This will be a multi-site, open-label, randomized clinical trial. The investigators will randomize 300 eligible participants in a 1:1 ratio to two different treatment regimens that are to be followed when using a contraceptive vaginal ring delivering a daily dose of Nestorone® and estradiol (NES-E2 CVR).

The total duration of the study for each participant is expected to be approximately 13.5-15.5 months: including screening and enrollment (up to 8 weeks), 12 months of participation, and a post-removal follow up period removal of at least 17 days. After enrollment, subject visits occur at day 31, 92, 183, 274, and 364 with telephone calls at day 60, 120, 150, 210, 240, 300, and 330. Subjects will use a home pregnancy test 17 days post-removal of the ring and will call the site report the result and for safety follow-up. Another phone call will be required after that if the subject chooses not to being a hormonal contraceptive; this call will occur at the time of the subject's first spontaneous menses.

Subject recruitment is expected to begin Q1 (in the first quarter of) 2018 and is planned to continue through Q1 2019. However, if the enrollment rate declines, the enrollment period may be extended beyond this date. If this enrollment timeline is met, all subjects should finish active treatment by approximately the end of Q1 2020. The end of the study will occur when the last subject to be enrolled has completed her post-removal telephone call(s).

Preliminary results of the study are expected to be available Q3 of 2020 based on the current study plan.

Inclusion Criteria:

1. Good general overall health with no chronic medical conditions that result in periodic exacerbations requiring significant medical care.
2. Age 18-35 years, inclusive, at the enrollment visit. (Note: subjects must be at least 18 years of age to provide consent.)
3. Have a regular menstrual cycle 21-35 days in duration when not using hormonal contraception
4. Have an intact uterus and at least one ovary.
5. Consistent use of effective contraception during the preceding cycle with no unprotected intercourse since last use (NOTE: women who use oral, transdermal, vaginal, or implantable hormonal contraceptives in the preceding cycle must have discontinued hormone use at least 4 days prior to start of treatment and must not have had unprotected intercourse since discontinuing the method. Copper IUD or Levonorgestrel releasing IUD users must have discontinued IUD use at least 4 days prior to start of treatment and have experienced a spontaneous menses following IUD removal.)
6. No use of injectable contraceptives (e.g. depomedroxyprogesterone acetate) during the 10 months prior to screening unless the subject has returned to normal menses (two consecutive menses) since last injection.
7. Have a negative pregnancy test at the enrollment visit.
8. Have a diastolic blood pressure (BP) <90 mm Hg and systolic BP <140 mm Hg after 5 minutes rest in sitting position at the admission visit (below hypertension stage 2). (Note: History of hypertension stage 2 or higher, even if controlled with treatment, is exclusionary.)
9. Willing to abstain from use of non-water based (including silicone based) vaginal lubricants during the study that could adversely affect the ring, causing it to expand.
10. Understand and sign an IRB-approved informed consent form prior to screening activities (including fasting blood draws).
11. BMI ≤ 35 kg/m2 and not having previously undergone bariatric surgery.
12. Planning to have at least one act of heterosexual intercourse without the use of another contraceptive method each month during study participation until end of treatment and at risk for pregnancy.

Exclusion Criteria:

1. Planning pregnancy during study participation through the end of treatment visit.

2. Within 30 days post-partum, currently breast-feeding, or has not had a spontaneous menses.

3. Post-abortal and has not had a spontaneous menses.

4. Abnormal genital bleeding.

5. 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.

6. Not living in the catchment area of the study site.

7. Known hypersensitivity to progestins or estrogens.

8. Contraindications to combined estrogen-progestin contraceptive use including:

   1. Thrombophlebitis or thromboembolic disorders.
   2. Personal history of deep vein thrombophlebitis or thromboembolic disorders.
   3. History of venous thrombosis or embolism in a first-degree relative <55 years of age suggesting a familial defect in the blood coagulation system.
   4. History of thrombosis or embolism OR any other personal or family history which in the opinion of the investigator suggests increased risk.
   5. History of stroke.
   6. Known history of any of the following genetic mutations: Factor V Leiden mutation, prothrombin mutation, antithrombin deficiency, or other clinically significant thrombophilia.
   7. Known or suspected carcinoma of the breast.
   8. Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasm.
   9. History of cholestatic jaundice of pregnancy or jaundice with prior hormonal contraceptive use.
   10. History of hepatic adenomas or carcinomas.
   11. Known or suspected pregnancy.
   12. Smoking in women who are 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. Individuals who use other forms of tobacco should be evaluated similarly by the investigator for inclusion based on the amount of tobacco use and their risk factors.
   13. History of retinal vascular lesions, unexplained partial or complete loss of vision.
   14. History of headaches with focal neurological symptoms (e.g., migraines with auras).
   15. Impaired mobility (e.g. wheelchair bound, bed-ridden) that, in the opinion of the investigator, places the woman at increased risk of thrombosis.

9. Unevaluated vaginal discharge or vaginal lesions. Subjects diagnosed at screening with a chlamydia or gonococcal infection may be included in the trial following treatment completion; partner treatment is also recommended. Subjects with yeast, trichomoniasis, or bacterial vaginosis infection requiring treatment may be enrolled after treatment completion. Investigators should determine if subjects are at an elevated risk for reinfection, e.g. multiple sex partners, untreated partner, and whether such subjects can be included. Women with a history of genital herpes can be included if outbreaks are infrequent.

10. Have a known clinically significant Pap test abnormality, as managed by normal standard of care guidelines, that would require repeat evaluation or treatment during study participation based on the initial Pap findings.

11. Known benign or malignant liver tumors, renal disease or active liver disease.

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

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

14. Known or suspected current alcohol dependence, chronic marijuana use, or any illicit drug use that may affect metabolism/transformation of study product and/or study treatment compliance. A chronic marijuana user is defined as someone who uses marijuana 4 or more times per week for study purposes.

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

16. Uncontrolled thyroid disease.

17. Known impaired hypothalamic-pituitary-adrenal axis.

18. Known hypersensitivity to silicone rubber.

19. History of toxic shock syndrome.

20. Vaginal anatomic abnormality such as cystocele or rectocele that would preclude correct use of a vaginal ring.

21. Planning major surgery during study participation.

22. Severe current constipation.

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

24. Known HIV infection.

25. Use of any medications, including antibiotics that can significantly interfere with the metabolism of hormonal contraceptives.

26. Have an anticipated need for regular condom use, defined as use of at least one condom per month after enrollment.

27. 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.

28. Any site staff member with delegated study responsibilities or a family member of a site staff member with delegated study responsibilities.