Pharmacokinetics/Pharmacodynamics of Albiglutide

Diabetes Mellitus, Type 2 Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01357889
• Other study ID #: 114856
• Status: Completed
• Phase: Phase 2
• First received: May 19, 2011
• Last updated: May 29, 2014
• Start date: July 2011
• Est. completion date: October 2012

Study information

• Verified date: April 2014
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 283
• Est. completion date: October 2012
• Est. primary completion date: October 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2

Intervention

Biological:
• albiglutide (GSK716155)
subcutaneous injection administered once a week
• albiglutide (GSK716155)
subcutaneous injection administered once a week

Locations

Country	Name	City	State
United States	GSK Investigational Site	Bensalem	Pennsylvania
United States	GSK Investigational Site	Blue Ridge	Georgia
United States	GSK Investigational Site	Bountiful	Utah
United States	GSK Investigational Site	Clarksville	Tennessee
United States	GSK Investigational Site	Columbia	South Carolina
United States	GSK Investigational Site	Columbus	Ohio
United States	GSK Investigational Site	Dothan	Alabama
United States	GSK Investigational Site	Greensboro	North Carolina
United States	GSK Investigational Site	Gulfport	Mississippi
United States	GSK Investigational Site	Hallandale Beach	Florida
United States	GSK Investigational Site	Houston	Texas
United States	GSK Investigational Site	Irving	Texas
United States	GSK Investigational Site	Jacksonville	Florida
United States	GSK Investigational Site	Lewisburg	West Virginia
United States	GSK Investigational Site	Lexington	Kentucky
United States	GSK Investigational Site	Long Beach	California
United States	GSK Investigational Site	Mason	Ohio
United States	GSK Investigational Site	McKenzie	Tennessee
United States	GSK Investigational Site	North Myrtle Beach	South Carolina
United States	GSK Investigational Site	Omaha	Nebraska
United States	GSK Investigational Site	Orlando	Florida
United States	GSK Investigational Site	Paducah	Kentucky
United States	GSK Investigational Site	Picayune	Mississippi
United States	GSK Investigational Site	Riverside	California
United States	GSK Investigational Site	San Antonio	Texas
United States	GSK Investigational Site	San Antonio	Texas
United States	GSK Investigational Site	San Antonio	Texas
United States	GSK Investigational Site	Simpsonville	South Carolina
United States	GSK Investigational Site	Sugarland	Texas
United States	GSK Investigational Site	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Primary	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	No
Secondary	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)	No
Secondary	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)	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No