Clinical Trial: The Use of Rituximab in Acute Thrombotic Thrombocytopenic Purpura (TTP)

Study Status: Recruiting
Recruit Status: Unknown status
Study Type: Interventional

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 Purpu

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 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 R

Detailed Summary:

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 pa
Sponsor: University College, London

Current Primary Outcome: The primary objective of this study is to investigate whether Rituximab and PEX decreases the time to remission of TTP patients. [ Time Frame: One year ]

Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Improved mortality ot TTP patients [ Time Frame: 3 months ]
  • Safety and toxicity of Rituximab in conjunction with standard therapy for acute TTP [ Time Frame: 3 months ]
  • Effect of Rituximab on B lymphocyte function [ Time Frame: One year ]
  • Effect of Rituximab on ADAMTS 13 activity and antibody production and time to relapse [ Time Frame: One year ]


Original Secondary Outcome: Same as current

Information By: University College, London

Dates:
Date Received: July 9, 2009
Date Started: March 2006
Date Completion: June 2010
Last Updated: July 9, 2009
Last Verified: July 2009