Study to Evaluate Safety and Efficacy of SYHX1901 Tablets in Severe Alopecia Areata Patients

The purpose of this study is to evaluate the efficacy and safety of different doses of SYHX1901 tablets in the treatment of severe alopecia areata.

This is a multicenter, randomized, double-blind, placebo-controlled phase II study to evaluate the efficacy and safety of two different doses of SYHX1901 tablets compared with placebo in the treatment of severe alopecia areata. The total duration of the study will be 56 weeks which will be comprised of: a screening period (4 weeks); a core treatment period (24 weeks),a extended treatment period（28 weeks）and a follow-up assessment period (4 weeks). Eligible subjects will be randomly assigned to SYHX1901 dose 1 , dose 2，dose 3 or placebo group at a 1:2:2:1 ratio for continuous oral administration for 24 weeks, then placebo group will receive SYHX1901 at dose 3 for 28 weeks, the SYHX1901 dose 1, dose 2，dose 3 group will remain the same dose for 28 weeks. The SALT（Severity of ALopecia Tool） score will be a stratification factor. Subjects will be monitored for the safety throughout the study.

Eligibility Criteria:
Inclusion Criteria:

1. Subjects aged ≥18 to ≤ 65 years;
2. Clinical diagnosis of alopecia areata,with at least 50% scalp hair loss，as defined by a SALT score ≥50 at screening and baseline visit;
3. The current episode of hair loss was less than 10 years ago, and there was no evidence of spontaneous hair regrowth within 6 months before screening (the overall duration of alopecia areata more than 10 years could be included);
4. Subjects must be volunteer and be able to understand informed consent Forms;
5. Subjects and their partners should voluntarily take contraceptive measures considered effective by the investigator during the study period and for at least 28 days after the study;

Exclusion Criteria:

1. Participants who have received hair implants;
2. Alopecia caused by other reasons;
3. Other active scalp or systemic diseases that may cause severe alopecia or affect the clinical evaluation of alopecia areata;
4. Participants who have shaved their heads;
5. Participants who have a clinically significant (as assessed by the investigator) abnormality in TSH or free T4 at screening and who were deemed by the investigator to be ineligible for the study;
6. Participants who wore stick-on wigs and refused to stop wearing them during the study;
7. Participants who have received treatments before the first dose of the study drug：

   1. Traditional Chinese medicine with alopecia areata treatment had been used within 2 weeks before the first dose;
   2. Treatment with other medications that may affect hair regrowth or the immune response within 4 weeks before the first dose or during the study, such as oral or injectable corticosteroids , Platelet-rich plasma injection; Contact immunotherapy, topical stimulants or topical application of minoxidil;
   3. A potent inhibitor/potent inducer of CYP3A4, or a potent inhibitor/inducer of P-gp had been used within 4 weeks before the first dose;
   4. Have used physical therapy within 4 weeks before the first dose; (including phototherapy);
   5. Have used systemic immunosuppressive drugs within 12 weeks before the first dose;
   6. Have used any JAK inhibitor within 12 weeks before the first dose; Have used B cell-depleting therapy within 6 months before the first dose or during the study;
   7. Have used immunomodulatory biologic within 6 months before the first dose;
   8. Have used non B-cell selective lymphodepletion;
   9. Use of BCRP-sensitive substrate drugs assessed by the investigator during the study;
8. Participation in any interventional clinical trial within 4 weeks before the first dose of the study drug or within the five half-lives of the study drug, whichever was longer;
9. Bacterial, fungal, or viral infection requiring hospitalization/intravenous treatment within 4 weeks before the first dose of study drug or requiring oral treatment within 2 weeks before the first dose of study drug;
10. Have any chronic infection that requires systemic anti-infective therapy;
11. Have received a live vaccine within 60 days before the first dose of the study drug or plan to receive a live vaccine between the middle of the study and 60 days after the end of the study;
12. History of severe herpes zoster or sever herpes simplex infection;
13. HBV-related tests are abnormal at screening;
14. HCV antibody positive and HCV RNA positive at screening;
15. Human immunodeficiency virus antibody positive or treponema pallidum antibody positive;
16. Any known or suspected condition of congenital or acquired immunodeficiency;
17. Previous or current active tuberculosis infection or latent tuberculosis infection (LTBI) deemed by the investigator/specialist to require treatment;
18. Major surgery within 8 weeks prior to first dose of the study drug or planned surgery during the study;
19. Organ transplantation (except corneal transplantation more than 3 months before the initiation of the investigational drug);
20. Symptoms or signs of progressive or uncontrolled kidney, liver, blood, gastrointestinal, endocrine, lung, heart, neurological, psychiatric, or brain disease, or with other chronic diseases that the investigator has determined are not suitable for participation in this clinical trial;
21. History of malignancy or lymphoproliferative disease within 5 years (except for cured basal cell carcinoma and in situ cervical cancer, etc.);
22. Uncontrolled hypertension, systolic blood pressure \>160 mmHg or diastolic blood pressure \>100 mmHg after systemic treatment;
23. Having unstable cardiovascular disease defined as presence of a clinical cardiovascular event in the last 3 months or hospitalized for heart disease within the last 3 months; or NYHA≥grade 3, or abnormal ECG suggesting clinically significant and assessed by the investigator as carrying unforeseen risks;
24. Patients with a history of arterial or venous thrombosis or high risk factors for thrombosis within 6 months before the first dose of study drug;
25. Combined with active lipid-lowering drugs but poorly controlled hyperlipidemia: total cholesterol (TC)≥ 6.2mmol/L or low-density lipoprotein cholesterol (LDL-C)≥3.4mmol/L; or familial hypercholesterolemia (FH);
26. Significant gastrointestinal disorders, such as erosion, hemorrhagic gastroenteritis, a history of bleeding from gastrointestinal ulcers, inflammatory bowel disease, and other disorders that investigator consider to be at risk for gastrointestinal perforation or that may interfere with drug ingestion, transport, or absorption;
27. Laboratory abnormalities of clinical significance assessed by the investigator to pose a risk:

    1. AST or ALT \>2×ULN;
    2. Total bilirubin and/or direct bilirubin \>2×ULN;
    3. Neutrophil absolute value (NEUT#) \<1.5×10\^9/L;
    4. Serum creatinine \> 1.5 x ULN；
28. History of neurological or psychiatric diseases, such as severe depression, suicidal tendency, epilepsy, dementia, and so on, which may affect the safety and efficacy evaluation
29. Any other medical and/or social reasons for inappropriate participation in the study as determined by the investigator.