Type 2 Diabetes Mellitus
Conditions
Keywords
diabetes, exenatide, metformin, thiazolidinedione, Byetta, Amylin, Lilly
Brief summary
This study will assess safety and efficacy of exenatide in combination with a thiazolidinedione (TZD) and a TZD plus metformin over 26 weeks in adult patients with type 2 diabetes who have not achieved adequate glycemic control.
Interventions
DRUGexenatide
subcutaneous injection, 5 mcg or 10 mcg, twice a day (BID)
DRUGplacebo
subcutaneous injection, volume equivalent to 5 mcg or 10 mcg of active drug, twice a day
Sponsors
Eli Lilly and Company
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosed with type 2 diabetes * If treated with a thiazolidinedione (TZD) alone, the TZD dose must have been stable for at least 120 days * The dose of TZD must be: Rosiglitazone (≥4 mg/day) or pioglitazone (≥30 mg/day) * The metformin dose has been stable for at least 90 days * Have suboptimal glycemic control as evidenced by an HbA1c between 7.1% and 10.0%, inclusive. * Have a body mass index (BMI): 25 kg/m2 \< BMI \< 45 kg/m2.
Exclusion criteria
* Have participated in this study previously or any other study using exenatide (AC2993/LY2148568) or glucagon-like peptide-1 (GLP-1) analogs, or have been previously treated with exenatide or GLP-1 analogs * Have participated in an interventional medical, surgical, or pharmaceutical study (a study in which an experimental, drug, medical, or surgical treatment was given) within 30 days of screening. This criterion includes drugs that have not received regulatory approval for any indication at the time of study entry. * Have been treated with exogenous insulin for more than 1 week within the 2 months prior to screening * Used drugs for weight loss (e.g., orlistat, rimonabant, sibutramine, or similar over-the-counter medications) within 3 months prior to screening. * Are currently treated with any of the following excluded medications: * Sulfonylurea or meglitinide derivatives (e.g., repaglinide or nateglinide) within 3 months prior to screening * Alpha-glucosidase inhibitor (e.g., miglitol or acarbose) within 3 months of screening * Dipeptidyl peptidase-4 (DPP-4) inhibitors (e.g., sitagliptin or vildagliptin) within 3 months prior to screening * Pramlintide acetate injection within 3 months prior to screening * Drugs that directly affect gastrointestinal motility, including, but not limited to: Metoclopramide, cisapride, and chronic macrolide antibiotics * Are receiving chronic (lasting longer than 2 weeks) systemic glucocorticoid therapy (excluding topical and inhaled preparations) or have received such therapy within the 4 weeks immediately preceding study start
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Glycosylated Hemoglobin (HbA1c) | baseline and 26 weeks | Change in HbA1c from baseline to endpoint after 26 weeks of treatment (i.e., HbA1c at endpoint minus HbA1c at baseline) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Achieving HbA1c <= 6.5% | 26 weeks | Percentage of ITT patients who had achieved HbA1c \<= 6.5% at endpoint (Week 26 or early discontinuation) |
| Change in Fasting Serum Glucose (FSG) | baseline and 26 weeks | Change in FSG from baseline to endpoint (26 weeks) |
| Change in Body Weight | baseline and 26 weeks | Change in body weight from baseline to endpoint (26 weeks) |
| Change in Waist Circumference | baseline and 26 weeks | Change in waist circumference from baseline to endpoint (26 weeks) |
| Percentage of Patients Achieving HbA1c <= 7% | 26 weeks | Percentage of intent-to-treat (ITT) patients who had HbA1c \> 7% at baseline that decreased to \<= 7% at endpoint (Week 26 or early discontinuation) |
| Change in Insulin Sensitivity. | baseline and 26 weeks | Change in homeostatic model assessment-insulin sensitivity (HOMA-S) from baseline to endpoint (26 weeks) (outcome measure is presented as the ratio of endpoint HOMA-S divided by baseline HOMA-S). |
| Number of Subjects Who Experienced an Episode of Minor Hypoglycemia | 26 weeks | Overall number of subjects who experienced an episode of minor hypoglycemia. |
| Change in Impact of Weight on Quality of Life (IWQOL)-Lite Score | baseline and 26 weeks | IWQOL-Lite analysis of change from baseline to endpoint (26 weeks). IWQOL-Lite is a 31-item questionnaire, assessing the domains of physical function, self-esteem, sexual life, public distress, and work. Response categories for each item range from 1 = never true to 5 = always true. |
| Change in Euroqol - 5 Domain Quality of Life (EQ-5D) Score | baseline and 26 weeks | EQ-5D Score - change from baseline to endpoint (26 weeks). EQ-5D is a 5-item questionnaire used to characterize current health states. The tool and accompanying visual analog scale (VAS) assess 5 domains of quality of life, including mobility, self-care, usual activity, pain, and anxiety/depression. Weights are used to score the responses to the 5 domains, with 3 options possible in each domain: extreme problems, some/moderate problems, or no problems. Scores range from 0 to 1, with a score of 1 representing a perfect health state. |
| Change in Beta-cell Function | baseline and 26 weeks | Change in homeostatic model assessment-beta cell (HOMA-B) from baseline to endpoint (Week 26) (outcome measure is presented as the ratio of endpoint HOMA-B divided by baseline HOMA-B). HOMA-B is a measure of pancreatic beta-cell function. |
Countries
Canada, Mexico, Romania, South Africa, United States
Participant flow
Pre-assignment details
A total of 165 patients, experiencing inadequate glycemic control using a thiazolidinedione (TZD) alone or in combination with metformin, following a 2-week placebo lead-in period, were randomly assigned in a proportion of 2:1 to add exenatide (111 patients) or placebo (54 patients) to their current therapy regimen.
Participants by arm
| Arm | Count |
|---|---|
| Exenatide Twice Daily (BID) Exenatide 5 mcg twice daily for 4 weeks, followed by 10 mcg twice daily for 22 weeks | 111 |
| Placebo Placebo equivalent volume to exenatide 5 mcg for 4 weeks, follwed by placebo equivalent volume to exenatide 10 mcg twice daily for 22 weeks | 54 |
| Total | 165 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 1 |
| Overall Study | Entry criteria not met | 0 | 1 |
| Overall Study | Loss of glucose control | 3 | 0 |
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | Physician Decision | 2 | 0 |
| Overall Study | Protocol Violation | 2 | 0 |
| Overall Study | Subject decision | 2 | 1 |
Baseline characteristics
| Characteristic | Exenatide Twice Daily (BID) | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 14 Participants | 7 Participants | 21 Participants |
| Age, Categorical Between 18 and 65 years | 97 Participants | 47 Participants | 144 Participants |
| Age, Continuous | 54.93 years STANDARD_DEVIATION 8.27 | 54.12 years STANDARD_DEVIATION 9.36 | 54.67 years STANDARD_DEVIATION 8.62 |
| Sex: Female, Male Female | 44 Participants | 23 Participants | 67 Participants |
| Sex: Female, Male Male | 67 Participants | 31 Participants | 98 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 22 / 111 | 1 / 54 |
| serious Total, serious adverse events | 1 / 111 | 0 / 54 |
Outcome results
Primary
Change in Glycosylated Hemoglobin (HbA1c)
Change in HbA1c from baseline to endpoint after 26 weeks of treatment (i.e., HbA1c at endpoint minus HbA1c at baseline)
Time frame: baseline and 26 weeks
Population: The number of participants was determined based on sample size calculations using parameter estimates from prior study H8O-MC-GWAP (NCT00099320), with change from baseline HbA1c as the primary efficacy measure. Primary analysis is reported for intent to treat population (ITT), last observation carried forward (LOCF).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Twice Daily (BID) | Change in Glycosylated Hemoglobin (HbA1c) | -0.84 Percentage | Standard Error 0.2 |
| Placebo | Change in Glycosylated Hemoglobin (HbA1c) | -0.10 Percentage | Standard Error 0.23 |
Comparison: Null hypothesis = Change from baseline in HbA1c is equal between the two treatment groups. Greater than 99% power to detect a difference between treatment groups of 0.88% in change in HbA1c from baseline using a 2-sided t-test at a significance level of 0.05.p-value: <0.001ANCOVA
Secondary
Change in Beta-cell Function
Change in homeostatic model assessment-beta cell (HOMA-B) from baseline to endpoint (Week 26) (outcome measure is presented as the ratio of endpoint HOMA-B divided by baseline HOMA-B). HOMA-B is a measure of pancreatic beta-cell function.
Time frame: baseline and 26 weeks
Population: Based on primary efficacy sample size calculations. Analyses performed on ITT patient population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Twice Daily (BID) | Change in Beta-cell Function | 1.08 ratio | Standard Error 0.12 |
| Placebo | Change in Beta-cell Function | 0.84 ratio | Standard Error 0.11 |
Comparison: Null hypothesis = Change form baseline in HOMA-B is equal between the two treatment groups.p-value: 0.009ANCOVA
Secondary
Change in Body Weight
Change in body weight from baseline to endpoint (26 weeks)
Time frame: baseline and 26 weeks
Population: Based on primary efficacy sample size calculations. Analyses performed on ITT patient population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Twice Daily (BID) | Change in Body Weight | -1.43 kg | Standard Error 0.61 |
| Placebo | Change in Body Weight | -0.75 kg | Standard Error 0.7 |
Comparison: Null hypothesis = Change from baseline to endpoint in body weight is equal between the two treatment groups.p-value: 0.176ANCOVA
Secondary
Change in Euroqol - 5 Domain Quality of Life (EQ-5D) Score
EQ-5D Score - change from baseline to endpoint (26 weeks). EQ-5D is a 5-item questionnaire used to characterize current health states. The tool and accompanying visual analog scale (VAS) assess 5 domains of quality of life, including mobility, self-care, usual activity, pain, and anxiety/depression. Weights are used to score the responses to the 5 domains, with 3 options possible in each domain: extreme problems, some/moderate problems, or no problems. Scores range from 0 to 1, with a score of 1 representing a perfect health state.
Time frame: baseline and 26 weeks
Population: Based on primary efficacy sample size calculations. Analyses performed on ITT patient population.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide Twice Daily (BID) | Change in Euroqol - 5 Domain Quality of Life (EQ-5D) Score | Change in Health State Score | 0.79 units on a scale | Standard Error 3.54 |
| Exenatide Twice Daily (BID) | Change in Euroqol - 5 Domain Quality of Life (EQ-5D) Score | Change in Mobility component | 0.14 units on a scale | Standard Error 0.15 |
| Exenatide Twice Daily (BID) | Change in Euroqol - 5 Domain Quality of Life (EQ-5D) Score | Change in Self Care component | 0.08 units on a scale | Standard Error 0.14 |
| Exenatide Twice Daily (BID) | Change in Euroqol - 5 Domain Quality of Life (EQ-5D) Score | Change Usual Activities component | 0.17 units on a scale | Standard Error 0.15 |
| Exenatide Twice Daily (BID) | Change in Euroqol - 5 Domain Quality of Life (EQ-5D) Score | Change in Pain/Discomfort component | 0.29 units on a scale | Standard Error 0.16 |
| Exenatide Twice Daily (BID) | Change in Euroqol - 5 Domain Quality of Life (EQ-5D) Score | Change in Anxiety/Depression component | -0.10 units on a scale | Standard Error 0.16 |
| Placebo | Change in Euroqol - 5 Domain Quality of Life (EQ-5D) Score | Change in Pain/Discomfort component | 0.23 units on a scale | Standard Error 0.18 |
| Placebo | Change in Euroqol - 5 Domain Quality of Life (EQ-5D) Score | Change in Health State Score | -2.94 units on a scale | Standard Error 3.97 |
| Placebo | Change in Euroqol - 5 Domain Quality of Life (EQ-5D) Score | Change Usual Activities component | 0.19 units on a scale | Standard Error 0.17 |
| Placebo | Change in Euroqol - 5 Domain Quality of Life (EQ-5D) Score | Change in Mobility component | 0.15 units on a scale | Standard Error 0.17 |
| Placebo | Change in Euroqol - 5 Domain Quality of Life (EQ-5D) Score | Change in Anxiety/Depression component | -0.26 units on a scale | Standard Error 0.18 |
| Placebo | Change in Euroqol - 5 Domain Quality of Life (EQ-5D) Score | Change in Self Care component | 0.03 units on a scale | Standard Error 0.16 |
Comparison: Null hypothesis = Change from baseline in EQ-5D score is equal between the two treatment groups. This statistical analysis is for the EQ-5D Health State Score only.p-value: 0.186ANCOVA
Secondary
Change in Fasting Serum Glucose (FSG)
Change in FSG from baseline to endpoint (26 weeks)
Time frame: baseline and 26 weeks
Population: Based on primary efficacy sample size calculations. Analyses performed on ITT patient population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Twice Daily (BID) | Change in Fasting Serum Glucose (FSG) | -0.65 mmol/L | Standard Error 0.46 |
| Placebo | Change in Fasting Serum Glucose (FSG) | 0.37 mmol/L | Standard Error 0.52 |
Comparison: Null hypothesis = Change from baseline in FSG is equal between the two treatment groups.p-value: 0.009ANCOVA
Secondary
Change in Impact of Weight on Quality of Life (IWQOL)-Lite Score
IWQOL-Lite analysis of change from baseline to endpoint (26 weeks). IWQOL-Lite is a 31-item questionnaire, assessing the domains of physical function, self-esteem, sexual life, public distress, and work. Response categories for each item range from 1 = never true to 5 = always true.
Time frame: baseline and 26 weeks
Population: Based on primary efficacy sample size calculations. Analyses performed on ITT patient population.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide Twice Daily (BID) | Change in Impact of Weight on Quality of Life (IWQOL)-Lite Score | Change in Total Score | -1.56 units on a scale | Standard Error 2.21 |
| Exenatide Twice Daily (BID) | Change in Impact of Weight on Quality of Life (IWQOL)-Lite Score | Change in Physical Function component | -3.84 units on a scale | Standard Error 3.06 |
| Exenatide Twice Daily (BID) | Change in Impact of Weight on Quality of Life (IWQOL)-Lite Score | Change in Self-Esteem component | 0.20 units on a scale | Standard Error 2.92 |
| Exenatide Twice Daily (BID) | Change in Impact of Weight on Quality of Life (IWQOL)-Lite Score | Change in Sexual Life component | 0.12 units on a scale | Standard Error 5.52 |
| Exenatide Twice Daily (BID) | Change in Impact of Weight on Quality of Life (IWQOL)-Lite Score | Change in Public Distress component | -0.48 units on a scale | Standard Error 2.61 |
| Exenatide Twice Daily (BID) | Change in Impact of Weight on Quality of Life (IWQOL)-Lite Score | Change in Work component | -0.91 units on a scale | Standard Error 2.41 |
| Placebo | Change in Impact of Weight on Quality of Life (IWQOL)-Lite Score | Change in Public Distress component | -0.28 units on a scale | Standard Error 2.92 |
| Placebo | Change in Impact of Weight on Quality of Life (IWQOL)-Lite Score | Change in Total Score | 0.11 units on a scale | Standard Error 2.49 |
| Placebo | Change in Impact of Weight on Quality of Life (IWQOL)-Lite Score | Change in Sexual Life component | 5.01 units on a scale | Standard Error 6.12 |
| Placebo | Change in Impact of Weight on Quality of Life (IWQOL)-Lite Score | Change in Physical Function component | -1.05 units on a scale | Standard Error 3.43 |
| Placebo | Change in Impact of Weight on Quality of Life (IWQOL)-Lite Score | Change in Work component | 0.08 units on a scale | Standard Error 2.71 |
| Placebo | Change in Impact of Weight on Quality of Life (IWQOL)-Lite Score | Change in Self-Esteem component | -0.54 units on a scale | Standard Error 3.28 |
Comparison: Null hypothesis = Change from baseline in IWQOL-Lite Total Score is equal between the two treatment groups. This statistical analysis is for the Total Score only.p-value: 0.342ANCOVA
Secondary
Change in Insulin Sensitivity.
Change in homeostatic model assessment-insulin sensitivity (HOMA-S) from baseline to endpoint (26 weeks) (outcome measure is presented as the ratio of endpoint HOMA-S divided by baseline HOMA-S).
Time frame: baseline and 26 weeks
Population: Based on primary efficacy sample size calculations. Analyses performed on ITT patient population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Twice Daily (BID) | Change in Insulin Sensitivity. | 1.09 ratio | Standard Error 0.11 |
| Placebo | Change in Insulin Sensitivity. | 1.07 ratio | Standard Error 0.13 |
Comparison: Null hypothesis = Change from baseline in HOMA-S is equal between the two treatment groups.p-value: 0.794ANCOVA
Secondary
Change in Waist Circumference
Change in waist circumference from baseline to endpoint (26 weeks)
Time frame: baseline and 26 weeks
Population: Based on primary efficacy sample size calculations. Analyses performed on ITT patient population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Twice Daily (BID) | Change in Waist Circumference | -2.26 cm | Standard Deviation 3.83 |
| Placebo | Change in Waist Circumference | -1.85 cm | Standard Deviation 3.75 |
Secondary
Number of Subjects Who Experienced an Episode of Minor Hypoglycemia
Overall number of subjects who experienced an episode of minor hypoglycemia.
Time frame: 26 weeks
Population: Based on primary efficacy sample size calculations. Analyses performed on ITT patient population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide Twice Daily (BID) | Number of Subjects Who Experienced an Episode of Minor Hypoglycemia | 4 Participants |
| Placebo | Number of Subjects Who Experienced an Episode of Minor Hypoglycemia | 1 Participants |
Comparison: Null hypothesis = Incidence of minor hypoglycemia episodes is equal between the two treatment groups.p-value: 1Fisher Exact
Secondary
Percentage of Patients Achieving HbA1c <= 6.5%
Percentage of ITT patients who had achieved HbA1c \<= 6.5% at endpoint (Week 26 or early discontinuation)
Time frame: 26 weeks
Population: Based on primary efficacy sample size calculations. Analyses performed on ITT patient population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide Twice Daily (BID) | Percentage of Patients Achieving HbA1c <= 6.5% | 33.6 percentage of participants |
| Placebo | Percentage of Patients Achieving HbA1c <= 6.5% | 13.0 percentage of participants |
Comparison: Null hypothesis = Proportion of subjects achieving HbA1c \<= 6.5% is equal between the two treatment groups.p-value: 0.004CMH test
Secondary
Percentage of Patients Achieving HbA1c <= 7%
Percentage of intent-to-treat (ITT) patients who had HbA1c \> 7% at baseline that decreased to \<= 7% at endpoint (Week 26 or early discontinuation)
Time frame: 26 weeks
Population: Based on primary efficacy sample size calculations. Analyses performed on ITT patient population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide Twice Daily (BID) | Percentage of Patients Achieving HbA1c <= 7% | 49.0 percentage of participants |
| Placebo | Percentage of Patients Achieving HbA1c <= 7% | 36.5 percentage of participants |
Comparison: Null hypothesis = Proportion of subjects with HbA1c \<= 7% is equal between the two treatment groups.p-value: 0.113CMH test