Efficacy and Safety of Eculizumab in Pediatric Patients Affected by Shiga Toxin-Related Hemolytic and Uremic Syndrome: A Randomized, Placebo-Controlled Trial

Abstract

Significance statement: Shiga toxin-related hemolytic uremic syndrome (STEC-HUS) is a serious condition, characterized by multiorgan thrombotic microangiopathy, mainly affecting children. Renal involvement is severe, with approximately half of patients requiring dialysis. So far, no specific treatment has been proven efficient in STEC-HUS. The use of eculizumab, a monoclonal antibody inhibiting terminal complement complex, has demonstrated remarkable success in atypical hemolytic uremic syndrome, but its use in uncontrolled studies to treat STEC-HUS has yielded inconsistent results. In this Phase 3 randomized, placebo-controlled trial in 100 pediatric patients with STEC-HUS, the findings did not show efficacy of eculizumab during the acute phase of the disease. However, the results indicated a reduction of renal sequelae in eculizumab-treated patients at 1-year follow-up. Larger prospective studies would be needed to further explore eculizumab as a potential treatment.

Background: Shiga toxin-related hemolytic uremic syndrome (STEC-HUS) in children is a severe condition, resulting in approximately 50% of patients requiring RRT. Furthermore, at least 30% of survivors experience kidney sequelae. Recently, activation of the complement alternative pathway has been postulated as a factor in STEC-HUS pathophysiology, leading to compassionate use of eculizumab, a monoclonal antibody inhibiting the terminal complement complex, in affected patients. Given the lack of therapy for STEC-HUS, a controlled study of eculizumab efficacy in treating this condition is a priority.

Methods: We conducted a Phase 3 randomized trial of eculizumab in children with STEC-HUS. Patients were randomly assigned in a 1:1 ratio to receive either eculizumab or placebo during 4 weeks. Follow-up lasted for 1 year. The primary end point was RRT duration <48 hours after randomization. Secondary endpoints included hematologic and extrarenal involvement.

Results: Baseline characteristics were similar among the 100 patients who underwent randomization. The rate of RRT <48 hours did not differ significantly between the two groups (48% in the placebo versus 38% in the eculizumab group; P = 0.31) or in the course of ARF. The two groups also exhibited similar hematologic evolution and extrarenal manifestations of STEC-HUS. The proportion of patients experiencing renal sequelae at 1 year was lower in the eculizumab group than in the placebo group (43.48% and 64.44%, respectively, P = 0.04). No safety concern was reported.

Conclusions: In pediatric patients with STEC-HUS, eculizumab treatment does not appear to be associated with improved renal outcome during acute phase of the disease but may reduce long-term kidney sequelae.

Clinical trials registrations: EUDRACT (2014-001169-28) ClinicalTrials.gov ( NCT02205541 ).

Graphical abstract

Figure 1.

Trial flowchart. STEC-HUS, Shiga toxin–related hemolytic uremic syndrome.

Figure 2.

Evolution of renal function. (A and B) Predicted mean eGFR and plasma creatinine levels, respectively, according to treatment allocation (eculizumab: black lines, placebo: gray lines) and visit.

Figure 3.

Prevalence of renal sequels (high BP and/or eGFR <90 ml/min per 1.73 m² and/or urinary protein/creatinine ratio >0.2 g/mmol) 6 and 12 months after inclusion according to treatment allocation (eculizumab: black blocks, placebo gray blocks).

Figure 4.

Evolution of hematological parameters. (A–D) Predicted means of hemoglobin level, platelet counts, LDH level, and schizocytes percentage, respectively, according to treatment allocation (eculizumab: black lines, placebo: gray lines) and the visit. LDH, lactate dehydrogenase.

Figure 5.

Complement exploration. (A and B) CAP activation parameters during treatment phase. (A) C3 levels (lower limit of normal 660 mg/L) and (B) CD46 leukocyte expression (lower limit of normal mean fluorescence intensity 13) according to treatment allocation (eculizumab: black boxes, placebo: gray boxes) and the visit. (C) Inhibition of TCC during treatment phase according to treatment allocation (eculizumab: black dots, placebo: gray dots) and the visit. Full inhibition TCC was considered when CH50 was ≤20% (dotted line). CAP, complement alternative pathway; CH50, 50% hemolytic complement; TCC, terminal complement complex.