Lung Disease
Conditions
Keywords
Preemie, Inhaled Nitric Oxide
Brief summary
The purpose of this study is to assess the safety and efficacy of inhaled nitric oxide to reduce the risk of chronic lung disease in pre-term infants with respiratory distress, and to assess the long-term effects of the therapy on the development of these children over 7 years of clinical follow-up.
Detailed description
Although the effects of inhaled Nitric Oxide on pulmonary vascular tone are well-described and relevant to term infants with persistent pulmonary hypertension, the pathophysiology of respiratory failure in preterm infants may be quite different. Chronic lung disease (CLD) represents the final pathway of a heterogeneous group of pulmonary disorders of infancy that usually start in the neonatal period. CLD most commonly occurs in preterm (\<30 weeks of gestational age (GA) infants with birth weights less than 1,500 grams (g), and especially in those very preterm (\<26 weeks GA) with birth weights less than 1,000 g, and who have been treated for respiratory distress syndrome (RDS).
Interventions
DRUGNitric oxide
Nitric Oxide vapour (gas) for inhalation (400 ppm)
DRUGPlacebo
Placebo gas for inhalation
Sponsors
Mallinckrodt
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
No minimum to 26 Hours
Healthy volunteers
No
Inclusion criteria
* Inborn preterm infants 24+0 weeks-28+6 days weeks gestational age (defined by first trimester ultrasound or if not available based on the last menstrual period) who requires the use of surfactant within 24 hours of birth (either prophylactically, or for signs of developing respiratory distress), or who requires the use of continuous positive airway pressure (CPAP) (fraction of inspired oxygen concentration (FiO2) ≥ 0.30 on a mean airway pressure ≥ 4cm water (H2O)) within 24 hours of birth in order to maintain an oxygen saturation (SpO2) ≥ 85%. * Informed consent of the guardian.
Exclusion criteria
* Outborn infants. * Infants ≥ 29 weeks gestational age. * Infants requiring FiO2 \>0.5 to maintain SpO2 \>85%, on a sufficient mean airway pressure (e.g., \> 8 cm H2O on controlled mechanical ventilation (CMV)) in order to achieve adequate chest inflation (8-9 ribs on Chest X-ray) two hours after the proper administration of exogenous surfactant. * Any suspected congenital heart disease other than patent ductus arteriosus or atrial septal defect. * Any infant with severe bleeding or coagulation abnormalities at high-risk of diathesis, e.g., platelet \<50,000 per millimeter cube (mm³), fibrinogen \<0.5 gram per liter (g/L), other clotting factors \<10%. * Any infant in whom a decision has been made not to provide full treatment, e.g., chromosomal abnormalities, severe multiple abnormalities, severe birth asphyxia, etc. * Use of another investigational drug or device before or during the active study period.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Survival Without Bronchopulmonary Dysplasia (BPD) in Preterm Infants With Respiratory Distress | 21 days | Survival without BPD is defined as the number of preterm infants of 36 weeks gestational age who survived the treatment period without the need for supplemental oxygen |
Other
| Measure | Time frame | Description |
|---|---|---|
| Mortality at 7-year Follow-up | at 7-year Follow-up | Number of participants who died between 2 years and the 7-year Follow-up Period |
| Strengths and Difficulties Questionnaire Results for Participants at 7-year Follow-up | At 7-year Follow-up | The Strengths and Difficulties Questionnaire contained 25 questions that were used to create 5 scales (ranging from 10=most normal to 0=most abnormal) for emotional symptoms, conduct problems, hyperactivity, peer problems, and (10=most abnormal, 0=most normal) for prosocial. |
Countries
Belgium, Finland, France, Germany, Italy, Netherlands, Spain, Sweden, United Kingdom
Participant flow
Recruitment details
Thirty-five Medical Centers participated and enrolled a total of 800 participants (Intent to treat population).
Pre-assignment details
800 participants were enrolled at 35 medical centers around the world for the Treatment period, and 305 had data at the 7-year Follow-up period.
Participants by arm
| Arm | Count |
|---|---|
| Inhaled Nitric Oxide (INO) INO administered by nasal continuous positive airway pressure, nasal cannula or face mask at 5 parts per million (ppm) for between 7 and 21 days during the Treatment period, but no intervention during the 7-year Follow-up | 399 |
| Placebo Placebo gas administered by nasal continuous positive airway pressure, nasal cannula or face mask, for a maximum of 21 days during the Treatment period, but no intervention during the 7-year Follow-up | 401 |
| Total | 800 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Treatment Period | Adverse Event | 15 | 12 |
| Treatment Period | Death | 33 | 31 |
| Treatment Period | Delivery device failure | 1 | 3 |
| Treatment Period | Inclusion/Exclusion criteria | 4 | 4 |
| Treatment Period | Physician Decision | 0 | 1 |
| Treatment Period | Protocol Deviation | 6 | 11 |
| Treatment Period | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | Inhaled Nitric Oxide (INO) | Placebo | Total |
|---|---|---|---|
| Age, Customized Preterm newborn infants (gestational age < 37 wks) | 399 Participants | 401 Participants | 800 Participants |
| Sex: Female, Male Female | 192 Participants | 181 Participants | 373 Participants |
| Sex: Female, Male Male | 207 Participants | 220 Participants | 427 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 56 / 395 | 48 / 397 |
| other Total, other adverse events | 358 / 395 | 334 / 397 |
| serious Total, serious adverse events | 170 / 395 | 177 / 397 |
Outcome results
Primary
Survival Without Bronchopulmonary Dysplasia (BPD) in Preterm Infants With Respiratory Distress
Survival without BPD is defined as the number of preterm infants of 36 weeks gestational age who survived the treatment period without the need for supplemental oxygen
Time frame: 21 days
Population: All participants with efficacy data
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Inhaled Nitric Oxide (INO) | Survival Without Bronchopulmonary Dysplasia (BPD) in Preterm Infants With Respiratory Distress | 258 Participants |
| Placebo | Survival Without Bronchopulmonary Dysplasia (BPD) in Preterm Infants With Respiratory Distress | 262 Participants |
p-value: 0.734Wald Chi-square
Other Pre-specified
Mortality at 7-year Follow-up
Number of participants who died between 2 years and the 7-year Follow-up Period
Time frame: at 7-year Follow-up
Population: Participants with 7-year follow-up data
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Inhaled Nitric Oxide (INO) | Mortality at 7-year Follow-up | 0 Participants |
| Placebo | Mortality at 7-year Follow-up | 0 Participants |
Other Pre-specified
Strengths and Difficulties Questionnaire Results for Participants at 7-year Follow-up
The Strengths and Difficulties Questionnaire contained 25 questions that were used to create 5 scales (ranging from 10=most normal to 0=most abnormal) for emotional symptoms, conduct problems, hyperactivity, peer problems, and (10=most abnormal, 0=most normal) for prosocial.
Time frame: At 7-year Follow-up
Population: Participants with Questionnaire Results at the 7-year follow-up
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Inhaled Nitric Oxide (INO) | Strengths and Difficulties Questionnaire Results for Participants at 7-year Follow-up | Conduct (0=most normal, 10=most abnormal) | 1.4 score on a scale | Standard Deviation 1.55 |
| Inhaled Nitric Oxide (INO) | Strengths and Difficulties Questionnaire Results for Participants at 7-year Follow-up | Peer problems (0=most normal, 10=most abnormal) | 1.2 score on a scale | Standard Deviation 1.41 |
| Inhaled Nitric Oxide (INO) | Strengths and Difficulties Questionnaire Results for Participants at 7-year Follow-up | Hyperactivity (0=most normal, 10=most abnormal) | 3.8 score on a scale | Standard Deviation 2.64 |
| Inhaled Nitric Oxide (INO) | Strengths and Difficulties Questionnaire Results for Participants at 7-year Follow-up | Prosocial (10=most abnormal, 0=most normal) | 8.6 score on a scale | Standard Deviation 1.73 |
| Inhaled Nitric Oxide (INO) | Strengths and Difficulties Questionnaire Results for Participants at 7-year Follow-up | Emotional (0=most normal, 10=most abnormal) | 1.9 score on a scale | Standard Deviation 1.79 |
| Placebo | Strengths and Difficulties Questionnaire Results for Participants at 7-year Follow-up | Prosocial (10=most abnormal, 0=most normal) | 8.4 score on a scale | Standard Deviation 1.81 |
| Placebo | Strengths and Difficulties Questionnaire Results for Participants at 7-year Follow-up | Emotional (0=most normal, 10=most abnormal) | 2.1 score on a scale | Standard Deviation 1.96 |
| Placebo | Strengths and Difficulties Questionnaire Results for Participants at 7-year Follow-up | Conduct (0=most normal, 10=most abnormal) | 1.4 score on a scale | Standard Deviation 1.58 |
| Placebo | Strengths and Difficulties Questionnaire Results for Participants at 7-year Follow-up | Hyperactivity (0=most normal, 10=most abnormal) | 3.4 score on a scale | Standard Deviation 2.66 |
| Placebo | Strengths and Difficulties Questionnaire Results for Participants at 7-year Follow-up | Peer problems (0=most normal, 10=most abnormal) | 1.5 score on a scale | Standard Deviation 1.74 |