Clinical trial NCT03171480
Conditions: Preeclampsia Labor, Premature
Keywords: Preeclampsia Induction
Sponsor: Ohio State University
Start date: 2017-10-30; Completion date: 2020-07-01
Enrollment: 176 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A randomized controlled trial (RCT) of nitric-oxide donor (NOD) isosorbide mononitrate (IMN) versus placebo as an adjuvant to misoprostol/ intra-cervical Foley bulb for induction of labor to decrease rate of cesarean deliveries in pregnancies complicated by preeclampsia (≥24/0 weeks' gestation)

Detailed description:
The investigators are proposing a double blinded, placebo controlled, randomized clinical trial of patients undergoing induction of labor for preeclampsia. Once the decision to induce will be taken, the participants will be randomized to receive either intravaginal IMN (40mg) or identical appearing placebo placed every 4hrs in the posterior vaginal fornix X 3 doses. IMN or placebo will be discontinued when active labor occurs or when the physician decides to proceed with augmentation with oxytocin or AROM. Participants will be induced using the investigators routine induction agents, Misoprostol (25 mcg every 4 hrs for maximum of 6 doses) and an intra-cervical foley bulb will be inserted with 2nd dose of IMN or placebo. Regarding management of labor, physician decides when to proceed with augmentation with oxytocin or AROM.

Arms: arm 1: Isosorbide mononitrate is a drug used principally in the treatment of angina pectoris\[1\] and acts by dilating the blood vessels so as to reduce the blood pressure. It is sold in the USA by Kremers Urban under the trade name Monoket, also sold in the USA under the name Imdur, arm 2: The pharmacy has compounded an identical appearing placebo
Interventions: intervention 1: Monoket Pill intervention 2: Placebo
Intervention descriptions: intervention 1: Intra-vaginal application of Monoket as a cervical ripening agent for pregnant women undergoing induction of labor intervention 2: The pharmacy has compounded an identical appearing placebo

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
Use of Nitrous Oxide Donor for Labor Induction in Women with 
PreEclampsia (NOPE) 
 
 
NCT03171480 
 
November 2017 
 


 
 
 
 
Use of Nitrous Oxide Donor for Labor Induction in Women with PreEclampsia or 
Gestational Hypertension (NOPE): A Randomized Controlled Trial 
  
Draft Protocol 
 
 
 
 
 
 
 
 
Kara Rood MD  
The Ohio State Wexner Medical Center 
Department of OB/GYN, Maternal Fetal Medicine 
 
 
 
 
 
 
November 2017 
 
Version 1.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
1. Introduction 
 
 
1.1 Background: 
 
Hypertensives diseases of pregnancy, including preeclampsia and gestational 
hypertension affects at least 5-10% of all pregnancies. Preeclampsia is the most severe 
form and is a rapidly progressive condition characterized by high blood pressure and 
the presence of protein in the urine. Gestational hypertension is defined as systolic blood 
pressure (SBP) >140 mmHg and diastolic blood pressure (DBP) >90 mmHg and approximately 
half of women diagnosed with gestational hypertension will progress to preeclampsia. 
 
To date there is no cure for preeclampsia except delivery. Given the potential of 
adverse consequences for both mother and fetus, preeclampsia and gestational 
hypertension is the leading diagnosis triggering medically indicated preterm birth. 
Therefore, most patients with gestational hypertension or preeclampsia who require 
delivery will not be in spontaneous labor and must undergo induction of labor. The 
obstetrician then faces a dilemma regarding the optimal method of induction. As to date 
there is no consensus to guide the physician on the best method for induction of labor. 
The ideal induction agent(s) should result in a relatively short induction to delivery 
interval without risk to fetus and with low rates of cesarean sections. The induction to 
delivery interval and low rates of CD is especially important in preeclampsia, to 
minimize significant maternal and infant morbidity associated with CD and to preventing 
worsening of disease.  
 
Nitric oxide (NO) is a free radical that plays a fundamental role in human physiology, 
being involved in the homeostasis of different functions. In obstetrics, this molecule is 
determinant in the physiology of labor and cervical ripening and it has been implicated 
as playing a fundamental role in the etiology of preeclampsia. In blood vessels, NO is a 
potent vasodilator and platelet-aggregation-inhibitor. It has been postulated that lack of 
NO during gestation is related to the development of gestational hypertension and 
preeclampsia. Studies investigating the replenishment of NO in preeclampsia have 
shown improvements in blood pressure, uterine artery pulsatility index (which is 
classically abnormally high in preeclampsia), and a reduction in platelet activation.  
 
Another proven role of NO, is induction of the physiological process of cervical ripening. 
Compelling animal data showed that all known Nitric-Oxide Synthase isoforms (iNOS, 
nNOS, eNOS) were present in the cervix. An increase in iNOS occurred during labor at 
term compared with early gestation. In rats, during preterm labor, iNOS concentrations 
increased significantly in the cervix. Labor duration was significantly prolonged when 
NOS was inhibited by L-NAME. Furthermore, cervical extensibility decreased 
significantly after in-vitro incubation with L-NAME. Overall, the above experimental data 
suggests NO system plays an active role in the cascade of processes involved in 
preparing the uterus and cervix for parturition, and its administration can speed the 
process of cervical dilatation. 
 
Human cervical tissues display the same augmentation of iNOS, in women approaching 
term. NO-production in the cervix is low during gestation and becomes upregulated 
once pregnancy advances to term. Vaginal application of NO releasing drugs is 
effective on pre-induction cervical ripening process of the labor. It directly and through 
stimulation of prostaglandin and cyclooxygenase-2 (COX2), release of cytokines, and 


inhabitation of thromboxane-A2 (TXA2) facilitates cervical ripening without causing 
complications such as fetal distress. Several clinical trials have ascertained the ability of 
the topical application of NO donors to promote cervical ripening, and labor induction.   
 
 
Recent evidence has emerged about the role that locally applied NO donors play in 
cervical ripening and that NO-donors are effective and safe cervical ripening agents. A 
recent Cochrane Database review of the existing evidence in humans suggest that NO 
donors can be a useful tool in the process of induction of labor causing the cervix to be 
more favorable in comparison to placebo. The authors concluded that, additional data 
are needed to assess the true impact of NO donors on all important labor process and 
delivery outcomes. 
 
We hypothesize that using a NO donor as an adjuvant to misoprostol/ intra-cervical 
Foley bulb for induction of labor in women with gestational hypertension and/or 
preeclampsia will have a synergistic effect by ripening the cervix, and shortening the 
overall duration of labor. If our hypothesis is confirmed, this approach may represent a 
significant advancement in clinical care because it will potentially significantly decrease 
the rate of Cesarean delivery women with gestational hypertension or preeclampsia, 
where the rates of surgical interventions are very high.   The existing evidence also 
implies the NO adjuvant method will be reducing maternal blood pressures, thereby 
decreasing the utilization of intrapartum anti-hypertensives.  
 
Here, we propose a randomized controlled trial (RCT) of nitric-oxide donor (NOD) 
isosorbide mononitrate (IMN) versus placebo as an adjuvant to misoprostol/ intra-
cervical Foley bulb for induction of labor to decrease rate of cesarean deliveries in 
pregnancies complicated by gestational hypertension or preeclampsia (≥24/0 weeks' 
gestation) 
 
The primary outcome will be rate of cesarean delivery. Secondary outcomes include 
interval time to delivery, acute use of anti-hypertensives and incidence of 
maternal/neonatal complications associated with use of IMN, to the point of 
discharge/transfer.  
 
 
 
2.0 Specific Aims: 
 
Specific aim 1: To determine if intravaginal administration of NOD isosorbide 
mononitrate (IMN) as an adjuvant to misoprostol/ intra-cervical Foley bulb for induction 
of labor decreases the rate of cesarean deliveries in pregnancies complicated by 
gestational hypertension or preeclampsia (≥24/0 weeks' gestation)  
 
Specific aim 2: To determine if the use of intravaginal administration of NOD isosorbide 
mononitrate (IMN) as an adjuvant to misoprostol/ intra-cervical Foley bulb for induction 
of labor reduces the interval time to delivery. 
 
Specific aim 3: To evaluate the safety of NOD isosorbide mononitrate (IMN) 
administered at the time of induction of labor in terms of frequency of intrapartum 
outcomes including placental abruption, need to treat with acute antihypertensive 


medications, uterine hyperstimulation, maternal hypotension, atony, side effects 
(headache, nausea, vomiting, dizziness), and neonatal resuscitation. 
 
 
 
 
 
 
  


 
 
3. Study Design 
 
3.1 Primary Research Question: 
 
Does intravaginal administration of NOD isosorbide mononitrate (IMN) as an adjuvant to 
misoprostol/ intra-cervical Foley bulb for induction of labor decreases the rate of 
cesarean deliveries in pregnancies complicated by gestational hypertension or 
preeclampsia? 
 
Hypothesis 1: Compared to placebo, administration of intravaginal IMN as adjuvant to 
induction of labor decreases rate of cesarean deliveries in pregnancies complicated by 
gestational hypertension or preeclampsia.  
 
3.2 Secondary Research Questions: 
 
 
3.2.1 Does use of intravaginal NOD isosorbide mononitrate (IMN) as an adjuvant to 
misoprostol/ intra-cervical Foley bulb for induction of labor reduces the interval time to 
delivery? 
 
Hypothesis 2: Compared to placebo, administration of intravaginal IMN at the time of 
induction of labor reduces the time interval from induction to vaginal delivery.  
 
3.2.2 Is use of intravaginal IMN as an adjuvant induction agent in pregnancies complicated 
by preeclampsia associated with a favorable risk/benefit ratio? 
 
Hypothesis 3: Administration of intravaginal IMN as an induction agent is safe and not 
associated with an increased risk of placental abruption, use of anti-hypertensives, 
maternal hypotension and uterine hyperstimulation, atony, meconium stained fluid 
compared to placebo, need for neonatal resuscitation. 
 
3.3 Design Summary 
 
We are proposing a double blinded, placebo controlled, randomized clinical trial of patients 
undergoing induction of labor for gestational hypertension or preeclampsia. Once the decision to 
induce will be taken, mothers will be randomized to receive either intravaginal IMN (30mg) or 
identical appearing placebo placed every 4hrs in the posterior vaginal fornix X 3 doses. IMN or 
placebo will be discontinued when active labor occurs or when the physician decides to proceed 
with augmentation with oxytocin or AROM. Participants will be induced using our routine 
induction agents, Misoprostol (25 mcg every 4 hrs for maximum of 6 doses) and an intra-cervical 
foley bulb will be inserted with 2nd dose of IMN or placebo. See figure 1, for further details. 
Regarding management of labor, physician decides when to proceed with augmentation with 
oxytocin or AROM. 
 
An intra-cervical foley bulb will be placed with 2nd dose of IMN (or placebo). If unable to be 
placed, a higher level provided must attempt placement, if sill unable to be placed the patient will 
be examined every 4 hours and Foley bulb placement was reattempted if Bishop's score is still 6 
or less. When the Foley bulb had fallen out, further management of labor will be at the discretion 
of the labor team and included expectant management, amniotomy, or IV oxytocin. If indicated, 


IV oxytocin will be started per standard protocol after 4 hours from the last misoprostol dose. The 
rest of the obstetrical care will be similar in all arms and guided by clinical guidelines. 
 
 
 
Figure 1. Detailed algorithm of enrollment 
 
 
 
 
 
 
IMN should be administered intravaginal every 4 hours for maximum of 3 doses 
 
Misoprostol should be administered intravaginal every 4 hours for maximum of 6 doses, if < 4 contractions in 10 minutes and bishop 
score <6 
 
If cervical Foley bulb cannot be placed at initial exam, a second higher level provider must attempt. If still unable to place, repeat 
exam in 1-2 hours from misoprostol placement to reattempt Foley placement. 
 
In order to call it a failed placement attempt, an attempt must be made with patient placed in stirrups and under direct visualization. 
 
Remove Foley if still in place after 12 hours from placement. Can continue with misoprostol use after Foley is removed as long as it 
meets criteria noted above. 
 
Oxytocin can be initiated 4 hours after placement of last misoprostol, regardless of whether cervical Foley 
still in situ  
 
 
 
 


 
 
3.4 Eligibility Criteria 
 
3.4.1 Inclusion Criteria: 
 
• Women older than 18 years at the time of induction of labor with the 
ability to give informed consent 
 
• Induction of labor for clinical diagnosis of preeclampsia  
• Unfavorable cervix (Bishop’s score of less than 6) See below 
• Cervical dilation 2cm or less 
• Singleton 
• Gestational age ≥ 24 weeks 
• English speaking 
 
3.4.1.1 Bishop Score 
 
The Bishop Score is the most commonly used method to rate the readiness of the 
cervix for induction of labor. The Bishop Score gives points to 5 measurements of the 
pelvic examination dilation, effacement of the cervix, station of the fetus, consistency of 
the cervix, and position of the cervix.  The link below has a calculator that examiner will 
use to calculate a Bishop score prior to randomization. 
http://perinatology.com/calculators/Bishop%20Score%20Calculator.htm 
 
 
 
  
3.4.1.2 Gestational Age Determination 
 
Gestational age is determined in the following manner and is denoted as “project 
gestational age (GA).” The “project estimated date of confinement (EDC),” which 
is based on the project GA, cannot be revised once a determination has been 


made. Because the project EDC depends on information from the earliest dating 
ultrasound, if no ultrasound has been performed previously, one must be 
performed before the patient can be enrolled. 
 
1. The first day of the last menstrual period (LMP) is determined and a 
judgment is made as to whether or not the patient has a “sure” LMP date. 
2. If the LMP date is unsure, the ultrasound measurements obtained 
at the patient’s first ultrasound examination are used to determine the 
project GA by the standard method of ultrasound GA determination at that 
institution. 
3. If the LMP date is sure and the ultrasound confirms this GA within the 
number of days specified in Table 3 1, then the LMP-derived GA is used to 
determine the project GA. 
4. If the ultrasound-determined GA does not confirm the LMP-
generated GA within the number of days specified in Table 3-1, then the 
ultrasound is used to determine the project GA. 
 
 
Table 3-1. 
Cutoffs for Using LMP to Determine Gestational Age 
 
Gestational age range at first Method of 
Ultrasound agreement 
ultrasound by LMP 
Measurement 
with LMP 
≤ 8 6/7 weeks 
CRL 
± 5 days 
9 0/7 weeks to 13 6/7 weeks 
CRL 
± 7 days 
14 0/7 weeks to 15 6/7 weeks 
BPD, HC, AC, FL 
± 7 days 
16 0/7 weeks to 21 6/7 weeks 
BPD, HC, AC, FL 
± 10 days 
22 0/7 weeks to 27 6/7 weeks 
BPD, HC, AC, FL 
± 14 days 
28 0/7 weeks and beyond 
BPD, HC, AC, FL 
± 21 days 
 
 
3.4.2 Exclusion Criteria: 
 
• Contraindication to vaginal delivery 
• Contraindication to misoprostol 
• Fetal Demise 
• Major fetal anomaly 
• Non-english speaking women 
• HIV 
• Medical conditions requiring assisted second stage 
• Category III tracing 
• Eclampsia 
• Hemolysis Elevated Liver enzymes Low Platelets syndrome 
• DIC or active hemorrhage before randomization 
• Hypersensitivity to isosorbide mononitrate  
• Isosorbide mononitrate should not be used in cases of acute myocardial 
infarction with low filling pressure, acute circulatory failure (shock, vascular 
collapse), or hypertrophic obstructive cardiomyopathy (HOCM), constrictive 
pericarditis, low cardiac filling pressures, aortic/mitral valve stenosis and 
diseases associated with a raised intra-cranial pressure e.g following a head 
trauma and including cerebral hemorrhage. 
• Isosorbide mononitrate should not be used in patients with severe anemia, 
severe hypotension, closed angle glaucoma or severe hypovolaemia. 


• Isosorbide mononitrate tablets contain lactose and therefore patients with rare 
hereditary problems of galactose intolerance, the Lapp lactase deficiency or 
glucose-galactose malabsorption should not take this medicine. 
 
 
 
3.5 Study Procedures 
 
3.5.1 Informed consent 
 
Written informed consent must be obtained from patients before they can be 
randomized into the study. Full disclosure of the nature and potential risks of 
participating in the trial are to be made. Consent forms will be according to the 
requirements of the IRB and are required by the Health Insurance Portability and 
Accountability Act (HIPAA) Privacy Rule. Women who are not fluent in English will not 
be enrolled. A copy of the signed consent form will be provided to the patient. 
 
3.5.2 Screening 
 
Under the direction of the PI, trained research nurses will be available to screen and 
consent patients according to study protocol. We will enroll patients at the time of 
admission to labor and delivery (L&D) for induction of labor. All patients admitted for 
induction of labor for preeclampsia will be approached by the research nurses and 
will be provided with information and consent forms for the study so that if an 
emergent cesarean delivery is required in the near future the patient will already be 
informed about the study. Medical records of all potential patients will be reviewed 
and those who satisfy inclusion and exclusion criteria will be approached for 
informed consent. A screening and enrollment log will be used to track all patients 
approached for the study. 
 
 
3.5.3 Randomization and Masking 
After obtaining informed consent, women undergoing an induction of labor for 
preeclampsia will be randomized to either 30mg IMN given intravaginal with placement 
of misoprostol/foley bulb (as clinically indicated) or placebo in a 1:1 ratio. 
Randomization in each group will be by simple randomization, and will be computer 
generated. A confidential computer-generated simple randomization will be prepared 
and provided on an ongoing basis to a designated investigational pharmacist (all other 
study staff will be blinded). The investigational pharmacy will prepare identical 
appearing suppositories of IMN (30mg) or placebo according to the randomization 
sequence and deliver to a dedicated secure area in the labor and delivery area. A 
randomization log with study medication number, patient name and medical record 
number will be used to track the randomization process.  
 
 
3.5.4 Drug Administration 
When the decision is made to proceed with induction of labor for preeclampsia, and 
after ensuring for a consented patient, an order to give the study medication will be 
activated and the available study medication will be administered by the provider. The 
patient is considered randomized once the medication is dispensed. The 
investigational drug pharmacy will deliver the next study medication to the labor and 
delivery unit if a subsequent consented patient is already identified. 
 


 
3.5.5 Baseline Procedures 
 
• Routine intrapartum and postpartum care at each center will be provided to 
patients by their clinical providers who will be blinded to the study interventions. 
 
• Trained and experienced research nurses in obstetric and perinatal outcomes 
abstraction at each center (also blinded to study medications) will be responsible 
for research data abstraction from patient medical records


Maternal and delivery outcomes will be collected during hospital stay. Occurrence of 
medication adverse effects or any of the pre-specified outcomes will be recorded by 
review of medical records by research nurses. 
 
4. Outcome Measures 
 
4.1 Primary Outcome: The primary outcome of the study is rate of cesarean delivery 
 
4.2 Secondary outcomes: 
 
a. Time to active labor (defined as dilatation 5 cm or greater),  
Delivery within 12 hours 
Delivery within 24 hours 
Maternal length of stay (defined as length of time from admission for induction to 
discharge postpartum, days) 
Indication for cesarean delivery 
Need to treat with acute antihypertensive medications 
Uterine hyperstimulation (either a series of single contractions lasting 2 minutes 
or more OR a contraction frequency of five or more in 10 minutes) 
Maternal hypotension (Symptomatic with blood pressure systolic of less than 90 
millimeters of mercury (mm Hg) or diastolic of less than 60 mm Hg) 
 
 
b. Maternal side-effects (headache, nausea, vomiting, dizziness, or any other 
unexpected adverse effect)  
 
A composite maternal morbidity outcome is pre-specified to include one or more of the 
following during labor, delivery, or in the immediate postpartum during admission:  
• 
third- or fourth-degree perineal laceration 
• 
blood transfusion 
• 
endometritis 
• 
wound separation–infection (defined by the need for additional wound closure or 
the need for antibiotics) 
• 
hysterectomy 
• 
intensive care unit admission 
• 
maternal death  
 
Other maternal secondary outcomes analyzed will be: 
• 
placental abruption 
• 
chorioamnionitis (defined by the presence of maternal fever 100.4°F or greater in 
the presence of maternal or fetal tachycardia or fundal tenderness) 
• 
use of terbutaline 
• 
intrauterine pressure bulb 
• 
amnioinfusion 
• 
analgesia use 
 
A composite neonatal morbidity outcome is pre-specified to include one or more of the 
following before neonatal discharge:  
• 
severe respiratory distress syndrome (defined as intubation and mechanical 
ventilation for a minimum of 12 hours), culture proven presumed neonatal sepsis 
• 
neonatal blood transfusion 


• 
hypoxic–ischemic encephalopathy 
• 
intraventricular hemorrhage grade 3 or 4 
• 
necrotizing enterocolitis 
• 
receipt of head cooling 
• 
Other neonatal outcomes analyzed will be neonatal intensive care unit 
admission, neonatal intensive care unit admission greater than 48 hours, and 
neonatal length of stay (days). 
 
5. Statistical Considerations 
 
5.1 Sample size calculation: 
 
Using data from our prior studies using the intended study population at The Ohio State 
Wexner Medical Center the incidence of gestational hypertension or preeclampsia is 
10-15%.  
 
Data abstracted from those enrolled in biorepository for gestational hypertension or 
preeclampsia over one year period and excluding those who were delivered 
for gestational hypertension or preeclampsia who had cesarean section for breech, prior 
cesarean section or uterine surgery, HELLP syndrome, eclampsia. 
  
295 women underwent induction of labor for gestational hypertension or preeclampsia 
48% (n=141) ended up with cesarean delivery after failed induction of labor or non-
reassuring fetal well being.  
  
Gestational Age Distribution for Gestational Hypertension or Preeclampsia Induction 
  
Gestational Age in 
weeks 
Number of women IOL 
for gHTN or PE 
CS rate 
24-28 wks 
13 
10 (77%) 
28-30 wks 
15 
11 (73%) 
30-32 wks 
26 
18 (69%) 
32-34 wks 
39 
19 (49%) 
34-36 wks 
56 
20 (34%) 
36-37 wks 
35 
12 (34%) 
37-38 wks 
57 
22 (38%) 
38-39 wks 
17 
3 (18%) 
39-40 wks 
8 
2 (25%) 
40-41 wks 
2 
1 (50%) 
 
 
Review of literature reveals is similar to OSU numbers, with the overall rate of cesarean 
delivery after induction of labor for gestational hypertension or preeclampsia ranges 
from 40% to 70%. Based on available data, we anticipate that the expected rate of the 
primary outcome in the women undergoing induction of labor for gestational 
hypertension or preeclampsia 45%. For this proposal, we will estimate a conservative 
relative reduction effect of 30-35%. 
 
The table below provides the sample size calculations needed to achieve 80-90% 
power to detect 30-35% difference in the primary outcome between women 
receiving IMN or placebo at time of their induction of labor for preeclampsia, using a 
two-tailed alpha of 0.05. 


 
 
Table 1. Total sample size required to detect a difference in primary outcome 
women undergoing induction of labor and receiving IMN or placebo (alpha at 0.05, 
variable primary outcome rates, power, and effect sizes) 
 
Relative 
Primary Outcome Rate in Placebo group 
reduction 
Power 
(%) 
(%) 
35% 
40% 
45% 
50% 
55% 
30 
90 
784 
644 
540 
462 
380 
85 
670 
550 
460 
394 
326 
80 
   586 
480 
404 
346 
284 
33 
90 
656 
540 
430 
368 
306 
85 
562 
462 
368 
316 
276 
80 
490 
404 
322 
276 
242 
35 
90 
586 
482 
406 
330 
290 
85 
502 
412 
348 
282 
248 
80 
438 
362 
304 
248 
216 
 
 


Assuming the primary outcome to be 45 %, close to 1:1 enrollment and anticipating that 
no more than 2% of randomized women to be lost to follow up, a sample size of 400 
women will achieve >85% power to detect a 33% relative reduction in primary outcome 
overall.  
Given the study design and that randomization will occur once decision to proceed with 
induction occurs, there will be no concern for loss to follow up or missing outcome data 
on any women.  Regarding concern for non-compliance, given study design we 
propose that it is unlikely that participant would not get their assigned treatment.  
 
5.2 
Interim Analysis 
 
Interim statistical analyses of clinical trials will be at least once a year to review trial 
results; however, the exact timing of the interim analyses is at the discretion of the PI. 
A formal detailed statistical report will be written by the PI which presents the results of 
every aspect of the study, including all baseline variables, protocol adherence, all 
outcome variables, adverse events reported and center performance in terms of 
recruitment, data quality, loss to follow-up and protocol violations. However, the main 
emphasis is on the primary outcome as well as maternal safety outcomes. It is 
recognized that any decision to terminate the study would not be reached solely on 
statistical grounds but on a number of complex clinical and statistical considerations. 
 
5.3 
Unblinding Criteria 
 
This is a double-blind study—neither the patients nor the physician/health care 
providers are aware of the drug allocation during the duration of the study. In the event 
of a SAE thought to be related to the study drug, the patient will be treated as if she 
has received IMN. If medical care requires unblinding of the medication, the pharmacist 
will unblind the patient treatment assignment and notify the PI. 


 
 
5.4 Feasibility: There are 5000 deliveries per year in at The Ohio State Wexner 
Medical Center and approximately 8% of women are diagnosed with gestational 
hypertension or preeclampsia and approximately 2/3 undergo induction of labor 
therefore approximately 264 women per year would be eligible for enrollment. Given the 
high-risk nature of this population it is reasonable to anticipate a consent and 
randomization rate which is higher than that which is accounted for above. With only 
50% consent rate, 132 women may be randomized annually. Our conservative estimate 
suggests that this study can be completed in approximately 3 years. 
 
 
5.5 Data analysis: Analysis will be by intent-to-treat. Preliminary analyses will be 
conducted to test homogeneity of treatment groups for demographic data (gravidity, 
gestational age at randomization, race/ethnicity, BMI, number of prior cesarean) using 
the two-sample t test for continuous measurements and the Pearson chi-square test 
for categorical measurements. Primary and secondary outcomes will be analyzed 
between the two groups using univariable and multivariable analyses as needed. 
 
6.0 Medication 
 
6.1 Study drug: Isosorbide mononitrate is a drug used principally in the treatment of 
angina pectoris and acts by dilating the blood vessels so as to reduce the blood 
pressure. Research on extended release Isosorbide mononitrate as a cervical ripener 
to reduce time at hospital to birth is supportive. Isosorbide mononitrate is an active 
metabolite of isosorbide dinitrate and exerts qualitatively similar effects.  
It reduces the workload of the heart by producing venous and arterial dilation. By 
reducing the end diastolic pressure and volume, isosorbide mononitrate lowers 
intramural pressure, hence leading to an improvement in the subendocardial blood 
flow. The net effect when administering isosorbide mononitrate is therefore a reduced 
workload for the heart and an improvement in the oxygen supply/demand balance of 
the myocardium. 
 
For purpose of this study 30mg Isosorbide mononitrate suppositories and matching 
placebo have been compounded by an investigational pharmacy using using a 
commercial extended release tablets formulated into suppositories by SBH Medical 
and IDS an investigational pharmacy will manage the storage and dispensing. A 
prototype suppository was used to determine feasibility. Potency testing was 
preformed to get initial baseline then rechecked in 90 days, the results supported the 
shelf life and proof of concept (potency) on the suppositories. Per State Board of 
Pharmacy, Investigational Drug Service are not allowed to possess more than 7 days 
worth of non-patient specific compounded medication, and given our expected 
enrollment of approximately 5-6 patients per week, they will store 20 tablets of 
compounded medication/placebo. Suppositories will be refrigerated, and BUD is 30 
days, protected from light and moisture. 
 
The suppositories are manufacturer by: 
SBH Medical, Ltd 
Robert J. DuPont R.Ph. (rdupont@sbhmed.com) 
655 Dearborn Park Lane, Worthington (OH) 43085 
Phone: 614-847-6007; Fax: 614-847-6015 
Web: 


 
 
 
And will be stored at:  
Investigational Drug Service 
Doan Hall, Room 342 
410 West 10th Avenue 
Columbus, OH (43210) 
 
 
 
6.1 Reported adverse reactions: 
 
Headache  
Tiredness 
Sleep disturbances  
Gastrointestinal disturbances 
Hypotension  
Poor appetite  
Nausea  
 
Other reactions that have been reported less frequently with isosorbide mononitrate 
modified release tablets include tachycardia, vomiting, diarrhea, vertigo and heartburn 
 
6.2 Interaction with other medicinal products and other forms of interaction 
The antihypertensive effect of Isosorbide mononitrate will increase when it is used 
concomitantly with phosphodiesterase type 5 inhibitors, which are used in erectile 
dysfunction. This can lead to life-threatening vascular complications. Patients treated 
with isosorbide mononitrate must not use phosphodiesterase type 5 inhibitors (e.g. 
sildenafil, tadalafil, vardenafil) 
Concomitant use of drugs with an antihypertensive action, e.g. beta blockers, calcium 
antagonists, vasodilators (including neuroleptics and tricyclic antidepressants), 
alprostadil, aldesleukin, antihypertensives, diuretics, angiotensin II receptor antagonists 
etc. and / or alcohol can potentiate the hypotensive effect of Isosorbide mononitrate.  
Reports suggest that concomitant use of Isosorbide mononitrate increases the blood 
levels of dihydroergotamine and that the hypertensive effect is potentiated. 
 
6.3 Mechanism of action: Like all organic nitrates, isosorbide mononitrate acts as a 
donor of nitric oxide (NO). NO causes a relaxation of vascular smooth muscle via the 
stimulation of guanylyl cyclase and the subsequent increase of intracellular cyclic 
guanosine monophosphate (cGMP) concentration. A cGMP-dependent protein kinase is 
thus stimulated, with resultant alteration of the phosphorylation of various proteins in the 
smooth muscle cell. This eventually leads to the dephosphorylation of the light chain of 
myosin and the lowering of smooth muscle tone.  
 
6.4 Pharmacokinetic properties: Isosorbide mononitrate is rapidly absorbed and peak 
plasma levels are reached approximately 1 hour after oral dosing. 
Following oral administration, bioavailability of Isosorbide mononitrate is 100%. It does 
not undergo a first-pass effect. Isosorbide mononitrate is eliminated from plasma with a 
half-life of approximately 5.1 hours. It is metabolised to isosorbide-5-MN-glucuronide, 
which has a half-life of approximately 2.5 hours. It is also excreted unchanged in the 
urine. 


 
6.5 Use in pregnancy 
Studies have shown no teratogenic effects with use of isosorbide mononitrate during 
pregnancy.  
 
6.6 Placebo 
Placebo will be an identically appearing suppository that has been outsourced by OSU 
pharmacy to a compounding pharmacy. 
 
 
7.0 Conclusion 
Overall, the quality of the available trials assessing the efficacy of intravaginal 
administration of NOD isosorbide mononitrate (IMN) as an adjuvant to misoprostol/ 
intra-cervical Foley bulb for induction of labor pregnancies complicated by gestational 
hypertension or preeclampsia is limited. The available data, however, point to potential 
benefit. Most studies report that NO donors probably help in causing the cervix to be 
more favorable at 12 to 24 hours after administration and some report women who 
received NO donors were less likely to experience uterine hyperstimulation without 
FHR rate changes, meconium-stained amniotic fluid, Apgar score less than seven at 
five minutes and analgesia requirements. Our objective is to determine whether NOD 
isosorbide mononitrate (IMN) as an adjuvant to induction of labor decreases rate of 
cesarean delivery in pregnancies complicated by gestational hypertension or 
preeclampsia.  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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