Heart FailurePhase 2INDIE-HFpEFNCT02742129
Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF
A Phase 2 study testing Nebulized Sodium Nitrite in people with Heart Failure, run by Adrian Hernandez at 20 sites in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 40 years and older
- Conditions the study is for
- Heart Failure
- What is being tested?
- Nebulized Sodium Nitrite
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 105 participants
- Where
- 20 sitesUnited States
- Study dates
- 10 Aug 2016to 27 Dec 2017
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 40 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Show all 15Show fewer
- 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
- 6. Peak VO2 ≤75% predicted with peak respiratory exchange ratio≥1.0 CPET Normal Values for Peak VO2 Criteria (ml/kg/min) 7. No chronic nitrate therapy or not using intermittent sublingual nitroglycerin (requirement for >1 SL nitroglycerin per week) within last 7 days 8. 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 9. Ambulatory (not wheelchair / scooter dependent) 10. 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) 11. Willingness to wear the accelerometer belt for the duration of the trial 12. Willingness to provide informed consent
Who cannot join
- 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
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- 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
Trial locations and contacts
20 sites in 1 country.
20 sites in 1 country
United States20 sites
Abington Memorial Hospital
Abington, Pennsylvania, 19001
Emory University School of Medicine
Atlanta, Georgia, 30322
Johns Hopkins Hospital
Baltimore, Maryland, 21287
Tufts Medical Center
Boston, Massachusetts, 02111
Massachusetts General Hospital
Boston, Massachusetts, 02114
Brigham and Women's Hospital
Boston, Massachusetts, 02115
The University of Vermont - Fletcher Allen Health Care
Burlington, Vermont, 05401
Northwestern University
Chicago, Illinois, 60611
University Hospitals Cleveland Medical Center
Cleveland, Ohio, 44106
Metro Health System
Cleveland, Ohio, 44109
Cleveland Clinic Foundation
Cleveland, Ohio, 44195
University of Missouri Health System
Columbia, Missouri, 65212
Duke University Medical Center
Durham, North Carolina, 27705
University of Pennsylvania Health System
Philadelphia, Pennsylvania, 19104
Jefferson Medical College
Philadelphia, Pennsylvania, 19107
Mayo Clinic
Rochester, Minnesota, 55905
V.A St. Louis Health Care System
St Louis, Missouri, 63106
Washington University School of Medicine
St Louis, Missouri, 63110
Stony Brook University Medical Center
Stony Brook, New York, 11794
Boston V.A. Healthcare System
West Roxbury, Massachusetts, 02132
About this study
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.
Read the detailed description
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)
- Participant holds study drug on day of visit.
- Review history, assess NYHA class, perform physical exam and KCCQ.
- Obtain blood draws ** - CBC, complete chemistry panel, biomarkers, biorepository (if agreed to participate).
- Obtain limited echocardiogram **.
- Perform CPET with Study Drug administered immediately before starting the CPET (primary endpoint).
- Change out accelerometer and dispense phase-2 study drug.
- Participants take no study drug for two weeks (washout).
- 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 3 (at least 42 but up to 49 days after study visit 2).
- If side effects develop Participants can down-titrate to the previously tolerated dose.
- Participants are called frequently to reinforce study procedures and assess compliance.
Study Visit 3 (42-49 Days Post Study Visit 2) • Participant holds study drug on day of visit.
- Review history, assess NYHA class, perform physical exam and KCCQ
- Obtain blood draws** - CBC, complete chemistry panel, biomarkers, biorepository (if agreed to participate).
- Obtain limited echocardiogram**.
- Perform CPET with Study Drug administered immediately before starting the CPET (primary endpoint).
- Return accelerometer and phase-2 study drug.
- End of study drug (phase out).
Phone Visit and End of Study (14 Days Post Study Visit 3)
- A final phone visit is conducted to assess for adverse events.
*Visit 1: baseline blood draw needs to be completed prior to the CPET (if this is not feasible, then they cannot be obtained for at least 3 hours post the CPET and prior to the run-in test dose).
**Visit 2 and Visit 3: blood draws and limited echo need to be obtained prior to study drug administration (if this is not feasible, then it cannot be obtained for at least 3 hours post study drug administration)
- Conditions
- Heart Failure
- Being tested
- Nebulized Sodium Nitrite, Placebo
- Medical subject headings
- Heart Failure
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Nebulized Sodium NitriteDrug
Also called AIR001
Inhaled, nebulized inorganic sodium nitrite vs. inhaled, nebulized placebo at a dose of 80 mg (or maximally tolerated dose) administered at a minimum of 4 hours apart, three times per day, during the active part of the day.
PlaceboDrug
Inhaled, nebulized placebo vs. inhaled, nebulized inorganic sodium nitrite at a dose of 80 mg (or maximally tolerated dose) administered at a minimum of 4 hours apart, three times per day, during the active part of the day.
| Study group | Role | What they receive |
|---|---|---|
| AIR001 Crossover to Placebo | Experimental | 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. Receives: Drug: Nebulized Sodium Nitrite; Drug: Placebo |
| Placebo crossover to AIR001 | Placebo comparator | 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. Receives: Drug: Nebulized Sodium Nitrite; Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Peak VO2
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.
Measured: End of Phase 1 & End of Phase 2
Secondary outcomes (10)
Average Arbitrary Accelerometer Units (AAU)
Average arbitrary accelerometer units (AAU) during at least 14 days and up to 21 days of the maximally tolerated dose of study drug (from 28 days post Study Visit 1 until Study Visit 2 and from 28 days post Study Visit 2 until Study Visit 3). An arbitrary accelerometer unit is calculated within the accelerometer device that is worn by the patient and represents level of activity based upon patient movement. Higher values indicate more movement. Zero indicates no movement.
Measured: End of Phase 1 & End of Phase 2
Medial E/e' Ratio as Measured by Echocardiography Core Lab
To evaluate whether AIR001 improves Medial E/e' ratio (the ratio between early mitral inflow velocity and mitral annular early diastolic velocity for diastolic evaluation) in comparison to placebo.
Measured: End of Phase 1 & End of Phase 2
Left Atrial Volume Index as Measured by Echocardiography
To evaluate whether AIR001 improves Left atrial volume index in comparison to placebo.
Measured: End of Phase 1 & End of Phase 2
Pulmonary Artery Systolic Pressure as Measured by Echocardiography
To evaluate whether AIR001 improves pulmonary artery systolic pressure in comparison to placebo.
Measured: End of Phase 1 & End of Phase 2
Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Score
To evaluate whether AR001 improves quality of life in comparison to placebo. The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a disease-specific patient-reported outcomes measure for patients with heart failure. It consists of 23 items, is comprised of 7 clinically relevant scales (Symptom Frequency, Symptom Burden, Symptom Stability, Physical Limitation, Social Limitation, Quality of Life, and Self-Efficacy), and yields 3 summary scores (Clinical Summary, Total Symptom, and Overall Summary Scores). Scale and summary scores range between 0 and 100, with higher scores indicating better health status (eg, better functioning, fewer symptoms, better quality of life). Higher values of the overall KCCQ score are considered to be better than lower values.
Measured: End of Phase 1 & End of Phase 2
N-terminal Pro-B-type Natriuretic Peptide Level (NT-proBNP)
Evaluate whether AIR001 improves natriuretic peptide levels in comparison to placebo
Measured: End of Phase 1 & End of Phase 2
NYHA (New York Heart Association) Class
To evaluate whether AR001 improves NYHA Class in comparison to placebo. NYHA class was measured at the end of each phase. The site physician evaluated the patient based upon the criteria for NYHA class I-IV used by the American Heart Association. NYHA functional classification provides a way of classifying the extent of heart failure. Class I (least severe): No limitation of physical activity; Class II: Slight limitation of physical activity; Class III: Marked limitation of physical activity; Class IV (most severe): Unable to carry on any physical activity without discomfort.
Measured: End of Phase 1 & End of Phase 2
Patient Preference for AIR001 Treatment at the End of Study
Self-reported participant preference for study period 1 (Phase 1) vs. study period 2 (Phase 2)
Measured: End of Phase 2
VE/VCO2 Slope (Ventilatory Efficiency) as Provided by Cardiopulmonary Exercise Testing Core Lab
To evaluate whether ARI001 in comparison to placebo improves ventilator efficiency as measured by Slope of Ve/VCO2 during study drug administration. The Ve/VCO2 slope is defined as the slope of the linear relationship between ventilation and carbon dioxide output and is a measure of the velocity.
Measured: End of Phase 1 & End of Phase 2
VO2 at Ventilatory Threshold (Submaximal Exercise Capacity) as Provided by Cardiopulmonary Exercise Testing Core Lab
To evaluate whether ARI001 in comparison to placebo improves submaximal exercise capacity as measured by VO2 (rate of oxygen consumption measured during incremental exercise) at ventilatory threshold during study drug administration.
Measured: End of Phase 1 & End of Phase 2
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Apr 2016 (estimated)
- Study start10 Aug 2016
- Primary completion13 Dec 2017
- Study completion27 Dec 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Heart FailureStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 105 participants (actual)
Sponsor and investigators
- Lead sponsor
- Adrian Hernandez
- Sponsor type
- University, hospital or other
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI), Aires Pharmaceuticals, Inc., University of Vermont, Université de Montréal, Mayo Clinic, Massachusetts General Hospital
- Responsible party
- Sponsor-investigator, Adrian Hernandez, Duke University
- Investigators
- Kevin Hernandez, MD, Principal investigator, Duke Clinical Research InstituteEugene Braunwald, MD, Study chair, Harvard University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02742129
- Sponsor's protocol ID
- Pro00071526
- Other IDs
- 5U10HL084904
- Acronym
- INDIE-HFpEF
- Status last verified
- Feb 2019
- First submitted
- 8 Apr 2016
- Last updated
- 13 Mar 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- Yes: After study completion, and upon site request, site specific participant data will be shared upon site requests. Sites may share this data with participants according to their individual institution's Institutional Review Board (IRB) policy.
Publications
Reddy YNV, Rikhi A, Obokata M, Shah SJ, Lewis GD, AbouEzzedine OF, Dunlay S, McNulty S, Chakraborty H, Stevenson LW, Redfield MM, Borlaug BA. Quality of life in heart failure with preserved ejection fraction: importance of obesity, functional capacity, and physical inactivity. Eur J Heart Fail. 2020 Jun;22(6):1009-1018. doi: 10.1002/ejhf.1788. Epub 2020 Mar 9.
PubMed 32150314Borlaug BA, Anstrom KJ, Lewis GD, Shah SJ, Levine JA, Koepp GA, Givertz MM, Felker GM, LeWinter MM, Mann DL, Margulies KB, Smith AL, Tang WHW, Whellan DJ, Chen HH, Davila-Roman VG, McNulty S, Desvigne-Nickens P, Hernandez AF, Braunwald E, Redfield MM; National Heart, Lung, and Blood Institute Heart Failure Clinical Research Network. Effect of Inorganic Nitrite vs Placebo on Exercise Capacity Among Patients With Heart Failure With Preserved Ejection Fraction: The INDIE-HFpEF Randomized Clinical Trial. JAMA. 2018 Nov 6;320(17):1764-1773. doi: 10.1001/jama.2018.14852.
PubMed 30398602Reddy YNV, Lewis GD, Shah SJ, LeWinter M, Semigran M, Davila-Roman VG, Anstrom K, Hernandez A, Braunwald E, Redfield MM, Borlaug BA. INDIE-HFpEF (Inorganic Nitrite Delivery to Improve Exercise Capacity in Heart Failure With Preserved Ejection Fraction): Rationale and Design. Circ Heart Fail. 2017 May;10(5):e003862. doi: 10.1161/CIRCHEARTFAILURE.117.003862.
PubMed 28476756
Study at a glance
From the registry record, last updated by the sponsor on 13 Mar 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF
- ClinicalTrials.gov ID
- NCT02742129
- Acronym / sponsor ID
- INDIE-HFpEF / Pro00071526
- Conditions
- Heart Failure
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 105 participants (actual)
- Lead sponsor
- Adrian HernandezUniversity, hospital or other
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI), Aires Pharmaceuticals, Inc., University of Vermont, Université de Montréal, Mayo Clinic, Massachusetts General Hospital
- Study start
- 10 Aug 2016 (actual)
- Primary completion
- 13 Dec 2017 (actual)
- Study completion
- 27 Dec 2017 (actual)
- First posted
- 18 Apr 2016 (estimated)
- Results
- Posted 13 Mar 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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)
- Participant holds study drug on day of visit.
- Review history, assess NYHA class, perform physical exam and KCCQ.
- Obtain blood draws ** - CBC, complete chemistry panel, biomarkers, biorepository (if agreed to participate).
- Obtain limited echocardiogram **.
- Perform CPET with Study Drug administered immediately before starting the CPET (primary endpoint).
- Change out accelerometer and dispense phase-2 study drug.
- Participants take no study drug for two weeks (washout).
- 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 3 (at least 42 but up to 49 days after study visit 2).
- If side effects develop Participants can down-titrate to the previously tolerated dose.
- Participants are called frequently to reinforce study procedures and assess compliance.
Study Visit 3 (42-49 Days Post Study Visit 2) • Participant holds study drug on day of visit.
- Review history, assess NYHA class, perform physical exam and KCCQ
- Obtain blood draws** - CBC, complete chemistry panel, biomarkers, biorepository (if agreed to participate).
- Obtain limited echocardiogram**.
- Perform CPET with Study Drug administered immediately before starting the CPET (primary endpoint).
- Return accelerometer and phase-2 study drug.
- End of study drug (phase out).
Phone Visit and End of Study (14 Days Post Study Visit 3)
- A final phone visit is conducted to assess for adverse events.
*Visit 1: baseline blood draw needs to be completed prior to the CPET (if this is not feasible, then they cannot be obtained for at least 3 hours post the CPET and prior to the run-in test dose).
**Visit 2 and Visit 3: blood draws and limited echo need to be obtained prior to study drug administration (if this is not feasible, then it cannot be obtained for at least 3 hours post study drug administration)
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| AIR001 Crossover to Placebo | Experimental | Drug: Nebulized Sodium Nitrite, Drug: PlaceboPhase 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. |
| Placebo crossover to AIR001 | Placebo comparator | Drug: Nebulized Sodium Nitrite, Drug: PlaceboPhase 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. |
Who may qualify
- Ages
- 40 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (15 listed)
- 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 :
- Heart failure is primary factor limiting activity as indicated by answering # 2 to the following question:
Key exclusion criteria (26 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Nebulized Sodium NitriteAlso: AIR001Inhaled, nebulized inorganic sodium nitrite vs. inhaled, nebulized placebo at a dose of 80 mg (or maximally tolerated dose) administered at a minimum of 4 hours apart, three times per day, during the active part of the day. | Drug | AIR001 Crossover to Placebo, Placebo crossover to AIR001 |
| PlaceboInhaled, nebulized placebo vs. inhaled, nebulized inorganic sodium nitrite at a dose of 80 mg (or maximally tolerated dose) administered at a minimum of 4 hours apart, three times per day, during the active part of the day. | Drug | AIR001 Crossover to Placebo, Placebo crossover to AIR001 |
Primary outcome
Peak VO2
Time frame: 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.
10 secondary outcomes
Average Arbitrary Accelerometer Units (AAU)
Time frame: End of Phase 1 & End of Phase 2
Medial E/e' Ratio as Measured by Echocardiography Core Lab
Time frame: End of Phase 1 & End of Phase 2
Left Atrial Volume Index as Measured by Echocardiography
Time frame: End of Phase 1 & End of Phase 2
Pulmonary Artery Systolic Pressure as Measured by Echocardiography
Time frame: End of Phase 1 & End of Phase 2
Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Score
Time frame: End of Phase 1 & End of Phase 2
N-terminal Pro-B-type Natriuretic Peptide Level (NT-proBNP)
Time frame: End of Phase 1 & End of Phase 2
NYHA (New York Heart Association) Class
Time frame: End of Phase 1 & End of Phase 2
Patient Preference for AIR001 Treatment at the End of Study
Time frame: End of Phase 2
VE/VCO2 Slope (Ventilatory Efficiency) as Provided by Cardiopulmonary Exercise Testing Core Lab
Time frame: End of Phase 1 & End of Phase 2
VO2 at Ventilatory Threshold (Submaximal Exercise Capacity) as Provided by Cardiopulmonary Exercise Testing Core Lab
Time frame: End of Phase 1 & End of Phase 2
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Mar 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 32150314Reddy YNV, Rikhi A, Obokata M, Shah SJ, Lewis GD, AbouEzzedine OF, Dunlay S, McNulty S, Chakraborty H, Stevenson LW, Redfield MM, Borlaug BA. Quality of life in heart failure with preserved ejection fraction: importance of obesity, functional capacity, and physical inactivity. Eur J Heart Fail. 2020 Jun;22(6):1009-1018. doi: 10.1002/ejhf.1788. Epub 2020 Mar 9.
- Derived from this study: PubMed 30398602Borlaug BA, Anstrom KJ, Lewis GD, Shah SJ, Levine JA, Koepp GA, Givertz MM, Felker GM, LeWinter MM, Mann DL, Margulies KB, Smith AL, Tang WHW, Whellan DJ, Chen HH, Davila-Roman VG, McNulty S, Desvigne-Nickens P, Hernandez AF, Braunwald E, Redfield MM; National Heart, Lung, and Blood Institute Heart Failure Clinical Research Network. Effect of Inorganic Nitrite vs Placebo on Exercise Capacity Among Patients With Heart Failure With Preserved Ejection Fraction: The INDIE-HFpEF Randomized Clinical Trial. JAMA. 2018 Nov 6;320(17):1764-1773. doi: 10.1001/jama.2018.14852.
- Derived from this study: PubMed 28476756Reddy YNV, Lewis GD, Shah SJ, LeWinter M, Semigran M, Davila-Roman VG, Anstrom K, Hernandez A, Braunwald E, Redfield MM, Borlaug BA. INDIE-HFpEF (Inorganic Nitrite Delivery to Improve Exercise Capacity in Heart Failure With Preserved Ejection Fraction): Rationale and Design. Circ Heart Fail. 2017 May;10(5):e003862. doi: 10.1161/CIRCHEARTFAILURE.117.003862.
- Individual participant dataSharing planned: Yes. After study completion, and upon site request, site specific participant data will be shared upon site requests. Sites may share this data with participants according to their individual institution's Institutional Review Board (IRB) policy.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Kevin Hernandez, MD principal investigator
Duke Clinical Research Institute
Eugene Braunwald, MD study chair
Harvard University
20 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Nebulized Sodium Nitrite in people with Heart Failure, run by Adrian Hernandez at 20 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 15 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 13 Mar 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 20 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 13 Mar 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Peak VO2 (time frame: End of Phase 1 & End of Phase 2). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02742129, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Mar 2019.