Safety Study of Ethinylestradiol/Drospirenone in Dysmenorrhea

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)

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

Study Overview

• Status: Completed
• Conditions: Dysmenorrhea
• Intervention / Treatment: Drug: DRSP 3 mg/EE 20 µg (13 cycles); Drug: DRSP 3 mg/EE 30 µg (6 cycles)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 420
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Japan
  • Osaka, Japan, 530-0013
  • Osaka, Japan, 534-0014
  • Aichi
    • Nagoya, Aichi, Japan, 460-0007
    • Nagoya, Aichi, Japan, 460-0011
    • Nagoya, Aichi, Japan, 464-0066
  • Gunma
    • Maebashi, Gunma, Japan, 371-0024
    • Takasaki, Gunma, Japan, 370-0883
  • Hyogo
    • Kobe, Hyogo, Japan, 650-0021
    • Nishinomiya, Hyogo, Japan, 663-8204
  • Kanagawa
    • Yamato, Kanagawa, Japan, 242-0007
    • Yokohama, Kanagawa, Japan, 231-0861
  • Miyagi
    • Sendai, Miyagi, Japan, 980-0021
    • Sendai, Miyagi, Japan, 981-0933
    • Sendai, Miyagi, Japan, 984-0042
  • Osaka
    • Toyonaka, Osaka, Japan, 560-0022
  • Tokyo
    • Chuo-ku, Tokyo, Japan, 104-0061
    • Hachioji, Tokyo, Japan, 192-0046
    • Machida, Tokyo, Japan, 194-0022
    • Musashino, Tokyo, Japan, 180-0003
    • Ota-ku, Tokyo, Japan, 144-0052
    • Setagaya-ku, Tokyo, Japan, 157-0066
    • Setagaya-ku, Tokyo, Japan, 156-0042
    • Shibuya-ku, Tokyo, Japan, 150-0013
    • Shinagawa-ku, Tokyo, Japan, 140-0013
    • Suginami-ku, Tokyo, Japan, 167-0051
    • Toshima-ku, Tokyo, Japan, 171-0021

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: DRSP 3 mg/EE 20 µg (13 cycles); 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); 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)
Experimental: DRSP 3 mg/EE 30 µg (6 cycles); 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); 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)

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Bayer

Study record dates

Study Major Dates

• Study Start: February 1, 2007
• Primary Completion (Actual): January 1, 2009
• Study Completion (Actual): August 1, 2009

Study Registration Dates

• First Submitted: April 17, 2007
• First Submitted That Met QC Criteria: April 17, 2007
• First Posted (Estimate): April 18, 2007

Study Record Updates

• Last Update Posted (Estimate): January 24, 2013
• Last Update Submitted That Met QC Criteria: January 22, 2013
• Last Verified: January 1, 2013

More Information

Terms related to this study

• Keywords: Dysmenorrhea; Intracyclic bleeding; Drospirenone (DRSP); Ethinylestradiol
• Additional Relevant MeSH Terms: Pathologic Processes; Pain; Neurologic Manifestations; Menstruation Disturbances; Pelvic Pain; Dysmenorrhea; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Diuretics; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Drospirenone
• Other Study ID Numbers: 91616; 310284 (Other Identifier: Company Internal)