APOSTEL 8: Atosiban Versus Placebo in the Treatment of Late Threatened Pre-term Birth

Sponsor

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) (Other)

Overall Status

Recruiting

CT.gov ID

NCT05693688

Collaborator

ZonMw: The Netherlands Organisation for Health Research and Development (Other), Nottingham University Hospitals NHS Trust (Other), Amphia Hospital (Other), ST. Antonius hospital Nieuwegein (Other), Deventer Ziekenhuis (Other), Erasmus Medical Center (Other), Flevoziekenhuis (Other), Franciscus Gasthuis (Other), Gelre Hospitals (Other), Groene Hart Ziekenhuis (Other), Isala (Other), Leiden University Medical Center (Other), Martini Hospital Groningen (Other), Maxima Medical Center (Other), Medical Centre Leeuwarden (Other), Haaglanden Medical Centre (Other), Maastricht University Medical Center (Other), Medisch Spectrum Twente (Other), OLVG (Other), Radboud University Medical Center (Other), Rijnstate Hospital (Other), Spaarne Gasthuis (Other), Tergooi Hospital (Other), University Medical Center Groningen (Other), UMC Utrecht (Other), Diakonessenhuis, Utrecht (Other), Ziekenhuisgroep Twente (Other), Zuyderland Medical Centre (Other), National Maternity Hospital, Ireland (Other)

760

Enrollment

Location

Arms

Anticipated Duration (Months)

9.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The aim of this study is to investigate if tocolysis with atosiban in late preterm birth (30 to 34 weeks) is (cost-) effective compared with placebo in improving neonatal morbidity and mortality.

Condition or Disease	Intervention/Treatment	Phase
Preterm Birth	Drug: Atosiban	Phase 4

Detailed Description

Research question Does tocolysis with atosiban reduce neonatal mortality and mortality in women with threatened preterm birth between 30 and 34 weeks when compared to placebo?

Study design Multicenter, double blinded, placebo controlled RCT

Study population Women with threatened preterm birth between 30 and 34 weeks of gestation are eligible for the trial. More than 20 hospitals (including all 10 perinatal centres) in the Netherlands will participate in this trial, as well as 15 hospitals in the UK and 1 in Dublin, Ireland.

Threatened preterm birth is defined as listed below in the inclusion criteria. Our previous APOSTEL III study showed that half of the women with these criteria deliver within seven days, validating this definition of women at high risk for preterm birth.

Inclusion criteria

Women ≥ 18 years old
Singleton or twin pregnancy
Gestational age between 30 0/7 and 33 6/7 weeks
Threatened preterm birth defined by regular uterine contractions, AND one of the following:
Cervical length of < 15 mm OR
Cervical length of 15-30 mm and a positive Fibronectine test (≥ 50 ng/mL) OR
In case of absence of cervical length measurement in local protocol a positive Fibronectin test or Partus test OR
Ruptured amniotic membranes

Exclusion criteria

Previous treatment for threatened preterm birth with corticosteroids.
Contra-indication for tocolysis
Signs of fetal distress
Signs of intra uterine infection

Participants RCT: 760 (380 per group)

Description of intervention(s) Tocolysis with atosiban versus placebo.

Outcome measures The primary outcome is a combined perinatal outcome of severe neonatal morbidity and perinatal mortality Secondary outcomes will be birth within 48 hours, time to delivery, gestational age at delivery, birth weight, number of days on invasive mechanical ventilation, length of admission in NICU, convulsions, asphyxia, meningitis, pneumothorax and mortality until 3 months corrected age, maternal infection, maternal side effects and costs.

All outcomes are in the electronic patient file. No additional tests are required for mother or baby.

Power / data analysis Based on the APOSTEL 3 data, the proportion of adverse perinatal outcome in women randomized between 30 and 34 weeks gestation and treated with atosiban was 6%. Based on two recent studies, we expect a 49,8% reduction of 11,95% adverse perinatal outcome in the placebo group to 6% in the atosiban group. Therefore we need to randomize 722 women (beta-error 0.2; alpha error 0.05). Assuming a 5% drop-out rate, we need to randomize 760 women (380 in each arm).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

760 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

International, multicenter, double blinded, placebo controlled RCTInternational, multicenter, double blinded, placebo controlled RCT

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

Double blinded

Primary Purpose:

Treatment

Official Title:

Atosiban Versus Placebo in the Treatment of Late Threatened Preterm Birth

Actual Study Start Date :

Dec 1, 2017

Anticipated Primary Completion Date :

Jul 1, 2023

Anticipated Study Completion Date :

Jul 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: atosiban Atosiban: bolus injection of 6.75 mg/0.9 ml atosiban in one minute followed by a continuous infusion of 18 mg/hour (=24ml/hour) for 3 hours followed by a continuous infusion of 6 mg/hour (=8 ml/hour) for the remaining 45 hours.	Drug: Atosiban atosiban i.v. administred for 48 hours. The medication will be administered by a bolus injection of 6.75 mg/0.9 mL in 1 min followed by a continuous infusion of 18 mg/hour for 3 hours followed by a continuous infusion of 6 mg/hour for the remaining 45 hours. Other Names: Tractocile
Placebo Comparator: placebo Placebo: injection of 0.9 ml saline in one minute followed by a saline infusion for 3 hours (24 ml/hour) followed by a continuous infusion (8 ml/hour) for the remaining 45 hours.	Drug: Atosiban atosiban i.v. administred for 48 hours. The medication will be administered by a bolus injection of 6.75 mg/0.9 mL in 1 min followed by a continuous infusion of 18 mg/hour for 3 hours followed by a continuous infusion of 6 mg/hour for the remaining 45 hours. Other Names: Tractocile

Arm

Intervention/Treatment

Experimental: atosiban

Atosiban: bolus injection of 6.75 mg/0.9 ml atosiban in one minute followed by a continuous infusion of 18 mg/hour (=24ml/hour) for 3 hours followed by a continuous infusion of 6 mg/hour (=8 ml/hour) for the remaining 45 hours.

Drug: Atosiban

atosiban i.v. administred for 48 hours. The medication will be administered by a bolus injection of 6.75 mg/0.9 mL in 1 min followed by a continuous infusion of 18 mg/hour for 3 hours followed by a continuous infusion of 6 mg/hour for the remaining 45 hours.

Other Names:

Tractocile

Placebo Comparator: placebo

Placebo: injection of 0.9 ml saline in one minute followed by a saline infusion for 3 hours (24 ml/hour) followed by a continuous infusion (8 ml/hour) for the remaining 45 hours.

Drug: Atosiban

Other Names:

Tractocile

Outcome Measures

Primary Outcome Measures

Adverse neonatal outcome [Up to 3 months corrected age]
Combination perinatal mortality and severe neonatal morbidity (BPD, NEC, ROP, IVH, PVL, sepsis,

Secondary Outcome Measures

Birth within 48 hours [48 hours]
Time to delivery [Not applicible]
Gestational age at delivery [At birth]
Birth weight [At birth]
Mechanical ventilation [Up to 3 months corrected age]
Number of days on invasive ventilation
NICU [Up to 3 months corrected age]
Lengt of admission in NICU
Convulsions [Up to 3 months corrected age]
Asphyxia [Up to 3 months corrected age]
Meningitis [Up to 3 months corrected age]
Pneumothorax [Up to 3 months corrected age]
Maternal infection [Up to 3 months corrected age]
Maternal side effects [Up to 3 months corrected age]

Other Outcome Measures

Costs [Up to 3 months corrected age]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Women ≥ 18 years
Singleton or twin pregnancy
Gestational age between 30 0/7 and 33 6/7 weeks
Threatened preterm birth defined by regular uterine contractions, AND one of the following:
Cervical length of < 15 mm OR
Cervical length of 15-30 mm and a positive Fibronectine test (≥ 50 ng/mL) OR
In case of absence of cervical length measurement in local protocol a positive Fibronectin test or Partus test OR
Ruptured amniotic membranes

Exclusion Criteria:

Previous treatment for threatened preterm birth with corticosteroids in current pregnancy
Contra indication for tocolysis
Signs of fetal distress
Signs of intra uterine infection