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

Inclusion Criteria:

Women who meet all the following criteria are eligible for enrollment in the trial:

1. Healthy women of reproductive age (18-39 years, inclusive, at the enrollment visit).

2. Have a regular menstrual cycle that is 21-35 days in duration.

3. Have intact uterus and both ovaries.

4. Will be able and willing to comply with the protocol and sign an informed consent.

5. 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).

6. Will have diastolic blood pressure (BP) ≤85 mm Hg and systolic BP ≤135 mm Hg after 5
minutes in sitting position.

7. 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:

1. 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.

2. Not living in the catchment area of the clinic.

3. Known hypersensitivity to progestins or estrogen.

4. 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).

5. Desire to become pregnant during the study.

6. Breastfeeding.

7. 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.

8. 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.

9. Known benign or malignant liver tumors; known active liver disease.

10. Invasive cancer (past history of any carcinoma or sarcoma, except non-melanoma skin
cancer).

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

12. Known or suspected current alcoholism or drug abuse.

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

14. Uncontrolled thyroid disease.

15. Known impaired hypothalamic-pituitary-adrenal reserve.

16. Body mass index (BMI) >35.

17. 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.

18. 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).

19. 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.

20. 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.

21. Known hypersensitivity to silicone rubber.

22. History of toxic shock syndrome.

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

24. Planning to undergo major surgery during the study.

25. Severe constipation.

26. Use of liver enzyme inducers or inhibitors on a regular basis.

27. Known HIV infection.

28. Bariatric surgery within the past year prior to enrollment.

29. Any abnormalities found during the transvaginal ultrasound (TVUS) that the PI or
medically qualified sub-investigator deems to put the subject at risk.

30. 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.