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

Atosiban Versus Placebo in the Treatment of Late Threatened Preterm Birth

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.

Study Overview

• Status: Completed
• Conditions: Preterm Birth
• Intervention / Treatment: Drug: Atosiban

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 Type: Interventional
• Enrollment (Actual): 760
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Noord-Holland
    • Amsterdam, Noord-Holland, Netherlands, 1105 AZ
      • Amsterdam University Medical Centres, location AMC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse neonatal outcome	Combination perinatal mortality and severe neonatal morbidity (BPD, NEC, ROP, IVH, PVL, sepsis,	Up to 3 months corrected age

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Birth weight		At birth
Birth within 48 hours		48 hours
Time to delivery		Not applicible
Gestational age at delivery		At birth
Mechanical ventilation	Number of days on invasive ventilation	Up to 3 months corrected age
NICU	Lengt of admission in NICU	Up to 3 months corrected age
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

Outcome Measure	Time Frame
Costs	Up to 3 months corrected age

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Collaborators: Radboud University Medical Center; University Medical Center Groningen; Maastricht University Medical Center; UMC Utrecht; Erasmus Medical Center; Nottingham University Hospitals NHS Trust; St. Antonius Hospital; Leiden University Medical Center; ZonMw: The Netherlands Organisation for Health Research and Development; Medical Centre Leeuwarden; Franciscus Gasthuis; Maxima Medical Center; Rijnstate Hospital; Diakonessenhuis, Utrecht; Groene Hart Ziekenhuis; Flevoziekenhuis; National Maternity Hospital, Ireland; Spaarne Gasthuis; OLVG; Deventer Ziekenhuis; Isala; Ziekenhuisgroep Twente; Zuyderland Medical Centre; Martini Hospital Groningen; Gelre Hospitals; Medisch Spectrum Twente; Amphia Hospital; Tergooi Hospital; Haaglanden Medical Centre

Publications and helpful links

General Publications

• Klumper J, Breebaart W, Roos C, Naaktgeboren CA, van der Post J, Bosmans J, van Kaam A, Schuit E, Mol BW, Baalman J, McAuliffe F, Thornton J, Kok M, Oudijk MA. Study protocol for a randomised trial for atosiban versus placebo in threatened preterm birth: the APOSTEL 8 study. BMJ Open. 2019 Nov 26;9(11):e029101. doi: 10.1136/bmjopen-2019-029101. Erratum In: BMJ Open. 2022 Oct 21;12(10):e029101corr1. doi: 10.1136/bmjopen-2019-029101corr1.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2017
• Primary Completion (Actual): February 29, 2024
• Study Completion (Actual): February 29, 2024

Study Registration Dates

• First Submitted: January 12, 2023
• First Submitted That Met QC Criteria: January 12, 2023
• First Posted (Actual): January 23, 2023

Study Record Updates

• Last Update Posted (Actual): July 25, 2024
• Last Update Submitted That Met QC Criteria: July 24, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: preterm labour; preterm birth; atosiban; threatened preterm birth; adverse neonatal outcome
• Additional Relevant MeSH Terms: Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Premature Birth; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Reproductive Control Agents; Tocolytic Agents; Atosiban
• Other Study ID Numbers: NL80-84800-98-41027

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No