Clinical trial NCT03049735: LIBERTY 1: Efficacy & Safety Study of Relugolix in Women With Heavy Menstrual Bleeding Associated With Uterine Fibroids
Official title: LIBERTY 1: An International Phase 3 Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study to Evaluate Relugolix Co-Administered With and Without Low-Dose Estradiol and Norethindrone Acetate in Women With Heavy Menstrual Bleeding Associated With Uterine Fibroids
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Heavy Menstrual Bleeding
Uterine Fibroid
Keywords: Uterine Fibroid
Heavy Menstrual Bleeding
Menstrual Blood Volume
Lead sponsor: Myovant Sciences GmbH
Sponsor class: INDUSTRY
First posted: 2017-02-10
Enrollment: 388
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine the benefit of relugolix 40 milligrams (mg) once a day co-administered with estradiol (E2) 1 mg and norethindrone acetate (NETA) 0.5 mg compared with placebo for 24 weeks on heavy menstrual bleeding associated with uterine fibroids.

Detailed description: This study is an international phase 3 randomized, double-blind, placebo-controlled efficacy and safety study to evaluate 24 weeks of oral daily relugolix 40 mg co-administered with low-dose E2 and NETA (Group A) and 12 weeks of daily oral relugolix 40 mg alone followed by 12 weeks of daily oral relugolix 40 mg co-administered with low-dose E2 and NETA (Group B) compared with 24 weeks of placebo (Group C).

All participants completing the Week 24 visit, including women randomized to placebo, were offered the opportunity to enroll in an open-label extension study in which all eligible participants will receive relugolix co-administered with low-dose E2 and NETA. Participants who did not enroll into the extension study had a follow-up visit approximately 30 days after the end of treatment (that is, after the participant's last dose of study medication).

Safety will be assessed throughout the study by monitoring adverse events, vital signs, physical examinations, clinical laboratory tests, 12-lead electrocardiograms, and assessments of bone mineral density.

Eligibility criteria: Key Inclusion Criteria:

1. Premenopausal female aged 18 to 50 years old (inclusive) on the day of signing and dating the informed consent form.
2. Has regularly occurring menstrual periods of ≤ 14 days duration with a cycle of 21 to 38 days from the start of 1 menstrual period until the start of the next, by participant history for at least 3 months prior to the first screening visit.
3. Has a diagnosis of uterine fibroids that is confirmed by a transvaginal and/or transabdominal ultrasound performed during the screening period.
4. Has heavy menstrual bleeding associated with uterine fibroids as evidenced by an MBL of ≥ 160 milliliter (mL) during 1 cycle or ≥ 80 mL per cycle for 2 menstrual cycles as measured by the alkaline hematin method during the screening period.

Key Exclusion Criteria:

1. Has transvaginal and/or transabdominal ultrasound during the screening period demonstrating pathology other than uterine fibroids that could be responsible for or contributing to the patient's heavy menstrual bleeding.
2. Has known rapidly enlarging uterine fibroids in the opinion of the investigator.
3. Has a weight that exceeds the weight limit of the DXA scanner or has a condition that precludes an adequate DXA measurement at the lumbar spine and proximal femur.
4. Has a history of or currently has osteoporosis, or other metabolic bone disease, hyperparathyroidism, hyperprolactinemia, hyperthyroidism, anorexia nervosa, or low traumatic (from the standing position) or atraumatic fracture (toe, finger, skull, face and ankle fractures are allowed). A history of successfully treated hyperparathyroidism, hyperprolactinemia, or hyperthyroidism is allowed if the participant's bone mineral density is within normal limits.
5. Has a history of the use of bisphosphonates, calcitonin, calcitriol, ipriflavone, teriparatide, denosumab, or any medication other than calcium and vitamin D preparations to treat bone mineral density loss.
6. Has been a participant in an investigational drug or device study within the 1 month prior to the first screening visit.

Primary outcomes:
measure: Percentage Of Participants Who Achieved A Menstrual Blood Loss (MBL) Volume Of < 80 mL And A ≥ 50% Reduction From Baseline MBL Volume With Relugolix Plus E2/NETA
timeFrame: From Baseline up to last 35 days of treatment (up to Week 24)
Secondary outcomes:
measure: Percentage Of Participants With Amenorrhea Over The Last 35 Days Of Treatment
timeFrame: From Baseline up to last 35 days of treatment (up to Week 24)
measure: Percent Change From Baseline At Week 24 In MBL Volume
timeFrame: Baseline, Week 24
measure: Percentage Of Participants With A Hemoglobin Level ≤ 10.5 g/dL At Baseline Who Achieved An Increase Of > 2 g/dL From Baseline At Week 24
timeFrame: From Baseline up to Week 24
measure: Percentage Of Participants With A Maximum NRS Score ≤ 1 For Uterine Fibroid-Associated Pain Over The Last 35 Days Of Treatment
timeFrame: From Baseline up to Week 24
measure: Percent Change From Baseline At Week 24 In Primary Uterine Fibroid Volume
timeFrame: Baseline, Week 24
measure: Percent Change From Baseline At Week 24 In Uterine Volume
timeFrame: Baseline, Week 24
measure: Change From Baseline At Week 24 In UFS-QoL Bleeding And Pelvic Discomfort Scale Score As Measured By The UFS-QoL (Q1, Q2, Q5)
timeFrame: Baseline, Week 24
measure: Percent Change From Baseline At Week 12 In Bone Mineral Density At The Lumbar Spine (L1 To L4), As Assessed By DXA
timeFrame: Baseline, Week 12
measure: Percent Change From Baseline At Week 24 In Bone Mineral Density At The Lumbar Spine (L1 To L4), Total Hip, And Femoral Neck
timeFrame: Baseline, Week 24
measure: Percentage Of Participants Experiencing Vasomotor Symptoms Through Week 12
timeFrame: Baseline through Week 12
measure: Percentage Of Participants Experiencing Vasomotor Symptoms Through Week 24
timeFrame: Baseline through Week 24
measure: Predose Trough Concentrations Of Relugolix And Norethindrone (NET) In The Relugolix Plus E2/NETA Group At Week 24
timeFrame: Week 24
measure: Predose Trough Concentrations Of E2 In The Relugolix Plus E2/NETA Group At Week 24
timeFrame: Week 24
measure: Change From Baseline At Week 24 In Predose Concentrations Of Estradiol In The Relugolix Plus E2/NETA Group
timeFrame: Baseline, Week 24
measure: Time To MBL Response
timeFrame: From Baseline through Week 24
measure: Sustained Amenorrhea Rate (No Or Negligible Bleeding)
timeFrame: Week 24
measure: Time To Achieving Sustained Amenorrhea (No Or Negligible Bleeding)
timeFrame: From Baseline through Week 24
measure: Time To Achieving Amenorrhea (No Or Negligible Bleeding)
timeFrame: From Baseline through Week 24
measure: Number Of Participants With Hemoglobin ≤ 10.5 g/dL At Baseline And Achieved An Increase Of > 2 g/dL At Week 24
timeFrame: From Baseline through Week 24
measure: Percent Change From Baseline In Hemoglobin For Women With a Hemoglobin ≤ 10.5 g/dL At Baseline
timeFrame: Week 24
measure: Number Of Participants With Hemoglobin Increase Of ≥ 1 g/dL From Baseline To Week 24 Among Those With Below Lower Limit Of Normal
timeFrame: Week 24
measure: Change From Baseline At Week 24 In The UFS-QoL Symptom Severity Scale Score
timeFrame: Baseline, Week 24
measure: Change From Baseline At Week 24 In The UFS-QoL Activities Scale Score
timeFrame: Baseline, Week 24
measure: Change From Baseline At Week 24 In The UFS-QoL Revised Activities Scale Score
timeFrame: Baseline, Week 24
measure: Change From Baseline In UFS-QoL Score By Health-Related Quality Of Life Total Score
timeFrame: Baseline, Week 24
measure: Number Of Responders With At Least 20 Points Increase From Baseline At Week 24 In UFS-QoL Revised Activities Scale Score
timeFrame: From Baseline through Week 24
measure: Change From Baseline In UFS-QoL Bleeding And Pelvic Discomfort Scale Score
timeFrame: Baseline, Week 24
measure: Number Of Responders With At Least 20 Points Decrease In UFS-QoL Bleeding And Pelvic Discomfort Scale Score
timeFrame: Baseline, Week 24
measure: Change From Baseline At Week 24 In The Interference Of Uterine Fibroids With Physical Activities Based On UFS-QoL Question 11
timeFrame: Baseline, Week 24
measure: Change From Baseline At Week 24 In The Interference Of Uterine Fibroids With Social Activities Based On UFS-QoL Question 20
timeFrame: Baseline, Week 24
measure: Change From Baseline At Week 24 In Embarrassment Caused By Uterine Fibroids Based On UFS-QoL Question 29
timeFrame: Baseline, Week 24
measure: Change From Baseline At Week 24 In Symptoms Assessed Using The Patient Global Assessment (PGA) Questionnaire
timeFrame: Baseline, Week 24
measure: Change From Baseline At Week 24 In Function Assessed Using The PGA Questionnaire
timeFrame: Baseline, Week 24
measure: Participants Achieving Improvement From Baseline In The PGA Questionnaire For Symptoms From Baseline At Week 24
timeFrame: From Baseline through Week 24
measure: Participants Achieving Improvement From Baseline In The PGA Questionnaire For Uterine Fibroid-related Function From Baseline At Week 24
timeFrame: From Baseline through Week 24
measure: Change From Baseline At Week 24 In The Menorrhagia Impact Questionnaire Score For Physical Activities
timeFrame: Baseline, Week 24
measure: Change From Baseline At Week 24 In The Menorrhagia Impact Questionnaire Score For Social Activities
timeFrame: Baseline, Week 24
measure: Number Of Participants Who Achieved A Maximum NRS Score ≤ 1 For Uterine Fibroid-associated Pain Over The Last 35 Days Of Treatment Who Had Maximum Pain Scores ≥ 4 During The 35 Days Prior To Randomization
timeFrame: From Baseline up to the last 35 days of treatment (up to 24 weeks)
measure: Number Of Participants With A ≥ 30% Reduction in NRS Score From Baseline to Last 35 Days of Treatment Who Had Maximum Pain Scores ≥ 4 At Baseline
timeFrame: Baseline, Week 24
measure: Change From Baseline In Luteinizing Serum Concentration At Week 24
timeFrame: Baseline, Week 24
measure: Change From Baseline In Follicle Stimulating Serum Concentration At Week 24
timeFrame: Baseline, Week 24
measure: Change From Baseline In E2 Serum Concentration At Week 24
timeFrame: Baseline, Week 24
measure: Change From Baseline In Progesterone Serum Concentration At Week 24
timeFrame: Baseline, Week 24
Other outcomes:
Locations:
city: Andalusia
country: United States
facility: Andalusia
state: Alabama
city: Mobile
country: United States
facility: Mobile
state: Alabama
city: Little Rock
country: United States
facility: Little Rock
state: Arkansas
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facility: La Mesa
state: California
city: Lomita
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facility: Lomita
state: California
city: Norwalk
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facility: Norwalk
state: California
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country: United States
facility: Oceanside
state: California
city: San Diego
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facility: San Diego
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facility: Denver
state: Colorado
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facility: Aventura
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city: Brandon
country: United States
facility: Brandon
state: Florida
city: Clearwater
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facility: Clearwater
state: Florida
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country: United States
facility: Clermont
state: Florida
city: Fort Myers
country: United States
facility: Fort Myers
state: Florida
city: Hialeah
country: United States
facility: Hialeah
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city: Hialeah
country: United States
facility: Hialeah
state: Florida
city: Jacksonville
country: United States
facility: Jacksonville
state: Florida
city: Lauderdale Lakes
country: United States
facility: Lauderdale Lakes
state: Florida
city: Margate
country: United States
facility: Margate
state: Florida
city: Miami
country: United States
facility: Miami
state: Florida
city: Miami
country: United States
facility: Miami
state: Florida
city: Miami
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facility: Miami
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country: United States
facility: Orlando
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city: South Miami
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city: Atlanta
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state: Georgia
city: Atlanta
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facility: Atlanta
state: Georgia
city: Augusta
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facility: Augusta
state: Georgia
city: College Park
country: United States
facility: College Park
state: Georgia
city: Richland
country: United States
facility: Richland
state: Georgia
city: Oakbrook Terrace
country: United States
facility: Oakbrook
state: Illinois
city: Lafayette
country: United States
facility: Lafayette
state: Indiana
city: Covington
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facility: Covington
state: Louisiana
city: Shreveport
country: United States
facility: Shreveport
state: Louisiana
city: Saint Louis
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facility: St. Louis
state: Missouri
city: Lincoln
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facility: Lincoln
state: Nebraska
city: Omaha
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facility: Omaha
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city: Las Vegas
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city: Durham
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state: North Carolina
city: Morehead City
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city: Raleigh
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state: North Dakota
city: Cincinnati
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facility: Cincinnati
state: Ohio
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state: Ohio
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state: South Carolina
city: Charleston
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state: Tennessee
city: Memphis
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state: Texas
city: Houston
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city: Houston
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state: Texas
city: Irving
country: United States
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state: Texas
city: San Antonio
country: United States
facility: San Antonio
state: Texas
city: Sugar Land
country: United States
facility: Sugar Land
state: Texas
city: Webster
country: United States
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state: Texas
city: Salt Lake City
country: United States
facility: Salt Lake City
state: Utah
city: Salt Lake City
country: United States
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state: Utah
city: Norfolk
country: United States
facility: Norfolk
state: Virginia
city: Seattle
country: United States
facility: Seattle
state: Washington
city: Curitiba
country: Brazil
facility: Curitiba
city: Porto Alegre
country: Brazil
facility: Porto Alegre
city: Ribeirão Preto
country: Brazil
facility: Ribeirao Preto
city: Santo André
country: Brazil
facility: Santo Andre
city: São Paulo
country: Brazil
facility: Sao Paulo
city: Bologna
country: Italy
facility: Bologna
city: Catanzaro
country: Italy
facility: Catanzaro
city: Firenze
country: Italy
facility: Fiernze
city: Genova
country: Italy
facility: Genova
city: Milano
country: Italy
facility: Milano
city: Modena
country: Italy
facility: Modena
city: Monserrato
country: Italy
facility: Monserrato
city: Napoli
country: Italy
facility: Napoli
city: Roma
country: Italy
facility: Roma
city: Roma
country: Italy
facility: Roma
city: Siena
country: Italy
facility: Siena
city: Torino
country: Italy
facility: Torino
city: Katowice
country: Poland
facility: Katowice
city: Lublin
country: Poland
facility: Lublin
city: Lublin
country: Poland
facility: Lublin
city: Poznań
country: Poland
facility: Poznan
city: Szczecin
country: Poland
facility: Szczecin
city: Warszawa
country: Poland
facility: Warszawa
city: Warszawa
country: Poland
facility: Warszawa
city: Łódź
country: Poland
facility: Lodz
city: Łódź
country: Poland
facility: Lodz
city: Durban
country: South Africa
facility: Durban
city: Durban
country: South Africa
facility: Durban
city: Port Elizabeth
country: South Africa
facility: Port Elizabeth
city: Roodepoort
country: South Africa
facility: Roodepoort
city: Birmingham
country: United Kingdom
facility: Birmingham
city: Isleworth
country: United Kingdom
facility: Isleworth
city: London
country: United Kingdom
facility: London
city: Nottingham
country: United Kingdom
facility: Nottingham
Study officials:
affiliation: Myovant Sciences
name: Myovant Medical Monitor
role: STUDY_DIRECTOR
References:
citation: Al-Hendy A, Lukes AS, Poindexter AN 3rd, Venturella R, Villarroel C, McKain L, Li Y, Wagman RB, Stewart EA. Long-term Relugolix Combination Therapy for Symptomatic Uterine Leiomyomas. Obstet Gynecol. 2022 Dec 1;140(6):920-930. doi: 10.1097/AOG.0000000000004988. Epub 2022 Nov 2.
citation: Stewart EA, Lukes AS, Venturella R, Arjona Ferreira JC, Li Y, Hunsche E, Wagman RB, Al-Hendy A. Relugolix Combination Therapy for Uterine Leiomyoma-Associated Pain in the LIBERTY Randomized Trials. Obstet Gynecol. 2022 Jun 1;139(6):1070-1081. doi: 10.1097/AOG.0000000000004787. Epub 2022 May 2.
citation: Hunsche E, Rakov V, Scippa K, Witherspoon B, McKain L. The Burden of Uterine Fibroids from the Perspective of US Women Participating in Open-Ended Interviews. Womens Health Rep (New Rochelle). 2022 Mar 4;3(1):286-296. doi: 10.1089/whr.2021.0086. eCollection 2022.
citation: Al-Hendy A, Lukes AS, Poindexter AN 3rd, Venturella R, Villarroel C, Critchley HOD, Li Y, McKain L, Arjona Ferreira JC, Langenberg AGM, Wagman RB, Stewart EA. Treatment of Uterine Fibroid Symptoms with Relugolix Combination Therapy. N Engl J Med. 2021 Feb 18;384(7):630-642. doi: 10.1056/NEJMoa2008283.