Study of Contraceptive Efficacy & Safety of Phexxi™ (Previously Known as Amphora) Gel Compared to Conceptrol Vaginal Gel

Clinical Trial Design

This is a multicenter, open-label, randomized, controlled, Phase III study of repeated use of Amphora™ gel compared to Conceptrol® Vaginal Gel as the method of contraception over seven cycles of use. In addition, there is an opportunity for Amphora™ gel subjects to continue with study treatment for up to 13 cycles of treatment upon completion of the first seven cycles of treatment.

A subset of subjects (Amphora™ gel and Conceptrol® Vaginal Gel) will undergo colposcopy at the Admission Visit and at the visits after Cycles 1, 3, and 7 (Treatment Exit). Subjects participating for 13 cycles will also undergo colposcopy after Cycles 10 and 13. Colposcopic photographs will be taken at all visits independent of presence of any suspicious areas. Any suspicious areas and clinical findings will be recorded on the colposcopy case report form. The colposcopy evaluator for the subset will be blinded regarding the treatment group of the subject. If at any time during the study the investigator deems colposcopy necessary, colposcopy will be performed on any subject and will not be limited to subjects in the colposcopy subset.

A subset of subjects (Amphora™ gel and Conceptrol® Vaginal Gel) will also have semi-quantitative cultures for E. coli and clinical yeast performed at the Admission Visit and after Cycles 1, 3, and 7 (Treatment Exit) Visits. Subjects participating for 13 cycles will also undergo the assessments after Cycles 10 and 13. Another subgroup will have quantitative vaginal cultures performed after Cycles 1 and 7 (Treatment Exit) Visits, and also after Cycle 13 for subjects participating in the extension.

Selected research centers will also recruit subjects into the subset of women 36-45 years of age at enrollment.

• Conceptrol (Drug): • Conceptrol® Vaginal Gel, which contains 100 mg (4% concentration) of nonoxynol-9 (N-9) in 2.5 mL volume of gel.
• Amphora (Drug): • Amphora™ gel, which will be delivered in 5 mL doses, is a clear, water-based, petroleum-free gel.

Primary outcomes

• 6-Month (183 Days) Cumulative Pregnancy Percentage [183 days]: The primary endpoint was the evaluation of contraceptive efficacy over six months (183 days) of Amphora™ Gel use when compared to Conceptrol® Vaginal Gel. Kaplan-Meier methods were used to estimate the six-month cumulative pregnancy percentage of women in the MITT population by treatment group

Secondary outcomes

• 6-Month (183 Days) Cumulative Pregnancy Percentage for Subjects With Perfect Use [183 days]: Perfect use contraceptive efficacy over six months (183 days) of Amphora™ Gel use when compared to Conceptrol® Vaginal Gel. Kaplan-Meier methods were used to estimate the six-month cumulative pregnancy percentage of women in the efficacy evaluable (EE) population by treatment group

Sex: Female, ages: 18 Years to 35 Years, accepts healthy volunteers

Inclusion Criteria:

* Be healthy women, who are sexually active, at risk for pregnancy, and desiring contraception.
* Be within the age range of 18 through 35 (inclusive) at enrollment if not in the subset of women with an age of 36-45 at enrollment (age subset at select sites).
* Be at low-risk for both human immunodeficiency virus (HIV) and sexually transmitted disease (STD) infection and currently have a single sex partner (≥ 4 months) who is also at low-risk for both HIV and STD infection.
* Have a negative urine pregnancy test prior to enrollment.
* Have normal cyclic menses with a usual length of 21 to 40 days over the last two cycles or at least one spontaneous, normal menstrual cycle (two menses) since delivery, abortion, or after discontinuing hormonal contraception/hormonal therapy.
* Be willing to accept a risk of pregnancy.
* Be willing to engage in at least two acts of heterosexual vaginal intercourse per cycle.
* Be willing to be randomized to either study treatment.
* Be willing to use the study product as the only method of contraception over the course of the study (with the exception of emergency contraception (EC)), when indicated).
* Be capable of using the study product properly and agree to observe all study directions and requirements.
* Be willing to keep a daily diary to record coital information, product use information, information about the use of other vaginal products, and sign and symptom data for both the subject and her partner.
* Agree not to participate in any other clinical trials during the course of the study with the exception of enrolling in the Amphora™ gel extension study.
* Be willing to give written informed consent to participate in the trial.

Exclusion Criteria:

* Have a history of allergy or sensitivity to spermicides or products containing N-9 (nonoxynol-9).
* Have had three or more urinary tract infections (UTIs) in the past year.
* Have a UTI by urine culture, symptomatic yeast vaginitis, or symptomatic bacterial vaginosis diagnosed by wet mount unless treated and proof of cure is documented.
* Have a history of any recurrent vaginal infections/disorders (either less than or equal to four times in the past year or less than or equal to three times in the previous six months).
* Be pregnant, have a suspected pregnancy, or desire to become pregnant during the course of the study.
* Have a history of infertility or of conditions that may lead to infertility, without subsequent intrauterine pregnancy.
* Have any contraindications to pregnancy (medical condition) or chronic use of medications for which significant evidence of fetal risk exists.
* Have had more than one sexual partner in the last four months.
* Have shared injection drug needles in the past unless has a negative HIV test at least six weeks since last use.
* Have or have been suspected to have HIV infection.
* Have been diagnosed with genital herpes simplex virus (HSV), with the first occurrence (initial episode) within three months prior to screening.
* Have three or more outbreaks of HSV within the last year.
* Have evidence of Chlamydia trachomatis or Neisseria gonorrhoeae unless she and her partner complete treatment and proof of cure is documented.
* Have been diagnosed with any other STDs in the six months prior to the Randomization Visit (with the exception of human papillomavirus (HPV), trichomonas, gonorrhea, adn Chlamydia).
* Be lactating or breastfeeding.
* Have any clinically significant abnormal vaginal bleeding or spotting within the month prior to screening.
* Have any clinically significant abnormal finding on pelvic examination or baseline labs, which in the view of the investigator, precludes her from participating in the trial.
* Have clinically significant signs of vaginal or cervical irritation on pelvic examination.
* Have had vaginal or cervical biopsy or vaginal surgery within three months prior to screening (with the exception of cervical biopsies performed for eligibility determination).
* Have used vaginal or systemic antibiotics or antifungals within 14 days prior to screening or enrollment/randomization, with the exception of systemic antibiotics taken for a UTI and trichomonas diagnosed at screening. Subjects should not have used systemic antibiotics prescribed at the Screening Visit for a UTI within seven days of the enrollment/randomization visit.
* Have had a Depo-Provera® injection in the ten months prior to enrollment.
* Have an abnormal Pap test based on the following criteria:
* Pap test in the past 15 months with ASC-US unless:
* less than 21 years of age;
* a repeat Pap test at least six months later was normal;
* reflex HPV testing was performed and was negative for high-risk HPV; or
* a colposcopy (with or without biopsy) found no evidence of dysplasia requiring treatment or treatment was performed and follow-up at least six months after the treatment showed no evidence of disease;
* Pap test in the past 15 months with LSIL unless:
* less than 21 years of age;
* a colposcopy (with or without biopsy) found no evidence of dysplasia requiring treatment or treatment was performed and follow-up at least six months after the treatment showed no evidence of disease;
* Pap test in the past 15 months with ASC-H, atypical glandular cells, or HSIL unless colposcopy and/or treatment was performed and follow-up at least six months after the colposcopy and/or treatment showed no evidence of disease;
* Pap test in the past 15 months with malignant cells.
* Consume (on average) greater than three drinks of an alcoholic beverage per day.
* Have a past history (within 12 months) or current history which, in the PI's judgment, constitutes of drug abuse (recreational, prescription, or over-the-counter (OTC)).
* Have taken an investigational drug or used an investigational device within the past 30 days.
* Have issues or concerns (in the judgment of the investigator) that may compromise the safety of the subject or confound the reliability of compliance and information acquired in this study.

In addition, in order to be eligible to participate in the trial, potential subjects must state that, to her best knowledge, her sexual partner meets the following criteria:

* Is not infertile.
* Has had untreated chlamydia or gonorrhea in the past six months.
* Has not had more than one sexual partner in the past four months.
* Has no history of allergy or sensitivity to spermicides or products containing N-9.
* Has not been previously diagnosed with or suspected of HIV infection unless he has subsequently had a negative HIV test.
* Has not been known to have engaged in homosexual intercourse in the past five years unless he has had negative HIV test results since then.
* Has not shared injection drug needles in the past unless he has had a negative HIV test at least six weeks since last use.

Participant flow

Outcome results

• 6-Month (183 Days) Cumulative Pregnancy Percentage (Primary), Mean, pregnancy percentage: Conceptrol 10.0 (8.1 to 11.9); Amphora 10.5 (8.6 to 12.3)
• 6-Month (183 Days) Cumulative Pregnancy Percentage for Subjects With Perfect Use (Secondary), Mean, pregnancy percentage: Conceptrol 4.2 (2.8 to 5.6); Amphora 4.1 (2.7 to 5.4)

Adverse events

Time frame: 183 days

Serious adverse events by term

Other adverse events by term

• Kelly Culwell, MD, Study director, Evofem Inc.