Thrombotic Thrombocytopenic Purpura
Conditions
Keywords
TTP, Rituximab, Plasma Exchange
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.
Interventions
DRUGRituximab
Dose of 375 mg/m2, given intravenously, repeated at 1-week intervals for a total of four doses
PROCEDUREPlasma 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.
DRUGCorticosteroids
1 mg/kg of prednisone (or equivalent) each day until plasma exchange is stopped
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Genentech, Inc.
Carelon Research
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| 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
| Measure | Time frame |
|---|---|
| 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 |
| Use of Non-study Treatment | 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 |
| 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Rituximab Participants will receive rituximab in addition to plasma exchange and corticosteroids. | 2 |
| Standard of Care Participants will receive plasma exchange and corticosteroids. | 1 |
| Total | 3 |
Baseline characteristics
| Characteristic | Standard of Care | Rituximab | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 2 Participants | 3 Participants |
| Age Continuous | 24 years | 43.5 years STANDARD_DEVIATION 26.2 | 37 years STANDARD_DEVIATION 22 |
| Region of Enrollment United States | 1 participants | 2 participants | 3 participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 |
Outcome results
Primary
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
Population: The STAR informed consent form told subjects their data would be combined with other subjects' data in study reports. Because one treatment arm included only one subject, this subject's data cannot be combined with other subjects' data. Therefore, to protect subject confidentiality, results are not being released for this study.
Secondary
All Cause Mortality
Time frame: Measured at Month 36
Population: The STAR informed consent form told subjects their data would be combined with other subjects' data in study reports. Because one treatment arm included only one subject, this subject's data cannot be combined with other subjects' data. Therefore, to protect subject confidentiality, results are not being released for this study.
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
Time frame: Measured at Month 12
Population: The STAR informed consent form told subjects their data would be combined with other subjects' data in study reports. Because one treatment arm included only one subject, this subject's data cannot be combined with other subjects' data. Therefore, to protect subject confidentiality, results are not being released for this study.
Secondary
Effect of Plasma Exchange on Rituximab Levels
Time frame: Measured at Month 6
Population: The STAR informed consent form told subjects their data would be combined with other subjects' data in study reports. Because one treatment arm included only one subject, this subject's data cannot be combined with other subjects' data. Therefore, to protect subject confidentiality, results are not being released for this study.
Secondary
Effect of Rituximab Levels on the Extent of B-cell Depletion (CD-19+ Cells)
Time frame: Measured at Month 12
Population: The STAR informed consent form told subjects their data would be combined with other subjects' data in study reports. Because one treatment arm included only one subject, this subject's data cannot be combined with other subjects' data. Therefore, to protect subject confidentiality, results are not being released for this study.
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
Time frame: Measured at Month 36
Population: The STAR informed consent form told subjects their data would be combined with other subjects' data in study reports. Because one treatment arm included only one subject, this subject's data cannot be combined with other subjects' data. Therefore, to protect subject confidentiality, results are not being released for this study.
Secondary
Incidence of Relapse Among Participants in the Two Study Groups Who Achieve Early Treatment Response
Time frame: Measured at Month 36
Population: The STAR informed consent form told subjects their data would be combined with other subjects' data in study reports. Because one treatment arm included only one subject, this subject's data cannot be combined with other subjects' data. Therefore, to protect subject confidentiality, results are not being released for this study.
Secondary
Relationship Between Clinical and Laboratory Data and Response to Treatment
Time frame: Measured at Days 52 and 82
Population: The STAR informed consent form told subjects their data would be combined with other subjects' data in study reports. Because one treatment arm included only one subject, this subject's data cannot be combined with other subjects' data. Therefore, to protect subject confidentiality, results are not being released for this study.
Secondary
Rituximab Response in Participants With Varying Levels of ADAMTS-13 Activity and Antibodies Against ADAMTS-13
Time frame: Measured at Month 36
Population: The STAR informed consent form told subjects their data would be combined with other subjects' data in study reports. Because one treatment arm included only one subject, this subject's data cannot be combined with other subjects' data. Therefore, to protect subject confidentiality, results are not being released for this study.
Secondary
Treatment-related Complications
Time frame: Measured at Day 52
Population: The STAR informed consent form told subjects their data would be combined with other subjects' data in study reports. Because one treatment arm included only one subject, this subject's data cannot be combined with other subjects' data. Therefore, to protect subject confidentiality, results are not being released for this study.
Secondary
Use of Non-study Treatment
Time frame: Measured at Month 36
Population: The STAR informed consent form told subjects their data would be combined with other subjects' data in study reports. Because one treatment arm included only one subject, this subject's data cannot be combined with other subjects' data. Therefore, to protect subject confidentiality, results are not being released for this study.
Secondary
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
Population: The STAR informed consent form told subjects their data would be combined with other subjects' data in study reports. Because one treatment arm included only one subject, this subject's data cannot be combined with other subjects' data. Therefore, to protect subject confidentiality, results are not being released for this study.