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Trial registered on ANZCTR


Registration number
ACTRN12609000859280
Ethics application status
Approved
Date submitted
30/09/2009
Date registered
2/10/2009
Date last updated
21/07/2015
Type of registration
Retrospectively registered

Titles & IDs
Public title
Inhaled nitric oxide in preterm infants: a systematic review and individual patient data meta-analysis
Scientific title
A systematic review of preterm infants inhalation of nitric oxide vs placebo for reduction in infant mortality and morbidity
Universal Trial Number (UTN)
Trial acronym
MAPPINO
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Preterm infant Mortality 251945 0
Preterm infant morbidity e.g Chronic Lung Disease or severe adverse neurological events 251946 0
Condition category
Condition code
Reproductive Health and Childbirth 252130 252130 0 0
Complications of newborn
Respiratory 252131 252131 0 0
Other respiratory disorders / diseases
Neurological 252132 252132 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Inhaled Nitric Oxide (iNO) relaxes vascular smooth muscle by activating guanyl cyclase and leading to the production of cyclic GMP (guanosine monophosphate).

Infants received multiple randomized doses of iNO from 5 to 80 ppm until weaned if effective. Maximum treatment days ranged from 3 days to 24 days. Frequencies and duration of doses varied between the 11 trials.
Intervention code [1] 241364 0
Treatment: Drugs
Intervention code [2] 241372 0
Prevention
Comparator / control treatment
Most studies used inhaled oxygen or nitrogen gas or ventilatory support without iNO as the placebo gas. Maximum treatment days ranged from 3 days to 24 days. Frequencies and duration of doses varied between the 11 trials.
Control group
Placebo

Outcomes
Primary outcome [1] 253009 0
All cause of mortality or chronic lung disease (CLD) using best available definition e.g alive and Oxygen (O2) dependent at 36 weeks PMA ( Post Menstrual Age) if calculable, or trialist own definition.
Found in medical records
Timepoint [1] 253009 0
36 weeks PMA
Primary outcome [2] 253010 0
Severe adverse neurological event after randomization (intraventricular hemorrhage (IVH) grade III or IV, or cystic periventricular leukomalacia (PVL) or other pathologies such as periventricular echodensity, periventricular cysts,ventriculomegaly or hydrocephalus) assessed using cranial ultrasound.
Timepoint [2] 253010 0
Assessed at 28 weeks and 36 weeks PMA
Secondary outcome [1] 257785 0
All cause of mortality at any time as assessed by medical records
Timepoint [1] 257785 0
prior to discharge and last follow up date (ranging from 1-3 years adjusted age between trials)
Secondary outcome [2] 257786 0
Severe IVH (grade III or IV) (with and without adjustment for baseline IVH severity) assessed by cranial ultrasound
Timepoint [2] 257786 0
enrolment, after randomisation, at discharge, longer term follow up (ranges from 1-3 years corrected age)
Secondary outcome [3] 257787 0
Survivors without CLD assessed by medical records e.g alive and O2 non-dependent at 36 weeks PMA ( Post Menstrual Age) if calculable, or trialist own definition.
Timepoint [3] 257787 0
36 weeks PMA
Secondary outcome [4] 257794 0
Postnatal steroid use assessed by medical records
Timepoint [4] 257794 0
at enrolment
Secondary outcome [5] 257795 0
Gross pulmonary air leak (at least one of the following: pneumothorax, pneumomediastinum, pneumoperitoneum or pneumopericardium)assessed by clinical examination and medical records
Timepoint [5] 257795 0
assessed continually after randomisation until discharge
Secondary outcome [6] 257796 0
Pulmonary haemorrhage assessed by clinical examination and medical records
Timepoint [6] 257796 0
assessed continually after randomisation until discharge
Secondary outcome [7] 257797 0
Failure of assigned treatment as defined by each trial and assessed by clinical examination and medical records
Timepoint [7] 257797 0
assessed continually after randomisation and prior to discharge
Secondary outcome [8] 257798 0
Duration of oxygen therapy assessed by medical records
Timepoint [8] 257798 0
assessed continually after randomisation until discharge and follow up after discharge (1-3 years adjusted age)
Secondary outcome [9] 257825 0
Duration of hospital stay by assessment of medical records
Timepoint [9] 257825 0
date of discharge
Secondary outcome [10] 257826 0
Severe ROP (Retinopathy of Prematurity) stage >=3; surgical or laser therapy for ROP) assessed by by medical record of eye examinations recorded
Timepoint [10] 257826 0
enrolment, after randomisation, at discharge
Secondary outcome [11] 257827 0
Postmenstrual age when ETT (endotracheal tube) ceased assessed by medical records
Timepoint [11] 257827 0
date ETT ceased
Secondary outcome [12] 257828 0
Postmenstrual age when respiratory support ceased assessed by medical records
Timepoint [12] 257828 0
date when respiratory support ceased
Secondary outcome [13] 257829 0
neurodevelopmental abnormality at follow-up (at least one of the following: cerebral palsy, developmental delay, blindness or hearing loss)
cerebral palsy assesed by GMFCS (Gross Motor Function Classification System),
major developmental delays asssessed by the Bayley mental development index II (MDI) score, Bayley psychomotor developmental index II (PDI)
blindness assessed by no useful vision in either eye and hearing loss assessed by requiring hearing aids
Timepoint [13] 257829 0
Longer term follow up ranging between 1- 3 years corrected age between trials

Eligibility
Key inclusion criteria
For the purposes of this meta-analysis it was decided to include any trials that were:

Studies will be included if they are randomised controlled trials
preterm infants (<37 weeks) receiving assisted ventilation
Minimum age
24 Weeks
Maximum age
37 Weeks
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
For the purposes of this meta-analysis it was decided to exclude any trials that were:

Non randomised controlled trials using term infants

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
18/12/2006
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
3567
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 2194 0
United States of America
State/province [1] 2194 0
California
Country [2] 2195 0
United Kingdom
State/province [2] 2195 0
London
Country [3] 2196 0
United States of America
State/province [3] 2196 0
Alabama
Country [4] 2197 0
United States of America
State/province [4] 2197 0
Ohio
Country [5] 2198 0
United Kingdom
State/province [5] 2198 0
Leicester
Country [6] 2199 0
France
State/province [6] 2199 0
Nancy
Country [7] 2200 0
Italy
State/province [7] 2200 0
Florence
Country [8] 2201 0
United States of America
State/province [8] 2201 0
Denver
Country [9] 2202 0
France
State/province [9] 2202 0
Paris
Country [10] 2203 0
United States of America
State/province [10] 2203 0
Chicago
Country [11] 2204 0
Thailand
State/province [11] 2204 0
Bangkok
Country [12] 2205 0
United Kingdom
State/province [12] 2205 0
Liverpool
Country [13] 2206 0
United States of America
State/province [13] 2206 0
Stanford
Country [14] 2207 0
Canada
State/province [14] 2207 0
Montreal
Country [15] 2208 0
United States of America
State/province [15] 2208 0
Connecticut

Funding & Sponsors
Funding source category [1] 243826 0
Commercial sector/Industry
Name [1] 243826 0
iNO Therapeutics
Country [1] 243826 0
United States of America
Primary sponsor type
University
Name
National Health and Medical Research Council, Clinical Trials Centre, University of Sydney
Address
Level 6 Medical Foundation Building, 92 Parramatta Road, Locked Bag 77, Camperdown NSW 2050 Australia
Country
Australia
Secondary sponsor category [1] 237174 0
None
Name [1] 237174 0
Address [1] 237174 0
Country [1] 237174 0

Ethics approval
Ethics application status
Approved

Summary
Brief summary
Several randomized controlled trials have been conducted in preterm infants to determine whether inhaled nitric oxide (iNO) reduces the rates of death and/or chronic lung disease. The results of these studies appear contradictory. Some studies have shown a reduction in lung injury, one has shown a reduction in cerebral injury, and several others have shown no effect. The different patient characteristics and different trial characteristics within these trials may explain this difference.

The purpose of this systematic review and individual patient data meta-analysis is to determine whether inhaled nitric oxide in preterm infants receiving assisted ventilation improves survival without morbidity, specifically without chronic lung disease (CLD), cerebral injury, retinal injury, and improves survival without long-term disability.

Secondly to determine whether the effects of inhaled nitric oxide differ according to the risk profile of the patient in terms of gestational age at birth, severity of illness, antenatal steroid use, postnatal age at the time of randomization, ventilation mode at randomization, administration of exogenous surfactant, inhaled nitric dosage and duration of nitric oxide administration.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 30345 0
Address 30345 0
Country 30345 0
Phone 30345 0
Fax 30345 0
Email 30345 0
Contact person for public queries
Name 13592 0
Dr Lisa Askie
Address 13592 0
Level 6 Medical Foundation Building, 92 Parramatta Road, Locked Bag 77, Camperdown NSW 2050
Country 13592 0
Australia
Phone 13592 0
+61 29562 5040
Fax 13592 0
Email 13592 0
[email protected]
Contact person for scientific queries
Name 4520 0
Angela Carberry
Address 4520 0
Level 6 Medical Foundation Building, 92 Parramatta Road, Locked Bag 77, Camperdown NSW 2050
Country 4520 0
Australia
Phone 4520 0
+612 9562 5028
Fax 4520 0
Email 4520 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.