| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| The medical condition to be investigated is gastroparesis due to diabetes mellitus. |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10018043 |
| E.1.2 | Term | Gastroparesis |
|
| 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 trial is to evaluate the effect of TZP-102 (administered once-daily for four weeks) on gastric emptying rate in patients with gastroparesis due to diabetes mellitus. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
• to evaluate the safety of TZP-102
• to evaluate the effects of TZP-102 on gastroparesis symptoms
• to assess the effects of TZP-102 on health-related quality of life
• to evaluate the effects of TZP-102 on serum growth hormone and serum IGF-1
concentrations
• to assess plasma TZP-102 concentrations in conjunction with once-daily
administrations of TZP-102 |
|
| 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.Female patients of childbearing potential must have a negative serum pregnancy test and use 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.[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).]
4.Patient has a HbA1c)level ≤ 10.0 % at the Screening Visit.
5.Patient has a diagnosis of gastroparesis (all three of the following requirements apply):
i.Delayed gastric emptying documented by at least one of the following procedures prior to the Screening Visit:
-2-hour or 4-hour scintigraphy, with ≥ 60% retention at 2 hours and/or ≥ 10% retention at 4 hours. [ Note: If any pre-stydy scintigraphy report does not provide 2- and/or 4 hour meal retention percentages, but instead reports a gastric half-emptying time that is above the upper limit of normal, or reports an overall conclusion of "delayed gastric emptying", that test will be valid to satisfy Inclusion Criterion 5 (i).]
-a 4-hour (or longer) 13C-octanoate breath test, with a half-emptying time ≥ the lab-specified limit for defining delayed gastric emptying
-a 4-hour (or longer) 13C-acetate breath test, with a half-emptying time ≥ the lab-specified limit for defining delayed gastric emptying
-the SmartPill® GI Monitoring System, with a gastric residence time ≥ 5 hours
ii.A history of symptoms of gastroparesis (excessive stomach fullness after meals, bloating, epigastric discomfort, early satiety, loss of appetite, belching, nausea, retching, vomiting) for at least 3 months leading up to the Screening Visit
iii.A GCSI Total Score ≥ 2.66 at the Screening Visit and ≥ 1.90 at the Day 1 Visit (prior to randomization and administration of the first dose of study drug)
[ Note: In the development and validation of the GCSI (Revicki et al., 2004) the standard deviation for repoducibility (intra-subject variability) of the GCSI Total score was 0.72. The score of 1.90 required on Day 1 prior to randomisation is one standard deviation less than the score of 2.66 required at the Screening Visit, rounded to the nearest 1/10th.] [ Note:If a given patient satisfies Inclusion Criteria 5 (ii) and 5 (iii), but does not have a pre-study assessment of gastric emptying, the Gastric Motility Breath Test (GMBT) performed at the Baseline GMBT Visit may be used to satisfy Inclusion Criterion 5 (i) and thereby confirm the diagnosis of gastroparesis.]
6.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.
7.Dosing regimens of all concomitant medications must be stable for at least 2 weeks leading up to the Baseline GMBT Visit and patients must agree to continue the same regimens until completion of the Day 28 Visit. Specific medications that are not permitted are addressed below in the section on Exclusion Criteria.
8.Patient has a BMI)< 35.
9.Patient has a Baseline GMBT Visit gastric half-emptying time ≥ 150 minutes.
|
|
| E.4 | Principal exclusion criteria |
1.Patient has persistent daily vomiting that would preclude daily oral intake, make it difficult for the patient to take daily study medication each morning for 28 days, and/or make it difficult for the patient to consume the 350 kcal test meal (low-fat muffin) for each of the 3 breath test assessments of gastric emptying that will be performed during the study.
2.Patient has had a gastrectomy, obesity surgery (gastric bypass, vertical banding gastroplasty, lap band), fundoplication, or vagotomy/pyloropasty. Patients who have had endoscopy pyloric injections of botulinum toxin A within 6 months prior to the Screening Visit and during the full duration of the study.
3.Patient has a NG, PEG or 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.
4.Patient required inpatient hospitalization for treatment of his/her gastroparesis within 2 weeks prior to the Screening Visit.
5.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.
6.Patient has (or had within the 3 months leading up to the Screening Visit) an active gastric pacemaker . [Note: if an inactive gastric pacemaker is still in place, it may not be activated during the course of the study.]
7.Patient participated in an investigational study within 30 days prior to study entry (or, if longer, within five half-lives of the last dose of any investigational drug). [Note: the use of domperidone (an investigational drug in the U.S.) is not permitted within 14 days prior to the Baseline GMBT Visit, and is not permitted during the study.]
8.Patient has chronic severe diarrhea. [ Note: Patients with a history of intermittent diarrhea, or chronic mild diarrhea, may still be considered for study participation.]
9.Patient had diabetic ketoacidosis, that required in-patient hospitalisation within 30 days prior to study entry.
10.Patient has a history of any eating disorder (anorexia nervosa, binge eating, bulimia) within 2 years prior to study entry.
11.Patient has significant, symptomatic chronic obstructive pulmonary disease or chronic asthma that would interfere with performing the GMBT during the study.
12.Patient is a heavy smoker and unable or unwilling to abstain from smoking during each of the three 7- to 8-hour study visits during which the gastric emptying breath tests will be performed.
13.Patient has a history of risk factors for Torsades de Pointes (heart failure, chronic hypokalemia, personal or family history of Long QT Syndrome).
14.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 (see the list of medications provided in Section 10.2).
15.Patient has a history of cardiovascular ischemia (specifically, acute myocardial infarction (MI) or unstable angina) within 12 months prior to study entry.
16.Patient has a history of any psychiatric disorder or cognitive impairment that would interfere with participation in the study.
17.Patient has a history of alcohol dependency within 2 years prior to study entry.
18.Patient is taking opiates for abdominal pain. [Note: the use of opiates for neuropathic or other chronic pain conditions is permitted, but as with other concomitant medications, a stable dosing regimen must be maintained throughout the study.]
19.Patient has a known history of Hepatitis B or Hepatitis C infection currently associated with symptoms and/or abnormal liver funciton that might be expected to worsen during the course of the study; or the patient has a known history of HIV infection.
20.Patient requires dialysis or has severely impaired renal function, defined as a serum creatinine > 2.0 mg/dL (> 180 mmol/L) at the Screening Visit.
21.Patient has severe impairment of liver function, defined as a serum albumin level ≤ 2.5 g/dL and/or a PT INR > 2.3 (or Prothrombin Time > 6 seconds above the upper limit of normal) at the Screening Visit.
22.Patient has hypo- or hyperthyroidism that is not well-controlled on a stable treatment regimen.
23.Patient has a history of adrenal insufficiency.
24.Patient is pregnant or is breast-feeding.
25.Patient is allergic to or intolerant of wheat, egg, soy or milk products (all are components of the low-fat muffin test meal used for the GMBT that will be performed in this study), or is allergic to tree nuts (the test meal product is made on equipment that also makes products containing tree nuts).
26.Patient requires a gluten-free diet.
27.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.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the change from baseline in gastric half-emptying time (T½), on Day 1 and Day 28. |
|
| 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 | Yes |
| 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.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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
|
| Please refer to the protocol. |
|
| 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 | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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