A Phase II/III Study of Efficacy and Safety of SHR7280 Tablets in Subjects With Menorrhagia With Uterine Fibroids

Study Overview
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Brief Summary
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Phase II:To explore the optimal effective dose of SHR7280 tablets in subjects with menorrhagia with uterine fibroids as a phase III treatment dose. Phase III:To evaluate the efficacy of the selected dose of SHR7280 compared with placebo in reducing menstrual bleeding in subjects with menorrhagic uterine fibroids in phase II studies.

Official Title
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A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled Phase II/III Clinical Study to Explore the Optimal Therapeutic Dose of SHR7280 Tablets and the Efficacy and Safety of SHR7280 Tablets in Subjects With Menorrhagia for Uterine Fibroids

Conditions
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Uterine Fibroids With Menorrhagia

Intervention / Treatment
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* Drug: SHR7280 tablets
* Drug: SHR7280 tablets
* Drug: PlaceboSHR7280 tablets blank preparation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The informed consent has been signed and dated; Non-menopausal women between the ages of 18 and 49 (including 18 and 49); Single or multiple uterine fibroids were confirmed by ultrasound examination during screening, and the maximum diameter of at least one fibroid was ≥2 cm; Heavy menstrual bleeding measured by the alkaline hematin method during screening; 3 months before screening, the subject's menstrual cycle is 21-38 days, and the period is no more than 14 days; The pregnancy test was negative on the day of screening visit and randomization; Human papillomavirus (HPV) testing should be added for subjects who have cervical cytology at the time of screening visit and whose TCT results are atypical squamous cells (ASC-US) of uncertain significance, or who test negative for high-risk HPV. Exclusion Criteria: Excessive menstrual bleeding and anemia caused by other reasons; A history of depression or clinically significant depression; Have a history of drug abuse, drug dependence; History of smoking and alcohol abuse within 3 months prior to screening; A history of delivery, breastfeeding and miscarriage within 6 months prior to screening; Patients who received myomectomy within 3 months before screening, and patients who received uterine artery embolization, or high intensity focused ultrasound (HIFU) ablation within 6 months before screening; Patients who underwent endometrial resection within 1 year prior to screening; Patients with severe infection (one organ or whole body infection caused by pathogenic microorganism, and failure or death of the organ or multiple organs caused by infection), severe trauma (ISS ≥16 points) or major surgery (grade III/IV surgery in Surgical Classification Catalogue) within 6 months prior to screening; Previous clinical major systemic disease, endocrine or metabolic abnormalities; Having past or current thromboembolic disease or having a risk factor for thromboembolic disease (stage 2 only); Previous history of malignant tumors such as ovary, breast, uterus, liver, hypothalamus and pituitary gland;Known or suspected sex hormone-dependent malignancies; Any pre-existing disease or symptom (e.g., chronic intestinal disease, Crohn's disease, ulcerative colitis) that may affect systemic functioning of the body and may affect absorption, excessive accumulation, metabolism, or change the excretion pattern of the test drug; Persons with prior known serious mental illness or inability to understand the purpose, methods, etc. of the clinical trial, and who did not follow the study procedures; Live (attenuated) vaccine (other than influenza vaccine) received within 1 month prior to screening or planned during the trial; Other reasons that the investigator considered inappropriate for participation in the study. Follicle-stimulating hormone (FSH) ≥25U/L during screening; Hb < 6 g/dL during screening; Moderate to severe liver impairment during screening, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), or bilirubin (unless Gilbert's diagnosis is known) ≥2.0 times the upper limit of the reference range; During screening, endometrial biopsy should be performed if endometrial thickness > 18 mm is indicated by gynecological ultrasound or if the investigator deems it necessary. Endometrial histological abnormalities indicated by endometrial biopsy should be performed (only in the first stage). Active pelvic inflammatory disease (PID) during screening; QTcF≥450ms during screening; Infectious disease screening resultshave clinical significance; 6 months before enrollment, endometrial biopsy revealed significant endometrial histological abnormalities;If the subject has no sexual life history or the investigator determines that it is not necessary, the subject may be exempted (stage 2 only); Two or more blood transfusions within 9 months prior to enrollment, or requiring transfusion therapy within 2 months prior to enrollment, or having any condition requiring immediate transfusion; 1 month before admission, she used any drugs that inhibited or induced liver metabolism of drugs (liver drug enzyme inhibitors such as chloramphenicol, allopurinol,ketoconazole, fluoroquinolones, etc., and liver drug enzyme inducers such as carbamazepine, dexamethasone, phenobarbital, phenytoin sodium, rifamequine); Participants in and enrolled in clinical trials of any drug or medical device within 3 months prior to enrollment, or who were still in the follow-up period of a clinical study or within 5 half-lives of the tested drug prior to screening, whichever is longer.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 49 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Phase one：300mg/400mgSHR7280 tablets were compared with placebo Phase two：SHR7280 monotherapy group, SHR7280 reverse therapy group and placebo group were controlled
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment group A: SHR7280 tablets<br> | Drug: SHR7280 tablets<br>* SHR7280 tablets 300mg for 12 weeks<br>|
| Experimental: Treatment group B:SHR7280 tablets<br> | Drug: SHR7280 tablets<br>* SHR7280 tablets 400mg for 12 weeks<br>|
| Placebo Comparator: Treatment group C:Intervention: Drug: PlaceboSHR7280 tablets blank preparation<br> | Drug: PlaceboSHR7280 tablets blank preparation<br>* Placebo group: SHR7280 tablets blank preparation for 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase one：Percentage of subjects with menstrual bleeding < 80 mL and a reduction of ≥50% from baseline |  | After treatment at week 12 | 
| Phase two：Percentage of subjects with menstrual bleeding < 80 mL and a reduction of ≥50% from baseline |  | After treatment at week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of subjects with menstrual bleeding < 80 mL and a reduction of ≥50% from baseline（Phase one） |  | The treatment ended at week 4 and 8 | 
| percentage of subjects without menstrual bleeding or spotting （Phase one） |  | The treatment ended at week 4, 8 and 12 | 
| Changes in hemoglobin concentration from baseline（Phase one） |  | The treatment ended at week 4, 8 and 12 | 
| Changes in uterine volume and maximum fibroid volume from baseline（Phase one） |  | The treatment ended at week 8 and 12 | 
| patient global impression of change scale evaluation，The minimum is 1, the maximum is 7, and higher scores mean worse results（Phase one） |  | The treatment ended at week 12 | 
| Changes in uterine fibroid symptoms from baseline（Phase one） |  | The treatment ended at week 12 | 
| Changes in health related Quality of Life Questionnaire (UFS-QOL) scores from baseline，The minimum is 37 and the maximum is 185, with higher scores indicating worse results（Phase one） |  | The treatment ended at week 12 | 
| Number of Participants with Adverse events（Phase one） |  | Stage ⅱ ended, about 30 weeks | 
| The interval between stopping the medication and resuming menstruation（Phase one） |  | Stage ⅱ ended, about 30 weeks | 
| The amount of menstrual bleeding when the medication was stopped until menstruation resumed（Phase one） |  | Stage ⅱ ended, about 30 weeks | 
| Number of days of menstruation from the time of discontinuation of the medication to the time of resumption of menstruation(Phase one) |  | Stage ⅱ ended, about 30 weeks | 
| SHR7280 concentration in plasma(Phase one) |  | Before and at week 4, 8 and 12 after administration | 
| Serum concentrations of estradiol, luteinizing hormone, follicle stimulating hormone and progesterone(Phase one) |  | Before and at week 4, 8 and 12 after administration | 
| Percentage of subjects with menstrual bleeding < 80 mL and a reduction of ≥50% from baseline（Phase two） |  | At the end of weeks 4,8,12,16,20,28,32,36,40,44,48,52 | 
| Changes in menstrual bleeding from baseline were assessed using the Alkaline hematin method (AH)（Phase two） |  | At the end of weeks 4,8,12,16,20,24,28,32,36,40,44,48,52 | 
| percentage of subjects without menstrual bleeding or spotting (Phase two) |  | Weeks 4,8,12,16,20,24,28,32,36,40,44,48,52 | 
| change in Hb concentration from baseline (Phase two） |  | The treatment ended at 4, 8, 12, 16, 20, 24, 36, 44, 52 weeks | 
| Changes in uterine volume and maximum fibroid volume from baseline(Phase two) |  | The treatment ended at weeks 12, 24, and 52 | 
| patient global impression of change scale evaluation，The minimum is 1, the maximum is 7, and higher scores mean worse results(Phase two) |  | The treatment ended at weeks 12, 24, and 52 | 
| Changes in health related Quality of Life Questionnaire (UFS-QOL) scores from baseline，The minimum is 37 and the maximum is 185, with higher scores indicating worse results(Phase two) |  | The treatment ended at weeks 12, 24, and 52 | 
| Number of Participants with Adverse events(Phase two) |  | Stage ⅲ ended at about 74 weeks | 
| The interval between stopping the medication and resuming menstruation(Phase two) |  | Stage ⅲ ended at about 74 weeks | 
| The amount of menstrual bleeding when the medication was stopped until menstruation resumed(Phase two) |  | Stage ⅲ ended at about 74 weeks | 
| Number of days of menstruation from the time of discontinuation of the medication to the time of resumption of menstruation(Phase two) |  | Stage ⅲ ended at about 74 weeks | 
| plasma SHR7280 concentration data(Phase two) |  | Treatment ended at 4, 24, 36, 52 weeks before administration | 
| serum E2, LH, FSH and P concentrations at each point of view(Phase two) |  | Treatment was completed at 4, 8, 12, 16, 20, 24, 36, 44, 52 weeks before administration |