Impact of Contraceptives on Cervico-Vaginal Mucosa

This clinical study will complete approximately 12 healthy, non-pregnant, HIV-uninfected women aged 18-50 years per contraceptive arm, who are at low risk for sexually transmitted infections (STIs) at two clinical sites, for a total of approximately 96 completed participants. The study will examine changes from baseline, pre-contraceptive dosing to post contraceptive dosing of cervico-vaginal mucosal safety and adverse events.

Participants at each site will be randomized (1:1:1:1) to one of four, marketed, approved contraceptive dosing forms: Levonorgestrel (LNG) 52 mg. Intrauterine System (IUS), Copper Intrauterine Device (IUD), etonogestrel (ETG, Nexplanon, Implanon) contraceptive implant, or DMPA SC contraceptive injection.

Enrollment is expected to take approximately 8 months and each participant is expected to complete the study within 4 months.

• Copper IUD (Drug), also known as Paragard: Participants randomized to Copper IUD will receive Paragard IUD at Visit 2.
• Etonogestrel implant (Drug), also known as Nexplanon, Implanon: Participants randomized to ETG implant will receive the implant at Visit 2.
• Levonorgestrel IUS (Drug), also known as Mirena, Liletta: Participants randomized to LNG intrauterine system will receive the IUS at Visit 2.
• DMPA Sub-cutaneous (Drug), also known as Subcutaneous depot medroxyprogesterone acetate: Participants randomized to DMPA SC will receive the injection at Visit 2.

Primary outcomes

• Number of participants with changes to mucosal function [4 weeks and 3 months after product use]: Evaluate mucosal factors and microbiome changes from baseline associated with mucosal function and reproductive health, including vaginal glycogen, pH, lactic acid, soluble markers and immune cells.
• Number of participants with changes to mucosal health [4 weeks and 3 months after product use]: Evaluate mucosal factors and microbiome changes from baseline associated with mucosal function and reproductive health, including vaginal glycogen, pH, lactic acid, soluble markers and immune cells.

Secondary outcomes

• Number of participants with systemic inflammation [4 weeks and 3 months after product use]: Evaluate changes from baseline in systemic factors associated with reproductive health, including C reactive protein and hormone concentrations.

Other outcomes

• Mucosal susceptibility to pathogens [4 weeks and 3 months after product use]: Model mucosal susceptibility to STIs ex vivo at baseline and after contraceptive use

Sex: Female, ages: 18 Years to 50 Years, accepts healthy volunteers

Inclusion Criteria:

* Age 18 to 50 years, inclusive
* In general good health without any significant systemic disease and with an intact uterus and cervix.
* History of Pap smears and follow-up consistent with standard, local clinical practice or willing to undergo a Pap smear at Visit 1
* Willing to give voluntary consent and sign an informed consent form
* Willing and able to comply with protocol requirements, including accepting randomization to study contraceptive products
* If currently on a contraceptive product, willing to go off products and use condoms for birth control for a specified time
* If in a relationship, must be with a partner who is not known to be HIV positive and has no know risk of sexually transmitted infections (STIs)

Exclusion Criteria:

* Positive pregnancy test or plans to become pregnant during the course of the study
* Currently exclusively breastfeeding or planning to exclusively breastfeed during the course of the study
* Less than six weeks from a delivery of an infant greater than 20 weeks gestation
* Use of DMPA in the past 4 months
* Clinical signs and symptoms of menopause
* Current WHO or CDC medical eligibility criteria level 3 or 4 for any contraceptive product to which a participant could receive at the clinical site
* History of sensitivity/allergy to any component of the study product, topical anesthetic, or to both silver nitrate and Monsel's solution
* Current infection with Trichomonas vaginalis (TV), Neisseria gonorrhea (NG), Chlamydia trachomatis (CT)
* Current positive test for HIV
* History of a pulmonary embolus or deep vein thrombosis
* Chronic or acute vulvar or vaginal symptoms (pain, irritation, spotting/bleeding, discharge, etc)
* Known blood disorder, eg. von Willebrands disease, that could lead to prolonged or continuous bleeding with biopsy
* Chronic use systemic corticosteroids, antibiotics, antimycobacterials, anticoagulants or other drugs known to prolong bleeding and/or promote clotting, antifungals, or antivirals or antiretrovirals.
* Current or anticipated chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen for the duration of the study
* Participation in any other investigational trial with use of a drug/device within the last 30 days or planned participation in any other investigational trial with use of a drug/device during the study
* Abnormal finding on laboratory or physical examination or a social or medical condition in which, in the opinion of the investigator, would make participation in the study unsafe or would complicate interpretation of the data

• Andrea Thurman, Principal investigator, Eastern Virginia Medical School, CONRAD