Sustained clinical response as an endpoint in treatment trials of Clostridium difficile-associated diarrhea.

Occurrence of diarrhea following initially successful treatment l i i s a major shortcoming in the treatment of Clostridium difficile-associated diarrhea (CDAD). Sustained response is a clinical endpoint proposed to account for differences among treatment agents with respect to a combination of initial response/cure and recurrence. Until recently, vancomycin was the only FDA-approved treatment for C. difficile infection (CDI). Treatment guidelines have recommended metronidazole for a first occurrence of nonsevere CDI and for a first relapse or reinfection (2,3,4). Vancomycin and metronidazole are both effective in providing initial response, with 2:85% cure rates, but 20 to 40% of patients whose symptoms resolve have recurrent disease caused by relapse of the original infection or reinfection from external sources (2, 3, 4). In parallel with changes in strain prevalence and severity of disease, clinical response rates have changed with metronidazole during the last decade, with a reduced initial response, longer time to resolution of diarrhea, and an increased rate of recurrence (15, 17). Most chnical trials for new agents to treat CDAD have used cure/resolution of diarrhea and/or time to resolution of diarrhea as the primary outcomes. In 2006, a trial of nitazoxanide versus metronidazole introduced sustained responses at 31 days after the first dose of treatment as an additional endpoint (16). Initial response was assessed within the span of days 11 to 13, allowing an additional 18 to 20 days for documenting recurrences. Recurrence generally occurs within 7 to 14 days after cessation of therapy with vancomycin or metronidazole (1, 7, 14). In one study, mean time to relapse with the same strain was reported as 14.5 days and mean time to reinfection with another stram was 42.5 days after the end of treatment for the preceding episode (9). Relapse and reinfection can be difficult to distinguish, since infection with more than one strain has been reported rarely (6, 22) and the same or a new strain may be acquired from the environment. In addition, recurrence with the same strain may be more common among patients infected with the epidemic BI/NAPl/027 strain (7,10). Because of the high rate of recurrence, an agent that provides both initial clinical cure and a sustained response is desirable. Fidaxomicin was recently approved for the treatment of CDAD on the basis of noniiiferiority to vancomycin for an initial cure at the end of therapy and superiority for a sustained response 25 days after therapy. This agent, which achieves high stool concentrations and which is highly active against clinical isolates of C, difficile (MlCjo of —0.125 mg/ml), has a narrow spectrum of activity with miniiTial impact on bacterial species in the microbiome which are thought to provide colonization resistance in the colon (12,20). Preservation ofthe commensal florals thought to reduce the risk of relapse from persistent spores in the gut or reinfection from the environment. In this paper, we contrast data from two phase 3 trials comparing fidaxomicin to vancomycin (5, 13) and from the first phase 3 trial comparing a toxin-binding polymer and metronidazole (11). These data are analyzed using the new endpoint, sustained clinical response, which may provide an additional, clinically meaningful benchmark for practitioners treating patients with CDAD. Fidaxomicin clinical trials. Two phase 3 randomized, controUed, double-blind trials enrolled patients at multiple sites in the United States, Canada, and Europe and compared fidaxomicin (200 mg twice daily for 10 days) with vancomycin (125 mg four times daily for 10 days) (5, 13). Patients may have had no more than one prior episode of CDAD within the 3 months prior to randomization. The primary outcome was the clinical response (or cure) rate determined at the end of therapy and was based upon improvement in diarrhea or other symptoms such that, in the investigator's judgment, further CDAD treatment was not needed. The protocol-specified exploratory endpoint in study 003 and the secondary endpoint in study 004 was global cure, currently referred to as the sustauied clinical response. Sustained clinical response was defined as the clinical response at the end of therapy followed by survival without proven or suspected CDAD recurrence through 25 days beyond the end of therapy.