Evaluating the Clinical Efficacy of Resveratrol in Improving Metabolic and Skeletal Muscle Function in Patients With Heart Failure
Condition: Congestive Heart Failure Chronic
MeSH terms: Heart Failure
Study type: Interventional
Phase: Phase 2

Summary: 
      This is a randomized, double-blind, placebo-controlled trial evaluating the effect of
      resveratrol on metabolic and skeletal muscle function. Patients will be randomized and
      allocated to either resveratrol or placebo, for 8 weeks with a 2-week run-in period before
      the intervention period (to ensure they are not on any nutritional supplement that contains
      resveratrol).
    

Detailed description: 
      Trial Objectives Primary outcome- Change in Isolated Skeletal Muscle Blood Flow, Oxygen
      Extraction and Consumption and Metabolic Rate of Recovery with Exercise by Cardiac MRI (CMR).
      In order to evaluate potential changes in skeletal muscle vascular function and oxygen
      extraction with resveratrol therapy, the investigators will use a lower limb (calf muscle)
      targeted exercise protocol in conjunction with magnetic resonance imaging (MRI)32. MRI will
      be used to measure, simultaneously, the peak rate of blood flow in the calf muscle along with
      the whole calf muscle extraction of oxygen, which together are used to determine oxygen
      consumption. This method allows the determinants of oxygen consumption (blood flow and oxygen
      extraction) to be evaluated, which is necessary to understand the mechanisms of therapy
      action.

      Secondary outcomes-

        1. Change in Vascular Function by CMR. Measurement of aortic distensibility will be used to
           assess changes in the compliance of vascular system with therapy. Compliance will be
           defined as the fractional change in cross-sectional area of the aorta over the cardiac
           cycle (measured at both ascending and descending locations) divided by the corresponding
           change in pressure (pulse pressure = systolic blood pressure - diastolic blood pressure,
           measured with arm cuff at time of aorta imaging).

        2. Change in Body Composition by CMR. Assessment of adipose and visceral fat content in
           abdomen and skeletal muscle will be made using multi-echo DIXON magnetic resonance image
           acquisition with automated fat/water decomposition using VARPO post-processing.

        3. Phosphocreatinine (PCr) uptake/recovery on skeletal muscle by CMR. Skeletal muscle
           metabolism will be measured on a 3T PRISMA MRI system (Peter S Allen MRI Centre)
           equipped with a plantar-flexion exercise setup and phosphorous imaging capabilities.
           Supine subjects will perform exercise (toe-push on one leg) until exhaustion. P NMR
           spectra will be acquired continuously during exercise to measure PCr utilization, change
           in muscle pH, and most importantly, the recovery rate following exercise. PCr recovery
           following exercise is a direct measure of substrate utilization and oxygen supply, which
           is measured as the rate of PCr replenishment. The rate constant (in seconds)
           characterizes the exponential recovery of PCr to resting values (providing a
           quantitative measure of oxidative phosphorylation. Normal values from healthy controls
           are 30-35 seconds with prior studies of patients with HF show values of 76 seconds. A
           study of reproducibility showed a coefficient of variability of 4.6% for this rate
           constant (from repeated studies on separate days).

        4. Change in LVEF, LVEDV and longitudinal strain by CMR. CMR remains the most precise
           measure of cardiac structure and function and allows for very small sample sizes to
           detect changes in important variables such as left ventricular ejection fraction (LVEF),
           left ventricular end diastolic volume (LVEDV) and longitudinal strain. Longitudinal
           strain is complimentary to volume and ejection fraction and is increasingly used to
           detect subclinical changes in heart function even in cases of preserved ejection
           fraction, and is predictive of HF outcomes. The investigators have reported a
           coefficient of variability of 2.6% for measurement of ventricular volumes with MRI,
           similar or better than previous studies, which would enable the measurement of a change
           of 5 ml in LVEDV with therapy, for example, with only 10 subjects (α=0.05, power=0.95).

        5. Distance walked on 6-minute walk test (6-MWT). The 6-MWT is a validated and reproducible
           clinical endpoint that has been used to demonstrate differences in early phase work of
           medications such as ACE inhibitors, cardiac resynchronization therapy, and exercise
           interventions.

        6. Change in the Kansas City Cardiomyopathy Questionnaire (KCCQ). The KCCQ has been used
           for multiple large RCT and is sensitive to change, validated in patients with heart
           failure and linked to prognosis in the short and long-term. A minimal clinically
           important difference is 5 points.

        7. Change in Functional Assessment of Chronic Illness Therapy (FACIT-F). The FACIT-F was
           developed as a quality of life tool to evaluate small changes in fatigue for patients
           undergoing anemia or cancer therapy. There are no other validated tools specific to
           heart failure that address fatigue, despite the principal importance of this symptom.
           Therefore, the FACIT-F will be used to measure fatigue.

        8. Change in Sleep Quality. The Medical Outcomes Study (MOS) Sleep Scale is a
           patient-reported, non-disease-specific instrument for evaluating sleep outcomes. The MOS
           Sleep Scale measures subjective experiences of sleep across several different domains.
    

Intervention name(s): Resveratrol; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Subject participation will be approximately 10 weeks in duration. Participants will be randomized to receive one treatment: either resveratrol for 8 weeks OR placebo for 8 weeks. There will be a 2-week run-in period prior to the treatment period.
The schedule for the study is:
Week 0 Screening and randomization Weeks 1-2 Run-in; no treatment Weeks 3-10 Treatment Phase (resveratrol or placebo); Participants will be randomized to receive one treatment: either resveratrol for 8 weeks OR placebo for 8 weeks. There will be a 2-week run-in period prior to the treatment period.
Other intervention name(s): (Transmax) trans- resveratrol; Subject participation will be approximately 10 weeks in duration. Participants will be randomized to receive one treatment: either resveratrol for 8 weeks OR placebo for 8 weeks
Intervention MeSH terms: Resveratrol
Allocation: Randomized
Intervention model: Sequential Assignment
Intervention model description: After providing written informed consent, patients who qualify will be randomized via the web-based system coordinated by Research Electronic Data Capture (REDCap) at the University of Alberta. A patient's eligibility will be confirmed and a unique identifier will be assigned.
Blinding of the patients and study personnel is preserved by using matching placebo capsules. Clinical outcomes will be adjudicated by a Clinical Events Committee, and core laboratories will assess the CMR measures and biomarkers independently and blinded to treatment assignment.
Masking: Double (Participant, Care Provider)
Primary purpose: Diagnostic
Keywords: Skeletal Muscle Blood Flow; (calf muscle) targeted exercise