Efficacy and Safety Study of the Combined Oral Contraceptive NOMAC-E2 Compared to a COC Containing DRSP/EE (292002)(P05722)

Study Overview
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Brief Summary
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The primary purpose of this study is to assess contraceptive efficacy, vaginal bleeding patterns (cycle control), general safety and acceptability of the nomegestrol acetate-estradiol (NOMAC-E2) combined oral contraceptive (COC) in a large group of women aged 18-50 years.

Official Title
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A Randomized, Open-Label, Comparative, Multi -Center Trial to Evaluate Contraceptive Efficacy, Cycle Control, Safety and Acceptability of a Monophasic Combined Oral Contraceptive (COC) Containing 2.5 mg Nomegestrol Acetate (NOMAC) and 1.5 mg Estradiol (E2), Compared to a Monophasic COC Containing 3 mg Drospirenone (DRSP) and 30 µg Ethinyl Estradiol (EE)

Conditions
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Contraception

Intervention / Treatment
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* Drug: NOMAC-E2
* Drug: DRSP-EE


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Sexually active women, at risk for pregnancy and not planning to use condoms; Women in need for contraception and willing to use an oral contraceptive (OC) for 12 months (13 cycles); At least 18 but not older than 50 years of age at the time of screening; Body mass index >=17 and <=35; Good physical and mental health; Willing to give informed consent in writing. Exclusion Criteria: Contraindications for contraceptive steroids In accordance with the Summary of Product Characteristics (SmPC)/Package Insert of DRSP-EE, additional contraindications related to the antimineralocorticoid activity of drospirenone (conditions that predispose to hyperkalemia): Renal insufficiency; Hepatic dysfunction; Adrenal insufficiency. An abnormal cervical smear (i.e.: dysplasia, cervical intraepithelial neoplasia [CIN], squamous intraepithelial lesion [SIL], carcinoma in situ, invasive carcinoma) at screening; Clinically relevant abnormal laboratory result at screening as judged by the investigator; Use of an injectable hormonal method of contraception; within 6 months of an injection with a 3-month duration, within 4 months of an injection with a 2-month duration, within 2 months of an injection with a 1-month duration; Before spontaneous menstruation has occurred following a delivery or abortion; Breastfeeding or within 2 months after stopping breastfeeding prior to the start of trial medication; Present use or use within 2 months prior to the start of the trial medication of the following drugs: phenytoin, barbiturates, primidone, carbamazepine, oxcarbazepine, topiramate, felbamate, rifampicin, nelfinavir, ritonavir, griseofulvin, ketoconazole, sex steroids (other than pre- and posttreatment contraceptive method) and herbal remedies containing Hypericum perforatum (St John's Wort); Administration of investigational drugs and/or participation in another clinical trial within 2 months prior to the start of the trial medication or during the trial period. Subjects with a diagnosis of the endometrial biopsy such as hyperplasia, atypical hyperplasia, carcinoma or any other abnormality judged clinically relevant by the investigator (This is applicable only for the subjects participating in the endometrial biopsy substudy).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NOMAC-E2<br>Nomegestrol Acetate (NOMAC) and Estradiol (E2), 2.5 mg NOMAC and 1.5 mg E2 monophasic combined oral contraceptive | Drug: NOMAC-E2<br>* Nomegestrol Acetate and Estradiol Tablets, 2.5 mg NOMAC and 1.5 mg E2 taken once daily from Day 1 of menstrual period up to and including Day 28 for 13 consecutive 28-day menstrual cycles (1 year).<br>* Other names: ORG10486-ORG2317;|
| Active Comparator: DRSP-EE<br>Drospirenone (DRSP) and Ethinyl Estradiol (EE), 3 mg DRSP and 30 mcg EE monophasic combined oral contraceptive | Drug: DRSP-EE<br>* Drospirenone and Ethinyl Estradiol Tablets, 3 mg DRSP and 30 mcg EE taken once daily from Day 1 of menstrual period up to and including Day 28 for 13 consecutive 28-day menstrual cycles (1 year).<br>* Other names: Yasmin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of In-treatment Pregnancies (With +2 Day Window) Per 100 Woman Years of Exposure (Pearl Index) | In-treatment pregnancies were pregnancies with an estimated date of conception from the day of first intake of trial medication up to and including the day of last (active or placebo) intake of trial medication extended with a maximum of two days. Each 13 cycles (28 days per cycle) of exposure constitutes a woman year. The Pearl Index was obtained by dividing the number of in-treatment pregnancies that occurred by the time (in 100 women years) that the women were under risk of becoming pregnant. | 1 year (13 cycles) | 
| Number of In-treatment Pregnancies (With +14 Day Window) Per 100 Woman Years of Exposure (Pearl Index) | In-treatment pregnancies were pregnancies with an estimated date of conception from the day of first intake of trial medication up to and including the day of last (active or placebo) intake of trial medication extended with a period of 14 days. Each 13 cycles (28 days per cycle) of exposure constitutes a woman year. The Pearl Index was obtained by dividing the number of in-treatment pregnancies that occurred by the time (in 100 women years) that the women were under risk of becoming pregnant. | 1 year (13 cycles) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With an Occurrence of Breakthrough Bleeding/Spotting | Cycle control was evaluated on the basis of vaginal bleeding pattern as recorded daily by participants using e-diaries. Participants documented whether vaginal bleeding was present, and if present, indicated whether it was considered to be spotting or bleeding. Breakthrough bleeding/spotting was defined as any episode that occurred during the expected non-bleeding period that was neither an early nor a continued withdrawal bleeding. Expected non-bleeding period: DRSP-EE group: 21-day period starting on Day 1 of the cycle; NOMAC-E2: 21-day period starting on Day 4 of the cycle. | Every 28-day cycle for 13 cycles (one year total) | 
| Number of Participants With an Occurrence of Absence of Withdrawal Bleeding | Cycle control was evaluated on the basis of vaginal bleeding pattern as recorded daily by participants using e-diaries. Participants documented whether vaginal bleeding was present, and if present, indicated whether it was considered to be spotting or bleeding. Absence of withdrawal bleeding was defined as no bleeding/spotting episode that began during or continued into the expected bleeding period. Expected bleeding period: DRSP-EE group: 7-day period starting on Day 22 of the cycle; NOMAC-E2: 7-day period starting on Day 25 of the cycle and ending on Day 3 of the next cycle. | Every 28-day cycle for 13 cycles (one year total) | 
| Number of Participants With an Occurrence of Breakthrough Bleeding | Cycle control was evaluated on the basis of vaginal bleeding pattern as recorded daily by participants using e-diaries. Participants documented whether vaginal bleeding was present, and if present, indicated whether it was considered to be spotting or bleeding. Breakthrough bleeding was defined as any bleeding episode that occurred during the expected non-bleeding period that was neither part of an early nor continued withdrawal bleeding. Expected non-bleeding period: DRSP-EE group: 21-day period starting on Day 1 of the cycle; NOMAC-E2: 21-day period starting on Day 4 of the cycle. | Every 28-day cycle for 13 cycles (one year total) | 
| Number of Participants With an Occurrence of Breakthrough Spotting (Spotting Only) | Cycle control was evaluated on the basis of vaginal bleeding pattern as recorded daily by participants using e-diaries. Participants documented whether vaginal bleeding was present, and if present, indicated whether it was considered to be spotting or bleeding. Breakthrough spotting was defined as any spotting episode that occurred during the expected non-bleeding period that was neither part of an early nor continued withdrawal bleeding. Expected non-bleeding period: DRSP-EE group: 21-day period starting on Day 1 of the cycle; NOMAC-E2: 21-day period starting on Day 4 of the cycle. | Every 28-day cycle for 13 cycles (one year total) | 
| Number of Participants With an Occurrence of Early Withdrawal Bleeding | Cycle control was evaluated on the basis of vaginal bleeding pattern as recorded daily by participants using e-diaries. Participants documented whether vaginal bleeding was present, and if present, indicated whether it was considered to be spotting or bleeding. Early withdrawal bleeding was defined as any withdrawal bleeding that started before the current expected bleeding period. Expected bleeding period: DRSP-EE group: 7-day period starting on Day 22 of the cycle; NOMAC-E2: 7-day period starting on Day 25 of the cycle and ending on Day 3 of the next cycle. | Every 28-day cycle for 13 cycles (one year total) | 
| Number of Participants With an Occurrence of Continued Withdrawal Bleeding | Cycle control was evaluated on the basis of vaginal bleeding pattern as recorded daily by participants using e-diaries. Participants documented whether vaginal bleeding was present, and if present, indicated whether it was considered to be spotting or bleeding. Continued withdrawal bleeding was defined as any withdrawal bleeding that continued into the expected non-bleeding period of the next cycle. Expected non-bleeding period: DRSP-EE group: 21-day period starting on Day 1 of the cycle; NOMAC-E2: 21-day period starting on Day 4 of the cycle. | Every 28-day cycle for 12 cycles | 
| Average Number of Breakthrough Bleeding/Spotting Days | Cycle control was evaluated on the basis of vaginal bleeding pattern as recorded daily by participants using e-diaries. Participants documented whether vaginal bleeding was present, and if present, indicated whether it was considered to be spotting or bleeding. Breakthrough bleeding/spotting was defined as any episode that occurred during the expected non-bleeding period that was neither an early nor a continued withdrawal bleeding. Expected non-bleeding period: DRSP-EE group: 21-day period starting on Day 1 of the cycle; NOMAC-E2: 21-day period starting on Day 4 of the cycle. | Every 28-day cycle for 13 cycles (one year total) | 
| Average Number of Withdrawal Bleeding/Spotting Days | Cycle control was evaluated on the basis of vaginal bleeding pattern as recorded daily by participants using e-diaries. Participants documented whether vaginal bleeding was present, and if present, indicated whether it was considered to be spotting or bleeding. Withdrawal bleeding was defined as bleeding/spotting episode that started during or continued into the expected bleeding period. Expected bleeding period: DRSP-EE group: 7-day period starting on Day 22 of the cycle; NOMAC-E2: 7-day period starting on Day 25 of the cycle and ending on Day 3 of the next cycle. | Every 28-day cycle for 13 cycles (one year total) |