Clinical trial NCT01429545: Single Versus Combination Therapy in Acute Tocolysis
Official title: Phase 2 Study of Clinical Utility of Combination Tocolysis in Preterm Labor
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Preterm Labour
Keywords: Tocolysis
atosiban
nifedipine
combination
Lead sponsor: Tawam Hospital
Sponsor class: OTHER
First posted: 2011-09-07
Enrollment: 110
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants with Adverse Events as a Measure of Safety and Tolerability
timeFrame: Participants will be followed for the duration of pregnancy, an expected average of 10 weeks
measure: Number of women undelivered 48 hrs and seven days of initiation of therapy
timeFrame: Participants who are not delivered within seven days of initiation of therapy
measure: Number of Babies with Adverse Events as a Measure of Safety and Tolerability
timeFrame: participants will be followed for the duration of hospital stay, an expected average of 7 weeks
Secondary outcomes:
measure: Prolongation of pregnancy
timeFrame: Assessed till the date of delivery, an expected average of 10 weeks
measure: Neonatal intensive care unit (NICU) admission
timeFrame: Till the time of discharge, an expected avearge of 7 weeks
Other outcomes:
Locations:
city: Al Ain
country: United Arab Emirates
facility: Department of obstetrics and Gynecology, Tawam Hospital
state: Abudhabi
city: Al Ain
country: United Arab Emirates
facility: Tawam Hospital
state: Abudhabi
Study officials:
affiliation: Tawam Hospital
name: Wafa R AlOmari
role: PRINCIPAL_INVESTIGATOR
References:
citation: Vogel JP, Nardin JM, Dowswell T, West HM, Oladapo OT. Combination of tocolytic agents for inhibiting preterm labour. Cochrane Database Syst Rev. 2014 Jul 11;2014(7):CD006169. doi: 10.1002/14651858.CD006169.pub2.
citation: Doret M, Mellier G, Gaucherand P, Saade GR, Benchaib M, Frutoso J, Pasquier JC. The in vitro effect of dual combinations of ritodrine, nicardipine and atosiban on contractility of pregnant rat myometrium. BJOG. 2003 Aug;110(8):731-4.
citation: Wilson A, Hodgetts-Morton VA, Marson EJ, Markland AD, Larkai E, Papadopoulou A, Coomarasamy A, Tobias A, Chou D, Oladapo OT, Price MJ, Morris K, Gallos ID. Tocolytics for delaying preterm birth: a network meta-analysis (0924). Cochrane Database Syst Rev. 2022 Aug 10;8(8):CD014978. doi: 10.1002/14651858.CD014978.pub2.