Randomized, Double-blind, Active-controlled, Study of Rivoglitazone in Type 2 Diabetes Mellitus

Study Overview
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Brief Summary
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This is a 26-week, multicenter, randomized, double-blind, placebo and active comparator-controlled, parallel-group study in participants with type 2 diabetes currently sub-optimally controlled by diet and exercise or with non-thiazolidinedione antihyperglycemic monotherapy. Pioglitazone is used as active comparator. The total duration of a participant's participation will be approximately 30 weeks, including a 2-week placebo lead-in period, a 26-week double-blind treatment period, and a 2-week post-treatment follow-up period. Participants who complete the randomized portion of the study per protocol may have the opportunity to continue in a long-term extension study of active treatments.

Official Title
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A Randomized, Double-blind, Placebo, and Active Comparator-controlled, Parallel-group Study of the Efficacy and Safety of Rivoglitazone as Monotherapy Treatment of Type 2 Diabetes Mellitus

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Rivoglitazone HCl
* Drug: rivoglitazone HCl
* Drug: rivoglitazone HCl
* Drug: placebo
* Drug: pioglitazone HCl
* Drug: pioglitazone HCl
* Drug: pioglitazone HCl 45 mg
* Drug: placebo
* Drug: metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provided written informed consent at screening. Diagnosed with type 2 diabetes mellitus. Glycosylated hemoglobin (A1c) >7.0% and ≤8.5% at screening. Male or female ≥18 years of age. Women of childbearing potential must have been using an adequate method of contraception to avoid pregnancy throughout the study, and for up to 4 weeks after study completion. Fasting C-peptide level >0.5 ng/mL at screening. Currently being treated with a stable dose of an approved non-thiazolidinedione antihyperglycemic medication (including sulfonylureas, meglitinides, insulin secretagogues, metformin, or α-glucosidase inhibitors) given as monotherapy, for at least 3 months prior to screening, and could discontinue that antihyperglycemic medication at Visit 2 (Week -2) and for the duration of the study. OR Untreated and had not taken any antihyperglycemic agent during the 2 months prior to screening; if not treated with an oral antihyperglycemic agent, the participant was considered by the investigator to have failed diet and exercise modification as the sole treatment for type 2 diabetes mellitus. Clinically stable in regard to medical conditions other than type 2 diabetes mellitus. Concomitant medications (other than oral antihyperglycemic agents) were at stable doses for at least 30 days prior to enrollment and were not anticipated to need adjustment during the study period. Exclusion Criteria: History of type 1 diabetes and/or history of ketoacidosis. History of long-term (>2 months) therapy with insulin. History of prior treatment failure with, or intolerance of, a thiazolidinedione (ie, rosiglitazone, troglitazone, or pioglitazone). Treatment with a fibrate lipid-lowering agent (eg, fenofibrate, gemfibrozil). Confirmed repeat fasting glucose (≥2 readings of fasting blood glucose) >240 mg/dL (13.3 mmol/L) during the 2-week washout/stabilization and placebo run-in period (Period A). Body mass index (BMI) >45 kg/m2 at screening. History of weight loss >10% over the 3 months prior to screening. Female participant who was pregnant or breastfeeding. Systolic blood pressure ≥180 mmHg and/or diastolic blood pressure ≥110 mmHg. Any known history of congestive heart failure prior to screening. History of unstable angina, myocardial infarction, cerebrovascular accident, transient ischemic attack, or any revascularization within 6 months prior to screening. History of malignancy (except participants who had been disease-free for >10 years), or whose malignancy was a basal or squamous cell skin carcinoma. Any history of bladder cancer was an exclusion from participation. Women with a history of cervical dysplasia (CIN2 or higher) were to be excluded unless 2 consecutive normal cervical smears had subsequently been recorded prior to enrollment. Impaired liver function including evidence of acute or chronic hepatitis or liver disease by medical history, clinical signs or symptoms, or laboratory results. Evidence for ongoing infectious liver disease with positive hepatitis A antigen or immunoglobulin M antibody, hepatitis B surface antigen, or antibodies to hepatitis C virus. Participants with normal liver function tests and isolated positive antibodies to hepatitis B virus could have been included. Known (or evidence of) infection with human immunodeficiency virus. Known hemoglobinopathy or chronic anemia that required specific treatment within 5 years of the screening visit. History of alcohol or drug abuse within 1 year prior to screening. History of unstable major psychiatric disorders. Known or suspected allergy or hypersensitivity to thiazolidinedione agents. Clinically significant abnormalities in any pre-randomization laboratory analyses that, in the investigator's opinion, comprised an undue risk with the participant's participation, or could potentially confound results of the study. Unexplained hematuria (>3 red blood cells per high-powered field by urine microscopy). Blood donation of ≥1 pint (0.5 liter) within the past 30 days prior to screening or plasma donation within 7 days prior to the screening visit (Visit 1). Prior known or possible exposure to rivoglitazone. Contraindication to treatment with pioglitazone once daily. Known or suspected allergy, hypersensitivity, or intolerance to the excipients of the investigational study medication. Participation in an interventional medical, surgical, or pharmaceutical study within 30 days prior to the screening visit (Visit 1). Any condition or concomitant therapy that, in the opinion of the investigator, might have posed a risk to the participant or made participation not in the participant's best interest. A direct or familial relationship with the Sponsor, investigator, or site personnel affiliated with the study.

Ages Eligible for Study
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Minimum Age: 18 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: 1<br>rivoglitazone HCl 0.5mg | Drug: Rivoglitazone HCl<br>* 0.5 mg tablets administered orally, once daily<br>* Other names: CS-011;Drug: metformin<br>* Oral tablets. Rescue medication.<br>|
| Experimental: 2<br>rivoglitazone HCl 1.0 mg | Drug: rivoglitazone HCl<br>* 1.0 mg tablets administered orally, once daily<br>* Other names: CS-011;Drug: metformin<br>* Oral tablets. Rescue medication.<br>|
| Experimental: 3<br>rivoglitazone HCl 1.5 mg | Drug: rivoglitazone HCl<br>* 1.5 mg tablets administered orally, once daily<br>* Other names: CS-011;Drug: metformin<br>* Oral tablets. Rescue medication.<br>|
| Placebo Comparator: 4<br>placebo matching rivoglitazone HCl tablets | Drug: placebo<br>* placebo tablets matching rivoglitazone tablets administered orally, once daily<br>Drug: metformin<br>* Oral tablets. Rescue medication.<br>|
| Active Comparator: 5<br>pioglitazone HCl 15 mg | Drug: pioglitazone HCl<br>* 15 mg capsules administered orally, once daily<br>Drug: metformin<br>* Oral tablets. Rescue medication.<br>|
| Active Comparator: 6<br>pioglitazone HCl 30 mg | Drug: pioglitazone HCl<br>* 30 mg capsules administered orally, once daily<br>Drug: metformin<br>* Oral tablets. Rescue medication.<br>|
| Active Comparator: 7<br>pioglitazone HCl 45 mg | Drug: pioglitazone HCl 45 mg<br>* 45 mg capsules administered orally, once daily<br>Drug: metformin<br>* Oral tablets. Rescue medication.<br>|
| Placebo Comparator: 8<br>matching placebo for pioglitazone | Drug: placebo<br>* placebo capsules for pioglitazone administered orally, once daily<br>Drug: metformin<br>* Oral tablets. Rescue medication.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in A1c From Baseline Through Week 20 Following Rivoglitazone Compared to Pioglitazone as Monotherapy Treatment of Type 2 Diabetes Mellitus | Glycosylated hemoglobin (A1c) levels and mean changes in A1c were used to measure glycemic control. A1c categorical targets are <7.0% and <6.5%. | Baseline up to week 2, week 4, week 6, week 8, week 10, week 12, week 16, and week 20 post-dose. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Fasting Plasma Glucose From Baseline Through Week 20 Following Rivoglitazone Compared to Pioglitazone as Monotherapy Treatment of Type 2 Diabetes Mellitus | Normal fasting plasma glucose (FPG) -- or blood sugar -- is between 70 and 100 milligrams per deciliter (mg/dL) for people who do not have diabetes. People with Type 2 diabetes typically have FPG that is too high, so a negative change from baseline and a lower FPG means improvement. | Baseline up to week 2, week 4, week 6, week 8, week 12, week 16, and week 20 post-dose. | 
| Change in Total Cholesterol From Baseline Through Week 12 Following Rivoglitazone Compared to Pioglitazone as Monotherapy Treatment of Type 2 Diabetes Mellitus | Total cholesterol is a measure of the total amount of cholesterol in the blood, including low-density lipoprotein cholesterol (LDL-C) - the bad cholesterol, high-density lipoprotein cholesterol (HDL-C) - the good cholesterol, and triglycerides. The equation to calculate total cholesterol is: LDL + HDL + (triglycerides/5) = total cholesterol. | Baseline up to week 12 post-dose. | 
| Percent Change in Total Cholesterol From Baseline Through Week 12 Following Rivoglitazone Compared to Pioglitazone as Monotherapy Treatment of Type 2 Diabetes Mellitus | Total cholesterol is a measure of the total amount of cholesterol in the blood, including low-density lipoprotein cholesterol (LDL-C) - the bad cholesterol, high-density lipoprotein cholesterol (HDL-C) - the good cholesterol, and triglycerides. The equation to calculate total cholesterol is: LDL + HDL + (triglycerides/5) = total cholesterol. | Baseline up to week 12 post-dose. | 
| Change in Total Triglycerides From Baseline Through Week 12 Following Rivoglitazone Compared to Pioglitazone as Monotherapy Treatment of Type 2 Diabetes Mellitus | Total Triglycerides (TG) is a measure of the total amount of triglycerides in the blood. The equation to calculate total triglycerides is: (total cholesterol-Low-density Lipoprotein cholesterol (LDL- C) - High-density lipoprotein cholesterol (HDL- C)) x 5 = Total Triglycerides. A negative change means improvement. | Baseline up to week 12 post-dose. | 
| Percent Change in Total Triglycerides From Baseline Through Week 12 Following Rivoglitazone Compared to Pioglitazone as Monotherapy Treatment of Type 2 Diabetes Mellitus | Total Triglycerides (TG) is a measure of the total amount of triglycerides in the blood. The equation to calculate total triglycerides is: (total cholesterol-Low-density Lipoprotein cholesterol (LDL- C) - High-density lipoprotein cholesterol (HDL- C)) x 5 = Total Triglycerides. A negative change means improvement. | Baseline up to week 12 post-dose. | 
| Change in Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline Through Week 12 Following Rivoglitazone Compared to Pioglitazone as Monotherapy Treatment of Type 2 Diabetes Mellitus | Low-density lipoprotein cholesterol (LDL-C) is a measure of the total amount of low-density lipoprotein cholesterol in the blood. LDL-C was measured as part of the fasting lipid panel. LDL-C is considered bad cholesterol, so a lower score (negative change) means improvement. | Baseline up to week 12 post-dose. | 
| Percent Change in Low-Density Lipoprotein Cholesterol (LDL-C) From Baseline Through Week 12 Following Rivoglitazone Compared to Pioglitazone as Monotherapy Treatment of Type 2 Diabetes Mellitus | Low-density lipoprotein cholesterol (LDL-C) is a measure of the total amount of low-density lipoprotein cholesterol in the blood. LDL-C was measured as part of the fasting lipid panel. LDL-C is considered bad cholesterol, so a lower score (negative change) means improvement. | Baseline up to week 12 post-dose. | 
| Change in High-Density Lipoprotein Cholesterol From Baseline Through Week 12 Following Rivoglitazone Compared to Pioglitazone as Monotherapy Treatment of Type 2 Diabetes Mellitus | High-density lipoprotein cholesterol (HDL-C) is a measure of the total amount of high-density lipoprotein cholesterol in the blood. HDL-C was measured as part of the fasting lipid panel. HDL-C is considered good cholesterol, so a higher score (positive change) means improvement. | Baseline up to week 12 post-dose. | 
| Percent Change in High-Density Lipoprotein Cholesterol From Baseline Through Week 12 Following Rivoglitazone Compared to Pioglitazone as Monotherapy Treatment of Type 2 Diabetes Mellitus | High-density lipoprotein cholesterol (HDL-C) is a measure of the total amount of high-density lipoprotein cholesterol in the blood. HDL-C was measured as part of the fasting lipid panel. HDL-C is considered good cholesterol, so a higher score (positive change) means improvement. | Baseline up to week 12 post-dose. | 
| Change in Apolipoprotein (Apo) A-I From Baseline Through Week 12 Following Rivoglitazone Compared to Pioglitazone as Monotherapy Treatment of Type 2 Diabetes Mellitus | Apolipoprotein (Apo) A-I is a measure of the total amount of Apolipoprotein (Apo) A-I in the blood. Apo A-I was measured as part of the fasting lipid panel. | Baseline up to week 12 post-dose. | 
| Percent Change in Apolipoprotein (Apo) A-I From Baseline Through Week 12 Following Rivoglitazone Compared to Pioglitazone as Monotherapy Treatment of Type 2 Diabetes Mellitus | Apolipoprotein (Apo) A-I is a measure of the total amount of Apolipoprotein (Apo) A-I in the blood. Apo A-I was measured as part of the fasting lipid panel. | Baseline up to week 12 post-dose. | 
| Change in Apolipoprotein (Apo) B From Baseline Through Week 12 Following Rivoglitazone Compared to Pioglitazone as Monotherapy Treatment of Type 2 Diabetes Mellitus | Apolipoprotein (Apo) B is a measure of the total amount of Apolipoprotein (Apo) B in the blood. Apo B was measured as part of the fasting lipid panel. | Baseline up to week 12 post-dose. | 
| Percent Change in Apolipoprotein (Apo) B From Baseline Through Week 12 Following Rivoglitazone Compared to Pioglitazone as Monotherapy Treatment of Type 2 Diabetes Mellitus | Apolipoprotein (Apo) B is a measure of the total amount of Apolipoprotein (Apo) B in the blood. Apo B was measured as part of the fasting lipid panel. | Baseline up to week 12 post-dose. | 
| Number of Participants With Treatment-Emergent Adverse Events by System Organ Class and Preferred Term Following Rivoglitazone or Pioglitazone as Monotherapy Treatment of Type 2 Diabetes Mellitus | Treatment-emergent adverse events (TEAEs) were defined as adverse events (AEs) that occurred on or after the first dose of randomized study medication and ongoing adverse events that started prior to the first dose of randomized study medication and increased in severity on or after the first dose of randomized study medication. | Baseline up to week 26 post-dose, approximately a total of 27 weeks. |