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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01586000

Enrollment

197

Registered

2012-04-26

Start date

2012-03-31

Completion date

2015-05-31

Last updated

2025-12-08

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Suppression of Ovulation

Keywords

vaginal ring

Brief summary

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.

Interventions

DRUG10 µg/day E2 with NES 200® µg/day

10 µg/day E2 with NES 200® µg/day delivered by CVR continuously for 6 months (180 days)

DRUG20 µg/day E2 with NES 200® µg/day

20 µg/day E2 with NES 200® µg/day delivered by CVR continuously for 6 months (180 days)

DRUG40 µg/day E2 with NES 200® µg/day

40 µg/day E2 with NES 200® µg/day delivered by CVR continuously for 6 months (180 days)

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

PREVENTION

Masking

NONE

Eligibility

Sex/Gender

FEMALE

Age

18 Years to 39 Years

Healthy volunteers

Yes

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.

Design outcomes

Primary

Measure	Time frame	Description
Number of Days Bleeding is Reported.	Three months	The primary outcome will be the number of days that bleeding or spotting is reported in the first 3 cycles (90 days) of treatment.

Secondary

Measure	Time frame	Description
Area Under the Curve of NES and E2 at Specified Time Points	Visits 12, 32, and 41 (Treatment Period)	Pharmacokinetic assessments will be performed to measure absorption in a substudy of 22 women (7-8 in each dose group) at a single center (Oregon Health and Science University) at initiation of each ring use and at final ring removal. Blood will be collected for measurements before insertion of the first ring (at Visit 12), before removal of the second ring (at Visit 41), and at 2, 4, 6, 8, 10, 12, 24, 48 and approximately 72 hours after the first ring is inserted (at Visit 12) and after the second ring is removed (at Visit 41). PK samples will also be collected at the time of removal of the first ring (0 hours) at Visit 32, 2 hours after removal of the first ring and insertion of the second ring, and at 24 hours after removal of the first ring and insertion of the second ring.
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).	Through Recovery Cycle 8, up to 8 months	Clinical safety will be evaluated by collection of adverse events (AEs).
Number of Days Bleeding is Reported.	Three months	The primary outcome will be the number of days that bleeding or spotting is reported in the last 3 cycles (90 days) of treatment.
Changes From Baseline in Albumin (g/dL)	Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)	Clinical safety will also be evaluated by changes from baseline through end of treatment of blood chemistry and hematologic profile to assess safety of the three treatment groups.
Changes From Baseline in ALT/SGPT (U/L)	Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)	Clinical safety will also be evaluated by changes from baseline through end of treatment of blood chemistry and hematologic profile to assess safety of the three treatment groups.
Changes From Baseline in AST/SGOT (U/L)	Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)	Clinical safety will also be evaluated by changes from baseline through end of treatment of blood chemistry and hematologic profile to assess safety of the three treatment groups.
Changes From Baseline in BUN (mg/dL)	Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)	Clinical safety will also be evaluated by changes from baseline through end of treatment of blood chemistry and hematologic profile to assess safety of the three treatment groups.
Changes From Baseline in Calcium (mg/dL)	Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)	Clinical safety will also be evaluated by changes from baseline through end of treatment of blood chemistry and hematologic profile to assess safety of the three treatment groups.
Changes From Baseline in Triglycerides (mg/dL)	Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)	Clinical safety will also be evaluated by changes from baseline through end of treatment of blood chemistry and hematologic profile to assess safety of the three treatment groups.
Changes From Baseline in Creatinine (mg/dL)	Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)	Clinical safety will also be evaluated by changes from baseline through end of treatment of blood chemistry and hematologic profile to assess safety of the three treatment groups.
Changes From Baseline in Glucose (mg/dL)	Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)	Clinical safety will also be evaluated by changes from baseline through end of treatment of blood chemistry and hematologic profile to assess safety of the three treatment groups.
Changes From Baseline in GGT (U/L)	Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)	Clinical safety will also be evaluated by changes from baseline through end of treatment of blood chemistry and hematologic profile to assess safety of the three treatment groups.
Changes From Baseline in Total Bilirubin (mg/dL)	Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)	Clinical safety will also be evaluated by changes from baseline through end of treatment of blood chemistry and hematologic profile to assess safety of the three treatment groups.
Changes From Baseline in Total Protein (g/dL)	Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)	Clinical safety will also be evaluated by changes from baseline through end of treatment of blood chemistry and hematologic profile to assess safety of the three treatment groups.
Changes From Baseline in Total Cholesterol (mg/dL)	Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)	Clinical safety will also be evaluated by changes from baseline through end of treatment of blood chemistry and hematologic profile to assess safety of the three treatment groups.
Number of Subjects With Ovulation at During Each Cycle	Control Cycle 1, Treatment Cycles 2, 3, and 7, Recovery Cycle 8, up to 8 months	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. Number of subjects considered to have ovulated during each cycle is reported.
Changes From Baseline in LDL Cholesterol (mg/dL)	Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)	Clinical safety will also be evaluated by changes from baseline through end of treatment of blood chemistry and hematologic profile to assess safety of the three treatment groups.
Changes From Baseline in Chloride (mmol/L)	Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)	Clinical safety will also be evaluated by changes from baseline through end of treatment of blood chemistry and hematologic profile to assess safety of the three treatment groups.
Changes From Baseline in Potassium (mmol/L)	Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)	Clinical safety will also be evaluated by changes from baseline through end of treatment of blood chemistry and hematologic profile to assess safety of the three treatment groups.
Changes From Baseline in Sodium (mmol/L)	Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)	Clinical safety will also be evaluated by changes from baseline through end of treatment of blood chemistry and hematologic profile to assess safety of the three treatment groups.
Changes From Baseline in RBC (MIL/uL)	Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)	Clinical safety will also be evaluated by changes from baseline through end of treatment of blood chemistry and hematologic profile to assess safety of the three treatment groups.
Changes From Baseline in WBC (THOU/uL)	Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)	Clinical safety will also be evaluated by changes from baseline through end of treatment of blood chemistry and hematologic profile to assess safety of the three treatment groups.
Changes From Baseline in Hemoglobin (g/dL)	Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)	Clinical safety will also be evaluated by changes from baseline through end of treatment of blood chemistry and hematologic profile to assess safety of the three treatment groups.
Changes From Baseline in Hematocrit (%)	Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)	Clinical safety will also be evaluated by changes from baseline through end of treatment of blood chemistry and hematologic profile to assess safety of the three treatment groups.
Changes From Baseline in Platelet Count (THOU/uL)	Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)	Clinical safety will also be evaluated by changes from baseline through end of treatment of blood chemistry and hematologic profile to assess safety of the three treatment groups.
Changes From Baseline in Basophils (%)	Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)	Clinical safety will also be evaluated by changes from baseline through end of treatment of blood chemistry and hematologic profile to assess safety of the three treatment groups.
Changes From Baseline in Eosinophils (%)	Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)	Clinical safety will also be evaluated by changes from baseline through end of treatment of blood chemistry and hematologic profile to assess safety of the three treatment groups.
Changes From Baseline in Lymphocytes (%)	Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)	Clinical safety will also be evaluated by changes from baseline through end of treatment of blood chemistry and hematologic profile to assess safety of the three treatment groups.
Changes From Baseline in Monocytes (%)	Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)	Clinical safety will also be evaluated by changes from baseline through end of treatment of blood chemistry and hematologic profile to assess safety of the three treatment groups.
Changes From Baseline in Neutrophils (%)	Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)	Clinical safety will also be evaluated by changes from baseline through end of treatment of blood chemistry and hematologic profile to assess safety of the three treatment groups.
Changes From Baseline in HDL Cholesterol (mg/dL)	Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)	Clinical safety will also be evaluated by changes from baseline through end of treatment of blood chemistry and hematologic profile to assess safety of the three treatment groups.

Countries

United States

Participant flow

Participants by arm

Arm	Count
10 µg/Day E2 Two consecutive 3-month (90-day) rings will be used continuously for six months (180 days). 10 µg/day E2 with NES 200® µg/day: 10 µg/day E2 with NES 200® µg/day delivered by CVR continuously for 6 months (180 days)	67
20 µg/Day E2 Two consecutive 3-month (90-day) rings will be used continuously for six months (180 days). 20 µg/day E2 with NES 200® µg/day: 20 µg/day E2 with NES 200® µg/day delivered by CVR continuously for 6 months (180 days)	66
40 µg/Day E2 Two consecutive 3-month (90-day) rings will be used continuously for six months (180 days). 40 µg/day E2 with NES 200® µg/day: 40 µg/day E2 with NES 200® µg/day delivered by CVR continuously for 6 months (180 days)	64
Total	197

Baseline characteristics

Characteristic	10 µg/Day E2	20 µg/Day E2	40 µg/Day E2	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	67 Participants	66 Participants	64 Participants	197 Participants
Age, Continuous	28.8 Years	28.2 Years	29.6 Years	28.8 Years
Alcohol Use Current	56 Participants	54 Participants	50 Participants	160 Participants
Alcohol Use Former	3 Participants	5 Participants	1 Participants	9 Participants
Alcohol Use Never	8 Participants	7 Participants	13 Participants	28 Participants
Body Mass Index (BMI)	26.4 kg/m^2 STANDARD_DEVIATION 4.21	25.35 kg/m^2 STANDARD_DEVIATION 4.412	25.70 kg/m^2 STANDARD_DEVIATION 4.232	25.82 kg/m^2 STANDARD_DEVIATION 4.287
Ethnicity (NIH/OMB) Hispanic or Latino	10 Participants	9 Participants	10 Participants	29 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	57 Participants	57 Participants	54 Participants	168 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants
Highest Level of Education Completed College degree or higher	33 Participants	29 Participants	27 Participants	89 Participants
Highest Level of Education Completed Has not completed high school	0 Participants	1 Participants	2 Participants	3 Participants
Highest Level of Education Completed High school diploma or equivalent	10 Participants	8 Participants	6 Participants	24 Participants
Highest Level of Education Completed Some college	24 Participants	28 Participants	29 Participants	81 Participants
Marital Status Divorced	5 Participants	4 Participants	8 Participants	17 Participants
Marital Status Married	10 Participants	17 Participants	11 Participants	38 Participants
Marital Status Never Married	50 Participants	41 Participants	43 Participants	134 Participants
Marital Status Separated	2 Participants	2 Participants	2 Participants	6 Participants
Marital Status Widowed	0 Participants	2 Participants	0 Participants	2 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	5 Participants	2 Participants	3 Participants	10 Participants
Race (NIH/OMB) Black or African American	28 Participants	31 Participants	20 Participants	79 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants	6 Participants	7 Participants	14 Participants
Race (NIH/OMB) White	33 Participants	27 Participants	34 Participants	94 Participants
Sex: Female, Male Female	67 Participants	66 Participants	64 Participants	197 Participants
Sex: Female, Male Male	0 Participants	0 Participants	0 Participants	0 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	0 / 67	0 / 66	0 / 64
other Total, other adverse events	58 / 67	57 / 66	55 / 64
serious Total, serious adverse events	0 / 67	0 / 66	1 / 64

Outcome results

Primary

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.

Time frame: Three months

Population: All Safety population subjects with at least one non-missing bleeding record (from their diaries). All subjects enrolled in the study were included in the Safety population. In total, 2 subjects (both in the 200 µg/day NES and 40 µg/day E2 group) were not included in the Bleeding and Ovulation populations

Arm	Measure	Group	Value (MEAN)	Dispersion
10 µg/day E2	Number of Days Bleeding is Reported.	Bleeding Only	14.7 Days	Standard Deviation 15.36
10 µg/day E2	Number of Days Bleeding is Reported.	Bleeding or Spotting	34.0 Days	Standard Deviation 23.17
10 µg/day E2	Number of Days Bleeding is Reported.	Spotting Only	19.3 Days	Standard Deviation 18.61
20 µg/day E2	Number of Days Bleeding is Reported.	Bleeding Only	16.3 Days	Standard Deviation 16.3
20 µg/day E2	Number of Days Bleeding is Reported.	Bleeding or Spotting	42.1 Days	Standard Deviation 24.51
20 µg/day E2	Number of Days Bleeding is Reported.	Spotting Only	25.8 Days	Standard Deviation 22.2
40 µg/day E2	Number of Days Bleeding is Reported.	Bleeding or Spotting	39.8 Days	Standard Deviation 22.83
40 µg/day E2	Number of Days Bleeding is Reported.	Spotting Only	24.8 Days	Standard Deviation 19.06
40 µg/day E2	Number of Days Bleeding is Reported.	Bleeding Only	15.0 Days	Standard Deviation 14.8

Secondary

Area Under the Curve of NES and E2 at Specified Time Points

Pharmacokinetic assessments will be performed to measure absorption in a substudy of 22 women (7-8 in each dose group) at a single center (Oregon Health and Science University) at initiation of each ring use and at final ring removal. Blood will be collected for measurements before insertion of the first ring (at Visit 12), before removal of the second ring (at Visit 41), and at 2, 4, 6, 8, 10, 12, 24, 48 and approximately 72 hours after the first ring is inserted (at Visit 12) and after the second ring is removed (at Visit 41). PK samples will also be collected at the time of removal of the first ring (0 hours) at Visit 32, 2 hours after removal of the first ring and insertion of the second ring, and at 24 hours after removal of the first ring and insertion of the second ring.

Time frame: Visits 12, 32, and 41 (Treatment Period)

Population: The number analyzed at each time point is dependent on the number of subjects that completed each time point.

Arm	Measure	Group	Value (MEAN)	Dispersion
10 µg/day E2	Area Under the Curve of NES and E2 at Specified Time Points	Visit 41 NES 0-72 hrs post Ring 2 Removal	742.7 hour*pg/mL	Standard Deviation 352.83
10 µg/day E2	Area Under the Curve of NES and E2 at Specified Time Points	Visit 12 NES 0-72 hrs post Ring 1 Insertion	38685.7 hour*pg/mL	Standard Deviation 9770.06
10 µg/day E2	Area Under the Curve of NES and E2 at Specified Time Points	Visit 32 NES 0-24 hrs after Removal of Ring 1 and Insertion of Ring 2	12906.4 hour*pg/mL	Standard Deviation 2574.38
10 µg/day E2	Area Under the Curve of NES and E2 at Specified Time Points	Visit 32 E2 0-24 hrs after Removal of Ring 1 and Insertion of Ring 2	1237.10 hour*pg/mL	Standard Deviation 605.026
10 µg/day E2	Area Under the Curve of NES and E2 at Specified Time Points	Visit 41 E2 0-72 hrs post Ring 2 Removal	2098.36 hour*pg/mL	Standard Deviation 628.917
10 µg/day E2	Area Under the Curve of NES and E2 at Specified Time Points	Visit 12 E2 0-72 hrs post Ring 1 Insertion	3690.77 hour*pg/mL	Standard Deviation 1414.324
20 µg/day E2	Area Under the Curve of NES and E2 at Specified Time Points	Visit 32 NES 0-24 hrs after Removal of Ring 1 and Insertion of Ring 2	16495.3 hour*pg/mL	Standard Deviation 3512.32
20 µg/day E2	Area Under the Curve of NES and E2 at Specified Time Points	Visit 41 NES 0-72 hrs post Ring 2 Removal	902.0 hour*pg/mL	Standard Deviation 460.43
20 µg/day E2	Area Under the Curve of NES and E2 at Specified Time Points	Visit 12 E2 0-72 hrs post Ring 1 Insertion	4910.31 hour*pg/mL	Standard Deviation 1067.716
20 µg/day E2	Area Under the Curve of NES and E2 at Specified Time Points	Visit 12 NES 0-72 hrs post Ring 1 Insertion	31201.4 hour*pg/mL	Standard Deviation 4912.98
20 µg/day E2	Area Under the Curve of NES and E2 at Specified Time Points	Visit 32 E2 0-24 hrs after Removal of Ring 1 and Insertion of Ring 2	2470.0 hour*pg/mL	Standard Deviation 801.086
20 µg/day E2	Area Under the Curve of NES and E2 at Specified Time Points	Visit 41 E2 0-72 hrs post Ring 2 Removal	3208.62 hour*pg/mL	Standard Deviation 2470.399
40 µg/day E2	Area Under the Curve of NES and E2 at Specified Time Points	Visit 41 E2 0-72 hrs post Ring 2 Removal	2317.45 hour*pg/mL	Standard Deviation 963.316
40 µg/day E2	Area Under the Curve of NES and E2 at Specified Time Points	Visit 32 E2 0-24 hrs after Removal of Ring 1 and Insertion of Ring 2	1198.83 hour*pg/mL	Standard Deviation 453.937
40 µg/day E2	Area Under the Curve of NES and E2 at Specified Time Points	Visit 41 NES 0-72 hrs post Ring 2 Removal	863.5 hour*pg/mL	Standard Deviation 361.81
40 µg/day E2	Area Under the Curve of NES and E2 at Specified Time Points	Visit 32 NES 0-24 hrs after Removal of Ring 1 and Insertion of Ring 2	14073.3 hour*pg/mL	Standard Deviation 1729.37
40 µg/day E2	Area Under the Curve of NES and E2 at Specified Time Points	Visit 12 E2 0-72 hrs post Ring 1 Insertion	3648.83 hour*pg/mL	Standard Deviation 1341.309
40 µg/day E2	Area Under the Curve of NES and E2 at Specified Time Points	Visit 12 NES 0-72 hrs post Ring 1 Insertion	32845.0 hour*pg/mL	Standard Deviation 5370.53

Secondary

Changes From Baseline in Albumin (g/dL)

Clinical safety will also be evaluated by changes from baseline through end of treatment of blood chemistry and hematologic profile to assess safety of the three treatment groups.