Phase III Study on HMPL-523 for Treatment of ITP

This study consists of a double-blind phase (primary study) followed by an open-label phase (sub-study). The double-blind phase(n=188) is a randomized, double-blind, placebo-controlled phase III clinical trial in adult patients with primary ITP to determine whether HMPL-523 (sovleplenib) is safe and effective in the treatment of chronic ITP. The sub-study provides open-label HMPL-523 treatment to assess long-term safety and efficacy. The open-label phase have Cohort1 and Cohort 2. Cohort 1 enrolled patients from primary study who have received double-blind study treatment for 12 weeks with sustained platelet count <50×10⁹/L or have received double-blind study treatment for 24 weeks. Cohort 2 enrolled primary ITP patients(n=84) with disease duration >3 months.

Inclusion criteria

for double-blind phase:

• Voluntary signature of written informed consent form;
• Male or female aged 18~75 years;
• Performance Status score [Eastern Cooperative Oncology Group (ECOG) score] 0~1;
• Having been diagnosed as ITP prior to randomization, and duration of disease is more than 6 months;
• Intolerance or insufficient response, or recurrence after at least one anti-ITP standard drug therapy;
• Patients must have a history of response to previous ITP therapy;
• One combined anti-ITP therapy is allowed in this study, however, the following criteria need to be met:

• The dose of glucocorticoid has been stable for 4 weeks prior to randomization (<20 mg Prednisone equivalent);
• The dose of Danazol has been stable for 3 months prior to randomization;
• The dose of immunosuppressant (only including Azathioprine, Ciclosporin A, Mycophenolate mofetil) has been stable for 3 months prior to randomization.
• The condition is relatively stable; WHO bleeding scale grade is 0-1; no emergency treatment is expected within 2 weeks as judged by investigators.
• The laboratory examinations need to meet the following conditions (no treatment for this abnormal variable is given within one week prior to blood collection):

• Average platelet count <30×10^9 /L (and none > 35×10^9 /L unless as a result of rescue therapy) from at least 3 qualifying counts;
• Hemoglobin ≥100 g/L, neutrophil count >1.5×10^9/L;
• Total bilirubin (TBIL), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤1.5×upper limit of normal (ULN);
• Serum creatinine concentration ≤1.5×ULN and creatinine clearance ≥50 mL/min;
• Serum amylase and lipase ≤1.5×ULN;
• International normalized ratio (INR), activated partial thromboplastin time (APTT) not exceeding 20% of normal range.
• Male or female patients of childbearing potential must agree to use effective contraceptive methods during the study and within 90 days after last dose of study drug, e.g., double barrier contraceptive method, condom, oral or injectable contraceptives, intrauterine device, etc. Postmenopausal women (>50 years old and no menses for >1 year) and surgically sterilized women are not subject to this condition.

Exclusion criteria

for double-blind phase:

• Evidence on the presence of secondary causes of immune thrombocytopenia;
• Clinically serious hemorrhage requiring immediate adjustment of platelet (e.g., hypermenorrhea with significantly decreased hemoglobin);
• Clinically symptomatic gastrointestinal hemorrhage within 6 months prior to screening visit (e.g., haematemesis, tarry stool, however, the positive occult blood test without any sign or symptom of gastrointestinal hemorrhage will not be considered as "clinically symptomatic", or hemorrhoids hemorrhage is one exception);
• known history of vital organ transplantation or hematopoietic stem cell / bone marrow transplantation;
• Has received live vaccine within 8 weeks prior to Day 1 (baseline visit); or plan for immunization with live vaccine during the study;
• Splenectomy within 12 weeks prior to randomization;
• Major surgery within 4 weeks prior to the randomization, or plan for major elective surgery during the study;
• Previous history of malignant tumors (except for the basal cell carcinoma of skin or cervical carcinoma in situ that have been cured);
• History of important arterial / venous embolic disease;
• Intracranial hemorrhage within 6 months before screening visit;
• History of serious cardiovascular disease (e.g., grade III/IV congestive heart failure, arrhythmia or angina pectoris requiring drug therapy, unstable angina pectoris, intracoronary stent implantation, angioplasty or coronary artery bypass grafting, or QTc ≥450 ms);
• Hypertension that can not be controlled with drugs (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg);
• Previous history of serious gastrointestinal disease, such as dysphagia, active gastric ulcer, inability to take drugs orally or absorption disorder for oral drugs;
• Human immunodeficiency virus (HIV) infection, or hepatitis B (in case of positive HBsAg or HBcAb, positive HBV DNA needs to be determined), or hepatitis C (positive HCV RNA), or liver cirrhosis;
• Significant active infection that is not controlled clinically (e.g., sepsis, pneumonia or abscess), or serious infection within 6 weeks prior to randomization (leading to hospitalization or requiring treatment with antibiotic injections);
• Has received rescue therapy for ITP within 2 weeks prior to randomization; Has received the treatment for the objective of increasing platelet within 4 weeks prior to randomization (including but not limited to glucocorticoid, thrombopoietin, thrombopoietin receptor agonist, Cyclosporine A, Mycophenolate mofetil, etc.), except those meeting the inclusion criterion 7;
• Having received Rituximab within 14 weeks prior to randomization;
• Having received traditional Chinese medicine within 1 week prior to randomization;
• Requiring long-term/continuous use of the drugs that may affect platelet function [including but not limited to aspirin, Clopidogrel, ticagrelor, NSAIDs, etc.], or anticoagulants;
• Intake of potent CYP3A inhibitor or inducer, as well as sensitive or narrow therapeutic window substrates of CYP3A, CYP1A2 or CYP2B6 two weeks (three weeks for Hypericum perforatum) or 5 half-lives prior to randomization (whichever is longer);
• Having participated in the clinical study for drugs or invasive medical device 4 weeks prior to randomization (or within 5 half-lives of the study drug prior to randomization, whichever is longer);
• Having received spleen tyrosine kinase Syk inhibitor (e.g., Fostamatinib) previously;
• Known allergy to the active ingredient or excipient of study drug;
• Presence of serious psychological or mental disorder;
• Alcoholic or drug abuser;
• Female patients in pregnancy or breast feeding;
• Being unsuitable to participate in this study, as considered by investigators.

Inclusion criteria

for open label phase:

• Voluntary signing of the ICF for the sub-study;
• Performance status score (ECOG score) 0-1;
• Relatively stable disease, WHO bleeding grade 0-1;
• Female patients of childbearing potential must agree to use highly effective treatment of contraception from screening until 30 days after discontinuation of study treatment of;
• Male patients with fertile female partners must consent to use barrier contraception during the study period and for 30 days after the termination of study treatment.

Exclusion criteria

for open label phase:

• History of significant arterial/venous embolic disease;
• History of serious cardiovascular disease；
• Hypertension uncontrolled by medications；
• Known hypersensitivity to the active ingredient or excipients of the study drug;
• Patients with severe psychological or mental disorders;
• Alcoholics or drug abusers;
• Female patients who are pregnant and lactating;
• Patients who, in the opinion of the investigator, are not suitable for this study.