Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 105
- 试验地点
- 20
- 主要终点
- Peak VO2
研究概览
简要总结
A randomized, double-blind, placebo-controlled crossover study to assess the effect of inorganic nitrite (NO2) on aerobic capacity (peak VO2) after four weeks of dosing. Approximately 100 participants will be enrolled in this 2*2 crossover study.
详细描述
Screen potential HFpEF patients for eligibility criteria and interest
Study Visit 1
• Initiate consent process and obtain written informed consent.
- Confirm with the participant that HF symptoms are the primary limitation to activity. If so, they proceed to CPET screening. If not, they are considered a screen fail.
- Obtain baseline bloods *- CBC, complete chemistry panel, biomarkers, biorepository and genetics (if agreed to participate) .
- Obtain CPET to verify patient eligibility peak VO2 ≤ 75% predicted and RER ≥ 1.0 (within 3 days prior to randomization) and establish baseline value.
- Qualifying patients perform additional baseline studies: history, assess NYHA class, physical exam, ECG, and KCCQ.
- Open label, single-dose run-in where patient receives maximal dose (80 mg) inhaled inorganic nitrite. Patients who do not tolerate the run-in are considered screen failures.
- Randomize qualifying patients.
- Dispense phase-1 study drug, nebulizers and accelerometers
- Participants take no study drug for two weeks (baseline).
- Participants take 46 mg study drug at a minimum of 4 hours apart, 3 times a day, during active part of the day for 7 days.
- Participants take 80 mg study drug at a minimum of 4 hours apart, 3 times a day, during active part of the day until returning for study visit 2 (at least 42 days but up to 49 days post-baseline visit).
- If side effects develop, participants can down-titrate to the previous dose.
- Participants are called frequently to reinforce study procedures and assess compliance.
Study Visit 2 (42-49 Days Post Study Visit 1)
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 40 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 40 years
- •Symptoms of dyspnea (NYHA class II-IV) without evidence of a non-cardiac or ischemic explanation for dyspnea
- •EF ≥ 50% as determined on imaging study within 12 months of enrollment with no change in clinical status suggesting potential for deterioration in systolic function
- •One of the following :
- •Previous hospitalization for HF with radiographic evidence (pulmonary venous hypertension, vascular congestion, interstitial edema, pleural effusion) of pulmonary congestion or
- •Catheterization documented elevated filling pressures at rest (PCWP ≥15 or LVEDP ≥18) or with exercise (PCWP ≥25) or
- •Elevated NT-proBNP (>400 pg/ml) or BNP(>200 pg/ml) or
- •Echo evidence of diastolic dysfunction/elevated filling pressures manifest by medial E/e' ratio≥15 and/or left atrial enlargement and chronic treatment with a loop diuretic for signs or symptoms of heart failure
- •Heart failure is primary factor limiting activity as indicated by answering # 2 to the following question:
- •My ability to be active is most limited by:
- •Joint, foot, leg, hip or back pain
- •Shortness of breath and/or fatigue and/or chest pain
- •Unsteadiness or dizziness
- •Lifestyle, weather, or I just don't like to be active
- •Peak VO2 ≤75% predicted with peak respiratory exchange ratio≥1.0 CPET Normal Values for Peak VO2* Criteria (ml/kg/min)
- •No chronic nitrate therapy or not using intermittent sublingual nitroglycerin (requirement for >1 SL nitroglycerin per week) within last 7 days
- •No daily use of phosphodiesterase 5 inhibitors or soluble guanylyl cyclase activators and willing to withhold prn use of phosphodiesterase 5 inhibitors for duration of study
- •Ambulatory (not wheelchair / scooter dependent)
- •Body size allows wearing of the accelerometer belt as confirmed by ability to comfortably fasten the test belt provided for the screening process (belt designed to fit persons with BMI 20-40 kg/m2 but belt may fit some persons outside this range)
- •Willingness to wear the accelerometer belt for the duration of the trial
- •Willingness to provide informed consent
排除标准
- •Recent (< 1 month) hospitalization for heart failure
- •Ongoing requirement for PDE5 inhibitor, organic nitrate or soluble guanylyl cyclase activators
- •Hemoglobin (Hgb) < 8.0 g/dl within 90 days prior to randomization
- •GFR < 20 ml/min/1.73 m2 within 90 days prior to randomization
- •Systolic blood pressure < 115 mmHg seated or < 90 mmHg standing just prior to test dose
- •Resting HR > 110 just prior to test dose
- •Previous adverse reaction to the study drug which necessitated withdrawal of therapy
- •Significant chronic obstructive pulmonary disease thought to contribute to dyspnea
- •Ischemia thought to contribute to dyspnea
- •Documentation of previous EF < 45%
- •Acute coronary syndrome within 3 months defined by electrocardiographic (ECG) changes and biomarkers of myocardial necrosis (e.g., troponin) in an appropriate clinical setting (chest discomfort or anginal equivalent)
- •PCI, coronary artery bypass grafting, or new biventricular pacing within past 3 months
- •Primary hypertrophic cardiomyopathy
- •Infiltrative cardiomyopathy (amyloid)
- •Constrictive pericarditis or tamponade
- •Active myocarditis
- •Complex congenital heart disease
- •Active collagen vascular disease
- •More than mild aortic or mitral stenosis
- •Intrinsic (prolapse, rheumatic) valve disease with moderate to severe or severe mitral, tricuspid or aortic regurgitation
- •Acute or chronic severe liver disease as evidenced by any of the following: encephalopathy, variceal bleeding, INR > 1.7 in the absence of anticoagulation treatment
- •Terminal illness (other than HF) with expected survival of less than 1 year
- •Regularly (> 1x per week) swims or does water aerobics
- •Enrollment or planned enrollment in another therapeutic clinical trial in next 3 months.
- •Inability to comply with planned study procedures
- •Pregnancy or breastfeeding mothers
研究组 & 干预措施
AIR001 Crossover to Placebo
Phase 1: Participants will wear an accelerometer device daily but take no study drug for 14 days (washout period). On day 15, participants begin phase I study drug Nebulized Sodium Nitrite (AIR001) at 46 mg, at minimum of 4 hours apart, for 3 doses per day during the active portion of the participant's day. On day 22 participants increase study drug dose to 80 mg at the same frequency. Regardless of participant's ability to tolerate study drug or if the participant requires down-titration, participants will begin Phase 2. Phase 2: Is identical to Phase 1 except subject will be taking Placebo instead of AIR001.
干预措施: Nebulized Sodium Nitrite (Drug)
AIR001 Crossover to Placebo
Phase 1: Participants will wear an accelerometer device daily but take no study drug for 14 days (washout period). On day 15, participants begin phase I study drug Nebulized Sodium Nitrite (AIR001) at 46 mg, at minimum of 4 hours apart, for 3 doses per day during the active portion of the participant's day. On day 22 participants increase study drug dose to 80 mg at the same frequency. Regardless of participant's ability to tolerate study drug or if the participant requires down-titration, participants will begin Phase 2. Phase 2: Is identical to Phase 1 except subject will be taking Placebo instead of AIR001.
干预措施: Placebo (Drug)
Placebo crossover to AIR001
Phase 1: Participants will wear an accelerometer device daily but take no study drug for 14 days (washout period). On day 15, participants begin phase I study drug (Placebo) at 46 mg, at minimum of 4 hours apart, for 3 doses per day during the active portion of the participant's day. On day 22 participants increase study drug dose to 80 mg at the same frequency. Regardless of participant's ability to tolerate study drug or if the participant requires down-titration, participants will begin Phase 2. Phase 2: Is identical to Phase 1 except subject will be taking Nebulized Sodium Nitrite (AIR001) instead of Placebo.
干预措施: Nebulized Sodium Nitrite (Drug)
Placebo crossover to AIR001
Phase 1: Participants will wear an accelerometer device daily but take no study drug for 14 days (washout period). On day 15, participants begin phase I study drug (Placebo) at 46 mg, at minimum of 4 hours apart, for 3 doses per day during the active portion of the participant's day. On day 22 participants increase study drug dose to 80 mg at the same frequency. Regardless of participant's ability to tolerate study drug or if the participant requires down-titration, participants will begin Phase 2. Phase 2: Is identical to Phase 1 except subject will be taking Nebulized Sodium Nitrite (AIR001) instead of Placebo.
干预措施: Placebo (Drug)
结局指标
主要结局
Peak VO2
时间窗: End of Phase 1 & End of Phase 2
The primary endpoint will be the peak VO2 after 4 weeks treatment with inorganic nitrite as compared to the peak VO2 after 4 weeks treatment with placebo as assessed by cardiopulmonary exercise testing (CPET) performed at peak drug levels.
次要结局
- Average Arbitrary Accelerometer Units (AAU)(End of Phase 1 & End of Phase 2)
- Medial E/e' Ratio as Measured by Echocardiography Core Lab(End of Phase 1 & End of Phase 2)
- Patient Preference for AIR001 Treatment at the End of Study(End of Phase 2)
- Left Atrial Volume Index as Measured by Echocardiography(End of Phase 1 & End of Phase 2)
- Pulmonary Artery Systolic Pressure as Measured by Echocardiography(End of Phase 1 & End of Phase 2)
- Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Score(End of Phase 1 & End of Phase 2)
- N-terminal Pro-B-type Natriuretic Peptide Level (NT-proBNP)(End of Phase 1 & End of Phase 2)
- NYHA (New York Heart Association) Class(End of Phase 1 & End of Phase 2)
- VE/VCO2 Slope (Ventilatory Efficiency) as Provided by Cardiopulmonary Exercise Testing Core Lab(End of Phase 1 & End of Phase 2)
- VO2 at Ventilatory Threshold (Submaximal Exercise Capacity) as Provided by Cardiopulmonary Exercise Testing Core Lab(End of Phase 1 & End of Phase 2)
研究者
Adrian Hernandez
Professor of Medicine, DUMC; Director, Health Services and Outcomes Research, DCRI
Duke University