Evaluating the Effectiveness of Adding Rituximab to Standard Treatment for Thrombotic Thrombocytopenic Purpura (TTP) (STAR)

STAR - Study of TTP and Rituximab, A Randomized Clinical Trial

Thrombotic thrombocytopenic purpura (TTP) is a rare disorder that causes blood clots to form in blood vessels. The main treatment for TTP is plasma exchange, in which affected patients receive transfusions of plasma, the liquid part of blood, from healthy donors. This study will examine the effectiveness of an antibody, rituximab, in combination with plasma exchange, at improving the immune response in people with TTP and decreasing the recurrence of TTP.

Study Overview

• Status: Terminated
• Conditions: Thrombotic Thrombocytopenic Purpura
• Intervention / Treatment: Drug: Rituximab; Procedure: Plasma exchange; Drug: Corticosteroids

Detailed Description

TTP is a disorder that causes blood clots to form in the small blood vessels throughout the body. If the clots in fact block the blood vessels, blood flow is restricted to various organs, including the brain, kidneys, and heart. This can lead to neurological problems, stroke, abnormal kidney function, and heart problems. Because a large number of platelets are used in the blood clotting process, people with TTP have a reduced number of platelets circulating in their blood. They also have fewer red blood cells circulating in their blood because the red blood cells break down prematurely as blood squeezes past a blood clot.

The primary treatment for TTP is plasmapheresis, also called plasma exchange, which is a procedure that circulates a person's blood through a machine that first removes the damaged plasma and then adds healthy donor plasma into the blood. Next, patients receive a blood transfusion with the new blood. Corticosteroids, a type of medication that reduces the amount of antibodies a person's body makes, are also commonly used in conjunction with plasma exchange to treat TTP. Plasma exchange is usually effective, with platelet and red blood cell counts returning to normal after the procedure is complete. However, some people do experience a relapse of TTP and will require repeat plasma exchanges. Rituximab, an antibody currently used to treat lymphoma and rheumatoid arthritis, may improve immune system response and decrease the number of days needed to undergo the plasma exchange procedure. The purpose of this study is to evaluate the effectiveness of rituximab in combination with plasma exchange at improving an early treatment response in people with TTP and decreasing the likelihood of a relapse of TTP.

This 3-year study will enroll people who have recently been diagnosed with TTP or recently experienced a relapse and have not yet had six plasma exchanges during the current episode of TTP. Participants will be randomly assigned to receive either plasma exchanges and corticosteroids or plasma exchanges, corticosteroids, and rituximab. Blood will be collected from participants at baseline and each day they undergo the plasma exchange procedure. All participants will receive a plasma exchange every day until their platelet counts are normal and signs of tissue damage have improved. Participants will receive corticosteroid medication every day until plasma exchange is stopped, at which time the dosage will be gradually tapered until 7 weeks after the last plasma exchange. Participants receiving rituximab will receive the first dose intravenously within 7 days of the first plasma exchange; they will continue to receive rituximab once a week for 4 weeks. After the plasma exchanges are completed, all participants will have routine follow-up care with their doctors to make sure there is no TTP relapse. In the 1 year after study entry, additional blood collections will occur at varying times. Study researchers will monitor participants' health in the 3 years after study entry by following up with their doctors or through periodic phone calls. A portion of blood will be collected and stored for future TTP research purposes; this is optional.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35249
      • University of Alabama, Birmingham
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane University Health Sciences Center
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Johns Hopkins Hospital
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02115
      • Children's Hospital Boston
    • Boston, Massachusetts, United States, 02115
      • Beth Israel Deaconess Medical Center
  • New York
    • New York, New York, United States, 10021
      • New York-Presbyterian Hospital/Weill Cornell Medical Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • University of North Carolina Hospitals
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospital Cleveland
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
    • Oklahoma City, Oklahoma, United States, 73112
      • Integris Baptist Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Children's Hospital of Pittsburgh
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Presbyterian and Shadyside Hospital
  • Washington
    • Seattle, Washington, United States, 98104
      • Puget Sound Blood Center
  • Wisconsin
    • LaCrosse, Wisconsin, United States, 54601
      • Gunderson Clinic, Ltd
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin at Madison
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert Memorial Lutheran Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Differential or admission diagnosis of TTP-like syndrome, defined as the following:

  1. Platelet count of less than 80,000/µL for newly diagnosed patients and less than 120,000/µL for relapsed patients
  2. Microangiopathic hemolytic anemia (MHA) with red blood cell fragmentation
  3. Lactate dehydrogenase (LDH) level greater than two times the upper limit of normal for newly diagnosed patients and greater than the upper limit of normal for relapsed patients
• Receiving or will receive treatment for TTP with plasma exchange
• Has not started the sixth plasma exchange in the current TTP episode

Exclusion Criteria:

• Treated for TTP in the 2 months before study entry
• Previously enrolled in this study
• Severe active infection indicated by sepsis (requirement for pressors with or without positive blood cultures) or clinical evidence of enteric infection with E. coli 0157 or related organism
• Currently under treatment for cancer or has a current diagnosis of cancer (other than localized skin carcinoma)
• Microangiopathic hemolytic anemia due to a mechanical heart valve
• Severe high blood pressure, as defined by systolic blood pressure of greater than 180 and diastolic blood pressure of greater than 120, or papilledema
• Has ever had an organ or stem cell transplant
• Has received calcineurin inhibitors (e.g., sirolimus, tacrolimus, cyclosporin A) in the 6 months before TTP diagnosis

• Diagnosis of disseminated intravascular coagulation (DIC), defined as the following:

  1. International normalized ratio (INR) level greater than 2.0 (unrelated to anticoagulation, unresponsive to vitamin K administration) OR
  2. Fibrinogen less than 100 mg/dL
• Pregnant
• Requires ventilator assistance or intravenous pressors for treatment of TTP. If no longer required prior to study entry, patient is eligible for the study.
• Known congenital TTP or family history of TTP

• Established diagnosis of lupus, and/or actively treated for lupus in the 60 days before study entry. In addition, people with two or more of the following systemic lupus erythematosus (SLE) clinical criteria in the 60 days before study entry will be excluded:

  1. Characteristic skin rash, either malar or photosensitive
  2. Symmetric polyarthritis
  3. Serositis, either pleurisy or pericarditis
• Previously received rituximab
• Has taken the following drugs known to be associated with TTP-like syndrome in the 3 months before study entry: clopidogrel (Plavix), ticlopidine (Ticlid), or quinine
• Will receive more than 1.5 plasma volumes per day after study entry
• HIV history or positive serology
• History of hepatitis B or positive serology for HBsAg or Anti-hepatitis B core antigen (Anti-HBc)
• History of hepatitis C
• Known persistent or unexplained platelet count below 150,000/µL in the 3 months before current TTP episode
• Known hypersensitivities or allergies to murine and/or humanized antibodies
• Currently participating in trials of investigational therapies or devices (other than investigational central catheters)
• Has ever had a diagnosis of ventricular tachycardia
• Acute transmural heart attack during the current hospital admission

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; Participants will receive rituximab in addition to plasma exchange and corticosteroids.	Drug: Rituximab; Dose of 375 mg/m2, given intravenously, repeated at 1-week intervals for a total of four doses; Other Names: Rituxan; Procedure: Plasma exchange; Target volume of 1.25 plasma volume replacement; fresh frozen plasma (FFP) is the required replacement fluid; provided daily until platelet counts are normal and signs of tissue damage have improved.; Drug: Corticosteroids; 1 mg/kg of prednisone (or equivalent) each day until plasma exchange is stopped
Active Comparator: 2; Participants will receive plasma exchange and corticosteroids.	Procedure: Plasma exchange; Target volume of 1.25 plasma volume replacement; fresh frozen plasma (FFP) is the required replacement fluid; provided daily until platelet counts are normal and signs of tissue damage have improved.; Drug: Corticosteroids; 1 mg/kg of prednisone (or equivalent) each day until plasma exchange is stopped

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Role of Rituximab in Increasing Early Treatment Response in Participants With TTP Who Are Also Treated With Plasma Exchange and Corticosteroids	Measured at Day 52

Secondary Outcome Measures

Outcome Measure	Time Frame
Use of Non-study Treatment	Measured at Month 36
Whether Participants Receiving Rituximab Achieve Early or Late Treatment Response Faster and Require Fewer Plasma Exchanges Than Participants Not Receiving Rituximab	Measured at Days 52 and 82
Relationship Between Clinical and Laboratory Data and Response to Treatment	Measured at Days 52 and 82
Incidence of Relapse Among Participants in the Two Study Groups Who Achieve Early Treatment Response	Measured at Month 36
All Cause Mortality	Measured at Month 36
Treatment-related Complications	Measured at Day 52
Evaluating How Levels of ADAMTS-13 Enzyme and Autoantibody at Specific Time Points or Over the Course of the Study Correlate With Other Indicators of Disease Activity, Remission Rates, Rapidity of Achieving a Remission, and Recurrence Rate	Measured at Month 36
Rituximab Response in Participants With Varying Levels of ADAMTS-13 Activity and Antibodies Against ADAMTS-13	Measured at Month 36
Effect of Plasma Exchange on Rituximab Levels	Measured at Month 6
Effect of Rituximab Levels on the Extent of B-cell Depletion (CD-19+ Cells)	Measured at Month 12
B-cell Depletion in Relation to ADAMTS-13 Activity and to ADAMTS-13 Antibody Levels and Disease Activity in Participants Who Receive Rituximab Versus Those Who do Not	Measured at Month 12

Collaborators and Investigators

• Sponsor: HealthCore-NERI
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Genentech, Inc.
• Investigators: Principal Investigator: Thomas Ortel, MD, Duke University; Principal Investigator: Jan McFarland, MD, Froedtert Hospital; Principal Investigator: Paul Ness, MD, Johns Hopkins University; Principal Investigator: Ronald Strauss, MD, University of Iowa; Principal Investigator: James George, MD, University of Oklahoma; Principal Investigator: Darrell Triulzi, MD, University of Pittsburgh Presbyterian and Shadyside/Children's Hospital Pittsburgh; Principal Investigator: Susan F. Assmann, PhD, New England Research Institutes, Inc.; Principal Investigator: Eliot Williams, MD, PhD, University of Wisconsin, Madison; Principal Investigator: Keith McCrae, MD, University Hospitals Cleveland Medical Center; Principal Investigator: James Bussel, MD, Weill Medical Colllege, Cornell University; Principal Investigator: Christopher Hillyer, MD, Emory University; Principal Investigator: Sherrill Slichter, MD, University of Washington Medical Center/Fred Hutchinson Cancer Research Center (FHCRC); Principal Investigator: John Hess, MD, University of Maryland; Principal Investigator: Mark Brecher, MD, University of North Carolina, Chapel Hill; Study Chair: Joseph Kiss, MD, University of Pittsburgh

Study record dates

Study Major Dates

• Study Start: April 1, 2009
• Primary Completion (Actual): February 1, 2010
• Study Completion (Actual): February 1, 2010

Study Registration Dates

• First Submitted: November 26, 2008
• First Submitted That Met QC Criteria: November 26, 2008
• First Posted (Estimate): December 1, 2008

Study Record Updates

• Last Update Posted (Estimate): July 22, 2013
• Last Update Submitted That Met QC Criteria: July 18, 2013
• Last Verified: July 1, 2013

More Information

Terms related to this study

• Keywords: Rituximab; TTP; Plasma Exchange
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Hematologic Diseases; Hemorrhage; Blood Coagulation Disorders; Skin Manifestations; Thrombocytopenia; Blood Platelet Disorders; Thrombophilia; Thrombotic Microangiopathies; Purpura; Purpura, Thrombocytopenic; Purpura, Thrombotic Thrombocytopenic; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab
• Other Study ID Numbers: 558; U01HL072268 (U.S. NIH Grant/Contract); HL072268; HL072033; HL072291; HL072196; HL072248; HL072191; HL072305; HL072028; HL072072; HL072355; HL072283; HL072346; HL072331; HL072290