Effect of Albiglutide, When Added to Standard Blood Glucose Lowering Therapies, on Major Cardiovascular Events in Subjects With Type 2 Diabetes Mellitus

Study Overview
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Brief Summary
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Albiglutide is an analogue of glucagon-like peptide-1 (GLP-1), used to treat type 2 diabetes This study will test whether albiglutide affects the occurrence of major cardiovascular events such as heart attacks or strokes and other important medical outcomes in persons with type 2 diabetes, when used alone or added to other diabetes treatments.

Official Title
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A Long Term, Randomised, Double Blind, Placebo-controlled Study to Determine the Effect of Albiglutide, When Added to Standard Blood Glucose Lowering Therapies, on Major Cardiovascular Events in Patients With Type 2 Diabetes Mellitus

Conditions
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Diabetes Mellitus

Intervention / Treatment
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* Biological: Albiglutide 30 mg
* Biological: Albiglutide 50 mg
* Biological: Albiglutide matching placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women at least 40 years old. Women must be post-menopausal or using a highly effective method for avoidance of pregnancy. Diagnosis of type 2 diabetes. Established cardiovascular disease with at least one of the following: coronary artery disease, cerebrovascular disease, or peripheral arterial disease. HbA1c >7.0% (53 mmol/mol) (based on the most recent documented laboratory measurement within 6 months). Able and willing to provide informed consent. Exclusion Criteria: Severely reduced kidney function: eGFR <30 ml/min/1.73 m^2 (based on the last measured and documented laboratory measurement within 6 months) or renal replacement therapy. Use of a GLP-1 receptor agonist at Screening. Severe gastroparesis History of pancreatitis or considered clinically at significant risk of developing pancreatitis during the course of the study. Personal or family history of medullary carcinoma of the thyroid or subject with multiple endocrine neoplasia type 2 (MEN-2). Personal history of pancreatic neuroendocrine tumours. Medical history which might limit the subject's ability to take trial treatments for the duration of the study or to otherwise complete the study. Breastfeeding, pregnancy, or planning a pregnancy during the course of the study. Note: a pregnancy test will be performed on all women of child bearing potential prior to study entry. Known allergy to any GLP-1 receptor agonist or excipients of albiglutide. Use of another investigational product within 30 days or according to local regulations, or currently enrolled in a study of an investigational device. Any other reason the investigator deems the subject to be unsuitable for the study.

Ages Eligible for Study
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Minimum Age: 40 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Albiglutide<br>Albiglutide once weekly by subcutaneous injection. Starting dose 30 mg may be increased to 50 mg if needed. Albiglutide will be administered in addition to standard therapy for diabetes and cardiovascular health. | Biological: Albiglutide 30 mg<br>* Once weekly subcutaneous injection. Starting dose 30 mg may be increased to 50 mg if needed.<br>Biological: Albiglutide 50 mg<br>* Once weekly subcutaneous injection. Starting dose 30 mg may be increased to 50 mg if needed.<br>|
| Placebo Comparator: Placebo<br>Placebo once weekly by subcutaneous injection. Placebo will be administered in addition to standard therapy for diabetes and cardiovascular health. | Biological: Albiglutide matching placebo<br>* Once weekly subcutaneous injection. Matched to 30 mg and 50 mg albiglutide.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to First Occurrence of Major Adverse Cardiovascular Events (MACE) During Cardiovascular (CV) Follow-up Time Period | Time to MACE defined as the time to first occurrence of Cardiovascular Endpoint Committee (CEC)-adjudicated MACE (CV death, myocardial infarction [MI] or stroke) was analyzed using a Cox Proportional Hazards regression model with treatment group as the only covariate. The incidence rate per 100 person years (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% confidence interval. First event person-years=(cumulative total time to first event for participants who have the event+cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period. The analysis was performed on the Intent to Treat (ITT) Population which comprised of all randomized participants excluding participants who did not provide consent. | Median of 1.65 person years for CV follow-up time period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to First Occurrence of MACE or Urgent Revascularization for Unstable Angina | Time to first occurrence of CEC-adjudicated MACE (CV death, MI or stroke) or urgent revascularization for unstable angina was analyzed using a Cox Proportional Hazards regression model with treatment group as the only covariate. The incidence rate per 100 person years (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% confidence interval. First event person-years=(cumulative total time to first event for participants who have the event+cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period. | Median of 1.65 person years for CV follow-up time period | 
| Time to Adjudicated CV Death | Time to adjudicated CV death was analyzed using a Cox Proportional Hazards regression model with treatment group as the only covariate. The incidence rate per 100 person years (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% confidence interval. First event person-years=(cumulative total time to first event for participants who have the event+cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period. | Median of 1.65 person years for the CV follow-up time period | 
| Time to First Occurrence of Adjudicated MI | Time to first occurrence of adjudicated MI was analyzed using a Cox Proportional Hazards regression model with treatment group as the only covariate. The incidence rate per 100 person years (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% confidence interval. First event person-years=(cumulative total time to first event for participants who have the event+cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period. | Median of 1.65 person years for CV follow-up time period | 
| Time to First Occurrence of Adjudicated Stroke | Time to first occurrence of adjudicated stroke was analyzed using a Cox Proportional Hazards regression model with treatment group as the only covariate. The incidence rate per 100 person years (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% confidence interval. First event person-years=(cumulative total time to first event for participants who have the event+cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period. | Median of 1.65 person years for CV follow-up time period | 
| Time to First Occurrence of Adjudicated CV Death or Hospitalization for Heart Failure (HF) | Time to first occurrence of adjudicated CV death or hospitalization for HF was analyzed using a Cox Proportional Hazards regression model with treatment group as the only covariate. The incidence rate per 100 person years (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% confidence interval. First event person-years=(cumulative total time to first event for participants who have the event+cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period. | Median of 1.65 person years for CV follow-up time period | 
| Time to Initiation of Insulin of More Than 3 Months Duration for Those Participants Not Treated With Insulin at Study Start | Time to initiation of insulin of more than 3 months duration in participants not treated with insulin at study start was analyzed using a Cox Proportional Hazards regression model with treatment group as the only covariate. The incidence rate per 100 person years (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% confidence interval. First event person-years=(cumulative total time to first event for participants who have the event+cumulative total of censored time for participants without the event)/365.25, based on the on-therapy and post-therapy AE time period. The analysis was performed on Non-Insulin Population which comprised of participants in the ITT Population who were not on insulin at Baseline. | Up to 2.7 years | 
| Time to Initiation of Prandial Insulin in Those Participants on Basal Insulin at Study Start | Time to initiation of prandial insulin in those participants on basal insulin at study start was analyzed using a Cox Proportional Hazards regression model with treatment group as the only covariate. The incidence rate per 100 person years (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% confidence interval. First event person-years=(cumulative total time to first event for participants who have the event+cumulative total of censored time for participants without the event)/365.25, based on the on-therapy and post-therapy AE time period. The analysis was performed on Basal Insulin Population which comprised of participants in the ITT Population who were on basal insulin but not on other insulin at Baseline (i.e., will not include a participant on a mixed insulin or on a prandial-only insulin). | Up to 2.7 years | 
| Percentage of Participants Achieving Composite Metabolic Endpoint | Percentage of participants achieving composite metabolic endpoint defined as the percentage of participants achieving glycemic control (glycated hemoglobin [HbA1c] <=7% ) with no severe hypoglycemic incidents and weight gain < 5%. Final Assessment is the latest post-Baseline assessment of both HbA1c and weight. | Months 8, 16, 24 and final assessment (up to 2.7 years) | 
| Time to First Occurrence of a Clinically Important Microvascular Event | Clinically important microvascular events were defined as the following: need for renal transplant or dialysis, new diabetes-related blindness, and procedures (laser photocoagulation or anti-vascular endothelial growth factor treatment or vitrectomy for diabetic retinopathy/eye disease). Time to first occurrence of a clinically important microvascular event was analyzed using a Cox Proportional Hazards regression model with treatment group as the only covariate. The incidence rate per 100 person years (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% confidence interval. First event person-years=(cumulative total time to first event for participants who have the event+cumulative total of censored time for participants without the event)/365.25, based on the on-therapy and post-therapy AE time period. | Up to 2.7 years | 
| Change From Baseline in HbA1c | Change from Baseline in HbA1c was analyzed using mixed model repeated measures (MMRM) including observed case data (does not impute any missing data). Baseline is the last non-missing value assessed on or before treatment start date. Change from Baseline is the value at specified time point minus the Baseline value. Change from Baseline in HbA1c using Baseline data from Local or Central Laboratory, and post-Baseline Central Laboratory data is presented. | Baseline and Months 8 and 16 | 
| Change From Baseline in Body Weight | Change from Baseline in body weight was analyzed using mixed model repeated measures including observed case data (does not impute any missing data). Baseline is the last non-missing value assessed on or before treatment start date. Change from Baseline is the value at specified time point minus the Baseline value. | Baseline and Months 8 and 16 | 
| Change From Baseline in Treatment Related Impact Measures-Diabetes (TRIM-D) Total Score | The TRIM-D is a 28 item treatment satisfaction measure with 5 domains assessing Treatment Burden, Daily Life, Diabetes Management, Compliance and Psychological Health. The raw score ranges for each subscale were: treatment burden (6 to 30), daily life (5 to 25), diabetes management (5 to 25), compliance (4 to 20) and psychological health (8 to 40), higher scores indicating better health state. Total raw score was determined by summing the raw scores for each of the subscales and the total score (transformed) was determined as [(raw score minus lowest possible raw score)/possible raw score range] x100. The possible total (transformed) score range is 0-100, where higher scores indicated better health state. Baseline is the last non-missing value assessed on or before treatment start date. Change from Baseline is the value at specified time point minus the Baseline value. | Baseline and Months 8 and 16 | 
| Change From Baseline in EuroQol- 5 Dimension (EQ-5D) Visual Analogue Scale (VAS) Score | The EQ-5D is a standardized instrument used to evaluate generic health-related quality of life, comprising 5 domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. It provides a simple descriptive profile and a single index value for health status. The EQ-5D self-reported questionnaire includes a visual analog scale (VAS), which records the respondent's self-rated health status on a graduated (0-100) scale, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. Baseline is the last non-missing value assessed on or before treatment start date. Change from Baseline is the value at specified time point minus the Baseline value. | Baseline and Months 8 and 16 | 
| Time to Death | Time to death was analyzed using a Cox Proportional Hazards regression model with treatment group as the only covariate. The incidence rate per 100 person years (100*number of participants who died/endpoint person-years) is presented along with 95% confidence interval. Endpoint person-years=(cumulative total time to event for participants who have the event+cumulative total of censored time for participants without the event)/365.25, based on the Vital Status follow-up time period. | Median of 1.73 years for the Vital Status follow-up time period | 
| Number of Participants With Non-fatal Serious Adverse Events (SAEs) | SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; is a congenital anomaly/birth defect; other important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed before; is associated with liver injury and impaired liver function. Number of participants with on-therapy non-fatal SAEs are presented. Safety Population comprised of all randomized participants who received at least one dose of study treatment. | Up to 2.7 years | 
| Number of Participants With Adverse Events (AEs) Leading to Discontinuation of Investigational Product (AELD) | The number of participants with on-therapy AEs leading to discontinuation of investigational product is reported. | Up to 2.7 years | 
| Number of Participants With AEs of Special Interest | The protocol defined AEs of special interest included: development of thyroid cancer; hematologic malignancy; pancreatic cancer; pancreatitis (investigator reported and pancreatitis positively adjudicated by the Pancreatic Adjudication Committee [PAC]); investigational product injection site reactions; immunological reactions; severe hypoglycemic events; hepatic events; hepatic enzyme elevations (including gamma glutamyl transferase [GGT]); serious gastrointestinal (GI) events; appendicitis; atrial fibrillation/flutter; pneumonia; worsening renal function and diabetic retinopathy. The number of participants with on-therapy AEs of special interest is reported. | Up to 2.7 years | 
| Change in Estimated Glomerular Filtration Rate (eGFR) Calculated Using Modification of Diet in Renal Disease (MDRD) Formula | Blood samples were collected for the measurement of serum creatinine. Serum creatinine values were used to calculate eGFR using the MDRD formula, eGFR=175 x (serum creatinine)^-1.154 x (Age)^-0.203 x (0.742 if female) x (1.212 if African American). Baseline is the last non-missing value assessed on or before treatment start date. Change from Baseline is the value at specified time point minus the Baseline value. Change from Baseline in eGFR using Baseline data from Local or Central Laboratory, and post-Baseline Central Laboratory data for the on-treatment time period is presented. | Baseline and Months 8 and 16 | 
| Change From Baseline in Blood Pressure | Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were taken with the participant in a semi-recumbent or seated position after at least a 5-minute rest period. Baseline is the last non-missing value assessed on or before treatment start date. Change from Baseline is the value at specified time point minus the Baseline value. | Baseline and Months 8,16,24 and end of study (up to 2.7 years) | 
| Change From Baseline in Heart Rate | Heart rate was measured with the participant in a semi-recumbent or seated position after at least a 5-minute rest period. Baseline is the last non-missing value assessed on or before treatment start date. Change from Baseline is the value at specified time point minus the Baseline value. | Baseline and Months 8, 16, 24 and end of study (up to 2.7 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cardiovascular events /outcomes, Type 2 diabetes mellitus, albiglutide, glucagon-like peptide-1 receptor agonist