The trial was called off because of futility of the toxoid vaccine candidate.
Without an approved vaccine, Clostridium difficile (C. diff) infections represent a tremendous health burden in the US.
However, a team, led by Guy de Bruyn, MD, Sanofi Pasteur, evaluated the efficacy, immunogenicity, and safety of a toxoid vaccine candidate.
In the phase 3, multicenter, observer-blind, randomized, controlled trial, the investigators tested the new vaccine at 326 hospitals, clinics, and clinical research centers in 27 countries including the US and Canada in 9302 patients between July 2013 and November 2017.
Each participant was at least 50 years old and considered to be at an increased risk of C. diff infection due to 2 previous hospital stays of at least 24 hours and received systemic antibiotics in the previous 12 months or were anticipating being admitted to the hospital for 72 hours or more for elective surgery within 60 days of enrollment.
The eligible patients were stratified by geographical region, as well as by the 2 risk strata. Each participant was randomly assigned (2:1), with a fixed block size of 3, to receive either a C. diff toxoid vaccine candidate (n = 6201), containing toxoids A and B (C. diff vaccine candidate group) or a placebo vaccine (n = 3101). A total of 6173 (99.5%) of participants in the study vaccine group and 3085 (99.5%) in the placebo group received at least 1 dose of the vaccine.
Each participant received 1 dose of either the target vaccine or placebo intramuscularly on days 0, 7, and 30.
The investigators sought a primary outcome of the efficacy of the vaccine in preventing symptomatic C. diff infection, defined as having 3 or more loose stools in a period of 24 hours of less, loose stools for 24 hours or more, and a PCR-positive test for C. diff toxin B in a loose stool sample, within 3 years following the final vaccine dose.
The team measured the primary outcome in the modified intention—to-treat population, which included all participants who received at least 1 injection of the assigned vaccine.
However, the study was terminated following the first planned interim analysis due to futility.
In the C. diff vaccine group, there were 34 infections reported over 11,697.2 person years at risk (0.29 infections per 100 person-years; 95% CI, 0.20–0.41) compared with 16 infections over 5789.4 person-years at risk in the placebo group (0.28 infections per 100 person-years; 95% CI, 0.16–0.45).
This indicates the vaccine’s efficacy is -5.2% (95% CI, -104.1-43.5).
In the C. diff vaccine group, 2847 (46.6%) reported an adverse event within 30 days of injection, while 1282 (41.9%) in the placebo group reported an adverse event.
The proportion of patients who had an adverse event leading to discontinuation was 4.8% in both groups (296 participants in the C. diff vaccine candidate group and 146 participants in the placebo group) and 1662 (27.2%) participants in the C. diff vaccine candidate group reported at least 1 serious adverse event compared with 851 (27.8%) participants in the placebo group.
“In adults at risk for C difficile infection, a bivalent C difficile toxoid vaccine did not prevent C difficile infection,” the authors wrote. “Since the C difficile vaccine candidate met the criteria for futility, the study was terminated and clinical development of this vaccine candidate was stopped.”
The study, “Safety, immunogenicity, and efficacy of a Clostridioides difficile toxoid vaccine candidate: a phase 3 multicenter, observer-blind, randomized, controlled trial,” was published online in The Lancet Infectious Diseases.