Low Dose Rituximab in Thrombotic Thrombocytopenic Purpura

• ClinicalTrials.gov Identifier: NCT01554514
• Recruitment Status: Completed
• First Posted: March 15, 2012
• Results First Posted: August 13, 2021
• Last Update Posted: August 17, 2021
• Sponsor: Washington University School of Medicine
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): Washington University School of Medicine

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Thrombotic Thrombocytopenic Purpura	Biological: rituximab	Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 19 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Adjuvant Low Dose Rituximab for Acquired TTP With Severe ADAMTS13 Deficiency
• Study Start Date: August 2012
• Actual Primary Completion Date: February 14, 2020
• Actual Study Completion Date: February 14, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: low dose rituximab; this is a single-arm trial	Biological: rituximab; rituximab intravenously 100 mg every week for four doses; Other Name: Rituxan

Outcome Measures

Primary Outcome Measures :

1. Incidence of the Composite Primary Outcome of Exacerbation or Refractory TTP [ Time Frame: 60 days ]
   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.

Secondary Outcome Measures :

1. Incidence of Durable Treatment Response [ Time Frame: 60 days ]
   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
2. Number of Days to Durable Treatment Response [ Time Frame: 60 days ]
   Median time to treatment response
3. Incidence of Relapse [ Time Frame: Between 30 days and 2 years ]
   Relapse is recurring TTP >30 days after Treatment Response
4. Months to Relapse [ Time Frame: 2 years ]
   Mean months to relapse
5. Incidence of Death [ Time Frame: 2 years ]
   Incidence of death will be assessed at 4 weeks, 1 year and 2 years
6. Treatment-related Adverse Events [ Time Frame: 2 years ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Age 18 or greater

2. Diagnosis of suspected thrombotic thrombocytopenic purpura (TTP)

   1. Platelet count of < 80,000 for newly diagnosed patients and < 120,000 for relapsed patients
   2. Microangiopathic hemolytic anemia with RBC fragmentation
   3. LDH >1 x ULN
3. Subjects who will receive treatment for TTP with plasma exchange
4. Subjects who have not started the 5th plasma exchange
5. Plasma ADAMTS13 activity <10%

Exclusion Criteria:

1. Treatment for TTP within the past 2 months
2. 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
3. Currently under treatment for cancer (subjects with localized skin carcinoma will be accepted)
4. Microangiopathic hemolytic anemia due to a mechanical heart valve
5. Severe hypertension, as defined by systolic BP >180 AND diastolic BP >120, or papilledema
6. Organ or stem cell transplant
7. Use of calcineurin inhibitors (sirolimus, tacrolimus, cyclosporin A) within 6 months prior to diagnosis of TTP

8. Disseminated intravascular coagulation as defined by:

   a. INR >2.0 (unrelated to anticoagulation, unresponsive to Vitamin K) or b. Fibrinogen <100 mg/dl

9. Pregnancy
10. Known congenital TTP.
11. Rituximab within the previous year.
12. HIV history or positive serology
13. History of hepatitis B or positive serology for HBsAg or Anti-HBc
14. Persistent or unexplained platelet count below 150,000/μL within 3 months of current TTP presentation
15. Hypersensitivities or allergies to murine and/or humanized antibodies
16. Current participation in trials of investigational therapies or devices, other than central catheters

Contacts and Locations

Locations

United States, Georgia

Emory University

Atlanta, Georgia, United States, 30322

United States, Massachusetts

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States, 02215

United States, Missouri

Washington University

Saint Louis, Missouri, United States, 63110

United States, North Carolina

Duke University Medical Center

Durham, North Carolina, United States, 27710

Sponsors and Collaborators

Washington University School of Medicine

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Elaine M Majerus, MD, PhD; Washington University School of Medicine

  Study Documents (Full-Text)

Documents provided by Washington University School of Medicine:

Study Protocol and Statistical Analysis Plan  [PDF] October 18, 2018

More Information

Publications of Results:

Kiss JE. Thrombotic thrombocytopenic purpura: recognition and management. Int J Hematol. 2010 Jan;91(1):36-45. doi: 10.1007/s12185-009-0478-z.

Westwood JP, Webster H, McGuckin S, McDonald V, Machin SJ, Scully M. Rituximab for thrombotic thrombocytopenic purpura: benefit of early administration during acute episodes and use of prophylaxis to prevent relapse. J Thromb Haemost. 2013 Mar;11(3):481-90. doi: 10.1111/jth.12114.

Ahmad A, Aggarwal A, Sharma D, Dave HP, Kinsella V, Rick ME, Schechter GP. Rituximab for treatment of refractory/relapsing thrombotic thrombocytopenic purpura (TTP). Am J Hematol. 2004 Oct;77(2):171-6. doi: 10.1002/ajh.20166.

Chemnitz J, Draube A, Scheid C, Staib P, Schulz A, Diehl V, Sohngen D. Successful treatment of severe thrombotic thrombocytopenic purpura with the monoclonal antibody rituximab. Am J Hematol. 2002 Oct;71(2):105-8. doi: 10.1002/ajh.10204.

Other Publications:

Froissart A, Buffet M, Veyradier A, Poullin P, Provot F, Malot S, Schwarzinger M, Galicier L, Vanhille P, Vernant JP, Bordessoule D, Guidet B, Azoulay E, Mariotte E, Rondeau E, Mira JP, Wynckel A, Clabault K, Choukroun G, Presne C, Pourrat J, Hamidou M, Coppo P; French Thrombotic Microangiopathies Reference Center. Efficacy and safety of first-line rituximab in severe, acquired thrombotic thrombocytopenic purpura with a suboptimal response to plasma exchange. Experience of the French Thrombotic Microangiopathies Reference Center. Crit Care Med. 2012 Jan;40(1):104-11. doi: 10.1097/CCM.0b013e31822e9d66.

• Responsible Party: Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT01554514
• Other Study ID Numbers: 201108256-LDrituximab; 1U54HL112303-01 ( U.S. NIH Grant/Contract )
• First Posted: March 15, 2012
• Results First Posted: August 13, 2021
• Last Update Posted: August 17, 2021
• Last Verified: August 2021

Keywords provided by Washington University School of Medicine:

ADAMTS13; Rituximab; Thrombotic thrombocytopenic purpura; TTP; Plasma exchange

Additional relevant MeSH terms:

Purpura; Purpura, Thrombocytopenic; Purpura, Thrombotic Thrombocytopenic; Blood Coagulation Disorders; Hematologic Diseases; Hemorrhage; Pathologic Processes; Skin Manifestations; Thrombotic Microangiopathies; Thrombocytopenia; Blood Platelet Disorders; Immune System Diseases; Thrombophilia; Rituximab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents