Ignite Creation Date:
2024-05-05 @ 9:38 PM
Last Modification Date:
2024-10-26 @ 10:07 AM
Study NCT ID:
NCT00937131
Status:
COMPLETED
Last Update Posted:
2023-05-16
First Post:
2009-07-09
Brief Title:
The Use of Rituximab in Acute Thrombotic Thrombocytopenic Purpura TTP
Sponsor:
University College London
Organization:
University College London
Study Overview
Official Title:
A Study to Assess the Safety Efficacy and Tolerability of Rituximab Mabthera in Combination With Plasma Exchange PEX in Patients With Acute Thrombotic Thrombocytopenic Purpura TTP
Status:
COMPLETED
Status Verified Date:
2023-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
TTP is a rare and serious blood disorder characterized by the formation of small clots micro thrombi within the circulation and can be fatal The formation of blood clots occurs primarily in the smaller blood vessels the arterioles and capillaries associated with multisystem organ involvement especially the brain and kidneys TTP has an incidence of approximately 1-3 peoplemillion of the populationyear
TTP is due to a decrease in an enzyme ADAMTS 13 that is released by cells lining blood vessels endothelial cells ADAMTS 13 cleaves or breaks down very large von Willebrand Factor vWF strands vWF is used in blood clotting Deficiency or inhibition of the enzyme results in release of the ultra large vWF into the circulation Platelets bind to these ultra large vWF multimers promoting blood clot formation and platelet consumption thrombocytopenia In more then 70 of TTP cases no precipitating cause can be found and the majority of these patients have antibodies against ADAMTS 13 Plasma Exchange PEX was introduced in the management of TTP in 1977 and the mortality of TTP patients has since decreased from approximately 90 to 15-20 PEX is essential in TTP treatment as plasma contains the missing enzyme ADAMTS 13
Rituximab licensed and internationally used monoclonal antibody selectively acts on white blood cells known as B-lymphocytes or B cells that produce the antibody to ADAMTS 13 By inhibiting ADAMTS 13 antibody production ADAMTS 13 activity increases resulting in remission Rituximab has been used in our institutions in patients with acute TTP that are refractory to standard treatment - PEX The resulting remission has been dramatic with a non-toxic side effect profile and no patients to date has relapsed longest follow-up 19 months following Rituximab therapy Therefore we plan to use Rituximab with PEX in patients who present with acute TTP
TTP is due to a decrease in an enzyme ADAMTS 13 that is released by cells lining blood vessels endothelial cells ADAMTS 13 cleaves or breaks down very large von Willebrand Factor vWF strands vWF is used in blood clotting Deficiency or inhibition of the enzyme results in release of the ultra large vWF into the circulation Platelets bind to these ultra large vWF multimers promoting blood clot formation and platelet consumption thrombocytopenia In more then 70 of TTP cases no precipitating cause can be found and the majority of these patients have antibodies against ADAMTS 13 Plasma Exchange PEX was introduced in the management of TTP in 1977 and the mortality of TTP patients has since decreased from approximately 90 to 15-20 PEX is essential in TTP treatment as plasma contains the missing enzyme ADAMTS 13
Rituximab licensed and internationally used monoclonal antibody selectively acts on white blood cells known as B-lymphocytes or B cells that produce the antibody to ADAMTS 13 By inhibiting ADAMTS 13 antibody production ADAMTS 13 activity increases resulting in remission Rituximab has been used in our institutions in patients with acute TTP that are refractory to standard treatment - PEX The resulting remission has been dramatic with a non-toxic side effect profile and no patients to date has relapsed longest follow-up 19 months following Rituximab therapy Therefore we plan to use Rituximab with PEX in patients who present with acute TTP
Detailed Description:
This is multi-centre study within the South East England SEE Thrombotic Thrombocytopenic Purpura TTP study group primarily involving tertiary centres with expertise in treating TTP apheresis units and specialist medical professionals Feedback and discussions with TTP patients during treatment and discussion with those attending out-patient clinics have been incorporated into the development of this study We have reviewed treatment protocols for TTP patients published in peer reviewed journals and consulted SEE TTP study groups on the study design Medical professionals with expertise in TTP treatment and management have also been consulted
This is a non-randomised Phase ll feasibility study to assess i whether Rituximab with PEX decreases the time to remission of patients with acute TTP ii the mortality of TTP patients assessed at 3 months from presentation iii the safety and toxicity of Rituximab in conjunction with standard therapy for acute TTP iv the effect of Rituximab on B cell function v the effect of Rituximab on ADAMTS 13 activity and antibody production and time to relapse The study design and methodology has been devised to specifically address questions regarding the use of Rituximab with PEX to further improve the treatment of TTP patients with the least disruption and inconvenience to their standard and local treatment and care to decrease TTP patient mortality
Adult patients across up to 8 participating UK sites presenting with acute TTP and who fall within the study protocol inclusion criteria as determined by the Lead Consultant Haematologist per institution will be offered entry into the study We wish to recruit 40 patients to this study and although the incidence of TTP is low it is generally considered to be under diagnosed and therefore underestimated Recruiting 40 patients is achievable considering the number of patients presenting with acute TTP within the SEE TTP study group over the past 18 months Some TTP patients may be unconscious or may have a neurological dysfunction associated with acute TTP such as personality or memory symptoms In these cases consent will be requested from the patients legal representative in compliance with the International Conference on Harmonisation ICH guidance for Good Clinical Practice GCP
Given the significant benefit in terms of remission the increased level of ADAMTS 13 level in patients with acute refractory TTP and documented benefit of patients with other antibody driven disorders with Rituximab therapy Rituximab in conjunction with standard therapy - PEX is to be investigated This is to reduce mortality further that the 15-20 reducing the number of PEXs and therefore decreasing the exposure to blood component products that may contain fatal proteins such as variant Creutzfeldt-Jakob Disease vCJD As between 30-60 relapse with a further episode of TTP follow up to determine time to relapse will be observed and compared to historical controls During this period blood counts and ADAMTS 13 levels will be assessed We have a specific assay to determine the benefit following treatments and historical data to compare previous patient admission that can be matched Researcher bias will be reduced as the time taken for a specific platelet level count 150 x 10 to the power of 9L must be determined and recorded within the routine laboratory in each institution the number of PEX will be recorded by the patients nurse continuing until the platelet count is maintained above 150 x 10 to the power of 9L In addition there will be a clear audit trail which will allow data and records to be cross checked
The investigators know from the literature and data collected as part of the SEE TTP study group the epidemiology of TTP and mortality rate With the improvement in laboratory techniques there is improved detection of antibodies against ADAMTS 13 As antibodies to ADAMTS 13 can be detected in up to 90 of cases having excluded specific precipitating causes monitoring of ADAMTS 13 levels and the ADAMTS 13 antibody can be made regularly in our research facility As per the patients local treatment protocol for TTP ie PEX and steroid treatment all patients will have a daily PEX until their platelet level count is 150 X 10 to the power of 9L Patients will receive pre-Rituximab medication Hydrocortison Piriton and Paracetamol as per local protocol 30 minutes prior to Rituximab infusion to reduce any potential side effects Rituximab will be administered intravenously immediately following PEX PEX should be withheld for 24 hours following Rituximab therapy if appropriate to the patients clinical condition Rituximab will be given once a week for 4 weeks in the first instance The first treatment will be given within the first 3 days of admission as there is a need to administer Rituximab in working office hours and allows participating sites to obtain the test results to ascertain whether the patient meets the studys inclusion criteria If patients are well enough to be discharged before their 4th treatment treatment will be continued in their local haematology day unit If there is still evidence of antibodies to ADAMTS 13 and the ADAMTS 13 level has not been correctednormalised up to a maximum 4 additional Rituximab infusion will be given weekly Nurses will monitor the patients blood pressure pulse breathing rate temperature and oxygen saturation level every 15 min for the first hour of Rituximab infusion and then hourly until infusion is complete The patient will continue to be monitored as per the local protocol
The side effects of Rituximab are generally mild such as flu-like symptoms low blood pressure nausea flushing and rigor and if experienced usually occur during the first infusion Pre-medication as noted above will be given prior to Rituximab infusion If any side effects are experienced the rate of the infusion will be reviewed slowed or suspended if necessary and intervention appropriate to the side effect will be given Anaphylaxis is a potential risk with the first dose but all patients will receive appropriate pre-medication Very rare side effects are more likely to be associated with people who have extensive lymphoma disease andor as a result of several years use of Rituximab in clinical trials primarily for malignant disease often with other chemotherapeutic agents as well as post marketing surveillance
All patients will have standard haematological and biochemical blood tests as well having their ADAMTS 13 levels assessed Regular blood tests will be arranged for patients discharged from hospital to check their full blood count electrolytes and liver function results and ADAMDTS 13 level TTP patients will be reviewed initially weekly at their local out-patients clinic following discharge and as time passes and if their results are stable the period between appointments will be lengthened
The study has been designed to cause the least disruption and inconvenience to patients and their standard and treatmentcare It is imperative that patients are continuously assessed and monitored during and post study treatment Any potential risk is offset by i improving time to remission associated with a decreased time of active TTP and organ damage ii reduced exposure to plasma products and thus the risk of vCJD and iii improved management of acute TTP and mortality of these patients
All patients will be reviewed in local haematology clinics or the TTP clinic at UCLH Patients or their legal representatives will be informed or any update of TTP information in general or if new information becomes available about the treatmentdrug during the study or during regular outpatient consultations Review of ongoing data will be presented at the SEE TTP study group as well as national and international meetings The final report will be presented in peer reviewed journals Patient will also be kept informed of any publications arising from the study and hardcopies will be made available to all patients or their next of kinlegal representative
This is a non-randomised Phase ll feasibility study to assess i whether Rituximab with PEX decreases the time to remission of patients with acute TTP ii the mortality of TTP patients assessed at 3 months from presentation iii the safety and toxicity of Rituximab in conjunction with standard therapy for acute TTP iv the effect of Rituximab on B cell function v the effect of Rituximab on ADAMTS 13 activity and antibody production and time to relapse The study design and methodology has been devised to specifically address questions regarding the use of Rituximab with PEX to further improve the treatment of TTP patients with the least disruption and inconvenience to their standard and local treatment and care to decrease TTP patient mortality
Adult patients across up to 8 participating UK sites presenting with acute TTP and who fall within the study protocol inclusion criteria as determined by the Lead Consultant Haematologist per institution will be offered entry into the study We wish to recruit 40 patients to this study and although the incidence of TTP is low it is generally considered to be under diagnosed and therefore underestimated Recruiting 40 patients is achievable considering the number of patients presenting with acute TTP within the SEE TTP study group over the past 18 months Some TTP patients may be unconscious or may have a neurological dysfunction associated with acute TTP such as personality or memory symptoms In these cases consent will be requested from the patients legal representative in compliance with the International Conference on Harmonisation ICH guidance for Good Clinical Practice GCP
Given the significant benefit in terms of remission the increased level of ADAMTS 13 level in patients with acute refractory TTP and documented benefit of patients with other antibody driven disorders with Rituximab therapy Rituximab in conjunction with standard therapy - PEX is to be investigated This is to reduce mortality further that the 15-20 reducing the number of PEXs and therefore decreasing the exposure to blood component products that may contain fatal proteins such as variant Creutzfeldt-Jakob Disease vCJD As between 30-60 relapse with a further episode of TTP follow up to determine time to relapse will be observed and compared to historical controls During this period blood counts and ADAMTS 13 levels will be assessed We have a specific assay to determine the benefit following treatments and historical data to compare previous patient admission that can be matched Researcher bias will be reduced as the time taken for a specific platelet level count 150 x 10 to the power of 9L must be determined and recorded within the routine laboratory in each institution the number of PEX will be recorded by the patients nurse continuing until the platelet count is maintained above 150 x 10 to the power of 9L In addition there will be a clear audit trail which will allow data and records to be cross checked
The investigators know from the literature and data collected as part of the SEE TTP study group the epidemiology of TTP and mortality rate With the improvement in laboratory techniques there is improved detection of antibodies against ADAMTS 13 As antibodies to ADAMTS 13 can be detected in up to 90 of cases having excluded specific precipitating causes monitoring of ADAMTS 13 levels and the ADAMTS 13 antibody can be made regularly in our research facility As per the patients local treatment protocol for TTP ie PEX and steroid treatment all patients will have a daily PEX until their platelet level count is 150 X 10 to the power of 9L Patients will receive pre-Rituximab medication Hydrocortison Piriton and Paracetamol as per local protocol 30 minutes prior to Rituximab infusion to reduce any potential side effects Rituximab will be administered intravenously immediately following PEX PEX should be withheld for 24 hours following Rituximab therapy if appropriate to the patients clinical condition Rituximab will be given once a week for 4 weeks in the first instance The first treatment will be given within the first 3 days of admission as there is a need to administer Rituximab in working office hours and allows participating sites to obtain the test results to ascertain whether the patient meets the studys inclusion criteria If patients are well enough to be discharged before their 4th treatment treatment will be continued in their local haematology day unit If there is still evidence of antibodies to ADAMTS 13 and the ADAMTS 13 level has not been correctednormalised up to a maximum 4 additional Rituximab infusion will be given weekly Nurses will monitor the patients blood pressure pulse breathing rate temperature and oxygen saturation level every 15 min for the first hour of Rituximab infusion and then hourly until infusion is complete The patient will continue to be monitored as per the local protocol
The side effects of Rituximab are generally mild such as flu-like symptoms low blood pressure nausea flushing and rigor and if experienced usually occur during the first infusion Pre-medication as noted above will be given prior to Rituximab infusion If any side effects are experienced the rate of the infusion will be reviewed slowed or suspended if necessary and intervention appropriate to the side effect will be given Anaphylaxis is a potential risk with the first dose but all patients will receive appropriate pre-medication Very rare side effects are more likely to be associated with people who have extensive lymphoma disease andor as a result of several years use of Rituximab in clinical trials primarily for malignant disease often with other chemotherapeutic agents as well as post marketing surveillance
All patients will have standard haematological and biochemical blood tests as well having their ADAMTS 13 levels assessed Regular blood tests will be arranged for patients discharged from hospital to check their full blood count electrolytes and liver function results and ADAMDTS 13 level TTP patients will be reviewed initially weekly at their local out-patients clinic following discharge and as time passes and if their results are stable the period between appointments will be lengthened
The study has been designed to cause the least disruption and inconvenience to patients and their standard and treatmentcare It is imperative that patients are continuously assessed and monitored during and post study treatment Any potential risk is offset by i improving time to remission associated with a decreased time of active TTP and organ damage ii reduced exposure to plasma products and thus the risk of vCJD and iii improved management of acute TTP and mortality of these patients
All patients will be reviewed in local haematology clinics or the TTP clinic at UCLH Patients or their legal representatives will be informed or any update of TTP information in general or if new information becomes available about the treatmentdrug during the study or during regular outpatient consultations Review of ongoing data will be presented at the SEE TTP study group as well as national and international meetings The final report will be presented in peer reviewed journals Patient will also be kept informed of any publications arising from the study and hardcopies will be made available to all patients or their next of kinlegal representative
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None