient has a GEBT T! greater than about 80 minutes, as measured by a gastric emptying breath test (GEBT) using13C-spirulina platensis. In some embodiments, the human patient has a GEBT T! greater than about 110 minutes, as measured by a GEBT using13C- spirulina platensis. In other embodiments, the patient has a GEBT T! greater than about 200 minutes, as measured by a GEBT using13C-spirulina platensis.

[0021] In other embodiments, prior to administration of deudomperidone, the human patient has a resting oxygen saturation of about 92% or greater on room air. as measured by pulse oximetry.

[0022] In further embodiments, prior to administration of deudomperidone, the human patient has (i) one or more symptom of cystic fibrosis and (ii) two cystic fibrosis transmembrane conductance regulator (CFTR) causing alleles on genetic testing or a sweat chloride of about 60 mEq / L or greater.

[0023] Prior to administration of deudomperidone, the human may be experiencing one or more of an upper gastrointestinal symptom. In some embodiments, the upper gastrointestinal symptom is postprandial nausea, postprandial vomiting, postprandial fullness, early satiety, bloating, epigastric pain, abdominal pain, or combinations thereof. In other embodiments, the upper gastrointestinal symptom is postprandial nausea. In further embodiments, the upper gastrointestinal symptom is postprandial vomiting. In yet other embodiments, the gastrointestinal symptom is postprandial fullness. In still further embodiments, the gastrointestinal symptom is early satiety. In other embodiments, the gastrointestinal symptom is bloating. In further embodiments, the gastrointestinal symptom is epigastric pain. In yet other embodiments, the gastrointestinal symptom is abdominal pain.

[0024] The methods include orally administering 5 mg to 120 mg of deudomperidone daily to the human. Preferably, the free base of deudomperidone is administered. In some embodiments, the daily dose of deudomperidone is about 5, about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, or about 120 mg. In other embodiments, the daily dose of deudomperidone about 5 to about 110, about 5 to about 100, about 5 to about 90, about 5 to about 80, about 5 to about 70. about 5 to about 60, about 5 to about 50, about 5 to about 40. about 5 to about 30, about 5 to about 20, about 5 to about 10, about 10 to about 120, about 10 to about 110, about 10 to about 100, about 10 to about 90, about 10 to about 80, about 10 to about 70, about 10 to about 60, about 10 to about 50, about 10 to about 40, about 10 to about 30, about 10 to about 20, about 20 to about 120, about 20 to about 110, about 20 to about 100, about 20 to about 90, about 20 to about 80, about 20 to about 70, about 20 to about 60, about 20 to about 50, about 20 to about 40, about 20 to about 30, about 30 to about 120, about 30 to about 110, about 30 to about 100, about 30 to about 90, about 30 to about 80, about 30 to about 70, about 30 to about 60, about 30 to about 50, about 30 to about 40, about 40 to about 120, about 40 to about 110, about 40 to about 100, about 40 to about 90. about 40 to about 80. about 40 to about 70, about 40 to about 60, about 40 to about 50, about 50 to about 120, about 50 to about 110, about 50 to about 100, about 50 to about 90, about 50 to about 80, about 50 to about 70,about 50 to about 60, about 60 to about 120, about 60 to about 110, about 60 to about 100, about 60 to about 90, about 60 to about 80, about 60 to about 70, about 70 to about 120, about 70 to about 110, about 70 to about 100, about 70 to about 90, about 70 to about 80. about 80 to about 120, about 80 to about 110, about 80 to about 100, about 80 to about 90, about 90 to about 120, about 90 to about 110, about 90 to about 100, about 100 to about 120, about 100 to about 110, or about 110 to about 120 mg. In further embodiments, the daily dose of deudomperidone is about 10 mg. In yet other embodiments, the daily dose of deudomperidone is about 20 mg. In still further embodiments, the daily dose of deudomperidone is about 30 mg. In other embodiments, the daily dose of deudomperidone is about 60 mg. In further embodiments, the daily dose of deudomperidone is about 120 mg.

[0025] Deudomperidone may be administered as needed to attain the desired daily dosage. For example, the deudomperidone can be administered in divided doses. In some aspects, deudomperidone is administered in one dose. In other aspects, deudomperidone is administered in two doses. In further aspects, deudomperidone is administered in three doses. In yet other aspects, deudomperidone is administered in four doses. In some embodiments, the deudomperidone is administered one time daily (QD). In other embodiments, the deudomperidone is administered two times daily (BID). In further embodiments, the deudomperidone is administered three times daily (TID). In yet other embodiments, the deudomperidone is administered four time daily (QID). In some aspects, a daily 10 mg dose of deudomperidone is 10 mg QD. In other aspects, a daily 10 mg dose of deudomperidone is 5 mg BID. In further aspects, a daily 20 mg dose of deudomperidone is 20 mg QD. In yet other aspects, a daily 20 mg dose of deudomperidone is 10 mg BID. In still further aspects, a daily 20 mg dose of deudomperidone is 5 mg QID. In other aspects, a daily 60 mg dose of deudomperidone is 30 mg BID. In further aspects, a daily 120 mg dose of deudomperidone is 60 mg BID. In other aspects, a daily 30 mg dose of deudomperidone is 10 mg TID. In further aspects, a daily 60 mg dose of deudomperidone is 30 mg BID. In yet other aspects, a daily 80 mg dose of deudomperidone is 20 mg QD. In still further aspects, a daily 30 mg does of deudomperidone is 15 mg BID. In further aspects, a daily 15 mg dose of deudomperidone comprises 5 mg and 10 mg doses of deudomperidone.

[0026] The deudomperidone formulations described herein are useful in a variety of treatment methods including, without limitation, methods for improving a gastrointestinalsymptom in a human patient The methods include administering to the patient a pharmaceutical formulation described herein.

[0027] In some embodiments, administration of deudomperidone results in a clinically significant improvement in postprandial nausea, early satiety, postprandial fullness, upper abdominal pain, vomiting, and bloating as measured by an American Neurogastroenterology and Motility Society Gastroparesis Cardinal Symptom Index Daily- Diary (ANMS GCSI-DD) score after administration, such as about 6 to about 12 weeks after administration. In certain aspects, administration of deudomperidone results in a clinically significant improvement in postprandial nausea, early satiety, postprandial fullness, upper abdominal pain, vomiting, and bloating as measured by an ANMS GSI-DD score about 6, about 7, about 8, about 9, about 10, about 11, or about 12 weeks after administration. In other aspects, administration of deudomperidone results in a clinically significant improvement in postprandial nausea, early satiety, postprandial fullness, upper abdominal pain, vomiting, and bloating as measured by an ANMS GSI-DD score about 6 to about 11, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 12. about 7 to about 11, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 12, about 8 to about 11, about 8 to about 10, about 8 to about 9, about 9 to about 12, about 9 to about 11, about 9 to about 10, about 10 to about 12, about 10 to about 11, or about 11 to about 12 weeks after administration.

[0028] In other embodiments, administration of deudomperidone may result in a clinically significant improvement in an average composite score of the ANMS GCSI-DD score after administration, such as about 6 to about 12 weeks after administration. In certain aspects, administration of deudomperidone may result in a clinically significant improvement in an average composite score of the ANMS GCSI-DD score after about 6, about 7, about 8, about 9, about 10, about 11, or about 12 weeks of administration. In other aspects, administration of deudomperidone may result in a clinically significant improvement in an average composite score of the ANMS GCSI-DD score after about 6 to about 11, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 12, about 7 to about 11, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 12, about 8 to about 11, about 8 to about 10. about 8 to about 9. about 9 to about 12, about 9 to about 11, about 9 to about 10, about 10 to about 12, about 10 to about 11, or about 11 to about 12 weeks of administration.

[0029] In further embodiments, administration of deudomperidone may result in a clinically significant improvement in a nausea subscale score of the ANMS GCSI-DD score after administration, such as about 6 to about 12 weeks after administration. In certain aspects, administration of deudomperidone may result in a clinically significant improvement in a nausea subscale score of the ANMS GCSI-DD score after about 6, about 7, about 8, about 9, about 10, about 11, or about 12 weeks of administration. In other aspects, administration of deudomperidone may result in a clinically significant improvement in a nausea subscale score of the ANMS GCSI-DD score after about 6 to about 11, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 12, about 7 to about 11, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 12, about 8 to about 11, about 8 to about 10, about 8 to about 9. about 9 to about 12, about 9 to about 11. about 9 to about 10, about 10 to about 12. about 10 to about 11, or about 11 to about 12 weeks of administration.

[0030] In yet other embodiments, administration of deudomperidone may result in a clinically significant improvement in a vomiting subscale score of the ANMS GCSI-DD score after administration, such as about 6 to about 12 weeks after administration. In certain aspects, administration of deudomperidone may result in a clinically significant improvement in a vomiting subscale score of the ANMS GCSI-DD score after about 6, about 7, about 8, about 9, about 10, about 11, or about 12 weeks of administration. In other aspects, administration of deudomperidone may result in a clinically significant improvement in a vomiting subscale score of the ANMS GCSI-DD score after about 6 to about 11. about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 12, about 7 to about 11, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 12, about 8 to about 11, about 8 to about 10. about 8 to about 9. about 9 to about 12, about 9 to about 11. about 9 to about 10, about 10 to about 12, about 10 to about 11, or about 11 to about 12 weeks of administration.

[0031] In still further embodiments, administration of deudomperidone may result in a clinically significant improvement in a total score of the ANMS GCSI-DD score after administration, such as about 6 to about 12 weeks after administration. In certain aspects, administration of deudomperidone may result in a clinically significant improvement in a total score of the ANMS GCSI-DD score after about 6, about 7, about 8, about 9, about 10, about 11, or about 12 weeks of administration. In other aspects, administration ofdeudomperidone may result in a clinically significant improvement in a total score of the ANMS GCSI-DD score after about 6 to about 11, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 12, about 7 to about 11. about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 12, about 8 to about 11, about 8 to about 10, about 8 to about 9, about 9 to about 12, about 9 to about 11, about 9 to about 10, about 10 to about 12, about 10 to about 11, or about 11 to about 12 weeks of administration.

[0032] In other embodiments, administration of deudomperidone may result in a clinically significant improvement in an early satiety subscale score of the ANMS GCSI-DD score after administration, such as about 6 to about 12 weeks after administration. In certain aspects, administration of deudomperidone may result in a clinically significant improvement in an early satiety subscale score of the ANMS GCSI-DD score after about 6, about 7, about 8, about 9, about 10, about 1 1, or about 12 weeks of administration. In other aspects, administration of deudomperidone may result in a clinically significant improvement in an early satiety subscale score of the ANMS GCSI-DD score after about 6 to about 11, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 12, about 7 to about 11, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 12, about 8 to about 11, about 8 to about 10, about 8 to about 9, about 9 to about 12, about 9 to about 11, about 9 to about 10, about 10 to about 12, about 10 to about 11, or about 11 to about 12 weeks of administration.

[0033] In further embodiments, administration of deudomperidone may result in a clinically significant improvement in a post-prandial fullness subscale score of the ANMS GCSI-DD score after administration, such as about 6 to about 12 weeks after administration. In certain aspects, administration of deudomperidone may result in a clinically significant improvement in a post-prandial fullness subscale score of the ANMS GCSI-DD score after about 6, about 7, about 8, about 9, about 10, about 1 1, or about 12 weeks of administration. In other aspects, administration of deudomperidone may result in a clinically significant improvement in a post-prandial fullness subscale score of the ANMS GCSI-DD score after about 6 to about 11 , about 6 to about 10, about 6 to about 9. about 6 to about 8. about 6 to about 7, about 7 to about 12. about 7 to about 11, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 12, about 8 to about 11, about 8 to about 10, about 8 toabout 9, about 9 to about 12, about 9 to about 11, about 9 to about 10, about 10 to about 12, about 10 to about 11, or about 11 to about 12 weeks of administration.

[0034] In still other embodiments, administration of deudomperidone may result in a clinically significant improvement in an upper abdominal pain subscale score of the ANMS GCSI-DD score after administration, such as about 6 to about 12 weeks after administration. In certain aspects, administration of deudomperidone may result in a clinically significant improvement in an upper abdominal pain subscale score of the ANMS GCSI-DD score after about 6, about 7. about 8, about 9. about 10. about 11. or about 12 weeks of administration. In other aspects, administration of deudomperidone may result in a clinically significant improvement in an upper abdominal pain subscale score of the ANMS GCSI-DD score after about 6 to about 11, about 6 to about 10, about 6 to about 9. about 6 to about 8. about 6 to about 7, about 7 to about 12. about 7 to about 11, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 12, about 8 to about 11, about 8 to about 10, about 8 to about 9, about 9 to about 12, about 9 to about 11, about 9 to about 10, about 10 to about 12, about 10 to about 11, or about 11 to about 12 weeks of administration.

[0035] In yet further embodiments, administration of deudomperidone may result in a clinically significant improvement in symptom severity as measured by a reflux disease questionnaire (RDQ) after administration, such as about 6 to about 12 weeks after administration. In certain aspects, administration of deudomperidone may result in a clinically significant improvement in symptom severity as measured by a RDQ after about 6, about 7, about 8. about 9, about 10, about 11, or about 12 weeks of administration. In other aspects, administration of deudomperidone may result in a clinically significant improvement in symptom severity as measured by a RDQ after about 6 to about 11, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 12, about 7 to about 11. about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 12, about 8 to about 11, about 8 to about 10, about 8 to about 9, about 9 to about 12, about 9 to about 11, about 9 to about 10, about 10 to about 12, about 10 to about 11, or about 11 to about 12 weeks of administration.

[0036] In other embodiments, administration of deudomperidone may result in a clinically significant improvement in gastric emptying as measured by ANMS GCSI-DD subscale scores after administration, such as about 6 to about 12 weeks after administration. In certain aspects, administration of deudomperidone may result in a clinically significantimprovement in gastric emptying as measured by ANMS GCSI-DD subscale scores after about 6, about 7, about 8, about 9, about 10, about 11, or about 12 weeks of administration. In other aspects, administration of deudomperidone may result in a clinically significant improvement in gastric emptying as measured by ANMS GCSI-DD subscale scores after about 6 to about 11, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 12, about 7 to about 11, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 12, about 8 to about 11. about 8 to about 10, about 8 to about 9, about 9 to about 12. about 9 to about 11, about 9 to about 10, about 10 to about 12, about 10 to about 11, or about 11 to about 12 weeks of administration.

[0037] In further embodiments, administration of deudomperidone may result in a clinically significant improvement in gastric emptying as measured by GEBT after administration, such as about 6 to about 12 weeks after administration. In certain aspects, administration of deudomperidone may result in a clinically significant improvement in gastric emptying as measured by GEBT after about 6, about 7, about 8, about 9, about 10, about 11, or about 12 weeks of administration. In other aspects, administration of deudomperidone may result in a clinically significant improvement in gastric emptying as measured by GEBT after about 6 to about 11, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 12, about 7 to about 1 1, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 12, about 8 to about 11, about 8 to about 10. about 8 to about 9, about 9 to about 12, about 9 to about 11, about 9 to about 10, about 10 to about 12, about 10 to about 11, or about 11 to about 12 weeks of administration.

[0038] In yet other embodiments, administration of deudomperidone may result in a clinically significant improvement in gastric emptying as measured by ANMS GCSI-DD total scores after administration, such as about 6 to about 12 weeks after administration. In certain aspects, administration of deudomperidone may result in a clinically significant improvement in gastric emptying as measured by ANMS GCSI-DD total scores after about 6, about 7, about 8, about 9, about 10, about 11, or about 12 weeks of administration. In other aspects, administration of deudomperidone may result in a clinically significant improvement in gastric emptying as measured by ANMS GCSI-DD total scores after about 6 to about 11, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 6 to about 7, about 7 to about 12, about 7 to about 11, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 12, about 8 to about 11, about 8 to about 10, about 8 to about 9, about 9 toabout 12, about 9 to about 11, about 9 to about 10, about 10 to about 12, about 10 to about 11, or about 11 to about 12 weeks of administration.

[0039] In still further embodiments, administration of deudomperidone may result in a clinically significant improvement in a variable related to cystic fibrosis, as measured by the cystic fibrosis questionnaire (CFQ), such as health-related quality of life, cystic fibrosis symptom, or overall health perception after administration, such as about 6 to about 12 weeks after administration. In certain aspects, administration of deudomperidone may result in a clinically significant improvement in a variable related to cystic fibrosis, as measured by the CFQ after about 6, about 7, about 8, about 9, about 10, about 11, or about 12 weeks of administration. In other aspects, administration of deudomperidone may result in a clinically significant improvement in a variable related to cystic fibrosis, as measured by the CFQ after about 6 to about 11, about 6 to about 10, about 6 to about 9. about 6 to about 8. about 6 to about 7, about 7 to about 12, about 7 to about 11, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 12, about 8 to about 11, about 8 to about 10, about 8 to about 9, about 9 to about 12, about 9 to about 11, about 9 to about 10, about 10 to about 12, about 10 to about 11, or about 11 to about 12 weeks of administration.

[0040] The pharmaceutical formulations may be administered by any route that would be acceptable for humans. In some embodiments, the pharmaceutical formulations the administration is oral, transdermal, parenteral, or a combination thereof. In further embodiments, administration is oral.

[0041] The pharmaceutical formulations may be formulated for administration in solid or liquid forms. In some embodiments, the pharmaceutical formulations are formulated in the form of a tablet, caplet, capsule, powder, softgel, suspension or liquid, or a combination thereof. In other embodiments, the pharmaceutical formulations are formulated in the form of a tablet. In further embodiments, the pharmaceutical formulations are formulated in the form of a caplet. In yet other embodiments, the pharmaceutical formulations are formulated in the form of a capsule. In still further embodiments, the pharmaceutical formulations are formulated in the form of a powder. In other embodiments, the pharmaceutical formulations are formulated in the form of a softgel. In further embodiments, the pharmaceutical formulations are formulated in the form of suspension. In yet other embodiments, the pharmaceutical formulations are formulated in the form of a liquid.Aspects

[0042] Aspect 1. A method for improving one or more gastrointestinal symptom in a human patient having cystic fibrosis and gastroparesis, comprising orally administering 5 mg to 120 mg of deudomperidone daily to the human patient.

[0043] Aspect 2. The method of Aspect 1, wherein the upper gastrointestinal symptom is postprandial nausea, postprandial vomiting, postprandial fullness, early satiety, bloating, epigastric pain, abdominal pain, or combinations thereof.

[0044] Aspect 3. The method of any one of the preceding Aspects, wherein, prior to administering the deudomperidone, the human has a T! greater than about 80 minutes, or such as greater than about 110 minutes, or such as greater than about 200 minutes, as measured by a gastric emptying breath test (GEBT) using1’C-spirulina platensis.

[0045] Aspect 4. The method of any one of the preceding Aspects, wherein the human patient has a resting oxygen saturation of about 92% or greater on room air, as measured by pulse oximetry.

[0046] Aspect 5. The method of any one of the preceding Aspects, wherein the human patient has (i) one or more symptom of cystic fibrosis and (ii) two cystic fibrosis transmembrane conductance regulator (CFTR) causing alleles on genetic testing or a sweat chloride of about 60 mEq / L or greater.

[0047] Aspect 6. The method of any one of the preceding Aspects, wherein the human patient has delayed gastric emptying.

[0048] Aspect 7. The method of Aspect 1 or 2, wherein the gastroparesis is acute or recurrent gastroparesis.

[0049] Aspect 8. The method of any one of the preceding Aspects, further comprising improving gastric emptying, as measured by a gastric empty ing breath test (GEBT) using13C-spirulina platensis.

[0050] Aspect 9. The method of any one of the preceding Aspects, wherein about 10 mg, or about 20 mg, or about or about 30 mg, or about 60 mg, or about 120 mg of deudomperidone is administered to the human.

[0051] Aspect 10. The method of any one of the preceding Aspects, wherein the deudomperidone is administered in divided doses, such as two doses.

[0052] Aspect 11. The method of any one of the preceding Aspects, wherein the deudomperidone is administered daily.

[0053] Aspect 12. The method of any one of the preceding Aspects, wherein the human is an adult.

[0054] Aspect 13. The method of any one of the preceding Aspects, wherein administration results in a clinically significant improvement in postprandial nausea, early satiety, postprandial fullness, upper abdominal pain, vomiting, and bloating as measured by an American Neurogastroenterology and Motility Society Gastroparesis Cardinal Symptom Index Daily Diary (ANMS GCSI-DD) score after administration, such as about 6 to about 12 weeks after administration, such as about 6 to about 12 weeks after administration.

[0055] Aspect 14. The method of any one of the preceding Aspects, wherein the administration results in a clinically significant improvement in an average composite score of the ANMS GCSI-DD score after administration, such as about 6 to about 12 weeks after administration.

[0056] Aspect 15. The method of any one of the preceding Aspects, wherein the administration results in a clinically significant improvement in a nausea subscale score of the ANMS GCSI-DD score after administration, such as about 6 to about 12 weeks after administration.

[0057] Aspect 16. The method of any one of the preceding Aspects, wherein the administration results in a clinically significant improvement in a vomiting subscale score of the ANMS GCSI-DD score after administration, such as about 6 to about 12 weeks after administration.

[0058] Aspect 17. The method of any one of the preceding Aspects, wherein the administration results in a clinically significant improvement in a total score of the ANMS GCSI-DD score after administration, such as about 6 to about 12 weeks after administration.

[0059] Aspect 18. The method of any one of the preceding Aspects, wherein the administration results in a clinically significant improvement in an early satiety subscale score of the ANMS GCSI-DD score after administration, such as about 6 to about 12 weeks after administration.

[0060] Aspect 19. The method of any one of the preceding Aspects, wherein the administration results in a clinically significant improvement in a post-prandial fullness subscale score of the ANMS GCSI-DD score after administration, such as about 6 to about 12 weeks after administration.

[0061] Aspect 20. The method of any one of the preceding Aspects, wherein the administration results in a clinically significant improvement in an upper abdominal pain subscale score of the ANMS GCSI-DD score after administration, such as about 6 to about 12 weeks after administration.

[0062] Aspect 21. The method of any one of the preceding Aspects, wherein the administration results in a clinically significant improvement in symptom severity7as measured by a reflux disease questionnaire (RDQ) after administration, such as about 6 to about 12 weeks after administration.

[0063] Aspect 22. The method of any one of the preceding Aspects, wherein the administration results in a clinically significant improvement in gastric emptying as measured by ANMS GCSI-DD subscale scores after administration, such as about 6 to about 12 weeks after administration.

[0064] Aspect 23. The method of any one of the preceding Aspects, wherein the administration results in a clinically significant improvement in gastric emptying as measured by GEBT after administration, such as about 6 to about 12 weeks after administration.

[0065] Aspect 24. The method of any one of the preceding Aspects, wherein the administration results in a clinically significant improvement in gastric emptying as measured by ANMS GCSI-DD total scores after administration, such as about 6 to about 12 weeks after administration.

[0066] Aspect 25. The method of any one of the preceding Aspects, wherein the administration results in a clinically significant improvement in a variable related to cystic fibrosis, as measured by the cystic fibrosis questionnaire (CFQ), such as health-related quality of life, cystic fibrosis symptom, or overall health perception after administration, such as about 6 to about 12 weeks after administration.

[0067] The following Examples are provided to illustrate some of the concepts described within this disclosure. In the following Example, efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but some experimental error and deviation should be accounted for.

[0068] Example 1: In Vitro Studies

[0069] This example is an in vitro study assessing the dissolution of a deudomperidone formulation at various pH values to obtain an initial assessment of the potential for acid-reducing agents to affect the pharmacokinetics of the deudomperidone formulation. Specifically, the dissolution profile of the deudomperidone formulation will be characterized at pH values ranging from about 1 to about 7 over a period of about 120 minutes. This in vitro study will characterize the solubility of the deudomperidone formulation across a physiologically relevant range to determine the inflection point at which the profile may be affected.

[0070] Example 2: Drug-Drug Interaction Studies

[0071] In this example, drug-drug interactions between deudomperidone and a potent CYP3A4 inhibitor (itraconazole) will be analyzed. Specifically, the safety and PK of deudomperidone drug product will be determined. This example also characterizes the effect of a potent CYP3A4 inducer (rifampin) on the safety and PK of deudomperidone drug product.

[0072] Example 3: Efficacy and Safety

[0073] A. Objectives

[0074] The objectives are the following:

[0075] • To evaluate the safety7and tolerability7of the deudomperidone formulation in subjects with cystic fibrosis (CF) and gastroparesis;

[0076] • To assess the effect of the deudomperidone formulation on overall health, daily life, perceived well-being, and symptoms of CF as measured by the CFQ;

[0077] • To assess the effect of the deudomperidone formulation on symptom severity7of gastroparesis as measured by the ANMS GCSI-DD questionnaire; and

[0078] • To assess the effect of the deudomperidone formulation on symptom severity of reflux disease as measured by the RDQ.

[0079] The exploratory7objective is to assess the effect of the deudomperidone formulation on GER and DGER as measured by EPM-MII.

[0080] B. Population

[0081] The population is adult subjects 18 to 75 years old with a confirmed diagnosis of CF (by the following criteria: signs and symptoms of CF plus either two CFTR causing alleles on genetic testing or sweat chloride > 60 mEq / L) and a diagnosis ofgastroparesis defined by upper gastrointestinal symptoms felt to be consistent with gastroparesis or previously documented delayed gastric emptying.

[0082] C. Selection and Withdrawal of Subjects

[0083] (i) Inclusion Criteria:

[0084] Subjects who meet all of the following criteria will be eligible to participate:

[0085] 1. Male and female subjects 18 to 75 years old, inclusive.

[0086] 2. Confirmed diagnosis of CF, as documented in the subject's medical record, by the following criteria: signs and symptoms of CF plus either two CFTR causing alleles on genetic testing OR sweat chloride > 60 mEq / L.

[0087] 3. Current diagnosis DGE as defined by either of the following:

[0088] a) Gastrointestinal (GI) symptoms felt to be 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

[0089] b) Has documented DGE symptoms within the past 2 years as determined by GEBT, scintigraphy, WMC, or manometry. Subjects who present with symptoms noted in 3a, but do not have documented delayed gastric emptying within the past 2 years of Visit 1 may complete a GEBT using13C-spirulina platensis during the Screening Period. The GEBT T 1 / 2 must be >110 min to be eligible to participate. Subj ects with a GEBT T 1 / 2 <1 10 min may7be considered.

[0090] 4. Has a BMI between 16 and 45 kg / m2, inclusive.

[0091] 5. Glycosylated hemoglobin level <11%.

[0092] 6. Resting oxygen saturation (as measured by pulse oximetry) >92% on room air.

[0093] 7. Male subjects with female partners of child-bearing potential must agree to use 2 medically accepted, highly effective methods of birth control from Day 1 through 60 days following the final dose of study drug. Medically accepted, highly effective methods of birth control for male subjects with female partners of child-bearing potential include the following: latex condom with spermicide, diaphragm with intravaginal spermicide, cervical cap with spermicide, indwelling intrauterine device (hormonal or nonhormonal), implanted contraceptives, and oral contraceptives.

[0094] 8. Male subjects must agree to abstain from sperm donation from Day' 1 through 60 days following the final dose of study drug.

[0095] 9. Female subjects with male partners must be surgically sterile (hysterectomy and / or bilateral oophorectomy), postmenopausal for at least 1 year (with confirmed follicle-stimulating hormone in postmenopausal range at the Screening Visit), or agree to use 2 medically accepted, highly effective methods of birth control from Day -14 until 60 days following the final dose of study drug. Medically accepted, highly effective methods of birth control for female subjects with male partners include the following: latex condom with spermicide, diaphragm with intravaginal spermicide, cervical cap with spermicide, and nonhormonal indwelling intrauterine device.

[0096] 10. Negative alcohol and drug screen at Screening and Randomization Visits. Subjects who utilize medical marijuana or THC-containing products may be considered if they are able to discontinue within 14 days prior to baseline scintigraphy until the end.

[0097] 11. Willing to refrain from the below during the course of the study. Subjects may be on any of these medications at enrollment as long as they have discontinued per the below timelines:

[0098] a) Tobacco or nicotine-containing product use after midnight on the day of the GEBT (if applicable) test and throughout the time that GEBT is being administered.

[0099] b) Moderate or strong cytochrome P450 (CYP)3A4 inhibitors and / or inducers within 14 days or 5 half-lives (whichever is longer) of the first dose of study drug until the end.

[0100] c) Any medication, herbal supplements, dietary supplements, or nutraceuticals with potential to prolong QT within 14 days prior to the first dose of study drug until the end.

[0101] d) Motility agents (including but not limited to metoclopramide, domperidone, erythromycin, etc.), other medications that may affect gastric emptying (e.g. opiates and anticholinergics, marijuana and THC containing products), and antiemetics (except for protocol-specified rescue antiemetic medication) within 7 days or 5 half-lives (whichever is longer) prior to the start of the 14-day ANMS GCSI-DD baseline period and kept off until the end.

[0102] For subjects who are required to complete a GEBT for eligibility, these agents must be discontinued at least 14 days or 5 half-lives (whichever is longer) prior to the GEBT.

[0103] e) Grapefruit, grapefruit products, star fruit products, and Seville oranges from 48 hours prior to randomization until the end of treatment;

[0104] f) Long-acting GLP-1 agonists, SGLT-2 inhibitor, or pramlintide. Subjects who are taking SGTL2 inhibitors or GLP-1 agonists other than Bydureon (exenatide extended release), Victoza (liraglutide), Tanzeum (albiglutide), or Trulicity (dulaglutide) may be considered for if they can discontinue the medication for 3 days prior to the baseline visit and agree to remain off of the medications throughout the treatment period.

[0105] 12. Subjects who participate in the reflux sub-study agree to maintain their baseline PPI and / or H2-blocker if they are taking such medication prior to screening or agree to not initiate such therapy while they are on study drug unless prior approval is obtained.

[0106] 13. Able to understand and willing to comply with all visits, procedures, restrictions, discontinuation of medications, including those to treat gastroparesis, and provide written informed consent / assent according to institutional and regulatory guidelines.

[0107] (ii) Exclusion Criteria

[0108] Subjects who meet any of the following criteria will be excluded from participation:

[0109] 1. History of, or current, clinically significant arrhythmias, including ventricular tachycardia, ventricular fibrillation, atrial fibrillation, and Torsades de Pointes. Subjects with minor forms of ectopy (e.g., premature atrial contractions) are not necessarily excluded.

[0110] 2. Clinically significant bradycardia with a resting heart rate under 50 beats per minute, sinus node dysfunction, or heart block.

[0111] 3. Prolonged QTcF (QTcF >450 msec for males or QTcF >470 msec for females) based on the average of triplicate ECGs.

[0112] 4. A personal or family history of long QT syndrome, Torsades de pointes, or other complex ventricular arrhythmias or family history of sudden death;

[0113] 5. Any change (initiation, change in type of drug, dose modification, schedule modification, interruption, discontinuation, or re-initiation) in a chronic treatment / prophylaxis regimen for CF or for CF-related conditions (e.g., dyspepsia or GERD with H2 blockers or PPIs) within 2 weeks prior to screening. Subjects on CFTR modulators [e.g., Trikafta (elexacaftor / tezacaftor / ivacaftor and ivacaftor)] may be considered for enrollment if they have been on a stable dose for 3 months. A subject can be enrolled who isusing inhaled medications such as aztreonam, colistin, domase alfa, hypertonic saline, corticosteroids, or P2 agonists: or systemic drugs such as azithromycin or ibuprofen. Expected cycling of inhaled aztreonam or inhaled colistin is permitted. Other than for treatment of CF pulmonary exacerbations, subjects should remain on a stable medical regimen of treatment / prophylaxis for CF-related conditions to avoid confounding interpretation of results.

[0114] 6. Evidence (based on screening or baseline assessments) or history of clinically significant immunologic, hematologic, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies); surgical conditions; cancer (with the exception of basal or squamous cell carcinoma of the skin and cancer that resolved or has been 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 the procedure occurred >6 months prior to the screening visit.

[0115] 7. History of prolactin-releasing pituitary tumor (i.e., prolactinoma).

[0116] 8. Known or suspected hypogonadism, current clinically significant menstrual abnormalities (e.g., oligomenorrhea or amenorrhea), gynecomastia, galactorrhea, or other clinical features that may be consistent with hyperprolactinemia.

[0117] 9. Has had pyloric injection of botulinum toxin within 6 months of screening and / or planned injection(s) during the course of the study;

[0118] 10. History of pyloroplasty, pyloromyotomy, or G-POEM procedure;

[0119] 11. Has a serum creatinine level greater than 1.5 x the upper limit of normal or has an eGFR <30 mL / min / 1.73 m2using the equation at screening.

[0120] 12. Has bilirubin, alkaline phosphatase, AST, or ALT levels greater than 2 x the upper limit of normal or has a Child-Pugh classification grade of B or C.

[0121] 13. Has a hemoglobin level <10 g / dL at Screening.

[0122] 14. TSH levels that are abnormal at screening.

[0123] 15. History of solid organ or hematological transplantation.

[0124] 16. Recent pulmonary exacerbation requiring parenteral antibiotics within the prior 1 month of the screening visit.

[0125] 17. Major complications of lung disease (including massive hemoptysis, pneumothorax, or pleural effusion) within 8 weeks prior to screening.

[0126] 18. Inability to perform a gastric emptying breath test. Applies only to subjects who are required to complete a GEBT for eligibility.

[0127] 19. Allergic to egg or intolerant to gluten. Applies only to subjects who are required to complete a GEBT for eligibility.

[0128] 20. History of alcoholism or drug abuse within 2 years prior to dosing as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition.

[0129] 21. Typical consumption of >14 alcoholic drinks weekly.

[0130] 22. History or evidence of illicit drug use within 2 years prior to dosing.

[0131] 23. Positive for HIV, HCV by RNA, or HBsAg at the Screening Visit.

[0132] 24. Currently undergoing treatment with weight loss medication or prior weight loss surgery’ (e.g., gastric bypass surgery).

[0133] 25. Pregnant, breastfeeding, or planning to become pregnant during the course of study.

[0134] 26. Inability to swallow medication.

[0135] 27. Currently receiving parenteral feeding or presence of a nasogastric or other enteral tube (e.g., PEG or PEJ tube) for feeding or decompression.

[0136] 28. Known or suspected gastric outlet obstruction (e g., peptic stricture) or other gastrointestinal mechanical obstruction.

[0137] 29. History7of gastric surgery such as fundoplication, gastrectomy, gastric pacemaker placement, vagotomy7, pyloroplasty, or bariatric procedure. A history of diagnostic endoscopy is not exclusionary. Cholecystectomy and appendectomy are allowed if the procedure occurred >6 months prior to the screening visit.

[0138] 30. Actively participating in an experimental therapy study; received experimental therapy with a small molecule within 30 days of Day -1, or 5 half-lives, whichever is longer; or received experimental therapy with a large molecule within 90 days of Day -1, or 5 half-lives, whichever is longer.

[0139] 31. History' or presence of any medical condition or psychiatric disease, which could interfere with the conduct of the study or would put the subject at unacceptable risk.

[0140] 32. Known hypersensitivity to domperidone or any of the excipients in the deudomperidone formulation.

[0141] 33. After reviewing medical and psychiatric history', physical examination, and laboratory evaluation, to be unsuitable for any other reason that may either place the subject at increased risk during participation or interfere with the interpretation of the outcomes.

[0142] (iii) Randomization Criteria

[0143] In addition to the inclusion / exclusion criteria, in order to be randomized, subjects must meet the following criteria at the Randomization Visit:

[0144] 1. Has been off all motility agents and antiemetics for at least 14 days prior to randomization and is willing to remain off such medications (except for protocol-specified antiemetic rescue medication) during the course of the clinical trial.

[0145] 2. Has an ANMS GCSI-DD score that satisfies the following:

[0146] A Nausea Subscale score of >2 at least 4 of 7 days each week; AND

[0147] At least 1 episode of vomiting each w eek for 2-weeks prior to randomization during the portion of the Screening Period during w hich the subject has not been taking motility7agents or antiemetics (w ith the exception of protocol-specified rescue medication).

[0148] 3. Adherence with the ANMS GCSI-DD during the Baseline Period, defined as adherence >75% or approval.

[0149] D. Study Design and Duration

[0150] This is a randomized, double-blind, placebo-controlled study to investigate the effect of the oral deudomperidone formulation on gastric emptying and upper GI motility7in adults with CF and gastroparesis. The safety, tolerability and PD of the deudomperidone formulation will also be assessed in this population.

[0151] The study will begin by randomizing subjects in to either the deudomperidone formulation 10 mg BID or placebo BID in a 2: 1 ratio such that approximately 50 subjects receive the deudomperidone formulation and 25 subjects receive placebo for 12 weeks. Subjects will be stratified at randomization by sex at birth (female, male).

[0152] The safety of the deudomperidone formulation will be assessed from the time of randomization until the end of the follow-up period. Subjects will be followed for efficacy and adherence throughout the double-blind treatment period.

[0153] Randomized subjects may choose to participate in a reflux sub-study. Here subjects will have (1) one baseline EPM-MII done prior to the first dose of study drug administration and after 14 days of wash-out from prohibited concomitant medications (see Inclusion / Exclusion criteria) and (2) a second EPM-MII performed after the subject has been on a stable dose of study drug for at least 6 weeks or by week 12. Subjects who choose to participate in the reflux sub-study should stay off PPIs and H2-blockers for >1 week prior to the examination. The following will be measured: (1) reflux index; (2) number of acid and non-acidic events; (3) mean duration of acid and non-acidic events; (4) number of events lasting >5 minutes; and (5) DeMeester score. The reflux index is the percentage of total study time below pH 4. The DeMeester score is a composite of several acid exposure parameters during the 24-hour pH monitoring.

[0154] See, Tables 1 A and IB for the schedule of activities. At the Screening Visit, all subjects will sign informed consent prior to any study procedures being performed. Subjects must meet all of the inclusion criteria and none of the exclusion criteria to be eligible for study participation.

[0155] Subjects will be evaluated as follows:

[0156] Screening Period of up to 5 weeks: Days -35 to -1

[0157] • Visit 1 (Day -35 to -22):

[0158] o Screening procedures will be performed and the subject will begin washout of any applicable excluded medications.

[0159] o The RDQ and CFQ will be provided to the subject to complete while at the clinic.

[0160] c Beginning in the evening of Visit 1, the subject will begin daily recording of the ANMS GCSI-DD and the use of allowable rescue medications. Subjects who experience severe symptoms of gastroparesis may receive a single dose of promethazine (Phenergan®) per day during the screening and treatment periods. Subjects who requirefurther treatment with prohibited medications may be discontinued from study treatment and undergo follow-up study procedures.

[0161] o Subjects participating in the reflux sub-study will have a baseline EPM- MII study performed anytime between signing informed consent / assent and beginning of study drug administration as long as they have washed out of prohibited concomitant medications for 14 days and PPIs and H2-blockers for 7 days.

[0162] • Visit 2 ANMS GCSI-DD Baseline (Day -21 to Day -1):

[0163] o For those subjects with documented delayed gastric emptying within 2 years of Visit 1, this visit will be completed via a telephone call to the subject to assess adherence to the subject diaries, concomitant medications adverse events. If the subject would require additional evaluation requiring a visit to the clinic, the subject may report to the clinic for additional procedures falling under Unscheduled Visits.

[0164] o The subject will be asked to continue completing the ANMS GCSI-DD questionnaire daily and will record the use of allowable rescue medication daily via electronic diary. The subject must complete at least 14 days of the ANMS GCSI-DD questionnaire daily diary prior to randomization. The average of ANMS GCSI-DD daily measurements obtained from the period of 14 days prior to the subject taking the study drug will constitute “baseline” measurements.

[0165] c GEBT: For subjects who do not have documented delayed gastric emptying within 2 years of Visit 1, a GEBT will be performed on a single day between Days -21 to -12, inclusive, within this window . The GEBT will have breath samples obtained twice prior to consumption of a standardized,13C-enriched meal and then at 45, 90, 120, 150, 180, and 240 minutes after meal consumption after an 8-hour fast prior to the start of the GEBT.

[0166] On the day of the GEBT, subjects will present at the clinic after an overnight fast and should take regular medications, including any treatment for diabetes, with the exception of any prohibited concomitant medication. Subjects requiring insulin will selfadminister their usual morning insulin injection, taking into consideration their fasting status. Subjects will be instructed to bring in their insulin, as needed, to the clinic. Fasting blood glucose will be assessed before gastric emptying assessments to ensure a blood glucose of <275 mg / dL. Additional insulin may be given (prorated based on meal caloric content) to ensure a blood glucose of <275 mg / dL prior to the gastric emptying procedure. Likewise, low blood sugar (hypoglycemia; <60 mg / dL) should be managed.

[0167] Double Blind Treatment Period of 12 weeks: Visit 3 to Visit 7 (Days 1 to84)

[0168] • Subjects who meet all inclusion / exclusion criteria and randomization criteria will be randomized at Visit 3.

[0169] • Study drug will be administered (the deudomperidone formulation or placebo BID for 12 weeks) and safety assessments, prolactin, will be completed; the ANMS GCSI-DD questionnaire will be completed daily.

[0170] • On Day 1, CFQ and RDQ questionnaires will be completed prior to the first dose of study drug and will constitute baseline for these measures. On Day 84, these measures will be completed prior to the final dose of study drug.

[0171] • Reflux sub-study subjects will have a post-baseline EPM-MII any time after they have been on a stable dose of study drug for at least 6 weeks or by week 12. Subjects who are participating in the reflux sub study should fast for at least 6 hours prior to initiation of the EPM-MII. Subjects should be instructed to bring in their medication. Diabetic subjects on insulin should self-administer their usual morning insulin injection or a portion of their morning insulin dose, considering their fasting status. Fasting blood glucose will be assessed before study drug administration and gastric emptying assessments to ensure a blood glucose of <275 mg / dL. Additional insulin may be given to ensure a blood glucose of <275 mg / dL prior to the gastric empty ing procedure.

[0172] • Safety will be evaluated through assessments of adverse events, vital signs, physical examinations, clinical laboratory evaluations (including prolactin), and electrocardiogram findings. Additionally, a single, optional pharmacogenomic blood sample may be collected at any time during the subject’s participation in the study treatment period.

[0173] Follow-Up Period: Visit 8 (Day 91 ±3 days)

[0174] Subjects will have a follow-up visit approximately 1 week after the final dose of study drug to assess adverse events and changes to concomitant medications (including use of rescue medication), and vital signs.

[0175] Unscheduled visits and / or additional follow-up may be required. For example, subjects with clinically significant abnormal laboratory findings, unresolved treatment-emergent adverse events, serious adverse events that require follow-up laboratories and review, and clinically significant adverse events may necessitate further assessments.

[0176] E. Dosage Forms and Route of Administration

[0177] All randomized subjects will take a dose of blinded study drug (the deudomperidone formulation or placebo capsules) orally with approximately 240 mL of water twice-daily. An approximate 12-hour interval (i. e. , 8:00 am and 8:00 pm) will be maintained between each dose for a given individual. Subjects will be required to fast 2 hours before and 1 hour after all doses. Subjects will be provided study drug for selfadministration for doses not administered at the site.

[0178] F. Rescue Medications

[0179] Subjects who experience severe symptoms of gastroparesis may receive a single dose of promethazine (Phenergan®) per day. Subjects who require further treatment with prohibited medications may be discontinued from treatment and undergo follow-up procedures.

[0180] G. Efficacy Variables

[0181] The efficacy variables to be evaluated with the deudomperidone formulation versus placebo are as follows:

[0182] • The change from baseline in CFQ Modules:

[0183] o HRQoL;

[0184] o Symptoms; and

[0185] o Overall health perception.

[0186] • The change from baseline compared to the last 6 weeks of the 12-week treatment period in symptom severity as measured by the ANMS GCSI-DD:

[0187] o A composite of the Nausea and Vomiting Sub-Scale Scores

[0188] o Nausea Sub-Scale Score

[0189] o Vomiting Sub-Scale Score

[0190] c Total Score

[0191] o Early Satiety Sub-Scale Score

[0192] o Post-Prandial Fullness Sub-Scale Score

[0193] o Upper Abdominal Pain Sub-Scale Score

[0194] • The change from baseline of symptom severity7as measured by the RDQ.

[0195] The exploratory efficacy variable is the change from baseline with the deudomperidone formulation versus placebo in pH parameters, including reflux index, number of total acid reflux events, number of acid reflux events lasting >5 minutes, and DeMeester score.

[0196] H. Safety Variables

[0197] Safety of the deudomperidone formulation will be assessed by physical examinations, ECGs, vital sign assessments, clinical laboratory evaluations, and adverse events.

[0198] I. Statistical Analyses

[0199] ITT Population: All subjects who are randomized.

[0200] MITT Population: All subjects in the ITT Population who received any amount of study drug.

[0201] The primary analysis population will be the MITT Population.

[0202] The Safety Population will consist of all randomized subjects who receive any study drug.

[0203] The EPM-MII population will include subjects who have a baseline and a post-baseline EPM-MII study.

[0204] Symptom scores at various time points will be compared to baseline using paired t tests and significance determined. The change from baseline in the scores of the various PROs will be compared between the deudomperidone formulation-treated and placebo groups.

[0205] EPM-MII will be analyzed by software provided by Sandhill Scientific (Highlands Ranch, Colorado) was used to generate a report for each subject. EPM will measure: (I) reflux index; (II) number of acid events; (III) mean duration of acid events; (IV) number of events lasting >5 minutes; and (V) DeMeester score. The reflux index is the percentage of total study time below pH 4. The DeMeester score is a composite of several acid exposure parameters. See, e.g., DeMeester, Am. J. Gastroenterol. 1974; 62:325-32.

[0206] If the data permit, an attempt may be made to correlate plasma concentrations with select safety measures, prolactin data, and / or measures of gastric emptying time and symptoms of gastroparesis and reflux.

[0207] Safety data, including physical examinations, ECGs, vital sign assessments, clinical laboratory' evaluations (including prolactin), and adverse events, will be summarized by treatment group (placebo subjects from all dose levels will be pooled) and time of collection, when appropriate. Individual and mean time course of absolute prolactin values and change from baseline prolactin by treatment may also be generated.

[0208] Descriptive statistics (arithmetic mean, standard deviation, median, minimum, and maximum) will be calculated for quantitative safety data, as well as for the difference from baseline, when appropriate. Absolute and change from baseline values in QT and QTc (using Fridericia’s correction factor) will be presented.

[0209] Shift tables describing out-of-normal range shifts will be provided for clinical laboratory7results.

[0210] J. Sample Size Determination

[0211] A total of approximately 75 subjects will be randomized to the deudomperidone formulation 10 mg BID or placebo BID. The sample size is considered adequate to provide the necessary data to evaluate the objectives. No formal statistical assessment for sample size determination has been performed. Additional dosing cohorts or subjects may be added, but no more than 30 additional subjects will be added without a protocol amendment. There is no minimal or maximum number of subjects who may participate in the reflux sub study.

[0212] It is to be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof, that the foregoing description and the examples that follow are intended to illustrate and not limit the scope of the invention. It will be understood by those skilled in the art that various changes may be made, and equivalents may be substituted without departing from the scope of the invention, and further that other aspects, advantages and modifications will be apparent to those skilled in the art to which the invention pertains. In addition to the embodiments described herein, the present invention contemplates and claims those inventions resulting from the combination of features of the invention cited herein and those of the cited prior art references which complement the features of the present invention. Similarly, it will be appreciated that any described material, feature, or article may be used in combination with any other material, feature, or article, and such combinations are considered within the scope of this invention.

[0213] The disclosures of each patent, patent application, and publication cited or described in this document are hereby incorporated herein by reference, each in its entirety, for all purposes.

Claims

WHAT IS CLAIMED IS:

1. Deudomperidone for use in improving one or more gastrointestinal symptom in a human patient having cystic fibrosis and gastroparesis, comprising orally administering 5 mg to 120 mg of deudomperidone daily to the human patient.

2. Deudomperidone of claim 1. wherein the upper gastrointestinal symptom is postprandial nausea, postprandial vomiting, postprandial fullness, early satiety, bloating, epigastric pain, abdominal pain, or combinations thereof.

3. Deudomperidone of claim 1 or 2, wherein, prior to administering the deudomperidone, the human has a T'Z> greater than about 80 minutes, or such as greater than about 110 minutes, or such as greater than about 200 minutes, as measured by a gastric emptying breath test (GEBT) using13C-spirulina platensis.

4. Deudomperidone of any one of the preceding claims, wherein the human patient has a resting oxygen saturation of about 92% or greater on room air, as measured by pulse oximetry7.

5. Deudomperidone of any one of the preceding claim, wherein the human patient has (i) one or more symptom of cystic fibrosis and (ii) two cystic fibrosis transmembrane conductance regulator (CFTR) causing alleles on genetic testing or a sweat chloride of about 60 mEq / L or greater.

6. Deudomperidone of any one of the preceding claims, wherein the human patient has delayed gastric emptying.

7. Deudomperidone of claim 1 or 2, wherein the gastroparesis is acute or recurrent gastroparesis.

8. Deudomperidone of any one of the preceding claims, further comprising improving gastric emptying, as measured by a gastric emptying breath test (GEBT) using13C- spirulina platensis.

9. Deudomperidone of any one of the preceding claims, wherein about 10 mg, or about 20 mg, or about or about 30 mg, or about 60 mg, or about 120 mg of deudomperidone is administered to the human.

10. Deudomperidone of any one of the preceding claims, wherein the deudomperidone is administered in divided doses, such as two doses.1 1. Deudomperidone of any one of the preceding claims, wherein the deudomperidone is administered daily.

12. Deudomperidone of any one of the preceding claims, wherein the human is an adult.

13. Deudomperidone of any one of the preceding claims, wherein administration results in a clinically significant improvement in postprandial nausea, early satiety, postprandial fullness, upper abdominal pain, vomiting, and bloating as measured by an American Neurogastroenterology and Motility Society Gastroparesis Cardinal Symptom Index Daily Diary (ANMS GCSI-DD) score after administration, such as about 6 to about 12 weeks after administration, such as about 6 to about 12 weeks after administration.

14. Deudomperidone of any one of the preceding claims, wherein the administration results in a clinically significant improvement in an average composite score of the ANMS GCSI-DD score after administration, such as about 6 to about 12 weeks after administration.

15. Deudomperidone of any one of the preceding claims, wherein the administration results in a clinically significant improvement in a nausea subscale score of the ANMS GCSI-DD score after administration, such as about 6 to about 12 weeks after administration.

16. Deudomperidone of any one of the preceding claims, wherein the administration results in a clinically significant improvement in a vomiting subscale score of the ANMS GCSI-DD score after administration, such as about 6 to about 12 weeks after administration.

17. Deudomperidone of any one of the preceding claims, wherein the administration results in a clinically significant improvement in a total score of the ANMS GCSI- DD score after administration, such as about 6 to about 12 weeks after administration.

18. Deudomperidone of any one of the preceding claims, wherein the administration results in a clinically significant improvement in an early satiety’ subscale score of the ANMS GCSI-DD score after administration, such as about 6 to about 12 weeks after administration.

19. Deudomperidone of any one of the preceding claims, wherein the administration results in a clinically significant improvement in a post-prandial fullness subscale score of the ANMS GCSI-DD score after administration, such as about 6 to about 12 weeks after administration.

20. Deudomperidone of any one of the preceding claims, wherein the administration results in a clinically significant improvement in an upper abdominal pain subscale score of the ANMS GCSI-DD score after administration, such as about 6 to about 12 weeks after administration.

21. Deudomperidone of any one of the preceding claims, wherein the administration results in a clinically significant improvement in symptom severity as measured by a reflux disease questionnaire (RDQ) after administration, such as about 6 to about 12 weeks after administration.

22. Deudomperidone of any one of the preceding claims, wherein the administration results in a clinically significant improvement in gastric empty ing as measured by ANMS GCSI-DD subscale scores after administration, such as about 6 to about 12 weeks after administration.

23. Deudomperidone of any one of the preceding claims, wherein the administration results in a clinically significant improvement in gastric emptying as measured by GEBT after administration, such as about 6 to about 12 weeks after administration.

24. Deudomperidone of any one of the preceding claims, wherein the administration results in a clinically significant improvement in gastric empty ing as measured by ANMS GCSI-DD total scores after administration, such as about 6 to about 12 weeks after administration.

25. Deudomperidone of any one of the preceding claims, wherein the administration results in a clinically significant improvement in a variable related to cystic fibrosis, as measured by the cystic fibrosis questionnaire (CFQ), such as health-related quality of life, cystic fibrosis symptom, or overall health perception after administration, such as about 6 to about 12 weeks after administration.

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