Surgical Myomectomy Followed by Oral Myfembree Versus Standard of Care Trial (SOUL)

Inclusion Criteria:

• Inclusion Criteria (all inclusion criteria must have been met prior to randomizationunless otherwise specified):

1. Has voluntarily signed and dated the informed consent form prior to initiation ofany screening or study-specific procedures
2. Premenopausal female aged 18 years and older on the day of signing of theinformed consent form
3. Has a diagnosis of uterine fibroids that is confirmed by a pelvic ultrasound (transvaginal and/or transabdominal) performed during the screening period.
4. Has at least one or more of the following symptoms:
5. Heavy menses defined as PBAC (Pictorial Bleeding Assessment Chart) score ≥ 120
6. Pelvic pain during menses measured on NRS (Numeric Pain Rating Scale) ≥ 4 atbaseline
7. Moderately severe fibroid-related symptoms (a score ≥ 25 on the UterineFibroid UF quality of life symptoms severity subscale)
8. Has a negative urine pregnancy test at the Screening, Baseline and intervalclinic visits
9. Agrees to not be pregnant for at least 12 months. Participant may use any form ofnon-hormonal contraception consistently during the screening period . These mayinclude: Diaphragm, cervical cap, spermicides, male and female condoms, copperIUD ( intra uterine device) and sponge. Each one will be explained in detail forthe participants. However, the patient is not required to use dual contraceptionif she:
10. Has a sexual partner(s) who was vasectomized at least 6 months prior to thescreening period.
11. Had a bilateral tubal occlusion (including ligation and blockage methodssuch as Essure™), at least 4 months prior to the first screening visit (patients with Essure™ must have prior confirmation of tubal occlusion byhysterosalpingogram);
12. Is not sexually active with men; periodic sexual relationship(s) with menrequires the use of dual non-hormonal contraception as noted above; or
13. Practices total abstinence from sexual intercourse as her preferredlifestyle; periodic abstinence is not acceptable.
14. Has an endometrial (aspiration) biopsy, if clinically indicated, performed duringthe screening period, with results showing no clinically significant endometrialpathology (hyperplasia, endometritis, or endometrial cancer).

Exclusion Criteria: Participants who choose not to undergo randomization and instead optfor the parallel group, selecting the standard of care (SOC) arm, are exempted from meetingthe exclusion criteria (4-5-6-7-8(C&D)-9-11-12) specified for the study drug.

1. Has transvaginal and/or transabdominal ultrasound during the screening perioddemonstrating pathology other than uterine fibroids that could be responsible for orcontributing to the patient's heavy menstrual bleeding, such as uterine or cervicalpolyps > 2.0 cm, or any other clinically significant gynecological disorder determinedby the investigator to require further evaluation and/or treatment. Note: Saline or gel contrast is not routinely required. Use of such contrast isrequired only when the endometrium cannot be evaluated or when there are ambiguous andpotentially exclusionary findings on the transvaginal and/or transabdominal ultrasound (e.g., suspected intrauterine masses, equivocal endometrial findings, etc.)
2. Has unexplained vaginal bleeding outside of the patient's regular menstrual cycle
3. Has undergone ultrasound-guided laparoscopic radiofrequency ablation, or any othersurgical procedure for fibroids, uterine artery embolization, magneticresonance-guided focused ultrasound for fibroids, as well as endometrial ablation forabnormal uterine bleeding within 6 months prior to the Screening visit
4. Has a history of or currently has osteoporosis, or other metabolic bone disease,hyperparathyroidism, hyperprolactinemia, hyperthyroidism, anorexia nervosa, or lowtraumatic (from the standing position) or atraumatic fracture (toe, finger, skull,face, and ankle fractures are allowed). A history of successfully treatedhyperparathyroidism, hyperprolactinemia, or hyperthyroidism is allowed if thepatient'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 Dpreparations to treat bone mineral density loss
6. Anticipated use of systemic glucocorticoids at an oral prednisone-equivalent dose ofmore than 5 mg every other day during the study. Note: topical, inhaled, intranasal,optic, ophthalmic, intraarticular, or intralesional subcutaneous are permitted withoutrestriction
7. Gastrointestinal disorder affecting absorption or gastrointestinal motility
8. Has any additional contraindication to treatment with low-dose estradiol andnorethindrone acetate, including:
9. Current, known, suspected, or history of breast cancer
10. Current, known, or suspected hormone -dependent neoplasia
11. High risk of arterial, venous thrombotic disorder or thromboembolic disorder i. women over 35 years of age who smoke or women with uncontrolled hypertension d. Active thrombotic or thromboembolic disease or history of these conditions prior tothe Baseline Day 1 visit or risk factors for such conditions. These conditionsinclude: i. deep vein thrombosis ii. pulmonary embolism iii. vascular disease (e.g.,cerebrovascular disease, coronary artery disease, peripheral vascular disease) iv.inherited or acquired hypercoagulopathies, known protein C, protein S, or antithrombindeficiency, or other known thrombophilia disorders, including Factor V Leidenthrombogenic valvular or thrombogenic rhythm diseases of the heart (for example,subacute bacterial endocarditis with valvular disease, or atrial fibrillation) v.uncontrolled hypertension vi. headaches with focal neurological symptoms or migraineheadaches with aura if over 35 years of age vii. Women at increased risks forthrombotic or thromboembolic events e. Known anaphylactic reaction or angioedema or hypersensitivity to estradiol ornorethindrone acetate f. Currently pregnant or lactating, or intends to become pregnant or to donate ovaduring the study period or within 1 month after the end of the study
12. Has jaundice or known current active liver disease from any cause, including hepatitisA (HAV IgM), hepatitis B (HBsAg), or hepatitis C (HCV Ab positive, confirmed by HCVRNA);
13. Has any of the following cervical pathology: high grade cervical neoplasia, atypicalglandular cells, atypical endocervical cells, atypical squamous cells favoring highgrade. Of note, patients with atypical squamous cells of undetermined significance andlow-grade cervical neoplasia may be included in the study if high risk human papillomavirus testing is negative or if DNA testing for human papilloma virus 16 and 18 DNAtesting is negative
14. Has any of the following clinical laboratory abnormalities indicating hepatic orgallbladder impairment:
15. Alanine aminotransferase or aspartate aminotransferase > 2.0 times the upperlimit of normal (ULN), or bilirubin (total bilirubin) > 1.5 x ULN on clinicallaboratory testing at either the Screening 1 or Screening 2 visit (or > 2.0 x ULNif secondary to Gilbert syndrome or pattern consistent with Gilbert syndrome);
16. Estimated glomerular filtration rate < 60 mL/min/m2 using the Modification ofDiet in Renal Disease method
17. Has clinically significant cardiovascular disease including:
18. Prior history of myocardial infarction
19. History of angina
20. History of congestive heart failure
21. History of clinically significant ventricular arrhythmias such as ventriculartachycardia, ventricular fibrillation, or torsade de pointes, or Mobitz II seconddegree or third-degree heart block without a permanent pacemaker in place oruntreated supraventricular tachycardia (heart rate ≥ 120 beats per minute)
22. QT interval by the Fridericia correction formula (QTcF) of > 470 msec
23. Hypotension, as indicated by systolic blood pressure < 84 millimeters of mercury (mmHg) on 2 repeat measures at least 15 minutes apart or treated ongoingsymptomatic orthostatic hypotension with > 20 mmHg decrease in systolic bloodpressure one minute or more after assuming an upright position.
24. Uncontrolled hypertension, as indicated by systolic blood pressure > 160 mmHg on 2 repeat measures at least 15 minutes apart or diastolic blood pressure > 100mmHg at any screening visit or the Baseline Day 1 visit.
25. Bradycardia as indicated by a heart rate of < 45 beats per minute on thescreening electrocardiogram.
26. Has been a participant in an investigational drug or device study within the 1 monthprior to Screening visit.
27. Has a history of clinically significant condition(s) including, but not limited to:
28. Untreated thyroid dysfunction or palpable thyroid abnormality (patients withadequately treated hypothyroidism who are stable on medication are not excluded).
29. History of malignancy within the past 5 years or ongoing malignancy other thancuratively treated nonmelanoma skin cancer or surgically cured Stage 0 in situmelanoma
30. Any current psychiatric disorder that would, in the opinion of the investigator ormedical monitor, impair the ability of the patient to participate in the study orwould impair interpretation of their data. Patients with major depression,post-traumatic stress disorder, bipolar disorder, schizophrenia, or other psychoticdisorders, based on Diagnostic and Statistical Manual of Mental Disorders-5 criteriawho have been unstable based on the investigator's or mental health professional'sjudgement or whose psychiatric drug regimen has changed during the 3 months prior toScreening or is expected to change during the study should not be enrolled. Has acontraindication or history of sensitivity to any of the study treatments orcomponents thereof; or has a history of drug or other allergy that, in the opinion ofthe investigator or medical monitor, contraindicates study participation
31. Has a prior (within 1 year of Screening 1 visit) or current history of drug or alcoholabuse disorder according to Diagnostic and Statistical Manual of Mental Disorders V (all patients must be questioned about their drug and alcohol use, and this should bedocumented in the electronic case report form)
32. Has participated in a previous clinical study that included the use of Relugolix orhas received this treatment within 3 months of the study.
33. Is inappropriate for participation in this study for other reasons, as determined bythe investigator, sub-investigator, or medical monitor.