A Dose-finding Study to Evaluate the Effect of a Contraceptive Vaginal Ring, Releasing Nestorone® and Estradiol, on Cycle Control, Ovulation Inhibition, and Pharmacokinetics in Normal Cycling Women

Study Overview
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Brief Summary
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This clinical trial is an experimental research study using a potential new form of birth control. Clinical trials include people who volunteer to take part in a study. Take your time to decide if you want to be part of this experimental research study. If you want to know more about this study first, ask the study doctor or study site staff. The investigators can also give you the study information written for doctors and clinic staff.

Official Title
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A Dose-finding Study to Evaluate the Effect of a Contraceptive Vaginal Ring, Releasing Nestorone® and Estradiol, on Cycle Control, Ovulation Inhibition, and Pharmacokinetics in Normal Cycling Women

Conditions
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Suppression of Ovulation

Intervention / Treatment
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* Drug: 10 µg/day E2 with NES 200® µg/day
* Drug: 20 µg/day E2 with NES 200® µg/day
* Drug: 40 µg/day E2 with NES 200® µg/day


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women who meet all the following criteria are eligible for enrollment in the trial: Healthy women of reproductive age (18-39 years, inclusive, at the enrollment visit). Have a regular menstrual cycle that is 21-35 days in duration. Have intact uterus and both ovaries. Will be able and willing to comply with the protocol and sign an informed consent. Will not be at risk for pregnancy. They will be consistently using a non-hormonal method, have a surgically sterile male partner with a vasectomy, be abstinent, or be in a same-sex relationship from the control period through study exit (including recovery period). Will have diastolic blood pressure (BP) ≤85 mm Hg and systolic BP ≤135 mm Hg after 5 minutes in sitting position. Willing to abstain from use of non-water based vaginal lubricant during the study. Exclusion Criteria: Women who meet any of the following criteria are not eligible for enrollment in the trial: Participating in another clinical trial involving an investigational product within the last 30 days (prior to screening) or planning to participate in another clinical trial during this study. Not living in the catchment area of the clinic. Known hypersensitivity to progestins or estrogen. All contraindications to combined estrogen-progestin contraceptive use including: Thrombophlebitis or thromboembolic disorders. Past personal history of deep vein thrombophlebitis or thromboembolic disorders. History of venous thrombosis or embolism in a first-degree relative <55 years of age suggesting familial defect in blood coagulation system, which in the opinion of the investigator, suggests use of a hormonal contraceptive could pose a significant risk. History of stroke. Known or suspected carcinoma of the breast. Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia. Undiagnosed abnormal genital bleeding. Cholestatic jaundice of pregnancy or jaundice with prior oral contraceptive use. Hepatic adenomas or carcinomas. Known or suspected pregnancy. Smoking in women who are 35 years and over or will be 35 years during the course of the trial; women <35 years who smoke 15 cigarettes or more per day must be evaluated by the investigator for inclusion based on risk factors that would increase their risk for cardiovascular disease (CVD) and thromboembolism, e.g. lipid levels, glucose level, BP, BMI, family history of CVD at a young age. History of retinal vascular lesions, unexplained partial or complete loss of vision. Headaches with focal neurological symptoms (e.g., migraines with auras). Desire to become pregnant during the study. Breastfeeding. Undiagnosed vaginal discharge or 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. Subjects with vaginitis (yeast, trichomonas, or bacterial vaginitis) may be enrolled after treatment. 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. In accordance with PI/medical designee assessment and local standards of practice, women with a history of genital herpes can be included if outbreaks are infrequent. A clinically significant Pap test abnormality, as managed by current local or national guidelines. Women with a current abnormal Pap (within the last nine months): In accordance with the Bethesda system of classification: smear suggestive of high-grade pre-cancerous lesion(s), including high grade squamous intraepithelial lesions (HGSILs), are excluded; Women with low grade squamous intraepithelial lesion (LGSIL) or atypical squamous cells of undetermined significance (ASCUS)/high-risk human papillomavirus (HPV) positive, or Atypical squamous cells, cannot rule out a high grade lesion (ASC-H) may participate if further evaluated with colposcopy and biopsy determines no evidence of a lesion with a severity greater than cervical intraepithelial neoplasia (CIN) I. Women with a biopsy finding of CIN I should have follow-up for this finding per standard of care; women are excluded if treatment is indicated. In accordance with other Pap class systems: Women with high grade dysplasia are excluded. Women with low grade dysplasia or CIN I interpretation on Pap test may participate following exclusion of a high grade lesion by colposcopic evaluation based on Investigator discretion and provided there is appropriate follow up in accordance with local standards. Known benign or malignant liver tumors; known active liver disease. Invasive cancer (past history of any carcinoma or sarcoma, except non-melanoma skin cancer). Current or past medically diagnosed severe depression, which, in the opinion of the investigator, could be exacerbated by use of a hormonal contraceptive. Known or suspected current alcoholism or drug abuse. Elevated serum fasting clinical chemistry values or complete blood count (CBC) values designated clinically significant by the investigator or medically qualified sub-investigator. Uncontrolled thyroid disease. Known impaired hypothalamic-pituitary-adrenal reserve. Body mass index (BMI) >35. Use of injectable contraceptives (e.g. cyclofem or depo-medroxyprogesterone acetate) during the 6 months prior to enrollment or no spontaneous menses since last injection. Use of oral contraceptives within one month prior to start of control cycle (subjects must undergo informed consent process and screening procedures before stopping oral contraceptives to participate in the study). Use of hormonal contraceptives. NOTE: Removal of implanted hormonal contraceptives must have been for personal reasons unrelated to the purpose of enrollment in this study. Current use of an intrauterine device (IUD). NOTE: Removal of an IUD must have been for personal reasons unrelated to the purpose of enrollment in this study. Known hypersensitivity to silicone rubber. History of toxic shock syndrome. Cystoceles or rectoceles or other anatomical abnormality that would preclude use of a vaginal ring. Planning to undergo major surgery during the study. Severe constipation. Use of liver enzyme inducers or inhibitors on a regular basis. Known HIV infection. Bariatric surgery within the past year prior to enrollment. Any abnormalities found during the transvaginal ultrasound (TVUS) that the PI or medically qualified sub-investigator deems to put the subject at risk. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 39 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 10 µg/day E2<br>Two consecutive 3-month (90-day) rings will be used continuously for six months (180 days). | Drug: 10 µg/day E2 with NES 200® µg/day<br>* 10 µg/day E2 with NES 200® µg/day delivered by CVR continuously for 6 months (180 days)<br>|
| Experimental: 20 µg/day E2<br>Two consecutive 3-month (90-day) rings will be used continuously for six months (180 days). | Drug: 20 µg/day E2 with NES 200® µg/day<br>* 20 µg/day E2 with NES 200® µg/day delivered by CVR continuously for 6 months (180 days)<br>|
| Experimental: 40 µg/day E2<br>Two consecutive 3-month (90-day) rings will be used continuously for six months (180 days). | Drug: 40 µg/day E2 with NES 200® µg/day<br>* 40 µg/day E2 with NES 200® µg/day delivered by CVR continuously for 6 months (180 days)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of days bleeding is reported. | The primary outcome will be the number of days that bleeding or spotting is reported in the first 3 cycles (90 days) of treatment. | Six months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in ovulation. | Regular evaluation of follicle diameter will be made with transvaginal ultrasonography (TVUS) to determine the time of ovulation or, in the absence of ovulation, the fate of any dominant follicle. A subject will be considered to have ovulated if she has two consecutive progesterone values of ≥10 nmol/L (≥3 ng/mL) preceded by a follicular measurement of >10 mm in the previous 10 days. If the two qualifying progesterone peaks occur in different 30 day intervals, ovulation will be counted as occurring in the 30 day interval during which the first elevated progesterone was noted. | Six months | 
| The absorption of NES and E2 in subjects receiving 200 µg/day of NES and one of three doses (10, 20, or 40 µg/day) of E2 delivered by CVR continuously for 6 months (180 days). | Pharmacokinetic assessments will be performed to measure absorption in a substudy of 18 women (6 in each dose group) at a single center (Oregon Health and Science University) at initiation of each ring use and at final ring removal. | Six months | 
| The safety of administering 200 µg/day of NES and one of three doses (10, 20, or 40 µg/day) of E2 delivered by CVR continuously for 6 months (180 days). | Clinical safety will also be evaluated by collection of adverse events (AEs). Blood chemistry and hematologic profile as well as measures of sex hormone binding globulin (SHBG) and lipids will assess safety of the three treatment groups. | Six months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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vaginal ring