A Randomized Double-blinded Comparison of 24-hour Interval-Mifepristone and Buccal Misoprostol Versus Mifepristone and Vaginal Misoprostol for Cervical Preparation in Second-Trimester Surgical Abortion
Phase: PHASE4
Conditions: Abortion, Second Trimester
Sponsor: Virginia Commonwealth University

TITLE: A Randomized Double-­­blinded Comparison of 24-­­hour interval-
­­Mifepristone and Buccal Misoprostol versus Mifepristone and Vaginal 
Misoprostol for Cervical Preparation in Second-­­Trimester Surgical Abortion  
 
PI: Frances Casey, MD, MPH 
 
NCT03134183  
 
Unique Protocol ID: HM20005740 
 
Document Approval Date: April 15, 2015 
 
Document Type: Protocol and SAP 
 
 

 
A Randomized Double-­­blinded Comparison of 24-­­hour interval-­­Mifepristone and 
Buccal Misoprostol versus Mifepristone and Vaginal Misoprostol for Cervical 
Preparation in Second-­­Trimester Surgical Abortion  
  
Principal Investigator:  
Frances Casey, MD, MPH, Virginia Commonwealth University Medical Center  
  
Co-­­Investigators:  
Randi Falls, MD, Virginia League of Planned Parenthood  
  
1. Abstract  
Patient preference for medications in place of osmotic dilators as cervical preparation is 
well known.  Twenty-­­four to 48 hours following mifepristone, vaginal and buccal 
misoprostol have demonstrated equal efficacy in second-­­trimester medical abortion but 
have not been compared as cervical preparation for second-­­trimester surgical abortion.  
  
This study will randomize participants undergoing a second-­­trimester surgical abortion 
between 16 0/7-­­20 6/7 weeks gestation to 200mg mifepristone followed 20-­­24 hours later 
with 400mcg vaginal misoprostol and buccal placebo versus 400mcg buccal misoprostol and 
vaginal placebo 1-­­2 hours prior to the procedure. Primary outcome is intraoperative 
procedure time as measured by time of first instrument in the uterus (dilator if further 
dilation is required or forceps if no further dilation required) to last instrument out of the 
uterus.  The study uses a superiority design and is powered to detect a 4-­­minute difference  
in procedure time from a baseline of 10±5 minutes with 90% power and two-­­tailed alpha  
of 0.05 requiring 33 participants in each arm. To account for 10% dropout or 
disqualification, 72 participants will be recruited. Secondary outcomes include cervical 
dilation assessed with largest Pratt dilator initially accepted without resistance, patient 
report of pain (as measured on an 11-­­point VAS scale), side effects, acceptability, and 
recommendation to friends (as measured on a 5-­­point Likert scale), and provider 
estimation of blood loss, complications, ease of dilation (as measured on an 11-­­point VAS 
scale), acceptability, and recommendation to other patients (as measured on a 5-­­point 
Likert scale).   
  
 
  
  

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2. Specific Aims 
This study aims to compare mifepristone and buccal misoprostol to mifepristone and 
vaginal misoprostol for cervical preparation for second trimester D&E. We hypothesize 
that giving oral mifepristone 20-­­24 hours and vaginal misoprostol 1-­­2 hours prior to D&E 
will provide better cervical dilation than mifepristone 20-­­24 hours and buccal misoprostol 
1-­­2 hours prior to D&E. The primary outcome of the study will be length of procedure as 
measured by first instrument in the uterus (dilator if further dilation is required or forceps if 
no further dilation required) to last instrument out of the uterus. Secondary outcomes will 
include cervical dilation achieved as measured by the largest size Pratt dilator accepted 
without resistance prior to the start of the procedure, total dilation required, blood loss, 
pain, complications, provider assessment of difficulty, and provider and patient acceptance 
and recommendation for other patients. 
 
3. Previous research 
The addition of mifepristone, a progesterone antagonist, to a misoprostol regimen has been 
shown to significantly decrease the medication-­­to-­­abortion interval in second-­­trimester 
induction terminations.1 Vaginal administration has demonstrated improved dilation as 
compared to buccal administration but it is known that patients prefer buccal 
administration.2  A comparison of mifepristone and vaginal versus mifepristone and buccal 
misoprostol has not been studied prior to second-­­trimester surgical abortion. 
 
A Cochrane review (2010) of cervical preparation for second-­­trimester D&E did not 
recommend mifepristone and misoprostol for cervical priming due to high rates of pre-­­ 
procedural expulsions. 3 However, the primary basis for this conclusion is the trial by 
Carbonell et al. in which the 48-­­hour interval between the medications accounts for the 
high out-­­of-­­facility expulsion risk.4  A retrospective cohort of over 200 women between 14 
and 19 6/7 weeks gestation showed no difference in difficulty of cervical dilation for 
patients receiving mifepristone 24-­­48 hours misoprostol as compared to osmotic dilators 
prior to surgical abortion. Two out of facility expulsions occurred in the mifepristone-­­ 
misoprostol arms but the timing of medication to expulsion interval is not reported.5 
 
More recent studies have limited the timing of mifepristone to 24 hours or less prior to 
procedure. Mifepristone only has been shown to provide adequate cervical dilation as 
compared to osmotic dilators to 16 weeks gestation with noninferiority design to detect a 
3-­­minute difference in procedure time.6  A 24-­­hour interval between 200mg mifepristone 
and 400mcg buccal misoprostol has been shown as non-­­inferior to osmotic dilators for 
total procedure time for 15-­­18 week surgical abortions.7 Mifepristone and one-­­set of 
osmotic dilators was found to be non-­­inferior for total procedure time as compared to two 
sets of osmotic dilators for surgical abortion 19-­­23 6/7 weeks gestation.8 
 
The addition of mifepristone has benefit as a cervical priming agent as an adjunct or 
alternative to osmotic dilators for surgical abortion, but it is not known whether the 
addition of vaginal versus buccal misoprostol changes cervical dilation and thus procedure 
time outcomes. 
 
4. Rationale 

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Second-­­trimester dilation and evacuation (D&E) procedures at 14 weeks or greater require 
cervical preparation. 9 Osmotic dilators have traditionally been used for cervical dilation 
but it is known that patients prefer medication to dilators.10    Misoprostol alone can be used 
for early second trimester dilation but is associated with increased requirement for 
dilation.11  Adding mifepristone to buccal misoprostol was found to be non-­­inferior to 
osmotic dilators for procedure time for 15-­­18 weeks gestation.7  Mifepristone alone was 
found to provide adequate cervical preparation up to 16 weeks gestation.6  Vaginal 
misoprostol is associated with fewer gastrointestinal side effects as compared to buccal 
administration and is associated with a shorter induction to delivery interval.12  This study 
aims to evaluate mifepristone and buccal versus mifepristone and vaginal misoprostol 
(with an interval of at least 20 hours between the medications) for gestational ages 16 0/7 
to 20 6/7. This study will contribute to the literature evaluating medication only cervical 
preparation prior to second-­­trimester procedures. 
 
5. Research design and General Methodological Approach 
We have chosen a randomized controlled trial to ensure that neither patient nor provider 
will be biased by medication choice. Seventy-­­two English or Spanish-­­speaking women 
greater than 18 years of age and at 16 0/7-­­20 6/7 weeks gestation will be enrolled with 36 
women in each arm. 
 
Computer-­­generated randomization will be utilized to assign treatment arms and the 
vaginal misoprostol and buccal placebo and buccal misoprostol and vaginal misoprostol 
will be prepared according to randomization scheme by the research pharmacy in opaque-­­ 
sealed envelopes as to blind participants and providers. 
 
One arm will receive mifepristone 200mg orally 20-­­24 hours prior and misoprostol 
400mcg (two 200mcg tablets) vaginally 1-­­2 hours prior and placebo (two lactose tablets 
designed to appear similar to misoprostol) buccally 1-­­2 hours prior to D&E. The second arm 
will receive mifepristone 200mg orally 20-­­24 hours prior and misoprostol 400mcg (two 
200mcg tablets) buccally and placebo (two lactose tablets designed to appear similar to 
misoprostol) vaginally 1-­­2 hours prior to surgical abortion. The patients will place the 
tablets in the pre-­­operative area from pre-­­marked envelopes. The patient will be instructed 
to take the medication in the envelope marked buccally (misoprostol 400 mcg or placebo) to 
be placed in the cheek pouch for 30 minutes and then remaining swallowed and the 
envelope marked vaginally (misoprostol 400mcg or placebo) to be placed vaginally as far 
as the patient can insert with her finger. The patient will be witnessed taking the buccal 
medication but the patient will be given privacy for vaginal administration. The time will 
be recorded in the patient's chart. Prior to the procedure, patient assessment of 
medications will be obtained as detailed in 5.5. 
 
At 1-­­2 hours after misoprostol and placebo administration, the participant will be brought 
into a procedure room for a dilation and evacuation (D&E). Prior to the D&E, an assessment 
of cervical dilation will be made as assessed by largest size Pratt dilator accepted without 
resistance starting with 39-­­French. Only the attending will assess cervical dilation but 
procedures will be performed by the attending and residents-­­in-­­training.  Type of provider 
will be recorded. 

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Five time estimates will be recorded: 1) time interval between mifepristone and 
misoprostol/placebo placement, 2) time interval between misoprostol insertion and 
assessment of cervical dilation 3) total procedure time (speculum in to speculum out), 4) 
intraoperative procedure time designated as start of additional dilation (if required) or 
start of uterine instrumentation (if further dilation not required) to time of last instrument 
removed from uterus. Following the procedure, provider assessment will be obtained as 
detailed in section 5.5. 
 
5.1 Criteria for selection of subjects 
The trial will be conducted at Virginia Commonwealth University Medical Center (VCUHS) 
and Virginia League of Planned Parenthood (VLPP) over the course of approximately 
fourteen months. The study will enroll healthy women, over 18 years of age, eligible for 
non-­­urgent D&E at 16 0/7 weeks to 20 6/7 weeks gestation, confirmed by sonogram. 
Patients presenting to either office in consultation for a D&E will be recruited for 
participation.  Exclusion criteria will include: emergent need for D&E, intrauterine 
infection, fetal demise, molar pregnancy, multiple pregnancy, uterine anomaly or 
significant distortion of the uterus with fibroids, intolerance, allergy or contraindication to 
mifepristone or misoprostol. 
 
5.2 Subject recruitment and allocation 
Both VCUHS and VLPP serve representative samples of Richmond, Virginia. Second 
trimester services at VLPP started in 03/2014. 
 
After the patient has completed the counseling process and decided to proceed with an 
induced abortion, she will be approached by either a co-­­investigator or research staff 
member and asked to participate in the study. A detailed explanation of the study will be 
provided and informed consent obtained in English or Spanish, according to patient 
preference. A copy of the informed consent will be given to the patient. Eligibility for the 
study will be confirmed. 
 
The VCU Investigational Research pharmacy will prepare the allocation sequence for 
preparation of allocation envelopes. Subjects will be allocated in blocks of 4-­­6.  A 
researcher not involved in subject recruitment and without participant contact will 
prepare sequentially numbered opaque envelopes with the assigned, blinded pills for 
vaginal or buccal administration (misoprostol or placebo) enclosed. The envelope will not 
contain information that would reveal the group assignment. The envelope will not be 
assigned to a participant until eligibility is confirmed. The envelope will not be opened 
until just prior buccal and vaginal placement. The allocation number will be recorded 
twice in the participant’s chart. The envelope will be attached to the chart. The envelope 
will only have the allocation number on the outside and the blinded pills inside. 
 
 
 
5.3 Description of the drugs and devices to be studied 

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Mifepristone is a progesterone receptor antagonist. The brand name Mifeprex is 
manufactured for Danco Laboratories, LLC with address: 640 5th Avenue Floor 13 
New York, NY 10019. The dose of mifepristone to be utilized in this study is 200 mg. 
 
Misoprostol is a synthetic prostaglandin E1 analogue.  Generic misoprostol is 
manufactured by Taj Pharmaceuticals Ltd. with address as follows: Plot No. 32/2B, Village 
Tondali, Taluka-­­Khalapur, Dist. Raigarh, Maharashtra-­­410 203 India (US FDA approved 
manufacturer). Brand name misoprostol, Cytotec, is manufactured by Pfizer, Inc. with 
address: 235 East 42nd Street New York, NY 10017-­­5703.  The dose of misoprostol to be 
utilized in this study is 400 mcg. 
 
Both misoprostol and placebo pills will either be encapsulated or will be supplied in a 
troche. This is to be determined. They will be created by the VCU investigational research 
pharmacy: VCU research pharmacy: 410 North 12th Street, P.O. Box 980581, Richmond, 
Virginia 23298-­­0581 
 
 
 
5.4 Admission procedure 
Recruitment will begin July 2015 and extend for approximately fourteen-­­months, 
ending once enrollment is complete. Patients presenting to VCUHS or VLPP will be 
enrolled, as described in 5.2. Following enrollment, the patient will complete an admission 
form including baseline demographics and reproductive history. 
 
After ensuring the patient meets eligibility criteria, has signed consents and 
following the preoperative assessment, a research staff member will give the patient 
mifepristone 200mg to take orally in the staff member's presence and the time will be 
recorded in the patient's chart. The following day, a research assistant will dispense two 
numbered (one vaginal and one buccal) envelopes as described in 5.2 upon arrival to VCU 
Medical Center for the procedure. Prior to dispensing the envelope, the research staff 
member will examine the allocation numbers as recorded in the patient's chart to ensure a 
match. 
 
5.5 Patient and Provider Assessment 
The patient will complete the survey immediately prior to the procedure to provide an 
accurate assessment of medication acceptability and side effects prior to anesthesia. The 
patient survey will assess pain (as measured using an 11-­­point visual analog scale) and 
acceptability of treatment with respect to ease of use, side effects, and recommendation to 
others (as measured using a 5-­­point Likert scale). 
 
The provider will complete the assessment immediately following the procedure. The 
provider assessment elicits estimated blood loss, complications, ease of cervical dilation 
(with responses rated on an 11-­­point visual analog scale), procedure difficulty, 
recommendation for same patient and recommendation for other patients (as measured 
using a 5-­­point Likert scale). 
 
5.6 Criteria for discontinuation 

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Any participants who meet any one of the following criteria at any point after enrollment 
will be discontinued from the study: 
• Urgent need for a D&E 
• Decision not to proceed with the D&E 
• Decision to stop participation in the study 
 
5.7 Data management 
Data will be entered by the research coordinator and stored on a computer at each center 
accessible only to the primary and co-­­investigators and research coordinator via password 
protection. 
 
5.9 Data analysis 
STATA statistical software (StataCorp LP, College Station, TX, www.stata.com) will be used 
to analyze the baseline characteristics of the populations based on the study questionnaires 
completed by participants prior to their procedure. Primary and secondary outcomes will 
be recorded as described above in 5.4. Both primary and secondary outcomes will be 
analyzed using t-­­tests or appropriate non-­­parametric comparison tests as appropriate. The 
perception assessments (VAS) will be assessed using non-­­parametric analysis. The 
primary analysis will be based on intention to treat. 
 
5.10 Number of subjects and statistical power 
Sample size is based on prior studies assuming that longer procedure times reflect a need 
for further dilation and manipulation.  Procedure time is defined in this study as first 
instrument passing into the uterus until last instrument out of the uterus. Previous studies 
have defined a 3-­­minute for 14-­­16 week gestations or 5-­­minute change for 19-­­24 week 
gestations as clinically significant.6  For this study evaluating 16 -­­   20 6/7 week gestations, 
we chose 4-­­minute difference as clinically significant. Using a superiority design, in order to 
detect a 4-­­minute change in procedure time from a baseline of 10 minutes with a standard 
deviation (SD) 5 minutes), with a two-­­tailed alpha of 0.05 and power of 90%, 33 women 
will be needed in each arm. We plan to recruit 72 participants due to post-­­ enrollment 
exclusion. 
 
5.11 Study limitations 
While there are many possible regimens of mifepristone and misoprostol, which could be 
compared, we have tried to select the most reasonable and practical regimen for use in our 
setting. Additional studies may be needed in the future to compare other regimens. 
As this study will recruit patients from VCU Medical Center and Virginia League of Planned 
Parenthood, the study may be generalizable only to patients of similar characteristics. 
However, since the biologic response to mifepristone and misoprostol is not known to vary 
significantly, the results should be widely generalizable. Loss of blinding is a concern. 
Steps have been taken to ensure internal validity in that both participants and practitioners 
will be blinded to allocation of treatment versus placebo. We will ask both providers and 
participants which group they believe the participant was in to determine if group 
assignment was detectable. 

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Limitations of this study will include potential extension of time for recruitment and a 
relatively small sample size. 
 
6. Links with other projects 
There is a multicenter trial comparing the addition of mifepristone versus misoprostol to 
osmotic dilators versus dilators alone. 
 
7. Expected outcomes of the study and dissemination of findings 
If 20-­­24 hour mifepristone and 2-­­4 hour misoprostol produces better cervical dilation than 
misoprostol only for second trimester D&E's, this regimen could increase the medication 
only options for surgical procedures. We plan on publishing the study in a reproductive 
health journal and giving oral presentations of results. 
 
8. Budget justification 
 
8.1. Personnel 
Principal investigator: Frances Casey will assist in subject recruitment, obtaining consent, 
data analysis, dissemination of findings, and performing procedures related to data 
acquisition. The following physicians will also assist in subject recruitment and obtaining 
consent: Randi Falls. The research coordinator will be a paid position. He/she will assist in 
subject recruitment, obtaining consent, treatment allocation and concealment. We 
anticipate supplementing an existing research coordinator for approximately $5,755 with 
34.3% fringe. Please see attached budget document for further details. 
 
8.2. Equipment 
We anticipate utilizing the ultrasound machine and computers currently available at the 
study sites. 
 
8.3. Materials and Supplies 
These include the cost of the medication and placebo, concealment for misoprostol and 
placebo, envelopes. The total is $7,161 
 
8.4. Participant Incentives 
Each participant will receive a $10 Target gift card as reimbursement for time after 
completion of the study, approximately $720. 
 
8.5. Travel 
No travel reimbursement required. 
 
9. Timeline 
Recruitment will begin July 2015 and extend for approximately 9-­­months or once 
enrollment is complete. As recruitment will occur on patient's initial consultation for 
procedure and allocation and assessment will occur on the day of procedure, data 
collection will be complete the day of the patient's procedure. Data analysis will follow and 
will complete prior to the writing of the final report-­­please see timeline attached. 

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10. References 
 
1. 
Wildschut H, Both MI, Medema S, Thomee E, Wildhagen MF, Kapp N. Medical 
methods for mid-­­trimester termination of pregnancy. Cochrane Database Syst Rev.  
2011(1):CD005216. 
2. 
Borgatta L, Kapp N. Clinical guidelines. Labor induction abortion in the second 
trimester. Contraception. Jul 2011;84(1):4-­­18. 
3. 
Newmann SJ, Dalve-­­Endres A, Diedrich JT, Steinauer JE, Meckstroth K, Drey EA. 
Cervical preparation for second trimester dilation and evacuation. Cochrane 
Database of Systematic Reviews. 2010(8). 
http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD007310/fr 
ame.html. 
4. 
Carbonell JL, Gallego FG, Llorente MP, et al. Vaginal vs. sublingual misoprostol with 
mifepristone for cervical priming in second-­­trimester abortion by dilation and 
evacuation: a randomized clinical trial. Contraception. 2007;75(3):230-­­237. 
5. 
Searle L, Tait J, Langdana F, Maharaj D. Efficacy of mifepristone for cervical priming 
for second-­­trimester surgical termination of pregnancy. Int. J. Gynaecol. Obstet. Jan 
2014;124(1):38-­­41. 
6. 
Borgatta L, Roncari D, Sonalkar S, et al. Mifepristone vs. osmotic dilator insertion for 
cervical preparation prior to surgical abortion at 14-­­16 weeks: a randomized trial. 
Contraception. Nov 2012;86(5):567-­­571. 
7. 
L. Borgatta SS, J. McClusky, D. Kattan, A. Paris, R. Petricone, M. Finesseth. 
Mifepristone and misoprostol versus osmotic dilator use prior to surgical abortion 
at 15–18 weeks: a noninferiority study. Contraception. 2014;90(3):307. 
8. 
Shaw KA, Shaw JG, Hugin M, Velasquez G, Hopkins FW, Blumenthal PD. Adjunct 
mifepristone for cervical preparation prior to dilation and evacuation: a randomized 
trial. Contraception. Apr 2015;91(4):313-­­319. 
9. 
Creinin MD, Schreiber CA, Bednarek P, Lintu H, Wagner M-­­S, Meyn LA. Mifepristone 
and Misoprostol Administered Simultaneously Versus 24 Hours Apart for Abortion: 
A Randomized Controlled Trial. Obstet Gynecol. April 1, 2007 2007;109(4):885-­­894. 
10. 
Goldberg AB, Drey EA, Whitaker AK, Kang MS, Meckstroth KR, Darney PD. 
Misoprostol compared with laminaria before early second-­­trimester surgical 
abortion: a randomized trial. Obstet Gynecol. Aug 2005;106(2):234-­­241. 
11. 
Bartz D, Maurer R, Allen RH, Fortin J, Kuang B, Goldberg AB. Buccal misoprostol 
compared with synthetic osmotic cervical dilator before surgical abortion: a 
randomized controlled trial. Obstet Gynecol. Jul 2013;122(1):57-­­63. 
12. 
Ellis SC, Kapp N, Vragpvoc O, Borgata L. Randomized trial of buccal versus vaginal 
misoprostol for induction of second trimester abortion. Contraception. May 
2010;81(5):441-­­445.