## Protocol Section
### Identification Module
**NCT ID:** NCT03665779

**Brief Title:** Nitric Oxide Donor Isosorbide Mono Nitrate for Induction of Labor With Pre-labor Rupture of Membranes

**Official Title:** Nitric Oxide Donor Isosorbide Mono Nitrate for Cervical Ripening in Induction of Labor in Term or Post Term Pregnancies in Females With Pre-labor Rupture of Membranes

#### Organization Study ID Info
**ID:** AN1988
#### Organization
**Class:** OTHER
**Full Name:** Cairo University
### Status Module
#### Completion Date
**Date:** 2019-05-01

**Type:** ACTUAL

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2020-06-23

**Type:** ACTUAL

**Last Update Submit Date:** 2020-06-21

**Overall Status:** COMPLETED

#### Primary Completion Date
**Date:** 2019-04-30

**Type:** ACTUAL

#### Start Date
**Date:** 2018-08-01

**Type:** ACTUAL

**Status Verified Date:** 2020-06

#### Study First Post Date
**Date:** 2018-09-11
**Type:** ACTUAL
**Study First Submit Date:** 2018-08-30
**Study First Submit QC Date:** 2018-09-08
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** OTHER

**Name:** ahmed nagy shaker ramadan

#### Responsible Party

**Investigator Affiliation:** Cairo University

**Investigator Full Name:** ahmed nagy shaker ramadan

**Investigator Title:** resident of obstetrics and gynecology

**Type:** SPONSOR_INVESTIGATOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

### Description Module

**Brief Summary:** The study aims to evaluate and assess the effectiveness and safety of vaginal administration of isosorbide mono nitrate (IMN) to induce cervical ripening and shorten the interval time between induction and delivery in women undergoing induction of labor at term or post term with prelabor rupture of membrane.

Research Hypothesis:

In women undergoing induction of labor at term or post term with pre-labor rupture of membrane, vaginal administration of isosorbide mono nitrate (IMN) is effective to induce cervical ripening and shorten the interval time between induction and delivery.

Research Questions:

Does vaginal administration of isosorbide mono nitrate (IMN) induce cervical ripening and shorten the interval time between induction and delivery in women undergoing induction of labor at term or post term with prelabor rupture of membrane?

**Detailed Description:** * Study Design: Prospective double blinded randomized placebo-controlled Clinical trial
* Time plan: Approximately 6 months according to calculated sample size.
* study setting: this study will be conducted obstetrics and gynecology department at Cairo university.
* study population: patient will be recruited in this study those attending labor ward for induction of labor in term or post term pregnancies in females with pre-labor rupture of membranes
* Methodology in details

All women will be subjected to

-History taking:

* Verbal consent.
* Detailed clinical history.
* Personal history: Name, Age, Parity, Occupation, Residency and Special habits.
* Present history: History of onset, course and duration of vaginal bleeding or bloody vaginal discharge, presence of uterine contraction, PROM, IUGR or any indication of induction of labor.
* Obstetric history: History of previous preterm labor, previous abortion, previous full term deliveries, RH incompatibility, mode of delivery and fetal outcome.
* Menstrual history: For estimation of gestational age using Naegele's rule, provided that she had regular cycles for the last three months before she got pregnant and was not taking contraceptive pills during this period and she was sure of her dates.

Term pregnancy defined as delivery between 37 and 42 weeks of gestation. Gestational age was assessed from the menstrual history and confirmed by measurement of fetal crown-rump length at a first-trimester scan. Post-term pregnancy defined as delivery after 42 weeks of gestation.

* Past history: History of medical disorders, drug therapy or allergy or history of intake of other tocolytic drugs.
* Family history : For any similar condition

  -Examination
* Full clinical examination (pulse, temperature and the blood pressure).
* General examination including chest, heart and abdominal examination for fundal level.
* Local clinical examination; with special attention to pelvic examination to assess the state of the cervix (dilatation, effacement, PROM, station and presenting part) and to assess vaginal bleeding or amniotic fluid in vagina if present and to exclude cephalic-pelvic disproportion.
* Routine ante-natal investigations (Rh, Hb, fasting and postprandial blood sugar and complete urine analysis).(CBC with differential and CRP to exclude chorioamnionitis)
* Ultrasonography examination : to assess the following data:
* Gestational age
* Fetal viability
* Fetal presentation and EFW.
* Exclusion of any fetal congenital anomalies.
* To ensure that the all inclusion criteria are present.
* Check amniotic fluid index.

  * Intervention:

After admission for labor induction, cervical assessment is done to see dilatation (cm), length (cm), position, consistency, and station of presenting part to get the modified Bishop score and to confirm pre-labor rupture of membrane.

In vaginal IMN group (group 1) 40 mg tablet of intra-vaginal IMN (Effox; MINAPHARMA, Cairo, Egypt) will be placed into the posterior fornix of the vagina, through a digital vaginal examination, every 4 h for a maximum of four doses. The medication will be stopped with the onset of labor. Oxytocin will be started 6 h after the last dose of IMN in women not in active phase of labor but have Bishop score is \>6. Intravenous oxytocin is initiated at an infusion flow rate of 4 mIU/min and will be doubled as necessary, with 30-min intervals between increasing the doses, up to a maximum of 16 mIU/min. To obtain this concentration, 5 IU of synthetic oxytocin are added to 500 ml of a 5% dextrose solution. Further management of labor will be done according to the hospitals protocols.

In placebo group (group 2) 40 mg intra-vaginal pyridoxine placebos every 4 h for a maximum of four doses will be given, followed by intravenous oxytocin infusion and management of labor as in group 1.

In both groups, the pregnant females who don't progress to labor (regular contractions with continued cervical changes) with no cervical changes ( bishop score equal to or less than 6) after a maximum of four doses and oxytocin infusion, this will be considered failure of induction and those patients will delivered by cesarean section.

Subjects will be followed-up regularly after taking the medications by obstetricians who are unaware of the group to which the patient belongs. Uterine contraction and fetal heart rate (FHR) will be checked every 30 min. Prophylactic or "latency" antibiotics, typically ampicillin and erythromycin for prevention of chorioamnionitis. Symptoms and vital signs will be monitored at regular intervals. Subjects will be asked to report when they have uterine contraction or abnormal symptoms such as headache, nausea, shivering.

signs of chorioamnionitis (e.g : fever, uterine fundal tenderness, maternal and fetal tachycardia, purulent or foul smelling discharge) will be checked at regular intervals.

Pelvic examination will be done with each dose and with the onset of uterine contractions. Doses will be stopped with the onset of uterine contractions or when the maximum doses reached.

After documentation of all the collected data, the following will be studied:

* Induction to onset of labor time.
* Induction to delivery time.
* Failure of induction due to maternal or fetal cause.
* Need for augmentation of labor by oxytocin.
* Recording any maternal or fetal morbidities.

Possible Risk:

Risks of induction of labor as failure of induction or maternal or fetal morbidities.

Side effects of the used drugs. Complications of PROM either maternal or fetal.

### Conditions Module

**Conditions:**

- Induction of Labor Affected Fetus / Newborn

- Rupture of Membranes Prior to Onset of Labor

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** PARALLEL

**Intervention Model Description:** The patients will be divided into 2 groups:

Group 1:

70 pregnant females, induction of labor will be done by Intra vaginal isosorbide mono nitrate (Effox 40 mg MINAPHARM)

Group 2:

70 pregnant females, induction will be done by placebo (pyridoxine) administered in the posterior vaginal fornix.

##### Masking Info

**Masking:** DOUBLE

**Masking Description:** A double-blind study is one in which neither the participants nor the experimenters know who is receiving a particular treatment. This procedure is utilized to prevent bias in research results. Double-blind studies are particularly useful for preventing bias due to demand characteristics or the placebo effect. In a double-blind study, the investigators who interact with the participants would not know who was receiving the actual drug and who was receiving a placebo.

**Who Masked:**

- PARTICIPANT

- INVESTIGATOR

**Primary Purpose:** SUPPORTIVE_CARE

#### Enrollment Info

**Count:** 140

**Type:** ACTUAL

**Phases:**

- PHASE3

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** 70 pregnant females, induction of labor will be done by Intra vaginal isosorbide mono nitrate (Effox 40 mg MINAPHARM)

**Intervention Names:**

- Drug: isosorbide mononitrate

**Label:** isosorbide mono-nitrate group

**Type:** EXPERIMENTAL

#### Arm Group 2

**Description:** 70 pregnant females, induction will be done by placebo (pyridoxine) administered in the posterior vaginal fornix.

**Intervention Names:**

- Drug: Placebo

**Label:** placebo group

**Type:** PLACEBO_COMPARATOR

### Interventions

#### Intervention 1

**Arm Group Labels:**

- isosorbide mono-nitrate group

**Description:** 70 pregnant females, induction of labor will be done by Intra vaginal isosorbide mono nitrate (Effox 40 mg MINAPHARM) repeated every 4 hours maximum 4 times

**Name:** isosorbide mononitrate

**Other Names:**

- Effox

**Type:** DRUG

#### Intervention 2

**Arm Group Labels:**

- placebo group

**Description:** 70 pregnant females, induction will be done by placebo (pyridoxine) administered in the posterior vaginal fornix.repeated every 4 hours maximum 4 times

**Name:** Placebo

**Other Names:**

- pyridoxine

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**Description:** the effectiveness and safety of vaginal administration of isosorbide mono nitrate (IMN) to induce cervical ripening for induction of labor at term or post term pregnancy with prelabor rupture of membrane regarding (Induction to onset of labor time, Induction to delivery time)

**Measure:** induction of labor

**Time Frame:** up to 24 hours

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

* Singleton pregnancy.
* Cephalic presentation.
* Bishop score \< or = 6.
* Average size of the fetus.
* Adequate pelvic dimensions.
* Prelabour rupture of membranes.
* Term or post-term pregnancies with an indication for labor induction either maternal or fetal.

Exclusion Criteria:

* Previous uterine scar (e.g. caesarian delivery or unknown uterine incision , previous hysterotomy or myomectomy of the uterine corpus involving entry of the uterine cavity or extensive myometrial dissection, previous uterine rupture)
* Patients with regular uterine contractions.
* Malpresentation.
* Multifetal gesta1tion.
* Established fetal distress ( e.g. thick meconium stained liguor or non reassuring CTG changes)
* Indication for CS, e.g. Major degree of cephalopelvic disproportion and fetal macrosomia.
* Placenta previa or vasa previa.
* Active genital herpes infection.
* Severe maternal illness (e.g. severe preeclampsia).
* Laboratory and clinical sign of chorioamnionitis.

**Gender Based:** True

**Maximum Age:** 40 Years

**Minimum Age:** 18 Years

**Sex:** FEMALE

**Standard Ages:**

- ADULT

### Contacts Locations Module

#### Locations

**Location 1:**

**City:** Cairo

**Country:** Egypt

**Facility:** faculty of medicine - Cairo university

**State:** Kasr El Ainy

**Zip:** 11562

#### Overall Officials

**Official 1:**

**Affiliation:** university

**Name:** waleed M EL Khyat, MD

**Role:** PRINCIPAL_INVESTIGATOR

### IPD Sharing Statement Module

**IPD Sharing:** NO

### References Module

#### References

**Citation:** Afifi AN, Taymour MA, El-Khayat WM. Isosorbide mononitrate for cervical ripening in induction of labor for pregnant women with PROM at or post term. Int J Gynaecol Obstet. 2021 Dec;155(3):512-517. doi: 10.1002/ijgo.13604. Epub 2021 Feb 18.

**PMID:** 33458819

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000014947

- Term: Wounds and Injuries

- ID: D000007744

- Term: Obstetric Labor Complications

- ID: D000011248

- Term: Pregnancy Complications

- ID: D000005261

- Term: Female Urogenital Diseases and Pregnancy Complications

- ID: D000091642

- Term: Urogenital Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC26

- Name: Wounds and Injuries

- Abbrev: All

- Name: All Conditions

- Abbrev: BXS

- Name: Urinary Tract, Sexual Organs, and Pregnancy Conditions

### Condition Browse Module - Browse Leaves

- ID: M15241

- Name: Rupture

- Relevance: HIGH

- As Found: Rupture

- ID: M8452

- Name: Fetal Membranes, Premature Rupture

- Relevance: HIGH

- As Found: Rupture of Membranes Prior to Onset of Labor

- ID: M14149

- Name: Pregnancy, Prolonged

- Relevance: LOW

- As Found: Unknown

- ID: M25869

- Name: Premature Birth

- Relevance: LOW

- As Found: Unknown

- ID: M17685

- Name: Wounds and Injuries

- Relevance: LOW

- As Found: Unknown

- ID: M10764

- Name: Obstetric Labor Complications

- Relevance: LOW

- As Found: Unknown

- ID: M14127

- Name: Pregnancy Complications

- Relevance: LOW

- As Found: Unknown

- ID: M2875

- Name: Urogenital Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M27093

- Name: Female Urogenital Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M8399

- Name: Female Urogenital Diseases and Pregnancy Complications

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000005322

- Term: Fetal Membranes, Premature Rupture

- ID: D000012421

- Term: Rupture

### Intervention Browse Module - Ancestors

- ID: D000014803

- Term: Vitamin B Complex

- ID: D000014815

- Term: Vitamins

- ID: D000018977

- Term: Micronutrients

- ID: D000045505

- Term: Physiological Effects of Drugs

- ID: D000004234

- Term: Diuretics, Osmotic

- ID: D000004232

- Term: Diuretics

- ID: D000045283

- Term: Natriuretic Agents

- ID: D000014665

- Term: Vasodilator Agents

- ID: D000020030

- Term: Nitric Oxide Donors

- ID: D000045504

- Term: Molecular Mechanisms of Pharmacological Action

### Intervention Browse Module - Browse Branches

- Abbrev: Micro

- Name: Micronutrients

- Abbrev: All

- Name: All Drugs and Chemicals

- Abbrev: NaAg

- Name: Natriuretic Agents

- Abbrev: NiOxD

- Name: Nitric Oxide Donors

- Abbrev: VaDiAg

- Name: Vasodilator Agents

- Abbrev: Resp

- Name: Respiratory System Agents

- Abbrev: Hemat

- Name: Hematinics

- Abbrev: Vi

- Name: Vitamins

### Intervention Browse Module - Browse Leaves

- ID: M23026

- Name: Vitamin B 6

- Relevance: LOW

- As Found: Unknown

- ID: M14583

- Name: Pyridoxal

- Relevance: LOW

- As Found: Unknown

- ID: M14589

- Name: Pyridoxine

- Relevance: HIGH

- As Found: Asparaginase

- ID: M10578

- Name: Isosorbide

- Relevance: HIGH

- As Found: 210

- ID: M10579

- Name: Isosorbide Dinitrate

- Relevance: HIGH

- As Found: Recumbent

- ID: M244430

- Name: Isosorbide-5-mononitrate

- Relevance: HIGH

- As Found: Recumbent

- ID: M12507

- Name: Nitric Oxide

- Relevance: LOW

- As Found: Unknown

- ID: M8618

- Name: Folic Acid

- Relevance: LOW

- As Found: Unknown

- ID: M17558

- Name: Vitamins

- Relevance: LOW

- As Found: Unknown

- ID: M17546

- Name: Vitamin B Complex

- Relevance: LOW

- As Found: Unknown

- ID: M21009

- Name: Micronutrients

- Relevance: LOW

- As Found: Unknown

- ID: M16885

- Name: Trace Elements

- Relevance: LOW

- As Found: Unknown

- ID: M7411

- Name: Diuretics

- Relevance: LOW

- As Found: Unknown

- ID: M17412

- Name: Vasodilator Agents

- Relevance: LOW

- As Found: Unknown

- ID: T474

- Name: Vitamin B6

- Relevance: LOW

- As Found: Unknown

- ID: T459

- Name: Pyridoxal

- Relevance: LOW

- As Found: Unknown

- ID: T461

- Name: Pyridoxine

- Relevance: HIGH

- As Found: Asparaginase

- ID: T446

- Name: Folic Acid

- Relevance: LOW

- As Found: Unknown

- ID: T448

- Name: Folate

- Relevance: LOW

- As Found: Unknown

- ID: T475

- Name: Vitamin B9

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: D000011736

- Term: Pyridoxine

- ID: D000007547

- Term: Isosorbide

- ID: D000007548

- Term: Isosorbide Dinitrate

- ID: C000030397

- Term: Isosorbide-5-mononitrate

### Misc Info Module

- Version Holder: 2024-05-24
