Pharmacokinetics/Pharmacodynamics of Albiglutide

Study Overview
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Brief Summary
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The first part of the study includes a single dose treatment period to evaluate the pharmacokinetic bioequivalence of a subcutaneous injection of albiglutide from process 2 drug substance compared with process 3 drug substance. The second part of the treatment period will evaluate additional pharmacokinetic and pharmacodynamic parameters and safety and tolerability of repeat doses of albiglutide given weekly for 12 weeks from process 2 drug substance compared with process 3 drug substance. Subjects with type 2 diabetes whose glycemia is inadequately controlled on their current regimen of diet and exercise or stable dose of metformin will be recruited into the study.

Detailed Description
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This is a randomized, double-blind, multicenter, 2 parallel group study. The first part of the treatment period will evaluate the pharmacokinetic bioequivalence of a single dose of a subcutaneous injection of 30mg of albiglutide from process 2 drug substance compared with process 3 drug substance. The second part of the treatment period will evaluate additional pharmacokinetic parameters, pharmacodynamic parameters, immunogenicity, effects on glycosylated hemoglobin and fasting plasma glucose, and safety and tolerability of repeat doses of subcutaneous injections of 30mg of albiglutide given weekly for 12 weeks from process 2 drug substance compared with process 3 drug substance. Subjects with type 2 diabetes whose glycemia is inadequately controlled on their current regimen of diet and exercise or stable dose of metformin will be recruited into the study.

Official Title
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A Multidose Study in Subjects With Type 2 Diabetes Mellitus to Assess the Pharmacokinetics and Pharmacodynamics of Albiglutide

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Biological: albiglutide (GSK716155)
* Biological: albiglutide (GSK716155)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with a historical diagnosis of type 2 diabetes mellitus who are experiencing inadequate glycemic control on their current regimen of diet and exercise or on a stable dose of metformin Body mass index ≥20 kg/m2 and ≤45 kg/m2 Fasting C-peptide ≥0.8 ng/mL (≥0.26 nmol/L) Thyroid-stimulating hormone level is normal or clinically euthyroid Female subjects of childbearing potential (i.e., not surgically sterile and/or not postmenopausal) must be practicing adequate contraception. Exclusion Criteria: Current ongoing symptomatic biliary disease or history of pancreatitis History of significant GI surgery Recent clinically significant cardiovascular and/or cerebrovascular disease History of human immunodeficiency virus infection History of, or current hepatic disease History of alcohol or substance abuse Female subject is pregnant, lactating, or <6 weeks postpartum History of type 1 diabetes Receipt of any investigational drug 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 any GLP-1 agents including albiglutide History of, or family history of thyroid disease

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: process 2 albiglutide<br>albiglutide 30mg from process 2 drug substance | Biological: albiglutide (GSK716155)<br>* subcutaneous injection administered once a week<br>* Other names: process 2;|
| Active Comparator: process 3 albiglutide<br>albiglutide 30mg from process 3 drug substance | Biological: albiglutide (GSK716155)<br>* subcutaneous injection administered once a week<br>* Other names: process 3;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration Versus Time Curve (AUC) From Time Zero to Infinity (0-inf) of Albiglutide in the Bioequivalence (BE) Phase | To assess the bioequivalence of the two formulations of albiglutide, an analysis of variance (ANOVA) model with treatment as a fixed effect was applied to the natural-log-transformed parameter AUC(0-inf) estimated from the BE Phase. AUC is a measure of how much albiglutide is in the blood at certain time points. The Process 2 treatment group (albiglutide derived from process 2) was the reference group and was compared with the Process 3 treatment group (albiglutide derived from process 3) as the test group (i.e., treatment comparisons based on the ratio of Process 3:Process 2). Blood samples for pharmacokinetic analysis were collected prior to dosing at Baseline and 24 hours (hr), 48 hr, 96 hr, 120 hr, 216 hr, 312 hr, 480 hr, and 672 hr after administration of the Baseline study medication. | Pre-dose at Baseline; 24 hours (hr), 48 hr, 96 hr, 216 hr, 312 hr, 480 hr, and 672 hr post-dose | 
| Maximum Observed Plasma Concentration (Cmax) of Albiglutide in the BE Phase | To assess the bioequivalence of the two formulations of study drug, an analysis of variance (ANOVA) model with treatment as a fixed effect was applied to the natural-log-transformed parameter Cmax estimated from the BE phase. The Process 2 treatment group (albiglutide derived from process 2) was the reference group and was compared with the Process 3 treatment group (albiglutide derived from process 3) as the test group (i.e., treatment comparisons based on the ratio of Process 3:Process 2). Blood samples for pharmacokinetic analysis were collected prior to dosing at Baseline and 24 hours (hr), 48 hr, 96 hr, 120 hr, 216 hr, 312 hr, 480 hr, and 672 hr after administration of the Baseline study medication. | Pre-dose at Baseline; 24 hr, 48 hr, 96 hr, 216 hr, 312 hr, 480 hr, and 672 hr post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trough (Pre-dose) Plasma Concentrations of Albiglutide in the Mutiple-dose Phase (MDP) | The trough concentration of albiglutide at Week 5, Week 9, Week 13, Week 17 (EOT), and Week 25 (Follow-up) following multiple-dose administration was estimated. The time and date of sample collection pre-dose was to be recorded. | Immediately pre-dose at Week 5, Week 9, Week 13, Week 17 (End of Treatment [EOT]), and Week 25 (Follow-up) | 
| Number of Participants With Anti-albiglutide Antibody Formation at Baseline and Weeks 5, 9, 13, 17, and 25 in the Multiple-dose Phase | The presence of anti-albiglutide antibodies after repeat-dose administration was assessed using a qualified enzyme-linked immunosorbent assay. The assay involved screening, confirmation, and titration steps (tiered-testing approach). The number of participants who tested positive for anti-albiglutide antibodies are presented by visit. | Baseline, Week 5, Week 9, Week 13, Week 17, and Week 25 (Follow-up) | 
| AUC (0-last) and AUC (0-inf) of Albiglutide in the BE Phase | The area under the concentration-time (AUC) curve from time zero to the last quantifiable concentration (0-last) and AUC (0-inf) of albiglutide in the BE Phase were measured. AUC is a measure of how much albiglutide is in the blood at certain time points. Blood samples for PK analysis were collected prior to dosing at Baseline and 24 hr, 48 hr, 96 hr, 120 hr, 216 hr, 312 hr, 480 hr, and 672 hr after administration of the Baseline study medication. | Pre-dose at Baseline; 24 hr, 48 hr, 96 hr, 216 hr, 312 hr, 480 hr, and 672 hr post-dose | 
| Tmax and Tlag of Albiglutide in the BE Phase | Time of the maximum observed plasma concentration (tmax) and the observed time prior to the first quantifiable plasma concentration (tlag) of albiglutide in the BE Phase were measured. Blood samples for PK analysis were collected prior to dosing at Baseline and 24 hr, 48 hr, 96 hr, 120 hr, 216 hr, 312 hr, 480 hr, and 672 hr after administration of the Baseline study medication. | Pre-dose at Baseline; 24 hr, 48 hr, 96 hr, 216 hr, 312 hr, 480 hr, and 672 hr post-dose | 
| Cmax of Albiglutide in the BE Phase | Cmax of albiglutide in the BE Phase was measured. Blood samples for PK analysis were collected prior to dosing at Baseline and 24 hr, 48 hr, 96 hr, 120 hr, 216 hr, 312 hr, 480 hr, and 672 hr after administration of the Baseline study medication. | Pre-dose at Baseline; 24 hr, 48 hr, 96 hr, 216 hr, 312 hr, 480 hr, and 672 hr post-dose | 
| t1/2 of Albiglutide in the BE Phase | The terminal elimination half-life (t1/2) of albiglutide in the BE Phase was measured. Blood samples for PK analysis were collected prior to dosing at Baseline and 24 hr, 48 hr, 96 hr, 120 hr, 216 hr, 312 hr, 480 hr, and 672 hr after administration of the Baseline study medication. | Pre-dose at Baseline; 24 hr, 48 hr, 96 hr, 216 hr, 312 hr, 480 hr, and 672 hr post-dose | 
| Apparent Clearance of Albiglutide in the BE Phase | The apparent clearance (CL/F) of albiglutide in the BE Phase was measured. Blood samples for PK analysis were collected prior to dosing at Baseline and 24 hr, 48 hr, 96 hr, 120 hr, 216 hr, 312 hr, 480 hr, and 672 hr after administration of the Baseline study medication. | Pre-dose at Baseline; 24 hr, 48 hr, 96 hr, 216 hr, 312 hr, 480 hr, and 672 hr post-dose | 
| Apparent Volume of Distribution in the Terminal Phase of Albiglutide in BE Phase | The apparent volume of distribution in the terminal phase (V/F) of albiglutide in the BE Phase was measured. Blood samples for PK analysis were collected prior to dosing at Baseline and 24 hr, 48 hr, 96 hr, 120 hr, 216 hr, 312 hr, 480 hr, and 672 hr after administration of the Baseline study medication. | Pre-dose at Baseline; 24 hr, 48 hr, 96 hr, 216 hr, 312 hr, 480 hr, and 672 hr post-dose | 
| Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 17 | HbA1c is a form of hemoglobin that is measured primarily to identify the average plasma glucose concentration over prolonged periods of time. This analysis used the last observation carried forward (LOCF) method for missing post-Baseline HbA1c values. HbA1c values obtained after hyperglycemic rescue were treated as missing and replaced with pre-rescue values. Baseline is defined as the last available assessment on or prior to the day on which the first dose of study drug was received. Based on analysis of covariance (ANCOVA): Change = treatment + Baseline HbA1c + age category + weight category + background antidiabetic therapy category. | Baseline and Week 17 | 
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 17 | This analysis used the LOCF method for missing post-Baseline FPG values. FPG values obtained after hyperglycemic rescue were treated as missing and replaced with pre-rescue values. Baseline is defined as the last available assessment on or prior to the day on which the first dose of study drug was received. Based on ANCOVA: Change = treatment + Baseline FPG + age category + weight category + background antidiabetic therapy category. | Baseline and Week 17 | 
| Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) | 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 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, or is an event of possible drug-induced liver injury. Refer to the general Adverse AE/SAE module for a complete list of AEs and SAEs. Hypoglycemic events are excluded from this table, except for serious adverse events. | From the time the participant consented to participate in the study through Visit 28 (Week 25) or the final follow-up visit, for participants who discontinued active participation in the study | 
| Number of Participants With Indicated Adverse Events of Special Interest | Adverse events of special interest included cardiovascular events, hypoglycemic events, pancreatitis events, thyroid events, gastrointestinal (GI) events, diabetic retinopathy events, systemic allergic reactions (SAR), injection site reactions (ISR), and liver events (AEs from investigations and hepatobiliary disorders were considered). | From the time the participant consented to participate in the study through Visit 28 (Week 25) or the final follow-up visit, for participants who discontinue active participation in the study | 
| Number of Participants With a Change From Baseline of Clinical Concern in Hematology Values by Any On-therapy Visit | Criteria for values of potential concern were determined by the medical monitors. For hematocrit, a >0.1 decrease from Baseline was considered to be of clinical concern. For hemoglobin, a >25 grams per liter (g/L) decrease from Baseline was considered to be of clinical concern. | Week 1 through Week 25 | 
| Number of Participants With a Change From Baseline of Clinical Concern in Vital Signs by Any On-therapy Visit | Vital signs measured included systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate. Criteria for values of potential concern were determined by the medical monitors. For SBP, a decrease or increase >30 millimeters of mercury (mmHg) from Baseline was considered to be of clinical concern. For DBP, a decrease or increase >20 mmHg from Baseline was considered to be of clinical concern. For heart rate, a decrease or increase >30 beats per minute (bpm) was considered to be of clinical concern. | Week 1 through Week 25 | 
| Number of Participants With the Indicated Change From the Screening Assessment in Physical Examination at Week 17 | A complete physical examination was performed at Screening and at Week 17 and included evaluation of the following organ or body systems: skin (including injection site); head; eyes; ears, sose, and throat (ENT); thyroid; respiratory system; cardiovascular system; abdomen (liver, spleen); lymph nodes; central nervous system (CNT); and extremities. The assessment was categorized as improved, no change, worsened, and not done. | Screening and Week 17 | 
| Number of Participants With a Change From Baseline of Clinical Concern in Electrocardiogram (ECG) Values by Any On-therapy Visit | ECG parameters include heart rate, QRS interval, QTinterval, QT interval - Bazett correction (QTcB), QT interval - Fridericia correction (QTcF), RR interval, and PR interval. Criteria for values of potential concern were determined by the medical monitors. For the QRS interval, an increase of >25% when Baseline QRS >100 milliseconds (msec) and an increase of >50% when Baseline QRS <=100 msec was considered to be of clinical concern. For QTcF, a >=60 msec change from Baseline was considered to be of clinical concern. For the PR interval, an increase of >25% when Baseline PR >200 msec and an increase of >50% when Baseline PR <=200 msec was considered to be of clinical concern. | Week 1 through Week 25 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pharmacokinetics, pharmacodynamics, GSK716155, albiglutide