Inhaled Nitric Oxide (iNO) in Post-Pulmonary Embolism (Post-PE)

NCT04920695 | Completed

• 1 other identifier: DMED 2415-20
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief Summary

Following acute pulmonary embolism (PE), up to a third of patients develop post-PE syndrome described as having persistent breathlessness (dyspnea), impaired exercise capacity, and a reduced quality of life. The post-PE syndrome includes patients with chronic thromboembolic pulmonary hypertension (CTEPH), patients with chronic thromboembolic disease (CTED) those with an obstruction of the pulmonary arteries without pulmonary hypertension, and patients with post-PE related dyspnea without obstruction or pulmonary hypertension. Although therapies exist for the most severe form of the post-PE syndrome (CTEPH) - for most patients there are no available disease specific therapies that reduce symptoms. Despite studies showing increased breathlessness and abnormal exercise responses in patients with CTED, a detailed examination of what causes breathlessness in post-PE syndrome has never been undertaken. It is suspected that reduced blood flow to the lungs contributes to the feelings of breathlessness, particularly during exercise. This study will use inhaled nitric oxide, a medication that increases blood flow to the lungs. Inhaled nitric oxide is used primarily in hospitalized patients in the intensive care unit with respiratory failure, its use in people with post-PE syndrome is experimental. The investigators believe use of this medication may help to relieve symptoms of breathlessness. In order to test this medication, in volunteers with post-PE syndrome, the following will be measured: 1) breathlessness, 2) the signal to breathe sent from the brain to the lungs, 3) the activity of the muscles involved with breathing and 4) the amount of different gasses in the blood during exercise. The investigators will compare breathlessness and exercise tolerance during exercise while receiving: 1) a placebo (normal medical grade air) and 2) inhaled nitric oxide (a medication that improves blood flow to the lungs). By comparing symptoms during these two conditions, it is hoped to obtain a better understanding of what causes breathlessness in people with post-PE syndrome. This clinical research study will recruit approximately 20 clinically stable participants with CTED or post-PE related breathlessness.

Conditions

Dyspnea; Pulmonary Embolism

Keywords

Dyspnea; Post-Pulmonary Embolism Syndrome

Outcome Measures

Primary Outcomes (3)

• Dyspnea Intensity

  Dyspnea (respiratory discomfort) will be defined as the perceived "sensation of breathing discomfort" experienced at rest or during pedaling. Measurements will be made at rest (the steady-state period after at least 3 minutes of breathing on the mouthpiece before exercise starts), at two-minute intervals during exercise, and at end-exercise (at 2 minutes or the last 30-sec of loaded pedaling achieved by the participants). The intensity (strength) of sensations will be rated using the 10-point Borg scale (Modified Borg Dyspnoea Scale; scale from 0 to 10 in 1 unit increments, where 0 represents "Nothing at all" intensity and 10 represents "Maximal" intensity).

  At isotime (maximum exercise time achieved by all participants during a standard CPET) from baseline (rest) up to 20 minutes.

• Leg discomfort Intensity

  Leg discomfort will be defined as the perceived "sensation of leg discomfort" experienced at rest or during pedaling. Measurements will be made at rest (the steady-state period after at least 3 minutes of breathing on the mouthpiece before exercise starts), at two-minute intervals during exercise, and at end-exercise (at 2 minutes or the last 30-sec of loaded pedaling achieved by the participants). The intensity (strength) of sensations will be rated using the 10-point Borg scale (Modified Borg Dyspnoea Scale; scale from 0 to 10 in 1 unit increments, where 0 represents "Nothing at all" intensity and 10 represents "Maximal" intensity).

  At isotime (maximum exercise time achieved by all participants during a standard CPET) from baseline (rest) up to 20 minutes..

• Inspiratory Neural Drive (IND) as measured by Diaphragmatic electromyography (EMGdi)

  An esophageal electrode-balloon catheter consisting of 5 electrode pairs and two balloons, will be inserted nasally and positioned for optimal recording. Electromyogram output of the diaphragm (used as an index of inspiratory neural drive to crural diaphragm or diaphragm activation; EMGdi) will be recorded continuously at rest and during exercise. Maximal EMGdi (EMGdi,max) will be determined from IC maneuvers. EMGdi/EMGdi,max will be used as an index of the inspiratory neural drive to the crural diaphragm.

  At isotime (maximum exercise time achieved by all participants during a standard CPET) from baseline (rest) up to 20 minutes..

Secondary Outcomes (8)

• Ventilation

  At isotime (maximum exercise time achieved by all participants during a standard CPET) from baseline (rest) up to 20 minutes..

• Respiratory Frequency

  At isotime (maximum exercise time achieved by all participants during a standard CPET) from baseline (rest) up to 20 minutes..

• Inspiratory Capacity

  At isotime (maximum exercise time achieved by all participants during a standard CPET) from baseline (rest) up to 20 minutes..

• Carbon Dioxide Output (VECO2)

  At isotime (maximum exercise time achieved by all participants during a standard CPET) from baseline (rest) up to 20 minutes..

• Oxygen Uptake (VEO2)

  At isotime (maximum exercise time achieved by all participants during a standard CPET) from baseline (rest) up to 20 minutes..

Study Arms (2)

Placebo Control

PLACEBO COMPARATOR

Inhaled medical grade normoxic gas (FiO2 = 0.21; DIN 02238755 Air Liquid Healthcare, Montreal, Quebec, Canada).

Drug: Placebo

Inhaled Nitric Oxide

ACTIVE COMPARATOR

Inhaled 40 ppm nitric oxide from a KINOX™ gas cylinder system (Air Liquid Healthcare, Montreal, Quebec, Canada; Control # 198879, DIN 02451328).

Drug: Nitric Oxide

Interventions

Nitric Oxide DRUG

Pulmonary vasodilator (gas).

Also known as: KINOX

Inhaled Nitric Oxide

Placebo DRUG

medical grade normoxic gas (FiO2 = 0.21)

Also known as: Medical Grade Air

Placebo Control

Eligibility Criteria

• Age: 20 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• clinically stable CTED or post-PE syndrome patients, as defined by stable hemodynamic status, optimized medical treatment, no changes in medication dosage or frequency of administration with no hospital admissions in the preceding 6 weeks;
• a diagnosis of persistent, moderate to severe exertional dyspnea ≥ 6 months following PE as confirmed by study physician at time of enrollment by a modified Medical Research Council (mMRC) dyspnea scale =2, or Baseline Dyspnea Index (BDI) focal score \<=6;
• male or female non-pregnant adults \>20 years of age;
• ability to perform all study procedures
• ability to provide informed consent

You may not qualify if:

• women of childbearing potential who are pregnant or trying to become pregnant;
• echocardiographic evidence of pulmonary hypertension
• prior history of unstable pulmonary thromboembolism or systemic connective tissue vasculopathy,
• active cardiopulmonary disease or other comorbidities that could contribute to dyspnea and exercise limitation;
• history/clinical evidence of asthma, atopy and/or nasal polyps;
• history of hypercapnic respiratory failure or a clinical diagnosis of sleep disordered breathing;
• important contraindications to clinical exercise testing, including inability to exercise because of neuromuscular or musculoskeletal disease(s);
• body mass index (BMI) \<18.5 or ≥35.0 kg/m2;
• use of daytime oxygen or exercise-induced O2 desaturation (\<80% on room air).

Sponsors & Collaborators

• Dr. Denis O'Donnell: lead

Study Sites (1)

Respiratory Investigation Unit, Kingston General Hospital

Kingston, Ontario, K7L 2V7, Canada

Location

MeSH Terms

Conditions

Dyspnea; Pulmonary Embolism

Interventions

Nitric Oxide

Condition Hierarchy (Ancestors)

Respiration Disorders; Respiratory Tract Diseases; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Lung Diseases; Embolism; Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Reactive Nitrogen Species; Free Radicals; Inorganic Chemicals; Nitrogen Oxides; Nitrogen Compounds; Oxides; Oxygen Compounds; Organic Chemicals

Study Officials

• Denis E O'Donnell, MD

  Director Respiratory Investigation Unit, Professor

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Neither the participant, nor the clinical research coordinator conducting the exercise test will know which treatment is being administered. A separate, unblinded research associate will handle and administer treatment using the SoKINOX™ NO Delivery and Monitoring System
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Doctor, Professor, Director of RIU

Model Details: Randomized, double-blind, placebo-controlled crossover design

Study Record Dates

• First Submitted: January 21, 2021
• First Posted: June 10, 2021
• Study Start: May 14, 2021
• Primary Completion: May 30, 2023
• Study Completion: May 30, 2023
• Last Updated: April 3, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)