Background:

Tolevamer sodium is a novel, nonabsorbed, nonantibiotic polymer that binds C. difficile toxins A and B, and is being developed to treat C. difficile-associated diarrhoea (CDAD). C. difficile is the most common cause of infectious nosocomial diarrhea, affecting ~1% of hospitalised patients. C. difficile proliferates when normal colonic flora are altered, typically by antibiotics. Pathogenic strains of C. difficile produce two toxins, A and B, that induce colonic inflammation and fluid loss. CDAD treatment with metronidazole or vancomycin also disrupts normal flora, and CDAD recurs in 20% of treated patients. We have completed a phase 2 trial demonstrating that tolevamer and vancomycin have similar efficacy in the treatment of mild-moderate CDAD.

Primary objective:

To demonstrate noninferiority vs. vancomycin with respect to time to resolution of diarrhoea (TTROD).

Methods:

A randomised, double-blind, double-dummy, active-controlled phase 2 trial was conducted to determine the safety and efficacy of monotherapy with 1 or 2 g tolevamer TID vs. a standard oral dose of 125 mg vancomycin QID. 289 patients with a first episode or recurrent CDAD were enrolled at 58 US, UK and Canadian sites.

Results

Preliminary data showed that the median TTROD in the per protocol population (PP) was 2.0 days with vancomycin, and 2.5 days with 6 g tolevamer. Noninferiority testing demonstrated that these response times were comparable (P = 0.015), and that the 6 g tolevamer TTROD risk ratio relative to vancomycin was 0.98 (95% CI: 0.68–1.41). In the ITT population, the median TTROD was 3.0 days for both groups. There was no statistically significant difference in TTROD between vancomycin and 6 g tolevamer in either primary or recurrent CDAD patients. The 3 g TTROD was 4.0 days, showing a tolevamer dose response. In the PP, the definitive recurrence rate (DRR: confirmed by a positive toxin assay) was 19% with vancomycin and 10% with 6 g tolevamer, but this advantage did not achieve statistical significance (P = 0.185). In the PP with recurrent CDAD at enrollment, the DRR was 27% with vancomycin and 0% with 6 g tolevamer (P = 0.07). Overall rates of serious and nonserious adverse events were similar between groups.

Conclusion:

Tolevamer dosed at 6 g/day rapidly resolved CDAD similarly to vancomycin and demonstrated a trend towards reduced recurrence. Tolevamer may provide a nonantibiotic alternative for the treatment of this antibiotic induced disease.