Efficacy and safety of ridinilazole compared with vancomycin for the treatment of Clostridium difficile infection: a phase 2, randomised, double-blind, active-controlled, non-inferiority study

Abstract

SummaryBackgroundClostridium difficile infection is the most common health-care-associated infection in the USA. We assessed the safety and efficacy of ridinilazole versus vancomycin for treatment of C difficile infection.MethodsWe did a phase 2, randomised, double-blind, active-controlled, non-inferiority study. Participants with signs and symptoms of C difficile infection and a positive diagnostic test result were recruited from 33 centres in the USA and Canada and randomly assigned (1:1) to receive oral ridinilazole (200 mg every 12 h) or oral vancomycin (125 mg every 6 h) for 10 days. The primary endpoint was achievement of a sustained clinical response, defined as clinical cure at the end of treatment and no recurrence within 30 days, which was used to establish non-inferiority (15% margin) of ridinilazole versus vancomycin. The primary efficacy analysis was done on a modified intention-to-treat population comprising all individuals with C difficile infection confirmed by the presence of free toxin in stool who were randomly assigned to receive one or more doses of the study drug. The study is registered with ClinicalTrials.gov, number NCT02092935.FindingsBetween June 26, 2014, and August 31, 2015, 100 patients were recruited; 50 were randomly assigned to receive ridinilazole and 50 to vancomycin. 16 patients did not complete the study, and 11 discontinued treatment early. The primary efficacy analysis included 69 patients (n=36 in the ridinilazole group; n=33 in the vancomycin group). 24 of 36 (66·7%) patients in the ridinilazole group versus 14 of 33 (42·4%) of those in the vancomycin group had a sustained clinical response (treatment difference 21·1%, 90% CI 3·1–39·1, p=0·0004), establishing the non-inferiority of ridinilazole and also showing statistical superiority at the 10% level. Ridinilazole was well tolerated, with an adverse event profile similar to that of vancomycin: 82% (41 of 50) of participants reported adverse events in the ridinilazole group and 80% (40 of 50) in the vancomycin group. There were no adverse events related to ridinilazole that led to discontinuation.InterpretationRidinilazole is a targeted-spectrum antimicrobial that shows potential in treatment of initial C difficile infection and in providing sustained benefit through reduction in disease recurrence. Further clinical development is warranted.FundingWellcome Trust and Summit Therapeutics.

Novel therapies and preventative strategies for primary and recurrent Clostridium difficile infections

“…This trial showed that ridinilazole caused a higher sustained response rate compared with vancomycin (67% versus 42%) as well as a reduction in recurrence (14.3% versus 34.8%). 92 There were no adverse events that necessitated discontinuation of ridinilazole, and the adverse events were similar between ridinilazole and vancomycin treatment. An additional phase II trial (NCT02784002) was completed in 2016 comparing ridinilazole to fidaxomicin; study results are being analyzed.…”

“…A phase II trial with 100 patients with CDI compared a 10‐day oral ridinilazole treatment (200 mg every 12 h) with a 10‐day oral vancomycin treatment (125 mg every 6 h). This trial showed that ridinilazole caused a higher sustained response rate compared with vancomycin (67% versus 42%) as well as a reduction in recurrence (14.3% versus 34.8%) . There were no adverse events that necessitated discontinuation of ridinilazole, and the adverse events were similar between ridinilazole and vancomycin treatment.…”

Narrow-spectrum antibacterial agents

“…61 A recent phase 2 clinical trial (completed August 2015) affirmed that ridinilazole was well tolerated, established non-inferiority compared to vancomycin and demonstrated statistical superiority at the 10% level. 63 …”

A Review of Experimental and Off-Label Therapies for Clostridium difficile Infection

“…In a hamster model, better 28-day survival rates were observed in animals treated with ridinilazole than in the ones given vancomycin or fidaxomicin [136]. A phase II RCT was completed recently, where ridinilazole achieved the non-inferiority goal set in terms of clinical cure and was superior to vancomycin in terms of sustained clinical response after 30 days of follow-up [137]. Summit Therapeutics is currently preparing phase III RCTs with this compound [138].…”