Clinical trial NCT01357850: A Multi-center, Placebo-controlled Study to Evaluate the Safety of GSK716155 and Its Effects on Myocardial Metabolism, Myocardial Function, and Exercise Capacity in Patients With NYHA Class II/III Congestive Heart Failure
Official title: A Multi-center, Placebo-controlled Study to Evaluate the Safety of GSK716155 and Its Effects on Myocardial Metabolism, Myocardial Function, and Exercise Capacity in Patients With NYHA Class II/III Congestive Heart Failure
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Heart Failure, Congestive
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2011-05-23
Enrollment: 82
Sex: ALL
Minimum age (years): 21
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: This exploratory proof of concept study will be conducted in patients with stable New York Heart Association (NYHA) Class II-III heart failure. The focus of the efficacy endpoints is to test the hypothesis that GSK716155 administration will increase glucose uptake and utilization in the myocardium, resulting in increased myocardial efficiency and increased exercise capacity. A positive result, defined as either statistically significant effects on one or more of the efficacy endpoints or as an overall signal suggesting a clinically relevant effect on myocardial physiology, would provide evidence for potential progression into further development in a chronic heart failure population.


Eligibility criteria: Inclusion Criteria:

* Chronic dilated cardiomyopathy of ischemic or non-ischemic origin
* Clinically stable on optimal therapies for at least 3 months prior to screening/baseline visit.
* Left ventricular ejection fraction greater than or equal to 40% as assessed by any measurement in the previous 24 months.
* NYHA Class II/III heart failure for a minimum of 6 months prior to enrolment
* Male or female between 21 and 75 years of age inclusive, at the time of signing the informed consent. However the optimal age range for this study will be 40 to 65 years of age.
* A female subject is eligible to participate if she is of:

Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \> 40 MlU/ml and estradiol \< 40 pg/ml (\<140 pmol/L) is confirmatory\].

Child-bearing potential and agrees to use one of the contraception methods listed in Section 8.1 for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until the follow-up visit \~28 days post-last dose.

* Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
* Confirmed QTcB or QTcF \< 480 msec; or QTc \< 500 msec in subjects with Bundle Branch Block.
* AST and ALT \< 2xULN; alkaline phosphatase and bilirubin greater than or equal to 1.5xULN (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
* Subjects must be able to perform performance/exercise testing

Exclusion Criteria:

* A subject will not be eligible for inclusion in this study if any of the following criteria apply:
* Active ischemia manifest as a history of myocardial infarction or unstable angina in the past 12 months or a history of coronary revascularization (percutaneous coronary intervention and/or coronary artery bypass grafting) in the past 6 months.

  -. High suspicion of active myocardial ischemia, in the opinion of the treating physician
* A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
* History of drug/alcohol abuse.
* A positive test for HIV antibody.
* Calcitonin \> 100 pg./mL
* Triglycerides \> 850 mg/dL
* History of significant gastrointestinal surgery, including gastric bypass and banding, antrectomy, Roux-en-Y bypass, gastric vagotomy, small bowel resection, or surgeries thought to significantly affect upper gastrointestinal function.
* History of regular alcohol consumption within 6 months of the study defined as:

For UK: an average weekly intake of \>21 units for males or \>14 units for females. One unit is equivalent to 8 g of alcohol: a half-pint (\~240 ml) of beer, 1 glass (125 ml) of wine or 1 (25 ml) measure of spirits.

For US: an average weekly intake of \>14 drinks for males or \>7 drinks for females. One drink is equivalent to 12 g of alcohol: 12 ounces (360 ml) of beer, 5 ounces (150 ml) of wine or 1.5 ounces (45 ml) of 80 proof distilled spirits.

* The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
* Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
* Known allergy or history of sensitivity to albiglutide, any other GLP-1 analogue, , or Baker's yeast.
* Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
* Pregnant females as determined by positive serum or urine hCG test at screening or prior to dosing.
* Lactating females.
* Unwillingness or inability to follow the procedures outlined in the protocol (e.g.. related to psychiatric disorder)
* Subject is mentally or legally incapacitated.
* Known diagnosis of diabetes mellitus, fasting glucose \>140mg/dL, or HbA1c \> 7%.
* Uncorrected thyroid disease manifest as an abnormal thyroid-stimulating hormone (TSH) (outside reference range at screening).
* Other medical problems with life expectancy less than 1yr.
* Other causes of cardiomyopathy or left ventricular dysfunction including:

Uncorrected primary obstructive or regurgitant valvular disease Restrictive cardiomyopathy due to amyloidosis, hemochromatosis, sarcoidosis or other cause Cardiac hypertrophy with wall thickness \>1.5cm Alcohol-induced cardiomyopathy Women with heart failure during the 12 months following childbirth. Complex congenital heart disease Anthracycline induced cardiomyopathy

* Subjects with genetic disorders of skeletal muscle (e.g. Duchenne muscular dystrophy)
* Clinically significant pericardial disease.
* Listed as a status 1A or 1B on heart transplant waiting list.
* History of deep vein thrombosis or a known coagulation disorder
* History of pancreatitis
* History of or family history of medullary thyroid carcinoma
* History of or family history of multiple endocrine neoplasia type 2
* History of renal dysfunction with estimated GFR \< 40 ml/min at screening
* Resting systolic blood pressure \< 85 mmHg or \>170 mmHg; or diastolic blood pressure \>110 mgHg at screening.
* Inability of the patient to lie flat for a combined total of up to 4 hours to complete imaging assessments.
* No subjects will be enrolled at the single site performing the CMR sub-study who have contraindications to MRI scanning including, but not limited to:

Intracranial aneurysm clips with an appropriate operative conformation History of intra- orbital metal fragments Pacemakers or non-MR compatible heart valves Inner ear implants History of claustrophobia deemed significant by the investigator

Primary outcomes:
measure: Change From Baseline in Myocardial Glucose Utilization as Assessed by [18F]Fluoro-2-deoxy-glucose Positron Emission Tomography (FDG-PET) Imaging
timeFrame: Baseline and Week 13
measure: Change From Baseline in Myocardial Efficiency (Work Performed/Myocardial Oxygen Consumption [MVO2]) Assessed at Rest
timeFrame: Baseline and Week 13
measure: Change From Baseline in Peak Oxygen Uptake (Peak VO2) as Assessed by Bicycle Cardiopulmonary Exercise Testing
timeFrame: Baseline and Week 13
Secondary outcomes:
measure: Change From Baseline in Left Ventricular Ejection Fraction (LVEF) as Assessed by Echocardiogram
timeFrame: Baseline and Week 13
measure: Change From Baseline in Left Ventricular (LV) Volumes in Systole and Diastole as Assessed by Echocardiogram
timeFrame: Baseline and Week 13
measure: Change From Baseline in LV and RV Function Assessed by Cardiac Magnetic Resonance (CMR) (LVEF), Myocardial Strain Assessed by Myocardial Tagging Indices
timeFrame: Baseline and Week 13
measure: Change From Baseline in LV and RV Function Assessed by CMR (LV and RV Volumes in Systole and Diastole), Myocardial Strain Assessed by Myocardial Tagging Indices
timeFrame: Baseline and Week 13
measure: Change From Baseline in LV and RV Function Assessed by CMR (LV Mass), Myocardial Strain Assessed by Myocardial Tagging Indices
timeFrame: Baseline and Week 13
measure: Change From Baseline in Cardiac Energetics (PCr/ATP) Measured by 31P Magnetic Resonance Spectroscopy (MRS)
timeFrame: Baseline and Week 13
measure: Change From Baseline in Cardiac and Liver Fat by Proton Spectroscopy (1H MRS)
timeFrame: Baseline and Week 13
measure: Change From Baseline in Exercise Capacity Assessed by 6-minute Walk Test
timeFrame: Baseline and Week 13
measure: Change From Baseline in Serum N-terminal Fragment Brain Natriuretic Peptide (NT-BNP) Level
timeFrame: Change from Baseline at Week 13
measure: Change From Baseline in Plasma Levels of Glucose, and Free Fatty Acids (FFA)
timeFrame: Baseline and Week 13
measure: Change From Baseline in Plasma Levels of Insulin
timeFrame: Baseline and Week 13
measure: Change From Baseline in Quality of Life as Assessed by the Minnesota Living With Heart Failure Questionnaire
timeFrame: Baseline and Week 13
measure: Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Baseline and Week 13
measure: Number of Participants With Adverse Events by the Indicated Severity
timeFrame: Baseline and Week 13
Other outcomes:
Locations:
city: Savannah
country: United States
facility: GSK Investigational Site
state: Georgia
city: Metairie
country: United States
facility: GSK Investigational Site
state: Louisiana
city: Auburn
country: United States
facility: GSK Investigational Site
state: Maine
city: Baltimore
country: United States
facility: GSK Investigational Site
state: Maryland
city: Detroit
country: United States
facility: GSK Investigational Site
state: Michigan
city: Minneapolis
country: United States
facility: GSK Investigational Site
state: Minnesota
city: Saint Louis
country: United States
facility: GSK Investigational Site
state: Missouri
city: Newark
country: United States
facility: GSK Investigational Site
state: New Jersey
city: Stony Brook
country: United States
facility: GSK Investigational Site
state: New York
city: Columbus
country: United States
facility: GSK Investigational Site
state: Ohio
city: New York
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Philadelphia
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Cambridge
country: United Kingdom
facility: GSK Investigational Site
state: Cambridgeshire
city: London
country: United Kingdom
facility: GSK Investigational Site
city: Oxford
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Lepore JJ, Olson E, Demopoulos L, Haws T, Fang Z, Barbour AM, Fossler M, Davila-Roman VG, Russell SD, Gropler RJ. Effects of the Novel Long-Acting GLP-1 Agonist, Albiglutide, on Cardiac Function, Cardiac Metabolism, and Exercise Capacity in Patients With Chronic Heart Failure and Reduced Ejection Fraction. JACC Heart Fail. 2016 Jul;4(7):559-566. doi: 10.1016/j.jchf.2016.01.008. Epub 2016 Mar 30.