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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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10012594 |
E.1.2 | Term | Diabetes |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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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 |
The primary objective of this study is to test the hypothesis that exenatide QW given once weekly for 26 weeks is superior to a titration of insulin detemir, given once or twice daily (titrated to reach a target of pre-breakfast and pre-dinner glucose concentrations of <5.5 mmol/L) when given for 26 weeks in the treatment of patients with type 2 diabetes not adequately controlled using OAD therapy. The primary efficacy measure will be assessed by the proportion of patients on each therapy who have achieved HbA1c concentration ≤7.0% with weight loss (≥1.0 kg) at endpoint. |
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E.2.2 | Secondary objectives of the trial |
The secondary efficacy measure of the study are to compare exenatide QW with insulin detemir over 26 weeks with respect to:
•the proportion of patients who have achieved HbA1c ≤7.0% with weight loss (≥1.0 kg) at 12 weeks.
•the proportion of patients who have achieved HbA1c ≤7.4% with weight loss (≥1.0 kg) at endpoint
•the proportion of patients who have achieved HbA1c ≤7.0% and ≤7.4%, with minimal weight gain (≤1 kg) at endpoint
•HbA1c change from baseline
•change in body weight
•the proportion of patients achieving HbA1c ≤7.4%, ≤7.0% and ≤6.5%
•change in fasting serum glucose
•7-point self-monitored blood glucose (SMBG) profile (blood glucose measurements before and 2 hours after the start of the morning, midday, and evening meals, and at bedtime)
•changes in cardiovascular risk parameters:
•incidence and rate of hypoglycaemic events
•resource utilisation
•safety and tolerability
•health outcomes.
•safety and tolerability (including anti exenatide antibodies).
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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 |
Protocol Sample Banking Addendum H8O-EW-GWDL(1): Efficacy of Once-Weekly Exenatide versus Once or Twice Daily Insulin Detemir in Patients with Type 2 Diabetes Treated with Metformin Alone or in Combination with Sulphonylurea.
Protocol Addendum (1) Approved by Lilly: 18 May 2009
Samples are collected and banked for research to identify the genes associated with diseases and/or response to clinical trial medication or other medication taken during the trial.
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E.3 | Principal inclusion criteria |
[1] Present with type 2 diabetes based on the disease diagnostic criteria as described by the World Health Organization (WHO) (refer to Attachment GWDL.3).
[2] Are at least 18 years of age at screening.
[3] Have suboptimal glycaemic control as evidenced by an HbA1c 7.1% to 10.0%, inclusive.
[4] Have a history of stable body weight (not varying by >5% for at least 3 months prior to screening).
[5] Have a body mass index (BMI) of 25 kg/m2 to 45 kg/m2, inclusive.
[6] Are receiving metformin at a stable dose (consistent with country specific requirements) of a minimum of 1000mg for at least 3 months prior to visit 3
Or
Are receiving metformin at a minimum dose (consistent with country specific requirements) of 1000mg and sulphonylurea (as separate medications not as a fixed dose combination) at stable doses for 3 months prior to visit 3.
[7] For females of child-bearing potential (not surgically sterilised and between menarche and 1-year postmenopause) only:
•Are not breastfeeding
•Test negative for pregnancy at the time of screening based on a urine pregnancy test
•Intend not to become pregnant during the study
•Have practiced a reliable method of birth control (e.g. use of oral contraceptives or Norplant®; diaphragms with contraceptive jelly; cervical caps with contraceptive jelly; condoms with contraceptive foam; intrauterine devices; partner with vasectomy for at least 6 weeks prior to screening)
•Agree to continue to use a reliable method of birth control (as above) during the study, as determined by the investigator.
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E.4 | Principal exclusion criteria |
[8] Are Lilly, Amylin, or Alkermes employees.
[9] Are investigator site personnel directly affiliated with this study and/or their immediate families; immediate family is defined as a spouse, parent, child or sibling, whether biological or legally adopted.
[10] Have had a clinically significant history of cardiac disease or presence of active cardiac disease within the year prior to inclusion in the study, including myocardial infarction, clinically significant arrhythmia, unstable angina, moderate to severe congestive heart failure (New York Heart Association Class III or IV), coronary artery bypass surgery or angioplasty; or are expected to require coronary artery bypass surgery or angioplasty during the course of the study.
[11] Have obvious clinical signs or symptoms of liver disease, acute or chronic hepatitis, alanine aminotransaminase (ALT), or serum glutamic pyruvic transaminase (SGPT), greater than three times the upper limit of the reference range.
[12] Have a history of renal transplantation or are currently receiving renal dialysis or have a creatinine clearance of <30 mL/min (using the Cockcroft-Gault formula).
[13] Have active or untreated malignancy, or have been in remission from clinically significant malignancy (other than basal cell or squamous cell skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer) for less than 5 years.
[14] Have known haemoglobinopathy or chronic anaemia (haemoglobin concentration <11.5 g/dL [115 g/L] for males, <10.5 g/dL [105 g/L] for females).
[15] Patients with a history of severe gastrointestinal disorder (e.g. gastroparesis)
[16] Have had greater than three episodes of major hypoglycaemia within 6 months prior to screening (refer to Section 9.5.1.1 for more information on hypoglycaemia).
[17] Have any contraindication for the OAD that they have been using.
[18] Have a known allergy or hypersensitivity to insulin detemir, exenatide or excipients contained in these agents.
[19] Are known to have active proliferative retinopathy.
[20] Have fasting triglycerides levels > 500mg/dL (>5.64mmol/L)
[21] Have been treated within 4 weeks of screening with systemic glucocorticoid therapy by oral, intravenous (IV) or intramuscular (IM) route, or are regularly treated with potent, inhaled intranasal steroids that are known to have a high rate of systemic absorption. Exceptions to this criterion include patients who are receiving glucocorticoid therapy for corticotropic hypopituitary deficiency (e.g. Addison disease).
[22] Have been treated with drugs that promote weight loss, within 3 months of screening.
[23] Have been treated for longer than 2 weeks with any of the following excluded medications within 3 months prior to screening:
•insulin
•alpha-glucosidase
•meglitinides
•Byetta® (exenatide BID formulation)
•thiazolidinediones (TZD)
•dipeptidyl peptidase (DPP)-4 inhibitors.
[24] Have had an organ transplant.
[25] Have donated blood within 30 days of screening.
[26] Have previously completed or withdrawn from this study or any other study investigating exenatide QW.
[27] Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry.
[28] Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an off-label use of an investigational drug or device (other than the study drug/device used in this study), or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study.
[29] Have a history of confirmed pancreatitis.
[30] Have any other condition (including known drug or alcohol abuse or psychiatric disorder) that, in the opinion of the investigator, renders them unable to understand the nature, scope and possible consequences of the study or precludes them from following and completing the protocol.
[31] Fail to satisfy the investigator of suitability to participate for any other reason.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy measure will be assessed by the proportion of patients on each therapy who have achieved HbA1c concentration ≤7.0% with weight loss (≥1.0 kg) at endpoint. |
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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) |
The secondary efficacy measure of the study are to compare exenatide QW with insulin detemir over 26 weeks with respect to:
•the proportion of patients who have achieved HbA1c ≤7.0% with weight loss (≥1.0 kg) at 12 weeks.
•the proportion of patients who have achieved HbA1c ≤7.4% with weight loss (≥1.0 kg) at endpoint
•the proportion of patients who have achieved HbA1c ≤7.0% and ≤7.4%, with minimal weight gain (≤1 kg) at endpoint
•HbA1c change from baseline
•change in body weight
•the proportion of patients achieving HbA1c ≤7.4%, ≤7.0% and ≤6.5%
•change in fasting serum glucose
•7-point self-monitored blood glucose (SMBG) profile (blood glucose measurements before and 2 hours after the start of the morning, midday, and evening meals, and at bedtime)
•changes in cardiovascular risk parameters:
oBMI (body mass index)
owaist circumference
osystolic and diastolic blood pressure (SBP and DBP)
olipid profile
ochanges in plasminogen activator inhibitor (PAI1)
ochanges in high sensitivity C reactive protein (hsCRP) concentrations
ochanges in adiponectin levels
•incidence and rate of hypoglycaemic events
•resource utilisation
•safety and tolerability
•health outcomes.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
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 | Yes |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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) | Yes |
E.8.2.2 | Placebo | No |
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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 35 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | No |
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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End of study (trial) is the date of the last visit or last scheduled procedure shown in the Study Schedule for the last active subject in Study Period III. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 3 |