Type 2 Diabetes
Conditions
Keywords
Mechanism of action insulin sensitivity
Brief summary
This study is designed to assess the potential mechanism of action by which WelChol® (colesevelam) may improve blood glucose control in patients with type 2 diabetes
Interventions
DRUGColesevelam
Colesevelam 3.8g for 12 weeks
DRUGColesevelam matching placebo
Colesevelam matching placebo for 12 weeks
Insulin glargine for 12 weeks
Sponsors
Daiichi Sankyo
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Patients between the ages of 18 - 75, inclusive * Diagnosed with type 2 diabetes * Hemoglobin A1c value greater than or equal to 8.0% * Antidiabetic treatments may include sulfonylurea agents (non-sulfonylurea agents must be withdrawn) * Overweight, obese (body mass index 25-45 kg/m2)
Exclusion criteria
* Change of dose of lipid or blood pressure lowering therapy within past three months * Previous treatment with colesevelam for hyperlipidemia * Serum triglyceride greater than 500 mg/dL * Serum low density lipoprotein-cholesterol less than 60 mg/dL
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Difference in Endogenous (Hepatic) Glucose Output During a High-dose Insulin Infusion From Baseline to After 12 Weeks of Treatment. | Baseline to 12 weeks | The parameter measured is the endogenous (hepatic) glucose output during a high-dose insulin infusion. A decrease after treatment with colesevelam is indicative of greater sensitivity of the liver to insulin. |
| Difference in Endogenous (Hepatic) Glucose Output During a Low-dose Insulin Infusion From Baseline to Week 12. | Baseline to 12 weeks | The parameter measured is the endogenous (hepatic) glucose output during a low-dose insulin infusion. A decrease is indicative of greater senstitivity of the liver to insulin. |
| Acute Effect of a Single Dose of Colesevelam on Oral Glucose Absorption From Baseline to First Dose | Baseline (Day -4) to first dose (Day 1) | Change in area under the curve for glucose (AUCg) after a glucose tolerance test. A decrease in AUCg is indicative of a drug effect. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Acute Effect of Colesevelam (Multiple Doses) on Oral Glucose Absorption From Baseline to 12 Weeks | Baseline to 12 weeks | The parameter measured is the change in area under the curve for glucose(AUCg) after an oral glucose tolerance test. A decrease in AUCg indicative of drug effect on glucose absorption. |
| Change in Hemoglobin A1C Due to Effect of Colesevelam From Baseline to 12 Weeks | Baseline to 12 weeks | The parameter measured is the percent of hemoglobin A that is glycosylated. A decrease in this parameter is indicative of improved glucose control. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited from 21 June 2005 to 22 January 2008 at 3 clinical research sites in the United States of America.
Pre-assignment details
Subjects were taken off any non-sulfonylurea oral anti-diabetic agents for a period of time appropriate to the drug. Qualified subjects were randomized to colesevelam hydrochloride, placebo, or open-label insulin glargine for 12 weeks. Difficulties enrolling into the insulin group caused the size of this group to decrease from 15 to 6 subjects.
Participants by arm
| Arm | Count |
|---|---|
| Colesevelam 3.8g colesevelam 3.8g administered daily for 12 weeks | 16 |
| Colesevelam Matching Placebo Colesevelam matching placebo for 12 weeks | 14 |
| Open-label Insulin Glargine open-label Insulin Glargine for 12 weeks | 6 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Open-label Insulin Glargine | Colesevelam Matching Placebo | Colesevelam 3.8g |
|---|---|---|---|---|
| Age, Continuous | 54.6 years | 52.8 years | 54.0 years | 55.7 years |
| Body Mass | 34.0 kg/m2 | 35.2 kg/m2 | 33.7 kg/m2 | 33.7 kg/m2 |
| Fasting Plasma Glucose | 186.3 mg/dL | 199.0 mg/dL | 207.9 mg/dL | 162.6 mg/dL |
| HbA1c | 8.5 percent | 9.3 percent | 8.5 percent | 8.2 percent |
| Height | 170.4 cm | 170.8 cm | 168.6 cm | 171.7 cm |
| Race/Ethnicity, Customized Black or African American | 9 Participants | 1 Participants | 3 Participants | 5 Participants |
| Race/Ethnicity, Customized Hispanic | 5 Participants | 2 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 20 Participants | 3 Participants | 9 Participants | 8 Participants |
| Region of Enrollment United States | 36 participants | 6 participants | 14 participants | 16 participants |
| Sex: Female, Male Female | 11 Participants | 1 Participants | 6 Participants | 4 Participants |
| Sex: Female, Male Male | 25 Participants | 5 Participants | 8 Participants | 12 Participants |
| Weight | 98.3 kg | 103.4 kg | 95.8 kg | 98.6 kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 14 / 16 | 10 / 14 | 4 / 6 |
| serious Total, serious adverse events | 0 / 16 | 0 / 14 | 0 / 6 |
Outcome results
Primary
Acute Effect of a Single Dose of Colesevelam on Oral Glucose Absorption From Baseline to First Dose
Change in area under the curve for glucose (AUCg) after a glucose tolerance test. A decrease in AUCg is indicative of a drug effect.
Time frame: Baseline (Day -4) to first dose (Day 1)
Population: The entire study population was included in this analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Colesevelam 3.8g | Acute Effect of a Single Dose of Colesevelam on Oral Glucose Absorption From Baseline to First Dose | -38.4 mg*hr/dL | Standard Deviation 105.75 |
p-value: 0.0362t-test, 2 sided
Primary
Difference in Endogenous (Hepatic) Glucose Output During a High-dose Insulin Infusion From Baseline to After 12 Weeks of Treatment.
The parameter measured is the endogenous (hepatic) glucose output during a high-dose insulin infusion. A decrease after treatment with colesevelam is indicative of greater sensitivity of the liver to insulin.
Time frame: Baseline to 12 weeks
Population: The population analyzed was all randomized subjects who received medication and had a baseline and at least 1 post-randomization assessment of an efficacy variable. One placebo participant did not have a valid post-randomization insulin clamp study. Therefore, the number included in the placebo group for this analysis was 13.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Colesevelam 3.8g | Difference in Endogenous (Hepatic) Glucose Output During a High-dose Insulin Infusion From Baseline to After 12 Weeks of Treatment. | -0.06 mg/kg/min | Standard Error 0.048 |
| Colesevelam Matching Placebo | Difference in Endogenous (Hepatic) Glucose Output During a High-dose Insulin Infusion From Baseline to After 12 Weeks of Treatment. | -0.011 mg/kg/min | Standard Error 0.051 |
| Open-label Insulin Glargine | Difference in Endogenous (Hepatic) Glucose Output During a High-dose Insulin Infusion From Baseline to After 12 Weeks of Treatment. | -0.01 mg/kg/min | Standard Error 0.076 |
p-value: 0.549995% CI: [-0.1, 0.19]ANCOVA
p-value: 0.572395% CI: [-0.23, 0.13]ANCOVA
p-value: 0.313895% CI: [-0.09, 0.28]ANCOVA
Primary
Difference in Endogenous (Hepatic) Glucose Output During a Low-dose Insulin Infusion From Baseline to Week 12.
The parameter measured is the endogenous (hepatic) glucose output during a low-dose insulin infusion. A decrease is indicative of greater senstitivity of the liver to insulin.
Time frame: Baseline to 12 weeks
Population: The population analyzed was all randomized subjects who received medication and had a baseline and at least 1 post-randomization assessment of an efficacy variable. One placebo participant did not have a valid post-randomization insulin clamp study. Therefore, the number included in the placebo group for this analysis was 13.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Colesevelam 3.8g | Difference in Endogenous (Hepatic) Glucose Output During a Low-dose Insulin Infusion From Baseline to Week 12. | -0.08 mg/kg/min | Standard Error 0.044 |
| Colesevelam Matching Placebo | Difference in Endogenous (Hepatic) Glucose Output During a Low-dose Insulin Infusion From Baseline to Week 12. | -0.16 mg/kg/min | Standard Error 0.048 |
| Open-label Insulin Glargine | Difference in Endogenous (Hepatic) Glucose Output During a Low-dose Insulin Infusion From Baseline to Week 12. | -0.04 mg/kg/min | Standard Error 0.07 |
p-value: 0.204295% CI: [-0.05, 0.22]ANCOVA
p-value: 0.685595% CI: [-0.2, 0.14]ANCOVA
p-value: 0.172795% CI: [-0.05, 0.29]ANCOVA
Secondary
Change in Hemoglobin A1C Due to Effect of Colesevelam From Baseline to 12 Weeks
The parameter measured is the percent of hemoglobin A that is glycosylated. A decrease in this parameter is indicative of improved glucose control.
Time frame: Baseline to 12 weeks
Population: One participant in the colesevelam 3.8g group discontinued. Therefore, 15 participants were included in this analysis.~The least squares mean is adjusted for baseline values. This corrects for differences in baseline values between treatment groups.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Colesevelam 3.8g | Change in Hemoglobin A1C Due to Effect of Colesevelam From Baseline to 12 Weeks | -0.29 percent | Standard Error 0.258 |
| Colesevelam Matching Placebo | Change in Hemoglobin A1C Due to Effect of Colesevelam From Baseline to 12 Weeks | 0.16 percent | Standard Error 0.26 |
| Open-label Insulin Glargine | Change in Hemoglobin A1C Due to Effect of Colesevelam From Baseline to 12 Weeks | -0.81 percent | Standard Error 0.426 |
p-value: 0.228695% CI: [-1.2, 0.3]ANCOVA
p-value: 0.318495% CI: [-0.53, 1.57]ANCOVA
p-value: 0.061395% CI: [-1.99, 0.05]ANCOVA
Secondary
The Acute Effect of Colesevelam (Multiple Doses) on Oral Glucose Absorption From Baseline to 12 Weeks
The parameter measured is the change in area under the curve for glucose(AUCg) after an oral glucose tolerance test. A decrease in AUCg indicative of drug effect on glucose absorption.
Time frame: Baseline to 12 weeks
Population: One participant in the colesevelam 3.8g group discontinued. Therefore, 15 participants were included in this analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Colesevelam 3.8g | The Acute Effect of Colesevelam (Multiple Doses) on Oral Glucose Absorption From Baseline to 12 Weeks | -49.1 mg*hr/dL | Standard Error 36.75 |
| Colesevelam Matching Placebo | The Acute Effect of Colesevelam (Multiple Doses) on Oral Glucose Absorption From Baseline to 12 Weeks | -4.7 mg*hr/dL | Standard Error 36.93 |
| Open-label Insulin Glargine | The Acute Effect of Colesevelam (Multiple Doses) on Oral Glucose Absorption From Baseline to 12 Weeks | -59.3 mg*hr/dL | Standard Error 57.27 |
p-value: 0.410495% CI: [-152.8, 64.1]ANCOVA
p-value: 0.885795% CI: [-132.6, 152.9]ANCOVA
p-value: 0.422695% CI: [-191.3, 82.3]ANCOVA