Clinical Trial: Eculizumab in Shiga-toxin Related Hemolytic and Uremic Syndrome Pediatric Patients - ECULISHU

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: Early Treatment With the Monoclonal C5 Antibody Eculizumab in Pediatric Patients Affected by Shiga-toxin Related Hemolytic and Uremic Syndrome: A Phase III Prospective Randomized Controlled Therapeuti

Brief 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 Summary:

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 par
Sponsor: University Hospital, Toulouse

Current Primary Outcome: the duration in days of extrarenal epuration [ Time Frame: From the inclusion date and assessed up to 13 months ]

Extrarenal epuration means peritoneal dialysis or hemodialysis, and is assessed at each visit.


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Number of adverse events as a measure of Safety and tolerance of treatment injections (ECZ or placebo) [ Time Frame: At each injection (treatment visits 2, 3, 4, 5, 6 at respectively day 0, 7, 14, 21, 28) and at each follow-up visit (7, 8, 9 respectively at month 2, 7, 13) ]
  • Adverse reactions related to the treatment (ECZ or placebo) [ Time Frame: At each injection (treatment visits 2, 3, 4, 5, 6 at respectively day 0, 7, 14, 21, 28) and at each follow-up visit (7, 8, 9 respectively at month 2, 7, 13) ]
  • Duration of Acute Renal Failure (ARF) [ Time Frame: Inclusion Visit (1 at day -3 to -1 ), treatment period (visits 2, 3, 4, 5, 6 respectively at day 0, 7, 14, 21, 28), follow-up period (visits 7, 8, 9 respectively at month 2, 7, 13) ]
    Duration of ARF will be evaluated as follow : urine output measurement, creatinin clearance estimated with the Schwartz 2009 assay (based on creatinin plasma levels), ionogram, proteinuria.
  • Renal sequels [ Time Frame: At 1, 6 and 12 months after last injection of ECZ (follow-up visits 7, 8, 9) ]
    Renal sequels will be evaluated as follow : blood pressure, creatinin clearance, ionogram, proteinuria and microalbuminuria.
  • Hematological abnormalities [ Time Frame: Inclusion Visit (1 at day -3 to -1), treatment period (visits 2, 3, 4, 5, 6 respectively at day 0, 7, 14, 21, 28), follow-up period (visits 7, 8, 9 respectively at month 2, 7, 13) ]
    • Duration (in days) of the thrombocytopenia
    • Duration (in days) of the hemolytic anemia
  • Blood parameters of Complement Alternative Pathway (CAP) [ Time Frame: Inclusion visit (1 at day -3 to -1), Treatment visits (3, 4, 5, 6 at day 7, 14, 21, 28), follow-up visit (7 at month 2) ]
    Blood parameters of CAP will be evaluated with plasmatic dosages of the complement components C3 and CD46.
  • Inhibition of the Terminal Complement Complex (TCC) [ Time Frame: Inclusion visit (1 at day -3 to -1), Treatment visits (3, 4, 5, 6 at day 7, 14, 21, 28), follow-up visit (7 at month 2) ]
    Inhibition of the TCC will be evaluated trough the CH50 assay and plasmatic free ECZ levels.
  • Incidence of extrarenal manifestations [ Time Frame: Inclusion Visit (1 at day -3 to -1), treatment period (visits 2, 3, 4, 5, 6 respectively at day 0, 7, 14, 21, 28) ]
    • Neurological involvement (seizures, coma, focal deficit)
    • Cardiac involvement (cardiac failure, ischemic myocarditis, conduction or rhythm troubles)
    • Digestive involvement (pancreatitis, hepatitis, hemorrhagic colitis, bowel perforation, rectal prolapsus)
  • Mortality [ Time Frame: Inclusion Visit (1 at day -3 to -1), treatment period (visits 2, 3, 4, 5, 6 respectively at day 0, 7, 14, 21, 28), follow-up period (visits 7, 8, 9 respectively at month 2, 7, 13) ]


Original Secondary Outcome: Same as current

Information By: University Hospital, Toulouse

Dates:
Date Received: July 28, 2014
Date Started: June 2015
Date Completion: June 2018
Last Updated: May 17, 2017
Last Verified: May 2017