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

Study Description

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Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Contraception	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)	Phase 3

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	1166 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Prevention
Official Title:	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
Study Start Date :	December 2005
Actual Primary Completion Date :	October 2008
Actual Study Completion Date :	October 2008

Arms and Interventions

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Arm	Intervention/treatment
Experimental: 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.	Drug: 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.
Experimental: 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.	Drug: 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.
Active Comparator: 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.	Drug: 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.

Outcome Measures

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Primary Outcome Measures :

1. Number of Days With Bleeding Including Spotting [ Time Frame: 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.
2. Number of Unintended Pregnancies in Yaz Flexible Arm [ Time Frame: up to 2 years ]
   Pregnancies with conception date within 4 days after end of study medication were regarded as during treatment.
3. Pearl Index [ Time Frame: 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.
4. Number of Unintended Pregnancies Due to Method Failure [ Time Frame: Up to 2 years ]
   Not included in this analysis are pregnancies due to subject failure eg. non-compliance with tablet intake rules.
5. Adjusted Pearl Index [ Time Frame: 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.

Secondary Outcome Measures :

1. Number of Days With Bleeding Excluding Spotting [ Time Frame: 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.
2. Number of Bleeding Days During One Year of Treatment in Subjects With at Least 248 Days of Exposure Normalized to 372 Days [ Time Frame: 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.
3. Number of Bleeding / Spotting Days by 90-day Reference Period [ Time Frame: 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.
4. Number of Bleeding / Spotting Episodes in 90 Day Reference Period [ Time Frame: Up to one year ]
   The mean number of bleeding / spotting episodes was analyzed using reference periods of 90 days as recommended by the WHO.
5. Days With Scheduled Versus Unscheduled Bleeding [ Time Frame: 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.

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 35 Years (Adult)
Sexes Eligible for Study:	Female
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

• Healthy women who desire contraception
• smokers ≤ 30 Years old

Exclusion Criteria:

• Contraindication against use of hormonal contraceptives

Contacts and Locations

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Locations

Canada, Quebec
Drummondville, Quebec, Canada, J2B 1H8
Montreal, Quebec, Canada, H1T 1P6
Pointe-Claire, Quebec, Canada, H9R 4S3
Shawinigan, Quebec, Canada, G9N 2H6
Ste-Foy, Quebec, Canada, G1V 4X7
Canada
Quebec, Canada, G1S 2L6
Germany
Ettlingen, Baden-Württemberg, Germany, 76275
Karlsruhe, Baden-Württemberg, Germany, 76199
Ansbach, Bayern, Germany, 91522
Krumbach, Bayern, Germany, 86381
Nürnberg, Bayern, Germany, 90491
Dietzenbach, Hessen, Germany, 63128
Frankfurt, Hessen, Germany, 60322
Frankfurt, Hessen, Germany, 60439
Frankfurt, Hessen, Germany, 65929
Frankfurt, Hessen, Germany, 65936
Mühlheim, Hessen, Germany, 63165
Bovenden, Niedersachsen, Germany, 37120
Hannover, Niedersachsen, Germany, 30459
Osnabrück, Niedersachsen, Germany, 49074
Bernburg, Sachsen-Anhalt, Germany, 06406
Jessen, Sachsen-Anhalt, Germany, 06917
Magdeburg, Sachsen-Anhalt, Germany, 39104
Magdeburg, Sachsen-Anhalt, Germany, 39126
Magdeburg, Sachsen-Anhalt, Germany, 39130
Wurzen, Sachsen, Germany, 04808
Gera, Thüringen, Germany, 07545
Jena, Thüringen, Germany, 07747
Kahla, Thüringen, Germany, 07768
Berlin, Germany, 10115
Berlin, Germany, 10247
Berlin, Germany, 12435
Berlin, Germany, 13187
Hamburg, Germany, 21073
Netherlands
Groningen, Netherlands, 9713 GZ

Sponsors and Collaborators

Bayer

Investigators

Study Director:	Bayer Study Director	Bayer

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:

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Publications of Results:

Klipping C, Duijkers I, Fortier MP, Marr J, Trummer D, Elliesen J. Long-term tolerability of ethinylestradiol 20 μg/drospirenone 3 mg in a flexible extended regimen: results from a randomised, controlled, multicentre study. J Fam Plann Reprod Health Care. 2012 Apr;38(2):84-93. doi: 10.1136/jfprhc-2011-100214.

Klipping C, Duijkers I, Fortier MP, Marr J, Trummer D, Elliesen J. Contraceptive efficacy and tolerability of ethinylestradiol 20 μg/drospirenone 3 mg in a flexible extended regimen: an open-label, multicentre, randomised, controlled study. J Fam Plann Reprod Health Care. 2012 Apr;38(2):73-83. doi: 10.1136/jfprhc-2011-100213.

Reif S, Snelder N, Blode H. Characterisation of the pharmacokinetics of ethinylestradiol and drospirenone in extended-cycle regimens: population pharmacokinetic analysis from a randomised Phase III study. J Fam Plann Reprod Health Care. 2013 Apr;39(2):e1-13. doi: 10.1136/jfprhc-2012-100397.

Responsible Party:	Bayer
ClinicalTrials.gov Identifier:	NCT00266032 History of Changes
Other Study ID Numbers:	91450; 2005-002125-32 ( EudraCT Number ); 308683 ( Other Identifier: Company Internal )
First Posted:	December 15, 2005
Results First Posted:	March 3, 2010
Last Update Posted:	November 3, 2014
Last Verified:	October 2014

Additional relevant MeSH terms:

Estradiol; Polyestradiol phosphate; Ethinyl Estradiol; Drospirenone; Estradiol 3-benzoate; Estradiol 17 beta-cypionate; Estradiol valerate; Contraceptive Agents; Contraceptives, Oral; Betadex; Estrogens; Hormones	Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Reproductive Control Agents; Contraceptive Agents, Female; Mineralocorticoid Receptor Antagonists; Hormone Antagonists; Diuretics, Potassium Sparing; Diuretics; Natriuretic Agents; Sequestering Agents; Molecular Mechanisms of Pharmacological Action