Induction With Misoprostol: Oral Mucosa Versus Vaginal Epithelium (IMPROVE) (IMPROVE)

Induction With Misoprostol: Oral Mucosa Versus Vaginal Epithelium

The primary objective of this study is to compare the efficacy and safety of vaginal and buccal misoprostol for women undergoing labor induction at greater than or equal to 37+ 0 completed weeks gestation. Thus, the investigators have both efficacy and a safety primary outcomes.

The secondary objective of this study is to assess the pharmacokinetic(PK) parameters with these two routes of administration in a sub-cohort of this trial. The long term objective of this line of research is to inform providers' clinical decision making for the large number of women having labor induction. By providing robust PK and pharmacodynamic (PD) evaluation, clinical outcomes data for these two routes of administration, clinicians will be informed for evidence-based decisions about the preferred route of administration of misoprostol.

Study Overview

• Status: Completed
• Conditions: Pregnancy
• Intervention / Treatment: Drug: misoprostol/placebo

Detailed Description

Misoprostol is currently administered in many different ways. It can be administered vaginally, rectally, orally, buccally, and sublingually. Each route has its benefits and potential drawbacks. While vaginal administration is most common, recent trends in practice have yielded more buccal use of this drug. There is extensive clinical experience with this agent and a large body of published reports supporting its safety and efficacy when used appropriately. However, we only found one published trial directly comparing buccal to vaginal misoprostol head-to-head. In that trial, there were no significant differences in any of the outcomes other than higher rates of tachysystole in the buccal group. However, this trial utilized higher doses of misoprostol (up to 100mcg) than are typically used clinically per the ACOG Practice Bulletin (starting at 25 mcg).

Additionally, there are few comparisons of the pharmacokinetics of misoprostol between the buccal and vaginal routes. In fact, all of the PK studies comparing these routes are in women undergoing pregnancy terminations in the 1st or 2nd trimesters and do not include women undergoing labor induction at term. As the physiological changes in pregnancy have a profound impact on drug metabolism and disposition, this is an important gap in the current knowledge.

The 3 Specific Aims of this trial are:

1. To compare the efficacy and safety of 25 mcg of misoprostol initially followed by 50mcg thereafter administered by either buccal or vaginal route in a placebo-controlled, double blind RCT. We will recruit women at term undergoing labor induction to accomplish this trial.
2. To compare the PK parameters of 25 mcg and 50 mcg of misoprostol administered by either buccal or vaginal routes. Further, we will analyze the clinical outcomes in Aim 1 based on the PK parameters, controlling for patient characteristics, to assess the impact of PK parameters on clinical success of this drug. In this way, we hope to comment on the strategic dose and individualized dosing model potential for labor induction with misoprostol.
3. To compare the trial participant satisfaction with each route of administration to improve patient-based outcomes. This will be done by administering a satisfaction survey at the end of the trial. As participants will have study drug placed both buccally and vaginally, they will be uniquely able to comment on comfort and preference for route of delivery.

We will recruit women who are admitted for term labor induction and for whom the provider plans to utilize misoprostol. Women will be randomized to receive either buccal or vaginal misoprostol; first dose will be 25 mcg followed by 50mcg for subsequent doses. Three hundred women will be recruited to the overall trial and a subcohort of 60 women will be recruited to participate in the PK portion of the trial.

• Study Type: Interventional
• Enrollment (Actual): 300
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Sidney and Lois Eskenazi Hospital
    • Indianapolis, Indiana, United States, 46202
      • IU Health Methodist Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 45 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• A medical indication for induction of labor at a gestational age between 37 +0 and 38 +6 weeks OR an elective or medical indication for induction of labor at a gestational age greater than or equal to 39 + 0 completed weeks
• Participant age of greater than or equal to14 years old
• Singleton pregnancy
• Modified Bishop score of less than or equal to 6
• Vertex fetal presentation by examination or ultrasound
• Any membrane status

Exclusion Criteria:

• Elective inductions between 37 +0 and 38 +6 completed weeks are specifically excluded
• Known intrauterine fetal demise
• Any uterine scar including prior cesarean section and myomectomy
• Known major fetal congenital malformations that may impact neonatal health
• Other evidence of fetal compromise (such as Category 2 or 3 tracing) before the induction begins
• Prior induction/cervical ripening methods utilized during this pregnancy
• Allergy to misoprostol
• Known untreated cervical infection (e.g. Gonorrhea, Chlamydia)
• Planned cesarean section due to maternal or fetal condition
• Any other contraindication to labor induction or misoprostol therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: misoprostol/placebo using buccal; Randomized for buccal route of administration/ placebo	Drug: misoprostol/placebo; buccal or vaginal routes of administration/ placebo to compare methods for efficacy and safety during induction.; Other Names: Cytotec
Placebo Comparator: misoprostol/placebo using vaginal; Randomized for vaginal route of administration/ placebo	Drug: misoprostol/placebo; buccal or vaginal routes of administration/ placebo to compare methods for efficacy and safety during induction.; Other Names: Cytotec

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Delivery	number of hours from placement of study drug to delivery Cesarean delivery for fetal non--reassurance indication	from study entry until delivery- anticipated 3 days
Number of Participants With Cesarean Deliveries Based on Fetal Non-Reassurance Indications	Rate of cesarean deliveries performed for fetal non-reassurance as the indication	from study entry until delivery- anticipated 3 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Vaginal Deliveries That Occurred Within 24 Hours	rate of achieving vaginal delivery within 24 hours	from study entry until delivery- anticipated 3 days
Number of Participants Who Had Uterine Hyperstimulation	Presence of uterine hyperstimulation, tachysystole as defined as 6 uterine contractions in a 10 minute period	from study entry until delivery- anticipated 3 days
Number of Neonatal Intensive Care Unit (NICU) Admission	Admission to NICU	from study entry until discharge of newborn- anticipated up to 28 days
Number of Doses Misoprostol Used	Number of doses of misoprostol needed	from study entry until delivery- anticipated 3 days
Uterine Rupture	Presence of uterine rupture	from study entry until delivery- anticipated 3 days
Dose of Oxytocin Used for Augmentation	dose of oxytocin used for augmentation of labor	from study entry until delivery- anticipated 3 days
Number of Participants With Neonatal Cord Gases Measured	cord gases from newborn	from study entry until delivery- anticipated 3 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic Profiling of Misoprostol	pharmacokinetic parameters (Area under the curve, half-life, maximum concentration) measured over first 2 study drug doses	from study entry until delivery- anticipated 3 days
Participant Satisfaction	participant satisfaction with labor induction and preference for method of drug administration. This will use a questionnaire developed for this study with some similarity to the referenced Nassar study below.	from study entry until discharge- anticipated 5 days

Collaborators and Investigators

• Sponsor: Indiana University
• Investigators: Principal Investigator: David M Haas, MD, IU School of Medicine

Publications and helpful links

General Publications

• Nassar AH, Awwad J, Khalil AM, Abu-Musa A, Mehio G, Usta IM. A randomised comparison of patient satisfaction with vaginal and sublingual misoprostol for induction of labour at term. BJOG. 2007 Oct;114(10):1215-21. doi: 10.1111/j.1471-0528.2007.01492.x.
• Vorontsova Y, Haas DM, Flannery K, Masters AR, Silva LL, Pierson RC, Yeley B, Hogg G, Guise D, Heathman M, Quinney SK. Pharmacokinetics of vaginal versus buccal misoprostol for labor induction at term. Clin Transl Sci. 2022 Aug;15(8):1937-1945. doi: 10.1111/cts.13306. Epub 2022 Jun 12.
• Haas DM, Daggy J, Flannery KM, Dorr ML, Bonsack C, Bhamidipalli SS, Pierson RC, Lathrop A, Towns R, Ngo N, Head A, Morgan S, Quinney SK. A comparison of vaginal versus buccal misoprostol for cervical ripening in women for labor induction at term (the IMPROVE trial): a triple-masked randomized controlled trial. Am J Obstet Gynecol. 2019 Sep;221(3):259.e1-259.e16. doi: 10.1016/j.ajog.2019.04.037. Epub 2019 May 7.

Study record dates

Study Major Dates

• Study Start: September 1, 2015
• Primary Completion (Actual): November 1, 2017
• Study Completion (Actual): December 1, 2021

Study Registration Dates

• First Submitted: February 10, 2015
• First Submitted That Met QC Criteria: March 31, 2015
• First Posted (Estimate): April 3, 2015

Study Record Updates

• Last Update Posted (Actual): April 13, 2022
• Last Update Submitted That Met QC Criteria: March 28, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: safety; pharmacokinetic; misoprostol; induction of labor
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Gastrointestinal Agents; Reproductive Control Agents; Anti-Ulcer Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Oxytocics; Misoprostol
• Other Study ID Numbers: IMPROVE

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Will share as needed for IPD.
• IPD Sharing Time Frame: After study completion and for 1 year after
• IPD Sharing Access Criteria: Email contact to study contact.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF