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

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

Official Title
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Atosiban Versus Placebo in the Treatment of Late Threatened Preterm Birth

Conditions
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Preterm Birth

Intervention / Treatment
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* Drug: Atosiban


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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
Interventional Model Description: International, multicenter, double blinded, placebo controlled RCT
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: atosiban<br>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<br>* 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.<br>* Other names: Tractocile;|
| Placebo Comparator: placebo<br>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<br>* 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.<br>* Other names: Tractocile;|

What is the study measuring?
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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 within 48 hours |  | 48 hours | 
| Time to delivery |  | Not applicible | 
| Gestational age at delivery |  | At birth | 
| Birth weight |  | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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preterm birth, threatened preterm birth, preterm labour, atosiban, adverse neonatal outcome