Safety and Efficacy of Zanubrutinib in the Treatment of Antiphospholipid Syndrome With Secondary Thrombocytopenia

Prospective, Single Arm and Open Clinical Observation of Zanubrutinib in the Treatment of Antiphospholipid Syndrome With Secondary Thrombocytopenia

To evaluate the safety and efficacy of zanubrutinib in the treatment of antiphospholipid syndrome with secondary thrombocytopenia in 10 patients.

Study Overview

• Status: Recruiting
• Conditions: Thrombocytopenia; Antiphospholipid Syndrome; Treatment
• Intervention / Treatment: Drug: zanubrutinib

Detailed Description

Antiphospholipid syndrome (APS) is a disease spectrum characterized by thrombosis and/or pathological pregnancy, and characterized by persistent antiphospholipid antibodies (APL) positive in laboratory examination. The incidence of thrombocytopenia in APS patients is 29.6%. Thrombocytopenia is usually mild to moderate without clinical manifestations, and the risk of bleeding is low. The platelet count of most patients is > 50 × 10^9/L. If APS has severe thrombocytopenia and severe bleeding, it is very difficult to treat it. According to previous literature reports, Some patients were treated with hormones, rituximab and immunosuppressants. Platelets can be obviously increased, but they are easy to relapse and difficult to maintain. aPL is not obviously decreased and difficult to be completely eliminated. Thrombosis still occurs in some patients with obviously decreased platelets. Thrombopoietin receptor agonists increase the risk of thrombosis, which is a difficult point in hematology treatment at present.

Bruton tyrosine kinase (BTK), a member of the Tec family of non-receptor tyrosine kinases, is expressed in all hematopoietic cells except T cells and terminal differentiated plasma cells. BTK is a key kinase in BCR signaling pathway, which regulates B cell proliferation, survival, differentiation and cytokine expression. BTK inhibitors can affect autoimmune diseases (AID) involving B cells and non-B cells through B cell receptor, Fc receptor and RANK receptor signals, such as systemic lupus erythematosus (SLE), multiple sclerosis (MS) and rheumatoid arthritis (RA).

Besides its activity in B cells, BTK is also expressed in platelets and mediates the signal of cell surface receptor glycoprotein VI (GPVI). It is believed that BTK/Tec pathway may affect GP VI specific platelet signal deficiency and interfere with collagen adhesion and vWF-mediated platelet activation. BTK plays an important role in vWF-mediated signal transduction and GPIb-dependent thrombosis in vivo. Moreover, recent studies have found that BTK inhibitors can block the activation of platelets stimulated by FcγRIIA through antibody-mediated crosslinking (inducing platelet aggregation and secretion) or anti-CD9 antibody (only inducing platelet aggregation). Therefore, BTK inhibitors have certain antithrombotic effects at the same time. At present, there is no related report on BTK inhibitor in the treatment of APS abroad. BTK inhibitors can regulate B cell proliferation, survival, differentiation and cytokine expression, reduce antibody formation, and inhibit platelet adhesion and platelet activation, so they may have a good therapeutic effect on antiphospholipid syndrome.

Therefore, the investigators designed this clinical trial to provide a new treatment option for the clinical treatment of antiphospholipid syndrome with secondary thrombocytopenia.

• Study Type: Interventional
• Enrollment (Anticipated): 10
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Yunfei Chen, MD; Phone Number: +8618502220788; Email: chenyunfei@ihcams.ac.cn

Study Locations

• China
  • Tianjin
    • Tianjin, Tianjin, China, 300020
      • Recruiting
      • Chinese Academy of Medical Science and Blood Disease Hospital
      • Contact: Yunfei Chen, MD; Phone Number: +86-22-23909009; Email: chenyunfei@ihcams.ac.cn
    • Tianjin, Tianjin, China, 300020
      • Recruiting
      • Institute of Hematology & Blood Diseases Hospital
      • Contact: Lei Zhang, MD; Phone Number: +862223909240; Email: zhanglei1@ihcams.ac.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 18 and above, male or female；
• Diagnosis of antiphospholipid syndrome；
• Failure to receive glucocorticoid treatment in the past (the curative effect cannot be maintained, or recurs, or cannot be tolerated); Can not choose other second-line treatment, such as rituximab, cyclosporine, cyclophosphamide, etc.; Or rituximab, cyclosporine and other treatments are ineffective, relapsed or intolerable;
• Plt < 30×10^9/L；
• Liver and kidney function, such as ALT, AST, BUN, SCR < 1.5 × upper limit of normal value, passing physical examination;
• ECOG physical state score ≤ 2 points；
• Cardiac function of the New York Society of Cardiac Function ≤ 2；
• Signed and dated written informed consent.

Exclusion Criteria:

• Uncontrollable primary diseases of important organs, such as malignant tumors, liver failure, heart failure, renal failure and other diseases；
• HIV positive;
• Accompanied by uncontrollable active infection, including hepatitis B, hepatitis C, cytomegalovirus, EB virus and syphilis positive;
• Accompanied by extensive and severe bleeding, such as hemoptysis, upper gastrointestinal hemorrhage, intracranial hemorrhage, etc.;
• At present, there are heart diseases, arrhythmias that need treatment or hypertension that researchers judge is poorly controlled;
• Patients with thrombotic diseases such as new pulmonary embolism and unstable period of various arteriovenous thrombosis;
• Those who have received allogeneic stem cell transplantation or organ transplantation in the past;
• Patients with mental disorders who cannot normally obtain informed consent and conduct trials and follow-up;
• Patients whose toxic symptoms caused by pre-trial treatment have not disappeared;
• Other serious diseases that may limit the subject's participation in this test (such as diabetes; Severe cardiac insufficiency; Myocardial obstruction or unstable arrhythmia or unstable angina pectoris in recent 6 months; Gastric ulcer，etc.);
• Patients with septicemia or other irregular severe bleeding;
• Pregnant women, suspected pregnancies (positive pregnancy test for human chorionic gonadotropin in urine at screening) and lactating patients.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Intervention ( zanubrutinib); 10 enrolled patients are picked up to take zanubrutinib at the indicated dose.

Drug: zanubrutinib; The initial dose is 80mg/day. If the treatment is ineffective after 4 weeks, and under the condition of good safety, the researcher will judge that the dosage should be added to 80mg twice/day，or a higher dose for oral maintenance. The maximum dose is 160mg twice a day. The duration of zanubrutinib is 24 weeks. In case of intolerable adverse reactions, such as severe infection, severe bleeding, hematopenia, arrhythmia, etc., investigator can reduce the dose of zanubrutinib, or withdraw from clinical trials as appropriate.; Other Names: The treatment of zanubrutinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of subjects with a platelet count ≥ 30 × 10^9/L and 50×10^9/L at week 12(Day 85)	Observe the changes of blood routine platelet count after 12 weeks of treatment, and calculate the proportion and times of subjects ≥ 30 × 10^9/L and 50 × 10^9/L.	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Persistent platelet response with clinical significance at 24 weeks	Response defined as as the proportion of subjects with platelet count ≥ 50 × 109/L in at least 4 of the last 6 visits within 24 weeks without rescue treatment.	24 weeks
Number of participants with clinically significant bleeding as assessed using the world health organization (WHO) bleeding scale.	The WHO Bleeding Scale is a measure of bleeding severity with the following grades: grade 0 = no bleeding, grade 1= petechiae, grade 2= mild blood loss, grade 3 = gross blood loss, and grade 4 = debilitating blood loss.	24 weeks
The occurrence of adverse events during treatment (AE/SAE), treatment-related adverse events (TRAE) and serious adverse events (TRSAE)	The occurrence of adverse events during treatment (AE/SAE), treatment-related adverse events (TRAE) and serious adverse events (TRSAE)	24 weeks
Evaluate the occurrence of thrombosis during treatment	Evaluate the occurrence of thrombosis during treatment	24 weeks
Antiphospholipid antibody titre	To monitor antiphospholipid antibody titre during treatment in all participants.	24 weeks

Collaborators and Investigators

• Sponsor: Zhang Lei, MD
• Investigators: Principal Investigator: Lei Zhang, MD, Chinese Academy of Medical Science and Blood Disease Hospital

Study record dates

Study Major Dates

• Study Start (Actual): January 25, 2022
• Primary Completion (Anticipated): December 31, 2023
• Study Completion (Anticipated): June 30, 2024

Study Registration Dates

• First Submitted: December 30, 2021
• First Submitted That Met QC Criteria: January 19, 2022
• First Posted (Actual): January 20, 2022

Study Record Updates

• Last Update Posted (Estimate): January 26, 2023
• Last Update Submitted That Met QC Criteria: January 24, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Autoimmune Diseases; Disease; Hematologic Diseases; Blood Platelet Disorders; Syndrome; Thrombocytopenia; Antiphospholipid Syndrome; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Zanubrutinib
• Other Study ID Numbers: IIT2021048-EC-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Researchers qualified can request the dataset, including de-identified individual subject data. Data may be requested from PI from 12 months 36 months after study completion.
• IPD Sharing Time Frame: 12 months to 36 months after study completion.
• IPD Sharing Access Criteria: Upon request to PI.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes