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Enteral High-dose DHA Supplementation on Bronchopulmonary Dysplasia in Very Preterm Infants: a Collaborative Study

Primary Purpose

Bronchopulmonary Dysplasia, Child Development, Neonatal and Perinatal Conditions

Status
Active
Phase
Not Applicable
Locations
Canada
Study Type
Interventional
Intervention
High-dose DHA
Control
Sponsored by
CHU de Quebec-Universite Laval
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Bronchopulmonary Dysplasia focused on measuring Omega-3, Fatty acids, Preterm infants, Bronchopulmonary dysplasia, Individual participant data meta-analysis

Eligibility Criteria

undefined - 14 Weeks (Child)All SexesAccepts Healthy Volunteers

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.

Sites / Locations

  • CHU de Québec-Université Laval

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

High-dose DHA

Control

Arm Description

Enteral supplementation with high-dose DHA in the neonatal period.

Control.

Outcomes

Primary Outcome Measures

Severe BPD
A priori defined based on a team consensus, grades of severity (no BPD, grade 1-, 2-, 3-BPD) are defined on the mode of respiratory support at 36 weeks' PMA, regardless of prior or current oxygen therapy according to Jensen's criteria. Infants will be classified as severe BPD (Yes) if they presented a "grade 2- or 3-BPD" at 36 weeks' PMA, the two most severe grades of BPD according to Jensen's classification. Grade 2 is defined as respiratory support with nasal cannula >2 L/min ("high" flow) or noninvasive positive airway pressure (including nasal intermittent positive pressure ventilation or nasal continuous positive airway pressure). Grade 3 is defined as use of invasive mechanical ventilation. Infants will be classified as not severe BPD (No) if they presented "no BPD or grade 1-BPD" at 36 weeks' PMA. No BPD is defined as no support. Grade 1 is defined as respiratory support with nasal cannula ≤2 L/min ("low" flow).

Secondary Outcome Measures

"Grade 2- or 3-BPD or death"
Mortality is defined as death from any cause before 36 weeks' PMA and "Grade 2- or 3-BPD" is defined using Jensen's classification as previously described.
Severity grades of BPD
Defined as no BPD, grade 1-, 2- or 3-BPD according to Jensen's criteria as previously described.
Mortality
Defined as death from any cause.

Full Information

First Posted
May 30, 2023
Last Updated
September 8, 2023
Sponsor
CHU de Quebec-Universite Laval
Collaborators
Canadian Institutes of Health Research (CIHR), Laval University, South Australian Health and Medical Research Institute, McGill University Health Centre/Research Institute of the McGill University Health Centre
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1. Study Identification

Unique Protocol Identification Number
NCT05915806
Brief Title
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

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
July 30, 2023 (Actual)
Primary Completion Date
September 2023 (Anticipated)
Study Completion Date
March 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
CHU de Quebec-Universite Laval
Collaborators
Canadian Institutes of Health Research (CIHR), Laval University, South Australian Health and Medical Research Institute, McGill University Health Centre/Research Institute of the McGill University Health Centre

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Bronchopulmonary Dysplasia, Child Development, Neonatal and Perinatal Conditions
Keywords
Omega-3, Fatty acids, Preterm infants, Bronchopulmonary dysplasia, Individual participant data meta-analysis

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
The prior systematic review included a meta-analysis of aggregated data of trials that examined the effects of an enteral supplementation with high-dose DHA during the neonatal period on the risk for BPD (any definition), death, BPD severity (any definition) and a combined outcome of BPD or death in preterm infants born less than 29 weeks of gestation. Information on data sources (searched up to August 1st, 2022), search strategy, selection process, data extraction and risk of bias assessment were detailed in the prior protocol and publication. All four trials included in the prior systematic review will be considered for inclusion in this IPD meta-analysis. Upon the early period of selecting studies for the prior systematic review, the principal investigator (IM) has contacted the primary author of trials for potential agreement to share de-identified IPD for the purpose of this participant-level meta-analysis. All IPD datasets will be harmonised and combined into one large dataset.
Allocation
Randomized
Enrollment
1801 (Actual)

8. Arms, Groups, and Interventions

Arm Title
High-dose DHA
Arm Type
Experimental
Arm Description
Enteral supplementation with high-dose DHA in the neonatal period.
Arm Title
Control
Arm Type
Placebo Comparator
Arm Description
Control.
Intervention Type
Dietary Supplement
Intervention Name(s)
High-dose DHA
Intervention Description
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.
Intervention Type
Dietary Supplement
Intervention Name(s)
Control
Intervention Description
Control with no or low-dose DHA.
Primary Outcome Measure Information:
Title
Severe BPD
Description
A priori defined based on a team consensus, grades of severity (no BPD, grade 1-, 2-, 3-BPD) are defined on the mode of respiratory support at 36 weeks' PMA, regardless of prior or current oxygen therapy according to Jensen's criteria. Infants will be classified as severe BPD (Yes) if they presented a "grade 2- or 3-BPD" at 36 weeks' PMA, the two most severe grades of BPD according to Jensen's classification. Grade 2 is defined as respiratory support with nasal cannula >2 L/min ("high" flow) or noninvasive positive airway pressure (including nasal intermittent positive pressure ventilation or nasal continuous positive airway pressure). Grade 3 is defined as use of invasive mechanical ventilation. Infants will be classified as not severe BPD (No) if they presented "no BPD or grade 1-BPD" at 36 weeks' PMA. No BPD is defined as no support. Grade 1 is defined as respiratory support with nasal cannula ≤2 L/min ("low" flow).
Time Frame
At 36 weeks' PMA
Secondary Outcome Measure Information:
Title
"Grade 2- or 3-BPD or death"
Description
Mortality is defined as death from any cause before 36 weeks' PMA and "Grade 2- or 3-BPD" is defined using Jensen's classification as previously described.
Time Frame
At 36 weeks' PMA
Title
Severity grades of BPD
Description
Defined as no BPD, grade 1-, 2- or 3-BPD according to Jensen's criteria as previously described.
Time Frame
At 36 weeks' PMA
Title
Mortality
Description
Defined as death from any cause.
Time Frame
Up to 36 weeks' PMA
Other Pre-specified Outcome Measures:
Title
Rate of serious brain injury
Description
Defined as intraventricular hemorrhage of grade 3 or 4 or periventricular leukomalacia.
Time Frame
Up to 40 weeks' PMA
Title
Rate of severe retinopathy of prematurity (ROP)
Description
Defined as unilateral or bilateral ROP of stages 4 or 5 or any stage of ROP requiring any treatment.
Time Frame
Up to 40 weeks' PMA
Title
Neonatal morbidity count
Description
Including "grade 2- or 3-BPD", serious brain injury and severe ROP. A score from 0 to 3 will be attributed according to the presence or absence of each morbidity.
Time Frame
Up to 40 weeks' PMA
Title
Rate of patent ductus arteriosus
Description
Defined as any patent ductus arteriosus requiring surgical treatment.
Time Frame
Up to 40 weeks' PMA
Title
Rate of necrotising enterocolitis
Description
Defined as any necrotising enterocolitis requiring surgery.
Time Frame
Up to 40 weeks' PMA
Title
Rate of culture-proven sepsis
Description
Defined as any episode of sepsis confirmed by positive blood culture and requiring antibiotics for therapeutic intent.
Time Frame
Up to 40 weeks' PMA
Title
Child's weight
Description
Child anthropometry (i.e. weight in grams).
Time Frame
Up to 36 weeks' PMA
Title
Child's length
Description
Child anthropometry (i.e. length in cm).
Time Frame
Up to 36 weeks' PMA
Title
Child's head circumference
Description
Child anthropometry (i.e. head circumference in cm).
Time Frame
Up to 36 weeks' PMA

10. Eligibility

Sex
All
Maximum Age & Unit of Time
14 Weeks
Accepts Healthy Volunteers
Accepts Healthy Volunteers
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Isabelle Marc, MD, PhD
Organizational Affiliation
CHU de Québec-Université Laval
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Pascal M. Lavoie, MD, PhD
Organizational Affiliation
University of British Columbia
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Andrew J. McPhee, MB, BS
Organizational Affiliation
South Australian Health and Medical Research Institute
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Carmel T. Collins, PhD
Organizational Affiliation
South Australian Health and Medical Research Institute
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
David Simonyan, MSc
Organizational Affiliation
CHU de Québec-Université Laval
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Etienne Pronovost, BSc
Organizational Affiliation
CHU de Québec-Université Laval
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Mireille Guillot, MD
Organizational Affiliation
CHU de Québec-Université Laval
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Jacqueline F. Gould, PhD
Organizational Affiliation
South Australian Health and Medical Research Institute
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Ibrahim Mohamed, MD, PhD
Organizational Affiliation
St. Justine's Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Marc Beltempo, MD
Organizational Affiliation
McGill University Health Centre/Research Institute of the McGill University Health Centre
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Amélie Boutin, PhD
Organizational Affiliation
CHU de Québec-Université Laval
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Isabel Fortier, PhD
Organizational Affiliation
Research Institute of the McGill University Health Centre
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Thomas R. Sullivan, PhD
Organizational Affiliation
South Australian Health and Medical Research Institute
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Lynne Moore, PhD
Organizational Affiliation
Laval University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Maria Makrides, PhD
Organizational Affiliation
South Australian Health and Medical Research Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
CHU de Québec-Université Laval
City
Québec
State/Province
Quebec
ZIP/Postal Code
G1V 4G2
Country
Canada

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
There are currently no plan to share IPD obtained during this IPD meta-analysis. However, principal investigators will examine request from any groups for future collaboration.
Citations:
PubMed Identifier
36253040
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.
Results Reference
background
PubMed Identifier
36943265
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.
Results Reference
background
PubMed Identifier
30995069
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.
Results Reference
background
PubMed Identifier
305471
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.
Results Reference
background
PubMed Identifier
12622582
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.
Results Reference
background

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Enteral High-dose DHA Supplementation on Bronchopulmonary Dysplasia in Very Preterm Infants: a Collaborative Study

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