Clinical trial NCT01554514: Low Dose Rituximab in Thrombotic Thrombocytopenic Purpura
Official title: Adjuvant Low Dose Rituximab for Acquired TTP With Severe ADAMTS13 Deficiency
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Thrombotic Thrombocytopenic Purpura
Keywords: ADAMTS13
Rituximab
Thrombotic thrombocytopenic purpura
TTP
Plasma exchange
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2012-03-15
Enrollment: 19
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Incidence of the Composite Primary Outcome of Exacerbation or Refractory TTP
timeFrame: 60 days
Secondary outcomes:
measure: Incidence of Durable Treatment Response
timeFrame: 60 days
measure: Number of Days to Durable Treatment Response
timeFrame: 60 days
measure: Incidence of Relapse
timeFrame: Between 30 days and 2 years
measure: Months to Relapse
timeFrame: 2 years
measure: Incidence of Death
timeFrame: 2 years
measure: Treatment-related Adverse Events
timeFrame: 2 years
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
Study officials:
affiliation: Washington University School of Medicine
name: Elaine M Majerus, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: Kiss JE. Thrombotic thrombocytopenic purpura: recognition and management. Int J Hematol. 2010 Jan;91(1):36-45. doi: 10.1007/s12185-009-0478-z.
citation: 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.
citation: 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.
citation: 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.