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NCT03015402: PH-HFpEF

Oral Nitrite in Patients With Pulmonary Hypertension and Heart Failure With Preserved Ejection Fraction

Completed Phase 2 Results posted Last updated 7 June 2024
What this trial tests

Phase 2 trial testing Sodium Nitrite in Pulmonary Hypertension Secondary in 33 participants. Completed in 25 January 2023.

Timeline
30 October 2017
Primary endpoint
25 January 2023
25 January 2023

Quick facts

Lead sponsorUniversity of Pittsburgh
PhasePhase 2
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designcrossover
Maskingquadruple
Primary purposetreatment
Enrollment33
Start date30 October 2017
Primary completion25 January 2023
Estimated completion25 January 2023
Sites1 location across United States

Drugs / interventions tested

Conditions studied

Sponsor

University of Pittsburgh

Who can join

18 and older, any sex, with Pulmonary Hypertension Secondary or Heart Failure. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Mean Pulmonary Artery Pressure (mPAP) During Submaximal Exercise as Compared Between Placebo and Nitrite Primary · Baseline and 10 weeks

Mean Pulmonary Artery Pressure measurement at submaximal exercise as compared between Placebo and Oral Nitrite at 10 weeks.

Supine Mean Pulmonary Artery Pressure at Baseline
GroupValue95% CI
Oral Nitrite48.75± 11.73
Placebo48.68± 11.34
Supine Mean Pulmonary Artery Pressure at 10 Weeks
GroupValue95% CI
Oral Nitrite56.81± 9.87
Placebo55.0± 8.10
Difference in 6-minute Walk Test Secondary · Baseline to 10 weeks

The 6-minute walk test measures the distance an individual is able to walk over 6 minutes on a hard, flat surface. The subject is allowed to self-pace and rest as needed. The number of subjects with available 6-minute walk tests do not match the total number of subjects in the study due to: one subject fracturing a foot and several subjects missing visit timepoints due to health issues resulting in 6 minute walk test not being performed.

Baseline Distance
GroupValue95% CI
Oral Nitrite269.5± 130.3
Placebo253.2± 59.7
10 Weeks Distance
GroupValue95% CI
Oral Nitrite267.6± 164.1
Placebo255.2± 89.3
Change in Right Heart Catheterization (RHC) Hemodynamics - Pulmonary Capillary Wedge Pressure Secondary · During Week 10 follow-up at rest and at exercise

Right heart catheterization hemodynamic measures will be aggregated to determine if overall hemodynamic on Pulmonary Capillary Wedge Pressure are improved over the course of treatment.

Pulmonary Capillary Wedge Pressure (Rest)
GroupValue95% CI
Oral Nitrite28.2± 8.7
Placebo26.3± 7.9
Pulmonary Capillary Wedge Pressure (Exercise)
GroupValue95% CI
Oral Nitrite29.9± 11.8
Placebo28.4± 10.5
Change in Severity of Heart Failure Secondary · Baseline to Week 10

Determined by N-terminal pro b-type natriuretic peptide (NT-proBNP) plasma levels. The number of subjects with available NT-proBNP values do not match the total number in the study as several subjects missed visit timepoints due to health issues resulting in NT-proBNP not being obtained.

GroupValue95% CI
Oral Nitrite4146.055± 3357.261
Placebo4215.096± 3372.754
Change in Right Heart Catheterization (RHC) Hemodynamics - Trans Pulmonary Gradient Secondary · During Week 10 follow-up at rest and at exercise

Right heart catheterization hemodynamic measures will be aggregated to determine if overall hemodynamic on Trans Pulmonary Gradient are improved over the course of treatment.

Trans Pulmonary Gradient (Rest)
GroupValue95% CI
Oral Nitrite20.6± 12.1
Placebo22.6± 11.1
Trans Pulmonary Gradient (Exercise)
GroupValue95% CI
Oral Nitrite27.1± 11.2
Placebo26.6± 8.4
Change in Right Heart Catheterization (RHC) Hemodynamics - Pulmonary Vascular Resistance Secondary · During Week 10 follow-up at rest and at exercise

Right heart catheterization hemodynamic measures will be aggregated to determine if overall hemodynamic on Pulmonary Vascular Resistance are improved over the course of treatment.

Pulmonary Vascular Resistance (Rest)
GroupValue95% CI
Oral Nitrite3.2± 2.5
Placebo3.2± 2.5
Pulmonary Vascular Resistance (Exercise)
GroupValue95% CI
Oral Nitrite3.4± 2.4
Placebo2.9± 1.5
Change in Right Heart Catheterization (RHC) Hemodynamics - Cardiac Output Secondary · During Week 10 follow-up at rest and at exercise

Right heart catheterization hemodynamic measures will be aggregated to determine if overall hemodynamic on Cardiac Output are improved over the course of treatment.

Cardiac Output (Rest)
GroupValue95% CI
Oral Nitrite8.1± 2.4
Placebo8.8± 3.1
Cardiac Output (Exercise)
GroupValue95% CI
Oral Nitrite9.4± 3.1
Placebo10± 3.1
Number of Participants With Different Severities of Heart Failure Secondary · 10 weeks

Determined by NYHA functional classification changes. Class I - No symptoms and no limitation in ordinary physical activity, e.g. shortness of breath when walking, climbing stairs etc. Class II - Mild symptoms (mild shortness of breath and/or angina) and slight limitation during ordinary activity. Class III - Marked limitation in activity due to symptoms, even during less-than-ordinary activity, e.g. walking short distances (20-100 m). Comfortable only at rest. Class IV - Severe limitations. Experiences symptoms even while at rest. Mostly bedbound patients. While the change in severity of

Class I
GroupValue95% CI
Oral Nitrite2
Placebo1
Class II
GroupValue95% CI
Oral Nitrite8
Placebo5
Class III
GroupValue95% CI
Oral Nitrite6
Placebo9
Class IV
GroupValue95% CI
Oral Nitrite0
Placebo1
Change in Endurance Exercise Time Secondary · 10 weeks

The endurance exercise time will be measured from the start of loaded pedaling to volitional exhaustion and the worklaod has returned to unloaded pedaling.

GroupValue95% CI
Nitrite-0.056± 2.526
Placebo-0.904± 3.705

Adverse events — posted to ClinicalTrials.gov

Time frame: From Baseline through study completion, up to 26 weeks. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Oral Nitrite
Serious: 0/24 (0%)
Deaths: 0/24
Placebo
Serious: 0/24 (0%)
Deaths: 0/24
Other adverse events (45 terms — click to expand)

ReactionSystemOral NitritePlacebo
Shortness of breathRespiratory, thoracic and mediastinal disorders
Dizziness/LightheadednessNervous system disorders
HeadacheNervous system disorders
FatigueGeneral disorders
NauseaGastrointestinal disorders
Muscle StrainMusculoskeletal and connective tissue disorders
Swelling of ExtremityGeneral disorders
TachycardiaCardiac disorders
Chest TightnessCardiac disorders
Joint PainMusculoskeletal and connective tissue disorders
Dry MouthGastrointestinal disorders
InfluenzaGeneral disorders
Back PainMusculoskeletal and connective tissue disorders
CoughRespiratory, thoracic and mediastinal disorders
EczemaSkin and subcutaneous tissue disorders
AnemiaBlood and lymphatic system disorders
Volume OverloadCardiac disorders
Atrial FibrillationCardiac disorders
HypotensionCardiac disorders
HyperglycemiaMetabolism and nutrition disorders
WheezingRespiratory, thoracic and mediastinal disorders
Increased Respiratory RateRespiratory, thoracic and mediastinal disorders
HeartburnGastrointestinal disorders
ConstipationGastrointestinal disorders
DiarrheaGastrointestinal disorders
Hand,Food, and mouthInfections and infestations
Inflammation Right EarInfections and infestations
BradycardiaCardiac disorders
Systolic MurmurCardiac disorders
EaracheEar and labyrinth disorders
Inflammation of EarEar and labyrinth disorders
Vision DisturbanceEye disorders
ConjuctivitisEye disorders
ChillsGeneral disorders
SARS-CoV-2 VirusGeneral disorders
Abscess of toothGeneral disorders
CrampsGeneral disorders
Increased PotassiumGeneral disorders
CirrhosisHepatobiliary disorders
HypoglycemiaMetabolism and nutrition disorders

Data from ClinicalTrials.gov NCT03015402 adverse events section.

Sponsor's own description

The main objective of this study is to determine the clinical efficacy of oral inorganic nitrite verses placebo and the therapeutic response with regards to exercise tolerance in patients with pulmonary hypertension and heart failure with preserved ejection fraction (PH-HFpEF).

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Effect of Inorganic Nitrite vs Placebo on Exercise Capacity Among Patients With Heart Failure With Preserved Ejection Fraction: The INDIE-HFpEF Randomized Clinical Trial.
    Borlaug BA, Anstrom KJ, Lewis GD, Shah SJ, et al · · 2018 · cited 197× · PMID 30398602 · DOI 10.1001/jama.2018.14852
  2. Nitrite and nitrate chemical biology and signalling.
    DeMartino AW, Kim-Shapiro DB, Patel RP, Gladwin MT. · · 2019 · cited 92× · PMID 30152056 · DOI 10.1111/bph.14484
  3. Therapeutic approaches in heart failure with preserved ejection fraction: past, present, and future.
    Wintrich J, Kindermann I, Ukena C, Selejan S, et al · · 2020 · cited 76× · PMID 32236720 · DOI 10.1007/s00392-020-01633-w
  4. The NO-cGMP-PKG Axis in HFpEF: From Pathological Mechanisms to Potential Therapies.
    Cai Z, Wu C, Xu Y, Cai J, et al · · 2023 · cited 33× · PMID 36818566 · DOI 10.14336/ad.2022.0523
  5. Pulmonary Hypertension in the Context of Heart Failure With Preserved Ejection Fraction.
    Inampudi C, Silverman D, Simon MA, Leary PJ, et al · · 2021 · cited 25× · PMID 34391755 · DOI 10.1016/j.chest.2021.08.039
  6. Endogenous Hemoprotein-Dependent Signaling Pathways of Nitric Oxide and Nitrite.
    Dent MR, DeMartino AW, Tejero J, Gladwin MT. · · 2021 · cited 25× · PMID 34313417 · DOI 10.1021/acs.inorgchem.1c01048
  7. Effects of Oral Sodium Nitrite on Blood Pressure, Insulin Sensitivity, and Intima-Media Arterial Thickening in Adults With Hypertension and Metabolic Syndrome.
    Hughan KS, Levine A, Helbling N, Anthony S, et al · · 2020 · cited 23× · PMID 32755471 · DOI 10.1161/hypertensionaha.120.14930
  8. Pulmonary vascular disease in the setting of heart failure with preserved ejection fraction.
    Levine AR, Simon MA, Gladwin MT. · · 2019 · cited 22× · PMID 30177249 · DOI 10.1016/j.tcm.2018.08.005

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