SH T00186 Phase II/ III Optimal Drospirenone (DRSP) Dose Finding and Placebo-controlled Comparative Study

Study Overview
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Brief Summary
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The purpose of this study is to investigate efficacy of drospirenone for dysmenorrhea.

Official Title
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A Multicenter, Double-blind, Randomized, Placebo-controlled Comparative Study to Investigate the Optimal Dose of Drospirenone for Dysmenorrhea With SH T04740A [Drospirenone 1 mg/Ethinylestradiol 20 µg (as ß-cyclodextrin Clathrate)], SH T 04740E [Drospirenone 2 mg/Ethinylestradiol 20 µg (as ß-cyclodextrin Clathrate)] and SH T00186D [Drospirenone 3 mg/ Ethinylestradiol 20 µg (as ß-cyclodextrin Clathrate)] Administered Orally for 16 Weeks (4 Cycles), and to Confirm the Efficacy of SH T00186D for Dysmenorrhea.

Conditions
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Dysmenorrhea

Intervention / Treatment
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* Drug: SH T04740B
* Drug: SH T00186DF
* Drug: SH T04740F
* Drug: Placebo


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 (28+/-3 days) in the latest two menses before the final enrollment Patients having a total dysmenorrhea score of at least 3 points in two menstrual cycles before the final enrollment Exclusion Criteria: Patients with ovarian chocolate cysts and symptomatic uterine fibroids (as defined in greater detail in the study protocol) Patients with estrogen-dependent tumors (e.g. breast cancer, cancer of the uterine body or breast fibrocystic, etc.), and patients with cervical cancer or suspected cervical cancer (e.g. class III or greater in the cervical smear or endometrial smear examination.) Patients with undiagnosed abnormal vaginal bleeding Patients with thrombophlebitis, pulmonary embolism, cerebrovascular disease(including transient ischemic attack, etc.), or coronary artery disease(e.g. myocardial infarction and angina pectoris, etc.), 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 prodrome (e.g. scintillating scotoma or star-shaped scintillation) Patients with pulmonary hypertension or valvular heart disease complicated by atrial fibrillation, and patients with a history of subacute bacterial endocarditis Patients who are regularly taking nutritional products that contain St. John's Wort Patients who underwent surgical treatment for endometriosis by laparotomy, or laparoscopy within 2 months prior to screening Patients who need to use analgesics regularly 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DRSP 1 mg/EE 20 μg<br>1 tablet per day Drospirenone (DRSP) 1 mg/Ethinylestradiol (EE) 20 μg for 24 days and 1 tablet per day placebo for 4 days in each 28-day cycle | Drug: SH T04740B<br>* Drospirenone 1mg/EE 20µg (ß-CDC)<br>|
| Experimental: DRSP 2 mg/EE 20 μg<br>1 tablet per day Drospirenone (DRSP) 2 mg/Ethinylestradiol (EE) 20 μg for 24 days and 1 tablet per day placebo for 4 days in each 28-day cycle | Drug: SH T04740F<br>* Drospirenone 2 mg/EE 20µg (ß-CDC)<br>|
| Experimental: DRSP 3 mg/EE 20 μg<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 | Drug: SH T00186DF<br>* Drospirenone 3 mg/EE 20µg (ß-CDC)<br>|
| Placebo Comparator: Placebo<br>1 tablet per day placebo for 28 days in each 28-day cycle | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Total Dysmenorrheal Score at Final Evaluation | 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). Total possible best is 0, and total possible worst is 6. Note: used with permission of Nobelpharma Co., Ltd. from the phase 3 clinical study protocol (Prog Med 2005:25 (3):739-758) of IKH-01 in dysmenorrhea (associated with endometriosis) (Nobelpharma Co., Ltd.) | Baseline and up to 4 Cycles (28 days per cycle) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Total Dysmenorrheal Score at Cycle 1 up to Cycle 4 | 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). Total possible best is 0, and total possible worst is 6. | Baseline and up to 4 Cycles (28 days per cycle) | 
| Number of Participants With Severity of Lower Abdominal Pain During Menstruation at Cycle 4 | 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). | Cycle 4 (28 days per cycle) | 
| Number of Participants With Severity of Low Back Pain During Menstruation at Cycle 4 | Severity of low back 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). | Cycle 4 (28 days per cycle) | 
| Number of Participants With Severity of Headache During Menstruation at Cycle 4 | 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). | Cycle 4 (28 days per cycle) | 
| Number of Participants With Severity of Nausea or Vomiting During Menstruation at Cycle 4 | 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). | Cycle 4 (28 days per cycle) | 
| Number of Participants With Total Pelvic Pain Score at Times Other Than During Menstruation at Cycle 4 | 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. | Cycle 4 (28 days per cycle) | 
| Change From Baseline in Visual Analogue Scale (VAS) for Dysmenorrhea at Times Other Than During Menstruation at Cycle 4 | 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 4 (28 days per cycle) | 
| Visual Analogue Scale (VAS) for Pelvic Pain at Times Other Than During Menstruation at Cycle 4 | 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). | Cycle 4 (28 days per cycle) | 
| Change From Baseline in Endometrial Thickness After 4-cycle Treatment | Endometrial thickness was measured via transvaginal ultrasound examination. The endometrium is the inner membrane of the uterus. During the menstrual cycle, the endometrium grows to a thick, blood vessel-rich, glandular tissue layer. | From baseline to Cycle 4 (28 days per cycle) | 
| Number of Bleeding / Spotting Episodes | Bleeding data were captured from the diary a participant recorded by herself. Bleeding is a genital bleeding. Spotting is a slight genital bleeding with participant's experience. An episode means a series of bleeding and/or spotting. The bleeding /spotting analyses are by intensity. | For the first 90 days | 
| Number of Bleeding / Spotting Days | Bleeding data were captured from the diary a participant recorded by herself. Bleeding is a genital bleeding. Spotting is a slight genital bleeding with participant's experience. The bleeding /spotting analyses are by intensity. | For the first 90 days | 
| Participants With Withdrawal Bleeding | Withdrawal bleedings were defined as bleedings while a participant takes placebo tablets. | At Cycle 4 (28 days per cycle) | 
| Participants With Intracyclic Bleeding | Intracyclic bleedings were defined as bleedings while a participant takes active drugs. | At Cycle 4 (28 days per cycle) | 
| Participants With Non-heavy Intracyclic Bleeding | Non-heavy bleedings were defined as those other than heavy bleeding (less or normal bleeding). | At Cycle 4 (28 days per cycle) | 
| Participants With Non-heavy Withdrawal Bleeding | Non-heavy bleedings were defined as those other than heavy bleeding (less or normal bleeding). | At Cycle 4 (28 dyas per cycle) | 
| Change From Baseline in Serum Carbohydrate Antigen-125 (CA125) After 4-cycle Treatment | 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 to Cycle 4 (28 days per cycle) | 
| Change From Baseline in Serum C-reactive Protein (CRP) After 4-cycle Treatment | CRP is a laboratory parameter giving an indication of inflammation, whose elevated levels that were defined by a lab suggest a potential inflammation. | From baseline to Cycle 4 (28 days per cycle) | 
| Change From Baseline in Serum Estradiol Level After 4-cycle Treatment | Estradiol is a predominant sex hormone that presents in female. | From baseline to Cycle 4 (28 days per cycle) | 
| Change From Baseline in Serum Progesterone Level at Cycle 4 | Progesterone is a steroid hormone involving in the female menstrual cycle, pregnancy, etc. | From baseline to Cycle 4 (28 days per cycle) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dysmenorrhea, Dysmenorrheal score, Drospirenone, DRSP, Ethinylestradiol