Clinical trial NCT05915806: Enteral High-dose DHA Supplementation on Bronchopulmonary Dysplasia in Very Preterm Infants: a Collaborative Study
Official title: Enteral Supplementation With High-dose Docosahexaenoic Acid on the Risk for Bronchopulmonary Dysplasia in Very Preterm Infants: A Collaborative Study Protocol for an Individual Participant Data Meta-analysis
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Bronchopulmonary Dysplasia
Child Development
Neonatal and Perinatal Conditions
Keywords: Omega-3
Fatty acids
Preterm infants
Bronchopulmonary dysplasia
Individual participant data meta-analysis
Lead sponsor: CHU de Quebec-Universite Laval
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
name: Laval University
name: South Australian Health and Medical Research Institute
name: McGill University Health Centre/Research Institute of the McGill University Health Centre
First posted: 2023-06-23
Enrollment: 1801
Sex: ALL
Maximum age (years): 14
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This one-stage individual participant data (IPD) meta-analysis study will aim to determine whether high-dose docosahexaenoic acid (DHA) enteral supplementation during the neonatal period is associated with the risk for severe bronchopulmonary dysplasia (BPD) at 36 weeks' postmenstrual age (PMA) compared to control, in contemporary cohorts of preterm infants born at less than 29 weeks of gestation. The association between high-dose DHA and severe BPD will also be explored in important subgroups according to sex, gestational age, small-for-gestational age and mode of delivery.

Detailed description: Severe BPD is a well-known factor consistently associated with impaired cognitive outcomes. Regarding reported benefits on long-term neurodevelopmental outcomes, the potential adverse effects of high-dose DHA supplementation on this short-term neonatal morbidity needs further investigations in infants born very preterm.

Therefore, based on previous systematic review findings and a known association between more severe BPD and unfavorable neurodevelopmental outcomes, a deeper understanding of the association between DHA and severe BPD needs further investigations. Harmonization of the severe BPD definition across the recent DHA trials, reclassified according to modern criteria will strengthen the results and allow their interpretation in balance with the potential efficacy of DHA on long-term neurodevelopmental outcomes. Moreover, inconsistent differential responses of DHA on BPD were previously reported according to subgroups such as sex, gestational age and mode of delivery and need to be further explored in this more vulnerable population.

Eligibility criteria: Trials included in our prior systematic review and traditional meta-analysis will be eligible for this IPD meta-analysis if they were registered randomized clinical trials of infants born preterm at less than 29 weeks of gestation and with adequate levels of blinding and allocation concealment. Moreover, eligibility will be restricted to trials conducted in a population of infants born after 2010 receiving contemporary respiratory care, similar to Jensen's cohort within which the severity-based definition of BPD was developed.

The intervention has to involve enteral administration of high-dose DHA supplementation during the neonatal period. A high-dose DHA supplementation is defined as direct enteral DHA supplementation at a dose of at least 40 mg/kg/day or DHA supplementation of breast milk or formula aiming for at least 0.4% of total fatty acids. The intervention should be randomly assigned as either enteral administration of high-dose DHA supplementation OR a control with no or low-dose DHA.

Trials evaluating intravenous DHA interventions or combined interventions (e.g. DHA combined to other nutrients or long-chain polyunsaturated fatty acids) are not considered for inclusion in this IPD meta-analysis to isolate the DHA effects and avoid heterogeneity in the intervention.

The IPD meta-analysis will be conducted using a harmonized severity-based definition of BPD in eligible trials. This definition will be based on Jensen's criteria that adequately predict childhood outcomes in a contemporary cohort of infants born very preterm. To be included, prospectively collected data from eligible trials should allow BPD severity outcome classification and harmonization according to Jensen's severity-based BPD criteria at 36 weeks' PMA.

Primary outcomes:
measure: Severe BPD
timeFrame: At 36 weeks' PMA
Secondary outcomes:
measure: "Grade 2- or 3-BPD or death"
timeFrame: At 36 weeks' PMA
measure: Severity grades of BPD
timeFrame: At 36 weeks' PMA
measure: Mortality
timeFrame: Up to 36 weeks' PMA
Other outcomes:
measure: Rate of serious brain injury
timeFrame: Up to 40 weeks' PMA
measure: Rate of severe retinopathy of prematurity (ROP)
timeFrame: Up to 40 weeks' PMA
measure: Neonatal morbidity count
timeFrame: Up to 40 weeks' PMA
measure: Rate of patent ductus arteriosus
timeFrame: Up to 40 weeks' PMA
measure: Rate of necrotising enterocolitis
timeFrame: Up to 40 weeks' PMA
measure: Rate of culture-proven sepsis
timeFrame: Up to 40 weeks' PMA
measure: Child's weight
timeFrame: Up to 36 weeks' PMA
measure: Child's length
timeFrame: Up to 36 weeks' PMA
measure: Child's head circumference
timeFrame: Up to 36 weeks' PMA
Locations:
city: Québec
country: Canada
facility: CHU de Québec-Université Laval
state: Quebec
Study officials:
affiliation: CHU de Québec-Université Laval
name: Isabelle Marc, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of British Columbia
name: Pascal M. Lavoie, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: South Australian Health and Medical Research Institute
name: Andrew J. McPhee, MB, BS
role: PRINCIPAL_INVESTIGATOR
affiliation: South Australian Health and Medical Research Institute
name: Carmel T. Collins, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU de Québec-Université Laval
name: David Simonyan, MSc
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU de Québec-Université Laval
name: Etienne Pronovost, BSc
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU de Québec-Université Laval
name: Mireille Guillot, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: South Australian Health and Medical Research Institute
name: Jacqueline F. Gould, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: St. Justine's Hospital
name: Ibrahim Mohamed, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: McGill University Health Centre/Research Institute of the McGill University Health Centre
name: Marc Beltempo, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU de Québec-Université Laval
name: Amélie Boutin, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Research Institute of the McGill University Health Centre
name: Isabel Fortier, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: South Australian Health and Medical Research Institute
name: Thomas R. Sullivan, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Laval University
name: Lynne Moore, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: South Australian Health and Medical Research Institute
name: Maria Makrides, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Marc I, Boutin A, Pronovost E, Guillot M, Bergeron F, Moore L, Makrides M. High doses of enteral docosahexaenoic acid omega-3 supplementation for prevention of bronchopulmonary dysplasia in very preterm infants: a protocol for a systematic review and meta-analysis. BMJ Open. 2022 Oct 17;12(10):e064515. doi: 10.1136/bmjopen-2022-064515.
citation: Marc I, Boutin A, Pronovost E, Perez Herrera NM, Guillot M, Bergeron F, Moore L, Sullivan TR, Lavoie PM, Makrides M. Association Between Enteral Supplementation With High-Dose Docosahexaenoic Acid and Risk of Bronchopulmonary Dysplasia in Preterm Infants: A Systematic Review and Meta-analysis. JAMA Netw Open. 2023 Mar 1;6(3):e233934. doi: 10.1001/jamanetworkopen.2023.3934.
citation: Jensen EA, Dysart K, Gantz MG, McDonald S, Bamat NA, Keszler M, Kirpalani H, Laughon MM, Poindexter BB, Duncan AF, Yoder BA, Eichenwald EC, DeMauro SB. The Diagnosis of Bronchopulmonary Dysplasia in Very Preterm Infants. An Evidence-based Approach. Am J Respir Crit Care Med. 2019 Sep 15;200(6):751-759. doi: 10.1164/rccm.201812-2348OC.
citation: Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr. 1978 Apr;92(4):529-34. doi: 10.1016/s0022-3476(78)80282-0.
citation: Schmidt B, Asztalos EV, Roberts RS, Robertson CM, Sauve RS, Whitfield MF; Trial of Indomethacin Prophylaxis in Preterms (TIPP) Investigators. Impact of bronchopulmonary dysplasia, brain injury, and severe retinopathy on the outcome of extremely low-birth-weight infants at 18 months: results from the trial of indomethacin prophylaxis in preterms. JAMA. 2003 Mar 5;289(9):1124-9. doi: 10.1001/jama.289.9.1124.