Diabetes Mellitus
Conditions
Keywords
diabetes mellitus, Amylin, Lilly
Brief summary
A multicenter, randomized, double-blind, placebo-controlled trial will assess the effects of twice-daily subcutaneous injection with exenatide versus treatment with matching placebo injection on abdominal visceral fat content.
Interventions
DRUGplacebo
subcutaneous injection, twice a day
DRUGexenatide
subcutaneous injection, twice a day, 10mcg
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 85 Years
Healthy volunteers
No
Inclusion criteria
* Patients between 18 and 85 years of age, inclusive. * Patients with type 2 diabetes * Patients have been treated with metformin, at a stable dose for at least 3 months prior to Visit 1 * Patients have HbA1c of 7.0% to 8.9%, inclusive. * Patients have a body mass index \>27 kg/m2 and \<40 kg/m2 and meet local CT scan body weight requirements. For South Asian, Japanese, and Chinese patients, a body mass index \>=25 kg/m2 is acceptable as the lower limit. * Patients have a history of stable body weight (not varying by \>2 kg in the 3 months prior to Visit 1). * Medications for the treatment of high blood pressure are stable with respect to treatment regimen for 4 weeks prior to Visit 1. * Stable regimen of lipid-lowering agents for 6 weeks prior to Visit 1.
Exclusion criteria
* Have received treatment in the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry. * Have an active or untreated malignancy, or have been in remission from clinically significant malignancy (other than basal cell or squamous cell skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer) for less than 5 years. * Have a history of renal transplantation, or are currently receiving renal dialysis. * Have had a clinically significant history of cardiac disease or presence of active cardiac disease within 1 year prior to Visit 1, including myocardial infarction, clinically significant arrhythmia, unstable angina, moderate to severe congestive heart failure, coronary artery bypass surgery, or angioplasty; or is expected to require coronary artery bypass surgery or angioplasty during the course of the study. * Have known hemoglobinopathy or clinically significant, chronic anemia. * Known or are likely to become transfusion dependent during the study. * Have active, symptomatic proliferative retinopathy. * Are receiving chronic treatment for gastrointestinal disease with a drug directly affecting gastrointestinal motility. (i.e. metoclopramide, cisapride, and chronic use of macrolide antibiotics) * Have severe gastrointestinal disease, including gastroparesis. * Are receiving chronic (lasting longer than 2 weeks) systemic glucocorticoid therapy (excluding topical and inhaled preparations) or have received such therapy within 2 months immediately prior to Visit 1. * Have taken exenatide, liraglutide or any other GLP-1 receptor agonist in the past 6 months, either in a clinical study or as commercially available medication. Patients with known allergy to exenatide should be excluded. * Have used any prescription or over the counter drug to promote weight loss within 3 months prior to Visit 1, or intend to use such a drug during the study. (Examples: Xenical \[orlistat\], Meridia \[sibutramine\], Acutrim \[phenylpropanolamine\], Acomplia \[rimonabant\]). * Have participated in a structured weight loss program within 3 months prior to Visit 1, or intend to participate in such a plan during this study. * Have been treated for longer than 2 weeks with any of the following excluded medications within 3 months prior to Visit 1: Insulin; Thiazolidinediones; Alpha-glucosidase inhibitors; Sulfonylureas; Oral DPP-IV inhibitors; Meglitinides. * Are taking warfarin, or a coumarol derivative.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change in Abdominal Visceral Fat From Baseline to 6 Months | baseline, 6 months | Percentage change in abdominal visceral fat |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change in Subcutaneous Abdominal Fat From Baseline to 6 Months | baseline, 6 months | Percentage change in subcutaneous abdominal fat |
| Change in HbA1c From Baseline to 6 Months | baseline, 6 months | Change in HbA1c from baseline to 6 months. HbA1c is a measurement of the amount of hemogobin that is glycosylated. |
| Percentage of Patients With HbA1c <=7.0% at 6 Months | 6 months | Percentage of patients with HbA1c values \<= 7.0% measured at 6 months. HbA1c is a measurement of the amount of hemogobin that is glycosylated. |
| Change in Fasting Plasma Glucose From Baseline to 6 Months | baseline, 6 months | Change in Fasting plasma glucose |
| Change in Weight From Baseline to 6 Months | baseline, 6 months | Change in weight |
| Percentage Change in Total Abdominal Fat From Baseline to 6 Months | baseline, 6 months | Percentage change in total abdominal fat |
| Change in Diastolic Blood Pressure From Baseline to 6 Months | baseline, 6 months | Change in Diastolic blood pressure |
| Change in Total Cholesterol From Baseline to 6 Months | baseline, 6 months | Change in total cholesterol |
| Change in Triglycerides From Baseline to 6 Months | baseline, 6 months | Change in triglycerides |
| Change in High-Density Lipoprotein (HDL) Cholesterol From Baseline to 6 Months | baseline, 6 months | Change in HDL cholesterol |
| Assessment of Event Rate of Treatment- Emergent Hypoglycemic Event | baseline, 6 months | All hypoglycemia episodes defined as major (results in loss of consciousness, seizure or coma resolving after administration of glucagon or glucose OR needing third-party assistance to resolve due to severe impairment in consciousness and associated with glucose concentration \< 2.8 mol/L.) or minor (non-major event with symptoms consistent with hypoglycemia and glucose value \< 2.8 mmol/L prior to treating) or symptoms of hypoglycemia (does not meet the criteria for a major or minor event). |
| Change in Systolic Blood Pressure From Baseline to 6 Months | baseline, 6 months | Change in Systolic blood pressure |
Countries
Canada, United States
Participant flow
Recruitment details
Initial planned enrolment was 12 months, starting August 2008. Eventual enrolment time was 3+ years - decision made to close end of 2011. Number of patients initially planned: 94 randomized and 74 completers Final number of patients: 80 randomized and 53 completers
Participants by arm
| Arm | Count |
|---|---|
| Exenatide BID Subcutaneous injection of exenatide, twice a day (5 mcg exenatide per dose for first 4 weeks, then 10 mcg exenatide per dose for remainder of 6 months) | 43 |
| Placebo Subcutaneous injection of placebo twice a day for 6 months | 37 |
| Total | 80 |
Baseline characteristics
| Characteristic | Exenatide BID | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 58.2 years STANDARD_DEVIATION 12.2 | 57.9 years STANDARD_DEVIATION 11 | 58.1 years STANDARD_DEVIATION 11.6 |
| Sex: Female, Male Female | 20 Participants | 18 Participants | 38 Participants |
| Sex: Female, Male Male | 23 Participants | 19 Participants | 42 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 38 / 43 | 25 / 37 |
| serious Total, serious adverse events | 3 / 43 | 1 / 37 |
Outcome results
Primary
Percentage Change in Abdominal Visceral Fat From Baseline to 6 Months
Percentage change in abdominal visceral fat
Time frame: baseline, 6 months
Population: Primary analysis done on the Intent To Treat (ITT) Population including all randomized patients receiving at least one dose of study drug according to the treatment the subjects are randomized to regardless of what study drug patients received
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide BID | Percentage Change in Abdominal Visceral Fat From Baseline to 6 Months | -5.28 % change | Standard Error 3.23 |
| Placebo | Percentage Change in Abdominal Visceral Fat From Baseline to 6 Months | -4.30 % change | Standard Error 3.53 |
Comparison: The power calculation is based on a two-sided t-test and significance level of 0.05.~Hypotheses for sample size:~Power: 80% Drop-out rate: 20% Difference in the percentage change in abdominal visceral fat from baseline to 6 months between exenatide and placebo: 10% Common standard deviation: 15%~94 patients are needed to attain the 37 patients randomized and analyzed in each group.p-value: 0.825295% CI: [-9.92, 7.95]ANCOVA
Secondary
Assessment of Event Rate of Treatment- Emergent Hypoglycemic Event
All hypoglycemia episodes defined as major (results in loss of consciousness, seizure or coma resolving after administration of glucagon or glucose OR needing third-party assistance to resolve due to severe impairment in consciousness and associated with glucose concentration \< 2.8 mol/L.) or minor (non-major event with symptoms consistent with hypoglycemia and glucose value \< 2.8 mmol/L prior to treating) or symptoms of hypoglycemia (does not meet the criteria for a major or minor event).
Time frame: baseline, 6 months
Population: Analysis done on the ITT Population including all randomized patients receiving at least one dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide BID | Assessment of Event Rate of Treatment- Emergent Hypoglycemic Event | 0.41 hypoglycemia rate/year | Standard Error 0.15 |
| Placebo | Assessment of Event Rate of Treatment- Emergent Hypoglycemic Event | 0.12 hypoglycemia rate/year | Standard Error 0.09 |
Comparison: Event rate per subject year was calculated for each subject : (number of events observed from a subject/exposure from a subject)\*365.25 where exposure = last post-baseline visit date - baseline visit date.p-value: 0.138895% CI: [0.68, 15.77]Regression, Linear
Secondary
Change in Diastolic Blood Pressure From Baseline to 6 Months
Change in Diastolic blood pressure
Time frame: baseline, 6 months
Population: Analysis done on the ITT Population including all randomized patients receiving at least one dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide BID | Change in Diastolic Blood Pressure From Baseline to 6 Months | -2.86 mmHg | Standard Deviation 6.99 |
| Placebo | Change in Diastolic Blood Pressure From Baseline to 6 Months | -0.18 mmHg | Standard Deviation 8.97 |
Secondary
Change in Fasting Plasma Glucose From Baseline to 6 Months
Change in Fasting plasma glucose
Time frame: baseline, 6 months
Population: Analysis done on the ITT Population including all randomized patients receiving at least one dose of study drug according to the treatment the subjects are randomized to regardless of what study drug patients received. Analysis done only for patients with measurement at Month 6.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide BID | Change in Fasting Plasma Glucose From Baseline to 6 Months | -1.47 mmol/L | Standard Error 0.36 |
| Placebo | Change in Fasting Plasma Glucose From Baseline to 6 Months | -0.08 mmol/L | Standard Error 0.38 |
p-value: 0.007395% CI: [-2.38, -0.4]ANCOVA
Secondary
Change in HbA1c From Baseline to 6 Months
Change in HbA1c from baseline to 6 months. HbA1c is a measurement of the amount of hemogobin that is glycosylated.
Time frame: baseline, 6 months
Population: Analysis done on the ITT Population including all randomized patients receiving at least one dose of study drug according to the treatment the subjects are randomized to regardless of what study drug patients received. Last observation (month 6 or early discontinuation) was analysed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide BID | Change in HbA1c From Baseline to 6 Months | -0.69 % change | Standard Error 0.12 |
| Placebo | Change in HbA1c From Baseline to 6 Months | 0.19 % change | Standard Error 0.15 |
p-value: <0.000195% CI: [-1.19, -0.57]ANCOVA
Secondary
Change in High-Density Lipoprotein (HDL) Cholesterol From Baseline to 6 Months
Change in HDL cholesterol
Time frame: baseline, 6 months
Population: Analysis done on the ITT Population including all randomized patients receiving at least one dose of study drug according to the treatment the subjects are randomized to regardless of what study drug patients received
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide BID | Change in High-Density Lipoprotein (HDL) Cholesterol From Baseline to 6 Months | 0.06 mmol/L | Standard Error 0.04 |
| Placebo | Change in High-Density Lipoprotein (HDL) Cholesterol From Baseline to 6 Months | 0.04 mmol/L | Standard Error 0.04 |
p-value: 0.791595% CI: [-0.08, 0.11]ANCOVA
Secondary
Change in Systolic Blood Pressure From Baseline to 6 Months
Change in Systolic blood pressure
Time frame: baseline, 6 months
Population: Analysis done on the ITT Population including all randomized patients receiving at least one dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide BID | Change in Systolic Blood Pressure From Baseline to 6 Months | -7.48 mmHg | Standard Deviation 12.57 |
| Placebo | Change in Systolic Blood Pressure From Baseline to 6 Months | 1.79 mmHg | Standard Deviation 12.41 |
Secondary
Change in Total Cholesterol From Baseline to 6 Months
Change in total cholesterol
Time frame: baseline, 6 months
Population: Analysis done on the ITT Population including all randomized patients receiving at least one dose of study drug according to the treatment the subjects are randomized to regardless of what study drug patients received
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide BID | Change in Total Cholesterol From Baseline to 6 Months | -0.06 mmol/L | Standard Error 0.18 |
| Placebo | Change in Total Cholesterol From Baseline to 6 Months | 0.14 mmol/L | Standard Error 0.2 |
p-value: 0.414595% CI: [-0.71, 0.3]ANCOVA
Secondary
Change in Triglycerides From Baseline to 6 Months
Change in triglycerides
Time frame: baseline, 6 months
Population: Analysis done on the ITT Population including all randomized patients receiving at least one dose of study drug according to the treatment the subjects are randomized to regardless of what study drug patients received
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide BID | Change in Triglycerides From Baseline to 6 Months | -0.17 mmol/L | Standard Error 0.21 |
| Placebo | Change in Triglycerides From Baseline to 6 Months | 0.06 mmol/L | Standard Error 0.23 |
p-value: 0.400795% CI: [-0.8, 0.33]ANCOVA
Secondary
Change in Weight From Baseline to 6 Months
Change in weight
Time frame: baseline, 6 months
Population: Analysis done on the ITT Population including all randomized patients receiving at least one dose of study drug according to the treatment the subjects are randomized to regardless of what study drug patients received. Last observation (month 6 or early discontinuation) was analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide BID | Change in Weight From Baseline to 6 Months | -2.54 kg | Standard Error 0.57 |
| Placebo | Change in Weight From Baseline to 6 Months | -0.33 kg | Standard Error 0.72 |
p-value: 0.003595% CI: [-3.66, -0.76]ANCOVA
Secondary
Percentage Change in Subcutaneous Abdominal Fat From Baseline to 6 Months
Percentage change in subcutaneous abdominal fat
Time frame: baseline, 6 months
Population: Analysis done on the ITT Population including all randomized patients receiving at least one dose of study drug according to the treatment the subjects are randomized to regardless of what study drug patients received
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide BID | Percentage Change in Subcutaneous Abdominal Fat From Baseline to 6 Months | -7.27 % change | Standard Error 1.93 |
| Placebo | Percentage Change in Subcutaneous Abdominal Fat From Baseline to 6 Months | -3.56 % change | Standard Error 1.97 |
p-value: 0.175595% CI: [-9.15, 1.73]ANCOVA
Secondary
Percentage Change in Total Abdominal Fat From Baseline to 6 Months
Percentage change in total abdominal fat
Time frame: baseline, 6 months
Population: Analysis done on the ITT Population including all randomized patients receiving at least one dose of study drug according to the treatment the subjects are randomized to regardless of what study drug patients received
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide BID | Percentage Change in Total Abdominal Fat From Baseline to 6 Months | -5.81 % change | Standard Error 2.28 |
| Placebo | Percentage Change in Total Abdominal Fat From Baseline to 6 Months | -3.74 % change | Standard Error 2.36 |
p-value: 0.520795% CI: [-8.53, 4.39]ANCOVA
Secondary
Percentage of Patients With HbA1c <=7.0% at 6 Months
Percentage of patients with HbA1c values \<= 7.0% measured at 6 months. HbA1c is a measurement of the amount of hemogobin that is glycosylated.
Time frame: 6 months
Population: Analysis done on the ITT Population including all randomized patients receiving at least one dose of study drug according to the treatment the subjects are randomized to regardless of what study drug patients received.Analysis done only for patients with measurement at Month 6.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide BID | Percentage of Patients With HbA1c <=7.0% at 6 Months | 60.7 Percentage of patients |
| Placebo | Percentage of Patients With HbA1c <=7.0% at 6 Months | 21.4 Percentage of patients |