E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10012602 |
E.1.2 | Term | Diabetes mellitus (incl subtypes) |
E.1.2 | System Organ Class | 100000004860 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the effect on glycemic control, as measured by glycosylated hemoglobin (HbA1c), of exenatide once weekly (EQW) following 24 weeks of treatment compared to placebo in children and adolescents with type 2 diabetes mellitus
To evaluate the safety and tolerability of EQW compared to placebo following 24 weeks of treatment in children and adolescents with type 2 diabetes mellitus |
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E.2.2 | Secondary objectives of the trial |
To compare the effects of EQW following 24 weeks of treatment to those achieved by placebo in children and adolescents with T2D on the following: Fasting plasma glucose concentration, Proportion of patients achieving HbA1c goals, Body weight and Tanner pubertal stage, Blood pressure and lipids
To assess the effects of long-term EQW therapy (~1 year) in children and adolescents with T2D on the following: Long-term safety and tolerability, Parameters related to glycemic control, including HbA1c, fasting plasma glucose concentration, and proportion of patients achieving HbA1c goals, Body weight and Tanner pubertal stage, Blood pressure and lipids
To examine the effect of exenatide once weekly on beta-cell function (HOMA-B) and insulin sensitivity (HOMA-S) as measured by the homeostatic model assessment (HOMA) in children and adolescents with T2D who are not taking insulin
Assess pk of exenatide once weekly in children and adolescents with T2D
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Mixed Meal Substudy, Amendment 3.0, 09 April 15 (Appendix F of protocol)
The primary objective of this exploratory substudy is: To evaluate the effect of exenatide once weekly on postprandial beta-cell function as assessed by C peptide secretion during a mixed meal test, following approximately 28 weeks of exenatide once weekly treatment and at approximately 10 to 12 weeks following cessation of drug therapy.
The secondary objective of this exploratory substudy is: To assess postprandial glucose and glucagon responses during a mixed meal test following approximately 28 weeks of exenatide once weekly treatment and at approximately 10 to 12 weeks following cessation of drug therapy.
Blood samples for pharmacokinetic measurements of plasma exenatide concentrations for potential future analysis will be collected within the 30 min prior to the start of the standardized meal |
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E.3 | Principal inclusion criteria |
Each patient must meet the following criteria to be enrolled in this study.
1. Is a child or an adolescent of 10 to <18 years old, at Visit 1 (Screening)
2. Has been diagnosed with type 2 diabetes mellitus per American Diabetes Association diagnostic criteria
3. HbA1c of 6.5% to 11.0%, inclusive, in patients not taking insulin/SU, and of 6.5% to 12.0%, inclusive, in patients taking insulin/SU, at Visit 1 (Screening)
4. Has a C-peptide of >0.6 ng/mL at Visit 1 (Screening)
5. Has been treated with diet and exercise alone or in combination with a stable dose of an oral antidiabetic agent (e.g., metformin and/or SU) and/or insulin for their type 2 diabetes for at least 2 months prior to Visit 1 (Screening)
6. Has a fasting plasma glucose concentration <280 mg/dL (15.5 mmol/L) at Visit 1(Screening) |
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E.4 | Principal exclusion criteria |
Patients who meet any of the following criteria will be excluded from the study.
1. Has a clinically significant medical condition that could potentially affect study participation and/or personal well-being, as judged by the Investigator, including but not limited to the following conditions: a. Hepatic disease (defined by aspartate or alanine transaminase >3.0 times the upper limit of normal (ULN), b. Renal disease or serum creatinine >1.5 mg/dL (132.6 μmol/L) (males) or 1.4 mg/dL (123.8 μmol/L) (females), c. Gastrointestinal disease deemed significant by the Investigator, d. Organ transplantation, e. Chronic infection (e.g., tuberculosis, human immunodeficiency virus, hepatitis B virus, or hepatitis C virus), f. Clinically significant malignant disease (with the exception of basal and squamous cell carcinoma of the skin) within 5 years of Visit 1 (Screening)
2. Has positive antibody titers to glutamic acid decarboxylase (GAD65) or islet cell antigen (ICA512) at Visit 1 (Screening)
3. Has a personal or family history of elevated calcitonin, calcitonin >100 ng/L, medullary thyroid carcinoma, or multiple endocrine neoplasia-2
4. Has ever used exenatide (exenatide once weekly [exenatide LAR], exenatide BID, BYETTA, or any other formulation) or any glucagon-like peptide-1 (GLP-1) receptor agonist (e.g., liraglutide [Victoza®])
5. Is pregnant |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in HbA1c from baseline Visit 2 (Week 0) to Visit 7 (Week 24) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1. Change in HbA1c
2. Change in fasting plasma glucose concentration
3. Proportions of patients achieving HbA1c goals of ≤6.5% and <7.0%
4. Change in body weight
5. Change in fasting insulin and C-peptide
6. Change in beta-cell function (HOMA-B) and insulin sensitivity (HOMA-S) as measured by HOMA in EQW patients not taking insulin
7. Change in lipids
8. Change in blood pressure
9. Plasma exenatide concentrations
10. Proportions of patients discontinuing the study, needing rescue due to failure to maintain glycemic control, and number of rescue episodes
11. Proportions of patients reporting different injection site reactions
12. Change in body mass index (BMI)
13. Change in body weight percentile and height percentile
14. Safety and tolerability endpoints including incidence of treatment emergent AEs, antibodies to exenatide, physical examinations, laboratory measurements (clinical, chemistry/hematology), and vital sign measurements
15. Change in calcitonin, pancreatic amylase, and lipase
16. Change in TSH, free T4, prolactin, cortisol, IGF-1, and DHEAS
17. Tanner pubertal stage |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1 Visit 2 to Visit 10 & interm.visit
2 Visit 2 to Visit 7, Visit 10, & interm.visit
3 Visit 7,Visit 10, and each intermediate visit
4 Visit 2 to Visit 7, Visit 10, & interm.visit
5 Visit 2 to Visit 7, Visit 10, & interm.visit
6 Visit 2 to Visit 7, Visit 10, & interm.visit
7 Visit 2 to Visit 5, Visit 7, Visit 10
8 Visit 2 to Visit 7, Visit 10, & interm.visit
9 Visit 2,Visit 7, Visit 10 & interm.visit
10 Visit 7, Visit 10 & interm.visit
11 Visit 3 to Visit 10
12,13, 14 Visit 2 to Visit 5,Visit 10, &interm.visit
15 Visit 2 to Visit 5 & Visit 10
16 Visit 2 to Visit 5,Visit 7,&Visit 10
17 Visit 2, Visit 5, Visit 7, Visit 9, & Visit 10 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 7 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Bulgaria |
Hungary |
Israel |
Kuwait |
Mexico |
Ukraine |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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LVLS. Following V11 (week 62) pts with height increase at least 5 mm between V8 and V11 will enter Extended Safety Follow-up Period (F/U pd). Please refer to Appendix E of protocol for further detail |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 7 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 8 |