Safety and Efficacy of Albiglutide + Insulin Glargine Versus Insulin Lispro + Insulin Glargine Subjects With Type 2 Diabetes Mellitus

GlaxoSmithKline (GSK)

Status and phase: Completed; Phase 3

Conditions: Diabetes Mellitus, Type 2

Treatments: Drug: Albiglutide; Drug: Insulin Glargine and Insulin Lispro

Study type: Interventional

Funder types: Industry

Identifiers

NCT02229227

2014-001821-34 (EudraCT Number)

200977

Details and patient eligibility

About

This Phase IIIb, randomized, open-label, parallel group, active control, multicenter, treat to-target study of 26 weeks' treatment duration will evaluate the efficacy and safety of once-weekly albiglutide as replacement of prandial insulin in subjects with type 2 diabetes mellitus (T2DM) failing to achieve adequate glycemic control on their current basal bolus insulin regimen (with or without metformin). Approximately 794 subjects will be randomly assigned in a 1:1 ratio to 1 of 2 treatment groups: albiglutide + insulin glargine (with insulin lispro discontinuation at Week 4) (with or without metformin) or to intensification of insulin glargine + insulin lispro (with or without metformin). The study will comprise 4 study periods : Screening (2 weeks), Standardization (4 weeks), Treatment (26 weeks), and Post treatment Follow up (4 weeks). The total duration of a subject's participation will be approximately 36 weeks.

Enrollment: 814 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Male or female, 18 years of age or older (inclusive at the time of Screening) with T2DM
• HbA1c >= 7.0% and <= 9.0% at Screening.
• 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., glucagon-like peptide-1 receptor (GLP-1R) agonist, dipeptidyl peptidase-IV inhibitor, SU, or thiazolidinedione). Subjects receiving commercially available premixed basal and prandial insulin are not eligible for this study.
• Fasting C-peptide >= 0.8 nanogram (ng) per milliliter (mL) [>= 0.26 nanomoles per litre (nmol/L)]
• Body mass index <= 40 kilogram per square meter( kg/m^2)
• Thyroid-stimulating hormone (TSH) level is normal or clinically euthyroid as demonstrated by further thyroid tests (e.g., free T4)
• Female subjects of childbearing potential (i.e., not surgically sterile and/or not postmenopausal) must be practicing adequate contraception (as defined in the protocol) for the duration of participation in the study including the 4-week post treatment Follow-up Period..
• Willing and able to comply with all study procedures including performance of frequent self-monitored blood glucose (SMBG) profiles according to the protocol
• Able and willing to provide written informed consent

Exclusion criteria

• Type 1 diabetes mellitus
• 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)
• Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2
• Current symptomatic biliary disease or history of acute or chronic pancreatitis
• Severe gastroparesis, i.e., requiring regular therapy within 6 months before Screening
• 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]
• History of severe hypoglycemia unawareness
• 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
• 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
• Current or history of heart failure (New York Heart Association class III or IV)
• Alanine aminotransferase (ALT) >2.5 × upper limit of normal (ULN) or bilirubin >1.5 × ULN (isolated bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
• 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])
• Hemoglobin <11 gram (g) per (dL) [<110 g/L] for male subjects and <10 g/dL (<100 g/L) for female subjects at Screening
• Estimated glomerular filtration rate (eGFR) <= 30 millilitre per minute per 1.73 square meters (mL/min/1.73 m^2) (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.
• Fasting triglyceride level >750 mg/dL at Screening
• Hemoglobinopathy that may affect proper interpretation of HbA1c
• 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)
• 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
• Female subject is pregnant (confirmed by laboratory testing) or lactating
• 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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814 participants in 2 patient groups

Albiglutide + Insulin Glargine Arm

Experimental group

Description:

During standardization period, subjects will transit from basal bolus regimen received during screening period to insulin glargine plus insulin lispro. During treatment period, subject will receive Albiglutide 30 milligrams (mg) weekly subcutaneous (SC) injection and insulin lispro dose will be downtitrated to half that used in the standardization period. At Week 4, Albiglutide will be uptitrated to 50 mg weekly SC injection and insulin lispro will be stopped for the remainder of the treatment Period. Insulin lispro may be re-introduced after Week 8 according to pre-defined hyperglycemia thresholds. Insulin will be adjusted according to protocol-defined insulin titration algorithms

Treatment:

Drug: Albiglutide

Insulin Glargine + Insulin Lispro Arm

Experimental group

Description:

During standardization period, subjects will transit from basal bolus regimen received during screening period to insulin glargine plus insulin lispro. During treatment period, subject will continue with the same doses as at the end of the standardization period and doses will be adjusted according to protocol-defined insulin titration algorithms

Treatment:

Drug: Insulin Glargine and Insulin Lispro