Low Dose Rituximab in Thrombotic Thrombocytopenic Purpura

Study Overview
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Brief Summary
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Thrombotic thrombocytopenic purpura (TTP) is a disease characterized by small blood clots throughout the body that can damage major organs and cause death. TTP is treated with plasma exchange (also called plasmapheresis). Patients who do not respond initially to plasma exchange often are helped by later treatment with rituximab. The purpose of this study is to see whether combining low doses of rituximab with plasma exchange will help patients get better sooner and reduce the chance of getting TTP again.

Detailed Description
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This is a pilot safety/efficacy study of adjuvant low dose rituximab (100 mg/week x 4 doses) plus standard plasma exchange and corticosteroids for the treatment of thrombotic thrombocytopenic purpura (TTP) with severe ADAMTS13 deficiency. Results for study subjects will be compared to historical controls treated initially with plasma exchange and corticosteroids. This study proposes to test the hypothesis that adjuvant low dose rituximab may decrease the incidence of a composite primary endpoint (exacerbations or refractory disease) in acquired TTP with severe ADAMTS13 deficiency. A novel ADAMTS13 assay will be used to identify patients with TTP and severe ADAMTS13 deficiency for enrollment, and to assess the utility of ADAMST13 as a biomarker for response to therapy and prognosis.

Official Title
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Adjuvant Low Dose Rituximab for Acquired TTP With Severe ADAMTS13 Deficiency

Conditions
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Thrombotic Thrombocytopenic Purpura

Intervention / Treatment
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* Biological: rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 or greater Diagnosis of suspected thrombotic thrombocytopenic purpura (TTP) Platelet count of < 80,000 for newly diagnosed patients and < 120,000 for relapsed patients Microangiopathic hemolytic anemia with RBC fragmentation LDH >1 x ULN Subjects who will receive treatment for TTP with plasma exchange Subjects who have not started the 5th plasma exchange Plasma ADAMTS13 activity <10% Exclusion Criteria: Treatment for TTP within the past 2 months Severe active infection indicated by sepsis (requirement for pressors with or without positive blood cultures) or clinical evidence of enteric infection with E. coli O157:H7 or related organism Currently under treatment for cancer (subjects with localized skin carcinoma will be accepted) Microangiopathic hemolytic anemia due to a mechanical heart valve Severe hypertension, as defined by systolic BP >180 AND diastolic BP >120, or papilledema Organ or stem cell transplant Use of calcineurin inhibitors (sirolimus, tacrolimus, cyclosporin A) within 6 months prior to diagnosis of TTP Disseminated intravascular coagulation as defined by: a. INR >2.0 (unrelated to anticoagulation, unresponsive to Vitamin K) or b. Fibrinogen <100 mg/dl Pregnancy Known congenital TTP. Rituximab within the previous year. HIV history or positive serology History of hepatitis B or positive serology for HBsAg or Anti-HBc Persistent or unexplained platelet count below 150,000/μL within 3 months of current TTP presentation Hypersensitivities or allergies to murine and/or humanized antibodies Current participation in trials of investigational therapies or devices, other than central catheters

Ages Eligible for Study
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Minimum 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: low dose rituximab<br>this is a single-arm trial | Biological: rituximab<br>* rituximab intravenously 100 mg every week for four doses<br>* Other names: Rituxan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of the Composite Primary Outcome of Exacerbation or Refractory TTP | Exacerbation is recurring TTP ≤30 days after a Treatment Response (normal platelet count for 2 days) and discontinuation of plasma exchange. Refractory TTP is failure to achieve a Treatment Response by day 28, or failure to achieve a Durable Treatment Response (lasting at least 30 days) by day 60. | 60 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Durable Treatment Response | Treatment Response is 2 consecutive days with platelet count ≥150, 000/µL Durable Treatment Response is a Treatment Response that persists for ≥30 days after discontinuation of plasma exchange and includes those with exacerbations | 60 days | 
| Number of Days to Durable Treatment Response | Median time to treatment response | 60 days | 
| Incidence of Relapse | Relapse is recurring TTP >30 days after Treatment Response | Between 30 days and 2 years | 
| Months to Relapse | Mean months to relapse | 2 years | 
| Incidence of Death | Incidence of death will be assessed at 4 weeks, 1 year and 2 years | 2 years | 
| Treatment-related Adverse Events | Incidence, type and severity of treatment-related adverse events will be assessed. Patient reports, lab values, and physical exam were used to identify treatment-related adverse events. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TTP, ADAMTS13, Rituximab, Thrombotic thrombocytopenic purpura, Plasma exchange