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

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

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.

Study Overview

• Status: Completed
• Conditions: Neonatal Complications
• Intervention / Treatment: Drug: betamethasone 24 mg; Drug: 12mg betamethasone +placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 3250
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Paris, France, 75019
    • Hopital Robert Debre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: 12mg betamethasone+12mg betamethasone; 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
PLACEBO_COMPARATOR: 12 mg betamethasone+ placebo; 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Schmitz Thomas, PHD, APHP

Publications and helpful links

General Publications

• 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.
• 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.
• 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. Erratum In: Lancet. 2022 Oct 22;400(10361):1404.

Study record dates

Study Major Dates

• Study Start: January 1, 2017
• Primary Completion (ACTUAL): January 5, 2020
• Study Completion (ACTUAL): January 5, 2020

Study Registration Dates

• First Submitted: September 7, 2016
• First Submitted That Met QC Criteria: September 7, 2016
• First Posted (ESTIMATE): September 13, 2016

Study Record Updates

• Last Update Posted (ACTUAL): February 3, 2023
• Last Update Submitted That Met QC Criteria: February 1, 2023
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Premature Birth; Physiological Effects of Drugs; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Anti-Asthmatic Agents; Respiratory System Agents; Betamethasone; Betamethasone Valerate; Betamethasone-17,21-dipropionate; Betamethasone benzoate; Betamethasone sodium phosphate
• Other Study ID Numbers: P150944

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO