Telitacicept for the Treatment of Connective Tissue Disease-associated Thrombocytopenia

Study Overview
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Brief Summary
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The goal of this clinical trial is to evaluate the efficacy and safety of Telitacicept for the treatment of connective tissue disease-associated thrombocytopenia.

Detailed Description
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In this randomized, double-blind placebo-controlled study, the investigators aim to evaluate the efficacy and safety of Telitacicept for the treatment of connective tissue disease-associated thrombocytopenia. After screening, eligible participants will be randomized at a 1: 1 ratio to receive either subcutaneous Telitacicept 160 mg or placebo once a week for 24 weeks. The background standard therapy is maintained stable during the whole treatment period.

Official Title
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A Randomized, Double-blind Placebo-controlled Study of Recombinant Human B Lymphocyte Stimulating Factor Receptor-Fc Fusion Protein for the Treatment of Connective Tissue Disease-associated Thrombocytopenia

Conditions
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Connective Tissue Diseases, Thrombocytopenia

Intervention / Treatment
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* Biological: Telitacicept
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who have been diagnosed with connective tissue disease (CTD)-associated thrombocytopenia. And CTD includes primary Sjögren syndrome (according to the 2002 American College of Rheumatology (ACR)/ European League against Rheumatism (EULAR) classification criteria), systemic lupus erythematosus (SLE, according to the 1997 or the 2009 ACR classification criteria), and undifferentiated connective tissue disease (according to the 1999 international classification criteria) Refractory thrombocytopenia defined as: Either: Failure to maintain sustained remission after treatment by oral glucocorticoid dose ≥1 mg/kg/day for at least 4 weeks (prednisone or equivalent) and at least one immunosuppressant (i.e. cyclophosphamide, cyclosporine, mycophenolate mofetil, azathioprine, tacrolimus, methotrexate, leflunomide and hydroxychloroquine, et al.) Or: Relapse during oral glucocorticoid tapering or after withdrawal 50×10^9/L>PLT ≥20×10^9/L anti-nuclear antibody (ANA) positive (≥1:80, any karyotype) detected in the laboratory of each research center Standard therapy should be maintained stable for at least 28 days prior to the first dose of the experimental drug or placebo. Standard therapy refers to the following treatment (monotherapy or in combination): glucocorticoid, hydroxychloroquine, and other immunosuppressants (i.e. cyclophosphamide, cyclosporine, mycophenolate mofetil, azathioprine, tacrolimus, methotrexate and leflunomide, et al.) Signed informed consent form, willing or able to participate in all required study evaluations and procedures Exclusion Criteria: Vital organ lethal bleeding (including but not limited to central nervous system bleeding, digestive tract bleeding) at screening, or intracranial bleeding 6 months prior to screening Antiphospholipid syndrome, thrombotic thrombocytopenia purpura, hemolytic uremic syndrome, or thrombocytopenia secondary to other causes (such as sepsis, Epstein-Barr virus infection, cytomegalovirus infection, Corona Virus Disease-19 (COVID-19) infection, drugs, etc.) Hematopoietic system disorders, such as myelodysplastic syndrome, paroxysmal sleep hemoglobinuria, aplastic anemia, leukemia, lymphoma, myelofibrosis and so on Severe cardiovascular system disease, including: unstable or uncontrollable disease or condition affecting the function of the heart (such as angina pectoris, congestive heart failure, uncontrolled hypertension or arrhythmia) Arteriovenous thromboembolism events Receiving antiplatelet or anticoagulant therapy at screening Clinically significant electrocardiogram changes corrected Q-T interval (QTc)>450ms for male, QTc>470ms for female Severe pulmonary disease, including: unstable or uncontrollable disease or condition affecting respiratory function [e.g., diffuse alveolar hemorrhage, severe pulmonary hypertension, severe pulmonary interstitial disease (peripheral blood oxygen saturation <92% at rest without oxygen, or forced vital capacity (FVC)<50%, or carbon monoxide diffusing capacity (DLCO)<50%)] Severe kidney disease, including: severe lupus nephritis (urinary protein > 6 g/24 hours or endogenous creatinine clearance < 30 ml /min) 8 weeks prior to randomization, active nephritis requiring current protocol disallowed drugs, severe renal insufficiency requiring hemodialysis or prednisone ≥100mg/ day (or equivalent) for ≥14 days SLE or non-SLE related central nervous system disease (including epilepsy, psychosis, organic encephalopathy syndrome, cerebrovascular accident, encephalitis, central nervous system vasculitis) 8 weeks prior to randomization Active hepatitis, a history of severe liver disease. Subjects positive for hepatitis B surface antigen (HBsAg) or antibodies to hepatitis C virus are excluded. As for subjects with antibodies to hepatitis B core antigen (HBcAb), further hepatitis B virus (HBV)-DNA should be tested. If HBV-DNA is negative, subjects could be enrolled; otherwise, subjects should be excluded Abnormal laboratory results (including but not limited to: alanine aminotransferase (ALT) or aspertate aminotransferase (AST)≥3×ULN (upper limit of normal), white blood cell count <1.5×10^9/L) Subjects with known active infections (e.g., shingles, COVID-19, HIV, active tuberculosis, etc.), and active or recurrent gastrointestinal ulcers Pregnant or lactating women, and subjects with a during plan during the trial Allergic reaction: history of allergic reactions to human biological products Treatment with B cell-targeting agents such as Rituximab or Epratuzumab or Belimumab six months prior to randomization Treatment with tumor necrosis factor (TNF) inhibitors or TNF-receptor blockers six months prior to randomization Participating in clinical trial 28 days or 5 drug half-lives of the investigational agents prior to randomization Received live vaccine 28 days prior to randomization Treatment with thrombopoietin receptor agonists such as Eltrombopag or Romiplostim 28 days prior to randomization Subjects with depression or suicidal thoughts Previous treatment with telitacicept B cell targeting drug therapy is not tolerated or responsive Investigator considers candidates not appropriating for the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Telitacicept plus standard therapy<br>Telitacicept (160mg ih qw for 24 weeks) combined with standard therapy. Standard therapy refers to the following treatment (monotherapy or in combination): glucocorticoid, hydroxychloroquine, and other immunosuppressants (i.e. cyclophosphamide, cyclosporine, mycophenolate mofetil, azathioprine, tacrolimus, methotrexate and leflunomide, et al.). | Biological: Telitacicept<br>* subcutaneous telitacicept 160 mg weekly for 24 weeks.<br>* Other names: Tai'ai®;|
| Placebo Comparator: Placebo plus standard therapy<br>Placebo combined with standard therapy. Standard therapy refers to the following treatment (monotherapy or in combination): glucocorticoid, hydroxychloroquine, and other immunosuppressants (i.e. cyclophosphamide, cyclosporine, mycophenolate mofetil, azathioprine, tacrolimus, methotrexate and leflunomide, et al.). | Drug: Placebo<br>* subcutaneous placebo weekly for 24 weeks.<br>* Other names: control;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response (CR + PR) rate | Response is deemed as complete (CR) if the platelet (PLT) count is ≥ 100×10^9/L, partial (PR) if the platelet count ranges from 50×10^9/L to 100×10^9/L and at least doubled from baseline. No active bleeding is allowed in participants classified as CR or PR. | at week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response (CR + PR) rate | Response is deemed as complete (CR) if the platelet count is ≥ 100×10^9/L, partial (PR) if the platelet count ranges from 50×10^9/L to 100×10^9/L and at least doubled from baseline. No active bleeding is allowed in participants classified as CR or PR. | at week 12 | 
| Rescue treatment rate | Rescue treatment is initiated if the platelet count is <10×10^9/L, or the participant is with active bleeding, or based on the investigator's judgement when the platelet count ranges from 10×10^9/L to 20×10^9/L. | at week 24 | 
| Time to rescue treatment | Time to rescue treatment refers to period duration from the initiation of Telitacicept or placebo (day 1) to rescue treatment. | at week 24 | 
| Relapse rate | No response refers to the platelet count is < 50×10^9/L, or increases for less than 1-fold from baseline, or with active central nervous system or digestive tract bleeding, or rescue treatment is initiated. Relapse is defined as no response recurring after a complete or partial response lasting for at least 7 days with treatment. | at week 24 | 
| Time to relapse | Time to relapse refers to period duration from the initiation of Telitacicept or placebo (day 1) to relapse. | at week 24 | 
| treatment related adverse event | According to the NCI CTCAE 5.0 | at week 24 | 
| treatment related severe adverse event | According to the NCI CTCAE 5.0 | at week 24 | 
| bleeding scale | According to the ITP bleeding scale (IBLS). The IBLS comprises of 11 grades from 0 (none) to 2 (marked bleeding) by history over the previous week or by exam; 2 being worse. These 11 grades include: skin by physical exam, oral by physical exam, skin by history, oral by history, epistaxis, gastrointestinal, urinary, gynecological, pulmonary, intracranial hemorrhage, and subconjunctival hemorrhage. | at week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Connective Tissue Diseases, Thrombocytopenia, biological agents, B cell, targeted therapy