Albiglutide Glucose Clamp Study in Subjects With Type 2 Diabetes

The insulin secretion rate (ISR) was estimated by the deconvolution of peripheral C-peptide concentrations using a 2-compartment model that utilizes population C-peptide kinetic parameters. ISR was measured at 1 hr, 1 hr 15 min, 1 hr 45 min, 2 hr, 2 hr 45 min, 3 hr, 3 hr 30 min, 3 hr 45 min, 4 hr 15 min, and 4 hr 30 min. Repeated-measures analysis of variance was performed on insulin secretion rate using a model with treatment, time, and treatment-by-time as fixed effects, and participant as a random effect.

Epinephrine levels were measured at all stages of glycemia during the glucose clamp period. Epinephrine levels were measured at each clamped glucose concentration: 9 millimoles per liter (mmol/L) (0 hour [hr], 1hr, 1 hr 15 minutes [min]), 5 mmol/L (1 hr 45 min, 2 hr), 4 mmol/L (2 hr 45 min, 3 hr), 3.3 mmol/L (3 hr 30 min, 3 hr 45 min), and 2.8 mmol/L (4 hr 15 min, 4 hr 30 min), and clamp released (4 hr 45 min, 5 hr, 5 hr 15 min, 5 hr 30 min). Repeated-measures analysis of variance was performed on log-transformed pharmacodynamic parameters using a model with treatment, time, and treatment-by-time as fixed effects, and participant as a random effect. Values below the lower limit of quantification were set to the quantification limit for summary.

Norepinephrine levels were measured at all stages of glycemia during the glucose clamp period. Epinephrine levels were measured at each clamped glucose concentration: 9 millimoles per liter (mmol/L) (0 hour [hr], 1hr, 1 hr 15 minutes [min]), 5 mmol/L (1 hr 45 min, 2 hr), 4 mmol/L (2 hr 45 min, 3 hr), 3.3 mmol/L (3 hr 30 min, 3 hr 45 min), and 2.8 mmol/L (4 hr 15 min, 4 hr 30 min), and clamp released (4 hr 45 min, 5 hr, 5 hr 15 min, 5 hr 30 min). Repeated-measures analysis of variance was performed on log-transformed pharmacodynamic parameters using a model with treatment, time, and treatment-by-time as fixed effects, and participant as a random effect. Values below the lower limit of quantification were set to the quantification limit for summary.

Growth hormone levels were measured at all stages of glycemia during the glucose clamp period. Epinephrine levels were measured at each clamped glucose concentration: 9 millimoles per liter (mmol/L) (0 hour [hr], 1hr, 1 hr 15 minutes [min]), 5 mmol/L (1 hr 45 min, 2 hr), 4 mmol/L (2 hr 45 min, 3 hr), 3.3 mmol/L (3 hr 30 min, 3 hr 45 min), and 2.8 mmol/L (4 hr 15 min, 4 hr 30 min), and clamp released (4 hr 45 min, 5 hr, 5 hr 15 min, 5 hr 30 min). Repeated-measures analysis of variance was performed on log-transformed pharmacodynamic parameters using a model with treatment, time, and treatment-by-time as fixed effects, and participant as a random effect. Values below the lower limit of quantification were set to the quantification limit for summary.

Insulin levels were measured at all stages of glycemia during the glucose clamp period. Epinephrine levels were measured at each clamped glucose concentration: 9 millimoles per liter (mmol/L) (0 hour [hr], 1hr, 1 hr 15 minutes [min]), 5 mmol/L (1 hr 45 min, 2 hr), 4 mmol/L (2 hr 45 min, 3 hr), 3.3 mmol/L (3 hr 30 min, 3 hr 45 min), and 2.8 mmol/L (4 hr 15 min, 4 hr 30 min), and clamp released (4 hr 45 min, 5 hr, 5 hr 15 min, 5 hr 30 min). Repeated-measures analysis of variance was performed on log-transformed pharmacodynamic parameters using a model with treatment, time, and treatment-by-time as fixed effects, and participant as a random effect. Values below the lower limit of quantification were set to the quantification limit for summary.

Cortisol levels were measured at all stages of glycemia during the glucose clamp period. Epinephrine levels were measured at each clamped glucose concentration: 9 millimoles per liter (mmol/L) (0 hour [hr], 1hr, 1 hr 15 minutes [min]), 5 mmol/L (1 hr 45 min, 2 hr), 4 mmol/L (2 hr 45 min, 3 hr), 3.3 mmol/L (3 hr 30 min, 3 hr 45 min), and 2.8 mmol/L (4 hr 15 min, 4 hr 30 min), and clamp released (4 hr 45 min, 5 hr, 5 hr 15 min, 5 hr 30 min). Repeated-measures analysis of variance was performed on log-transformed pharmacodynamic parameters using a model with treatment, time, and treatment-by-time as fixed effects, and participant as a random effect. Values below the lower limit of quantification were set to the quantification limit for summary.

C-peptide levels were measured at all stages of glycemia during the glucose clamp period. Epinephrine levels were measured at each clamped glucose concentration: 9 millimoles per liter (mmol/L) (0 hour [hr], 1hr, 1 hr 15 minutes [min]), 5 mmol/L (1 hr 45 min, 2 hr), 4 mmol/L (2 hr 45 min, 3 hr), 3.3 mmol/L (3 hr 30 min, 3 hr 45 min), and 2.8 mmol/L (4 hr 15 min, 4 hr 30 min), and clamp released (4 hr 45 min, 5 hr, 5 hr 15 min, 5 hr 30 min). Repeated-measures analysis of variance was performed on log-transformed pharmacodynamic parameters using a model with treatment, time, and treatment-by-time as fixed effects, and participant as a random effect. Values below the lower limit of quantification were set to the quantification limit for summary.

The effect of albiglutide and placebo on the recovery time of plasma glucose levels to >=3.9 mmol/L (7>=0 mg/dL) from the hypoglycemic clamp level of 2.8 nmol/L (50.4 mg/dL) was calculated as the time in minutes between switching off of the insulin infusion and reaching the level of >=3.9 mmol/L (>=70 mg/dL). Censored values were censored at 70 minutes. The median and 95% confidence interval data are obtained from Kaplan-Meier estimates.

Plasma samples were taken from participants at two time points on Day 4 (at 0 hours and 4 hours and 45 minutes post-dose) of Week 1 of the study for albiglutide study drug level analyses. The average concentration for each participant was calculated as the mean of the concentrations at 0 hours and 4 hours 45 minutes. The clamp procedure is a glucose-controlled insulin infusion system. Variable infusions of glucose are administered to achieve various glucose target levels. It is a way of quantifying insulin secretion and resistance.

Treatment-emergent AEs are defined as those with an onset on or after study drug administration. An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An 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, or is a congenital anomaly/birth defect.