The Pharmacokinetic(PK)/Pharmacodynamics(PD) Study of SHR7280 Tablets in Premenopausal Subjects With Endometriosis.

Study Overview
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Brief Summary
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The primary objective of this study is to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of SHR7280 tablets in premenopausal subjects with endometriosis. In addition, this study will provide information on efficacy of SHR7280 tablets in premenopausal subjects with endometriosis.

Detailed Description
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Endometriosis is a common disease, aﬀecting 5-10% of women of reproductive age . It is an estrogen-dependent and estrogen-driven disease and so hormonal manipulation and suppression of estrogen production form the basis of the majority of medical treatment. The primary objective of this study is to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of SHR7280 tablets in premenopausal subjects with endometriosis. In addition, this study will provide information on efficacy of SHR7280 tablets in premenopausal subjects with endometriosis.

Official Title
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A Phase I/II, Randomized, Double-Blind, Placebo-Controlled, Multiple-Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics ,Pharmacodynamics and Efficacy of SHR7280 Tablets in Premenopausal Subjects With Endometriosis.

Conditions
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Endometriosis

Intervention / Treatment
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* Drug: SHR7280
* Drug: Placebo oral tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Phase I/II premenopausal females, aged 18-45 History of regular menstrual cycles Endometriosis participant diagnosed by surgical (e.g., laparoscopy or laparotomy) or by magnetic resonance imaging or ultrasonography. Participant must agree to use only protocol specified rescue analgesics during the Screening and Treatment Periods for endometriosis-associated pain. Participant in general good health. No clinically significant findings in laboratory parameters or clinically significant abnormality on X-ray Phase I (only) Participant has mild or moderate pelvic pain associated with endometriosis at Screening. Phase II(only) Participant has moderate or severe pelvic pain associated with endometriosis at Screening. Exclusion Criteria: Phase I/II Subjects with severe trauma or surgery within 6 months prior to the screening； Known blood donation within 30 days pre-dose; donating≥200 ml of blood 2 months pre-dose; Pregnant or Serum β-human chorionic gonadotropin (hCG)> 5 Million International Units(mIU)/mL at screening or baseline Pregnant or breast feeding ; Have pelvic pain that is not caused by endometriosis Abnormal uterine bleeding Are currently receiving gonadotropin-releasing hormone (GnRH) agonist, a GnRH antagonist or danazol or have received any of these agents within 6 months of the start of screening. Are currently receiving subcutaneous medroxyprogesterone acetate (DMPA-SC) or intramuscular medroxyprogesterone acetate (DMPA-IM) or have received any of these agents within 3 months of the start of screening. Are currently using hormonal contraception or other forms of hormonal therapy or received such treatment within 2 months of the start of screening. Phase I (only) one month prior to screening involved in any drug or medical device clinical subjects, or within 5 half-life of drugs before screening; Phase II (only) Screening dual-energy x-ray absorptiometry (DXA) scan results of the lumbar spine, femoral neck, or total hip bone mineral density corresponding to 1.5 or more standard deviations below normal (T-score at or below -1.5)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SHR7280 dose 1<br>oral administration for 21days,Phase I | Drug: SHR7280<br>* treatment<br>Drug: Placebo oral tablet<br>* blank control<br>|
| Experimental: SHR7280 dose 2<br>oral administration for 21days,Phase I | Drug: SHR7280<br>* treatment<br>Drug: Placebo oral tablet<br>* blank control<br>|
| Experimental: SHR7280 dose 3<br>oral administration for 21days,Phase I | Drug: SHR7280<br>* treatment<br>Drug: Placebo oral tablet<br>* blank control<br>|
| Experimental: SHR7280 dose 4<br>oral administration for 21days,Phase I | Drug: SHR7280<br>* treatment<br>Drug: Placebo oral tablet<br>* blank control<br>|
| Active Comparator: SHR7280 low dose<br>oral administration for 84days,Phase II | Drug: SHR7280<br>* treatment<br>|
| Active Comparator: SHR7280 high dose<br>oral administration for 84days, Phase II | Drug: SHR7280<br>* treatment<br>|
| Placebo Comparator: Placebo<br>oral administration for 84days, Phase II | Drug: Placebo oral tablet<br>* blank control<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Adverse events | Phase I | Pre-dose to 28±2 days after dose administration | 
| Change From Baseline in the 7-day mean score for pelvic pain as measured by VAS at weeks 12 | Phase II daily assessment of dysmenorrhea score on a 4-point scale (0 = none, 1 = mild, 2 = moderate, 3 = severe) using an e-Diary. | Baseline and weeks 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK markers of SHR7280: area under the plasma concentration versus time curve (AUC) | Phase I & II | At pre-defined intervals from initial dose through final study visit | 
| PK markers of SHR7280: time to maximum plasma concentration(Tmax) | Phase I & II | At pre-defined intervals from initial dose through final study visit | 
| PK markers of SHR7280: maximum plasma concentration(Cmax) | Phase I & II | At pre-defined intervals from initial dose through final study visit | 
| PK markers of SHR7280: half-time(t1/2) | Phase I & II | At pre-defined intervals from initial dose through final study visit | 
| PK markers of SHR7280: apparent clearance(CL/F) | Phase I & II | At pre-defined intervals from initial dose through final study visit | 
| PK markers of SHR7280: apparent volume of distribution(Vz/F) | Phase I & II | At pre-defined intervals from initial dose through final study visit | 
| PD markers of SHR7280: Concentration of Estradiol(E2) | Phase I & II | At pre-defined intervals from initial dose through final study visit | 
| PD markers of SHR7280: Concentration of Progesterone(P) | Phase I & II | At pre-defined intervals from initial dose through final study visit | 
| PD markers of SHR7280: Concentration of Follicle stimulating hormone(FSH) | Phase I & II | At pre-defined intervals from initial dose through final study visit | 
| PD markers of SHR7280: Concentration of Luteinizing hormone(LH) | Phase I & II | At pre-defined intervals from initial dose through final study visit | 
| Change From Baseline in the 7-day mean score for pelvic pain as measured by VAS | Phase II | Baseline and weeks 4、8 | 
| Change From Baseline in the Monthly Mean score for pelvic pain as measured by VAS | Phase II | Baseline and weeks 4、8、12 | 
| Change From Baseline in the Monthly Mean Dysmenorrhea Score | Phase II | Baseline and weeks 8、12 | 
| Change From Baseline in the Monthly Mean Non-menstrual Pelvic Pain Score and Dyspareunia Score | Phase II | Baseline and weeks 4、8、12 | 
| Change from baseline to monthly analgesic use to treat endometriosis-associated pain | Phase II | Baseline and weeks 4、8、12 | 
| Patient Global Impression of Change (PGIC) score at week 12 | Phase II | Week 12 | 
| Adverse events |  | during Pre and 28±3 days after dose administration |