Conditions: Preterm Labor
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 88
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine if nifedipine treatment of women in preterm labor receiving corticosteroids results in postponement of delivery when compared to placebo.

Detailed description:

Arms:
arm 1: Women with preterm labor will receive nifedipine. arm 2: Women with preterm labor will receive placebo.

Interventions: intervention 1: Nifedipine intervention 2: Placebo intervention 3: Usual care
Intervention descriptions: intervention 1: Nifedipine 20 mg orally, then nifedipine 20 mg orally after 90 minutes if still contracting. Continue nifedipine 20 mg orally every 4 hours after the first dose for 48 hours. intervention 2: Placebo orally, then placebo orally after 90 minutes if still contracting. Continue placebo orally every 4 hours after the first dose for 48 hours. intervention 3: Usual evaluation, monitoring and care for women with preterm labor.

Protocol document:
Prot_SAP_000.pdf: 
 
Version 5.1 September 18, 2015 
Page 1 of 20 
 
Protocol:   
Nifedipine for Acute Tocolysis of Preterm Labor 
 
Principal Investigator:   
Edward Wells, MD 
 
Co-Investigators:   
David Nelson, MD; Donald D. McIntire, PhD; Kenneth J. Leveno, MD 
 
 
Funding:   
Internally funded by Department of Obstetrics and Gynecology 
 
IND Number:  Not applicable 
 
Version 8.0, March 22, 2018 


 
Version 5.1 September 18, 2015 
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The University of Texas Southwestern Medical Center at Dallas 
Institutional Review Board 
 
Protocol Template (for Investigator Initiated Studies) 
 
 
Title:  Nifedipine for acute tocolysis of preterm labor 
 
1. Introduction and Purpose: 
 
1. Describe why this research project will be done.  Clearly state the overall objectives, specific 
aims, hypotheses and rationale for performing the study. 
 
Preterm birth, defined as birth at less than 37 weeks, affects 11 - 13% of all births in the United States 
and results in significant morbidity and mortality for the approximately 500,000 infants born preterm 
each year. The leading cause of preterm birth is preterm labor, and obstetrical interventions have 
included various tocolytic medications. Efficacy studies on these have yielded disappointing results. 
(Leveno et al, 1986; Leveno et al 1990; Canadian Preterm Labor Investigators Group, 1992; Leveno 
and Cunningham, 1992, Mercer and Merlino, 2009). There has been recent interest in nifedipine as a 
tocolytic for preterm labor (Conde-Agudelo et al, 2011).  In 2008, a survey of maternal-fetal medicine 
specialists reported that 32% were using nifedipine as their tocolytic of choice (Fox et al, 2008), 
despite that there are no placebo-controlled, randomized studies of nifedipine for acute tocolysis 
preterm labor showing a benefit. 
 
This is a randomized, double-blinded, placebo-controlled trial of nifedipine for acute tocolysis of 
preterm labor. Our objective is to determine whether nifedipine decreases the rate of preterm birth. 
Our null hypothesis is that nifedipine does not reduce the rate of preterm birth.  
 
2. Indicate the Primary and Secondary Study Endpoints. Also indicate the Primary Safety 
Endpoints (unless the study is a safety study). 
 
The primary outcome will be prolongation of pregnancy until at least 37 weeks. Secondary outcomes 
will include 1) number of patients who receive at least 2 doses of betamethasone, 2) delivery within 48 
hours of diagnosis of preterm labor and 3) delivery within 7 days. 
 
3. Explain why the study risks are reasonable in relation to the potential benefits to subjects and 
society.   
 
Given the prevalence of this off-label use of nifedipine, it is unlikely that serious adverse events are 
commonly encountered. The main serious risk associated with nifedipine is pulmonary edema, but in 
the 17 reported cases, this risk was reported in the context of other specific risk factors, such as use 
with other tocolytic drugs, use of rapid-acting formulations, prolonged tocolysis, and use when there 
was evidence of preexisting maternal cardiac disease/dysfunction. Importantly, in 26 published trials 
involving isolated use of nifedipine for acute tocolysis, there were no cases of pulmonary edema 
among patients receiving nifedipine (References 8a-aa). 
 
We plan to restrict use to healthy, normotensive women with singleton pregnancies not receiving 
additional tocolytic agents.  We will also not use prolonged or sublingual (rapid acting) administration 
of nifedipine.  Therefore, these reported adverse reactions are most unlikely. Milder side effects 
associated with nifedipine include headache, flushing and low blood pressure, which resolve with 
discontinuation of the medication. The balance of benefits and risks favors performing this study to 
quantify benefits, if any, given the potential for nifedipine to stop preterm labor and its high use rate in 
the community. 


 
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2. Background: 
 
1. State the purpose of the research and describe the related theory/data supporting the intent of 
the study.   
 
The purpose of this research is to determine whether nifepidine is effective compared to placebo for 
delaying delivery sufficient to ensure delivery of corticosteroids and thus reducing preterm birth 
related morbidity. Nifedipine interferes in calcium transport across cell membranes and is an effective 
smooth muscle relaxant. We believe that uterine relaxation (tocolysis) from nifedipine may reduce 
preterm birth.    
 
2. Describe what is considered standard care (approved and/or customary) for the medical 
condition being studied, if applicable. 
 
Although tocolysis is not currently used at Parkland Hospital, it is considered within the standard of 
care for physicians caring for women in preterm labor.  
 
 
3. Explain how the new treatment or procedure may improve standard care, if applicable. Clearly 
delineate what is considered research study items from the “standard care”. 
 
If nifedipine is identified as an effective tocolytic for reducing preterm birth, it would be included as 
part of the standard care for women with preterm labor. 
 
4. Provide a short statement concerning the status of the drug, drug combination, delivery 
method, device, or other interventions/concepts to be studied. 
 
Nifedipine is FDA approved for treatment of angina and hypertension, but it is widely used off-label as 
a tocolytic for preterm labor.  
 
5. Indicate whether the research is confirming or an extension of previous work, or whether it is 
pioneering with little prior information.  Include an evaluation of existing knowledge and identify 
the information gaps that the project intends to address.   
 
No placebo controlled, randomized trials of nifedipine as an intervention for acute tocolysis of preterm 
labor (defined as cervical dilatation with contractions) have been reported, therefore, this study will be 
an important contribution to the medical literature.  
 
6. Describe published research with animals and/or humans that supports the study hypothesis 
or objectives.  If applicable, include information regarding toxicity.  Include a bibliography of 
key references/citations as applicable. 
 
Ex Vivo Data 
 
In human myometrium collected at the time of cesarean section Nitrendipine, a dihyropyridine calcium 
channel blocker similar to nifedpine, depressed myometrial contractions. (Maigaard, 1986). 
 
Randomized Trials of Nifedipine  
 
Vis et al (2014) recently reported an unusual study of “randomized women” and “nonrandomized 
eligible women” with nifedipine tocolysis versus placebo in women between 24 and 34 weeks’ 
gestation with intact membranes, a short cervix by ultrasound, a negative fetal fibronectin (in theory, 
low risk of preterm birth) and “symptoms of preterm labor” (symptoms were not further defined). This 


 
Version 5.1 September 18, 2015 
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was a non-inferiority trial and the authors reported that placebo was not inferior to nifedipine tocolysis. 
The very small sample size and its very unusual design raise questions about its utility.   
 
No placebo-controlled, randomized trials of nifedipine for acute tocolysis of preterm labor (defined as 
cervical dilatation and contractions) have been reported. Published studies of nifedipine as a 
treatment for preterm labor are comparisons to other tocolytic agents (References 8a-aa). These 
other agents include magnesium sulfate, atosiban and beta-agonist drugs such as ritodrine, none of 
which have been demonstrated to improve birth outcomes. 
 
Meta-Analyses of Trials Involving Nifedipine 
 
Cochrane Review of Calcium Channel Blockers for Inhibiting Preterm Labor 
 
The authors included published and unpublished data from 12 trials (1029 women) comparing calcium 
channel blockers to other tocolytic agents. The relative risk for giving birth within 7 days was 
decreased (RR 0.76, 95% confidence interval, 0.60-0.97) with nifedipine, and the relative risk for 
maternal side effects was less (RR 0.32 95% CI, 0.24-0.41). There were fewer adverse neonatal 
outcomes among patients treated with nifedipine, with the relative risks (95% CI) for RDS, necrotizing 
enterocolitis & intraventricular hemorrhage being 0.63 (0.46-0.88), 0.21 (0.05-0.96), 0.59 (0.36-0.98).  
 
Other Meta-Analyses 
 
Tsatsaris et al (2001) analyzed 9 randomized trials involving 679 patients comparing nifedipine to 
beta-agonists. The relative risks (95% confidence intervals) for delaying delivery at least 48 hours, 
side effects, respiratory distress syndrome and neonatal intensive care unit admission compared to 
other beta-agonists were 1.52 (1.03-2.24), 0.12 (0.05-0.29), 1.51 (0.63-3.65) and 0.65 (0.43-0.97), 
respectively. Conde-Agudelo et al (2011) reviewed 26 trials with 2179 women. Compared to beta-
agonists, nifedipine significantly reduced risk of delivery within 7 days and before 34 weeks, RDS, 
necrotizing enterocolitis, IVH, neonatal jaundice and ICU admission. Compared to magnesium sulfate, 
nifedipine showed no significant differences. Maintenance tocolysis is ineffective. 
 
Safety  
 
Reviews of Adverse Outcomes Involving Nifedipine:  In a review of the literature on adverse events 
following the use of calcium channel blockers like nifedipine for tocolysis, Oei (2006) concluded that: 
1) calcium channel blockers should not be combined with intravenous beta-adrenergic agonists (such 
as ritodrine hydrochloride or terbutaline), 2) intravenous nicardipine or high oral doses of nifedipine 
should not be used in cases of multiple gestation or when the mother is compromised 
cardiovascularly, and 3) blood pressure should be monitored and cardiotocography should be 
recorded when immediate release tablets are used.  
 
Importantly, in the proposed study, only healthy women with singleton pregnancies will be consented 
for participation, sub-lingual (rapid-acting) administration will not be used and multiple tocolytics will 
not be employed. Compared to the only FDA approved tocolytic (ritodrine), nifedipine has fewer side 
effects.  
 
Recently, Xiao et al (2014) reported the effect of magnesium sulfate and nifedipine on the risk of 
developing pulmonary edema in preterm births: “nifedipine did not increase the odds of developing 
pulmonary edema [adjusted odds ratio (OR)=1.22 (confidence interval (CI) 0.50, 3.01), P=0.67]” 
 
Hemodynamic and Metabolic Effects 
 


 
Version 5.1 September 18, 2015 
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Papatsonis et al (2003) compared 95 patients randomized to oral nifedipine to 90 patients randomized 
to intravenous ritodrine. Compared to nifedipine, patients who received ritodrine had significantly 
lower mean diastolic blood pressures at 24 and 48 hours (65 +/- 12 versus 70 +/- 8, p=.001, and 65 
+/- 12 versus 71 +/-8, p=.004, respectively), and significantly higher mean maternal pulses at 24 and 
48 hours (105 +/- 17 versus 86 +/- 13, p<.0001, and 100 +/- 21 versus 85 +/- 12, p<.0001). Gucglu et 
al (2006) studied maternal hemodynamic parameters as well as Doppler waveforms of various fetal 
structures in 28 women who received nifedipine for preterm labor. The maternal and fetal heart rates 
were unaffected despite that maternal mean systolic and diastolic blood pressures were lower at 24 
hours. Changes in the umbilical artery Doppler measurements were “minimal and not sustained.” 
Additionally, De Heus et al (2009) reported the effects of the tocolytics atosiban and nifedipine on fetal 
movements, heart rate and blood flow and concluded: “tocolysis with either atosiban or nifedipine 
combined with betamethasone administration appears to have no direct fetal adverse effects.”  
 
Recently, Ulubasoglu (2014) reported that there were no statistically significant differences between 
24-hour values for the umbilical artery pulsatility index, resistance index (RI), systolic-diastolic (S:D) 
ratio, right uterine artery measures (pulsatility index, RI, S:D ratio) or left uterine artery measures (RI 
and S:D ratio), and they concluded that “oral nifedipine is a safe tocolytic agent with no long-term 
effect on fetomaternal circulation in pregnant women at risk of preterm delivery.” 
 
3. Concise Summary of Project: 
 
1. Provide a brief description of the study design.  If applicable, describe the treatment arms, use 
of placebo or comparison drug/device and randomization. 
 
This will be a randomized, double-blinded, placebo-controlled trial of nifedipine for acute tocolysis (48 
hours total duration) of preterm labor in women with singleton gestations between 28-0/7 weeks and 
33-6/7 weeks’ gestation. After initial monitoring on Labor & Delivery, all women will be admitted to the 
antepartum ward until approximately 34 weeks’ gestation and completion of the full course of 
corticosteroids, although the provider will determine when it is safe for the patient to be discharged, as 
is our current routine without tocolysis. Discharge can be affected by whether the patient is 
considered stable (is she contracting again?), if her cervical exam has changed (if her cervix has 
increased dilatation, particularly to 4 cm or more, she may not be considered safe for discharge) and if 
she is receiving any other interventions. We will avoid creating an expectation that by participating in 
this study, then an exact or particular discharge date is assured.  
 
2. Include specific details regarding the study drug(s) being used, including the generic/trade 
name of the study drug. Include details about drug preparation, packaging, shipping, storage, 
dispensing, return and destruction. Include details of any dose reductions or dose escalations 
that may occur including the dose change and duration of transition from one dose to another. 
 
The generic name is nifedipine which is marketed as Adalat or Procardia as trade names. Generic 
nifedipine in 20 mg doses will be obtained from a distributor in the United States. The Investigational 
Drug Service at Parkland Hospital has arranged for the placebo and study drug to be encapsulated by 
Abrams-Royal Pharmacy, 8220 Abrams Road, Dallas, TX 752313550 Parkwood Blvd, Bldg F, Ste 
#630, Frisco TX 75034. This pharmacy has experience with drug encapsulation for randomized 
controlled trials. The Investigational Drug Service at Parkland Hospital is aware that Abrams-Royal 
Pharmacy will be encapsulating the placebo and study drug.  Unused or expired study drug will be 
returned to the investigational drug service (IDS) pharmacy. 
 
Women who consent to participate in the above study will be randomized by the IDS pharmacy to 
receive either placebo or a loading dose of nifedipine 20 mg oral capsule, which will then be repeated 
after 90 minutes if there are persistent contractions. Four hours after the first dose, they will begin 
nifedipine 20 mg oral capsule every 4 hours for a total duration of 48 hours, up to a maximum of 160 


 
Version 5.1 September 18, 2015 
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mg the first 24 hour period (120 mg the second 24 hour period), unless delivery occurs sooner. We 
anticipate that women will remain on Labor & Delivery for monitoring for at least 24 hours prior to 
consideration of transfer to the high-risk antepartum unit. 
 
3. Include information regarding the study drug(s) classification and the mechanism of action, if 
known.  
 
Nifedipine is a dihydropyridine class of calcium channel blocker, and are selective for smooth muscle. 
The dihydropyridines are thought to inhibit uterine myometrial contractions by causing relaxation of 
the uterine smooth muscle.  
 
4. Include a brief description of outcome variables and study endpoints, as appropriate.   
 
The primary outcome will be delay of delivery until 37 weeks’. Secondary outcomes will include 1) at 
least 2 doses of betamethasone, 2) delivery within 48 hours’ gestation and 3) delivery within 7 days. 
 
5. Indicate the maximum number of local subjects to be consented on this protocol, including 
projected screen failures and early withdrawals.  Include subjects who will receive 
interventions as well as controls, if applicable.  For multi-center research, indicate the total 
sample size for the entire project across all sites. 
 
Assuming a 50% consent rate, we will be approaching approximately 300 women for consent.  
Sample size calculations indicate we need 75 women per arm or 150 total women to demonstrate a 
33% reduction in preterm birth, based upon 2 prior Randomized Placebo Controlled Trials of tocolysis 
(magnesium sulfate and ritodrine) performed at Parkland Hospital (Leveno et al, 1986; Cox and 
Leveno, 1990).   
 
6. If the study involves use of existing charts, records, or specimens, specify the maximum 
number that will be reviewed to compile the data or the sample population necessary to 
address the research question. 
 
This is a prospective trial and existing records will not be reviewed. 
 
7. Provide the total number of subjects to be studied at this site and approximately how long the 
study will last. 
 
It is anticipated that the study will take approximately 4-5 years to consent and study a total of 150 
women with preterm labor between 28-0/7 weeks and 33-6/7 weeks. 
 
8. Include conditions which would result in the subject exiting the study prior to the expected 
completion date, such as non-compliance, safety reasons, subject withdrawal of consent, 
disease progression, etc. 
 
This is an intent to treat study.  Withdrawal of consent would be the only indication for early exit. 
 
4. Study Procedures: 
 
1. Provide a chronological description of all study procedures.  If applicable, divide procedures 
into pilot, screening, and procedures performed at each regular visit.  Indicate how many total 
visits and approximately how long visits will last.  For studies that are providing medication(s), 
give the name(s), dosage, and route of administration.  For studies that have more than one 
arm/part, provide the above information for each. 
 


 
Version 5.1 September 18, 2015 
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Women presenting with symptoms of preterm labor will be assessed using electronic external fetal 
heart rate and uterine contraction monitoring. Women will receive a baseline and subsequent cervical 
exams as necessary. If at any time during her evaluation, the woman is dilated to at least 2 cm and 
has uterine contractions, she will be potentially eligible for study.  Women with a singleton gestation 
between 28-0/7 weeks and 33-6/7 will be approached for consent to participate by Research Nurses 
employed by the Department of Obstetrics & Gynecology or Dr. Wells if a Research Nurse is 
unavailable. They will be randomized by the IDS Pharmacy into treatment (study drug, nifedipine) or 
control (placebo) groups. 
 
Study women will receive nifedipine 20 mg or placebo oral capsule followed by a second dose after 
90 minutes if there are persistent contractions. Four hours after the initial dose, they will begin 
nifedipine 20 mg or placebo oral capsule every 4 hours for a total duration of 48 hours, up to a 
maximum of 160 mg the first 24 hour period (120 mg the second 24 hour period), unless delivery 
occurs sooner. We anticipate that women will remain on Labor & Delivery for monitoring for at least 24 
hours prior to consideration of transfer to the high-risk antepartum unit. 
 
There will be a “HOLD DOSE” parameter in which a dose will be held if an enrolled patient: 
 
refuses medication 
 
has heart rate greater than 120  
If a dose is held, the nurse will contact the 4th year resident who will ensure Dr. Wells is notified. 
 
There will be a “STOPPING RULE” for further individual participation in the study for any of the 
following criteria: withdrawal of consent, diffuse rash or anaphylaxis reaction to medication (requires 
confirmation by house officer), hypotension requiring delivery or medication such as ephedrine, or 
development of any obstetrical outcomes that would normally preclude tocolysis (development of 
ruptured membranes, development of chorioamnionitis, development of preeclampsia/gestational 
hypertension, development of bleeding suspicious for abruption, cervical dilatation of 6 cm or more or 
fetal death), or if a decision is made to either deliver the patient or to use regional anesthesia. 
 
Women without further cervical change after monitoring on Labor and Delivery will be admitted to the 
antepartum unit for surveillance until approximately 34 weeks’ gestation and completion of the full 
course of corticosteroids, although the provider will determine when it is safe for the patient to be 
discharged. This is our current practice in such women and is not a study procedure. Discharge can 
be affected by whether the patient is considered stable (is she contracting again?), if her cervical 
exam has changed (if her cervix has increased dilatation, particularly to 4 cm or more, she may not be 
considered safe for discharge) and if she is receiving any other interventions. We will avoid creating 
an expectation that by participating in this study, then an exact or particular discharge date is assured. 
Some patients choose to leave earlier (usually due to family obligations) despite the recommendation 
to stay until 34 weeks’ gestation.  Women who are discharged from the antepartum unit will be 
followed-up in the OB Complications Clinic of Parkland Hospital weekly until delivery. This method of 
outpatient follow-up for patients after discharge from the antepartum unit is also our routine and is not 
a study specific procedure. 
 
2. You may include tables, figures and/or flow diagrams if necessary to clarify highly complex 
studies.    
N/A 
 
3. Indicate the timing of all study procedures and the anticipated duration of the subject’s 
involvement.   
 
Study participants involvement in study related procedures will last 48 hours. 
 


 
Version 5.1 September 18, 2015 
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4. As applicable, include the amount and blood to be drawn, tissue samples to be collected, 
radiation exposure, questionnaires, or other interventions. 
 
No additional blood, tissue, imaging studies, questionnaires or other interventions are planned. 
 
 
5. Note if the subject will be responsible for any research-related costs and estimate the amount 
of these costs, if applicable. 
 
This study will be locally funded by the Department of Obstetrics & Gynecology and participants will 
not be responsible for any research-related costs.  Study drug is the only research related cost.  All 
other procedures such as inpatient hospitalization are part of routine care for women with preterm 
labor and a cervix of 2 cm or more.  
 
6. If applicable, describe end-of-study procedures, including transition of the subject to alternative 
care. 
N/A 
 
5. Sub-Study Procedures: 
 
1. For any sub-studies that may be a part of the research, please provide a subsection title and 
include information about the procedures that will be performed and whether subjects have the 
option to participate or not (e.g., pharmacokinetics, biomarkers). 
N/A 
 
2. For studies that collect blood and/or tissue for DNA analysis where the genetic portion is 
described in the Master Protocol provide a genetic subsection to include information about the 
procedures that will be performed and whether subjects have the option to participate in the 
sub-study. 
N/A 
 
6. Criteria for Inclusion of Subjects: 
 
1. Describe the characteristics of the subject population.  For example, list any characteristics 
required for eligibility, such as diagnosis, prior therapy, age, or gender.  
 
Inclusion criteria include: 
 
Mothers between 16 and 44 years of age inclusive. 
 
Singleton pregnancy  
 
Intact membranes 
 
Between 28-0/7 weeks and 33-6/7 weeks’ gestation inclusive 
 
Reported or documented uterine activity  
 
Cervical dilation between 2 cm and 4 cm inclusive 
 
2. Explain the rationale for the use of special classes of subjects who are more likely to be 
vulnerable, such as pregnant women, children, cognitively impaired people or prisoners. 
 
Pregnant women are included as this study is for an intervention for preterm labor. 
 
7. Criteria for Exclusion of Subjects: 
 
1. Describe the exclusion criteria. For example, list any characteristics that would preclude 
participation, such as prior therapy, concomitant treatments and co-morbid conditions.  If 
exclusion is based on age, gender, language barriers or social/ethnic group, describe the need 


 
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for the exclusion in terms of scientific validity.  Do not justify exclusion in terms of convenience 
or other non-scientific issues, such as lack of funding. 
 
Exclusion criteria: 
Oppose inclusion criteria: 
 
Multifetal gestation 
 
Less than 28 weeks’ gestation 
 
34 or more weeks’ gestation 
 
Ruptured membranes 
 
More than 4 cm dilated 
Corticosteroids contraindicated: 
 
Previously received a course of 
corticosteroids for fetal lung 
maturation  
 
Tocolysis contraindicated: 
 
Low amniotic fluid 
(oligohydramnios) 
 
Fetal growth restriction 
 
Chorioamnionitis or temperature of 
at least 38.0 degrees Celsius 
 
Fetal death 
 
Preeclampsia 
 
Suspected placental abruption or 
placenta previa 
 
Lethal fetal malformation or 
amniotic fluid index at least 35 
 
 
 
 
      Nifedipine contraindicated: 
 
Systolic BP < 90 mmHg or diastolic 
BP < 50 mmHg 
 
Baseline tachycardia (pulse >120 
after 2 consecutive measurements 
30 minutes apart) 
 
Chronic hypertension treated with 
antihypertensives in pregnancy 
 
Seizure disorder or HIV* 
 
Women who have received 
progesterone therapy in the 2nd or 
3rd trimester 
 
Maternal allergy to nifedipine  
 
Known maternal cardiac disease 
* See July 2013 FDA warning regarding nifedipine and phenytoin, also several protease inhibitors 
are strong inhibitors of metabolizing enzyme CYP3A4 
 
2. Include situations or conditions, unknown at the time of enrollment that might cause a 
screening failure. 
 
No situations known. 
 
8. Sources of Research Material: 
 
1. Identify the source(s) of materials/data to be used in the research, such as information or 
specimens from medical records, databases, repositories or other sources.   If a combination 
of these sources are used, and/or new clinical data generated, describe how the research 
material is acquired. 
 
Data on obstetrical and neonatal outcomes for all women delivered at Parkland Hospital are routinely 
entered into Dr. Leveno’s obstetrical operations database.  Outcomes recorded for study women and 
their offspring will be linked by Don McIntire, PhD, who is the only person who has access to this 
password protected and encrypted dataset.   
 
2. State whether the material or data will be obtained specifically for research purposes, or 
whether existing records, specimens or other data will be used. If existing records or 
specimens are being used, please indicate the dates from which data or samples will be 
extracted (start and stop dates). 
 
This will be a prospective, double-blind, placebo controlled trial and therefore existing records or 
specimens will not be used. 
 


 
Version 5.1 September 18, 2015 
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9. Recruitment Methods and Consenting Process: 
 
1. Indicate if the potential subjects will be patients of the investigators.  
 
All investigators are faculty members and oversee obstetrical care at Parkland Hospital. 
 
2. Describe and provide details of the recruitment process.  Include when, where, by whom and 
how potential subjects will be approached. Indicate if non-English speaking subjects are being 
consented and if so, indicate how informed consent process will be conducted.  
 
Research nurses employed by the Department of Obstetrics & Gynecology, and who are on-call and 
monitoring Labor & Delivery, will identify, approach and provide informed consent to all potential 
participants (these tasks will be performed by Dr. Wells if a research nurse is unavailable when a 
patient presents with preterm labor). If potential participants are non-English speaking, a language-
appropriate translator will be obtained as per current Department of Obstetrics & Gynecology 
research protocols. 
 
3. Explain measures that will be taken to respect the privacy of the potential subjects. 
 
Patients will generally be consented in one of the private rooms on Labor & Delivery. 
 
4. Explain what precautions will be taken to minimize the potential for undue influence or 
coercion. 
 
Professional research nurses already on staff with the Department of Obstetrics & Gynecology, and 
who do not have an interest in a particular study outcome, will be providing the informed consent 
during weekdays and most weeknights. If a patient presents with active preterm labor when a 
research nurse is unavailable, Dr. Wells will obtain informed consent. Dr. Wells has observed several 
of these nurses obtain informed consent in a dispassionate and thorough manner, which emphasizes 
to the patient that the usual care that we provide will not be affected by her decision to participate or 
not. 
 
5. If you are requesting a waiver of informed consent, explain how the criteria for waiver are met. 
N/A 
 
6. If vulnerable populations will be included, describe the additional protections that will be 
provided, such as methods to obtain surrogate consent (cognitively impaired subjects), and 
plans for obtaining assent and/or the permission of one or both parents (minors). 
N/A 
 
10. Potential Risks: 
 
1. Describe the known risks and/or potential discomforts associated with each intervention or 
research procedure.  Risks may be physical, psychological, social or economic. 
 
Mild side effects associated with nifedipine include headache, flushing and low blood pressure, which 
generally resolve with discontinuation of the medication and without further intervention. In a 
systematic review, Khan et al (2010) reported that the use of calcium channel blockers for tocolysis or 
for hypertension in pregnancy was associated with a 3-fold increased risk of tachycardia and an 8 to 
9-fold increased risk of hypotension when the dose exceeded 60 mg per day. However, this analysis 
included all pregnant women receiving all different types of calcium channel blockers (including 
severely hypertensive women, particularly women with preeclampsia and severe gestational 
hypertension, a very different population that we propose to study), and thus was not limited to 


 
Version 5.1 September 18, 2015 
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women with preterm labor, the sub-population than we propose to study. Regarding the possibility of 
hypotension, Luewan et al (2010) studied blood pressure in normotensive pregnant women treated 
with nifedipine 10 mg every 15 minutes up to 40 mg, followed by 60 mg controlled release tablet in 4 
to 6 hours. The authors defined hypotension as a decrease in diastolic blood pressure of at least 15 
mmHg from baseline, and reported up to 17% of patients met these criteria. They concluded that 
“hypotension secondary to nifedipine was not associated with significant clinical symptoms, 
suggesting that nifedipine is relatively safe in terms of hypotensive effect.” 
 
Houtzager et al (2006) performed long-term follow-up of children exposed in utero to nifedipine or 
ritodrine for preterm labor and reported: “The results do not support any differential postnatal effect of 
the tocolytic agents ritodrine or nifedipine on the child's long-term psychosocial and motor functioning. 
The slightly better outcome of children randomised in the nifedipine group is most likely due to more 
favourable perinatal outcomes in this group.” 
 
More serious side effects are rare when the widespread use of nifedipine in the community is 
considered.  In the English-language medical literature, there are 22 reported cases of pulmonary 
edema, 1 stillbirth and 2 cases of myocardial infarction associated with nifedipine tocolysis, but these 
risks were reported in association with other particular risk factors such as use with other tocolytic 
drugs, use of rapid-acting formulations, prolonged tocolysis and use when there was evidence of 
preexisting maternal cardiac disease/dysfunction (Bal et al, 2004; Vaast et al, 2004; Abbas et al, 
2006; Van Geijn et al, 2005; Nassar et al, 2007; Gatault et al, 2008; ; Kutuk et al, 2013; Serena et al, 
2014; Van Veen et al, 2005; Oei et al, 1999; Verhaert and Acker, 2004). The single report of stillbirth 
was disputed and provoked a series of follow-up letters in response to the controversy (Johnson, 
2005; Kandysamy, 2005; Papatsonis et al, 2005). Importantly, in 26 published trials involving isolated 
use of nifedipine for acute tocolysis, there were no cases of pulmonary edema or more serious side 
effects among patients receiving nifedipine (References 8a-aa). More recently, Kutuk (2013) reported 
a case of pulmonary edema with nifedipine use in a woman with ruptured membranes at 33 weeks. 
The authors note that the pulmonary edema occurred on the 4th day of her admission in association 
with prolonged tocolysis. In this case report of a single patient, there was prolonged use of nifedipine 
in a woman with ruptured membranes, which was arguably not acute tocolysis at all since the event 
occurred during a period typically associated with maintenance tocolysis. Our study restricts use to 
acute tocolysis with only 48 hours’ duration, and in women with intact membranes. Four other cases 
of pulmonary edema were reported by Serena et al (2014), but these were all in women with 
prolonged intravenous use of nicardipine, and intravenous tocolysis is a recognized risk factor for 
pulmonary edema (Oei, 2006). We are not using intravenous formulations nor will we be using 
nifedipine for prolonged periods (maximum 48 hours of acute tocolysis). 
 
Recently, Xiao et al (2014) reported the effect of magnesium sulfate and nifedipine on the risk of 
developing pulmonary edema in preterm births: “nifedipine did not increase the odds of developing 
pulmonary edema [adjusted odds ratio (OR)=1.22 (confidence interval (CI) 0.50, 2.01), P=0.67]”. Of 
note, Sciscione et al (2003) reviewed 62,917 consecutive pregnancies delivered between 1989 and 
1999 and reported that acute pulmonary edema due to tocolytics was exclusively in women who 
received multiple simultaneous tocolytic agents “the most common combination was intravenous 
magnesium sulfate and subcutaneous terbutaline.” In the current study, we are not using multiple 
tocolytics, and women in this study will not be receiving magnesium sulfate, so this risk is felt to be 
very low.  
 
A single case report of severe resistant maternal hypotension following tocolysis with nifedipine was 
published in December 2014 (Khoo and Mathur, 2014). There are several aspects of patient 
management within this case report that raise concern, and which are distinct from protocols in our 
present study. First, the patient in the case report presented with hypotension (87/51 mmHg) and 
ruptured membranes. In our present study, we exclude women with low blood pressure (systolic value 
less than 90 mmHg and/or a diastolic value less than 50 mmHg), as well as women with ruptured 


 
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membranes. Second, more aggressive dosing of nifedipine was used in the case report (nifedipine 10 
mg every 15 minutes for 4 doses). This more aggressive dosing amounted to 40 mg in the first hour, 
compared to the protocol in our present study, which calls for 20 mg, with an additional 20 mg after 90 
minutes if there are persistent contractions and hold-dosing parameters are not met. Third, the 
nifedipine was continued despite tachycardia (135 beats per minute) and persistent hypotension 
(88/43 mmHg). In the case report, despite the patient feeling weak and having persistent hypotension 
and tachycardia (83/43 mmHg and 121 beats per minute) 5 hours after the first dose of medication, 
the medication was continued. In our study, there is a hold dose parameter for heart rates of 120 
beats per minute or more. In the case report, the blood pressure dropped further to 76/42 with 
persistent tachycardia at 7 hours after the first dose of nifedipine, and the blood pressure at delivery 
was 56/43.  The authors could not be sure of the hypotension being attributable to the nifedipine and 
the authors considered sepsis in the differential diagnosis, and her intravenous antibiotics were noted 
to be “oralised” on the third postoperative day. Again, this single case report was notable for more 
aggressive nifedipine dosing in a woman with baseline hypotension and ruptured membranes at the 
outset, and the nifedipine was continued despite worsening clinical status and persistent tachycardia. 
We exclude women with ruptured membranes and baseline hypotension, and our hold-dose 
parameters offer further protection; therefore, the outcome reported in this single case report is most 
unlikely to occur given the protections set up in the present study. 
 
Two recent reviews of the literature recommend nifedipine as the first choice tocolytic for its possible 
beneficial effect and favorable side effect profile: 
1) Van Vliet et al (2014) wrote: “for the initial tocolysis, the use of atosiban or nifedipine for 48 h is 
recommended based on the largest effectiveness and most favorable side effect profile.” 
2) Haram et al (2014) wrote: “nifedipine may be a reasonable first choice because it is easy to 
administer and also of limited side effects relative to Beta2-mimetics.” 
We plan to restrict use to healthy, normotensive women with singleton pregnancies not receiving 
additional tocolytic agents.  We will also not use sublingual administration of nifedipine.  Therefore, 
these reported adverse reactions are most unlikely.  
 
2. Estimate the probability (chance or likelihood of occurrence) that a given harm may occur and 
its severity (mild, moderate or severe) and define risks by percentages, when available, or by 
categorizing with the terms rare, unlikely, likely. 
 
Mild Events: 
Mild headache or flushing: Likely;  Moderate headache, Dizziness or Nausea: Unlikely 
A review (Chan et al, 2008) of nifedipine for first-line tocolysis of 212 episodes of preterm labor in 203 
women reported that moderate headache was the most common side effect (9 of the 203 women, 
4.4%). Other side effects included flushing (9 of the 203 women, 4.4%), dizziness (4 of the 203 
women, 2%), nausea (3 of the 203 women, 1.5%), shortness of breath (1 of the 203 women, 0.5%). A 
study by Guclu (2006) found that up to 71% of patients had flushing and 25% had headache. A review 
(Marin et al, 2007) of nifedipine tocolysis in 24 patients reported that 11 (45.8%) had mild headache. 
 
Moderate Events: 
Hypotension or Tachycardia: Unlikely 
A review (Chan et al, 2008) of 203 women for whom nifedipine was prescribed as the first-line 
tocolytic in 212 episodes of preterm labor reported that nifedipine was discontinued for hypotension 
less than 90/60 in 3 women (1.5%). One woman (0.5%) developed tachycardia of at least 140 BPM. 
 
Pulmonary Edema: Rare 
There are 8 case reports/case series (Bal et al, 2004; Vaast et al, 2004; Abbas et al, 2006; Van Geijn 
et al, 2005; Nassar et al, 2007; Gatault et al, 2008; Kutuk et al, 2013; Serena et al, 2014) including a 
total of 22 patients with pulmonary edema in the English-language medical literature. Risk factors 
appear to be multiple gestation, sublingual (rapid-acting) or intravenous dosing of nifedipine or 


 
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nicardipine, use of multiple tocolytics, prolonged use of tocolysis and maternal cardiac disease or 
dysfunction. These risk factors will be avoided due to our very specific inclusion and exclusion criteria 
and the non-sub-lingual formulation of nifedipine used. In an expert review of the literature, Oei (2006) 
recommends that intravenous nicardipine or high doses of nifedipine should not be used in cases of 
multiple gestation or when the mother is compromised cardiovascularly.  Intravenous formulations will 
not be used in this study, and multiple gestations will be excluded. Importantly, in 26 published trials 
involving nifedipine for acute tocolysis, there were no cases of pulmonary edema among patients 
receiving nifedipine . 
 
Severe Events: 
Stillbirth or myocardial infarction: Extremely rare 
Van Veen et al (2005) reported the only identified case of stillbirth in the English language literature 
after use of nifedipine. Importantly, this patient received multiple tocolytics (atosiban, indomethacin, 
nifedipine) which will not be the case in our study. Only 2 case reports were found of myocardial 
infarction associated with nifedipine tocolysis in the literature (Oei et al, 1999; Verhaert and Acker, 
2004). In both cases healthy babies were ultimately delivered and there were no abnormalities on 
maternal follow-up testing. Importantly, in these cases nifedipine was used with another tocolytic 
(ritodrine), and in one case there were ruptured membranes. We will not be using nifedipine in 
conjunction with another tocolytic (in this case ritodrine), nor will we be using nifedipine in patients 
with ruptured membranes (at higher risk for infection). Of note, there have been 3 placebo-controlled 
trials of nifedipine for maintenance tocolysis over prolonged periods (Lyell et al, 2008; Parry et al, 
2012; Roos et al, 2013). Importantly, none of these reported severe adverse events for nifedipine 
during the long periods that maintenance tocolysis was employed. 
 
3.  Compare the risks of the research to standard of care.  If placebo controls are used, justify their 
use over active or other kinds of controls. 
 
At Parkland Hospital, patients receive corticosteroids for fetal lung maturity, ampicillin as prophylaxis 
for Group B streptococcus, sedation and hydration. Tocolytic drugs are not used for preterm labor. 
However, use of tocolytic agents is within the standard of care for women with preterm labor. Given 
that it is uncertain whether nifedipine for acute tocolysis results in a benefit by delaying preterm birth 
and its associated risks, or only carries risks of side effects without benefits, it is ethical to compare 
nifedipine to placebo. 
 
11. Subject Safety and Data Monitoring: 
 
1. Describe what measures have been taken and/or will be taken to prevent and minimize any 
risks or discomforts. 
 
Only singleton pregnancies in women with preterm labor and unruptured membranes will receive 
either placebo or nifedipine.  Multiple tocolytics will not be used. Additionally, intravenous or 
sublingual (rapid-acting) forms of nifedipine will not be used. Only women with preterm labor at 28-0/7 
weeks to 33-6/7 weeks will be included, as women with preterm labor between 24-0/7 weeks and 27-
6/7 weeks receive magnesium sulfate for neuroprophylaxis and magnesium sulfate can synergize with 
nifedipine to block calcium movement through calcium channels. Women with hypotension, 
tachycardia or significant maternal cardiac disease or hypertension treated with antihypertensives will 
be excluded at the outset. Women with potential indications for delivery will be excluded.  Hold dose 
parameters and stopping rule for further participation are detailed in Section 4(1) above. 
 
2. If applicable, discuss provisions for insuring necessary medical or professional intervention in 
the event of adverse events.   
 


 
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All study participants will undergo regular vital sign monitoring while on Labor & Delivery and on the 
antepartum unit. Patients on Labor and Delivery will have continuous electronic fetal monitoring and 
tocometer evaluation, and patients on the antepartum unit will have daily fetal heart testing. If a 
maternal or fetal complication is identified, physicians will be immediately available to intervene on 
behalf of the mother and fetus. 
 
3. Describe the plan for monitoring study data collected to protect subject safety and data 
integrity. Please review Guidance on Data and Safety Monitoring Plans for instructions on 
what information should be provided.  If desired, the DSMP Template may be used and 
included in your application packet. 
See DSMP 
 
4. Note: investigator-initiated studies involving administration of an experimental (i.e. not FDA 
approved for the indication/population under study) drug, device or intervention must submit a 
Data Safety Monitoring Plan (DSMP Template) and may be required by the IRB to establish a 
Data Safety monitoring Board (DSMB). 
See DSMP 
Summary of Sections 66.0 and 67.0 of the Smart Form for the Data Safety Monitoring Plan and 
Committee  
Who comprises the Data Safety Monitoring Committee (DSMC)? 
The DSMC is composed of Dr. Don McIntire, PhD, Professor and Statistician within the 
Department of Obstetrics and Gynecology, as well as two faculty physicians from the 
Department of Obstetrics and Gynecology not participating in the study (Dr. Scott Roberts and 
Dr. Oscar Andujo). 
When will the DSMC meet: 
The DSMC will meet at least annually during the projected 4 year duration of the study. 
Additionally, after accrual of 75 patients (half of the planned 150 patients for recruitment), an 
interim analysis will be performed.  
What will be analyzed by the DSMC? 
The DSMC will monitor study accrual rate, study attrition including participant 
withdrawals/dropouts, patterns of AEs and/or unanticipated events, patterns of protocol 
deviations and/or violations and changes in risk/benefit. Efficacy (positive and negative) as 
well as possible futility of further study will be examined at the interim analysis. Significance 
levels for the interim analysis will be altered by the method of Lan-DeMets. Safety will be 
evaluated at each meeting of the Data Safety and Monitoring Board.  
How will safety be evaluated and what study-specific stopping rules will be used by the DSMC? 
Safety will be evaluated by analyzing situations in which administration of the study drug is 
stopped according to the “STOPPING RULE” below.  
The study would be stopped if nifedipine is found to significantly delay preterm birth, or if a 
significantly greater number of stillbirths or emergency deliveries due to nonreassuring fetal 
heart tracing attributable to study drug during the 48 hour period during which the study drug 
will be administered for acute tocolysis of preterm labor.  
What safety mechanisms are built into the Nifedipine study protocol? 
Apart from the strict inclusion and exclusion criteria and the plan to continue maternal and fetal 
monitoring for at least 24 hours after beginning the study, the following safety parameters are 
part of the study protocol: 
There will be a “HOLD DOSE” parameter in which a dose will be held if an enrolled patient 
either refuses medication or has a heart rate greater than 120.  If a dose is held, the nurse will 
contact the 4th year resident who will ensure Dr. Wells is notified. 
There will be a “STOPPING RULE” for further individual participation in the study for any of the 
following criteria: withdrawal of consent, diffuse rash or anaphylaxis reaction to medication 
(requires confirmation by house officer), hypotension requiring delivery or medication such as 
ephedrine, or development of any obstetrical outcomes that would normally preclude tocolysis 


 
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(development of ruptured membranes, development of chorioamnionitis, development of 
preeclampsia/gestational hypertension, development of bleeding suspicious for abruption, 
cervical dilatation of 6 cm or more or fetal death), or if a decision is made to either deliver the 
patient or to give regional anesthesia. 
 
12. Procedures to Maintain Confidentiality: 
 
1. Describe how data/specimens will be collected and stored and the security methods in place.  
Note: the more sensitive the study data, the more sophisticated the methods should be to 
maintain confidentiality. 
 
Data on all obstetrical and neonatal outcomes are routinely entered into Dr. Leveno’s obstetrical 
operations database (a secure, password-protected database at UT Southwestern). 
 
2. If data/specimens will be disclosed to outside persons or entities, list the entities and the 
method used to code or de-identify the data/specimens. 
 
No data or specimens are anticipated to be disclosed to any outside persons or entities. 
 
3. State if you intend to apply for a Certificate of Confidentiality from the NIH. 
N/A 
 
13. Potential Benefits: 
 
1.  Describe the potential benefits of the research to the subjects, to others with similar problems, 
and to society.  If there is no prospect of direct benefit to the subjects, state how the knowledge 
to be gained will benefit society enough to justify any risks to subjects. 
 
Potential direct benefits to the study participant are prolongation of pregnancy and avoidance of 
preterm birth. Potential benefits to society include a better understanding of whether nifedipine is an 
effective intervention for tocolysis of preterm labor. 
 
14. Biostatistics: (omit this section for peer-reviewed research such as cooperative group, or NIH- 
sponsored studies, and for industry-sponsored research which has been submitted to FDA) 
 
 
1.  Describe the statistical methods to be used to answer the study question(s).  Pilot studies also 
require a method of analysis, but the justification of the target sample size is not required. 
 
T-tests (two-sided) will be used for continuous variables and Chi-squared tests for categorical 
variables. Power will be 80% and an alpha of 0.05 will be used. 
 
2. Explain how the target sample size was determined.   
 
Previous studies done on preterm patients at Parkland Hospital include Leveno et al (1986), Cox and 
Leveno (1990) and Chao et al (2011). In Chao et al (2011), there were 153 patients in 12 months. 
Over 4 years, we would anticipate four-times that (153 x 4 = 612).  In Chao et al (2011, The Diagnosis 
and Natural History of False Preterm Labor, Obstet Gynecol), 27% of the patients diagnosed with 
contractions and with cervical dilation of less than 2 cm delivered prior to 37 weeks’ gestation. 
However, this study by Chao et al was not a prospective study. Additionally, it focused on women with 
cervical dilatation less than 2 cm, whereas the current study includes women with cervical dilation of 2 
to 4 cm dilated. Importantly, women with more cervical dilation are more likely to deliver early, and it is 
appropriate to revise the target enrollment.  
 


 
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Fortunately, 2 prior Randomized, (placebo) Controlled Trials (RCT) of tocolysis (magnesium and 
ritodrine) from Parkland Hospital have been published. For the RCT by Leveno et al of ritodrine 
versus placebo (“Single-Centre Randomised Trial of Ritodrine Hydrochloride for Preterm Labour”, 
Lancet, 1986) in which women with singleton pregnancies and preterm labor with cervical dilation up 
to 4 cm, 39 of 52 (75%) patients randomized to the control group delivered between 27 and 35 
completed weeks. Similarly, for the RCT of magnesium sulfate versus placebo by Cox and Leveno 
(“Randomized investigation of magnesium sulfate for prevention of preterm birth” Am J Obstet 
Gynecol 1990) in which women with singleton pregnancies and preterm labor with cervical dilation 
less  than 5 cm, 55 of 80 (68.8%) of patients randomized to the control group delivered between 27 
and 35 completed weeks’ gestation. These are important data derived from randomized, placebo-
controlled, prospective trials done here at Parkland Hospital and we feel that our sample size should 
incorporate this prospectively obtained data. An average of the above preterm birth rates for these 
two RCTs at Parkland Hospital is 71.2% (39+55 / 52+80). In slight distinction to the above studies, for 
the current study, we are including women beginning at 28 weeks’ gestation, and we will be assessing 
preterm birth as delivery at less than 37 weeks. In theory, the preterm labor rate for delivery at less 
than 37 weeks (the primary outcome of the current trial) would be higher than this average preterm 
birth rate for women prior to 35 completed weeks’ gestation. However, using these prospectively 
obtained numbers from past studies of preterm labor at Parkland hospital, we would need 
approximately 150 women (75 women in each of the 2 arms) in order to detect a 1/3 reduction (from 
71.2% to 47.5%) in the rate of preterm birth with 80% power and an alpha of 5%. 
 
Analysis of internal obstetrics operations data indicates that for the month of March 2015, there were 
10 women between 28-0/7 weeks and 33-6/7 weeks with preterm labor and a cervix of 2 to 4 cm 
dilation. Of these 10 women, 6 were ineligible for participation in the study (2 had diabetes in 
pregnancy, 1 women had a twin gestation, 1 women was only 15 years of age and 1 woman had 
bleeding concerning for abruption). Of the 4 eligible women in March of 2015, 2 elected to participate 
in the study, consistent with our ongoing consent rate of approximately 50%. 
 
Effective September 17, 2015, there has been a protocol change at the level of the Division of 
Maternal-Fetal Medicine at Parkland Hospital. This protocol change will be to give corticosteroids for 
fetal lung maturity to women with diabetes and to all women with hypertension who are at risk of 
preterm birth. This MFM Division level protocol change will affect this study of women at risk of 
preterm birth. 
 
Given that 2 of the formerly ineligible women (due to diabetes) who presented in March 2015 would 
now be eligible due to the above protocol change, we estimate that up to 24 additional women (2 x 12 
= 24) would be screened per year, and up to 12 additional women (50% of the 24 additional 
screened) would participate. Given that there were 29 women recruited over the intitial13 months 
(which equates to approximately 27 over 12 months), under the new practice in which corticosteroids 
will be given more broadly (and women with diabetes and mild hypertension not treated with 
medications are eligible for participation), we estimate that up to 78-90 women would now be 
screened, and of these, we estimate that 39-40 women would participate per year. 
 
Therefore, over ~4-5 years, we would expect 300 patients screened and 150 patients consented. In 
order to detect a 33% reduction in the rate of preterm birth less than 37 weeks’ gestation, assuming 
80% power and a 2-sided alpha of 5%, a sample size of 75 patients per arm (two arms, study drug 
and placebo), 150 patients total, will need to be recruited. So far in the current study, we have had 
about a 50% consent rate. Assuming a 50% recruiting rate (50% x 300 = 150), it is estimated that this 
study will take 4 to 5 years to complete. 
 
 
References  
 


 
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