Eculizumab in Shiga-toxin Related Hemolytic and Uremic Syndrome Pediatric Patients - ECULISHU
Eculizumab in Shiga-toxin Related Hemolytic and Uremic Syndrome Pediatric Patients - ECULISHU
The investigators aim to perform the first controlled randomized prospective study using ECZ
 in pediatric STEC-HUS. This is of great interest as there is still no efficient specific
 therapy in that potentially devastating disease.

 Furthermore, published data concerning the use of ECZ in STEC-HUS are controversial,
 reflecting statistical bias in retrospective or uncontrolled studies, thus emphasizing the
 need for prospective studies.
Hemolytic and uremic syndrome (HUS), characterized by thrombocytopenia, hemolytic anemia and
 acute renal failure (ARF), mainly affects children younger than 5 years old. Shiga-toxin
 (Stx) related HUS (STEC-HUS) is due to Stx secreting bacteria (mainly enterohemorrhagic
 Escherichia Coli strains). Acute phase of STEC-HUS is severe with at least 50% of affected
 children requiring dialysis, 20% presenting neurological involvement and 5% cardiac
 involvement. Mortality rates can reach 5% in pediatric series and long-term renal sequels
 have been reported in at least 30% of surviving patients. Apart from supportive care, no
 specific treatment (such as plasma exchange) has proven its efficacy in this life-threatening
 disease.

 Recently, activation of the complement alternative pathway (CAP) has been demonstrated in
 STEC-HUS patients and experimental studies have highlighted that Stx induce CAP activation on
 human endothelial cells and platelet-leucocytes complexes, in addition to its direct cell
 toxicity inducing apoptosis, both processes ending up in microvasculature thrombosis. CAP
 activation has been demonstrated as the cause of atypical HUS (aHUS) and ECZ, a monoclonal C5
 antibody, which inhibits the terminal complement complex (TCC) formation, can efficiently
 prevent evolution to end stage renal disease in aHUS patients. In 2011, Lapeyraque et al.
 reported its possible efficacy in 3 severe STEC-HUS pediatric patients. Nevertheless, in
 STEC-HUS, ECZ has only been used in uncontrolled studies, mostly during the 2011 German
 outbreak, with conflicting results. Considering the lack of therapy to prevent
 life-threatening complications and renal sequels in STEC-HUS and the logically expected
 efficacy of ECZ, controlled studies are mandatory. In recruiting centers, STEC-HUS patients
 with ARF will be proposed to enroll the trial with the exception of patients with multiorgan.
 After parental consent, patients will be randomized to receive either ECZ or a dextrose-based
 placebo in a single blinded fashion. According to the patient body weight, there will be 3 to
 5 injections at day (D) 0, D7, D14, D21 and D28. According to the length of initial hospital
 stay, patients may have the remaining injections in the day ward of the recruiting center.
 Dosage of ECZ will be based on previous trials using ECZ in pediatric aHUS patients. We
 designed a single blinded study because patients treated with placebo who will develop severe
 multiorgan involvement will be switched to the ECZ arm. ECZ or placebo will be administrated
 intravenously as a 30-minute injection. In patients receiving hemodialysis, ECZ injection
 will be performed after a dialysis session. Before first injection, patients will receive a
 tetravalent meningococcal vaccine and an oral antibiotic prophylaxis to be continued up to 14
 days after last injection.

 This is a single blinded, phase III, randomized, multi-center controlled versus placebo
 clinical trial of eculizumab in STEC-HUS patients.
Inclusion Criteria:

 -  Pediatric patient (1 month-18 years old)

 -  Affected by STEC-HUS defined by :

 -  Thrombocytopenia (<150 000/mm3)

 -  Mechanic hemolytic anemia (Hemoglobin < 10g/dL, haptoglobin <LLN, lactate
 dehydrogenase (LDH) >upper limit of normal (ULN) and/or bilirubin > ULN, presence of
 schizocytes)

 -  ARF defined by an estimated Schwartz 2009 creatinin clearance <75ml/min/1,73m²

 -  With prodromal diarrhea and/or presence of an enterohemorrhagic strain of Escherichia
 Coli and/or identification of the Stx 1 or 2 genes in the stool sample or rectal swab

 -  Written consent of the 2 parents

 -  Female patients of childbearing potential must be practicing an effective, reliable
 and medically acceptable contraceptive regimen during the entire duration of the study
 and 5 months after the end of the participation.

 Exclusion Criteria:

 -  Neonatal HUS

 -  Malignancy

 -  Known HIV infection

 -  Pregnancy or lactation

 -  Identified drug exposure-related HUS

 -  Infection-related HUS

 -  Known systemic lupus erythematosus or antiphospholipid antibody positivity or syndrome

 -  Patient already enrolled in a drug trial

 -  Patient with ongoing meningococcal infection

 -  Patient affected by aHUS or family history of aHUS

 -  STEC-HUS patient with severe multiorgan involvement at diagnostic:

 -  Neurological involvement (seizures, coma, focal deficit) with signs of
 microangiopathy on cerebral Magnetic Resonance Imaging.

 -  Cardiac involvement (cardiac failure, ischemic myocarditis, conduction or rhythm
 troubles)

 -  Digestive involvement (severe pancreatitis defined by lipasemia>500UI/L, severe
 hepatitis defined by transaminase >x10ULN and/or prothrombin time<60%,
 hemorrhagic colitis, bowel perforation, rectal prolapsus)