A Dose-finding Study to Evaluate the Effect of a Contrace... | NCT01586000

Name	Class
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)	NIH
Population Council	OTHER

Label	Type	Description	Intervention Names
10 µg/day E2	Experimental	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
20 µg/day E2	Experimental	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
40 µg/day E2	Experimental	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

Name	Type	Description	Arm Group Labels	Other Names
10 µg/day E2 with NES 200® µg/day	Drug	10 µg/day E2 with NES 200® µg/day delivered by CVR continuously for 6 months (180 days)	10 µg/day E2

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.	Three months

Measure	Description	Time Frame
Number of Subjects With Ovulation at During Each Cycle	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.	Control Cycle 1, Treatment Cycles 2, 3, and 7, Recovery Cycle 8, up to 8 months

Eligibility Module

Eligibility Criteria

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.

Facility	Status	City	State	ZIP	Country	Contacts
Johns Hopkins School of Medicine		Baltimore	Maryland	21224	United States
NYU School of Medicine

ID	Title	Description
FG000	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)
FG001	20 µg/day E2

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

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.

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

Posted

Mean

Standard Deviation

Days

Three months

ID	Title	Description
OG000	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)
OG001	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)
OG002	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)

Units	Counts
Participants	OG00067 OG00166 OG00262

Title

Denominators

Categories

Bleeding or Spotting

Title	Measurements
	OG00034.0± 23.17 OG00142.1± 24.51 OG00239.8± 22.83

Bleeding Only

Secondary

Number of Subjects With Ovulation at During Each Cycle

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.

All Safety population subjects that had any cycle with a progesterone value and a TVUS assessment. 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

Posted

Count of Participants

Participants

Control Cycle 1, Treatment Cycles 2, 3, and 7, Recovery Cycle 8, up to 8 months

ID	Title	Description
OG000	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)
OG001	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)
OG002	40 µg/day E2

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.

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

Posted

Mean

Standard Deviation

hour*pg/mL

Visits 12, 32, and 41 (Treatment Period)

ID	Title	Description
OG000	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)
OG001	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)

Secondary

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 be evaluated by collection of adverse events (AEs).

Posted

Count of Participants

Participants

Through Recovery Cycle 8, up to 8 months

ID	Title	Description
OG000	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)
OG001	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)
OG002	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)

Secondary

Number of Days Bleeding is Reported.

The primary outcome will be the number of days that bleeding or spotting is reported in the last 3 cycles (90 days) of treatment.

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

Posted

Mean

Standard Deviation

Days

Three months

ID	Title	Description
OG000	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)
OG001	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)
OG002	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)

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.

Change from Baseline to Final Evaluation. Subjects that had lab values at Visit 1 and Visit 41 were analyzed.

Posted

Mean

Standard Deviation

g/dL

Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)

ID	Title	Description
OG000	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)
OG001	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)
OG002	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)

Secondary

Changes From Baseline in ALT/SGPT (U/L)

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.

Change from Baseline to Final Evaluation. Subjects that had lab values at Visit 1 and Visit 41 were analyzed.

Posted

Mean

Standard Deviation

U/L

Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)

ID	Title	Description
OG000	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)
OG001	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)
OG002	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)

Secondary

Changes From Baseline in AST/SGOT (U/L)

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.

Change from Baseline to Final Evaluation. Subjects that had lab values at Visit 1 and Visit 41 were analyzed.

Posted

Mean

Standard Deviation

U/L

Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)

ID	Title	Description
OG000	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)
OG001	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)
OG002	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)

Secondary

Changes From Baseline in BUN (mg/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.

Change from Baseline to Final Evaluation. Subjects that had lab values at Visit 1 and Visit 41 were analyzed.

Posted

Mean

Standard Deviation

mg/dL

Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)

ID	Title	Description
OG000	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)
OG001	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)
OG002	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)

Secondary

Changes From Baseline in Calcium (mg/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.

Change from Baseline to Final Evaluation. Subjects that had lab values at Visit 1 and Visit 41 were analyzed.

Posted

Mean

Standard Deviation

mg/dL

Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)

ID	Title	Description
OG000	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)
OG001	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)
OG002	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)

Secondary

Changes From Baseline in Creatinine (mg/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.

Change from Baseline to Final Evaluation. Subjects that had lab values at Visit 1 and Visit 41 were analyzed.

Posted

Mean

Standard Deviation

mg/dL

Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)

ID	Title	Description
OG000	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)
OG001	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)
OG002	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)

Secondary

Changes From Baseline in Glucose (mg/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.

Change from Baseline to Final Evaluation. Subjects that had lab values at Visit 1 and Visit 41 were analyzed.

Posted

Mean

Standard Deviation

mg/dL

Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)

ID	Title	Description
OG000	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)
OG001	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)
OG002	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)

Secondary

Changes From Baseline in GGT (U/L)

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.

Change from Baseline to Final Evaluation. Subjects that had lab values at Visit 1 and Visit 41 were analyzed.

Posted

Mean

Standard Deviation

U/L

Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)

ID	Title	Description
OG000	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)
OG001	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)
OG002	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)

Secondary

Changes From Baseline in Total Bilirubin (mg/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.

Change from Baseline to Final Evaluation. Subjects that had lab values at Visit 1 and Visit 41 were analyzed.

Posted

Mean

Standard Deviation

mg/dL

Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)

ID	Title	Description
OG000	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)
OG001	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)
OG002	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)

Secondary

Changes From Baseline in Total Protein (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.

Change from Baseline to Final Evaluation. Subjects that had lab values at Visit 1 and Visit 41 were analyzed.

Posted

Mean

Standard Deviation

g/dL

Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)

ID	Title	Description
OG000	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)
OG001	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)
OG002	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)

Secondary

Changes From Baseline in Total Cholesterol (mg/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.

Change from Baseline to Final Evaluation. Subjects that had lab values at Visit 1 and Visit 41 were analyzed.

Posted

Mean

Standard Deviation

mg/dL

Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)

ID	Title	Description
OG000	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)
OG001	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)
OG002	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)

Secondary

Changes From Baseline in HDL Cholesterol (mg/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.

Change from Baseline to Final Evaluation. Subjects that had lab values at Visit 1 and Visit 41 were analyzed.

Posted

Mean

Standard Deviation

mg/dL

Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)

ID	Title	Description
OG000	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)
OG001	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)
OG002	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)

Secondary

Changes From Baseline in LDL Cholesterol (mg/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.

Change from Baseline to Final Evaluation. Subjects that had lab values at Visit 1 and Visit 41 were analyzed.

Posted

Mean

Standard Deviation

mg/dL

Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)

ID	Title	Description
OG000	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)
OG001	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)
OG002	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)

Secondary

Changes From Baseline in Triglycerides (mg/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.

Change from Baseline to Final Evaluation. Subjects that had lab values at Visit 1 and Visit 41 were analyzed.

Posted

Mean

Standard Deviation

mg/dL

Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)

ID	Title	Description
OG000	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)
OG001	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)
OG002	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)

Secondary

Changes From Baseline in Chloride (mmol/L)

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.

Change from Baseline to Final Evaluation. Subjects that had lab values at Visit 1 and Visit 41 were analyzed.

Posted

Mean

Standard Deviation

mmol/L

Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)

ID	Title	Description
OG000	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)
OG001	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)
OG002	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)

Secondary

Changes From Baseline in Potassium (mmol/L)

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.

Change from Baseline to Final Evaluation. Subjects that had lab values at Visit 1 and Visit 41 were analyzed.

Posted

Mean

Standard Deviation

mmol/L

Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)

ID	Title	Description
OG000	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)
OG001	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)
OG002	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)

Secondary

Changes From Baseline in Sodium (mmol/L)

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.

Change from Baseline to Final Evaluation. Subjects that had lab values at Visit 1 and Visit 41 were analyzed.

Posted

Mean

Standard Deviation

mmol/L

Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)

ID	Title	Description
OG000	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)
OG001	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)
OG002	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)

Secondary

Changes From Baseline in RBC (MIL/uL)

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.

Change from Baseline to Final Evaluation. Subjects that had lab values at Visit 1 and Visit 41 were analyzed.

Posted

Mean

Standard Deviation

MIL/uL

Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)

ID	Title	Description
OG000	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)
OG001	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)
OG002	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)

Secondary

Changes From Baseline in WBC (THOU/uL)

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.

Change from Baseline to Final Evaluation. Subjects that had lab values at Visit 1 and Visit 41 were analyzed.

Posted

Mean

Standard Deviation

THOU/uL

Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)

ID	Title	Description
OG000	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)
OG001	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)
OG002	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)

Secondary

Changes From Baseline in Hemoglobin (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.

Change from Baseline to Final Evaluation. Subjects that had lab values at Visit 1 and Visit 41 were analyzed.

Posted

Mean

Standard Deviation

g/dL

Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)

ID	Title	Description
OG000	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)
OG001	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)
OG002	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)

Secondary

Changes From Baseline in Hematocrit (%)

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.

Change from Baseline to Final Evaluation. Subjects that had lab values at Visit 1 and Visit 41 were analyzed.

Posted

Mean

Standard Deviation

percentage

Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)

ID	Title	Description
OG000	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)
OG001	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)
OG002	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)

Secondary

Changes From Baseline in Platelet Count (THOU/uL)

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.

Change from Baseline to Final Evaluation. Subjects that had lab values at Visit 1 and Visit 41 were analyzed.

Posted

Mean

Standard Deviation

THOU/uL

Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)

ID	Title	Description
OG000	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)
OG001	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)
OG002	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)

Secondary

Changes From Baseline in Basophils (%)

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.

Change from Baseline to Final Evaluation. Subjects that had lab values at Visit 1 and Visit 41 were analyzed.

Posted

Mean

Standard Deviation

percentage

Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)

ID	Title	Description
OG000	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)
OG001	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)
OG002	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)

Secondary

Changes From Baseline in Eosinophils (%)

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.

Change from Baseline to Final Evaluation. Subjects that had lab values at Visit 1 and Visit 41 were analyzed.

Posted

Mean

Standard Deviation

percentage

Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)

ID	Title	Description
OG000	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)
OG001	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)
OG002	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)

Secondary

Changes From Baseline in Lymphocytes (%)

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.

Change from Baseline to Final Evaluation. Subjects that had lab values at Visit 1 and Visit 41 were analyzed.

Posted

Mean

Standard Deviation

percentage

Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)

ID	Title	Description
OG000	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)
OG001	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)
OG002	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)

Secondary

Changes From Baseline in Monocytes (%)

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.

Change from Baseline to Final Evaluation. Subjects that had lab values at Visit 1 and Visit 41 were analyzed.

Posted

Mean

Standard Deviation

percentage

Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)

ID	Title	Description
OG000	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)
OG001	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)
OG002	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)

Secondary

Changes From Baseline in Neutrophils (%)

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.

Change from Baseline to Final Evaluation. Subjects that had lab values at Visit 1 and Visit 41 were analyzed.

Posted

Mean

Standard Deviation

percentage

Visit 41 (end of Treatment Cycle 7) compared to Visit 1 (Screening)

ID	Title	Description
OG000	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)
OG001	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)
OG002	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)

Other Adverse Events

Term	Organ System	Assessment Type	Statistical Information
Headache	Nervous system disorders	Systematic Assessment	EG00062 events28 affected67 at risk EG00162 events20 affected66 at risk EG00262 events14 affected64 at risk
Upper Respiratory Tract Infection	Infections and infestations	Systematic Assessment	EG00043 events16 affected67 at risk EG00143 events13 affected66 at risk EG00243 events14 affected64 at risk
NASOPHARYNGITIS	Infections and infestations	Systematic Assessment	EG00037 events9 affected67 at risk EG00137 events16 affected66 at risk EG00237 events12 affected64 at risk
Nausea	Gastrointestinal disorders	Systematic Assessment	EG00025 events5 affected67 at risk EG00125 events10 affected66 at risk EG00225 events10 affected64 at risk
OROPHARYNGEAL PAIN	Respiratory, thoracic and mediastinal disorders	Systematic Assessment	EG00023 events10 affected67 at risk EG00123 events7 affected66 at risk EG00223 events6 affected64 at risk
VULVOVAGINAL MYCOTIC INFECTION	Infections and infestations	Systematic Assessment	EG00022 events7 affected67 at risk EG00122 events10 affected66 at risk EG00222 events5 affected64 at risk
BACK PAIN	Musculoskeletal and connective tissue disorders	Systematic Assessment	EG00019 events5 affected67 at risk EG00119 events5 affected66 at risk EG00219 events9 affected64 at risk
VAGINITIS BACTERIAL	Infections and infestations	Systematic Assessment	EG00017 events8 affected67 at risk EG00117 events4 affected66 at risk EG00217 events5 affected64 at risk
DIARRHOEA	Gastrointestinal disorders	Systematic Assessment	EG00016 events6 affected67 at risk EG00116 events4 affected66 at risk EG00216 events6 affected64 at risk
INFLUENZA	Infections and infestations	Systematic Assessment	EG00016 events9 affected67 at risk EG00116 events5 affected66 at risk EG00216 events2 affected64 at risk
ACNE	Skin and subcutaneous tissue disorders	Systematic Assessment	EG00015 events8 affected67 at risk EG00115 events6 affected66 at risk EG00215 events1 affected64 at risk
MOOD SWINGS	Psychiatric disorders	Systematic Assessment	EG00014 events4 affected67 at risk EG00114 events7 affected66 at risk EG00214 events3 affected64 at risk
ARTHRALGIA	Musculoskeletal and connective tissue disorders	Systematic Assessment	EG00012 events4 affected67 at risk EG00112 events4 affected66 at risk EG00212 events4 affected64 at risk
DIZZINESS	Nervous system disorders	Systematic Assessment	EG00012 events3 affected67 at risk EG00112 events5 affected66 at risk EG00212 events4 affected64 at risk
FUNGAL INFECTION	Infections and infestations	Systematic Assessment	EG00012 events3 affected67 at risk EG00112 events6 affected66 at risk EG00212 events3 affected64 at risk
ANXIETY	Psychiatric disorders	Systematic Assessment	EG00011 events4 affected67 at risk EG00111 events3 affected66 at risk EG00211 events4 affected64 at risk
DYSPAREUNIA	Psychiatric disorders	Systematic Assessment	EG00011 events4 affected67 at risk EG00111 events5 affected66 at risk EG00211 events2 affected64 at risk
MYALGIA	Musculoskeletal and connective tissue disorders	Systematic Assessment	EG00011 events3 affected67 at risk EG00111 events4 affected66 at risk EG00211 events4 affected64 at risk
VAGINAL DISCHARGE	Reproductive system and breast disorders	Systematic Assessment	EG00011 events5 affected67 at risk EG00111 events2 affected66 at risk EG00211 events4 affected64 at risk
VOMITING	Gastrointestinal disorders	Systematic Assessment	EG00010 events2 affected67 at risk EG00110 events4 affected66 at risk EG00210 events4 affected64 at risk
VULVOVAGINAL PRURITUS	Reproductive system and breast disorders	Systematic Assessment	EG00010 events2 affected67 at risk EG00110 events4 affected66 at risk EG00210 events4 affected64 at risk

ID	Title	Description
BG000	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)
BG001	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)
BG002	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)
BG003	Total	Total of all reporting groups

ID	Title	Description	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	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	0	67	58	67
EG001	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	0	66	57	66
EG002	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	1	64	55	64