Type 2 Diabetes Mellitus
Conditions
Brief summary
The current study investigates colesevelam as add-on therapy to pioglitazone to improve glycemic control in subjects with type 2 diabetes mellitus not adequately controlled with pioglitazone monotherapy or pioglitazone in combination with either metformin or a sulfonylurea. The study will evaluate if colesevelam add-on to pioglitazone therapy for type 2 diabetes mellitus will be safe, well tolerated, and efficacious.
Interventions
DRUGColesevelam
Colesevelam 625 mg tablets
DRUGPlacebo
Placebo tablets appearing to be colesevelam
DRUGPioglitazone
30 mg or 45 mg pioglitazone therapy
Sponsors
Daiichi Sankyo
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of Type 2 diabetes mellitus * Inadequate glycemic control on a stable dose (at least 2 months prior to screening) of pioglitazone at 30 or 45 mg/day, with or without one or two other oral antidiabetic medications \[metformin or a sulfonylurea, or dipeptidyl peptidase (DPP-IV) inhibitor\] * Hemoglobin A1c (HbA1c) \>= 7.5% and =\< 9.5% at screening * Fasting plasma glucose =\<240 mg/dL at randomization (Week 0/Day 1). * Male or female \>= 18 years of age. * Women of childbearing potential must be using an adequate method of contraception as detailed per-protocol * Fasting C-peptide level \>0.5 ng/mL at screening * Clinically stable in regards to medical conditions other than type 2 diabetes * Concomitant medications are at stable doses for at least 30 days prior to enrollment, and are not anticipated to need adjustment during the study period
Exclusion criteria
* History of Type 1 diabetes and/or history of ketoacidosis * History of bowel obstruction * History of hypertriglyceridemia-induced pancreatitis * Fasting serum triglyceride concentration \>500 mg/dL * History of dysphagia, swallowing disorders, gastroparesis, other gastrointestinal motility disorders, major gastrointestinal surgery * History of insulin use \>= 2 weeks duration during the previous 3 months or a total of \>2 months insulin therapy at any time prior to screening * Treatment with bile acid sequestrants, including colesevelam within 3 months prior to screening * Female subject who is pregnant or breastfeeding * History of unstable angina, myocardial infarction, cerebrovascular accident, transient ischemic attack, or any revascularization within 6 months prior to screening
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change From Baseline in Hemoglobin A1c (HbA1c) at Week 24 | Baseline, Week 24 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in HbA1c at Week 8 | Baseline, Week 8 | — |
| Change From Baseline in HbA1c at Week 16 | Baseline, Week 16 | — |
| Number of Participants Achieving an HbA1c Goal of <7.0% | Week 24 | — |
| Change From Baseline in Fasting Plasma Glucose (FPG) | Baseline, Week 24 | In this study a reduction in FPG of at least 30 mg/dL is considered glycemic response. |
| Number of Participants With a Decrease of >= 0.7 Percent in HbA1c | Week 24 | — |
| Number of Participants With a Decrease of >= 0.5 Percent in HbA1c | Week 24 | — |
| Number of Participants With a Reduction in FPG of >= 30 mg/dL | Week 24 | — |
| Percent Change From Baseline in Total Cholesterol (TC) | Baseline, Week 24 | TC is measured in milligrams per deciliter (mg/dL) |
| Change From Baseline in HbA1c at Week 4 | Baseline, Week 4 | — |
| Percent Change From Baseline in High-density Lipoprotein Cholesterol (HDL-C) | Baseline, Week 24 | HDL-C is measured in mg/dL |
| Percent Change From Baseline in Non-HDL-C | Baseline, Week 24 | Non-HDL-C is measured in mg/dL |
| Percent Change From Baseline in Triglycerides (TG) | Baseline, Week 24 | TG are measured in mg/dL |
| Percent Change From Baseline in Apolipoprotein A-1 (Apo A-I) | Baseline, Week 24 | Apo A-1 is measured in mg/dL |
| Percent Change From Baseline in Apolipoprotein B (Apo B) | Baseline, Week 24 | Apo B is measured in mg/dL |
| Change From Baseline in Fasting Insulin Levels | Baseline, Week 24 | — |
| Change From Baseline in Fasting C-peptide | Baseline, Week 24 | — |
| Change From Baseline in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) | Baseline, Week 24 | HOMA-IR is a calculation of fasting insulin and fasting glucose that shows the level of insulin resistance. Lower numbers are better. |
| Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) | Baseline, Week 24 | LDL-C is measured in mg/dL |
Countries
United States
Participant flow
Recruitment details
The safety set includes all randomized participants who took at least one dose of study medication and have at least one post-baseline safety measurement. The intent-to-treat set includes all randomized subjects who took at least one dose of study medication, and had a baseline and at least one post-baseline HbA1c or FPG measurement.
Pre-assignment details
There was a lead-in period that occurred after participant enrollment, but before randomization.1538 were screened, and a total of 562 participants were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Colesevelam Colesevelam tablets with pioglitazone therapy | 280 |
| Placebo Placebo tablets with pioglitazone therapy | 282 |
| Total | 562 |
Baseline characteristics
| Characteristic | Total | Placebo | Colesevelam |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 120 Participants | 60 Participants | 60 Participants |
| Age, Categorical Between 18 and 65 years | 442 Participants | 222 Participants | 220 Participants |
| Age, Continuous | 56.0 years STANDARD_DEVIATION 10.41 | 55.6 years STANDARD_DEVIATION 10.61 | 56.3 years STANDARD_DEVIATION 10.22 |
| Race/Ethnicity, Customized American Indian or Alaskan Native | 37 Participants | 21 Participants | 16 Participants |
| Race/Ethnicity, Customized Asian | 53 Participants | 30 Participants | 23 Participants |
| Race/Ethnicity, Customized Black | 115 Participants | 56 Participants | 59 Participants |
| Race/Ethnicity, Customized Caucasian | 351 Participants | 172 Participants | 179 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 5 Participants | 2 Participants | 3 Participants |
| Region of Enrollment United States | 562 participants | 282 participants | 280 participants |
| Sex: Female, Male Female | 242 Participants | 106 Participants | 136 Participants |
| Sex: Female, Male Male | 320 Participants | 176 Participants | 144 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 274 | 0 / 277 |
| other Total, other adverse events | 11 / 274 | 17 / 277 |
| serious Total, serious adverse events | 11 / 274 | 4 / 277 |
Outcome results
Primary
Change From Baseline in Hemoglobin A1c (HbA1c) at Week 24
Time frame: Baseline, Week 24
Population: Intent-to-treat, last observation carried forward
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Colesevelam | Change From Baseline in Hemoglobin A1c (HbA1c) at Week 24 | -0.34 percent | Standard Error 0.083 |
| Placebo | Change From Baseline in Hemoglobin A1c (HbA1c) at Week 24 | -0.02 percent | Standard Error 0.083 |
Comparison: Treatment difference = Colesevelam - Placebop-value: <0.00195% CI: [-0.49, -0.16]ANCOVA
Secondary
Change From Baseline in Fasting C-peptide
Time frame: Baseline, Week 24
Population: Intent-to-treat set, with values at both baseline and Week 24 with last observation carried forward
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Colesevelam | Change From Baseline in Fasting C-peptide | 0.1 ng/mL | Standard Error 0.1 |
| Placebo | Change From Baseline in Fasting C-peptide | 0.3 ng/mL | Standard Error 0.1 |
Comparison: Treatment difference = Colesevelam - Placebop-value: 0.065395% CI: [-0.4, 0]ANCOVA
Secondary
Change From Baseline in Fasting Insulin Levels
Time frame: Baseline, Week 24
Population: Intent-to-treat set, with values at both baseline and Week 24 with last observation carried forward
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Colesevelam | Change From Baseline in Fasting Insulin Levels | 0.2 µIU/mL | Standard Error 1.76 |
| Placebo | Change From Baseline in Fasting Insulin Levels | 0.8 µIU/mL | Standard Error 1.76 |
Comparison: Treatment difference = Colesevelam - Placebop-value: 0.728695% CI: [-4.1, 2.9]ANCOVA
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG)
In this study a reduction in FPG of at least 30 mg/dL is considered glycemic response.
Time frame: Baseline, Week 24
Population: Participants in the intent-to-treat set with values at both baseline and Week 24 with last observation carried forward
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Colesevelam | Change From Baseline in Fasting Plasma Glucose (FPG) | -4.8 mg/dL | Standard Error 3.66 |
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) | 9.9 mg/dL | Standard Error 3.66 |
Comparison: Treatment difference = Colesevelam - Placebop-value: <0.000195% CI: [-21.93, -7.49]ANCOVA
Secondary
Change From Baseline in HbA1c at Week 16
Time frame: Baseline, Week 16
Population: Intent to treat set, with baseline and post-baseline measures at the given time point
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Colesevelam | Change From Baseline in HbA1c at Week 16 | -0.50 percent | Standard Error 0.078 |
| Placebo | Change From Baseline in HbA1c at Week 16 | -0.15 percent | Standard Error 0.078 |
Comparison: Treatment difference = Colesevelam - Placebop-value: <0.00195% CI: [-0.51, -0.2]ANCOVA
Secondary
Change From Baseline in HbA1c at Week 4
Time frame: Baseline, Week 4
Population: Intent to treat set, with baseline and post-baseline measures at the given time point
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Colesevelam | Change From Baseline in HbA1c at Week 4 | -0.28 percent | Standard Error 0.037 |
| Placebo | Change From Baseline in HbA1c at Week 4 | -0.11 percent | Standard Error 0.037 |
Comparison: Treatment difference = Colesevelam - Placebop-value: <0.00195% CI: [-0.24, -0.1]ANCOVA
Secondary
Change From Baseline in HbA1c at Week 8
Time frame: Baseline, Week 8
Population: Intent to treat set, with baseline and post-baseline measures at the given time point
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Colesevelam | Change From Baseline in HbA1c at Week 8 | -0.35 percent | Standard Error 0.055 |
| Placebo | Change From Baseline in HbA1c at Week 8 | -0.14 percent | Standard Error 0.056 |
Comparison: Treatment difference = Colesevelam - Placebop-value: 0.000295% CI: [-0.32, -0.1]ANCOVA
Secondary
Change From Baseline in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)
HOMA-IR is a calculation of fasting insulin and fasting glucose that shows the level of insulin resistance. Lower numbers are better.
Time frame: Baseline, Week 24
Population: Intent-to-treat set, with values at both baseline and Week 24 with last observation carried forward
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Colesevelam | Change From Baseline in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) | 0.2 calculation | Standard Error 0.71 |
| Placebo | Change From Baseline in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) | 0.3 calculation | Standard Error 0.72 |
Comparison: Treatment difference = Colesevelam - Placebop-value: 0.886295% CI: [-1.5, 1.3]ANCOVA
Secondary
Number of Participants Achieving an HbA1c Goal of <7.0%
Time frame: Week 24
Population: Intent-to-treat set, with last observation carried forward
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Colesevelam | Number of Participants Achieving an HbA1c Goal of <7.0% | 56 Participants |
| Placebo | Number of Participants Achieving an HbA1c Goal of <7.0% | 35 Participants |
p-value: 0.012Cochran-Mantel-Haenszel
Secondary
Number of Participants With a Decrease of >= 0.5 Percent in HbA1c
Time frame: Week 24
Population: Intent-to-treat set, with last count carried forward
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Colesevelam | Number of Participants With a Decrease of >= 0.5 Percent in HbA1c | 147 Participants |
| Placebo | Number of Participants With a Decrease of >= 0.5 Percent in HbA1c | 106 Participants |
p-value: <0.001Cochran-Mantel-Haenszel
Secondary
Number of Participants With a Decrease of >= 0.7 Percent in HbA1c
Time frame: Week 24
Population: Intent-to-treat set, with last count carried forward
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Colesevelam | Number of Participants With a Decrease of >= 0.7 Percent in HbA1c | 108 Participants |
| Placebo | Number of Participants With a Decrease of >= 0.7 Percent in HbA1c | 70 Participants |
p-value: 0.0003Cochran-Mantel-Haenszel
Secondary
Number of Participants With a Reduction in FPG of >= 30 mg/dL
Time frame: Week 24
Population: Intent-to-treat set, with last count carried forward
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Colesevelam | Number of Participants With a Reduction in FPG of >= 30 mg/dL | 60 Participants |
| Placebo | Number of Participants With a Reduction in FPG of >= 30 mg/dL | 47 Participants |
p-value: 0.132Cochran-Mantel-Haenszel
Secondary
Percent Change From Baseline in Apolipoprotein A-1 (Apo A-I)
Apo A-1 is measured in mg/dL
Time frame: Baseline, Week 24
Population: Intent-to-treat, with values at both baseline and Week 24 with last observation carried forward
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Colesevelam | Percent Change From Baseline in Apolipoprotein A-1 (Apo A-I) | 3.2 percentage of change | Standard Error 0.92 |
| Placebo | Percent Change From Baseline in Apolipoprotein A-1 (Apo A-I) | -0.2 percentage of change | Standard Error 0.92 |
Comparison: Treatment difference = Colesevelam - Placebop-value: 0.000395% CI: [1.58, 5.23]ANCOVA
Secondary
Percent Change From Baseline in Apolipoprotein B (Apo B)
Apo B is measured in mg/dL
Time frame: Baseline, Week 24
Population: Intent-to-treat set, with values at both baseline and Week 24 with last observation carried forward
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Colesevelam | Percent Change From Baseline in Apolipoprotein B (Apo B) | -5.2 percentage of change | Standard Error 1.51 |
| Placebo | Percent Change From Baseline in Apolipoprotein B (Apo B) | 3.6 percentage of change | Standard Error 1.51 |
Comparison: Treatment difference = Colesevelam - Placebop-value: <0.000195% CI: [-11.75, -5.78]ANCOVA
Secondary
Percent Change From Baseline in High-density Lipoprotein Cholesterol (HDL-C)
HDL-C is measured in mg/dL
Time frame: Baseline, Week 24
Population: Intent-to-treat set, with values at both baseline and Week 24 with last observation carried forward
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Colesevelam | Percent Change From Baseline in High-density Lipoprotein Cholesterol (HDL-C) | 2.9 percentage of change | Standard Error 1.3 |
| Placebo | Percent Change From Baseline in High-density Lipoprotein Cholesterol (HDL-C) | 1.1 percentage of change | Standard Error 1.3 |
Comparison: Treatment difference = Colesevelam - Placebop-value: 0.165295% CI: [-0.75, 4.39]ANCOVA
Secondary
Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C)
LDL-C is measured in mg/dL
Time frame: Baseline, Week 24
Population: Intent-to-treat set, with values at both baseline and Week 24 with last count carried forward
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Colesevelam | Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) | -9.1 percentage of change | Standard Error 2.14 |
| Placebo | Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) | 7.3 percentage of change | Standard Error 2.12 |
Comparison: Treatment difference = Colesevelam - Placebop-value: <0.00195% CI: [-20.62, -12.18]ANCOVA
Secondary
Percent Change From Baseline in Non-HDL-C
Non-HDL-C is measured in mg/dL
Time frame: Baseline, Week 24
Population: Intent-to-treat set, with values at both baseline and Week 24 with last observation carried forward
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Colesevelam | Percent Change From Baseline in Non-HDL-C | -5.2 percentage of change | Standard Error 1.85 |
| Placebo | Percent Change From Baseline in Non-HDL-C | 4.6 percentage of change | Standard Error 1.84 |
Comparison: Treatment difference = Colesevelam - Placebop-value: <0.000195% CI: [-13.44, -6.16]ANCOVA
Secondary
Percent Change From Baseline in Total Cholesterol (TC)
TC is measured in milligrams per deciliter (mg/dL)
Time frame: Baseline, Week 24
Population: Intent-to-treat set, with values at both baseline and Week 24 with last observation carried forward
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Colesevelam | Percent Change From Baseline in Total Cholesterol (TC) | -3.4 percentage of change | Standard Error 1.33 |
| Placebo | Percent Change From Baseline in Total Cholesterol (TC) | 3.1 percentage of change | Standard Error 1.32 |
p-value: <0.001ANCOVA
Secondary
Percent Change From Baseline in Triglycerides (TG)
TG are measured in mg/dL
Time frame: Baseline, Week 24
Population: Intent-to-treat set, with values at both baseline and Week 24 with last observation carried forward
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Colesevelam | Percent Change From Baseline in Triglycerides (TG) | 14.1 percentage of change |
| Placebo | Percent Change From Baseline in Triglycerides (TG) | 2.2 percentage of change |
Comparison: Treatment difference = Colesevelam - Placebop-value: 0.000495% CI: [5.3, 17.5]ANCOVA