UH Rainbow Gastroenterology Chief Plays Pivotal Role in FDA Approval of C. difficile Drug in Kids

Clinical trial results support extrapolation to the pediatric population of bezlotoxumab efficacy and safety established in adults

Innovations in Pediatrics | Fall 2023

Although Clostridioides difficile infection (C.diff or CDI) is less common in children than in adults, it also has a slightly different risk profile among pediatric patients that’s worth noting.

Thomas J. Sferra, MD

“CDI in pediatric patients is strongly associated with predisposing factors and medical conditions, including antibiotic use, malignancy, inflammatory bowel disease and immune suppression,” says Thomas J. Sferra, MD, Division Chief of Pediatric Gastroenterology at UH Rainbow Babies & Children’s Hospital and the Martin and Betty Rosskamm Endowed Chair in Pediatric Gastroenterology. “In hospitalized children, CDI risk is highest in those patients with malignancy. Because of this, therapies to prevent recurrence of CDI in pediatric patients are needed.

It’s a clinical challenge worth confronting," Dr. Sferra says.

“Children are resilient, as we know, but CDI can lead to a severe illness and complicate an existing one,” he says. “It also can be an issue if it becomes recurrent. Once you have two infections with C. difficile, it's much more common to have three. Many patients struggle to clear this infection.”

Pivotal role: To address this issue and advance the standard of care, Dr. Sferra and UH Rainbow have played a key role in the clinical trial and recent FDA approval of the agent bezlotoxumab (Zinplava) for use in children with CDI. The monoclonal antibody, given in conjunction with antibiotics, had previously just been approved for adults as a preventive measure against the condition.

Dr. Sferra sat on the Scientific Advisory Committee for the pharmaceutical industry-initiated MODIFY III trial, an international, multicenter, double-blind, placebo-controlled study of bezlotoxumab in children ages 1 to 17 years. In fact, UH Rainbow was one of the trial’s highest-enrolling sites. In addition, he served as first author on the paper reporting the trial’s positive findings, published recently in the Journal of the Pediatric Infectious Diseases Society.

Behind the study: The MODIFY III trial included 143 participants, 107 of whom received a single 10 milligram infusion of bezlotoxumab, and 36 of whom received a placebo. They came from 49 centers in 15 countries around the world. Participants were divided into two age cohorts at the time of randomization – ages 1 to 11 years, and ages 12 to 17 years. The research team monitored safety, tolerability and efficacy of bezlotoxumab for 12 weeks post-infusion.

“We assessed the pharmacokinetics, safety, tolerability and efficacy of bezlotoxumab in pediatric patients, but this study was primarily designed to evaluate the dosing for this medication in children and adolescents,” Dr. Sferra says.

Positive findings: Results show that bezlotoxumab given to children in a dose of 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 percent) and placebo (14.7 percent).

“These results support the extrapolation to the pediatric population of bezlotoxumab efficacy and safety established in adults for the prevention of CDI recurrence,” Dr. Sferra says. “There were no clinically meaningful trends in bezlotoxumab exposure with body weight or age, supporting the conclusion that dosing proportional to body weight is appropriate in the pediatric population, as it is in adults. The results of this study support the bezlotoxumab dose of 10 mg/kg for pediatric patients.”

Leadership on CDI: This current project is just the latest example of research excellence from Dr. Sferra and UH Rainbow on issues related to C. difficile infections in children. He previously showed that CDI is more common among patients taking proton pump inhibitors and those with inflammatory bowel disease. In fact, Dr. Sferra has published nearly 20 scientific papers on this crucial topic in child health, making him one of the country’s leading experts.

He says he’s gratified that because of the FDA’s recent approval of bezlotoxumab for pediatric patients, fewer will suffer the ill effects of recurrent CDI.

“If we can avoid even a small number of recurrent disease, it has a beneficial impact on patients,” he says.

Contributing Expert:
Thomas J. Sferra, MD
Division Chief, Pediatric Gastroenterology
UH Rainbow Babies & Children’s Hospital
Martin and Betty Rosskamm Endowed Chair in Pediatric Gastroenterology
Professor of Pediatrics
Case Western Reserve University School of Medicine