Oral Mifepristone and Buccal Misoprostol Administered Simultaneously for Abortion Through 63 Days Gestation
Oral Mifepristone and Buccal Misoprostol Administered Simultaneously for Abortion Through 63 Days Gestation
HYPOTHESIS: For women with pregnancies at <49, 50-56, and 57-63 days gestation who receive
 mifepristone 200 mg orally and misoprostol 800 mcg buccally at the same time, the complete
 abortion rate 24 hours after misoprostol administration will be 90% (95% CI 78%, 97%) within
 each gestational age group.

 This is a prospective clinical trial. Women will be enrolled such that 40 women are in each
 of three gestational age ranges: ≤49, 50-56, and 57-63 days gestation on the day treatment is
 initiated. Once a gestational age range includes 40 subjects, enrollment in that group will
 be closed. Subjects will swallow mifepristone 200 mg and then place four 200 µg misoprostol
 tablets between the check and gum (2 tablets on each side). The women will be instructed to
 keep the tablets in place for 30 minutes; any remaining portions of the tablets will be
 swallowed after this time. Participants will follow-up 24 hours after receiving the
 misoprostol. Vaginal ultrasonography will be performed to assess for expulsion of the
 gestational sac. Women who have not aborted by the first follow-up visit will be given a dose
 of vaginal misoprostol and will return for a follow-up visit in one week. Subjects who have
 not aborted by the two-week follow-up will be offered a surgical abortion. At each visit,
 data will be collected on bleeding, cramping, other side effects, and medication use.
1. TELEPHONE SCREEN:

 Initial contact will be by a phone call (or, rarely, a drop-in visit) initiated by a
 potential study participant. A member of the research staff will advise the potential
 participant of the study rationale, protocol, risks, benefits, and visit schedule. We
 request a waiver of the requirement to obtain signed informed consent for the screening
 process, which will usually take place over the phone. We believe we meet the criteria
 for the use of this waiver because the screening procedure presents no more than minimal
 risk of harm to the subjects and involves no procedures for which written consent is
 normally required outside of the research context. The information obtained during the
 screening phone call is the same type of information that would be collected on patients
 setting up an appointment for an abortion. The telephone script and screen are included
 in Attachment 2. If the subject does not meet inclusion criteria, the information
 collected during the screening process will be destroyed. Potential subjects interested
 in participation will be scheduled for a screening visit.

 Each subject will undergo a minimum of 3 visits all of which will be performed in the
 Family Planning Research Office at Magee-Womens Hospital. She will also receive a
 minimum of 3 follow-up telephone calls. Those subjects who do not pass the pregnancy by
 the first follow-up visit will be scheduled for return visits as indicated on the Study
 Flow Sheet (see attachment) and described below.

 2. SCREENING AND ENROLLMENT: Visit length 1 ½ hours.

 1. After obtaining consent for a screening ultrasound evaluation, a transvaginal and a
 transabdominal ultrasound examination will be performed to ascertain gestational
 age. The transvaginal ultrasound results will be used to confirm gestational age
 and document an intrauterine gestation for the study protocol. Vaginal ultrasound
 to confirm estimated gestational age (EGA) will use the following criteria:

 -  EGA (days) = mean sac diameter + 3025

 -  EGA (days) = embryonic pole + 4226

 -  Mean sac diameter ([length + width + depth]/3) should be used only when no
 embryonic pole is present.

 -  If the ultrasound EGA is different from LMP EGA by 4 days or more, then the
 ultrasound EGA should be used as the study EGA.

 2. Written informed consent will be obtained at the screening visit prior to any
 research activities. The investigator or one of the co-investigators, who are
 physicians, will sign the informed consent document.

 3. After obtaining informed consent, a medical history and initial laboratory tests
 (hemoglobin and blood type) will be obtained. If the pelvic examination is normal,
 the endovaginal ultrasound confirms that the gestational age will be less than 63
 days on the day of the mifepristone administration, and the laboratory tests
 satisfy the entry criteria, the subject will be asked to participate in the study.

 4. A HIPAA compliant "Release of Medical Records" form will be signed to allow future
 access to medical records related to any care provided during the study by another
 health care provider.

 3. VISIT 1: The subject will return prior to reaching 64 days gestation. This day will be
 considered Study Day 1. Visit length 30 minutes.

 1. The research staff will administer a pre-study questionnaire. The subject will
 complete a Visual Analogue Scale (VAS) assessment.

 2. Eligibility criteria will be reviewed and, if indicated by a history of bleeding
 since screening, a vaginal ultrasound will be performed.

 3. A licensed clinician will distribute the medications after completion of the
 questionnaire. The medications will be kept in a locked file in the research office
 and a log will be generated to track medication usage, lot numbers, and expiration
 dates. All subjects will take the mifepristone and misoprostol in front of the
 research clinician.

 -  She will receive mifepristone 200 mg orally and swallow the tablet in front of
 one of the researchers. THE SUBJECT CANNOT RECEIVE THE MIFEPRISTONE UNTIL A
 MINIMUM OF 24 HOURS AFTER COMPLETION OF THE INFORMED CONSENT.

 -  Within 5 minutes of mifepristone administration, the subject will be given
 four 200 µg tablets of misoprostol to place between the cheek and gum (2 on
 each side) and to allow them to remain in that location for 30 minutes. After
 this time lapse, any remaining tablets will be swallowed. The subject will not
 need to wait in the office during the 30 minutes.

 4. The subject will receive a prescription for codeine (30 mg) or hydrocodone (5 mg),
 #20 and an instruction sheet with the phone numbers to call if she has any
 questions or problems.

 5. Rh-immune globulin will be administered if she is Rh-negative.

 6. The subject will be scheduled for follow-up 24 ± 1 hours after administration of
 the misoprostol.

 4. VISIT 2: 24 ± 1 hours after misoprostol administration. Visit length 1 hour.

 1. Endovaginal and abdominal ultrasound examinations will be performed.

 -  If the vaginal ultrasound examination demonstrates a gestational sac, the
 subject will receive a "rescue" dose of vaginal misoprostol (four 200 µg
 tablets of misoprostol), which will be placed by the clinician. A follow-up
 appointment will be scheduled for study Day 15 (range Day 13-17)

 -  If the vaginal ultrasound does not demonstrate a sac the abortion will be
 considered complete and telephone follow-up contacts will be the only
 scheduled evaluations from this point forward.

 2. All subjects will complete a post-study VAS, which will take about 5 minutes to
 complete.

 5. TELEPHONE FOLLOW-UP #1: Study Day 8 (range Day 6-10). Call length 10 minutes. Subjects
 will be contacted to assess their clinical status including bleeding, cramping, and
 medication requirements. If necessary, based on the subject's responses, appointments
 for evaluation by a clinician will be made at that time.

 6. VISIT 3/TELEPHONE FOLLOW-UP #2: Study Day 15 (range Day 13-17). Visit length (if
 required) 1 hour, call length 10 minutes)

 1. Subjects who had expelled the gestational sac as based on prior ultrasound
 examination will receive telephone follow-up to assess their clinical status.
 Appointments for evaluation by a clinician will be made as necessary. A post-study
 acceptability questionnaire will be performed with these subjects over the
 telephone, which will take about 5 minutes to complete.

 2. Subjects who had not expelled the gestational sac on prior examination will return
 to the office for this visit. Endovaginal and abdominal ultrasounds will be
 performed.

 -  If the vaginal ultrasound shows an intrauterine gestation with embryonic
 cardiac activity, the subject will be offered and advised to have a surgical
 abortion to be done as soon as possible. After the D&C, the subject will
 complete a 5-minute post-study acceptability questionnaire. She will also have
 a telephone follow-up on Study Day 36.

 -  If the vaginal ultrasound shows the gestational sac to be present without
 embryonic cardiac activity, the subject may have a D&C and complete the
 acceptability questionnaire or can pursue expectant management and return on
 Study Day 36 (range Day 32-40).

 -  If the vaginal ultrasound demonstrates absence of the gestational sac, she
 will complete a post-study acceptability questionnaire at the end of her visit
 which will take about 5 minutes to complete and all further follow up will be
 performed by telephone.

 7. VISIT 4/TELEPHONE FOLLOW_UP #3: Study Day 36 (range Day 32-40). Visit length (if
 required) 30 minutes-1 hour, call length 10 minutes.

 1. Subjects who had expelled the gestational sac as based on prior ultrasound
 examination or who had a D&C will receive telephone follow-up to assess their
 clinical status. Appointments to be evaluated by a clinical will be made as
 necessary.

 2. If the subject must return for this visit, endovaginal and abdominal ultrasound
 examinations will be performed. If the vaginal ultrasound shows the gestational sac
 to still be present, the patient will be offered a surgical abortion.

 3. At the completion of the surgical abortion or if the ultrasound demonstrates
 absence of a sac, a 5-minute post-study acceptability questionnaire will be
 performed.

 8. OTHER

 1. The subject will be questioned at each visit regarding side effects experienced
 from the medications, bleeding and cramping, pain medication required, and other
 medications used since the last visit.

 2. If the subject does not return for a scheduled visit, she should be telephoned to
 reschedule the visit. If the patient is unable to return for her follow-up, the
 required information regarding bleeding history, medications, medication side
 effects, and questionnaire answers can be obtained over the phone. If the subject
 is unable to be reached by phone within two weeks of her scheduled visit, a
 certified letter must be sent indicating her need to return. Subjects will be
 considered lost to follow-up only if the final visit is not completed by the time
 the study is closed.

 3. If the subject fails to return for her Visit 2, but returns at some later time
 during her study participation period and is found to have a retained gestational
 sac or continuing pregnancy on ultrasound, she may receive an additional vaginal
 dose of misoprostol (4 tablets; up to Study Day 12) or be offered a D&C (at any
 time).

 4. The subject will be counseled not have intercourse or drink alcohol until the
 completion of the abortion is confirmed.

 5. Contraceptive counseling will be performed throughout the study. A method of
 contraception should be instituted after the abortion has occurred and before the
 subject resumes sexual activity.

 6. Endovaginal ultrasound may be performed at any time other than what is required by
 the protocol if felt to be necessary by the clinician.

 7. Standard suction curettage will be performed for continuing pregnancy at visit 3 or
 persistent sac at visit 4, uterine hemorrhage, or incomplete abortion.
Inclusion Criteria:Healthy females: 1) 18 years of age or older, 2) requesting an elective
 termination of pregnancy by medical abortion, 3) with an intrauterine pregnancy no more
 than 63 days gestation on the day of mifepristone administration as documented by
 endovaginal ultrasound, 4) willing and able to sign informed consent, 5) willing to comply
 with the study protocol and visit schedule, 6) willing to have a surgical abortion/D&C if
 indicated, and 7) with easy and ready access to a telephone.

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 Exclusion Criteria:1) ultrasound evidence at the evaluation(s) prior to mifepristone
 treatment of an early pregnancy failure, 2) contraindication to mifepristone (known allergy
 to mifepristone, chronic corticosteroid administration, adrenal disease), 3)
 contraindication to misoprostol (glaucoma, mitral stenosis, sickle cell anemia, poorly
 controlled seizure disorder, or known allergy to prostaglandin), 4) known or suspected
 extrauterine pregnancy, 5) known or suspected pelvic infection, 6) hemoglobin <10 mg/dL, 7)
 known clotting defect or receiving anticoagulants, 8) cardiovascular disease (angina,
 valvular disease, arrhythmia, or cardiac failure), 9) current breastfeeding, 10) pregnancy
 with an IUD in situ, 11) current use of any experimental drug, 12) suspected or confirmed
 endometrial arteriovenous malformation, 13) active oral herpes lesions per subject report,
 14) prior participation in this research study, or 15) current participation in another
 research study that, in the opinion of the investigator, would interfere with the conduct
 of this study.

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