Effects of Metformin Hydrochloride (HCl) in Combination With Colesevelam HCl, Compared to Metformin HCl Alone, in Patients With Type 2 Diabetes Mellitus and the Effects of Colesevelam HCl on Lipids and Glucose on Pre-diabetic Patients.

Study Overview
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Brief Summary
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This is a 16-week double-blind, placebo-controlled (for colesevelam hydrochloride (HCl)) study in the type 2 diabetic subjects and pre-diabetic subjects. Diabetic participants will also be treated with open label, background,metformin HCl. Two-hundred sixty subjects with type 2 diabetes (T2DM) and 200 pre-diabetic subjects are planned to be be enrolled. Qualified subjects with T2DM will be randomized 1:1 to receive metformin HCl plus colesevelam HCl or metformin HCl plus placebo matching colesevelam HCl. Qualified pre-diabetic subjects will be randomized 1:1 to receive colesevelam HCl or matching placebo.

Official Title
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Effects of Metformin HCl in Combination With Colesevelam HCl, Compared to Metformin HCl Alone, as Initial Therapy in Drug naïve Subjects With Type 2 Diabetes Mellitus, and the Effects of Colesevelam HCl on the Lipid Profile in Subjects With Pre Diabetes

Conditions
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Type 2 Diabetes Mellitus, Hypercholesterolemia, Pre-diabetes

Intervention / Treatment
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* Drug: Metformin HCl and Colesevelam Placebo
* Drug: Metformin HCl tablets and Colesevelam tablets
* Drug: Colesevelam placebo
* Drug: Colesevelam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 to 79 years, inclusive. HbA1C in the range of greater than or equal to 6.5 percent to small than or equal to 10.0 percent, to be enrolled in the T2DM cohort. 2-hour post 75 g OGTT glucose levels in the range of: greater than or equal to 200 mg/dL to be enrolled in the T2DM cohort, or greater than or equal to 140 to 200 mg/dL to be enrolled in the pre-diabetes cohort. FPG levels in the range of: greater than or equal to 126 mg/dL to be enrolled in the T2DM cohort, or greater than or equal to 110 to smaller than or equal to 125 mg/dL to be enrolled in the pre-diabetes cohort. LDL-C levels greater than or equal to 100 mg/dL. Drug-naïve, defined as having never received treatment for T2DM or not having received antidiabetic drug therapy during the 3 months prior to screening visit. Previous diagnosis of: T2DM or prediabetes, to be enrolled in the respective cohorts, or CHD, CVD, and/or primary hypercholesterolemia + BMI greater than or equal to 25 mg/kg2 to be screened for T2DM or pre-diabetes. Understanding of the study procedures and agreement to participate in the study by giving written informed consent at screening visit. Women may be enrolled if all 3 of the following criteria (in addition to the above criteria)are met: They are not pregnant (women of childbearing potential must have a negative serum pregnancy test [serum beta human chorionic gonadotropin )] at screening visit); They are not breast-feeding; and They do not plan to become pregnant during the study. In addition to all of the above criteria, women must also meet 1 of the following 3 criteria to be enrolled: They have been post-menopausal for at least 1 year; or They are of childbearing potential and will practice 1 of the following methods of birth control throughout the study: oral, injectable, or implantable hormonal contraceptives; intrauterine device; diaphragm plus spermicide; or female condom plus spermicide. Methods of contraception that are not acceptable are partner's use of condoms or partner's vasectomy. Exclusion Criteria: History of type 1 diabetes and/or history of acute or chronic metabolic acidosis, including diabetic ketoacidosis. History of chronic (requiring daily for greater than 2 months) use of insulin therapy, except for the treatment of gestational diabetes. Current or prior (within the past 3 months) treatment with an oral antidiabetic drug. Current or prior (within the past 3 months) treatment with colesevelam HCl (WelChol), colestipol, colestimide, or cholestyramine. History of dysphagia, swallowing disorders, or intestinal motility disorder. Any serious disorder, including pulmonary, hepatic, gastrointestinal (including clinically significant malabsorption), uncontrolled endocrine/metabolic, hematologic/oncologic (within the last 5 years), neurologic, and psychiatric diseases, that would interfere with the conduct of the study or interpretation of the data. Acute coronary syndrome (eg, myocardial infarction or unstable angina), coronary intervention (coronary artery bypass graft or percutaneous transluminal coronary angioplasty or similar procedure), congestive heart failure (requiring pharmacological treatment), or transient ischemic attack within 3 months of screening visit. History of pancreatitis. History of acquired immune deficiency syndrome or human immunodeficiency virus. History of drug or alcohol abuse within the past 2 years. Hospitalization for any cause within 14 days prior to screening visit. History of an allergic or toxic response to colesevelam HCl or any of its components. Known hypersensitivity to metformin HCl. Serum TG greater than or equal to 500 mg/dL. Body mass index (BMI) greater than 40 kg/m2 .

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 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 |
| --- | --- |
| Placebo Comparator: Diabetic Participants: Metformin HCl+Placebo for Colesevelam<br>Participants will receive either 850 mg or 1700 mg of metformin HCl, depending on tolerability + 6 placebo tablets matching colesevelam 625 mg. Study medication is to be administered once daily for 16 weeks. | Drug: Metformin HCl and Colesevelam Placebo<br>* One or two Metformin HCl tablets 850 mg (depending on tolerability) and 6 colesevelam 625 mg placebo tablets once daily for 16 weeks<br>|
| Experimental: Diabetic participants: Metformin HCl + Colesevelam<br>Participants will receive either 850 mg or 1700 mg of metformin HCl, depending on tolerability + 6 colesevelam tablets, 625 mg. Study medication is to be administered once daily for 16 weeks. | Drug: Metformin HCl tablets and Colesevelam tablets<br>* One or two Metformin HCl tablets 850 mg (depending on tolerability) and 6 colesevelam 625 mg tablets once daily for 16 weeks<br>|
| Placebo Comparator: Pre-diabetic Participants: Colesevelam Placebo<br>Participants will receive 6 placebo tablets matching colesevelam 625 mg. Study medication is to be administered once daily for 16 weeks. | Drug: Colesevelam placebo<br>* Six colesevelam 625 mg placebo tablets will be given once a day for 16 weeks<br>|
| Experimental: Pre-diabetes Participants: Colesevelam<br>Participants will receive 6 colesevelam tablets, 625 mg. Study medication is to be administered once daily for 16 weeks. | Drug: Colesevelam<br>* Six colesevelam 625 mg tablets will be given once a day for 16 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change of Hemoglobin A1C (HbA1C) From Baseline to 16 Weeks When Given as Initial Therapy to Drug-naïve, Diabetic Subjects. |  | Baseline to 16 weeks | 
| Percent Change in Low Density Lipoprotein-Cholesterol (LDL-C) in Pre-Diabetic Subjects From Baseline to 16 Weeks |  | Baseline to 16 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Hemoglobin A1C (HbA1C) When Given to Drug-naïve, Diabetic Subjects From Baseline to 4, 8, 12 and 16 Weeks. |  | Baseline to 4, 8, 12, and 16 weeks | 
| Fasting Plasma Glucose When Given to Drug-naïve, Diabetic Subjects From Baseline to 4, 8, 12, and 16 Weeks |  | Baseline to 4, 8, 12, and 16 weeks | 
| Fasting Insulin When Given to Drug-naïve, Diabetic Subjects From Baseline to 4, 8, 12, and 16 Weeks |  | Baseline to 4, 8, 12, and 16 weeks | 
| Fasting C-Peptide Levels When Given to Drug-naïve, Diabetic Subjects From Baseline to 16 Weeks |  | Baseline to 16 weeks | 
| 30 Minute Post-Meal Glucose Levels When Given to Drug-naïve, Diabetic Subjects From Baseline to 16 Weeks |  | Baseline to 16 weeks | 
| 1 Hour Post-Meal Glucose Levels When Given to Drug-naïve, Diabetic Subjects From Baseline to 16 Weeks |  | Baseline to 16 weeks | 
| 2 Hour Post-Meal Glucose Levels to in Drug-naïve, Diabetic Subjects From Baseline to 16 Weeks |  | Baseline to 16 weeks | 
| 2 Hour Post-Meal Insulin Levels When Given to Drug-naïve, Diabetic Subjects From Baseline to 16 Weeks |  | Baseline to 16 weeks | 
| 2 Hour Post-Meal C-Peptide Levels When Given to Drug-naïve, Diabetic Subjects From Baseline to 16 Weeks |  | Baseline to 16 weeks | 
| The Percent Change of Low Density Lipoprotein Cholesterol (LDL-C) When Given to Drug-naïve, Diabetic Subjects From Baseline to 8, and 16 Weeks |  | Baseline to 8, and 16 weeks | 
| Percent Change of Non-High Density Lipoprotein (Non-HDL) Levels When Given to Drug-naïve, Diabetic Subjects From Baseline to 8, and 16 Weeks |  | Baseline to 8, and 16 weeks | 
| Percent Change of High Density Lipoprotein Cholesterol(HDL-C) When Given to Drug-naïve, Diabetic Subjects From Baseline to 8, and 16 Weeks |  | Baseline to 8, and 16 weeks | 
| Percent Change of Total Cholesterol (TC) When Given to Drug-naïve, Diabetic Subjects From Baseline to 8, and 16 Weeks |  | Baseline to 8, and 16 weeks | 
| Percent Change of Triglycerides (TG)When Given to Drug-naïve, Diabetic Subjects From Baseline to 8, and 16 Weeks |  | Baseline to 8, and 16 weeks | 
| Percent Change of Apolipoprotein A-1 (Apo A-1) When Given to Drug-naïve, Diabetic Subjects From Baseline to 8, and 16 Weeks |  | Baseline to 8, and 16 weeks | 
| Percent Change of Apolipoprotein B (Apo B)When Given to Drug-naïve, Diabetic Subjects From Baseline to 8, and 16 Weeks |  | Baseline to 8, and 16 weeks | 
| Percent Change of Apolipoprotein C3 (Apo C3)When Given to Drug-naïve, Diabetic Subjects From Baseline to 8, and 16 Weeks |  | Baseline to 8, and 16 weeks | 
| Change in the Levels of Various Lipoprotein Particles When Given to Drug-naïve, Diabetic Subjects From Baseline to 16 Weeks |  | Baseline to 16 weeks | 
| Change in the Size of Various Lipoprotein Particles When Given to Drug-naïve, Diabetic Subjects From Baseline to 16 Weeks |  | Baseline to 16 Weeks | 
| Change in the Calculated Total Triglycerides When Given to Drug-naïve, Diabetic Subjects From Baseline to 16 Weeks |  | Baseline to 16 Weeks | 
| Change in the Calculated Very Low Density Lipoprotein Triglycerides When Given to Drug-naïve, Diabetic Subjects From Baseline to 16 Weeks | These calculated values are reported as part of an NMR analysis. The calculations are done by LipoScience, Inc., and are proprietary. | Baseline to 16 Weeks | 
| Change in the Calculated High Density Lipoprotein Cholesterol When Given to Drug-naïve, Diabetic Subjects From Baseline to 16 Weeks | These calculated values are reported as part of an NMR analysis. The calculations are done by LipoScience, Inc., and are proprietary. | Baseline to 16 Weeks | 
| Percent of Subjects Achieving HbA1c Goal of <7.0% at Weeks 4, 8, 12, and 16 if Baseline HbA1c Was > or = to 7.0% When Given to Drug-naïve, Diabetics |  | Baseline to 4, 8, 12, and 16 Weeks | 
| Percent of Subject Achieving HbA1c Goal of <6.5% at Weeks 4, 8, 12, and 16 When Given to Drug-naïve, Diabetic Subjects |  | Baseline to 4, 8, 12 and 16 weeks | 
| Percent of Subjects Achieving Low Density Lipoprotein-Cholesterol of <100 mg/dL at Weeks 8, 16 When Given to Drug-naïve, Diabetic Subjects |  | Baseline to Weeks 8, and 16 | 
| Percent of Subjects Achieving Low Density Lipoprotein-Cholesterol Goal of <70 mg/dL at Weeks 8, 16 When Given as to Drug-naïve, Diabetics |  | Baseline to Weeks 8, and 16 | 
| Change in Body Weight When Given to Drug-naïve, Diabetic Subjects From Baseline to 16 Weeks |  | Baseline to 16 Weeks | 
| Change in Waist-to-Hip Ratio When Given to Drug-Naive Diabetic Subjects From Baseline to 16 Weeks |  | Baseline to 16 Weeks | 
| Change in Plasma Glucose Area Under the Curve (0 to 120 Minutes) From the Baseline Glucose Tolerance Test (GTT) to the 16 Week GTT |  | Baseline vs. 16 Weeks | 
| Percent Change of Various Calculated Lipid Parameters When Given as Initial Therapy to Drug-naïve, Diabetic From Baseline to 16 Weeks Subjects | These calculated values are reported as part of an NMR analysis. The calculations are done by LipoScience, Inc., and are proprietary. | Baseline to 16 Weeks | 
| Percent of Subjects Achieving 2-Hr. Post Meal Glucose Goal of <180 mg/dL When Given to Drug-naïve, Diabetic Subjects From Baseline to Week 16 |  | Baseline to Week 16 | 
| Percent of Subjects Achieving Hs-C-Reactive Protein Goal of <2.0 mg/L When Given to Drug-naïve, Diabetic Subjects From Baseline to 16 Weeks |  | Baseline to 16 Weeks | 
| Percent Change in Low Density Lipoprotein-Cholesterol in Pre-Diabetic Subjects From Baseline to 8, and 16 Weeks |  | Baseline to 8, and 16 Weeks | 
| Percent Change in Non-High Density Lipoprotein-Cholesterol in Pre-Diabetic Subjects From Baseline to 8, and 16 Weeks |  | Baseline to 8, and 16 Weeks | 
| Percent Change in High Density Lipoprotein-Cholesterol in Pre-Diabetic Subjects From Baseline to 8, and 16 Weeks |  | Baseline to 8, and 16 Weeks | 
| Percent Change in Total Cholesterol in Pre-Diabetic Subjects From Baseline to 8, and 16 Weeks |  | Baseline to 8, and 16 Weeks | 
| Percent Change in Apolipoprotein A-1 in Pre-Diabetic Subjects From Baseline to 8, and 16 Weeks |  | Baseline to 8, and 16 Weeks | 
| Percent Change in Apolipoprotein B in Pre-Diabetic Subjects From Baseline to 8, and 16 Weeks |  | Baseline to 8, and 16 Weeks | 
| Percent Change in Apolipoprotein CIII in Pre-Diabetic Subjects From Baseline to 8, and 16 Weeks |  | Baseline to 8, and 16 Weeks | 
| Percent Change in Triglycerides in Pre-Diabetic Subjects From Baseline to 8, and 16 Weeks |  | Baseline to 8, and 16 Weeks | 
| Percent Change in Hs-C-Reactive Protein in Pre-Diabetic Subjects From Baseline to 16 Weeks |  | Baseline 16 Weeks | 
| Level of Various Lipoprotein Particles in Pre-Diabetic Subjects From Baseline to 16 Weeks |  | Baseline to 16 Weeks | 
| Particle Size of Various Lipoprotein Particles in Pre-Diabetic Subjects From Baseline to 16 Weeks |  | Baseline to 16 Weeks | 
| Change of Various Calculated Lipid Parameters in Pre-Diabetic Subjects From Baseline to 16 Weeks | These calculated values are reported as part of an NMR analysis. The calculations are done by LipoScience, Inc., and are proprietary. | Baseline to 16 Weeks | 
| Percent Change of HbA1c in Pre-Diabetic Subjects From Baseline to 4, 8, 12, and 16 Weeks |  | Baseline to 4, 8, 12, and 16 Weeks | 
| Percent Change of Fasting Plasma Glucose in Pre-Diabetic Subjects From Baseline to 4, 8, 12, and 16 Weeks |  | Baseline to 4, 8, 12, and 16 weeks | 
| Percent Change of Fasting Insulin in Pre-Diabetic Subjects From Baseline to 4, 8, 12, and 16 Weeks |  | Baseline to 4, 8, 12, and 16 Weeks | 
| Change of Fasting C-peptide Levels in Pre-Diabetic Subjects From Baseline to 16 Weeks |  | Baseline to 16 Weeks | 
| Change of Glucose Levels 30 Minutes Post Oral Glucose Tolerance Test in Pre-Diabetic Subjects From Baseline to 16 Weeks |  | Baseline to 16 Weeks | 
| Change of Glucose Levels 1 Hour Post Oral Glucose Tolerance Test in Pre-Diabetic Subjects From Baseline to 16 Weeks |  | Baseline to 16 Weeks | 
| Change of Glucose Levels 2 Hours Post Oral Glucose Tolerance Test in Pre-Diabetic Subjects From Baseline to 16 Weeks |  | Baseline to 16 Weeks | 
| Change of Insulin Levels 2 Hours Post Oral Glucose Tolerance Test in Pre-Diabetic Subjects From Baseline to 16 Weeks |  | Baseline to 16 Weeks | 
| Change of C-Peptide Levels 2 Hours Post Oral Glucose Tolerance Test in Pre-Diabetic Subjects From Baseline to 16 Weeks |  | Baseline to 16 Weeks | 
| Percent of Subjects Achieving Low Density Lipoprotein-Cholesterol of <100 mg/dL at Weeks 8, 16 in Pre-Diabetic Subjects |  | Baseline to 8, and 16 Weeks | 
| Percent of Subjects Achieving Low Density Lipoprotein-Cholesterol of <70 mg/dL at Weeks 8, 16 in Pre-Diabetic Subjects |  | Baseline to 8, and 16 Weeks | 
| Change in Body Weight in Pre-Diabetic Subjects From Baseline to 16 Weeks |  | Baseline to 16 Weeks | 
| Change in Waist-to-Hip Ratio in Pre-Diabetic Subjects From Baseline to 16 Weeks |  | Baseline to 16 Weeks | 
| Area Under the Curve for Plasma Glucose From 0 to 120 Minutes During the Oral Glucose Tolerance Tests in Pre-Diabetic Subjects From Baseline to 16 Weeks |  | Baseline to 16 Weeks | 
| Percent Achievement of <140 mg/dL Plasma Glucose 2 Hours Post the Oral Glucose Tolerance Test in Pre-Diabetic Subjects Whose Corresponding Baseline Value Was >or= to 140 mg/dL From Baseline to 16 Weeks |  | Baseline to 16 Weeks | 
| Percent Achievement of <110 mg/dL Fasting Plasma Glucose in Pre-Diabetic Subjects Whose Corresponding Baseline Value Was > or = to 110 mg/dL From Baseline to 4, 8, 12, and 16 Weeks |  | Baseline to 4, 8, 12, and 16 Weeks | 
| Percent Achievement of <100 mg/dL Fasting Plasma Glucose in Pre-Diabetic Subjects Whose Corresponding Baseline Value Was > or = to 100 mg/dL From Baseline to 4, 8, 12 and 16 Weeks |  | Baseline to 4, 8, 12 and 16 weeks | 
| Percent Achievement of <140 mg/dL Plasma Glucose Post 2 Hour Glucose Tolerance Test and Fasting Plasma Glucose <110 mg/dL in Pre-Diabetic Subjects From Baseline to 16 Weeks |  | Baseline to 16 Weeks | 
| Percent Achievement of Hs-C-Reactive Protein <2.0 mg/L in Pre-Diabetic Subjects Whose Corresponding Baseline Value Was > or = to 2.0 mg/L From Baseline to 16 Weeks |  | Baseline to 16 Weeks | 
| Percent of Subjects Meeting Type 2 Diabetes Criteria (Fasting Plasma Glucose >or= to 126 mg/dL or Plasma Glucose >or= to 200 mg/dL Post 2 Hr Glucose Tolerance Test in Pre-Diabetic Subjects From Baseline to 16 Weeks |  | Baseline to 16 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Colesevelam, Type 2 Diabetes Mellitus, Pre-diabetes, Metformin