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

2020. január 10. frissítette: 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.

A tanulmány áttekintése

Állapot

Befejezve

Körülmények

Beavatkozás / kezelés

Részletes leírás

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.

Tanulmány típusa

Beavatkozó

Beiratkozás (Tényleges)

15

Fázis

  • 2. fázis

Kapcsolatok és helyek

Ez a rész a vizsgálatot végzők elérhetőségeit, valamint a vizsgálat lefolytatásának helyére vonatkozó információkat tartalmazza.

Tanulmányi helyek

  • Egyesült Államok
    • Pennsylvania
      • Pittsburgh, Pennsylvania, Egyesült Államok, 15213
        • UPMC Montefiore Hospital

Részvételi kritériumok

A kutatók olyan embereket keresnek, akik megfelelnek egy bizonyos leírásnak, az úgynevezett jogosultsági kritériumoknak. Néhány példa ezekre a kritériumokra a személy általános egészségi állapota vagy a korábbi kezelések.

Jogosultsági kritériumok

Tanulmányozható életkorok

70 év és régebbi (Idősebb felnőtt)

Egészséges önkénteseket fogad

Nem

Tanulmányozható nemek

Összes

Leírás

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,

Tanulási terv

Ez a rész a vizsgálati terv részleteit tartalmazza, beleértve a vizsgálat megtervezését és a vizsgálat mérését.

Hogyan készül a tanulmány?

Tervezési részletek

  • Elsődleges cél: Kezelés
  • Kiosztás: Véletlenszerűsített
  • Beavatkozó modell: Párhuzamos hozzárendelés
  • Maszkolás: Négyszeres

Fegyverek és beavatkozások

Résztvevő csoport / kar
Beavatkozás / kezelés
Kísérleti: Treatment
20 or 40 mg sodium nitrite tid
Drog: sodium nitrite
Subjects to receive active study drug three times daily during treatment period and then post treatment testing period.
Más nevek:
  • nitrite
Placebo Comparator: Control
20 or 40 mg placebo tid
Drog: Control
Subjects randomized to placebo to receive three times daily during treatment period and then post treatment testing period.
Más nevek:
  • Placebo

Mit mér a tanulmány?

Elsődleges eredményintézkedések

Eredménymérő
Intézkedés leírása
Időkeret
Cardiorespiratory Fitness
Időkeret: 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

Másodlagos eredményintézkedések

Eredménymérő
Intézkedés leírása
Időkeret
Perceived Fatigability
Időkeret: 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
Időkeret: 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
Időkeret: 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
Időkeret: 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
Időkeret: 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
Időkeret: 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
Időkeret: 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
Időkeret: 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
Időkeret: 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
Időkeret: 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
Időkeret: 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
Időkeret: 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
Időkeret: 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
Időkeret: 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

Egyéb eredményintézkedések

Eredménymérő
Intézkedés leírása
Időkeret
Adiponectin
Időkeret: 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
Időkeret: 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
Időkeret: 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
Időkeret: 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
Időkeret: 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
Időkeret: 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
Időkeret: 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
Időkeret: Week 1 pre drug to week 16 post drug
Medications for comorbidity managment
Week 1 pre drug to week 16 post drug
Echocardiogram
Időkeret: Week 1 pre-drug to week 16 post drug
Change in cardiac strain
Week 1 pre-drug to week 16 post drug
Fatigability
Időkeret: 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
Időkeret: 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
Időkeret: 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
Időkeret: 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
Időkeret: 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
Időkeret: Week 1 pre drug to week 16 post drug
Change in hematocrit
Week 1 pre drug to week 16 post drug
Hemoglobin
Időkeret: Week 1 pre drug to week 16 post drug
Change in hemoglobin
Week 1 pre drug to week 16 post drug
Hemodynamics; Blood Pressure
Időkeret: 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
Időkeret: Week 1 pre drug to week 16 post drug
Change in heart rate
Week 1 pre drug to week 16 post drug
Muscle Protein
Időkeret: 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
Időkeret: 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
Időkeret: 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
Időkeret: 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
Időkeret: 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
Időkeret: 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
Időkeret: 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
Időkeret: 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
Időkeret: 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

Együttműködők és nyomozók

Itt találhatja meg a tanulmányban érintett személyeket és szervezeteket.

Szponzor

Gladwin, Mark, MD

Együttműködők

National Institute on Aging (NIA)

Nyomozók

  • Kutatásvezető: Daniel E Forman, MD, University of Pittsburgh

Tanulmányi rekorddátumok

Ezek a dátumok nyomon követik a ClinicalTrials.gov webhelyre benyújtott vizsgálati rekordok és összefoglaló eredmények benyújtásának folyamatát. A vizsgálati feljegyzéseket és a jelentett eredményeket a Nemzeti Orvostudományi Könyvtár (NLM) felülvizsgálja, hogy megbizonyosodjon arról, hogy megfelelnek-e az adott minőség-ellenőrzési szabványoknak, mielőtt közzéteszik őket a nyilvános weboldalon.

Tanulmány főbb dátumok

Tanulmány kezdete (Tényleges)

2017. április 3.

Elsődleges befejezés (Tényleges)

2018. december 2.

A tanulmány befejezése (Tényleges)

2018. december 31.

Tanulmányi regisztráció dátumai

Először benyújtva

2016. szeptember 13.

Először nyújtották be, amely megfelel a minőségbiztosítási kritériumoknak

2016. szeptember 28.

Első közzététel (Becslés)

2016. szeptember 29.

Tanulmányi rekordok frissítései

Utolsó frissítés közzétéve (Tényleges)

2020. január 22.

Az utolsó frissítés elküldve, amely megfelel a minőségbiztosítási kritériumoknak

2020. január 10.

Utolsó ellenőrzés

2020. január 1.

Több információ

A tanulmányhoz kapcsolódó kifejezések

További vonatkozó MeSH feltételek

Egyéb vizsgálati azonosító számok

  • STUDY19070450
  • 1R56AG051637-01A1 (Az Egyesült Államok NIH támogatása/szerződése)

Terv az egyéni résztvevői adatokhoz (IPD)

Tervezi megosztani az egyéni résztvevői adatokat (IPD)?

Igen

IPD terv leírása

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

IPD megosztási időkeret

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

IPD-megosztási hozzáférési feltételek

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

Gyógyszer- és eszközinformációk, tanulmányi dokumentumok

Egy amerikai FDA által szabályozott gyógyszerkészítményt tanulmányoz

Igen

Egy amerikai FDA által szabályozott eszközterméket tanulmányoz

Nem

Ezt az információt közvetlenül a clinicaltrials.gov webhelyről szereztük be, változtatás nélkül. Ha bármilyen kérése van vizsgálati adatainak módosítására, eltávolítására vagy frissítésére, kérjük, írjon a következő címre: register@clinicaltrials.gov. Amint a változás bevezetésre kerül a clinicaltrials.gov oldalon, ez a webhelyünkön is automatikusan frissül. .

Klinikai vizsgálatok a sodium nitrite

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