Ta strona została przetłumaczona automatycznie i dokładność tłumaczenia nie jest gwarantowana. Proszę odnieść się do angielska wersja za tekst źródłowy.

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

10 stycznia 2020 zaktualizowane przez: 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.

Przegląd badań

Status

Zakończony

Warunki

Interwencja / Leczenie

Szczegółowy opis

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.

Typ studiów

Interwencyjne

Zapisy (Rzeczywisty)

15

Faza

  • Faza 2

Kontakty i lokalizacje

Ta sekcja zawiera dane kontaktowe osób prowadzących badanie oraz informacje o tym, gdzie badanie jest przeprowadzane.

Lokalizacje studiów

  • Stany Zjednoczone
    • Pennsylvania
      • Pittsburgh, Pennsylvania, Stany Zjednoczone, 15213
        • UPMC Montefiore Hospital

Kryteria uczestnictwa

Badacze szukają osób, które pasują do określonego opisu, zwanego kryteriami kwalifikacyjnymi. Niektóre przykłady tych kryteriów to ogólny stan zdrowia danej osoby lub wcześniejsze leczenie.

Kryteria kwalifikacji

Wiek uprawniający do nauki

70 lat i starsze (Starszy dorosły)

Akceptuje zdrowych ochotników

Nie

Płeć kwalifikująca się do nauki

Wszystko

Opis

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,

Plan studiów

Ta sekcja zawiera szczegółowe informacje na temat planu badania, w tym sposób zaprojektowania badania i jego pomiary.

Jak projektuje się badanie?

Szczegóły projektu

  • Główny cel: Leczenie
  • Przydział: Randomizowane
  • Model interwencyjny: Przydział równoległy
  • Maskowanie: Poczwórny

Broń i interwencje

Grupa uczestników / Arm
Interwencja / Leczenie
Eksperymentalny: Treatment
20 or 40 mg sodium nitrite tid
Lek: sodium nitrite
Subjects to receive active study drug three times daily during treatment period and then post treatment testing period.
Inne nazwy:
  • nitrite
Komparator placebo: Control
20 or 40 mg placebo tid
Lek: Control
Subjects randomized to placebo to receive three times daily during treatment period and then post treatment testing period.
Inne nazwy:
  • Placebo

Co mierzy badanie?

Podstawowe miary wyniku

Miara wyniku
Opis środka
Ramy czasowe
Cardiorespiratory Fitness
Ramy czasowe: 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

Miary wyników drugorzędnych

Miara wyniku
Opis środka
Ramy czasowe
Perceived Fatigability
Ramy czasowe: 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
Ramy czasowe: 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
Ramy czasowe: 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
Ramy czasowe: 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
Ramy czasowe: 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
Ramy czasowe: 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
Ramy czasowe: 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
Ramy czasowe: 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
Ramy czasowe: 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
Ramy czasowe: 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
Ramy czasowe: 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
Ramy czasowe: 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
Ramy czasowe: 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
Ramy czasowe: 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

Inne miary wyników

Miara wyniku
Opis środka
Ramy czasowe
Adiponectin
Ramy czasowe: 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
Ramy czasowe: 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
Ramy czasowe: 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
Ramy czasowe: 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
Ramy czasowe: 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
Ramy czasowe: 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
Ramy czasowe: 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
Ramy czasowe: Week 1 pre drug to week 16 post drug
Medications for comorbidity managment
Week 1 pre drug to week 16 post drug
Echocardiogram
Ramy czasowe: Week 1 pre-drug to week 16 post drug
Change in cardiac strain
Week 1 pre-drug to week 16 post drug
Fatigability
Ramy czasowe: 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
Ramy czasowe: 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
Ramy czasowe: 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
Ramy czasowe: 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
Ramy czasowe: 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
Ramy czasowe: Week 1 pre drug to week 16 post drug
Change in hematocrit
Week 1 pre drug to week 16 post drug
Hemoglobin
Ramy czasowe: Week 1 pre drug to week 16 post drug
Change in hemoglobin
Week 1 pre drug to week 16 post drug
Hemodynamics; Blood Pressure
Ramy czasowe: 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
Ramy czasowe: Week 1 pre drug to week 16 post drug
Change in heart rate
Week 1 pre drug to week 16 post drug
Muscle Protein
Ramy czasowe: 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
Ramy czasowe: 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
Ramy czasowe: 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
Ramy czasowe: 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
Ramy czasowe: 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
Ramy czasowe: 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
Ramy czasowe: 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
Ramy czasowe: 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
Ramy czasowe: 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

Współpracownicy i badacze

Tutaj znajdziesz osoby i organizacje zaangażowane w to badanie.

Sponsor

Gladwin, Mark, MD

Współpracownicy

National Institute on Aging (NIA)

Śledczy

  • Główny śledczy: Daniel E Forman, MD, University of Pittsburgh

Daty zapisu na studia

Daty te śledzą postęp w przesyłaniu rekordów badań i podsumowań wyników do ClinicalTrials.gov. Zapisy badań i zgłoszone wyniki są przeglądane przez National Library of Medicine (NLM), aby upewnić się, że spełniają określone standardy kontroli jakości, zanim zostaną opublikowane na publicznej stronie internetowej.

Główne daty studiów

Rozpoczęcie studiów (Rzeczywisty)

3 kwietnia 2017

Zakończenie podstawowe (Rzeczywisty)

2 grudnia 2018

Ukończenie studiów (Rzeczywisty)

31 grudnia 2018

Daty rejestracji na studia

Pierwszy przesłany

13 września 2016

Pierwszy przesłany, który spełnia kryteria kontroli jakości

28 września 2016

Pierwszy wysłany (Oszacować)

29 września 2016

Aktualizacje rekordów badań

Ostatnia wysłana aktualizacja (Rzeczywisty)

22 stycznia 2020

Ostatnia przesłana aktualizacja, która spełniała kryteria kontroli jakości

10 stycznia 2020

Ostatnia weryfikacja

1 stycznia 2020

Więcej informacji

Terminy związane z tym badaniem

Dodatkowe istotne warunki MeSH

Inne numery identyfikacyjne badania

  • STUDY19070450
  • 1R56AG051637-01A1 (Grant/umowa NIH USA)

Plan dla danych uczestnika indywidualnego (IPD)

Planujesz udostępniać dane poszczególnych uczestników (IPD)?

TAk

Opis planu IPD

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

Ramy czasowe udostępniania IPD

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

Kryteria dostępu do udostępniania IPD

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

Informacje o lekach i urządzeniach, dokumenty badawcze

Bada produkt leczniczy regulowany przez amerykańską FDA

Tak

Bada produkt urządzenia regulowany przez amerykańską FDA

Nie

Te informacje zostały pobrane bezpośrednio ze strony internetowej clinicaltrials.gov bez żadnych zmian. Jeśli chcesz zmienić, usunąć lub zaktualizować dane swojego badania, skontaktuj się z register@clinicaltrials.gov. Gdy tylko zmiana zostanie wprowadzona na stronie clinicaltrials.gov, zostanie ona automatycznie zaktualizowana również na naszej stronie internetowej .

Subskrybuj