A Survey on Efficacy and Safety in Patients With Endometriosis

Sponsor
Mylan Inc. (Industry)
Overall Status
Completed
CT.gov ID
NCT02921763
Collaborator
(none)
60
15
13.7
4
0.3

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase

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.

Study Design

Study Type:
Observational [Patient Registry]
Actual Enrollment :
60 participants
Observational Model:
Cohort
Time Perspective:
Prospective
Official Title:
Duphaston® Tablets 5 mg - A Survey on Efficacy and Safety in Patients With Endometriosis
Actual Study Start Date :
Aug 23, 2016
Actual Primary Completion Date :
Sep 21, 2017
Actual Study Completion Date :
Oct 13, 2017

Arms and Interventions

Arm Intervention/Treatment
Dydrogesterone

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
Other Names:
  • Duphaston
  • Outcome Measures

    Primary Outcome Measures

    1. Change in the Volume of Ovarian Chocolate Cyst (If There Are Two or More Cysts, a Total Volume) [Before treatment initiation (baseline), 3 months, and 5 months.]

      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."

    2. Volume of Ovarian Chocolate Cyst Over Time (If There Are Two or More Cysts, a Total Volume) [Before treatment initiation (baseline), 3 months, and 5 months.]

      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.

    3. Volume of Ovarian Chocolate Cyst Over Time (If There Are Two or More Cysts, a Total Volume), Absolute Change From Baseline [Before treatment initiation (baseline), 3 months, and 5 months.]

      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.

    4. Volume of Ovarian Chocolate Cyst Over Time (If There Are Two or More Cysts, a Total Volume), % Change From Baseline [Before treatment initiation (baseline), 3 months, and 5 months.]

      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.

    Secondary Outcome Measures

    1. Change Over Time in Dysmenorrhea Score (Total of the Dysmenorrhea Severity Score and the Analgesic Use Score) [Baseline, 1 month, 2 months, 3 months, 4 months, and 5 months.]

      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.

    2. Change Over Time in Visual Analogue Scale (VAS) for Dysmenorrhea [Baseline, 1 month, 2 months, 3 months, 4 months, and 5 months.]

      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".

    3. Change in Serum CA125 [Baseline, and 5 months.]

      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.

    4. Change Over Time in Dysmenorrhea Score (Total of the Dysmenorrhea Severity Score and the Analgesic Use Score), Difference From Baseline [Baseline, 1 month, 2 months, 3 months, 4 months, and 5 months.]

      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

    5. Change Over Time in Visual Analogue Scale (VAS) for Dysmenorrhea, Difference From Baseline [Baseline, 1 month, 2 months, 3 months, 4 months, and 5 months.]

      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.

    6. Change Over Time in Visual Analogue Scale (VAS) for Dysmenorrhea, Change Rate From Baseline (%) [Baseline, 1 month, 2 months, 3 months, 4 months, and 5 months.]

      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.

    7. Change in Serum CA125, Difference From Baseline [Baseline, and 5 months.]

      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.

    8. Change in Serum CA125, Change Rate From Baseline (%) [Baseline, and 5 months.]

      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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    20 Years to 49 Years
    Sexes Eligible for Study:
    Female
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Mylan Investigational Site G Tokyo Chiyodaku Japan 101-0062
    2 Mylan Investigational Site N Tokyo Chuouku Japan 104-8560
    3 Mylan Investigational Site C Kyoto Fushimiku Japan 612-0064
    4 Mylan Investigational Site D Saitama Iwatsukiku Japan 339-0057
    5 Mylan Investigational Site M Okayama Kurashikishi Japan 710-0824
    6 Mylan Investigational Site H Kyoto Kyotanabeshi Japan 610-0357
    7 Mylan Investigational Site A Kamigyo-ku Kyoto Japan 602-8566
    8 Mylan Investigational Site I Kyoto Nakagyoku Japan 604-0965
    9 Mylan Investigational Site K Kyoto Nakagyoku Japan 604-8381
    10 Mylan Investigational Site F Kyoto Nakagyoku Japan 604-8453
    11 Mylan Investigational Site J Tokyo Shibuyaku Japan 151-0051
    12 Mylan Investigational Site B Bunkyō Tokyo Japan 113-8655
    13 Mylan Investigational Site E Kyoto Ukyouku Japan 615-0883
    14 Mylan Investigational Site L Kyoto Yosanocho Japan 629-2261
    15 Mylan Investigational Site O Tokushima Japan 770-8503

    Sponsors and Collaborators

    • Mylan Inc.

    Investigators

    • Principal Investigator: Jo Kitawaki, MD., PhD., Kyoto Prefectural University of Medicine

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Mylan Inc.
    ClinicalTrials.gov Identifier:
    NCT02921763
    Other Study ID Numbers:
    • DUPKST16002
    First Posted:
    Oct 3, 2016
    Last Update Posted:
    Jul 6, 2022
    Last Verified:
    Jun 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Undecided
    Plan to Share IPD:
    Undecided
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Dydrogesterone
    Arm/Group Description 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. Dydrogesterone
    Period Title: Overall Study
    STARTED 60
    COMPLETED 42
    NOT COMPLETED 18

    Baseline Characteristics

    Arm/Group Title Dydrogesterone
    Arm/Group Description 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. Dydrogesterone
    Overall Participants 59
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    37.1
    (7.0)
    Age, Customized (Count of Participants)
    >= 20 and < 30 years old
    11
    18.6%
    >= 30 and < 40 years old
    21
    35.6%
    >= 40 and < 50 years old
    27
    45.8%
    Sex: Female, Male (Count of Participants)
    Female
    59
    100%
    Male
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    59
    100%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    0
    0%
    White
    0
    0%
    More than one race
    0
    0%
    Unknown or Not Reported
    0
    0%
    Region of Enrollment (participants) [Number]
    Japan
    59
    100%
    Height (cm) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [cm]
    159.8
    (5.0)
    Weight (kg) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [kg]
    54.4
    (9.3)
    Menstrual cycle (days) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [days]
    28.6
    (2.3)
    History of surgical treatment (for endometriosis) (Count of Participants)
    No
    48
    81.4%
    Yes
    11
    18.6%

    Outcome Measures

    1. Primary Outcome
    Title Change in the Volume of Ovarian Chocolate Cyst (If There Are Two or More Cysts, a Total Volume)
    Description 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."
    Time Frame Before treatment initiation (baseline), 3 months, and 5 months.

    Outcome Measure Data

    Analysis Population Description
    57 subjects were included in the efficacy analysis set. Of 57 subjects in the efficacy analysis set, changes in the volume of ovarian chocolate cyst before and after treatment in 52 subjects with values before and after Duphaston treatment.
    Arm/Group Title Dydrogesterone
    Arm/Group Description 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. Dydrogesterone
    Measure Participants 52
    Decreased
    26
    44.1%
    Unchanged
    13
    22%
    Increased
    13
    22%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Dydrogesterone
    Comments For the volume calculated from the major and minor axes of ovarian chocolate cyst, the values before treatment initiation and at last observation were compared, frequency of increase and decrease was summarized and the sign test was performed separately in the "efficacy analysis set" and "study completers."
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.0533
    Comments
    Method Sign test
    Comments
    2. Primary Outcome
    Title Volume of Ovarian Chocolate Cyst Over Time (If There Are Two or More Cysts, a Total Volume)
    Description 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.
    Time Frame Before treatment initiation (baseline), 3 months, and 5 months.

    Outcome Measure Data

    Analysis Population Description
    Of the safety analysis set (59 subjects), 57 subjects were included in the "efficacy analysis set," after excluding twe subjects (reason: one subject, use of concomitant medication indicated for endometriosis; one subject, violation of entry criteria).
    Arm/Group Title Dydrogesterone
    Arm/Group Description 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. Dydrogesterone
    Measure Participants 57
    Cycle -1
    45.76
    (40.70)
    Cycle 3
    51.97
    (50.20)
    Cycle 5
    60.27
    (109.04)
    3. Primary Outcome
    Title Volume of Ovarian Chocolate Cyst Over Time (If There Are Two or More Cysts, a Total Volume), Absolute Change From Baseline
    Description 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.
    Time Frame Before treatment initiation (baseline), 3 months, and 5 months.

    Outcome Measure Data

    Analysis Population Description
    Of the safety analysis set (59 subjects), 57 subjects were included in the "efficacy analysis set," after excluding twe subjects (reason: one subject, use of concomitant medication indicated for endometriosis; one subject, violation of entry criteria).
    Arm/Group Title Cycle 3 Cycle 5
    Arm/Group Description 2 Cycles of dydrogesterone treatment completed 4 Cycles of dydrogesterone treatment completed (at the completion of the observation period)
    Measure Participants 39 40
    Mean (Standard Deviation) [cm^3]
    0.04
    (24.91)
    8.48
    (83.69)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Dydrogesterone
    Comments For the volume calculated from the major and minor axes of ovarian chocolate cyst (a total volume if there were two or more cysts), the value, difference from the value before treatment and change rate were calculated using the summary statistics at each measurement point and last observation in each analysis set, namely "efficacy analysis set" and "study completers," and the Wilcoxon signed-rank test was performed for the difference and change rate.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.7328
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Cycle 5
    Comments For the volume calculated from the major and minor axes of ovarian chocolate cyst (a total volume if there were two or more cysts), the value, difference from the value before treatment and change rate were calculated using the summary statistics at each measurement point and last observation in each analysis set, namely "efficacy analysis set" and "study completers," and the Wilcoxon signed-rank test was performed for the difference and change rate.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.1193
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    4. Primary Outcome
    Title Volume of Ovarian Chocolate Cyst Over Time (If There Are Two or More Cysts, a Total Volume), % Change From Baseline
    Description 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.
    Time Frame Before treatment initiation (baseline), 3 months, and 5 months.

    Outcome Measure Data

    Analysis Population Description
    Of the safety analysis set (59 subjects), 57 subjects were included in the "efficacy analysis set," after excluding twe subjects (reason: one subject, use of concomitant medication indicated for endometriosis; one subject, violation of entry criteria).
    Arm/Group Title Cycle 3 Cycle 5
    Arm/Group Description 2 Cycles of dydrogesterone treatment completed 4 Cycles of dydrogesterone treatment completed (at the completion of the observation period)
    Measure Participants 39 40
    Mean (Standard Deviation) [percent change]
    3.97
    (46.06)
    -6.40
    (86.88)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Dydrogesterone
    Comments For the volume calculated from the major and minor axes of ovarian chocolate cyst (a total volume if there were two or more cysts), the value, difference from the value before treatment and change rate were calculated using the summary statistics at each measurement point and last observation in each analysis set, namely "efficacy analysis set" and "study completers," and the Wilcoxon signed-rank test was performed for the difference and change rate.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.7221
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Cycle 5
    Comments For the volume calculated from the major and minor axes of ovarian chocolate cyst (a total volume if there were two or more cysts), the value, difference from the value before treatment and change rate were calculated using the summary statistics at each measurement point and last observation in each analysis set, namely "efficacy analysis set" and "study completers," and the Wilcoxon signed-rank test was performed for the difference and change rate.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0861
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    5. Secondary Outcome
    Title Change Over Time in Dysmenorrhea Score (Total of the Dysmenorrhea Severity Score and the Analgesic Use Score)
    Description 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.
    Time Frame Baseline, 1 month, 2 months, 3 months, 4 months, and 5 months.

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Cycle -1 Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5
    Arm/Group Description Before treatment initiation (Baseline) At treatment initiation (the administration could be started during menstruation of cycle 1) 1 Cycles of dydrogesterone treatment completed 2 Cycles of dydrogesterone treatment completed 3 Cycles of dydrogesterone treatment completed 4 Cycles of dydrogesterone treatment completed (at the completion of the observation period)
    Measure Participants 57 57 52 50 45 42
    Mean (Standard Deviation) [score on a scale]
    2.30
    (1.89)
    1.75
    (1.83)
    1.31
    (1.67)
    1.12
    (1.42)
    1.00
    (1.38)
    1.05
    (1.40)
    6. Secondary Outcome
    Title Change Over Time in Visual Analogue Scale (VAS) for Dysmenorrhea
    Description 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".
    Time Frame Baseline, 1 month, 2 months, 3 months, 4 months, and 5 months.

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Cycle -1 Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5
    Arm/Group Description Before treatment initiation (Baseline) At treatment initiation (the administration could be started during menstruation of cycle 1) 1 Cycles of dydrogesterone treatment completed 2 Cycles of dydrogesterone treatment completed 3 Cycles of dydrogesterone treatment completed 4 Cycles of dydrogesterone treatment completed (at the completion of the observation period)
    Measure Participants 55 53 41 43 39 35
    Mean (Standard Deviation) [cm]
    4.33
    (2.92)
    3.35
    (2.66)
    2.54
    (2.36)
    2.37
    (2.41)
    2.03
    (2.39)
    2.01
    (2.26)
    7. Secondary Outcome
    Title Change in Serum CA125
    Description 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.
    Time Frame Baseline, and 5 months.

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Cycle -1 Cycle 5
    Arm/Group Description Before treatment initiation (Baseline) 4 Cycles of dydrogesterone treatment completed (at the completion of the observation period)
    Measure Participants 56 33
    Mean (Standard Deviation) [U/mL]
    55.66
    (70.57)
    47.52
    (47.37)
    8. Secondary Outcome
    Title Change Over Time in Dysmenorrhea Score (Total of the Dysmenorrhea Severity Score and the Analgesic Use Score), Difference From Baseline
    Description 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
    Time Frame Baseline, 1 month, 2 months, 3 months, 4 months, and 5 months.

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5
    Arm/Group Description At treatment initiation (the administration could be started during menstruation of cycle 1) 1 Cycles of dydrogesterone treatment completed 2 Cycles of dydrogesterone treatment completed 3 Cycles of dydrogesterone treatment completed 4 Cycles of dydrogesterone treatment completed (at the completion of the observation period)
    Measure Participants 57 52 50 45 42
    Mean (Standard Deviation) [score on a scale]
    -0.54
    (1.45)
    -0.90
    (1.61)
    -1.02
    (1.30)
    -0.96
    (1.28)
    -1.00
    (1.47)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Dydrogesterone
    Comments The score value and difference from the value before treatment were calculated at the same points using the summary statistics, and the Wilcoxon signed-rank test was performed.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.0020
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Cycle 5
    Comments The score value and difference from the value before treatment were calculated at the same points using the summary statistics, and the Wilcoxon signed-rank test was performed.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.0001
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Cycle 2
    Comments The score value and difference from the value before treatment were calculated at the same points using the summary statistics, and the Wilcoxon signed-rank test was performed.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Cycle 3
    Comments The score value and difference from the value before treatment were calculated at the same points using the summary statistics, and the Wilcoxon signed-rank test was performed.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Cycle 4
    Comments The score value and difference from the value before treatment were calculated at the same points using the summary statistics, and the Wilcoxon signed-rank test was performed.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    9. Secondary Outcome
    Title Change Over Time in Visual Analogue Scale (VAS) for Dysmenorrhea, Difference From Baseline
    Description 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.
    Time Frame Baseline, 1 month, 2 months, 3 months, 4 months, and 5 months.

    Outcome Measure Data

    Analysis Population Description
    One patient had a pain score at Cycle 1 but did not have a pain score at baseline and the absolute change could not be calculated in this instance
    Arm/Group Title Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5
    Arm/Group Description At treatment initiation (the administration could be started during menstruation of cycle 1) 1 Cycles of dydrogesterone treatment completed 2 Cycles of dydrogesterone treatment completed 3 Cycles of dydrogesterone treatment completed 4 Cycles of dydrogesterone treatment completed (at the completion of the observation period)
    Measure Participants 52 41 43 39 35
    Mean (Standard Deviation) [cm]
    -0.93
    (2.24)
    -1.61
    (2.11)
    -1.98
    (2.38)
    -1.94
    (2.82)
    -1.52
    (2.18)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Dydrogesterone
    Comments The difference from the value before treatment and change rate were calculated using the summary statistics at each observation point and last observation, and the Wilcoxon signed-rank test was performed for the difference and change rate.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.0024
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Cycle 5
    Comments The difference from the value before treatment and change rate were calculated using the summary statistics at each observation point and last observation, and the Wilcoxon signed-rank test was performed for the difference and change rate.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Cycle 2
    Comments The difference from the value before treatment and change rate were calculated using the summary statistics at each observation point and last observation, and the Wilcoxon signed-rank test was performed for the difference and change rate.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Cycle 3
    Comments The difference from the value before treatment and change rate were calculated using the summary statistics at each observation point and last observation, and the Wilcoxon signed-rank test was performed for the difference and change rate.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Cycle 4
    Comments The difference from the value before treatment and change rate were calculated using the summary statistics at each observation point and last observation, and the Wilcoxon signed-rank test was performed for the difference and change rate.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    10. Secondary Outcome
    Title Change Over Time in Visual Analogue Scale (VAS) for Dysmenorrhea, Change Rate From Baseline (%)
    Description 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.
    Time Frame Baseline, 1 month, 2 months, 3 months, 4 months, and 5 months.

    Outcome Measure Data

    Analysis Population Description
    A number of patients at each timepoint had pain scores of "zero" or discontinued treatment and a % change could not be calculated in these instances
    Arm/Group Title Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5
    Arm/Group Description At treatment initiation (the administration could be started during menstruation of cycle 1) 1 Cycles of dydrogesterone treatment completed 2 Cycles of dydrogesterone treatment completed 3 Cycles of dydrogesterone treatment completed 4 Cycles of dydrogesterone treatment completed (at the completion of the observation period)
    Measure Participants 47 37 39 34 31
    Mean (Standard Deviation) [percent change]
    -9.23
    (95)
    -33.97
    (65.48)
    -38.01
    (80.00)
    -41.24
    (76.62)
    -35.75
    (79.68)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Dydrogesterone
    Comments The difference from the value before treatment and change rate were calculated using the summary statistics at each observation point and last observation, and the Wilcoxon signed-rank test was performed for the difference and change rate.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.0037
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Cycle 5
    Comments The difference from the value before treatment and change rate were calculated using the summary statistics at each observation point and last observation, and the Wilcoxon signed-rank test was performed for the difference and change rate.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Cycle 2
    Comments The difference from the value before treatment and change rate were calculated using the summary statistics at each observation point and last observation, and the Wilcoxon signed-rank test was performed for the difference and change rate.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Cycle 3
    Comments The difference from the value before treatment and change rate were calculated using the summary statistics at each observation point and last observation, and the Wilcoxon signed-rank test was performed for the difference and change rate.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Cycle 4
    Comments The difference from the value before treatment and change rate were calculated using the summary statistics at each observation point and last observation, and the Wilcoxon signed-rank test was performed for the difference and change rate.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.0003
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    11. Secondary Outcome
    Title Change in Serum CA125, Difference From Baseline
    Description 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.
    Time Frame Baseline, and 5 months.

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Cycle 5
    Arm/Group Description 4 Cycles of dydrogesterone treatment completed (at the completion of the observation period)
    Measure Participants 32
    Mean (Standard Deviation) [U/mL]
    -6.47
    (97.38)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Dydrogesterone
    Comments Separately in the "efficacy analysis set" and "study completers," the values before treatment initiation and at last observation were compared, the value, difference from the value before treatment and change rate were calculated using the summary statistics, and the Wilcoxon signed-rank test was performed for the difference and change rate.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.8035
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments
    12. Secondary Outcome
    Title Change in Serum CA125, Change Rate From Baseline (%)
    Description 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.
    Time Frame Baseline, and 5 months.

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Cycle 5
    Arm/Group Description 4 Cycles of dydrogesterone treatment completed (at the completion of the observation period)
    Measure Participants 32
    Mean (Standard Deviation) [percent change]
    38
    (183.02)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Dydrogesterone
    Comments Separately in the "efficacy analysis set" and "study completers," the values before treatment initiation and at last observation were compared, the value, difference from the value before treatment and change rate were calculated using the summary statistics, and the Wilcoxon signed-rank test was performed for the difference and change rate.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value =0.8185
    Comments
    Method Wilcoxon (Mann-Whitney)
    Comments

    Adverse Events

    Time Frame AE information during the survey was collected during a period from the start of Duphaston treatment to the end of the observation period or discontinuation. Approximately 5 months in the study completers.(From date of dosage start, up to 5 months)
    Adverse Event Reporting Description An adverse event (AE) is any unfavorable and unintended sign (including an abnormal laboratory value), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered causally related to the drug. If an AE was noted, a follow-up investigation was performed until it resolved whenever possible. AE information during the survey was collected during a period from the start of Duphaston treatment to the end of the observation period or discontinuation.
    Arm/Group Title Dydrogesterone
    Arm/Group Description 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. Of 60 subjects whose case report forms were collected, 59 subjects were included in the "safety analysis set," after excluding one subject (reason: one subject, no data entered).
    All Cause Mortality
    Dydrogesterone
    Affected / at Risk (%) # Events
    Total 0/59 (0%)
    Serious Adverse Events
    Dydrogesterone
    Affected / at Risk (%) # Events
    Total 1/59 (1.7%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer 1/59 (1.7%)
    Other (Not Including Serious) Adverse Events
    Dydrogesterone
    Affected / at Risk (%) # Events
    Total 7/59 (11.9%)
    Gastrointestinal disorders
    Constipation 1/59 (1.7%)
    Infections and infestations
    Nasopharyngitis 1/59 (1.7%)
    Nervous system disorders
    Headache 1/59 (1.7%)
    Somnolence 1/59 (1.7%)
    Reproductive system and breast disorders
    Menorrhagia 1/59 (1.7%)
    Menstruation irregular 1/59 (1.7%)
    Metrorrhagia 3/59 (5.1%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Takumi Kanzo
    Organization Mylan EPD G.K.
    Phone +81-3-5656-0516
    Email takumi.kanzo@viatris.com
    Responsible Party:
    Mylan Inc.
    ClinicalTrials.gov Identifier:
    NCT02921763
    Other Study ID Numbers:
    • DUPKST16002
    First Posted:
    Oct 3, 2016
    Last Update Posted:
    Jul 6, 2022
    Last Verified:
    Jun 1, 2022