Clinical trial NCT00570739: 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.
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Type 2 Diabetes Mellitus
Hypercholesterolemia
Pre-diabetes
Keywords: Colesevelam
Type 2 Diabetes Mellitus
Pre-diabetes
Metformin
Lead sponsor: Daiichi Sankyo
Sponsor class: INDUSTRY
First posted: 2007-12-11
Enrollment: 502
Sex: ALL
Minimum age (years): 18
Maximum age (years): 79
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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 .

Primary outcomes:
measure: Percent Change of Hemoglobin A1C (HbA1C) From Baseline to 16 Weeks When Given as Initial Therapy to Drug-naïve, Diabetic Subjects.
timeFrame: Baseline to 16 weeks
measure: Percent Change in Low Density Lipoprotein-Cholesterol (LDL-C) in Pre-Diabetic Subjects From Baseline to 16 Weeks
timeFrame: Baseline to 16 Weeks
Secondary outcomes:
measure: Percent Change in Hemoglobin A1C (HbA1C) When Given to Drug-naïve, Diabetic Subjects From Baseline to 4, 8, 12 and 16 Weeks.
timeFrame: Baseline to 4, 8, 12, and 16 weeks
measure: Fasting Plasma Glucose When Given to Drug-naïve, Diabetic Subjects From Baseline to 4, 8, 12, and 16 Weeks
timeFrame: Baseline to 4, 8, 12, and 16 weeks
measure: Fasting Insulin When Given to Drug-naïve, Diabetic Subjects From Baseline to 4, 8, 12, and 16 Weeks
timeFrame: Baseline to 4, 8, 12, and 16 weeks
measure: Fasting C-Peptide Levels When Given to Drug-naïve, Diabetic Subjects From Baseline to 16 Weeks
timeFrame: Baseline to 16 weeks
measure: 30 Minute Post-Meal Glucose Levels When Given to Drug-naïve, Diabetic Subjects From Baseline to 16 Weeks
timeFrame: Baseline to 16 weeks
measure: 1 Hour Post-Meal Glucose Levels When Given to Drug-naïve, Diabetic Subjects From Baseline to 16 Weeks
timeFrame: Baseline to 16 weeks
measure: 2 Hour Post-Meal Glucose Levels to in Drug-naïve, Diabetic Subjects From Baseline to 16 Weeks
timeFrame: Baseline to 16 weeks
measure: 2 Hour Post-Meal Insulin Levels When Given to Drug-naïve, Diabetic Subjects From Baseline to 16 Weeks
timeFrame: Baseline to 16 weeks
measure: 2 Hour Post-Meal C-Peptide Levels When Given to Drug-naïve, Diabetic Subjects From Baseline to 16 Weeks
timeFrame: Baseline to 16 weeks
measure: The Percent Change of Low Density Lipoprotein Cholesterol (LDL-C) When Given to Drug-naïve, Diabetic Subjects From Baseline to 8, and 16 Weeks
timeFrame: Baseline to 8, and 16 weeks
measure: Percent Change of Non-High Density Lipoprotein (Non-HDL) Levels When Given to Drug-naïve, Diabetic Subjects From Baseline to 8, and 16 Weeks
timeFrame: Baseline to 8, and 16 weeks
measure: Percent Change of High Density Lipoprotein Cholesterol(HDL-C) When Given to Drug-naïve, Diabetic Subjects From Baseline to 8, and 16 Weeks
timeFrame: Baseline to 8, and 16 weeks
measure: Percent Change of Total Cholesterol (TC) When Given to Drug-naïve, Diabetic Subjects From Baseline to 8, and 16 Weeks
timeFrame: Baseline to 8, and 16 weeks
measure: Percent Change of Triglycerides (TG)When Given to Drug-naïve, Diabetic Subjects From Baseline to 8, and 16 Weeks
timeFrame: Baseline to 8, and 16 weeks
measure: Percent Change of Apolipoprotein A-1 (Apo A-1) When Given to Drug-naïve, Diabetic Subjects From Baseline to 8, and 16 Weeks
timeFrame: Baseline to 8, and 16 weeks
measure: Percent Change of Apolipoprotein B (Apo B)When Given to Drug-naïve, Diabetic Subjects From Baseline to 8, and 16 Weeks
timeFrame: Baseline to 8, and 16 weeks
measure: Percent Change of Apolipoprotein C3 (Apo C3)When Given to Drug-naïve, Diabetic Subjects From Baseline to 8, and 16 Weeks
timeFrame: Baseline to 8, and 16 weeks
measure: Change in the Levels of Various Lipoprotein Particles When Given to Drug-naïve, Diabetic Subjects From Baseline to 16 Weeks
timeFrame: Baseline to 16 weeks
measure: Change in the Size of Various Lipoprotein Particles When Given to Drug-naïve, Diabetic Subjects From Baseline to 16 Weeks
timeFrame: Baseline to 16 Weeks
measure: Change in the Calculated Total Triglycerides When Given to Drug-naïve, Diabetic Subjects From Baseline to 16 Weeks
timeFrame: Baseline to 16 Weeks
measure: Change in the Calculated Very Low Density Lipoprotein Triglycerides When Given to Drug-naïve, Diabetic Subjects From Baseline to 16 Weeks
timeFrame: Baseline to 16 Weeks
measure: Change in the Calculated High Density Lipoprotein Cholesterol When Given to Drug-naïve, Diabetic Subjects From Baseline to 16 Weeks
timeFrame: Baseline to 16 Weeks
measure: 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
timeFrame: Baseline to 4, 8, 12, and 16 Weeks
measure: Percent of Subject Achieving HbA1c Goal of <6.5% at Weeks 4, 8, 12, and 16 When Given to Drug-naïve, Diabetic Subjects
timeFrame: Baseline to 4, 8, 12 and 16 weeks
measure: Percent of Subjects Achieving Low Density Lipoprotein-Cholesterol of <100 mg/dL at Weeks 8, 16 When Given to Drug-naïve, Diabetic Subjects
timeFrame: Baseline to Weeks 8, and 16
measure: Percent of Subjects Achieving Low Density Lipoprotein-Cholesterol Goal of <70 mg/dL at Weeks 8, 16 When Given as to Drug-naïve, Diabetics
timeFrame: Baseline to Weeks 8, and 16
measure: Change in Body Weight When Given to Drug-naïve, Diabetic Subjects From Baseline to 16 Weeks
timeFrame: Baseline to 16 Weeks
measure: Change in Waist-to-Hip Ratio When Given to Drug-Naive Diabetic Subjects From Baseline to 16 Weeks
timeFrame: Baseline to 16 Weeks
measure: Change in Plasma Glucose Area Under the Curve (0 to 120 Minutes) From the Baseline Glucose Tolerance Test (GTT) to the 16 Week GTT
timeFrame: Baseline vs. 16 Weeks
measure: Percent Change of Various Calculated Lipid Parameters When Given as Initial Therapy to Drug-naïve, Diabetic From Baseline to 16 Weeks Subjects
timeFrame: Baseline to 16 Weeks
measure: 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
timeFrame: Baseline to Week 16
measure: 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
timeFrame: Baseline to 16 Weeks
measure: Percent Change in Low Density Lipoprotein-Cholesterol in Pre-Diabetic Subjects From Baseline to 8, and 16 Weeks
timeFrame: Baseline to 8, and 16 Weeks
measure: Percent Change in Non-High Density Lipoprotein-Cholesterol in Pre-Diabetic Subjects From Baseline to 8, and 16 Weeks
timeFrame: Baseline to 8, and 16 Weeks
measure: Percent Change in High Density Lipoprotein-Cholesterol in Pre-Diabetic Subjects From Baseline to 8, and 16 Weeks
timeFrame: Baseline to 8, and 16 Weeks
measure: Percent Change in Total Cholesterol in Pre-Diabetic Subjects From Baseline to 8, and 16 Weeks
timeFrame: Baseline to 8, and 16 Weeks
measure: Percent Change in Apolipoprotein A-1 in Pre-Diabetic Subjects From Baseline to 8, and 16 Weeks
timeFrame: Baseline to 8, and 16 Weeks
measure: Percent Change in Apolipoprotein B in Pre-Diabetic Subjects From Baseline to 8, and 16 Weeks
timeFrame: Baseline to 8, and 16 Weeks
measure: Percent Change in Apolipoprotein CIII in Pre-Diabetic Subjects From Baseline to 8, and 16 Weeks
timeFrame: Baseline to 8, and 16 Weeks
measure: Percent Change in Triglycerides in Pre-Diabetic Subjects From Baseline to 8, and 16 Weeks
timeFrame: Baseline to 8, and 16 Weeks
measure: Percent Change in Hs-C-Reactive Protein in Pre-Diabetic Subjects From Baseline to 16 Weeks
timeFrame: Baseline 16 Weeks
measure: Level of Various Lipoprotein Particles in Pre-Diabetic Subjects From Baseline to 16 Weeks
timeFrame: Baseline to 16 Weeks
measure: Particle Size of Various Lipoprotein Particles in Pre-Diabetic Subjects From Baseline to 16 Weeks
timeFrame: Baseline to 16 Weeks
measure: Change of Various Calculated Lipid Parameters in Pre-Diabetic Subjects From Baseline to 16 Weeks
timeFrame: Baseline to 16 Weeks
measure: Percent Change of HbA1c in Pre-Diabetic Subjects From Baseline to 4, 8, 12, and 16 Weeks
timeFrame: Baseline to 4, 8, 12, and 16 Weeks
measure: Percent Change of Fasting Plasma Glucose in Pre-Diabetic Subjects From Baseline to 4, 8, 12, and 16 Weeks
timeFrame: Baseline to 4, 8, 12, and 16 weeks
measure: Percent Change of Fasting Insulin in Pre-Diabetic Subjects From Baseline to 4, 8, 12, and 16 Weeks
timeFrame: Baseline to 4, 8, 12, and 16 Weeks
measure: Change of Fasting C-peptide Levels in Pre-Diabetic Subjects From Baseline to 16 Weeks
timeFrame: Baseline to 16 Weeks
measure: Change of Glucose Levels 30 Minutes Post Oral Glucose Tolerance Test in Pre-Diabetic Subjects From Baseline to 16 Weeks
timeFrame: Baseline to 16 Weeks
measure: Change of Glucose Levels 1 Hour Post Oral Glucose Tolerance Test in Pre-Diabetic Subjects From Baseline to 16 Weeks
timeFrame: Baseline to 16 Weeks
measure: Change of Glucose Levels 2 Hours Post Oral Glucose Tolerance Test in Pre-Diabetic Subjects From Baseline to 16 Weeks
timeFrame: Baseline to 16 Weeks
measure: Change of Insulin Levels 2 Hours Post Oral Glucose Tolerance Test in Pre-Diabetic Subjects From Baseline to 16 Weeks
timeFrame: Baseline to 16 Weeks
measure: Change of C-Peptide Levels 2 Hours Post Oral Glucose Tolerance Test in Pre-Diabetic Subjects From Baseline to 16 Weeks
timeFrame: Baseline to 16 Weeks
measure: Percent of Subjects Achieving Low Density Lipoprotein-Cholesterol of <100 mg/dL at Weeks 8, 16 in Pre-Diabetic Subjects
timeFrame: Baseline to 8, and 16 Weeks
measure: Percent of Subjects Achieving Low Density Lipoprotein-Cholesterol of <70 mg/dL at Weeks 8, 16 in Pre-Diabetic Subjects
timeFrame: Baseline to 8, and 16 Weeks
measure: Change in Body Weight in Pre-Diabetic Subjects From Baseline to 16 Weeks
timeFrame: Baseline to 16 Weeks
measure: Change in Waist-to-Hip Ratio in Pre-Diabetic Subjects From Baseline to 16 Weeks
timeFrame: Baseline to 16 Weeks
measure: 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
timeFrame: Baseline to 16 Weeks
measure: 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
timeFrame: Baseline to 16 Weeks
measure: 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
timeFrame: Baseline to 4, 8, 12, and 16 Weeks
measure: 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
timeFrame: Baseline to 4, 8, 12 and 16 weeks
measure: 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
timeFrame: Baseline to 16 Weeks
measure: 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
timeFrame: Baseline to 16 Weeks
measure: 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
timeFrame: Baseline to 16 Weeks
Other outcomes:
Locations:
city: Birmingham
country: United States
state: Alabama
city: Los Gatos
country: United States
state: California
city: Tarzana
country: United States
state: California
city: Ocala
country: United States
state: Florida
city: Pocatello
country: United States
state: Idaho
city: Gary
country: United States
state: Indiana
city: New Orleans
country: United States
state: Louisiana
city: Olive Branch
country: United States
state: Mississippi
city: Dundee
country: United States
state: New York
city: West Seneca
country: United States
state: New York
city: Statesville
country: United States
state: North Carolina
city: Kent
country: United States
state: Ohio
city: Marion
country: United States
state: Ohio
city: Portland
country: United States
state: Oregon
city: Corpus Christi
country: United States
state: Texas
city: Dallas
country: United States
state: Texas
city: San Antonio
country: United States
state: Texas
city: Barranquilla
country: Colombia
state: Atlántico
city: Bogota
country: Colombia
state: Cundinamarca
city: Bucaramanga
country: Colombia
state: Santander
city: Mumbai
country: India
state: Dadar
city: Durgapura
country: India
state: Jaipur
city: Bangalore
country: India
state: Karnataka
city: Cochin
country: India
state: Kerala
city: Nasik
country: India
state: Mahārāshtra
city: Las Palmas
country: Mexico
state: Chihuahua
city: Delegacion
country: Mexico
state: Cuauhtemoc
city: Guadalajara
country: Mexico
state: Jalisco
city: Monterrey
country: Mexico
state: Nuevo Leon
city: Hermosillo
country: Mexico
state: Sonora
city: Merida
country: Mexico
state: Yucatan
Study officials:
affiliation: DSI
name: Michael Jones
role: STUDY_DIRECTOR
References:
citation: Rosenstock J, Hernandez-Triana E, Handelsman Y, Misir S, Jones MR. Clinical effects of colesevelam in Hispanic subjects with primary hyperlipidemia and prediabetes. Postgrad Med. 2012 Jul;124(4):14-20. doi: 10.3810/pgm.2012.07.2564.
citation: Goldberg RB, Rosenson RS, Hernandez-Triana E, Misir S, Jones MR. Initial combination therapy with metformin plus colesevelam improves lipoprotein particles in patients with early type 2 diabetes mellitus. J Clin Lipidol. 2012 Jul-Aug;6(4):318-24. doi: 10.1016/j.jacl.2012.05.005. Epub 2012 May 29.
citation: Handelsman Y, Goldberg RB, Garvey WT, Fonseca VA, Rosenstock J, Jones MR, Lai YL, Jin X, Misir S, Nagendran S, Abby SL. Colesevelam hydrochloride to treat hypercholesterolemia and improve glycemia in prediabetes: a randomized, prospective study. Endocr Pract. 2010 Jul-Aug;16(4):617-28. doi: 10.4158/EP10129.OR.
citation: Rosenstock J, Fonseca VA, Garvey WT, Goldberg RB, Handelsman Y, Abby SL, Lai YL, Jin X, Misir S, Nagendran S, Jones MR. Initial combination therapy with metformin and colesevelam for achievement of glycemic and lipid goals in early type 2 diabetes. Endocr Pract. 2010 Jul-Aug;16(4):629-40. doi: 10.4158/EP10130.OR.