Pharmacokinetics/Pharmacodynamics of Albiglutide

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01357889
First received: May 19, 2011
Last updated: May 29, 2014
Last verified: April 2014
  Purpose

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.


Condition Intervention Phase
Diabetes Mellitus, Type 2
Biological: albiglutide (GSK716155)
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A Multidose Study in Subjects With Type 2 Diabetes Mellitus to Assess the Pharmacokinetics and Pharmacodynamics of Albiglutide

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Area Under the Plasma Concentration Versus Time Curve (AUC) From Time Zero to Infinity (0-inf) of Albiglutide in the Bioequivalence (BE) Phase [ Time Frame: Pre-dose at Baseline; 24 hours (hr), 48 hr, 96 hr, 216 hr, 312 hr, 480 hr, and 672 hr post-dose ] [ Designated as safety issue: No ]
    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.

  • Maximum Observed Plasma Concentration (Cmax) of Albiglutide in the BE Phase [ Time Frame: Pre-dose at Baseline; 24 hr, 48 hr, 96 hr, 216 hr, 312 hr, 480 hr, and 672 hr post-dose ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Trough (Pre-dose) Plasma Concentrations of Albiglutide in the Mutiple-dose Phase (MDP) [ Time Frame: Immediately pre-dose at Week 5, Week 9, Week 13, Week 17 (End of Treatment [EOT]), and Week 25 (Follow-up) ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With Anti-albiglutide Antibody Formation at Baseline and Weeks 5, 9, 13, 17, and 25 in the Multiple-dose Phase [ Time Frame: Baseline, Week 5, Week 9, Week 13, Week 17, and Week 25 (Follow-up) ] [ Designated as safety issue: No ]
    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.

  • AUC (0-last) and AUC (0-inf) of Albiglutide in the BE Phase [ Time Frame: Pre-dose at Baseline; 24 hr, 48 hr, 96 hr, 216 hr, 312 hr, 480 hr, and 672 hr post-dose ] [ Designated as safety issue: No ]
    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.

  • Tmax and Tlag of Albiglutide in the BE Phase [ Time Frame: Pre-dose at Baseline; 24 hr, 48 hr, 96 hr, 216 hr, 312 hr, 480 hr, and 672 hr post-dose ] [ Designated as safety issue: No ]
    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.

  • Cmax of Albiglutide in the BE Phase [ Time Frame: Pre-dose at Baseline; 24 hr, 48 hr, 96 hr, 216 hr, 312 hr, 480 hr, and 672 hr post-dose ] [ Designated as safety issue: No ]
    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.

  • t1/2 of Albiglutide in the BE Phase [ Time Frame: Pre-dose at Baseline; 24 hr, 48 hr, 96 hr, 216 hr, 312 hr, 480 hr, and 672 hr post-dose ] [ Designated as safety issue: No ]
    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.

  • Apparent Clearance of Albiglutide in the BE Phase [ Time Frame: Pre-dose at Baseline; 24 hr, 48 hr, 96 hr, 216 hr, 312 hr, 480 hr, and 672 hr post-dose ] [ Designated as safety issue: No ]
    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.

  • Apparent Volume of Distribution in the Terminal Phase of Albiglutide in BE Phase [ Time Frame: Pre-dose at Baseline; 24 hr, 48 hr, 96 hr, 216 hr, 312 hr, 480 hr, and 672 hr post-dose ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 17 [ Time Frame: Baseline and Week 17 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Fasting Plasma Glucose (FPG) at Week 17 [ Time Frame: Baseline and Week 17 ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With Indicated Adverse Events of Special Interest [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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).

  • Number of Participants With a Change From Baseline of Clinical Concern in Hematology Values by Any On-therapy Visit [ Time Frame: Week 1 through Week 25 ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With a Change From Baseline of Clinical Concern in Vital Signs by Any On-therapy Visit [ Time Frame: Week 1 through Week 25 ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With the Indicated Change From the Screening Assessment in Physical Examination at Week 17 [ Time Frame: Screening and Week 17 ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With a Change From Baseline of Clinical Concern in Electrocardiogram (ECG) Values by Any On-therapy Visit [ Time Frame: Week 1 through Week 25 ] [ Designated as safety issue: No ]
    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.


Enrollment: 283
Study Start Date: July 2011
Study Completion Date: October 2012
Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: process 2 albiglutide
albiglutide 30mg from process 2 drug substance
Biological: albiglutide (GSK716155)
subcutaneous injection administered once a week
Other Name: process 2
Active Comparator: process 3 albiglutide
albiglutide 30mg from process 3 drug substance
Biological: albiglutide (GSK716155)
subcutaneous injection administered once a week
Other Name: process 3

Detailed 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.

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01357889

  Hide Study Locations
Locations
United States, Alabama
GSK Investigational Site
Dothan, Alabama, United States, 36301
United States, California
GSK Investigational Site
Long Beach, California, United States, 90806
GSK Investigational Site
Riverside, California, United States, 92506
United States, Florida
GSK Investigational Site
Hallandale Beach, Florida, United States, 33009
GSK Investigational Site
Jacksonville, Florida, United States, 32205
GSK Investigational Site
Orlando, Florida, United States, 32822
GSK Investigational Site
Tampa, Florida, United States, 33603
United States, Georgia
GSK Investigational Site
Blue Ridge, Georgia, United States, 30513
United States, Kentucky
GSK Investigational Site
Lexington, Kentucky, United States, 40504
GSK Investigational Site
Paducah, Kentucky, United States, 42003
United States, Mississippi
GSK Investigational Site
Gulfport, Mississippi, United States, 39501
GSK Investigational Site
Picayune, Mississippi, United States, 39466
United States, Nebraska
GSK Investigational Site
Omaha, Nebraska, United States, 68131
United States, North Carolina
GSK Investigational Site
Greensboro, North Carolina, United States, 27405
United States, Ohio
GSK Investigational Site
Columbus, Ohio, United States, 43213
GSK Investigational Site
Mason, Ohio, United States, 45040
United States, Pennsylvania
GSK Investigational Site
Bensalem, Pennsylvania, United States, 19020
United States, South Carolina
GSK Investigational Site
Columbia, South Carolina, United States, 29201
GSK Investigational Site
North Myrtle Beach, South Carolina, United States, 29582
GSK Investigational Site
Simpsonville, South Carolina, United States, 29681
United States, Tennessee
GSK Investigational Site
Clarksville, Tennessee, United States, 37043
GSK Investigational Site
McKenzie, Tennessee, United States, 38201
United States, Texas
GSK Investigational Site
Houston, Texas, United States, 77074
GSK Investigational Site
Irving, Texas, United States, 75039
GSK Investigational Site
San Antonio, Texas, United States, 78218
GSK Investigational Site
San Antonio, Texas, United States, 78215
GSK Investigational Site
San Antonio, Texas, United States, 78229
GSK Investigational Site
Sugarland, Texas, United States, 77479
United States, Utah
GSK Investigational Site
Bountiful, Utah, United States, 84010
United States, West Virginia
GSK Investigational Site
Lewisburg, West Virginia, United States, 24901
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01357889     History of Changes
Other Study ID Numbers: 114856
Study First Received: May 19, 2011
Results First Received: April 24, 2014
Last Updated: May 29, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by GlaxoSmithKline:
pharmacokinetics
pharmacodynamics
GSK716155
albiglutide

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Albiglutide
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on August 28, 2014