Immune Thrombocytopenia, Treatment
Conditions
Brief summary
This randomized, open-label study aim to compare the efficacy and safety of Daratumumab (anti-CD38 monoclonal antibody) with Rituximab in pediatric ITP patients.This study will be conducted in pediatric ITP patients who had not responded to or had relapsed after previous glucocorticoid treatment.
Detailed description
Pediatric Immune thrombocytopenia (ITP) is an organ-specific autoimmune disease, which is characterized by decreased platelet count and skin and mucosal bleeding. Pediatric ITP is a kind of disease with increased platelet destruction and impaired platelet production caused by autoimmunity. Conventional treatment of pediatric 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 pediatric 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. The main pathogenesis of ITP is the loss of platelet autoantigen immune tolerance, which leads to abnormal activation of humoral and cellular immunity. It is characterized by antibody mediated platelet destruction and insufficient platelet production by megakaryocytes. The residual long-term autoreactive plasma cells may be a source of therapeutic resistance to autoimmune cytopenia. Antiplatelet specific plasma cells have been detected in the spleen of patients with rituximab refractory ITP. Therefore, the strategy of simply eliminating B cells may not work, because LLPC will continue to produce pathogenic antibodies. In view of this, anti-CD38 monoclonal antibody can eliminate LLPC, thereby profoundly reducing the production of pathogenic antibodies and achieving good efficacy. Some pediatric patients in our center have been treated with this Daratumumab (anti-CD38 monoclonal antibody) in the past, with good efficacy and safety. Therefore, we planned to conduct a clinical study to evaluate the safety and efficacy of Daratumumab (anti-CD38 monoclonal antibody) versus rituximab in relapsed pediatric patients with primary immune thrombocytopenia, in order to provide more treatment options for pediatric patients with ITP.
Interventions
DRUGRituximab
All subjects were randomly assigned to group A (active comparator) and group B (experimental). For subjects in group A (active comparator) , rituximab (375mg/m2) was given once.
DRUGDaratumumab
All subjects were randomly assigned to group A (active comparator) and group B (experimental). For subjects in group B (experimental), Daratumumab (anti-CD38 monoclonal antibody ) (16mg/kg) was given once a week for eight times.
Sponsors
Institute of Hematology & Blood Diseases Hospital, China
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
* Age ≥6，\<18 years, male or female. * Before enrollment, the subjects have been clinically diagnosed with primary immune thrombocytopenia for no less than three months according to the American Society of Hematology guidelines 2011 Evidence-Based Practice Guideline (Neunert et al. 2011) or the International Consensus Report for the Investigation and Management of Primary Immune Thrombocytopenia (Provan et al. 2010), as applicable locally. * Patients have failed glucocorticoid therapy (either due to inefficacy, efficacy could not be maintained, or relapse). Patients were required to have a response history (PLT≥50×10\^9/L) to standard first-line treatment of ITP (glucocorticoid and/or intravenous immunoglobulin). * Subjects with a platelet count of \<30×10\^9/L within the 24 hours prior to the first dose of the study drug; The mean platelet count of at least two separate assessments (at least 1 week apart) \<30×10\^9/L during the screening visit, and no platelet count \> 35×10\^9/L. * ECOG performance status score of ≤2. * Enrollment of subjects receiving maintenance therapy with a stable dosage is permitted, including glucocorticoids (≤0.5 mg/kg of prednisone or equivalent) or TPO receptor agonists. However, at the time of enrollment, subjects are restricted to using only one concomitant medication with a stable dose, and the concomitant medication must have been stable for a minimum of 4 weeks prior to the initial infusion of the study drug. * Subjects and the legal guardian comprehensively understand and can adhere to the study protocol requirements and willingly signed the informed consent form.
Exclusion criteria
* Subjects with a history of using CD20 monoclonal antibody or CD38 monoclonal antibody. * Subjects who are diagnosed with autoimmune hemolytic anemia or various secondary thrombocytopenic disorders. * Subjects with history of any thrombotic or embolic events or extensive and severe bleeding, such as hemoptysis, major upper gastrointestinal bleeding, intracranial hemorrhage, or the presence of sepsis or other irregular bleeding within the 12 months preceding the initiation of the first dose of study drug. * Subjects who have participated in any other investigational drug studies (including vaccine studies) or been exposed to other investigational drugs within the first 4 weeks or 5 half-lives (whichever was longer) prior to the first dose of study drug. * Subjects who have used anticoagulants or any agents with antiplatelet effects, such as aspirin, within 3 weeks prior to the first dose of study drug. * Subjects who have received emergency treatment for ITP (e.g., methylprednisolone, platelet transfusion, intravenous immunoglobulin infusion, or thrombopoietin receptor agonist therapy) within 2 weeks prior to the first dose of study drug. * Subjects who have been treated with medications including azathioprine, danazol, dapsone, cyclosporine A, tacrolimus, and sirolimus within 4 weeks prior to the first dose of study drug. Subjects who have receive medications including cyclophosphamide and vindesine within 6 months prior to the first dose of study drug. * Subjects who have undergone splenectomy within 6 months prior to the first dose of study drug. * Subjects who have received live vaccines within 4 weeks prior to the first dose of study drug, or plan to receive any live vaccines during the course of the study. * Subjects who are diagnosed with Myelodysplastic syndromes (MDS); Subjects with a with a history of malignancy within the 5 years prior to screening (excluding completely cured in situ cervical cancer and non-metastatic skin squamous cell carcinoma or basal cell carcinoma). * Subjects who have undergone allogeneic stem cell transplantation or organ transplantation. * Subjects with a clinically significant medical history, as perceived by investigators, that will pose risks to subjects' safety during the study or potentially affect the safety or efficacy analyses, includes major clinical histories such as circulatory system abnormalities, endocrine system abnormalities, nervous system diseases, blood system diseases, immune system diseases, mental diseases and metabolic abnormalities and so on. e.g., subjects with acute myocardial infarction, unstable angina pectoris, or severe arrhythmias (multifocal ventricular premature contractions, ventricular tachycardia, or ventricular fibrillation) within the 6 months before screening ; New York Heart Association (NYHA) class III-IV heart failure; subjects who were known to have had moderate or severe persistent asthma or chronic obstructive pulmonary disease within the 5 years prior to screening, or whose condition was currently poorly controlled; * Subjects with a history of severe recurrent or chronic infections, or acute infections requiring systemic treatment with antibiotics, antiviral drugs, antiparasitic drugs, anti-amoebic drugs, or antifungal drugs within 4 weeks prior to the first dose and during the screening period, or superficial skin infections requiring systemic treatment within one week prior to the first dose of study drug. Notably, after the resolution of the infection, the subject may be re-screened. * Subjects with a history of known or suspected immunosuppression, including invasive opportunistic infections such as histoplasmosis, listeriosis, coccidioidomycosis, pneumocystis pneumonia, and aspergillosis, even if the infection has resolved; or unusually frequent, recurrent, or prolonged infections (as judged by the investigator). * Significant laboratory abnormalities during screening included: 1. Alanine aminotransferase or aspartate aminotransferase greater than three times the upper limit of normal (ULN). 2. Total bilirubin greater than 1.5 times the ULN (note: subjects diagnosed with Gilbert syndrome based on medical records should not be excluded based on this criterion). 3. absolute neutrophil count \< 1500/mm3. 4. hemoglobin \< 9g/dL. 5. IgG \< 500 mg/dL. 6. lymphocyte count \< 500/mm3. 7. Creatinine clearance (CrCl) \< 30 mL/min (i.e., CrCl ≥30 mL/min is allowed) * Positive for HIV antibodies or syphilis antibodies. * Subjects test positive for Hepatitis B surface antigen (HBsAg) or subjects test positive for hepatitis B core antibody and HBV-DNA (through polymerase chain reaction testing), or subjects test positive for hepatitis C virus antibody and HCV-RNA during the screening period. Subjects with positive hepatitis B core antibody but negative HBV-DNA can be enrolled, with HBV-DNA monitoring every 4 weeks. * Any other conditions unsuitable for participation in this study, as assessed by the investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall response rate at week 12 | 12 weeks | Overall response rate was defined as either partial response or complete response at week 12. Partial response was characterised by at least two consecutive (≥7 days apart) platelet counts of ≥30 to \<100×10\^9/L, with a minimum doubling from baseline and no bleeding. Complete response was characterised by at least two consecutive (≥7 days apart) platelet counts of ≥100×10\^9/L, with no bleeding. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete response rate at week 12 | 12 weeks | Complete response was characterised by at least two consecutive (≥7 days apart) platelet counts of ≥100×10\^9/L, with no bleeding at week 12. |
| Partial response rate at week 12 | 12 weeks | Partial response was characterised by at least two consecutive (≥7 days apart) platelet counts of ≥30 to \<100×10\^9/L, with a minimum doubling from baseline and no bleeding at week 12. |
| Overall response rate at week24 | 6 months | Overall response rate was defined as either partial response or complete response at week 24. Partial response was characterised by at least two consecutive (≥7 days apart) platelet counts of ≥30 to \<100×10\^9/L, with a minimum doubling from baseline and no bleeding. Complete response was characterised by at least two consecutive (≥7 days apart) platelet counts of ≥100×10\^9/L, with no bleeding. |
| Long term sustained platelet count response rate | 6 months | Long term sustained platelet count response rate was defined as proportion of patients with a platelet count ≥30×10\^9/L, with at least doubling from baseline and no bleeding, for at least six of the eight visits between weeks 17 and 24. |
| Cumulative durations of platelet counts ≥50×10^9/L and ≥30×10^9/L, at least doubling from baseline | 1 year | Cumulative durations of platelet counts ≥50×10\^9/L and ≥30×10\^9/L, at least doubling from baseline was defined as time from first two consecutive counts meeting criteria, to first two consecutive counts decreasing to below cut-off |
| Response at each visit | 1 year | Response at each visit was defined as either overall response, partial response, or complete response at each visit. Overall response rate was defined as either partial response or complete response. Partial response was characterised by at least two consecutive (≥7 days apart) platelet counts of ≥30 to \<100×10\^9/L, with a minimum doubling from baseline and no bleeding. Complete response was characterised by at least two consecutive (≥7 days apart) platelet counts of ≥100×10\^9/L, with no bleeding. |
| Platelet counts at each visit | 1 year | Platelet counts at each visit was defined as the platelet counts at each visit |
| Time to the first two consecutive platelet counts ≥50×10^9/L | 1 year | Time to the first two consecutive platelet counts ≥50×10\^9/L was defined as time to first two consecutive platelet counts ≥50×10\^9/L with at least doubling from baseline |
| Time to response | 1 year | Time to response was defined as time to first two consecutive platelet counts ≥30×10\^9/L with at least doubling from baseline |
| Rescue treatment | 1 year | Proportion of patients receiving rescue drugs at each visit throughout the trial |
| Concomitant treatment | 12 weeks | Changes in concomitant treatment at week12 compared with that at baseline |
| Changes in world health organization (WHO) bleeding scale | 1 year | Changes in world health organization (WHO) bleeding scale without rescue treatment. Changes of every subject in WHO bleeding score after 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. |
| Overall response rate at week52 | 1 year | Overall response rate was defined as either partial response or complete response at week 52. Partial response was characterised by at least two consecutive (≥7 days apart) platelet counts of ≥30 to \<100×10\^9/L, with a minimum doubling from baseline and no bleeding. Complete response was characterised by at least two consecutive (≥7 days apart) platelet counts of ≥100×10\^9/L, with no bleeding. |
| Adverse events | 1 year | Incidence, severity, and relationship of treatment emergent adverse events after treatment |
Countries
China
Contacts
CONTACTLei Zhang, MD
CONTACTTing Sun, MD
Outcome results
None listed