Single Versus Combination Therapy in Acute Tocolysis

Study Overview
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Brief Summary
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The purpose of this study is to compare the tocolytic efficacy, effectiveness and safety of Atosiban in comparison with the combination of Atosiban and Nifedipine together.

Detailed Description
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Preterm birth, defined as birth at less than 37+0 weeks of gestation, is the most important determinant of adverse infant outcomes. It accounts for 5 to 11% of births in the world, but represents the single largest cause of mortality and morbidity for newborns and a major cause of morbidity for pregnant women. These babies are at increased risk of cerebral palsies, chronic pulmonary insufficiency and other handicaps resulting in suboptimal performance in school and decreased abstractive thinking compared with infants born at term. The economic burden on society in catering for these preterm babies is high. A multi-level modeling of hospital service utilization and cost profile of preterm birth done in 2005 in the United Kingdom, has outlined the huge economic consequences of preterm birth in the first 10 years of life. Furthermore, recent data from Denmark have shown an overall increase in the proportion of preterm deliveries by 22% from 1995 to 2004(from 5.2% to 6.3%). Neonatal mortality has declined, mostly due to improved management of very low birth weight babies rather than prevention of preterm labor (PTL). The most common treatment used in the management of PTL involves pharmacological inhibition of preterm uterine contractions. Perinatal death and morbidity resulting from PTL are not only strongly related to early gestational age but also to antenatal administration of steroids and transfer to a tertiary care centre in utero or after birth.6 Hence, the choice of tocolytic agent depends on its ability to delay the delivery by at least 48 hours from the time of administration of steroids and preferably longer without maternal or fetal side effects. There is considerable variation in the type of tocolytic agent used in different parts of the world. Single agent tocolysis using ritodrine (β-agonist), atosiban (oxytocin antagonist) or nifedipine (calcium channel blocker) is a common practice. Atosiban has been shown to have comparable effectiveness to β-agonists but with improved side-effect profile similar to that seen in placebo studies. Meta analysis from Cochrane systematic review failed to demonstrate the superiority of atosiban over betamimetics or placebo in terms of tocolytic efficacy or infant outcomes, but, the maternal drug reactions that required treatment cessation were fewer with atosiban. Nifedipine is the only agent associated with improved perinatal outcomes and fewer maternal side-effects than betamimetics. A direct comparison between atosiban and nifedipine has shown that both drugs are equally effective in acute tocolysis, however maternal side-effects were more pronounced with nifedipine. Due to the differences in their pharmacokinetics and pharmacodynamics, one may expect to have improved tocolysis when two agents are combined. In vitro studies have demonstrated that simultaneous blockade of these different pathways could result in an additive or even synergistic effect capable of producing better uterine relaxation than induced by each drug alone. Accordingly, the use of multiple agent therapies has been suggested as a way forward in tocolytic search. In an observational study, combination therapy without serious side effects has been used in the management of PTL at extremely early gestations by Ingemarsson et al.3 However, this was not tested in structured human trials. The objective of this study was to compare the tocolytic efficacy and safety of the combination of atosiban and nifedipine against the single agent, atosiban in the treatment of PTL.

Official Title
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Phase 2 Study of Clinical Utility of Combination Tocolysis in Preterm Labor

Conditions
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Preterm Labour

Intervention / Treatment
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* Drug: Atosiban
* Drug: Atosiban and nifedipine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis of preterm labour Women with singleton pregnancies Exclusion Criteria: Women with preterm prelabour rupture of membranes Women with any indication for emergency delivery for whom prolongation of pregnancy is contraindicated

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group 1 - Atosiban<br>Patients on single agent atosiban alone | Drug: Atosiban<br>* Atosiban was given as a bolus (6.7 mg. IV) over 1 min then an infusion of 18 mg/hr for 3 hrs followed by 6 mg/hr for 48 hrs.<br>* Other names: Tractocile;|
| Experimental: Group 2<br>Patients on combination of atosiban and nifedipine | Drug: Atosiban and nifedipine<br>* This group were given simultaneously as follows:Atosiban was given as a bolus (6.7 mg. IV) over 1 min then an infusion of 18 mg/hr for 3 hrs followed by 6 mg/hr for 48 hrs.Nifedipine was given in the dose of 10 mg orally every 15 min till uterine quiescence was achieved (<4 contractions/hr). Maximum dose was 40 mg in the first hour then maintenance dose of 10 mg every 4-6 h for 48 hrs was given.<br>* Other names: Tractocile and nifedipine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Adverse Events as a Measure of Safety and Tolerability | Safety was assessed by maternal, fetal and neonatal adverse events. Particular emphasis was placed on serious adverse cardiovascular events, including cardiac arrest, respiratory arrest, admission to intensive care unit and death were assessed as serious maternal outcomes and perinatal complications were recorded by neonatal morbidity and mortality until discharge from the hospital | Participants will be followed for the duration of pregnancy, an expected average of 10 weeks | 
| Number of women undelivered 48 hrs and seven days of initiation of therapy | Tocolytic efficacy was assessed in terms of the proportion of women undelivered 48 hrs and seven days of initiation of therapy without the need for rescue tocolysis. | Participants who are not delivered within seven days of initiation of therapy | 
| Number of Babies with Adverse Events as a Measure of Safety and Tolerability | Safety was assessed by maternal, fetal and neonatal adverse events. Perinatal complications were recorded by neonatal morbidity and mortality until discharge from the hospital | participants will be followed for the duration of hospital stay, an expected average of 7 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prolongation of pregnancy |  | Assessed till the date of delivery, an expected average of 10 weeks | 
| Neonatal intensive care unit (NICU) admission | Number of neonates who are needing NICU admission after delivery. | Till the time of discharge, an expected avearge of 7 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tocolysis, atosiban, nifedipine, combination