Conditions: Hypertension, Pregnancy-Induced Pre-eclampsia
Keywords: ibuprofen acetaminophen blood pressure post-partum pain control pre-eclampsia gestational hypertension
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 74
Healthy volunteers: no

Brief summary:
To assess the effect of routine doses of ibuprofen on post-partum blood pressure control in women with gestational hypertension (gHTN) or preeclampsia without severe features (preE).

Detailed description:
Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently prescribed for post-partum analgesia. This use is supported by limited data on post-partum pain specifically; however, ibuprofen and other NSAIDs are superior to acetaminophen in ameliorating uterine pain and cramping in dysmenorrhea. The effect of NSAIDs on blood pressure (BP) in women post-partum is less well-known. In non-pregnant hypertensive patients NSAIDs are associated with increased BP over short courses of days to months, though effects of various NSAIDs differ. Pooled analyses suggest changes in mean BP of up to 3-6 mm Hg depending on the measurement method.There are case reports of hypertensive crises after NSAID administration post-partum in both normotensive and hypertensive women. A larger, recent retrospective cohort study found no difference in mean arterial pressure (MAP) or need for antihypertensive therapy in women with severe hypertensive disorders of pregnancy who were exposed to NSAIDs post-partum.

In light of the potential for worsening blood pressure in women with hypertensive disorders of pregnancy, the Task Force on Hypertension in Pregnancy of American College of Obstetricians and Gynecologists stated that "providers should be reminded of the contribution of nonsteroidal anti-inflammatory agents to increased BP." Additionally the task force recommends that NSAIDS "be replaced by other analgesics in women with hypertension that persists for more than 1 day postpartum". However, provider practices since the publication of these guidelines have varied.

Hypothesis: When compared to acetaminophen, ibuprofen does not increase post-partum systolic blood pressure (SBP) above baseline to a clinically relevant degree (≥10 mmHg) in women with gHTN and preE.

Aim 1: To assess the mean difference in SBP during 24 hours of exposure to ibuprofen and acetaminophen.

Aim 2: To assess whether ibuprofen results in higher satisfaction with pain control in the immediate post-partum period (48 hours) compared to acetaminophen.

Aim 3: To prospectively assess the need for post-partum anti-hypertensive therapy and readmission for blood pressure control in women with gHTN and preE. The post-partum period is defined as delivery through 6 weeks after delivery.

Arms:
arm 1: Ibuprofen administered immediately post-partum, 600 mg (3 x 200 mg tablets) every 6 hours for 24 hours followed by acetaminophen, 650 mg (2 x 325 mg tablets) every 6 hours for 24 hours. arm 2: Acetaminophen administered immediately post-partum, 650 mg (2 x 325 mg tablets) every 6 hours for 24 hours followed by ibuprofen, 600 mg (3 x 200 mg tablets) every 6 hours for 24 hours.

Interventions: intervention 1: Ibuprofen intervention 2: Acetaminophen
Intervention descriptions: intervention 1: At the time of delivery, eligibility will be reviewed. If the participant remains eligible, she will be randomized by the study pharmacy to begin post-partum analgesic therapy with ibuprofen followed by acetaminophen. intervention 2: At the time of delivery, eligibility will be reviewed. If the participant remains eligible, she will be randomized by the study pharmacy to begin post-partum analgesic therapy with acetaminophen followed by ibuprofen.

Protocol document:
Prot_SAP_000.pdf: 
The Effect of Ibuprofen on Post-partum Blood Pressure in 
Women With Hypertensive Disorders of Pregnancy 
 
NCT02891174 
 
IRB final approval: 1-10-17 


OBGYN Research Program Study Protocol Template 
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Title:  A randomized-controlled trial to assess the effect of ibuprofen on post-partum 
blood pressure in women with hypertensive disorders of pregnancy 
 
Principal Investigator: Elizabeth Langen, MD  
 
Co-Investigators: Alexander Tsodikov, PhD; Jourdan Triebwasser, MD, MA 
 
1. Objective  
To assess the effect of routine doses of ibuprofen on post-partum blood pressure 
control in women with gestational hypertension (gHTN) or preeclampsia without 
severe features (preE).   
 
2. Specific Aims  
 
Hypothesis: When compared to acetaminophen, ibuprofen does not increase post-
partum systolic blood pressure (SBP) above baseline to a clinically relevant degree 
(10 mmHg) in women with gHTN and preE. 
 
Aim 1: To assess the mean difference in SBP during 24 hours of exposure to 
ibuprofen and acetaminophen.  
 
Aim 2: To assess whether ibuprofen results in higher satisfaction with pain control in 
the immediate post-partum period (48 hours) compared to acetaminophen. 
 
Aim 3: To prospectively assess the need for post-partum anti-hypertensive therapy 
and readmission for blood pressure control in women with gHTN and preE.  The 
post-partum period is defined as delivery through 6 weeks after delivery. 
 
3. Background  
 
Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently prescribed for post-
partum analgesia. This use is supported by limited data on post-partum pain specifically; 
however, ibuprofen and other NSAIDs are superior to acetaminophen in ameliorating 
uterine pain and cramping in dysmenorrhea.1-4 The effect of NSAIDs on blood pressure 
(BP) in women post-partum is less well-known. In non-pregnant hypertensive patients 
NSAIDs are associated with increased BP over short courses of days to months, though 
effects of various NSAIDs differ.5,6 Pooled analyses suggest changes in mean BP of up 
to 3-6 mm Hg depending on the measurement method.5,6 There are case reports of 
hypertensive crises after NSAID administration post-partum in both normotensive and 
hypertensive women.7 A larger, recent retrospective cohort study found no difference in 
mean arterial pressure (MAP) or need for antihypertensive therapy in women with 
severe hypertensive disorders of pregnancy who were exposed to NSAIDs post-partum.8 
 
In light of the potential for worsening blood pressure in women with hypertensive 
disorders of pregnancy, the Task Force on Hypertension in Pregnancy of American 
College of Obstetricians and Gynecologists stated that “providers should be reminded of 
the contribution of nonsteroidal anti-inflammatory agents to increased BP.” Additionally 
the task force recommends that NSAIDS “be replaced by other analgesics in women 
with hypertension that persists for more than 1 day postpartum”.9 However, provider 
practices since the publication of these guidelines have varied. 


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4. Study Team Expertise  
 
Elizabeth Langen, MD, is an Assistant Professor in the Department of Obstetrics and 
Gynecology in the Division of Maternal Fetal Medicine.  She is director of research for 
the division of Maternal-Fetal Medicine.  Her research has focused on both the causes 
and prevention of preterm birth, as well as evaluation of normal labor and has included 
both prospective observational and randomized controlled trials. 
 
Jourdan Triebwasser, MD, MA, is a fellow in the Department of Obstetrics and 
Gynecology in the Division of Maternal Fetal Medicine.  She has training in study design, 
biostatistics, and scientific writing through Master’s-level coursework.  She has 
previously recruited participants to randomized-controlled trials involving obstetric 
patients. 
 
Alexander Tsodikov, PhD: Professor of Biostatistics. Alexander is a faculty member of 
the Michigan Institute for Clinical & Health Research (MICHR) Biostatistics Group.  Dr. 
Tsodikov's research interests are in various areas of biostatistics and biomathematics, 
including failure time and survival analysis models, cure models, semiparametric 
inference, stochastic models, optimal control, and inference algorithms based on self-
consistency. 
 
Marjorie C. Treadwell, MD, is a Professor of Obstetrics and Gynecology with specialty 
certification in Maternal Fetal Medicine. With a primary interest in prenatal diagnosis and 
fetal therapy, she has worked closely with sub-specialists across the spectrum of 
pediatrics and adult medicine to advance the knowledge as well as clinical care of fetal 
conditions.  While at Wayne State University, she worked closely with the extramural 
Perinatal Research Branch of the NIH.  Multiple publications resulted from the 
collaborative relationship with that group, predominantly in the area of improving 
diagnosis and understanding of fetal cardiac abnormalities.  Since being based at the 
University of Michigan, she represents our fetal therapy program in the North American 
Fetal Therapy Network (NAFTNet), which is a consortium of (currently) 24 fetal therapy 
centers across North America.  University of Michigan participates in several multicenter 
trials and projects through this organization. Within the university, we recently completed 
a project with Radiology utilizing software developed by our biomedical team developing 
an innovative method of determining volume flow in patients with high risk pregnancies.  
As the Director, Fetal Diagnostic Center, she facilitates and coordinates multiple projects 
recruiting from our prenatal unit.  These projects involve multiple specialties across the 
spectrum of medicine and basic science.  
 
Lori J. Day, MD, is a Clinical Assistant Professor of Maternal Fetal Medicine. Her 
research interests include genetic contribution to prematurity and the physiology of 
premature labor. She has engaged in research specimen collection and storage for 
women in term and preterm labor and their newborns.  
 
Deborah Berman, MD, is an Associate Professor of Maternal Fetal Medicine. Her 
research interests include prenatal diagnosis, counseling, and management of fetal 
anomalies. Additionally, she has been a long time member and participant in the 
Perinatal Mood Disorders Team, collaborating on research on women with mood 
disorders throughout the pre-pregnancy, prenatal, and postpartum periods. She is 
actively involved in research on impaired fetal growth and other deleterious effects of 


OBGYN Research Program Study Protocol Template 
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depression in pregnant women, as well as maternal and fetal outcomes at a clinical and 
biochemical level in pregnancies complicated by maternal mood disorders. She is 
collaborating on a project with the School of Social Work that focuses on the mental 
health of male partners throughout pregnancy. Additionally, she had multidisciplinary 
collaborations on the neuroprotective effects and biochemical changes with 
Docosohexanoic Acid administration in models of intrapartum hypoxia-ischemia (HI) and 
neonatal encephalopathy.   
 
Clark Nugent, MD, is a Clinical Professor of Maternal Fetal Medicine. His prior research 
has included work on ultrasound assessment of the cervix and multiple gestation. 
 
Cosmas JM Van de Ven, MD, is the J. Robert Willson Professor of Obstetrics and the 
Director of Maternal Fetal Medicine in the Department of OBGYN. In the early 1980’s Dr. 
Van de Ven studied the role of sodium and potassium channels in the setting of 
hypertension in the department of physiology at UofM. This interest transitioned to 
endothelial cell function and paracrine control of the vascular smooth muscle in the 
setting of pre-eclampsia.  Dr. Van de Ven’s clinical interest focusses on maternal 
physiology and pathology. He is engaged in many departmental and institutional 
committees and administrative functions. 
 
Alissa Carver, MD, is a Clinical Assistant Professor of Maternal Fetal Medicine.  Her 
prior research has included work on preeclampsia, multifetal gestation, maternal 
infection, and labor. 
 
Mark Chames, MD, is a Clinical Assistant Professor in the Department of Obstetrics and 
Gynecology and specializes in Maternal and Fetal medicine with clinical interests in 
ultrasound, multiple pregnancies and medical complications and pregnancy with focus 
on hypersensitive disorders and diabetes. 
 
5. Methodology  
i. 
Trial design: 
1. 
 Cross-over randomized trial with 1:1 allocation ratio. 
2. 
 Double-blind design with drug encapsulation performed by 
research pharmacy. 
3. 
 Intervention (ibuprofen), control (acetaminophen). 
 
ii. 
Inclusion/Exclusion Criteria 
 
Inclusion: 
1. 
 Antepartum women diagnosed with gHTN or preE by blood 
pressure ≥140 systolic or ≥90 diastolic, on at least 2 measurements ≥ 
4 hours apart; with or without proteinuria (urine protein-creatinine ratio 
≥0.3 or 24 hour-urine protein ≥300 mg). 
2. 
 18-45 years of age. 
3. 
 Taking one or fewer oral medications for blood pressure control. 
4. 
 Singleton gestation. 
5. 
 English-speaking. 
 
Exclusion: 
i. 
Allergy to NSAIDs, aspirin, or acetaminophen. 
ii. 
Severe features of preeclampsia prior to enrollment: 


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a. More than 1 severe range blood pressure (≥160 systolic or 
≥110 diastolic). 
b. Neurologic symptoms attributed to hypertension (headache, 
visual changes). 
c. Pulmonary edema. 
d. Elevated AST (>60 international units/L) or ALT (>70 
international units/L). 
e. Low platelet count (<100,000/microliter). 
f. Renal insufficiency (creatinine > 1.1 or double the baseline 
creatinine if known).  
iii. 
Chronic hypertension defined as hypertension pre-existing pregnancy 
or diagnosed prior to 20-weeks’ gestation. 
iv. 
Moderate- or severe-persistent asthma. 
v. 
Therapeutic anticoagulation. 
vi. 
Chronic opiate use during the pregnancy (opiate therapy given daily 
for > 2 weeks). 
vii. 
Lactose intolerance or allergy due to placebo containing lactose. 
viii. 
Cesarean delivery. 
ix. 
Additional anesthesia at time of delivery (spinal anesthesia, sedation) 
that would change routine pain management. 
 
iii. 
Recruitment Plan and Study Design 
1. 
Number of Subjects: 40 (see details of power calculation in 
statistical analysis plan); however, we anticipate that up to 300 
women will sign consent to participate in the trial in order to have 40 
women undergo randomization. 
2. 
Method of Contact and Consenting:  
 
1. Antepartum Recruitment:  
a. Patients with diagnoses of gHTN and preE will be 
recruited as outpatients through the Fetal Diagnostic 
Center and OB-Gyn clinics at VonVoightlander 
Women’s Hospital.  Study  team members will review 
daily appointments in MiChart to determine eligibility.  
b. Once the patient is determine eligible a study team 
member will approach the potential subject prior to or 
after their scheduled appointment.   
2. Intrapartum Recruitment: 
a. Patients admitted to Labor & Delivery at 
VonVoightlander Women’s Hospital with diagnoses of 
gHTN and preE will also be recruited if not previously 
approached as an outpatient. Study team members will 
identify potential participants through monitoring triage 
admissions through the electronic medical system.  
b. To reduce possible burden on the participants who 
have personal or medical situations that might make 
recruitment contact upon check-in to triage distressing, 
we have added a step of contacting the attending 
provider or nurse prior to approaching the women. This 
will decrease the likelihood of recruiting someone 


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where special factors, such as a difficult social 
situation, exist.  
c. Once we consult with the provider to make sure they 
feel it would be acceptable for us to contact the 
potential volunteer, a study team member will approach 
the woman and explain the study. The potential 
participant will then be approached in a private location 
(such as a patient room) to discuss possible 
enrollment.  If enrollment is declined, a record will be 
made that the study was offered and declined so that 
the study team does not approach the participant 
again. 
 
3. Written informed consent will be obtained if all 
inclusion/exclusion criteria are satisfied at time of recruitment. 
4. If exclusion criteria develop in the interim (i.e. 
thrombocytopenia) between recruitment and delivery, the 
participant will not be randomized.  However, data from their 
delivery admission and post-partum period will be collected to 
compare to women who maintained trial eligibility. 
3. 
Method of Interaction/Procedure/Intervention:  
1. At the time the participant signs the consent document, a 
study team member will administer a survey to capture 
demographic and obstetric characteristics of participants. 
2. Patients will be managed intrapartum without regard to study 
involvement.  Mode of delivery will be determined by routine 
obstetric indications. 
3. If a participant undergoes cesarean delivery, she will not be 
randomized. 
4. At the time of delivery, eligibility will be reviewed.  If the 
participant remains eligible, she will be randomized by the 
study pharmacy to begin post-partum analgesic therapy with 
ibuprofen or acetaminophen.  Providers will be blinded to 
allocation group.  
5. The intervention will be conducted in cross over-fashion.  
Either ibuprofen or acetaminophen will be given for 24 hours 
with time starting at first dispense time (period 1).  Then the 
other drug will be given for the subsequent 24 hours (period 
2).  
a. Study drugs will be encapsulated for blinding purposes 
and given with in the following schedule: ibuprofen 
(600 mg every 6 hours) or acetaminophen (650 mg 
every 6 hours).   
b. The study drug doses will come in packets.  Ibuprofen 
packets will have three 200 mg tabs.  Acetaminophen 
packets will have two 325 mg tabs and one placebo 
tab.   
c. Oxycodone will be available for uncontrolled pain (5-10 
mg every 6 hours as needed). The number of doses 
taken will be recorded as measure of pain control. 
6. Pain assessment: 


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a. Prior to the first dose of pain medication, participants 
will take a brief, self-administered survey to assess 
pain. 
i. Abdominal pain and perineal pain will be 
assessed separately using 0 (no pain) to 10 
(worst possible pain) scale. 
ii. Overall pain will also be assessed using 0 (no 
pain) to 10 (worst possible pain) scale. 
b. Two hours after the first dose of study drug, 
participants will repeat the self-administered survey to 
assess abdominal, perineal, and overall pain using a 0-
10 scale. 
c. Pain scores as assessed by nursing will also be 
abstracted from the medical record.  
d. A brief survey on satisfaction with pain control during 
period 1 and period 2, as well as overall during post-
partum stay will be administered prior to discharge. 
i. Satisfaction will be assessed using a 5-point 
scale of (1) not at all satisfied (2) slightly 
satisfied (3) moderately satisfied (4) very 
satisfied (5) extremely satisfied. 
7. Blood pressure assessment: 
a. Standard blood pressure monitoring per post-partum 
protocol:  every 15 min x 1 hour, then every 30 min x 1 
hour, then every 4-8 hours until discharge per the 
discretion of the treating team.   
i. Additional blood pressures may be recorded 
according to provider preference (i.e. concern 
for spurious value, need to initiate 
antihypertensive therapy). 
b. Additional blood pressure monitoring will be performed 
during the period of study drug administration using a 
Spacelabs model 90207 ambulatory blood pressure 
monitor beginning at the time of first pain medication 
administration.  This monitor has been validated in 
pregnant patients.10 
i. The monitor will be set to record values every 
60 minutes.   
ii. The blood pressure monitor display will be 
covered in the accompanying carrying pouch to 
blind participants and providers to values. 
iii. The ambulatory blood pressure monitor will be 
discontinued after period 2 is complete. 
8. If the participant remains inpatient beyond the 48 hours of 
study drug administration, she will be given pain medication 
according to provider preference.   
9. Initiating antihypertensive therapy, repeating lab tests 
(creatinine, liver function tests, blood counts), time of 
discharge, and discharge pain medications will be at the 
discretion of treating physicians.   


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a. Antihypertensives are generally initiated with sustained 
SBP >150 mmHG at our institution. 
b. Discharge prescriptions for pain medications will be 
recorded. 
10. Data will be abstracted from the medical record regarding 
delivery, anesthesia, medical comorbidities, post-partum blood 
pressures readings, antihypertensives given, need for 
magnesium, pain medication usage, and hospital readmission. 
 
Study Schedule 
Recruitment 
 
Outpatient with diagnosis of preE or gHTN. 
 
Inpatient-if not previously approached as an outpatient or with 
new diagnosis of preE or gHTN upon admission. 
Consent 
 
Written informed consent will be obtained if all 
inclusion/exclusion criteria are satisfied at time of recruitment. 
Randomization 
 
Eligibility criteria reviewed at time of delivery. 
 
If participant remains eligible, will be randomized to 
ibuprofen/acetaminophen versus acetaminophen/ibuprofen by 
research pharmacy. 
Intervention 
 
Pain medications will be dispensed by the research pharmacy 
and administered by floor nurses. 
 
Blood pressure monitoring 
o Standard post-partum blood pressure monitoring will be 
performed by floor nurses and abstracted from the 
medical record. 
o Ambulatory blood pressure monitoring (Spacelabs model 
90207) will be performed during 48 hours of study drug 
administration. 
 
Inpatient pain assessment 
o Pain survey will be administered prior to first dose of 
medication in period 1. 
o Pain survey will be repeated 2 hours after first dose of 
medication in period 1. 
o Pain control satisfaction survey administered prior to 
discharge. 
Data abstraction 
 
The following will be abstracted from the electronic medical 
record after hospital discharge until 6 weeks post-partum: 
delivery mode, anesthesia, medical comorbidities, post-partum 
blood pressures readings, antihypertensives given, need for 
magnesium, pain medication usage, and hospital readmission. 
  
Compensation: $25 check per participant who undergoes randomization.  This is 
a one-time payment for participation. 
 
iv. 
Subject Withdrawal 


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1. 
Under what conditions will a subject be withdrawn prior to 
completion:  
1. Those who develop any exclusion criteria between enrollment 
and delivery. 
2. Those who require a second increase in antihypertensive 
medications post-partum. 
3. Those who develop renal insufficiency (creatinine > 1.1 or 
double the baseline creatinine). 
4. Those who develop thrombocytopenia (platelets < 
100,000/µL). 
2. 
If a subject withdraws prior to completion, what is the plan for the 
use of their data: 
1. If the participant withdraws prior to randomization, data on 
baseline characteristics, hospital course, and post-partum 
course will continue to be collected and analyzed unless the 
participant requests otherwise in writing. 
2. If the participant underwent randomization, data on hospital 
course and post-partum course will continue to be collected 
and analyzed.  Her information will be included in intention-to-
treat analysis. 
 
v. 
Data Retention and/or Data Destruction Plan: 
 
The patient data will be entered from paper enrollment forms into a REDCap database.  
All PHI will be marked as such in the REDCap database.  When data is downloaded for 
analysis, no PHI will be downloaded from the REDCap database.  REDCap is a secure 
web application designed to support data capture for research studies. REDCap servers 
are physically located in the University of Michigan Medical School Information Systems 
(MSIS) data center. Physical security for the databases is provided in a professionally 
managed and equipped tier-2data center with tightly controlled access.  Remote data 
access employs SSL encryption and 2-tier Kerberos/Level 1 and UMHS Level 2 
password challenges via LDAP authentication. Access to the application, the database, 
and the underlying systems infrastructure are consistent with industry best practices 
including HIPAA security and privacy requirements and the HITECH Act. The application 
provides audit trails on user access to MICHR and MSIS technical and support teams. 
Data will subsequently be deleted after being maintained for the prescribed period of 
time post study closure.  The original signed consent forms will be kept in a locked office 
in the University of Michigan Hospital.  These will be destroyed in hospital PHI 
destruction bins after being maintained for the prescribed period of time post study 
closure.   
 
6. Risks & Benefits  
i. 
Risks: 
1. 
  Possible increase in blood pressure with ibuprofen (Rare) 
2. 
  Risks of ibuprofen (package labeling warnings) 
a. Severe allergic reaction, especially in people allergic to 
aspirin (Rare) 
i. Hives 
ii. Facial swelling 
iii. Asthma/wheezing 
iv. Shock 


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v. Skin reddening 
vi. Rash 
vii. Blisters 
b. Severe stomach bleeding (Rare) 
i. Risk is higher if you are age 60 or older, have 
had a stomach ulcer or bleeding, take a blood 
thinning (anticoagulant) or steroid drug, take 
other drugs containing prescription or non-
prescription NSAIDs, have 3 or more alcoholic 
drinks every day while using this product 
c. The risk of heart attack or stroke may increase if you 
use more than directed or for longer than directed. 
(Rare) 
3. 
  Risks of acetaminophen (package labeling warnings) 
a. Severe liver damage (Rare) 
i. Risk is higher if you take more than 4 grams in 
24 hours, with other drugs containing 
acetaminophen, or with 3 or more alcoholic 
drinks every day while using this product. 
 
ii. 
Benefits:  
1. 
  Likely better pain control when receiving ibuprofen. 
 
7. Study Agent 
The study agents (ibuprofen and acetaminophen) will be procured by Research 
Pharmacy (RP) from commercial supply; RP will compound into blinded supply by 
over-encapsulating the tablets in matching gelatin capsules. RP will package the 
blinded supplies into kits as follows: the ibuprofen packets will have three 200 mg 
tablets and acetaminophen packets will have two 325 mg tablets and 1 placebo 
tablet.  The placebo tablet will contain lactose. The Research Pharmacy will be 
responsible for drug accountability according to their standard SOPs for drug 
accountability.  The medications will be administered by floor nurses. 
 
8. Statistical Design  
 
Randomization: 
- 
A random allocation sequence using 1:1 allocation will be generated by the 
biostatistician and provided to the research pharmacy. 
- 
Allocation concealment mechanism: randomization sequence given directly to 
study pharmacy.  Providers will call study pharmacy at time of delivery with 
randomization number.  This will be unblinded at the completion of study 
recruitment. 
Blinding:  
- 
Providers and participants blind to treatment allocation with capsules from 
pharmacy. 
 
Statistical methods:  
 
Sample size calculation: 
- 
There is limited post-partum or short-term NSAID data from which to base our 
sample size.   


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- 
In a study of hypertensive men and women treated with NSAIDs or placebo for 4 
weeks, the standard deviation of the difference in BP from baseline of 13 mmHg 
was observed.11  
- 
We are assuming the margin of equivalence (equivalence limit difference) to be 
approximately 10 mmHg. We also assume that intra-participant variation will be 
less than across-group variation seen in the Palmer study; we then assume a 
standard deviation of 8 mmHg.   
- 
With these parameters, a two-sided test of equivalence performed at the 
significance level of 0.05 will have at least 80% power to prove the hypothesis of 
equivalence with a total of 44 measurements. We are planning to recruit 40 
women over 12 months. This will bring the expected number of measurements 
available for the analysis (accounting for each woman bringing two-measurement 
in a cross-over trial) to 68 with a 15% expected drop-out rate. The reserve of 
sample size will be used to ensure we have more power to detect the carry-over 
effects of treatment into the next study drug period. 
 
Primary outcome: difference in SBP from baseline during 24 hours of drug exposure.  
- 
Baseline SBP will be calculated as the arithmetic mean of the initial 5 blood 
pressures recorded after admission for labor or induction of labor. 
- 
A linear mixed model with Gaussian subject-specific intercept term will be used 
to regress the longitudinal BP measurements on the treatment type, group 
(Ibuprofen-Acetaminophen, Acetaminophen-Ibuprofen), and time. The main 
effect of time that expresses differences at baseline before the drugs had a 
chance to have an effect will likely be removed from the model as no such 
differences are expected due to randomization. The time by treatment and group 
interaction terms will be of main interest. The primary hypothesis is that of 
equivalence. Equivalence testing (no meaningful difference in BP between the 
two drugs) will be done using two one-sided 95% confidence intervals for the 
regression parameter representing the effect. The hypothesis of equivalence will 
be accepted if the intersection of the two one-sided intervals is contained entirely 
inside the region of equivalence.  
 
Secondary outcomes: 
- 
Mean change in pain score after 1 dose of pain medication 
- 
Satisfaction with pain control (treated as an ordinal categorical score) 
o Linear models will be used to analyze pain. Ordinal logistic regression 
(the Proportional Odds Model) will be used to analyze the satisfaction 
endpoint.  Hypotheses of significance will be tested by the likelihood ratio 
test. Model diagnostics will be performed using standardized residual 
plots. Variable transformations and Generalized Linear (Mixed) Models 
will be considered with continuous responses in case model diagnostics 
reveals a departure from linearity or normality assumptions. Reasons for 
missing data will be analyzed using a multinomial logistic model. Analysis 
results with missing data excluded will be presented along with the 
analysis where missing data will be imputed using predictive matching. 
 
- 
Need for antihypertensive therapy in the post-partum period (descriptive statistics 
only) 
- 
Incidence of severe hypertension during period 1 versus period 2 (Fisher exact 
test) and during the post-partum period (descriptive statistics only). 
 


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Descriptive statistics such as means and proportions will be calculated for each variable 
of interest (obstetric and demographic characteristics). Statistically significant differences 
will be assessed at the p<.05 level. Data will be analyzed using R and SAS 9.4 (SAS 
Institute, Cary, NC).  
9. Adverse Event Reporting 
Adverse Event Definition 
An adverse event (AE) is any untoward medical occurrence in a subject participating in 
an investigation study or protocol regardless of causality assessment. An adverse event 
can be an unfavorable and unintended sign (including an abnormal laboratory finding), 
symptoms, syndrome or disease associated with or occurring during the use of an 
investigational product whether or not considered related to the investigational product. 
 
These events may be: 
a) Definitely related: clearly associated with study drug/treatment 
b) Probably related: likely associated with study drug/treatment 
c) Possibly related: may be associated with study drug or other treatment 
d) Unlikely to be related or 
e) Definitely not related to the study drug/treatment 
 
For reporting purposes, an AE should be regarded as definitely or probably related to the 
regimen if the investigator believes that at least one of the following criteria are met: 
a) There is a clinically plausible time sequence between onset of the AE and the 
administration of the study drug or treatment. 
b) There is a biologically plausible mechanism for the study drug or treatment 
causing or contributing to the AE. 
c) The AE cannot be attributed solely to concurrent/underlying illness, other drugs, 
or procedures. 
d) A potential alternative cause does not exist. 
 
Serious Adverse Events (SAE):  An adverse drug experience occurring at any dose 
that results in any of the following outcomes: 
a) Death 
b) A life-threatening adverse drug experience 
c) A persistent or significant disability and/or incapacity 
d) A congenital anomaly or birth defect 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may 
required medical or surgical intervention to prevent one of the outcomes listed in this 
definition. A serious adverse experience includes any experience that is fatal or 
immediately life threatening, results in a persistent or significant disability/incapacity, 
requires or prolongs in-patient hospitalization, or is a congenital anomaly, cancer, or 
overdose. 
 
Other important medical events that may not result in death, not be life-threatening, or 
not require hospitalization may be considered a serious adverse experience when, 
based upon appropriate medical judgment, the event may jeopardize the subject/patient 
and may required medical or surgical intervention to prevent one of the outcomes listed 
previously. 


OBGYN Research Program Study Protocol Template 
Page 12 of 12 
 
Expected adverse events are those adverse events that are listed in the protocol, the 
package inserts or in the study informed consent document. 
Unexpected adverse events are those that are not described in the package insert or are 
not anticipated in the study informed consent document. This includes adverse events 
for which the specificity or severity is not consistent with the description in the informed 
consent. 
 
The severity or grade of an adverse event may be measured using the following 
definitions: 
Mild: Noticeable to the subject, but does not interfere with subject’s expected daily 
activities, usually does not require additional therapy or intervention, dose reduction, or 
discontinuation of the study. 
Moderate: Interferes with the subject’s expected daily activities, may require some 
additional therapy or intervention but does not require discontinuation of the study. 
Severe: Extremely limits the subject’s daily activities and may require discontinuation of 
study therapy, and/or additional treatment or intervention resolve 
 
Adverse Event Reporting 
The study will comply with the IRB & FDA reporting requirements and guidelines. 
 
10. 
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postpartum episiotomy pain. J Clin Pharmacol. 1989;29:550-3. 
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intrauterine pressure and menstrual pain in dysmenorrhea. Br J Obstet Gynaecol 
1984;91:1129-35. 
3. Zhang WY, Po ALW. Efficacy of minor analgesic in primary dysmenorrhea: a 
systematic review. Br J Obstet Gynaecol 1998;105:780-9. 
4. Marjoribanks J, Ayeleke RO, Farquhar C, Proctor M. Nonsteroidal anti-inflammatory 
drugs for dysmenorrhea. Cochrane Database of Systematic Reviews 2015;7:CD001751. 
5. Pope JE, Anderson JJ, Felson DT. A meta-analysis of the effects of nonsteroidal anti-
inflammatory drugs on blood pressure.  Arch Intern Med. 1993;153:477-84. 
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