Study to Evaluate the Safety, Tolerability and Efficacy of Three Dose Levels of Mitoglitazone in Type 2 Diabetic Patients

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability and efficacy of three dose levels of Mitoglitazone™ (MSDC-0160) in patients with type 2 diabetes.

Detailed Description
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The primary study objectives are to characterize the reduction in fasting plasma glucose in response to three different doses of Mitoglitazone as compared to placebo following once-daily dosing for 84 consecutive days (12 weeks) in patients with Type 2 diabetes and to investigate the safety and tolerability of three different doses of Mitoglitazone following once-daily dosing for 84 consecutive days (12 weeks) in patients with Type 2 diabetes.

Official Title
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Phase 2B, Randomized, Double-Blind, Comparator- & Placebo-Controlled, Dose Ranging Study to Evaluate Safety, Tolerability & Efficacy of 3 Dose Levels of Mitoglitazone in Type 2 Diabetic Patients

Conditions
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Type 2 Diabetes

Intervention / Treatment
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* Drug: Mitoglitazone
* Drug: Mitoglitazone
* Drug: Mitoglitazone
* Drug: Pioglitazone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Males and females with Type 2 diabetes (fasting plasma glucose ≥126 mg/dL at screening, glycosylated hemoglobin [HbA1c] >7 and ≤10%, and Insulin C-peptide >1 ng/mL). Patients can be naïve to diabetes therapy or if taking metformin should be on a stable dose level for a period of at least 3 months prior to screening visit (no dose limit). Between the ages of 18-75 years, inclusive. Females should be either postmenopausal (at least 12 months since last menses) or surgically sterilized (bilateral tubal ligation or hysterectomy). Menopausal status will be verified by a follicle-stimulating hormone (FSH) test. If FSH levels are below 40 mIL/mL, some method of birth control must be used. Those with bilateral tubal ligation must also use a barrier method of birth control. In addition, all females must have a negative pregnancy test at Screen and Day 15 regardless of childbearing potential. Males with female partners of child-bearing potential must agree to use adequate contraceptive methods (including a condom, plus one other form of contraception) if engaging in sexual intercourse. Body Mass Index (BMI) = 23 kg/m2 to 45 kg/m2 (inclusive). Willing and able to make a screening visit to the clinic and seven visits over a 21 week period. Willing and able to sign an informed consent document indicating understanding the purpose of and procedures required for the study and willingness to participate in the study. Exclusion Criteria Use of TZDs or diabetes medications other than metformin (generic or Glucophage®) 3 months prior to screening. History of diabetic ketoacidosis or hyperosmolar non-ketotic coma. Fasting plasma glucose in excess of 240 mg/dl at screening History of heart failure (including CHF) or previous cardiovascular event (myocardial infarct, by-pass surgery, or PTCA) within the past 6 months prior to screening. ALT and/or AST levels that are twice the upper limit of normal; bilirubin levels that exceed 2 mg/dL; serum creatinine >1.5 mg/dL in men or > 1.4 mg/dL in women. History nephropathy, neuropathy, or retinopathy within 6 months of screening. Use of glucocorticoids (oral, injectible, intraarticular, or chronic inhaled) or weight-loss drugs within 3 months of randomization. Current or recurrent disease that may affect the action, absorption or disposition of the study treatment, or clinical or laboratory assessments. Current or history of severe or unstable disorder (medical or psychiatric) requiring treatment that may make the patient unlikely to complete the study. Febrile illness within the 5 days prior to the first dose. Known history of HIV, hepatitis B, or hepatitis C. Clinically significant findings on physical examination, including BP, pulse rate and 12-lead ECG. Blood pressure greater than 160/100 mmHg. Patients with elevated BP (<160/100 mmHg) with or without current treatment will be allowed at the discretion of the Principal Investigator (PI) and primary care physician. Individuals with hypertension must have been stabilized to the current treatment regimen for at least 6 weeks prior to screening. Change in BP or lipid-lowering medication within 6 weeks or change in dose of metformin or thyroid replacement within 3 months prior to screening. Known or suspected intolerance or hypersensitivity to the study drugs, closely related compounds or any of their stated ingredients. History of alcohol or drug abuse within 6 months of Screening. Have participated in an investigational study or received an investigational drug within 30 days or 5 half-lives (whichever is longer) prior to study drug administration. Blood donation of 1 pint or more within 56 days of screening. Plasmapheresis or plasma donation within 30 days of screening. Single 12-lead ECG demonstrating a QTc >450 msec at Screening. A single repeat ECG may be done at the investigator's discretion. Any surgical or medical condition which may significantly alter the absorption of any drug substance including, but not limited to, any of the following: history of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, bowel resection, gastric bypass, gastric stapling, or gastric banding, currently active inflammatory bowel syndrome. Evidence of clinically relevant pathology that could interfere with the study results or put the patient's safety at risk. Malignancy, including leukemia and lymphoma (not including basal cell skin cancer) within the last 5 years.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mitoglitazone 50 mg capsules<br>Mitoglitazone 50 mg capsules self administered once-daily each morning after an overnight fast and 30 minutes before the morning meal for 84 days. | Drug: Mitoglitazone<br>* 50 mg capsules, once daily for 84 days<br>* Other names: MSDC-0160;|
| Experimental: Mitoglitazone 100 mg capsules<br>Mitoglitazone 100 mg capsules self administered once-daily each morning after an overnight fast and 30 minutes before the morning meal for 84 days. | Drug: Mitoglitazone<br>* Mitoglitazone 100 mg capsules, once daily for 84 days<br>* Other names: MSDC-0160;|
| Experimental: Mitoglitazone 150 mg capsules<br>Mitoglitazone 150 mg capsules self administered once-daily each morning after an overnight fast and 30 minutes before the morning meal for 84 days. | Drug: Mitoglitazone<br>* Mitoglitazone 150 mg capsules, once daily for 84 days<br>* Other names: MSDC-0160;|
| Active Comparator: Pioglitazone 45 mg capsules<br>Pioglitazone 45 mg capsules self administered once-daily each morning after an overnight fast and 30 minutes before the morning meal for 84 days. | Drug: Pioglitazone<br>* Pioglitazone 45 mg, once daily for 84 days<br>* Other names: ACTOS;|
| Placebo Comparator: Matching placebo<br>Placebo capsules self administered once-daily each morning after an overnight fast and 30 minutes before the morning meal for 84 days. | Drug: Placebo<br>* Placebo, once daily for 84 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 12. | Change from baseline in fasting plasma glucose in response to three different doses of Mitoglitazone as compared to pioglitazone following once-daily dosing for 84 consecutive days (12 weeks) in patients with Type 2 diabetes. | Baseline, Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in HbA1c | Change from baseline in plasma glucose measured by hemoglobin A1c in response to three different doses of Mitoglitazone and pioglitazone as compared to placebo following once-daily dosing for 84 consecutive days (12 weeks) in patients with Type 2 diabetes. | 12 weeks | 
| Percent Change From Baseline to Week 12 Endpoint in HMW Adiponectin | Percent change from baseline to week 12 endpoint in high molecular weight adiponectin | 12 weeks | 
| Change From Baseline to Week 12 Endpoint in Hematocrit | Change from baseline to week 12 endpoint in hematocrit as an indication of fluid retention | 12 weeks | 
| Change From Baseline in Hemoglobin | Change from baseline at week 12 endpoint in hemoglobin concentration | 12 weeks | 
| Change From Baseline in RBC | Change from baseline at week 12 endpoint in red blood cell concentration | 12 week | 
| Change in Body Weight From Baseline to Week 12 Endpoint | Effects of 3 different doses of Mitoglitazone and pioglitazone as compared to placebo on body weight following once-daily dosing for 12 | 12 weeks | 
| Change From Baseline in Waist Circumference at Week 12 Endpoint | Effects of 3 different doses of Mitoglitazone and pioglitazone as compared to placebo on waist circumference following once-daily dosing for 12 weeks | 12 weeks | 
| Presence of Edema Post Baseline During 12 Weeks Active Treatment | Effects of 3 different doses of Mitoglitazone and pioglitazone as compared to placebo on presence of edema following once-daily dosing for 12 weeks | 12 weeks | 
| Changes in HDL Particle Size Subfractions From Baseline to Week 12 | Effects of 3 different doses of Mitoglitazone and pioglitazone as compared to placebo on HDL particle size profile as characterized by changes in NMR analysis of subfractions following once-daily dosing for 12 weeks | 12 weeks | 
| Changes in LDL Particle Size Subfractions From Baseline to Week 12 | Effects of 3 different doses of Mitoglitazone and pioglitazone as compared to placebo on LDL particle size profile as characterized by changes in NMR analysis of subfractions following once-daily dosing for 12 weeks | 12 week | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes