Clinical trial NCT03931915: Clinical Study to Evaluate Efficacy and Safety of TAK-385 40 mg Compared With Leuprorelin in Patients With Endometriosis
Official title: Phase III Clinical Study to Evaluate Efficacy and Safety of TAK-385 40 mg Compared With Leuprorelin in Patients With Endometriosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Endometriosis
Lead sponsor: ASKA Pharmaceutical Co., Ltd.
Sponsor class: INDUSTRY
First posted: 2019-04-30
Enrollment: 335
Sex: FEMALE
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change of maximum Visual Analogue Scale (VAS) score for endometriosis associated pelvic pain
timeFrame: Baseline and the last 28 days of treatment period
Secondary outcomes:
measure: Change of mean VAS score for endometriosis associated pelvic pain
timeFrame: Baseline and the last 28 days of treatment period
measure: VAS score for endometriosis associated pelvic pain
timeFrame: Up to Week 24
measure: Change of VAS score for endometriosis associated pelvic pain
timeFrame: Baseline and up to Week 24
measure: VAS score for menstrual pain
timeFrame: Up to Week 24
measure: Change of VAS score for menstrual pain
timeFrame: Baseline and up to Week 24
measure: VAS score for endometriosis associated pelvic pain outside the menstruation period
timeFrame: Up to Week 24
measure: Change of VAS score for endometriosis associated pelvic pain outside the menstruation period
timeFrame: Baseline and up to Week 24
measure: VAS score for dyspareunia
timeFrame: Up to Week 24
measure: Change of VAS score for dyspareunia
timeFrame: Baseline and up to Week 24
measure: Adverse event
timeFrame: Up to Week 28
measure: Bone mineral density
timeFrame: Up to Week 24
measure: Serum concentrations of NTx (N-telopeptide)
timeFrame: Up to Week 24
measure: Serum concentrations of BAP (Bone alkaline phosphatase)
timeFrame: Up to Week 24
measure: Period from the last dose of study drug to return of menstrual cycles
timeFrame: From Week 24 to Week 28
Other outcomes:
Locations:
city: Aichi
country: Japan
facility: Chubu Rosai Hospital
city: Aichi
country: Japan
facility: Meitetsu Hospital
city: Chiba
country: Japan
facility: Aiiku Ladies Clinic
city: Chiba
country: Japan
facility: Chiba Aoba Municipal Hospital
city: Chiba
country: Japan
facility: Tokyo Bay Urayasu Ichikawa Medical Center
city: Chiba
country: Japan
facility: Tsujinaka Hospital Kashiwanoha
city: Hiroshima
country: Japan
facility: Fujito Clinic
city: Hokkaido
country: Japan
facility: Hashimoto Clinic
city: Hokkaido
country: Japan
facility: Tokeidai Memorial Hospital
city: Hokkaido
country: Japan
facility: Yoshio Obstetrics Gynecology Hospital
city: Hyogo
country: Japan
facility: Shinsuma Hospital
city: Kagawa
country: Japan
facility: Kagawa Prefectural Central Hospital
city: Kagawa
country: Japan
facility: Takamatsu Red Cross Hospital
city: Kanagawa
country: Japan
facility: Fujisawa City Hospital
city: Kanagawa
country: Japan
facility: Rinkan Clinic
city: Kanagawa
country: Japan
facility: Second Kawasaki Saiwai Clinic
city: Kanagawa
country: Japan
facility: Tawada Ladies Clinic
city: Kumamoto
country: Japan
facility: Japanese Red Cross Kumamoto Hospital
city: Okayama
country: Japan
facility: Kurashiki Medical Clinic
city: Osaka
country: Japan
facility: Chayamachi Ladies Clinic
city: Osaka
country: Japan
facility: Hayakawa Clinic
city: Osaka
country: Japan
facility: Minami-Morimachi Ladies Clinic
city: Osaka
country: Japan
facility: Nomura Clinic Nanba
city: Osaka
country: Japan
facility: Rikako Ladies Clinic
city: Osaka
country: Japan
facility: Tanabe Ladies Clinic
city: Osaka
country: Japan
facility: Yoshimura Ladies Clinic
city: Saitama
country: Japan
facility: Dantsuka Clinic
city: Saitama
country: Japan
facility: Kashiwazaki Ladies Clinic
city: Saitama
country: Japan
facility: Maruyama Memorial General Hospital
city: Shiga
country: Japan
facility: Kusatsu General Hospital
city: Tokyo
country: Japan
facility: Akasaka-Mitsuke Miyazaki Clinic
city: Tokyo
country: Japan
facility: Ginza Yoshida Hospital
city: Tokyo
country: Japan
facility: Hamada Hospital
city: Tokyo
country: Japan
facility: Ikebukuro Metroporitan Clinic
city: Tokyo
country: Japan
facility: NS Clinic
city: Tokyo
country: Japan
facility: Sei Women's Clinic
city: Tokyo
country: Japan
facility: Seijo Kinoshita Hospital
city: Tokyo
country: Japan
facility: Shimamura Memorial Hospital
city: Tokyo
country: Japan
facility: Toranomon Women's Clinic
city: Tokyo
country: Japan
facility: Yokokura Clinic
city: Tokyo
country: Japan
facility: Yukawa Women's Clinic
Study officials:
References:
citation: Harada T, Osuga Y, Suzuki Y, Fujisawa M, Fukui M, Kitawaki J. Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, reduces endometriosis-associated pain compared with leuprorelin in Japanese women: a phase 3, randomized, double-blind, noninferiority study. Fertil Steril. 2022 Mar;117(3):583-592. doi: 10.1016/j.fertnstert.2021.11.013. Epub 2021 Dec 8.