| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 11.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045242 |
| E.1.2 | Term | <Manually entered code. Term in E.1.1> |
|
| 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 the study is to demonstrate superiority of rimonabant/metformin combinations in A1C reduction over the corresponding single agent metformin doses and rimonabant alone in patients with type 2 diabetes at 9 months. |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objective of the study is to investigate the effects of rimonabant/metformin combinations for reducing fasted plasma glucose, body weight and triglycerides, and raising HDL-C in comparison with metformin at 9 months, as well as to demonstrate the safety of rimonabant/metformin combinations. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patients who signed the informed consent
2. History of type 2 diabetes mellitus, diagnosed before the screening visit *
3. Patients must not have used any oral or injectable glucose lowering medication at least 12 weeks prior to the screening visit to establish a stable, comparable baseline A1C assessment in all patients
*1. FPG ≥126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h (in the absence of unequivocal hyperglycemia, these criteria should be confirmed by repeat testing on a different day)
OR
2. Symptoms of hyperglycemia and a casual plasma glucose ≥200 mg/dl (11.1 mmol/l). Casual is defined as any time of day without regard to time since last meal. The classic symptoms of hyperglycemia include polyuria, polydipsia, and unexplained weight loss.
OR
3. 2-h plasma glucose ≥200 mg/dl (11.1 mmol/l) during an OGTT. The test should be performed as described by the World Health Organization, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water (in the absence of unequivocal hyperglycemia, these criteria should be confirmed by repeat
testing on a different day) |
|
| E.4 | Principal exclusion criteria |
Related to methodology
1. A1C at screening visit <7.0 % and >10.0 %; The A1C test may be repeated within the screening period using the same patient number if A1C is within 0.2% out of range for eligibility
2. Fasted plasma glucose at screening visit >260 mg/dL (14.44 mmol/L);The FPG test may be repeated within the screening period using the same patient number if FPG within 20 mg/dL (1.11 mmol/L) out of range for eligibility
3. Diabetes other than type 2 diabetes mellitus
4. Age <18 years old or below legal age
5. Treatment with any anti-diabetic oral agent, or injectable antidiabetic agent, eg, incretin mimetics such as glucagon-like-petide 1 within 12 weeks prior to screening visit 1
6. Likelihood of requiring treatment during the study period with glucose lowering agents other than metformin
7. Likelihood of requiring treatment with insulin or incretin mimetics during the study period
8. Patients receiving not permitted comedication
9. History or presence of clinically significant diabetic retinopathy (stage 3 or higher)
10. History or presence of macular edema likely to require laser treatment within the study period
11. History of positive glutamic acid decarboxylase (GAD) antibody prior to screening visit 1 (in order to exclude known Latent Autoimmune Diabetes of the Adult - LADA)
12. Use of any anti-obesity agent or drugs for weight loss (eg, sibutramine, orlistat, herbal preparations, phentermine, amphetamines, other CB1 antagonists) in the 3 months prior to Screening visit
13. Administration of long acting systemic corticosteroids of any duration or other systemic corticosteroids for more than 7 days in the previous 3 months from Screening Visit
14. Presence of any severe medical or psychological condition that, in the opinion of the investigator, would compromise the patient’s safe participation including uncontrolled serious psychiatric illness such a major depression within the last 2 years, suicidal ideation of type 4 or type 5 on the C-SSRS or suicidal behavior within the last month, medical history of suicide attempt, and history of other severe psychiatric disorders
15. Presence of any clinically significant endocrine disease (other than type 2 diabetes) according to the Investigator; Patients diagnosed with polycystic ovarian syndrome (POCS) and patients on thyroid replacement therapy may be included if the dosage of thyroxine is stable for at least three months prior to Screening Visit)
16. Presence or emergence of any condition (medical, psychological, social, or geographical), actual or anticipated, that the Investigator feels would restrict or limit the patient’s successful participation for the duration of the study
17. Presence or history of cancer within the past five years with the exception of adequately treated localized basal skin cancer or in situ uterine cervical cancer
18. Positive lab test for Hepatitis B surface antigen and/or Hepatitis C antibody at Screening Visit
19. Administration of other investigational drugs within 30 days or 5 half lives, whichever is longer, prior to Screening Visit
20. Patient’s decision not to participate in the study
21. Patient not attending randomization visit
22. Inability to follow verbal and written instructions
23. Participation in a previous rimonabant study
24. Prior exposure to CB1 antagonists including rimonabant
25. Pregnant or breast-feeding women
26. Women of childbearing potential not protected by effective method of birth control and/or who are unwilling or unable to be tested for pregnancy
Related to rimonabant
27. Known allergy to rimonabant or excipients
28. Known hypersensitivity/intolerance to rimonabant or any of the excipients of rimonabant tablets such as lactose (such as history of rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption)
29. History of severe hepatic impairment
Related to metformin
30. Known hypersensitivity to metformin hydrochloride
31. Patients with creatinine clearance <60 mL/min at screening visit 1
32. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.
Neuropsychiatric status
At Screening:
• A baseline PHQ-9 score of ≥15
• Any suicidal behavior in the last month
• Any suicidal ideation of type 4 or 5 on the C-SSRS in the last month
During study conduct:
A subject should be referred to a mental health professional (MHP) if he/she has:
• A baseline PHQ-9 score of ≥10
• If a PHQ-9 score of ≥10 is detected post randomization, the subject must be referred to a MHP to decide upon continuation in the study
• A GAD-7 score ≥10
• Any suicidal behavior
• Any suicidal ideation of type 4 or 5 on the C-SSRS |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the change in A1C from baseline at 9 months. |
|
| 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 | No |
| 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 | 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 | 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 | 23 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 23 |
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