Lusutrombopag in the Treatment of Immune Thrombocytopenia (ITP)

An Open-label, Single-arm Study to Evaluate the Efficacy and Safety of Lusutrombopag in Chinese Adults With Persistent or Chronic Immune Thrombocytopenia

This exploratory study is to investigate the efficacy, safety and tolerability of Lusutrombopag in the treatment of primary immune thrombocytopenia in Chinese patients who have failed first-line therapy

This is an open-label, single-arm study of lusutrombopag initiated at a dose of 3mg daily titrated to a maximum dose of 6mg daily in the treatment of Chinese adults with persistent or chronic Immune thrombocytopenia (ITP) with or without prior splenectomy after failing first line therapy such corticosteroids and IV immunoglobulin. The study consists of three phases: Screening, Core Study（participants are treated with lusutrombopag 3mg daily for up to 4 weeks), and Titration study (participants are treated with lusutrombopag titrated to a maximum dose of 6mg daily according to their platelet counts）

Inclusion Criteria:

1. Males and females ≥18 years of age
2. Subjects>60 years must have had a diagnostic bone marrow aspiration in the last 3 years or responded to treatment (platelet count ≥50 x 10^9/L)
3. Participants diagnosed with primary persistent/chronic ITP (greater than or equal to 3 months duration) and an average of two platelet count less than 30 x 10^9/L. Conditions which may cause thrombocytopenia other than ITP should be ruled out, including but not limited to systemic lupus erythematosus (SLE)，aplastic anemia (AA), and myelodysplastic syndromes (MDS)
4. Relapsed persistent or chronic ITP status, with or without prior splenectomy. Participants who previously received one or more ITP therapies
5. Subjects receiving rescue therapy (including but not limited to corticosteroids, immunoglobulins and immunosuppressant) must have completed these therapies for at least 1 week or failed within 1 week prior to dosing on the first day (Visit 1)
6. Subjects receiving stable dosages of cyclosporine A, mycophenolate mofetil, azathioprine, or danazol are allowed, but must be receiving a dose that has been stable for at least 4 weeks prior to dosing on the first day (Visit 1)
7. Subjects receiving Chinese herbal medicine must be stopped 1 weeks prior to dosing on the first day (Visit 1), and Chinese herbal medicine is not allowed during the study
8. Subjects receiving steroid therapy must be on a stable dose for at least 2 weeks prior to screening (same milligram amount ± 10%； and ≤20 mg of equivalent dose of prednisone)
9. Two consecutive mean platelet count < 30×10^9/(a single platelet count of< 35×10^9/L is allowed） during screening if subjects were not receiving steroids, or two consecutive mean platelet count < 50×10^9/ if they were receiving steroids. Two Platelet counts must be measured at an interval of greater than 2 days and less than 14 days，and the second platelet count must be measured within 96 hours of day1（Visit 1）
10. Prothrombin time (PT) and activated partial thromboplastin time (APTT) within 20% of the upper limit of normal (ULN) at Screening or PT did not exceed normal value by ±3s and APTT by ±10s. No other history of coagulation state except ITP.
11. A complete blood count within the reference range ，including count of white blood cell (WBC) differential not indicative of a disorder other than ITP, with the following exceptions: a) Hemoglobin: participants with hemoglobin levels between 10 g/dL (100 g/L) and the lower limit of normal (LLN) are eligible for inclusion; participants with anemia(hemoglobin levels <10g/dl ) clearly attributable to ITP (excessive blood loss) are also eligible for inclusion; b) Absolute neutrophil count (ANC) greater than or equal to 1.5x10^9/L (elevated WBC/ANC due to corticosteroid treatment is acceptable).
12. All subjects must agree to take progestin or barrier contraception: patients with potential fertility (excluding hysterectomy, bilateral salpingectomy, bilateral tubal ligation or postmenopausal women for more than one year; Men with bilateral vasectomy) must take effective contraceptive measures at least 2 weeks before taking the study drug for the first time, throughout the study and within 28 days after the end of the study (or early termination of the study); Women with potential fertility must have a negative pregnancy test during the screening period and on the 0th day of the trial.
13. A signed and dated written consent obtained prior to the performance of Screening procedures

Exclusion Criteria:

1. History of inherited or acquired, clinically important hemorrhagic clotting disorder

2. Females who were pregnant or lactating, or receiving other hormone/chemical contraceptives

3. Patients with potential fertility refused to take contraceptive methods

4. Laboratory abnormalities

   • Hemoglobin <10.0 g/dL for men or women, not clearly related to ITP
   • Absolute neutrophil count < 1000/mm3
   • Abnormal peripheral blood smear with evidence of fibrosis confirmed by bone marrow biopsy
   • Total bilirubin > 1.5 x ULN
   • Alanine aminotransferase (ALT) > 1.5 x ULN
   • Aspartate aminotransferase (AST) > 1.5 x ULN
   • Creatinine > 1.5 x ULN
   • Human immunodeficiency virus positive
   • Hepatitis A Immunoglobulin M（IgM) antibody positive, hepatitis B surface antigen positive and HBV DNA ≥1000IU/ml or hepatitis C antibody positive，with a history of acute hepatitis, cirrhosis, portal hypertension or chronic active hepatitis.
   • Thyroid stimulating hormone (TSH) > 1.5 x ULN; or
   • Free thyroxine (T4) > 1.5 x ULN

5. Exposure to previous thrombopoietin (TPO) mimetics/agonists (e.g. romiplostim, recombinant human thrombopoietin (rhTPO), avatrombopag, eltrombopag and herombopag) within 4 weeks prior to initial screening.In addition, participants are allowed to be enrolled at the discretion of the investigator when platelet counts are below 30 x 10^9/L within the 4 weeks after withdrawal of thrombopoietin (TPO) mimetics/agonists

6. Subjects unresponsive to previous TPO mimetics/agonists

7. Exposure to an investigative medication within 4 weeks prior to the initial Screening Visit or Use of the following drugs or treatment prior to Visit 1 (Day 1):

   • Within 12 weeks - alemtuzumab, multi-drug systemic chemotherapy, stem cell therapy
   • Within 12weeks - rituximab

8. History of clinically significant cardiovascular or thromboembolic disease within 26 weeks prior to Initial screening

9. Splenectomy within 4 weeks prior to Initial Screening

10. Other abnormalities except ITP or situations that investigators deem inappropriate to participate in this study