Dose Reduction of Antenatal Betamethasone Given to Prevent the Neonatal Complications Associated With Very Preterm Birth

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Neonatal Complications

Intervention / Treatment
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* Drug: betamethasone 24 mg
* Drug: 12mg betamethasone +placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 12mg betamethasone+12mg betamethasone<br>A betamethasone course consists in 2 intramuscular injections of 12 mg betamethasone 24 hours apart for a total dose of 24 mg. In the BETADOSE trial, the first injection will be unmasked in both groups. In both groups, women will received a first 12 mg injection of betamethasone according to local protocols. Randomization will be performed after the first injection. Women will then received either a blinded placebo injection (50% reduced dose regimen, 12 mg only from the first injection) or a second blinded 12 mg betamethasone injection (standard full dose regimen, 12 mg from the first injection and 12 mg from the second injection=24 mg). | Drug: betamethasone 24 mg<br> <br> |
| Placebo Comparator: 12 mg betamethasone+ placebo<br>A betamethasone course consists in 2 intramuscular injections of 12 mg betamethasone 24 hours apart for a total dose of 24 mg. In the BETADOSE trial, the first injection will be unmasked in both groups. In both groups, women will received a first 12 mg injection of betamethasone according to local protocols. Randomization will be performed after the first injection. Women will then received either a blinded placebo injection (50% reduced dose regimen, 12 mg only from the first injection) or a second blinded 12 mg betamethasone injection (standard full dose regimen, 12 mg from the first injection and 12 mg from the second injection=24 mg). | Drug: 12mg betamethasone +placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| severe RDS defined as need for exogenous intra-tracheal surfactant in the first 48 hours of life | The primary assessment criterion is severe respiratory distress syndrome(RDS) defined as need for exogenous intra-tracheal surfactant in the first 48 hours of life. It is considered as a binary endpoint: failure if there is occurrence of RDS, or not failure. | 48 hours of life | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| highest appropriate fractional inspired oxygen (FiO2) |  | 48 hours of life | 
| maximum appropriate Mean Airway Pressure (MAP) |  | 48 hours of life | 
| duration of mechanical ventilation |  | 36 weeks post conception | 
| duration of oxygen therapy |  | 36 weeks post conception | 
| oxygen therapy |  | 36 weeks post conception | 
| neonatal death |  | 36 weeks post conception | 
| admission to neonatal intensive care unit |  | 36 weeks post conception | 
| inotropic support |  | 36 weeks post conception | 
| air leak syndrome |  | 36 weeks post conception | 
| patent ductus arteriosus |  | 36 weeks post conception | 
| necrotising enterocolitis |  | 36 weeks post conception | 
| intraventricular hemorrhage and grade |  | 36 weeks post conception | 
| periventricular leukomalacia |  | 36 weeks post conception | 
| use of postnatal steroids |  | 36 weeks post conception | 
| retinopathy of prematurity |  | 36 weeks post conception | 
| length of hospital stay |  | 36 weeks post conception | 
| early onset sepsis |  | 36 weeks post conception | 
| Composite endpoint of any of the 4 prematurity-induced complications related to the use of betamethasone | Related to betamethasone impact on other prematurity-induced complications, is a composite outcome taking into account multiple clinical events : neonatal death, severe RDS defined as need for exogenous intra-tracheal surfactant in the first 48 hours of life, intraventricular hemorrhage high grade, and necrotising enterocolitis. | 36 weeks post conception |