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Oral Nitrite for Older Heart Failure With Preserved Ejection Fraction (ONOH)

10 gennaio 2020 aggiornato da: Daniel Forman, MD, Gladwin, Mark, MD

Nitrite Benefits to Mediate Fatigability in Older HFpEF Patients

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.

Panoramica dello studio

Stato

Completato

Condizioni

Intervento / Trattamento

Descrizione dettagliata

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.

Tipo di studio

Interventistico

Iscrizione (Effettivo)

15

Fase

  • Fase 2

Contatti e Sedi

Questa sezione fornisce i recapiti di coloro che conducono lo studio e informazioni su dove viene condotto lo studio.

Luoghi di studio

  • Stati Uniti
    • Pennsylvania
      • Pittsburgh, Pennsylvania, Stati Uniti, 15213
        • UPMC Montefiore Hospital

Criteri di partecipazione

I ricercatori cercano persone che corrispondano a una certa descrizione, chiamata criteri di ammissibilità. Alcuni esempi di questi criteri sono le condizioni generali di salute di una persona o trattamenti precedenti.

Criteri di ammissibilità

Età idonea allo studio

70 anni e precedenti (Adulto più anziano)

Accetta volontari sani

No

Sessi ammissibili allo studio

Tutto

Descrizione

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,

Piano di studio

Questa sezione fornisce i dettagli del piano di studio, compreso il modo in cui lo studio è progettato e ciò che lo studio sta misurando.

Come è strutturato lo studio?

Dettagli di progettazione

  • Scopo principale: Trattamento
  • Assegnazione: Randomizzato
  • Modello interventistico: Assegnazione parallela
  • Mascheramento: Quadruplicare

Armi e interventi

Gruppo di partecipanti / Arm
Intervento / Trattamento
Sperimentale: Treatment
20 or 40 mg sodium nitrite tid
Droga: sodium nitrite
Subjects to receive active study drug three times daily during treatment period and then post treatment testing period.
Altri nomi:
  • nitrite
Comparatore placebo: Control
20 or 40 mg placebo tid
Droga: Control
Subjects randomized to placebo to receive three times daily during treatment period and then post treatment testing period.
Altri nomi:
  • Placebo

Cosa sta misurando lo studio?

Misure di risultato primarie

Misura del risultato
Misura Descrizione
Lasso di tempo
Cardiorespiratory Fitness
Lasso di tempo: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Assessment of peak Oxygen uptake (VO2) maximum via symptom limited exercise testing
Week 2(pre drug) to Week 10( post drug); approx. 8 weeks

Misure di risultato secondarie

Misura del risultato
Misura Descrizione
Lasso di tempo
Perceived Fatigability
Lasso di tempo: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
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
Bioenergetics: In-Vivo 31P MRS Respirations
Lasso di tempo: Week 3 (pre drug) to week 10(post drug); approx. 8 weeks
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
Bioenergetics: Ex-Vivo Mitochondrial Respiration Analysis
Lasso di tempo: Week 5 (pre-drug) to week 16 (post-drug); approx. 8 weeks
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
Exercise-induced Changes in Pulmonary Arterial Pressure
Lasso di tempo: Week 3 (pre-drug) to week 10 (post drug); approx 8 weeks
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
Exercise-induced Changes in Pulmonary Capillary Wedge Pressure
Lasso di tempo: Week 3 (pre-drug) to week 10 (post drug); approx 8 weeks
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
Patients With Pulmonary Hypertension
Lasso di tempo: Week 3 (pre-drug) to week 10 (post drug); approx 8 weeks
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
Steps From Accelerometry Assessment of Daily Activity
Lasso di tempo: Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks
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
Sedentary Events From Accelerometry Assessment of Daily Activity
Lasso di tempo: Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks

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
Light Activity Duration From Accelerometry Assessment of Daily Activity
Lasso di tempo: Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks

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
Moderate to Vigorous Physical Activity From Accelerometry Assessment of Daily Activity
Lasso di tempo: Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks

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
Vector Magnitude Counts From Accelerometry Assessment of Daily Activity
Lasso di tempo: Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks

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
Sedentary Event Duration From Accelerometry Assessment of Daily Activity
Lasso di tempo: Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks

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
Light Activity Events Percentage of Day From Accelerometry Assessment of Daily Activity
Lasso di tempo: Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks

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
Moderate to Vigorous Physical Activity Percentage From Accelerometry Assessment of Daily Activity
Lasso di tempo: Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks

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

Altre misure di risultato

Misura del risultato
Misura Descrizione
Lasso di tempo
Adiponectin
Lasso di tempo: Week 5 (pre drug) to week 16 (post drug); approx. 8 weeks
Change in adiponectin
Week 5 (pre drug) to week 16 (post drug); approx. 8 weeks
Blood Nitrate
Lasso di tempo: Week 5 (pre drug) to week 16 (post drug); approx. 8 week
Change in blood levels to assess efficacy of study drug
Week 5 (pre drug) to week 16 (post drug); approx. 8 week
Brain Natriuretic Protein
Lasso di tempo: Week 5 (pre drug) to week 16 (post drug); approx. 8 weeks
Change in brain natriuretic protein (BNP)
Week 5 (pre drug) to week 16 (post drug); approx. 8 weeks
Cardiopulmonary Exercise Testing: iCPET
Lasso di tempo: Week 3 (pre-drug) to week 10 (post drug); approx. 8 weeks
Invasive cardiopulmonary exercise testing
Week 3 (pre-drug) to week 10 (post drug); approx. 8 weeks
Cardiopulmonary Exercise Testing; nCPET
Lasso di tempo: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Non-invasive cardiopulmonary exercise testing
Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Cognitive Function
Lasso di tempo: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Change in pre and post scores on the Montreal Cognitive Assessment
Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Co-morbid Illness
Lasso di tempo: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Change in pre and post scores on the Charlson Comorbidity Index
Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Co-morbidity Medications
Lasso di tempo: Week 1 pre drug to week 16 post drug
Medications for comorbidity managment
Week 1 pre drug to week 16 post drug
Echocardiogram
Lasso di tempo: Week 1 pre-drug to week 16 post drug
Change in cardiac strain
Week 1 pre-drug to week 16 post drug
Fatigability
Lasso di tempo: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Change in pre and post scores on the Pittsburgh Fatigability Index
Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Frailty Index Assessment
Lasso di tempo: Week 1 screening pre-drug to week 16 post drug
Physician assessment of frailty using the Canadian Clinical Frailty Scale
Week 1 screening pre-drug to week 16 post drug
Gene Expression
Lasso di tempo: Week 5 (pre drug) to week 16 (post drug); approx. 8 week
Change in DNA from Polymerase Chain Reaction analysis
Week 5 (pre drug) to week 16 (post drug); approx. 8 week
Glomerular Filtration Rate
Lasso di tempo: Week 5 (pre drug) to week 16 (post drug); approx. 8 week
Change in glomerular filtration rate (GFR)
Week 5 (pre drug) to week 16 (post drug); approx. 8 week
Glycosylated Hemoglobin
Lasso di tempo: Week 5 (pre drug) to week 16 (post drug); approx. 8 week
Change in glycosylated hemoglobin (HgbA1c)
Week 5 (pre drug) to week 16 (post drug); approx. 8 week
Hematocrit
Lasso di tempo: Week 1 pre drug to week 16 post drug
Change in hematocrit
Week 1 pre drug to week 16 post drug
Hemoglobin
Lasso di tempo: Week 1 pre drug to week 16 post drug
Change in hemoglobin
Week 1 pre drug to week 16 post drug
Hemodynamics; Blood Pressure
Lasso di tempo: Week 1 pre drug to week 16 post drug
Change in Blood pressure
Week 1 pre drug to week 16 post drug
Hemodynamics; Heart Rate
Lasso di tempo: Week 1 pre drug to week 16 post drug
Change in heart rate
Week 1 pre drug to week 16 post drug
Muscle Protein
Lasso di tempo: Week 5 (pre drug) to week 16 (post drug); approx. 8 week
Change in protein content of muscle fiber
Week 5 (pre drug) to week 16 (post drug); approx. 8 week
Near Infrared Spectroscopy
Lasso di tempo: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Assessment of blood flow during exercise
Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Pain
Lasso di tempo: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Change in pre and post scores on the McGill Pain Questionnaire
Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Physical Frailty and Balance
Lasso di tempo: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
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
Physical Activity
Lasso di tempo: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
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
Quality of Life
Lasso di tempo: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
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
Submaximal Exercise Performance
Lasso di tempo: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Change in distance on six minute walk test
Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
Self-efficacy
Lasso di tempo: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
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
Thyroid Stimulating Hormone
Lasso di tempo: Week 5 (pre drug) to week 16 (post drug); approx. 8 weeks
Change in thyroid stimulating hormone (TSH)
Week 5 (pre drug) to week 16 (post drug); approx. 8 weeks

Collaboratori e investigatori

Qui è dove troverai le persone e le organizzazioni coinvolte in questo studio.

Sponsor

Gladwin, Mark, MD

Collaboratori

National Institute on Aging (NIA)

Investigatori

  • Investigatore principale: Daniel E Forman, MD, University of Pittsburgh

Studiare le date dei record

Queste date tengono traccia dell'avanzamento della registrazione dello studio e dell'invio dei risultati di sintesi a ClinicalTrials.gov. I record degli studi e i risultati riportati vengono esaminati dalla National Library of Medicine (NLM) per assicurarsi che soddisfino specifici standard di controllo della qualità prima di essere pubblicati sul sito Web pubblico.

Studia le date principali

Inizio studio (Effettivo)

3 aprile 2017

Completamento primario (Effettivo)

2 dicembre 2018

Completamento dello studio (Effettivo)

31 dicembre 2018

Date di iscrizione allo studio

Primo inviato

13 settembre 2016

Primo inviato che soddisfa i criteri di controllo qualità

28 settembre 2016

Primo Inserito (Stima)

29 settembre 2016

Aggiornamenti dei record di studio

Ultimo aggiornamento pubblicato (Effettivo)

22 gennaio 2020

Ultimo aggiornamento inviato che soddisfa i criteri QC

10 gennaio 2020

Ultimo verificato

1 gennaio 2020

Maggiori informazioni

Termini relativi a questo studio

Termini MeSH pertinenti aggiuntivi

Altri numeri di identificazione dello studio

  • STUDY19070450
  • 1R56AG051637-01A1 (Sovvenzione/contratto NIH degli Stati Uniti)

Piano per i dati dei singoli partecipanti (IPD)

Hai intenzione di condividere i dati dei singoli partecipanti (IPD)?

Sì

Descrizione del piano IPD

De-identified data may be shared with other future investigators as research questions arise.

Periodo di condivisione IPD

A limit in time frame for sharing has not been defined.

Criteri di accesso alla condivisione IPD

Only de-identified data approved for sharing by the PI.

Informazioni su farmaci e dispositivi, documenti di studio

Studia un prodotto farmaceutico regolamentato dalla FDA degli Stati Uniti

Sì

Studia un dispositivo regolamentato dalla FDA degli Stati Uniti

No

Queste informazioni sono state recuperate direttamente dal sito web clinicaltrials.gov senza alcuna modifica. In caso di richieste di modifica, rimozione o aggiornamento dei dettagli dello studio, contattare register@clinicaltrials.gov. Non appena verrà implementata una modifica su clinicaltrials.gov, questa verrà aggiornata automaticamente anche sul nostro sito web .

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