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

GlaxoSmithKline (GSK)

Status and phase: Completed; Phase 2

Conditions: Heart Failure, Congestive

Treatments: Drug: Placebo; Drug: GSK716155

Study type: Interventional

Funder types: Industry

Identifiers

NCT01357850

112670

Details and patient eligibility

About

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.

Enrollment: 82 patients

Sex: All

Ages: 21 to 75 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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82 participants in 4 patient groups, including a placebo group

GSK716155 (3.75mg)

Experimental group

Description:

GSK716155 (3.75mg)

Treatment:

Drug: GSK716155

GSK716155 (15mg)

Experimental group

Description:

GSK716155 (15mg)

Treatment:

Drug: GSK716155

GSK716155 (30mg)

Experimental group

Description:

GSK716155 (30mg)

Treatment:

Drug: GSK716155

GSK716155-matched placebo

Placebo Comparator group

Description:

GSK716155-matcued placebo

Treatment:

Drug: Placebo