The Use of Rituximab in Acute Thrombotic Thrombocytopenic Purpura (TTP)
Condition: Thrombotic Thrombocytopenic Purpura (TTP)
MeSH terms: Purpura; Purpura, Thrombocytopenic; Purpura, Thrombotic Thrombocytopenic
Study type: Interventional
Phase: Phase 2

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.
    

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 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.
    

Intervention name(s): Rituximab
Intervention type(s): Drug
Intervention description(s): Concentrate for solution for infusion, Intravenous use, 375mg/m2, Maximum 8 weekly infusions
Other intervention name(s): Rituximab (MabThera)
Intervention MeSH terms: Rituximab
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment