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

Thrombotic Thrombocytopenic Purpura Clinical Trial

— STAR  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00799773
• Other study ID #: 558
• Secondary ID: U01HL072268HL072
• Status: Terminated
• Phase: Phase 3
• First received: November 26, 2008
• Last updated: July 18, 2013
• Start date: April 2009
• Est. completion date: February 2010

Study information

• Verified date: July 2013
• Source: New England Research Institutes
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 3
• Est. completion date: February 2010
• Est. primary completion date: February 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 12 Years and older

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Purpura
• Purpura, Thrombocytopenic
• Purpura, Thrombotic Thrombocytopenic
• Thrombotic Thrombocytopenic Purpura

Intervention

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

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

Locations

Country	Name	City	State
United States	Emory University	Atlanta	Georgia
United States	Johns Hopkins Hospital	Baltimore	Maryland
United States	University of Maryland Medical Center	Baltimore	Maryland
United States	University of Alabama, Birmingham	Birmingham	Alabama
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	Massachusetts General Hospital	Boston	Massachusetts
United States	University of North Carolina Hospitals	Chapel Hill	North Carolina
United States	University Hospital Cleveland	Cleveland	Ohio
United States	Duke University Medical Center	Durham	North Carolina
United States	University of Iowa	Iowa City	Iowa
United States	Gunderson Clinic, LTD	LaCrosse	Wisconsin
United States	University of Wisconsin at Madison	Madison	Wisconsin
United States	Froedtert Memorial Lutheran Hospital	Milwaukee	Wisconsin
United States	Tulane University Health Sciences Center	New Orleans	Louisiana
United States	New York-Presbyterian Hospital/Weill Cornell Medical Center	New York	New York
United States	Integris Baptist Medical Center	Oklahoma City	Oklahoma
United States	University of Oklahoma Health Sciences 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

Sponsors (3)

Lead Sponsor	Collaborator
New England Research Institutes	Genentech, Inc., National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	Use of Non-study Treatment		Measured at Month 36	No
Secondary	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	No
Secondary	Relationship Between Clinical and Laboratory Data and Response to Treatment		Measured at Days 52 and 82	No
Secondary	Incidence of Relapse Among Participants in the Two Study Groups Who Achieve Early Treatment Response		Measured at Month 36	No
Secondary	All Cause Mortality		Measured at Month 36	No
Secondary	Treatment-related Complications		Measured at Day 52	Yes
Secondary	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	No
Secondary	Rituximab Response in Participants With Varying Levels of ADAMTS-13 Activity and Antibodies Against ADAMTS-13		Measured at Month 36	No
Secondary	Effect of Plasma Exchange on Rituximab Levels		Measured at Month 6	No
Secondary	Effect of Rituximab Levels on the Extent of B-cell Depletion (CD-19+ Cells)		Measured at Month 12	No
Secondary	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	No