Study on Safety and Efficacy of an Oral Contraceptive in Long Cycles

Study Overview
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Brief Summary
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The purpose of the study is to determine safety and efficacy of long-cycle regimens of an oral contraceptive.

Detailed Description
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The study has previously been posted by Schering AG, Germany. Schering AG, Germany has been renamed to Bayer Schering Pharma AG (BSP AG), Germany. Bayer Schering Pharma AG, Germany is the sponsor of the trial. The previously posted secondary Outcome Measure Parameters of safety and tolerability has been removed from result posting as it is covered by the Adverse Event section.

Official Title
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A Multicenter, Open, Randomized, Parallel Group Comparison to Assess the Safety and Efficacy of the Oral Contraceptive SH T00186D (0.02 mg Ethinylestradiol as Betadex Clathrate and 3 mg Drospirenone) in Two Variations of an Extended Regimen vs. a Standard Regimen (24 + 4 Days) in 1122 Healthy Female Volunteers for One Year, Followed by a One Year Safety Extension

Conditions
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Contraception

Intervention / Treatment
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* Drug: Flexible (extended) treatment of EE20/DRSP (YAZ, BAY86-5300)
* Drug: Fixed extended treatment of EE20/DRSP (YAZ, BAY86-5300)
* Drug: Standard 24+4 treatment of EE20/DRSP (YAZ, BAY86-5300)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy women who desire contraception smokers ≤ 30 Years old Exclusion Criteria: Contraindication against use of hormonal contraceptives

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 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: Flexible (extended) treatment of EE20/DRSP (YAZ, BAY86-5300)<br>3 cycles of treatment, each cycle comprising 120 days intended treatment with one tablet daily of 20µg ethinyl estradiol as betadex clathrate (EE20) plus 3 mg drospirenone (DRSP) followed by a 4 day tablet-free interval. If 3 consecutive days of bleeding and/or spotting occurred during the 120 day treatment period, a 4 day tablet free interval was advised. The minimum period between 2 tablet free intervals was 24 days. After each 4 day tablet free interval, a new 120 day intended treatment period was to be restarted, resulting in a minimum of 3 and maximum of 13 withdrawal bleeding episodes during one year of treatment. | Drug: Flexible (extended) treatment of EE20/DRSP (YAZ, BAY86-5300)<br>* 3 cycles of treatment, each cycle comprising 120 days intended treatment with one tablet daily of 20µg ethinyl estradiol as betadex clathrate (EE20) plus 3 mg drospirenone (DRSP) followed by a 4 day tablet-free interval. If 3 consecutive days of bleeding and/or spotting occurred during the 120 day treatment period, a 4 day tablet free interval was advised. The minimum period between 2 tablet free intervals was 24 days. After each 4 day tablet free interval, a new 120 day intended treatment period was to be restarted, resulting in a minimum of 3 and maximum of 13 withdrawal bleeding episodes during one year of treatment.<br>|
| Experimental: Fixed extended treatment of EE20/DRSP (YAZ, BAY86-5300)<br>3 cycles of treatment, each cycle comprising 120 days uninterrupted treatment with one tablet daily of 20µg ethinyl estradiol as betadex clathrate plus 3 mg drospirenone followed by a 4 day tablet free interval, 3 withdrawal bleeding episodes during one year of treatment were expected. | Drug: Fixed extended treatment of EE20/DRSP (YAZ, BAY86-5300)<br>* 3 cycles of treatment, each cycle comprising 120 days uninterrupted treatment with one tablet daily of 20µg ethinyl estradiol as betadex clathrate plus 3 mg drospirenone followed by a 4 day tablet free interval, 3 withdrawal bleeding episodes during one year of treatment were expected.<br>|
| Active Comparator: Standard 24+4 treatment of EE20/DRSP (YAZ, BAY86-5300)<br>13 cycles of treatment, each cycle comprising an intake of one tablet daily with 24 days of active tablets (20µg ethinyl estradiol as betadex clathrate plus 3 mg drospirenone) followed by 4 days of placebo tablets, 13 withdrawal bleeding episodes during one year of treatment were expected. | Drug: Standard 24+4 treatment of EE20/DRSP (YAZ, BAY86-5300)<br>* 13 cycles of treatment, each cycle comprising an intake of one tablet daily with 24 days of active tablets (20µg ethinyl estradiol as betadex clathrate plus 3 mg drospirenone) followed by 4 days of placebo tablets, 13 withdrawal bleeding episodes during one year of treatment were expected.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Days With Bleeding Including Spotting | The number of bleeding days per volunteer was calculated by summing up all days with bleeding intensity spotting or worse. The primary evaluation was the comparison of the flexible extended vs the standard regimen for this primary target variable, which was done for data within the first year of treatment only. As no further comparison or testing was done, no multiplicity issue arose. | up to 1 year | 
| Number of Unintended Pregnancies in Yaz Flexible Arm | Pregnancies with conception date within 4 days after end of study medication were regarded as during treatment. | up to 2 years | 
| Pearl Index | The Pearl Index (PI) is defined as the number of pregnancies per 100 woman years. The 2-year PI was obtained by dividing the number of pregnancies that occurred during the two years of treatment by the time (in 100 women years) that the women were under risk of getting pregnant. 95% confidence interval according to European Medicine Agency Note for guidance on clinical investigation of steroid contraceptives in women. | Up to 2 years | 
| Number of Unintended Pregnancies Due to Method Failure | Not included in this analysis are pregnancies due to subject failure eg. non-compliance with tablet intake rules. | Up to 2 years | 
| Adjusted Pearl Index | The adjusted Pearl Index was based on pregnancies due to method failures and compliant treatment cycles, i.e. cycle length between 24 and 124 day, pill break not longer than 7 days, and number of pills taken not smaller than 90% of the number of days in that cycle minus 7 days. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Days With Bleeding Excluding Spotting | The number of bleeding days per volunteer was calculated by summing up all days with bleeding intensity light, normal, or heavy. | up to 1 year | 
| Number of Bleeding Days During One Year of Treatment in Subjects With at Least 248 Days of Exposure Normalized to 372 Days | For early dropouts and pregnant subjects with an exposure period of less than 1 year but at least 248 days, the number of bleeding/spotting days was normalized to correspond to a 1-year exposure period. | up to 1 year | 
| Number of Bleeding / Spotting Days by 90-day Reference Period | The mean number of bleeding / spotting days, spotting-only and bleeding days was analyzed using reference periods of 90 days as recommended by the WHO. | up to 1 year | 
| Number of Bleeding / Spotting Episodes in 90 Day Reference Period | The mean number of bleeding / spotting episodes was analyzed using reference periods of 90 days as recommended by the WHO. | Up to one year | 
| Days With Scheduled Versus Unscheduled Bleeding | Days with scheduled and unscheduled bleeding were evaluated for extended regimens only. Unscheduled is any bleeding/spotting that occurred while taking active hormones regardless of the duration of intake, unless they occurred after tablet-free interval during days 1-4 of subsequent treatment cycle, or unless they occurred during days 1-7 of first treatment cycle. Scheduled is any bleeding/spotting that occurred during tablet-free interval, regardless of duration of tablet intake, or during next 4 days of subsequent treatment cycle. | Up to one year |