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

• ClinicalTrials.gov Identifier: NCT00799773
• Recruitment Status: Terminated
• First Posted: December 1, 2008
• Results First Posted: July 22, 2013
• Last Update Posted: July 22, 2013
• Sponsor: HealthCore-NERI
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Genentech, Inc.
• Information provided by (Responsible Party): HealthCore-NERI

Tracking Information

• First Submitted Date: November 26, 2008
• First Posted Date: December 1, 2008
• Results First Submitted Date: May 7, 2013
• Results First Posted Date: July 22, 2013
• Last Update Posted Date: July 22, 2013
• Study Start Date: April 2009
• Actual Primary Completion Date: February 2010 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: July 18, 2013): Role of Rituximab in Increasing Early Treatment Response in Participants With TTP Who Are Also Treated With Plasma Exchange and Corticosteroids [ Time Frame: Measured at Day 52 ]
• Original Primary Outcome Measures (submitted: November 26, 2008): Role of rituximab in increasing early treatment response in participants with TTP who are also treated with plasma exchange and corticosteroids [ Time Frame: Measured at Day 52 ]

Current Secondary Outcome Measures (submitted: July 18, 2013)

• Use of Non-study Treatment [ Time Frame: 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 [ Time Frame: Measured at Days 52 and 82 ]
• Relationship Between Clinical and Laboratory Data and Response to Treatment [ Time Frame: Measured at Days 52 and 82 ]
• Incidence of Relapse Among Participants in the Two Study Groups Who Achieve Early Treatment Response [ Time Frame: Measured at Month 36 ]
• All Cause Mortality [ Time Frame: Measured at Month 36 ]
• Treatment-related Complications [ Time Frame: 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 [ Time Frame: Measured at Month 36 ]
• Rituximab Response in Participants With Varying Levels of ADAMTS-13 Activity and Antibodies Against ADAMTS-13 [ Time Frame: Measured at Month 36 ]
• Effect of Plasma Exchange on Rituximab Levels [ Time Frame: Measured at Month 6 ]
• Effect of Rituximab Levels on the Extent of B-cell Depletion (CD-19+ Cells) [ Time Frame: 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 [ Time Frame: Measured at Month 12 ]

Original Secondary Outcome Measures (submitted: November 26, 2008)

• Use of non-study treatment among participants in the two study groups [ Time Frame: Measured at Month 36 ]
• Evaluating if participants receiving rituximab achieve early or late treatment response faster, and require fewer plasma exchanges, than participants who do not receive rituximab [ Time Frame: Measured at Days 52 and 82 ]
• Relationship between clinical and laboratory data and response to treatment [ Time Frame: Measured at Days 52 and 82 ]
• Incidence of relapse among participants in the two study groups who achieve early treatment response [ Time Frame: Measured at Month 36 ]
• All cause mortality [ Time Frame: Measured at Month 36 ]
• Treatment-related complications [ Time Frame: 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 [ Time Frame: Measured at Month 36 ]
• Rituximab response in participants with varying levels of ADAMTS-13 activity and antibodies against ADAMTS-13 [ Time Frame: Measured at Month 36 ]
• Effect of plasma exchange on rituximab levels [ Time Frame: Measured at Month 6 ]
• Effect of rituximab levels on the extent of B-cell depletion (CD-19+ cells) [ Time Frame: Measured at Month 12 ]
• B-cell depletion in relation to ADAMTS-13 activity and ADAMTS-13 antibody levels and disease activity in participants who receive rituximab versus those who do not [ Time Frame: Measured at Month 12 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Evaluating the Effectiveness of Adding Rituximab to Standard Treatment for Thrombotic Thrombocytopenic Purpura (TTP)
• Official Title: STAR - Study of TTP and Rituximab, A Randomized Clinical Trial
• Brief Summary: 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.

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
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Thrombotic Thrombocytopenic Purpura

Intervention

• Drug: Rituximab
  Dose of 375 mg/m2, given intravenously, repeated at 1-week intervals for a total of four doses
  Other Name: 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

Study Arms

• Experimental: 1
  Participants will receive rituximab in addition to plasma exchange and corticosteroids.
  Interventions:

  • Drug: Rituximab
  • Procedure: Plasma exchange
  • Drug: Corticosteroids
• Active Comparator: 2
  Participants will receive plasma exchange and corticosteroids.
  Interventions:

  • Procedure: Plasma exchange
  • Drug: Corticosteroids

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: June 25, 2010): 3
• Original Estimated Enrollment (submitted: November 26, 2008): 238
• Actual Study Completion Date: February 2010
• Actual Primary Completion Date: February 2010 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00799773
• 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
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: HealthCore-NERI
• Original Responsible Party: Susan Assmann, New England Research Institutes
• Current Study Sponsor: HealthCore-NERI
• Original Study Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Collaborators

• National Heart, Lung, and Blood Institute (NHLBI)
• Genentech, Inc.

Investigators

• Principal Investigator: Susan F. Assmann, PhD; New England Research Institutes, Inc.
• Principal Investigator: Jan McFarland, MD; Froedtert Hospital
• Principal Investigator: Eliot Williams, MD, PhD; University of Wisconsin, Madison
• Principal Investigator: Keith McCrae, MD; University Hospitals Cleveland Medical Center
• Principal Investigator: Ellis Neufeld, MD; Boston Children's Hospital
• Principal Investigator: James Bussel, MD; Weill Medical Colllege, Cornell University
• Principal Investigator: Thomas Ortel, MD; Duke University
• Principal Investigator: Christopher Hillyer, MD; Emory University
• Principal Investigator: Paul Ness, MD; Johns Hopkins University
• Principal Investigator: David Kuter, MD; Massachusetts General Hospital
• Principal Investigator: Sherrill Slichter, MD; University of Washington Medical Center/Fred Hutchinson Cancer Research Center (FHCRC)
• Principal Investigator: Cindy Leissinger, MD; Tulane University
• Principal Investigator: Ronald Strauss, MD; University of Iowa
• Principal Investigator: John Hess, MD; University of Maryland
• Principal Investigator: Mark Brecher, MD; University of North Carolina, Chapel Hill
• Principal Investigator: James George, MD; University of Oklahoma
• Principal Investigator: Barbara Konkle, MD; University of Pennsylvania
• Principal Investigator: Darrell Triulzi, MD; University of Pittsburgh Presbyterian and Shadyside/Children's Hospital Pittsburgh
• Study Chair: Joseph Kiss, MD; University of Pittsburgh

• PRS Account: HealthCore-NERI
• Verification Date: July 2013