Clinical trial NCT04236258
Conditions: Hypertension in Pregnancy Preeclampsia Severe Gestational Hypertension Postpartum Preeclampsia Postpartum
Sponsor: Brigham and Women's Hospital
Start date: 2020-01-24; Completion date: 2021-06-30
Enrollment: 94 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study evaluates whether nifedipine or enalapril is better at decreasing the amount of medical resources used in the postpartum period by women who have high blood pressure in pregnancy and the postpartum period. Half of participants will receive enalapril while the other half will receive enalapril. We will compare the two groups in the amount of medical resources used which we are defining as prolonged hospitalizations, unscheduled medical visits and/or hospital readmissions in the postpartum period.

Detailed description:
This is randomized controlled trial to investigate if enalapril is superior to nifedipine in terms of medical resources used in postpartum women with hypertension. These are both antihypertensives we commonly use in the postpartum period for women with hypertension in pregnancy but we do not know which medication works better at decreasing prolonged hospitalizations, the number of unscheduled medical visits and/or readmissions to the hospital.

Nifedipine is more traditionally used and well-validated by current medical literature. However, enalapril's mechanism of action is better suited to the dysregulation of blood pressure that can occur with hypertensive disorders of pregnancy. Therefore, we hypothesize that enalapril is superior to nifedipine in terms of medical resources used in the postpartum period.

Arms: arm 1: This arm will be postpartum women with high blood pressure who need an antihypertensive and have been assigned to start nifedipine extended release 30 mg daily as their starting antihypertensive. arm 2: This arm will be postpartum women with high blood pressure who need an antihypertensive and have been assigned to start enalapril 10 mg daily as their starting antihypertensive.
Interventions: intervention 1: NIFEdipine ER intervention 2: Enalapril
Intervention descriptions: intervention 1: Postpartum women with high blood pressure will be randomized to receive nifedipine extended release 30mg daily as their starting antihypertensive. intervention 2: Postpartum women with high blood pressure will be randomized to receive enalapril 10 mg daily as their starting antihypertensive.

Protocol documents:
Prot_000.pdf: 
PARTNERS HUMAN RESEARCH COMMITTEE 
PROTOCOL SUMMARY 
Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
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Answer all questions accurately and completely in order to provide the PHRC with the relevant 
information to assess the risk-benefit ratio for the study.  Do not leave sections blank. 
 
PRINCIPAL/OVERALL INVESTIGATOR 
Thomas McElrath, MD, PhD 
 
PROTOCOL TITLE 
A Randomized Controlled Trial Comparing Nifedipine and Enalapril in Medical 
Resources Used in the Postpartum Period 
 
 
FUNDING 
None 
 
 
VERSION DATE 
2/3/21 
 
 
SPECIFIC AIMS 
Concisely state the objectives of the study and the hypothesis being tested. 
This project aims to determine if enalapril is superior to nifedipine at 
preventing prolonged hospitalizations, unplanned medical visits and/or 
readmissions in women with hypertension in the postpartum period. Our 
hypothesis is that women with hypertensive disorders of pregnancy 
randomized to enalapril as their primary antihypertensive will require fewer 
resources in the postpartum period than women randomized to nifedipine. 
 
 
 
BACKGROUND AND SIGNIFICANCE 
Provide a brief paragraph summarizing prior experience important for understanding the 
proposed study and procedures. 
 
Hypertension is a common complication of pregnancy and the postpartum 
period and is responsible for a significant use of medical resources as women 
often require prolonged hospitalizations, unscheduled clinic visits and 
readmissions to control their blood pressure. (Stevens 2012, Clapp 2016) 
Many women may require antihypertensives to control it. Currently, at 
Brigham and Women’s Hospital, we interchangeably use nifedipine, enalapril 
and/or labetalol to control postpartum hypertension. We do not know which 
medication is best, especially at preventing the use of extra medical 
resources. Nifedipine and enalapril are dosed daily so likely patients are 
more able to comply with treatment. We theorize that the mechanism of 


Partners Human Subjects Research Application Form 
  
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action of enalapril is best suited for patients with hypertension in pregnancy 
as there appears to be a dysregulation of the renin-angiotensin-system. 
(Gant 1973) 
 
 
RESEARCH DESIGN AND METHODS 
Briefly describe study design and anticipated enrollment, i.e., number of subjects to be enrolled 
by researchers study-wide and by Partners researchers.  Provide a brief summary of the 
eligibility criteria (for example, age range, gender, medical condition).  Include any local site 
restrictions, for example, “Enrollment at Partners will be limited to adults although the sponsor’s 
protocol is open to both children and adults.”
 
This is an open-label randomized controlled trial in which participants will be 
randomized to receive either nifedipine or enalapril in the postpartum period 
for hypertension requiring antihypertensives. Women who are pregnant or 
recently postpartum (within 6 weeks) with hypertension can be recruited for 
the study. They must also be at least 18 years old and planning to follow-up 
at Brigham and Women’s Hospital. They can be on no more than one 
antihypertensive and if they are, it must have been started in pregnancy. 
Women are not eligible for the study if they have any strict contraindications 
to nifedipine, enalapril or labetalol or a history of failed treatment with any 
of those agents. Their creatinine during admission must be less than 1.5. 
There will be 45 women recruited to each arm for a total of 90 women in the 
study. They will officially enter the trial once they are postpartum and their 
provider wants them to start or continue an antihypertensive.  
 
All women will be enrolled by physician investigators or other physicians at 
Brigham and Women’s Hospital who have agreed to help consent patients for 
this study. All patients will give written consent and will be informed that a 
licensed physician investigator is available to speak with them at any time 
during the consent process. 
 
Briefly describe study procedures.  Include any local site restrictions, for example, “Subjects 
enrolled at Partners will not participate in the pharmacokinetic portion of the study.”  Describe 
study endpoints.
 
Patients who participate in the study will be randomized to receive nifedipine 
or enalapril in the postpartum period to control hypertension. The assigned 
antihypertensive should be titrated to control blood pressure so that systolic 
blood pressure is consistently less than 150 mmHg and diastolic blood 
pressure is consistently less than 95 mmHg. If a patient reaches 90mg daily 
of nifedipine or 40mg daily of enalapril without achieving this blood pressure 
goal or the patient’s provider believes the assigned agent (nifedipine or 
enalapril) is ineffective, labetalol 200mg twice daily should be added to the 
regimen. Patients will follow-up in clinic in one week after discharge and six 
weeks for blood pressure checks and to have basic metabolic panels drawn. 


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At the six week visit, patients will be asked to complete a short survey. 
These are standard visits for postpartum patients. The study will be over 
once the patient has had her six-week postpartum visit.  
 
The patient may be contacted via telephone by study staff to verify any 
additional interactions with outside hospitals or medical providers (which 
would influence the primary outcome). 
  
For studies involving treatment or diagnosis, provide information about standard of care at 
Partners (e.g., BWH, MGH) and indicate how the study procedures differ from standard care.  
Provide information on available alternative treatments, procedures, or methods of diagnosis.
 
There is no consensus on the best antihypertensive to use during the 
postpartum period. Currently at BWH, providers usually choose to use 
nifedipine, enalapril and/or labetalol to control postpartum hypertension as 
they are effective and safe during breastfeeding. The study procedures differ 
from standard care only in that it is formally randomized and not provider 
dependent.  
 
There are alternative antihypertensives to use such as methyldopa or 
clonidine but these are rarely used at BWH. 
 
 
Describe how risks to subjects are minimized, for example, by using procedures which are 
consistent with sound research design and which do not unnecessarily expose subjects to risk or 
by using procedures already being performed on the subject for diagnostic or treatment purposes.
 
Risks to participants are minimized because the protocol is not deviating 
from standard care as we are giving medications that we would normally 
give in the postpartum period. 
 
Describe explicitly the methods for ensuring the safety of subjects.  Provide objective criteria for 
removing a subject from the study, for example, objective criteria for worsening disease/lack of 
improvement and/or unacceptable adverse events.  The inclusion of objective drop criteria is 
especially important in studies designed with placebo control groups.
, 
Patients will be monitored closely in the hospital and then in the postpartum 
period. We will monitor their vital signs and any symptoms or side effects 
they may have. We would remove a patient from the study if she has an 
adverse reaction to any of the antihypertensives such as significant 
hypotension, uncontrollable hypertension or intolerance of the medication. 
We will follow-up with these patients one week after they are discharged 
from their hospitalization and at six weeks postpartum.  
 


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FORESEEABLE RISKS AND DISCOMFORTS 
Provide a brief description of any foreseeable risks and discomforts to subjects.  Include those 
related to drugs/devices/procedures being studied and/or administered/performed solely for 
research purposes.  In addition, include psychosocial risks, and risks related to privacy and 
confidentiality.  When applicable, describe risks to a developing fetus or nursing infant.
 
There is always the risk that the antihypertensive to which a participant is 
randomized will not work to control blood pressure or cause side effects.  
 
We think there is minimal risk to our trial because these are all medications 
we routinely use in the postpartum period. We plan to carefully monitor 
patient’s blood pressures and symptoms and providers will be able to titrate 
the antihypertensives and add additional antihypertensives if needed to 
control blood pressure.  
 
 
EXPECTED BENEFITS 
Describe both the expected benefits to individual subjects participating in the research and the 
importance of the knowledge that may reasonably be expected to result from the study.  Provide 
a brief, realistic summary of potential benefits to subjects, for example, “It is hoped that the 
treatment will result in a partial reduction in tumor size in at least 25% of the enrolled subjects.”  
Indicate how the results of the study will benefit future patients with the disease/condition being 
studied and/or society, e.g., through increased knowledge of human physiology or behavior, 
improved safety, or technological advances. 
 
Because this study is a randomized controlled trial, there is no direct benefit 
to individuals. Given the nature of the study we do not know if, and which 
treatment is better. Furthermore, the study is randomly allocated so there is 
an equal chance of the patient being in either treatment arm. However, it is 
hoped that prescribing enalapril for postpartum women will decrease the 
frequency that women have prolonged hospitalizations, unscheduled clinic 
visits, triage visits or readmissions in the postpartum period by 30 
percentage points. 
 
This study will also ideally benefit women in the future. By determining 
which antihypertensive decreases the use of resources in the postpartum 
period (i.e. prolonged hospitalizations, unscheduled clinic visits, triage visits 
or readmissions), we will be able to help future patients by prescribing the 
antihypertensive that is best to minimize disturbances to their postpartum 
period. In addition, we will add to the limited body of knowledge regarding 
the use of ACE inhibitors in the postpartum period. 
 
EQUITABLE SELECTION OF SUBJECTS 
The risks and benefits of the research must be fairly distributed among the populations that stand 
to benefit from it.  No group of persons, for example, men, women, pregnant women, children, 
and minorities, should be categorically excluded from the research without a good scientific or 


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ethical reason to do so.  Please provide the basis for concluding that the study population is 
representative of the population that stands to potentially benefit from this research.
 
Postpartum women with hypertension are the only group of women who will 
benefit from a study evaluating antihypertensives in the postpartum period. 
We are including all women who initially need a single antihypertensive to 
control their blood pressure in the postpartum period.  
 
 
When people who do not speak English are excluded from participation in the research, provide 
the scientific rationale for doing so.  Individuals who do not speak English should not be denied 
participation in research simply because it is inconvenient to translate the consent form in 
different languages and to have an interpreter present.
 
 
 
For guidance, refer to the following Partners policy: 
          Obtaining and Documenting Informed Consent of Subjects who do not Speak English
          https://www.partners.org/Assets/Documents/Medical-Research/Clinical-
Research/Non-English-Speaking-Subjects.pdf 
 
 
 
RECRUITMENT PROCEDURES 
Explain in detail the specific methodology that will be used to recruit subjects.  Specifically 
address how, when, where and by whom subjects will be identified and approached about 
participation.  Include any specific recruitment methods used to enhance recruitment of women 
and minorities.
Women will be enrolled from Labor and Delivery, the inpatient antepartum 
service or from the postpartum service. They will be identified by their 
diagnosis of hypertension.  The patient’s clinician will ask the patient 
permission to be approached by study investigators. Once permission 
granted, patients will be approached by physician investigators who will 
explain the study and obtain consent. If patients are recruited while they are 
pregnant, they will not enter the trial until they are postpartum and need an 
antihypertensive. If patients are recruited while they are postpartum, they 
will enter the trial once they need an antihypertensive. 
 
 
Provide details of remuneration, when applicable.  Even when subjects may derive medical 
benefit from participation, it is often the case that extra hospital visits, meals at the hospital, 
parking fees or other inconveniences will result in additional out-of-pocket expenses related to 
study participation.  Investigators may wish to consider providing reimbursement for such 
expenses when funding is available


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Subjects will not be provided remuneration for participation in this study. 
Given that the study will occur in an admission and in routine postpartum 
visits, there will be no extra hospital visits, parking or meals. 
 
 
 
 
For guidance, refer to the following Partners policies: 
          Recruitment of Research Subjects 
          https://www.partners.org/Assets/Documents/Medical-Research/Clinical-
Research/Recruitment-Of-Research-Subjects.pdf
 
          Guidelines for Advertisements for Recruiting Subjects
          https://www.partners.org/Assets/Documents/Medical-Research/Clinical-
Research/Guidelines-for-Advertisements.pdf 
 
          Remuneration for Research Subjects
          https://www.partners.org/Assets/Documents/Medical-Research/Clinical-Research/Remuneration-for-
Research-Subjects.pdf 
 
 
CONSENT PROCEDURES 
Explain in detail how, when, where, and by whom consent is obtained, and the timing of consent 
(i.e., how long subjects will be given to consider participation).  For most studies involving more 
than minimal risk and all studies involving investigational drugs/devices, a licensed physician 
investigator must obtain informed consent.  When subjects are to be enrolled from among the 
investigators’ own patients, describe how the potential for coercion will be avoided.
Patients will be consented on Labor and Delivery or during an inpatient 
admission for antepartum or postpartum care by the physician investigators. 
If a patient is still pregnant, she may consent to the study and will not 
formally be randomized until she is postpartum and her provider determines 
she needs an antihypertensive. If a patient is postpartum when she is 
consented, her provider may want to start antihypertensives shortly after 
she has been consented to the study. Therefore, pregnant patients may 
have several hours or days to decide if they want to participate in the study. 
Postpartum patients will likely have less than 1 hour to decide if they want 
to be in the study if their provider wants to start antihypertensives as it 
would be unsafe to delay treatment.  
 
If a patient is approached to be in the trial by her own provider, there will be 
additional objective providers available from the inpatient Maternal Fetal 
Medicine team to talk with the potential participant about the study.  
 
 
 


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NOTE: When subjects are unable to give consent due to age (minors) or impaired decision-
making capacity, complete the forms for Research Involving Children as Subjects of Research 
and/or Research Involving Individuals with Impaired Decision-making Capacity, available on 
the New Submissions page on the PHRC website: 
      https://partnershealthcare.sharepoint.com/sites/phrmApply/aieipa/irb 
 
For guidance, refer to the following Partners policy: 
     Informed Consent of Research Subjects:
     https://www.partners.org/Assets/Documents/Medical-Research/Clinical-
Research/Informed-Consent-of-Research-Subjects.pdf
 
 
 
DATA AND SAFETY MONITORING 
Describe the plan for monitoring the data to ensure the safety of subjects.  The plan should 
include a brief description of (1) the safety and/or efficacy data that will be reviewed; (2) the 
planned frequency of review; and (3) who will be responsible for this review and for determining 
whether the research should be altered or stopped.  Include a brief description of any stopping 
rules for the study, when appropriate.  Depending upon the risk, size and complexity of the 
study, the investigator, an expert group, an independent Data and Safety Monitoring Board 
(DSMB) or others might be assigned primary responsibility for this monitoring activity.        
 
NOTE: Regardless of data and safety monitoring plans by the sponsor or others, the principal 
investigator is ultimately responsible for protecting the rights, safety, and welfare of subjects 
under his/her care. 
 
The principal investigator will review the entries for each participant to 
ensure they are complete. We will not have a data safety committee for this 
study given that we would not stop the study early because we feel there is 
minimal increased risk from the study protocol. Serious adverse events 
(including but not limited to cardiovascular events, severe allergic reaction, 
uncontrollable hypertension) will be reviewed by the head of labor and 
delivery, Julian Robinson MD, and the study staff to ensure the outcome is 
not related to study protocol. Dr. Robinson will serve as a safety monitor 
during the study. 
 
 
Describe the plan to be followed by the Principal Investigator/study staff for review of adverse 
events experienced by subjects under his/her care, and when applicable, for review of sponsor 
safety reports and DSMB reports.  Describe the plan for reporting adverse events to the sponsor 
and the Partners’ IRB and, when applicable, for submitting sponsor safety reports and DSMB 
reports to the Partners’ IRBs.  When the investigator is also the sponsor of the IND/IDE, include 
the plan for reporting of adverse events to the FDA and, when applicable, to investigators at 
other sites.   
 


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NOTE: In addition to the adverse event reporting requirements of the sponsor, the principal 
investigator must follow the Partners Human Research Committee guidelines for Adverse Event 
Reporting
 
When adverse events occur they will be reported to the Partners’ IRB within 
5 days with a detailed description of the event, as assessment if the event is 
related to research and corrective actions, if applicable. Adverse events 
(including but not limited to cardiovascular events, severe allergic reaction, 
uncontrollable hypertension) will be reviewed by the head of labor and 
delivery and the study staff to ensure the outcome is not related to study 
protocol. 
 
 
MONITORING AND QUALITY ASSURANCE 
Describe the plan to be followed by the principal investigator/study staff to monitor and assure 
the validity and integrity of the data and adherence to the IRB-approved protocol.  Specify who 
will be responsible for monitoring, and the planned frequency of monitoring.  For example, 
specify who will review the accuracy and completeness of case report form entries, source 
documents, and informed consent.   
 
NOTE: Regardless of monitoring plans by the sponsor or others, the principal investigator is 
ultimately responsible for ensuring that the study is conducted at his/her investigative site in 
accordance with the IRB-approved protocol, and applicable regulations and requirements of the 
IRB.
 
The data will be entered into a REDCap database. This will allow the principal 
investigator and study staff access to all the data. The quality of the data 
can therefore be assessed within the database. The principal investigator will 
review the entries for each case report. They will also review each informed 
consent to ensure it is adequately filled out in accordance with IRB protocol. 
 
 
For guidance, refer to the following Partners policies: 
          Data and Safety Monitoring Plans and Quality Assurance
         https://www.partners.org/Assets/Documents/Medical-Research/Clinical-Research/DSMP-in-
Human-Subjects-Research.pdf 
 
          Reporting Unanticipated Problems (including Adverse Events)
          https://www.partners.org/Assets/Documents/Medical-Research/Clinical-
Research/Reporting-Unanticipated-Problems-including-Adverse-Events.pdf
 
 
 
PRIVACY AND CONFIDENTIALITY 
Describe methods used to protect the privacy of subjects and maintain confidentiality of data 
collected.  This typically includes such practices as substituting codes for names and/or medical 


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record numbers; removing face sheets or other identifiers from completed 
surveys/questionnaires; proper disposal of printed computer data; limited access to study data; 
use of password-protected computer databases; training for research staff on the importance of 
confidentiality of data, and storing research records in a secure location.   
 
NOTE: Additional measures, such as obtaining a Certificate of Confidentiality, should be 
considered and are strongly encouraged when the research involves the collection of sensitive 
data, such as sexual, criminal or illegal behaviors.
 
Each subject will be deidentified and given a study number. This study 
number will be linked to the MRN within the REDCap database but will be the 
only personal health identifier. The REDCap database will be limited only to 
study staff. This REDCap database has been used broadly within the 
Partners system as it is a password-protected database. 
 
 
SENDING SPECIMENS/DATA TO RESEARCH COLLABORATORS OUTSIDE 
PARTNERS 
Specimens or data collected by Partners investigators will be sent to research collaborators 
outside Partners, indicate to whom specimens/data will be sent, what information will be sent, 
and whether the specimens/data will contain identifiers that could be used by the outside 
collaborators to link the specimens/data to individual subjects.
 
No specimens or data will be sent to research collaborators for use outside of 
the Partners system. 
 
 
Specifically address whether specimens/data will be stored at collaborating sites outside 
Partners for future use not described in the protocol.  Include whether subjects can withdraw 
their specimens/data, and how they would do so.  When appropriate, submit documentation of 
IRB approval from the recipient institution.
 
 
 
RECEIVING SPECIMENS/DATA FROM RESEARCH COLLABORATORS OUTSIDE 
PARTNERS 
When specimens or data collected by research collaborators outside Partners will be sent to 
Partners investigators, indicate from where the specimens/data will be obtained and whether the 
specimens/data will contain identifiers that could be used by Partners investigators to link the 
specimens/data to individual subjects.  When appropriate, submit documentation of IRB 
approval and a copy of the IRB-approved consent form from the institution where the 
specimens/data were collected.
 
No specimens or data will be collected by research collaborators outside of 
Partners.  


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SAP_001.pdf: 
Study Title: Randomized Controlled Trial Comparing Nifedipine and Enalapril in Medical Resources Used 
in the Postpartum Period 
NCT04236258 
1/3/2022 
 
 


 
Biostatistical analysis:  
The primary outcome is a composite of additional medical resources used in the postpartum period in 
order to control hypertension and/or the symptoms associated with the antihypertensives. The 
composite includes prolonged hospitalization beyond the typical stay (>2 days for a vaginal delivery, >4 
days for a cesarean delivery), unscheduled clinic visits, Labor and Delivery triage visits or a postpartum 
readmission. The primary outcome is binary; if a patient has at least one of the composite outcomes she 
is considered to have the primary outcome. The secondary outcomes will include time to sustained 
blood pressure control (hours from initiation of medication to no additional changes to regimen), need 
to add additional antihypertensives (yes/no), clinically significant episodes of hyper- or hypotension 
(yes/no), creatinine levels at one week after discharge and six weeks postpartum, continued need for 
antihypertensives one week after discharge and six weeks postpartum (yes/no), side effects (listed), 
adverse events (listed), patient reported compliance (yes/no) and a patient satisfaction survey 
administered on the day of discharge from the delivery admission.  The appointments at one week after 
discharge and six weeks postpartum are standard practice.  
 
We plan to analyze this trial on an intention-to-treat basis. The primary outcome will be measured as 
the proportion of patients within each group that had at least one of the composite outcomes.  To 
determine the baseline rate of our primary outcome, we looked at a small sample of randomly selected 
patients with postpartum hypertension who were discharged home on antihypertensives and observed 
the primary outcome occurs 70% of the time in this cohort. We believe that a clinically relevant 
decrease in this outcome would be to decrease this proportion below 50%. Therefore, we have chosen 
40% as our target for what we would consider a successful intervention.  For sample size, we are 
assuming an alpha of 0.05 and a power of 80%.  Using a two-sided T-test in R comparing proportions of 
the two outcomes, we determined we will need 40 participants in each arm. Accounting for possible lack 
of follow-up, we will aim to enroll 45 in each arm, for a total of 90 patients.