A Study Evaluating the Effect of Albiglutide on Gallbladder Emptying in Healthy Subjects

Study Overview
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Brief Summary
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Albiglutide, a novel analogue of glucagon-like peptide-1 (GLP-1), has been developed and approved for the treatment of type 2 diabetes mellitus. The primary objective of this study is to assess if a single dose of albiglutide can affect cholecystokinin-induced gallbladder emptying. To make this assessment, each study participant will receive a dose of albiglutide and a dose of placebo followed by cholecystokinin (CCK) infusion and ultrasound measurement of the gallbladder. The study will be comprised of two periods and 20 subjects. The screening visit will occur within 42 days of the start of Treatment Period 1. The Treatment Periods will be separated by a washout period of a minimum of 42 days. Subjects will return for a follow-up visit after 28 days following the last dose of albiglutide or placebo. The total duration of a subject's participation from Screening to Follow-up will be approximately 17.5 weeks. This study is a post marketing commitment to the United States Food and Drug Administration (USFDA).

Official Title
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A Randomized, Double-blind, Single-dose, Placebo Controlled, 2-way Cross-over Study Evaluating Effect of Albiglutide on Cholecystokinin-induced Gallbladder Emptying in Fasting Healthy Subjects

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Albiglutide 50 mg
* Drug: Placebo
* Drug: CCK (Kinevac)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Between 18 and 65 years of age Healthy Have venous access sufficient to allow for intravenous (IV) infusion and blood sampling as per protocol Subject's body mass index (BMI) is >=18 kilogram (kg)/meter(m)^2 and <=30 kg/m^2 Male or Female: if she is not pregnant (as confirmed by a test at screening and at other timepoints), not lactating, and at least one of the following conditions applies: a) cannot bear children OR b) agrees to follow contraception requirements defined in the protocol Capable of giving signed informed consent Exclusion Criteria: Alanine aminotransferase (ALT) >1.5x Upper limit of normal (ULN) Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%) Current or chronic history of liver disease, or known hepatic or biliary abnormalities QT interval corrected for heart rate according to Fridericia's formula (QTcF) > 450 milliseconds (msec) Systolic blood pressure is >=140 millimetre (mm) mercury (Hg) at Screening Diastolic blood pressure is >=90 mm Hg at Screening Heart rate is >100 beats/min at Screening Fasting triglyceride level >300 milligram/decilitre at Screening History of cholecystitis or other gallbladder disease History of gallstones, biliary motility dysfunction, or any condition rendering the subject unsuitable for ultrasonography assessments Prior cholecystectomy or any other gallbladder or biliary ducts procedure, prior ileal or gastric surgery, or any other medical procedure that precluded gallbladder emptying History of significant cardiovascular or pulmonary dysfunction prior to screening History of thyroid dysfunction History of intestinal obstruction, ileus, lap-band, gastrointestinal surgery or any other procedures that in the opinion of the investigator could influence gastric emptying (e.g., gastrectomy, gastric bypass) History of acute or chronic pancreatitis History of abdominal pain of unknown cause History of severe gastrointestinal disease, including gastroparesis, inflammatory bowel disease, Crohn's disease, or irritable bowel syndrome Personal or family history of multiple endocrine neoplasia type 2 Personal or family history of medullary carcinoma of the thyroid Unable to refrain from the use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days Current or past use of medications that may have significantly affected gastrointestinal and/or gallbladder motility or pancreatic or hepatobiliary systems History of regular alcohol consumption within 6 months of the study Urinary cotinine levels indicative of smoking or history of regular use of tobacco- or nicotine-containing products within 3 months prior to screening Subject has a history of significant weight loss or is currently attempting weight loss History of sensitivity or contraindication to any of the study medications or components thereof or a history of drug or other allergy Subject has previously received any GLP-1 mimetic compound (e.g., exenatide, liraglutide, lixisenatide, dulaglutide) A biliary pathology as assessed by ultrasound An abnormal (i.e., outside the normal reference range) thyroid function test assessed by thyroid stimulating hormone at screening An abnormal amylase or lipase test at screening A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result A positive pre-study drug/alcohol screen A positive test for Human immunodeficiency virus (HIV) antibody A screening ultrasound which demonstrates inadequate imaging of gallbladder, main pancreatic duct, or common duct Where participation in the study would result in donation of blood or blood products in excess of 500 mL within 56-day period The subject participated in a clinical trial and received an investigational product within 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer) Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Albiglutide / Placebo or Placebo / Albiglutide<br>In treatment period 1, subjects will receive Albiglutide 50 mg or Placebo subcutaneously (SC) after fasting overnight for at least 10 hours according to randomization schedule on Day 1. Subject will also receive CCK (Kinevac) infusion intravenously for a period of 50 minutes after fasting overnight for at least 10 hours on Day 4. After washout period of a minimum of 42 days in treatment period 2, subjects will receive same treatment according to randomization schedule in a cross-over fashion | Drug: Albiglutide 50 mg<br>* Albiglutide 50 mg pen is a single-use fixed dose, fully disposable pen injector system for SC delivery in the abdomen containing 67 mg lyophilized albiglutide and 0.65 mL diluents designed to deliver a dose of 50 mg in a volume of 0.5 mL after reconstitution<br>Drug: Placebo<br>* Placebo is a single-use fixed dose, fully disposable pen injector system for SC delivery of 0.5 mL injector volume in the abdomen<br>Drug: CCK (Kinevac)<br>* CCK (Kinevac) will be infused intravenously. Kinevac is supplied in vials containing 5 microgram (mcg)/vial. Infusion prepared aseptically by adding 5 mL of Sterile Water for Injection United States Pharmacopeia (USP) to the vial to create a solution of 1 mcg/mL. Infuse 0.003 mcg/kg dose in 100 mL of Sodium Chloride Injection USP, 0.9%<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Absolute Value of Gallbladder Ejection Fraction (Emax GEF) During Cholecystokinin (CCK) Infusion, as a Measure of Maximum Effect | Gallbladder ejection fraction (EF) is defined as the reduction in gallbladder volume at any time point from Baseline divided by baseline gallbladder volume and multiplied by 100. Baseline gallbladder volume is the average of the 3 gallbladder volume measurements prior to CCK infusion on Day 4, for each treatment period. Gallbladder ultrasonography was done at Day 1 (-15, -10, and -5 minutes [min] relative to start of albiglutide/placebo injection) and Day 4 ([prior to CCK infusion] -15, -10, -5 min, followed by [during CCK infusion] every 5 min between 0 and 50 min, then [after CCK infusion] at 60, 70, and 80 min, relative to the start of CCK infusion). Adjusted mean and its standard error have been presented. | Day 4 in each treatment period | 
| Area Under the Effect Curve for Gallbladder Ejection Fraction (AUEC GEF) | Gallbladder ultrasonography was done at Day 1 (-15, -10, and -5 minutes [min] relative to start of albiglutide/placebo injection) and Day 4 ([prior to CCK infusion] -15, -10, -5 min, followed by [during CCK infusion] every 5 min between 0 and 50 min, then [after CCK infusion] at 60, 70, and 80 min, relative to the start of CCK infusion). Adjusted mean and its standard error have been presented. | Day 4 in each treatment period | 
| Time at Which the Maximum Effect (Emax GEF) Occurred (TEMAXEF) During the CCK Infusion | Gallbladder ultrasonography was done at Day 1 (-15, -10, and -5 minutes [min] relative to start of albiglutide/placebo injection) and Day 4 ([prior to CCK infusion] -15, -10, -5 min, followed by [during CCK infusion] every 5 min between 0 and 50 min, then [after CCK infusion] at 60, 70, and 80 min, relative to the start of CCK infusion). | Day 4 in each treatment period | 
| Maximum Gallbladder Ejection Fraction Value During CCK Infusion | Gallbladder ultrasonography was done at Day 1 (-15, -10, and -5 minutes [min] relative to start of albiglutide/placebo injection) and Day 4 ([prior to CCK infusion] -15, -10, -5 min, followed by [during CCK infusion] every 5 min between 0 and 50 min, then [after CCK infusion] at 60, 70, and 80 min, relative to the start of CCK infusion). | Day 1 and Day 4 in each treatment period | 
| Area Under the Effect Curve for Gallbladder Volume (AUEC VL) | Gallbladder ultrasonography was done at Day 1 (-15, -10, and -5 minutes [min] relative to start of albiglutide/placebo injection) and Day 4 ([prior to CCK infusion] -15, -10, -5 min, followed by [during CCK infusion] every 5 min between 0 and 50 min, then [after CCK infusion] at 60, 70, and 80 min, relative to the start of CCK infusion). Adjusted mean and its standard error is presented. | Day 4 in each treatment period | 
| Maximum Absolute Change From Baseline in Value of Gallbladder Volume (Emax VL) During CCK Infusion, as a Measure of Maximum Effect | Gallbladder ultrasonography was done at Day 1 (-15, -10, and -5 minutes [min] relative to start of albiglutide/placebo injection) and Day 4 ([prior to CCK infusion] -15, -10, -5 min, followed by [during CCK infusion] every 5 min between 0 and 50 min, then [after CCK infusion] at 60, 70, and 80 min, relative to the start of CCK infusion). Baseline gallbladder volume is the average of the 3 gallbladder volume measurements prior to CCK infusion on Day 4, for each treatment period. Adjusted mean and its standard error are presented. | Day 4 in each treatment period | 
| Time at Which the Maximum Effect (Emax VL) Occurred (TEmax VL) During the CCK Infusion | Gallbladder ultrasonography was done at Day 1 (-15, -10, and -5 minutes [min] relative to start of albiglutide/placebo injection) and Day 4 ([prior to CCK infusion] -15, -10, -5 min, followed by [during CCK infusion] every 5 min between 0 and 50 min, then [after CCK infusion] at 60, 70, and 80 min, relative to the start of CCK infusion). | Day 4 in each treatment period | 
| Maximum Change From Baseline in Main Pancreatic Duct Diameter During CCK Infusion | Pancreatic duct ultrasonography was done at Day 1 (-15, -10, and -5 minutes [min] relative to start of albiglutide/placebo injection) and Day 4 ([prior to CCK infusion] -15, -10, -5 min, followed by [during CCK infusion] every 5 min between 0 and 50 min, then [after CCK infusion] at 60, 70, and 80 min, relative to the start of CCK infusion). Baseline is the average of the three diameter assessments at -15, -10, and -5 minutes relative to start of CCK infusion on Day 4. Change from Baseline was calculated as the value at the indicated time point minus the Baseline value. Adjusted mean and its standard error are presented. Baseline was calculated as the value at the indicated time point minus the Baseline value. Only those participants available at the indicated time points were analyzed. | Day 4 in each treatment period | 
| Maximum Change From Baseline in Common Bile Duct Diameter During CCK Infusion | Common bile duct ultrasonography was done at Day 1 (-15, -10, and -5 minutes [min] relative to start of albiglutide/placebo injection) and Day 4 ([prior to CCK infusion] -15, -10, -5 min, followed by [during CCK infusion] every 5 min between 0 and 50 min, then [after CCK infusion] at 60, 70, and 80 min, relative to the start of CCK infusion). Baseline is the average of the three diameter assessments at -15, -10, and -5 minutes relative to start of CCK infusion on Day 4. Change from Baseline was calculated as the value at the indicated time point minus the Baseline value. Adjusted mean and its standard error have been presented. | Day 4 in each treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Baseline is defined as Day 1 (pre-dose) visit. SBP and DBP were measured in a semi-supine position after 5 minutes of rest, at each indicated time point. Assessments were performed on Day -1, Day 1 (pre-dose), Day 2, Day 3 and 15 minutes (-15 min) prior to dosing and 80 min post dosing on Day 4. Change from Baseline was calculated as value at indicated time point minus Baseline value. Only those participants available at the indicated time points (represented by n=X,X in the category titles) were analyzed. | Day -1, Baseline Day 1(Pre-dose), Day 2, Day 3, and 15 minutes (-15 min) prior to dosing and 80 min post dosing on Day 4 in each treatment period and Follow-up (assessed up to a total of approximately 12 weeks) | 
| Change From Baseline in Heart Rate | Baseline is defined as Day 1 (pre-dose) visit. Heart rate was measured in a semi-supine position after 5 minutes of rest, at each indicated time point. Assessments were performed on Day -1, Day 2, Day 3 and 15 minutes (-15 min) prior to dosing and 80 min post dosing on Day 4. Change from Baseline was calculated as value at indicated time point minus Baseline value. Only those participants available at the indicated time points (represented by n=X,X in the category titles) were analyzed. | Day -1, Baseline Day 1(Pre-dose), Day 2, Day 3, and 15 minutes (-15 min) prior to dosing and 80 min post dosing on Day 4 in each treatment period and Follow-up (a total of approximately 12 weeks) | 
| Number of Participants With Clinical Chemistry and Hematology Abnormalities of Potential Clinical Importance | The following parameters were measured through blood sampling. Hematology: Hematocrit, Hemoglobin, Lymphocytes, Neutrophil Count, Platelet Count, While Blood Cell Count (WBC); Clinical Chemistry: Albumin, Calcium, Creatinine, Glucose, Magnesium, Phosphorus, Potassium, Sodium, Total carbon dioxide; Liver Function Tests: Alanine transaminase (ALT), Aspartate transaminase, Alkaline Phosphatase, Total Bilirubin, Total Bilirubin + ALT. Values were considered to be of potential clinical importance if they had a 'low' or 'high' flag with respect to a pre-defined clinical concern range. Only participants starting each period (represented by n=X) with a particular treatment were analyzed. The follow-up time point is not restricted to a treatment or treatment period. | Day -1 in each treatment period and Follow-up (at approximately Week 12) | 
| Change From Baseline in Electrocardiogram (ECG) Parameters | Single 12-lead ECG was obtained in a semi-supine position after 5 minutes of rest at each indicated time point using an ECG machine that automatically calculated the heart rate and measured the PR, QRS, QT, and QT corrected by Fridericia's formula (QTcF) intervals. Change from Baseline was calculated as value at indicated time point minus Baseline value. | Baseline (Day -1) and Day 4 in each treatment period, and at Follow-up (at approximately Week 12) | 
| Part A: Number of Participants With at Least One Non-serious Adverse Event (AE), Serious Adverse Event (SAE), or Drug-related Adverse Event | An AE is defined as any untoward medical occurrence in a 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, or is a congenital anomaly/birth defect, may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition, associated with liver injury and impaired liver function defined as alanine aminotransferase >=3 x upper limit of normal (ULN), and total bilirubin >=2 x ULN or international normalised ratio >1.5. AEs were classified as potentially drug-related, based on the investigator's judgement. Refer to the general AE/SAE module for a list of AEs and SAEs. | From Day -1 in treatment period 1 and up to Follow-up Visit (a total of approximately 12 weeks) | 
| Number of Participants for the Indicated Urinalysis Parameters Tested by Dipstick | Urine dipstick test was carried out on Day -1 and at Follow-up. Urinalysis parameters assessed were glucose, ketones, nitrite and protein. Dipstick results were categorized as Normal (glucose), Negative or Trace (ketones), and Negative (nitrite and protein). Only participants available at the indicated time points (as represented by n=X, X, X in the category titles) were analyzed. The resultant fields with no available data have been represented by 'NA'. | Day -1 and Follow-up (assessed up to a total of approximately 12 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cholecystokinin, ultrasonography, Albiglutide, Gallbladder ejection fraction