| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Non insulin-dependent diabetes mellitus |
|
| 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 | 19.1 |
| 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 |
| To evaluate the glycemic effectiveness of once-weekly albiglutide as replacement of prandial insulin in subjects with T2DM receiving basal-bolus insulin therapy. |
|
| E.2.2 | Secondary objectives of the trial |
- To determine the proportion of subjects treated with once-weekly albiglutide that are
able to replace prandial insulin without the need for re-introduction of insulin lispro.
- To demonstrate a significant difference in the frequency of hypoglycemic events between treatment groups.
- To demonstrate a significant difference in body weight between treatment groups.
- To demonstrate a significant reduction in total daily dose of insulin between treatment
groups. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects eligible for enrollment in the study must meet all of the following criteria:
1. Male or female, 18 to 75 years of age (inclusive at the time of Screening) with
T2DM
2. HbA1c ≥7.0% and ≤9.5% at Screening. If the first screening HbA1c does not meet the eligibility criterion, the HbA1c value may be checked up to 2 times during Screening, and if the average of these determinations meets the criterion, the subject may be eligible for further participation in the study
3. Currently treated with a basal-bolus insulin regimen (with or without metformin) for at least 3 months before Screening. The subject must be taking the following:
•Basal insulin (1 or 2 daily injections of neutral protamine Hagedorn insulin, insulin glargine, insulin detemir, or insulin degludec)
AND
• Bolus insulin (at least 2 injections of regular insulin, insulin glulisine, insulin aspart, or insulin lispro) with a total daily dose of bolus insulin ≤70 units
•In addition, the total daily dose of insulin must be ≤140 units
•If taking metformin, a stable dose for at least 8 weeks before Screening
Note: Subject should not have received any other antidiabetic medication within 30 days before Screening (e.g., GLP-1R agonist, dipeptidyl peptidase-IV inhibitor, SU, meglitinide, sodium-glucose transporter 2 inhibitor or thiazolidinedione). Subjects receiving commercially available premixed basal and prandial insulin are not eligible for this study.
4. Fasting C-peptide ≥0.8 ng/mL (≥0.26 nmol/L). If the fasting C-peptide is <0.8 ng/mL (<0.26 nmol/L) but stimulated C-peptide 90 minutes after a standardized mixed meal is 1.5 ng/mL (0.5 nmol/L), the subject may be eligible for further
participation in the study [Jones, 2013; Maldonado, 2005]
Note: Plasma glucose will also be measured 90 minutes after the standardized mixed meal; if the concurrent plasma glucose collected 90 minutes after the standardized mixed meal is not 144.0 mg/dL (8.0 mmol/L), the stimulated C-peptide test may be repeated during an unscheduled visit.
5. Body mass index ≤40 kg/m2
6. Thyroid-stimulating hormone (TSH) level is normal or clinically euthyroid as demonstrated by further thyroid tests (e.g., free T4)
7. Female subjects of childbearing potential (i.e., not surgically sterile and/or not postmenopausal) must be practicing adequate contraception (as defined below) for the duration of participation in the study including the 4-week Posttreatment Follow-up Period
•Abstinence from penile-vaginal intercourse, when this is the female’s preferred and usual lifestyle
•Oral contraceptive, either combined or progestogen alone
Note: For subjects participating at sites in Germany, progestogen-only pills are only acceptable if they have a Pearl Index of less than 1.0 (e.g., those containing 75 ng desogestrel)
•Injectable progestogen
•Implants of etonogestrel or levonorgestrel
•Estrogenic vaginal ring
•Percutaneous contraceptive patches
•Intrauterine device or intrauterine system that has a failure rate of less than 1% per year when used consistently and correctly as stated in the product label
•Male partner sterilization prior to the female subject’s entry into the study, and this male is the sole partner for that subject. The information on the male sterility can come from the site personnel’s review of the female subject’s medical records, medical examination of the subject and/or semen analysis, or interview with the female subject on her male partner’s his medical history.
•Male condom combined with a female diaphragm, either with or without a vaginal spermicide (foam, gel, film, cream, or suppository) [Hatcher, 2007]
8. Willing and able to comply with all study procedures including performance of frequent SMBG profiles and use of an e-diary according to the protocol
9. Able and willing to provide written informed consent after a thorough explanation of the study by the investigator or designee, which will include the opportunity for the subjects to ask questions
10.Suitable for participation in a treat-to-target study, including intensified basal bolus insulin therapy utilizing the prespecified glycemic targets defined in the protocol. |
|
| E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria must not be enrolled in the study:
1. Type 1 diabetes mellitus
2. History of cancer that has not been in full remission for at least 3 years before Screening. (A history of squamous cell or basal cell carcinoma of the skin or treated cervical intra-epithelial neoplasia I or II is allowed)
3. Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2
4. Current symptomatic biliary disease or history of acute or chronic pancreatitis
5. Severe gastroparesis, i.e., requiring regular therapy within 6 months before Screening
6. History of significant GI surgery that in the opinion of the investigator is likely to significantly affect upper GI or pancreatic function (e.g., gastric bypass and banding, antrectomy, Roux-en-Y bypass, gastric vagotomy, small bowel resection, or surgeries thought to significantly affect upper GI function)
7. History of hypoglycemia unawareness (i.e., the absence of autonomic warning symptoms before the development of neuroglycopenic symptoms such as blurred vision, difficulty speaking, feeling faint, difficulty thinking, and confusion)
8. Diabetic complications (e.g., active proliferative retinopathy or severe diabetic neuropathy) or any other clinically significant abnormality (including a psychiatric disorder) that, in the opinion of the investigator, may pose additional risk in administering the investigational product
9. Clinically significant CV and/or cerebrovascular disease within 3 months before Screening including, but not limited to, the following:
- Stroke or transient ischemic attack
- Acute coronary syndrome (myocardial infarction [MI] or unstable angina not responsive to nitroglycerin)
- Cardiac surgery or percutaneous coronary procedure
10. Any history of New York Heart Association class III or IV heart failure
11. Alanine aminotransferase (ALT) >2.5 x upper limit of normal (ULN) or bilirubin > 1.5 x ULN (isolated bilirubin> 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%)
12. Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice), cirrhosis, known biliary abnormalities (with the exception of Gilbert’s
syndrome or asymptomatic gallstones). (Chronic stable hepatitis B and C are acceptable if subject otherwise meets entry criteria and is not on active antiviral treatment [e.g., presence of hepatitis B surface antigen or positive hepatitis C test result within 3 months of Screening])
13. Hemoglobin <11 g/dL (<110 g/L) for male subjects and <10 g/dL (<100 g/L) for female subjects at Screening
14. Estimated glomerular filtration rate (eGFR) ≤30 mL/min/1.73 m2 (calculated using the Modification of Diet in Renal Disease [MDRD] formula) at Screening
Note: As the use of metformin in subjects with varying degrees of renal function may differ from country to country, use of metformin should be in accordance with the metformin product label within the participating country.
15. Fasting triglyceride level >750 mg/dL at Screening
16. Hemoglobinopathy that may affect proper interpretation of HbA1c
17. Known allergy to albiglutide or any product components (including yeast and human albumin), any other GLP-1 analogue, insulin, or other study medication’s excipients OR other contraindications (per the prescribing information) for the use of potential study medications (e.g., insulin glargine, insulin lispro)
18. Use of oral or systemically injected glucocorticoids within the 3 months before randomization or high likelihood of a requirement for prolonged treatment (>1 week) in the 6 months following randomization. However, short courses of oral steroids (single dose or multiple doses for up to 7 days) may be permitted provided these cases are discussed with the medical monitor. Inhaled, intra-articular, epidural, and topical corticosteroids are allowed
19. Female subject is pregnant (confirmed by laboratory testing) or lactating
20. Receipt of any investigational drug within the 30 days or 5 half-lives, whichever is longer, before Screening, a history of receipt of an investigational antidiabetic drug within the 3 months before randomization, or receipt of albiglutide in previous studies.
21. Persons who have been put in an institution because of official or legal order
22. Employees (or the employees's relatives) of the sponsor, the contract research organisation, or the investigative site, including the investigator or site staff |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary:
- Change from Baseline in HbA1c at Week 26
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Key Secondary:
- Proportion of subjects treated with once-weekly albiglutide that are able to discontinue insulin lispro at Week 4 and do not meet prespecified criteria for severe, persistent hyperglycemia through Week 26.
- Percentage of subjects with severe or documented symptomatic hypoglycemia through Week 26.
- Change from Baseline in body weight at Week 26 and over time.
- Total daily insulin dose at Week 26. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | 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 | 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 | Yes |
| 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 | 94 |
| 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 |
| Brazil |
| Canada |
| France |
| Germany |
| Hungary |
| Italy |
| Korea, Republic of |
| Mexico |
| Philippines |
| Poland |
| South Africa |
| Spain |
| United Kingdom |
| United States |
|
| 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
|
| The end of the study is when the last subject completes the final follow-up visit (Week 30). |
|
| 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 | 0 |
| 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 | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 15 |
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