Dataset Information

Double-Blind, Placebo-Controlled Study of Bezlotoxumab in Children Receiving Antibacterial Treatment for Clostridioides difficile Infection (MODIFY III).

ABSTRACT:

Background

Therapies to prevent recurrence of Clostridioides difficile infection (CDI) in pediatric patients are needed. Bezlotoxumab is a fully human monoclonal antibody approved for prevention of recurrent CDI in adults. We assessed the pharmacokinetics, safety, tolerability, and efficacy of bezlotoxumab in pediatric patients.

Methods

MODIFY III was a multicenter, double-blind, placebo-controlled study of bezlotoxumab in children (1 to <18 years) receiving antibacterial treatment for CDI. Participants were randomized 3:1 to receive a single infusion of bezlotoxumab (10 mg/kg) or placebo and were stratified by age at randomization (cohort 1: 12 to <18 years, cohort 2: 1 to <12 years). The primary objective was to characterize bezlotoxumab pharmacokinetics to support dose selection for pediatric patients; the primary endpoint was the area under the bezlotoxumab serum concentration-time curve (AUC0-inf). Safety, tolerability, and efficacy were monitored for 12 weeks post-infusion.

Results

A total of 148 participants were randomized and 143 were treated: 107 with bezlotoxumab and 36 with placebo (cohort 1 n = 60, cohort 2 n = 83; median age 9.0 years); 52.4% of participants were male and 80.4% were white. Geometric mean ratios (90% CI) for bezlotoxumab AUC0-inf were 1.06 (0.95, 1.18) and 0.82 (0.75, 0.89) h * μg/mL for cohorts 1 and 2, respectively. Bezlotoxumab 10 mg/kg was generally well-tolerated with an adverse event profile similar to placebo, including no treatment discontinuations due to adverse events. CDI recurrence was low and comparable for bezlotoxumab (11.2%) and placebo (14.7%).

Conclusions

The results of this study support the bezlotoxumab dose of 10 mg/kg for pediatric patients.

Trial registration

NCT03182907 at ClinicalTrials.gov.

SUBMITTER: Sferra TJ

PROVIDER: S-EPMC10312293 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Publications

Double-Blind, Placebo-Controlled Study of Bezlotoxumab in Children Receiving Antibacterial Treatment for Clostridioides difficile Infection (MODIFY III).

Sferra Thomas J TJ Merta Tomas T Neely Michael M Murta de Oliveira Claudia C Lassaletta Alvaro A Fortuny Guasch Claudia C Dorr Mary Beth MB Winchell Gregory G Su Feng-Hsiu FH Perko Sarah S Fernsler Doreen D Waskin Hetty H Holden Stephen R SR

Journal of the Pediatric Infectious Diseases Society 20230601 6

<h4>Background</h4>Therapies to prevent recurrence of Clostridioides difficile infection (CDI) in pediatric patients are needed. Bezlotoxumab is a fully human monoclonal antibody approved for prevention of recurrent CDI in adults. We assessed the pharmacokinetics, safety, tolerability, and efficacy of bezlotoxumab in pediatric patients.<h4>Methods</h4>MODIFY III was a multicenter, double-blind, placebo-controlled study of bezlotoxumab in children (1 to <18 years) receiving antibacterial treatmen ...[more]

PMID: 37389891

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Project description:Clostridioides difficile is the most common cause of infectious antibiotic-associated diarrhea, with disease mediated by two major toxins TcdA and TcdB. In severe cases, systemic disease complications may arise, resulting in fatal disease. Systemic disease in animal models has been described, with thymic damage an observable consequence of severe disease in mice. Using a mouse model of C. difficile infection, we examined this disease phenotype, focussing on the thymus and serum markers of systemic disease. The efficacy of bezlotoxumab, a monoclonal TcdB therapeutic, to prevent toxin mediated systemic disease complications was also examined. C. difficile infection causes toxin-dependent thymic damage and CD4+CD8+ thymocyte depletion in mice. These systemic complications coincide with changes in biochemical markers of liver and kidney function, including increased serum urea and creatinine, and hypoglycemia. Administration of bezlotoxumab during C. difficile infection prevents systemic disease and thymic atrophy, without blocking gut damage, suggesting the leakage of gut contents into circulation may influence systemic disease. As the thymus has such a crucial role in T cell production and immune system development, these findings may have important implications in relapse of C. difficile disease and impaired immunity during C. difficile infection. The prevention of thymic atrophy and reduced systemic response following bezlotoxumab treatment, without altering colonic damage, highlights the importance of systemic disease in C. difficile infection, and provides new insights into the mechanism of action for this therapeutic.Abbreviations: Acute kidney injury (AKI); Alanine Transaminase (ALT); Aspartate Aminotransferase (AST); C. difficile infection (CDI); chronic kidney disease (CKD); combined repetitive oligo-peptides (CROPS); cardiovascular disease (CVD); Double positive (DP); hematoxylin and eosin (H&E); immunohistochemical (IHC); multiple organ dysfunction syndrome (MODS); phosphate buffered saline (PBS); standard error of the mean (SEM); surface layer proteins (SLP); Single positive (SP); wild-type (WT).

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Dataset Information

Double-Blind, Placebo-Controlled Study of Bezlotoxumab in Children Receiving Antibacterial Treatment for Clostridioides difficile Infection (MODIFY III).

Background

Methods

Results

Conclusions

Trial registration

Publications

Double-Blind, Placebo-Controlled Study of Bezlotoxumab in Children Receiving Antibacterial Treatment for Clostridioides difficile Infection (MODIFY III).

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