| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| diabetic or idiopathic gastroparesis. |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10021227 |
| E.1.2 | Term | Idiopathic gastroparesis |
| E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10051153 |
| E.1.2 | Term | Diabetic gastroparesis |
| E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the effect of velusetrag on symptoms in subjects with gastroparesis |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the effect of velusetrag on gastric emptying
To evaluate the effect of velusetrag for improving nausea
To evaluate the pharmacokinetics (PK) of velusetrag in subjects with gastroparesis
To evaluate the psychometric properties of a gastroparesis PRO measure
To assess the safety and tolerability of velusetrag |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Serial Pharmacokinetics will be done only on a subset of subjects who
will have to consent specifically before participating.
Assessment of plasma velusetrag and THRX-830449 (metabolite)
concentrations at 0.5, 1, 2, 3, 4, 5 and 6 hours after dosing. Plasma
samples from selected subjects may be used for exploratory metabolite
profiling studies. |
|
| E.3 | Principal inclusion criteria |
1.Is male or female, 18 to 75 years of age, inclusive, at Screening
2. Willing and able to provide written, signed informed consent
3. Symptoms of gastroparesis (eg, nausea, early satiety, fullness, bloating, upper abdominal pain, retching or vomiting) for at least 3 months prior to Screening
4. Composite score ≥2 and <5 on nausea, bloating, feeling excessively full after meals, and not able to finish a normal-sized meal items (on the GCSI-2W) at Screening
5. At least two of the four symptoms (ie, nausea, bloating, feeling excessively full after meals, and not able to finish a normal-sized meal) with a score ≥3 (on the GCSI-2W) at Screening
6. Delayed gastric emptying at Screening, defined as:
a. 99mTc GES: gastric emptying retention >10% at 4 hours or,
b. GEBT: tmax (time of maximum 13CO2 excretion rate) at 240 minutes or gastric emptying delay at 2 of 3 time points (90, 120 or 150 minutes). If a subject fails either the GES or GEBT at Screening then the subject will be allowed to perform a second gastric emptying test during the Screening Period using the GEBT in order to qualify for the study. GES or GEBT is not required if subject has had a comparable, qualifying 4-hour gastric emptying test within 1 year of Screening.
7. Body Mass Index (BMI) between 18 and 42 kg/m2, inclusive
8. Screening ECG with a QTcF in the normal range (males ≤450 msec and females ≤470 msec)
9. Upper gastrointestinal obstruction ruled out by endoscopy or other imaging (eg, computed tomography) after the onset of gastroparesis symptoms
10. Stable concomitant medications, in particular those that may affect gastroparesis symptoms, for at least 3 weeks prior to Screening. Subjects must be willing to continue these medications without changes throughout the study. Routine adjustments in daily insulin treatment are permitted.
11. Willing to abstain from prohibited medications, including but not limited to, anticholinergics, acetylcholinesterase antagonists, or promotility medications (eg, metoclopramide, domperidone, prucalopride, erythromycin) for 24 hours prior to gastric emptying test during Screening, if applicable, 24 hours prior to start of the Baseline Period; during the Baseline Period
12. For women of childbearing potential, documentation of a negative serum pregnancy test at Screening and a negative urine pregnancy test on Day 1. All females are considered to be of childbearing potential unless they are
postmenopausal (ie, amenorrheic for at least 2 years) or documented to be surgically sterile (eg, bilateral tubal ligation or total hysterectomy).
13. For a sexually active subject: is willing to use an acceptable method of contraception during the study and for at least 2 weeks after completion of study drug dosing
14. Able to communicate effectively with the investigator and comply with all study requirements, restrictions, and directions of the clinic staff.
Additional Inclusion Criteria for Randomization into Treatment Period: The Baseline Period can last up to 5 weeks and be no less than 7 days (the start of the Baseline Period (Visit 2) may be combined with the Screening Visit if a Screening gastric emptying test is not needed. In cases when the Baseline Period is longer than 7 days, the last consecutive 7 days prior to Day 1 will be used to determine eligibility for randomization. Subjects who meet the following additional criteria after the Baseline Period will be eligible for randomization:
15. GCSI-24H 7-day mean composite score ≥2.5 and <5 at Day 1
16. Electronic diary completion compliance of at least 5 days per week during the 7 days of the Baseline Period, measured by completion of the GRS and GCSI-24H |
|
| E.4 | Principal exclusion criteria |
1. Have received velusetrag in a prior clinical trial
2. Acute severe gastroenteritis within 2 weeks prior to Screening
3. If Type 1 or Type 2 diabetic, a glycosylated hemoglobin(HbA1c) level >11%
4. History of gastric outlet obstruction
5. Prior history of gastric surgery, including but not limited to gastrectomy, gastric bypass, gastric banding, pyloroplasty, vagotomy, or fundoplication, which has manipulated the natural anatomy of the stomach
6. History of intrapyloric botulinum toxin injection within 3 months of Screening or currently has functioning implantable electric stimulator
7. Recurrent and unremitting vomiting, defined as 2 or more vomiting episodes per day for 4 or more days per week
8. Pronounced dehydration, in the opinion of the investigator
9. Hospitalization for treatment of gastroparesis or a complication of diabetes(eg, hyperglycemic coma, ketoacidosis) within 4 weeks of Screening
10. Concurrent eating disorder(eg, anorexia nervosa, bulimia) at Screening
11. Presence of thyroid dysfunction not controlled by treatment. Subjects with abnormal thyroid stimulating hormone(TSH), hypothyroidism, or hyperthyroidism at Screening unless adequately treated.
12. Known secondary causes of gastroparesis, including but not limited to Parkinson's Disease, cancer, viral illness, or connective tissue diseases.
13. Subject is unwilling to abstain from nicotine-containing products(eg. cigarettes, chewing tabacco, nicotine-containing gum) and/or alcohol on the morning of and throughout testing on the day of a gastric emptying
test, if applicable.
14. Subject is unwilling or unable to perform gastric emptying test, if applicable(eg, allergic to eggs, gluten, lactose or Spirulina)
15. Aspartate aminotransferase(AST), alanine transaminase(ALT) levels >2 times the upper limit of Normal at Screening;bilirubin, alkaline phosphatase(ALP), or creatinine levels >1.5 times the upper limit of normal; or hemoglobin <10 g/dL at Screening
16. Use of a prohibited medication, including but not limited to, opioids(eg. for chronic pain), linaclotide, or lubiprostone within 2 weeks prior to Screening and throughout the duration of the study
17. Received strong CYP3A4 inhibitors(eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, grapefruit juice) or strong CYP3A4 inducers(eg, rifampin, rifabutin, rifapentin, dexamethasone, phenytoin,carbamazepine, phenobarbital, St. John's wort) within 2 weeks prior to Screening and throughout the duration of the study.
18. Received strong P-glycoprotein(P-gp) transporter inhibitors(eg, ritonavir, cyclosporine) within 2 weeks prior to Screening and throughout the duration of the study
19. Active treatment for cancer or malignancy(other than nonmelanomatous skin cancer) within 1 year prior to Screening
20. Participation in an investigational study, involving an investigational drug, within 30 days prior to Screening or approximately five half-lives of the investigational drug if half-life is known, whichever occurs later, or has need of any investigational agent before completion of all scheduled study evaluations
21. Presence of disease states that would affect safety and efficacy evaluation, such as cardiovascular disease (eg, acute coronary syndrome, acute myocardial infarction or life-threatening tachyarrhythmia within 3 months prior to Screening), respiratory (eg, requires oxygen), hepatic(eg, cirrhosis, or evidence of clinically significant cholestasis), renal (eg, dialysis), gastrointestinal (eg, symptomatic diverticulitis, predominant symptoms of irritable bowel syndrome or inflammatory bowel disease, Crohn's disease), hematological, neurologic or brain disorders (eg, Parkinson's disease, strokes, and brain injury), psychiatric (eg, bipolar disorder, severe active depression, severe active anxiety), or any other significant condition which, in the opinion of the Investigator, could confound or interfere with evaluation of safety, or tolerability of the investigational drug, or
prevent compliance with the study protocol.
22. History of alcohol or drug abuse or dependence within the last year prior to Screening
23. Positive urine drug screen for cannabinoids, cocaine, fentanyl, methadone, tramadol or other opioids at Screening.
24. Females who are pregnant, breast-feeding or planning a pregnancy
25. Known hypersensitivity to, or intolerance of, study medications or their formulation excipients
26. In the opinion of the Investigator, any relevant deviations from normal in clinical laboratory tests results (eg, potassium)
27. Unwilling or unable to maintain a consistent diet from Screening until the end of the study
28. Nasogastric tube, gastrostomy tube, or jejunostomy feeding tube, or parenteral nutrition, within 2 weeks of Screening
29. Any condition that, in the opinion of the investigator, would prevent compliance with the study protocol or assessment of safety and efficacy |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| change from baseline and change from placebo of the 7-day mean GCSI-24H composite score at Week 4. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- Change from baseline in daily and 7-day mean composite GCSI-24H
score over Weeks 1-3 and Weeks 5-12 of treatment
- Change from baseline in daily and 7-day mean GCSI-24H individual
component scores over Weeks 1-12 of treatment
- Proportion of subjects with at least 1 point improvement from baseline
in the GCSI-24H individual components at each Week (1-12)
- Change from baseline in daily and 7-day mean composite GRS score
over Weeks 1-12 of treatment
- Change from baseline in daily and 7-day mean GRS individual
component scores over Weeks 1-12 of treatment
- Proportion of subjects with at least 1 point improvement from baseline
in the GRS individual components at each Week (1-12)
-Change from baseline in gastric emptying at Week 4 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Change from baseline in daily and 7-day mean composite GCSI-24 score over Weeks 1-3 and Weeks 5-12 of treatment
- Weeks 1-12 of treatment
- over Weeks 1-12 of treatment
- at each Week (1-12)
- Week 4
- Week 12 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Czech Republic |
| Poland |
| Sweden |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last visit of the last subject |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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