Clinical trial NCT02655237: A Phase 3 Study to Evaluate the Efficacy and Safety of Relugolix (TAK-385) 40 mg Compared With Leuprorelin in the Treatment of Uterine Fibroids
Official title: A Multicenter, Randomized, Double-Blind, Parallel-Group, Phase 3 Study to Evaluate the Efficacy and Safety of Oral TAK-385 40 mg Compared With Leuprorelin in the Treatment of Uterine Fibroids
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Uterine Fibroids
Keywords: Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2016-01-13
Enrollment: 281
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 purpose of this study is to evaluate the efficacy of Relugolix (TAK-385) 40 mg administered orally once daily for 12 weeks, compared with leuprorelin injection (once every 4 weeks, 1.88 mg or 3.75 mg subcutaneously \[SC\]/time) in patients with uterine fibroids.

Detailed description: The drug tested in this study was called Relugolix (TAK-385). Relugolix was tested to treat people who had uterine fibroids.

The study enrolled 281 patients. Participants received relugolix placebo and leuprorelin acetate placebo in run in period for 3 to 6 weeks. After run-in period, participants were randomly assigned (by chance, like flipping a coin) to one of the two treatment groups in 1:1 ratio:

* Relugolix 40 mg
* Leuprorelin 1.88 or 3.75 mg

Participants received relugolix tablets once daily along with leuprorelin 1.88 mg or 3.75 mg subcutaneous injection once in 4 weeks for 24 weeks in treatment period.

This multi-center trial was conducted in Japan. The overall time to participate in this study was approximately 32 to 40 weeks including run-in period of 3 to 6 weeks and a treatment period of 24 weeks. Participants will make multiple visits to the clinic, and a final visit 4 weeks after last dose of study drug for a follow-up assessment.

Eligibility criteria: Inclusion Criteria:

Inclusion Criteria for Entering the Screening (at VISIT 1)

1. In the opinion of the investigator or subinvestigator, the participant is capable of understanding and complying with protocol requirements.
2. The participant signs and dates a written, informed consent form prior to the initiation of any study procedures.
3. Prior to VISIT 1, the participant has a diagnosis of uterine fibroids confirmed by transvaginal ultrasound, abdominal ultrasound, magnetic resonance imaging (MRI), computed tomography (CT), or laparoscopy, and has never received any surgical treatment for the myoma (measurable noncalcified myoma with the longest diameter of ≥ 3 cm).
4. The participant is a premenopausal Japanese woman.
5. The participant is aged 20 years or older on the day of signing and dating the informed consent form.
6. The participant has 1 or more measurable noncalcified myomas with the longest diameter of ≥ 3 cm confirmed by transvaginal ultrasound.
7. The participant has experienced 1 or more regular menstrual cycles (25 to 38 days) immediately prior to VISIT 1 and that should include menstrual bleeding for at least 3 consecutive days.
8. The participant who is sexually active with a nonsterilized male partner agrees to use routinely adequate contraception from signing of informed consent throughout the study.

   Inclusion Criteria for Entering the Run-in (at VISIT 2)
9. The participant has experienced regular menstrual cycles (25 to 38 days) immediately prior to VISIT 2 that should include menstrual bleeding of at least 3 consecutive days (at least 2 regular menstruation cycles to be confirmed by Inclusion criteria #7 and #9).

   Inclusion Criteria for Entering the Treatment (at VISIT 3)
10. The participant has 1 or more measurable noncalcified myomas, with a longest diameter of ≥ 3 cm confirmed by transvaginal ultrasound (the same myoma should be measured as in Inclusion criterion #6).
11. The participant has a diagnosis of menorrhagia with a total Pictorial Blood loss Assessment Chart (PBAC) score of ≥ 120 in 1 menstrual cycle just before VISIT 3.
12. The participant has experienced regular menstrual cycles (25 to 38 days) after VISIT 1 that should include menstrual bleeding for at least 3 consecutive days (at least 3 regular menstruation cycles to be confirmed by Inclusion criteria #7, #9 and #12).

Exclusion Criteria:

1. The participant has received any investigational compound within 24 weeks prior to the start of the administration of the study medication for the Run-in (VISIT 2).
2. The participant has received relugolix (including placebo) in a previous clinical study.
3. The participant is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress.
4. The participant has a previous or current history of blood disorders (eg, thalassemia, sickle cells anemia, folic-acid deficiency, and coagulopathy), excluding (latent) iron-deficiency anemia.
5. The participant has a known history of severe hypersensitivity or severe allergy to sanitary goods.
6. The participant has lower abdominal pain due to irritable bowel syndrome or severe interstitial cystitis.
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 a previous or current history of pelvic inflammatory disease within 8 weeks prior to VISIT 1.
9. The participant has a positive Pap smear test result obtained within 1 year prior to VISIT 1 (if there are no previous test results, those who were judged positive in the test conducted before VISIT 2).
10. The participant has a history of panhysterectomy or bilateral oophorectomy.
11. The participant has had markedly abnormal uterine bleeding or anovulatory bleeding, as determined by the investigator or subinvestigator.
12. The participant has a malignant tumor or a history of a malignant tumor within 5 years prior to VISIT 1.
13. The participant has been treated with any of the following drugs (excluding drugs for external use and dietary supplements) within 4 weeks prior to VISIT 2: anti-coagulant drugs, anti-platelet drugs, tranexamic acid, selective estrogen receptor modulators (SERMs), activated vitamin D preparations, other vitamin D preparations, calcitonin, ipriflavone, steroid hormones, vitamin K preparations, teriparatide, or denosumab.
14. The participant has been treated with any of the following drugs within 8 weeks prior to VISIT 2: oral contraceptive or sex hormone preparations (norethindrone, norethisterone, medroxyprogesterone, estrogen, or other progestins), and within 16 weeks prior to VISIT 2: gonadotropin-releasing hormone (GnRH) analogues, dienogest, danazol, or aromatase inhibitors (for 1- and 3-month sustained-release preparations, within 20 and 28 weeks prior to VISIT 2, respectively).
15. The participant has been treated with a bisphosphonate preparation within 24 weeks prior to VISIT 2.
16. The participant has a previous or current history of hypersensitivity or allergies to leuprorelin, synthetic GnRH, GnRH agonists or GnRH antagonists, or has a previous or current history of severe hypersensitivity or severe allergy to other drugs.
17. The participant has nondiagnosable abnormal genital bleeding.
18. Female participant who is pregnant, lactating, or intending to become pregnant or to donate ova prior to the signing of informed consent, during the study period, or within 1 month after the end of the study.
19. The participant has a previous or current history of osteoporosis, osteopenia, or other metabolic bone diseases.
20. The participant has clinically significant cardiovascular disease (eg, myocardial infarction or unstable angina pectoris within 24 weeks prior to VISIT 1) or uncontrollable hypertension (eg, resting systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 110 mmHg at Screening and Run-in).
21. The participant is inappropriate for participation in this study based on standard 12-lead electrocardiogram (ECG) findings, as determined by the investigator or subinvestigator.
22. The participant has active liver disease or jaundice, or with alanine aminotransferase (ALT), aspartate aminotransferase (AST), or bilirubin (total bilirubin) \> 1.5 times the upper limit of normal (ULN) in the clinical laboratory tests at VISITs 1 and 2.
23. 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, neurological disease, urological disease, immune disease, or mental disorder (especially depression-like symptoms) or suicide attempt resulting from a mental disorder.
24. The participant has a previous or current history of drug abuse (defined as any illicit drug use) or alcohol abuse.
25. The participant is inappropriate for participation in this study for other reasons, as determined by the investigator or subinvestigator.

Primary outcomes:
measure: Percentage of Participants With Total PBAC Score of <10 From Week 6 to 12
timeFrame: Week 6 to 12
Secondary outcomes:
measure: Percentage of Participants With Total PBAC Score of <10 From Week 2 to 6
timeFrame: Week 2 to 6
measure: Percentage of Participants With Total PBAC Score of <10 From Week 18 to 24
timeFrame: Week 18 to 24
measure: Percentage of Participants With Total PBAC Score of <10 for 6 Weeks Before the Final Dose of Study Drug
timeFrame: For 6 weeks before the final dose of study drug (up to Week 24)
measure: Percent Change From Baseline in Myoma Volumes at Weeks 2, 4, 8, 12 and 24
timeFrame: Baseline, Weeks 2, 4, 8, 12 and 24
measure: Percent Change From Baseline in Uterine Volumes at Weeks 2, 4, 8, 12 and 24
timeFrame: Baseline, Weeks 2, 4, 8, 12 and 24
measure: Change From Baseline in Hemoglobin at Weeks 4, 8, 12, 16, 20, 24 and Follow up
timeFrame: Baseline, Weeks 4, 8, 12, 16, 20, 24 and Follow up (up to Week 28)
measure: Numerical Rating Scale (NRS) Score
timeFrame: From Week 6 to 12, from Week 2 to 6, from Week 18 to 24, and for 6 weeks before the final dose (up to Week 24)
measure: Change From Baseline in Uterine Fibroid Symptom and Quality of Life (UFS-QOL)- Symptom Severity Score at Weeks 4, 8, 12, 16, 20, 24 and Follow-up
timeFrame: Baseline, Weeks 4, 8, 12, 16, 20, 24 and Follow-up (up to Week 28)
measure: Change From Baseline in Uterine Fibroid Symptom and Quality of Life (UFS-QOL)- HRQL Total Scores at Weeks 4, 8, 12, 16, 20, 24 and Follow-up
timeFrame: Baseline, Weeks 4, 8, 12, 16, 20, 24 and Follow-up (up to Week 28)
measure: Number of Participants Who Had One or More Treatment Emergent Adverse Event (TEAE)
timeFrame: Up to Week 28
measure: Number of Participants With Markedly Abnormal Values of Vital Signs
timeFrame: Up to Week 28
measure: Number of Participants With TEAE Related to Weight
timeFrame: Up to Week 28
measure: Number of Participants With TEAE Related to Standard 12-Lead ECGs
timeFrame: Up to Week 28
measure: Number of Participants With Markedly Abnormal Values of Laboratory Test
timeFrame: Up to Week 28
measure: Number of Participants With TEAE (Bone Density Decreased) Related to Bone Mineral Density
timeFrame: Up to Week 28
measure: Number of Participants With TEAE Related to Biochemical Bone Metabolism Markers
timeFrame: Up to Week 28
Other outcomes:
Locations:
city: Nagoya
country: Japan
state: Aichi
city: Matsudo
country: Japan
state: Chiba
city: Kouriyama
country: Japan
state: Fukushima
city: Ebetsu
country: Japan
state: Hokkaido
city: Sapporo
country: Japan
state: Hokkaido
city: Kako-gun
country: Japan
state: Hyogo
city: Nishinomiya
country: Japan
state: Hyogo
city: Kawasaki
country: Japan
state: Kanagawa
city: Yamato
country: Japan
state: Kanagawa
city: Yokohama
country: Japan
state: Kanagawa
city: Ibaraki
country: Japan
state: Osaka
city: Sakai
country: Japan
state: Osaka
city: Suita
country: Japan
state: Osaka
city: Yao
country: Japan
state: Osaka
city: Bunkyo-ku
country: Japan
state: Tokyo
city: Chiyoda-ku
country: Japan
state: Tokyo
city: Chuou-ku
country: Japan
state: Tokyo
city: Minato-ku
country: Japan
state: Tokyo
city: Setagaya-ku
country: Japan
state: Tokyo
city: Suginami-ku
country: Japan
state: Tokyo
city: Taitou-ku
country: Japan
state: Tokyo
city: Kagoshima
country: Japan
city: Kyoto
country: Japan
city: Osaka
country: Japan
city: Saitama
country: Japan
Study officials:
affiliation: Takeda
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Osuga Y, Enya K, Kudou K, Tanimoto M, Hoshiai H. Oral Gonadotropin-Releasing Hormone Antagonist Relugolix Compared With Leuprorelin Injections for Uterine Leiomyomas: A Randomized Controlled Trial. Obstet Gynecol. 2019 Mar;133(3):423-433. doi: 10.1097/AOG.0000000000003141.