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
Condition: Heart Failure, Congestive
MeSH terms: Heart Failure
Intervention: GSK716155; Placebo
Intervention description: GSK716155; Placebo
Phase: Phase 2
Study type: Interventional
Primary purpose: Basic Science
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 82.0
Sex: All
Minimum age: 21 Years
Maximum age: 75 Years
Healthy volunteers: No

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