A Placebo-Controlled, Phase 3 Study of Relugolix (TAK-385) 40 mg in the Treatment of Pain Symptoms Associated With Uterine Fibroids

A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Oral TAK-385 40 mg in the Treatment of Pain Symptoms Associated With Uterine Fibroids

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02655224

Enrollment

Registered

2016-01-13

Start date

2016-03-26

Completion date

2017-05-19

Last updated

2019-03-22

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Uterine Fibroids

Keywords

Drug Therapy

Brief summary

The purpose of this study is to evaluate the efficacy and safety of Relugolix (TAK-385) in patients having pain symptoms associated with uterine fibroids.

Detailed description

The drug being tested in this study is called relugolix (TAK-385). Relugolix is being tested to treat people who have uterine fibroids. The study enrolled 65 patients. Participants received relugolix placebo in run in period for 3 to 6 weeks. After run-in period, participants were randomly assigned to one of the two treatment groups in 1:1 ratio: 1. Relugolix 40 mg 2. Placebo (dummy inactive pill) - this is a tablet that looks like the study drug but has no active ingredient All participants were asked to take one tablet at the same time each day throughout the study. This multi-center trial was conducted in Japan. The overall time to participate in this study was 20 to 28 weeks, including run-in period of 3 to 6 weeks and a treatment period of 12 weeks. Participants made multiple visits to the clinic, and 4 weeks after last dose of study drug for a follow-up assessment.

Interventions

DRUGRelugolix

Relugolix Tablets

DRUGRelugolix placebo

Relugolix placebo-matching tablets

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

FEMALE

Age

20 Years to No maximum

Healthy volunteers

Inclusion criteria

Inclusion Criteria for Entering the Screening Period (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 a 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 a 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 Period (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 for 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 Period (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 in Inclusion criterion #6). 11. The participant has a maximum Numerical Rating Scale (NRS) score of ≥4 during 1 menstrual cycle just before VISIT 3. 12. The participant has pain symptoms associated with uterine fibroids for at least 2 days during 1 menstrual cycle just before VISIT 3. 13. 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 #13).

Exclusion criteria

1. The participant has received any investigational compound within 24 weeks prior to the start of the administration of the study drug for the day of first menstruation after VISIT 1. 2. The participant has received relugolix (including placebo) in a previous clinical study. 3. The participant is an immediate family member or 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, or sibling) or may consent under duress. 4. The participant has lower abdominal pain due to irritable bowel syndrome or severe interstitial cystitis. 5. 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. 6. The participant has a previous or current history of pelvic inflammatory disease within 8 weeks prior to VISIT 1. 7. 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). 8. The participant has a history of panhysterectomy or bilateral oophorectomy. 9. The participant has had markedly abnormal uterine bleeding or anovulatory bleeding, as determined by the investigator or subinvestigator. 10. The participant has a malignant tumor or a history of a malignant tumor within 5 years prior to VISIT 1. 11. The participant has been treated with selective estrogen receptor modulators (SERMs) (excluding drugs for external use and dietary supplements) within 4 weeks prior to VISIT 2. 12. 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). 13. The participant has a previous or current history of severe hypersensitivity or severe allergies to drugs. 14. The participant has nondiagnosable abnormal genital bleeding. 15. 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. 16. 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 Period). 17. The participant is ineligible for this study based on standard 12-lead electrocardiogram (ECG) findings, as determined by the investigator or subinvestigator. 18. 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 VISIT 1 and 2. 19. The participant has a previous or current history of diseases considered to be ineligible for 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, mental disorder (especially depression-like symptoms) and suicide attempt resulting from a mental disorder. 20. The participant has a previous or current history of drug abuse (defined as any illicit drug use) or alcohol abuse. 21. The participant is ineligible for this study for other reasons, as determined by the investigator or subinvestigator.

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Participants With a Maximum NRS Score of 1 or Less During the 28 Days Before the Final Dose of Study Drug	For 28 days before the final dose of study drug (up to Week 12)	Pain symptoms were evaluated using the NRS score. NRS score is a self-reported instrument assessing pain from 0 to 10. Higher scores reflect greater level of pain. The percentage of participants with a score of 1 or less is reported.

Secondary

Measure	Time frame	Description
Mean NRS Score During the 28 Days Before the Final Dose of Study Drug	For 28 days before the final dose of study drug (up to Week 12)	Pain symptoms were evaluated using the NRS score. NRS score is a self-reported instrument assessing pain from 0 to 10. Higher scores reflect greater level of pain.
Percentage of Days Without Pain Symptoms (NRS = 0) During the 28 Days Before the Final Dose of Study Drug	For 28 days before the final dose of study drug (up to Week 12)	Percentage of day without pain symptoms (NRS = 0) was reported. Number of days without pain symptoms is determined by a zero score on the NRS. Pain symptoms were evaluated using the NRS score. NRS score is a self-reported instrument assessing pain from 0 to 10. Higher scores reflect greater level of pain. Percentage of days without pain symptoms (NRS=0) during the 28 days before the final dose of study drug (%) = \[(number of days without pain symptoms (NRS=0) during the last 28 days of the treatment)/(number of days with available data during the last 28 days of the treatment)\]\*100.
Percentage of Participants With Maximum NRS Score of 1 or Less From Day 1 to 28, From Day 29 to 56, and From Day 57 to 84	Day 1 to 28, Day 29 to 56, and Day 57 to 84	Pain symptoms were evaluated using the NRS score. NRS score is a self-reported instrument assessing pain from 0 to 10. Higher scores reflect greater level of pain. The percentage of participants with a score of 1 or less is reported.
Percentage of Participants With a Maximum NRS Score of 0 From Day 1 to 28, From Day 29 to 56, and From Day 57 to 84	Day 1 to 28, Day 29 to 56, and Day 57 to 84	Pain symptoms were evaluated using the NRS score. NRS score is a self-reported instrument assessing pain from 0 to 10. Higher scores reflect greater level of pain. The percentage of participants with a score of 0 is reported.
Mean NRS Score From Day 1 to 28, From Day 29 to 56, and From Day 57 to 84	Day 1 to 28, Day 29 to 56, and Day 57 to 84	Pain symptoms were evaluated using the NRS score. NRS score is a self-reported instrument assessing pain from 0 to 10. Higher scores reflect greater level of pain.
Percentage of Participants With a Maximum NRS Score of 0 During the 28 Days Before the Final Dose of Study Drug	For 28 days before the final dose of study drug (up to Week 12)	Pain symptoms were evaluated using the NRS score. NRS score is a self-reported instrument assessing pain from 0 to 10. Higher scores reflect greater level of pain. The percentage of participants with a score of 0 is reported.
Number of Participants Reporting Who Had One or More Treatment-emergent Adverse Event (TEAE)	Up to Week 16	An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.
Number of Participants With Markedly Abnormal Values of Vital Signs	Up to Week 16	Vital signs included sitting blood pressure (after the participant has rested for at least 5 minutes), body temperature (oral or tympanic measurement) (degree Celsius \[°C\]) and pulse (beats per minute \[bpm\]) are reported.
Number of Participants With TEAEs Related to Weight	Up to Week 16	Number of participants with TEAEs of which threshold was 5% or above in either treatment group related to weight was reported.
Number of Participants With TEAEs Related to Standard 12-lead Electrocardiogram (ECG)	Up to Week 16	Number of participants with TEAEs of which threshold was 5% or above in either treatment group related to ECG was reported.
Number of Participants With Markedly Abnormal Values of Laboratory Tests	Up to Week 16	Number of participants with any markedly abnormal values in laboratory tests collected throughout study is reported. WBC = White blood cells, GGT = gamma-glutamyl transferase, LLN = lower limit of normal or lower reference limit, ULN = upper limit of normal or upper reference limit.
Percentage of Days Without Pain Symptoms (NRS = 0) From Day 1 to 28, From Day 29 to 56, and From Day 57 to 84	Day 1 to 28, Day 29 to 56, and Day 57 to 84	Percentage of day without pain symptoms (NRS = 0) was reported. Number of days without pain symptoms is determined by a zero score on the NRS. Pain symptoms were evaluated using the NRS score. NRS score is a self-reported instrument assessing pain from 0 to 10. Higher scores reflect greater level of pain. Percentage of days without pain symptoms (NRS=0) (%) = \[(number of days without pain symptoms (NRS=0) during the last 28 days of the treatment)/(number of days with available data during the last 28 days of the treatment)\]\*100.

Countries

Japan

Participant flow

Recruitment details

Participants took part in the study at 15 investigative sites in Japan from 26 March 2016 to 19 May 2017.

Pre-assignment details

Participants with a diagnosis of uterine fibroids were enrolled in a 1:1 ratio in one of two treatment groups: relugolix 40 mg or placebo.

Participants by arm

Arm	Count
Relugolix 40 mg Relugolix placebo-matching tablet, orally, once daily before breakfast for 3 to 6 weeks in the run-in period, followed by relugolix 40 mg, tablet, orally once daily before breakfast for 12 weeks.	33
Placebo Relugolix placebo-matching tablet, orally, once daily before breakfast for 3 to 6 weeks in the run-in period, followed by relugolix placebo-matching tablet, orally once daily before breakfast for 12 weeks.	32
Total	65

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	1	1

Baseline characteristics

Characteristic	Placebo	Relugolix 40 mg	Total
Age, Continuous	42.6 years STANDARD_DEVIATION 5.24	40.5 years STANDARD_DEVIATION 3.95	41.5 years STANDARD_DEVIATION 4.72
Birth Experience Had Birth Experience	12 Participants	12 Participants	24 Participants
Birth Experience Had No Birth Experience	20 Participants	21 Participants	41 Participants
Body Mass Index (BMI)	22.56 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 3.714	23.15 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 4.146	22.86 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 3.919
Height	159.2 centimeter (cm) STANDARD_DEVIATION 4.25	157.5 centimeter (cm) STANDARD_DEVIATION 6.4	158.3 centimeter (cm) STANDARD_DEVIATION 5.48
Maximum Numerical Rating Scale (NRS) Score	6.28 score on a scale STANDARD_DEVIATION 1.689	6.64 score on a scale STANDARD_DEVIATION 1.817	6.46 score on a scale STANDARD_DEVIATION 1.751
Number of Participants With No Surgery for Uterine Fibroids	32 Participants	33 Participants	65 Participants
Race and Ethnicity Not Collected	—	—	0 Participants
Region of Enrollment Japan	32 Participants	33 Participants	65 Participants
Sex: Female, Male Female	32 Participants	33 Participants	65 Participants
Sex: Female, Male Male	0 Participants	0 Participants	0 Participants
Smoking Classification Current Smoker	8 Participants	6 Participants	14 Participants
Smoking Classification Ex-Smoker	3 Participants	7 Participants	10 Participants
Smoking Classification Never Smoked	21 Participants	20 Participants	41 Participants
Stopped Any Medications for Uterine Fibroids Had not Stopped Any Medications	25 Participants	28 Participants	53 Participants
Stopped Any Medications for Uterine Fibroids Had Stopped Any Medications	7 Participants	5 Participants	12 Participants
Type of Uterine Fibroid Intramural Fibroid	29 Participants	22 Participants	51 Participants
Type of Uterine Fibroid Subserosal Fibroid	9 Participants	17 Participants	26 Participants
UFS-QOL Score: Health Relate Quality of Life (HRQL) Total	80.0 score on a scale STANDARD_DEVIATION 15	83.9 score on a scale STANDARD_DEVIATION 12.47	82.0 score on a scale STANDARD_DEVIATION 13.81
Uterine Fibroid Symptom and Quality of Life (UFS-QOL) Score: Symptom Severity	30.3 score on a scale STANDARD_DEVIATION 13.07	25.5 score on a scale STANDARD_DEVIATION 8.59	27.9 score on a scale STANDARD_DEVIATION 11.2
Volume of Myoma	101.38 cm^3 STANDARD_DEVIATION 172.738	78.83 cm^3 STANDARD_DEVIATION 84.189	89.94 cm^3 STANDARD_DEVIATION 134.633
Volume of Uterus	300.09 cm^3 STANDARD_DEVIATION 295.341	252.29 cm^3 STANDARD_DEVIATION 202.938	275.82 cm^3 STANDARD_DEVIATION 251.837
Weight	57.47 kilogram (kg) STANDARD_DEVIATION 11.511	57.55 kilogram (kg) STANDARD_DEVIATION 11.775	57.51 kilogram (kg) STANDARD_DEVIATION 11.555

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 33	0 / 32
other Total, other adverse events	27 / 33	14 / 32
serious Total, serious adverse events	0 / 33	0 / 32

Outcome results

Primary

Percentage of Participants With a Maximum NRS Score of 1 or Less During the 28 Days Before the Final Dose of Study Drug

Pain symptoms were evaluated using the NRS score. NRS score is a self-reported instrument assessing pain from 0 to 10. Higher scores reflect greater level of pain. The percentage of participants with a score of 1 or less is reported.

Time frame: For 28 days before the final dose of study drug (up to Week 12)

Population: Full Analysis Set (FAS) included all participants who were randomized and received at least 1 dose of study drug for the treatment period.

Arm	Measure	Value (NUMBER)
Relugolix 40 mg	Percentage of Participants With a Maximum NRS Score of 1 or Less During the 28 Days Before the Final Dose of Study Drug	57.6 percentage of participants
Placebo	Percentage of Participants With a Maximum NRS Score of 1 or Less During the 28 Days Before the Final Dose of Study Drug	3.1 percentage of participants

p-value: <0.000195% CI: [5.113, 346.181]Fisher's Exact Test

Secondary

Mean NRS Score During the 28 Days Before the Final Dose of Study Drug

Pain symptoms were evaluated using the NRS score. NRS score is a self-reported instrument assessing pain from 0 to 10. Higher scores reflect greater level of pain.

Time frame: For 28 days before the final dose of study drug (up to Week 12)

Population: FAS included all participants who were randomized and received at least 1 dose of study drug for the treatment period.

Arm	Measure	Value (MEAN)	Dispersion
Relugolix 40 mg	Mean NRS Score During the 28 Days Before the Final Dose of Study Drug	0.50 score on a scale	Standard Deviation 0.967
Placebo	Mean NRS Score During the 28 Days Before the Final Dose of Study Drug	0.99 score on a scale	Standard Deviation 1.274

95% CI: [-1.05, 0.069]

Secondary

Mean NRS Score From Day 1 to 28, From Day 29 to 56, and From Day 57 to 84

Pain symptoms were evaluated using the NRS score. NRS score is a self-reported instrument assessing pain from 0 to 10. Higher scores reflect greater level of pain.

Time frame: Day 1 to 28, Day 29 to 56, and Day 57 to 84

Population: FAS included all participants who were randomized and received at least 1 dose of study drug for the treatment period. The number analyzed is the number of participants with data available for analysis at the given time-point.

Arm	Measure	Group	Value (MEAN)	Dispersion
Relugolix 40 mg	Mean NRS Score From Day 1 to 28, From Day 29 to 56, and From Day 57 to 84	Day 1 to 28	1.26 score on a scale	Standard Deviation 1.49
Relugolix 40 mg	Mean NRS Score From Day 1 to 28, From Day 29 to 56, and From Day 57 to 84	Day 29 to 56	0.59 score on a scale	Standard Deviation 0.991
Relugolix 40 mg	Mean NRS Score From Day 1 to 28, From Day 29 to 56, and From Day 57 to 84	Day 57 to 84	0.43 score on a scale	Standard Deviation 0.776
Placebo	Mean NRS Score From Day 1 to 28, From Day 29 to 56, and From Day 57 to 84	Day 1 to 28	1.17 score on a scale	Standard Deviation 1.141
Placebo	Mean NRS Score From Day 1 to 28, From Day 29 to 56, and From Day 57 to 84	Day 29 to 56	1.16 score on a scale	Standard Deviation 1.457
Placebo	Mean NRS Score From Day 1 to 28, From Day 29 to 56, and From Day 57 to 84	Day 57 to 84	0.97 score on a scale	Standard Deviation 1.279

Comparison: Day 1 to 2895% CI: [-0.574, 0.745]

Comparison: Day 29 to 5695% CI: [-1.19, 0.049]

Comparison: Day 57 to 8495% CI: [-1.074, -0.012]

Secondary

Number of Participants Reporting Who Had One or More Treatment-emergent Adverse Event (TEAE)

An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.

Time frame: Up to Week 16