NOPE: Use of Nitrous Oxide Donor for Labor Induction in Women With PreEclampsia

• Sponsor: Ohio State University (Other)
• Overall Status: Completed
• CT.gov ID: NCT03171480
• Collaborator: (none)
• Enrollment: 176
• Location: 1
• Arms: 2
• Actual Duration (Months): 32
• Patients Per Site Per Month: 5.5

Study Details

Study Description

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)

Condition or Disease	Intervention/Treatment	Phase
Preeclampsia; Labor, Premature	Drug: Monoket Pill; Drug: Placebo	Phase 4

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 176 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: A double blinded, placebo controlled, randomized clinical trial of patients undergoing induction of labor for preeclampsia. Study drug or identical appearing placebo will be delivered to labor floor by pharmacist, after randomization.
• Primary Purpose: Prevention
• Official Title: Randomized Controlled Trial of Nitric-oxide Donor (NOD) Isosorbide Mononitrate (IMN) Versus Placebo for Induction of Labor in Pregnancies Complicated by Preeclampsia
• Actual Study Start Date: Oct 30, 2017
• Actual Primary Completion Date: Jul 1, 2020
• Actual Study Completion Date: Jul 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Monoket pill 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,	Drug: Monoket Pill; Intra-vaginal application of Monoket as a cervical ripening agent for pregnant women undergoing induction of labor; Other Names: Isosorbide mononitrate
Placebo Comparator: Placebo pill The pharmacy has compounded an identical appearing placebo	Drug: Placebo; The pharmacy has compounded an identical appearing placebo

Outcome Measures

Primary Outcome Measures

1. Cesarean Delivery Rate [7 days]

   Rate of cesarean section for those enrolled in study

Secondary Outcome Measures

1. Placental Abruption, Use of IV Antihypertensive Drug, Maternal Hypotension, Uterine Hyperstimulation and Meconium Stained Fluid [during the induction of labor till delivery for all outcomes]

   placenta abruption at time of delivery, administration of IV antihypertensive medication for BP >160/110, maternal hypotensive defined as <90/50, Uterine hyperstimulation defined as >3 contractions in 10 minutes and meconium stained amniotic fluid anytime during labor induction/augmentation

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 42 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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)

• Cervical dilation 2cm or less

• Singleton

• Gestational age ≥ 24 weeks

• English speaking

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Ohio State Medical Center Labor and Delivery Unit	Columbus	Ohio	United States	43210

Sponsors and Collaborators

• Ohio State University

Investigators

• Principal Investigator: Kara Rood, MD, The Ohio State Wexner Medical Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 15, 2017

More Information

Publications

• Buhimschi I, Ali M, Jain V, Chwalisz K, Garfield RE. Differential regulation of nitric oxide in the rat uterus and cervix during pregnancy and labour. Hum Reprod. 1996 Aug;11(8):1755-66.
• Chanrachakul B, Herabutya Y, Punyavachira P. Randomized trial of isosorbide mononitrate versus misoprostol for cervical ripening at term. Int J Gynaecol Obstet. 2002 Aug;78(2):139-45.
• El-Khayat W, Alelaiw H, El-kateb A, Elsemary A. Comparing vaginal misoprostol versus Foley catheter plus vaginal isosorbide mononitrate for labor induction. J Matern Fetal Neonatal Med. 2016;29(3):487-92. doi: 10.3109/14767058.2015.1007036. Epub 2015 Feb 19.
• Ghosh A, Lattey KR, Kelly AJ. Nitric oxide donors for cervical ripening and induction of labour. Cochrane Database Syst Rev. 2016 Dec 5;12:CD006901. doi: 10.1002/14651858.CD006901.pub3. Review.
• Thomson AJ, Lunan CB, Cameron AD, Cameron IT, Greer IA, Norman JE. Nitric oxide donors induce ripening of the human uterine cervix: a randomised controlled trial. Br J Obstet Gynaecol. 1997 Sep;104(9):1054-7.

• Responsible Party: Kara M Rood, MD, MD, Ohio State University
• ClinicalTrials.gov Identifier: NCT03171480
• Other Study ID Numbers: 2017H0195
• First Posted: May 31, 2017
• Last Update Posted: Jan 4, 2022
• Last Verified: Dec 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Kara M Rood, MD, MD, Ohio State University: Preeclampsia; Induction
• Additional relevant MeSH terms: Pre-Eclampsia; Obstetric Labor, Premature; Isosorbide; Isosorbide Dinitrate; Isosorbide-5-mononitrate

Study Results

Participant Flow

Arm/Group Title	Monoket Pill	Placebo
Arm/Group Description	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, Monoket Pill: Intra-vaginal application of Monoket as a cervical ripening agent for pregnant women undergoing induction of labor	The pharmacy has compounded an identical appearing placebo Monoket Pill: Intra-vaginal application of Monoket as a cervical ripening agent for pregnant women undergoing induction of labor
Period Title: Overall Study
STARTED	89	87
COMPLETED	89	87
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Monoket Pill	Placebo Pill	Total
Arm/Group Description	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, Monoket Pill: Intra-vaginal application of Monoket as a cervical ripening agent for pregnant women undergoing induction of labor	The pharmacy has compounded an identical appearing placebo Monoket Pill: Intra-vaginal application of Monoket as a cervical ripening agent for pregnant women undergoing induction of labor	Total of all reporting groups
Overall Participants	89	87	176
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	89 100%	87 100%	176 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	28	27	28
Sex: Female, Male (Count of Participants)
Female	89 100%	87 100%	176 100%
Male	0 0%	0 0%	0 0%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%

Outcome Measures

1. Primary Outcome

Title	Cesarean Delivery Rate
Description	Rate of cesarean section for those enrolled in study
Time Frame	7 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Monoket Pill	Placebo
Arm/Group Description	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, Monoket Pill: Intra-vaginal application of Monoket as a cervical ripening agent for pregnant women undergoing induction of labor	The pharmacy has compounded an identical appearing placebo Monoket Pill: Intra-vaginal application of Monoket as a cervical ripening agent for pregnant women undergoing induction of labor
Measure Participants	89	87
Count of Participants [Participants]	29 32.6%	22 25.3%

2. Secondary Outcome

Title	Placental Abruption, Use of IV Antihypertensive Drug, Maternal Hypotension, Uterine Hyperstimulation and Meconium Stained Fluid
Description	placenta abruption at time of delivery, administration of IV antihypertensive medication for BP >160/110, maternal hypotensive defined as <90/50, Uterine hyperstimulation defined as >3 contractions in 10 minutes and meconium stained amniotic fluid anytime during labor induction/augmentation
Time Frame	during the induction of labor till delivery for all outcomes

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Monoket Pill	Placebo Pill
Arm/Group Description	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, Monoket Pill: Intra-vaginal application of Monoket as a cervical ripening agent for pregnant women undergoing induction of labor	The pharmacy has compounded an identical appearing placebo Monoket Pill: Intra-vaginal application of Monoket as a cervical ripening agent for pregnant women undergoing induction of labor
Measure Participants	89	87
Abruption	0 0%	0 0%
Anti-hypertensives	29 32.6%	32 36.8%
hypotension	9 10.1%	8 9.2%
uterine hyperstimulation	3 3.4%	1 1.1%
MSAF	0 0%	0 0%

Adverse Events

Time Frame	During hospitalization for delivery
Adverse Event Reporting Description	Adverse event was defined as unexpected and unanticipated side effect form administration of the medication (IMN)
Arm/Group Title	Monoket Pill		Placebo
Arm/Group Description	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, Monoket Pill: Intra-vaginal application of Monoket as a cervical ripening agent for pregnant women undergoing induction of labor		The pharmacy has compounded an identical appearing placebo Monoket Pill: Intra-vaginal application of Monoket as a cervical ripening agent for pregnant women undergoing induction of labor
All Cause Mortality
	Monoket Pill		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/89 (0%)		0/87 (0%)
Serious Adverse Events
	Monoket Pill		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/89 (0%)		0/87 (0%)
Other (Not Including Serious) Adverse Events
	Monoket Pill		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/89 (0%)		0/87 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.