Conditions: Pregnancy
Keywords: induction of labor safety pharmacokinetic misoprostol
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 300
Healthy volunteers: no

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.

Arms:
arm 1: Randomized for buccal route of administration/ placebo arm 2: Randomized for vaginal route of administration/ placebo

Interventions: intervention 1: misoprostol/placebo
Intervention descriptions: intervention 1: buccal or vaginal routes of administration/ placebo to compare methods for efficacy and safety during induction.

Protocol document:
Prot_SAP_000.pdf: 
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IMPROVE STUDY 
Induction with Misoprostol: Oral Mucosa versus Vaginal Epithelium  
 
Principal Investigator David M Haas, MD, MS 
  
Co-Investigators 
Sara K. Quinney Pharm.D, PhD 
Meredith L. Dorr, MD 
Rachel E. Towns, MD 
 
 
 
Rebecca C. Pierson, MD 
Carrie F. Bonsack, CNM, MS 
Anthony Lathrop, CNM 
Sarah E. Morgan, MD 
Joanne K. Daggy, PhD 
 
Kathleen M. Flannery, BS, Study Coordinator 
 
Departments of OB/GYN, Medicine- Division of Clinical Pharmacology, and Biostatistics 
Indiana University School of Medicine 
 
 
NCT clinicaltrials.gov number: NCT 02408315 
FDA PIND#: 
 
 
 


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Table of Contents: 
 
1.0 
Abbreviations 
1.0 
Background 
2.0 
Rationale and Specific Aims 
3.0 
Inclusion/Exclusion Criteria 
4.0 
Enrollment/Randomization 
5.0 
Study Procedures 
6.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk to Participants or Others 
7.0 
Study Withdrawal/Discontinuation 
8.0 
Statistical Considerations 
9.0 
Privacy/Confidentiality Issues 
10.0 
Follow-up and Record Retention 
 
Appendix A 
 
 
List of Abbreviations 
 
ACOG American Congress of Obstetrics and Gynecology 
CRF 
Case Report Form 
DSMB Data Safety Monitoring Board 
FDA 
U. S. Food and Drug Administration 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation  
IOL 
Induction of Labor 
IRB 
Institutional Review Board 
PK 
Pharmacokinetic 
PD 
Pharmacodynamic 
 
 
 




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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. 
 
Population and Study procedure 
    
 
 
   
 
Inclusion/Exclusion Criteria 
 
The following are inclusion criteria for the IMPROVE study. 
Inclusion Criteria: 
 
• 
A medical indication for induction of labor at a gestational age between 37 0/7 and 38 6/7 weeks OR an 
elective or medical indication for induction of labor at a gestational age ≥ 39 0/7 completed weeks 
• 
Participant age ≥ 14 years old 
• 
Singleton pregnancy 
• 
Modified Bishop score ≤ 6 
• 
Vertex fetal presentation by examination or ultrasound 
• 
Any membrane status 
Exclusion Criteria: 
 
• 
Elective inductions between 37 0/7 and 38 6/7 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 
 
 Enrollment/Randomization and study drug procedures 
 
 
 


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dose 
 
 
 
 
 
 
 
 
 
 
 
 






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Number of doses needed of Misoprostol 
Maximum/total dose of oxytocin utilized for uterine stimulation 
Other drugs used for cervical ripening or induction of labor after beginning the study drug 
Participant satisfaction  
Induction to active labor time (as defined by reaching at least 6 cm per new guidelines) 
 
Safety 
Uterine tachysystole and hyperstimulation 
Uterine rupture 
Maternal or fetal death 
NICU admission and total maternal and newborn hospital days 
Assisted vaginal delivery 
Neonatal cord blood gases, Apgar score, birth weight 
Chorioamnionitis  
 
Data Collection 
 
 
 
 
 
 
 
 
Participant Satisfaction  
• 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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Statistical Considerations 
 
In our preliminary retrospective analysis of our institutional data over the last 1-2 years, there was just over a 4 
hour difference in the time to delivery between the routes of administration.  This was confirmed using a 
survival estimate for the two groups, with buccal misoprostol having a median time to delivery of 16.95 hours 
and vaginal 12.78 hours. In order to demonstrate a significant difference in a non-inferiority test of two survival 
curves with a limit of 4.5 hours, we will need 143 women in each group (see table below). We will recruit 300 
women total to accommodate up to 5% withdrawals. We do not anticipate loss to follow-up as once women 
begin an induction, it is extremely rare that induction is terminated. Women remain admitted to labor and 
delivery until they are discharged after delivery. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Non-inferiority test for two exponential survival curves (Nquery), 80% power at a .05 significance level: 
Limit 
4 hours 
4.25 hours 
4.5 hours 
5 hours 
Maximum follow-up 
60 hours 
60 hours 
60 hours 
60 hours 
Denominator lambda 
.0409 
.0409 
.0409 
.0409 
Median survival (buccal) 
16.95 
16.95 
16.95 
16.95 
Median survival (vaginal) 12.95 
12.7 
12.45 
11.95 
Non-inferiority limit on 
hazard ratio 
1.309 
1.335 
1.361 
1.418 
 
N per group 
187 
163 
143 
111 
Total number of events 
(vaginal births required) 
341 
296 
260 
203 
 
N per group if Null 
hypothesis is true 
183 
158 
139 
108 
 
We plan to analyze the primary outcome using survival curve analysis due to the possibility of cesarean delivery 
truncating the time to delivery. All outcomes will be compared using an intent-to-treat methodology. Discreet 
outcomes will be compared using chi-square testing and continuous variables will use appropriate parametric 
and nonparametric tests. 
 
PK analysis will follow standard techniques for comparison of standard parameters and will be fitted to the most 
appropriate compartmental model. Our investigator team has the expertise to perform these analyses and has a 
large body of experience with pregnancy pharmacology studies. 
 
 
Privacy/Confidentiality Issues 
 
 
 
Follow-up and Record Retention 
 
  
 
 


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Appendix A: Administration of Study Drug and Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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References 
1. 
MARTIN JA, HAMILTON BE, SUTTON PD, et al. Births: Final data for 2006. Natl Vital Stat Rep 
2009;57. 
2. 
ACOG Practice Bulletin No. 107: Induction of labor. Obstet Gynecol 2009;114:386-97. 
3. 
CARLAN SJ, BLUST D, O'BRIEN WF. Buccal versus intravaginal misoprostol administration for 
cervical ripening. American Journal of Obstetrics & Gynecology 2002;186:229-33. 
4. 
TANG OS, GEMZELL-DANIELSSON K, HO PC. Misoprostol: pharmacokinetic profiles, effects on 
the uterus and side-effects. Int J Gynaecol Obstet 2007;99 Suppl 2:S160-7. 
5. 
FREDERIKSEN MC. Physiologic changes in pregnancy and their effect on drug disposition. Semin 
Perinatol 2001;25:120-3. 
6. 
MATTISON DR, MALEK A, CISTOLA C. Physiologic adaptations to pregnancy: impact on 
pharmacokinetics. In: Yaffe SJ, Aranda JV, eds. Pediatric Pharmacology: Therapeutic 
principles in practice. Philadelphia: WB Saunders, 1992. 
7. 
HAAS DM, GALLAURESI B, SHIELDS K, et al. Pharmacotherapy and Pregnancy: Highlights from 
the Third International Conference for Individualized Pharmacotherapy in Pregnancy. Clinical 
and Translational Science 2011;4:204-09. 
8. 
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;114:1215-21.