A Study of the Efficacy and Safety of Albiglutide in Subjects With Type 2 Diabetes With Renal Impairment.

Study Overview
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Brief Summary
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This randomized, double-blind, active-controlled study evaluates the efficacy and safety of a weekly dose of albiglutide as compared with sitagliptin. Subjects who are renally impaired with a historical diagnosis of type 2 diabetes mellitus and whose glycemia is inadequately controlled on their current regimen of diet and exercise or their antidiabetic therapy of metformin, thiazolidinedione, sulfonylurea, or any combination of these oral antidiabetic medications will be recruited into the study.

Detailed Description
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This randomized, double-blind, active-controlled, 2 parallel-group, multicenter study evaluates the efficacy and safety of a weekly subcutaneously injected dose of albiglutide as compared with sitagliptin. Subjects who are renally impaired with a historical diagnosis of type 2 diabetes mellitus and whose glycemia is inadequately controlled on their current regimen of diet and exercise or their antidiabetic therapy of metformin, thiazolidinedione, sulfonylurea, or any combination of these oral antidiabetic medications will be recruited into the study.

Official Title
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A Randomized, Double-Blind, Active-Controlled, Parallel-Group, Multicenter Study to Determine the Efficacy and Safety of Albiglutide as Compared With Sitagliptin in Subjects With Type 2 Diabetes Mellitus With Renal Impairment

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Biological: albiglutide
* Drug: sitagliptin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Renally impaired with a historical diagnosis of type 2 diabetes mellitus and is experiencing inadequate glycemic control on their current regime of diet and exercise or their antidiabetic therapy of metformin, TZD, SU, or any combination of these oral antidiabetic medications BMI >/=20 kg/m2 and </=45 kg/m2 Fasting C-peptide >/=0.8 ng/mL (>/=0.26 nmol/L) HbA1c between 7.0% and 10.0%, inclusive. Exclusion Criteria: History of cancer History of treated diabetic gastroparesis Current biliary disease or history of pancreatitis History of significant gastrointestinal surgery Recent clinically significant cardiovascular and/or cerebrovascular disease History of human immunodeficiency virus infection Abnormal liver function or acute symptomatic infection with hepatitis B or hepatitis C Female subject is pregnant (confirmed by laboratory testing), lactating, or <6 weeks postpartum Known allergy to any GLP 1 analogue, sitagliptin, other study medications' excipients, excipients of albiglutide, or Baker's yeast Receipt of any investigational drug or sitagliptin within the 30 days or 5 half lives, whichever is longer, before Screening or a history of receipt of an investigational antidiabetic drug within the 3 months before randomization or receipt of albiglutide in previous studies

Ages Eligible for Study
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Minimum Age: 18 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<br>albiglutide weekly subcutaneous injection + sitagliptin matching placebo | Biological: albiglutide<br>* albiglutide weekly subcutaneous injection + sitagliptin matching placebo<br>|
| Active Comparator: sitagliptin<br>albiglutide matching placebo + sitagliptin | Drug: sitagliptin<br>* albiglutide matching placebo + sitagliptin (25mg, 50mg or 100mg depending on level of renal impairment)<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 26 | 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 in HbA1c was calculated as the value at Week 26 minus the value at Baseline. The analysis was performed using an Analysis of Covariance (ANCOVA) model with treatment group, region, history of prior myocardial infarction (yes versus no), and age category (<65 years versus >=65 years) as factors and Baseline HbA1c as a continuous covariate. 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 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in HbA1c at Weeks 4, 8, 12, 16, and 20: LOCF | 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 in HbA1c was calculated as the post-Baseline value minus the Baseline value. The 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. Participants were analyzed in a particular treatment week if they had received at least one dose in that treatment week. | Baseline; Weeks 4, 8, 12, 16, and 20 | 
| Mean Change From Baseline in HbA1c at Weeks 4, 8, 12, 16, 20, 26, 36, 48, and Week 52: Observed Cases | 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 in HbA1c was calculated as the post-Baseline value minus the Baseline value. The Observed Cases (OC) method (no imputation of missing data) was used. If a participant had missing observation(s) immediately after Baseline, the Baseline observation was not carried forward and was left as missing. Participants were analyzed in a particular treatment week if they had received at least one dose in that treatment week. | Baseline; Weeks 4, 8, 12, 16, 20, 26, 36, 48, and 52 | 
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 | The FPG test measures blood sugar levels after the participant has not eaten (fasted) for 12 to 14 hours. The Baseline FPG value is define as the last non-missing value before the start of treatment. Change from Baseline in FBG was calculated as the post-Baseline value minus the Baseline value. The 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. Participants were analyzed in a particular treatment week if they had received at least one dose in that treatment week. Based on ANCOVA: Change = treatment + Baseline FPG + renal impairment + prior myocardial infarction history + age category + region. | Baseline; Week 26 | 
| Mean Change From Baseline in FPG at Weeks 4, 8, 12, 16, 20, and 26: LOCF | 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. Change from Baseline in FBG was calculated as the post-Baseline value minus the Baseline value. The 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. Participants were analyzed in a particular treatment week if they had received at least one dose in that treatment week. | Baseline; Weeks 4, 8, 12, 16, 20, and 26 | 
| Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Weeks 1, 2, 3, 4, 8, 12, 16, 20, 26, 36, 48, and Week 52: OC | The FPG test measures blood sugar levels after the participant has not eaten (fasted) for 12 to 14 hours. The Baseline FPG value is defined as the last non-missing value prior to treatment. Change from Baseline in FBG was calculated as the post-Baseline value minus the Baseline value. The OC method (no imputation of missing data) was used. If a participant had missing observation(s) immediately after Baseline, the Baseline observation was not carried forward and was left as missing. Participants were analyzed in a particular treatment week if they had received at least one dose in that treatment week. | Baseline; Weeks 1, 2, 3, 4, 8, 12, 16, 20, 26, 36, 48, Week 52 | 
| Number of Participants Who Achieved Clinically Meaningful HbA1c Response Levels of <6.5% and <7.0% at Week 26: LOCF | The number of participants who acheieved the HbA1c treatment goal (i.e., the number of participants who achieved HbA1c <7% and <6.5% at Week 26) was assessed. The 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. | Week 26 | 
| Number of Participants Who Achieved a Clinically Meaningful Improvement in the HbA1c Response Level of >=1.0%, >=1.5%, and >=2.0% at Week 26: LOCF | The number of participants who a clinically meaningful improvement from Baseline in the HbA1c response level of >=1.0%, >=1.5%, and >=2.0% at Week 26 were assessed. The 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. | Week 26 | 
| Number of Participants Who Achieved a Clinically Meaningful HbA1c Response Level of <6.5% and <7.0% at Week 52: OC | The number of participants who acheieved the HbA1c treatment goal (i.e., number of participants who achieved HbA1c <7% and <6.5% at Week 26) was assessed. The OC method (no imputation of missing data) was used. If a participant had missing observation(s) immediately after Baseline, the Baseline observation was not carried forward and was left as missing. | Week 52 | 
| Number of Participants Who Achieved a Clinically Meaningful Improvement in the HbA1c Response Level of >=1.0%, >=1.5%, and >=2.0% at Week 52: OC | The number of participants who a clinically meaningful improvement from Baseline in the HbA1c response level of >=1.0%, >=1.5%, and >=2.0% at Week 52 assessed. The OC method (no imputation of missing data) was used. If a participant had missing observation(s) immediately after Baseline, the Baseline observation was not carried forward and was left as missing. | Week 52 | 
| Number of Participants With the Indicated Time to Hyperglycemic Rescue Through Week 52 | Hyperglycemic rescue was defined as meeting one of the following criteria, confirmed by a second sample drawn within 7 days and analyzed by the central laboratory: for the Week 2 to Week 4 visit, a single FPG value >=280 milligrams per deciliter (mg/dL); for the >Week 4 and <Week 12 visits, a single FPG value >=250 mg/dL and previous titration for >=4 weeks; for the >=Week 12 and <Week 26 visits, HbA1c >=8.5% and a <=0.5% reduction from Baseline and previous titration for >=4 weeks; for the >=Week 26 and <Week 48 visits, HbA1c >=8.5% and previous titration for >=4 weeks; for the >=Week 48 and <Week 52 visits, HbA1c >=8.0% and previous titration for >=4 weeks. Time to hyperglycemia rescue is the time between the date of first dose and the date of hyperglycemia rescue plus 1 day, or the time between the date of first dose and the date of last visit during active treatment period plus 1 day for participants not requiring rescue. | Week 2 to Week 52 | 
| Time to Hyperglycemic Rescue Through Week 52 | Hyperglycemic rescue was defined as meeting one of the following criteria, confirmed by a second sample drawn within 7 days and analyzed by the central laboratory: for the Week 2 to Week 4 visit, a single FPG value >=280 milligrams per deciliter (mg/dL); for the >Week 4 and <Week 12 visits, a single FPG value >=250 mg/dL and previous titration for >=4 weeks; for the >=Week 12 and <Week 26 visits, HbA1c >=8.5% and a <=0.5% reduction from Baseline and previous titration for >=4 weeks; for the >=Week 26 and <Week 48 visits, HbA1c >=8.5% and previous titration for >=4 weeks; for the >=Week 48 and <Week 52 visits, HbA1c >=8.0% and previous titration for >=4 weeks. Time to hyperglycemia rescue is the time between the date of first dose and the date of hyperglycemia rescue plus 1 day, or the time between the date of first dose and the date of last visit during active treatment period plus 1 day for participants not requiring rescue. This time is divided by 7 to express the result in weeks. | Week 2 to Week 52 | 
| Change From Baseline in Body Weight at Week 26: LOCF | Change from Baseline was calculated as the post-Baseline weight minus the Baseline weight. The Baseline weight value is defined as the last non-missing value prior to treatment. This analysis used the LOCF method for missing post-Baseline weight values. Weight values obtained after hyperglycemia rescue werre treated as missing and were replaced with pre-rescue values. Based on ANCOVA: Change = treatment + Baseline weight + renal impairment + prior myocardial infarction history + age category + region. | Baseline; Week 26 | 
| Change From Baseline in Body Weight Through Week 26: LOCF | Change from Baseline was calculated as the post-Baseline weight minus the Baseline weight. The Baseline weight value is defined as the last non-missing value prior to treatment. This analysis used the LOCF method for missing post-Baseline weight values. Weight values obtained after hyperglycemia rescue werre treated as missing and were replaced with pre-rescue values. | Baseline; Week 1, Week 2 , Week 3, Week 4, Week 8, Week 12, Week 16, Week 20, and Week 26 | 
| Change From Baseline in Body Weight Through Week 52: OC | Change from Baseline was calculated as the post-Baseline weight minus the Baseline weight. The Baseline weight value is defined as the last non-missing value prior to treatment. This analysis used observed weight values excluding those obtained after hyperglycemia rescue; no missing data imputation was performed. | Baseline; Week 1, Week 2 , Week 3, Week 4, Week 8, Week 12, Week 16, Week 20, Week 26, Week 36, Week 48, and Week 52 | 
| Plasma Concentrations (Conc.) of Albiglutide at Week 8 and Week 16 | Sparse population pharmacokinetic (PK) data were collected for population PK and PK/pharmacodynamic (PD) analyses. Participants (par.) who received albiglutide were initiated on a 30 mg weekly dosing regimen. Beginning at Week 4, uptitration of albiglutide was allowed based on glycemic parameters. As such, albiglutide plasma conc. achieved at each sampling time represent a mixed population of par. who received either 30 mg or 50 mg weekly for various durations. The PK and PK/PD of albiglutide were characterized using a population modeling approach. Mean albiglutide plasma conc. observed at Weeks 8 and 16 are presented. Par. came to the clinic at Weeks 8 and 16 without taking albiglutide/matching placebo. The pre-dose PK sample was taken immediately prior to dosing. The Week 8 post-dose sample was taken between Weeks 8 and 10, >=2 days after a dose of medication. The Week 16 post-dose PK sample was taken any time between Weeks 16 and 20, >=2 days after the previous dose of albiglutide. | Week 8 Pre-dose (immediately prior to dose), Week 8 Post-dose (at least 2 days after a dose of medication), Week 16 Pre-dose (immediately prior to dose), and Week 16 Post-dose (at least 2 days after previous dose of albiglutide) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sitagliptin, albiglutide, renal impairment