| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045242 |
| E.1.2 | Term | Type II diabetes mellitus |
| E.1.2 | System Organ Class | 100000004861 |
|
| 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 the study is to evaluate the efficacy of albiglutide administered in combination with metformin and glimepiride compared with metformin plus glimepiride and placebo and with metformin plus glimepiride and pioglitazone on HbA1c change from Baseline at Week 52. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary efficacy objectives at time points to be specified in the statistical analysis plan (SAP) include the following evaluations of treatment with albiglutide administered in combination with metformin and glimepiride compared with metformin plus glimepiride and placebo and with metformin plus glimepiride and pioglitazone:
• HbA1c change from Baseline over time
• Other measures of glycemic control, including fasting plasma glucose (FPG), time to hyperglycemia rescue, and incidence of clinically meaningful levels of response in HbA1c (i.e., the proportion of subjects at or below treatment goal of 6.5%, 7.0%, and 7.5%)
• Changes from Baseline in body weight
• Population PK of albiglutide and the effect of plasma concentrations of albiglutide on glycemic control (population PK/PD)
|
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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 |
PHARMACOGENETIC SUB-STUDY IN ASSOCIATION WITH STUDY GLP112757
The objective of the pharmacogenetics research (if there is a potential unexpected or unexplained variation) is to investigate a possible genetic relationship to handling or response to albiglutide. |
|
| E.3 | Principal inclusion criteria |
Subjects eligible for enrollment in the study must meet all of the following criteria:
1. Male or female, 18 years of age or older, with a historical diagnosis of type 2 diabetes mellitus who is currently treated with metformin and a sulfonylurea but who is experiencing inadequate glycemic control. The subject should have received at least 1500 mg metformin daily and a sulfonylurea dose that is equivalent to at least 4 mg of glimepiride for at least the 3 months before Screening (see Section 3.1.2). Subjects who are receiving greater than 4 mg of glimepiride may be downtitrated to 4 mg of glimepiride at Screening. After Screening, the metformin and glimepiride doses must be stable for at least 8 weeks before randomization. Additional details regarding sulfonylurea dose equivalence is provided in the SPM/ISFN. Subjects with a documented MTD of <1500 mg metformin may also be enrolled if this dose has been stable for 8 weeks before randomization. The subject should not have received >7 contiguous days of any antidiabetic agents other than metformin and a sulfonylurea within the 3 months before Screening.
2. BMI ≥20 kg/m2 and ≤45 kg/m2
3. Fasting C-peptide ≥0.8 ng/mL (≥0.26 nmol/L)
4. HbA1c between 7.0% and 10.0%, inclusive, at Visit 7 (Week -1). The HbA1c value may be checked up to 4 times, and if the average of these determinations meets the criterion, the subject may be randomly assigned to treatment
5. For the regular use of other medications (does not include medications excluded by the protocol [see Section 5.6.2, for example, weight loss medications are excluded]), it is preferred that subjects be on a stable dose for at least 4 weeks before Screening; however, as necessary during the Run-in/Stabilization Period and the Treatment Period, prescription or over-the-counter medications are allowed and may be adjusted by the investigator to optimize treatment (e.g., increase or decrease of medication to treat blood pressure or hyperlipidemia in accordance with accepted local medical practice and relevant guidance documents)
6. Use of oral or systemically injected glucocorticoids is generally not allowed within the 3 months before randomization; however, short courses of oral steroids (single dose or multiple doses for up to 2 days) may be permitted provided these cases are discussed with the medical monitor. Inhaled, intra-articular, and topical corticosteroids are allowed
7. Hemoglobin ≥11 g/dL (≥110 g/L) for male subjects and ≥10 g/dL (≥100 g/L) for female subjects
8. Creatinine clearance >60 mL/min (calculated using the Cockcroft-Gault formula)
9. Thyroid-stimulating hormone level is normal or clinically euthyroid as demonstrated by further thyroid tests (e.g., T4, T3, thyroid-binding globulin)
10. Female subjects of childbearing potential (i.e., not surgically sterile and/or not postmenopausal) must be practicing adequate contraception. Methods of adequate contraception include the following: abstinence, injectable progestogen, implants of levonorgestrel, estrogenic vaginal ring, percutaneous contraceptive patches, intrauterine device or intrauterine system, male partner sterilization (vasectomy with documentation of azoospermia) before the female subjects entry into the study and this male partner is the sole partner for that subject, double-barrier method (condom and occlusive cap plus nonoxynol-9), or oral contraceptives in combination with a second method of contraception (e.g., condom and occlusive cap). Adequate contraception must be practiced for the duration of participation in the study including the 8-week Posttreatment Follow-up Period
11. Able and willing to monitor his or her own blood glucose concentrations with a home glucose monitor
12. No major illness or debility that in the investigator’s opinion prohibits the subject from completing the study
13. Able and willing to provide written informed consent |
|
| E.4 | Principal exclusion criteria |
1.History of cancer, other than squamous cell or basal cell carcinoma of the skin, that has not been in full remission for at least 3 years before Screening. (A history of treated cervical intraepithelial neoplasia I or cervical intraepithelial neoplasia II is allowed)
2.History of treated diabetic gastroparesis
3.Current ongoing symptomatic biliary disease or history of pancreatitis
4.History of significant gastrointestinal surgery, including gastric bypass and banding, antrectomy, Roux-en-Y bypass, gastric vagotomy, small bowel resection, or surgeries thought to significantly affect upper gastrointestinal function
5.Recent (as defined below) clinically significant cardiovascular and/or cerebrovascular disease including, but not limited to, the following:
•Previous history of stroke or transient ischemic attack within 1 month before Screening. However, subjects who are deemed clinically stable by the investigator may be enrolled 1 month after the cerebrovascular event
•Acute coronary syndrome, which includes the following:
•Documented MI within the 2 months before Screening and during the period up until receiving the first dose of study medication
•Any cardiac surgery including percutaneous transluminal coronary angioplasty, coronary stent placement, or coronary artery bypass graft surgery within the 2 months before Screening and during the period up until receiving the first dose of study medication
•Unstable angina not responsive to nitroglycerin within the 2 months before Screening and during the period up until receiving the first dose of study medication
•Unstable cardiac rhythm; however, as an example, controlled atrial fibrillation is allowed
•Current or history of heart failure (New York Heart Association class I to IV). Note: The starting dose of pioglitazone in this protocol is 30 mg daily. Investigators must consult the approved product labeling for pioglitazone in their country to determine a subject’s eligibility to participate in this study
•Resting systolic pressure is >160 mm Hg and/or diastolic pressure >100 mm Hg. If the subject’s systolic blood pressure is >160 mg Hg or the subject’s diastolic blood pressure is >100 mg Hg at Screening, blood pressure reading may be repeated at 5 minute intervals for a total of 3 determinations. If the average of the systolic or diastolic pressure readings still does not meet the criteria, the subject can be treated and rescreened. It is preferred that subjects be on a stable dose of medication for at least 4 weeks before being rescreened; however, when stable, they may be rescreened at the discretion of the investigator
Should a subject not meet this criterion on Visit 8 (first dose of study medication following the randomization visit), the subject may continue in the study at the discretion of the investigator with the understanding that the subject’s hypertension will be monitored and treated in accordance with accepted local medical practice and relevant guidance documents.
•Mean QTc interval (Fridericia) >470 ms confirmed by a central reader at Screening
6.Hemoglobinopathy that may affect determination of HbA1c
7. History of human immunodeficiency virus infection
9.ALT or aspartate aminotransferase (AST) >2.5 × ULN
10.Fasting triglyceride level >850 mg/dL at Screening or Week -1 (Visit 7). If the subject’s triglyceride level is >500 mg/dL at Screening and Week -1 (Visit 7), the subject is excluded from the study. If the subject meets the aforementioned exclusion criterion for triglycerides, the subject can be treated and rescreened. Treated subjects must be on a stable dose of medication for at least 4 weeks before being rescreened
11.Acute symptomatic (within 3 months before Screening) infection with hepatitis B; however, subjects with past or chronic hepatitis B or hepatitis C are allowed provided the requirements for ALT, AST, and total bilirubin are met
14.Positive urine drug screen result at Screening, unless the subject is taking a medically approved medication for which a positive drug screen simply verifies the use of this medication
17.Known allergy to any GLP-1 analogue, glimepiride, pioglitazone, other study medications' excipients, excipients of albiglutide, or Baker's yeast
18.History of type 1 diabetes, diabetic complications (e.g., active proliferative retinopathy or severe diabetic neuropathy) that in the opinion of the investigator would preclude effective participation in the study, or a history of ketoacidosis or hyperosmolar coma
19.Contraindications (as per the prescribing information) for the use of either background or potential randomized study medication (e.g., pioglitazone)
21.History of or family history of medullary carcinoma
22.History of or family history of multiple endocrine neoplasia type 2
For exclusion nos 8, 12, 13, 15, 16 and 20 , please refer to the protocol |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint will be Week 52 HbA1c change from Baseline |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| 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 | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 28 |
| 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 |
|
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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