Clinical trial NCT02918552: Oral Nitrite for Older Heart Failure With Preserved Ejection Fraction
Official title: Nitrite Benefits to Mediate Fatigability in Older HFpEF Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Heart Failure
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
First posted: 2016-09-29
Enrollment: 15
Sex: ALL
Minimum age (years): 70
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a randomized double blinded controlled trial of 20-40 mg sodium nitrite tid in subjects with HFpEF. Primary outcomes are measures of physical function with non-invasive and invasive cardiopulmonary exercise testing, and fatigability, skeletal muscle bioenergetics, serology including inflammatory markers and platelet bioenergetics, quality of life measures.

Detailed description: Age-related physiological changes predispose to heart failure with preserved ejection fraction (HFpEF). Thus, HFpEF prevalence is escalating as the older population expands. High mortality and morbidity, diminished quality of life, and spiraling healthcare costs are typical consequences, and no effective HFpEF therapy is known. Therefore, several small exercise training (ExT) trials for HFpEF stand out by showing that ExT result in improved aerobic exercise capacity and infer that ExT constitutes novel substantive therapy. Nonetheless, such benefit was evident only after months of moderate to high intensity ExT; regimens that are unfeasible for most patients. In fact, poor compliance with ExT is typical in most HFpEF patients. The investigators propose there are intrinsic physiological components of HFpEF pathophysiology that predispose to "fatigability". The investigators advance the concept of fatigability by quantifying it as a performance-based measure; i.e., subjective tiring during a standardized steady-state walking (perceived fatigability) and deterioration of self-selected walking speed over time (performance fatigability). The investigators assert that therapies to reduce fatigability will enhance HFpEF outcomes. Ongoing studies reveal pleiotropic benefits of oral inorganic nitrite (NO2), including enhanced performance of skeletal muscle (metabolism and bioenergetics) and vasomotor responses (systemic and pulmonary). The investigators' pilot work shows safety and biological efficacy of oral NO2 capsules. Thus, the investigators propose a randomized, controlled, double-blinded trial to study oral NO2 therapy in older (≥70 years) HFpEF patients. Aim 1 explores the utility of NO2 capsules to reduce perceived and performance fatigability (rated perceived exertion), improve aerobic capacity (peak oxygen uptake) and increase daily activity (accelerometry). Aim 2 delineates the mediating processes by which NO2 benefits are achieved. Skeletal muscle determinants are differentiated from the right and left heart vasomotor dynamics by integrating assessments using 31Phosphorus magnetic resonance spectroscopy and percutaneous needle muscle biopsies with those made using non-invasive and invasive cardiopulmonary exercise testing, near infrared spectroscopy and other techniques. The principal investigator is trained geriatrics and cardiology, and is solidly oriented to the dynamics of aging and cardiovascular disease (clinically and mechanistically) with particular expertise in functional assessment and skeletal muscle gene expression as determinants of performance. The investigative team provides formidable synergies that are well-suited to this translational investigation of systemic, cellular, and sub-cellular physiological dynamics. Our proposal is significant in multiple respects: 1) HFpEF is endemic with aging and constitutes a critical contemporary healthcare challenge today's growing population of older adults. 2) Fatigability is rooted in HFpEF pathophysiology, but it has not previously been addressed as a key part of management. 3) NO2 therapy is a novel and compelling therapeutic strategy. 4) Mechanisms underlying fatigability are clarified; we advance principles of patient-centered care by clarifying mechanisms that underlie a patient's experience of fatigability.

Eligibility criteria: Inclusion Criteria:

* Age ≥70 years
* Diagnosis of HFpEF \[adapted from the 2016 European Society of Cardiology (ESC) Guidelines to include:

  1. Prior diagnosis of HF via one of these:
* medical record diagnosis by attending cardiologist
* verbal confirmation of HFpEF with attending cardiologist
* PI review of medical record to confirm HFpEF AND 2. Ejection Fraction % ≥40
* Clinically stable (euvolemic; baseline heart rate \<100 bpm) and without hospitalization or invasive cardiac procedure for 6 weeks
* Patients using 81 milligram (mg) aspirin (ASA) will be eligible, but will be asked to hold the medication for 3 days prior to biopsy. This technique has previously been used with consistent safety. Patients will also be asked to avoid non-steroidal anti-inflammatory medications (NSAIDs) for 2 days prior to the biopsy.
* Patients using anti-thrombin and anti-platelet therapy will plan to modify prior to muscle biopsies individually in coordination with the participant's primary cardiologist.

Exclusion Criteria:

* Allergy to lidocaine
* BP \>180/95 or \<100/60
* Anemia: Hgb\<11.0 (♂),10.0 (♀)
* Dementia or inability to give informed consent
* End-stage malignancy
* Severe orthopedic exercise limitation
* Use of chronic oral corticosteroids or other medications that affect muscle function.
* Chronic alcohol or drug dependency.
* Any bleeding disorder that would contraindicate biopsy such as history of clinically significant bleeding diathesis (e.g., Hemophilia A or B, Von Willebrand's Disease or congenital Factor VII deficiency).
* Psychiatric hospitalization within the last 3 months
* Major cardiovascular event or procedure within the prior 6 weeks
* HF secondary to significant uncorrected primary valvular disease (except mitral regurgitation secondary to left ventricular dysfunction). If valve replacement has been performed, patient may not be enrolled for 12 months after this procedure.
* Severe uncorrected primary valvular heart disease (if valve replacement has been performed, patients will not be eligible for at least 12 months)
* Mechanical valve replacement requiring warfarin
* Peripheral or pulmonary artery disease
* Currently taking clopidogrel for a recent stent placement and/or a complex atherosclerotic lesion such that holding clopidogrel creates disproportionate risk.
* Current use of organic nitrates or phosphodiesterase type 5 inhibitors (PDE5s)
* Unable to hold warfarin or use bridging therapy, or to hold aspirin for 3 days (81 mg), 3 days (325 mg) prior to muscle biopsy or thienopyridine medications for 5 days prior to muscle biopsy.
* Subjects with diabetes whose HgbA1c \>10.0
* Other chronic unstable disease such as active neoplasm, end stage chronic kidney, liver or other organ disease,

Primary outcomes:
measure: Cardiorespiratory Fitness
timeFrame: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Secondary outcomes:
measure: Perceived Fatigability
timeFrame: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
measure: Bioenergetics: In-Vivo 31P MRS Respirations
timeFrame: Week 3 (pre drug) to week 10(post drug); approx. 8 weeks
measure: Bioenergetics: Ex-Vivo Mitochondrial Respiration Analysis
timeFrame: Week 5 (pre-drug) to week 16 (post-drug); approx. 8 weeks
measure: Exercise-induced Changes in Pulmonary Arterial Pressure
timeFrame: Week 3 (pre-drug) to week 10 (post drug); approx 8 weeks
measure: Exercise-induced Changes in Pulmonary Capillary Wedge Pressure
timeFrame: Week 3 (pre-drug) to week 10 (post drug); approx 8 weeks
measure: Patients With Pulmonary Hypertension
timeFrame: Week 3 (pre-drug) to week 10 (post drug); approx 8 weeks
measure: Steps From Accelerometry Assessment of Daily Activity
timeFrame: Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks
measure: Sedentary Events From Accelerometry Assessment of Daily Activity
timeFrame: Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks
measure: Light Activity Duration From Accelerometry Assessment of Daily Activity
timeFrame: Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks
measure: Moderate to Vigorous Physical Activity From Accelerometry Assessment of Daily Activity
timeFrame: Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks
measure: Vector Magnitude Counts From Accelerometry Assessment of Daily Activity
timeFrame: Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks
measure: Sedentary Event Duration From Accelerometry Assessment of Daily Activity
timeFrame: Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks
measure: Light Activity Events Percentage of Day From Accelerometry Assessment of Daily Activity
timeFrame: Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks
measure: Moderate to Vigorous Physical Activity Percentage From Accelerometry Assessment of Daily Activity
timeFrame: Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks
Other outcomes:
measure: Adiponectin
timeFrame: Week 5 (pre drug) to week 16 (post drug); approx. 8 weeks
measure: Blood Nitrate
timeFrame: Week 5 (pre drug) to week 16 (post drug); approx. 8 week
measure: Brain Natriuretic Protein
timeFrame: Week 5 (pre drug) to week 16 (post drug); approx. 8 weeks
measure: Cardiopulmonary Exercise Testing: iCPET
timeFrame: Week 3 (pre-drug) to week 10 (post drug); approx. 8 weeks
measure: Cardiopulmonary Exercise Testing; nCPET
timeFrame: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
measure: Cognitive Function
timeFrame: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
measure: Co-morbid Illness
timeFrame: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
measure: Co-morbidity Medications
timeFrame: Week 1 pre drug to week 16 post drug
measure: Echocardiogram
timeFrame: Week 1 pre-drug to week 16 post drug
measure: Fatigability
timeFrame: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
measure: Frailty Index Assessment
timeFrame: Week 1 screening pre-drug to week 16 post drug
measure: Gene Expression
timeFrame: Week 5 (pre drug) to week 16 (post drug); approx. 8 week
measure: Glomerular Filtration Rate
timeFrame: Week 5 (pre drug) to week 16 (post drug); approx. 8 week
measure: Glycosylated Hemoglobin
timeFrame: Week 5 (pre drug) to week 16 (post drug); approx. 8 week
measure: Hematocrit
timeFrame: Week 1 pre drug to week 16 post drug
measure: Hemoglobin
timeFrame: Week 1 pre drug to week 16 post drug
measure: Hemodynamics; Blood Pressure
timeFrame: Week 1 pre drug to week 16 post drug
measure: Hemodynamics; Heart Rate
timeFrame: Week 1 pre drug to week 16 post drug
measure: Muscle Protein
timeFrame: Week 5 (pre drug) to week 16 (post drug); approx. 8 week
measure: Near Infrared Spectroscopy
timeFrame: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
measure: Pain
timeFrame: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
measure: Physical Frailty and Balance
timeFrame: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
measure: Physical Activity
timeFrame: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
measure: Quality of Life
timeFrame: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
measure: Submaximal Exercise Performance
timeFrame: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
measure: Self-efficacy
timeFrame: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
measure: Thyroid Stimulating Hormone
timeFrame: Week 5 (pre drug) to week 16 (post drug); approx. 8 weeks
Locations:
city: Pittsburgh
country: United States
facility: UPMC Montefiore Hospital
state: Pennsylvania
Study officials:
affiliation: University of Pittsburgh
name: Daniel E Forman, MD
role: PRINCIPAL_INVESTIGATOR
References: