Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00937131 |
| Other study ID # |
BRD/05/011 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
March 2006 |
| Est. completion date |
June 2010 |
Study information
| Verified date |
May 2023 |
| Source |
University College, London |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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 people/million of the population/year.
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.
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 patient's 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 9/L) must be determined and recorded within the routine laboratory in each
institution, the number of PEX will be recorded by the patient's nurse, continuing until the
platelet count is maintained above 150 x 10 to the power of 9/L. 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 patient's local treatment protocol for TTP i.e. PEX and
steroid treatment, all patients will have a daily PEX until their platelet level count is >
150 X 10 to the power of 9/L. 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 patient's 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
study's 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
corrected/normalised, up to a maximum 4 additional Rituximab infusion will be given weekly.
Nurses will monitor the patient's 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 and/or 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 treatment/care. 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 treatment/drug 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
kin/legal representative.
