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A multi-center, randomized clinical trial to compare the safety and efficacy of LFF571 and vancomycin for Clostridium difficile infections

Mullane, Kathleen and Dabovic, Kristina and Praestgaard, Jens and Leeds, Jennifer and Blais, Johanne and Pertel, Peter (2015) A multi-center, randomized clinical trial to compare the safety and efficacy of LFF571 and vancomycin for Clostridium difficile infections. Antimicrobial Agents and Chemotherapy, 59 (3). pp. 1435-1440. ISSN 1098-6596

Abstract

Background: Clostridium difficile cause serious diarrheal disease with potentially fatal complications. Several drugs are available for the treatment of C. difficile, including vancomycin, metronidazole, and fidaxomicin. Recurrences after successful therapy, however, remain a significant problem. LFF571 is a semi-synthetic thiopeptide antibacterial that is potent against C. difficile in vitro and in animal models of infection. Here, we assess the safety and efficacy of LFF571 in patients with primary or first recurrent C. difficile infections.
Methods: This was a multi-center, randomized, evaluator-blind, active-controlled study to compare the safety and efficacy of LFF571 to those of vancomycin. Adults aged 18-90 with primary episodes or first recurrences of moderate C. difficile infection were eligible to enroll. Patients were randomized to receive 200 mg LFF571 or 125 mg vancomycin four times daily for 10 days. The primary endpoint was the proportion of clinical cures at the end of therapy, with the primary analysis comparing cure rates in the per-protocol population. Secondary endpoints included time to resolution of diarrhea and the recurrence rate 30 days following completion of treatment.
Results: Seventy-two patients were enrolled and randomized, of which 46 were assigned to receive LFF571. Based on the protocol-specified definition, the rates of clinical cure for LFF571 (90.6%) were non-inferior to those of vancomycin (78.3%). The 30-day sustained cure rates for LFF571- and vancomycin- treated patients were 56.7% and 65.0%, respectively, in the per-protocol population and were 58.7% and 60.0%, respectively, in the modified intent-to-treat population. Analysis of recurrence using only toxin-confirmed cases, however, indicated that recurrence rates were lower for LFF571 (19% compared to 25% for vancomycin in the per-protocol population). The incidence of adverse events was higher in the LFF571 group (76.1%) compared to vancomycin (69.2%), although more adverse events in the vancomycin group were suspected to be related to study drug (38.5% versus 32.6% for LFF571). One patient receiving LFF571 discontinued due to an adverse event.
Conclusion: LFF571 was non-inferior to vancomycin for the clinical cure of primary or first recurrent moderate C. difficile infections. The sustained cure rates at the end-of-study were slightly lower for LFF571, although toxic-confirmed recurrences were reduced compared to vancomycin. LFF571 was generally safe and well-tolerated in patients with moderate C. difficile infections.

Item Type: Article
Date Deposited: 29 Apr 2016 23:45
Last Modified: 29 Apr 2016 23:45
URI: https://oak.novartis.com/id/eprint/21545

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