| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
The study population is comprised of subjects with a prior diagnosis of type 2 diabetes who are either currently untreated (ie, not receiving antihyperglycemic medication within at least 2 months prior to screening) or are treated with a single, non-TZD agent as monotherapy.
The study will support an indication for rivoglitazone as oral monotherapy to improve glycemic control in subjects with type 2 diabetes mellitus not adequately controlled with diet and exercise alone. |
|
| 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 | 10063624 |
| E.1.2 | Term | Type II diabetes mellitus inadequate control |
|
| 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 compare the effects on mean change from baseline in A1C, for rivoglitazone versus pioglitazone administered as monotherapy in type 2 diabetics over a 26-week treatment period. |
|
| E.2.2 | Secondary objectives of the trial |
• To demonstrate the safety and tolerability of rivoglitazone as a treatment for type 2 diabetes mellitus
• To demonstrate the lowering of FPG with rivoglitazone, versus placebo, over 26 weeks in type 2 diabetics
• To assess the effects of each rivoglitazone dose on the percent of responders as defined by:
− Subjects experiencing a decrease of ≥ 0.7 percentage units in A1C
− Subjects achieving an A1C goal of <7.0%
− Subjects achieving an A1C goal of <6.5%
• To assess the effect of rivoglitazone versus placebo, on HOMA indices of insulin resistance and β-cell function in type 2 diabetics
• To assess the effects of rivoglitazone on change from baseline and percent change from baseline in plasma lipids (including TC, LDL-C, HDL-C and TG, and on other parameters including adiponectin, hs-CRP, insulin, Apo A1 and Apo B)
• To compare effects of rivoglitazone versus pioglitazone on secondary measures of glycemic control and lipid parameters |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must satisfy all of the following criteria to be included in the study:
1. Willing and able to give written informed consent at screening.
2. Diagnosed with type 2 diabetes.
3. A1C >7.0% and ≤ 8.5% at screening.
4. Male or female ≥ 18 years of age.
5. Women of childbearing potential (WOCBP) must be using an adequate method of
contraception as detailed per-protocol (See Section 4.1.3.2) to avoid pregnancy
throughout the study, and for up to 4 weeks after study completion.
6. Non-fasting C-peptide level >0.5 ng/mL at screening.
7. Subject is currently treated with a stable dose of an approved non-TZD
antihyperglycemic medication (including sulfonylureas, meglitinides, insulin secretagogues, metformin, or α-glucosidase inhibitors) given as monotherapy, for at least 3 months prior to screening, and is willing and able to discontinue that
antihyperglycemic medication at Visit 2 (Week -2) and for the duration of the study.
OR
8. Subject is currently untreated and has not taken any antihyperglycemic agent during the 2 months prior to screening.
9. If not treated with an oral antihyperglycemic agent, subject is considered by the
investigator to have failed diet and exercise modification as the sole treatment for type 2 diabetes.
10. Clinically stable in regards to medical conditions other than type 2 diabetes.
11. Concomitant medications (other than oral antihyperglycemic agents; see inclusion
criteria 7), are at stable doses for at least 30 days prior to enrollment, and are not
anticipated to need adjustment during the study period. |
|
| E.4 | Principal exclusion criteria |
1. History of Type 1 diabetes and/or history of ketoacidosis.
2. History of long-term (>2 months) therapy with insulin.
3. History of prior treatment failure with, or intolerance of, a TZD (ie, rosiglitazone,
troglitazone, or pioglitazone).
4. Treatment with a fibrate lipid lowering agent (eg, fenofibrate, gemfibrozil).
5. Confirmed repeat fasting glucose (≥ 2 readings of FBG) >240 mg/dL (13.3 mmol/L) during the 2 week washout/stabilization and placebo run-in period (Period A).
6. Body mass index >45 kg/m2 at screening.
7. History of weight loss >10% over the 3 months prior to screening.
8. Female subject who is pregnant or breastfeeding.
9. SBP ≥ 180 mmHg and/or DBP ≥ 110 mmHg.
10. Any known history of CHF prior to screening.
11. History of unstable angina, myocardial infarction, cerebrovascular accident, transient ischemic attack, or any revascularization within 6 months prior to screening.
12. History of malignancy (except subjects who have been disease-free for >10 years), or whose malignancy was a basal or squamous cell skin carcinoma. Any history of bladder cancer is an exclusion from participation. Women with a history of cervical dysplasia (CIN2 or higher) should be excluded unless 2 consecutive normal cervical smears have subsequently been recorded prior to enrollment.
13. Impaired liver function including evidence of acute or chronic hepatitis or liver
disease by medical history, clinical signs or symptoms or laboratory results (Table 4.1).
14. Evidence for ongoing infectious liver disease with positive hepatitis A antigen [(anti-HAV) or immunoglobulin M (IgM) antibody], hepatitis B surface antigen (HbsAg), or antibodies to hepatitis C virus (anti-HCV). Subjects with normal liver function tests and isolated positive antibodies to hepatitis B virus (anti-HBs) may be included.
15. Known (or evidence of) infection with human immunodeficiency virus (HIV).
16. Known hemoglobinopathy or chronic anemia requiring specific treatment within 5 years of the screening visit.
17. History of alcohol or drug abuse within 1 year prior to screening.
18. History of unstable major psychiatric disorders.
19. Known or suspected allergy or hypersensitivity to TZD agents.
20. Clinically significant abnormalities in any pre-randomization lab analyses which in the investigator’s opinion, would comprise an undue risk with the subject’s participation, or potentially confound results of the study.
21. Values for the analytes noted in Table 4.1 in protocol may not exceed the certain limits unless approved by the medical monitor and/or sponsor.
22. Unexplained hematuria (>3 RBCs per high-powered field by urine microscopy).
23. Blood donation of 1 pint (0.5 liter) or more within the past 30 days prior to
screening or plasma donation within 7 days prior to the screening visit (Visit 1).
24. Prior known or possible exposure to rivoglitazone.
25. Contraindication to treatment with pioglitazone QD.
26. Known or suspected allergy, hypersensitivity or intolerance to the excipients of the investigational study medication.
27. Participation in an interventional medical, surgical, or pharmaceutical study within 30 days prior to the screening visit (Visit 1).
28. Any condition or concomitant therapy which, in the opinion of the investigator,
might pose a risk to the subject or make participation not in the subject’s best
interest.
29. A direct or familial relationship with the sponsor, investigator, or site personnel
affiliated with the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
There are no specific endpoints for Pharmacokinetics or Pharmacogenomics. These
findings will be reported separately.
Primary Objectives:
To compare the effects on mean change from baseline in A1C, for rivoglitazone versus pioglitazone administered as monotherapy in type 2 diabetics over a 26-week treatment period.
Primary Efficacy:
The primary efficacy variable is the change in A1C from baseline to Week 26. |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| 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) | 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) | Yes |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 43 |
| 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 | 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
| |
| 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 | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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