Oral Nitrite for Older Heart Failure With Preserved Ejection Fraction (ONOH)
2020年1月10日 更新者：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.
調査の概要
詳細な説明
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.
研究の種類
介入
入学 (実際)
15
段階
- フェーズ2
連絡先と場所
このセクションには、調査を実施する担当者の連絡先の詳細と、この調査が実施されている場所に関する情報が記載されています。
研究場所
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-
Pennsylvania
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Pittsburgh、Pennsylvania、アメリカ、15213
- UPMC Montefiore Hospital
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参加基準
研究者は、適格基準と呼ばれる特定の説明に適合する人を探します。これらの基準のいくつかの例は、人の一般的な健康状態または以前の治療です。
適格基準
就学可能な年齢
70年歳以上 (高齢者)
健康ボランティアの受け入れ
いいえ
受講資格のある性別
全て
説明
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,
研究計画
このセクションでは、研究がどのように設計され、研究が何を測定しているかなど、研究計画の詳細を提供します。
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：ランダム化
- 介入モデル：並列代入
- マスキング：4倍
武器と介入
参加者グループ / アーム |
介入・治療 |
|---|---|
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実験的：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.
他の名前：
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プラセボコンパレーター：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.
他の名前：
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この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Cardiorespiratory Fitness
時間枠：Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
|
Assessment of peak Oxygen uptake (VO2) maximum via symptom limited exercise testing
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Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
|
二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Perceived Fatigability
時間枠：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
時間枠：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
|
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Bioenergetics: Ex-Vivo Mitochondrial Respiration Analysis
時間枠：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.
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Week 5 (pre-drug) to week 16 (post-drug); approx. 8 weeks
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Exercise-induced Changes in Pulmonary Arterial Pressure
時間枠：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
|
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Exercise-induced Changes in Pulmonary Capillary Wedge Pressure
時間枠：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
時間枠：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
時間枠：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
時間枠：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
時間枠：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
時間枠：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
時間枠：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
|
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Sedentary Event Duration From Accelerometry Assessment of Daily Activity
時間枠：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
時間枠：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
|
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Moderate to Vigorous Physical Activity Percentage From Accelerometry Assessment of Daily Activity
時間枠：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
|
その他の成果指標
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Adiponectin
時間枠：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
時間枠：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
時間枠：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
時間枠：Week 3 (pre-drug) to week 10 (post drug); approx. 8 weeks
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Invasive cardiopulmonary exercise testing
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Week 3 (pre-drug) to week 10 (post drug); approx. 8 weeks
|
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Cardiopulmonary Exercise Testing; nCPET
時間枠：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
|
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Cognitive Function
時間枠：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
時間枠：Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
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Change in pre and post scores on the Charlson Comorbidity Index
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Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
|
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Co-morbidity Medications
時間枠：Week 1 pre drug to week 16 post drug
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Medications for comorbidity managment
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Week 1 pre drug to week 16 post drug
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Echocardiogram
時間枠：Week 1 pre-drug to week 16 post drug
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Change in cardiac strain
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Week 1 pre-drug to week 16 post drug
|
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Fatigability
時間枠：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
|
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Frailty Index Assessment
時間枠：Week 1 screening pre-drug to week 16 post drug
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Physician assessment of frailty using the Canadian Clinical Frailty Scale
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Week 1 screening pre-drug to week 16 post drug
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Gene Expression
時間枠：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
|
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Glomerular Filtration Rate
時間枠：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
|
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Glycosylated Hemoglobin
時間枠：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
|
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Hematocrit
時間枠：Week 1 pre drug to week 16 post drug
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Change in hematocrit
|
Week 1 pre drug to week 16 post drug
|
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Hemoglobin
時間枠：Week 1 pre drug to week 16 post drug
|
Change in hemoglobin
|
Week 1 pre drug to week 16 post drug
|
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Hemodynamics; Blood Pressure
時間枠：Week 1 pre drug to week 16 post drug
|
Change in Blood pressure
|
Week 1 pre drug to week 16 post drug
|
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Hemodynamics; Heart Rate
時間枠：Week 1 pre drug to week 16 post drug
|
Change in heart rate
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Week 1 pre drug to week 16 post drug
|
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Muscle Protein
時間枠：Week 5 (pre drug) to week 16 (post drug); approx. 8 week
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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
時間枠：Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
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Assessment of blood flow during exercise
|
Week 2(pre drug) to Week 10( post drug); approx. 8 weeks
|
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Pain
時間枠：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
時間枠：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
|
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Physical Activity
時間枠：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
|
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Quality of Life
時間枠：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
|
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Submaximal Exercise Performance
時間枠：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
|
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Self-efficacy
時間枠：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
|
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Thyroid Stimulating Hormone
時間枠：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
|
協力者と研究者
ここでは、この調査に関係する人々や組織を見つけることができます。
スポンサー
捜査官
- 主任研究者：Daniel E Forman, MD、University of Pittsburgh
研究記録日
これらの日付は、ClinicalTrials.gov への研究記録と要約結果の提出の進捗状況を追跡します。研究記録と報告された結果は、国立医学図書館 (NLM) によって審査され、公開 Web サイトに掲載される前に、特定の品質管理基準を満たしていることが確認されます。
主要日程の研究
研究開始 (実際)
2017年4月3日
一次修了 (実際)
2018年12月2日
研究の完了 (実際)
2018年12月31日
試験登録日
最初に提出
2016年9月13日
QC基準を満たした最初の提出物
2016年9月28日
最初の投稿 (見積もり)
2016年9月29日
学習記録の更新
投稿された最後の更新 (実際)
2020年1月22日
QC基準を満たした最後の更新が送信されました
2020年1月10日
最終確認日
2020年1月1日
詳しくは
本研究に関する用語
個々の参加者データ (IPD) の計画
個々の参加者データ (IPD) を共有する予定はありますか?
はい
IPD プランの説明
De-identified data may be shared with other future investigators as research questions arise.
IPD 共有時間枠
A limit in time frame for sharing has not been defined.
IPD 共有アクセス基準
Only de-identified data approved for sharing by the PI.
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米国FDA規制医薬品の研究
はい
米国FDA規制機器製品の研究
いいえ
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