Futility Concerns Halt C difficile Vaccine Trial

The efficacy, immunogenicity, and safety of a Clostridioides difficile toxoid vaccine candidate was assessed.

A candidate Clostridioides (formerly Clostridium) difficile toxoid vaccine met the criteria for futility during phase 3 trials and the study was halted. The vaccine did not prevent C difficile infection and clinical development for this candidate was stopped, according to study data published in The Lancet Infectious Diseases.

In this phase 3 multicenter, observer-blind, randomized, controlled trial (ClinicalTrials.gov, NCT01887912) the candidate was evaluated in 326 hospitals, clinics, and clinical research centers in 27 countries. In total, 9302 participants were enrolled with 6201 randomly assigned to the vaccine group and 3101 to the placebo group. Of these, 99.5% of the vaccine and placebo groups received at least 1 dose of the vaccine.

At the first planned interim analysis, 34 infections were reported during 11,697.2 person-years at risk in the vaccine group (0.29 infections per 100 person-years; 95% CI, 0.20-0.41) compared with 16 infections during 5789.4 person-years at risk in the placebo group (0.28 infections per 100 person-years; 95% CI, 0.16-0.45). The vaccine efficacy was determined to be -5.2% (95% CI, -104.1-43.5) and the study was terminated because of futility. Adverse events within 30 days of injection were reported in 46.6% of the vaccine group and 41.9% of the placebo group. The percentage of participants experiencing an adverse event leading to discontinuation was 4.8% in both the vaccine and placebo groups. At least 1 serious adverse event was reported in 27.2% and 27.8% of the vaccine and placebo groups, respectively.

The study was limited by the absence of existing standardized reporting mechanisms for C difficile infection. Investigators were required to devise a study-specific surveillance system for case detection based on symptoms compatible with C difficile infection. They also acknowledged that, “despite the high adherence to routine contact with participants, it is possible that PCR-confirmed, symptomatic cases of C difficile infection were missed.” According to the investigators, the results also highlighted the inherent difficulties in studying the efficacy of a vaccine for a disorder with an unpredictable epidemiology and in an older population.

Based on findings, investigators concluded that although the vaccine candidate was immunogenic, it failed to prevent symptomatic infections in participants at risk. They added that their findings shine light on the important challenges associated with vaccine development against bacterial nosocomial infections. However, investigators believe the results will inform future vaccine development.

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


de Bruyn G, Gordon DL, Steiner T, et al. Safety, immunogenicity, and efficacy of a Clostridioides difficile toxoid vaccine candidate: a phase 3 multicentre, observer-blind, randomized, controlled trial. Published online September 15, 2020. Lancet Infect Dis. doi:10.1016/S1473-3099(20)30331-5.