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Relugolix

Leuprolide

Antineoplastic Agents, Hormonal

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Hormone Antagonists

Relugolix placebo matching tablets, orally, once daily along with leuprorelin acetate placebo matching injection, SC, once in 4 weeks for 3 to 6 weeks in run-in period followed by relugolix 40 mg, tablets, orally, once daily and leuprorelin acetate placebo matching injection, SC, once in 4 weeks for 24 weeks in treatment period.

Relugolix placebo matching tablets, orally, once daily along with leuprorelin acetate placebo matching injection, SC, once in 4 weeks for 3 to 6 weeks in run-in period followed by leuprorelin acetate 1.88 mg or 3.75 mg, injection, SC, once in 4 weeks and relugolix placebo matching tablets, orally, once daily for 24 weeks in treatment period.

Relugolix Placebo

Leuprorelin

Leuprorelin Placebo

Medical Director

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.

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.

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

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

PBAC score was used to measure volume of menstrual blood loss. Participants used sanitary products designated by sponsor and recorded the numbers of tampons or towels used, clots and flooding in patient diary. Three diagrams used which represented a lightly, moderately stained or completely saturated pad/tampon. Following scores assigned: 1) 1, 5, or 20 points for each pad; 2) 1, 5, or 10 points for each tampon; 3) 1 or 5 points for each blood clot of \<1 cm/=1 cm/\>1 in longest diameter; 4) 5 points for each episode of flooding. The total PBAC score (sum of points) ranges from 0 to \>500.

A transvaginal ultrasound was performed to determine myoma volumes. Only the largest myoma among those measurable at visit 1 was measured throughout the study. On the assumption that the myoma was spheroids, the myoma volumes were calculated using 3 diameters (D1, D2, and D3). D1: the longest diameter of the myoma; D2: the longest diameter of the myoma which was perpendicular to D1; D3: the diameter of the myoma which crossed the intersection of D1 and D2 (intersection "Z") and was perpendicular to D1/D2 plane. The formula used for calculation is Myoma volume= D1\*D2\*D3\*π/6.

A transvaginal ultrasound was performed for determination of uterine volumes. On the assumption that the uterus was spheroids, the uterine volumes were calculated using 3 diameters (D1, D2, and D3) measured as shown below: D1: the longest diameter of the uterus (unit of length: cm); D2: the longest diameter of the uterus which was perpendicular to D1 (unit of length: cm); D3: the diameter of the uterus which crossed the intersection of D1 and D2 (intersection "Z") and was perpendicular to D1/D2 plane (unit of length: cm). The formula used for calculation is Uterine volume=D1\*D2\*D3\*π/6.

Anemia-related measurements consisted of hemoglobin, which were determined at the central laboratory.

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.

UFS-QOL was a 37-item self-reporting tool for evaluating QOL in participants with uterine fibroid. It includes eight symptom-related questions and 29 HRQL questions across six subscales (concern, activities, energy/mood, control, self-consciousness, sexual function). The total symptom severity score is ranging from 0 to 100. The higher scores indicate greater severity.

UFS-QOL was a 37-item self-reporting tool for evaluating QOL in participants with uterine fibroid. It includes eight symptom-related questions and 29 HRQL questions across six subscales (concern, activities, energy/mood, control, self-consciousness, sexual function). The total HRQL score is ranging from 0 to 100. The higher scores indicate better QOL.

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.

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 \[bpm\]) is reported.

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 of which threshold was 5% or above in either treatment group related to ECG was reported.

Number of participants with any markedly abnormal values in laboratory tests collected throughout study is reported. WBC = White blood cells, AST = Aspartate Aminotransferase, ALT = Alanine Aminotransferase, GGT = gamma-glutamyl transferase, ULN = upper limit of normal or upper reference limit.

Number of participants with TEAEs of which threshold was 5% or above in either treatment group related to bone mineral density was reported.

Number of participants with TEAEs of which threshold was 5% or above in either treatment group related to biochemical bone metabolism markers was reported.

Takeda

At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.

Relugolix placebo matching tablets, orally, once daily along with leuprorelin acetate placebo matching injection, subcutaneously (SC), once in 4 weeks for 3 to 6 weeks in run-in period followed by relugolix 40 mg, tablets, orally, once daily and leuprorelin acetate placebo matching injection, SC, once in 4 weeks for 24 weeks in treatment period.

Relugolix 40 mg

Relugolix placebo matching tablets, orally, once daily along with leuprorelin acetate placebo matching injection, subcutaneously (SC), once in 4 weeks for 3 to 6 weeks in run-in period followed by leuprorelin acetate 1.88 mg or 3.75 mg, injection, SC, once in 4 weeks and relugolix placebo matching tablets, orally, once daily for 24 weeks in treatment period.

Leuprorelin 1.88 mg or 3.75 mg

Total

Age, Continuous

Sex: Female, Male

Race and Ethnicity were not collected from any participant.

Race and Ethnicity Not Collected

Japan

Region of Enrollment

Height

Here, number analyzed indicates participants who were evaluated for this baseline characteristic.

Weight

Body Mass Index = weight (kg)/\[height (m)\^2\]

Body Mass Index (BMI)

Never Smoked

Current Smoker

Ex-Smoker

Smoking Classification

Had Birth Experience

Had No Birth Experience

Birth Experience

Subserosal Fibroid

Intramural Fibroid

Submucosal Fibroid

Type of Uterine Fibroid

Had Stopped Any Medications

Had Not Stopped Any Medications

Stopped Any Medications for Uterine Fibroids

Had Any Surgery for Uterine Fibroids

Had Not Any Surgery for Uterine Fibroids

Any Surgery for Uterine Fibroids

Volume of Myoma

Volume of Uterus

PBAC score was used to measure volume of menstrual blood loss. Participants used sanitary products designated by sponsor and recorded numbers of tampons or towels used, clots and flooding in patient diary. Three diagrams used which represented a lightly, moderately stained or completely saturated pad/tampon. Following scores assigned: 1) 1, 5, or 20 points for each pad; 2) 1, 5, or 10 points for each tampon; 3) 1 or 5 points for each blood clot of \<1 cm/=1 cm/\>1 in longest diameter; 4) 5 points for each episode of flooding. The total PBAC score (sum of points) ranges from 0 to \>500.

Pictorial Blood Loss Assessment Chart (PBAC) Score

Numerical Rating Scale (NRS) Score

Uterine Fibroid Symptom and Quality of Life (UFS-QOL) Score: Symptom Severity

UFS-QOL Score: Health Related Quality of Life (HRQL) Total

Hemoglobin

1.88 mg

3.75 mg

Dosage of Leuprorelin Vial

Randomized Set included all participants who were randomized.

Medical Director, Clinical Science

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

Percentage of Participants With Total PBAC Score of <10 From Week 6 to 12

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

Percentage of Participants With Total PBAC Score of <10 From Week 2 to 6

Percentage of Participants With Total PBAC Score of <10 From Week 18 to 24

Percentage of Participants With Total PBAC Score of <10 for 6 Weeks Before the Final Dose of Study Drug

Change at Week 2

Change at Week 4

Change at Week 8

Change at Week 12

Change at Week 24

Percent Change From Baseline in Myoma Volumes at Weeks 2, 4, 8, 12 and 24

Percent Change From Baseline in Uterine Volumes at Weeks 2, 4, 8, 12 and 24

Change at Week 16

Change at Week 20

Change at Follow-Up (up to Week 28)

Change From Baseline in Hemoglobin at Weeks 4, 8, 12, 16, 20, 24 and Follow up

For 6 Weeks Before the Final Dose (up to Week 24)

Week 6 to 12

Week 2 to 6

Week 18 to 24

For 6 weeks before the final dose (up to Week 24)

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

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

Safety analysis set included all participants who received at least 1 dose of the study drug for the treatment period.

Number of Participants Who Had One or More Treatment Emergent Adverse Event (TEAE)

Systolic Blood Pressure Lower (<85 mmHg)

Systolic Blood Pressure Upper (>180 mmHg)

Diastolic Blood Pressure Lower (<50 mmHg)

Diastolic Blood Pressure Upper (>110 mmHg)

Pulse Rate Lower (<50 bpm)

Body temperature Lower (<35.6 °C)

Body temperature Upper (>37.7 °C)

Number of Participants With Markedly Abnormal Values of Vital Signs

Number of Participants With TEAE Related to Weight

Number of Participants With TEAE Related to Standard 12-Lead ECGs

WBC Upper (>1.5×ULN×10^3 cells/μL)

Eosinophils Upper (>2×ULN×10^3 cells/μL)

Total cholesterol Upper (>300 mg/dL)

Triglycerides Upper (>2.5×ULN mg/dL)

Creatine kinase Upper (>5×ULN U/L)

AST Upper (>3×ULN U/L)

ALT Upper (>3×ULN U/L)

GGT Upper (>3×ULN U/L)

Hemoglobin A1c Upper (>7%)

Number of Participants With Markedly Abnormal Values of Laboratory Test

Number of Participants With TEAE (Bone Density Decreased) Related to Bone Mineral Density

Bone Resorption Test Abnormal

Resorption Bone Increased

Number of Participants With TEAE Related to Biochemical Bone Metabolism Markers

Overall Study

Symptoms and General Pathology

Nervous System Diseases

Pain

Neurologic Manifestations

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.

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.

Relugolix placebo

Study Director

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.

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.

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

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.

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.

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 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.

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 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.

Placebo

Had not Stopped Any Medications

Number of Participants With No Surgery for Uterine Fibroids

Maximum Numerical Rating Scale (NRS) Score

UFS-QOL Score: Health Relate Quality of Life (HRQL) Total

Randomized Set included all randomized participants.

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

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

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

Percentage of Participants With a Maximum NRS Score of 0 During the 28 Days Before the Final Dose of Study Drug

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

Percentage of Days Without Pain Symptoms (NRS = 0) During the 28 Days Before the Final Dose of Study Drug

Day 1 to 28

Day 29 to 56

Day 57 to 84

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.

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

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

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

Percentage of Days Without Pain Symptoms (NRS = 0) From Day 1 to 28, From Day 29 to 56, and From Day 57 to 84

Safety Analysis Set included all participants who received at least 1 dose of study drug for the treatment period.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
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	NCT02655237	Uterine Fibroid...	Relugolix Relugolix Place... Leuprorelin Leuprorelin Pla...	20 Years -	Takeda
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	NCT02655237	Uterine Fibroid...	Relugolix Relugolix Place... Leuprorelin Leuprorelin Pla...	20 Years -	Takeda
A Placebo-Controlled, Phase 3 Study of Relugolix (TAK-385) 40 mg in the Treatment of Pain Symptoms Associated With Uterine Fibroids	NCT02655224	Uterine Fibroid...	Relugolix Relugolix place...	20 Years -	Takeda

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