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Follow-on RifAximin for the Prevention of recurrence following standard treatment of Infection with Clostridium Difficile (RAPID): a randomised placebo controlled trial
  1. Giles Major1,
  2. Lucy Bradshaw2,
  3. Nafisa Boota3,
  4. Kirsty Sprange2,
  5. Mathew Diggle4,
  6. Alan Montgomery2,
  7. Aida Jawhari4,
  8. Robin C Spiller1
  9. on behalf of RAPID Collaboration Group
    1. 1 Nottingham Digestive Diseases Centre and NIHR Nottingham Biomedical Research Centre at Nottingham University Hospitals NHS Trust, the University of Nottingham, Nottingham, Notts, UK
    2. 2 Nottingham Clinical Trials Unit (NCTU), University of Nottingham, Nottingham, UK
    3. 3 Leicester Clinical Trials Unit, University of Leicester, Leicester, UK
    4. 4 Clinical Microbiology Department, Nottingham University Hospitals NHS Trust, Nottingham, Nottinghamshire, UK
    1. Correspondence to Professor Robin C Spiller, Nottingham Digestive Diseases Centre, University of Nottingham, Queens Medical Centre, Nottingham NG7 2UH, UK; robin.spiller{at}


    Background Clostridium difficile infection (CDI) recurs after initial treatment in approximately one in four patients. A single-centre pilot study suggested that this could be reduced using ‘follow-on’ rifaximin treatment. We aimed to assess the efficacy of rifaximin treatment in preventing recurrence.

    Methods A multisite, parallel group, randomised, placebo controlled trial recruiting patients aged ≥18 years immediately after resolution of CDI through treatment with metronidazole or vancomycin. Participants received either rifaximin 400 mg three times a day for 2 weeks, reduced to 200 mg three times a day for a further 2 weeks or identical placebo. The primary endpoint was recurrence of CDI within 12 weeks of trial entry.

    Results Between December 2012 and March 2016, 151 participants were randomised to either rifaximin or placebo. Primary outcome data were available on 130. Mean age was 71.9 years (SD 15.3). Recurrence within 12 weeks was 29.5% (18/61) among participants allocated to placebo compared with 15.9% (11/69) among those allocated to rifaximin, a difference between groups of 13.7% (95% CI −28.1% to 0.7%, p=0.06). The risk ratio was 0.54 (95% CI 0.28 to 1.05, p=0.07). During 6-month safety follow-up, nine participants died in each group (12%). Adverse event rates were similar between groups.

    Conclusion While ‘follow-on’ rifaximin after CDI appeared to halve recurrence rate, we failed to reach our recruitment target in this group of frail elderly patients, so the estimated effect of rifaximin lacks precision. A meta-analysis including a previous trial suggests that rifaximin may be effective; however, further, larger confirmatory studies are needed.

    • diarrhoea
    • enteric infections
    • infective colitis
    • inflammation

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    • Contributors All authors contributed to study design, trial management, analysis and write up. RCS, GM, AJ and MD conceived and designed the study and contributed to interpretation. LB and AM analysed the trial data and contributed to their interpretation. NB and KS managed the trial and contributed to data analysis and interpretation. All authors participated in the drafting, review and approval of the report and in the decision to submit for publication.

    • Funding Trial protocol: The study was funded by the National Institute for Health Research (NIHR) through its Research for Patient Benefit (RfPB) programme, NIHR RfPB Grant PB-PG- 1010-23257. Trial drug and matched placebo were provided by Norgine without cost. National Institute for Health Research for Patient Benefit grant PB-PG-1010-23257. ISRCTN 65163992; EudraCT 2012-003205-10. Norgine supplied drug and placebo without charge. This is a summary of independent research funded by the National Institute for Health Research Nottingham Biomedical Research Centre.

    • Disclaimer The views and opinions expressed herein are those of the authors and do not necessarily reflect those of the Research for Patient Benefit (RfPB) Programme, NIHR, NHS or the Department of Health. The corresponding author had final responsibility for the decision to submit for publication.

    • Competing interests GM, LB, KS, MD, NB, AM, AJ, AS, NM declare no competing interests. RS received the IMP and matching placebo from Norgine Pharmaceuticals Ltd free of cost.

    • Patient consent Not required.

    • Ethics approval National Research Ethics Service for England and the Medicines and Healthcare products Regulatory Agency.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement Data sharing is available via Nottingham CTU.

    • Collaborators Nottingham Clinical Trials Unit: Alan Montgomery, Professor of Medical Statistics and Clinical Trials; Lucy Bradshaw, Medical Statistician; Nafisa Boota, Trial Manager; Sarah Fahy, Trial Manager; Rob Allen, Trial Coordinator; John Watson Trial Administrator; Sarah Walker, Data Coordinator; Kirsty Sprange, Senior Trial Manager; Margo Childs, Senior Trial Manager; Gill Bumphrey, Trial Pharmacist; Daniel Simpkins, IT and Data Manager; Keith Whitaker, IT Programmer. Nottingham University Hospitals NHS Trust, Clinical Trials Pharmacy: Sheila Hodgson, Lead Pharmacist; Bernie Cook, Lead Pharmacy Technician and Lisa Humphries, Lead Pharmacy Technician. NIHR Biomedical Research Unit in Gastrointestinal and Liver Diseases: Melanie Lingaya, NDDC Technician; Yirga Falcone, NDDC Technician Microbiology: Dr Mathew Diggle; Patrick Budd; Tim Sloan; Jonna Jalanka; Emma Stevenson Recruiting Centres: Queens Medical Centre, Nottingham: Aida Jawhari, Saqib Ahmad, Helen Foreman, Jill Garratt, Shirley Pyke, Brian Rorison, Mina Patel. Kings Mill Hospital, Sutton-in-Ashfield: Anthony Shonde, Sam Kemp, Lynn Allsop, Alison Mossad, Cheryl Heeley, Nicholas Taylor, Sharat Misra, Stephen Foley, Lynn Wade, Rebecca Clarke, Rebecca Kewley, Sally Palmer, Samantha Boam, Steve Haigh, Yassar Hussain. Royal Derby Hospital, Derby: Alison Mossad, Charlotte Downes, Claire Grant, Elizabeth Barnes, Jessica Williams, Kerry Horne, Lindsey Kimber, Margaret Harper, Peter Fox, Ryan Humphries, Tracy Brear, Wendy Abbott, Sarah Craig, Farah Yazdani, Helen Forrest, Julia Lacey, Klara Garsed, Rebecca Turner. Northern General Hospital, Sheffield: John Hebden, John Humphreys, Joyce Fofie, Julie Sorrel, Kelsey Armitage, Kim Ryalls, Mark Davy, Michael Agyemang, Sarah Birchall, Stephen Booth, David Partridge, Jim Lithgow. Chesterfield Royal Hospital, Chesterfield: Amanda Whileman, Charlotte Adams-Heath, David Elphick, Emily Hall, Greg Naylor, Julie Toms, Keith Dear, Lesley Stevenson, Stephanie Wright. Royal Shrewsbury Hospital, Shrewsbury: Alison Baker, Angela Yeomans, Charlotte Owen, Colene Adams, Doyin Wilfred, Heather Button, Jeffery Butterworth, John Jones, Mandy Carnahan, Sharen Painter. Darlington Memorial Hospital, Darlington: Anjan Dhar, Anne Clark, Claire Shaw, Jill Deane, Lynsey Stevenson, Michelle Wood, Rebecca Henthorn, Richard Nendick, Anthony Kennedy, Penny Gamble, Rachel Burnip, Deepa Nayar. Sunderland Royal Hospital, Sunderland: David Hobday, Michelle Edwards, Pauline Oates, Roderick Beard, Chris Settle, Eleanor Dungla, James Crosbie, Jill Holden, John Painter, Leigh Richardson, Louise Fairle, Pauline Carr, Simon Cowlam, Stephan Butler. Kettering General Hospital, Kettering: Andrew Dixon, Debashish Das, Dhiren Bharkhada, Jeannie Kessell, Jemma Tate, Jo Novasg, Julie Fosbrook, Parizade Raymode. Dorset County Hospital, Dorset: Andrew Harris, Anthony Homer, Arabis Oglesby, Catherine Jeppesen, Dennise Maitland, Jackie Gibbins, Simon Wilshire, Emma Noyle, Gloria Moss, Pauline Ashcroft. James Cook University Hospital, Middlesborough: Agnieska Skotnicka, Andrea Boyce, Gill Wheater, Jane Thompson, Jason Wong, Julie Tregonning, Arvind Ramadas, Danielle Sweeney, Helen Dallal, Julie McGivern, Wendy Jackson. Cumberland Infirmary, Cumbria: Clare Hanson, Chris Brewer, Clive Graham, Emily Hetherington, Hannah Crowther, Helen Fairlamb, Sarah Thronthwaite, Toni Wilson, Una Poultney, Anna Mcskeane, Elena Crucerson. Basingstoke Hospital, Basingstoke: Barbara King, Carley Merritt, Caroline Palmer, Christina Narh, Claire Williams, Mariam Ashrafi, Matthew Brown, Megan Topping, Sophia Stanford, Linda Swanson. North Hampshire Hospital, Hampshire: David Lloyd, Duncan Cooke, Johanna Hellstrom, John Gordon, Julie Elliott, Karen Gamble, Markus Gwiggner, Matthew Brown, Victoria Croome, Angela Frith. University Hospitals NHS Foundation Trust, Southampton: Cheryl Booker, Darren Ball, Emma Levell, Michelle Smith, Mike Stroud, Miranda Kean, Monica Fenn, Suranda Dharmasiri, ,Violetia Razanskaite, Meirion Ford, Rasha Said, Tracey Day, Graeme Jones, Julie Mitchell, Yazmin Bitouche. New Cross Hospital, Wolverhampton: Clare Hammond, Gurminder Sahota, Helen Steed, Jayne Rankin, Jaynesh Patel, Kelly Kauldhar, Marie Green, Matthew Reid, Michael Cooper. Doncaster Royal Infirmary, Doncaster: Anurag Agrawal, Gavin Hill, Helen Foot, Jane Dumville, Mark Fairweather, Nicola Lancaster, Sarah Hone, Thelma Commey. Russells Hall Hospital, Dudley: Clare Allcock, Jacqueline Smith, Lakshimpriya Mohankumar, Ranjit Gidda, Sauid Ishaq, Susan Merotra, Danielle Stacey. Stepping Hill Hospital, Stockport: Dave Das, Emma Taylor, Gail Foley, Janette Curtis, Lucy Orrell, Maureen Holland, Moira Taylor, Sarah Scanlon, Susan Graham, Zahid Mahmood. Queens Hospital, Romford: Parveen Dugh, Pranab Gyawali, Salina Tsui, Theresa McClusky, WanTei Wiseman, Butwana Rommel, Meera Patel, Purushothaman Premchand, Kevin Spencer, Rob Davis, Sacha Goodye. Kings College Hospital, London: Anisur Rahman, Eric Witele, Gaynor Notcheva, Guy Chung-Faye, Joanna Flanagan, Kirandip Mandar, Lee Meng Choong, Oluwafunmilayo Adedeji, Surabhi Tashi.

    • Correction notice This article has been corrected since it published Online First. An error in the Meta-analysis paragraph has been corrected.

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