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J Am Soc Nephrol 2023 Sep 1;34(9):1561-1573. doi: 10.1681/ASN.0000000000000182
. Epub 2023 Jun 12.
Efficacy and Safety of Eculizumab in Pediatric Patients Affected by Shiga Toxin-Related Hemolytic and Uremic Syndrome: A Randomized, Placebo-Controlled Trial
Arnaud Garnier, Karine Brochard, Theresa Kwon, Anne-Laure Sellier-Leclerc, Annie Lahoche, Emma Allain Launay, François Nobili, Mathilde Caillez, Sophie Taque, Jerôme Harambat, Guylhene Michel-Bourdat, Vincent Guigonis, Marc Fila, Sylvie Cloarec, Djeddi Djamal-Dine, Loïc de Parscaux, Lise Allard, Rémi Salomon, Tim Ulinski, Véronique Frémeaux-Bacchi, Christophe Morin, Pascale Olivier-Abbal, Hélène Colineaux, Françoise Auriol, Catherine Arnaud, Isabelle Kieffer, Clara Brusq
PMID: 37303085
Introduction
Hemolytic uremic syndrome (HUS) is characterized by a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Shiga toxin-related HUS (STEC-HUS) makes up the bulk of these cases, usually due to E. Coli infection. Transmission is typically from food-born related infections but can also be from person-to-person and animal contact (Tack et al, Microorganisms 2021). The incidence rate of STEC-HUS is much more common in children than adults, with estimates at 10 per 1,000,000 person-years versus 0.68 per 1,000,000 person-years, respectively, translating to a 10 fold difference (Travert et al, Toxins 2021). More than half of patients who develop HUS will need dialysis (Ylinen et al, Pediatric Nephrology 2020). Another Shiga-toxin producing bacteria is Shigella, which has been associated with more severe cases (Bhimma et al, Pediatric Nephrology 1997). To top those statistics, although much less common, Streptococcus pneumoniae-related HUS (Strept pneumo-HUS) has higher rates of morbidity and mortality, with estimates of needing dialysis to be as high as 75% (Copelovitch et al, Pediatric Nephrology 2008).
Despite the high morbidity and mortality with HUS, treatment has mainly been supportive (Garnier et al, JASN 2023). Over the last decade, we have developed a better understanding about the pathophysiology of HUS, opening the door for potential treatments. For Strept-pneumo-HUS, it is believed that the pneumococci produced neuraminidase cleaves celiac residues on glycoproteins of endothelial cells and subsequently exposes the Thomsen-Friedenreich antigen (T-antigen), allowing for IgM binding, cellular damage, and activation of the complement system (Brocklebank et al, CJASN 2018). Lastly, for STEC-HUS, the Shiga toxin combines with glycolipid Gb3 after gut translocation and enters the endothelial cell via GB3 receptor, affecting multiple proteins, including Factor H on endothelial surfaces and increasing the activation of the alternative pathway (Orth et al, J Immunol 2009).
Given the role of complement in the pathophysiology of infection associated HUS, there has been much interest in using eculizumab, a humanized monoclonal C5 antibody, as a potential treatment (Garnier et al, JASN 2023). Indeed, there has been many publications on the use of eculizumab in severe HUS, although the results have been mixed.
Because of the inconclusive data, Garnier et al conducted a randomized control trial, termed ECULISHU, looking at the efficacy of eculizumab in STEC-HUS.
The Study
Methods
Design
This trial was a phase 3, patient-blinded, randomized control study assessing the impact of eculizumab on the course of acute renal failure in patients with STEC-HUS. There were two phases in this trial: a 4 week treatment period (0, 7, 14, 21, and 28 days) followed by an 11 month follow-up period (2, 6 and 12 months). The trial was run over 18 sites participating in the French Society of Pediatric Nephrology.
Study Population
Inclusion
The trial involved recruiting 100 patients in the age range of 1 month to 18 years affected by STEC-HUS based on 3 criterias. Of note, female patients of childbearing potential had to use a medically acceptable contraceptive regimen during the treatment phase and 5 months after the last experimental treatment.
Exclusion
The trial had eight exclusionary points. Severe forms of STEC-HUS were excluded because many participating sites used eculizumab in those cases. If they were not excluded, it could cause difficult ethical considerations. Additionally, participants were prohibited from obtaining plasma therapy, erythropoietin, rituximab, and intravenous immunoglobulin, as they could impact the STEC-HUS course.
Interventions
Eculizumab and placebo (5%) were both injected intravenously over 30 minutes. Based on a participant’s body weight, he/she would receive injections at days 0, 7, 14, 21, and 28 during the treatment phase.This duration was chosen based on a study finding normalization of alternative pathway activation within a month of diagnosis (Thurman et al, CJASN 2009. For patients undergoing hemodialysis, eculizumab or placebo was given after a dialysis session. Additionally, all patients received meningococcal vaccination and type B meningococcal vaccination prior to treatment initiation and oral antibiotic prophylaxis with penicillin up to 60 days from last treatment dose.
Endpoints
The primary endpoint was the duration of days on renal replacement therapy after first injection of eculizumab or placebo. The treatment was considered successful if renal replacement therapy was less than 48 hours. Multiple secondary endpoints were assessed:
Plasma creatinine levels and eGFR from 0-60 days
Renal sequelae at 6 and 12 months after last administration, defined as the following:
Hypertension >= 95%tile for age, sex, and height
Decreased eGFR < 90mL/min/1.73m2 based on 2009 Schwartz Formula
Proteinuria, UPCr > 0.02g/mmol
Alternative pathway activation (C3, leukocyte CD46, CH50)
Signs of thrombotic microangiopathy
Extra-renal manifestation (neurological, digestive, hepatic, pancreatic, and cardiac)
Mortality
Statistics
Based on a power of 80% and type 1 error of 0.05, the authors calculated needing 100 participants (50 participants in each arm) to find 60% of participants needing renal replacement therapy for less than 48 hours in the eculizumab group as compared to a presumed 30% in the placebo group. Analysis of the primary endpoint was performed on an intention-to-treat basis and used chi-square test. Secondary endpoints involving lab values were performed using a mixed linear model for repeated data, as it took into account intrapatient correlations. The authors also took into account a potential interaction between measurement time and randomization arm.
Funding
This trial was funded by a grant through the Clinical Research Hospital Program, sponsored by the French Ministry of Health. The maker of eculizumab, Alexion, played no role in the study design, data collection, analysis, or manuscript preparation.
Results
After considering eligibility, 100 participants underwent randomization, with the following flow chart. The figure doesn’t state how many were screened to reach the 100 eligible.
Figure 1 from Garnier et al, JASN 2023.
The median age was with 2.6 yrs, 54% females. Median time for enrollment was 8 days after onset of symptoms, with diarrhea present in 94%. Those without diarrhea had a positive PCR in the rectal swab. Table 1 highlights the renal and hematological parameters in both groups. 29 patients were already on renal replacement therapy at time of inclusion.
Primary Endpoint:
The primary endpoint (duration of RRT < 48 hours) was reached in 19 pts (38%) in eculizumab group and 24 pts (48%) in placebo group (p=0.313); these numbers remained comparable when measured by per protocol population analysis (Table 3).
The incidence of RRT requirement was also comparable, 60% in eculizumab group and 50% in placebo (p=0.315). Median duration of dialysis was 9.5 days in the treatment arm and 6 days in placebo.
Secondary Endpoints:
eGFR evolution
No difference in the eGFR and plasma Cr in the two groups was observed during the first 60 days after inclusion (Figure 2).
Renal sequelae
Renal sequelae (high BP, proteinuria, declined eGFR) were similar at 6 months with 26 (31%) in eculizumab and 21 (25%) in placebo arm meeting the criteria. At 12 months however, there were significantly fewer sequelae in eculizumab arm with 20 (43%) and 29 (64%) in the placebo arm reaching at least one criteria for renal sequelae (p=0.04). This was mostly driven by lower proteinuria with eculizumab. These findings are highlighted in Figure 3 and supp table 3.
Supplemental table 3 from Garnier et al, JASN 2023
Signs of thombotic microangiopathy
No difference in the hematological parameters for TMA were seen between the two groups; blood and platelet transfusion requirements were also similar (Figure 4).
Extrarenal manifestations
Forty three patients (86%) in the eculizumab and 40 patients (80%) in the placebo arm experienced at least one extrarenal manifestation within the first 60 days after inclusion (p=0.42) (Table 2); with liver and pancreatic enzyme elevation being the most common. There was a possible trend towards fewer cardiac manifestations in eculizumab arm 1 vs 5 in placebo arm. Of note, 4 of these had isolated elevated cardiac enzymes as their manifestation.
Alternative pathway activation markers
C3 and CD46 levels were checked in nearly ⅔ of the patients on days 0,7 and 21. None of them had low C3. The CD46 expression was also low in 71% at day 0, 29% at day 7 and 16% at day 21. No statistical analysis was performed to examine any association of these with AKI. The CH50 levels were normal in the placebo group as expected, but in the eculizumab group, a proper terminal complement complex (TCC) blockade defined as CH50 <20% was obtained in only 54% at day 7 and 42% at day 21. But even with proper TCC, only 9/19 (47%) patients reached primary endpoint (RRT free at 48 hours.
Mortality
No deaths occurred during the study period.
Discussion
ECULISHU was a Phase 3 randomized placebo controlled trial to study the impact of early eculizumab on kidney function in pediatric patients with STEC-HUS. The study did not show clear benefit of using early eculizumab on duration of renal replacement therapy after initiation of study drug. The study’s primary endpoint of RRT <48 hr was reached in 38% pt in the eculizumab arm and 48% in placebo arm (p=0.313). There was also no difference in the evolution of AKI or ongoing need for renal replacement therapy between the two groups. Furthermore, the hematological parameters for thrombotic microangiopathy and transfusion requirement were similar in both arms. While proper terminal complement blockade was not achieved in nearly 50% pts, the primary endpoint was not met even in those who had adequate blockade early on raising some doubts on the true role of alternate complement pathway in organ damage in infection associated with HUS. Should the dosing be more tailored based on CH-50 levels?
Prior studies (Lapeyraque et al, NEJM 2011 and Percheron et al, Pediatric Nephrology 2018) showed beneficial effects of using eculizumab on severe neurological outcomes in STEC-HUS prompting many centers to use it off-label as compassionate use for this indication. The study describing the German outbreak (Kielstein et al, NDT 2012) with the largest number of patients with STEC-HUS, also did not report any major benefits with eculizumab, though it was a retrospective study not designed to examine this question rigorously. Most patients in this study had a milder presentation and those with severe complications were excluded due to the ethical reasons. As alluded to before, many centers use eculizumab in severe cases and could have posed an ethical dilemma if included in the study.
The study observed benefit on renal sequelae at 12 months follow up in the eculizumab arm; 20 (43%) versus 29 (64%) in the placebo arm having a renal sequelae (p=0.04), driven by lower proteinuria. Does this portend a true long-term benefit and justify using an extremely expensive drug? The average cost of a 30 ml vial (10mg/ml) is $7000 out of pocket, with doses ranging from 300-900 mg weekly, which makes for a rather expensive antiproteinuric agent. Although the safety profile was comparable and no serious adverse events were noted in eculizumab arm, the cost is prohibitive, especially when no clear benefit is noted in the acute phase.
A systematic review (Zwart et al, Pediatric Nephrology 2023) did not report any clear benefit of using eculizumab on medium to long term outcomes in infection associated with HUS (predominantly STEC-HUS) in pediatric patients. The studies included in the review were all observational, with inherent confounding biases. Unlike ECULISHU, the studies included in the review were predominantly sicker patients, raising concerns about whether the medication was started too late in the course, as a last-ditch effort.
Another consideration is underlying genetic variation in the complement pathway in patients with STEC-HUS that predispose them to more severe course and a subset where eculizumab could actually be beneficial.
Conclusion
Given the potential role of complement activation in STEC-HUS and lack of strong data for eculizumab use for infection-associated HUS, this was a much awaited RCT result. The study concluded that eculizumab did not alter the RRT duration in the acute phase, nor accelerate resolution of TMA parameters or eGFR evolution compared to placebo in milder forms of STEC-HUS. No difference in extra-renal manifestations as well. There was potential benefit for lower renal sequelae at 12 months follow-up in treatment arm compared to placebo. Did the study fail to show improvement due to milder disease severity? Does the extremely prohibitive cost justify its use in STEC-HUS when proper conservative care shows similar rates of dialysis?
We will await results of ECUSTEC, another randomized placebo-controlled study out of Bristol, on eculizumab use in pediatric STEC-HUS, primary endpoint will be clinical severity score at day 60. What we truly need is a multi-center, multi-nation study including a more diverse population and varying grades of severity.
Summary by
Shweta Shah
Assistant Professor
Pediatric Nephrologist
Texas Children’s Hospital
and
Melvin Chan
Pediatric Nephrology Fellow
University of Colorado
Reviewed by: Swapnil Hiremath, Swasti Chaturvedi
Header Image created by AI, based on prompts by Evan Zeitler