Type 2 Diabetes
Conditions
Keywords
diabetes, adolescents, exenatide, Astra Zeneca
Brief summary
The primary objective of this study is to test the hypothesis that glycemic control, as measured by change in hemoglobin A1c (HbA1c) from baseline to endpoint, with exenatide is superior to that of placebo after 28 weeks of treatment in adolescent patients with type 2 diabetes who are naïve to antidiabetes agents, or patients who are being treated with metformin, an SU, or a combination of metformin and an SU
Interventions
DRUGPlacebo
Subcutaneous injection, twice a day
DRUGExenatide
Subcutaneous injection, 5 µg, twice a day
Sponsors
Quintiles, Inc.
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
10 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
-patients are eligible to be included in the study only if they meet all of the following criteria: * are a male or a female between ages 10 to 17 years, inclusive. The number of patients ≥17 years of age will be limited to no more than 10% of patients in each treatment arm * have a history of type 2 diabetes with the original diagnosis based on at least one American Diabetes Association (ADA) diagnostic criteria * have been treated with metformin, an SU, or both metformin and an SU (with or without diet and exercise), for at least 3 months or are naïve to anti-diabetes agents and being treated with diet and exercise alone. The dose of oral agent(s) should be stable for the 30 days prior to the screening visit * have fasting C-peptide \>0.6 ng/mL * have HbA1c between 6.5% and 10.5%, inclusive. Disease Diagnostic Criteria-for the purposes of this study, patients with type 2 diabetes are defined by: * diagnosis of type 2 diabetes, as determined by ADA diagnostic criteria and antibody testing, documented and confirmed in the patient's medical record, which includes laboratory determinations consistent with one or more of the following in the patient's medical history * fasting blood glucose 126 mg/dL (7.0 mmol/L) * random blood glucose 200 mg/dL (11.1 mmol/L) * two-hour OGTT (Oral Glucose Tolerance Test) ≥ 200 mg/dL (11.1 mmol/L) AND one or more of the following: no antibodies to GAD65 OR no antibodies to islet cell antigen (ICA512).
Exclusion criteria
-patients will be excluded from the study if they meet any of the following criteria: * have previously been exposed to exenatide or, completed or withdrawn from this study or any other study investigating exenatide * are unwilling or unable to inject the study medication * currently use inhaled steroids at a dose equal to or above 1000g Flovent (fluticasone propionate) daily * have used oral steroids within the last 60 days or more than 20 days use within the past year * have used any weight loss medication(s) within 30 days of screening * have used insulin for more than 10 weeks during the 3 months prior to screening * have history of renal disease, or serum creatinine \>1.6 mg/dL (141.4 µmol/L) (males) or \>1.4 mg/dL (123.8 µmol/L) (females) * have hepatic dysfunction, defined by aspartate (AST) or alanine (ALT) transaminase \>3.0 times the upper limit of normal (ULN).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Change From Baseline in Glycated Hemoglobin A1c (HbA1c) at Week 28 | Baseline (Day 1) and Week 28 | Change from baseline in HbA1c is reported as adjusted least square (LS) mean values at Week 28. Baseline is defined as the last non-missing assessment (scheduled or unscheduled) on or prior to the first dose of study medication. A mixed model with repeated measures (MMRM) analysis was performed, excluding measurements after initiation of rescue medication and study drug discontinuation. |
| Number of Participants With Post-Treatment Adverse Events of Special Interest (AESI) During Safety Follow-up Period | From 1 day after the Week 28/ED visit to 3 years after Week 28/ED visit. | Post-treatment adverse events (AEs) were defined as AEs that started or worsened during the off-treatment period (Safety Follow-up Period), which was defined as the day after the Week 28/early discontinuation (ED) visit to the date of completion of the Safety Follow-up Period. The AESIs recorded were as follows: hematological malignancies, thyroid neoplasms, pancreas neoplasms, aplastic anemia, pancreatitis, pregnancy and pregnancy outcomes (including congenital anomalies). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Change From Baseline in Fasting Serum Glucose (FSG) at Week 28 | Baseline (Day 1) and Week 28 | Change from baseline in FSG is reported as adjusted LS mean values at Week 28. Baseline is defined as the last non-missing assessment (scheduled or unscheduled) on or prior to the first dose of study medication. An analysis of covariance (ANCOVA) analysis was performed, excluding measurements after initiation of rescue medication and study drug discontinuation. |
| Adjusted Change From Baseline in Self-Monitored Blood Glucose (SMBG) at Week 28 | Pre-meal and 2 hours post-meal on Baseline (Day 1) and Week 28 | Change from baseline in SMBG measurements are reported as adjusted LS mean values at Week 28. SMBG measurements were taken before (pre-prandial) and 2 hours after (post-prandial) the 2 main meals of the day on 3 separate days during the week before baseline (Day 1) and Week 28. Post-prandial excursions were calculated as the difference between the pre-prandial and post-prandial blood glucose concentrations (post-prandial - pre-prandial) and averaged (mean) over the 2 main meals over the 3 separate days in each period. Baseline is defined as the last non-missing assessment (scheduled or unscheduled) on or prior to the first dose of study medication. An ANCOVA analysis was performed, excluding measurements after initiation of rescue medication and study drug discontinuation. |
| Percentage of Participants Achieving HbA1c Goals of < 7%, <= 6.5%, and < 6.5% Through Week 28 | Weeks 0, 4, 12, 20 and 28 | The percentage of participants achieving HbA1c goals of \< 7%, \<= 6.5%, and \< 6.5% through Week 28 were compared between treatments using the Cochran-Mantel-Haenszel (CMH) procedure, in which screening HbA1c strata and background diabetes therapy strata served as the stratification factors. The CMH analysis excluded measurements after initiation of rescue medication and study drug discontinuation with missing data treated as non-responder. |
| Adjusted Change From Baseline in Homeostasis Model Assessments - Beta-Cell Function (HOMA-B) and Insulin Sensitivity (HOMA-S) at Week 28 | Baseline (Day 1) and Week 28 | Change from baseline in HOMA-B and HOMA-S are reported as adjusted LS mean values at Week 28. Baseline is defined as the last non-missing assessment (scheduled or unscheduled) on or prior to the first dose of study medication. An ANCOVA analysis was performed, excluding measurements after initiation of rescue medication and study drug discontinuation. |
| Percentage of Participants Discontinuing the Study Due to Failure to Maintain Glycemic Control Through Week 28 | Weeks 2, 4, 8, 12, 16, 20, 24 and 28 | Participants were discontinued from the study due to failure to maintain glycemic control if either discontinuation reason on summary case report form was Loss of glucose control or AE with lower level Medical Dictionary for Regulatory Activities (MedDRA) term Loss of control of blood sugar or Hyperglycaemia leading to study drug discontinuation, using MedDRA Version 23.0. |
| Adjusted Change From Baseline in Fasting Serum Insulin at Week 28 | Baseline (Day 1) and Week 28 | Change from baseline in fasting serum insulin is reported as adjusted LS mean values at Week 28. Baseline is defined as the last non-missing assessment (scheduled or unscheduled) on or prior to the first dose of study medication. An ANCOVA analysis was performed, excluding measurements after initiation of rescue medication and study drug discontinuation. |
| Adjusted Change From Baseline in Body Weight Through Week 28 | Baseline (Day 1) up to Week 28 | Change from baseline in body weight is reported as adjusted LS mean values at Weeks 4, 12, 20 and 28. Baseline is defined as the last non-missing assessment (scheduled or unscheduled) on or prior to the first dose of study medication. A MMRM analysis was performed, excluding measurements after initiation of rescue medication and study drug discontinuation. |
Countries
Brazil, India, Mexico, Philippines, Russia, South Africa, South Korea, United States
Participant flow
Recruitment details
This study was conducted in adolescents (aged 10 to 17 years inclusive) with type 2 diabetes who were naïve to antidiabetics, or were receiving metformin, an sulfonylurea (SU) or a combination of metformin and an SU in 7 countries (Brazil, India, South Korea, Mexico, Russia, the United States and South Africa) between 30 May 2008 and 01 April 2020.
Pre-assignment details
The study commenced with a 1-week, single-blind, injectable placebo lead-in period before participants were randomized to 1 of 3 treatment groups: exenatide 5 microgram (mcg) twice daily, exenatide 10 mcg twice daily, or placebo twice daily. A total of 122 participants were randomized in this study.
Participants by arm
| Arm | Count |
|---|---|
| Exenatide 5 mcg Adolescent participants received exenatide 5 mcg SC injection twice daily for 28 weeks. In the Safety Follow-up Period, participants with a height difference of at least 5 mm between Day 1 and Week 28 visits returned for study visits every 6 months for up to 3 years after completion of the treatment period. | 42 |
| Exenatide 10 mcg Adolescent participants received exenatide 5 mcg SC injection twice daily for 4 weeks after randomization. At the end of 4 weeks post-randomization, participants received exenatide 10 mcg SC injection twice daily for next 24 weeks. In the Safety Follow-up Period, participants with a height difference of at least 5 mm between Day 1 and Week 28 visits returned for study visits every 6 months for up to 3 years after completion of the treatment period. | 38 |
| Placebo Adolescent participants received placebo matching with exenatide 5 mcg or 10 mcg SC injection twice daily for 28 weeks. In the Safety Follow-up Period, participants with a height difference of at least 5 mm between Day 1 and Week 28 visits returned for study visits every 6 months for up to 3 years after completion of the treatment period. | 42 |
| Total | 122 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| 28-Week Treatment Period | Adverse Event | 3 | 1 | 0 |
| 28-Week Treatment Period | Developed study withdrawal criteria | 0 | 2 | 0 |
| 28-Week Treatment Period | Did not receive treatment | 2 | 0 | 0 |
| 28-Week Treatment Period | Loss of glucose control | 1 | 1 | 10 |
| 28-Week Treatment Period | Other | 2 | 3 | 1 |
| 28-Week Treatment Period | Physician Decision | 1 | 2 | 1 |
| 28-Week Treatment Period | Protocol Violation | 0 | 2 | 1 |
| 28-Week Treatment Period | Withdrawal by parent/guardian | 1 | 1 | 1 |
| 28-Week Treatment Period | Withdrawal by Subject | 1 | 1 | 3 |
| Long-term Safety Follow-up Period | Physician Decision | 0 | 2 | 0 |
| Long-term Safety Follow-up Period | Withdrawal by Subject | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Exenatide 5 mcg | Exenatide 10 mcg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 13.7 years STANDARD_DEVIATION 1.94 | 14.0 years STANDARD_DEVIATION 1.95 | 14.4 years STANDARD_DEVIATION 1.82 | 14.0 years STANDARD_DEVIATION 1.91 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 3 Participants | 2 Participants | 5 Participants | 10 Participants |
| Race/Ethnicity, Customized Black or African American | 14 Participants | 8 Participants | 7 Participants | 29 Participants |
| Race/Ethnicity, Customized Hispanic | 18 Participants | 22 Participants | 17 Participants | 57 Participants |
| Race/Ethnicity, Customized White | 7 Participants | 5 Participants | 13 Participants | 25 Participants |
| Sex: Female, Male Female | 31 Participants | 22 Participants | 29 Participants | 82 Participants |
| Sex: Female, Male Male | 11 Participants | 16 Participants | 13 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 41 | 0 / 37 | 0 / 42 |
| other Total, other adverse events | 26 / 41 | 24 / 37 | 23 / 42 |
| serious Total, serious adverse events | 3 / 41 | 1 / 37 | 1 / 42 |
Outcome results
Primary
Adjusted Change From Baseline in Glycated Hemoglobin A1c (HbA1c) at Week 28
Change from baseline in HbA1c is reported as adjusted least square (LS) mean values at Week 28. Baseline is defined as the last non-missing assessment (scheduled or unscheduled) on or prior to the first dose of study medication. A mixed model with repeated measures (MMRM) analysis was performed, excluding measurements after initiation of rescue medication and study drug discontinuation.
Time frame: Baseline (Day 1) and Week 28
Population: The Evaluable Analysis Set included all randomized participants who received at least 1 dose of randomized study medication and had a baseline and at least 1 post-baseline HbA1c assessment. For analysis of efficacy, a decision was made with agreement by the European Medicines Agency and the Food and Drug Administration to pool participants from both exenatide groups (Total EBID) and compare this pooled group with placebo.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Total Exenatide Twice Daily (EBID) | Adjusted Change From Baseline in Glycated Hemoglobin A1c (HbA1c) at Week 28 | 0.11 percentage (%HbA1c) | Standard Error 0.215 |
| Placebo | Adjusted Change From Baseline in Glycated Hemoglobin A1c (HbA1c) at Week 28 | 0.38 percentage (%HbA1c) | Standard Error 0.293 |
Comparison: Adjusted LS mean and treatment group difference in the change from baseline values at visit are obtained from a MMRM including treatment, baseline HbA1c, background diabetes therapy strata, week of visit, baseline HbA1c-by-visit interaction and treatment-by-visit interaction as fixed effects using an unstructured covariance matrix.p-value: 0.44495% CI: [-1.01, 0.45]Mixed Models Analysis
Primary
Number of Participants With Post-Treatment Adverse Events of Special Interest (AESI) During Safety Follow-up Period
Post-treatment adverse events (AEs) were defined as AEs that started or worsened during the off-treatment period (Safety Follow-up Period), which was defined as the day after the Week 28/early discontinuation (ED) visit to the date of completion of the Safety Follow-up Period. The AESIs recorded were as follows: hematological malignancies, thyroid neoplasms, pancreas neoplasms, aplastic anemia, pancreatitis, pregnancy and pregnancy outcomes (including congenital anomalies).
Time frame: From 1 day after the Week 28/ED visit to 3 years after Week 28/ED visit.
Population: The Safety Follow-up Analysis Set included all participants who had at least 1 safety follow-up period assessment visit.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Total Exenatide Twice Daily (EBID) | Number of Participants With Post-Treatment Adverse Events of Special Interest (AESI) During Safety Follow-up Period | 0 Participants |
| Placebo | Number of Participants With Post-Treatment Adverse Events of Special Interest (AESI) During Safety Follow-up Period | 0 Participants |
| Placebo | Number of Participants With Post-Treatment Adverse Events of Special Interest (AESI) During Safety Follow-up Period | 0 Participants |
Secondary
Adjusted Change From Baseline in Body Weight Through Week 28
Change from baseline in body weight is reported as adjusted LS mean values at Weeks 4, 12, 20 and 28. Baseline is defined as the last non-missing assessment (scheduled or unscheduled) on or prior to the first dose of study medication. A MMRM analysis was performed, excluding measurements after initiation of rescue medication and study drug discontinuation.
Time frame: Baseline (Day 1) up to Week 28
Population: The Full Analysis Set included all randomized participants who received at least 1 dose of randomized study medication. For analysis of efficacy, a decision was made with agreement by the European Medicines Agency and the Food and Drug Administration to pool participants from both exenatide groups (Total EBID) and compare this pooled group with placebo.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Total Exenatide Twice Daily (EBID) | Adjusted Change From Baseline in Body Weight Through Week 28 | Week 4 | -0.89 kilogram | Standard Error 0.196 |
| Total Exenatide Twice Daily (EBID) | Adjusted Change From Baseline in Body Weight Through Week 28 | Week 20 | -0.71 kilogram | Standard Error 0.559 |
| Total Exenatide Twice Daily (EBID) | Adjusted Change From Baseline in Body Weight Through Week 28 | Week 12 | -1.09 kilogram | Standard Error 0.401 |
| Total Exenatide Twice Daily (EBID) | Adjusted Change From Baseline in Body Weight Through Week 28 | Week 28 | -0.81 kilogram | Standard Error 0.632 |
| Placebo | Adjusted Change From Baseline in Body Weight Through Week 28 | Week 12 | -0.42 kilogram | Standard Error 0.534 |
| Placebo | Adjusted Change From Baseline in Body Weight Through Week 28 | Week 4 | 0.04 kilogram | Standard Error 0.26 |
| Placebo | Adjusted Change From Baseline in Body Weight Through Week 28 | Week 28 | -0.36 kilogram | Standard Error 0.857 |
| Placebo | Adjusted Change From Baseline in Body Weight Through Week 28 | Week 20 | -0.33 kilogram | Standard Error 0.755 |
Comparison: Treatment difference in body weight at Week 4:~Adjusted LS mean and treatment group difference in the change from baseline values at visit are obtained from a MMRM including treatment, baseline body weight, screening HbA1c strata, background diabetes therapy strata, week of visit, baseline body weight-by visit interaction and treatment-by-visit interaction as fixed effects using an unstructured covariance matrix.p-value: 0.00595% CI: [-1.58, -0.28]Mixed Models Analysis
Comparison: Treatment difference in body weight at Week 12:~Adjusted LS mean and treatment group difference in the change from baseline values at visit are obtained from a MMRM including treatment, baseline body weight, screening HbA1c strata, background diabetes therapy strata, week of visit, baseline body weight-by visit interaction and treatment-by-visit interaction as fixed effects using an unstructured covariance matrix.p-value: 0.31495% CI: [-2, 0.65]Mixed Models Analysis
Comparison: Treatment difference in body weight at Week 20:~Adjusted LS mean and treatment group difference in the change from baseline values at visit are obtained from a MMRM including treatment, baseline body weight, screening HbA1c strata, background diabetes therapy strata, week of visit, baseline body weight-by visit interaction and treatment-by-visit interaction as fixed effects using an unstructured covariance matrix.p-value: 0.69295% CI: [-2.24, 1.5]Mixed Models Analysis
Comparison: Treatment difference in body weight at Week 28:~Adjusted LS mean and treatment group difference in the change from baseline values at visit are obtained from a MMRM including treatment, baseline body weight, screening HbA1c strata, background diabetes therapy strata, week of visit, baseline body weight-by visit interaction and treatment-by-visit interaction as fixed effects using an unstructured covariance matrix.p-value: 0.67995% CI: [-2.56, 1.68]Mixed Models Analysis
Secondary
Adjusted Change From Baseline in Fasting Serum Glucose (FSG) at Week 28
Change from baseline in FSG is reported as adjusted LS mean values at Week 28. Baseline is defined as the last non-missing assessment (scheduled or unscheduled) on or prior to the first dose of study medication. An analysis of covariance (ANCOVA) analysis was performed, excluding measurements after initiation of rescue medication and study drug discontinuation.
Time frame: Baseline (Day 1) and Week 28
Population: The Full Analysis Set included all randomized participants who received at least 1 dose of randomized study medication. For analysis of efficacy, a decision was made with agreement by the European Medicines Agency and the Food and Drug Administration to pool participants from both exenatide groups (Total EBID) and compare this pooled group with placebo.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Total Exenatide Twice Daily (EBID) | Adjusted Change From Baseline in Fasting Serum Glucose (FSG) at Week 28 | 0.791 millimoles per liter (mmol/L) | Standard Error 0.401 |
| Placebo | Adjusted Change From Baseline in Fasting Serum Glucose (FSG) at Week 28 | 1.072 millimoles per liter (mmol/L) | Standard Error 0.5466 |
Comparison: Adjusted LS Mean and treatment group difference in the change from baseline values at Week 28 are obtained from multiple imputation ANCOVA including treatment, baseline fasting serum glucose, screening HbA1c strata and background diabetes therapy strata as fixed effects.p-value: 0.67995% CI: [-1.614, 1.052]ANCOVA
Secondary
Adjusted Change From Baseline in Fasting Serum Insulin at Week 28
Change from baseline in fasting serum insulin is reported as adjusted LS mean values at Week 28. Baseline is defined as the last non-missing assessment (scheduled or unscheduled) on or prior to the first dose of study medication. An ANCOVA analysis was performed, excluding measurements after initiation of rescue medication and study drug discontinuation.
Time frame: Baseline (Day 1) and Week 28
Population: The Full Analysis Set included all randomized participants who received at least 1 dose of randomized study medication. For analysis of efficacy, a decision was made with agreement by the European Medicines Agency and the Food and Drug Administration to pool participants from both exenatide groups (Total EBID) and compare this pooled group with placebo.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Total Exenatide Twice Daily (EBID) | Adjusted Change From Baseline in Fasting Serum Insulin at Week 28 | 1.67 picomoles per liter | Standard Error 25.323 |
| Placebo | Adjusted Change From Baseline in Fasting Serum Insulin at Week 28 | 12.49 picomoles per liter | Standard Error 34.825 |
Comparison: Adjusted LS Mean and treatment group difference in the change from baseline values at Week 28 are obtained from multiple imputation ANCOVA including treatment, baseline fasting serum insulin, screening HbA1c strata and background diabetes therapy strata as fixed effects.p-value: 0.80295% CI: [-95.48, 73.84]ANCOVA
Secondary
Adjusted Change From Baseline in Homeostasis Model Assessments - Beta-Cell Function (HOMA-B) and Insulin Sensitivity (HOMA-S) at Week 28
Change from baseline in HOMA-B and HOMA-S are reported as adjusted LS mean values at Week 28. Baseline is defined as the last non-missing assessment (scheduled or unscheduled) on or prior to the first dose of study medication. An ANCOVA analysis was performed, excluding measurements after initiation of rescue medication and study drug discontinuation.
Time frame: Baseline (Day 1) and Week 28
Population: The Full Analysis Set included all randomized participants who received at least 1 dose of randomized study medication. For analysis of efficacy, a decision was made with agreement by the European Medicines Agency and the Food and Drug Administration to pool participants from both exenatide groups (Total EBID) and compare this pooled group with placebo.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Total Exenatide Twice Daily (EBID) | Adjusted Change From Baseline in Homeostasis Model Assessments - Beta-Cell Function (HOMA-B) and Insulin Sensitivity (HOMA-S) at Week 28 | HOMA-B | -25.93 percentage (%HOMA-B and %HOMA-S) | Standard Error 10.404 |
| Total Exenatide Twice Daily (EBID) | Adjusted Change From Baseline in Homeostasis Model Assessments - Beta-Cell Function (HOMA-B) and Insulin Sensitivity (HOMA-S) at Week 28 | HOMA-S | -3.18 percentage (%HOMA-B and %HOMA-S) | Standard Error 2.172 |
| Placebo | Adjusted Change From Baseline in Homeostasis Model Assessments - Beta-Cell Function (HOMA-B) and Insulin Sensitivity (HOMA-S) at Week 28 | HOMA-B | -22.10 percentage (%HOMA-B and %HOMA-S) | Standard Error 14.885 |
| Placebo | Adjusted Change From Baseline in Homeostasis Model Assessments - Beta-Cell Function (HOMA-B) and Insulin Sensitivity (HOMA-S) at Week 28 | HOMA-S | -2.90 percentage (%HOMA-B and %HOMA-S) | Standard Error 3.117 |
Comparison: Treatment difference for HOMA-B: Adjusted LS Mean and treatment group difference in the change from baseline values at Week 28 are obtained from multiple imputation ANCOVA including treatment, baseline %HOMA-B, screening HbA1c strata and background diabetes therapy strata as fixed effects.p-value: 0.83695% CI: [-40.19, 32.51]ANCOVA
Comparison: Treatment difference for HOMA-S: Adjusted LS Mean and treatment group difference in the change from baseline values at Week 28 are obtained from multiple imputation ANCOVA including treatment, baseline %HOMA-S, screening HbA1c strata and background diabetes therapy strata as fixed effects.p-value: 0.94195% CI: [-7.82, 7.26]ANCOVA
Secondary
Adjusted Change From Baseline in Self-Monitored Blood Glucose (SMBG) at Week 28
Change from baseline in SMBG measurements are reported as adjusted LS mean values at Week 28. SMBG measurements were taken before (pre-prandial) and 2 hours after (post-prandial) the 2 main meals of the day on 3 separate days during the week before baseline (Day 1) and Week 28. Post-prandial excursions were calculated as the difference between the pre-prandial and post-prandial blood glucose concentrations (post-prandial - pre-prandial) and averaged (mean) over the 2 main meals over the 3 separate days in each period. Baseline is defined as the last non-missing assessment (scheduled or unscheduled) on or prior to the first dose of study medication. An ANCOVA analysis was performed, excluding measurements after initiation of rescue medication and study drug discontinuation.
Time frame: Pre-meal and 2 hours post-meal on Baseline (Day 1) and Week 28
Population: The Full Analysis Set included all randomized participants who received at least 1 dose of randomized study medication. For analysis of efficacy, a decision was made with agreement by the European Medicines Agency and the Food and Drug Administration to pool participants from both exenatide groups (Total EBID) and compare this pooled group with placebo.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Total Exenatide Twice Daily (EBID) | Adjusted Change From Baseline in Self-Monitored Blood Glucose (SMBG) at Week 28 | Pre-meal SMBG | -0.699 mmol/L | Standard Error 0.2709 |
| Total Exenatide Twice Daily (EBID) | Adjusted Change From Baseline in Self-Monitored Blood Glucose (SMBG) at Week 28 | Post-meal SMBG | -1.029 mmol/L | Standard Error 0.2722 |
| Total Exenatide Twice Daily (EBID) | Adjusted Change From Baseline in Self-Monitored Blood Glucose (SMBG) at Week 28 | Post-prandial excursion SMBG | -0.181 mmol/L | Standard Error 0.2107 |
| Total Exenatide Twice Daily (EBID) | Adjusted Change From Baseline in Self-Monitored Blood Glucose (SMBG) at Week 28 | Overall SMBG | -0.877 mmol/L | Standard Error 0.2468 |
| Placebo | Adjusted Change From Baseline in Self-Monitored Blood Glucose (SMBG) at Week 28 | Overall SMBG | -1.193 mmol/L | Standard Error 0.4117 |
| Placebo | Adjusted Change From Baseline in Self-Monitored Blood Glucose (SMBG) at Week 28 | Pre-meal SMBG | -0.888 mmol/L | Standard Error 0.4511 |
| Placebo | Adjusted Change From Baseline in Self-Monitored Blood Glucose (SMBG) at Week 28 | Post-prandial excursion SMBG | -0.391 mmol/L | Standard Error 0.3418 |
| Placebo | Adjusted Change From Baseline in Self-Monitored Blood Glucose (SMBG) at Week 28 | Post-meal SMBG | -1.542 mmol/L | Standard Error 0.4503 |
Comparison: Treatment difference for pre-meal SMBG: Adjusted LS Mean and treatment group difference in the change from baseline values at Week 28 are obtained from multiple imputation ANCOVA including treatment, baseline SMBG measure, screening HbA1c strata and background diabetes therapy strata as fixed effects.p-value: 0.71495% CI: [-0.821, 1.199]ANCOVA
Comparison: Treatment difference for post-meal SMBG: Adjusted LS Mean and treatment group difference in the change from baseline values at Week 28 are obtained from multiple imputation ANCOVA including treatment, baseline SMBG measure, screening HbA1c strata and background diabetes therapy strata as fixed effects.p-value: 0.32995% CI: [-0.516, 1.541]ANCOVA
Comparison: Treatment difference for post-prandial excursion SMBG: Adjusted LS Mean and treatment group difference in the change from baseline values at Week 28 are obtained from multiple imputation ANCOVA including treatment, baseline SMBG measure, screening HbA1c strata and background diabetes therapy strata as fixed effects.p-value: 0.60195% CI: [-0.577, 0.997]ANCOVA
Comparison: Treatment difference for overall SMBG: Adjusted LS Mean and treatment group difference in the change from baseline values at Week 28 are obtained from multiple imputation ANCOVA including treatment, baseline SMBG measure, screening HbA1c strata and background diabetes therapy strata as fixed effects.p-value: 0.50595% CI: [-0.615, 1.248]ANCOVA
Secondary
Percentage of Participants Achieving HbA1c Goals of < 7%, <= 6.5%, and < 6.5% Through Week 28
The percentage of participants achieving HbA1c goals of \< 7%, \<= 6.5%, and \< 6.5% through Week 28 were compared between treatments using the Cochran-Mantel-Haenszel (CMH) procedure, in which screening HbA1c strata and background diabetes therapy strata served as the stratification factors. The CMH analysis excluded measurements after initiation of rescue medication and study drug discontinuation with missing data treated as non-responder.
Time frame: Weeks 0, 4, 12, 20 and 28
Population: The Evaluable Analysis Set included all randomized participants who received at least 1 dose of randomized study medication and had a baseline and at least 1 post-baseline HbA1c assessment. For analysis of efficacy, a decision was made with agreement by the European Medicines Agency and the Food and Drug Administration to pool participants from both exenatide groups (Total EBID) and compare this pooled group with placebo.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Total Exenatide Twice Daily (EBID) | Percentage of Participants Achieving HbA1c Goals of < 7%, <= 6.5%, and < 6.5% Through Week 28 | HbA1c < 7%: Week 28 | 33.3 percentage of participants |
| Total Exenatide Twice Daily (EBID) | Percentage of Participants Achieving HbA1c Goals of < 7%, <= 6.5%, and < 6.5% Through Week 28 | HbA1c <=6.5%: Week 20 | 24.4 percentage of participants |
| Total Exenatide Twice Daily (EBID) | Percentage of Participants Achieving HbA1c Goals of < 7%, <= 6.5%, and < 6.5% Through Week 28 | HbA1c < 7%: Week 4 | 44.9 percentage of participants |
| Total Exenatide Twice Daily (EBID) | Percentage of Participants Achieving HbA1c Goals of < 7%, <= 6.5%, and < 6.5% Through Week 28 | HbA1c <=6.5%: Week 28 | 23.1 percentage of participants |
| Total Exenatide Twice Daily (EBID) | Percentage of Participants Achieving HbA1c Goals of < 7%, <= 6.5%, and < 6.5% Through Week 28 | HbA1c <=6.5%: Week 0 | 17.9 percentage of participants |
| Total Exenatide Twice Daily (EBID) | Percentage of Participants Achieving HbA1c Goals of < 7%, <= 6.5%, and < 6.5% Through Week 28 | HbA1c <6.5%: Week 0 | 15.4 percentage of participants |
| Total Exenatide Twice Daily (EBID) | Percentage of Participants Achieving HbA1c Goals of < 7%, <= 6.5%, and < 6.5% Through Week 28 | HbA1c < 7%: Week 20 | 35.9 percentage of participants |
| Total Exenatide Twice Daily (EBID) | Percentage of Participants Achieving HbA1c Goals of < 7%, <= 6.5%, and < 6.5% Through Week 28 | HbA1c <6.5%: Week 4 | 26.9 percentage of participants |
| Total Exenatide Twice Daily (EBID) | Percentage of Participants Achieving HbA1c Goals of < 7%, <= 6.5%, and < 6.5% Through Week 28 | HbA1c <=6.5%: Week 4 | 29.5 percentage of participants |
| Total Exenatide Twice Daily (EBID) | Percentage of Participants Achieving HbA1c Goals of < 7%, <= 6.5%, and < 6.5% Through Week 28 | HbA1c <6.5%: Week 12 | 30.8 percentage of participants |
| Total Exenatide Twice Daily (EBID) | Percentage of Participants Achieving HbA1c Goals of < 7%, <= 6.5%, and < 6.5% Through Week 28 | HbA1c < 7%: Week 12 | 43.6 percentage of participants |
| Total Exenatide Twice Daily (EBID) | Percentage of Participants Achieving HbA1c Goals of < 7%, <= 6.5%, and < 6.5% Through Week 28 | HbA1c <6.5%: Week 20 | 21.8 percentage of participants |
| Total Exenatide Twice Daily (EBID) | Percentage of Participants Achieving HbA1c Goals of < 7%, <= 6.5%, and < 6.5% Through Week 28 | HbA1c <=6.5%: Week 12 | 33.3 percentage of participants |
| Total Exenatide Twice Daily (EBID) | Percentage of Participants Achieving HbA1c Goals of < 7%, <= 6.5%, and < 6.5% Through Week 28 | HbA1c <6.5%: Week 28 | 23.1 percentage of participants |
| Total Exenatide Twice Daily (EBID) | Percentage of Participants Achieving HbA1c Goals of < 7%, <= 6.5%, and < 6.5% Through Week 28 | HbA1c < 7%: Week 0 | 37.2 percentage of participants |
| Placebo | Percentage of Participants Achieving HbA1c Goals of < 7%, <= 6.5%, and < 6.5% Through Week 28 | HbA1c <6.5%: Week 28 | 14.3 percentage of participants |
| Placebo | Percentage of Participants Achieving HbA1c Goals of < 7%, <= 6.5%, and < 6.5% Through Week 28 | HbA1c < 7%: Week 0 | 38.1 percentage of participants |
| Placebo | Percentage of Participants Achieving HbA1c Goals of < 7%, <= 6.5%, and < 6.5% Through Week 28 | HbA1c < 7%: Week 4 | 42.9 percentage of participants |
| Placebo | Percentage of Participants Achieving HbA1c Goals of < 7%, <= 6.5%, and < 6.5% Through Week 28 | HbA1c < 7%: Week 12 | 33.3 percentage of participants |
| Placebo | Percentage of Participants Achieving HbA1c Goals of < 7%, <= 6.5%, and < 6.5% Through Week 28 | HbA1c < 7%: Week 20 | 35.7 percentage of participants |
| Placebo | Percentage of Participants Achieving HbA1c Goals of < 7%, <= 6.5%, and < 6.5% Through Week 28 | HbA1c < 7%: Week 28 | 28.6 percentage of participants |
| Placebo | Percentage of Participants Achieving HbA1c Goals of < 7%, <= 6.5%, and < 6.5% Through Week 28 | HbA1c <=6.5%: Week 0 | 16.7 percentage of participants |
| Placebo | Percentage of Participants Achieving HbA1c Goals of < 7%, <= 6.5%, and < 6.5% Through Week 28 | HbA1c <=6.5%: Week 4 | 23.8 percentage of participants |
| Placebo | Percentage of Participants Achieving HbA1c Goals of < 7%, <= 6.5%, and < 6.5% Through Week 28 | HbA1c <=6.5%: Week 12 | 23.8 percentage of participants |
| Placebo | Percentage of Participants Achieving HbA1c Goals of < 7%, <= 6.5%, and < 6.5% Through Week 28 | HbA1c <=6.5%: Week 20 | 19.0 percentage of participants |
| Placebo | Percentage of Participants Achieving HbA1c Goals of < 7%, <= 6.5%, and < 6.5% Through Week 28 | HbA1c <=6.5%: Week 28 | 19.0 percentage of participants |
| Placebo | Percentage of Participants Achieving HbA1c Goals of < 7%, <= 6.5%, and < 6.5% Through Week 28 | HbA1c <6.5%: Week 0 | 7.1 percentage of participants |
| Placebo | Percentage of Participants Achieving HbA1c Goals of < 7%, <= 6.5%, and < 6.5% Through Week 28 | HbA1c <6.5%: Week 4 | 21.4 percentage of participants |
| Placebo | Percentage of Participants Achieving HbA1c Goals of < 7%, <= 6.5%, and < 6.5% Through Week 28 | HbA1c <6.5%: Week 12 | 19.0 percentage of participants |
| Placebo | Percentage of Participants Achieving HbA1c Goals of < 7%, <= 6.5%, and < 6.5% Through Week 28 | HbA1c <6.5%: Week 20 | 19.0 percentage of participants |
Comparison: Treatment difference in HbA1c \< 7% at Week 28:~Treatment group comparison is based on CMH test stratified by screening HbA1c and background diabetes therapy strata. P-value is from the general association statistics.p-value: 0.562Cochran-Mantel-Haenszel
Comparison: Treatment difference in HbA1c \<= 6.5% at Week 28:~Treatment group comparison is based on CMH test stratified by screening HbA1c and background diabetes therapy strata. P-value is from the general association statistics.p-value: 0.621Cochran-Mantel-Haenszel
Comparison: Treatment difference in HbA1c \< 6.5% at Week 28:~Treatment group comparison is based on CMH test stratified by screening HbA1c and background diabetes therapy strata. P-value is from the general association statistics.p-value: 0.229Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Discontinuing the Study Due to Failure to Maintain Glycemic Control Through Week 28
Participants were discontinued from the study due to failure to maintain glycemic control if either discontinuation reason on summary case report form was Loss of glucose control or AE with lower level Medical Dictionary for Regulatory Activities (MedDRA) term Loss of control of blood sugar or Hyperglycaemia leading to study drug discontinuation, using MedDRA Version 23.0.
Time frame: Weeks 2, 4, 8, 12, 16, 20, 24 and 28
Population: The Full Analysis Set included all randomized participants who received at least 1 dose of randomized study medication. For analysis of efficacy, a decision was made with agreement by the European Medicines Agency and the Food and Drug Administration to pool participants from both exenatide groups (Total EBID) and compare this pooled group with placebo.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Total Exenatide Twice Daily (EBID) | Percentage of Participants Discontinuing the Study Due to Failure to Maintain Glycemic Control Through Week 28 | Week 2 | 0 percentage of participants |
| Total Exenatide Twice Daily (EBID) | Percentage of Participants Discontinuing the Study Due to Failure to Maintain Glycemic Control Through Week 28 | Week 4 | 0 percentage of participants |
| Total Exenatide Twice Daily (EBID) | Percentage of Participants Discontinuing the Study Due to Failure to Maintain Glycemic Control Through Week 28 | Week 8 | 0 percentage of participants |
| Total Exenatide Twice Daily (EBID) | Percentage of Participants Discontinuing the Study Due to Failure to Maintain Glycemic Control Through Week 28 | Week 12 | 1.4 percentage of participants |
| Total Exenatide Twice Daily (EBID) | Percentage of Participants Discontinuing the Study Due to Failure to Maintain Glycemic Control Through Week 28 | Week 16 | 1.4 percentage of participants |
| Total Exenatide Twice Daily (EBID) | Percentage of Participants Discontinuing the Study Due to Failure to Maintain Glycemic Control Through Week 28 | Week 20 | 0 percentage of participants |
| Total Exenatide Twice Daily (EBID) | Percentage of Participants Discontinuing the Study Due to Failure to Maintain Glycemic Control Through Week 28 | Week 24 | 0 percentage of participants |
| Total Exenatide Twice Daily (EBID) | Percentage of Participants Discontinuing the Study Due to Failure to Maintain Glycemic Control Through Week 28 | Week 28 | 1.6 percentage of participants |
| Placebo | Percentage of Participants Discontinuing the Study Due to Failure to Maintain Glycemic Control Through Week 28 | Week 28 | 0 percentage of participants |
| Placebo | Percentage of Participants Discontinuing the Study Due to Failure to Maintain Glycemic Control Through Week 28 | Week 2 | 0 percentage of participants |
| Placebo | Percentage of Participants Discontinuing the Study Due to Failure to Maintain Glycemic Control Through Week 28 | Week 16 | 0 percentage of participants |
| Placebo | Percentage of Participants Discontinuing the Study Due to Failure to Maintain Glycemic Control Through Week 28 | Week 4 | 2.4 percentage of participants |
| Placebo | Percentage of Participants Discontinuing the Study Due to Failure to Maintain Glycemic Control Through Week 28 | Week 24 | 6.9 percentage of participants |
| Placebo | Percentage of Participants Discontinuing the Study Due to Failure to Maintain Glycemic Control Through Week 28 | Week 8 | 0 percentage of participants |
| Placebo | Percentage of Participants Discontinuing the Study Due to Failure to Maintain Glycemic Control Through Week 28 | Week 20 | 14.7 percentage of participants |
| Placebo | Percentage of Participants Discontinuing the Study Due to Failure to Maintain Glycemic Control Through Week 28 | Week 12 | 5.0 percentage of participants |