TPO-RAs Combining Anti-CD 20 Monoclonal Antibody Versus TPO-RAs in the Management of Pediatric Primary Immune Thrombocytopenia (ITP)

Study Overview
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Brief Summary
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This multicenter randomized, open-label study aime to compare the efficacy and safety of TPO-RAs combining anti-CD 20 monoclonal antibody with TPO-RAs in China pediatric ITP patients .This study will be conducted in persistent or chronic pediatric ITP patients who had not responded to or had relapsed after previous hormone treatment.

Detailed Description
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The primary objective of this study was to evaluate the efficacy and safety of TPO-RAs combining anti-CD 20 monoclonal antibody treating previously treated pediatric ITP patients compared to TPO-RAs. The secondary objective was to evaluate the efficacy of TPO-RAs combining anti-CD 20 monoclonal antibody in pediatric ITP patients with positive autoantibody compared to TPO-RAs.In addition, health-related quality of life (HRQoL) measure was assessed in all participants. 166 eligible subjects were randomized to either TPO-RAs combining anti-CD 20 monoclonal antibody or TPO-RAs treatment in 1:1 ratio. 83 enrolled patients are randomly picked up to take TPO-RAs combining with anti-CD 20 monoclonal antibody at the indicated dose. 83 enrolled patients are randomly picked up to take TPO-RAs at the indicated dose. Three TPO-RAs could be used in this study, including eltrombopag, hetrombopag and avatrombopag. The initial dose of eltrombopag administration was an oral 37.5 mg (6-11 years old) or 50 mg (12-17 years old) once daily in all participants. The initial dose of hetrombopag administration was an oral 3.75 mg (6-11 years old) or 5mg (12-17 years old) once daily in all participants. The initial dose of avatrombopag administration was an oral 10 mg (<30kg) or 20mg (≥30kg) once daily in all participants.The dose of TPO-RAs was adjusted according to the subject platelet count during the period from week 1 to week 24. Two kinds of anti-CD 20 monoclonal antibody could be used in this study, including Rituximab and Ortuzumab.Subjects in TPO-RAs combining anti-CD 20 monoclonal antibody treatment group received single dose infusion of Rituximab 375 mg/m2 within 14 days after enrollment. Subjects weighing less than 30kg will be given Rituximab 100 mg once a week for four times. Ortuzumab at 1000mg/ dose is also recommended for subjects weighing 45kg or greater. Ps.Participants in the TPO-RAs monotherapy group who have platelet count < 20×10^9/L or significant skin and mucosal bleeding at the end of 12 weeks of treatment will be given a single dose of Rituximab 375mg/m2.Ortuzumab at 1000mg/ dose is also recommended for subjects weighing 45kg or greater.

Official Title
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A Multicenter, Randomized, Open-label StudyTo Compare The Efficacy And Safety Of TPO-RAs Combining Anti-CD 20 Monoclonal Antibody Versus TPO-RAs in Persistent or Chronic Pediatric ITP Patients Who Failed or Relapse After Hormone Therapy

Conditions
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Primary Immune Thrombocytopenia (ITP)

Intervention / Treatment
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* Drug: TPO-RAs
* Drug: TPO-RAs combining anti-CD 20 monoclonal antibody


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 6-17 years old (including both ends), male and female; Patients aged 6-11 years (including values at both ends) were diagnosed with chronic ITP, and patients aged 12-17 years (including values at both ends) were diagnosed with persistent or chronic ITP, with platelet counts less than 20×109/L; Patients did not respond to glucocorticoid therapy or relapsed. Previous ITP treatment may include, but is not limited to, glucocorticoids, immunomodulators (IVIG), azathioprine, danazole, cyclophosphamide and immunomodulators. Treatment for ITP (including but not limited to glucocorticoids, recombinant human thrombopoietin, TPO agonist (TPO-RA), azathioprine, danazole, cyclosporin A, mycophenate) must be completed or dose stabilized before enrollment, and therapeutic dose should not be increased after enrollment (e.g. The glucocorticoid dose should be stable for ≥14 days and the immunosuppressant dose should be stable for > 3 months before the first administration of the study drug. TPO drugs should be stopped > 1 month, TPO-RA drugs should be stopped > 1 month). No infectious fever (including but not limited to lung infection) in the past 1 month. Laboratory examination of coagulation function should show that the prothrombin time (PT) and activated partial thrombin time (aPTT) values did not exceed 20% of the normal laboratory value range; No history of abnormal coagulation except for ITP. WBC count, neutrophil absolute value and hemoglobin should be within the normal range of laboratory values. No other abnormality except for ITP. Other exceptions except the following: If the anemia is clearly caused by excessive blood loss associated with ITP. If the increase in WBC count/neutrophil absolute value was clearly due to steroid therapy. Understand the study procedure and voluntarily sign the informed consent. For subjects aged 6-7 (including both ends), parents/guardians understand the study procedure and voluntarily sign the informed consent in person, and subjects are encouraged to participate in the informed process and voluntarily sign the informed consent in person; For subjects aged 8-16 (including both ends), parents/guardians and subjects themselves should understand the study procedure and voluntarily sign the informed consent in person; For the minor subjects > 16 years old, if the subjects rely on their own income as the main source of living, they are regarded as persons with full capacity for civil conduct and can independently carry out legal acts. The subjects can sign informed consent on the premise that they understand the research procedures and are willing to do so; For minor subjects > 16 years old, if the subjects do not rely on their own income as the main source of living, they cannot be regarded as persons with full capacity for civil conduct and cannot independently carry out legal acts. Parents/guardians and subjects should understand the study procedures and voluntarily sign the informed consent in person. Exclusion Criteria: Subjects who has any history of arterial/venous thrombosis and the following risk factors including clotting factor V Leiden disease, ATIII deficiency, antiphospholipid syndrome, etc.. Subjects known to have failed all standard TPO-RAs treatments. Subjects known to have taken anti-CD20 antibodytreatment within 3 months prior to initial use of the study drug. Within 2 weeks prior to the initial use of the study drug, subjects were treated with medications (including but not limited to aspirin, aspirin containing compounds, clopidogrel, salicylate, and/or NSAIDs) or anticoagulants that had an impact on platelet function for > 3 consecutive days. Subjects known to have participated in other investigational clinical trials within 3 months prior to first use of investigational drug. Suffering from severe, progressive, uncontrolled kidney, liver, gastrointestinal, endocrine, lung, heart, nervous system, brain or psychiatric disorders. HIV infection with laboratory or clinical diagnosis. Previous history of hepatitis C, chronic hepatitis B infection, or evidence of active hepatitis. Laboratory tests at the screening stage indicate seropositivity for hepatitis C or hepatitis B seropositivity (HBsAg positive). In addition, if HBsAg is negative but HBcAb is positive (regardless of HBsAb status), HBV DNA testing is required, and if positive, the subject should be excluded. During the screening period, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase were more than 1.5 times of the upper limit of normal value, serum creatinine and bilirubin were more than 1.2 times of the upper limit of normal value, and serum albumin was less than 10% of the lower limit of normal value. Bone marrow biopsy results within 6 months before enrollment showed that myelofibrosis score MF≥2. There is a history of abnormal platelet aggregation that may affect the reliability of platelet count measurements. Any medical history or condition that the investigator deems unsuitable for participation in the study.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 17 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: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: efficacy of TPO-RAs<br>After enrollment, all subjects receive TPO-RAs treatment. The initial dose of eltrombopag administration was an oral 37.5 mg (6-11 years old) or 50 mg (12-17 years old) once daily. The initial dose of hetrombopag administration was an oral 3.75 mg (6-11 years old) or 5mg (12-17 years old) once daily in all participants. The initial dose of avatrombopag administration was an oral 10 mg (<30kg) or 20mg (≥30kg) once daily in all participants. Complete blood count including platelet count was done once a week. The dose of TPO-RAs was adjusted according to the subject platelet count during the period from week 1 to week 24. If the platelet count >250×10^9/L, the TPO-RAs will stop until the platelet count <100×10^9/L. Efficacy and safety will be evaluated at Week 4, Week 8, Week 12 and Week 24. | Drug: TPO-RAs<br>* After enrollment, all subjects receive TPO-RAs treatment. The initial dose of eltrombopag, hetrombopag and avatrombopag administration were the same as described in arm description. Complete blood count including platelet count was done once a week. The dose of TPO-RAs was adjusted according to the subject platelet count during the period from week 1 to week 24. If the platelet count >250×10^9/L, the TPO-RAs will stop until the platelet count <100×10^9/L.<br>* Other names: TPO-R agonists;|
| Experimental: efficacy of TPO-RAs combining anti-CD 20 monoclonal antibody<br>After enrollment, all subjects receive TPO-RAs treatment. The initial dose of eltrombopag, hetrombopag and avatrombopag administration were the same as patients in TPO-RAs monotherapy group. The dose of TPO-RAs was adjusted according to the subject platelet count. Two kinds of anti-CD 20 monoclonal antibody could be used in this study. All subjects receive single dose infusion of rituximab 375 mg/m(2) within 14 days after enrollment. Subjects weighing less than 30kg will be given rituximab 100 mg once a week for four times. Ortuzumab at 1000mg/ dose is also recommended for subjects weighing 45kg or greater. Ps. Participants in the eltrombopag monotherapy group who have platelet count < 20×10^9/L or significant skin and mucosal bleeding at the end of 12 weeks of treatment will be given a single dose of rituximab 375mg/m2. Ortuzumab at 1000mg/ dose is also recommended for subjects weighing 45kg or greater. Efficacy and safety will be evaluated at Week 4, Week 8, Week 12 and Week 24. | Drug: TPO-RAs combining anti-CD 20 monoclonal antibody<br>* After enrollment, all subjects receive TPO-RAs treatment. The initial dose of eltrombopag, hetrombopag and avatrombopag administration were the same as described in arm description.The dose of TPO-RAs was adjusted according to the subject platelet count during the period from week 1 to week 24. Subjects in TPO-RAs combining anti-CD 20 monoclonal antibody treatment group received single dose infusion of Rituximab 375 mg/m2 within 14 days after enrollment. Subjects weighing less than 30kg will be given Rituximab 100 mg once a week for four times. Ortuzumab at 1000mg/ dose is also recommended for subjects weighing 45kg or greater. Ps.Participants in the TPO-RAs monotherapy group who have platelet count < 20×10^9/L or significant skin and mucosal bleeding at the end of 12 weeks of treatment will be given a single dose of Rituximab 375mg/m2 or Ortuzumab at 1000mg/ dose if weighing 45kg or greater.<br>* Other names: TPO-R agonist & anti-CD 20 monoclonal antibody;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment response | Number of participants achieving a platelet count >=30×10^9/L and at least doubling of the baseline count at Week 4, Week 8, and Week 12. | From the start of study treatment (Day 1) up to the end of week 4, week 8 and week 12. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Long-term treatment response | The proportion of subjects who achieve efficacy (R) at 24weeks of treatment. | From the start of study treatment (Day 1) up to the end of week 24. | 
| Withdrawal of eltrombopag | The proportion of subjects who successfully stop TPO-RAs within 24 weeks. | From the start of study treatment (Day 1) up to the end of week 24. | 
| Drug efficacy 1 | Number of participants achieving a platelet count >=30×10^9/L at week 4, week 8, week 12 and week 24 in ITP patients with or without positive autoantibody. | From the start of study treatment (Day 1) up to the end of week 4, week 8, week 12 and week 24. | 
| Time to Response | The time required from the start of treatment to the first time a subject's platelet count was greater than or equal to 30×109/L and at least a two-fold increase from the baseline platelet count. | From the start of study treatment (Day 1) up to the end of week 24. | 
| Duration of response | Total duration of subject's platelet count ≥30×109/L | From the start of study treatment (Day 1) up to the end of week 24. | 
| Drug efficacy 2 | Number of participants achieving a platelet count >=50×10^9/L at week 4, week 8, week 12 and week 24 | From the start of study treatment (Day 1) up to the end of week 4, week 8, week 12 and week 24. | 
| emergency treatment | The proportion of subjects receiving emergency treatment | From the start of study treatment (Day 1) up to the end of week 24. | 
| Evaluation of effectiveness | Number of participants that reduced or discontinued baseline concomitant ITP medications during the whole 24 weeks. | From the start of study treatment (Day 1) up to the end of week 24. | 
| 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. | From the start of study treatment (Day 1) up to the end of week 24. | 
| Number of participants with clinically significant bleeding as assessed using the bleeding scale for pediatric patients with ITP. | The bleeding scale for pediatric patients with ITP is a measure of bleeding severity with the following grades: Grade 1 (minor) Minor bleeding, few petechiae (≤100 total) and/or ≤5 small bruises (≤3 cm in diameter), no mucosal bleeding；Grade 2 (mild) Mild bleeding, many petechiae (>100 total) and/or >5 large bruises (>3 cm in diameter), no mucosal bleeding；Grade 3 (moderate) Moderate bleeding, overt mucosal bleeding, troublesome lifestyle；Grade 4 (severe) Severe bleeding, mucosal bleeding leading to decrease in Hb>2 g/dL or suspected internal hemorrhage； | From the start of study treatment (Day 1) up to the end of week 24. | 
| Health-related quality of life survey of subjects(HRQoL)-1 | In all participants ,use ITP-PAQ (ITP Patient Assessment Questionnaire) to assess the HRQoL before and after treatment. | From the start of study treatment (Day 1) up to the end of week 24. | 
| Health-related quality of life survey of subjects(HRQoL)-2 | In all participants ,use FACIT-F（functional assessment of chronic illness therapy- fatigue）to assess the HRQoL before and after treatment. | From the start of study treatment (Day 1) up to the end of week 24. | 
| Health-related quality of life survey of subjects(HRQoL)-3 | In all participants ,use Kids' ITP tool KIT、to assess the HRQoL before and after treatment. | From the start of study treatment (Day 1) up to the end of week 24. | 
| Health-related quality of life survey of subjects(HRQoL)-4 | In all participants ,use Pediatric Quality of Life Inventory PedsQL to assess the HRQoL before and after treatment. | From the start of study treatment (Day 1) up to the end of week 24. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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immune thrombocytopenia, autoantibody, eltrombopag, rituximab