Primary Outcomes From a Phase 3, Randomized, Double-Blind, Active-Controlled Trial of Surotomycin in Subjects With Clostridium difficile Infection

Vicente Boix, Richard N Fedorak, Kathleen M Mullane, Yves Pesant, Uschi Stoutenburgh, Mandy Jin, Adedayo Adedoyin, Laurent Chesnel, Dalya Guris, Kajal B Larson, Yoshihiko Murata, Vicente Boix, Richard N Fedorak, Kathleen M Mullane, Yves Pesant, Uschi Stoutenburgh, Mandy Jin, Adedayo Adedoyin, Laurent Chesnel, Dalya Guris, Kajal B Larson, Yoshihiko Murata

Abstract

Background: Although the incidence of Clostridium difficile infection (CDI) is increasing, available CDI treatment options are limited in terms of sustained response after treatment. This phase 3 trial assessed the efficacy and safety of surotomycin, a novel bactericidal cyclic lipopeptide, versus oral vancomycin in subjects with CDI.

Methods: In this randomized, double-blind, active-controlled, multicenter, international trial, subjects with CDI confirmed by a positive toxin result were randomized to receive surotomycin (250 mg twice daily) or vancomycin (125 mg 4 times daily) orally for 10 days. The primary endpoints were clinical response at end of treatment and evaluation of surotomycin safety. The key secondary endpoints were clinical response over time and sustained clinical response through a 30- to 40-day follow-up period. Clostridium difficile infection recurrence during follow-up and time to diarrhea resolution were also analyzed.

Results: In total, 570 subjects were randomized and had confirmed CDI; 290 subjects received surotomycin and 280 subjects received vancomycin. Surotomycin clinical cure rates at end of treatment (surotomycin/vancomycin: 79.0%/83.6%; difference of -4.6%; 95% confidence interval, -11.0 to 1.9]), clinical response over time (stratified log-rank test, P = .832), and sustained clinical response at end of trial (Day 40-50) (60.6%/61.4%; difference of -0.8%; 95% CI, -8.8 to 7.1) in the microbiological modified intent to treat population did not meet noninferiority or superiority criteria versus vancomycin. Both treatments were generally well tolerated.

Conclusions: Surotomycin failed to meet the criteria for noninferiority versus vancomycin for the primary and key secondary endpoints in this trial.

Keywords: Clostridium difficile infection; antibiotic; surotomycin; vancomycin.

© The Author 2017. Published by Oxford University Press on behalf of Infectious Diseases Society of America.

Figures

Figure 1.
Figure 1.
Trial design. BID, twice daily; CDI, Clostridium difficile infection; QID, 4 times daily.
Figure 2.
Figure 2.
Subject flow diagram. CDI, Clostridium difficile infection; mMITT, microbiological modified intent to treat.
Figure 3.
Figure 3.
Clinical outcomes according to treatment (microbiological modified intent to treat population). (A) Clinical cure rate at EOT (Day 10), (B) sustained clinical response at the end of the trial (Day 40–50), and (C) Kaplan-Meier analysis of clinical response over time. The estimated adjusted proportions were weighted averages across all strata, constructed using Mehrotra-Railkar continuity-corrected minimum-risk stratum weights. Sustained clinical response was defined as a subject deemed a cure at EOT who did not have recurrence, did not die, and was not lost to follow-up. BID, twice daily; EOT, end of treatment; QID, 4 times daily.
Figure 4.
Figure 4.
Clinical responses in subjects with infections deemed to be caused by (A) Clostridium difficile BI/NAP1/027 and (B) non-BI/NAP1/027 C difficile strains at baseline (microbiological modified intent to treat population). The estimated adjusted proportions were weighted averages across all strata, constructed using Mehrotra-Railkar continuity-corrected minimum-risk stratum weights. BID, twice daily; EOT, end of treatment; QID, 4 times daily.

References

    1. Reveles KR, Lee GC, Boyd NK, Frei CR. The rise in Clostridium difficile infection incidence among hospitalized adults in the United States: 2001–2010. Am J Infect Control 2014; 42:1028–32.
    1. Lessa FC, Gould CV, McDonald LC. Current status of Clostridium difficile infection epidemiology. Clin Infect Dis 2012; 55(Suppl 2):S65–70.
    1. Kelly CP, LaMont JT. Clostridium difficile–more difficult than ever. N Engl J Med 2008; 359:1932–40.
    1. O’Connor JR, Johnson S, Gerding DN. Clostridium difficile infection caused by the epidemic BI/NAP1/027 strain. Gastroenterology 2009; 136:1913–24.
    1. Lessa FC, Mu Y, Bamberg WM, et al. Burden of Clostridium difficile infection in the United States. N Engl J Med 2015; 372:825–34.
    1. Citron DM, Tyrrell KL, Dale SE, et al. Impact of surotomycin on the gut microbiota of healthy volunteers in a phase 1 clinical trial. Antimicrob Agents Chemother 2016; 60:2069–74.
    1. Lee CH, Patino H, Stevens C, et al. Surotomycin versus vancomycin for Clostridium difficile infection: phase 2, randomized, controlled, double-blind, non-inferiority, multicentre trial. J Antimicrob Chemother 2016; 71:2964–71.
    1. Arora V, Kachroo S, Ghantoji SS, et al. High Horn’s index score predicts poor outcomes in patients with Clostridium difficile infection. J Hosp Infect 2011; 79:23–6.
    1. Snydman DR, Jacobus NV, McDermott LA. Activity of a novel cyclic lipopeptide, CB-183,315, against resistant Clostridium difficile and other Gram-positive aerobic and anaerobic intestinal pathogens. Antimicrob Agents Chemother 2012; 56:3448–52.
    1. US Food and Drug Administration. Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation. Available at: Accessed 25 August 2016
    1. Crobach MJ, Planche T, Eckert C, et al. European Society of Clinical Microbiology and Infectious Diseases: update of the diagnostic guidance document for Clostridium difficile infection. Clin Microbiol Infect 2016; 22(Suppl 4):S63–81.
    1. Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med 2011; 364:422–31.
    1. Seekatz AM, Young VB. Clostridium difficile and the microbiota. J Clin Invest 2014; 124:4182–9.

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj