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

NCT ID: NCT00799773

Last Updated: 2013-07-22

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 3 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-04-30
• Study Completion Date: 2010-02-28

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.

Conditions

Thrombotic Thrombocytopenic Purpura

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

1

Participants will receive rituximab in addition to plasma exchange and corticosteroids.

Group Type: EXPERIMENTAL

Rituximab

Intervention Type: DRUG

Dose of 375 mg/m2, given intravenously, repeated at 1-week intervals for a total of four doses

Plasma exchange

Intervention Type: PROCEDURE

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.

Corticosteroids

Intervention Type: DRUG

1 mg/kg of prednisone (or equivalent) each day until plasma exchange is stopped

2

Participants will receive plasma exchange and corticosteroids.

Group Type: ACTIVE_COMPARATOR

Plasma exchange

Intervention Type: PROCEDURE

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.

Corticosteroids

Intervention Type: DRUG

1 mg/kg of prednisone (or equivalent) each day until plasma exchange is stopped

Interventions

Rituximab

Dose of 375 mg/m2, given intravenously, repeated at 1-week intervals for a total of four doses

Intervention Type: DRUG

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.

Intervention Type: PROCEDURE

Corticosteroids

1 mg/kg of prednisone (or equivalent) each day until plasma exchange is stopped

Intervention Type: DRUG

Other Intervention Names

Rituxan

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

• Minimum Eligible Age: 12 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Genentech, Inc.

INDUSTRY

Sponsor Role: collaborator

Carelon Research

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Susan F. Assmann, PhD

Role: PRINCIPAL_INVESTIGATOR

New England Research Institutes, Inc.

Jan McFarland, MD

Role: PRINCIPAL_INVESTIGATOR

Froedtert Hospital

Eliot Williams, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Wisconsin, Madison

Keith McCrae, MD

Role: PRINCIPAL_INVESTIGATOR

University Hospitals Cleveland Medical Center

Ellis Neufeld, MD

Role: PRINCIPAL_INVESTIGATOR

Boston Children's Hospital

James Bussel, MD

Role: PRINCIPAL_INVESTIGATOR

Weill Medical Colllege, Cornell University

Thomas Ortel, MD

Role: PRINCIPAL_INVESTIGATOR

Duke University

Christopher Hillyer, MD

Role: PRINCIPAL_INVESTIGATOR

Emory University

Paul Ness, MD

Role: PRINCIPAL_INVESTIGATOR

Johns Hopkins University

David Kuter, MD

Role: PRINCIPAL_INVESTIGATOR

Massachusetts General Hospital

Sherrill Slichter, MD

Role: PRINCIPAL_INVESTIGATOR

University of Washington Medical Center/Fred Hutchinson Cancer Research Center (FHCRC)

Cindy Leissinger, MD

Role: PRINCIPAL_INVESTIGATOR

Tulane University

Ronald Strauss, MD

Role: PRINCIPAL_INVESTIGATOR

University of Iowa

John Hess, MD

Role: PRINCIPAL_INVESTIGATOR

University of Maryland

Mark Brecher, MD

Role: PRINCIPAL_INVESTIGATOR

University of North Carolina, Chapel Hill

James George, MD

Role: PRINCIPAL_INVESTIGATOR

University of Oklahoma

Barbara Konkle, MD

Role: PRINCIPAL_INVESTIGATOR

University of Pennsylvania

Darrell Triulzi, MD

Role: PRINCIPAL_INVESTIGATOR

University of Pittsburgh Presbyterian and Shadyside/Children's Hospital Pittsburgh

Joseph Kiss, MD

Role: STUDY_CHAIR

University of Pittsburgh

Locations

University of Alabama, Birmingham

Birmingham, Alabama, United States

Emory University

Atlanta, Georgia, United States

University of Iowa

Iowa City, Iowa, United States

Tulane University Health Sciences Center

New Orleans, Louisiana, United States

University of Maryland Medical Center

Baltimore, Maryland, United States

Johns Hopkins Hospital

Baltimore, Maryland, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

Brigham and Women's Hospital

Boston, Massachusetts, United States

Children's Hospital Boston

Boston, Massachusetts, United States

New York-Presbyterian Hospital/Weill Cornell Medical Center

New York, New York, United States

University of North Carolina Hospitals

Chapel Hill, North Carolina, United States

Duke University Medical Center

Durham, North Carolina, United States

University Hospital Cleveland

Cleveland, Ohio, United States

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, United States

Integris Baptist Medical Center

Oklahoma City, Oklahoma, United States

University of Pennsylvania

Philadelphia, Pennsylvania, United States

Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, United States

University of Pittsburgh Presbyterian and Shadyside Hospital

Pittsburgh, Pennsylvania, United States

Puget Sound Blood Center

Seattle, Washington, United States

Gunderson Clinic, LTD

La Crosse, Wisconsin, United States

University of Wisconsin at Madison

Madison, Wisconsin, United States

Froedtert Memorial Lutheran Hospital

Milwaukee, Wisconsin, United States

Countries

United States

Other Identifiers

U01HL072268

Identifier Type: NIH

Identifier Source: secondary_id

View Link

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558

Identifier Type: -

Identifier Source: org_study_id