Trial Outcomes & Findings for Oral Nitrite in Patients With Pulmonary Hypertension and Heart Failure With Preserved Ejection Fraction (NCT NCT03015402)

NCT ID: NCT03015402

Last Updated: 2024-06-07

Results Overview

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

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 33 participants
• Primary outcome timeframe: Baseline and 10 weeks
• Results posted on: 2024-06-07

Participant Flow

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.

Participant milestones

Measure	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.	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.
First Intervention (10 Weeks) STARTED	13	11
First Intervention (10 Weeks) COMPLETED	13	9
First Intervention (10 Weeks) NOT COMPLETED	0	2
Washout (2 Weeks) STARTED	13	9
Washout (2 Weeks) COMPLETED	12	9
Washout (2 Weeks) NOT COMPLETED	1	0
Second Intervention (10 Weeks) STARTED	12	9
Second Intervention (10 Weeks) COMPLETED	12	9
Second Intervention (10 Weeks) NOT COMPLETED	0	0

Reasons for withdrawal

Measure	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.	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.
First Intervention (10 Weeks) Withdrawal by Subject	0	2
Washout (2 Weeks) Withdrawal by Subject	1	0

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Nitrite Then Placebo n=13 Participants Sodium Nitrite: 40 mg PO (by mouth) TID (three times each day) for 10 weeks, then crossover to receive placebo for 10 weeks.	Placebo Then Nitrite n=11 Participants 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.	Total n=24 Participants Total of all reporting groups
Age, Continuous	69.3 years STANDARD_DEVIATION 7.0 • n=5 Participants	69.6 years STANDARD_DEVIATION 7.4 • n=7 Participants	69.4 years STANDARD_DEVIATION 7.1 • n=5 Participants
Sex: Female, Male Female	7 Participants n=5 Participants	7 Participants n=7 Participants	14 Participants n=5 Participants
Sex: Female, Male Male	6 Participants n=5 Participants	4 Participants n=7 Participants	10 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants
Race (NIH/OMB) White	10 Participants n=5 Participants	10 Participants n=7 Participants	20 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	13 participants n=5 Participants	11 participants n=7 Participants	24 participants n=5 Participants
Sitting Systolic Blood Pressure	138 mmHg STANDARD_DEVIATION 17.4 • n=5 Participants	131.5 mmHg STANDARD_DEVIATION 17.1 • n=7 Participants	134.7 mmHg STANDARD_DEVIATION 17.2 • n=5 Participants
Sitting Diastolic Blood Pressure	74.5 mmHg STANDARD_DEVIATION 9.8 • n=5 Participants	75.9 mmHg STANDARD_DEVIATION 9.2 • n=7 Participants	75.2 mmHg STANDARD_DEVIATION 9.5 • n=5 Participants

PRIMARY outcome

Timeframe: 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.

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

Outcome measures

Measure	Oral Nitrite n=21 Participants Participants who received Oral Nitrite in the first or last 10 weeks of the study.	Placebo n=21 Participants Participants who received placebo in the first or last 10 weeks of the study.
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	48.68 mmHg Standard Deviation 11.34
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	55.0 mmHg Standard Deviation 8.10

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Oral Nitrite n=19 Participants Participants who received Oral Nitrite in the first or last 10 weeks of the study.	Placebo n=19 Participants Participants who received placebo in the first or last 10 weeks of the study.
Difference in 6-minute Walk Test Baseline Distance	269.5 meters Standard Deviation 130.3	253.2 meters Standard Deviation 59.7
Difference in 6-minute Walk Test 10 Weeks Distance	267.6 meters Standard Deviation 164.1	255.2 meters Standard Deviation 89.3

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Oral Nitrite n=21 Participants Participants who received Oral Nitrite in the first or last 10 weeks of the study.	Placebo n=21 Participants Participants who received placebo in the first or last 10 weeks of the study.
Change in Right Heart Catheterization (RHC) Hemodynamics - Pulmonary Capillary Wedge Pressure Pulmonary Capillary Wedge Pressure (Rest)	28.2 mmHg Standard Deviation 8.7	26.3 mmHg Standard Deviation 7.9
Change in Right Heart Catheterization (RHC) Hemodynamics - Pulmonary Capillary Wedge Pressure Pulmonary Capillary Wedge Pressure (Exercise)	29.9 mmHg Standard Deviation 11.8	28.4 mmHg Standard Deviation 10.5

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Oral Nitrite n=19 Participants Participants who received Oral Nitrite in the first or last 10 weeks of the study.	Placebo n=19 Participants Participants who received placebo in the first or last 10 weeks of the study.
Change in Severity of Heart Failure	4146.055 pg/ml Standard Deviation 3357.261	4215.096 pg/ml Standard Deviation 3372.754

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Oral Nitrite n=21 Participants Participants who received Oral Nitrite in the first or last 10 weeks of the study.	Placebo n=21 Participants Participants who received placebo in the first or last 10 weeks of the study.
Change in Right Heart Catheterization (RHC) Hemodynamics - Trans Pulmonary Gradient Trans Pulmonary Gradient (Rest)	20.6 mmHg Standard Deviation 12.1	22.6 mmHg Standard Deviation 11.1
Change in Right Heart Catheterization (RHC) Hemodynamics - Trans Pulmonary Gradient Trans Pulmonary Gradient (Exercise)	27.1 mmHg Standard Deviation 11.2	26.6 mmHg Standard Deviation 8.4

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Measure	Oral Nitrite n=21 Participants Participants who received Oral Nitrite in the first or last 10 weeks of the study.	Placebo n=21 Participants Participants who received placebo in the first or last 10 weeks of the study.
Change in Right Heart Catheterization (RHC) Hemodynamics - Pulmonary Vascular Resistance Pulmonary Vascular Resistance (Rest)	3.2 Wood Units Standard Deviation 2.5	3.2 Wood Units Standard Deviation 2.5
Change in Right Heart Catheterization (RHC) Hemodynamics - Pulmonary Vascular Resistance Pulmonary Vascular Resistance (Exercise)	3.4 Wood Units Standard Deviation 2.4	2.9 Wood Units Standard Deviation 1.5

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Measure	Oral Nitrite n=21 Participants Participants who received Oral Nitrite in the first or last 10 weeks of the study.	Placebo n=21 Participants Participants who received placebo in the first or last 10 weeks of the study.
Change in Right Heart Catheterization (RHC) Hemodynamics - Cardiac Output Cardiac Output (Rest)	8.1 liters per minute Standard Deviation 2.4	8.8 liters per minute Standard Deviation 3.1
Change in Right Heart Catheterization (RHC) Hemodynamics - Cardiac Output Cardiac Output (Exercise)	9.4 liters per minute Standard Deviation 3.1	10 liters per minute Standard Deviation 3.1

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Oral Nitrite n=16 Participants Participants who received Oral Nitrite in the first or last 10 weeks of the study.	Placebo n=16 Participants Participants who received placebo in the first or last 10 weeks of the study.
Number of Participants With Different Severities of Heart Failure Class I	2 Participants	1 Participants
Number of Participants With Different Severities of Heart Failure Class II	8 Participants	5 Participants
Number of Participants With Different Severities of Heart Failure Class III	6 Participants	9 Participants
Number of Participants With Different Severities of Heart Failure Class IV	0 Participants	1 Participants

SECONDARY outcome

Timeframe: 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).

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

Outcome measures

Measure	Oral Nitrite n=18 Participants Participants who received Oral Nitrite in the first or last 10 weeks of the study.	Placebo n=18 Participants Participants who received placebo in the first or last 10 weeks of the study.
Change in Endurance Exercise Time	-0.056 minutes Standard Deviation 2.526	-0.904 minutes Standard Deviation 3.705

Adverse Events

Oral Nitrite

Serious events: 0 serious events

Other events: 22 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 23 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Oral Nitrite n=24 participants at risk Participants who received Oral Nitrite in the first or last 10 weeks of the study.	Placebo n=24 participants at risk Participants who received placebo in the first or last 10 weeks of the study.
Gastrointestinal disorders Dry Mouth	12.5% 3/24 • Number of events 3 • From Baseline through study completion, up to 26 weeks	12.5% 3/24 • Number of events 3 • From Baseline through study completion, up to 26 weeks
Gastrointestinal disorders Nausea	25.0% 6/24 • Number of events 6 • From Baseline through study completion, up to 26 weeks	12.5% 3/24 • Number of events 3 • From Baseline through study completion, up to 26 weeks
Gastrointestinal disorders Heartburn	4.2% 1/24 • Number of events 1 • From Baseline through study completion, up to 26 weeks	4.2% 1/24 • Number of events 1 • From Baseline through study completion, up to 26 weeks
Gastrointestinal disorders Constipation	0.00% 0/24 • From Baseline through study completion, up to 26 weeks	4.2% 1/24 • Number of events 1 • From Baseline through study completion, up to 26 weeks
Gastrointestinal disorders Diarrhea	4.2% 1/24 • Number of events 1 • From Baseline through study completion, up to 26 weeks	4.2% 1/24 • Number of events 1 • From Baseline through study completion, up to 26 weeks
Blood and lymphatic system disorders Anemia	0.00% 0/24 • From Baseline through study completion, up to 26 weeks	8.3% 2/24 • Number of events 2 • From Baseline through study completion, up to 26 weeks
Infections and infestations Hand,Food, and mouth	4.2% 1/24 • Number of events 1 • From Baseline through study completion, up to 26 weeks	0.00% 0/24 • From Baseline through study completion, up to 26 weeks
Infections and infestations Inflammation Right Ear	0.00% 0/24 • From Baseline through study completion, up to 26 weeks	4.2% 1/24 • Number of events 1 • From Baseline through study completion, up to 26 weeks
Cardiac disorders Volume Overload	0.00% 0/24 • From Baseline through study completion, up to 26 weeks	8.3% 2/24 • Number of events 2 • From Baseline through study completion, up to 26 weeks
Cardiac disorders Tachycardia	16.7% 4/24 • Number of events 4 • From Baseline through study completion, up to 26 weeks	12.5% 3/24 • Number of events 3 • From Baseline through study completion, up to 26 weeks
Cardiac disorders Atrial Fibrillation	0.00% 0/24 • From Baseline through study completion, up to 26 weeks	8.3% 2/24 • Number of events 2 • From Baseline through study completion, up to 26 weeks
Cardiac disorders Chest Tightness	16.7% 4/24 • Number of events 4 • From Baseline through study completion, up to 26 weeks	8.3% 2/24 • Number of events 2 • From Baseline through study completion, up to 26 weeks
Cardiac disorders Hypotension	8.3% 2/24 • Number of events 2 • From Baseline through study completion, up to 26 weeks	8.3% 2/24 • Number of events 2 • From Baseline through study completion, up to 26 weeks
Cardiac disorders Bradycardia	4.2% 1/24 • Number of events 1 • From Baseline through study completion, up to 26 weeks	0.00% 0/24 • From Baseline through study completion, up to 26 weeks
Cardiac disorders Systolic Murmur	4.2% 1/24 • Number of events 1 • From Baseline through study completion, up to 26 weeks	0.00% 0/24 • From Baseline through study completion, up to 26 weeks
Nervous system disorders Dizziness/Lightheadedness	25.0% 6/24 • Number of events 6 • From Baseline through study completion, up to 26 weeks	33.3% 8/24 • Number of events 8 • From Baseline through study completion, up to 26 weeks
Nervous system disorders Headache	33.3% 8/24 • Number of events 8 • From Baseline through study completion, up to 26 weeks	20.8% 5/24 • Number of events 5 • From Baseline through study completion, up to 26 weeks
Ear and labyrinth disorders Earache	0.00% 0/24 • From Baseline through study completion, up to 26 weeks	4.2% 1/24 • Number of events 1 • From Baseline through study completion, up to 26 weeks
Ear and labyrinth disorders Inflammation of Ear	0.00% 0/24 • From Baseline through study completion, up to 26 weeks	4.2% 1/24 • Number of events 1 • From Baseline through study completion, up to 26 weeks
Eye disorders Vision Disturbance	0.00% 0/24 • From Baseline through study completion, up to 26 weeks	4.2% 1/24 • Number of events 1 • From Baseline through study completion, up to 26 weeks
Eye disorders Conjuctivitis	0.00% 0/24 • From Baseline through study completion, up to 26 weeks	4.2% 1/24 • Number of events 1 • From Baseline through study completion, up to 26 weeks
General disorders Influenza	12.5% 3/24 • Number of events 3 • From Baseline through study completion, up to 26 weeks	8.3% 2/24 • Number of events 2 • From Baseline through study completion, up to 26 weeks
General disorders Swelling of Extremity	16.7% 4/24 • Number of events 4 • From Baseline through study completion, up to 26 weeks	20.8% 5/24 • Number of events 5 • From Baseline through study completion, up to 26 weeks
General disorders Fatigue	29.2% 7/24 • Number of events 7 • From Baseline through study completion, up to 26 weeks	29.2% 7/24 • Number of events 7 • From Baseline through study completion, up to 26 weeks
General disorders Chills	4.2% 1/24 • Number of events 1 • From Baseline through study completion, up to 26 weeks	0.00% 0/24 • From Baseline through study completion, up to 26 weeks
General disorders SARS-CoV-2 Virus	0.00% 0/24 • From Baseline through study completion, up to 26 weeks	4.2% 1/24 • Number of events 1 • From Baseline through study completion, up to 26 weeks
General disorders Abscess of tooth	4.2% 1/24 • Number of events 1 • From Baseline through study completion, up to 26 weeks	0.00% 0/24 • From Baseline through study completion, up to 26 weeks
General disorders Cramps	0.00% 0/24 • From Baseline through study completion, up to 26 weeks	4.2% 1/24 • Number of events 1 • From Baseline through study completion, up to 26 weeks
General disorders Increased Potassium	0.00% 0/24 • From Baseline through study completion, up to 26 weeks	4.2% 1/24 • Number of events 1 • From Baseline through study completion, up to 26 weeks
Hepatobiliary disorders Cirrhosis	4.2% 1/24 • Number of events 1 • From Baseline through study completion, up to 26 weeks	0.00% 0/24 • From Baseline through study completion, up to 26 weeks
Metabolism and nutrition disorders Hyperglycemia	8.3% 2/24 • Number of events 2 • From Baseline through study completion, up to 26 weeks	4.2% 1/24 • Number of events 1 • From Baseline through study completion, up to 26 weeks
Metabolism and nutrition disorders Hypoglycemia	4.2% 1/24 • Number of events 1 • From Baseline through study completion, up to 26 weeks	0.00% 0/24 • From Baseline through study completion, up to 26 weeks
Musculoskeletal and connective tissue disorders Joint Pain	12.5% 3/24 • Number of events 3 • From Baseline through study completion, up to 26 weeks	16.7% 4/24 • Number of events 4 • From Baseline through study completion, up to 26 weeks
Musculoskeletal and connective tissue disorders Back Pain	12.5% 3/24 • Number of events 3 • From Baseline through study completion, up to 26 weeks	12.5% 3/24 • Number of events 3 • From Baseline through study completion, up to 26 weeks
Musculoskeletal and connective tissue disorders Gout Flare	4.2% 1/24 • Number of events 1 • From Baseline through study completion, up to 26 weeks	0.00% 0/24 • From Baseline through study completion, up to 26 weeks
Musculoskeletal and connective tissue disorders Muscle Strain	8.3% 2/24 • Number of events 2 • From Baseline through study completion, up to 26 weeks	25.0% 6/24 • Number of events 6 • From Baseline through study completion, up to 26 weeks
Respiratory, thoracic and mediastinal disorders Shortness of breath	37.5% 9/24 • Number of events 9 • From Baseline through study completion, up to 26 weeks	29.2% 7/24 • Number of events 7 • From Baseline through study completion, up to 26 weeks
Respiratory, thoracic and mediastinal disorders Asthma	0.00% 0/24 • From Baseline through study completion, up to 26 weeks	4.2% 1/24 • Number of events 1 • From Baseline through study completion, up to 26 weeks
Respiratory, thoracic and mediastinal disorders Wheezing	8.3% 2/24 • Number of events 2 • From Baseline through study completion, up to 26 weeks	8.3% 2/24 • Number of events 2 • From Baseline through study completion, up to 26 weeks
Respiratory, thoracic and mediastinal disorders Cough	12.5% 3/24 • Number of events 3 • From Baseline through study completion, up to 26 weeks	4.2% 1/24 • Number of events 1 • From Baseline through study completion, up to 26 weeks
Respiratory, thoracic and mediastinal disorders Increased Respiratory Rate	8.3% 2/24 • Number of events 2 • From Baseline through study completion, up to 26 weeks	0.00% 0/24 • From Baseline through study completion, up to 26 weeks
Respiratory, thoracic and mediastinal disorders Bibasilar Crackles	4.2% 1/24 • Number of events 1 • From Baseline through study completion, up to 26 weeks	0.00% 0/24 • From Baseline through study completion, up to 26 weeks
Respiratory, thoracic and mediastinal disorders Chest Cold	4.2% 1/24 • Number of events 1 • From Baseline through study completion, up to 26 weeks	4.2% 1/24 • Number of events 1 • From Baseline through study completion, up to 26 weeks
Vascular disorders Stent Procedure (leg)	0.00% 0/24 • From Baseline through study completion, up to 26 weeks	4.2% 1/24 • Number of events 1 • From Baseline through study completion, up to 26 weeks
Skin and subcutaneous tissue disorders Eczema	4.2% 1/24 • Number of events 1 • From Baseline through study completion, up to 26 weeks	12.5% 3/24 • Number of events 3 • From Baseline through study completion, up to 26 weeks

Additional Information

Dr. Michael Risbano, Director of Advanced Cardiopulmonary Exercise Testing Program

University of Pittsburgh

Phone: 412-692-2210

Email: risbanomg@upmc.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place