Clinical trial NCT03129945
Conditions: Obstetric Labor, Premature
Keywords: Obstetric Labor, Premature Tocolytic Agents
Sponsor: University of California, Irvine
Start date: 2017-01-17; Completion date: 2019-04-18
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this research study is to determine the best medication to stop preterm labor. Recent studies have identify nifedipine and indomethacin as the two medications that are most likely to delay delivery for 48 hours, decrease maternal side effects and decrease some complications related to preterm delivery to the neonate. Both of these medications are commonly used to stop pre-term labor, therefore it has become our institution's standard to use these two medications in the setting of preterm labor. There have been limited studies comparing these two medications directly.

A total of 450 participants will be asked to participate across all study sites.

Detailed description:
There are about 10 million births that occur before 37 weeks (prior to full term gestation) that occur annually worldwide. More than 1 million infants die from complications related to preterm birth. Tocolytics, medications that stop preterm labor, have been well studied. Results regarding prolongation of pregnancy are varied, but tocolytics have been shown to delay delivery for 48 hours, allowing time to administer corticosteroids. ACOG (American Congress of Obstetrics and Gynecologists) recommends giving tocolytics to provide time for corticosteroid administration, transfer to tertiary level care and to allow for magnesium infusion to protect the neonatal brain. Corticosteroid administration when the course is completed (48 hours from first dose) decreases some of the major risks associated with prematurity.

Recent meta-analyses have shown of the commonly used tocolytics, calcium channel blockers and prostaglandin inhibitors ranked consistently among the top three medications in several categories including delaying delivery by 48 hours. There have been only two published randomized control studies to date that have directly compared these two tocolytics. These studies lacked power and standardization to provide clinical guidelines. There is a high neonatal mortality and morbidity along with exceedingly high hospital costs associated with complications related to preterm birth, so it is important to intervene with superior medications. Here the investigators propose a multi institutional (based within the University of California system) randomized controlled study to directly compare nifedipine (most commonly used calcium channel blocker) to indomethacin (most commonly used prostaglandin inhibitor).

Objective:

The Investigator's objective is to compare the prolongation of pregnancy by 48 hours after women are diagnosed with preterm labor prior to 32 weeks gestational age and treated with either nifedipine or indomethacin. Investigators hypothesize that indomethacin will significantly arrest preterm labor by 48 hours in more women compared to nifedipine. The primary outcomes measures will be delaying preterm delivery by 48 hours; secondary outcomes measures will include delay of delivery by 7 days and decreasing delivery before 37 weeks.

Arms: arm 1: Participants will be given this medication orally arm 2: Participants will be given this medication orally
Interventions: intervention 1: Nifedipine intervention 2: Indomethacin
Intervention descriptions: intervention 1: Subjects will be given nifedipine 10mg orally and repeated every 20 minutes for a maximum dose of 30mg in the first hour followed by 20mg every 6 hours for the first 48 hours. intervention 2: Those randomized to indomethacin will be given 100mg orally as a loading dose followed by 50mg every 6 hours for the first 48 hours of treatment.

Protocol documents:
Prot_SAP_000.pdf: 
Comparison of Nifedipine Versus Indomethacin for Acute Preterm Labor 
NCT03129945 
 
Document Date: 10/17/16 
 
 


Objective: 
Our objective is to compare the prolongation of pregnancy by 48 hours after women are 
diagnosed with preterm labor prior to 32 weeks gestational age and treated with either 
nifedipine or indomethacin. We hypothesize that indomethacin will significantly arrest 
preterm labor by 48 hours in more women compared to nifedipine. The primary 
outcomes measured will be delaying preterm delivery by 48 hours; secondary outcomes 
measured will include delay of delivery by 7 days and decreasing delivery before 37 
weeks. 
 
Background: 
Preterm birth accounts for 70% of neonatal deaths, and 25-50% of cases of long term 
neurologic impairment in children. About 12% of all live births occur before term and 
50% of these were preceded by preterm labor.1 Tocolytics have been well described in 
the literature and are recommended to provide time for corticosteroid administration, 
transfer to a tertiary facility and allow time for magnesium infusion. There are four main 
categories of tocolytics described by ACOG: calcium channel blockers, prostaglandin 
inhibitors, magnesium sulfate and B2 agonists. B2 agonists are no longer used outside 
of an acute setting due to significant maternal side effects; a black box warning has 
been issued by the US Food and Drug Administration as a result. Magnesium sulfate 
serves dual purposes in obstetrical medicine: it is used for neonatal neuroprotection and 
as a tocolytic. However, a recent meta-analysis revealed that it is a weak tocolytic agent 
compared to other tocolytics. It also revealed that both calcium channel blockers and 
prostaglandin inhibitors are consistently ranked among the top three tocolytics in 
delaying delivery by 48 hours, decrease RDS, neonatal mortality and maternal side 
effects.2 The most commonly used and studied tocolytic within the calcium channel 
blocker class is nifedipine. The most commonly used and studied tocolytic within the 
prostaglandin inhibitor class is indomethacin.There have been only two published 
randomized control studies that directly compares nifedpine and indomethacin.3,4 These 
two studies did not have the power or standardization of enrollment to guide us 
clinically. Here we propose a multi-institutional randomized controlled study directly 
comparing nifedipine to indomethacin in the setting of preterm labor. We plan to 
capitalize on the developing network for obstetrical clinical trials within the University of 
California Fetal Therapy Consortium, and involve all five medical campuses in the state. 
 
Outcomes: 
1. To compare the prolongation of pregnancy by 48 hours after women are diagnosed 
with threatened preterm labor prior to 32 weeks gestational age and treated with either 
nifedipine or indomethacin. The primary outcome measured will be delay of (preterm 


delivery) by 48 hours. Secondary outcomes will be delay of delivery by 7 days and rate 
of delivery before 37 weeks. 
2. Other secondary maternal outcomes included will be maternal adverse side effects 
significant enough to stop or delay medication use, need for a second tocolytic to halt 
preterm contractions. Neonatal outcomes measured will be respiratory distress 
syndrome (RDS), interventricular hemorrhage (IVH), patent ductus arteriosus (PDA), 
necrotizing enterocolitis (NEC), intubation, number of NICU days and neonatal mortality. 
 
Existing Knowledge: 
Specifically we intend to answer the question of which of these two tocolytics should be 
used as afirst line agent. Again there is much evidence showing that calcium channel 
blockers and prostaglandin inhibitors are the two classes of medications that are 
superior in delaying delivery for up to 48 hours, decrease RDS, neonatal mortality and 
maternal side effects compared to other medications.2 There has been one poorly 
designed small study directly comparing nifedipine to indomethacin.3 Another study 
compared magnesium to nifedipine and to indomethacin. Again, this study had an 
inadequate sample size. In addition, there was crossover of tocolytic groups, which 
does not allow for direct comparison. Women in preterm labor typically present with 
painful contractions and some degree of cervical dilation. There is a small window to 
treat these patients in an attempt to arrest preterm labor. Using the optimal tocolytic 
agent initially can potentially prevent or delay preterm birth with its resultant neonatal 
morbidity and mortality. 
 
Previous Research: 
Nifedipine is a well-studied tocolytic. A Cochrane review in 2011 evaluated data on all 
calcium channel blockers used for tocolysis; over 1029 women were included in the 
review. When compared to other tocolytic agents, calcium channel blockers decrease 
delivery within 7 days, decrease delivery less than 34 weeks, and have less need to 
stop medication for maternal adverse effect. Furthermore calcium channel blockers 
(compared to other tocolytics) decreased the incidence of RDS, NEC, IVH and neonatal 
jaundice in the newborn.5 Nifedipine has thus shown benefit as a tocolytic. One meta-
analysis demonstrated that nifedipine compared to B2 agonists had a reduction of 
preterm labor within 7 days, delivery before 34 weeks and reduction of RDS, NEC, IVH, 
neonatal jaundice, admission to the NICU and NICU stay. Compared to magnesium, 
nifedipine was associated with fewer maternal side effects. Although no difference in 
major neonatal outcomes were demonstrated, there was a significant decrease in NICU 
admission and NICU length of stay with nifedipine.6  
Indomethacin has also been well studied. The Cochrane review looked at COX 
inhibitors and their use as a tocolytic. Of the 13 trials included, 10 specifically used 


indomethacin. When compared to placebo, there was reduction in birth before 37 weeks 
gestation, an increase in gestational age at time of delivery and increase in birth weight. 
When compared to other tocolytics there was a reduction in birth before 37 weeks as 
well as reduction in maternal drug reaction.7 
There have been two large meta-analyses comparing tocolytics to determine the 
optimal first line agent. The first was published in 2009 to compare the outcomes of 
delaying delivery at 48 hours, 7 days and until 37 weeks. A decision tree was created 
using the highest efficacy to toxicity ratio. The study concluded that all tocolytics were 
superior to placebo for delaying delivery for 48 hours and 7 days. In addition, 
prostaglandin inhibitors were superior to other tocolytic agents.8 As described above, 
the second open network meta-analysis reviewed all tocolytics to determine the best 
probability for delaying delivery by 48 hours, and to decrease RDS, neonatal mortality 
and maternal side effects. Both prostaglandin inhibitors and calcium channel blockers 
were ranked among the top three medication classes for each category. Specifically 
prostaglandin inhibitors were ranked the best tocolytic in delaying preterm delivery 
within 48 hours and maternal side effect. 
Calcium channel blockers ranked the best tocolytic for neonatal outcomes.2 As 
discussed above, there have been two randomized control studies comparing nifedipine 
versus indomethacin. The first study included a total of 79 patients comparing nifedipine 
to indomethacin. This study found that nifedipine was superior for arresting contractions 
during the first two hours; however, if there was a response to indomethacin within the 
first two hours, there was no difference in delivery at 48 hours or up to 7 days. There 
are several design flaws in the study including the small sample size for which a 
calculation was not described, use of dosing regimens for both nifedipine and 
indomethacin that are not commonly used, and generous, non-standard inclusion 
criteria for preterm labor.3 
The second randomized control study compared 3 different tocolytics: nifedipine, 
indomethacin and magnesium. This study had several flaws as well, including a small 
sample size (approximately 90-114 in each group) and tocolytic group cross over. 
Although tocolytic cross over was allowed, the subjects remained in their initial group for 
analysis and for this reason this study does not allow for direct comparison. In addition, 
twin gestations were included. This group is at high risk for preterm delivery and 
neonatal morbidity at baseline, are thought to have a different mechanism for preterm 
delivery, and likely have a different response to tocolytic agents, all of which could 
potentially skew data. They also reported a gestational age of enrollment from 20 to 32 
weeks. As the main goal of tocolytic therapy is to administer corticosteroids (given 
between 24-34 weeks gestation) and allow transfer to a tertiary center, inclusion of 
patients less than 23 weeks gestation – who fall within the non-viable range and 
typically are not considered candidates for intervention, with tocolytic treatment or 
corticosteroid administration, was problematic in this study.4 


This proposed study will be a multi-institutional study to directly compare the two 
tocolytics that have been shown to be superior in meta-analysis. Determining a first line 
treatment will help guide clinicians in the treatment of preterm labor. 
 
1. Management of preterm labor. Practice bulletin No. 127. American College of 
Obstetricians and Gynecologists. Obstet Gynecol 2012; 119: 1308-17. 
2. Haas DM, Caldwell DM, Kirkpatrick P et al. Tocolytic therapy for preterm delivery: 
systematic review and network meta-analysis. BMJ 2012;345:e6226 
3. Kashanian M, Bahasadri S, Zolali B. Comparison of the efficacy and adverse effects 
of nifedipine and indomethacin for the treatment of preterm labor. International Journal 
of Gynecology and Obstetrics 2011:113; 192-195 
4. Klauser CK, Briery CM, Martin RW. A comparison of three tocolytics for preterm 
labor: a randomized clinical trial. J Matern Fetal Neonatal Med 2013, Early online: 1-6. 
5. King JF, Flenady V, Papatsonis D et al. Calcium channel blockers for inhibiting 
preterm labour. Cochrane Database of Systematic Reviews 2003, issue 1. 
6. Conde-Agudelo A, Romero R, Kusanovic P. Nifedipine in the management of preterm 
labor: a systematic review and meta-analysis. Am J Obstet Gynecol 2011;204:134.e1-
20. 
7. King JF, Flenady V, Cole S, Thornton S. Cyclo-oxygenase (COX) inhibitors for 
treating preterm labour. Cochrane Database of Systematic Reviews 2005, Issue 2. 
8. Haas DM, Imperiale TF, Kirkpatrick PR. Tocolytic therapy A meta-analysis and 
decision analysis. Obstet Gynecol 2009;113:585-94 
 
 
 
 
 
 


Methods: 
This is a randomized controlled open-label trial comparing two groups of women with 
preterm labor who are treated with either indomethacin or nifedipine as a tocolytic 
agent. The study will be conducted at each of the five University of California medical 
center hospitals. In order to be admitted to the hospital for tocolytic treatment, subjects 
will have to be in preterm labor defined as regular uterine contractions (at least 6 per 
hour) associated with changes in cervical dilatation and/or effacement, cervical 
dilatation of > 2 cm at presentation or a change in cervical dilatation of > 1 cm, and > 25 
to 50% effacement and/or a short cervical length (per institution’s policy) as obtained by 
transvaginal cervical sonography with or without a positive fetal fibronectin. All women 
will be treated in a uniform fashion with initial hydration, evaluation for etiologic infection, 
administration of antenatal corticosteroids to accelerate fetal maturity, and magnesium 
sulfate for neuroprotection. Magnesium will be administered according to each 
institution’s magnesium for neuroprotection protocol. Women will be randomized to 
either tocolytic therapy with nifedipine or indomethacin by using computerized 
randomized block sequencing. 
Nifedipine Treatment: Subjects will be given nifedipine 10mg orally and repeated every 
20 minutes for a maximum dose of 30mg in the first hour followed by 20mg every 6 
hours for the first 48 hours of treatment. This is a commonly used dose and has been 
described in a large meta-analysis reviewing nifedipine in the management of preterm 
labor by Conde-Agudelo et al.1 Of the 26 studies reporting on nifedipine as an acute 
tocolytic, the dosing ranged from a loading dose of 10 to 30mg orally or sublingually, 
followed by 10 to 20mg orally every 4-8 hours. 12 of those studies used a repeat 
loading dose every 15-20 minutes. The decision was made to proceed with nifedipine 
10mg orally and repeated every 20 minutes for a maximum dose of 30mg followed by 
20mg every 6 hours since it a commonly prescribed dosing for acute tocolysis. 
Indomethacin Treatment: Those randomized to indomethacin will be given 100mg orally 
as a loading dose followed by 50mg every 6 hours for the first 48 hours of treatment. 
This regimen was decided after reviewing the Cochrane review on COX inhibitors for 
treating preterm labor.2 10 of the 13 trials included in the review used indomethacin. The 
dosing ranged from 50 to 100mg loading dose followed by 25mg to 50mg orally every 4-
6 hours. The loading dose was mostly given rectally. A recent randomized control trial 
compared indomethacin vs. two other tocolytics.3 The indomethacin dosing used was 
an initial 100mg suppository, repeated one time if contractions persisted after two hours, 
followed by 50mg orally every 6 hours. This regimen was associated with increased 
incidence of fetal ductal constriction (13/97) and oligohydramnios (5/97) when 
compared to the other two treatment groups. Therefore, we propose using a one time 
loading dose of 100mg orally followed by 50mg every 6 hours, which is a commonly 
prescribed dosing. Using the lower end of the normally prescribed dosing range should 
have decrease fetal and maternal side effects. 


Tocolytic failure will be defined as delivery within 48 hours of initiation or the start of 
magnesium for neuroprotection. Magnesium for neuroprotection is started when delivery 
is deemed imminent, so when initiated, it is implied that there has been tocolytic 
treatment failure. That being said, it is difficult to predict preterm birth, especially in the 
setting of preterm labor, and some clinicians may start magnesium for neuroprotection 
without labor proceeding to delivery. There is a theoretical risk of neuromuscular 
blockade with the concurrent use of magnesium and nifedipine, and there have been 2 
case reports of reversible neuromuscular blockade in this setting.4,5 One of these case 
reports used a total dose of 500mg of magnesium5 – which is significantly more than 
what would be administered for our neuroprotective dosing. There are studies, albeit 
small, that show concurrent use of nifedipine and magnesium is safe in the setting of 
preeclampsia.6,7,8 One such study describes expected hemodynamic changes with the 
concurrent use of nifedipine and magnesium including a decreased mean arterial 
pressure, systemic vascular resistance and increase in cardiac index.7 The magnesium 
dosing in the study was 5 grams over 20min followed by 3g/hr which is a higher 
maintenance dose than any of the campuses uses for neuroprotection. 
One of the largest studies that examined maternal and neonatal outcomes in the setting 
of preeclampsia was the Magpie trial,8 which had about 30% concurrent use with 
nifedipine and magnesium with no adverse effects reported. While on magnesium, all 5 
campuses have mechanisms in place to monitor closely for magnesium toxicity 
including serial neurologic exams and/or magnesium levels. If any early adverse signs 
are seen, magnesium will be discontinued and/or calcium gluconate administered to 
reverse any neuromuscular blockade. For this reason, concomitant use of magnesium 
with either nifedipine or indomethacin is left to the judgment of the providers at each 
institution. 
After 48 hours from the first dose of antenatal corticosteroids, the tocolytic agent will be 
discontinued. Maintenance tocolysis for longer than 48 hours will not be used on study 
patients. The study time required from each subject is the duration of hospital admission 
during which she is enrolled in the study and the duration of the birth hospitalization for 
each infant. To clarify, secondary outcomes measured will include delay of delivery by 7 
days and decreasing delivery before 37 weeks as outlined in section 1 on page 2. 
Section 3 specifically asks the time required by study participants. Gestational age at 
delivery is an endpoint we plan to collect and the end of the study participants’ time in 
the study. Gestational age at delivery will be collected as data but analyzed in a 
dichotomous fashion i.e. prior to 37 weeks. End points for tocolytic treatment are arrest 
of preterm labor (cervical dilation) or completion of betamethasone administration (e.g. 
48 hours from the first dose). The primary study outcome is extension of pregnancy by 
48 hours after admission. The secondary outcome is gestational age at delivery. We will 
also evaluate pregnancy extension by 7 days after treatment initiation. It is likely that 
some patients are discharged still pregnant and return later in gestation for delivery. 
Although no actual study time between these two time points are required of the subject 
or during subsequent hospitalization(s), data would be collected at the time of delivery. 


For the neonates, data will be collected through discharge. No neonatal follow up is 
required. There may be subjects who deliver at another hospital. If the patient gives 
permission, then we will obtain records from the appropriate hospital. 
Subject’s privacy will be protected by using HIPPA guidelines by limiting access to data 
collection study personnel only. In addition, data will always be kept in a secured, 
locked location. Subject screening, enrollment and case report forms will be kept in a 
binder that will be locked in a room/drawer at all times. These case report forms will be 
uploaded to a secure online database run by a well-established company Tiatros. 
Tiatros uses online software to organize, analysis and allow communication among 
principal investigators in the study. Most importantly this is done securely and follows 
HIPPA regulations. 
 
Summary 
This comparative study of nifedipine versus indomethacin for acute preterm labor will be 
conducted at the 5 UC medical campuses (UC Irvine, UC Davis, UC San Diego, UC 
San Francisco, UC Los Angeles) using the Reliance Agreement. UCI is the reviewing 
IRB. UC Davis, UCSD, UCSF, UCLA are the relying IRBs. All tocolytic treatment will be 
given in the primary hospital at each campus. Medication is discontinued once there is 
arrest of preterm labor, 48 hours from first dose of betamethasone, or when delivery is 
deemed imminent or unavoidable, and depending on institution’s policy at the time 
magnesium initiated for neuroprotection. No maintenance tocolytic medication will be 
given (i.e. longer than 48 hours) and none will be given as an outpatient. 
 
1. Conde-Agudelo A, Romero R, Kusanovic P. Nifedipine in the management of preterm 
labor: a systematic review and meta-analysis. Am J Obstet Gynecol 2011;204:134.e1-
20. 
2. King JF, Flenady V, Cole S, Thornton S. Cyclo-oxygenase (COX) inhibitors for 
treating preterm labour. Cochrane Database of Systematic Reviews 2005, Issue 2. 
3. Klauser CK, Briery CM, Martin RW. A comparison of three tocolytics for preterm 
labor: a randomized clinical trial. J Matern Fetal Neonatal Med 2013; early online: 1-6. 
4. Ben Ami M, Giladi Y, Shalev E. The combination of magnesium sulphate and 
nifedipine: a cause of neuromuscular blockade. Br J Obstet Gynaecol. 1994;101:262-3. 
5. Synder SW, Cardwell MS. Neuromuscular blockade with magnesium-sulfate and 
nifedipine. Am J Obstet Gynecol. 1989;161:35-6. 
6. Magee LA, Miremadi S, Li J et al. Therapy with both magnesium sulfate and 
nifedipine does not increase the risk of serious magnesium-related maternal side effects 
in women with preeclampsia. Am J Obstet Gynecol. 2005;193:153-63. 


7. Scardo JA, Vermillion ST, Hogg BB et al. Hemodynamic effects of oral nifedipine in 
preeclamptic hypertensive emergencies. Am J Obstet Gynecol ,1996; 175:336-8. 
8. Altman D, Carroli G, Duley L et al. Do women with pre-eclampsia, and their babies, 
benefit from magnesium sulphate? The Magpie trial: a randomized placebo-controlled 
trial. Lancet 2002;359:1877-90. 
 
 


Statistical Analysis: 
The purpose of this study is to determine whether nifedipine or indomethacin is superior 
in arresting preterm delivery by 48 hours. We expect the nifedipine group to arrest 
preterm labor for 48 hours in 72% of cases1 and the indomethacin group to arrest 
preterm labor for 48 hours 83% of cases.2 Using a power of 80%, alpha of 0.05 we 
calculate 225 subjects are needed in each group.  
The primary outcomes and other dichotomous outcomes will be evaluated using Chi-
square. We also anticipate a 25% difference between groups based on prolongation of 
pregnancy by one week based on a small RCT using nifedipine vs. ritodrine conducted 
by Papatsonis et al.3 Continuous variables will be compared using Student’s t-test. Sub-
group analyses will be done to compare differences across the sites. Regression 
analyses will be applied where appropriate such as for neonatal complications and the 
consideration of gestational age. 
 
1. Lyell DJ, Pullen K, Campbell L et al. Magnesium sulfate compared with nifedipine for 
acute tocolysis of preterm labor: a randomized controlled trial. Obstet Gynecol 2007; 
110:61-. 
2. Zuckerman H, Shalev E, Gilad G, Katzuni E. Further study of the inhibition of 
premature labor by indomethacin. Part II double-blind study. Journal of Perinatal 
Medicine 1984; 12(1):25-9. 
3. Papatsonis et al. Nifedipine and ritodrine in the management of preterm labor: a 
randomized multicenter trial. Obstet Gynecol 1997; 90:230-4.