A Prospective, One-arm and Open Clinical Study of Obinutuzumab in the Treatment of Pediatric Primary Immune Thrombocytopenia (ITP)

Study Overview
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Brief Summary
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To evaluate the safety and efficacy of Obinutuzumab in the treatment of pediatric primary immune thrombocytopenia in patients who have not responded adequately or relapsed after first-line glucocorticoid treatment.

Detailed Description
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Immune thrombocytopenia (ITP) is an organ-specific autoimmune disease, which is characterized by decreased platelet count and skin and mucosal bleeding. ITP is a kind of disease with increased platelet destruction and impaired platelet production caused by autoimmunity. Conventional treatment of adult ITP includes first-line glucocorticoid and immunoglobulin therapy, second line TPO and TPO receptor agonist, splenectomy and other immunosuppressive treatments (such as rituximab, vincristine, azathioprine, etc.). ITP is one of the most common hemorrhagic diseases. At present, the treatment response of ITP is not good, and a considerable number of patients need drug maintenance treatment, which seriously affects the quality of life of patients and increases the economic burden of patients. Therefore, there is still a lack of effective treatment for adult ITP, especially for recurrent and refractory ITP patients, which is one of the problems that have attracted more attention and need to be solved urgently. Obinutuzumab is the first personalized type Ⅱ glycosylation engineered CD20 monoclonal antibody. Studies have shown that compared with rituximab, obinutuzumab may improve its efficacy in lymphoma by increasing DCD and ADCC effects and reducing drug resistance by reducing CDC effects. In view of this, Obinutuzumab may have the same effect in the treatment of ITP, and may be more effective in the treatment of ITP, but there is also a risk of poor efficacy. At present, there is a lack of data on the efficacy and safety of Obinutuzumab in the treatment of ITP in China, especiallly pediatric ITP. Therefore, the investigators designed this clinical trial to evaluate the safety and efficacy of Obinutuzumab in the treatment of pediatric immune thrombocytopenia in patients who have not responded adequately or relapsed after first-line glucocorticoid treatment.

Official Title
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A Prospective, One-arm and Open Clinical Study to Assess Safety and Efficacy of Anti-Human CD20 Monoclonal Antibody Obinutuzumab in the Treatment of Pediatric Primary Immune Thrombocytopenia

Conditions
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Immune Thrombocytopenia, Treatment

Intervention / Treatment
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* Drug: Obinutuzumab Injection [Gazyva]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 12-18 years old, male or female Conform to the diagnostic criteria of persistent or chronic immune Thrombocytopenia (ITP) With a platelet count of <30 X 10^9/L measured within 2 days prior to administration（Platelet counts were measured at least 2 times during screening (at least 1 week apart) with platelets<30 X 10^9/L） Failure or recurrence of previous hormonal therapy or hormone dependence The previous emergency treatment of ITP (e.g. methylprednisolone, platelet transfusion, IVIG transfusion) must be completed at least 2 weeks before the first administration Signed and dated written informed consent With Liver and kidney function<1.5×upper limit of normal， such as ALT、AST，BUN，Cre，etc. ECOG physical state score ≤ 2 points Cardiac function of the New York Society of Cardiac Function ≤ 2 Patients receiving maintenance treatment (including corticosteroids (less than or equal to 0.5mg/kg prednisone), TPO receptor agonists, etc.) must have a stable dose at least 4 weeks before the first administration, and azathioprine, danazol, cyclosporin A, tacrolimus, sirolimus, etc. must be stopped at least 4 weeks before the first administration; The end of rituximab treatment was>3 months；More than 6 months after splenectomy. Exclusion Criteria: Subjects with primary disease of important organs (liver, kidney, heart, etc.), or with immune system diseases; Secondary thrombocytopenia caused by various reasons, such as connective tissue disorders, bone marrow hematopoietic failure disease, myelodysplastic syndrome, malignancy, drugs, inherited thrombocytopenia, common variable immune deficiency, lymphoma, etc.; Subjects infected with human immunodeficiency virus (HIV); Uncontrollable or active infections during the screening period, including hepatitis B, hepatitis C, cytomegalovirus, EB virus, or positive syphilis antigen; Subjects with extensive and severe bleeding, such as hemoptysis, upper gastrointestinal hemorrhage, intracranial hemorrhage; Subjects with heart disease that requires treatment or hypertension that has been judged by researchers to be poorly controlled currently; Subjects with any venous or arterial thrombosis, atherosclerosis, and other diseases; Subjects with a history of malignant solid tumor or have received allogeneic stem cell transplantation or organ transplantation; Subjects with mental disorders who are unable to sign normal informed consent and conduct trials and follow-up; Subjects whose toxic symptoms caused by pre-trial treatment have not disappeared; Subjects with other serious diseases that may limit their participation in this trial (diabetes; severe cardiac insufficiency; myocardial obstruction or unstable arrhythmia or unstable angina pectoris in the last 6 months; gastric ulcer; active autoimmune disease, etc.); Subjects with septicemia or other irregular bleeding; Patients taking antiplatelet drugs at the same time; 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: 12 Years
Maximum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention (Obinutuzumab)<br>60 enrolled subjects: one infusion | Drug: Obinutuzumab Injection [Gazyva]<br>* intravenous Obinutuzumab administration This study adopts a prospective, single arm, open design method. 60 subjects were enrolled in the study and were treated with CD20 monoclonal antibody (Obinutuzumab: 1000mg) for once. The first stage is the main research stage (d1-w12), which is the core treatment period. The subjects will receive intravenous infusion of 1000mg Obinutuzumab for once to observe the safety and efficacy during treatment. The second stage (w12-w48) is the stage of withdrawal from the visit, mainly to observe the safety and continuous efficacy of Obinutuzumab after treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of overall efficacy response after Obinutuzumab treatment within 12 weeks | Overall response rate defined as proportion of subjects with a platelet count ≥ 30 × 10^9/L and at least 2-fold from baseline at the meanwhile within 12 weeks after initial administration in absence of rescue therapy, and without having had dose increment of TPO-RA or corticosteroids during the study period | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of overall efficacy response after Obinutuzumab treatment within 8 weeks | Overall response rate defined as proportion of subjects with a platelet count ≥ 30 × 10^9/L and at least 2-fold from baseline at the meanwhile within 8 weeks after initial administration in absence of rescue therapy, and without having had dose increment of TPO-RA or corticosteroids during the study period | 8 weeks | 
| Evaluation of overall efficacy response after Obinutuzumab treatment within 6 months | Overall response rate defined as proportion of subjects with a platelet count ≥ 30 × 10^9/L and at least 2-fold from baseline at the meanwhile within 6 months after initial administration in absence of rescue therapy, and without having had dose increment of TPO-RA or corticosteroids during the study period | 6 months | 
| Evaluation of overall efficacy response after Obinutuzumab treatment within 12 months | Overall response rate defined as proportion of subjects with a platelet count ≥ 30 × 10^9/L and at least 2-fold from baseline at the meanwhile within 12 months after initial administration in absence of rescue therapy, and without having had dose increment of TPO-RA or corticosteroids during the study period | 12 months | 
| Evaluation of sustained response rate after Obinutuzumab treatment within 6 months | Sustained response rate defined as proportion of subjects who keep a platelet count ≥ 30 × 10^9/L and at least 2-fold from baseline at the meanwhile at 6 months after initial administration in absence of rescue therapy, and without having had dose increment of TPO-RA or corticosteroids during the study period | 6 months | 
| Evaluation of sustained response rate after Obinutuzumab treatment within 12 months | Sustained response rate defined as proportion of subjects who keep a platelet count ≥ 30 × 10^9/L and at least 2-fold from baseline at the meanwhile at 12 months after initial administration in absence of rescue therapy, and without having had dose increment of TPO-RA or corticosteroids during the study period | 12 months | 
| Time to onset response | Time to onset response defined as the time needed for subjects to have a platelet count ≥ 30 × 10^9/L and at least 2-fold from baseline at the meanwhile after initial administration in absence of rescue therapy, and without having had dose increment of TPO-RA or corticosteroids during the study period | 12 months | 
| Duration of response | The longest duration for which the subject sustained a platelet count ≥ 30 × 10^9/L and at least 2-fold from baseline at the meanwhile after initial administration in absence of rescue therapy, and without having had dose increment of TPO-RA or corticosteroids during the study period | 12 months | 
| Emergency treatment after Obinutuzumab treatment within 12 weeks | Percentage of subjects who received emergency treatment after Obinutuzumab treatment within 12 weeks | 12 weeks | 
| Reduction of concomitant drug after Obinutuzumab treatment within 12 weeks | Percentage of patients with reduced doses of corticosteroids and/or other concomitant immunosuppressive drugs at baseline by 12 weeks of Obinutuzumab treatment | 12 weeks | 
| Number of subjects with clinically significant bleeding as assessed using the world health organization (WHO) bleeding scale after Obinutuzumab treatment within 12 weeks | Changes of the subjects' numbers in WHO bleeding score after Anti-CD20 antibody treatment according to the reported World Health Organization's 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. | 12 weeks | 
| Number of subjects with clinically significant bleeding as assessed using the bleeding scale for pediatric patients with ITP after Obinutuzumab treatment within 12 weeks | Changes of the subjects' numbers in bleeding score after Anti-CD20 antibody treatment according to the reported 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； | 12 weeks | 
| One-year recurrence-free survival rate | Time from the start of treatment to the occurrence of a relapse or death event | 12 months | 
| Safety of Anti-CD20 antibody treatment | Incidence, severity, and relationship of treatment emergent adverse events after Anti-CD20 antibody treatment | 12 months | 
| 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. | 12 months | 
| 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. | 12 months | 
| 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. | 12 months | 
| 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. | 12 months |