Clinical trial NCT01469988: The VO2 Increase With Testosterone Addition - Heart Failure (VITA-HF) Trial
Official title: The VO2 Increase With Testosterone Addition - Heart Failure (VITA-HF) Trial
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Heart Failure
Lead sponsor: University of Alberta
Sponsor class: OTHER
First posted: 2011-11-10
Enrollment: 318
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Evaluate the efficacy and safety of testosterone supplementation on functional capacity, biomarkers, quality of life and clinical outcomes for patients with heart failure.

Detailed description: Background:Heart failure is a prevalent condition of major public health importance that leads to significant morbidity and mortality despite the use of current evidence-based therapy. Further development of novel therapies to alleviate symptoms, improve functional status and ultimately clinical outcomes are needed. Cardiac function alone cannot explain all aspects of the heart failure syndrome: hence a search for peripheral mechanisms and inter-connected cardiac and non-cardiac pathways has ensued. Testosterone plays an integral role in multiple organ systems for growth, development and maintenance of health with known effects on peripheral musculature, vasculature, sympathetic tone, endothelial function and restoration of muscle metabolic function which would be beneficial in HF. Chronic HF has been associated with reduced testosterone levels, and low testosterone levels have been linked to reduced VO2, increased BNP and ANP levels, and worse clinical outcomes. Testosterone supplementation acts as a peripheral vasodilator and acutely increases cardiac output,which would improve oxygen delivery to skeletal muscles and secondarily delay transfer to anaerobic metabolism and depletion of high-energy phosphates. The increase in muscle mass associated with testosterone therapy may also result in increased endurance and decreased muscle fatigability in HF patients. Early small trials demonstrate safety, tolerability and an improvement in exercise walking distance in patients with HF. We contend that the time is now ripe for an adequately-powered phase II trial in order to test if this therapy can improve symptoms and functional status for patients with heart failure.

Specific Aim:Evaluate the efficacy and safety of testosterone supplementation on functional capacity, biomarkers, quality of life and clinical outcomes for patients with heart failure.

Synopsis:We propose a phase II randomized controlled, multi-center, double-blind trial, "The VO2Increase with Testosterone Addition - Heart Failure (VITA-HF) Trial". We plan to enroll 318 patients with chronic HF and NYHA II-III in a 1:1 trial of testosterone therapy (versus placebo): our primary objective is to test the effects on peak VO2 at 26 weeks (a commonly used surrogate outcome in phase II HFRCTthat represents both central and peripheral effects of our interventions). Given the assumptions made (a peak VO2 standard deviation of 2.7 mls/kg/min, paired t-test, and 2-sided alpha 0.05), 318 patients will have 85% power to detect a 1.0 ml/kg/min difference between the groups in the change in peak VO2 over 26 weeks. The minimally clinically important difference for peak VO2 may be as small as 0.26 mls/kg/min but is possibly higher and therefore, we have taken a conservative approach similar to that of other CIHR and NIH trials. Additional measures of quality of life, biomarkers (BNP) and clinical outcomes will be performed at 26 and 52 weeks. Quantitative measurement of core laboratory echocardiographic imaging will also assess the effect on left ventricular remodeling and markers of systolic and diastolic function. Assessment at 26 weeks will allow for the early effects to be demonstrated whereas our secondary endpoint evaluated at 52 weeks will demonstrate clinical and other outcomes important for phase III planning (including clinical, biochemical and echocardiographic endpoints).Androgel 5g was selected due to compliance and prior RCT dosing to ensure efficacy with a broad safety margin.

Feasibility:The investigators on this grant are attending physicians in large, tertiary care heart failure clinics with large patient populations and extensive experience with recruiting patients into clinical studies. The 7 sites selected have both experience and expertise in enrolling HF patients in CIHR and NIH trials.

Importance:Our proposed trial (VITA-HF) tests a novel strategic target which could enhance the quality and potentially the quantity of life of patients with heart failure by modulating complementary peripheral and central HF mechanisms.

Eligibility criteria: Inclusion Criteria:

* Age \> 40 years
* NYHA Class II - III
* Left ventricular ejection fraction available by echo, nuclear or MRI \< 12 months
* On optimal medical therapy (as per CCS guidelines for Chronic Heart Failure)42 for \>3 months
* Female patients only: participants must be \>1 year post-menopausal (defined as 12 months of spontaneous amenorrhea and confirmed by screening FSH \>40 mIU/mL) OR \>6 weeks post surgical bilateral oophorectomy if surgically sterilized.

Exclusion Criteria:

* Already or likely to receive LVAD or organ transplant within 6 months
* History of illicit drug use or alcohol abuse within \<3 months, or history of HIV, Hepatitis B or C
* History of hypertrophic obstructive cardiomyopathy, active myocarditis, constrictive pericarditis, clinically significant congenital heart disease, severe aortic or mitral regurgitation or stenosis
* Non-cardiovascular diagnosis with reduced life expectancy \< 1 year including active cancer
* Recent (\<1 month) cardiovascular event (admission to hospital for unstable angina, acute coronary syndrome, hypertensive crisis or ventricular arrhythmia) or cerebrovascular event (transient ischemic attack or stroke) or recent (\<3 months) implantation of cardiac resynchronization therapy
* Hematocrit \> 48%
* Male patients only: PSA \> 4 ng/ml, or presence of a prostate nodule
* Total serum testosterone \> 350 ng/dl (12.1 nmol/L)
* Untreated severe obstructive sleep apnea per American Thoracic Society criteria
* Chronic glucocorticoid, or anabolic steroid therapy
* Chronic hemodialysis, serum creatinine \> 264 umol/L (3 mg/dL) or eGFR\< 15 ml/min (MDRD)
* Participation in a competing trial

Primary outcomes:
measure: In patients with chronic heart failure, does 26 weeks of treatment with transdermal testosterone improve peak VO2?
timeFrame: 26 weeks
Secondary outcomes:
measure: In patients with chronic heart failure, does 26 or 52 weeks of treatment with transdermal testosterone improve quality of life, biomarker (b-type natriuretic peptide, fasting glucose) or echocardiographic measures (LVEF, LVEDD, LVESD, SV)?
timeFrame: 52 weeks
measure: In patients with chronic heart failure, does 52 weeks of treatment with transdermal testosterone reduce ED visits or hospitalization for heart failure, or total mortality?
timeFrame: 52 weeks
Other outcomes:
Locations:
city: Ajax
country: Canada
facility: Ajax / Pickering
city: Brampton
country: Canada
facility: Brampton (McMaster University)
city: Calgary
country: Canada
facility: Foothills Hospital (University of Calgary)
city: Edmonton
country: Canada
facility: The University of Alberta (Mazankowski Alberta Heart Institute):
city: Surrey
country: Canada
facility: Surrey Memorial Hospital (University of British Columbia)
city: Toronto
country: Canada
facility: Toronto General Hospital (University of Toronto):
city: Vancouver
country: Canada
facility: Vancouver General Hospital (University of British Columbia)
Study officials:
affiliation: University of Alberta
name: Justin Ezekowitz
role: PRINCIPAL_INVESTIGATOR
References: