Type 2 Diabetes Mellitus
Conditions
Keywords
diabetes, exenatide once weekly, Byetta, insulin detemir, Levemir, Amylin, Lilly
Brief summary
The purpose of this study is to compare the effects of exenatide once weekly (QW) and insulin detemir with respect to glycemic control, body weight, lipids, safety, tolerability, and patient reported outcomes.
Interventions
subcutaneous injection, 2mg, once a week
DRUGinsulin detemir
subcutaneous injection, with dosage titrated according to the determir label and published titration schedule, once or twice a day
Sponsors
Eli Lilly and Company
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have suboptimal glycaemic control as evidenced by an HbA1c 7.1% to 10.0%, inclusive * Have a body mass index (BMI) of 25 kg/m2 to 45 kg/m2, inclusive * Are receiving metformin at a stable dose (consistent with country specific requirements) of a minimum of 1000mg for at least 3 months prior to start start OR are receiving metformin at a minimum dose (consistent with country specific requirements) of 1000mg and sulphonylurea (as separate medications not as a fixed dose combination) at stable doses for 3 months prior to study start
Exclusion criteria
* Have any contraindication for the OAD that they have been using * Have a known allergy or hypersensitivity to insulin detemir, exenatide or excipients contained in these agents * Have been treated within 4 weeks of screening with systemic glucocorticoid therapy by oral, intravenous (IV) or intramuscular (IM) route, or are regularly treated with potent, inhaled intranasal steroids that are known to have a high rate of systemic absorption. Exceptions to this criterion include patients who are receiving glucocorticoid therapy for corticotropic hypopituitary deficiency (e.g. Addison disease) * Have been treated with drugs that promote weight loss, within 3 months of screening * Have been treated for longer than 2 weeks with any of the following excluded medications within 3 months prior to screening: insulin, alpha-glucosidase, Byetta® (exenatide BID formulation), thiazolidinediones (TZD), dipeptidyl peptidase (DPP)-4 inhibitors * Have previously completed or withdrawn from this study or any other study investigating exenatide QW * Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry * Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an off-label use of an investigational drug or device (other than the study drug/device used in this study), or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Achieving Glycosylated Hemoglobin (HbA1c) Concentration ≤7.0% With Weight Loss (≥1.0 kg) at Endpoint (Week 26) | Baseline, Week 26 | The primary endpoint is the percentage of patients achieving HbA1c concentration ≤7.0% with weight loss (≥1.0 kg) at endpoint. The last post-baseline measurement set of both non-missing HbA1c concentration and weight (measured at the same time point, i.e. visit) is used as endpoint value. Patients who do not have a baseline weight measurement, have a protocol violation of baseline HbA1c \<=7.0%, and/or have missing post-baseline measurements for HbA1c concentration and/or weight, are included in the analysis as non-responders regarding the primary objective. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in HbA1c From Baseline to Week 26 | Baseline, Week 26 | Change in HbA1c from baseline to week 26 |
| Change in Body Weight From Baseline to Week 26 | Baseline, Week 26 | Change in body weight from baseline to week 26 |
| Percentage of Patients Achieving HbA1c ≤7.4% at Endpoint | Week 26 | Percentage of patients who have achieved HbA1c ≤.7.4% at endpoint |
| Percentage of Patients Achieving ≤7.0% at Endpoint | Week 26 | Percentage of patients achieving ≤7.0% at endpoint. |
| Percentage of Patients Achieving ≤6.5% at Endpoint | Week 26 | Percentage of patients achieving HbA1c ≤6.5% at endpoint |
| Change in Fasting Serum Glucose From Baseline to Endpoint (Week 26). | Baseline, Week 26 | Change in fasting serum glucose from baseline to endpoint (Week 26). |
| Percentage of Patients Who Have Achieved HbA1c ≤7.4% With Weight Loss (≥1.0 kg) at Endpoint (Week 26) | Baseline, Week 26 | Percentage of patients who have achieved HbA1c ≤7.4% with weight loss (≥1.0 kg) at endpoint (Week 26) |
| Change in Diastolic Blood Pressure From Baseline to Week 26. | Baseline, Week 26 | Change in diastolic blood pressure from baseline to week 26. |
| Change in Total Cholesterol From Baseline to Endpoint (Week 26). | Baseline, Week 26 | Change in total cholesterol from baseline to endpoint (week 26). |
| Change in High-density Lipoprotein (HDL) Cholesterol From Baseline to Endpoint (Week 26). | Baseline, Week 26 | Change in High-density lipoprotein (HDL) cholesterol from baseline to endpoint (week 26). |
| Change in Triglycerides From Baseline to Endpoint (Week 26). | Baseline, Week 26 | Change in triglycerides from baseline to endpoint (week 26). |
| Hypoglycemia Rate Per Year | Baseline, Week 26 | All confirmed hypoglycemia episodes defined as either minor (any time a patient feels that he or she is experiencing a sign or symptom associated with hypoglycaemia and blood glucose (BG) \<3.0 mmol/L (54 mg/dL)) or major (any hypoglycaemic episode with symptoms consistent with hypoglycaemia, resulting in loss of consciousness or seizure, and shows prompt recovery in response to administration of glucagon or glucose, or BG measurement \< 3.0mmol/L is available and the patient is not capable of self-treating were taken into account. |
| Changes in Systolic Blood Pressure From Baseline to Week 26 | Baseline, Week 26 | Change in systolic blood pressure from baseline to Week 26 |
Countries
Ireland, United Kingdom
Participant flow
Pre-assignment details
6 patients who were enrolled and randomized, subsequently discontinued the study before receiving study drug. These patients were not included in analysis.
Participants by arm
| Arm | Count |
|---|---|
| Exenatide Once Weekly Exenatide once weekly : subcutaneous injection, 2mg, once a week | 111 |
| Insulin Detemir Insulin detemir : subcutaneous injection, with dosage titrated according to the detemir label and published titration schedule, once or twice a day | 105 |
| Total | 216 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 12 | 5 |
| Overall Study | Loss of glucose control | 1 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Protocol Violation | 3 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 6 |
Baseline characteristics
| Characteristic | Exenatide Once Weekly | Total | Insulin Detemir |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 37 Participants | 64 Participants | 27 Participants |
| Age, Categorical Between 18 and 65 years | 74 Participants | 152 Participants | 78 Participants |
| Age, Continuous | 59.2 years STANDARD_DEVIATION 9.86 | 58.5 years STANDARD_DEVIATION 9.68 | 57.8 years STANDARD_DEVIATION 9.48 |
| HbA1c | 8.4 Percentage of total hemoglobin STANDARD_DEVIATION 0.85 | 8.4 Percentage of total hemoglobin STANDARD_DEVIATION 0.86 | 8.4 Percentage of total hemoglobin STANDARD_DEVIATION 0.88 |
| Sex: Female, Male Female | 40 Participants | 73 Participants | 33 Participants |
| Sex: Female, Male Male | 71 Participants | 143 Participants | 72 Participants |
| Weight | 96.7 Kilograms STANDARD_DEVIATION 17.03 | 97.3 Kilograms STANDARD_DEVIATION 16.42 | 97.9 Kilograms STANDARD_DEVIATION 15.82 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 87 / 111 | 58 / 105 |
| serious Total, serious adverse events | 6 / 111 | 6 / 105 |
Outcome results
Primary
Percentage of Patients Achieving Glycosylated Hemoglobin (HbA1c) Concentration ≤7.0% With Weight Loss (≥1.0 kg) at Endpoint (Week 26)
The primary endpoint is the percentage of patients achieving HbA1c concentration ≤7.0% with weight loss (≥1.0 kg) at endpoint. The last post-baseline measurement set of both non-missing HbA1c concentration and weight (measured at the same time point, i.e. visit) is used as endpoint value. Patients who do not have a baseline weight measurement, have a protocol violation of baseline HbA1c \<=7.0%, and/or have missing post-baseline measurements for HbA1c concentration and/or weight, are included in the analysis as non-responders regarding the primary objective.
Time frame: Baseline, Week 26
Population: The full analysis set (FAS) includes all data from all randomised patients receiving at least one dose of the study drug according to the treatment the patients were assigned.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide Once Weekly | Percentage of Patients Achieving Glycosylated Hemoglobin (HbA1c) Concentration ≤7.0% With Weight Loss (≥1.0 kg) at Endpoint (Week 26) | 44.1 Percentage |
| Insulin Detemir | Percentage of Patients Achieving Glycosylated Hemoglobin (HbA1c) Concentration ≤7.0% With Weight Loss (≥1.0 kg) at Endpoint (Week 26) | 11.4 Percentage |
Comparison: Primary objective: to test hypothesis that the percentage of patients with HbA1c ≤7.0% with weight loss (≥1.0 kg) after exenatide QW is superior to insulin detemir.~Sample size estimation: based on the test for difference in percentage between Exenatide QW and insulin detemir. Assuming: common drop-out rate 20%, response rate at endpoint 50% in the exenatide QW group and 25% in the insulin detemir group; 5% significance. 214 patients will provide 90% power to detect a difference.p-value: <0.000195% CI: [3.17, 13.73]Regression, Logistic
Secondary
Change in Body Weight From Baseline to Week 26
Change in body weight from baseline to week 26
Time frame: Baseline, Week 26
Population: The analysis was done for the FAS population (as randomised).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Change in Body Weight From Baseline to Week 26 | -2.79 kilograms | Standard Error 0.347 |
| Insulin Detemir | Change in Body Weight From Baseline to Week 26 | 0.88 kilograms | Standard Error 0.351 |
Comparison: Mixed model repeated measures MMRM) includes baseline value as covariate, study treatment, use of SU (yes/no), baseline HbA1c stratum, week of visit and treatment-by-week interaction as fixed effects and patient and error as random effects.p-value: <0.000195% CI: [-4.63, -2.71]Mixed Models Analysis
Secondary
Change in Diastolic Blood Pressure From Baseline to Week 26.
Change in diastolic blood pressure from baseline to week 26.
Time frame: Baseline, Week 26
Population: The analysis was done for the FAS population (as randomised).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Change in Diastolic Blood Pressure From Baseline to Week 26. | -0.79 mmHg | Standard Error 0.855 |
| Insulin Detemir | Change in Diastolic Blood Pressure From Baseline to Week 26. | -0.34 mmHg | Standard Error 0.859 |
Comparison: Mixed model repeated measures (MMRM) includes baseline value as covariate, study treatment, use of SU (yes/no), baseline HbA1c stratum, week of visit and treatment-by-week interaction as fixed effects and patient and error as random effects.p-value: 0.703495% CI: [-2.77, 1.88]Mixed Models Analysis
Secondary
Change in Fasting Serum Glucose From Baseline to Endpoint (Week 26).
Change in fasting serum glucose from baseline to endpoint (Week 26).
Time frame: Baseline, Week 26
Population: The analysis was done for the FAS population (as randomised).~The last observation carried forward (LOCF) of post baseline values was used for this analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Change in Fasting Serum Glucose From Baseline to Endpoint (Week 26). | -2.33 mmol/L | Standard Error 0.191 |
| Insulin Detemir | Change in Fasting Serum Glucose From Baseline to Endpoint (Week 26). | -2.43 mmol/L | Standard Error 0.196 |
Comparison: ANCOVA model includes treatment group, baseline value, use of SU (yes/no) and baseline HbA1c stratum as factors.p-value: 0.699395% CI: [-0.41, 0.61]ANCOVA
Secondary
Change in HbA1c From Baseline to Week 26
Change in HbA1c from baseline to week 26
Time frame: Baseline, Week 26
Population: The analysis was done for the FAS population (as randomised).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Change in HbA1c From Baseline to Week 26 | -1.32 Percentage of total hemoglobin | Standard Error 0.076 |
| Insulin Detemir | Change in HbA1c From Baseline to Week 26 | -0.91 Percentage of total hemoglobin | Standard Error 0.077 |
Comparison: Mixed model repeated measures (MMRM) includes baseline value as covariate, study treatment, use of SU (yes/no), week of visit and treatment-by-week interaction as fixed effects and patient and error as random effects.p-value: 0.000195% CI: [-0.62, -0.2]Mixed Models Analysis
Secondary
Change in High-density Lipoprotein (HDL) Cholesterol From Baseline to Endpoint (Week 26).
Change in High-density lipoprotein (HDL) cholesterol from baseline to endpoint (week 26).
Time frame: Baseline, Week 26
Population: The analysis was done for the FAS population (as randomised). The last observation carried forward (LOCF) of post baseline values was used for this analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Change in High-density Lipoprotein (HDL) Cholesterol From Baseline to Endpoint (Week 26). | 0.02 mmol/L | Standard Error 0.014 |
| Insulin Detemir | Change in High-density Lipoprotein (HDL) Cholesterol From Baseline to Endpoint (Week 26). | 0.04 mmol/L | Standard Error 0.015 |
Comparison: ANCOVA model includes treatment group, baseline value, use of SU (yes/no) and baseline HbA1c stratum as factors.p-value: 0.463895% CI: [-0.05, 0.02]ANCOVA
Secondary
Change in Total Cholesterol From Baseline to Endpoint (Week 26).
Change in total cholesterol from baseline to endpoint (week 26).
Time frame: Baseline, Week 26
Population: The analysis was done for the FAS population (as randomised).~The last observation carried forward (LOCF) of post baseline values was used for this analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Change in Total Cholesterol From Baseline to Endpoint (Week 26). | -0.09 mmol/L | Standard Error 0.067 |
| Insulin Detemir | Change in Total Cholesterol From Baseline to Endpoint (Week 26). | 0.06 mmol/L | Standard Error 0.068 |
Comparison: ANCOVA model includes treatment group, baseline value, use of SU (yes/no) and baseline HbA1c stratum as factors.p-value: 0.106195% CI: [-0.32, 0.03]ANCOVA
Secondary
Change in Triglycerides From Baseline to Endpoint (Week 26).
Change in triglycerides from baseline to endpoint (week 26).
Time frame: Baseline, Week 26
Population: The analysis was done for the FAS population (as randomised). The last observation carried forward (LOCF) of post baseline values was used for this analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Change in Triglycerides From Baseline to Endpoint (Week 26). | -0.01 mmol/L | Standard Error 0.079 |
| Insulin Detemir | Change in Triglycerides From Baseline to Endpoint (Week 26). | -0.08 mmol/L | Standard Error 0.081 |
Comparison: ANCOVA model includes treatment group, baseline value, use of SU (yes/no) and baseline HbA1c stratum as factors.p-value: 0.496795% CI: [-0.14, 0.28]ANCOVA
Secondary
Changes in Systolic Blood Pressure From Baseline to Week 26
Change in systolic blood pressure from baseline to Week 26
Time frame: Baseline, Week 26
Population: The analysis was done for the FAS population (as randomised).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Changes in Systolic Blood Pressure From Baseline to Week 26 | -7.37 mmHg | Standard Error 1.342 |
| Insulin Detemir | Changes in Systolic Blood Pressure From Baseline to Week 26 | -2.65 mmHg | Standard Error 1.339 |
Comparison: Mixed model repeated measures (MMRM) includes baseline value as covariate, study treatment, use of SU (yes/no), baseline HbA1c stratum, week of visit and treatment-by-week interaction as fixed effects and patient and error as random effects.p-value: 0.011695% CI: [-8.37, -1.07]Mixed Models Analysis
Secondary
Hypoglycemia Rate Per Year
All confirmed hypoglycemia episodes defined as either minor (any time a patient feels that he or she is experiencing a sign or symptom associated with hypoglycaemia and blood glucose (BG) \<3.0 mmol/L (54 mg/dL)) or major (any hypoglycaemic episode with symptoms consistent with hypoglycaemia, resulting in loss of consciousness or seizure, and shows prompt recovery in response to administration of glucagon or glucose, or BG measurement \< 3.0mmol/L is available and the patient is not capable of self-treating were taken into account.
Time frame: Baseline, Week 26
Population: Full analysis set (as randomized).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide Once Weekly | Hypoglycemia Rate Per Year | 0.06 events per subject-year |
| Insulin Detemir | Hypoglycemia Rate Per Year | 0.10 events per subject-year |
Comparison: The number of episodes by patient were compared between treatment groups using a poisson model with effects for treatment and baseline HbA1c and the logarithm of the days of exposure as the offset variable.p-value: 0.324795% CI: [0.19, 1.72]Poisson regression
Secondary
Percentage of Patients Achieving ≤6.5% at Endpoint
Percentage of patients achieving HbA1c ≤6.5% at endpoint
Time frame: Week 26
Population: The analysis was done for the FAS population (as randomised). Patients with baseline HbA1c ≤7.0% and/or no post-baseline HbA1c measurement were regarded as non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide Once Weekly | Percentage of Patients Achieving ≤6.5% at Endpoint | 27.9 Percentage |
| Insulin Detemir | Percentage of Patients Achieving ≤6.5% at Endpoint | 7.6 Percentage |
Comparison: Logistic regression model includes independent variables treatment group, use of SU (yes/no), and baseline HbA1c.p-value: 0.000295% CI: [2.1, 11.35]Regression, Logistic
Secondary
Percentage of Patients Achieving ≤7.0% at Endpoint
Percentage of patients achieving ≤7.0% at endpoint.
Time frame: Week 26
Population: The analysis was done for the FAS population (as randomised). Patients with baseline HbA1c ≤7.0% and/or no post-baseline HbA1c measurement were regarded as non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide Once Weekly | Percentage of Patients Achieving ≤7.0% at Endpoint | 51.4 Percentage |
| Insulin Detemir | Percentage of Patients Achieving ≤7.0% at Endpoint | 34.3 Percentage |
Comparison: Logistic regression model includes independent variables treatment group, use of SU (yes/no), and baseline HbA1c.p-value: 0.007495% CI: [1.24, 3.96]Regression, Logistic
Secondary
Percentage of Patients Achieving HbA1c ≤7.4% at Endpoint
Percentage of patients who have achieved HbA1c ≤.7.4% at endpoint
Time frame: Week 26
Population: The analysis was done for the FAS population (as randomised). Patients with baseline HbA1c ≤7.0% and/or no post-baseline HbA1c measurement were regarded as non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide Once Weekly | Percentage of Patients Achieving HbA1c ≤7.4% at Endpoint | 66.7 Percentage |
| Insulin Detemir | Percentage of Patients Achieving HbA1c ≤7.4% at Endpoint | 54.3 Percentage |
Comparison: Logistic regression model includes independent variables treatment group, use of SU (yes/no), and baseline HbA1c.p-value: 0.049795% CI: [1, 3.18]Regression, Logistic
Secondary
Percentage of Patients Who Have Achieved HbA1c ≤7.4% With Weight Loss (≥1.0 kg) at Endpoint (Week 26)
Percentage of patients who have achieved HbA1c ≤7.4% with weight loss (≥1.0 kg) at endpoint (Week 26)
Time frame: Baseline, Week 26
Population: The analysis was done for the FAS population (as randomised). For secondary analyses including both final HbA1c concentration and change in weight the last post-baseline measurement set of both non-missing HbA1c and weight was used as endpoint value.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide Once Weekly | Percentage of Patients Who Have Achieved HbA1c ≤7.4% With Weight Loss (≥1.0 kg) at Endpoint (Week 26) | 58.9 Percentage |
| Insulin Detemir | Percentage of Patients Who Have Achieved HbA1c ≤7.4% With Weight Loss (≥1.0 kg) at Endpoint (Week 26) | 17.8 Percentage |
p-value: <0.000195% CI: [3.64, 13.7]Regression, Logistic