E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10045242 |
E.1.2 | Term | Type II diabetes mellitus |
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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 is to estimate the difference in change in HbA1c from baseline to treatment endpoint (26 weeks) between 2 mg exenatide once weekly and 1.8 mg once-daily liraglutide in subjects with type 2 diabetes and inadequate glycemic control with lifestyle modification and oral antidiabetic agents (OADs) (metformin, a sulfonylurea [SU], metformin plus an SU, or metformin plus pioglitazone). Superiority of exenatide once weekly with respect to change in HbA1c will be concluded if the upper limit of the 95% confidence interval for the treatment difference (exenatide once weekly minus liraglutide) is less than zero. Non-inferiority will be concluded if the upper limit of the confidence interval is ≥0 and <0.25%. |
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E.2.2 | Secondary objectives of the trial |
To compare exenatide once weekly to once-daily liraglutide over 26 weeks with respect to: the proportion of subjects achieving HbA1c ≤7% and ≤6.5% fasting serum glucose change in body weight serum lipids (total cholesterol [TC], high-density lipoprotein cholesterol [HDL-C], fasting TG, calculated low-density lipoprotein cholesterol [LDL-C]) safety and tolerability hypoglycemia subject-reported health outcomes change in systolic blood pressure (SBP) and diastolic blood pressure (DBP), as measured while subject is seated |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects (males or females) are eligible to be included in the study only if they meet all of the following criteria: [1] Present with type 2 diabetes based on the disease diagnostic criteria as described by the World Health Organization (WHO); refer to Protocol Attachment GWDE.3 for the complete description. [2] Are at least 18 years of age at screening. [3] Have suboptimal glycemic control as evidenced by an HbA1c measurement at Visit 1 between 7.1% and 11.0%, inclusive. [4] Have a body mass index (BMI) ≤45 kg/m2. [5] Have a history of stable body weight (not varying by >5%) for at least 3 months prior to Visit 1. [6] Have been treated with lifestyle modification (diet and exercise) and with one of the following single OADs or combinations of OADs administered at maximum tolerated dose: metformin SU metformin plus an SU metformin plus pioglitazone According to the following parameters: Subjects taking metformin or SU must have been taking the medication(s) for at least 3 months (stable dose for at least 8 weeks) prior to Visit 1. Subjects taking pioglitazone must have been taking the medication for at least 4 months (stable dose for at least 12 weeks) prior to Visit 1. If combination OAD preparations are used, the total daily dose of each component must meet the criteria outlined above. [7] This inclusion criterion applies to females of child-bearing potential (not surgically sterilized and between menarche and 1-year post menopause) only. Page 29 Exenetide H8O-MC-GWDE Protocol Confidential Are not breastfeeding. Test negative for pregnancy at the time of screening based on a blood serum 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 approved hormonal implant; diaphragms with contraceptive jelly; cervical caps with contraceptive jelly, condoms with contraceptive foam; intrauterine devices; partner with vasectomy; or abstinence) for at least 6 weeks prior to screening. Agree to continue to use a reliable method of birth control (see above) during the study, as determined by the investigator. |
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E.4 | Principal exclusion criteria |
Subjects will be excluded from the study if they meet any of the following 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] Presence of active cardiac disease within 3 months of Visit 1, including myocardial infarction, clinically significant arrhythmia, unstable angina, coronary artery bypass surgery, or angioplasty; or are expected to require coronary artery bypass surgery or angioplasty during the course of the study. Subjects with stable cardiac disease are not excluded. [11] Presence or history of severe congestive heart failure (New York Heart Association Class IV [CCNYHA 1994]). See Protocol Attachment GWDE.4 for descriptions of cardiac disease classifications. Either the protocol or local label for the concomitant OADs should be followed, whichever is more restrictive. [12] Have clinically significant history or presence of inflammatory bowel disease or other severe gastrointestinal diseases, particularly those which may impact gastric emptying, such as gastroparesis, or pyloric stenosis, or subjects who have had gastric bypass surgery or gastric banding surgery. [13] Have a presence of medullary carcinoma or MEN II (multiple endocrine neoplasia) OR have a family history of medullary carcinoma or MEN II. Page 30 Exenetide H8O-MC-GWDE Protocol Confidential [14] 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. More stringent local label exclusions may apply. [15] Have a history of renal transplantation, or are currently receiving renal dialysis, or have an estimated creatinine clearance <60 mL/min as calculated using the Cockroft-Gault equation. If taking metformin, have serum creatinine ≥1.5 mg/dL (132 μmol/L) for males and ≥1.4 mg/dL (110 μmol/L) for females. Either the protocol or local label for concomitant OADs should be followed, whichever is more restrictive. [16] 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. [17] Have a history of, or currently have, acute or chronic pancreatitis. [18] Have known hemoglobinopathy, hemolytic anemia, or chronic anemia (hemoglobin concentration <11.5 g/dL [115 g/L] for males, <10.5 g/dL [105 g/L] for females) or any other condition known to interfere with the HbA1c methodology. [19] Have ≥2 episodes of major hypoglycemia within 6 months prior to Visit 1. Refer to Section 9.5.4.1 for more information on hypoglycemia. [20] Have any contraindication, allergy, or hypersensitivity for the study drug (exenatide once weekly or liraglutide), exenatide twice daily, the OAD(s) being used, or the excipients contained in these agents. [21] If taking metformin and have a contraindication to metformin use, including known metabolic or lactic acidosis, or any condition associated with hypoperfusion, hypoxemia, dehydration, or sepsis. [22] Have been treated within 8 weeks of Visit 1 with systemic glucocorticoid therapy by oral, intravenous, intra-articular, or intramuscular route. [23] Have been treated with drugs that promote weight loss (e.g., Xenical� [orlistat], Meridia� [sibutramine], Acomplia� [rimonabant], Acutrim� [phenylpropanolamine], or similar over-the-counter medications) within 3 months of Visit 1. [24] Have taken any of the following excluded medications for more than 1 week within the 3 months prior to Visit 1, or have taken any of t |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy measure is change in HbAlc |
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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 | 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 | 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.8.3 |
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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 73 |
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 | Information not present in EudraCT |
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 |
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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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |