E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
The medical condition to be investigated is symptomatic gastroparesis due to diabetes mellitus |
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E.1.1.1 | Medical condition in easily understood language |
Delayed emptying of the stomach. Symptoms of gastroparesis include but not limited to nausea, early satiety, bloating, upper abdominal pain, retching and or vomiting. |
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E.1.1.2 | Therapeutic area | Body processes [G] - Digestive System and Oral Physiological Phenomena [G10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10018043 |
E.1.2 | Term | Gastroparesis |
E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
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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 |
The primary objective of this study is to evaluate the effect of TZP-102 administered once daily for 12 weeks on symptoms associated with diabetic gastroparesis—specifically, nausea, early satiety, bloating, upper abdominal pain, vomiting and retching |
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E.2.2 | Secondary objectives of the trial |
• to evaluate the safety of TZP-102 administered once daily for 12 weeks
• to assess the effect of TZP-102 on health-related quality of life
• to evaluate the pharmacodynamic effects of TZP-102 on the rate of gastric emptying, and on serum growth hormone and serum IGF-1 concentrations
• to determine the dose of TZP-102 to potentially evaluate in phase 3 of clinical development
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patient must be 18 to 80 years of age, inclusive.
2. Patient has type 1 or type 2 diabetes mellitus.
3. Patient has a history of symptoms of gastroparesis (nausea, early satiety, bloating, upper abdominal pain, retching and/or vomiting) for at least 3 months leading up to the Screening Visit.
4. Patient has delayed gastric emptying, defined as a gastric half-emptying time (T½) > 82 minutes, demonstrated by the [13C]-Spirulina platensis Gastric Emptying Breath Test (GEBT) performed during the Screening Period OR has documented delayed gastric emptying within the previous 24 months by either scintigraphy or a GEBT.
5. Patient has an average Daily Diary of Gastroparesis Symptoms Questionnaire (GSDD) Composite Symptom Severity Score > 2.5 during the final 14 days of the Screening Period leading up to the Day 1 Visit (and the possible initiation of randomized study treatment).
[The GSDD Composite Symptom Severity Score (GSDD Composite Score) is defined as the mean of the four individual symptom severity scores for nausea, early satiety, bloating and upper abdominal pain, each graded on a 6-point scale (0 = none; 1 = very mild; 2 = mild; 3 = moderate; 4 = severe; and 5 = very severe).]
6. Patient has a Body Mass Index (BMI) < 45.0 at the Screening Visit.
7. Patient has a glycosylated hemoglobin (HbA1c) level < 11.0 % at the Screening Visit.
8. At the time the original diagnosis of gastroparesis was made, or more recently per routine standard of care practices (e.g., if the patient had new upper gastrointestinal bleeding, a significant worsening or change in symptoms of gastroparesis, new significant weight loss and/or new symptoms of dysphagia), the patient must have had an endoscopy or upper gastrointestinal barium scan to rule out the existence of any obstructive lesion(s) in the esophagus or stomach. If necessary, the procedure may be performed during the Screening Period.
9. Dosing regimens of all concomitant medications must be stable for at least 2 weeks leading up to the Baseline GEBT Visit and patients must agree to continue the same regimens until completion of the study, unless otherwise instructed by the study investigator (e.g., if a new medication or change in medication regimen is needed to treat an adverse event). Specific medications that are not permitted are addressed below in the section on Exclusion Criteria. Patients must be off all prohibited medications for at least 2 weeks leading up to the Baseline GEBT Visit.
10. Female patients of childbearing potential must have a negative serum pregnancy test and use (and agree to continue to use throughout the study) one of the following forms of contraception from the Screening Visit until completion of the final study follow-up visit 4 weeks after administration of the last dose of study drug: hormonal (oral, implant or injection) begun > 30 days prior to the Screening Visit, barrier (e.g., condom, diaphragm with spermicide), intra-uterine device (IUD) or vasectomized partner (6 months minimum). If required by the Regulatory/Competent Authorities in a specific country or by any given study site’s Institutional Review Board (IRB) or Independent Ethics Committee (IEC), male patients must also agree to practice throughout the study an approved method of birth control.
[Note: To be considered NOT of childbearing potential, female patients must be postmenopausal (with amenorrhea for at least 2 years prior to study entry) or surgically sterile (with physician or insurance documentation of bilateral tubal ligation at least 6 months prior to study entry, or of a hysterectomy and/or bilateral oophorectomy) |
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E.4 | Principal exclusion criteria |
1. Patient has persistent daily vomiting that would preclude daily oral intake.
2. Patient has had a gastrectomy, bariatric (obesity) surgery (gastric bypass, vertical banding gastroplasty, lap band), fundoplication, or vagotomy/pyloroplasty.
3. Patient has had endoscopic pyloric injections of botulinum toxin within 6 months prior to the Screening Visit.
4. Patient has a nasogastric (NG), percutaneous endoscopic gastrostomy (PEG) or percutaneous endoscopic jejunostomy (PEJ) feeding tube. If the patient recently had a feeding tube in place, it must have been removed at least 2 weeks prior to the Screening Visit.
5. Patient required inpatient hospitalization for treatment of his/her gastroparesis within 2 weeks prior to the Screening Visit.
6. Patient required parenteral nutrition for treatment of his/her gastroparesis within 2 months prior to the Screening Visit, or is expected to require parenteral nutrition within 1 month after study entry.
7. Patient has (or had within the 3 months leading up to the Screening Visit) an active gastric pacemaker (electrical neurostimulator).
8. Patient participated in an investigational study within 30 days prior to the Screening Visit (or, if longer, within five half-lives of the last dose of any investigational drug).
9. Patient has chronic severe diarrhea.
10. Patient had diabetic ketoacidosis that required inpatient hospitalization within 30 days prior to the Screening Visit.
11. Patient has a history of any eating disorder (anorexia nervosa, binge eating, bulimia) within 2 years prior to the Screening Visit.
12. Patient has significant, symptomatic chronic obstructive pulmonary disease (COPD) or chronic asthma that would interfere with performing the two gastric emptying breath tests during the study.
13. Patient, if a chronic smoker, is unable or unwilling to abstain from smoking during each of the two 4- to 5-hour study visits during which the gastric emptying breath tests will be performed.
14. Patient has a history of risk factors for Torsades de Pointes (heart failure, chronic hypokalemia, a personal diagnosis or family history of Long QT Syndrome).
15. Patient has a corrected QT interval calculated using Fredericia’s formula (QTcF) ≥ 500 msec recorded on any of the three 12-lead electrocardiography (ECG) assessments performed during the Screening Period (at the Screening Visit, at the Baseline GEBT Visit, or prior to randomization and administration of the first dose of study drug at the Day 1 Visit) and confirmed with a repeat ECG assessment performed at the same visit, based on the automated reports generated on-site at each visit with the ECG equipment provided by the Central ECG laboratory
16. Patient has clinically-significant bradycardia or hypotension, as judged by the Investigator.
17. Patient requires treatment with any concomitant medication that is both a substrate of Cytochrome P450 isoenzyme 3A4 and known to have a clinically recognized risk for Torsades de Pointes.
18. Patient has a history of an acute myocardial infarction, unstable angina, a cerebral vascular accident or any transient (cerebral) ischemic attack (TIA) within 12 months prior to the Screening Visit.
19. Patient has a history of severe depression or any psychiatric disorder or cognitive impairment that would interfere with participation in the study.
20. Patient has a history of alcohol or drug abuse or dependency within 2 years prior to the Screening Visit.
21. Patient is taking opiates for abdominal pain.
22. Patient has a known history of Hepatitis B or Hepatitis C infection currently associated with symptoms and/or abnormal liver function that might be expected to worsen during the course of the study; or the patient has a known history of HIV infection.
23. Patient requires dialysis or has a serum creatinine greater than 1.5 times the upper limit of normal (according to the Central Laboratory reference range) at the Screening Visit.
24. Patient has abnormal liver function tests [alanine transaminase (ALT or SGPT), aspartate transaminase (AST or SGOT) greater than two times the upper limit of normal (according to the Central Laboratory reference ranges)] at the Screening Visit.
25. Patient has hypo- or hyperthyroidism that is not well-controlled on a stable treatment regimen.
26. Patient has adrenal insufficiency.
27. Patient has an active malignancy of any type other than a basal cell or squamous cell carcinoma of the skin that is undergoing observation and/or treatment.
28. Patient is pregnant or is breast-feeding.
29. Patient is allergic to, or intolerant of Spirulina platensis, wheat, egg, or milk products (all of which are components of the GEBT meal), or has severe lactose intolerance (the GEBT test meal contains approximately 2.7 g of lactose).
30. Patient has any other medical condition or social circumstance that, in the investigator’s opinion, makes it inappropriate for the patient to participate in this clinical trial. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline in the GSDD symptom scores |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Final 14 days of the Screening Period that precede the Day 1 visit (baseline value).
Final 14 days of the 12-week Treatment Period |
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E.5.2 | Secondary end point(s) |
- The proportion of patients who achieve a pre-specified percent decrease from baseline in the GSDD symptom scores during the 12-week Treatment Period
- Change from baseline in the number of times the patient vomited each day during the 12-week treatment period
- Change from baseline in the number of times the patient retched during the 12-week treatment period Frequency (the number of patients) with one or more inpatient hospitalization(s) during the study (after randomization) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Please refer to protocol section 12.5 |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
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 | 3 |
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 | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
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 |
Belgium |
Denmark |
Finland |
Germany |
Norway |
Poland |
Sweden |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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
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The end of the trial is defined as the last visit of the last subject. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |