| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Weight management/treatment of obesity |
|
| 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 | 10029883 |
| E.1.2 | Term | Obesity |
|
| 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 |
1. To estimate the magnitude of change in HbA1C with a range of oral doses of CE-326,597 administered over 12 weeks in overweight and obese adult subjects with T2DM either treatment naïve or on stable, up to two, oral, anti-diabetic agents.
2. To estimate the magnitude of weight loss with a range of oral doses of CE-326,597 administered over 12 weeks in overweight and obese adult subjects with T2DM either treatment naïve or on stable, up to two, oral, anti-diabetic agents. |
|
| E.2.2 | Secondary objectives of the trial |
1. To estimate the magnitude of change in post-prandial glucose and insulin AUC following a MMTT with a range of oral doses of CE-326,597 in overweight and obese adult subjects with T2DM either treatment naïve or on stable, up to two, oral, anti-diabetic agents.
2. To evaluate the safety and tolerability of a range of oral doses of CE-326,597
administered over 12 weeks in overweight and obese adult subjects with T2DM either treatment naïve or on stable, up to two, oral, anti-diabetic agents – including use of a focused evaluation of GI-related AEs and episodes of hypoglycemia as well as assessment of cholelithiasis/cholecystolithiasis.
3. To characterize the pharmacokinetics of CE-326,597 in overweight and obese adult subjects with T2DM either treatment naïve or on stable, up to two, oral, anti-diabetic agents. |
|
| 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 |
Molecular profiling supplement
Samples for Pfizer's exploratory research biobank
A 12-week, phasa 2A, randomized, subject and investigator blinded, placebo-controlled trial to evaluate the safety, tolerability and efficacy of CE-326,597 on glucose control and body weight in overweight adult subjects with type 2 Diabetes Mellitus
Final Protocol, 28-August-2007
The primary objective of this additional research component is to collect, store, and use samples to investigate possible associations between genomic and metabonomic variation:
- In relation to response to the study drugs, and
- In relation to characteristics of the disease/condition under study in the associated clinical trial, and related conditions.
In addition, samples may be used as controls in genomic and metabonomic investigations of the causes, natural history, and other aspects of important diseases and conditions for which Pfizer is researching now or improved drug therapies.
Scientific information about these differences among groups of subjects can help researchers to better understand the response of subjects to investigational drugs and to learn more about diseases/conditions for which we are developing treatments.
Samples collected will be stored in Pfizer's Exploratory Research Biobank in the USA. |
|
| E.3 | Principal inclusion criteria |
Subjects must meet all the following inclusion criteria to be eligible for enrollment into the trial:
1. Males and/or females of non-childbearing potential between the ages of 18 and 65 years, inclusive, at screening:
• Women must be of non-childbearing potential as defined by one of the following:
• Females who are amenorrheic for ≥2 years prior to screening PLUS a serum follicle stimulating hormone (FSH) within central laboratory’s reference range for
postmenopausal women or
• Documented bilateral oophorectomy or hysterectomy ≥6 months prior to
screening.
2. Subjects must have a diagnosis of T2DM in accordance with the ADA guidelines;
subjects must have at least one of the following criteria previously documented:
• Symptoms of diabetes in addition to casual plasma glucose concentration
≥ 200 mg/dL (ie, 11.10 mmol/L)
• “Casual” is defined as plasma glucose concentration at any time of day without
regard to time since last meal
• Classic symptoms of diabetes include polyuria, polydipsia, and/or unexplained
weight loss
• Fasting plasma glucose (FPG) ≥126 mg/dL (ie, 6.99 mmol/L); term fasting is defined
as no caloric intake for at least 8 hours
• Two-hour post-load glucose ≥200 mg/dL (ie, 11.10 mmol/L) during an oral glucose
tolerance test (OGTT) as performed per WHO (World Health Organization), using a
glucose load containing the equivalent of 75 grams anhydrous glucose dissolved in
ambient temperature water
3. Subjects who have not previously received any pharmacological treatment for T2DM or are on stable doses of up to two, oral, anti-diabetic agents within at least 56 days prior to screening [Refer to Section 5.5 for acceptable anti-diabetic agents].
4. HbA1C ≥6.5% and ≤10% at screening (as assessed by trial-specific central laboratory).
5. Fasting plasma glucose levels < 270 mg/dL (ie, 15.04 mmol/L), at screening, (as assessed by trial-specific central laboratory) confirmed by a single repeat, if deemed necessary.
6. BMI of ≥27 kg/m2 and ≤ 45 kg/m2, at screening.
7. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the trial.
8. Subjects who are willing and able to comply with the scheduled visits, treatment regimen, laboratory tests and other trial procedures.
9. Subjects willing and able to perform self-test of blood sugars at least once daily for the duration of the trial. |
|
| E.4 | Principal exclusion criteria |
Subjects presenting with any of the following will not be included in the trial:
1. Recent (within 12 months prior to screening) evidence or medical history of unstable concurrent disease such as: documented evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal (including severe gastroparesis), cardiovascular, hepatic, psychiatric, neurologic, or clinically significant allergic disease (including any drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing).
2. History of cholecystitis or previously diagnosed biliary colic; subjects with documented cholecystectomy are eligible for the trial.
3. History of documented cholelithiasis/cholecystolithiasis or evidence of this on screening gallbladder transabdominal ultrasonography.
4. Any condition possibly affecting drug absorption (eg, gastrectomy or any area of
intestinal resection, active inflammatory bowel disease or pancreatic insufficiency).
5. Diagnosis of Type 1 diabetes mellitus.
6. Presence of positive glutamic acid decarboxylase (GAD) antibody titer at screening, as assessed by trial-specific central laboratory.
7. Treatment with any thiazolidinediones (TZDs), insulin, Byetta® (exenatide) or Symlin® (pramlintide) within 56 days prior to Day 1.
8. Subjects on concomitant agents known to be PgP substrates with narrow therapeutic margin such as digoxin within 7 days prior to Day 1.
9. History of evidence of diabetic complications with significant end-organ damage such as:
• Proliferative retinopathy and/or macular edema, or
• Diabetic neuropathy complicated by neuropathic ulcers, or
• Creatinine clearance ≤60 mL/min based on Cockcroft-Gault equation using serum
creatinine measured at screening [See below],
• Males -> [(140 - age in years) x total body weight (in kg)] divided by
[72 x serum creatinine (in mg/dL)]
• Females -> 0.85 x calculation for males
10. Clinically significant peripheral vascular disease such as that manifested by claudication.
11. History of stroke or transient ischemic attack.
12. Current medical history of unstable angina.
13. History of myocardial infarction within 1 year prior to screening.
14. History of repeated or frequent documented hypoglycemia within 6 months prior to screening.
15. Participation in any formal weight loss program, or fluctuation of >5% in body weight, within 3 months prior to screening.
16. History of human immunodeficiency virus (HIV) infection or treatment with
antiretroviral agents.
17. Subjects with ANY of the following abnormalities in clinical chemistry at screening as assessed by trial-specific central laboratory:
• Fasting serum triglycerides ≥500 mg/dL (ie, 5.65 mmol/L)
• AST/SGOT or ALT/SGPT ≥2x ULN
• Total bilirubin ≥1.5x ULN
• Direct bilirubin > ULN
• Serum lipase or amylase > ULN
18. At screening, 12-lead electrocardiogram (ECG) demonstrating QTc interval >450 msec, confirmed by a single repeat, if deemed necessary.
19. Persistent severe, uncontrolled hypertension; for example: supine systolic blood pressure ≥180 mm Hg and/or diastolic blood pressure ≥105 mm Hg on at least 2 consecutive measurements following at least 10 minutes of rest between measurements.
20. Any medical history or clinical evidence of congestive heart failure, NYHA (New York Heart Association) Functional Classification, Classes III-IV.
21. A positive urine drug test for illicit drugs, at screening.
22. Alcohol dependency: a subject will not be permitted to consume alcohol in a quantity exceeding 7 drinks per week for females or 14 drinks per week for males.
• 1 drink = 5 ounces (150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces
(45 mL) of hard liquor
23. Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) preceding Day 1 and/or during trial participation.
24. Pregnant, nursing, or females of childbearing potential.
25. Use of herbal supplements (including herbal weight-loss or “metabolism booster”
therapies), over the counter appetite or weight modifying medications or hormone
replacement therapy within 28 days prior to Day 1.
26. History of sensitivity or intolerance to CE-326,597.
27. History of sensitivity to heparin or heparin-induced thrombocytopenia (if heparin is used to flush intravenous catheters).
28. Blood donation of approximately 1 pint (500 mL) within 56 days prior to Day 1.
29. Unwilling or unable to comply with the Life Style Guidelines as presented in Section 4.4.
30. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with trial participation or investigational product administration or may interfere with the interpretation of trial results and, in the judgment of the investigator, would make the subject inappropriate for entry into this trial. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary comparisons of interest following 12 weeks of dosing with a range of oral doses of CE-326,597 (Day 84 minus baseline [ie, Day 1]) are,
1. Placebo-adjusted, change from baseline in HbA1C (%)
2. Placebo-adjusted, percent change from baseline in body-weight |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 45 |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 10 |
| 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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