Clinical trial NCT00799773: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Thrombotic Thrombocytopenic Purpura
Keywords: TTP
Rituximab
Plasma Exchange
Lead sponsor: Carelon Research
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: Genentech, Inc.
First posted: 2008-12-01
Enrollment: 3
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Role of Rituximab in Increasing Early Treatment Response in Participants With TTP Who Are Also Treated With Plasma Exchange and Corticosteroids
timeFrame: Measured at Day 52
Secondary outcomes:
measure: Use of Non-study Treatment
timeFrame: Measured at Month 36
measure: Whether Participants Receiving Rituximab Achieve Early or Late Treatment Response Faster and Require Fewer Plasma Exchanges Than Participants Not Receiving Rituximab
timeFrame: Measured at Days 52 and 82
measure: Relationship Between Clinical and Laboratory Data and Response to Treatment
timeFrame: Measured at Days 52 and 82
measure: Incidence of Relapse Among Participants in the Two Study Groups Who Achieve Early Treatment Response
timeFrame: Measured at Month 36
measure: All Cause Mortality
timeFrame: Measured at Month 36
measure: Treatment-related Complications
timeFrame: Measured at Day 52
measure: 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
timeFrame: Measured at Month 36
measure: Rituximab Response in Participants With Varying Levels of ADAMTS-13 Activity and Antibodies Against ADAMTS-13
timeFrame: Measured at Month 36
measure: Effect of Plasma Exchange on Rituximab Levels
timeFrame: Measured at Month 6
measure: Effect of Rituximab Levels on the Extent of B-cell Depletion (CD-19+ Cells)
timeFrame: Measured at Month 12
measure: 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
timeFrame: Measured at Month 12
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama, Birmingham
state: Alabama
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: New Orleans
country: United States
facility: Tulane University Health Sciences Center
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Children's Hospital Boston
state: Massachusetts
city: New York
country: United States
facility: New York-Presbyterian Hospital/Weill Cornell Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina Hospitals
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: University Hospital Cleveland
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Oklahoma City
country: United States
facility: Integris Baptist Medical Center
state: Oklahoma
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Presbyterian and Shadyside Hospital
state: Pennsylvania
city: Seattle
country: United States
facility: Puget Sound Blood Center
state: Washington
city: LaCrosse
country: United States
facility: Gunderson Clinic, LTD
state: Wisconsin
city: Madison
country: United States
facility: University of Wisconsin at Madison
state: Wisconsin
city: Milwaukee
country: United States
facility: Froedtert Memorial Lutheran Hospital
state: Wisconsin
Study officials:
affiliation: New England Research Institutes, Inc.
name: Susan F. Assmann, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Froedtert Hospital
name: Jan McFarland, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Wisconsin, Madison
name: Eliot Williams, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospitals Cleveland Medical Center
name: Keith McCrae, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Boston Children's Hospital
name: Ellis Neufeld, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Weill Medical Colllege, Cornell University
name: James Bussel, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Duke University
name: Thomas Ortel, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Emory University
name: Christopher Hillyer, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Johns Hopkins University
name: Paul Ness, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Massachusetts General Hospital
name: David Kuter, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Washington Medical Center/Fred Hutchinson Cancer Research Center (FHCRC)
name: Sherrill Slichter, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Tulane University
name: Cindy Leissinger, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Iowa
name: Ronald Strauss, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Maryland
name: John Hess, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of North Carolina, Chapel Hill
name: Mark Brecher, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Oklahoma
name: James George, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pennsylvania
name: Barbara Konkle, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pittsburgh Presbyterian and Shadyside/Children's Hospital Pittsburgh
name: Darrell Triulzi, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pittsburgh
name: Joseph Kiss, MD
role: STUDY_CHAIR
References: