Dose Ranging Study of Albiglutide in Japanese Subjects

Study Overview
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Brief Summary
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This is a randomized, double-blind, placebo-controlled, multicenter, 4-parallel-group, dose ranging study evaluating the dose response, efficacy and safety of subcutaneously injected GSK716155 (albiglutide) in Japanese subjects with type 2 diabetes mellitus.

Detailed Description
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This is a Phase IIb, randomized, double-blind, placebo-controlled, multicenter, 4-parallel-group, dose ranging, superiority study evaluating the dose response, efficacy and safety of weekly and every other week subcutaneously injected GSK716155 (albiglutide) in subjects with type 2 diabetes mellitus.

Official Title
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A Dose Finding Study of GSK716155 Versus Placebo in the Treatment of Type 2 Diabetes Mellitus

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Biological: albiglutide
* Biological: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject with a historical diagnosis of type 2 diabetes mellitus who is currently treated with diet and exercise only or one OAD BMI ≥18 kg/m2 and <35 kg/m2 at Screening HbA1c between 7.0% and 10.0%, inclusive Fasting C-peptide ≥0.8 ng/mL (≥0.26 nmol/L) Female subjects of childbearing potential must be practicing adequate contraception . Able and willing to monitor his/her own blood glucose concentrations with a home glucose monitor. Able and willing to provide written informed consent Exclusion Criteria: Diagnosis of type 1 diabetes mellitus Uncorrected thyroid dysfunction Previous use of insulin within one month prior to screening, or more than seven total days of insulin treatment within three months prior to screening Clinically significantly cardiovascular and/or cerebrovascular disease including, but not limited to the following: Previous history of stroke or transient ischemic attack Active, unstable coronary heart disease within the past six months before Screening Documented myocardial infarction within one year before Screening Any cardiac surgery including percutaneous transluminal coronary angioplasty, coronary stent placement, or coronary artery bypass graft surgery within one year before Screening Unstable angina Clinically significant arrhythmia or valvular heart disease Current heart failure NYHA class II to IV Resting systolic pressure >160 mm Hg or diastolic pressure >95 mm Hg at Screening ECG criteria at Screening Heart rate: <40 and >110 bpm PR interval: <120 and > 210 msec QRS interval: <70 and >120 msec QTc interval (Bazett): >450 msec or >480 msec with bundle branch block Fasting triglyceride level >400 mg/dL at Screening AST or ALT >2xULN, ALP and bilirubin >1.5xULN (except known Gilbert's syndrome and a fractionated bilirubin that shows conjugated bilirubin <35% of total bilirubin) If female, is currently lactating, within 6 weeks post-partum, pregnant, or actively trying to become pregnant Has significant renal disease as manifested by one or more of the following: Creatinine clearance at screening <60 mL/min (calculated by Cockcroft-Gault formula) at Screening Known loss of a kidney either by surgical ablation, injury or disease level A hemoglobinopathy that may affect determination of HbA1c level History of treated diabetic gastroparesis History of significant gastrointestinal surgery, including gastric bypass and banding, or surgeries thought to significantly affect upper gastrointestinal function Current ongoing symptomatic biliary disease or history of acute/chronic pancreatitis. Lipase and amylase at Screening > ULN Severe diabetic neuropathy, preproliferative retinopathy or proliferative retinopathy, history of ketoacidosis or hyperosmolar coma 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) Acute or chronic history of liver disease, positive hepatitis B surface antigen (HBsAg) or positive hepatitis C testing at Screening Current and history of alcohol or substance abuse Clinically significant anaemia or any other abnormal haematological profile that is considered by the investigator to be clinically significant Prior use of a GLP-1 analog Known allergy to any formulation excipients, or Baker's yeast, or history of drug, or other allergy which, in the opinion of the responsible study physician, contradicts participation History of or family history of medullary carcinoma of the thyroid. History of or family history of multiple endocrine neoplasia type 2 Receipt of any investigational drug within the 12 weeks before Screening

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: albiglutide 15mg weekly<br>once weekly subcutaneous injection of albiglutide 15mg | Biological: albiglutide<br>* subcutaneous injection of albiglutide<br>* Other names: albiglutide 30mg every other week;|
| Active Comparator: albiglutide 30mg weekly<br>once weekly subcutaneous injection of albiglutide 30mg | Biological: albiglutide<br>* subcutaneous injection of albiglutide<br>* Other names: albiglutide 30mg every other week;|
| Active Comparator: albiglutide 30mg every other week<br>subcutaneous injection of 30mg albiglutide every other week | Biological: albiglutide<br>* subcutaneous injection of albiglutide<br>* Other names: albiglutide 30mg every other week;|
| Placebo Comparator: placebo<br>once weekly subcutaneous injection of placebo to match albiglutide | Biological: placebo<br>* subcutaneous injection of placebo to match albiglutide<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 16 | HbA1c is a form of hemoglobin that is measured primarily to identify the average plasma glucose concentration over a 2- to 3-month period. The Baseline HbA1c value is defined as the last non-missing value before the start of treatment. Change from Baseline was calculated as the value at Week 16 minus the value at Baseline. Based on Analysis of Covariance (ANCOVA): Change = treatment + Baseline HbA1c + prior therapy. The last observation carried forward (LOCF) method was used to impute missing data, in which the last non-missing post-Baseline on-treatment measurement was used to impute the missing measurement. If a participant had missing observation(s) immediately after Baseline, the Baseline observation was not carried forward and was left as missing. | Baseline and Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in HbA1c at Weeks 4, 8, 12, and 16 | HbA1c is a form of hemoglobin that is measured primarily to identify the average plasma glucose concentration over a 2- to 3-month period. The Baseline HbA1c value is defined as the last non-missing value before the start of treatment. Change from Baseline was calculated as the value at Week 16 minus the value at Baseline. The last observation carried forward (LOCF) method was used to impute missing data, in which the last non-missing post-Baseline on-treatment measurement was used to impute the missing measurement. If a participant had missing observation(s) immediately after Baseline, the Baseline observation was not carried forward and was left as missing. | Baseline; Week 4, Week 8, Week 12, and Week 16 | 
| Change From Baseline in Fasting Plasma Glucose (FPG) at Weeks 4, 8, 12, and 16 | The FPG test measures blood sugar levels after the participant has not eaten (fasted) for 12 to 14 hours. The Baseline FPG value is the last non-missing value before the start of treatment. The LOCF method was used to impute missing post-Baseline FPG values. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline; Week 4, Week 8, Week 12, and Week 16 | 
| Change From Baseline in Body Weight at Week 4, 8, 12, and 16 | The Baseline value is the last non-missing value before the start of treatment. Change from Baseline was calculated as the post-Baseline weight minus the Baseline weight. The LOCF method was used to impute missing post-Baseline weight values. | Baseline; Week 4, Week 8, Week 12, and Week 16 | 
| Number of Participants Who Achieved Clinically Meaningful HbA1c Response Levels of <6.5% and <7% at Weeks 4, 8, 12, and 16 | The number of participants who achieved the HbA1c treatment goal (i.e., HbA1c response levels of <6.5% and <7%) were assessed. | Week 4, Week 8, Week 12, and Week 16 | 
| Mean Clearance of Albiglutide | Clearance is defined as the volume of plasma cleared of albiglutide per unit time. Samples were collected prior to the administration of study medication on dosing days (Weeks 0, 1, 4, 5, 8, 12, and 13) and on the day of the clinic visit at Weeks 16, 20, and 24. At Weeks 0, 1, 4, 8, and 12, pharmacokinetic (PK) samples were collected immediately prior to dosing if a dose was scheduled for that week. At Weeks 16, 20, and 24, PK samples were collected at any time during the visit. The Week 5 post-dose PK sampling was performed any time between Weeks 4 and 6, within 2 to 5 days after administration of a dose; Week 13 post-dose PK sampling was performed any time between Weeks 12 and 14, within 2 to 5 days after administration of a dose of study medication. Modeled population PK data are presented; data were analyzed using a non-linear mixed effect modeling approach. A one-compartment PK model with first-order absorption and elimination processes was selected to describe GSK716155 PK. | Weeks 0, 1, 4, 5, 8, 12, 13, 16, 20, and 24 | 
| Mean Volume of Distribution of Albiglutide | Volume of distribution is defined as the apparent volume in which albiglutide is distributed. Samples were collected prior to the administration of study medication on dosing days (Weeks 0, 1, 4, 5, 8, 12, and 13) and on the day of the clinic visit at Weeks 16, 20, and 24. At Weeks 0, 1, 4, 8, and 12, PK samples were collected immediately prior to dosing if a dose was scheduled for that week. At Weeks 16, 20, and 24, PK samples were collected at any time during the visit. The Week 5 post-dose PK sampling was performed any time between Weeks 4 and 6, within 2 to 5 days after administration of a dose; Week 13 post-dose PK sampling was performed any time between Weeks 12 and 14, within 2 to 5 days after administration of a dose of study medication. Modeled population PK data are presented; data were analyzed using a non-linear mixed effect modeling approach. A one-compartment PK model with first-order absorption and elimination processes was selected to describe GSK716155 PK. | Weeks 0, 1, 4, 5, 8, 12, 13, 16, 20, and 24 | 
| Mean Absorption Rate of Albiglutide | Absorption rate is defined as the rate at which albiglutide enters the blood circulation. Samples were collected prior to the administration of study medication on dosing days (Weeks 0, 1, 4, 5, 8, 12, and 13) and on the day of the clinic visit at Weeks 16, 20, and 24. At Weeks 0, 1, 4, 8, and 12, PK samples were collected immediately prior to dosing if a dose was scheduled for that week. At Weeks 16, 20, and 24, PK samples were collected at any time during the visit. The Week 5 post-dose PK sampling was performed any time between Weeks 4 and 6, within 2 to 5 days after administration of a dose; Week 13 post-dose PK sampling was performed any time between Weeks 12 and 14, within 2 to 5 days after administration of a dose of study medication. Modeled population PK data are presented; data were analyzed using a non-linear mixed effect modeling approach. A one-compartment PK model with first-order absorption and elimination processes was selected to describe GSK716155 PK. | Weeks 0, 1, 4, 5, 8, 12, 13, 16, 20, and 24 | 
| Mean Half-maximal Effective Concentration (EC50) of Albiglutide for HbA1c and FPG | EC50 is defined as the concentration of albiglutide that give a half-maximal HbA1c and FPG response. Samples were collected prior to the administration of study medication on dosing days (Weeks 0, 1, 4, 5, 8, 12, and 13) and on the day of the clinic visit at Weeks 16, 20, and 24. At Weeks 0, 1, 4, 8, and 12, PK samples were collected immediately prior to dosing if a dose was scheduled for that week. At Weeks 16, 20, and 24, PK samples were collected at any time during the visit. The Week 5 post-dose PK sampling was performed any time between Weeks 4 and 6, within 2 to 5 days after administration of a dose; Week 13 post-dose PK sampling was performed any time between Weeks 12 and 14, within 2 to 5 days after administration of a dose of study medication. EC50 estimates used PK data as well as HbA1c and FPG efficacy data. EC50 was estimated from an inhibitory Emax (maximal possible effect of albiglutide) model. | Weeks 0, 1, 4, 5, 8, 12, 13, 16, 20, and 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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dose-ranging, pharmacokinetics, GSK716155, Japan, albiglutide