Clinical trial NCT02408315: Induction With Misoprostol: Oral Mucosa Versus Vaginal Epithelium (IMPROVE)
Official title: Induction With Misoprostol: Oral Mucosa Versus Vaginal Epithelium
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pregnancy
Keywords: induction of labor
safety
pharmacokinetic
misoprostol
Lead sponsor: Indiana University
Sponsor class: OTHER
First posted: 2015-04-03
Enrollment: 300
Sex: FEMALE
Minimum age (years): 14
Maximum age (years): 45
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: DIAGNOSTIC

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Time to Delivery
timeFrame: from study entry until delivery- anticipated 3 days
measure: Number of Participants With Cesarean Deliveries Based on Fetal Non-Reassurance Indications
timeFrame: from study entry until delivery- anticipated 3 days
Secondary outcomes:
measure: Number of Vaginal Deliveries That Occurred Within 24 Hours
timeFrame: from study entry until delivery- anticipated 3 days
measure: Number of Participants Who Had Uterine Hyperstimulation
timeFrame: from study entry until delivery- anticipated 3 days
measure: Number of Neonatal Intensive Care Unit (NICU) Admission
timeFrame: from study entry until discharge of newborn- anticipated up to 28 days
measure: Number of Doses Misoprostol Used
timeFrame: from study entry until delivery- anticipated 3 days
measure: Uterine Rupture
timeFrame: from study entry until delivery- anticipated 3 days
measure: Dose of Oxytocin Used for Augmentation
timeFrame: from study entry until delivery- anticipated 3 days
measure: Number of Participants With Neonatal Cord Gases Measured
timeFrame: from study entry until delivery- anticipated 3 days
Other outcomes:
measure: Pharmacokinetic Profiling of Misoprostol
timeFrame: from study entry until delivery- anticipated 3 days
measure: Participant Satisfaction
timeFrame: from study entry until discharge- anticipated 5 days
Locations:
city: Indianapolis
country: United States
facility: IU Health Methodist Hospital
state: Indiana
city: Indianapolis
country: United States
facility: Sidney and Lois Eskenazi Hospital
state: Indiana
Study officials:
affiliation: IU School of Medicine
name: David M Haas, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.