Clinical trial: Safety, PK, and PD Study of IVRs Releasing TFV and LNG (NCT03279120)

Eligibility criteria:
Inclusion Criteria:

          -  Female, age 18-50 years, inclusive

          -  General good health (by volunteer history and per investigator discretion) without any
             clinically significant systemic disease (including, but not limited to significant
             liver disease/hepatitis, gastrointestinal disease, kidney disease, thyroid disease,
             osteoporosis or bone disease, and diabetes) and with an intact gastrointestinal tract,
             uterus, and cervix.

          -  Currently having regular menstrual cycles (approximately 26-35 days) by participant
             report

          -  History of Pap smears and follow-up consistent with standard clinical practice as
             outlined in the Study Manual or willing to undergo a Pap smear at Visit 1

          -  Protected from pregnancy by one of the following:

          -  Sterilization of either partner

          -  Abstinence from vaginal intercourse

          -  Consistent use of non-spermicidal condoms

          -  Willing to abstain from use of vaginal products (other than the study product and
             condoms) including tampons (except for menses), spermicides, lubricants, and douches
             for the whole study

          -  Willing to abstain from any vaginal and anal intercourse/activity starting 48 hours
             before cervical mucus collection, as possible, and 48 hours before Visits 4 and 29,
             and for 5 days after tissue collection

          -  Vaginal and cervical anatomy that, in the opinion of the investigator, lends itself to
             easy genital tract sample collection

          -  Negative urine pregnancy test

          -  P4 ≥3 ng/ml

          -  Willing to give voluntary consent and sign an informed consent form

          -  Willing and able to comply with protocol requirements

        Exclusion Criteria:

          -  BMI ≥ 30 kg/m2

          -  History of hysterectomy

          -  Currently pregnant or within two calendar months from the last pregnancy outcome.

        Note: If recently pregnant, must have had at least two spontaneous menses since pregnancy
        outcome

          -  Use of any hormonal contraceptive method in the last 3 months (oral, transdermal,
             transvaginal, implant, or hormonal intrauterine contraceptive device)

          -  Injection of Depo-Provera in the last 10 months

          -  Use of copper IUD

          -  Currently breastfeeding or having breastfed an infant in the last two months, or
             planning to breastfeed during the course of the study

          -  History of sensitivity/allergy to any component of the study products, topical
             anesthetic, or to both silver nitrate and Monsel's solution

          -  Contraindication to LNG

          -  In the last three months, diagnosed with or treated for any STI or pelvic inflammatory
             disease. Note: Women with a history of genital herpes or condylomata who have been
             asymptomatic for at least six months may be considered for eligibility.

          -  Nugent score greater than or equal to 7 or symptomatic bacterial vaginosis (BV) as
             defined by Amsel's criteria

          -  Positive test for Trichomonas vaginalis (TV), Neisseria gonorrhea (GC), Chlamydia
             trachomatis (CT), HIV-1, or Hepatitis B surface antigen (HBsAg)

          -  Known bleeding disorder, including deep vein thrombosis (DVT) and pulmonary embolism
             (PE), or those that could lead to prolonged or continuous bleeding with biopsy

          -  Chronic or acute vulvar or vaginal symptoms (pain, irritation, spotting/bleeding,
             discharge, etc.)

          -  Known current drug or alcohol abuse which could impact study compliance

          -  Grade 2 or higher laboratory abnormality, per the 2014 update of the Division of AIDS,
             National Institute of Allergy and Infectious Disease (DAIDS) Table for Grading the
             Severity of Adverse Events, or clinically significant laboratory abnormality as
             determined by the clinician

          -  Systemic use in the last two weeks or anticipated use during the study of any of the
             following: corticosteroids, antibiotics, anticoagulants or other drugs known to
             prolong bleeding and/or clotting, antifungals, or antivirals or antiretrovirals (e.g.
             acyclovir, valacyclovir, Viread®, Atripla®, Emtriva®, or Complera®), or CYP3A4
             inducers or inhibitors as detailed in the Study Manual (e.g., St. John's Wort or
             erythromycin).

        Note: Participants should avoid non-steroidal anti-inflammatory drugs (NSAIDs) except for
        treatment of dysmenorrhea during menses. Participants may use acetaminophen on an as-needed
        but not daily basis during 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

          -  History of gynecological procedures (including genital piercing) on the external
             genitalia, vagina, or cervix within the last 14 days

          -  Abnormal finding on laboratory or physical examination or a social or medical
             condition in the volunteer which, in the opinion of the investigator, would make
             participation in the study unsafe or would complicate interpretation of data
Female
Accepts Healthy Volunteers
Subject must be at least 18 Years old.
Subject must be at most 50 Years

Patient description (medical language): A 32-year-old woman comes to the hospital with vaginal spotting.  Her last menstrual period was 10 weeks ago. She has regular menses lasting for 6 days and repeating every 29 days. Medical history is significant for appendectomy and several complicated UTIs. She has multiple male partners, and she is inconsistent with using barrier contraceptives. Vital signs are normal.  Serum β-hCG level is 1800 mIU/mL, and a repeat level after 2 days shows an abnormal rise to 2100 mIU/mL.  Pelvic ultrasound reveals a thin endometrium with no gestational sac in the uterus.

Patient description (patient's own words): I just turned 32 and last morning I woke up with strange blood stains on my underwear. My last periods were more than 2 months ago, which is unusual for me because I used to have regular periods lasting for 6 days every 29 days, more or less. I had several UTIs in the past. I also had appendicitis. I'm currently seeing several men and, to be honest, some of them do struggle to wear a condom. I went to the hospital to check myself up and they told me that my vitals were normal. I also had a blood test on Monday, and my β-hCG level was 1800 mIU/mL, and then on Wednesday, it went up to 2100 mIU/mL. The gynecologist also did an ultrasound and she told me that, hopefully, there was no ovule.

Does the patient match the trial criteria? Contradiction