Type 2 Diabetes Mellitus
Conditions
Keywords
diabetes, exenatide once weekly, Byetta, liraglutide, Victoza, Amylin, Lilly
Brief summary
No head to head comparisons between exenatide once weekly and liraglutide have been performed. Therefore, the purpose of this study is to compare exenatide once weekly to once-daily liraglutide with regard to HbA1c, body weight, subject-reported outcomes, and other clinical benefits. The study includes a 26-week treatment period and a safety follow-up visit 10 weeks after the final study drug dose.
Interventions
subcutaneous injection, 2mg, once weekly
DRUGliraglutide
subcutaneous injection, forced titration to 1.8mg, once daily
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
* Diagnosed with type 2 diabetes * Have suboptimal glycemic control as evidenced by an HbA1c measurement at study start 7.1% and 11.0%, inclusive * Have a body mass index (BMI) ≤45 kg/m\^2 * Have been treated with lifestyle modification (diet and exercise) and with one of the following single oral antidiabetic agents (OADs) or combinations of OADs administered at maximum tolerated dose: * metformin * SU * metformin plus an SU * metformin plus pioglitazone
Exclusion criteria
* Have any contraindication, allergy, or hypersensitivity for the study drug (exenatide once weekly or liraglutide), exenatide twice daily, the OAD(s) being used, or the excipients contained in these agents * If taking metformin and have a contraindication to metformin use * Have been treated within 8 weeks of study start with systemic glucocorticoid therapy by oral, intravenous, intra-articular, or intramuscular route * Have been treated with drugs that promote weight loss (e.g., Xenical® \[orlistat\], Meridia® \[sibutramine\], Acomplia® \[rimonabant\], Acutrim® \[phenylpropanolamine\], or similar over-the-counter medications) within 3 months of study start * Have taken any of the following excluded medications for more than 1 week within the 3 months prior to study start, or have taken any of the following excluded medications within 1 month prior to study start: * Insulin * Alpha-glucosidase inhibitors (e.g., Glyser® \[miglitol\] or Precose® \[acarbose\]) * Meglitinides (e.g., Prandin® \[repaglinide\] or Starlix® \[nateglinide\]) * Avandia® (rosiglitazone) * Dipeptidyl peptidase (DPP)-4 inhibitors (e.g., Januvia™ \[sitagliptin\], Galvus® \[vildagliptin\], Onglyza™ \[saxagliptin\]) * Symlin® (pramlintide acetate) * Have donated blood within 30 days prior to study start or have had a blood transfusion or severe blood loss within 3 months prior to study start * Have at any time, including a clinical trial, taken exenatide once weekly, exenatide twice daily, liraglutide, or any other GLP-1 receptor agonist or GLP-1 analog * Are currently enrolled in, or discontinued within the last 3 months or longer if required by local guidelines, from a clinical trial involving use of an investigational drug or device, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study * Have previously been screen-failed from this study for any reason * If a subject discontinues metformin, sulfonylurea, or pioglitazone prior to screening, the subject can be included if they discontinued the medication (whether alone or as component of combined medication) according to a specific schedule.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in HbA1c From Baseline to Week 26 | Baseline, Week 26 | Change in HbA1c from baseline to the treatment endpoint at Week 26. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Fasting Serum Glucose From Baseline to Week 26 | Baseline, Week 26 | Change in fasting serum glucose from baseline to the treatment endpoint at Week 26. |
| Change in Body Weight From Baseline to Week 26 | Baseline, Week 26 | Change in body weight from baseline to the treatment endpoint at Week 26. |
| Change in Total Cholesterol From Baseline to Week 26 | Baseline, Week 26 | Change in total cholesterol from baseline to the treatment endpoint at Week 26. |
| Change in High-Density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 26 | Baseline, Week 26 | Change in HDL-C from baseline to the treatment endpoint at Week 26. |
| Percentage of Patients Achieving HbA1c <7.0% at Week 26 | Baseline, Week 26 | Percentage of patients achieving HbA1c \<7.0% at treatment endpoint at Week 26. |
| Change in Systolic Blood Pressure (SBP) From Baseline to Week 26 | Baseline, Week 26 | Change in SBP from baseline to the treatment endpoint at Week 26. |
| Change in Diastolic Blood Pressure (DBP) From Baseline to Week 26 | Baseline, Week 26 | Change in DBP from baseline to the treatment endpoint at Week 26. |
| Assessment of Event Rate of Treatment-emergent Hypoglycemic Events | Baseline to Week 26 | Major hypoglycemia: any episode with symptoms consistent with hypoglycemia that resulted in loss of consciousness or seizure with prompt recovery in response to administration of glucagon or glucose OR documented hypoglycemia (blood glucose \<3.0 mmol/L \[54 mg/dL\]) and required the assistance of another person. Minor hypoglycemia: any sign or symptom associated with hypoglycemia that is either self-treated by the patient or resolves on its own AND has a concurrent finger stick blood glucose \<3.0 mmol/L (54 mg/dL) and not classified as major hypoglycemia. 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. Mean and Standard Error were then derived from ITT. |
| Ratio of Fasting Triglycerides at Week 26 to Baseline | Baseline, Week 26 | Ratio of fasting triglycerides (measured in mmol/L) treatment endpoint at Week 26 to baseline. Log(Postbaseline fasting triglycerides) - log(Baseline fasting triglycerides); change from baseline to the treatment endpoint at Week 26 is presented as ratio of Week 26 to baseline. |
Countries
Argentina, Australia, Austria, Belgium, Canada, Czechia, France, Germany, Greece, Hungary, India, Israel, Italy, Mexico, Poland, Romania, Slovakia, South Africa, South Korea, Spain, Taiwan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Exenatide Once Weekly Subcutaneous injection, 2mg, once weekly | 461 |
| Liraglutide Once Daily Subcutaneous injection, forced titration to 1.8mg, once daily | 450 |
| Total | 911 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 12 | 25 |
| Overall Study | Entry Criteria Not Met | 13 | 5 |
| Overall Study | Loss Glucose Control | 7 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Physician Decision | 2 | 6 |
| Overall Study | Protocol Violation | 17 | 5 |
| Overall Study | Sponsor Decision | 1 | 0 |
| Overall Study | Withdrawal by Subject | 8 | 18 |
Baseline characteristics
| Characteristic | Exenatide Once Weekly | Liraglutide Once Daily | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 75 Participants | 90 Participants | 165 Participants |
| Age, Categorical Between 18 and 65 years | 386 Participants | 360 Participants | 746 Participants |
| Age, Continuous | 56.6 years STANDARD_DEVIATION 9.43 | 56.7 years STANDARD_DEVIATION 9.59 | 56.6 years STANDARD_DEVIATION 9.51 |
| Background Oral Antidiabetic Agent (OAD) Metformin (MET) | 150 participants | 136 participants | 286 participants |
| Background Oral Antidiabetic Agent (OAD) MET+PIO | 16 participants | 18 participants | 34 participants |
| Background Oral Antidiabetic Agent (OAD) MET+SU | 275 participants | 277 participants | 552 participants |
| Background Oral Antidiabetic Agent (OAD) MET+SU+PIO | 1 participants | 1 participants | 2 participants |
| Background Oral Antidiabetic Agent (OAD) Pioglitazone (PIO) | 1 participants | 0 participants | 1 participants |
| Background Oral Antidiabetic Agent (OAD) Sulfonylurea (SU) | 18 participants | 18 participants | 36 participants |
| Glycosylated hemoglobin (HbA1c) | 8.45 percentage of total hemoglobin STANDARD_DEVIATION 1.014 | 8.43 percentage of total hemoglobin STANDARD_DEVIATION 0.996 | 8.44 percentage of total hemoglobin STANDARD_DEVIATION 1.004 |
| Sex: Female, Male Female | 207 Participants | 205 Participants | 412 Participants |
| Sex: Female, Male Male | 254 Participants | 245 Participants | 499 Participants |
| Weight | 90.88 kg STANDARD_DEVIATION 19.472 | 91.13 kg STANDARD_DEVIATION 19.118 | 91.00 kg STANDARD_DEVIATION 19.288 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 160 / 461 | 212 / 450 |
| serious Total, serious adverse events | 13 / 461 | 7 / 450 |
Outcome results
Primary
Change in HbA1c From Baseline to Week 26
Change in HbA1c from baseline to the treatment endpoint at Week 26.
Time frame: Baseline, Week 26
Population: ITT Population: all patients who were randomized and received study drug. All observed data from all scheduled visits (including early termination visits) were included in the mixed-model repeated measures (MMRM) analysis. Data collected at the early termination visits were mapped into the following scheduled visits.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Change in HbA1c From Baseline to Week 26 | -1.28 percentage of total hemoglobin | Standard Error 0.05 |
| Liraglutide Once Daily | Change in HbA1c From Baseline to Week 26 | -1.48 percentage of total hemoglobin | Standard Error 0.05 |
Comparison: A sample of 408 subjects in each treatment arm would provide approximately 90% power to detect a true difference between treatments of 0.25% in change in HbA1c from baseline with a 2 sided t-test at a significance level of 0.05, assuming a common standard deviation of 1.1%. MMRM model includes treatment, baseline HbA1c, HbA1c stratum, country, background OAD, week of visit, and treatment-by-week interaction as fixed effects and subject and error as random effects.p-value: 0.00295% CI: [0.08, 0.33]Mixed Models Analysis
Secondary
Assessment of Event Rate of Treatment-emergent Hypoglycemic Events
Major hypoglycemia: any episode with symptoms consistent with hypoglycemia that resulted in loss of consciousness or seizure with prompt recovery in response to administration of glucagon or glucose OR documented hypoglycemia (blood glucose \<3.0 mmol/L \[54 mg/dL\]) and required the assistance of another person. Minor hypoglycemia: any sign or symptom associated with hypoglycemia that is either self-treated by the patient or resolves on its own AND has a concurrent finger stick blood glucose \<3.0 mmol/L (54 mg/dL) and not classified as major hypoglycemia. 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. Mean and Standard Error were then derived from ITT.
Time frame: Baseline to Week 26
Population: ITT Population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide Once Weekly | Assessment of Event Rate of Treatment-emergent Hypoglycemic Events | Major Hypoglycemia | 0.00 events per subject-year | Standard Error 0 |
| Exenatide Once Weekly | Assessment of Event Rate of Treatment-emergent Hypoglycemic Events | Minor Hypoglycemia | 0.76 events per subject-year | Standard Error 0.143 |
| Liraglutide Once Daily | Assessment of Event Rate of Treatment-emergent Hypoglycemic Events | Major Hypoglycemia | 0.00 events per subject-year | Standard Error 0 |
| Liraglutide Once Daily | Assessment of Event Rate of Treatment-emergent Hypoglycemic Events | Minor Hypoglycemia | 0.55 events per subject-year | Standard Error 0.126 |
| Exenatide Once Weekly Without SU Use at Screening | Assessment of Event Rate of Treatment-emergent Hypoglycemic Events | Minor Hypoglycemia | 0.67 events per subject-year | Standard Error 0.417 |
| Exenatide Once Weekly Without SU Use at Screening | Assessment of Event Rate of Treatment-emergent Hypoglycemic Events | Major Hypoglycemia | 0.00 events per subject-year | Standard Error 0 |
| Liraglutide Once Daily Without SU Use at Screening | Assessment of Event Rate of Treatment-emergent Hypoglycemic Events | Major Hypoglycemia | 0.00 events per subject-year | Standard Error 0 |
| Liraglutide Once Daily Without SU Use at Screening | Assessment of Event Rate of Treatment-emergent Hypoglycemic Events | Minor Hypoglycemia | 0.05 events per subject-year | Standard Error 0.026 |
Secondary
Change in Body Weight From Baseline to Week 26
Change in body weight from baseline to the treatment endpoint at Week 26.
Time frame: Baseline, Week 26
Population: ITT Population. All observed data from all scheduled visits (including early termination visits) were included in the MMRM analysis. Data collected at the early termination visits were mapped into the following scheduled visits.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Change in Body Weight From Baseline to Week 26 | -2.68 kg | Standard Error 0.18 |
| Liraglutide Once Daily | Change in Body Weight From Baseline to Week 26 | -3.57 kg | Standard Error 0.18 |
Comparison: MMRM model includes treatment, baseline body weight, HbA1c stratum, country, background OAD, week of visit, and treatment-by-week interaction as fixed effects and subject and error as random effects.p-value: <0.00195% CI: [0.39, 1.4]Mixed Models Analysis
Secondary
Change in Diastolic Blood Pressure (DBP) From Baseline to Week 26
Change in DBP from baseline to the treatment endpoint at Week 26.
Time frame: Baseline, Week 26
Population: ITT Population. All observed data from all scheduled visits (including early termination visits) were included in the MMRM analysis. Data collected at the early termination visits were mapped into the following scheduled visits.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Change in Diastolic Blood Pressure (DBP) From Baseline to Week 26 | -0.49 mmHg | Standard Error 0.37 |
| Liraglutide Once Daily | Change in Diastolic Blood Pressure (DBP) From Baseline to Week 26 | -0.51 mmHg | Standard Error 0.37 |
Comparison: MMRM model includes treatment, baseline DBP, HbA1c stratum, country, background OAD, week of visit, and treatment-by-week interaction as fixed effects and subject and error as random effects.p-value: 0.98195% CI: [-0.96, 0.98]Mixed Models Analysis
Secondary
Change in Fasting Serum Glucose From Baseline to Week 26
Change in fasting serum glucose from baseline to the treatment endpoint at Week 26.
Time frame: Baseline, Week 26
Population: ITT Population. All observed data from all scheduled visits (including early termination visits) were included in the MMRM analysis. Data collected at the early termination visits were mapped into the following scheduled visits.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Change in Fasting Serum Glucose From Baseline to Week 26 | -1.76 mmol/L | Standard Error 0.11 |
| Liraglutide Once Daily | Change in Fasting Serum Glucose From Baseline to Week 26 | -2.12 mmol/L | Standard Error 0.12 |
Comparison: MMRM model includes treatment, baseline fasting serum glucose, HbA1c stratum, country, background OAD, week of visit, and treatment-by-week interaction as fixed effects and subject and error as random effects.p-value: 0.02195% CI: [0.05, 0.66]Mixed Models Analysis
Secondary
Change in High-Density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 26
Change in HDL-C from baseline to the treatment endpoint at Week 26.
Time frame: Baseline, Week 26
Population: ITT Population. All observed data from all scheduled visits (including early termination visits) were included in the MMRM analysis. Data collected at the early termination visits were mapped into the following scheduled visits.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Change in High-Density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 26 | 0.02 mmol/L | Standard Error 0.01 |
| Liraglutide Once Daily | Change in High-Density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 26 | 0.02 mmol/L | Standard Error 0.01 |
Comparison: MMRM model includes treatment, baseline HDL-C, HbA1c stratum, country, background OAD, week of visit, and treatment-by-week interaction as fixed effects and subject and error as random effects.p-value: 0.83295% CI: [-0.02, 0.02]Mixed Models Analysis
Secondary
Change in Systolic Blood Pressure (SBP) From Baseline to Week 26
Change in SBP from baseline to the treatment endpoint at Week 26.
Time frame: Baseline, Week 26
Population: ITT Population. All observed data from all scheduled visits (including early termination visits) were included in the MMRM analysis. Data collected at the early termination visits were mapped into the following scheduled visits.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Change in Systolic Blood Pressure (SBP) From Baseline to Week 26 | -2.48 mmHg | Standard Error 0.56 |
| Liraglutide Once Daily | Change in Systolic Blood Pressure (SBP) From Baseline to Week 26 | -3.45 mmHg | Standard Error 0.57 |
Comparison: MMRM model includes treatment, baseline SBP, HbA1c stratum, country, background OAD, week of visit, and treatment-by-week interaction as fixed effects and subject and error as random effects.p-value: 0.20595% CI: [-0.53, 2.47]Mixed Models Analysis
Secondary
Change in Total Cholesterol From Baseline to Week 26
Change in total cholesterol from baseline to the treatment endpoint at Week 26.
Time frame: Baseline, Week 26
Population: ITT Population. All observed data from all scheduled visits (including early termination visits) were included in the MMRM analysis. Data collected at the early termination visits were mapped into the following scheduled visits.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Change in Total Cholesterol From Baseline to Week 26 | -0.06 mmol/L | Standard Error 0.04 |
| Liraglutide Once Daily | Change in Total Cholesterol From Baseline to Week 26 | -0.15 mmol/L | Standard Error 0.04 |
Comparison: MMRM model includes treatment, baseline total cholesterol, HbA1c stratum, country, background OAD, week of visit, and treatment-by-week interaction as fixed effects and subject and error as random effects.p-value: 0.07995% CI: [-0.01, 0.19]Mixed Models Analysis
Secondary
Percentage of Patients Achieving HbA1c <7.0% at Week 26
Percentage of patients achieving HbA1c \<7.0% at treatment endpoint at Week 26.
Time frame: Baseline, Week 26
Population: ITT Population. Missing data at endpoint was imputed using last observation carried forward approach.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide Once Weekly | Percentage of Patients Achieving HbA1c <7.0% at Week 26 | 52.7 percentage of patients |
| Liraglutide Once Daily | Percentage of Patients Achieving HbA1c <7.0% at Week 26 | 60.2 percentage of patients |
Comparison: Percentage of patients achieving HbA1c \<7.0% at Week 26 were compared between treatments using a Cochran-Mantel-Haenszel test, in which HbA1c stratum, country, and background OAD served as stratification factors.p-value: 0.011Cochran-Mantel-Haenszel
Secondary
Ratio of Fasting Triglycerides at Week 26 to Baseline
Ratio of fasting triglycerides (measured in mmol/L) treatment endpoint at Week 26 to baseline. Log(Postbaseline fasting triglycerides) - log(Baseline fasting triglycerides); change from baseline to the treatment endpoint at Week 26 is presented as ratio of Week 26 to baseline.
Time frame: Baseline, Week 26
Population: ITT Population. All observed data from all scheduled visits (including early termination visits) were included in the MMRM analysis. Data collected at the early termination visits were mapped into the following scheduled visits.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Ratio of Fasting Triglycerides at Week 26 to Baseline | 0.97 ratio | Standard Error 0.02 |
| Liraglutide Once Daily | Ratio of Fasting Triglycerides at Week 26 to Baseline | 0.89 ratio | Standard Error 0.02 |
Comparison: Fasting triglycerides were logarithm-transformed and the change at Week 26 to baseline, expressed as the ratio, was analyzed using a MMRM model with treatment, baseline fasting triglycerides, HbA1c stratum, country, background OAD, week of visit, and treatment-by-week interaction as fixed effects and subject and error as random effects.p-value: <0.00195% CI: [1.04, 1.15]Mixed Models Analysis