Clinical Study to Evaluate Efficacy and Safety of TAK-385 40 mg Compared With Leuprorelin in Patients With Endometriosis

Phase III Clinical Study to Evaluate Efficacy and Safety of TAK-385 40 mg Compared With Leuprorelin in Patients With Endometriosis

The objective is to evaluate the efficacy and safety of TAK-385 40 mg orally administrated once daily for 24 weeks compared with Leuprorelin [once/4 weeks, 3.75 or 1.88 mg subcutaneously (SC)/time] in patients with endometriosis.

This study is a phase III, multicenter, randomized, double-blind, parallel-group study to investigate the efficacy and safety of TAK-385 40 mg once daily compared with leuprorelin (once/4 weeks, 3.75 or 1.88 mg SC/time) in premenopausal subjects ≥ 20 years of age with endometriosis. 320 women with endometriosis will be enrolled in the study. This study consists of screening of approximately 1 to 6 weeks, run-in of approximately 3 to 6 weeks, treatment of 24 weeks, and follow-up of 4 weeks. After signing the informed consent form, subjects should record their symptoms in the electronic patient diary every day. During run-in period, daily data will be collected in the electronic patient diary for calculation of the baseline values for the efficacy evaluation.Following run-in period, subjects will receive investigational products (TAK-385 + leuprorelin placebo or TAK-385 placebo + leuprorelin) under double blind. During this study, subjects will visit the study center to undergo the designated examinations and evaluations at each visit. Safety will be assessed throughout the study by monitoring adverse events, vital signs, physical examinations, clinical laboratory tests, 12-lead electrocardiograms (ECG), and assessments of bone mineral density.Subjects will visit the study center to undergo the designated examinations and evaluations at 28 days after final administration.

Inclusion Criteria:

1. The participant is a premenopausal Japanese woman aged 20 years or older at the time consent is obtained.

2. The participant with endometriosis that falls under one of the following. However, in case of recurrence after surgery, it must be diagnosed again by either of the following.

   • The participant who has been diagnosed with endometriosis by Laparotomy or Laparoscopy.
   • The participant who has been confirmed ovarian chocolate cyst by Magnetic Resonance Imaging (MRI) or ultrasonic examination (vaginal, transabdominal or rectal).
   • The participant who has been diagnosed with clinical endometriosis and has the symptom of either induration of Douglas cavum, restriction of uterine mobility or pelvic tenderness confirmed by internal or rectal examination.

3. The participant must have dysmenorrhea or pelvic pain associated with endometriosis, of which either 1 or both should be at least "moderate" as determined by the investigator or subinvestigator using the B&B scale.

4. The participant must have maximum VAS score > 30 for pelvic pain associated with endometriosis.

5. The participant has experienced regular menstrual cycles (25 to 38 days) that should include menstrual bleeding of at least 3 consecutive days (at least 3 regular menstrual cycles to be confirmed).

6. The participant agrees to use routinely adequate contraception from signing of informed consent throughout the duration of the study.

Exclusion Criteria:

1. The participant has the following drug usage:

   • Use of the following drugs within 24 weeks:bisphosphonate preparation or other investigational agent
   • Use of the following drugs within 16 weeks (for 1-, 3- and 6-month sustained-release preparations, within 20, 28 and 40 weeks, respectively): gonadotropin-releasing hormone (GnRH) analogues, danazol, or aromatase inhibitors.
   • Use of the following drugs within 8 weeks:dienogest, oral contraceptive or sex hormone preparations (norethindrone, norethisterone, medroxyprogesterone, estrogen, or other progestins, etc.)
   • Use of the following drugs (excluding drugs for external use and supplements) within 4 weeks :anti-coagulant drugs, anti-platelet drugs, tranexamic acid, selective estrogen receptor modulators, activated vitamin D preparations, other vitamin D preparations, calcitonin, ipriflavone, steroid hormones, vitamin K preparations, teriparatide, or denosumab

2. The participant has received TAK-385 (including placebo) in a previous clinical study.

3. The participant has ovarian chocolate cyst of 10 cm or more and over 40 years old at the time imaging test is performed.

4. The participant has a history of panhysterectomy or bilateral oophorectomy.

5. The participant has had markedly abnormal uterine bleeding or anovulatory bleeding, as determined by the investigator or subinvestigator.

6. The participant has nondiagnosable abnormal genital bleeding.

7. The participant has a current history of thyroid gland disorder with irregular menstruation, or has a potential for irregular menstruation due to thyroid gland disorder, as determined by the investigator or subinvestigator.

8. The participant has uterine fibroid requiring treatment.

9. The participant has lower abdominal pain due to irritable bowel syndrome or severe interstitial cystitis.

10. The participant has a previous or current history of pelvic inflammatory disease within 8 weeks.

11. The participant has a previous or current history of osteoporosis, osteopenia, or other metabolic bone diseases.

12. The participant has a positive cervical cytology result [other than Negative for Intraepithelial Lesion or Malignancy (NILM) in accordance with the 2014 Bethesda system]. However, the following participant may participate in this study; Atypical Squamous Cells of Undetermined Significance (ASC-US) and negative by high-risk Human Papillomavirus (HPV) test. And furthermore, regarding the participant with negative cervical cytology result conducted within 1 year, she may participate in this study without additional test.

13. The participant has a malignant tumor or a history of a malignant tumor within 5 years.

14. The participant has clinically significant cardiovascular disease or uncontrollable hypertension.

15. The participant is inappropriate for participation in this study based on 12-lead ECG findings, as determined by the investigator or subinvestigator.

16. The participant has active liver disease or jaundice, or has Alanine aminotransferase (ALT), Aspartate aminotransferase (AST) or total bilirubin > 1.5 times the upper limit of normal in the clinical laboratory tests.

17. The participant has previous or current history of diseases considered to be inappropriate for participation in this study, including severe hepatic impairment, jaundice, renal impairment, cardiovascular disease, endocrine system disease, metabolic disorder, pulmonary disease, gastrointestinal disease, neural disease, urological disease, immune disease, or mental disorder (especially depression-like symptoms) or suicide attempt resulting from a mental disorder.

18. The participant has a previous or current history of hypersensitivity to GnRH analogues, or has a previous or current history of severe hypersensitivity to other drugs.

19. The participant is pregnant, lactating, or intending to become pregnant or to donate ova between the signing date of informed consent and 1 month after the end of the study.