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

• ClinicalTrials.gov Identifier: NCT02897076
• Recruitment Status: Completed
• First Posted: September 13, 2016
• Last Update Posted: February 3, 2023
• Sponsor: Assistance Publique - Hôpitaux de Paris
• Information provided by (Responsible Party): Assistance Publique - Hôpitaux de Paris

Tracking Information

• First Submitted Date: September 7, 2016
• First Posted Date: September 13, 2016
• Last Update Posted Date: February 3, 2023
• Study Start Date: January 2017
• Actual Primary Completion Date: January 5, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 7, 2016)

severe RDS defined as need for exogenous intra-tracheal surfactant in the first 48 hours of life [ Time Frame: 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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: October 7, 2016)

• highest appropriate fractional inspired oxygen (FiO2) [ Time Frame: 48 hours of life ]
• maximum appropriate Mean Airway Pressure (MAP) [ Time Frame: 48 hours of life ]
• duration of mechanical ventilation [ Time Frame: 36 weeks post conception ]
• duration of oxygen therapy [ Time Frame: 36 weeks post conception ]
• oxygen therapy [ Time Frame: 36 weeks post conception ]
• neonatal death [ Time Frame: 36 weeks post conception ]
• admission to neonatal intensive care unit [ Time Frame: 36 weeks post conception ]
• inotropic support [ Time Frame: 36 weeks post conception ]
• air leak syndrome [ Time Frame: 36 weeks post conception ]
• patent ductus arteriosus [ Time Frame: 36 weeks post conception ]
• necrotising enterocolitis [ Time Frame: 36 weeks post conception ]
• intraventricular hemorrhage and grade [ Time Frame: 36 weeks post conception ]
• periventricular leukomalacia [ Time Frame: 36 weeks post conception ]
• use of postnatal steroids [ Time Frame: 36 weeks post conception ]
• retinopathy of prematurity [ Time Frame: 36 weeks post conception ]
• length of hospital stay [ Time Frame: 36 weeks post conception ]
• early onset sepsis [ Time Frame: 36 weeks post conception ]
• Composite endpoint of any of the 4 prematurity-induced complications related to the use of betamethasone [ Time Frame: 36 weeks post conception ]
  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.

Original Secondary Outcome Measures (submitted: September 7, 2016)

• highest appropriate fractional inspired oxygen (FiO2) [ Time Frame: 48 hours of life ]
• maximum appropriate Mean Airway Pressure (MAP) [ Time Frame: 48 hours of life ]
• duration of mechanical ventilation [ Time Frame: 36 weeks post conception ]
• duration of oxygen therapy [ Time Frame: 36 weeks post conception ]
• oxygen therapy [ Time Frame: 36 weeks post conception ]
• neonatal death [ Time Frame: 36 weeks post conception ]
• admission to neonatal intensive care unit [ Time Frame: 36 weeks post conception ]
• inotropic support [ Time Frame: 36 weeks post conception ]
• air leak syndrome [ Time Frame: 36 weeks post conception ]
• patent ductus arteriosus [ Time Frame: 36 weeks post conception ]
• necrotising enterocolitis [ Time Frame: 36 weeks post conception ]
• intraventricular hemorrhage and grade [ Time Frame: 36 weeks post conception ]
• periventricular leukomalacia [ Time Frame: 36 weeks post conception ]
• use of postnatal steroids [ Time Frame: 36 weeks post conception ]
• retinopathy of prematurity [ Time Frame: 36 weeks post conception ]
• length of hospital stay [ Time Frame: 36 weeks post conception ]
• early onset sepsis [ Time Frame: 36 weeks post conception ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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

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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Neonatal Complications

Intervention

• Drug: betamethasone 24 mg
• Drug: 12mg betamethasone +placebo

Study Arms

• 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).

  Intervention: 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).

  Intervention: Drug: 12mg betamethasone +placebo

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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 17, 2019): 3250
• Original Estimated Enrollment (submitted: September 7, 2016): 3142
• Actual Study Completion Date: January 5, 2020
• Actual Primary Completion Date: January 5, 2020 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years to 60 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France

Administrative Information

• NCT Number: NCT02897076
• Other Study ID Numbers: P150944
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Assistance Publique - Hôpitaux de Paris
• Original Responsible Party: Same as current
• Current Study Sponsor: Assistance Publique - Hôpitaux de Paris
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Schmitz Thomas, PHD; APHP
• Study Chair: Baud Olivier, PHD; Hôpitaux Universitaires de Genève - Inserm U1141 Hôpital Robert Debré

• PRS Account: Assistance Publique - Hôpitaux de Paris
• Verification Date: April 2020