A Study of The Effect of Aleglitazar on Insulin Sensitivity in Patients With Type 2 Diabetes Mellitus Who Are Inadequately Controlled With Metformin

Study Overview
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Brief Summary
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This single-center, randomized, double-blind, placebo-controlled study will evaluate the effect of aleglitazar on insulin sensitivity in patients with type 2 diabetes mellitus who are inadequately controlled on metformin monotherapy. Patients will be randomized to receive either aleglitazar 150 mcg or placebo orally daily for 16 weeks, in addition to their existing dose and regimen of metformin.

Official Title
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A Single Centre, Randomized, Double-Blind, Placebo-Controlled, Phase II Study to Assess the Efficacy of Aleglitazar on Insulin Sensitivity in Patients With Type 2 Diabetes Mellitus (T2D) Who Are Inadequately Controlled With Metformin Monotherapy

Conditions
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Diabetes Mellitus Type 2

Intervention / Treatment
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* Drug: aleglitazar
* Drug: metformin
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients, 30 to 70 years of age inclusive at screening Type 2 diabetes mellitus patients treated with stable metformin therapy for at least 12 weeks prior to screening; metformin dose should not exceed the maximum dose specified in the label HbA1c >/= 6.5% and </= 9% at screening and baseline Fasting plasma glucose </= 13.3 mmol/L (</= 240 mg/dl) at screening and baseline Body mass index (BMI) >/= 25 at screening; BMI >/= 27 for subjects with HbA1c < 7% Stable weight +/- 5% for at least 12 weeks prior to screening Exclusion Criteria: Women who are pregnant, intending to become pregnant during the study period, currently lactating women, or women of child-bearing potential not using highly effective, medically approved birth control methods Diagnosis or history of type 1 diabetes mellitus, diabetes resulting from pancreatic injury, or secondary forms of diabetes Acute metabolic diabetic complications such as ketoacidosis or hyperosmolar coma within the past 6 months Any previous treatment with a thiazolidinedione or with a dual peroxisome proliferator activated receptor (PPAR) agonist Any body weight lowering or lipoprotein-modifying therapy (e.g. fibrates) within 12 weeks prior to screening with the exception of stable (>/= 1 month) statin therapy History of bariatric surgery or currently undergoing evaluation for bariatric surgery Prior intolerance to fibrate Treatment with any anti-diabetic medication other than metformin in the last 12 weeks prior to screening and/or herbal/over-the-counter preparations that may affect glycemic control within 12 weeks prior to screening Clinically apparent liver disease Positive for hepatitis B, hepatitis C or HIV infection Clinical evidence of anemia Symptomatic congestive heart failure (New York Heart Association Class II-IV) at screening Myocardial infarction, acute coronary syndrome, or transient ischemic attack/stroke within 6 months prior to screening Known macular edema at screening or prior to screening visit Uncontrolled hypertension despite stable (for at least 4 weeks) anti-hypertensive treatment Diagnosed and/or treated malignancy (except for treated cases of basal cell skin cancer, in situ carcinoma of the cervix or in situ prostate cancer) within the past 5 years Chronic oral or parenteral corticosteroid treatment (> 2 weeks) within 3 months prior to screening History of active substance abuse (including alcohol) within the past 2 years or positive test result for drugs of abuse or alcohol prior to first dosing Presence of any absolute or relative contraindication for the conduct of magnetic resonance imaging (MRI) investigation

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 70 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aleglitazar<br> | Drug: aleglitazar<br>* 150 mcg orally daily, 16 weeks<br>Drug: metformin<br>* patients will continue on their existing dose and regimen of metformin (but not more than the maximum dose specified in the label)<br>|
| Placebo Comparator: Placebo<br> | Drug: metformin<br>* patients will continue on their existing dose and regimen of metformin (but not more than the maximum dose specified in the label)<br>Drug: placebo<br>* orally daily, 16 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in whole-body insulin sensitivity as assessed by M-value (Insulin-stimulated glucose disposal rate) |  | from baseline to Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in hepatic insulin sensitivity (basal index of hepatic insulin resistance) |  | from baseline to Week 16 | 
| Change in parameters of beta cell function (first and second phase insulin secretion) |  | from baseline to Week 16 | 
| Change in HbA1c |  | from baseline to Week 16 | 
| Change in lipid profile |  | from baseline to Week 16 | 
| Change in mean 24h blood pressure |  | from baseline to Week 16 | 
| Change in hepatic fat content measured by magnetic resonance spectroscopy (MRI) |  | from baseline to Week 16 | 
| Change in fat content/distribution in the abdominal region measured by MRI |  | from baseline to Week 16 | 
| Change in total body fat content measured by air displacement phlethysmography |  | from baseline to Week 16 | 
| Change in homeostatic indexes of insulin sensitivity assessed by Homeostasis Model Assessment for Insulin Sensitivity (HOMA-IS) |  | from baseline to Week 16 | 
| Change in markers of cardiovascular risk (high sensitivity C-reactive protein, adiponectin, free fatty acid) |  | from baseline to Week 16 | 
| Safety: Incidence of adverse events |  | 22 weeks |