Nifedipine XL Versus Placebo for the Treatment of Preeclampsia With Severe Features During Induction of Labor
Phase: PHASE4
Conditions: Preeclampsia Severe
Sponsor: Ohio State University

 
 
 
 
 
Nifedipine XL versus placebo for the treatment of preeclampsia with severe features 
during induction of labor 
 
 
 
 
Protocol Proposal 
 
 
 
 
 
 
Erin Cleary, MD 
Ohio State University 
 
Kara Rood, MD 
Ohio State University 
 
Maged Costantine, MD 
Ohio State University 
 
NCT04392375 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
03/13/2020

 
 
 
1.0 Introduction 
 
1.1 Study Abstract 
Preeclampsia occurs in 5-8% of pregnancies and is associated with significant maternal and 
neonatal morbidity and mortality.1 Diagnosis of preeclampsia with severe features requires 
delivery when the diagnosis is made at or beyond 34 weeks gestation.  Delivery may be 
indicated prior to 34 weeks when criteria for expectant management are not met, such as in the 
setting of uncontrolled maternal hypertension, progression of disease with worsening of 
laboratory values or persistent clinical symptoms, or worsening fetal well being.  Although clear 
algorithmic guidelines exist for the treatment of acute-onset severe hypertension in the 
antepartum, intrapartum or postpartum period1, limited data exists on starting long acting 
antihypertensive medications to aid in management of elevated blood pressures during 
induction of labor.     
 
1.2 Primary Aim 
To compare Nifedipine 30mg XL with placebo for improved blood pressure control in women 
with preeclampsia with severe features undergoing induction of labor. 
 
1.3 Primary Hypothesis 
Among women with preeclampsia with severe features undergoing induction of labor, Nifedipine 
30mg XL decreases need for additional acute antihypertensive treatment compared with 
placebo. 
 
1.4 Secondary Aims 
The secondary aims of this study are to assess the effect of Nifedipine 30mg XL compared with 
placebo on mode of delivery, indications for cesarean delivery, maternal hypotension and other 
adverse events, and a composite of maternal and perinatal adverse outcomes.  
 
2.0 Background 
 
Preeclampsia complicates approximately 1 in 25 pregnancies2, and is therefore a relatively 
common obstetric complication.  It is the second leading cause of maternal mortality worldwide 
after hemorrhage, and may lead to maternal comorbidities including stroke, eclampsia, and 
organ failure. Fetal or neonatal outcomes include intrauterine growth restriction, low birth 
weight, and stillbirth. Many of the complications associated with preeclampsia lead to early 
induction of labor or cesarean delivery and subsequent preterm birth. 
 
Preeclampsia with severe features may be diagnosed in the absence of severe blood 
pressures, defined as systolic blood pressure (SBP) ≥160mm Hg or diastolic blood pressure 
(DBP) ≥110mm Hg, when other severely defining features are present.  These include clinical 
features (persistent headache or vision disturbances), laboratory features (liver enzymes twice 
the upper limit of normal, thrombocytopenia with platelet count less than 100,000/mL, or 
creatinine greater than 1.1mg/dL, or end organ injury. When severe blood pressures are 
present, prompt management is required to avoid sequelae such as stroke or placental 
abruption.  Existing data support the use of oral Nifedipine or intravenous hydralazine or 
labetalol for the treatment of hypertensive urgency in pregnancy1.  Optimal treatment for severe 
blood pressure during induction of labor for the diagnosis of preeclampsia with severe features 
has not been described, but inadequate blood pressure control is a risk factor for cesarean 

 
 
delivery.  In a review of the Consortium for Safe Labor, at least 27% of women undergoing 
induction of labor for preeclampsia with severe features between 24-34 weeks gestation 
required a cesarean delivery for hypertensive disease3.  In a review of over 200,000 women 
using the Prospective database, the frequency of any antihypertensive use in preeclampsia 
increased between 2006 and 2014, with corresponding risk reduction in stroke4.  
Acute blood pressure treatment is not without maternal or fetal risk.  In about 10% of pregnant 
patients treated with intravenous labetalol or hydralazine, hypotension (defined as a drop in 
30% of SBP) occurs5.  Rapid and profound decrease in maternal blood pressure may result in 
hypoperfusion of the uterus secondary to a rightward shift occurring in the pressure 
autoregulation curve of the uterine arteries6, whereas a gradual decrease in blood pressure is 
safer for both the patient and the fetus, with less risk for maternal dizziness or fetal distress.  
When a non-reassuring fetal monitoring cannot be adequately resuscitated through maternal 
volume expansion, repositioning, or improvement in blood pressure, cesarean delivery is 
indicated.  
In the antepartum or postpartum period, the most commonly prescribed oral agents for 
maintenance therapy include labetalol, methyldopa and Nifedipine.  Scant guidelines exist on 
the introduction of a maintenance or long-acting agent anti-hypertensive medication to control 
blood pressure during an induction of labor.  A recent randomized controlled trial compared oral 
nifedipine, labetalol and methyldopa in women with severe hypertension, with the primary 
outcome of non-severe blood pressure at 6 hours after administration of first dose, more 
common in patients assigned to Nifedipine7. In this study, the median time to delivery among all 
participants was 24 hours, with cesarean delivery for the indication of uncontrolled blood 
pressure occurring least frequently with Nifedipine (absolute difference of -5.2 compared to 
labetalol and -3.5 compared to methyldopa).    
We propose a randomized double blind placebo controlled trial in women with preeclampsia 
with severe features undergoing induction of labor, to evaluate the efficacy of Nifedipine XL 
initiated in the intrapartum period on the need for acute therapy to reduce persistently severe 
range blood pressure. 
 
 
2.1 Rationale for a Randomized Controlled Trial 
The lack of existing data on optimal hypertension management during induction of labor for 
preeclampsia with severe features leads to confusion among providers and significant variation 
in management.  Exhausting the algorithms for intravenous labetalol and hydralazine, as well as 
oral immediate-release nifedipine, necessitates consideration of a continuous infusion of an 
anti-hypertensive agent, often requiring ICU-level care.  Furthermore, intravenous therapy also 
introduces the risk for cesarean due to non-reassuring fetal status secondary to maternal 
hypotension.  Therefore, patients with persistently severe range blood pressures are at risk for 
multiple intravenous or immediate-acting oral agents, as well as at risk for cesarean delivery to 
expedite treatment of preeclampsia.   
To further describe best practice management of intrapartum preeclampsia with severe 
features, we aim to compare long-acting nifedipine 30mg to placebo. This dose will allow full 
range of options with intravenous labetalol or hydralazine, as well as immediate-release 
Nifedipine, for the treatment of hypertensive urgency.  
 
3.0 Study Design  
This is a randomized double blind placebo controlled trial comparing Nifedipine 30mg XL to 
placebo in 110 patients after decision has been made to proceed with induction of labor for the 
diagnosis of preeclampsia with severe features.    

 
 
Potential study participants will be identified at the time of admission to the labor & delivery unit.  
Eligibility criteria will be verified. At the time of enrollment, patients will be randomized to either 
the study drug (oral Nifedipine XL 30mg) or identical placebo. Participants will receive the first 
dose of the study medication after enrollment unless recorded blood pressure is <120/70.  
Dosing will continue every 24 hours through delivery. Algorithms for the administration of 
intravenous labetalol or hydralazine will be utilized by the primary provider at his or her 
discretion.  Postpartum management of hypertension with oral medications will be unblinded 
and at the provider’s discretion. 
 
This study is a randomized, double-blind, placebo controlled single center clinical trial 
conducted at The Ohio State University Wexner Medical Center, where approximately 
216 women are delivered for preeclampsia with severe features each year. These 
women will be randomized at the time of induction of labor into two groups. 
• 
Oral administration of 30mg Nifedipine XL q24 hours until delivery 
• 
Matching placebo group q24hrs until delivery 
• 
Women may take the study drug/placebo concurrently with intravenous labetalol 
or hydralazine or immediate release Nifedipine for the treatment of severe blood 
pressures during cervical ripening and/or induction of labor per unit protocol. 
• 
All other obstetric care will be at the discretion of the primary provider, including 
but not limited to cervical ripening and augmentation methods, intrapartum 
resuscitation, IV magnesium for seizure prophylaxis and recommendations 
regarding mode of delivery. Data will be collected on these components of routine 
obstetric care. Analysis will be by intent to treat. 
 
3.1 Preeclampsia with severe features diagnosis determination 
Among women without a history of chronic hypertension, preeclampsia without severe features 
is typically made based on elevated blood pressures and proteinuria greater than 300mg/24 
urine collection; however, in the absence of proteinuria, the severely-defining features below 
can be used for diagnostic purposes.  Preeclampsia with severe features is diagnosed based on 
the following: 
• 
Development of hypertension, defined as a persistent SBP of 160mm Hg or higher, or 
DBP of 110mm Hg or higher on two occasions at least 4 hours apart while the patient is 
on bedrest (unless antihypertensive therapy is initiated before this time) 
• 
Alternatively, the diagnosis can be made with a SBP of 140 mm Hg or higher, or a DBP 
of 90 mm Hg or higher after 20 weeks of gestation in a patient with previously normal 
blood pressure, plus any of the following: 
o Thrombocytopenia, with platelet count of less than 100,000/microliter  
o Impaired liver function as indicated by abnormally elevated blood concentrations 
of liver enzymes (to twice normal concentration), severe persistent right upper 
quadrant or epigastric pain unresponsive to medication and not accounted for by 
alternative diagnoses, or both 
o Progressive renal insufficiency (serum creatinine concentration greater than 
1.1mg/dL or a doubling of the serum creatinine concentration in the absence of 
other renal disease  
o Pulmonary edema 
o New-onset cerebral or visual disturbances  
 

 
 
• 
In women with baseline chronic hypertension, preeclampsia is diagnosed based on any 
of the following (not accounted for by alternative diagnoses):  
o Severe hypertension (SBP ≥160 mmHg or DBP ≥110 mmHg) ≥ 20 weeks in 
gestation on two occasions with measurements taken at least 4 hours apart or 1 
occasion with subsequent antihypertensive therapy, or an escalation of 
antihypertensive medications to control blood pressure  
o New onset of proteinuria or a doubling in protein in women with baseline 
proteinuria  
o Thrombocytopenia (platelet count <100,000 per microliter)  
o Progressive renal insufficiency (serum creatinine >1.1 mg/dl or doubling of the 
serum creatinine in the absence of other renal disease) 
o Impaired liver function (elevated transaminases ≥ 70 U/L, or severe persistent 
right upper quadrant or epigastric pain unresponsive to medication)  
o Pulmonary edema diagnosed clinically by exam or chest x-ray  
o New-onset and persistent (non-responsive to supportive treatment) cerebral or 
visual symptoms.  
o HELLP [hemolysis, elevated liver enzymes and low platelet count] syndrome 
defined as the occurrence of all of the following (not accounted for by alternative 
diagnoses):  
o Hemolysis: evidenced by (1) serum total bilirubin ≥ 1.2 mg/dL (20 μmol/L), (2) 
serum lactate dehydrogenase (LDH) ≥ 600 IU/L, or (3) hemolysis on peripheral 
smear  
o Thrombocytopenia (platelet count < 100,000 / microliter)  
o Serum aspartate aminotransferase (AST) or alanine transaminase (ALT) ≥ 70 
IU/L  
• 
Atypical HELLP defined as the occurrence of 2 of the 3 following (not accounted for by 
alternative diagnoses)  
o Hemolysis: evidenced by (1) serum total bilirubin ≥ 1.2 mg/dL (20 μmol/L), (2) 
serum lactate dehydrogenase (LDH) ≥ 600 IU/L, or (3) hemolysis on peripheral 
smear  
o Thrombocytopenia (platelet count < 100,000 / microliter)  
o Serum aspartate aminotransferase (AST) or alanine transaminase (ALT) ≥ 70 
IU/L 
Eclampsia defined as an occurrence of a seizure without any known cause  
 
3.2 Study Aims 
The primary aim is the need for intravenous or immediate-release oral therapy for acute 
treatment of severe hypertension. 
3.3 Secondary Aims 
The secondary aims of this study are to evaluate 
• 
Route of delivery 
• 
Indications for cesarean section (uncontrolled hypertension, failure to progress, non-
reassuring fetal well-being, etc) 
• 
Maternal hypotension (<30% baseline or mean arterial pressure <65 mmHg) 

 
 
• 
Time from enrollment to hospital discharge 
• 
Postpartum hypertension control, including frequency and dosing of acute or 
maintenance antihypertensive therapy 
• 
Composite of adverse maternal outcomes (time duration to need for acute 
antihypertensive therapy, receipt of second dose study drug, time from randomization to 
delivery, seizure, adverse CNS outcome (stroke or cortical blindness), pulmonary 
edema, oliguria, DIC, admission to ICU, dialysis, mechanical ventilation, abruption, post-
partum hemorrhage, receipt of blood products, maternal death) 
• 
Composite of adverse neonatal outcomes (intrapartum fetal demise, abruption, neonatal 
death, Apgar score <7 at 5 minutes, intubation, convulsions, IVH, confirmed sepsis, RDS 
requiring O2, NICU admission)   
.  
3.4 Study Groups  
This study is a randomized, double-blinded placebo controlled single center clinical trial 
conducted at OSU Wexner Medical Center of 110 women with diagnosis of preeclampsia with 
severe features. These women will be randomized at the time of admission to the labor & 
delivery unit to one of two groups: 
• 
Daily Nifedipine 30mg XL 
• 
Identical appearing placebo  
Participants in the study will have the study medication administered by their nurse at time of 
enrollment and randomization, and every 24 hours thereafter until delivery.  All other obstetric 
care will be at the discretion of the primary provider, including but not limited to: treatment of 
hypertensive urgency, timing and mode of delivery. Data will be collected on these components 
of routine obstetric care. 
 
3.5 Population and Eligibility Criteria  
a) Setting: This single center study will be conducted at The Ohio State University 
Wexner Medical Center. 
b) Inclusion criteria: 
1. Women aged 18-45 with a viable single or twin intrauterine pregnancy between 22 0/7 
and 41 6/7 weeks gestation based on the best obstetric estimate by ACOG criteria. 
2. Diagnosis of preeclampsia with severe features with decision made to induce labor.  
The patient may or may not have already received acute treatment for severe blood 
pressures. 
 
c) Exclusion criteria: 
• 
Known allergy or adverse reaction to Nifedipine or any medical condition where 
Nifedipine is contraindicated, such as galactose intolerance, severe GI stricture, 
and GI hypomotility disorder.  
• 
Currently receiving Nifedipine XL as part of hypertension management prior to 
induction of labor 
• 
Participation in another trial that affects the primary outcome without prior 
approval 
• 
Physician/provider or patient refusal 

 
 
• 
Participation in this trial in a prior pregnancy 
• 
Triplet or higher order pregnancy 
 
3.6 Gestational Age Determination  
Gestational age is determined using criteria proposed by the American Congress of 
Obstetricians and Gynecologists, the American Institute of Ultrasound in Medicine, and 
the Society for Maternal-Fetal Medicine, and is denoted “project gestational age.” The 
“project EDC,” which is based on the project gestational age, cannot be revised once a 
determination has been made. If the pregnancy is conceived by in-vitro fertilization, 
project gestational age is calculated from the date of embryo transfer and the embryo 
age at transfer. If the pregnancy is conceived spontaneously (including ovulation 
induction and artificial insemination) information from the earliest dating ultrasound and 
the last menstrual period are used to determine project gestational age. If no dating 
ultrasound has been performed previously, one must be performed before the patient can 
be randomized. 
The following algorithm is used: 
• 
The first day of the last menstrual period (LMP) is determined, and a judgment 
made as to whether or not the patient has a “sure” LMP date. 
• 
If the LMP date is unsure, ultrasound measurement(s) obtained at the patient’s 
first dating ultrasound examination is used to determine the project gestational 
age. If the first dating ultrasound was conducted before 14 weeks 0 days, the 
measurement must be based on crown rump length (CRL). 
• 
If the LMP date is sure, project gestational age is determined by a comparison 
between the ultrasound measurements based on the earliest dating ultrasound. If 
the ultrasound confirms the gestational age by LMP as in the table below, the 
LMP-derived gestational age is used to determine the project gestational age. 
Otherwise, project gestational age will be determined based upon the ultrasound 
measurement. 
 
 
Table 1. Cutoffs for using LMP to determine gestational age for sure LMP 
Gestational age at first ultrasound 
by LMP 
Ultrasound agreement with LMP 
up to 8 6/7 weeks (by CRL) 
≤5 days 
9 0/7 weeks to 13 6/7 weeks (by CRL) 
≤7 days 
14 0/7 to 15 6/7 weeks 
≤7 days 
16 0/7 to 21 6/7 weeks 
≤10 days 
*CRL = Crown Rump Length 
 
 
3.7 Randomization Method and Masking 
Randomization may occur upon confirmation that all inclusion/exclusion criteria are 
satisfied, after verification of participant consent and HIPAA authorization. 
Consenting women will be randomly assigned to nifedipine 30XL and placebo in a 1:1 

 
 
ratio according to a randomization sequence prepared by and maintained by independent 
statistician and available from central investigational pharmacy who will dispense study 
drug or placebo. The two study arms are double masked; neither the patient nor the 
clinical staff will be aware of the treatment assignment. 
The simple blocked randomization method will be used to generate the randomization 
sequences because it provides a high probability of balance in treatment assignments, it 
is unpredictable, and it allows an explicit randomization analysis to be conducted with 
relative ease.  
 
4.0 Study Procedures 
4.1 Screening and Eligibility and Consent 
The participant's inclusion and exclusion criteria will be verified as will her interest in the 
study. The informed consent process will be conducted by trained research staff and will 
include all aspects of the study and a full disclosure of the risks, benefits, procedures, 
and alternatives. The study consent and HIPAA authorization will be signed after all 
questions have been discussed and answered. Collection of baseline information, 
including contact information, demographic and pregnancy history information, will follow 
the informed consent process. 
 
 
4.2 Randomization and Baseline Visit Procedures 
Randomization may occur upon confirmation that all inclusion/exclusion criteria are 
satisfied, after verification of participant consent and HIPAA authorization. Study staff will 
also verify participant contact information and obtain a Release of Information, as 
permitted by local policy, to collect outcome and serious adverse event (SAE) 
documentation. Patients will be assigned next sequential number and central pharmacy 
will dispense study drug or placebo depending on randomization allocation sequence.  
Once the patient is randomized, the patient will receive a study drug or placebo from 
clinical nurse.  She will be instructed to take 1 pill daily until delivery.  
In addition to information collected for eligibility, gestational age, and EDC determination, 
the following information will be obtained at randomization from a patient interview 
followed by a review of her chart: 
• 
Demographic information: age, race, insurance status 
• 
Medical history: pre-pregnancy weight, current weight, height, chronic disease 
history 
• 
Obstetrical history including outcomes of all prior pregnancies and which 
pregnancy(ies) was complicated by preeclampsia.  
• 
Social history: marital status, years of education, alcohol use, tobacco use, and 
maternal drug use 
• 
Record baseline blood pressure, and baseline preeclampsia laboratory data 
including platelets, creatinine, liver function tests and proteinuria status, if 
performed 
• 
Medication use e.g. ASA prior to enrollment, antihypertensive medications 
including prior administration of acute antihypertensive medications, metformin, 
anti-platelet agents, etc 
 

 
 
4.3 Obstetric Management  
All aspects of obstetric management will be left to the patient’s provider. Data will be 
collected on baseline laboratory values (when obtained), surveillance ultrasounds for 
fetal growth, antenatal testing, and timing and mode of delivery. 
 
5.0 Sample Size and Power  
For the purposes of sample size estimation, it is assumed that 85% of women with diagnosis of 
preeclampsia with severe features receive acute IV antihypertensive therapy and 74% will 
require additional IV hypertensive therapy throughout induction of labor process. Assuming rate 
of additional acute IV antihypertensive (primary outcome) without use of maintenance long 
acting antihypertensive therapy is 74%. It is estimated that sample size of 110 women is 
required to demonstrate at least a 40% reduction in use of additional acute antihypertensive 
therapy with the use of nifedipine 30XL (from 74% to 44%), with a power of 80%, and type I 
error of 5% 2-sided. 
 
Primary Outcome  
Treatment Effect 
Power 
Total N 
Placebo 
Nifedipine 
 
 
 
75% 
52.5% 
30% reduction 
80% 
140 
 
 
 
85% 
160 
 
 
 
90% 
188 
 
45% 
40% reduction 
80% 
82 
 
 
 
85% 
92 
 
 
 
90% 
108 
70% 
49% 
30% reduction 
80% 
170 
 
 
 
85% 
194 
 
 
 
90% 
226 
 
42% 
40% reduction 
80% 
97 
 
 
 
85% 
110 
 
 
 
90% 
128 
65% 
45.5% 
30% reduction 
80% 
202 
 
 
 
85% 
230 
 
 
 
90% 
270 
 
 39% 
40% reduction 
80% 
114 
 
 
 
85% 
130 
 
 
 
90% 
150 
  
2.6 Statistical Analysis Plan 
Standard comparisons of characteristics between groups will be conducted at baseline. It 

 
 
is anticipated that the randomization scheme will balance the groups for these covariates 
and they will not be adjusted for in the primary analysis.  
The primary analysis will compare incidence of the outcome between the 2 study groups. 
If the two groups show a difference in the incidence of the primary outcome, interactions 
will be evaluated and subgroup analyses conducted to determine whether the effect 
prevails.  
Lost to follow up should not occur given study design and no follow up is scheduled. 
Since many of the secondary endpoints as dichotomous variables like the primary 
outcome, standard statistical methods for rates and proportions will be appropriate. 
Continuous variables will be compared using standard statistical methods,  
 
 
6.0 Data Management  
6.1 Data Collection Forms  
Data will be collected on standardized forms on which nearly all responses have been 
pre-coded. Each form is briefly described below. 
• 
Screening Log 
• 
Eligibility Checklist 
• 
Randomization: completed for all eligible women, lists randomized drug code 
number 
• 
Baseline Form: includes detailed demographic and social data, medical & 
obstetrical history, and current pregnancy complications (to date), as applicable 
• 
Study Drug lots: documents dispensing of study medication and the return of any 
unused study medication 
• 
Maternal delivery and outcome forms: documents labor, delivery and postpartum 
information through the first 7 days after delivery 
• 
Neonatal baseline form: records date and time of birth, delivery data and status at 
delivery for each fetus/infant 
• 
Neonatal outcome form: records outcome data for all infants admitted to the NICU 
or special care nursery 
• 
Patient status form: documents loss to follow-up/withdrawal status, side effects 
since the last dose 
• 
Will do an intrapartum BP log.  
 
6.2 Recruitment and Data Collection Period 
Over 200 women are diagnosed with preeclampsia with severe features at Ohio State 
Wexner Medical Center. Based on inclusion criteria it is estimated that at least 60% of 
women would meet inclusion criteria and undergo an induction of labor (n=120). Using a 
conservative 60%, 72 women per year would be eligible and consent for enrollment. 
Therefore this study can be completed in less than 2 years.  
 
 

 
 
 
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