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
Overview
- Phase
- Phase 2
- Intervention
- GSK716155
- Conditions
- Heart Failure, Congestive
- Sponsor
- GlaxoSmithKline
- Enrollment
- 82
- Locations
- 1
- Primary Endpoint
- Change From Baseline in Myocardial Glucose Utilization as Assessed by [18F]Fluoro-2-deoxy-glucose Positron Emission Tomography (FDG-PET) Imaging
- Status
- Completed
- Last Updated
- 8 years ago
Overview
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.
Investigators
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.
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:
Arms & Interventions
GSK716155 (3.75mg)
GSK716155 (3.75mg)
Intervention: GSK716155
GSK716155 (15mg)
GSK716155 (15mg)
Intervention: GSK716155
GSK716155 (30mg)
GSK716155 (30mg)
Intervention: GSK716155
GSK716155-matched placebo
GSK716155-matcued placebo
Intervention: Placebo
Outcomes
Primary Outcomes
Change From Baseline in Myocardial Glucose Utilization as Assessed by [18F]Fluoro-2-deoxy-glucose Positron Emission Tomography (FDG-PET) Imaging
Time Frame: Baseline and Week 13
FDG-PET imaging was performed at Baseline and Week 13 to assess myocardial glucose uptake. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Based on analysis using a mixed effects analysis of variance (ANOVA) model, fitting terms for treatment, visit and interaction of treatment and visit, with participants as random effects.
Change From Baseline in Peak Oxygen Uptake (Peak VO2) as Assessed by Bicycle Cardiopulmonary Exercise Testing
Time Frame: Baseline and Week 13
Peak VO2 was measured at Baseline and Week 13. Participants performed a maximal exercise test limited by dyspnea or fatigue on a cycle ergometer. After a rest period, the workloads were increased in a step fashion by 25 watts every 3 minutes. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Based on analysis using a mixed effects ANOVA model, fitting terms for treatment, visit and interaction of treatment and visit, with participants as random effects.
Change From Baseline in Myocardial Efficiency (Work Performed/Myocardial Oxygen Consumption [MVO2]) Assessed at Rest
Time Frame: Baseline and Week 13
MVO2 was estimated by measuring the rate of myocardial clearance of 11C-activity which represents overall myocardial oxidative flux through the TCA cycle. Cardiac work was measured by echocardiography and cardiac efficiency index was calculated as work (by echocardiography) divided by MVO2. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Based on analysis using a mixed effects ANOVA model, fitting terms for treatment, visit and interaction of treatment and visit, with participants as random effects.
Secondary Outcomes
- Change From Baseline in Left Ventricular Ejection Fraction (LVEF) as Assessed by Echocardiogram(Baseline and Week 13)
- Change From Baseline in Left Ventricular (LV) Volumes in Systole and Diastole as Assessed by Echocardiogram(Baseline and Week 13)
- 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(Baseline and Week 13)
- Change From Baseline in LV and RV Function Assessed by CMR (LV Mass), Myocardial Strain Assessed by Myocardial Tagging Indices(Baseline and Week 13)
- Change From Baseline in Cardiac Energetics (PCr/ATP) Measured by 31P Magnetic Resonance Spectroscopy (MRS)(Baseline and Week 13)
- Change From Baseline in Serum N-terminal Fragment Brain Natriuretic Peptide (NT-BNP) Level(Change from Baseline at Week 13)
- Change From Baseline in Plasma Levels of Glucose, and Free Fatty Acids (FFA)(Baseline and Week 13)
- Change From Baseline in LV and RV Function Assessed by Cardiac Magnetic Resonance (CMR) (LVEF), Myocardial Strain Assessed by Myocardial Tagging Indices(Baseline and Week 13)
- Change From Baseline in Cardiac and Liver Fat by Proton Spectroscopy (1H MRS)(Baseline and Week 13)
- Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)(Baseline and Week 13)
- Change From Baseline in Plasma Levels of Insulin(Baseline and Week 13)
- Change From Baseline in Exercise Capacity Assessed by 6-minute Walk Test(Baseline and Week 13)
- Number of Participants With Adverse Events by the Indicated Severity(Baseline and Week 13)
- Change From Baseline in Quality of Life as Assessed by the Minnesota Living With Heart Failure Questionnaire(Baseline and Week 13)