A Survey on Efficacy and Safety in Patients With Endometriosis

Study Overview
=================
Brief Summary
-----------------
This survey is intended to collect efficacy and safety data of Duphaston® Tablets in patients with endometriosis under actual condition of its use and to obtain data for effectively and safely utilizing this drug.

Detailed Description
-----------------
In Japan, Duphaston® Tablets have appeared in 1965 for the treatment of endometriosis and been used at some medical institutions. However, after releasing of danazol in the early 1980's and gonadotropin-releasing hormone (GnRH) agonists in the late 1980's, pseudomenopause therapy became mainstream because of its high efficacy. However, pseudopregnancy therapy was recognized again due to adverse reactions associated with pseudomenopause therapy. After 2000, low-dose estrogen/progestin (LEP) combination drugs (as LEP products, ethinylestradiol/norethisterone combination drug and ethinylestradiol/drospirenone combination drug) and dienogest have been utilized as drugs that are safer and can be administered for a long time. In recent years, Duphaston® Tablets are increasing recognized again from the viewpoints of its efficacy and safety because the drug has no effect to inhibit ovulation or effect on basal body temperature, a diagnosis of ovulation and other conditions may be made by following up basal body temperature, and pregnancy may be achieved even during treatment with Duphaston. As previously mentioned, Duphaston® Tablets are an old drug, and there are only few clinical data from Japanese patients; thus, its latest clinical efficacy and safety data are being demanded again mainly by obstetrician-gynecologists.

Official Title
-----------------
Duphaston® Tablets 5 mg - A Survey on Efficacy and Safety in Patients With Endometriosis

Conditions
-----------------
Endometriosis

Intervention / Treatment
-----------------
* Drug: Dydrogesterone


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Women aged 20 to < 50 years Subjects with a chocolate cyst of the ovary measuring 3 cm in diameter on transvaginal ultrasonography at patient enrollment Subjects with a menstrual cycle of 25 to 38 days who ovulate and are confirmed to have normal menstruation at patient enrollment Exclusion Criteria: Subjects who used GnRH agonists within 6 months before patient enrollment Subjects who utilized hormone preparations containing corpus luteum hormone or estrogen as an active ingredient, low-dose contraceptive pills, middle-dose contraceptive pills, testosterone derivatives, or herbal products indicated for endometriosis within 3 months before patient enrollment Subjects who received surgical treatment for endometriosis such as transvaginal alcohol fixation, laparotomy or laparoscopic surgery within 2 months before patient enrollment Subjects who are pregnant or may possibly be pregnant at patient enrollment Subjects who are in breast feeding at patient enrollment Subjects who are determined by the investigator/subinvestigator to be not suitable for the subjects of the survey because of other reasons Subjects with liver disorder or liver disease Subjects with known hypersensitivity to the active substance or to any of the excipients Subjects with known or suspected progestogen dependent neoplasms (e.g. meningioma) Subjects with undiagnosed vaginal bleeding Subjects with a past or current history of heart or kidney disease Subjects with porphyria Subjects with depression Subjects with abnormal liver function values caused by acute or chronic liver disease Subjects with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucosegalactose malabsorption

Ages Eligible for Study
-----------------
Minimum Age: 20 Years
Maximum Age: 49 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Dydrogesterone<br>Dydrogesterone 20 mg (4 tablets) per day should be orally administered in 2 divided doses (in the morning and evening). It should be administered for 21 days; dosage starts on the 5th day of each menstrual cycle until 25th day. The administration period will be from the start of Duphaston treatment (cycle 1) to cycle 4. | Drug: Dydrogesterone<br> <br> * Other names: Duphaston;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Volume of Ovarian Chocolate Cyst (If There Are Two or More Cysts, a Total Volume) | In measurement of ovarian chocolate cyst, on a section visualizing the maximum diameter, two radial directions, namely the maximum diameter (D1) and maximum diameter (D2) orthogonal to D1, will be measured. A chocolate cyst of the ovary will be deemed as a spheroid, and its volume will be calculated using the following formula: [(D1 + D2) × 1/2]3 × 0.52 (π = 3.1). If there are two or more chocolate cysts of the ovary, similarly, two radial directions (D1 and D2) of each cyst will be measured. Also, each of their volumes will be calculated in the same manner. The change rate within ±15% from the total volume measured before treatment was defined as unchanged, and the rate out of this range was defined as decreased or increased. | Before treatment initiation (baseline), 3 months, and 5 months. | 
| Volume of Ovarian Chocolate Cyst Over Time (If There Are Two or More Cysts, a Total Volume) | In measurement of ovarian chocolate cyst, on a section visualizing the maximum diameter, two radial directions, namely the maximum diameter (D1) and maximum diameter (D2) orthogonal to D1, will be measured. A chocolate cyst of the ovary will be deemed as a spheroid, and its volume will be calculated using the following formula: [(D1 + D2) × 1/2]3 × 0.52 (π = 3.1). If there are two or more chocolate cysts of the ovary, similarly, two radial directions (D1 and D2) of each cyst will be measured. Also, each of their volumes will be calculated in the same manner. | Before treatment initiation (baseline), 3 months, and 5 months. | 
| Volume of Ovarian Chocolate Cyst Over Time (If There Are Two or More Cysts, a Total Volume), Absolute Change From Baseline | The absolute change from baseline were calculated on an individual basis and these were totalled and means ± SD calculated. For the mean value of the absolute changes shown here, the mean value of the absolute changes of the cases that could be measured at each time point is calculated. In other words, of the 57 cases with the volume value of baseline, Cycle 3 calculates the mean value of the absolute change in 39 cases with the volume value at this time, and Cycle 5 calculates the mean value of the absolute change in 40 cases with the volume value at this time. The remaining 18 cases are excluded from this calculation because there is no volume value for Cycle 3 and the absolute change from baseline cannot be calculated. The same applies to the 17 cases of Cycle 5. For this reason, these values cannot be calculated directly from the volume mean value at each time point shown in the result measurement 2. | Before treatment initiation (baseline), 3 months, and 5 months. | 
| Volume of Ovarian Chocolate Cyst Over Time (If There Are Two or More Cysts, a Total Volume), % Change From Baseline | The % change from baseline were calculated on an individual basis and these were totalled and means ± SD calculated. For the mean value of the % changes shown here, the mean value of the % changes of the cases that could be measured at each time point is calculated. In other words, of the 57 cases with the volume value of baseline, Cycle 3 calculates the mean value of the % change in 39 cases with the volume value at this time, and Cycle 5 calculates the mean value of the % change in 40 cases with the volume value at this time. The remaining 18 cases are excluded from this calculation because there is no volume value for Cycle 3 and the % change from baseline cannot be calculated. The same applies to the 17 cases of Cycle 5. For this reason, these values cannot be calculated directly from the volume mean value at each time point shown in the result measurement 2. | Before treatment initiation (baseline), 3 months, and 5 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change Over Time in Dysmenorrhea Score (Total of the Dysmenorrhea Severity Score and the Analgesic Use Score) | The dysmenorrhea score is the sum of the dysmenorrhea severity score and the analgesic use score. Shown as the mean value for the number of cases at each time point. A dysmenorrhea severity score is defined as follows. None: Score 0, Rarely interfering with work (study and house work): Score 1, Interfering with work (study and house work) requiring lying down to rest: Score 2, Being confined to bed for 1 day, being unable to work (study and house work): Score 3. A analgesic use score is defined as follows. None: Score 0, An analgesic was used for a day during the last (or current) menstruation period: Score 1, An analgesic was used for 2 days during the last (or current) menstruation period: Score 2, An analgesic was used for 3 days during the last (or current) menstruation period: Score 3 The minimum dysmenorrhea score is 0 and the maximum dysmenorrhea score is 6. | Baseline, 1 month, 2 months, 3 months, 4 months, and 5 months. | 
| Change Over Time in Visual Analogue Scale (VAS) for Dysmenorrhea | A straight line with a total length of 10 cm was prepared. This straight line was defined as no pain at the left end and Worst pain imaginable at the right end. The cases marked the degree of pain on this straight line at each time point, and the length (cm) from the left end of the line (0) was measured. The minimum value of VAS is 0 cm (no pain) and the maximum value is 10 cm (Worst pain imaginable). The units on a scale is cm. | Baseline, 1 month, 2 months, 3 months, 4 months, and 5 months. | 
| Change in Serum CA125 | CA-125 is a glycoprotein antigen recognized by the monoclonal antibody OC125 made against ovarian cancer cell cultures. Serum CA125 is commonly used as a tumor marker for ovarian cancer, and since it increases at a high rate in endometriosis, it has an aspect of being used as a diagnostic aid for endometriosis. There are many reports that the normal value of serum CA-125 is 35 U/mL or less. The test was performed during a non-menstruation period, as serum CA-125 levels are high during the menstrual period. | Baseline, and 5 months. | 
| Change Over Time in Dysmenorrhea Score (Total of the Dysmenorrhea Severity Score and the Analgesic Use Score), Difference From Baseline | The dysmenorrhea score is the sum of the dysmenorrhea severity score and the analgesic use score. The difference from baseline were calculated on an individual basis and these were totalled and means ± SD calculated. A dysmenorrhea severity score is defined as follows. None: Score 0, Rarely interfering with work (study and house work): Score 1, Interfering with work (study and house work) requiring lying down to rest: Score 2, Being confined to bed for 1 day, being unable to work (study and house work): Score 3. A score for the use of analgesics is defined as follows. None: Score 0, An analgesic was used for a day during the last (or current) menstruation period: Score 1, An analgesic was used for 2 days during the last (or current) menstruation period: Score 2, An analgesic was used for 3 days during the last (or current) menstruation period: Score 3 | Baseline, 1 month, 2 months, 3 months, 4 months, and 5 months. | 
| Change Over Time in Visual Analogue Scale (VAS) for Dysmenorrhea, Difference From Baseline | A straight line with a total length of 10 cm was prepared. This straight line was defined as no pain at the left end and Worst pain imaginable at the right end. The cases marked the degree of pain on this straight line at each time point, and the length (cm) from the left end of the line (0) was measured. The minimum value of VAS is 0 cm (no pain) and the maximum value is 10 cm (Worst pain imaginable). The units on a scale is cm. The difference from baseline were calculated on an individual basis and these were totalled and means ± SD calculated. | Baseline, 1 month, 2 months, 3 months, 4 months, and 5 months. | 
| Change Over Time in Visual Analogue Scale (VAS) for Dysmenorrhea, Change Rate From Baseline (%) | A straight line with a total length of 10 cm was prepared. This straight line was defined as no pain at the left end and Worst pain imaginable at the right end. The cases marked the degree of pain on this straight line at each time point, and the length (cm) from the left end of the line (0) was measured. The minimum value of VAS is 0 cm (no pain) and the maximum value is 10 cm (Worst pain imaginable). The change rate from baseline were calculated on an individual basis and these were totalled and means ± SD calculated. | Baseline, 1 month, 2 months, 3 months, 4 months, and 5 months. | 
| Change in Serum CA125, Difference From Baseline | The difference from baseline were calculated on an individual basis and these were totalled and means ± SD calculated. For the mean value of the difference shown here, the mean value of the difference of the cases that could be measured at each time point is calculated. In other words, of the 56 cases with baseline serum CA125, cycle 5 can only calculate the difference in 32 cases with serum CA125 at this point. The mean difference between cycle 5 and baseline in these 32 cases is shown here. The remaining 24 cases in Baseline are excluded from this calculation because they do not have serum CA125 measurements in Cycle 5. For this reason, these values cannot be calculated directly from the serum CA125 mean value at each time point shown in the result measurement 7. | Baseline, and 5 months. | 
| Change in Serum CA125, Change Rate From Baseline (%) | The change rate from baseline were calculated on an individual basis and these were totalled and means ± SD calculated. For the mean value of the change rate shown here, the mean value of the change rate of the cases that could be measured at each time point is calculated. In other words, of the 56 cases with baseline serum CA125, cycle 5 can only calculate the change rate in 32 cases with serum CA125 at this point. The mean change rate between cycle 5 and baseline in these 32 cases is shown here. The remaining 24 cases in baseline are excluded from this calculation because they do not have serum CA125 measurements in Cycle 5. For this reason, these values cannot be calculated directly from the serum CA125 mean value at each time point shown in the result measurement 7. | Baseline, and 5 months. |