Colon ORIGINAL ARTICLE Gut: first published as 10.1136/gutjnl-2018-316794 on 25 September 2018. Downloaded from Follow-on RifAximin for the Prevention of recurrence following standard treatment of Infection with Clostridium Difficile (RAPID): a randomised placebo controlled trial Giles Major, 1 Lucy Bradshaw,2 Nafisa Boota,3 Kirsty Sprange,2 Mathew Diggle,4 Alan Montgomery,2 Aida Jawhari,4 Robin C Spiller, 1 on behalf of RAPID Collaboration Group ► Additional material is ABSTRact published online only. To view Background Clostridium difficile infection (CDI) recurs Significance of this study please visit the journal online after initial treatment in approximately one in four (http:// dx. doi. org/ 10. 1136/ What is already known on this subject? gutjnl- 2018- 316794). patients. A single-centre pilot study suggested that this could be reduced using ’follow-on’ rifaximin treatment. ► Recurrence after successful treatment of 1Nottingham Digestive Diseases We aimed to assess the efficacy of rifaximin treatment in Clostridium difficile infection (CDI) occurs in Centre and NIHR Nottingham approximately one in four patients. Biomedical Research Centre at preventing recurrence. Nottingham University Hospitals Methods A multisite, parallel group, randomised, ► Patients are typically frail with multiple NHS Trust, the University of placebo controlled trial recruiting patients aged ≥18 comorbidities. Nottingham, Nottingham, years immediately after resolution of CDI through ► A pilot study suggested that a course of Notts, UK rifaximin after successful treatment might 2Nottingham Clinical Trials treatment with metronidazole or vancomycin. Unit (NCTU), University of Participants received either rifaximin 400 mg three times reduce recurrence by around 50%. Nottingham, Nottingham, UK a day for 2 weeks, reduced to 200 mg three times a day 3 What are the new findings? Leicester Clinical Trials Unit, for a further 2 weeks or identical placebo. The primary University of Leicester, Leicester, ► Rifaximin ‘follow-on’ treatment 400 mg UK endpoint was recurrence of CDI within 12 weeks of trial three times a day for 2 weeks, followed by 4Clinical Microbiology entry. 200 mg three times a day for 2 weeks, reduced Department, Nottingham Results Between December 2012 and March 2016, recurrence by around 50%, but the 95% CI http://gut.bmj.com/ University Hospitals NHS Trust, 151 participants were randomised to either rifaximin spans from 70% relative reduction to no effect. Nottingham, Nottinghamshire, or placebo. Primary outcome data were available on UK ► Meta-analysis suggests rifaximin ‘follow-on’ 130. Mean age was 71.9 years (SD 15.3). Recurrence treatment is effective. Correspondence to within 12 weeks was 29.5% (18/61) among participants Professor Robin C Spiller, allocated to placebo compared with 15.9% (11/69) How might it impact on clinical practice in the Nottingham Digestive among those allocated to rifaximin, a difference between foreseeable future? Diseases Centre, University of groups of 13.7% (95% CI −28.1% to 0.7%, p=0.06). ► Rifaximin could be a useful additional on September 27, 2021 by guest. Protected copyright. Nottingham, Queens Medical The risk ratio was 0.54 (95% CI 0.28 to 1.05, p=0.07). therapeutic option to reduce recurrence of CDI Centre, Nottingham NG7 2UH, UK; During 6-month safety follow-up, nine participants died but larger studies would increase confidence in robin. spiller@ nottingham. ac. uk in each group (12%). Adverse event rates were similar its use. between groups. Received 12 May 2018 Conclusion While ’follow-on’ rifaximin after CDI Revised 28 August 2018 appeared to halve recurrence rate, we failed to reach our Accepted 29 August 2018 4–7 Published Online First recruitment target in this group of frail elderly patients, observational studies. Predictors of recurrence 25 September 2018 so the estimated effect of rifaximin lacks precision. A include advanced age, detection of toxin in stool meta-analysis including a previous trial suggests that and persistence of diarrhoea beyond the fourth day rifaximin may be effective; however, further, larger of treatment8 along with the presence of hepatic confirmatory studies are needed. and renal disease,9 disease severity10 and concom- itant antibiotic therapy.11 A diverse commensal colonic microbiota is believed to confer resistance to CDI but the © Author(s) (or their INTRODUCTION common treatments used to date, vancomycin and employer(s)) 2019. Re-use 12–14 permitted under CC BY-NC. No Clostridium difficile infection (CDI) is one of the metronidazole, further deplete the microbiota. commercial re-use. See rights most common nosocomial infections in the devel- The importance of this depletion in causing recur- and permissions. Published oped world. Oral metronidazole or vancomycin rence is strongly supported by the success of faecal by BMJ. has been widely used as primary treatment, with transplantation in treating recurrent disease.15 16 To cite: Major G, a variable cure rate of 70%–90% in most series, Newer agents with more selective effects on the gut Bradshaw L, Boota N, et al. but 15%–30% of patients suffer a recurrence microbiota such as fidaxomicin,17 18 cadazolid19 and Gut 2019;68:1224–1231. in the following months,1–3 with higher rates in ridinilalzole20 or monoclonal antibodies designed 1224 Major G, et al. Gut 2019;68:1224–1231. doi:10.1136/gutjnl-2018-316794 Colon to neutralise C. difficile toxins (CDTs) such as bezlotoxumab21 be given by a designated legal representative or an independent Gut: first published as 10.1136/gutjnl-2018-316794 on 25 September 2018. Downloaded from show some reduction in recurrence rates.15 16 health advocate in accordance with Schedule 1 of the Medicines Rifaximin is a rifamycin derivative, similar to rifampicin, with for Human Use (ClinicalTrials) Regulations 2004. a broad spectrum of antimicrobial activity including C. difficile. It was designed to be highly insoluble in water with very low bioavailability. It is widely used to treat traveller’s diarrhoea,22 Randomisation and blinding hepatic encephalopathy23 and irritable bowel syndrome24 as well Patients were randomised within 5 days of the last dose of stan- as for CDI treatment and recurrence prevention25–27 and has an dard therapy and were started the same day on the study drug excellent safety record.28 Minimal absorption occurs after inges- which was continued for the next 4 weeks. Participants were tion so that the drug is highly concentrated in the gut lumen. Bile randomly assigned in a 1:1 ratio to receive rifaximin or placebo. increases solubility 70-fold to 120-fold, so effective concentra- Randomisation was stratified by hospital and used a computer tions should be maximal in the distal small bowel and proximal generated pseudorandom code, using random permuted blocks colon, the site of C. difficile germination.29 Theoretically, rifax- of randomly varying size. Site research teams allocated partici- imin should suppress C. difficile proliferation while commensals pants to a treatment using a secure, internet-based randomisa- recover to re-establish an environment hostile to the pathogen. tion system developed and maintained by Nottingham Clinical Studies in hepatic encephalopathy, colitis and irritable bowel Trials Unit, ensuring allocation concealment. syndrome support this by showing little overall impact of regular Participants, clinicians, research nurses and the study team rifaximin on the faecal microbiota.30–32 were blind to the allocated treatment as active and placebo One previous randomised controlled trial suggested that a tablets were packaged in matching deidentified treatment packs course of rifaximin after successful primary treatment with and dispensed by the hospital pharmacy. vancomycin or metronidazole might reduce the likelihood of recurrence, but with only 68 participants, the estimated treat- ment effect was imprecise.27 Intervention The aim of the RAPID (RifAximin for the Prevention of Participants were given 126 tablets, containing either rifax- recurrence following standard treatment of Infection with Clos- imin 200 mg or an identical placebo formulation. Rifaximin tridium Difficile) trial was to assess whether treatment with and placebo were supplied by Norgine Pharmaceuticals rifaximin after CDI resolution with standard therapy reduced Limited as a gift and manufactured by Alfa Wassermann. The the rate of CDI recurrence compared with placebo. intended treatment regime was two tablets (400 mg rifaximin) taken three times a day for 14 days, reduced to one tablet (200 mg) three times a day for a further 14 days. Participants METHODS continued to receive standard care, including antibiotics for Trial design and oversight indications other than CDI, as determined by their physician. RAPID was a multisite, two arm, parallel group, blinded, The number of tablets taken was assessed from the difference randomised, placebo controlled trial conducted in 23 secondary between the number of tablets supplied (126) and the number care hospitals in England with hospital microbiology services returned at the week 4 visit or earlier if CDI recurred. Since that also provided for the local community. The study was recurrences meant that participants took drug for a variable http://gut.bmj.com/ conducted in accordance with Good Clinical Practice guidelines duration, compliance was assessed against the number of and the provisions of the Declaration of Helsinki. The trial was tablets expected to be taken by each participant at the end of prospectively registered