Thrombotic Thrombocytopenic Purpura
Conditions
Keywords
ADAMTS13, Rituximab, Thrombotic thrombocytopenic purpura, TTP, Plasma exchange
Brief summary
Thrombotic thrombocytopenic purpura (TTP) is a disease characterized by small blood clots throughout the body that can damage major organs and cause death. TTP is treated with plasma exchange (also called plasmapheresis). Patients who do not respond initially to plasma exchange often are helped by later treatment with rituximab. The purpose of this study is to see whether combining low doses of rituximab with plasma exchange will help patients get better sooner and reduce the chance of getting TTP again.
Detailed description
This is a pilot safety/efficacy study of adjuvant low dose rituximab (100 mg/week x 4 doses) plus standard plasma exchange and corticosteroids for the treatment of thrombotic thrombocytopenic purpura (TTP) with severe ADAMTS13 deficiency. Results for study subjects will be compared to historical controls treated initially with plasma exchange and corticosteroids. This study proposes to test the hypothesis that adjuvant low dose rituximab may decrease the incidence of a composite primary endpoint (exacerbations or refractory disease) in acquired TTP with severe ADAMTS13 deficiency. A novel ADAMTS13 assay will be used to identify patients with TTP and severe ADAMTS13 deficiency for enrollment, and to assess the utility of ADAMST13 as a biomarker for response to therapy and prognosis.
Interventions
BIOLOGICALrituximab
rituximab intravenously 100 mg every week for four doses
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Washington University School of Medicine
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age 18 or greater 2. Diagnosis of suspected thrombotic thrombocytopenic purpura (TTP) 1. Platelet count of \< 80,000 for newly diagnosed patients and \< 120,000 for relapsed patients 2. Microangiopathic hemolytic anemia with RBC fragmentation 3. LDH \>1 x ULN 3. Subjects who will receive treatment for TTP with plasma exchange 4. Subjects who have not started the 5th plasma exchange 5. Plasma ADAMTS13 activity \<10%
Exclusion criteria
1. Treatment for TTP within the past 2 months 2. Severe active infection indicated by sepsis (requirement for pressors with or without positive blood cultures) or clinical evidence of enteric infection with E. coli O157:H7 or related organism 3. Currently under treatment for cancer (subjects with localized skin carcinoma will be accepted) 4. Microangiopathic hemolytic anemia due to a mechanical heart valve 5. Severe hypertension, as defined by systolic BP \>180 AND diastolic BP \>120, or papilledema 6. Organ or stem cell transplant 7. Use of calcineurin inhibitors (sirolimus, tacrolimus, cyclosporin A) within 6 months prior to diagnosis of TTP 8. Disseminated intravascular coagulation as defined by: a. INR \>2.0 (unrelated to anticoagulation, unresponsive to Vitamin K) or b. Fibrinogen \<100 mg/dl 9. Pregnancy 10. Known congenital TTP. 11. Rituximab within the previous year. 12. HIV history or positive serology 13. History of hepatitis B or positive serology for HBsAg or Anti-HBc 14. Persistent or unexplained platelet count below 150,000/μL within 3 months of current TTP presentation 15. Hypersensitivities or allergies to murine and/or humanized antibodies 16. Current participation in trials of investigational therapies or devices, other than central catheters
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of the Composite Primary Outcome of Exacerbation or Refractory TTP | 60 days | Exacerbation is recurring TTP ≤30 days after a Treatment Response (normal platelet count for 2 days) and discontinuation of plasma exchange. Refractory TTP is failure to achieve a Treatment Response by day 28, or failure to achieve a Durable Treatment Response (lasting at least 30 days) by day 60. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Days to Durable Treatment Response | 60 days | Median time to treatment response |
| Incidence of Relapse | Between 30 days and 2 years | Relapse is recurring TTP \>30 days after Treatment Response |
| Incidence of Durable Treatment Response | 60 days | Treatment Response is 2 consecutive days with platelet count ≥150, 000/µL Durable Treatment Response is a Treatment Response that persists for ≥30 days after discontinuation of plasma exchange and includes those with exacerbations |
| Incidence of Death | 2 years | Incidence of death will be assessed at 4 weeks, 1 year and 2 years |
| Treatment-related Adverse Events | 2 years | Incidence, type and severity of treatment-related adverse events will be assessed. Patient reports, lab values, and physical exam were used to identify treatment-related adverse events. |
| Months to Relapse | 2 years | Mean months to relapse |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Low Dose Rituximab this is a single-arm trial
rituximab: rituximab intravenously 100 mg every week for four doses | 19 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | 1 patient ineligible with congenital TTP | 1 |
| Overall Study | Physician Decision | 1 |
Baseline characteristics
| Characteristic | Low Dose Rituximab |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants |
| Age, Continuous | 46.7 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 13 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 6 Participants |
| Region of Enrollment United States | 19 Participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 17 |
| other Total, other adverse events | 17 / 19 |
| serious Total, serious adverse events | 10 / 17 |
Outcome results
Primary
Incidence of the Composite Primary Outcome of Exacerbation or Refractory TTP
Exacerbation is recurring TTP ≤30 days after a Treatment Response (normal platelet count for 2 days) and discontinuation of plasma exchange. Refractory TTP is failure to achieve a Treatment Response by day 28, or failure to achieve a Durable Treatment Response (lasting at least 30 days) by day 60.
Time frame: 60 days
Population: Completed adjuvant riituximab therapy
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Low Dose Rituximab | Incidence of the Composite Primary Outcome of Exacerbation or Refractory TTP | Number with exacerbation | 2 Participants |
| Low Dose Rituximab | Incidence of the Composite Primary Outcome of Exacerbation or Refractory TTP | Number with refractory TTP | 0 Participants |
Secondary
Incidence of Death
Incidence of death will be assessed at 4 weeks, 1 year and 2 years
Time frame: 2 years
Population: Completed adjuvant rituximab
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low Dose Rituximab | Incidence of Death | 1 Participants |
Secondary
Incidence of Durable Treatment Response
Treatment Response is 2 consecutive days with platelet count ≥150, 000/µL Durable Treatment Response is a Treatment Response that persists for ≥30 days after discontinuation of plasma exchange and includes those with exacerbations
Time frame: 60 days
Population: Completed adjuvant rituximab therapy
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low Dose Rituximab | Incidence of Durable Treatment Response | 17 Participants |
Secondary
Incidence of Relapse
Relapse is recurring TTP \>30 days after Treatment Response
Time frame: Between 30 days and 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low Dose Rituximab | Incidence of Relapse | 5 Participants |
Secondary
Months to Relapse
Mean months to relapse
Time frame: 2 years
Population: Completed adjuvant rituximab
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Low Dose Rituximab | Months to Relapse | 17.3 months |
Secondary
Number of Days to Durable Treatment Response
Median time to treatment response
Time frame: 60 days
Population: Completed adjuvant rituximab therapy
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Low Dose Rituximab | Number of Days to Durable Treatment Response | 5 days |
Secondary
Treatment-related Adverse Events
Incidence, type and severity of treatment-related adverse events will be assessed. Patient reports, lab values, and physical exam were used to identify treatment-related adverse events.
Time frame: 2 years
Population: Completed adjuvant rituximab therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low Dose Rituximab | Treatment-related Adverse Events | 13 treatment-related adverse events |