Contraception
Conditions
Brief summary
The purpose of the study is to determine safety and efficacy of long-cycle regimens of an oral contraceptive.
Detailed description
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.
Interventions
DRUGFlexible (extended) treatment of EE20/DRSP (YAZ, BAY86-5300)
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.
DRUGFixed extended treatment of EE20/DRSP (YAZ, BAY86-5300)
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.
DRUGStandard 24+4 treatment of EE20/DRSP (YAZ, BAY86-5300)
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.
Sponsors
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 35 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy women who desire contraception * smokers ≤ 30 Years old
Exclusion criteria
* Contraindication against use of hormonal contraceptives
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Pearl Index | Up to 2 years | 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. |
| Number of Days With Bleeding Including Spotting | up to 1 year | 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. |
| Number of Unintended Pregnancies in Yaz Flexible Arm | up to 2 years | Pregnancies with conception date within 4 days after end of study medication were regarded as during treatment. |
| Pearl Index | Up to 2 years | 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. |
| Number of Unintended Pregnancies Due to Method Failure | Up to 2 years | Not included in this analysis are pregnancies due to subject failure eg. non-compliance with tablet intake rules. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Days With Bleeding Excluding Spotting | up to 1 year | The number of bleeding days per volunteer was calculated by summing up all days with bleeding intensity light, normal, or heavy. |
| Number of Bleeding Days During One Year of Treatment in Subjects With at Least 248 Days of Exposure Normalized to 372 Days | up to 1 year | 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. |
| Number of Bleeding / Spotting Days by 90-day Reference Period | up to 1 year | 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. |
| Number of Bleeding / Spotting Episodes in 90 Day Reference Period | Up to one year | The mean number of bleeding / spotting episodes was analyzed using reference periods of 90 days as recommended by the WHO. |
| Days With Scheduled Versus Unscheduled Bleeding | Up to one year | 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. |
Countries
Canada, Germany, Netherlands
Participant flow
Recruitment details
Randomization scheme in the subgroups was 1:1:1 for the 2 centers performing biopsies and measurements of Bone Mineral Density and metabolic parameters (82 subjects per treatment group). The remaining subjects were randomized according to the ratio 4:1:1.
Pre-assignment details
146 subjects failed screening, 96 of these 146 (65.8%) because inclusion or exclusion criteria were not met, 21 (14.4%) due to withdrawal of consent, 17 (11.6%) because of other reasons, 11 (7.5%) due to protocol deviations, 1 (0.7%) was lost to follow-up. 32 randomized subjects never took medication.
Participants by arm
| Arm | Count |
|---|---|
| Flexible (Extended) Treatment of EE20/DRSP (YAZ, BAY86-5300) 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. | 642 |
| Fixed Extended Treatment of EE20/DRSP (YAZ, BAY86-5300) 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. | 209 |
| Standard 24+4 Treatment of EE20/DRSP (YAZ, BAY86-5300) 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. | 216 |
| Total | 1,067 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Open-label Safety Extension | Adverse Event | 5 | 0 | 4 |
| Open-label Safety Extension | Lost to Follow-up | 2 | 5 | 4 |
| Open-label Safety Extension | patient moved/wish for pregnancy/no need | 10 | 2 | 1 |
| Open-label Safety Extension | Pregnancy | 4 | 1 | 2 |
| Open-label Safety Extension | Protocol Violation | 1 | 3 | 2 |
| Open-label Safety Extension | Withdrawal by Subject | 19 | 3 | 12 |
| Treatment | Adverse Event | 42 | 26 | 10 |
| Treatment | Lost to Follow-up | 19 | 4 | 2 |
| Treatment | patient moved/wish for pregnancy/no need | 13 | 5 | 8 |
| Treatment | Pregnancy | 3 | 2 | 2 |
| Treatment | Protocol Violation | 6 | 14 | 13 |
| Treatment | Withdrawal by Subject | 28 | 13 | 12 |
Baseline characteristics
| Characteristic | Flexible (Extended) Treatment of EE20/DRSP (YAZ, BAY86-5300) | Fixed Extended Treatment of EE20/DRSP (YAZ, BAY86-5300) | Standard 24+4 Treatment of EE20/DRSP (YAZ, BAY86-5300) | Total |
|---|---|---|---|---|
| Age, Continuous | 24.8 years | 24.8 years | 24.3 years | 24.7 years |
| Body-Mass-Index (BMI) | 22.541 kg/m² | 22.541 kg/m² | 22.566 kg/m² | 22.546 kg/m² |
| Sex: Female, Male Female | 642 Participants | 209 Participants | 216 Participants | 1067 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 | — / — | — / — | — / — |
| other Total, other adverse events | 310 / 642 | 116 / 209 | 121 / 216 |
| serious Total, serious adverse events | 19 / 642 | 7 / 209 | 3 / 216 |
Outcome results
Primary
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.
Time frame: Up to 2 years
Population: Full Analysis Set (reflecting ITT population), all treated subjects, no imputation, including switchers to flexible treatment in second year
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Flexible (Extended) Treatment of EE20/DRSP (YAZ, BAY86-5300) | Adjusted Pearl Index | 0.60 Pregnancies per 100 woman years |
Primary
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.
Time frame: up to 1 year
Population: Full Analysis Set (FAS) (reflecting Intention To Treat (ITT) population), all treated subjects with data available, no imputation
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Flexible (Extended) Treatment of EE20/DRSP (YAZ, BAY86-5300) | Number of Days With Bleeding Including Spotting | 41 days | Standard Deviation 29 |
| Fixed Extended Treatment of EE20/DRSP (YAZ, BAY86-5300) | Number of Days With Bleeding Including Spotting | 61 days | Standard Deviation 51 |
| Standard 24+4 Treatment of EE20/DRSP (YAZ, BAY86-5300) | Number of Days With Bleeding Including Spotting | 66 days | Standard Deviation 27 |
Comparison: Primary variable was tested for the hypothesis, whether the means are equal against the alternative (means are different) at a level of significance of alpha = 0.05 (t-test). For power calculation, a normal distribution, a absolute difference of 10 days, a Standard Deviation of 28 days and a drop-out rate of 40% was assumed.p-value: <0.000195% CI: [-29, -20]t-test, 2 sided
Primary
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.
Time frame: Up to 2 years
Population: Full Analysis Set (reflecting ITT population), all treated subjects, no imputation, including switchers to flexible treatment in second year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Flexible (Extended) Treatment of EE20/DRSP (YAZ, BAY86-5300) | Number of Unintended Pregnancies Due to Method Failure | 7 Pregnancies |
Primary
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.
Time frame: up to 2 years
Population: Full Analysis Set (reflecting ITT population), all treated subjects, no imputation, including switchers to flexible treatment in second year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Flexible (Extended) Treatment of EE20/DRSP (YAZ, BAY86-5300) | Number of Unintended Pregnancies in Yaz Flexible Arm | 8 pregnancies |
Primary
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.
Time frame: Up to 2 years
Population: Full Analysis Set (reflecting ITT population), all treated subjects, no imputation, including switchers to flexible treatment in second year
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Flexible (Extended) Treatment of EE20/DRSP (YAZ, BAY86-5300) | Pearl Index | 0.64 Pregnancies per 100 woman years |
Secondary
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.
Time frame: Up to one year
Population: FAS (reflecting ITT), all treated subjects, no imputation
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Flexible (Extended) Treatment of EE20/DRSP (YAZ, BAY86-5300) | Days With Scheduled Versus Unscheduled Bleeding | Scheduled bleeding | 23.3 Days | Standard Deviation 14.3 |
| Flexible (Extended) Treatment of EE20/DRSP (YAZ, BAY86-5300) | Days With Scheduled Versus Unscheduled Bleeding | Unscheduled bleeding | 17.1 Days | Standard Deviation 17.4 |
| Fixed Extended Treatment of EE20/DRSP (YAZ, BAY86-5300) | Days With Scheduled Versus Unscheduled Bleeding | Scheduled bleeding | 14.0 Days | Standard Deviation 5.9 |
| Fixed Extended Treatment of EE20/DRSP (YAZ, BAY86-5300) | Days With Scheduled Versus Unscheduled Bleeding | Unscheduled bleeding | 46.6 Days | Standard Deviation 48.4 |
Secondary
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.
Time frame: up to 1 year
Population: FAS (reflecting ITT population), all treated subjects, no imputation
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Flexible (Extended) Treatment of EE20/DRSP (YAZ, BAY86-5300) | Number of Bleeding Days During One Year of Treatment in Subjects With at Least 248 Days of Exposure Normalized to 372 Days | 44 Days | Standard Deviation 29 |
| Fixed Extended Treatment of EE20/DRSP (YAZ, BAY86-5300) | Number of Bleeding Days During One Year of Treatment in Subjects With at Least 248 Days of Exposure Normalized to 372 Days | 66 Days | Standard Deviation 55 |
| Standard 24+4 Treatment of EE20/DRSP (YAZ, BAY86-5300) | Number of Bleeding Days During One Year of Treatment in Subjects With at Least 248 Days of Exposure Normalized to 372 Days | 71 Days | Standard Deviation 24 |
Secondary
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.
Time frame: up to 1 year
Population: FAS (reflecting ITT), all treated subjects, no imputation
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Flexible (Extended) Treatment of EE20/DRSP (YAZ, BAY86-5300) | Number of Bleeding / Spotting Days by 90-day Reference Period | Reference period 1 | 7.2 Days | Standard Deviation 5.5 |
| Flexible (Extended) Treatment of EE20/DRSP (YAZ, BAY86-5300) | Number of Bleeding / Spotting Days by 90-day Reference Period | Reference period 2 | 5.3 Days | Standard Deviation 5.6 |
| Flexible (Extended) Treatment of EE20/DRSP (YAZ, BAY86-5300) | Number of Bleeding / Spotting Days by 90-day Reference Period | Reference period 3 | 4.6 Days | Standard Deviation 4.3 |
| Flexible (Extended) Treatment of EE20/DRSP (YAZ, BAY86-5300) | Number of Bleeding / Spotting Days by 90-day Reference Period | Reference period 4 | 3.9 Days | Standard Deviation 4.5 |
| Fixed Extended Treatment of EE20/DRSP (YAZ, BAY86-5300) | Number of Bleeding / Spotting Days by 90-day Reference Period | Reference period 4 | 2.6 Days | Standard Deviation 5.6 |
| Fixed Extended Treatment of EE20/DRSP (YAZ, BAY86-5300) | Number of Bleeding / Spotting Days by 90-day Reference Period | Reference period 1 | 9.0 Days | Standard Deviation 8.6 |
| Fixed Extended Treatment of EE20/DRSP (YAZ, BAY86-5300) | Number of Bleeding / Spotting Days by 90-day Reference Period | Reference period 3 | 5.1 Days | Standard Deviation 5.8 |
| Fixed Extended Treatment of EE20/DRSP (YAZ, BAY86-5300) | Number of Bleeding / Spotting Days by 90-day Reference Period | Reference period 2 | 6.3 Days | Standard Deviation 6.5 |
| Standard 24+4 Treatment of EE20/DRSP (YAZ, BAY86-5300) | Number of Bleeding / Spotting Days by 90-day Reference Period | Reference period 4 | 9.5 Days | Standard Deviation 4.9 |
| Standard 24+4 Treatment of EE20/DRSP (YAZ, BAY86-5300) | Number of Bleeding / Spotting Days by 90-day Reference Period | Reference period 2 | 10.2 Days | Standard Deviation 4.8 |
| Standard 24+4 Treatment of EE20/DRSP (YAZ, BAY86-5300) | Number of Bleeding / Spotting Days by 90-day Reference Period | Reference period 3 | 9.8 Days | Standard Deviation 4.8 |
| Standard 24+4 Treatment of EE20/DRSP (YAZ, BAY86-5300) | Number of Bleeding / Spotting Days by 90-day Reference Period | Reference period 1 | 14.6 Days | Standard Deviation 6.1 |
Secondary
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.
Time frame: Up to one year
Population: FAS (reflecting ITT), all treated subjects, no imputation
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Flexible (Extended) Treatment of EE20/DRSP (YAZ, BAY86-5300) | Number of Bleeding / Spotting Episodes in 90 Day Reference Period | Reference period 3 | 1.7 Episodes | Standard Deviation 1.5 |
| Flexible (Extended) Treatment of EE20/DRSP (YAZ, BAY86-5300) | Number of Bleeding / Spotting Episodes in 90 Day Reference Period | Reference period 4 | 1.5 Episodes | Standard Deviation 1.5 |
| Flexible (Extended) Treatment of EE20/DRSP (YAZ, BAY86-5300) | Number of Bleeding / Spotting Episodes in 90 Day Reference Period | Reference period 2 | 1.9 Episodes | Standard Deviation 1.5 |
| Flexible (Extended) Treatment of EE20/DRSP (YAZ, BAY86-5300) | Number of Bleeding / Spotting Episodes in 90 Day Reference Period | Reference period 1 | 1.7 Episodes | Standard Deviation 1.7 |
| Fixed Extended Treatment of EE20/DRSP (YAZ, BAY86-5300) | Number of Bleeding / Spotting Episodes in 90 Day Reference Period | Reference period 1 | 2.0 Episodes | Standard Deviation 1.9 |
| Fixed Extended Treatment of EE20/DRSP (YAZ, BAY86-5300) | Number of Bleeding / Spotting Episodes in 90 Day Reference Period | Reference period 2 | 2.1 Episodes | Standard Deviation 1.4 |
| Fixed Extended Treatment of EE20/DRSP (YAZ, BAY86-5300) | Number of Bleeding / Spotting Episodes in 90 Day Reference Period | Reference period 4 | 1.3 Episodes | Standard Deviation 1.5 |
| Fixed Extended Treatment of EE20/DRSP (YAZ, BAY86-5300) | Number of Bleeding / Spotting Episodes in 90 Day Reference Period | Reference period 3 | 2.1 Episodes | Standard Deviation 1.8 |
| Standard 24+4 Treatment of EE20/DRSP (YAZ, BAY86-5300) | Number of Bleeding / Spotting Episodes in 90 Day Reference Period | Reference period 4 | 3.2 Episodes | Standard Deviation 1 |
| Standard 24+4 Treatment of EE20/DRSP (YAZ, BAY86-5300) | Number of Bleeding / Spotting Episodes in 90 Day Reference Period | Reference period 1 | 3.4 Episodes | Standard Deviation 1.2 |
| Standard 24+4 Treatment of EE20/DRSP (YAZ, BAY86-5300) | Number of Bleeding / Spotting Episodes in 90 Day Reference Period | Reference period 2 | 3.4 Episodes | Standard Deviation 1.1 |
| Standard 24+4 Treatment of EE20/DRSP (YAZ, BAY86-5300) | Number of Bleeding / Spotting Episodes in 90 Day Reference Period | Reference period 3 | 3.2 Episodes | Standard Deviation 1 |
Secondary
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.
Time frame: up to 1 year
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Flexible (Extended) Treatment of EE20/DRSP (YAZ, BAY86-5300) | Number of Days With Bleeding Excluding Spotting | 21 Days | Standard Deviation 15 |
| Fixed Extended Treatment of EE20/DRSP (YAZ, BAY86-5300) | Number of Days With Bleeding Excluding Spotting | 24 Days | Standard Deviation 24 |
| Standard 24+4 Treatment of EE20/DRSP (YAZ, BAY86-5300) | Number of Days With Bleeding Excluding Spotting | 43 Days | Standard Deviation 20 |
Post Hoc
Number of Unintended Pregnancies Including Pregnancies Occuring Within 14 Days After End of Study Medication.
Pregnancies with conception date during treatment and within 14 days after end of study medication were included.
Time frame: Up to one year
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Flexible (Extended) Treatment of EE20/DRSP (YAZ, BAY86-5300) | Number of Unintended Pregnancies Including Pregnancies Occuring Within 14 Days After End of Study Medication. | 2 Pregnancies |
Post Hoc
Pearl Index (FDA Criteria)
Following an FDA request another PI evaluation was done for the first year of treatment only and taking into consideration also pregnancies with a conception date within 14 days after end of the study medication. Restricting the analysis to the required first year of treatment, it results in this PI estimation.
Time frame: Up to one year
Population: FAS
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Flexible (Extended) Treatment of EE20/DRSP (YAZ, BAY86-5300) | Pearl Index (FDA Criteria) | 0.34 Pregnancies per 100 woman years |