Eculizumab in Shiga-toxin Related Hemolytic and Uremic Syndrome Pediatric Patients - ECULISHU
Condition: Hemolytic Uremic Syndrome of Childhood
MeSH terms: Azotemia; Hemolytic-Uremic Syndrome; Syndrome; Hemolysis
Study type: Interventional
Phase: Phase 3

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Eculizumab; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): According to the patient body weight, there will be 3 to 5 injections at D0, 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.
ECZ or placebo will be administrated intravenously as a 30-minute injection; According to the patient body weight, there will be 3 to 5 injections at D0, D7, D14, D21 and D28.
ECZ or placebo will be administrated intravenously as a 30-minute injection
Other intervention name(s): Soloris®; Solution with 5% glucose
Intervention MeSH terms: Eculizumab
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Treatment
Keywords: Eculizumab; Shiga-toxin; hemolytic and uremic syndrome; pediatric