Comparing Buccal and Vaginal Misoprostol in Management of Early Pregnancy Loss

• Sponsor: University of California, San Diego (Other)
• Overall Status: Completed
• CT.gov ID: NCT02141555
• Collaborator: (none)
• Enrollment: 4
• Locations: 2
• Arms: 2
• Actual Duration (Months): 22
• Patients Per Site: 2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

First trimester miscarriages are common. When the failed pregnancy does not pass spontaneously on its own, it is called a missed abortion. There are several ways in which missed abortions are managed, one of which involves administering a medication called misoprostol which causes uterine contractions inducing expulsion of the failed pregnancy. Misoprostol can be administered in multiple ways but has been traditionally inserted vaginally when used for management of missed abortions. Some studies have shown that some women are not comfortable with vaginal insertion of misoprostol and prefer oral administration. Buccal misoprostol is a way of administering misoprostol by having the patients insert the tablets of misoprostol between their gum and cheek, letting it dissolve for 30 minutes, then swallowing the remaining remnants. Buccal misoprostol is used safely in medical abortion. In fact a study by Fjerstad et al (2009), found a decrease in infection rate for medical abortion when misoprostol administration was switched from vaginal to buccal route combined with routine administration of doxycycline. The efficacy of using buccal misoprostol to treat missed abortions has not been studied previously to the investigators' knowledge. In this pilot study, investigators aim to test the hypotheses that buccal misoprostol is equally effective as vaginal misoprostol in the medical management of early pregnancy loss. As secondary outcomes, investigators suspect that buccal misoprostol may be associated with higher rates of gastrointestinal side effect but that patient satisfaction will remain equally as high for buccal misoprostol as for vaginal misoprostol.

Condition or Disease	Intervention/Treatment	Phase
Spontaneous Abortion in First Trimester	Drug: Vaginal Misoprostol; Drug: Buccal Misoprostol	Phase 2/Phase 3

Detailed Description

Randomization:

Women who present to University of California, San Diego (UCSD) Medical Offices South clinic for evaluation and management of missed abortion will all be sent to the lab prior to the clinic visit for a type and screen and hemogram to determine blood type and hemoglobin level as is the current standard of care. Each woman will then be screened by a physician. The physician will notify a co-investigator of eligible patients who are interested in participating in the study. The co-investigator will consent the patient for the study. Once the written consent is obtained, patient will be asked to fill out an intake survey to obtain demographic information. Participants will be randomized into either the vaginal or buccal misoprostol group with a block size of four. Assignments will be concealed in sequentially numbered sealed opaque envelope. The envelope will be opened by the co-investigator who will reveal the route of misoprostol to the patient and review the written instructions on how to take the medication appropriately. Given the different routes of administration, neither the patient nor the provider will be blinded. Given that one of the secondary outcomes of interest was patient satisfaction based on the different route of administration, decision was made to not use placebo pills which could have been used to do a double-blinded study.

Intervention:

Dose of Misoprostol for both treatment groups: 800 micrograms administered as four tablets of 200 micrograms.

Currently, the standard of care is to prescribe vaginal misoprostol 800 mcg for women with an early pregnancy failure desiring medical management. The only "intervention" in this study is to change the route of administration from vaginal to buccal for the women randomized to this group. The dose of misoprostol, follow up plan (including ultrasound) and prescription for pain medications (described below) is unchanged from the current standard of care. Participants randomized to the vaginal misoprostol group will be instructed to insert four misoprostol tablets (total of 800 micrograms) deeply into the vagina with their fingers. Participants randomized to the buccal misoprostol group will be instructed to place two tablets of misoprostol between their gum and cheek on each side (total 800 micrograms), then swish and swallow the remnants after 30 minutes. If the patient is Rh negative, the patient will be given a dose of rhogam 300 mcg at the initial visit which is the current standard of care.

Patients will be prescribed an additional dose of misoprostol 800 mcg that they can take at their own discretion in the absence of vaginal bleeding 48 hours from initial dose using the same route of administration as the first dose. All participants will be prescribed ibuprofen with instructions to take 600 mg every 6 hours as needed for pain and a narcotic medication for breakthrough pain. The cost of these medications will be fully covered by the participant's insurance with no additional cost to the participant.

Follow up will be a clinic visit scheduled one week from the from the initial visit at UCSD Medical Offices South Clinic which time the participant will fill out a follow up survey assessing the participant's satisfaction and side effects experienced. The provider will also fill out a survey at this 1-week follow up visit assessing the success of the misoprostol in achieving a complete abortion. The participant's involvement in the study will conclude at this end of this one-week follow up visit.

Participant Commitment:

The research will require the following additional time commitment from participant in addition to the standard clinic visit:

1. Initial Visit: An additional 20 minutes will be required to review the study consent, randomize to the vaginal or buccal misoprostol group, and have the patient fill out a short intake survey.

2. Follow-up visit: The follow up visit will take one week from time of initial visit. An additional 10 minutes will be required to fill out the follow up survey. The participant's involvement in the study will conclude with this visit.

Study Design

• Study Type: Interventional
• Actual Enrollment: 4 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Comparing Buccal and Vaginal Misoprostol in Management of Early Pregnancy Loss: a Pilot Randomized Controlled Trial
• Actual Study Start Date: Aug 1, 2014
• Actual Primary Completion Date: Apr 1, 2015
• Actual Study Completion Date: Jun 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Vaginal misoprostol Participants will insert four misoprostol tablets (total of 800 micrograms) deeply into the vagina with their fingers.	Drug: Vaginal Misoprostol; Misoprostol inserted into vagina; Other Names: Vaginal Cytotec
Experimental: Buccal Misoprostol Participants will place two tablets of misoprostol between their gum and cheek on each side (total 800 micrograms), then swish and swallow the remnants after 30 minutes.	Drug: Buccal Misoprostol; Misoprostol placed between the gum and cheek and allowed to dissolve for 30 minutes with the remnants swallowed after this time.; Other Names: Buccal Cytotec

Outcome Measures

Primary Outcome Measures

1. Patient Enrollment [One year]

   The percentage of women who are offered enrollment and accept.

Secondary Outcome Measures

1. Number of Participants With Complete Abortion [one week]

   Number of participants with complete abortion without surgical intervention defined as no evidence of a gestational sac on transvaginal ultrasound at the follow up visit.

2. Number of Participants Who Answered 1 or 2 on a Scale of Satisfaction With the Procedure [one week]

   Written surveys patients will fill out at follow up visit assessing patient's satisfaction with the procedure. "How satisfied were you with your procedure?" The satisfaction scale used was: 1 =Very Satisfied, comfortable, likely to recommend 3= Neutral 5= Very unsatisfied/uncomfortable, unlike to recommend

3. Number of Participants Reporting 2 or 3 on a Scale of Medication Side Effects [one week]

   Assessment of medication side effects including: nausea, vomiting, headache, fever (over 100.4 F), dizziness, diarrhea, bad taste, dry mouth "Did you experience any of these side effects? If so, how long did they last?" Patients asked on a scale of 0 to 3, where: Side Effect scale: 0 = never 1= less than one day 2 = 1 to 2 days 3 = more than 2 days

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Women ages 18-50 who are English or Spanish speaking

• First trimester pregnancy (less than 13 weeks and 0 days)

• Desires medical management of an early pregnancy loss with misoprostol

• Diagnosed with an early pregnancy failure by UCSD Radiology or diagnosed early pregnancy failure defined by any of the following criteria (Bourne 2013):

• Crown-rump length > 7mm with no cardiac activity

• Mean gestational sac diameter of > 25 mm and no embryo

• Absence of an embryo with heartbeat > 2 weeks after a scan showing a gestational sac without a yolk sac

• Absence of embryo with heartbeat > 11 days after a scan showing a gestational sac with a yolk sac

Exclusion Criteria:

• Evidence of infection, acute hemorrhage, or hemodynamic instability

• Hemoglobin less than 9.5 including use of point of care Hgb testing

• Known allergy to misoprostol

• Underwent surgical or medical abortion during current pregnancy

• Currently breastfeeding

• Currently has intrauterine device in place

• Suspicion of ectopic or gestational trophoblastic disease

• History of clotting disorder or on anticoagulant therapy (excluding aspirin)

• Unreliable for follow up

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Universty of California San Diego Perlman Clinic	La Jolla	California	United States	92037
2	University of California San Diego Medical Offices South Clinic	San Diego	California	United States	92103

Sponsors and Collaborators

• University of California, San Diego

Investigators

• Study Director: Janie Pak, MD, MPH, University of California, San Diego
• Principal Investigator: Sheila Mody, MD, MPH, University of California, San Diego

Study Documents (Full-Text)

None provided.

More Information

Publications

• Aronsson A, Fiala C, Stephansson O, Granath F, Watzer B, Schweer H, Gemzell-Danielsson K. Pharmacokinetic profiles up to 12 h after administration of vaginal, sublingual and slow-release oral misoprostol. Hum Reprod. 2007 Jul;22(7):1912-8. Epub 2007 May 8.
• Danielsson KG, Marions L, Rodriguez A, Spur BW, Wong PY, Bygdeman M. Comparison between oral and vaginal administration of misoprostol on uterine contractility. Obstet Gynecol. 1999 Feb;93(2):275-80.
• Doubilet PM, Benson CB, Bourne T, Blaivas M; Society of Radiologists in Ultrasound Multispecialty Panel on Early First Trimester Diagnosis of Miscarriage and Exclusion of a Viable Intrauterine Pregnancy, Barnhart KT, Benacerraf BR, Brown DL, Filly RA, Fox JC, Goldstein SR, Kendall JL, Lyons EA, Porter MB, Pretorius DH, Timor-Tritsch IE. Diagnostic criteria for nonviable pregnancy early in the first trimester. N Engl J Med. 2013 Oct 10;369(15):1443-51. doi: 10.1056/NEJMra1302417. Review.
• Fjerstad M, Trussell J, Sivin I, Lichtenberg ES, Cullins V. Rates of serious infection after changes in regimens for medical abortion. N Engl J Med. 2009 Jul 9;361(2):145-51. doi: 10.1056/NEJMoa0809146.
• Herting RL, Clay GA. Overview of clinical safety with misoprostol. Dig Dis Sci. 1985 Nov;30(11 Suppl):185S-193S.
• Jones RK, Kost K. Underreporting of induced and spontaneous abortion in the United States: an analysis of the 2002 National Survey of Family Growth. Stud Fam Plann. 2007 Sep;38(3):187-97.
• Meckstroth KR, Whitaker AK, Bertisch S, Goldberg AB, Darney PD. Misoprostol administered by epithelial routes: Drug absorption and uterine response. Obstet Gynecol. 2006 Sep;108(3 Pt 1):582-90.
• Middleton T, Schaff E, Fielding SL, Scahill M, Shannon C, Westheimer E, Wilkinson T, Winikoff B. Randomized trial of mifepristone and buccal or vaginal misoprostol for abortion through 56 days of last menstrual period. Contraception. 2005 Nov;72(5):328-32. Epub 2005 Aug 9.
• Saraiya M, Berg CJ, Shulman H, Green CA, Atrash HK. Estimates of the annual number of clinically recognized pregnancies in the United States, 1981-1991. Am J Epidemiol. 1999 Jun 1;149(11):1025-9.
• Schaff EA, DiCenzo R, Fielding SL. Comparison of misoprostol plasma concentrations following buccal and sublingual administration. Contraception. 2005 Jan;71(1):22-5.
• Schaff EA, Fielding SL, Westhoff C. Randomized trial of oral versus vaginal misoprostol at one day after mifepristone for early medical abortion. Contraception. 2001 Aug;64(2):81-5.
• Sedgh G, Henshaw S, Singh S, Ahman E, Shah IH. Induced abortion: estimated rates and trends worldwide. Lancet. 2007 Oct 13;370(9595):1338-45.
• Tang OS, Gemzell-Danielsson K, Ho PC. Misoprostol: pharmacokinetic profiles, effects on the uterus and side-effects. Int J Gynaecol Obstet. 2007 Dec;99 Suppl 2:S160-7. Epub 2007 Oct 26. Review.
• Wilcox AJ, Weinberg CR, O'Connor JF, Baird DD, Schlatterer JP, Canfield RE, Armstrong EG, Nisula BC. Incidence of early loss of pregnancy. N Engl J Med. 1988 Jul 28;319(4):189-94.
• Winikoff B, Dzuba IG, Creinin MD, Crowden WA, Goldberg AB, Gonzales J, Howe M, Moskowitz J, Prine L, Shannon CS. Two distinct oral routes of misoprostol in mifepristone medical abortion: a randomized controlled trial. Obstet Gynecol. 2008 Dec;112(6):1303-1310. doi: 10.1097/AOG.0b013e31818d8eb4.

• Responsible Party: Sheila Mody, Assistant Adjunct Professor, Section of Family Planning, University of California, San Diego
• ClinicalTrials.gov Identifier: NCT02141555
• Other Study ID Numbers: 140250
• First Posted: May 19, 2014
• Last Update Posted: Aug 15, 2019
• Last Verified: Jul 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Sheila Mody, Assistant Adjunct Professor, Section of Family Planning, University of California, San Diego: misoprostol, early pregnancy loss, missed abortion
• Additional relevant MeSH terms: Abortion, Spontaneous; Misoprostol

Study Results

Participant Flow

Arm/Group Title	Vaginal Misoprostol	Buccal Misoprostol
Arm/Group Description	Participants will insert four misoprostol tablets (total of 800 micrograms) deeply into the vagina with their fingers. Vaginal Misoprostol: Misoprostol inserted into vagina	Participants will place two tablets of misoprostol between their gum and cheek on each side (total 800 micrograms), then swish and swallow the remnants after 30 minutes. Buccal Misoprostol: Misoprostol placed between the gum and cheek and allowed to dissolve for 30 minutes with the remnants swallowed after this time.
Period Title: Overall Study
STARTED	2	2
COMPLETED	2	2
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Vaginal Misoprostol	Buccal Misoprostol	Total
Arm/Group Description	Participants will insert four misoprostol tablets (total of 800 micrograms) deeply into the vagina with their fingers. Vaginal Misoprostol: Misoprostol inserted into vagina	Participants will place two tablets of misoprostol between their gum and cheek on each side (total 800 micrograms), then swish and swallow the remnants after 30 minutes. Buccal Misoprostol: Misoprostol placed between the gum and cheek and allowed to dissolve for 30 minutes with the remnants swallowed after this time.	Total of all reporting groups
Overall Participants	2	2	4
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	40	35	37.5
Sex: Female, Male (Count of Participants)
Female	2 100%	2 100%	4 100%
Male	0 0%	0 0%	0 0%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
United States	2 100%	2 100%	4 100%

Outcome Measures

1. Primary Outcome

Title	Patient Enrollment
Description	The percentage of women who are offered enrollment and accept.
Time Frame	One year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Vaginal Misoprostol	Buccal Misoprostol
Arm/Group Description	Participants will insert four misoprostol tablets (total of 800 micrograms) deeply into the vagina with their fingers. Vaginal Misoprostol: Misoprostol inserted into vagina	Participants will place two tablets of misoprostol between their gum and cheek on each side (total 800 micrograms), then swish and swallow the remnants after 30 minutes. Buccal Misoprostol: Misoprostol placed between the gum and cheek and allowed to dissolve for 30 minutes with the remnants swallowed after this time.
Measure Participants	2	2
Count of Participants [Participants]	2 100%	2 100%

2. Secondary Outcome

Title	Number of Participants With Complete Abortion
Description	Number of participants with complete abortion without surgical intervention defined as no evidence of a gestational sac on transvaginal ultrasound at the follow up visit.
Time Frame	one week

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Vaginal Misoprostol	Buccal Misoprostol
Arm/Group Description	Participants will insert four misoprostol tablets (total of 800 micrograms) deeply into the vagina with their fingers. Vaginal Misoprostol: Misoprostol inserted into vagina	Participants will place two tablets of misoprostol between their gum and cheek on each side (total 800 micrograms), then swish and swallow the remnants after 30 minutes. Buccal Misoprostol: Misoprostol placed between the gum and cheek and allowed to dissolve for 30 minutes with the remnants swallowed after this time.
Measure Participants	2	2
Count of Participants [Participants]	1 50%	2 100%

3. Secondary Outcome

Title	Number of Participants Who Answered 1 or 2 on a Scale of Satisfaction With the Procedure
Description	Written surveys patients will fill out at follow up visit assessing patient's satisfaction with the procedure. "How satisfied were you with your procedure?" The satisfaction scale used was: 1 =Very Satisfied, comfortable, likely to recommend 3= Neutral 5= Very unsatisfied/uncomfortable, unlike to recommend
Time Frame	one week

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Vaginal Misoprostol	Buccal Misoprostol
Arm/Group Description	Participants will insert four misoprostol tablets (total of 800 micrograms) deeply into the vagina with their fingers. Vaginal Misoprostol: Misoprostol inserted into vagina	Participants will place two tablets of misoprostol between their gum and cheek on each side (total 800 micrograms), then swish and swallow the remnants after 30 minutes. Buccal Misoprostol: Misoprostol placed between the gum and cheek and allowed to dissolve for 30 minutes with the remnants swallowed after this time.
Measure Participants	2	2
Count of Participants [Participants]	2 100%	2 100%

4. Secondary Outcome

Title	Number of Participants Reporting 2 or 3 on a Scale of Medication Side Effects
Description	Assessment of medication side effects including: nausea, vomiting, headache, fever (over 100.4 F), dizziness, diarrhea, bad taste, dry mouth "Did you experience any of these side effects? If so, how long did they last?" Patients asked on a scale of 0 to 3, where: Side Effect scale: 0 = never 1= less than one day 2 = 1 to 2 days 3 = more than 2 days
Time Frame	one week

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Vaginal Misoprostol	Buccal Misoprostol
Arm/Group Description	Participants will insert four misoprostol tablets (total of 800 micrograms) deeply into the vagina with their fingers. Vaginal Misoprostol: Misoprostol inserted into vagina	Participants will place two tablets of misoprostol between their gum and cheek on each side (total 800 micrograms), then swish and swallow the remnants after 30 minutes. Buccal Misoprostol: Misoprostol placed between the gum and cheek and allowed to dissolve for 30 minutes with the remnants swallowed after this time.
Measure Participants	2	2
Count of Participants [Participants]	0 0%	0 0%

Adverse Events

Time Frame	One week
Arm/Group Title	Vaginal Misoprostol		Buccal Misoprostol
Arm/Group Description	Participants will insert four misoprostol tablets (total of 800 micrograms) deeply into the vagina with their fingers. Vaginal Misoprostol: Misoprostol inserted into vagina		Participants will place two tablets of misoprostol between their gum and cheek on each side (total 800 micrograms), then swish and swallow the remnants after 30 minutes. Buccal Misoprostol: Misoprostol placed between the gum and cheek and allowed to dissolve for 30 minutes with the remnants swallowed after this time.
All Cause Mortality
	Vaginal Misoprostol		Buccal Misoprostol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2 (0%)		0/2 (0%)
Serious Adverse Events
	Vaginal Misoprostol		Buccal Misoprostol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2 (0%)		0/2 (0%)
Other (Not Including Serious) Adverse Events
	Vaginal Misoprostol		Buccal Misoprostol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2 (0%)		0/2 (0%)

Limitations/Caveats

Due to the small number of participants, no conclusions could be drawn and a larger study was not done.

More Information

Certain Agreements

All Principal Investigators ARE 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.