Clinical trial NCT04075123: CPAP vs NIPPV: A COMPARATIVE EFFECTIVENESS RESEARCH
Official title: Respiratory Management Of Extremely Preterm Neonates: Evidence Generation And Implementation By Comparative Effectiveness Research (CER) Using Real World Data (RWD) From A Practice-Based Research Network (PBRN)
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Respiratory Insufficiency Syndrome of Newborn
Keywords: CPAP
NIPPV
INFANT, PREMATURE
RESPIRATORY MANAGEMENT
POST-ESTUBATION
Lead sponsor: Canadian Neonatal Network
Sponsor class: OTHER
Collaborators: name: MOUNT SINAI HOSPITAL
name: Canadian Institutes of Health Research (CIHR)
First posted: 2019-08-30
Enrollment: 1829
Sex: ALL
Minimum age (years): 23
Maximum age (years): 28
Standard ages: CHILD
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Preterm neonates \<29 weeks gestational age (including outborns) who have required mechanical ventilation at any time during their clinical course.

Brief summary: Aim: Investigators aim is to conduct two complementary and concurrent CER projects using a pragmatic clinical trial design and registry-based RWD to identify the optimal respiratory management practices for extremely preterm neonates and reduce the risk of BPD and SNI.

Objectives: Two complementary objectives are proposed. Objective 1: To determine the efficacy and safety of "mandatory non-extubation" until 72 hours of postnatal age for preterm neonates born at 23 -25 weeks' GA who receive mechanical ventilation.

Objective 2: To determine whether optimal nasal continuous positive airway pressure post-extubation is as efficacious as nasal intermittent positive pressure ventilation in preterm neonates born at 23 -28 weeks' GA who have received mechanical ventilation.

Detailed description: Background and Importance: Preterm neonates \<29 weeks' gestational age (GA) have a 10% risk of mortality, 15% risk of severe neurological injury (SNI) and 45% risk of bronchopulmonary dysplasia (BPD). Both SNI and BPD are associated with significant long-term impairment. Various management approaches to prevent these complications are adopted without rigorous evaluation because conducting large-scale randomized trials can be challenging. One area consistently associated with SNI and BPD is respiratory management of these neonates which is also the area lacking evidence-informed approach. Comparative effectiveness research (CER) of different management strategies using Real World Data (RWD) is suggested as an alternative to generate Real World Evidence (RWE). Hypotheses Evaluating Treatment Effectiveness (HETE) studies are a form of CER where two or more practices are compared to evaluate presence or absence of anticipated effect using specific hypothesis. In this proposal, investigators will study two specific respiratory management practices for preterm neonates \<29 weeks' GA using this design under the auspices of our practice based research network of the Canadian Preterm Birth Network (CPTBN) which has extensive routine data collection for this population.

Aim: Investigators aim to conduct two complementary and concurrent CER projects using a pragmatic clinical trial design and registry-based RWD to identify the optimal respiratory management practices for extremely preterm neonates and reduce the risk of BPD and SNI.

Objectives: Two complementary objectives are proposed. Objective 1: To determine the efficacy and safety of "mandatory non-extubation" until 72 hours of postnatal age for preterm neonates born at 23 -25 weeks' GA who receive mechanical ventilation.

Objective 2: To determine whether optimal nasal continuous positive airway pressure post-extubation is as efficacious as nasal intermittent positive pressure ventilation in preterm neonates born at 23 -28 weeks' GA who have received mechanical ventilation.

Methods:

Approach: These two CER projects will compare respiratory management approaches at the unit-level allowing investigators to study all eligible preterm neonates admitted to participating units. Twenty units in Canada have agreed to participate in each project, and The units have participated in the conception of the study, standardizing two-arms of the protocol and agreed on the project-specific data requirements.

Duration: The study will run over 4 years. Sample size: Considering superiority approach investigators will study 800 neonates for project 1 (α=0.05, β=0.2, baseline rate 35-40% and 30% relative risk reduction).

If there was a true difference in risk of failure of 1% in CPAP group (30% vs 29%), then 1816 patients were required to be 80% sure that the upper limit of a one-sided 97.5% confidence interval (or equivalently a 95% two-sided confidence interval) would exclude a difference in favour of the NIPPV group of more than 5% for neonates of 23 -28 weeks' GA for project 2. (modification in Nov 2021, uploaded later)

Analyses: In order to generate information necessary for causal inference in a pragmatic experimental design, investigators will conduct three-pronged sensitivity analyses: logistic regression, propensity-score based analyses and instrumental variable analyses to confirm or refute our hypotheses and improve generalizability of results. Expertise: The research team includes the expertise of clinicians, researchers, epidemiologists, knowledge users, parents and statisticians.

Expected outcomes: Through use of RWD collected by the CPTBN and HETE design, the proposal will result in identifying a superior respiratory management strategy and reduced risk of mortality, SNI, and BPD for extremely preterm neonates.

Eligibility criteria: Inclusion Criteria: Must meet all criteria

1. Preterm neonates \<29 weeks gestational age
2. Receipt of mechanical ventilation

Exclusion Criteria:

1. Not received mechanical ventilation or active care
2. Congenital/genetic/chromosomal anomalies

Primary outcomes:
measure: Failure on assigned NRS mode within 72 hours post-initial extubation
timeFrame: 72 hours
Secondary outcomes:
measure: Failure on assigned NRS mode within 7 days post-initial extubation
timeFrame: 7 days
measure: Need for intubation within 72 hours and 7 days post-initial extubation
timeFrame: 72 hours and 7 days
measure: Bronchopulmonary dysplasia (BPD) at 36 weeks' PMA
timeFrame: 36 weeks post mestrual age
measure: Mortality before hospital discharge
timeFrame: through study completion, an average of 14 weeks
measure: PMA when off positive pressure support
timeFrame: through study completion, an average of 14 weeks
measure: Days of EMV (Post-initial extubation)
timeFrame: through study completion, an average of 14 weeks
measure: Days of non-invasive respiratory support including high flow (Post-initial extubation)
timeFrame: through study completion, an average of 14 weeks
measure: Days of any respiratory support (Post-initial extubation)
timeFrame: through study completion, an average of 14 weeks
measure: Days of supplemental oxygen requirement (Post-initial extubation)
timeFrame: through study completion, an average of 14 weeks
measure: Chronological age and post-menstrual age at time of full enteral feeds
timeFrame: through study completion, an average of 14 weeks
measure: Air leak (Post-initial extubation)
timeFrame: through study completion, an average of 14 weeks
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: Mount Sinai Hospital
state: Ontario
Study officials:
affiliation: MOUNT SINAI HOSPITAL
name: Prakesh Shah, MD
role: PRINCIPAL_INVESTIGATOR
References: