BETANINO (BETAmethasone dose reduction: Non-Inferiority on the Neurocognitive Outcomes
of children born before 32 weeks of gestation).
3-year follow-up of the BETADOSE trial: Non-inferiority of a 50% dose reduction of antenatal betamethasone therapy on the neurodevelopment of children born before 32 weeks of gestation
Coordinating Investigator: : Pr Valérie BIRAN, service de neonatologie, Hôpital Robert Debré, PARIS (AP-HP)
Scientific Directors: Pr Olivier BAUD, service de néonatologie, maternité Port-Royal, Hôpital Cochin, Paris and Pr Thomas SCHMITZ
Departement d’Obstetrique et de Gynécologie Hôpital Robert Debré, PARIS
Sponsor : Assistance Publique – Hôpitaux de Paris
Scientific justification :
Maternal antenatal corticosteroid therapy is the last major advance in the antenatal management of fetuses to prevent neonatal complications associated with prematurity. Long-term neurological outcomes in infants exposed to antenatal steroids have been
assessed in few cohorts and suggest that this therapy is able to prevent some neurodevelopmental impairments including cerebral
palsy. While >85% of neonates born very preterm in Europe have been exposed to antenatal betamethasone, Cochrane collaborative networks stated that trials of dosages comparing different regimens of commonly used corticosteroids are most urgently needed to avoid useless fetal exposure to excessive dosage of corticosteroids.
Because a half dosage was associated with maximal benefits on lung function in ewes, a randomized controlled trial (BETADOSE,
NCT02897076) is currently conducted to demonstrate that a 50% reduced betamethasone dose regimen is not inferior to a full dose
to prevent respiratory distress syndrome in preterm neonates. Follow-up of infants born from enrolled women is mandatory both
to investigate the long-term effect of dose reduction and to confirm the non-inferiority of the dose reduction on neurocognition.
The main hypothesis of BETANINO is that half dose regimen of betamethasone is not inferior to full dose regimen of betamethasone to prevent neurodevelopmental impairments in these high-risk children born very preterm.
Primary objective and assessment criterion
Primary objective: To demonstrate the non-inferiority of a 50% dose reduction of antenatal betamethasone, compared to a full dose, on cognition at 3 years of age in children born before 32 weeks of gestation.
Primary assessment criterion: Cognition will be assessed by certified neuropsychologists at 3 years of age using full scale IQ generated by Wechsler Preschool and Primary Scale of Intelligence (WPPSI-IV) test.
Secondary objectives and assessment criteria
ETo assess the effect of a 50% dose reduction of antenatal betamethasone compared to a full dose, on:
- 3-year survival without moderate-to-severe impairment,,
- Multiple aspects of cognition using ancillary indexes of WPPSI-IV subtests, NEPSY subtests and KABC-II (Kaufman Assessment Battery for Children II) subtests,
- Social Relativeness, using Social Relativeness Scale parental questionnaire,
- lParental stress using PSI questionnaire,
- Other neurodevelopmental impairments:
- Cerebral palsy using GMFCS scoring system,
- Blindness
- Deafness
- Seizures.
All assessments will be based on internationally recognized tests that have been validated for infants at 3 years of age and conducted by certified neuropsychologists.
- Morphometric measurements including height, weight, head circumference
- Blood pressure measurement
Experimental design
Prospective cohort study (following the BETADOSE non inferiority randomized controlled trial).
Population involved
Premature children at 3 years of age.
Inclusion criteria
- Singleton child born from mother enrolled in the BETADOSE trial,
- Gestational age at birth less than 32 weeks of gestation,
- Age between 41 months and 47 months, alive and not lost of follow up
- Informed consent of the holder (s) of the exercise of parental authority
- Affiliation to a social security scheme.
Non inclusion criteria
- Major malformations and chromosomal aberrations evidenced after birth,
- Parents’ refuse to participate.
Interventions
As part of the usual follow-up of premature children, a follow-upconsultation is planned around the age of 3 years. During this visit,a neurodevelopmental assessment will be carried out for theBetanino study. The duration of this evaluation is evaluated around 3h in total. This assessment will take place either in paediatrics service or in a clinical investigation centre that manages the study in the region.
Interventions will include:
- Santardized neurological exam
- Morphometric measurements including height, weight, head circumference
- Blood pressure measurement
- Multiple aspects of cognition using ancillary indexes of
- WPPSI-IV subtests, NEPSY subtests and KABC-II (Kaufman Assessment Battery for Children II) subtests,
- Social Relativeness, using Social Relativeness Scale parental questionnaire
- Parental stress using PSI questionnaire
Expected benefits for the participants and for society
No foreseeable benefits are expected for the research participants. However, advanced assessments of neurodevelopmental outcomes as planned in BETANINO study could have indirect beneficial impact on the developmental support of children.
Minimal risks and constraints added by the study
This follow-up study does not add any supplementary risks to the child’s usual care. The only constraint is the day of the assessment.
Scope of the study
The BETANINO cohort will follow at 3 years of age children born before 32 weeks of gestation from women enrolled in the BETADOSE trial started in January 2017. First patients to be assessed will be aged 3 years on January 2020.
Two main phases are planned in the BETANINO study and described in the Procedure for the Research below:
1)Preparation phase:
- to track eligible patients up to 3 years of age every 6 months (by clinical technician),
- to inform parents about BETANINO protocol during standard visit at 2 years of age (by a physician),
- to notify list of patients to be assessed in each reference perinatal outcome centers
- to confirm the date of the assessment visit few weeks before the age of 3 years (by clinical technician)
2) Assessment phase after verifying the non-opposition of parents: children eligible for the BETANINO study will be assessed by the
regional perinatal health networks using a standardized neurological, visual and auditory examinations, neuropsychological tests and questionnaires about patient’s status, parental behavior and status filled in by either the parents, paediatricians or certified neuropsychologists.
The inclusion in the BETANINO study will be undergone without un-blinding.
Number of subjects chosen
786
Number of centers
41 including 6 CIC
Schedule of the study
Duration of recruitment : 36 months +/- 3 months
Duration of participation of each patient : 1 day
Total duration of research: 39 months.
Number of inclusions expected per center and per month
2 à 6 inclusions per center and per month depending on center size and perinatal regional recruitment.
Statistical analysis
The statistical analysis will be performed after termination of inclusions on all neonates enrolled in the cohort. The difference between full scale IQ generated by WPPSI-IV observed in both arms along with its 2-sided 95% confidence interval (equivalent to a 1-sided 97.5% confidence interval) will be estimated. A 50% reduced regimen (12 mg) would not be found inferior to standard regimen if the upper limit of the confidence interval will not exceed 3 (the so-called non-inferiority margin).
- In a first analysis, the 95% confidence interval will be estimated in a crude analysis (without any adjustments)
- Secondary, to improve the accuracy of the estimates and to take into account potential unbalanced caracteristics between groups of the cohort, the 95% confidence interval will be estimated in a covariance model with the Full scale IQ as dependent variable (ANCOVA model with baseline characteristics; no interaction).
If the 95% confidence interval (both in ITT and PP analysis) for the difference between Full scale IQ not only lies entirely below the non-inferiority margin but also below zero, the p-value associated with a test of superiority will be calculated in order to evaluate if the 50% reduced dose regimen is superior to the full dose regimen.
Source de financement
Ministère de la Santé, PHRC 2017