Comparison of Inhaled Nitric Oxide and Oxygen in Participants Reactivity During Acute Pulmonary Vasodilator Testing

• Sponsor: Mallinckrodt (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00626028
• Collaborator: (none)
• Enrollment: 136
• Locations: 18
• Arms: 2
• Actual Duration (Months): 65
• Patients Per Site: 7.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Idiopathic Pulmonary Arterial Hypertension; Cardiomyopathy	Drug: Nitric Oxide for inhalation; Drug: Oxygen; Drug: Nitric Oxide plus Oxygen	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 136 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: Comparison of Supplemental Oxygen and Nitric Oxide for Inhalation Plus Oxygen in the Evaluation of the Reactivity of the Pulmonary Vasculature During Acute Pulmonary Vasodilator Testing
• Actual Study Start Date: Sep 1, 2004
• Actual Primary Completion Date: Feb 1, 2010
• Actual Study Completion Date: Feb 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: Nitric Oxide for inhalation; Nitric Oxide (NO) for inhalation, given at 80ppm over 10 minutes using an INOvent® delivery system; Other Names: INOmax® ; Drug: Oxygen; 100% oxygen (O2) for inhalation, given at 80ppm over 10 minutes using an INOvent® delivery system; Drug: Nitric Oxide plus Oxygen; Nitric Oxide (NO) for inhalation plus oxygen, given at 80ppm over 10 minutes using an INOvent® delivery system; Other Names: Inhaled Nitric Oxide, Oxygen
Experimental: 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.	Drug: Nitric Oxide for inhalation; Nitric Oxide (NO) for inhalation, given at 80ppm over 10 minutes using an INOvent® delivery system; Other Names: INOmax® ; Drug: Oxygen; 100% oxygen (O2) for inhalation, given at 80ppm over 10 minutes using an INOvent® delivery system; Drug: Nitric Oxide plus Oxygen; Nitric Oxide (NO) for inhalation plus oxygen, given at 80ppm over 10 minutes using an INOvent® delivery system; Other Names: Inhaled Nitric Oxide, Oxygen

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 4 Weeks to 18 Years
• Sexes Eligible for Study: All
• Accepts 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

1. Scheduled to undergo right heart catheterization to assess pulmonary vasoreactivity by acute pulmonary vasodilation testing.

2. Male or female, ages 4 weeks to 18 years, inclusive

3. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Lucile Salter Packard Children's Hospital at Stanford	Stanford	California	United States	94304
2	The Children's Hospital	Denver	Colorado	United States	80218
3	Children's Hospital Boston	Boston	Massachusetts	United States	02115
4	St. Louis Children's Hospital	Saint Louis	Missouri	United States	63110
5	New York Presbyterian Hospital	New York	New York	United States	10032
6	Cincinnati Children's Hospital	Cincinnati	Ohio	United States	45229
7	Columbus Children's Hospital	Columbus	Ohio	United States	43205
8	The Medical University of South Carolina	Charleston	South Carolina	United States	29425
9	CHU Timone - Département de cardiologie	Marseille		France
10	Hôpital d'Enfants	Nancy		France
11	Hôpital NECKER - Enfants Malades	Paris		France
12	Beatrix Children's Hospital / University Hospital Groningen	Groningen		Netherlands
13	Hospital Sant Joan de Déu de Barcelona	Barcelona		Spain
14	Unidad de Cardiologia Infantil - Hospital Vall d'Hebrón	Barcelona		Spain
15	Hospital Gregorio Maranon	Madrid		Spain
16	Instituto Pediátrico del Corazón - Hospital Materno Infatil Doce de Octubre	Madrid		Spain
17	Royal Brompton Hospital	London		United Kingdom
18	Southampton University Hospitals Trust - Wessex Cardiothoracic Centre	Southampton		United Kingdom

Sponsors and Collaborators

• Mallinckrodt

Investigators

• Study Director: Global Clinical Leader, MD, Mallinckrodt

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mallinckrodt
• ClinicalTrials.gov Identifier: NCT00626028
• Other Study ID Numbers: INOT22; 2004-000625-30
• First Posted: Feb 29, 2008
• Last Update Posted: Dec 20, 2019
• Last Verified: Sep 1, 2016

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Mallinckrodt: 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
• Additional relevant MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension; Cardiomyopathies; Nitric Oxide

Study Results

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 Detail	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.

Arm/Group Title	Nitric Oxide First, Oxygen Last	Oxygen First, Nitric Oxide Last
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	68	68
COMPLETED	62	59
NOT COMPLETED	6	9

Baseline Characteristics

Arm/Group Title	Nitric Oxide First, Oxygen Last	Oxygen First, Nitric Oxide Last	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	68	68	136
Age (Count of Participants)
<=18 years	68 100%	68 100%	136 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	5.9 (5.58)	5.9 (5.58)	5.9 (5.58)
Sex: Female, Male (Count of Participants)
Female	34 50%	34 50%	68 50%
Male	34 50%	34 50%	68 50%
Region of Enrollment (participants) [Number]
France	30 44.1%	27 39.7%	57 41.9%
United States	15 22.1%	17 25%	32 23.5%
Spain	12 17.6%	12 17.6%	24 17.6%
Netherlands	5 7.4%	6 8.8%	11 8.1%
United Kingdom	6 8.8%	6 8.8%	12 8.8%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Reversible Pulmonary Hypertension (Vasoreactivity)
Description	A composite of hemodynamic measurements were used to identify reversible pulmonary hypertension (vasoreactivity)
Time Frame	on Day 1

Outcome Measure Data

Analysis Population Description

All participants in the intent to treat analysis set who completed the study

Arm/Group Title	Nitric Oxide First, Oxygen Last	Oxygen First, Nitric Oxide Last
Arm/Group Description	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.	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.
Measure Participants	62	59
Count of Participants [Participants]	28 41.2%	16 23.5%

2. Secondary Outcome

Title	Number of Participants With Related Surgical Procedures Within 1 Year
Description	Number of participants who received surgery for pulmonary or cardiac disease within 1 year after treatment.
Time Frame	within 1 year

Outcome Measure Data

Analysis Population Description

All participants in the intent to treat analysis set who completed the study

Arm/Group Title	Nitric Oxide First, Oxygen Last	Oxygen First, Nitric Oxide Last
Arm/Group Description	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.	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.
Measure Participants	62	59
Count of Participants [Participants]	44 64.7%	21 30.9%

3. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs)
Description	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

Outcome Measure Data

Analysis Population Description

All participants in the intent to treat analysis set who completed the study

Arm/Group Title	Nitric Oxide First, Oxygen Last	Oxygen First, Nitric Oxide Last
Arm/Group Description	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.	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.
Measure Participants	62	59
Count of Participants [Participants]	5 7.4%	2 2.9%

4. Secondary Outcome

Title	Number of Participants With Serious Adverse Events (SAEs)
Description	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

Outcome Measure Data

Analysis Population Description

Participants in the intent to treat analysis set who completed the study

Arm/Group Title	Nitric Oxide First, Oxygen Last	Oxygen First, Nitric Oxide Last
Arm/Group Description	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.	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.
Measure Participants	62	59
Count of Participants [Participants]	3 4.4%	0 0%

5. Secondary Outcome

Title	Number of Participants With Related Surgical Procedures Within 3 Years
Description	Number of participants who received surgery related to pulmonary or cardiac disease within 3 years
Time Frame	within 3 years

Outcome Measure Data

Analysis Population Description

Participants in the intent to treat population who completed the study

Arm/Group Title	Nitric Oxide First, Oxygen Last	Oxygen First, Nitric Oxide Last
Arm/Group Description	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.	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.
Measure Participants	62	59
Count of Participants [Participants]	12 17.6%	6 8.8%

Adverse Events

Time Frame	within 3 years
Adverse Event Reporting Description	No non-serious adverse events reached the 5% reporting threshold
Arm/Group Title	Nitric Oxide First, Oxygen Last		Oxygen First, Nitric Oxide Last
Arm/Group Description	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.		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.
All Cause Mortality
	Nitric Oxide First, Oxygen Last		Oxygen First, Nitric Oxide Last
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Nitric Oxide First, Oxygen Last		Oxygen First, Nitric Oxide Last
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/62 (4.8%)		0/59 (0%)
Cardiac disorders
Bradycardia	1/62 (1.6%)	1	0/59 (0%)	0
Cardiac Arrest	1/62 (1.6%)	1	0/59 (0%)	0
Low Cardiac Output Syndrome	1/62 (1.6%)	1	0/59 (0%)	0
Investigations
ST Segment Elevation	1/62 (1.6%)	1	0/59 (0%)	0
Decreased oxygen saturation	1/62 (1.6%)	1	0/59 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pulmonary Hypertension	1/62 (1.6%)	1	0/59 (0%)	0
Vascular disorders
Hypotension	1/62 (1.6%)	1	0/59 (0%)	0
Other (Not Including Serious) Adverse Events
	Nitric Oxide First, Oxygen Last		Oxygen First, Nitric Oxide Last
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/62 (0%)		0/59 (0%)

Limitations/Caveats

Although the first and last treatments were randomly assigned, the second treatment was always the same. Therefore, a time/treatment interaction cannot be ruled out.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.