Ovarian Function With ENG Implant and UPA Use

Primary Objectives:

1. To determine point estimates for the incidence of ovulation within five days of oral ulipristal acetate (UPA) administration with same day etonogestrel (ENG) implant insertion in the presence of a dominant follicle.
2. To determine point estimates for the incidence of ovulation within five days of etonogestrel (ENG) implant insertion alone in the presence of a dominant follicle. .

Clinical hypotheses:

• Combined oral UPA administration with same day ENG implant insertion will interfere with UPA's effect in delaying ovulation as occurs with oral progestogens given within 1-2 days of UPA.

Study Design: Pilot randomized, single site clinical trial with blinded analysis

Participant recruitment and study site: The investigators will recruit participants interested in using the ENG contraceptive implant but not currently at risk for pregnancy from Planned Parenthood Association of Utah clinics, University of Utah Hospital and Community clinics, and through targeted social media ads. All study procedures will occur at the University of Utah Hospital Outpatient OBGYN Clinic or at the University Center for Reproductive Medicine clinic.

Sample size: This is a pilot proposal to recruit a total of 40 participants across 2 study arms: (1) ENG implant only (n=20) and (2) UPA + same day ENG implant insertion (n=20). The investigators null hypotheses are:

1. ENG implant along with UPA administration in the presence of a dominant ovarian follicle will not change the expected 97% ovulation suppression within 5 days of UPA use.
2. ENG implant insertion alone in the presence of a dominant ovarian follicle will not sufficiently interrupt ovulation.

Randomization scheme: block randomization with block size of 4

Blinding protocol: This study will not be blinded as a pilot. The feasibility of the study, including clinic space limitations and provider time, relies on the same healthcare provider for implant insertion and ultrasound in many patients. All statistical analyses will be blinded to the statistician.

Participant procedures:

Screening Visit (Screening Visit 1): Subjects will be screened for eligibility and interest in the study. Each subject will have the study explained and, if participation is desired, informed consent documents will be signed prior to any study procedures. The screening visit will include: review of medical, surgical and social history, medications, menstrual dating, sexual history and contraceptive use, physical exam, including breast and pelvic, pregnancy test and a transvaginal ultrasound to ensure ability to document ovarian follicular activity in the treatment cycle.

Progesterone Visit (Screening Visit 2): This brief visit will occur on days 20-24 of the menstrual cycle and may be combined with the screening visit (Visit 1) if the time-frame is met. This visit will include a review of any interim changes (if completed separate from the screening visit) in history, medications, pregnancy risk/contraception, and a serum progesterone level will be drawn. The participants will notify the study coordinator of the 1st day of their next menses.

Ovarian monitoring (Screening Visits 3-7 +/- 2 visits): Participants will undergo transvaginal ultrasound evaluation of their ovaries three times a week starting on cycle day #7 (+/- 2 days). If/ When investigators identify a lead follicle with a mean diameter of >13mm in at least 2 dimensions, study follow-up will switch to daily monitoring.

Treatment Day #1 (Treatment Visit #1): Once a lead follicle (>14mm) is identified then participants will be randomized to one of two treatment groups:

1. ENG implant insertion
2. UPA 30mg PO tablet and same-day ENG implant insertion Assigned treatment will be administered (UPA and/or ENG implant insertion). Study team will obtain serum progesterone, LH levels, and estradiol levels.

Treatment Days #2-8 (Treatment Visits #2-8): Participants will follow up daily for Days 2-8. Each day investigators will obtain transvaginal ultrasound measurement of ovarian follicle size, serum progesterone, LH levels, and estradiol levels. Daily transvaginal ultrasounds will continue until either follicle rupture is documented, the follicle is <12 mm on two consecutive visits, or Day 8 ultrasound occurs (7 days after implant insertion), whichever occurs first.

Treatment Day #14 (Exit Visit): Repeat ultrasound will occur on Day 14 following ENG implant insertion, and this will be the exit visit.

Data collection: Source documents for each participant and visit number will be completed by the study personnel at the time of the visit. Form development, data collection, and data management will occur in RedCAP, secure web platform for building and managing online databases and surveys. Source documents maintained in individual participant binders.

Assessing and reporting adverse events: The reporting period for AEs is the period immediately following the subject signing the informed consent through the 30 days following the final study visit. Each visit will include assessment of how the participant felt since the last visit, review of adverse event reports, implant insertion site reactions, lab results, and vital signs and physical exam findings. AEs will not be reported for screen failures unless a SAE is experienced during screening. For all AEs, the investigator will pursue and obtain information adequate to determine the outcome of the AE and to assess whether it met criteria for a SAE. Participants who have ongoing AEs or SAEs will be followed until resolution or stabilization or referred for additional care. AEs will be documented both on source documents and in the clinical database with SAEs reported per IRB guidelines. Participants will be provided instructions for contacting the study site to report any untoward medical occurrences. With permission from the participant, whenever possible records from all non-study medical providers related to medical occurrences will be obtained for review. AEs and SAEs will be reviewed by the Data Safety Monitoring Board.

Statistical Analyses:

The investigator and study team will be responsible for analyzing the study data. The official clinical database in RedCAP will not be analyzed until medical/scientific review has been completed, protocol violators have been identified (if appropriate), and data has been declared complete.

Variables/Time Points of Interest The primary outcome is delay in rupture of the dominant follicle by 5 days (yes/no) between group 1 (ENG implant alone) and group 2 (UPA with same day ENG implant). If the date of follicle rupture was unclear by ultrasound alone, investigators will utilize serum hormone levels to adjudicate day of rupture. These measures include day of follicle collapse, day and value of highest LH, day and value of highest progesterone level. Investigators will use an estradiol level of >100pg/ml to confirm the enlarged follicle is the dominant follicle on the treatment day.

Statistical Methods The primary and secondary dichotomous outcome measures of ovulation by 5 days will be assessed by Wilcoxon sign rank test and demographic will be analyzed using descriptive statistics.

Power/Sample Size:

The investigator and study team will be responsible for analyzing the study data. The official clinical database in RedCAP will not be analyzed until medical/scientific review has been completed, protocol violators have been identified (if appropriate), and data has been declared complete.

Variables/Time Points of Interest The primary outcome is delay in rupture of the dominant follicle by 5 days (yes/no) between group 1 (ENG implant alone) and group 2 (UPA with same day ENG implant). If the date of follicle rupture was unclear by ultrasound alone, investigators will utilize serum hormone levels to adjudicate day of rupture. These measures include day of follicle collapse, day and value of highest LH, day and value of highest progesterone level. Investigators will use an estradiol level of >100pg/ml to confirm the enlarged follicle is the dominant follicle on the treatment day.

This is a pilot study to obtain point estimates for future study proposals. Current data on ovulatory function with mid-cycle implant insertion or the pharmacodynamics interactions between same day UPA and ENG are lacking.

Should data show that ovulation occurs <15% within 5 days of combined UPA use and ENG implant initiation, investigators will pursue an adequately powered study assessing ovulation delay with UPA only vs. UPA with ENG implant initiation. This finding would show that UPA's relationship with the ENG implant may be different than what has been found with oral progestogens. If ovulation occurs 15% in the first 5 days with combined use of these medications, this would support the current practice of delaying implant insertion after UPA administration.

Should data show that the ENG implant insertion alone in the presence of a dominant follicle delays or stops ovulation >44% (the ovulation suppression of oral LNG EC), investigators will pursue an adequately powered study assessing the ENG implant alone for EC. If ovulation occurs >15%, this would support continuation of the practice of using a backup method when an implant is inserted after the first 7 days of the menstrual cycle.

These pre-specified criteria to judge if and how to proceed are consistent with CONSORT guidelines for randomized pilot and feasibility trials.[11]