Safety Study of Ethinylestradiol/Drospirenone in Dysmenorrhea

Study Overview
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Brief Summary
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The purpose of this study is to investigate efficacy of ethinylestradiol for intracyclic bleeding profile in patients with dysmenorrhea and to investigate the long term safety

Detailed Description
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The drospirenone 3 mg/ethinylestradiol 20 μg (13 cycles) group is to be treated by oral administration for 52 weeks, 13 cycles. The drospirenone 3 mg/ethinylestradiol 30 μg (6 cycles) group is to be treated by oral administration for 24 weeks, 6 cycles. The trial is sponsored by Bayer Yakuhin, Ltd.

Official Title
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A Multicenter, Single-blind, Randomized Study, to Investigate Efficacy of Ethinylestradiol for Intracyclic Bleeding Profile During 24 Weeks (6 Cycles) by Oral Administration of Drospirenone 3 mg/Ethinylestradiol 20 µg and Drospirenone 3 mg/ Ethinylestradiol 30 µg in Patients With Dysmenorrheal and to Investigate the Long Term Safety Oral Administration of Drospirenone 3 mg/Ethinylestradiol 20 µg Administered for 52 Weeks (13 Cycles)

Conditions
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Dysmenorrhea

Intervention / Treatment
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* Drug: DRSP 3 mg/EE 20 µg (13 cycles)
* Drug: DRSP 3 mg/EE 30 µg (6 cycles)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged 20 years or older at obtaining informed consent Patients having the normal menstrual cycle (25 to 38 days) in the latest two menses before the final enrollment Patients having a total dysmenorrheal score of at least 3 points in twice of the latest menstruation before the final enrollment Exclusion Criteria: Patients with ovarian chocolate cysts Patients with fibroid needed to be treated Patients with estrogen-dependent tumors and patients with cervical cancer or suspected cervical cancer Patients with undiagnosed abnormal vaginal bleeding Patients with thrombophlebitis, pulmonary embolism, cerebrovascular disease, or coronary artery disease or a history of those diseases Patients aged 35 years or older who smoke at least 15 cigarettes per day Patients with migraine accompanied by prodromata Patients with pulmonary hypertension or valvular heart disease Patients who are regularly taking nutritional products that contain St. John's Wort Patients who underwent surgical treatment for endometriosis within 2 months prior to screening Patients who may need to regularly use analgesics for therapeutic objectives other than relief from the pain of dysmenorrhea during this study (occasional use permitted)

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DRSP 3 mg/EE 20 µg (13 cycles)<br>1 tablet per day Drospirenone (DRSP) 3 mg/Ethinylestradiol (EE) 20 µg for 24 days and 1 tablet per day placebo for 4 days in each 28-day cycle; treatment duration 52 weeks (13 cycles) | Drug: DRSP 3 mg/EE 20 µg (13 cycles)<br>* 1 tablet per day Drospirenone (DRSP) 3 mg/Ethinylestradiol (EE) 20 µg for 24 days and 1 tablet per day placebo for 4 days in each 28-day cycle; treatment duration 52 weeks (13 cycles)<br>|
| Experimental: DRSP 3 mg/EE 30 µg (6 cycles)<br>1 tablet per day Drospirenone 3 mg/Ethinylestradiol 30 µg for 24 days and 1 tablet per day placebo for 4 days in each 28-day cycle; treatment duration 24 weeks (6 cycles) | Drug: DRSP 3 mg/EE 30 µg (6 cycles)<br>* 1 tablet per day Drospirenone 3 mg/Ethinylestradiol 30 µg for 24 days and 1 tablet per day placebo for 4 days in each 28-day cycle; treatment duration 24 weeks (6 cycles)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Intracyclic Bleeding at Cycle 6 | Intracyclic bleedings were defined as bleedings while a participant takes active tablets. | Up to Cycle 6 (168 days) with 28 days per cycle | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a Change in Total Dysmenorrhea Score From Baseline to Cycle 6 | Total dysmenorrheal score was defined as sum of 2 sub-scores: severity of dysmenorrhea (none: 0, mild: 1, moderate: 2, severe: 3) and use of analgesics (none: 0, mild: 1, moderate: 2, severe: 3). Note: used with permission of Nobelpharma Co., Ltd. from the phase 3 clinical study protocol of IKH-01 in dysmenorrhea (associated with endometriosis) (Nobelpharma Co., Ltd.). Changed total dysmenorrheal scores: -6 to -1 mean improvement, 1 to 6 mean worsening, 0 means no change. | From baseline up to Cycle 6 (168 days) with 28 days per cycle | 
| Number of Participants With a Change in Total Dysmenorrhea Score From Baseline to Cycle 13 | Total dysmenorrheal score was defined as sum of 2 sub-scores: severity of dysmenorrhea (none: 0, mild: 1, moderate: 2, severe: 3) and use of analgesics (none: 0, mild: 1, moderate: 2, severe: 3). Note: used with permission of Nobelpharma Co., Ltd. from the phase 3 clinical study protocol of IKH-01 in dysmenorrhea (associated with endometriosis) (Nobelpharma Co., Ltd.). Changed total dysmenorrheal scores: -6 to -1 mean improvement, 1 to 6 mean worsening, 0 means no change. | From baseline up to Cycle 13 (364 days) with 28 days per cycle | 
| Distribution of Total Dysmenorrhea Score at Cycle 6 | Total dysmenorrhea score was defined as sum of 2 sub-scores: severity of dysmenorrhea and use of analgesics. Higher score means it is more severe. 0=None, 6=Severest. | Up to Cycle 6 (168 days) with 28 days per cycle | 
| Distribution of Total Dysmenorrhea Score at Cycle 13 | Total dysmenorrhea score was defined as sum of 2 sub-scores: severity of dysmenorrhea and use of analgesics. Higher score means it is more severe. 0=None, 6=Severest. | Up to Cycle 13 (364 days) with 28 days per cycle | 
| Distribution of Severity of Lower Abdominal Pain During Menstruation at Cycle 6 | Severity of lower abdominal pain during menstruation was rated as none (none), mild (can be easily tolerated), moderate (noticeable, but does not interfere with daily activities), or severe (interferes with daily activities). | Up to Cycle 6 (168 days) with 28 days per cycle | 
| Distribution of Severity of Lower Abdominal Pain During Menstruation at Cycle 13 | Severity of lower abdominal pain during menstruation was rated as none (none), mild (can be easily tolerated), moderate (noticeable, but does not interfere with daily activities), or severe (interferes with daily activities). | Up to Cycle 13 (364 days) with 28 days per cycle | 
| Distribution of Severity of Lumbago During Menstruation at Cycle 6 | Severity of lumbago during menstruation was rated as none (none), mild (can be easily tolerated), moderate (noticeable, but does not interfere with daily activities), or severe (interferes with daily activities). | Up to Cycle 6 (168 days) with 28 days per cycle | 
| Distribution of Severity of Lumbago During Menstruation at Cycle 13 | Severity of lumbago during menstruation was rated as none (none), mild (can be easily tolerated), moderate (noticeable, but does not interfere with daily activities), or severe (interferes with daily activities). | Up to Cycle 13 (364 days) with 28 days per cycle | 
| Distribution of Severity of Headache During Menstruation at Cycle 6 | Severity of headache during menstruation was rated as none (none), mild (can be easily tolerated), moderate (noticeable, but does not interfere with daily activities), or severe (interferes with daily activities). | Up to Cycle 6 (168 days) with 28 days per cycle | 
| Distribution of Severity of Headache During Menstruation at Cycle 13 | Severity of headache during menstruation was rated as none (none), mild (can be easily tolerated), moderate (noticeable, but does not interfere with daily activities), or severe (interferes with daily activities). | Up to Cycle 13 (364 days) with 28 days per cycle | 
| Distribution of Severity of Nausea or Vomiting During Menstruation at Cycle 6 | Severity of nausea or vomiting during menstruation was rated as none (none), mild (can be easily tolerated), moderate (noticeable, but does not interfere with daily activities), or severe (interferes with daily activities). | Up to Cycle 6 (168 days) with 28 days per cycle | 
| Distribution of Severity of Nausea or Vomiting During Menstruation at Cycle 13 | Severity of nausea or vomiting during menstruation was rated as none (none), mild (can be easily tolerated), moderate (noticeable, but does not interfere with daily activities), or severe (interferes with daily activities). | Up to Cycle 13 (364 days) with 28 days per cycle | 
| Number of Participants With a Total Pelvic Pain Score of 0 up to 6 at Times Other Than During Menstruation at Cycle 6 | Total pelvic pain score was defined as sum of 2 sub-scores: severity of dysmenorrhea and use of analgesics. Higher score means it is more severe. 0=None, 6=Severest. | Up to Cycle 6 (168 days) with 28 days per cycle | 
| Number of Participants With a Total Pelvic Pain Score of 0 up to 6 at Times Other Than During Menstruation at Cycle 13 | Total pelvic pain score was defined as sum of 2 sub-scores: severity of dysmenorrhea and use of analgesics. Higher score means it is more severe. 0=None, 6=Severest. | Up to Cycle 13 (364 days) with 28 days per cycle | 
| Change in Visual Analogue Scale (VAS) for Dysmenorrhea at Times Other Than During Menstruation From Baseline to Cycle 6 | VAS is an unmarked scale on a line 100 mm in length, indicating from 0 mm (no pain) to 100 mm (worst pain a participant has ever experienced). | From baseline up to Cycle 6 (168 days) with 28 days per cycle | 
| Change in Visual Analogue Scale (VAS) for Dysmenorrhea at Times Other Than During Menstruation From Baseline to Cycle 13 | VAS is an unmarked scale on a line 100 mm in length, indicating from 0 mm (no pain) to 100 mm (worst pain a participant has ever experienced). | From baseline up to Cycle 13 (364 days) with 28 days per cycle | 
| Change in Visual Analogue Scale (VAS) for Pelvic Pain at Times Other Than During Menstruation From Baseline to Cycle 6 | VAS is an unmarked scale on a line 100 mm in length, indicating from 0 mm (no pain) to 100 mm (worst pain a participant has ever experienced). | From baseline up to Cycle 6 (168 days) with 28 days per cycle | 
| Change in Visual Analogue Scale (VAS) for Pelvic Pain at Times Other Than During Menstruation From Baseline to Cycle 13 | VAS is an unmarked scale on a line 100 mm in length, indicating from 0 mm (no pain) to 100 mm (worst pain a participant has ever experienced). | From baseline up to Cycle 13 (364 days) with 28 days per cycle | 
| Number of Any Bleeding Episodes From Cycle 1 to Cycle 6 | Vaginal bleeding was rated as none, spotting, light, normal, or heavy based on the participant's experience. A reference period is about 3 cycles (90 days): reference period 1 is from Cycle 1 to Cycle 3 (the 1st 90 days), reference period 2 is from Cycle 4 to Cycle 6 (the 2nd 90 days). | Up to Cycle 6 (168 days) with 28 days per cycle | 
| Number of Any Bleeding Episodes From Cycle 1 to Cycle 13 | Vaginal bleeding was rated as none, spotting, light, normal, or heavy based on the participant's experience. A reference period is about 3 cycles (90 days): reference period 1 is from Cycle 1 to Cycle 3 (the 1st 90 days), reference period 2 is from Cycle 4 to Cycle 6 (the 2nd 90 days), reference period 3 is from Cycle 7 to Cycle 9 (the 3rd 90 days), reference period 4 is from Cycle 10 to Cycle 12 (the 4th 90 days). | Up to Cycle 13 (364 days) with 28 days per cycle | 
| Number of Any Bleeding Days From Cycle 1 to Cycle 6 | Vaginal bleeding was rated as none, spotting, light, normal, or heavy based on the participant's experience. A reference period is about 3 cycles (90 days): reference period 1 is from Cycle 1 to Cycle 3 (the 1st 90 days), reference period 2 is from Cycle 4 to Cycle 6 (the 2nd 90 days). | Up to Cycle 6 (168 days) with 28 days per cycle | 
| Number of Any Bleeding Days From Cycle 1 to Cycle 13 | Vaginal bleeding was rated as none, spotting, light, normal, or heavy based on the participant's experience. A reference period is about 3 cycles (90 days): reference period 1 is from Cycle 1 to Cycle 4 (the 1st 90 days), reference period 2 is from Cycle 4 to Cycle 6 (the 2nd 90 days), reference period 3 is from Cycle 7 to Cycle 9 (the 3rd 90 days), reference period 4 is from Cycle 10 to Cycle 12 (the 4th 90 days). | Up to Cycle 13 (364 days) with 28 days per cycle | 
| Number of Participants With Intracyclic Bleeding From Cycle 1 to Cycle 6 | Intracyclic bleedings were defined as bleedings while a participant takes active tablets. | Up to Cycle 6 (168 days) with 28 days per cycle | 
| Number of Participants With Intracyclic Bleeding From Cycle 1 to Cycle 13 | Intracyclic bleedings were defined as bleedings while a participant takes active tablets. | Up to Cycle 13 (364 days) with 28 days per cycle | 
| Number of Participants With Withdrawal Bleeding From Cycle 1 to Cycle 6 | Withdrawal bleedings were defined as bleedings while a participant takes placebo tablets. | Up to Cycle 6 (168 days) with 28 days per cycle | 
| Number of Participants With Withdrawal Bleeding From Cycle 1 to Cycle 13 | Withdrawal bleedings were defined as bleedings while a participant takes placebo tablets. | Up to Cycle 13 (364 days) with 28 days per cycle | 
| Percentage of Participants With Non-heavy Intracyclic Bleeding From Cycle 1 to Cycle 6 | Non-heavy bleeding was defined as those other than heavy bleeding (i.e. spotting, light, or normal bleeding). | Up to Cycle 6 (168 days) with 28 days per cycle | 
| Percentage of Participants With Non-heavy Intracyclic Bleeding From Cycle 1 to Cycle 13 | Non-heavy bleeding was defined as those other than heavy bleeding (i.e. spotting, light, or normal bleeding). | Up to Cycle 13 (364 days) with 28 days per cycle | 
| Percentage of Participants With Non-heavy Withdrawal Bleeding From Cycle 1 to Cycle 6 | Non-heavy bleeding was defined as those other than heavy bleeding (i.e. spotting, light, or normal bleeding). | Up to Cycle 6 (168 days) with 28 days per cycle | 
| Percentage of Participants With Non-heavy Withdrawal Bleeding From Cycle 1 to Cycle 13 | Non-heavy bleeding was defined as those other than heavy bleeding (i.e. spotting, light, or normal bleeding). | Up to Cycle 13 (364 days) with 28 days per cycle | 
| Change in Serum Carbohydrate Antigen-125 (CA-125) From Baseline to Cycle 6 | CA125 is a laboratory parameter giving an indication of having tumor, whose elevated levels that were defined by a lab suggest a potential tumor. | From baseline up to Cycle 6 (168 days) with 28 days per cycle | 
| Change in Serum CA-125 From Baseline to Cycle 13 | CA125 is a laboratory parameter giving an indication of having tumor, whose elevated levels that were defined by a lab suggest a potential tumor. | From baseline up to Cycle 13 (364 days) with 28 days per cycle | 
| Change in Serum C-reactive Protein (CRP) From Baseline to Cycle 6 | CRP is a laboratory parameter giving an indication of inflammation, whose elevated level suggests a potential inflammation. | From baseline up to Cycle 6 (168 days) with 28 days per cycle | 
| Change in Serum CRP From Baseline to Cycle 13 | CRP is a laboratory parameter giving an indication of inflammation, whose elevated level suggests a potential inflammation. | From baseline up to Cycle 13 (364 days) with 28 days per cycle | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dysmenorrhea, Intracyclic bleeding, Drospirenone (DRSP), Ethinylestradiol