Cardiomyopathy, Idiopathic Pulmonary Arterial Hypertension
Conditions
Keywords
Pulmonary Vasculature, Nitric Oxide, INOmax®, Acute Lung Injury, Pulmonary Vasodilator Testing, Idiopathic Pulmonary Arterial Hypertension, Congenital Heart Disease, reversible pulmonary hypertension, vasoreactivity, Congenital Heart Disease with Pulmonary Hypertension
Brief summary
The primary purpose of this study is to compare the number of participants with reversible pulmonary hypertension (vasoreactivity) due to nitric oxide for inhalation and oxygen as compared to 100% oxygen.
Interventions
Nitric Oxide (NO) for inhalation, given at 80ppm over 10 minutes using an INOvent® delivery system
DRUGOxygen
100% oxygen (O2) for inhalation, given at 80ppm over 10 minutes using an INOvent® delivery system
DRUGNitric Oxide plus Oxygen
Nitric Oxide (NO) for inhalation plus oxygen, given at 80ppm over 10 minutes using an INOvent® delivery system
Sponsors
Mallinckrodt
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
4 Weeks to 18 Years
Healthy volunteers
No
Inclusion criteria
1. Must have any one of these three disease categories: * Idiopathic Pulmonary Arterial Hypertension * Mean pulmonary arterial pressure (PAPm) \> 25 millimeters of mercury (mmHg) at rest, pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg, and PVRI\> 3 u•m\^2 or diagnosed clinically with no previous catheterization * Congenital heart disease (CHD) with pulmonary hypertension repaired and unrepaired * PAPm \> 25 mmHg at rest and PVRI\> 3 u•m\^2 or diagnosed clinically with no previous catheterization * Cardiomyopathy * PAPm \> 25 mmHg at rest and Pulmonary vascular resistance index (PVRI)\> 3 u•m\^2 or diagnosed clinically with no previous catheterization 2. Scheduled to undergo right heart catheterization to assess pulmonary vasoreactivity by acute pulmonary vasodilation testing. 3. Male or female, ages 4 weeks to 18 years, inclusive 4. Signed informed consent/assent
Exclusion criteria
1. Focal pulmonary infiltrates on chest radiograph. 2. Diagnosed with severe obstructive or restrictive pulmonary disease that is significantly contributing to the patient's pulmonary hypertension. 3. Received treatment with nitric oxide for inhalation within 30 days prior to study initiation, are on other investigational medications, nitroglycerin, sodium nitroprusside, sildenafil, other Phosphodiesterase type 5 (PDE-5) inhibitors, or prostacyclin 4. Pregnant \[urine human chorionic gonadotropin positive (HCG +)\] 5. Baseline Pulmonary capillary wedge pressure (PCWP) \> 20 mmHg
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Reversible Pulmonary Hypertension (Vasoreactivity) | on Day 1 | A composite of hemodynamic measurements were used to identify reversible pulmonary hypertension (vasoreactivity) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Related Surgical Procedures Within 1 Year | within 1 year | Number of participants who received surgery for pulmonary or cardiac disease within 1 year after treatment. |
| Number of Participants With Adverse Events (AEs) | on Day 1 | An AE was defined as any untoward medical occurrence. An AE need not have a causal relationship with treatment and included any event that was not seen at baseline or, if present at baseline, increased in severity. |
| Number of Participants With Serious Adverse Events (SAEs) | within 12 hours | SAEs were collected during the 12 hours after discontinuation of gas or discharge (whichever came first). An SAE was defined as any event that resulted in death, was life threatening, resulted in permanent disability or incapacity, required or prolonged inpatient hospitalization, or was a congenital anomaly. Important medical events that, without medical or surgical intervention, would also have resulted in one of the outcomes listed above were also considered as SAEs. |
| Number of Participants With Related Surgical Procedures Within 3 Years | within 3 years | Number of participants who received surgery related to pulmonary or cardiac disease within 3 years |
Countries
France, Netherlands, Spain, United Kingdom, United States
Participant flow
Recruitment details
Children scheduled for clinically indicated right heart catheterization were screened for enrollment at 16 centers in the United States, United Kingdom, France, Spain and Netherlands.
Pre-assignment details
All 136 patients screened received all three study drugs in a crossover design, serving as their own controls. They were randomized 1:1 into two treatment sequences.
Participants by arm
| Arm | Count |
|---|---|
| Nitric Oxide First, Oxygen Last 10 minute dose of Nitric Oxide (NO) at 80 ppm, then 10 minute dose of NO plus Oxygen, then 10 minute washout, then 10 minute dose of 100% Oxygen on Day 1. | 68 |
| Oxygen First, Nitric Oxide Last 10 minute dose of 100% Oxygen, then 10 minute dose of NO plus Oxygen, then 10 minute washout, then 10 minute dose of NO at 80 ppm on Day 1. | 68 |
| Total | 136 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Device Failure | 0 | 1 |
| Overall Study | Inclusion/Exclusion Criteria | 3 | 6 |
| Overall Study | Physician Decision | 2 | 1 |
Baseline characteristics
| Characteristic | Nitric Oxide First, Oxygen Last | Oxygen First, Nitric Oxide Last | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 68 Participants | 68 Participants | 136 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 5.9 years STANDARD_DEVIATION 5.58 | 5.9 years STANDARD_DEVIATION 5.58 | 5.9 years STANDARD_DEVIATION 5.58 |
| Region of Enrollment France | 30 participants | 27 participants | 57 participants |
| Region of Enrollment Netherlands | 5 participants | 6 participants | 11 participants |
| Region of Enrollment Spain | 12 participants | 12 participants | 24 participants |
| Region of Enrollment United Kingdom | 6 participants | 6 participants | 12 participants |
| Region of Enrollment United States | 15 participants | 17 participants | 32 participants |
| Sex: Female, Male Female | 34 Participants | 34 Participants | 68 Participants |
| Sex: Female, Male Male | 34 Participants | 34 Participants | 68 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 62 | 0 / 59 |
| serious Total, serious adverse events | 3 / 62 | 0 / 59 |
Outcome results
Primary
Number of Participants With Reversible Pulmonary Hypertension (Vasoreactivity)
A composite of hemodynamic measurements were used to identify reversible pulmonary hypertension (vasoreactivity)
Time frame: on Day 1
Population: All participants in the intent to treat analysis set who completed the study
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nitric Oxide First, Oxygen Last | Number of Participants With Reversible Pulmonary Hypertension (Vasoreactivity) | 28 Participants |
| Oxygen First, Nitric Oxide Last | Number of Participants With Reversible Pulmonary Hypertension (Vasoreactivity) | 16 Participants |
Secondary
Number of Participants With Adverse Events (AEs)
An AE was defined as any untoward medical occurrence. An AE need not have a causal relationship with treatment and included any event that was not seen at baseline or, if present at baseline, increased in severity.
Time frame: on Day 1
Population: All participants in the intent to treat analysis set who completed the study
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nitric Oxide First, Oxygen Last | Number of Participants With Adverse Events (AEs) | 5 Participants |
| Oxygen First, Nitric Oxide Last | Number of Participants With Adverse Events (AEs) | 2 Participants |
Secondary
Number of Participants With Related Surgical Procedures Within 1 Year
Number of participants who received surgery for pulmonary or cardiac disease within 1 year after treatment.
Time frame: within 1 year
Population: All participants in the intent to treat analysis set who completed the study
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nitric Oxide First, Oxygen Last | Number of Participants With Related Surgical Procedures Within 1 Year | 44 Participants |
| Oxygen First, Nitric Oxide Last | Number of Participants With Related Surgical Procedures Within 1 Year | 21 Participants |
Secondary
Number of Participants With Related Surgical Procedures Within 3 Years
Number of participants who received surgery related to pulmonary or cardiac disease within 3 years
Time frame: within 3 years
Population: Participants in the intent to treat population who completed the study
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nitric Oxide First, Oxygen Last | Number of Participants With Related Surgical Procedures Within 3 Years | 12 Participants |
| Oxygen First, Nitric Oxide Last | Number of Participants With Related Surgical Procedures Within 3 Years | 6 Participants |
Secondary
Number of Participants With Serious Adverse Events (SAEs)
SAEs were collected during the 12 hours after discontinuation of gas or discharge (whichever came first). An SAE was defined as any event that resulted in death, was life threatening, resulted in permanent disability or incapacity, required or prolonged inpatient hospitalization, or was a congenital anomaly. Important medical events that, without medical or surgical intervention, would also have resulted in one of the outcomes listed above were also considered as SAEs.
Time frame: within 12 hours
Population: Participants in the intent to treat analysis set who completed the study
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nitric Oxide First, Oxygen Last | Number of Participants With Serious Adverse Events (SAEs) | 3 Participants |
| Oxygen First, Nitric Oxide Last | Number of Participants With Serious Adverse Events (SAEs) | 0 Participants |