Oral Nitrite for Older Heart Failure With Preserved Ejection Fraction

Heart Failure Clinical Trial

— ONOH  

Official title:

Nitrite Benefits to Mediate Fatigability in Older HFpEF Patients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02918552
• Other study ID #: STUDY19070450
• Secondary ID: 1R56AG051637-01A
• Status: Completed
• Phase: Phase 2
• Start date: April 3, 2017
• Est. completion date: December 31, 2018

Study information

• Verified date: January 2020
• Source: University of Pittsburgh
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 15
• Est. completion date: December 31, 2018
• Est. primary completion date: December 2, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 70 Years and older

Eligibility

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,

Related Conditions & MeSH terms

• Heart Failure

Intervention

Drug:
• sodium nitrite
Subjects to receive active study drug three times daily during treatment period and then post treatment testing period.
• Control
Subjects randomized to placebo to receive three times daily during treatment period and then post treatment testing period.

Locations

Country	Name	City	State
United States	UPMC Montefiore Hospital	Pittsburgh	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
Gladwin, Mark, MD	National Institute on Aging (NIA)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Adiponectin	Change in adiponectin	Week 5 (pre drug) to week 16 (post drug); approx. 8 weeks
Other	Blood Nitrate	Change in blood levels to assess efficacy of study drug	Week 5 (pre drug) to week 16 (post drug); approx. 8 week
Other	Brain Natriuretic Protein	Change in brain natriuretic protein (BNP)	Week 5 (pre drug) to week 16 (post drug); approx. 8 weeks
Other	Cardiopulmonary Exercise Testing: iCPET	Invasive cardiopulmonary exercise testing	Week 3 (pre-drug) to week 10 (post drug); approx. 8 weeks
Other	Cardiopulmonary Exercise Testing; nCPET	Non-invasive cardiopulmonary exercise testing	Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Other	Cognitive Function	Change in pre and post scores on the Montreal Cognitive Assessment	Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Other	Co-morbid Illness	Change in pre and post scores on the Charlson Comorbidity Index	Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Other	Co-morbidity Medications	Medications for comorbidity managment	Week 1 pre drug to week 16 post drug
Other	Echocardiogram	Change in cardiac strain	Week 1 pre-drug to week 16 post drug
Other	Fatigability	Change in pre and post scores on the Pittsburgh Fatigability Index	Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Other	Frailty Index Assessment	Physician assessment of frailty using the Canadian Clinical Frailty Scale	Week 1 screening pre-drug to week 16 post drug
Other	Gene Expression	Change in DNA from Polymerase Chain Reaction analysis	Week 5 (pre drug) to week 16 (post drug); approx. 8 week
Other	Glomerular Filtration Rate	Change in glomerular filtration rate (GFR)	Week 5 (pre drug) to week 16 (post drug); approx. 8 week
Other	Glycosylated Hemoglobin	Change in glycosylated hemoglobin (HgbA1c)	Week 5 (pre drug) to week 16 (post drug); approx. 8 week
Other	Hematocrit	Change in hematocrit	Week 1 pre drug to week 16 post drug
Other	Hemoglobin	Change in hemoglobin	Week 1 pre drug to week 16 post drug
Other	Hemodynamics; Blood Pressure	Change in Blood pressure	Week 1 pre drug to week 16 post drug
Other	Hemodynamics; Heart Rate	Change in heart rate	Week 1 pre drug to week 16 post drug
Other	Muscle Protein	Change in protein content of muscle fiber	Week 5 (pre drug) to week 16 (post drug); approx. 8 week
Other	Near Infrared Spectroscopy	Assessment of blood flow during exercise	Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Other	Pain	Change in pre and post scores on the McGill Pain Questionnaire	Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Other	Physical Frailty and Balance	Change in score on Standard Physical Performance Battery at visit 2 pre drug and visit 5	Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Other	Physical Activity	Change in pre and post scores on the CHAMPS (Community Healthy Activities Program for Seniors) Activities Questionnaire for Older Adults-physical activity	Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Other	Quality of Life	Change in pre and post scores on the Kansas City Cardiomyopathy Questionnaire subject self reported responses	Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Other	Submaximal Exercise Performance	Change in distance on six minute walk test	Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Other	Self-efficacy	Change in pre and post scores on the Sullivan Cardiac Self Efficacy questionnaire	Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Other	Thyroid Stimulating Hormone	Change in thyroid stimulating hormone (TSH)	Week 5 (pre drug) to week 16 (post drug); approx. 8 weeks
Primary	Cardiorespiratory Fitness	Assessment of peak Oxygen uptake (VO2) maximum via symptom limited exercise testing	Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Secondary	Perceived Fatigability	Assessment of Rate of Perceived Exertion (RPE) during steady state exercise testing at the last minute of the test. The RPE scale (Rate of Perceived Exertion) goes from 6-20 with a higher number indicating more effort and possibly a worse outcome.	Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Secondary	Bioenergetics: In-Vivo 31P MRS Respirations	Phosphocreatine reuptake after exercise during the kicking exercise in the 31P MRS (magnetic resonance spectroscopy)	Week 3 (pre drug) to week 10(post drug); approx. 8 weeks
Secondary	Bioenergetics: Ex-Vivo Mitochondrial Respiration Analysis	Mitochondrial respiration was analyzed by assessing O2 consumption by skeletal muscle mitochondria at Energetic State 3.1 using the Oroboros instrument. This state is generally used a marker for mitochondrial efficiency. Increases in consumption are generally linked to a better outcome.	Week 5 (pre-drug) to week 16 (post-drug); approx. 8 weeks
Secondary	Exercise-induced Changes in Pulmonary Arterial Pressure	Pulmonary arterial pressure, an indication of cardiopulmonary hemodynamics and cardiac function, was measured at rest and at peak exercise during an invasive cardiopulmonary exercise test.	Week 3 (pre-drug) to week 10 (post drug); approx 8 weeks
Secondary	Exercise-induced Changes in Pulmonary Capillary Wedge Pressure	Pulmonary capillary wedge pressure, an indication of cardiopulmonary hemodynamics and cardiac function, was measured at rest and at peak exercise during an invasive cardiopulmonary exercise test.	Week 3 (pre-drug) to week 10 (post drug); approx 8 weeks
Secondary	Patients With Pulmonary Hypertension	Right Ventricular-Pulmonary Artery Coupling, assessed by right ventricular ejection fraction (RVEF) and pulmonary artery systolic pressure (PASP), decreases with worsening right heart failure. We will be measuring this by assessing RVEF and PASP during invasive cardiopulmonary exercise testing in patients that meet criteria for pulmonary hypertension.	Week 3 (pre-drug) to week 10 (post drug); approx 8 weeks
Secondary	Steps From Accelerometry Assessment of Daily Activity	Actigraph device-specific activity steps on daily-wear wrist device based on movement.	Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks
Secondary	Sedentary Events From Accelerometry Assessment of Daily Activity	Assessment of daily activity using accelerometry on a daily-wear wrist device.; Sedentary bout is a triggered stint of time that the patient is not moving or has low level of activity sensed by the accelerometer.	Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks
Secondary	Light Activity Duration From Accelerometry Assessment of Daily Activity	Assessment of daily activity using accelerometry on a daily-wear wrist device.; Light activity is a triggered stint of time that the patient has a slightly elevated amount of activity based on biometrics such as movement and heart rate.	Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks
Secondary	Moderate to Vigorous Physical Activity From Accelerometry Assessment of Daily Activity	Assessment of daily activity using accelerometry on a daily-wear wrist device.; MVPA is Moderate-to-vigorous physical activity that is a triggered stint of time that the patient has a slightly elevated amount of activity based on biometrics such as movement and heart rate.	Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks
Secondary	Vector Magnitude Counts From Accelerometry Assessment of Daily Activity	Assessment of daily activity using accelerometry on a daily-wear wrist device.; Vector Magnitude in counts per day are accelerations in 3 dimensions that indicate activity. More counts is associated with more activity. More counts in a shorter duration of time indicate light, moderate, and vigorous activity.	Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks
Secondary	Sedentary Event Duration From Accelerometry Assessment of Daily Activity	Assessment of daily activity using accelerometry on a daily-wear wrist device.; Sedentary bout is a triggered stint of time that the patient is not moving or has low level of activity sensed by the accelerometer.	Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks
Secondary	Light Activity Events Percentage of Day From Accelerometry Assessment of Daily Activity	Assessment of daily activity using accelerometry on a daily-wear wrist device.; Light activity is a triggered stint of time that the patient has a slightly elevated amount of activity based on biometrics such as movement and heart rate.	Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks
Secondary	Moderate to Vigorous Physical Activity Percentage From Accelerometry Assessment of Daily Activity	Assessment of daily activity using accelerometry on a daily-wear wrist device.; MVPA is Moderate-to-vigorous physical activity that is a triggered stint of time that the patient has a slightly elevated amount of activity based on biometrics such as movement and heart rate.	Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks