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

• Sponsor: Indiana University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02408315
• Collaborator: (none)
• Enrollment: 300
• Locations: 2
• Arms: 2
• Duration (Months): 75
• Patients Per Site: 150
• Patients Per Site Per Month: 2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Pregnancy	Drug: misoprostol/placebo	Phase 3

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 Design

• Study Type: Interventional
• Actual Enrollment: 300 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Diagnostic
• Official Title: Induction With Misoprostol: Oral Mucosa Versus Vaginal Epithelium
• Study Start Date: Sep 1, 2015
• Actual Primary Completion Date: Nov 1, 2017
• Actual Study Completion Date: Dec 1, 2021

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Time to Delivery [from study entry until delivery- anticipated 3 days]

   number of hours from placement of study drug to delivery Cesarean delivery for fetal non--reassurance indication

2. Number of Participants With Cesarean Deliveries Based on Fetal Non-Reassurance Indications [from study entry until delivery- anticipated 3 days]

   Rate of cesarean deliveries performed for fetal non-reassurance as the indication

Secondary Outcome Measures

1. Number of Vaginal Deliveries That Occurred Within 24 Hours [from study entry until delivery- anticipated 3 days]

   rate of achieving vaginal delivery within 24 hours

2. Number of Participants Who Had Uterine Hyperstimulation [from study entry until delivery- anticipated 3 days]

   Presence of uterine hyperstimulation, tachysystole as defined as 6 uterine contractions in a 10 minute period

3. Number of Neonatal Intensive Care Unit (NICU) Admission [from study entry until discharge of newborn- anticipated up to 28 days]

   Admission to NICU

4. Number of Doses Misoprostol Used [from study entry until delivery- anticipated 3 days]

   Number of doses of misoprostol needed

5. Uterine Rupture [from study entry until delivery- anticipated 3 days]

   Presence of uterine rupture

6. Dose of Oxytocin Used for Augmentation [from study entry until delivery- anticipated 3 days]

   dose of oxytocin used for augmentation of labor

7. Number of Participants With Neonatal Cord Gases Measured [from study entry until delivery- anticipated 3 days]

   cord gases from newborn

Other Outcome Measures

1. Pharmacokinetic Profiling of Misoprostol [from study entry until delivery- anticipated 3 days]

   pharmacokinetic parameters (Area under the curve, half-life, maximum concentration) measured over first 2 study drug doses

2. Participant Satisfaction [from study entry until discharge- anticipated 5 days]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 14 Years to 45 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	IU Health Methodist Hospital	Indianapolis	Indiana	United States	46202
2	Sidney and Lois Eskenazi Hospital	Indianapolis	Indiana	United States	46202

Sponsors and Collaborators

• Indiana University

Investigators

• Principal Investigator: David M Haas, MD, IU School of Medicine

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 12, 2017

More Information

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.

• Responsible Party: David Haas, Professor Vice Chair for Research, Indiana University
• ClinicalTrials.gov Identifier: NCT02408315
• Other Study ID Numbers: IMPROVE
• First Posted: Apr 3, 2015
• Last Update Posted: Apr 13, 2022
• Last Verified: Mar 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by David Haas, Professor Vice Chair for Research, Indiana University: induction of labor; safety; pharmacokinetic; misoprostol
• Additional relevant MeSH terms: Misoprostol

Study Results

Participant Flow

Arm/Group Title	Buccal Misoprostol/Vaginal Placebo	Vaginal Misoprostol/Buccal Placebo
Arm/Group Description	Misoprostol administered buccally with placebo administered vaginally.	Misoprostol administered vaginally with placebo administered buccally.
Period Title: Overall Study
STARTED	148	152
COMPLETED	148	152
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Buccal Misoprostol/Vaginal Placebo	Vaginal Misoprostol/Buccal Placebo	Total
Arm/Group Description	Misoprostol administered buccally with placebo administered vaginally.	Misoprostol administered vaginally with placebo administered buccally.	Total of all reporting groups
Overall Participants	148	152	300
Age (Count of Participants)
<=18 years	2 1.4%	2 1.3%	4 1.3%
Between 18 and 65 years	146 98.6%	150 98.7%	296 98.7%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	27.59 (6.4)	28.21 (6.4)	27.91 (6.3)
Sex: Female, Male (Count of Participants)
Female	148 100%	152 100%	300 100%
Male	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 0.7%	1 0.3%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	1 0.7%	0 0%	1 0.3%
Black or African American	49 33.1%	45 29.6%	94 31.3%
White	66 44.6%	74 48.7%	140 46.7%
More than one race	5 3.4%	3 2%	8 2.7%
Unknown or Not Reported	27 18.2%	29 19.1%	56 18.7%
Region of Enrollment (participants) [Number]
United States	148 100%	152 100%	300 100%

Outcome Measures

1. Primary Outcome

Title	Time to Delivery
Description	number of hours from placement of study drug to delivery Cesarean delivery for fetal non--reassurance indication
Time Frame	from study entry until delivery- anticipated 3 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Buccal Misoprostol/Vaginal Placebo	Vaginal Misoprostol/Buccal Placebo
Arm/Group Description	Misoprostol administered buccally with placebo administered vaginally.	Misoprostol administered vaginally with placebo administered buccally.
Measure Participants	148	152
Median (95% Confidence Interval) [hours]	28.1	20.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Buccal Misoprostol/Vaginal Placebo, Vaginal Misoprostol/Buccal Placebo
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Estimates obtained from Kaplan-Meier method and results of Log-rank test. P-value for non-inferiority hypothesis based on Cox proportional hazards model (H0: HR ≤ 0.74 vs. HA: HR > .74), p-value < .05 provides evidence to reject inferiority and conclude BM is non-inferior to VM.
Statistical Test of Hypothesis	p-Value	0.663
	Comments
	Method	Cox proportional
	Comments

2. Primary Outcome

Title	Number of Participants With Cesarean Deliveries Based on Fetal Non-Reassurance Indications
Description	Rate of cesarean deliveries performed for fetal non-reassurance as the indication
Time Frame	from study entry until delivery- anticipated 3 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Buccal Misoprostol/Vaginal Placebo	Vaginal Misoprostol/Buccal Placebo
Arm/Group Description	Misoprostol administered buccally with placebo administered vaginally.	Misoprostol administered vaginally with placebo administered buccally.
Measure Participants	148	152
Count of Participants [Participants]	14 9.5%	5 3.3%

3. Secondary Outcome

Title	Number of Vaginal Deliveries That Occurred Within 24 Hours
Description	rate of achieving vaginal delivery within 24 hours
Time Frame	from study entry until delivery- anticipated 3 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Buccal Misoprostol/Vaginal Placebo	Vaginal Misoprostol/Buccal Placebo
Arm/Group Description	Misoprostol administered buccally with placebo administered vaginally.	Misoprostol administered vaginally with placebo administered buccally.
Measure Participants	148	152
Count of Participants [Participants]	58 39.2%	89 58.6%

4. Secondary Outcome

Title	Number of Participants Who Had Uterine Hyperstimulation
Description	Presence of uterine hyperstimulation, tachysystole as defined as 6 uterine contractions in a 10 minute period
Time Frame	from study entry until delivery- anticipated 3 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Buccal Misoprostol/Vaginal Placebo	Vaginal Misoprostol/Buccal Placebo
Arm/Group Description	Misoprostol administered buccally with placebo administered vaginally.	Misoprostol administered vaginally with placebo administered buccally.
Measure Participants	148	152
Count of Participants [Participants]	18 12.2%	22 14.5%

5. Secondary Outcome

Title	Number of Neonatal Intensive Care Unit (NICU) Admission
Description	Admission to NICU
Time Frame	from study entry until discharge of newborn- anticipated up to 28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Buccal Misoprostol/Vaginal Placebo	Vaginal Misoprostol/Buccal Placebo
Arm/Group Description	Misoprostol administered buccally with placebo administered vaginally.	Misoprostol administered vaginally with placebo administered buccally.
Measure Participants	148	152
Number [participants]	30 20.3%	31 20.4%

6. Secondary Outcome

Title	Number of Doses Misoprostol Used
Description	Number of doses of misoprostol needed
Time Frame	from study entry until delivery- anticipated 3 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Buccal Misoprostol/Vaginal Placebo	Vaginal Misoprostol/Buccal Placebo
Arm/Group Description	Misoprostol administered buccally with placebo administered vaginally.	Misoprostol administered vaginally with placebo administered buccally.
Measure Participants	148	152
Median (Full Range) [doses]	3	2

7. Secondary Outcome

Title	Uterine Rupture
Description	Presence of uterine rupture
Time Frame	from study entry until delivery- anticipated 3 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Buccal Misoprostol/Vaginal Placebo	Vaginal Misoprostol/Buccal Placebo
Arm/Group Description	Misoprostol administered buccally with placebo administered vaginally.	Misoprostol administered vaginally with placebo administered buccally.
Measure Participants	148	152
Count of Participants [Participants]	0 0%	0 0%

8. Secondary Outcome

Title	Dose of Oxytocin Used for Augmentation
Description	dose of oxytocin used for augmentation of labor
Time Frame	from study entry until delivery- anticipated 3 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Buccal Misoprostol/Vaginal Placebo	Vaginal Misoprostol/Buccal Placebo
Arm/Group Description	Misoprostol administered buccally with placebo administered vaginally.	Misoprostol administered vaginally with placebo administered buccally.
Measure Participants	148	152
Median (Full Range) [milliunits per minute]	6	4

9. Secondary Outcome

Title	Number of Participants With Neonatal Cord Gases Measured
Description	cord gases from newborn
Time Frame	from study entry until delivery- anticipated 3 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Buccal Misoprostol/Vaginal Placebo	Vaginal Misoprostol/Buccal Placebo
Arm/Group Description	Misoprostol administered buccally with placebo administered vaginally.	Misoprostol administered vaginally with placebo administered buccally.
Measure Participants	148	152
Count of Participants [Participants]	12 8.1%	15 9.9%

10. Other Pre-specified Outcome

Title	Pharmacokinetic Profiling of Misoprostol
Description	pharmacokinetic parameters (Area under the curve, half-life, maximum concentration) measured over first 2 study drug doses
Time Frame	from study entry until delivery- anticipated 3 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Other Pre-specified Outcome

Title	Participant Satisfaction
Description	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.
Time Frame	from study entry until discharge- anticipated 5 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Maternal and neonatal adverse events were tracked starting from the first dose and ending at neonatal discharge or thirty days of life, whichever is greater..
Arm/Group Title	Buccal Misoprostol/Vaginal Placebo		Vaginal Misoprostol/Buccal Placebo
Arm/Group Description	Misoprostol administered buccally with placebo administered vaginally.		Misoprostol administered vaginally with placebo administered buccally.
All Cause Mortality
	Buccal Misoprostol/Vaginal Placebo		Vaginal Misoprostol/Buccal Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/148 (0%)		0/152 (0%)
Serious Adverse Events
	Buccal Misoprostol/Vaginal Placebo		Vaginal Misoprostol/Buccal Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/148 (7.4%)		9/152 (5.9%)
General disorders
Inpatient or Postpartum Hospitalization	11/148 (7.4%)	11	8/152 (5.3%)	11
Pregnancy, puerperium and perinatal conditions
Other Life Threatening Event	0/148 (0%)		1/152 (0.7%)	1
Other (Not Including Serious) Adverse Events
	Buccal Misoprostol/Vaginal Placebo		Vaginal Misoprostol/Buccal Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	68/148 (45.9%)		71/152 (46.7%)
Pregnancy, puerperium and perinatal conditions
Any Maternal or Fetal Event	68/148 (45.9%)	68	71/152 (46.7%)	71

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.