Clinical trial: An Open-label Study to Evaluate the Effects of Concurrent Administration of Vaginal Antimycotic Medication Miconazole Nitrate on the Pharmacokinetics of Nestorone and Ethinyl Estradiol Delivered by a Contraceptive Vaginal Ring in Normal Ovulating Women (NCT02215395)

Eligibility criteria:
Inclusion Criteria:

          -  Healthy women, inclusive of ages 18-35* years at the enrollment visit

          -  Intact uterus and both ovaries

          -  Prior history of regular menstrual cycles that usually occur every 28 ± 7 days when
             not using hormonal contraception; if postpartum or post-abortal, history of regular
             menstrual cycles of 21-35 days in length and resumption of at least one cycle with a
             cycle length consistent with her past cycles

          -  In the opinion of the investigator, able to comply with the protocol, e.g. live within
             the study site catchment area or within a reasonable distance from the study site

          -  May be sterilized or at risk of becoming pregnant

          -  Willing to use a non-hormonal method of contraception for one month prior to the
             initial insertion of the NES/EE CVR and the one month washout period

          -  Willing to abstain from sexual intercourse during the miconazole nitrate treatment
             period(s)

          -  Signed informed consent prior to entry into the trial

        Exclusion Criteria:

          -  Known hypersensitivity to estrogens or progestins

          -  Pregnant, trying to become pregnant, or breastfeeding

          -  Known hypersensitivity to silicone rubber

          -  Undiagnosed abnormal vaginal bleeding

          -  Undiagnosed vaginal discharge, vaginal lesions or abnormalities. Subjects diagnosed at
             screening with a Chlamydia or gonococcus infection may be included in the trial
             following treatment; partner treatment is also recommended. Investigators should make
             a determination if subjects are at high risk for reinfection, e.g., multiple sex
             partners, untreated partner, and whether such subjects can be included

          -  History of pelvic inflammatory disease since the subject's last pregnancy

          -  History of toxic shock syndrome

          -  In accordance with the Bethesda system of classification: Women with a current (within
             the last 20 months) abnormal Pap smear suggestive of high-grade pre-cancerous lesion
             (s), including HGSIL

          -  Cystoceles or rectoceles or other anatomical abnormality that would preclude use of a
             vaginal ring

          -  Women planning to undergo major surgery during the trial

          -  Women who smoke 15 cigarettes or more per day must be evaluated by the PI for
             inclusion based on risk factors that would increase their risk for cardiovascular
             disease and thromboembolism, e.g., lipid levels, glucose level, BP, BMI, family
             history of cardiovascular disease at a young age

          -  Current or past thrombophlebitis or thromboembolic disorders

          -  History of venous thrombosis or embolism in a first-degree relative, <55 years of age
             suggesting a familial defect in the blood coagulation system, which in the opinion of
             the PI, suggests that use of a hormonal contraceptive could pose a significant risk

          -  Cerebrovascular or cardiovascular disease

          -  History of retinal vascular lesions, unexplained partial or complete loss of vision

          -  Known or suspected carcinoma of the breast

          -  Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia

          -  Past history of any other carcinoma unless in remission for more than five years

          -  Current or history of medically diagnosed severe depression, which, in the opinion of
             the investigator, could be exacerbated by the use of a hormonal contraceptive

          -  Headaches with focal neurological symptoms

          -  Severe constipation in the opinion of the investigator

          -  History of cholestatic jaundice of pregnancy or jaundice with prior steroid use

          -  Benign or malignant liver tumors; active liver disease

          -  Diastolic blood pressure (BP) >85 mm Hg and/or systolic BP >135 mm Hg after 5-10
             minutes rest (at screening)

          -  Known or suspected alcoholism or drug abuse within their lifetime

          -  Elevated serum fasting clinical chemistry values or complete blood count (CBC) values
             designated clinically significant by the investigator and/or medically qualified
             sub-investigator

          -  Screening hemoglobin levels less than 12.5 g/dL or hematocrit less than 38%.

          -  Participation in another clinical trial involving an investigational drug within the
             last 30 days (prior to screening)

          -  BMI >29

          -  Use of liver enzyme inducers on a regular basis

          -  Use of monthly injectable contraceptives, unless suspended 2 months before initiation
             of the treatment. Use of Depo-Provera [depo-medroxyprogesterone (DMPA)] unless
             suspended 6 months before treatment

          -  Current use of implanted hormonal contraceptives, including Mirena [progestin
             containing intrauterine system (IUS)], Jadelle, Norplant, Implanon or Nexplanon (if
             now available in the USA).**

          -  Known HIV, Hepatitis B or Hepatitis C infection

          -  History of frequent vaginal infections in the opinion of the investigator
Female
Accepts Healthy Volunteers
Subject must be at least 18 Years old.
Subject must be at most 35 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? 0