Safety and Efficacy of Exenatide as Monotherapy and Adjunctive Therapy to Oral Antidiabetic Agents in Adolescents With Type 2 Diabetes

Study Overview
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Brief Summary
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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

Official Title
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Safety and Efficacy of Exenatide as Monotherapy and Adjunctive Therapy to Oral Antidiabetic Agents in Adolescents With Type 2 Diabetes.

Conditions
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Type 2 Diabetes

Intervention / Treatment
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* Drug: Placebo
* Drug: Exenatide
* Drug: Exenatide


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Subcutaneous injection, twice a day | Drug: Placebo<br>* Subcutaneous injection, twice a day<br>|
| Experimental: Exenatide 5 µg<br>Subcutaneous injection, twice a day | Drug: Exenatide<br>* Subcutaneous injection, 5 µg, twice a day<br>|
| Experimental: Exenatide 10 µg<br>Subcutaneous injection, twice a day | Drug: Exenatide<br>* Subcutaneous injection,10 µg, twice a day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline (Day 1) and Week 28 | 
| 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). | From 1 day after the Week 28/ED visit to 3 years after Week 28/ED visit. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Weeks 0, 4, 12, 20 and 28 | 
| 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. | Baseline (Day 1) up to Week 28 | 
| 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. | Baseline (Day 1) and Week 28 | 
| 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. | Pre-meal and 2 hours post-meal on Baseline (Day 1) and Week 28 | 
| 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. | Baseline (Day 1) and Week 28 | 
| 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. | Baseline (Day 1) and Week 28 | 
| 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. | Weeks 2, 4, 8, 12, 16, 20, 24 and 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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diabetes, adolescents, exenatide, Astra Zeneca