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LIBERTY 2: Efficacy & Safety Study of Relugolix in Women With Heavy Menstrual Bleeding Associated With Uterine Fibroids

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03103087
Recruitment Status : Active, not recruiting
First Posted : April 6, 2017
Last Update Posted : June 23, 2020
Sponsor:
Information provided by (Responsible Party):
Myovant Sciences GmbH

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.

Condition or disease Intervention/treatment Phase
Heavy Menstrual Bleeding Uterine Fibroid Drug: Relugolix Drug: Estradiol/norethindrone acetate Drug: Relugolix placebo Drug: Estradiol/norethindrone acetate placebo Phase 3

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 participants 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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 382 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: LIBERTY 2: 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
Actual Study Start Date : June 14, 2017
Actual Primary Completion Date : July 1, 2019
Estimated Study Completion Date : December 31, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Relugolix plus E2/NETA (Group A)
Relugolix co-administered with E2/NETA for 24 weeks.
Drug: Relugolix
Relugolix (40 mg) tablet administered orally once daily.
Other Names:
  • TAK-385
  • MVT-601

Drug: Estradiol/norethindrone acetate
E2 (1.0 mg)/NETA (0.5 mg) co-formulated capsule administered orally once daily.
Other Names:
  • E2/NETA
  • low-dose hormonal add-back

Experimental: Relugolix plus Delayed E2/NETA (Group B)
Relugolix co-administered with E2/NETA placebo for 12 weeks, followed by relugolix co-administered with E2/NETA for 12 weeks.
Drug: Relugolix
Relugolix (40 mg) tablet administered orally once daily.
Other Names:
  • TAK-385
  • MVT-601

Drug: Estradiol/norethindrone acetate
E2 (1.0 mg)/NETA (0.5 mg) co-formulated capsule administered orally once daily.
Other Names:
  • E2/NETA
  • low-dose hormonal add-back

Drug: Estradiol/norethindrone acetate placebo
E2 (0 mg)/NETA (0 mg) placebo capsule administered orally once daily and designed to match the capsule containing E2/NETA in size, shape, color, and odor.
Other Name: E2/NETA placebo

Placebo Comparator: Placebo (Group C)
Relugolix placebo co-administered with E2/NETA placebo for 24 weeks.
Drug: Relugolix placebo
Relugolix (0 mg) placebo tablet administered orally once daily and manufactured to match the relugolix tablet in size, shape, color, and odor.

Drug: Estradiol/norethindrone acetate placebo
E2 (0 mg)/NETA (0 mg) placebo capsule administered orally once daily and designed to match the capsule containing E2/NETA in size, shape, color, and odor.
Other Name: E2/NETA placebo




Primary Outcome Measures :
  1. Percentage Of Participants Who Achieve A Menstrual Blood Loss (MBL) Volume Of < 80 mL And A ≥ 50% Reduction From Baseline MBL Volume Over The Last 35 Days Of Treatment [ Time Frame: From Baseline up to the last 35 days of treatment (up to 24 weeks) ]
    MBL volume is measured using the alkaline hematin method. For the primary analysis, the Relugolix plus E2/NETA group (Group A) will be compared with the Placebo group (Group C). Comparison of Relugolix plus Delayed E2/NETA group (Group A) with the Placebo group (Group C) will be a secondary analysis.


Secondary Outcome Measures :
  1. Percentage Of Participants With Amenorrhea (No Or Negligible Bleeding) Over The Last 35 Days Of Treatment [ Time Frame: From Baseline up to last 35 days of treatment (up to 24 weeks) ]
    Will be assessed using MBL volume measured using the alkaline hematin method and participant daily electronic diary (eDiary) data.

  2. Percent Change From Baseline At Week 24 In MBL Volume [ Time Frame: Baseline, Week 24 ]
    MBL volume is measured using the alkaline hematin method.

  3. Change From Baseline At Week 24 In Uterine Fibroid Symptom (UFS)-Quality of Life (QoL) Bleeding And Pelvic Discomfort Scale Score As Measured By The UFS-QoL Questions 1, 2, and 5 [ Time Frame: Baseline, Week 24 ]
    Will be assessed with 3 questions (each with a 5-point scale ranging from 'Not at all' to 'A very great deal') related to menstrual bleeding and pelvic tightness/pressure.

  4. Percentage Of Participants With A Maximum Numerical Rating Scale (NRS) Score ≤ 1 For Uterine Fibroid-Associated Pain Over The Last 35 Days Of Treatment [ Time Frame: From Baseline up to the last 35 days of treatment (up to 24 weeks) ]
    Uterine fibroid-associated pain will be assessed with a daily eDiary using an NRS score (11-point scale) in a subset of participants with a maximum NRS score ≥ 4 for pain associated with uterine fibroids during the last 35 days prior to randomization and at least 28 days with e-Diary entries of the last 35 days of treatment.

  5. Percentage Of Participants With A Hemoglobin Level ≤ 10.5 g/dL At Baseline Who Have An Increase In Hemoglobin > 2 g/dL From Baseline At Week 24 [ Time Frame: From Baseline up to Week 24 ]
    Blood samples will be collected from participants for hemoglobin measurements.

  6. Percent Change From Baseline At Week 24 In Primary Uterine Fibroid Volume [ Time Frame: Baseline, Week 24 ]
    Volume of the primary uterine fibroid will be measured by transvaginal or transabdominal ultrasound.

  7. Percent Change From Baseline At Week 24 In Uterine Volume [ Time Frame: Baseline, Week 24 ]
    Volume of the uterus will be measured by transvaginal or transabdominal ultrasound.

  8. Time To MBL Response [ Time Frame: From Baseline through Week 24 ]
    Defined as the time to achieve an MBL volume of < 80 mL and a ≥ 50% reduction from baseline MBL volume as measured by the alkaline hematin method.

  9. Change From Baseline At Week 24 In Impact On QoL, Assessed Using The UFS-QoL Questionnaire [ Time Frame: Baseline, Week 24 ]
  10. Change From Baseline At Week 24 In Symptoms Assessed Using The Patient Global Assessment (PGA) Questionnaire [ Time Frame: Baseline, Week 24 ]
    The PGA for symptoms is a 1-item questionnaire designed to assess participant's impression of the severity of their symptoms related to uterine fibroids.

  11. Change From Baseline At Week 24 In Function Assessed Using The PGA Questionnaire [ Time Frame: Baseline, Week 24 ]
    The PGA for function is a 1-item questionnaire designed to assess participant's impression of how their symptoms related to uterine fibroids affected their usual activities.

  12. Percent Change From Baseline At Week 12 In Bone Mineral Density At The Lumbar Spine (L1 - L4) [ Time Frame: Baseline, Week 12 ]
    Assessed by a dual-energy X-ray absorptiometry (DXA) scan.

  13. Percent Change From Baseline At Week 24 In Bone Mineral Density At The Lumbar Spine (L1 - L4), Total Hip, And Femoral Neck [ Time Frame: Baseline, Week 24 ]
    Assessed by a DXA scan.

  14. Percentage Of Participants Experiencing Vasomotor Symptoms Through Week 12 [ Time Frame: From Baseline through Week 12 ]
  15. Percentage Of Participants Experiencing Vasomotor Symptoms Through Week 24 [ Time Frame: From Baseline through Week 24 ]
  16. Predose Trough Concentrations Of Relugolix And NETA In The Relugolix Plus E2/NETA Group At Week 24 [ Time Frame: Week 24 ]
    Blood samples for determination of relugolix and NETA plasma concentrations will be collected for measurements.

  17. Predose Trough Concentrations Of E2 In The Relugolix Plus E2/NETA Group At Week 24 [ Time Frame: Week 24 ]
    Blood samples for determination of E2 plasma concentrations will be collected for measurements.

  18. Change In Serum Concentrations Of Luteinizing Hormone, Follicle-stimulating Hormone, Estradiol, And Progesterone [ Time Frame: Up to 24 weeks ]
    Blood samples will be collected from participants for hormonal measurements.

  19. Percent Change From Baseline At Weeks 4, 8, 12, 16, and 20 In MBL Volume [ Time Frame: Baseline to Weeks 4, 8, 12, 16, and 20 ]
  20. Time To Achieve An MBL Volume Of < 80 mL And At Least A 50% Reduction From Baseline MBL Volume [ Time Frame: From Baseline through Week 24 ]
    MBL volume is measured using the alkaline hematin method.

  21. Percentage Of Participants In The Relugolix Plus E2/NETA Group Versus The Placebo Group Who Achieve An MBL Volume Of < 80 mL And At Least A 50% Reduction From Baseline MBL Volume By Visit [ Time Frame: From Baseline through Week 24 ]
  22. Sustained Amenorrhea Rate (No Or Negligible Bleeding) By Visit [ Time Frame: From Baseline through Week 24 ]
  23. Time To Achieving Sustained Amenorrhea (No Or Negligible Bleeding) [ Time Frame: From Baseline through Week 24 ]
  24. Time To Achieving Amenorrhea (No Or Negligible Bleeding) [ Time Frame: From Baseline through Week 24 ]
  25. Percentage Of Participants With A Hemoglobin Concentration Below The Lower Limit Of Normal At Baseline Who Achieve An Increase Of ≥ 1 g/dL From Baseline At Week 24 [ Time Frame: From Baseline through Week 24 ]
  26. Change From Baseline At Week 24 In Hemoglobin For Participants With A Hemoglobin Concentration ≤ 10.5 g/dL At Baseline [ Time Frame: Baseline, Week 24 ]
  27. Change From Baseline At Week 24 In The UFS-QoL Symptom Severity Scale Score [ Time Frame: Baseline, Week 24 ]
  28. Change From Baseline At Week 24 In The UFS-QoL Activities Scale Score [ Time Frame: Baseline, Week 24 ]
  29. Change From Baseline At Week 24 In The UFS-QoL Revised Activities Scale Score [ Time Frame: Baseline, Week 24 ]
  30. Proportion Of Responders Who Achieve A Meaningful Increase Of At Least 20 Points From Baseline At Week 24 In UFS-QoL Revised Activities Scale Score [ Time Frame: From Baseline through Week 24 ]
  31. Proportion Of Responders Who Achieve A Meaningful Reduction Of At Least 20 Points From Baseline At Week 24 In UFS-QoL Bleeding And Pelvic Discomfort Scale Score [ Time Frame: From Baseline through Week 24 ]
  32. Change From Baseline At Week 24 In The Interference Of Uterine Fibroids With Physical Activities Based On UFS-QoL Question 11 [ Time Frame: Baseline, Week 24 ]
  33. Change From Baseline At Week 24 In The Interference Of Uterine Fibroids With Social Activities Based On UFS-QoL Question 20 [ Time Frame: Baseline, Week 24 ]
  34. Change From Baseline At Week 24 In Embarrassment Caused By Uterine Fibroids Based On UFS-QoL Question 29 [ Time Frame: Baseline, Week 24 ]
  35. Participants Achieving Improvement From Baseline In PGA For UFS From Baseline At Week 24 [ Time Frame: From Baseline through Week 24 ]
  36. Participants Achieving Improvement From Baseline In PGA For Uterine Fibroid-related Function From Baseline At Week 24 [ Time Frame: From Baseline through Week 24 ]
  37. Change From Baseline At Week 24 In The Menorrhagia Impact Questionnaire Score For Physical Activities [ Time Frame: Baseline, Week 24 ]
  38. Change From Baseline At Week 24 In The Menorrhagia Impact Questionnaire Score For Social And Leisure Activities [ Time Frame: Baseline, Week 24 ]
  39. Participants Who Achieve A Maximum NRS Score For Pain Associated With Uterine Fibroids Over The Last 35 Days Of Treatment [ Time Frame: From Baseline up to the last 35 days of treatment (up to 24 weeks) ]
    The maximum NRS score should be at least a 30% reduction from baseline in the subset of participants with a maximum pain score ≥ 4 during the 35 days prior to randomization.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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 participant'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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03103087


Locations
Show Show 127 study locations
Sponsors and Collaborators
Myovant Sciences GmbH
Investigators
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Study Director: Myovant Medical Monitor Myovant Sciences
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Responsible Party: Myovant Sciences GmbH
ClinicalTrials.gov Identifier: NCT03103087    
Other Study ID Numbers: MVT-601-3002
2016-005113-50 ( EudraCT Number )
First Posted: April 6, 2017    Key Record Dates
Last Update Posted: June 23, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leiomyoma
Myofibroma
Menorrhagia
Hemorrhage
Pathologic Processes
Neoplasms, Muscle Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Connective Tissue
Connective Tissue Diseases
Uterine Hemorrhage
Uterine Diseases
Genital Diseases, Female
Menstruation Disturbances
Estradiol 3-benzoate
Estradiol 17 beta-cypionate
Norethindrone
Norethindrone Acetate
Estradiol
Polyestradiol phosphate
Estrogens
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Contraceptive Agents
Reproductive Control Agents
Contraceptive Agents, Female
Contraceptives, Oral, Synthetic
Contraceptives, Oral