Heart Failure, Pulmonary Hypertension Secondary
Conditions
Brief summary
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).
Detailed description
This is a single-center, 22-week double-blind, randomized placebo-controlled cross-over trial of oral nitrite on exercise capacity and hemodynamic measurements in subjects with PH-HFpEF.
Interventions
DRUGSodium Nitrite
40 mg PO (by mouth) TID (three times each day) for 10 weeks
DRUGPlacebo Oral Capsule
Placebo capsule that is of identical size, shape, and color to experimental drug capsule PO (by mouth) TID (three times each day) for 10 weeks
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
University of Pittsburgh
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Age 18 years and older PH-HFpEF confirmed diagnosis by RHC: * Mean Pulmonary Arterial Pressure (mPAP) ≥ 25 mmHg AND * Pulmonary capillary wedge pressure (PWCP) ≥ 15 mmHg AND * Transpulmonary Gradient (TPG) ≥ 12 mmHg
Exclusion criteria
* Age less than 18 years; * SBP \> 170 or \< 110 mmHg * DBP \>95 or \< 60 mmHg * Hemoglobin A1C \> 10 * Positive urine pregnancy test or breastfeeding; * Ejection Fraction (EF) \< 40%; * Dementia * End-stage malignancy * Major cardiovascular event or procedure within 6 weeks prior to enrollment * Severe valvular disease * Known chronic psychiatric or medical conditions that may increase the risk associated with study participation in the judgment of the investigator, would make the subject inappropriate for entry into this study; * Smoker * Hemoglobin \<9 g/dL * Serum creatinine \> 3.0 mg/dL * Receipt of an investigational product or device, or participation in a drug research study within a period of 15 days; RHC \< 2 weeks from study screening RHC unless clinically indicated
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Pulmonary Artery Pressure (mPAP) During Submaximal Exercise as Compared Between Placebo and Nitrite | Baseline and 10 weeks | Mean Pulmonary Artery Pressure measurement at submaximal exercise as compared between Placebo and Oral Nitrite at 10 weeks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Right Heart Catheterization (RHC) Hemodynamics - Pulmonary Capillary Wedge Pressure | 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. |
| Change in Severity of Heart Failure | 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. |
| Change in Right Heart Catheterization (RHC) Hemodynamics - Trans Pulmonary Gradient | 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. |
| Difference in 6-minute Walk Test | 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. |
| Change in Right Heart Catheterization (RHC) Hemodynamics - Cardiac Output | 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. |
| Number of Participants With Different Severities of Heart Failure | 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 heart failure is listed as an end point, since this is ordinal data we cannot provide a p-value. We present the NYHA data at screening, crossover and 10 weeks. |
| Change in Endurance Exercise Time | 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. |
| Change in Right Heart Catheterization (RHC) Hemodynamics - Pulmonary Vascular Resistance | 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. |
Countries
United States
Participant flow
Pre-assignment details
A total of 33 subjects were enrolled and consented with 9 screen failed/ineligible and 24 randomized. Of the 24 randomized, 3 were on drug/placebo but withdrew at a later time, and 21 completed the study.
Participants by arm
| Arm | Count |
|---|---|
| Nitrite Then Placebo Sodium Nitrite: 40 mg PO (by mouth) TID (three times each day) for 10 weeks, then crossover to receive placebo for 10 weeks. | 13 |
| Placebo Then Nitrite Placebo Oral Capsule: Placebo capsule that is of identical size, shape, and color to experimental drug capsule PO (by mouth) TID (three times each day) for 10 weeks, then crossover to receive nitrite for 10 weeks. | 11 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention (10 Weeks) | Withdrawal by Subject | 0 | 2 |
| Washout (2 Weeks) | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Nitrite Then Placebo | Placebo Then Nitrite | Total |
|---|---|---|---|
| Age, Continuous | 69.3 years STANDARD_DEVIATION 7 | 69.6 years STANDARD_DEVIATION 7.4 | 69.4 years STANDARD_DEVIATION 7.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 10 Participants | 20 Participants |
| Region of Enrollment United States | 13 participants | 11 participants | 24 participants |
| Sex: Female, Male Female | 7 Participants | 7 Participants | 14 Participants |
| Sex: Female, Male Male | 6 Participants | 4 Participants | 10 Participants |
| Sitting Diastolic Blood Pressure | 74.5 mmHg STANDARD_DEVIATION 9.8 | 75.9 mmHg STANDARD_DEVIATION 9.2 | 75.2 mmHg STANDARD_DEVIATION 9.5 |
| Sitting Systolic Blood Pressure | 138 mmHg STANDARD_DEVIATION 17.4 | 131.5 mmHg STANDARD_DEVIATION 17.1 | 134.7 mmHg STANDARD_DEVIATION 17.2 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 24 | 0 / 24 |
| other Total, other adverse events | 22 / 24 | 23 / 24 |
| serious Total, serious adverse events | 0 / 24 | 0 / 24 |
Outcome results
Primary
Mean Pulmonary Artery Pressure (mPAP) During Submaximal Exercise as Compared Between Placebo and Nitrite
Mean Pulmonary Artery Pressure measurement at submaximal exercise as compared between Placebo and Oral Nitrite at 10 weeks.
Time frame: Baseline and 10 weeks
Population: All participants who received at least one dose of each intervention and completed all study visits were included in the efficacy analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oral Nitrite | Mean Pulmonary Artery Pressure (mPAP) During Submaximal Exercise as Compared Between Placebo and Nitrite | Supine Mean Pulmonary Artery Pressure at Baseline | 48.75 mmHg | Standard Deviation 11.73 |
| Oral Nitrite | Mean Pulmonary Artery Pressure (mPAP) During Submaximal Exercise as Compared Between Placebo and Nitrite | Supine Mean Pulmonary Artery Pressure at 10 Weeks | 56.81 mmHg | Standard Deviation 9.87 |
| Placebo | Mean Pulmonary Artery Pressure (mPAP) During Submaximal Exercise as Compared Between Placebo and Nitrite | Supine Mean Pulmonary Artery Pressure at Baseline | 48.68 mmHg | Standard Deviation 11.34 |
| Placebo | Mean Pulmonary Artery Pressure (mPAP) During Submaximal Exercise as Compared Between Placebo and Nitrite | Supine Mean Pulmonary Artery Pressure at 10 Weeks | 55.0 mmHg | Standard Deviation 8.1 |
p-value: 0.2ANOVA
Secondary
Change in Endurance Exercise Time
The endurance exercise time will be measured from the start of loaded pedaling to volitional exhaustion and the worklaod has returned to unloaded pedaling.
Time frame: 10 weeks
Population: All participants who received at least one dose of each intervention and completed all study visits were included in the efficacy analysis.~This value represents the change in endurance time (difference in time measured while pedaling) from baseline to week 10 during cardiopulmonary exercise testing in minutes.~Not all subjects had cardiopulmonary exercise testing performed due to missed visits related to personal health (i.e. fracture, or not feeling well to travel).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oral Nitrite | Change in Endurance Exercise Time | -0.056 minutes | Standard Deviation 2.526 |
| Placebo | Change in Endurance Exercise Time | -0.904 minutes | Standard Deviation 3.705 |
Secondary
Change in Right Heart Catheterization (RHC) Hemodynamics - Cardiac Output
Right heart catheterization hemodynamic measures will be aggregated to determine if overall hemodynamic on Cardiac Output are improved over the course of treatment.
Time frame: During Week 10 follow-up at rest and at exercise
Population: All participants who received at least one dose of each intervention and completed all study visits were included in the efficacy analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oral Nitrite | Change in Right Heart Catheterization (RHC) Hemodynamics - Cardiac Output | Cardiac Output (Rest) | 8.1 liters per minute | Standard Deviation 2.4 |
| Oral Nitrite | Change in Right Heart Catheterization (RHC) Hemodynamics - Cardiac Output | Cardiac Output (Exercise) | 9.4 liters per minute | Standard Deviation 3.1 |
| Placebo | Change in Right Heart Catheterization (RHC) Hemodynamics - Cardiac Output | Cardiac Output (Rest) | 8.8 liters per minute | Standard Deviation 3.1 |
| Placebo | Change in Right Heart Catheterization (RHC) Hemodynamics - Cardiac Output | Cardiac Output (Exercise) | 10 liters per minute | Standard Deviation 3.1 |
Secondary
Change in Right Heart Catheterization (RHC) Hemodynamics - Pulmonary Capillary Wedge Pressure
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.
Time frame: During Week 10 follow-up at rest and at exercise
Population: All participants who received at least one dose of each intervention and completed all study visits were included in the efficacy analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oral Nitrite | Change in Right Heart Catheterization (RHC) Hemodynamics - Pulmonary Capillary Wedge Pressure | Pulmonary Capillary Wedge Pressure (Rest) | 28.2 mmHg | Standard Deviation 8.7 |
| Oral Nitrite | Change in Right Heart Catheterization (RHC) Hemodynamics - Pulmonary Capillary Wedge Pressure | Pulmonary Capillary Wedge Pressure (Exercise) | 29.9 mmHg | Standard Deviation 11.8 |
| Placebo | Change in Right Heart Catheterization (RHC) Hemodynamics - Pulmonary Capillary Wedge Pressure | Pulmonary Capillary Wedge Pressure (Rest) | 26.3 mmHg | Standard Deviation 7.9 |
| Placebo | Change in Right Heart Catheterization (RHC) Hemodynamics - Pulmonary Capillary Wedge Pressure | Pulmonary Capillary Wedge Pressure (Exercise) | 28.4 mmHg | Standard Deviation 10.5 |
Secondary
Change in Right Heart Catheterization (RHC) Hemodynamics - Pulmonary Vascular Resistance
Right heart catheterization hemodynamic measures will be aggregated to determine if overall hemodynamic on Pulmonary Vascular Resistance are improved over the course of treatment.
Time frame: During Week 10 follow-up at rest and at exercise
Population: All participants who received at least one dose of each intervention and completed all study visits were included in the efficacy analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oral Nitrite | Change in Right Heart Catheterization (RHC) Hemodynamics - Pulmonary Vascular Resistance | Pulmonary Vascular Resistance (Rest) | 3.2 Wood Units | Standard Deviation 2.5 |
| Oral Nitrite | Change in Right Heart Catheterization (RHC) Hemodynamics - Pulmonary Vascular Resistance | Pulmonary Vascular Resistance (Exercise) | 3.4 Wood Units | Standard Deviation 2.4 |
| Placebo | Change in Right Heart Catheterization (RHC) Hemodynamics - Pulmonary Vascular Resistance | Pulmonary Vascular Resistance (Exercise) | 2.9 Wood Units | Standard Deviation 1.5 |
| Placebo | Change in Right Heart Catheterization (RHC) Hemodynamics - Pulmonary Vascular Resistance | Pulmonary Vascular Resistance (Rest) | 3.2 Wood Units | Standard Deviation 2.5 |
Secondary
Change in Right Heart Catheterization (RHC) Hemodynamics - Trans Pulmonary Gradient
Right heart catheterization hemodynamic measures will be aggregated to determine if overall hemodynamic on Trans Pulmonary Gradient are improved over the course of treatment.
Time frame: During Week 10 follow-up at rest and at exercise
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oral Nitrite | Change in Right Heart Catheterization (RHC) Hemodynamics - Trans Pulmonary Gradient | Trans Pulmonary Gradient (Rest) | 20.6 mmHg | Standard Deviation 12.1 |
| Oral Nitrite | Change in Right Heart Catheterization (RHC) Hemodynamics - Trans Pulmonary Gradient | Trans Pulmonary Gradient (Exercise) | 27.1 mmHg | Standard Deviation 11.2 |
| Placebo | Change in Right Heart Catheterization (RHC) Hemodynamics - Trans Pulmonary Gradient | Trans Pulmonary Gradient (Rest) | 22.6 mmHg | Standard Deviation 11.1 |
| Placebo | Change in Right Heart Catheterization (RHC) Hemodynamics - Trans Pulmonary Gradient | Trans Pulmonary Gradient (Exercise) | 26.6 mmHg | Standard Deviation 8.4 |
Secondary
Change in Severity of Heart Failure
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.
Time frame: Baseline to Week 10
Population: All participants who received at least one dose of each intervention and completed all study visits were included in the efficacy analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oral Nitrite | Change in Severity of Heart Failure | 4146.055 pg/ml | Standard Deviation 3357.261 |
| Placebo | Change in Severity of Heart Failure | 4215.096 pg/ml | Standard Deviation 3372.754 |
Secondary
Difference in 6-minute Walk Test
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.
Time frame: Baseline to 10 weeks
Population: All participants who received at least one dose of each intervention and completed all study visits were included in the efficacy analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oral Nitrite | Difference in 6-minute Walk Test | Baseline Distance | 269.5 meters | Standard Deviation 130.3 |
| Oral Nitrite | Difference in 6-minute Walk Test | 10 Weeks Distance | 267.6 meters | Standard Deviation 164.1 |
| Placebo | Difference in 6-minute Walk Test | Baseline Distance | 253.2 meters | Standard Deviation 59.7 |
| Placebo | Difference in 6-minute Walk Test | 10 Weeks Distance | 255.2 meters | Standard Deviation 89.3 |
Secondary
Number of Participants With Different Severities of Heart Failure
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 heart failure is listed as an end point, since this is ordinal data we cannot provide a p-value. We present the NYHA data at screening, crossover and 10 weeks.
Time frame: 10 weeks
Population: All participants who received at least one dose of each intervention and completed all study visits were included in the efficacy analysis.~Not all subjects had NYHA Functional class assessed as some subjects missed appointments and some were lost due to the pandemic.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Oral Nitrite | Number of Participants With Different Severities of Heart Failure | Class I | 2 Participants |
| Oral Nitrite | Number of Participants With Different Severities of Heart Failure | Class II | 8 Participants |
| Oral Nitrite | Number of Participants With Different Severities of Heart Failure | Class III | 6 Participants |
| Oral Nitrite | Number of Participants With Different Severities of Heart Failure | Class IV | 0 Participants |
| Placebo | Number of Participants With Different Severities of Heart Failure | Class IV | 1 Participants |
| Placebo | Number of Participants With Different Severities of Heart Failure | Class I | 1 Participants |
| Placebo | Number of Participants With Different Severities of Heart Failure | Class III | 9 Participants |
| Placebo | Number of Participants With Different Severities of Heart Failure | Class II | 5 Participants |