Type 2 Diabetes Mellitus
Conditions
Keywords
exenatide, diabetes, Amylin, Lilly, glimepiride
Brief summary
This study assesses the effects of twice-daily subcutaneous injection exenatide versus treatment with sulfonylurea (glimepiride) on long-term glycemic control and beta-cell function.
Interventions
DRUGexenatide
subcutaneous injection (5mcg or 10mcg), twice a day
DRUGglimepiride
oral tablet (titrated to maximally tolerated dose), 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 85 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosed with type 2 diabetes mellitus. * Treated with diet and exercise and a stable, maximally tolerated dose of metformin for at least 3 months prior to screening. * HbA1c \>=6.5% and \<=9.0%. * Body Mass Index (BMI) \>=25 kg/m\^2 and \<40 kg/m\^2.
Exclusion criteria
* Participated in an interventional medical, surgical, or pharmaceutical study within 30 days prior to screening. * Characteristics contraindicating metformin or glimepiride use. * Receiving drugs that directly affect gastrointestinal motility. * Receiving chronic (lasting longer than 2 weeks) systemic glucocorticoid therapy. * Have used any prescription drug to promote weight loss within 3 months prior to screening. * Treated for longer than 2 weeks with any of the following medications within 3 months prior to screening: \*insulin; \*thiazolidinediones; \*alpha-glucosidase inhibitors; \*sulfonylurea; \*meglitinides
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Treatment Failure | Baseline to end of Period II (up to 4.5 years) | Treatment failure is defined as one of the following:1. HbA1c exceeding 9% at any visit after the initial 3 months of treatment (i.e., earliest at Month 6), on the maximally tolerated dose of antidiabetic agents. 2. HbA1c exceeding 7% at 2 consecutive visits 3 months apart, after the initial 6 months of treatment (i.e., earliest at Month 9), on the maximally tolerated dose of antidiabetic agents. |
| Time to Treatment Failure | Baseline to end of Period II (up to 4.5 years) | Treatment failure is defined as one of the following:1. HbA1c exceeding 9% at any visit after the initial 3 months of treatment (i.e., earliest at Month 6), on the maximally tolerated dose of antidiabetic agents. 2. HbA1c exceeding 7% at 2 consecutive visits 3 months apart, after the initial 6 months of treatment (i.e., earliest at Month 9), on the maximally tolerated dose of antidiabetic agents. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Fasting Proinsulin/Insulin Ratio at Year 3 | Year 3 in Period II | Fasting proinsulin (measured in pmol/L)/insulin (measured in pmol/L) ratio at Year 3. |
| Change in Fasting Proinsulin/Insulin Ratio From Baseline to Endpoint. | Baseline, end of Period II (up to 4.5 years) | Change in fasting proinsulin (measured in pmol/L)/insulin (measured in pmol/L) ratio from baseline to endpoint. |
| Ratio of the 30 Minute Increment in Plasma Insulin Concentration and the 30 Minute Increment in Plasma Glucose During the Oral Glucose Tolerance Test (DI30/DG30 Ratio) at Year 3 | Year 3 in Period II | DI30/DG30 at Year 3. DI30/DG30 ratio was calculated as (30 minute post prandial insulin - fasting insulin) (measured in pmol/L)/(30 minute post prandial glucose - fasting glucose) (measured in mmol/L). |
| Change in DI30/DG30 Ratio From Baseline to Endpoint | Baseline, end of Period II (up to 4.5 years) | Change in DI30/DG30 ratio from baseline to endpoint. |
| Disposition Index at Year 3 | Year 3 in Period II | Disposition Index at Year 3. Disposition index was calculated as (DI30/DG30 ratio)/(HOMA index for insulin resistance (HOMA-IR)); where HOMA-IR=(fasting insulin (measured in pmol/L) x fasting glucose (measured in mmol/L))/(22.5 x 7.175). |
| Change in Disposition Index From Baseline to Endpoint | Baseline, end of Period II (up to 4.5 years) | Change in disposition index from baseline to endpoint. |
| Change in HbA1c From Baseline to Year 3 | Baseline, Year 3 in Period II | Change in HbA1c from baseline to Year 3. |
| Change in HbA1c From Baseline to Endpoint | Baseline, end of Period II (up to 4.5 years) | Change in HbA1c from baseline to endpoint. Endpoint for HbA1c was defined as the HbA1c measured at the treatment failure for patients reaching primary endpoint and was the last observation in study period II for other patients (either followed until the end of the study period II or discontinuing the study). |
| Fasting Plasma Glucose at Year 3 | Year 3 in Period II | Fasting plasma glucose at Year 3. |
| Change in Fasting Plasma Glucose From Baseline to Endpoint | Baseline, end of Period II (up to 4.5 years) | Change in fasting plasma glucose from baseline to endpoint. |
| Postprandial (2 Hours) Plasma Glucose at Year 3 | Year 3 in Period II | Postprandial (2 hours) plasma glucose at Year 3. |
| Homeostasis Model Assessment of Beta-cell Function (HOMA-B) at Year 3 | Year 3 in Period II | HOMA-B at Year 3. HOMA-B is an index of beta-cell function and was calculated as: HOMA-B = (20 x fasting insulin (measured in pmol/L))/((fasting glucose (measured in mmol/L) - 3.5) x 7.175). |
| Change in Body Weight From Baseline to Year 3 | Baseline, Year 3 in Period II | Change in Body weight from baseline to Year 3. |
| Systolic Blood Pressure at Year 3 | Year 3 in Period II | Systolic Blood pressure at Year 3. |
| Diastolic Blood Pressure at Year 3 | Year 3 in Period II | Diastolic Blood pressure at Year 3. |
| Heart Rate at Year 3 | Year 3 in Period II | Heart rate at Year 3. |
| Triglycerides at Year 3 | Year 3 in Period II | Triglycerides at Year 3. |
| Total Cholesterol at Year 3 | Year 3 in Period II | Total Cholesterol at Year 3. |
| High-density Lipoprotein (HDL) Cholesterol at Year 3 | Year 3 in Period II | HDL Cholesterol at Year 3. |
| Hypoglycemia Rate Per Year | Baseline to end of Period II (up to 4.5 years) | All hypoglycemia episodes were taken into account. Severe hypoglycemia: event requiring assistance of another person to administer carbohydrate, glucagons, or other resuscitative actions; Documented symptomatic hypoglycemia: event with typical symptoms accompanied by a measured plasma glucose concentration \<=70 mg/dL; Asymptomatic hypoglycemia: event not accompanied by typical symptoms but with a measured plasma glucose concentration \<=70 mg/dL; Probable symptomatic hypoglycemia: event with symptoms not accompanied by a plasma glucose determination. |
| Change in HbA1c From Baseline to Year 2 for Patients Randomized at Entry in Period III | Baseline in Period III, Year 2 in Period III | Change in HbA1c from baseline to Year 2. |
| Change in HbA1c From Baseline to Year 2 for Patients Not Randomized at Entry in Period III | Baseline in Period III, Year 2 in Period III | Change in HbA1c from baseline to Year 2. |
| Hypoglycemia Rate Per Year in Period III | Start of Period III to end of study | All hypoglycemia episodes were taken into account. Severe hypoglycemia: event requiring assistance of another person to administer carbohydrate, glucagons, or other resuscitative actions; Documented symptomatic hypoglycemia: event with typical symptoms accompanied by a measured plasma glucose concentration \<=70 mg/dL; Asymptomatic hypoglycemia: event not accompanied by typical symptoms but with a measured plasma glucose concentration \<=70 mg/dL; Probable symptomatic hypoglycemia: event with symptoms not accompanied by a plasma glucose determination. |
| Change in Postprandial (2 Hours) Plasma Glucose From Baseline to Endpoint | Baseline, end of Period II (up to 4.5 years) | Change from baseline in postprandial (2 hours) plasma glucose to endpoint. |
| Change in HOMA-B From Baseline to Endpoint | Baseline, end of Period II (up to 4.5 years) | Change in HOMA-B from baseline to endpoint. |
Countries
Austria, Czechia, Finland, France, Germany, Hungary, Ireland, Israel, Italy, Mexico, Poland, Spain, Switzerland, United Kingdom
Participant flow
Pre-assignment details
Patients meeting defined failure of HbA1c control (primary endpoint) in Study Period II were eligible for entry to Study Period III
Participants by arm
| Arm | Count |
|---|---|
| Exen + Met Exenatide 10 mcg twice daily subcutaneously injected (5 mcg exenatide per dose for first 4 weeks followed by 10 mcg exenatide per dose for the remainder of period II) and daily oral Metformin | 490 |
| Glim + Met Glimepiride one 1 mg tablet daily with subsequent titration every 4 weeks to maximally-tolerated dose for the remainder of Period II and daily oral Metformin | 487 |
| Total | 977 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Period II | Adverse Event | 17 | 0 | 0 | 0 | 49 |
| Period II | Death | 2 | 0 | 0 | 0 | 4 |
| Period II | Entry Criteria Not Met | 8 | 0 | 0 | 0 | 4 |
| Period II | Lack of Efficacy | 11 | 0 | 0 | 0 | 8 |
| Period II | Lost to follow up | 5 | 0 | 0 | 0 | 5 |
| Period II | Physician Decision | 17 | 0 | 0 | 0 | 23 |
| Period II | Protocol Violation | 18 | 0 | 0 | 0 | 11 |
| Period II | Subject Decision | 50 | 0 | 0 | 0 | 70 |
| Period III | Adverse Event | 0 | 3 | 4 | 10 | 0 |
| Period III | Entry Criteria Not Met | 0 | 1 | 0 | 1 | 0 |
| Period III | Lack of Efficacy | 0 | 7 | 5 | 9 | 0 |
| Period III | Lost to follow up | 0 | 1 | 1 | 2 | 0 |
| Period III | Physician Decision | 0 | 5 | 9 | 15 | 0 |
| Period III | Protocol Violation | 0 | 5 | 3 | 8 | 0 |
| Period III | Subject Decision | 0 | 7 | 8 | 20 | 0 |
Baseline characteristics
| Characteristic | Total | Glim + Met | Exen + Met |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 200 Participants | 98 Participants | 102 Participants |
| Age, Categorical Between 18 and 65 years | 777 Participants | 389 Participants | 388 Participants |
| Age, Continuous | 56.4 years STANDARD_DEVIATION 9.6 | 56.8 years STANDARD_DEVIATION 9.14 | 56.1 years STANDARD_DEVIATION 10.03 |
| Glycosylated hemoglobin (HbA1c) | 7.4 percentage of total hemoglobin STANDARD_DEVIATION 0.7 | 7.4 percentage of total hemoglobin STANDARD_DEVIATION 0.71 | 7.4 percentage of total hemoglobin STANDARD_DEVIATION 0.69 |
| Sex: Female, Male Female | 453 Participants | 235 Participants | 218 Participants |
| Sex: Female, Male Male | 524 Participants | 252 Participants | 272 Participants |
| Weight | 92.0 kg STANDARD_DEVIATION 15.78 | 91.1 kg STANDARD_DEVIATION 14.78 | 92.8 kg STANDARD_DEVIATION 16.7 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 248 / 508 | 39 / 74 | 39 / 76 | 91 / 166 | 311 / 511 |
| serious Total, serious adverse events | 68 / 508 | 7 / 74 | 13 / 76 | 19 / 166 | 73 / 511 |
Outcome results
Primary
Number of Patients With Treatment Failure
Treatment failure is defined as one of the following:1. HbA1c exceeding 9% at any visit after the initial 3 months of treatment (i.e., earliest at Month 6), on the maximally tolerated dose of antidiabetic agents. 2. HbA1c exceeding 7% at 2 consecutive visits 3 months apart, after the initial 6 months of treatment (i.e., earliest at Month 9), on the maximally tolerated dose of antidiabetic agents.
Time frame: Baseline to end of Period II (up to 4.5 years)
Population: ITT Efficacy Population: Enrolled patients with a baseline and at least one post-baseline measurement of HbA1c in Study Period II (including only Study Period II); patients analyzed according to treatment as randomized.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Exen + Met | Number of Patients With Treatment Failure | Number of patients with treatment failure | 203 number of patients |
| Exen + Met | Number of Patients With Treatment Failure | Number of patients censored | 287 number of patients |
| Glim + Met | Number of Patients With Treatment Failure | Number of patients with treatment failure | 262 number of patients |
| Glim + Met | Number of Patients With Treatment Failure | Number of patients censored | 225 number of patients |
Comparison: The null hypothesis (H0) and alternative hypothesis (H1) for the primary analysis (i.e., non-inferiority) are:H0: hazards of treatment for Exenatide/hazards of treatment for Glimepiride \>=1.25.H1: hazards of treatment for Exenatide/hazards of treatment for Glimepiride \< 1.25. With 527 patients in each arm, the study would have approximately 90% power to conclude non-inferiority of Exenatide to Glimepiride.p-value: 0.00295% CI: [0.623, 0.899]Regression, Cox
Primary
Time to Treatment Failure
Treatment failure is defined as one of the following:1. HbA1c exceeding 9% at any visit after the initial 3 months of treatment (i.e., earliest at Month 6), on the maximally tolerated dose of antidiabetic agents. 2. HbA1c exceeding 7% at 2 consecutive visits 3 months apart, after the initial 6 months of treatment (i.e., earliest at Month 9), on the maximally tolerated dose of antidiabetic agents.
Time frame: Baseline to end of Period II (up to 4.5 years)
Population: ITT Efficacy Population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Exen + Met | Time to Treatment Failure | 180.0 week |
| Glim + Met | Time to Treatment Failure | 142.1 week |
Comparison: Kaplan-Meier survival curves for time to treatment failure were compared between treatment groups using log rank test.p-value: 0.0315Log Rank
Secondary
Change in Body Weight From Baseline to Year 3
Change in Body weight from baseline to Year 3.
Time frame: Baseline, Year 3 in Period II
Population: ITT Safety Population: Enrolled patients receiving at least one dose of study medication in Study Period II with patients analyzed according to treatment actually received. The analysis included only time points up to that week where at least 25% of the originally enrolled population was still in the study. Missing data at Year 3 was not imputed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exen + Met | Change in Body Weight From Baseline to Year 3 | -3.92 kg | Standard Error 0.335 |
| Glim + Met | Change in Body Weight From Baseline to Year 3 | 1.47 kg | Standard Error 0.319 |
Comparison: MMRM analysis includes treatment, visit, and treatment by visit interaction and baseline value as a covariate. The unstructured covariance matrix was used.p-value: <0.000195% CI: [-6.31, -4.49]Mixed Models Analysis
Secondary
Change in DI30/DG30 Ratio From Baseline to Endpoint
Change in DI30/DG30 ratio from baseline to endpoint.
Time frame: Baseline, end of Period II (up to 4.5 years)
Population: ITT Efficacy Population. Missing data at endpoint was imputed using LOCF approach.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exen + Met | Change in DI30/DG30 Ratio From Baseline to Endpoint | 12.10 ratio | Standard Error 4.115 |
| Glim + Met | Change in DI30/DG30 Ratio From Baseline to Endpoint | 0.91 ratio | Standard Error 4.299 |
Comparison: Change in DI30/DG30 ratio from baseline to endpoint was analyzed by an ANCOVA model that includes treatment and baseline HbA1c stratum (\<=7.3%, \>7.3% to \<=8.2%, \>8.2%) as factors and baseline value as a covariate.p-value: 0.024695% CI: [1.44, 20.95]ANCOVA
Secondary
Change in Disposition Index From Baseline to Endpoint
Change in disposition index from baseline to endpoint.
Time frame: Baseline, end of Period II (up to 4.5 years)
Population: ITT Efficacy Population. Missing data at endpoint was imputed using LOCF approach.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exen + Met | Change in Disposition Index From Baseline to Endpoint | 9.15 ratio | Standard Error 1.764 |
| Glim + Met | Change in Disposition Index From Baseline to Endpoint | 1.82 ratio | Standard Error 1.849 |
Comparison: Change in disposition index from baseline to endpoint was analyzed by an ANCOVA model that includes treatment and baseline HbA1c stratum (\<=7.3%, \>7.3% to \<=8.2%, \>8.2%) as factors and baseline value as a covariate.p-value: 0.000695% CI: [3.15, 11.5]ANCOVA
Secondary
Change in Fasting Plasma Glucose From Baseline to Endpoint
Change in fasting plasma glucose from baseline to endpoint.
Time frame: Baseline, end of Period II (up to 4.5 years)
Population: ITT Efficacy Population. Missing data at endpoint was imputed using LOCF approach.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exen + Met | Change in Fasting Plasma Glucose From Baseline to Endpoint | -0.87 mmol/L | Standard Error 0.155 |
| Glim + Met | Change in Fasting Plasma Glucose From Baseline to Endpoint | -0.41 mmol/L | Standard Error 0.161 |
Comparison: Change in fasting plasma glucose from baseline to endpoint was analyzed by an ANCOVA model that includes treatment and baseline HbA1c stratum (\<=7.3%, \>7.3% to \<=8.2%, \>8.2%) as factors and baseline value as a covariate.p-value: 0.010995% CI: [-0.83, -0.11]ANCOVA
Secondary
Change in Fasting Proinsulin/Insulin Ratio From Baseline to Endpoint.
Change in fasting proinsulin (measured in pmol/L)/insulin (measured in pmol/L) ratio from baseline to endpoint.
Time frame: Baseline, end of Period II (up to 4.5 years)
Population: ITT Efficacy Population. Missing data at endpoint was imputed using LOCF approach.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exen + Met | Change in Fasting Proinsulin/Insulin Ratio From Baseline to Endpoint. | 0.03 ratio | Standard Error 0.014 |
| Glim + Met | Change in Fasting Proinsulin/Insulin Ratio From Baseline to Endpoint. | 0.05 ratio | Standard Error 0.015 |
Comparison: Change in fasting proinsulin/insulin ratio from baseline to endpoint was analyzed by an ANCOVA model that includes treatment and baseline HbA1c stratum (\<=7.3%, \>7.3% to \<=8.2%, \>8.2%) as factors and baseline value as a covariate.p-value: 0.2595% CI: [-0.05, 0.01]ANCOVA
Secondary
Change in HbA1c From Baseline to Endpoint
Change in HbA1c from baseline to endpoint. Endpoint for HbA1c was defined as the HbA1c measured at the treatment failure for patients reaching primary endpoint and was the last observation in study period II for other patients (either followed until the end of the study period II or discontinuing the study).
Time frame: Baseline, end of Period II (up to 4.5 years)
Population: ITT Efficacy Population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exen + Met | Change in HbA1c From Baseline to Endpoint | -0.36 percentage of total hemoglobin | Standard Error 0.035 |
| Glim + Met | Change in HbA1c From Baseline to Endpoint | -0.21 percentage of total hemoglobin | Standard Error 0.035 |
Comparison: Change in HbA1c from baseline to endpoint was analyzed by an ANCOVA model that includes treatment as factor and baseline value as a covariate.p-value: 0.001595% CI: [-0.26, -0.06]ANCOVA
Secondary
Change in HbA1c From Baseline to Year 2 for Patients Not Randomized at Entry in Period III
Change in HbA1c from baseline to Year 2.
Time frame: Baseline in Period III, Year 2 in Period III
Population: Extension ITT Efficacy population. The analysis included patients not randomized at entry in study period III. Missing data at Year 2 was not imputed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exen + Met | Change in HbA1c From Baseline to Year 2 for Patients Not Randomized at Entry in Period III | -0.47 percentage of total hemoglobin | Standard Deviation 0.984 |
Secondary
Change in HbA1c From Baseline to Year 2 for Patients Randomized at Entry in Period III
Change in HbA1c from baseline to Year 2.
Time frame: Baseline in Period III, Year 2 in Period III
Population: Extension ITT Efficacy Population: Extension enrolled patients with at least one post-baseline measurement of HbA1c in Study Period III. The analysis included patients randomized at entry in study period III. Missing data at Year 2 was not imputed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exen + Met | Change in HbA1c From Baseline to Year 2 for Patients Randomized at Entry in Period III | -0.19 percentage of total hemoglobin | Standard Error 0.099 |
| Glim + Met | Change in HbA1c From Baseline to Year 2 for Patients Randomized at Entry in Period III | -0.47 percentage of total hemoglobin | Standard Error 0.1 |
Comparison: MMRM analysis includes treatment, visit, and treatment by visit interaction, and baseline value at Period III as a covariate. The compound symmetric covariance structure was assumed.p-value: 0.050895% CI: [0, 0.55]Mixed Models Analysis
Secondary
Change in HbA1c From Baseline to Year 3
Change in HbA1c from baseline to Year 3.
Time frame: Baseline, Year 3 in Period II
Population: ITT Efficacy Population. The analysis included only time points up to that week where at least 25% of the originally enrolled population was still in the study. Missing data at Year 3 was not imputed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exen + Met | Change in HbA1c From Baseline to Year 3 | -0.30 percentage of total hemoglobin | Standard Error 0.051 |
| Glim + Met | Change in HbA1c From Baseline to Year 3 | -0.12 percentage of total hemoglobin | Standard Error 0.049 |
Comparison: MMRM analysis includes treatment, visit, and treatment by visit interaction, and baseline value as a covariate. The unstructured covariance matrix was used.p-value: 0.012895% CI: [-0.31, -0.04]Mixed Models Analysis
Secondary
Change in HOMA-B From Baseline to Endpoint
Change in HOMA-B from baseline to endpoint.
Time frame: Baseline, end of Period II (up to 4.5 years)
Population: ITT Efficacy Population. Missing data at endpoint was imputed using last observation carried forward (LOCF) approach.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exen + Met | Change in HOMA-B From Baseline to Endpoint | 5.56 ratio | Standard Error 6.147 |
| Glim + Met | Change in HOMA-B From Baseline to Endpoint | 19.92 ratio | Standard Error 6.34 |
Comparison: Change in HOMA-B from baseline to endpoint was analyzed by an analysis of covariance (ANCOVA) model that includes treatment and baseline HbA1c stratum (\<=7.3%, \>7.3% to \<=8.2%, \>8.2%) as factors and baseline value as a covariate.p-value: 0.052895% CI: [-28.88, 0.17]ANCOVA
Secondary
Change in Postprandial (2 Hours) Plasma Glucose From Baseline to Endpoint
Change from baseline in postprandial (2 hours) plasma glucose to endpoint.
Time frame: Baseline, end of Period II (up to 4.5 years)
Population: ITT Efficacy Population. Missing data at endpoint was imputed using LOCF approach.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exen + Met | Change in Postprandial (2 Hours) Plasma Glucose From Baseline to Endpoint | -2.72 mmol/L | Standard Error 0.275 |
| Glim + Met | Change in Postprandial (2 Hours) Plasma Glucose From Baseline to Endpoint | -0.53 mmol/L | Standard Error 0.286 |
Comparison: Change in postprandial (2 hours) plasma glucose from baseline to endpoint was analyzed by an ANCOVA model that includes treatment and baseline HbA1c stratum (\<=7.3%, \>7.3% to \<=8.2%, \>8.2%) as factors and baseline value as a covariate.p-value: <0.000195% CI: [-2.84, -1.55]ANCOVA
Secondary
Diastolic Blood Pressure at Year 3
Diastolic Blood pressure at Year 3.
Time frame: Year 3 in Period II
Population: ITT Safety Population. The analysis included only time points up to that week where at least 25% of the originally enrolled population was still in the study. Missing data at Year 3 was not imputed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exen + Met | Diastolic Blood Pressure at Year 3 | 77.45 mmHg | Standard Error 0.544 |
| Glim + Met | Diastolic Blood Pressure at Year 3 | 79.16 mmHg | Standard Error 0.517 |
Comparison: MMRM analysis includes treatment, visit, and treatment by visit interaction, and baseline value as a covariate. The unstructured covariance matrix was used.p-value: 0.022895% CI: [-3.18, -0.24]Mixed Models Analysis
Secondary
Disposition Index at Year 3
Disposition Index at Year 3. Disposition index was calculated as (DI30/DG30 ratio)/(HOMA index for insulin resistance (HOMA-IR)); where HOMA-IR=(fasting insulin (measured in pmol/L) x fasting glucose (measured in mmol/L))/(22.5 x 7.175).
Time frame: Year 3 in Period II
Population: ITT Efficacy Population. The analysis included only time points up to that week where at least 25% of the originally enrolled population was still in the study. Missing data at Year 3 was not imputed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exen + Met | Disposition Index at Year 3 | 12.56 ratio | Standard Error 1.179 |
| Glim + Met | Disposition Index at Year 3 | 7.89 ratio | Standard Error 1.078 |
Comparison: MMRM analysis includes treatment, visit, and treatment by visit interaction, and baseline value as a covariate. The unstructured covariance matrix was used.p-value: 0.003695% CI: [1.53, 7.81]Mixed Models Analysis
Secondary
Fasting Plasma Glucose at Year 3
Fasting plasma glucose at Year 3.
Time frame: Year 3 in Period II
Population: ITT Efficacy Population. The analysis included only time points up to that week where at least 25% of the originally enrolled population was still in the study. Missing data at Year 3 was not imputed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exen + Met | Fasting Plasma Glucose at Year 3 | 7.27 mmol/L | Standard Error 0.127 |
| Glim + Met | Fasting Plasma Glucose at Year 3 | 7.96 mmol/L | Standard Error 0.12 |
Comparison: MMRM includes treatment, visit, and treatment by visit interaction, and baseline value as a covariate. The unstructured covariance matrix was used.p-value: <0.000195% CI: [-1.03, -0.34]Mixed Models Analysis
Secondary
Fasting Proinsulin/Insulin Ratio at Year 3
Fasting proinsulin (measured in pmol/L)/insulin (measured in pmol/L) ratio at Year 3.
Time frame: Year 3 in Period II
Population: ITT Efficacy Population. The analysis included only time points up to that week where at least 25% of the originally enrolled population was still in the study. Missing data at Year 3 was not imputed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exen + Met | Fasting Proinsulin/Insulin Ratio at Year 3 | 0.22 ratio | Standard Error 0.023 |
| Glim + Met | Fasting Proinsulin/Insulin Ratio at Year 3 | 0.23 ratio | Standard Error 0.022 |
Comparison: MMRM analysis includes treatment, visit, and treatment by visit interaction, and baseline value as a covariate. The unstructured covariance matrix was used.p-value: 0.90495% CI: [-0.07, 0.06]Mixed Models Analysis
Secondary
Heart Rate at Year 3
Heart rate at Year 3.
Time frame: Year 3 in Period II
Population: ITT Safety Population. The analysis included only time points up to that week where at least 25% of the originally enrolled population was still in the study. Missing data at Year 3 was not imputed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exen + Met | Heart Rate at Year 3 | 73.51 beats per minute | Standard Error 0.583 |
| Glim + Met | Heart Rate at Year 3 | 74.23 beats per minute | Standard Error 0.555 |
Comparison: MMRM analysis includes treatment, visit, and visit by treatment interaction, and baseline value as a covariate. The unstructured covariance matrix was used.p-value: 0.373795% CI: [-2.3, 0.86]Mixed Models Analysis
Secondary
High-density Lipoprotein (HDL) Cholesterol at Year 3
HDL Cholesterol at Year 3.
Time frame: Year 3 in Period II
Population: ITT Safety Population. The analysis included only time points up to that week where at least 25% of the originally enrolled population was still in the study. Missing data at Year 3 was not imputed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exen + Met | High-density Lipoprotein (HDL) Cholesterol at Year 3 | 1.31 mmol/L | Standard Error 0.013 |
| Glim + Met | High-density Lipoprotein (HDL) Cholesterol at Year 3 | 1.25 mmol/L | Standard Error 0.013 |
Comparison: MMRM analysis includes treatment, visit, and treatment by visit interaction, and baseline value as a covariate. The unstructured covariance matrix was used.p-value: 0.001195% CI: [0.02, 0.1]Mixed Models Analysis
Secondary
Homeostasis Model Assessment of Beta-cell Function (HOMA-B) at Year 3
HOMA-B at Year 3. HOMA-B is an index of beta-cell function and was calculated as: HOMA-B = (20 x fasting insulin (measured in pmol/L))/((fasting glucose (measured in mmol/L) - 3.5) x 7.175).
Time frame: Year 3 in Period II
Population: ITT Efficacy Population. The analysis included only time points up to that week where at least 25% of the originally enrolled population was still in the study. Missing data at Year 3 was not imputed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exen + Met | Homeostasis Model Assessment of Beta-cell Function (HOMA-B) at Year 3 | 66.86 ratio | Standard Error 4.045 |
| Glim + Met | Homeostasis Model Assessment of Beta-cell Function (HOMA-B) at Year 3 | 68.52 ratio | Standard Error 3.813 |
Comparison: Mixed-model Repeated Measures (MMRM) analysis includes treatment, visit, and treatment by visit interaction, and baseline value as a covariate. The unstructured covariance matrix was used.p-value: 0.764895% CI: [-12.58, 9.25]Mixed Models Analysis
Secondary
Hypoglycemia Rate Per Year
All hypoglycemia episodes were taken into account. Severe hypoglycemia: event requiring assistance of another person to administer carbohydrate, glucagons, or other resuscitative actions; Documented symptomatic hypoglycemia: event with typical symptoms accompanied by a measured plasma glucose concentration \<=70 mg/dL; Asymptomatic hypoglycemia: event not accompanied by typical symptoms but with a measured plasma glucose concentration \<=70 mg/dL; Probable symptomatic hypoglycemia: event with symptoms not accompanied by a plasma glucose determination.
Time frame: Baseline to end of Period II (up to 4.5 years)
Population: ITT Safety Population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exen + Met | Hypoglycemia Rate Per Year | 1.52 events per subject-year | Standard Error 0.142 |
| Glim + Met | Hypoglycemia Rate Per Year | 5.32 events per subject-year | Standard Error 0.473 |
Comparison: The number of hypoglycemic episodes by patient were compared between treatment groups using a negative binomial model with effects for treatment and baseline HbA1c and the logarithm of the days of exposure as the offset variable.p-value: <0.000195% CI: [0.22, 0.37]Negative Binomial Model
Secondary
Hypoglycemia Rate Per Year in Period III
All hypoglycemia episodes were taken into account. Severe hypoglycemia: event requiring assistance of another person to administer carbohydrate, glucagons, or other resuscitative actions; Documented symptomatic hypoglycemia: event with typical symptoms accompanied by a measured plasma glucose concentration \<=70 mg/dL; Asymptomatic hypoglycemia: event not accompanied by typical symptoms but with a measured plasma glucose concentration \<=70 mg/dL; Probable symptomatic hypoglycemia: event with symptoms not accompanied by a plasma glucose determination.
Time frame: Start of Period III to end of study
Population: Extension ITT Safety Population: Extension enrolled patients receiving at least one dose of study medication in Study Period III.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exen + Met | Hypoglycemia Rate Per Year in Period III | 2.78 events per subject-year | Standard Deviation 5.456 |
| Glim + Met | Hypoglycemia Rate Per Year in Period III | 0.60 events per subject-year | Standard Deviation 1.674 |
| Glim + Met + Exen - Not Randomized | Hypoglycemia Rate Per Year in Period III | 4.62 events per subject-year | Standard Deviation 10.411 |
Secondary
Postprandial (2 Hours) Plasma Glucose at Year 3
Postprandial (2 hours) plasma glucose at Year 3.
Time frame: Year 3 in Period II
Population: ITT Efficacy Population. The analysis included only time points up to that week where at least 25% of the originally enrolled population was still in the study. Missing data at Year 3 was not imputed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exen + Met | Postprandial (2 Hours) Plasma Glucose at Year 3 | 12.65 mmol/L | Standard Error 0.311 |
| Glim + Met | Postprandial (2 Hours) Plasma Glucose at Year 3 | 15.45 mmol/L | Standard Error 0.289 |
Comparison: MMRM analysis includes treatment, visit, and treatment by visit interaction, and baseline value as a covariate. The unstructured covariance matrix was used.p-value: <0.000195% CI: [-3.64, -1.97]Mixed Models Analysis
Secondary
Ratio of the 30 Minute Increment in Plasma Insulin Concentration and the 30 Minute Increment in Plasma Glucose During the Oral Glucose Tolerance Test (DI30/DG30 Ratio) at Year 3
DI30/DG30 at Year 3. DI30/DG30 ratio was calculated as (30 minute post prandial insulin - fasting insulin) (measured in pmol/L)/(30 minute post prandial glucose - fasting glucose) (measured in mmol/L).
Time frame: Year 3 in Period II
Population: ITT Efficacy Population. The analysis included only time points up to that week where at least 25% of the originally enrolled population was still in the study. Missing data at Year 3 was not imputed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exen + Met | Ratio of the 30 Minute Increment in Plasma Insulin Concentration and the 30 Minute Increment in Plasma Glucose During the Oral Glucose Tolerance Test (DI30/DG30 Ratio) at Year 3 | 25.81 ratio | Standard Error 3.323 |
| Glim + Met | Ratio of the 30 Minute Increment in Plasma Insulin Concentration and the 30 Minute Increment in Plasma Glucose During the Oral Glucose Tolerance Test (DI30/DG30 Ratio) at Year 3 | 26.38 ratio | Standard Error 3.032 |
Comparison: MMRM analysis includes treatment, visit, and treatment by visit interaction, and baseline value as a covariate. The unstructured covariance matrix was used.p-value: 0.900195% CI: [-9.4, 8.27]Mixed Models Analysis
Secondary
Systolic Blood Pressure at Year 3
Systolic Blood pressure at Year 3.
Time frame: Year 3 in Period II
Population: ITT Safety Population. The analysis included only time points up to that week where at least 25% of the originally enrolled population was still in the study. Missing data at Year 3 was not imputed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exen + Met | Systolic Blood Pressure at Year 3 | 130.58 mmHg | Standard Error 0.891 |
| Glim + Met | Systolic Blood Pressure at Year 3 | 135.78 mmHg | Standard Error 0.845 |
Comparison: MMRM analysis includes treatment, visit, and treatment by visit interaction, and baseline value as a covariate. The unstructured covariance matrix was used.p-value: <0.000195% CI: [-7.61, -2.79]Mixed Models Analysis
Secondary
Total Cholesterol at Year 3
Total Cholesterol at Year 3.
Time frame: Year 3 in Period II
Population: ITT Safety Population. The analysis included only time points up to that week where at least 25% of the originally enrolled population was still in the study. Missing data at Year 3 was not imputed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exen + Met | Total Cholesterol at Year 3 | 4.77 mmol/L | Standard Error 0.057 |
| Glim + Met | Total Cholesterol at Year 3 | 4.75 mmol/L | Standard Error 0.054 |
Comparison: MMRM analysis includes treatment, visit, and treatment by visit interaction, and baseline value as a covariate. The unstructured covariance matrix was used.p-value: 0.791495% CI: [-0.13, 0.18]Mixed Models Analysis
Secondary
Triglycerides at Year 3
Triglycerides at Year 3.
Time frame: Year 3 in Period II
Population: ITT Safety Population. The analysis included only time points up to that week where at least 25% of the originally enrolled population was still in the study. Missing data at Year 3 was not imputed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exen + Met | Triglycerides at Year 3 | 1.69 mmol/L | Standard Error 0.065 |
| Glim + Met | Triglycerides at Year 3 | 1.95 mmol/L | Standard Error 0.062 |
Comparison: MMRM analysis includes treatment, visit, and treatment by visit interaction, and baseline value as a covariate. The unstructured covariance matrix was used.p-value: 0.004295% CI: [-0.43, -0.08]Mixed Models Analysis