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

GlaxoSmithKline814 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

814

Conditions

Diabetes Mellitus, Type 2

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (157)

GSK Investigational Site

Searcy, Arkansas, United States

GSK Investigational Site

Huntington Beach, California, United States

GSK Investigational Site

Long Beach, California, United States

GSK Investigational Site

Los Angeles, California, United States

GSK Investigational Site

Tustin, California, United States

Outcomes

Primary Outcomes

Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 26

HbA1c is glycosylated hemoglobin. It was measured at Baseline and at Week 26. The analysis was conducted using mixed-effect model with repeated measures (MMRM). The model included HbA1c change from Baseline as the dependent variable; treatment, region, age category, current metformin use, visit week, treatment-by-week interaction, and Baseline HbA1c-by-week interaction as fixed effects; Baseline HbA1c as a continuous covariate; and participant as a random effect. The Baseline value was the last available non-missing value prior to the first dose of the randomized treatment, thus Baseline was Day -1. Change from Baseline is defined as the post-Baseline value minus the Baseline value.

Time frame: Baseline (Day -1) and Week 26

Secondary Outcomes

Number of Participants Treated With Once-weekly Albiglutide That Were Able to Discontinue Insulin Lispro at Week 4 and Did Not Meet Prespecified Criteria for Severe, Persistent Hyperglycemia Through Week 26

Participants who did not meet prespecified criteria for severe, persistent hyperglycemia through Week 26 were those participants treated with once-weekly albiglutide that were able to replace prandial insulin without lispro re-introduction through Week 26. Number of participants treated with once-weekly albiglutide that were able to discontinue insulin lispro at Week 4 and did not meet prespecified criteria for severe, persistent hyperglycemia through Week 26 have been presented.

Time frame: Up to Week 26

Percentage of Participants With Severe or Documented Symptomatic Hypoglycemia Through Week 26

Severe hypoglycemia was considered as an event requiring assistance of another person to actively administer carbohydrates, glucagon, or take other corrective actions. Plasma glucose concentrations may not be available during an event, but neurological recovery following the return of plasma glucose to normal was considered sufficient evidence that the event was induced by a low plasma glucose concentration. Documented symptomatic hypoglycemia was an event during which typical symptoms of hypoglycemia are accompanied by a measured plasma glucose concentration \<=70 milligrams per deciliters (mg/dL) (\<=3.9 millimoles per liters \[mmol/L\]).

Time frame: Up to Week 26

Change From Baseline in Body Weight at Week 26

Time frame: Baseline (Day -1) and Week 26

Change From Baseline to Week 26 in Body Weight

Body weight was measured to the nearest 0.1 kilogram on a standard calibrated scale. Participants dressed in light indoor clothes (no coat, jacket, etc.) without shoes and with a voided bladder. The same equipment was used wherever possible. The Baseline value was the last available non-missing value prior to the first dose of the randomized treatment, thus Baseline was Day -1. Change from Baseline is defined as the post-Baseline value minus the Baseline value. Change from Baseline to Week 26 in body weight are presented. FA Population was analyzed. Only those participants available at the specified time points were analyzed represented by n=X,X in the category titles.

Time frame: Baseline (Day -1) to Week 26

Total Daily Insulin Dose at Week 26

Insulin dose at Week 26 was defined as the prescribed insulin dose at Week 25. Based on MMRM model, prescribed total daily basal insulin dose was equal to Baseline prescribed total daily basal insulin dose + treatment + Baseline HbA1c category + region + age category + current use of metformin + visit week + treatment-by-visit week interaction + Baseline prescribed total daily basal insulin dose-by-visit week interaction. Total daily insulin dose at Week 26 is presented. Only those participants available at the specified time points were analyzed.

Time frame: Week 26

Change From Baseline to Week 26 in HbA1c

HbA1c is glycosylated hemoglobin and was measured up to Week 26. The Baseline value was the last available non-missing value prior to the first dose of the randomized treatment, thus Baseline was Day -1. Change from Baseline is defined as the post-Baseline value minus the Baseline value. Only those participants available at the specified time points were analyzed represented by n=X,X in the category titles.

Time frame: Baseline to Week 26

Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26

FPG was measured at Baseline (Day -1). FPG values for all participants at Week 26 were not collected due to an error in the protocol and were imputed with the fasting serum glucose (FSG) values at this time point. The imputation of the FPG at Week 26 from the FSG values was deemed acceptable from the results of the analysis of the correlation between FPG and FSG at the screening visit. The Baseline value was the last available non-missing value prior to the first dose of the randomized treatment, thus Baseline was Day -1. Change from Baseline is defined as the post-Baseline value minus the Baseline value.

Time frame: Baseline and Week 26

Change From Baseline to Week 26 in FPG

FPG was measured at Baseline (Day -1) up to Week 26. FPG values for all participants at Week 26 were not collected due to an error in the protocol and were imputed with the FSG values at this time point. The imputation of the FPG at Week 26 from the FSG values was deemed acceptable from the results of the analysis of the correlation between FPG and FSG at the screening visit. The Baseline value was the last available non-missing value prior to the first dose of the randomized treatment, thus Baseline was Day -1. Change from Baseline is defined as the post-Baseline value minus the Baseline value.

Time frame: Baseline to Week 26

Number of Participants Achieving HbA1c <7.0% at Week 26

HbA1c is glycosylated hemoglobin. Number of participants achieving a HbA1c \<7.0% at Week 26 are presented.

Time frame: Week 26

Number of Participants Achieving HbA1c <7.0% up to Week 26

HbA1c is glycosylated hemoglobin. Number of participants achieving a HbA1c \<7.0% up to Week 26 are presented.

Time frame: Up to Week 26

Number of Participants Achieving a HbA1c <6.5% at Week 26

Number of participants achieving a HbA1c \<6.5% at Week 26 are presented.

Time frame: Week 26

Number of Participants Achieving a HbA1c <6.5% up to Week 26

Number of participants achieving a HbA1c \<6.5% up to Week 26 are presented.

Time frame: Up to Week 26

Number of Participants Who Met Prespecified Criteria for Severe, Persistent Hyperglycemia at Week 26

Meeting prespecified criteria for severe, persistent hyperglycemia was defined operationally as being withdrawn due to lack of efficacy as recorded on the Treatment Discontinuation and Study Conclusion electronic case report form pages. Number of participants who met prespecified criteria for severe, persistent hyperglycemia at Week 26 are presented.

Time frame: Week 26

Number of Participants Meeting Prespecified Criteria for Severe, Persistent Hyperglycemia up to Week 26

Meeting prespecified criteria for severe, persistent hyperglycemia was defined operationally as being withdrawn due to lack of efficacy as recorded on the Treatment Discontinuation and Study Conclusion electronic case report form pages. Number of participants meeting prespecified criteria for severe, persistent hyperglycemia up to Week 26 are presented.

Time frame: Up to Week 26

Total Daily Insulin Dose at Week 4, Week 10 and Week 18

Based on MMRM model, prescribed total daily basal insulin dose was equal to Baseline prescribed total daily basal insulin dose + treatment + Baseline HbA1c category + region + age category + current use of metformin + visit week + treatment-by-visit week interaction + Baseline prescribed total daily basal insulin dose-by-visit week interaction. Total daily insulin dose at Week 4, Week 10 and Week 18 is presented. Only those participants available at the specified time points were analyzed represented by n=X,X in the category titles.

Time frame: Weeks 4, 10, and 18

Total Daily Basal Insulin (Insulin Glargine) at Week 4, 10, 18, and 26 Visits

Based on MMRM model, prescribed total daily basal insulin dose was equal to Baseline prescribed total daily basal insulin dose + treatment + Baseline HbA1c category + region + age category + current use of metformin + visit week + treatment-by-visit week interaction + Baseline prescribed total daily basal insulin dose-by-visit week interaction. Total daily basal insulin (insulin glargine) at Week 4, 10, 18, and 26 visits is presented. Only those participants available at the specified time points were analyzed represented by n=X,X in the category titles.

Time frame: Weeks 4, 10, 18, and 26

Total Daily Bolus Insulin (Insulin Lispro) at Week 4, 10, 18, and 26 Visits

Based on MMRM model, prescribed total daily basal insulin dose was equal to Baseline prescribed total daily basal insulin dose + treatment + Baseline HbA1c category + region + age category + current use of metformin + visit week + treatment-by-visit week interaction + Baseline prescribed total daily basal insulin dose-by-visit week interaction. Total daily bolus insulin (insulin lispro) at Week 4, 10, 18, and 26 visits is presented. Only those participants available at the specified time points were analyzed represented by n=X,X in the category titles.

Time frame: Weeks 4, 10, 18, and 26

Total Number of Weekly Insulin Injections to Achieve Glycemic Control at Baseline/Randomization and Week 4, 10, 18, and 26

Total number of weekly insulin injections (7 days) to achieve glycemic control at Baseline/Randomization and Week 4, 10, 18, and 26 are presented. Only those participants available at the specified time points were analyzed represented by n=X,X in category titles.

Time frame: Baseline (Day -1) and Weeks 4, 10, 18 and 26

Percentage of Participants Achieving HbA1c <7.0% Without Weight Gain at Week 26

Percentage of participants achieving HbA1c \<7.0% without weight gain are presented.

Time frame: Week 26

Percentage of Participants Achieving HbA1c <7.0% Without Severe or Documented Symptomatic Hypoglycemia at Week 26

Percentage of participants achieving HbA1c \<7.0% without severe or documented symptomatic hypoglycemia are presented.

Time frame: Week 26

Percentage of Participants Achieving HbA1c <7.0% Without Weight Gain and Without Severe or Documented Hypoglycemia at Week 26

Percentage of participants achieving HbA1c \<7.0% without weight gain and without severe or documented hypoglycemia are presented.

Time frame: Week 26

Number of Participants With On-therapy Adverse Events (AE) and Serious AE (SAE), and AE Leading to Discontinuation of Randomized Study Medication

AE is any untoward medical occurrence in a participant, temporally associated with use of medicinal product (MP), whether or not considered related to MP. AE can be any unfavorable, unintended sign (also an abnormal laboratory finding), symptom, or disease (new/exacerbated) temporally associated with use of MP. SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, or is a congenital anomaly/birth defect or is medically significant or all events of possible drug induced liver injury with hyperbilirubinemia. Safety Population: All participants who received at least 1 dose of randomized study medication. A participant randomized to Albiglutide + Insulin glargine by mistake received Insulin Lispro + Insulin Glargine instead. Since this participant received actual treatment as Insulin Lispro + Insulin Glargine, was summarized as such in Safety Population.

Time frame: Up to Week 26

Number of Participants With Other AE of Special Interest

AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with use of a MP, whether or not considered related to MP. AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with use of MP. AE of special interest included hypoglycemic events, cardiovascular events, gastrointestinal events, injection site reactions, potential systemic allergic reactions, pancreatitis, pancreatic cancer, malignant neoplasms following treatment with insulin, diabetic retinopathy events, appendicitis, liver events, pneumonia, and atrial fibrillation/flutter.

Time frame: Up to Week 26

Percentage of Participants With Events of Hypoglycemia With Confirmed Home Blood Glucose Monitoring and/or Third-party Intervention Through Week 26

Hypoglycemic events with confirmed home plasma glucose monitoring \<3.9 millimoles per Liter and/or requiring third party intervention were severe, documented symptomatic (DS) and asymptomatic hypoglycemic events. Participants with more than one hypoglycemic event are counted in all categories reported. Any severe, documented symptomatic, and asymptomatic hypoglycemic events in 3-month intervals (i.e., from Day 0 to Week 12, \>Week 12 to Week 26) are presented.

Time frame: Up to Week 26

Number of Participants With Hypoglycemic Events (in Total and by Each Category as Defined by the American Diabetes Association Criteria)

The American Diabetes Association has categorized hypoglycemic events as follows: Severe, documented symptomatic, asymptomatic, probably symptomatic and pseudohypoglycemia. Number of participants with hypoglycemic events in total are also presented.

Time frame: Up to Week 26

Number of Participants With Daytime and Nocturnal Hypoglycemia

Daytime hypoglycemia was defined as hypoglycemic events with an onset between 06:00 hours and 00:00 hours (inclusive), and nocturnal hypoglycemia (in total and by category), defined as hypoglycemic events with an onset between 00:01 hours and 05:59 hours (inclusive). Number of participants with daytime and nocturnal hypoglycemia (in total and by category) are presented.

Time frame: Up to Week 26

Number of Participants With Hypoglycemia With Blood Glucose <56 Milligrams Per Deciliter (mg/dL) (<3.1 Millimoles Per Liter [mmol/L]), Regardless of Symptoms

Number of participants with hypoglycemia with blood glucose \<56 mg/dL (\<3.1 mmol/L), regardless of symptoms are presented.

Time frame: Up to Week 26

Number of Participants With Hematology Values of Clinical Concern

Hematology parameters included basophils, eosinophils, hematocrit, hemoglobin, lymphocytes, monocytes, neutrophils, neutrophil bands, platelets, red blood cell (RBC) count, segmented neutrophils and white blood cell (WBC) count. The potential clinical concern values were: Hematocrit \>0.05 below lower limit of normal (LLN) and \>0.04 above upper limit of normal (ULN), hemoglobin: \>20 grams cells per Liter (g/L) below LLN and \>10 g/L above ULN, lymphocytes: \<0.5 x LLN, neutrophils: \<1 giga cells per liter (GI/L), platelets: \<80 GI/L and \>500 GI/L, segmented neutrophils: \<0.5 x LLN, RBC count: \>1 GI/L below LLN and \>5 GI/L above ULN and none for basophils, eosinophils, monocytes, neutrophil bands and RBC count. Only those parameters for which at least one value of potential clinical concern was reported are summarized.

Time frame: Up to 30 weeks

Number of Participants With Clinical Chemistry Values of Clinical Concern

Clinical chemistry parameters and their potential clinical concern values were: albumin (\>5 g/L above ULN or below LLN), alkaline phosphatase(\>3 x ULN), alanine aminotransferase (\>3 x ULN), aspartate aminotransferase (\>3 x ULN), carbon dioxide content (\<16 millimoles per Liter \[mmol/L\] and \> 40 mmol/L), blood urea nitrogen (\>2 x ULN), calcium (\<1.8 mmol/L and \>3.0 mmol/L), chloride (none), creatinine (\>159 micromoles/Liter), direct bilirubin (\>1.35 x ULN), gamma glutamyl transferase (\>3 x ULN), glucose (fasting) (\<3 mmol/L and \>22 mmol/L), magnesium (\<0.411 mmol/L and \>1.644 mmol/L), phosphate (\>0.323 mmol/L above ULN or below LLN), potassium (\>0.5 mmol/L below LLN and \>1.0 mmol/L above ULN), sodium (\>5 mmol/L above ULN or below LLN), triglycerides (\> 9.04 mmol/L), total bilirubin (\>1.5 x ULN), total protein (\>15 g/L above ULN or below LLN) and uric acid (\>654 umol/L). Only those parameters for which at least one value of potential clinical concern was reported are summarized.

Time frame: Up to 30 weeks

Mean Urine Albumin/Creatinine Ratio at Week 0 and Week 26

Urine samples were collected for analysis of albumin/creatinine ratio. Only those participants available at the specified time points were analyzed represented by n=X,X in the category titles. Mean urine albumin/creatinine ratio at Week 0 and Week 26 are presented.