The Plasma Large-Volume Exchange RCT
The Plasma Large-Volume Exchange RCT
Thrombotic thrombocytopenia purpura / hemolytic uremic syndrome (TTP/HUS) is a rare,
 life-threatening disorder. TTP/HUS causes multiple blood clots to form, which prevents blood
 from reaching the brain and kidneys. TTP/HUS affects 3-5 people per million per year. Anyone
 can develop TTP/HUS, but it is most common among 30-40 year olds, and women are twice as
 likely as men to acquire the condition. TTP/HUS sometimes develops as a result of medication
 use, pregnancy or cancer; however, for the majority of patients (80%) the cause of TTP/HUS is
 unknown. In 1991, researchers discovered that plasma exchange was superior to plasma infusion
 in treating idiopathic TTP/HUS. During plasma exchange the patient's blood plasma is removed
 and replaced with healthy blood plasma. Without plasma exchange, the survival rate for
 TTP/HUS is extremely low, with fewer than 5% of patients surviving. Treating TTP/HUS with
 plasma exchange improved the survival rate to 80%. Although this represents a dramatic
 improvement, researchers are still searching for methods to improve survival. No major
 advances in treating TTP/HUS have occurred in the past 20 years. Recent research suggests
 that high-dose plasma exchange may improve the survival of TTP/HUS patients. The
 investigators will conduct a randomized controlled trial to test whether treating TTP/HUS
 patients with high-dose versus standard-dose plasma exchange improves the treatment response.
 The investigators will recruit 150 patients with TTP/HUS from 9 centres across Canada over
 three years. The investigators will evaluate whether high-dose plasma exchange improves the
 treatment response, survival, and whether it reduces the number and volume of plasma exchange
 procedures and duration of hospital stay.
Background: Thrombotic thrombocytopenia purpura / haemolytic uremic syndrome (TTP/HUS) is a
 rare blood disorder with a high mortality rate of >95% when left untreated. In 1991,
 researchers discovered that treating TTP/HUS with plasma exchange vs. plasma infusion
 dramatically improved the survival rate, from 60% to 80%.The optimal plasma dose for treating
 TTP/HUS is unknown; however, recent research suggests that high-dose plasma exchange may
 improve survival in patients with TTP/HUS.

 Hypothesis: Treatment of TTP/HUS with high-dose vs. standard-dose plasma exchange will
 significantly decrease the composite outcome of 1) treatment failure at day 5 and/or 2)
 non-response or death at 2 weeks.

 Methods: The investigators will conduct a multi-centre, parallel group randomized controlled
 trial. The investigators anticipate recruiting 150 eligible patients with idiopathic TTP/HUS
 from 9 centres across Canada over 2.25 years. Patients will be randomized to receive
 high-dose plasma exchange (125 ml/kg/day up to 10 L/day plasma volume) or standard-dose
 plasma exchange (50-75 ml/kg/day; approximately 1-1.5 plasma volume). The primary composite
 outcome includes treatment failure at day 5 or non-response or death from any cause at 2
 weeks. Secondary outcomes include the individual components of the primary outcome,
 non-response or death from any cause at month 1 and month 6, days to remission, duration of
 hospital stay, number and volume of plasma exchange treatments, and cost minimization.

 Research Team: Our multi-centre team is part of the Canadian Apheresis Group, which was
 established in 1980 and currently operates in 30 centres across Canada. Collectively, the
 Canadian Apheresis Group treats 150 TTP/HUS patients each year. Our team includes experienced
 haematologists, nephrologists, epidemiologists and a biostatistician. The investigators have
 successfully collaborated on several projects and have an excellent publication record (>50
 publications across more than 15 journals including the New England Journal of Medicine).

 Timeline and Budget: Because TTP/HUS is a relatively rare disorder (an orphan disease), the
 investigators will recruit patients over 2.25 years from across Canada to achieve a
 sufficiently large sample size. A cost minimization study will be carried out in conjunction
 with the RCT to provide insight into potential costing.

 Future Directions: If the investigators can demonstrate that high-dose plasma exchange
 significantly improves the primary outcome, the investigators will pursue a multi-national
 collaboration with American, Chinese and European Centres to investigate other important
 outcomes including optimal dosing, cost-effectiveness and survival.

 Implications: This study has the potential to be the first major advancement in treating
 TTP/HUS in twenty years.
Inclusion Criteria:

 1. Age > 18 year-old

 2. First presentation of TTP/HUS

 3. Meet all of the following diagnostic criteria:

 -  Platelet count < 150 x 109 /L

 -  Microangiopathic haemolytic anaemia (blood film with presence of red blood cell
 fragmentation)

 -  LDH > 1.25 X the upper limits of normal

 -  No alternative diagnosis

 Exclusion Criteria:

 1. Secondary TTP/HUS

 2. Relapsing TTP/HUS

 3. Hypersensitivity to blood product

 4. Patient has received 2 or more plasma exchange treatment since symptom started over
 the last 1 week

 5. Received medication, including cyclosporine, cyclophosphamide, rituximab for treatment
 of TTP/HUS

 6. Other causes of thrombocytopenia than TTP/HUS