Clinical trial NCT02897076: Dose Reduction of Antenatal Betamethasone Given to Prevent the Neonatal Complications Associated With Very Preterm Birth
Official title: Dose Reduction of Antenatal Betamethasone Given to Prevent the Neonatal Complications Associated With Very Preterm Birth: a Randomized, Multicentre, Double Blind Placebo-controlled Non Inferiority Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Neonatal Complications
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2016-09-13
Enrollment: 3250
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Extensive animal studies have indicated that antenatal betamethasone exposure results in altered developmental trajectories of several fetal systems. Follow up of a randomized controlled trial has shown that antenatal betamethasone exposure might result in insulin resistance 30 years later. Furthermore, animal studies and randomized trials in Humans have clearly demonstrated that betamethasone-induced growth alterations were dose-related.

In ewes, a 50% reduced dose regimen resulted in maximal improvement in preterm lamb lung function, similar to those obtained after a full dose.

Our hypothesis is that antenatal betamethasone after a 50% dose reduction, justified by the potential long term effects of this drug, is not inferior to a full dose to promote fetal lung maturation in Humans.

Detailed description: The BETADOSE project consist in a randomized, multicenter, double blind placebo-controlled non inferiority trial comparing a standard dose regimen (24 mg) to a reduced dose regimen (12 mg) of betamethasone given to prevent the neonatal complications associated with very preterm birth.A betamethasone course consists in 2 injections of 12 mg betamethasone 24 hours apart for a total dose of 24 mg.

The first injection will be unmasked in both group. In both group, women will receive a first 12 mg injection of betamethasone according to local protocols.

Randomization will be performed after the first injection. Women will then receive either a placebo injection (reduced dose regimen, 12 mg only from the first injection) or a second 12 mg betamethasone injection (standard dose regimen, 12 mg from the first injection and 12 mg from the second injection=24 mg). This protocol allows women sent from level 1 and 2 to level 3 perinatal centers after having already received their first injection to participate.

In case of multiple antenatal betamethasone courses, women will receive their second course according to the same design as in their first course.

Eligibility criteria: Inclusion Criteria:

* Singleton pregnancy
* Patient Having receipt the first injection of betamethasone and pregnancy term \< 32 weeks of gestation
* Age \> 18 years
* Patient affiliated to a social security regime

Exclusion Criteria:

* Chromosomal aberrations and major fetal malformations
* Cervical dilatation ≥ 4 cm and of cervical length ≥20mm.
* Patient who have already received a first course of betamethasone
* first intravenous injection of betamethasone

Primary outcomes:
measure: severe RDS defined as need for exogenous intra-tracheal surfactant in the first 48 hours of life
timeFrame: 48 hours of life
Secondary outcomes:
measure: highest appropriate fractional inspired oxygen (FiO2)
timeFrame: 48 hours of life
measure: maximum appropriate Mean Airway Pressure (MAP)
timeFrame: 48 hours of life
measure: duration of mechanical ventilation
timeFrame: 36 weeks post conception
measure: duration of oxygen therapy
timeFrame: 36 weeks post conception
measure: oxygen therapy
timeFrame: 36 weeks post conception
measure: neonatal death
timeFrame: 36 weeks post conception
measure: admission to neonatal intensive care unit
timeFrame: 36 weeks post conception
measure: inotropic support
timeFrame: 36 weeks post conception
measure: air leak syndrome
timeFrame: 36 weeks post conception
measure: patent ductus arteriosus
timeFrame: 36 weeks post conception
measure: necrotising enterocolitis
timeFrame: 36 weeks post conception
measure: intraventricular hemorrhage and grade
timeFrame: 36 weeks post conception
measure: periventricular leukomalacia
timeFrame: 36 weeks post conception
measure: use of postnatal steroids
timeFrame: 36 weeks post conception
measure: retinopathy of prematurity
timeFrame: 36 weeks post conception
measure: length of hospital stay
timeFrame: 36 weeks post conception
measure: early onset sepsis
timeFrame: 36 weeks post conception
measure: Composite endpoint of any of the 4 prematurity-induced complications related to the use of betamethasone
timeFrame: 36 weeks post conception
Other outcomes:
Locations:
city: Paris
country: France
facility: Hôpital Robert Debré
Study officials:
affiliation: APHP
name: Schmitz Thomas, PHD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpitaux Universitaires de Genève - Inserm U1141 Hôpital Robert Debré
name: Baud Olivier, PHD
role: STUDY_CHAIR
References:
citation: Schmitz T, Alberti C, Ursino M, Baud O, Aupiais C; BETADOSE study group and the GROG (Groupe de Recherche en Gynecologie Obstetrique). Full versus half dose of antenatal betamethasone to prevent severe neonatal respiratory distress syndrome associated with preterm birth: study protocol for a randomised, multicenter, double blind, placebo-controlled, non-inferiority trial (BETADOSE). BMC Pregnancy Childbirth. 2019 Feb 12;19(1):67. doi: 10.1186/s12884-019-2206-x.
citation: Aupiais C, Alberti C, Schmitz T, Baud O, Ursino M, Zohar S. A Bayesian non-inferiority approach using experts' margin elicitation - application to the monitoring of safety events. BMC Med Res Methodol. 2019 Sep 18;19(1):187. doi: 10.1186/s12874-019-0826-5.
citation: Schmitz T, Doret-Dion M, Sentilhes L, Parant O, Claris O, Renesme L, Abbal J, Girault A, Torchin H, Houllier M, Le Sache N, Vivanti AJ, De Luca D, Winer N, Flamant C, Thuillier C, Boileau P, Blanc J, Brevaut V, Bouet PE, Gascoin G, Beucher G, Datin-Dorriere V, Bounan S, Bolot P, Poncelet C, Alberti C, Ursino M, Aupiais C, Baud O; BETADOSE trial study group; Groupe de Recherche en Obstetrique et Gynecologie. Neonatal outcomes for women at risk of preterm delivery given half dose versus full dose of antenatal betamethasone: a randomised, multicentre, double-blind, placebo-controlled, non-inferiority trial. Lancet. 2022 Aug 20;400(10352):592-604. doi: 10.1016/S0140-6736(22)01535-5.