Oral Nitrite for Older Heart Failure With Preserved Ejection Fraction (ONOH)
10 januari 2020 bijgewerkt door: 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.
Studie Overzicht
Toestand
Voltooid
Conditie
Interventie / Behandeling
Gedetailleerde beschrijving
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.
Studietype
Ingrijpend
Inschrijving (Werkelijk)
15
Fase
- Fase 2
Contacten en locaties
In dit gedeelte vindt u de contactgegevens van degenen die het onderzoek uitvoeren en informatie over waar dit onderzoek wordt uitgevoerd.
Studie Locaties
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Pennsylvania
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Pittsburgh, Pennsylvania, Verenigde Staten, 15213
- UPMC Montefiore Hospital
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Deelname Criteria
Onderzoekers zoeken naar mensen die aan een bepaalde beschrijving voldoen, de zogenaamde geschiktheidscriteria. Enkele voorbeelden van deze criteria zijn iemands algemene gezondheidstoestand of eerdere behandelingen.
Geschiktheidscriteria
Leeftijden die in aanmerking komen voor studie
70 jaar en ouder (Oudere volwassene)
Accepteert gezonde vrijwilligers
Nee
Geslachten die in aanmerking komen voor studie
Allemaal
Beschrijving
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,
Studie plan
Dit gedeelte bevat details van het studieplan, inclusief hoe de studie is opgezet en wat de studie meet.
Hoe is de studie opgezet?
Ontwerpdetails
- Primair doel: Behandeling
- Toewijzing: Gerandomiseerd
- Interventioneel model: Parallelle opdracht
- Masker: Verviervoudigen
Wapens en interventies
Deelnemersgroep / Arm |
Interventie / Behandeling |
|---|---|
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Experimenteel: Treatment
20 or 40 mg sodium nitrite tid
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Subjects to receive active study drug three times daily during treatment period and then post treatment testing period.
Andere namen:
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Placebo-vergelijker: Control
20 or 40 mg placebo tid
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Subjects randomized to placebo to receive three times daily during treatment period and then post treatment testing period.
Andere namen:
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Wat meet het onderzoek?
Primaire uitkomstmaten
Uitkomstmaat |
Maatregel Beschrijving |
Tijdsspanne |
|---|---|---|
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Cardiorespiratory Fitness
Tijdsspanne: 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
|
Secundaire uitkomstmaten
Uitkomstmaat |
Maatregel Beschrijving |
Tijdsspanne |
|---|---|---|
|
Perceived Fatigability
Tijdsspanne: 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.
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Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
|
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Bioenergetics: In-Vivo 31P MRS Respirations
Tijdsspanne: 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
Tijdsspanne: 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
|
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Exercise-induced Changes in Pulmonary Arterial Pressure
Tijdsspanne: 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
Tijdsspanne: 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
|
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Patients With Pulmonary Hypertension
Tijdsspanne: 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.
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Week 3 (pre-drug) to week 10 (post drug); approx 8 weeks
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Steps From Accelerometry Assessment of Daily Activity
Tijdsspanne: Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks
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Actigraph device-specific activity steps on daily-wear wrist device based on movement.
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Week 1(pre-drug) to week 16(post-drug); approx. 16 weeks
|
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Sedentary Events From Accelerometry Assessment of Daily Activity
Tijdsspanne: 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
|
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Light Activity Duration From Accelerometry Assessment of Daily Activity
Tijdsspanne: 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
Tijdsspanne: 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
|
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Vector Magnitude Counts From Accelerometry Assessment of Daily Activity
Tijdsspanne: 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
Tijdsspanne: 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
|
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Light Activity Events Percentage of Day From Accelerometry Assessment of Daily Activity
Tijdsspanne: 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
Tijdsspanne: 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
|
Andere uitkomstmaten
Uitkomstmaat |
Maatregel Beschrijving |
Tijdsspanne |
|---|---|---|
|
Adiponectin
Tijdsspanne: 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
|
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Blood Nitrate
Tijdsspanne: 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
Tijdsspanne: 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
|
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Cardiopulmonary Exercise Testing: iCPET
Tijdsspanne: Week 3 (pre-drug) to week 10 (post drug); approx. 8 weeks
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Invasive cardiopulmonary exercise testing
|
Week 3 (pre-drug) to week 10 (post drug); approx. 8 weeks
|
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Cardiopulmonary Exercise Testing; nCPET
Tijdsspanne: 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
Tijdsspanne: 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
|
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Co-morbid Illness
Tijdsspanne: 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
|
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Co-morbidity Medications
Tijdsspanne: Week 1 pre drug to week 16 post drug
|
Medications for comorbidity managment
|
Week 1 pre drug to week 16 post drug
|
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Echocardiogram
Tijdsspanne: Week 1 pre-drug to week 16 post drug
|
Change in cardiac strain
|
Week 1 pre-drug to week 16 post drug
|
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Fatigability
Tijdsspanne: Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
|
Change in pre and post scores on the Pittsburgh Fatigability Index
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Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
|
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Frailty Index Assessment
Tijdsspanne: Week 1 screening pre-drug to week 16 post drug
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Physician assessment of frailty using the Canadian Clinical Frailty Scale
|
Week 1 screening pre-drug to week 16 post drug
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Gene Expression
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: Week 1 pre drug to week 16 post drug
|
Change in hematocrit
|
Week 1 pre drug to week 16 post drug
|
|
Hemoglobin
Tijdsspanne: Week 1 pre drug to week 16 post drug
|
Change in hemoglobin
|
Week 1 pre drug to week 16 post drug
|
|
Hemodynamics; Blood Pressure
Tijdsspanne: 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
Tijdsspanne: Week 1 pre drug to week 16 post drug
|
Change in heart rate
|
Week 1 pre drug to week 16 post drug
|
|
Muscle Protein
Tijdsspanne: 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
|
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Near Infrared Spectroscopy
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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
|
Medewerkers en onderzoekers
Hier vindt u mensen en organisaties die betrokken zijn bij dit onderzoek.
Sponsor
Medewerkers
Onderzoekers
- Hoofdonderzoeker: Daniel E Forman, MD, University of Pittsburgh
Studie record data
Deze datums volgen de voortgang van het onderzoeksdossier en de samenvatting van de ingediende resultaten bij ClinicalTrials.gov. Studieverslagen en gerapporteerde resultaten worden beoordeeld door de National Library of Medicine (NLM) om er zeker van te zijn dat ze voldoen aan specifieke kwaliteitscontrolenormen voordat ze op de openbare website worden geplaatst.
Bestudeer belangrijke data
Studie start (Werkelijk)
3 april 2017
Primaire voltooiing (Werkelijk)
2 december 2018
Studie voltooiing (Werkelijk)
31 december 2018
Studieregistratiedata
Eerst ingediend
13 september 2016
Eerst ingediend dat voldeed aan de QC-criteria
28 september 2016
Eerst geplaatst (Schatting)
29 september 2016
Updates van studierecords
Laatste update geplaatst (Werkelijk)
22 januari 2020
Laatste update ingediend die voldeed aan QC-criteria
10 januari 2020
Laatst geverifieerd
1 januari 2020
Meer informatie
Termen gerelateerd aan deze studie
Aanvullende relevante MeSH-voorwaarden
Andere studie-ID-nummers
- STUDY19070450
- 1R56AG051637-01A1 (Subsidie/contract van de Amerikaanse NIH)
Plan Individuele Deelnemersgegevens (IPD)
Bent u van plan om gegevens van individuele deelnemers (IPD) te delen?
Ja
Beschrijving IPD-plan
De-identified data may be shared with other future investigators as research questions arise.
IPD-tijdsbestek voor delen
A limit in time frame for sharing has not been defined.
IPD-toegangscriteria voor delen
Only de-identified data approved for sharing by the PI.
Informatie over medicijnen en apparaten, studiedocumenten
Bestudeert een door de Amerikaanse FDA gereguleerd geneesmiddel
Ja
Bestudeert een door de Amerikaanse FDA gereguleerd apparaatproduct
Nee
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