Contraception
Conditions
Brief summary
This is a research study of a new experimental vaginal gel that helps in vaginal pH regulation and results in immobilization of spermatozoa by maintaining the normally low vaginal pH, even in the presence of semen. This vaginal gel is called Phexxi™ (previously known as Amphora) and was compared to a commercially available spermicide called Conceptrol®, which contains nonoxynol 9; commonly abbreviated as N-9. Conceptrol® can help prevent pregnancy. This study objective was to determine if this product prevents pregnancy when inserted into the vagina before intercourse.
Detailed description
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.
Interventions
DRUGConceptrol
• Conceptrol® Vaginal Gel, which contains 100 mg (4% concentration) of nonoxynol-9 (N-9) in 2.5 mL volume of gel.
DRUGAmphora
• Amphora™ gel, which will be delivered in 5 mL doses, is a clear, water-based, petroleum-free gel.
Sponsors
Premier Research
Evofem Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 35 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
Russia, United States
Participant flow
Recruitment details
Healthy, sexually active women at risk of pregnancy who desired contraception, aged 18 to 35 years, with a single male sex partner, of which both partners were at low risk for HIV and sexually transmitted disease (STD) infection. Subjects were required to have regular, normal, cyclic menses with a usual length of 21 to 40 days.
Pre-assignment details
The study had 65 randomized screen failures and were not included in the ITT population due to being accidentally randomized (30 randomized to Amphora™ Gel and 35 to Conceptrol®).
Participants by arm
| Arm | Count |
|---|---|
| Conceptrol 100 mg (4% concentration) of nonoxynol-9 in 2.5 mL volume of gel
Conceptrol: • Conceptrol® Vaginal Gel, which contains 100 mg (4% concentration) of nonoxynol-9 (N-9) in 2.5 mL volume of gel. | 1,659 |
| Amphora Citric acid USP, potassium bitartrate USP, and L-lactic acid USP
Amphora: • Amphora™ gel, which will be delivered in 5 mL doses, is a clear, water-based, petroleum-free gel. | 1,665 |
| Total | 3,324 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 28 | 25 |
| Overall Study | Lost to Follow-up | 321 | 323 |
| Overall Study | Meth. no longer prim. meth. birth cntrl | 10 | 20 |
| Overall Study | Not sexually active | 29 | 28 |
| Overall Study | Other | 34 | 32 |
| Overall Study | Physician Decision | 26 | 22 |
| Overall Study | Pregnancy | 136 | 151 |
| Overall Study | Protocol Violation | 154 | 124 |
| Overall Study | Withdrawal by Subject | 163 | 152 |
Baseline characteristics
| Characteristic | Amphora | Total | Conceptrol |
|---|---|---|---|
| Age, Continuous | 27.6 years STANDARD_DEVIATION 5.6 | 27.6 years STANDARD_DEVIATION 5.64 | 27.6 years STANDARD_DEVIATION 5.7 |
| BMI at Enrollment (kg/m2) | 27.91 kg/m2 STANDARD_DEVIATION 7.95 | 27.83 kg/m2 STANDARD_DEVIATION 7.97 | 27.76 kg/m2 STANDARD_DEVIATION 7.98 |
| BMI Category at Enrollment (kg/m2) Normal (18.5 - 24.9) | 640 Participants | 1312 Participants | 672 Participants |
| BMI Category at Enrollment (kg/m2) Obese (>30.0) | 548 Participants | 1087 Participants | 539 Participants |
| BMI Category at Enrollment (kg/m2) Overweight (25.0 - 29.9) | 392 Participants | 761 Participants | 369 Participants |
| BMI Category at Enrollment (kg/m2) Underweight (<18.5) | 83 Participants | 158 Participants | 75 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 392 Participants | 777 Participants | 385 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1272 Participants | 2546 Participants | 1274 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 14 Participants | 23 Participants | 9 Participants |
| Race (NIH/OMB) Asian | 36 Participants | 81 Participants | 45 Participants |
| Race (NIH/OMB) Black or African American | 471 Participants | 935 Participants | 464 Participants |
| Race (NIH/OMB) More than one race | 102 Participants | 200 Participants | 98 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 9 Participants | 22 Participants | 13 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) White | 1031 Participants | 2061 Participants | 1030 Participants |
| Sex: Female, Male Female | 1665 Participants | 3324 Participants | 1659 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 1,477 | 0 / 1,458 |
| other Total, other adverse events | 857 / 1,477 | 793 / 1,458 |
| serious Total, serious adverse events | 19 / 1,477 | 11 / 1,458 |
Outcome results
Primary
6-Month (183 Days) Cumulative Pregnancy Percentage
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
Time frame: 183 days
Population: mITT Population - ITT subjects whose diaries indicated they had at least one episode of coitus while using the assigned study product (also referred as Typical-Use), between 18 to 35 years of age (inclusive) at enrollment, had at least 1 cycle without any backup contraception or EC, and for whom there was at least one report of pregnancy status.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Conceptrol | 6-Month (183 Days) Cumulative Pregnancy Percentage | 10.0 pregnancy percentage |
| Amphora | 6-Month (183 Days) Cumulative Pregnancy Percentage | 10.5 pregnancy percentage |
Comparison: The primary hypothesis test was performed using 95% confidence interval for the difference in cumulative pregnancy rates between the treatment arms. If the upper bound for the confidence interval of the difference was \< 5.5, then the null hypothesis would be rejected.95% CI: [-2.2, 3.2]
Secondary
6-Month (183 Days) Cumulative Pregnancy Percentage for Subjects With Perfect Use
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
Time frame: 183 days
Population: EE populations - a subset of the MITT population that includes only subjects with at least one EE cycle, where an EE cycle is a cycle where the diaries indicated they used the product correctly for every act of intercourse in the cycle.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Conceptrol | 6-Month (183 Days) Cumulative Pregnancy Percentage for Subjects With Perfect Use | 4.2 pregnancy percentage |
| Amphora | 6-Month (183 Days) Cumulative Pregnancy Percentage for Subjects With Perfect Use | 4.1 pregnancy percentage |