Advertisement

Digestive Diseases and Sciences

, Volume 63, Issue 10, pp 2519–2528 | Cite as

Placebo Rates in Randomized Controlled Trials of Pouchitis Therapy

  • Jonathan Athayde
  • Sarah C. Davies
  • Claire E. Parker
  • Leonardo Guizzetti
  • Christopher Ma
  • Reena Khanna
  • Brian G. Feagan
  • Vipul Jairath
Review
  • 73 Downloads

Abstract

Background

Approximately half of the patients with ulcerative colitis (UC) who undergo restorative proctocolectomy develop pouchitis within 10 years of surgery. Currently, there are no approved pouchitis treatments. It is important to quantify, and ultimately minimize, placebo rates to design and conduct efficient pouchitis trials.

Aims

To quantify the placebo rate observed in pouchitis randomized controlled trials (RCTs) in meta-analysis.

Methods

Embase, MEDLINE, and the Cochrane Library were searched from inception to November 3, 2017, for placebo-controlled RCTs enrolling adult UC patients with, or at risk for developing, pouchitis. A fixed-effect binomial-normal model was used to pool placebo rates on the log-odds (logit) scale. Proportions and 95% confidence intervals were reported. Outcomes of interest included development of pouchitis, induction of remission/response, and maintenance of remission/response. The Cochrane risk of bias tool was used to evaluate study quality.

Results

Twelve trials (five prevention, five induction, and two maintenance) enrolling a total of 229 placebo patients were eligible for inclusion. The pooled placebo rates for development of pouchitis and induction of response were 47% (95% CI 39–56%) and 24% (95% CI 14–37%), respectively. An insufficient number of trials prevented additional data pooling and meta-regression analysis and no consistent definitions of outcome were identified.

Conclusions

No consistent methods for measuring pouchitis disease activity or defining response and remission were identified, highlighting the need for standardized definitions of outcomes for use in pouchitis trials. Additional high-quality trials are required to evaluate existing and novel therapies in this area.

Keywords

Ulcerative colitis Pouchitis Placebo effect Trial design 

Notes

Acknowledgments

CM is supported by a Clinician Fellowship from the Canadian Association of Gastroenterology and the Canadian Institutes of Health Research.

Author’s contribution

JA, SCD, and CEP performed the data screening and data collection; LG performed the statistical analysis; JA, SCD, CEP, LG, RK, BGF, and VJ performed data interpretation; JA, SCD, and CEP drafted the manuscript; LG, CM, RK, BGF, and VJ edited the manuscript for intellectual content; VJ supervised the project. All authors provided final approval of the submitted manuscript.

Compliance with ethical standards

Conflicts of interest

JA, SD, CEP, LG none known; CM is supported by a Clinician Fellowship from the Canadian Association of Gastroenterology and the Canadian Institutes for Health Research; RK has received consulting fees from AbbVie, Janssen, Pfizer, Shire, and Takeda; BGF has received grant/research support from Millennium Pharmaceuticals, Merck, Tillotts Pharma AG, AbbVie, Novartis Pharmaceuticals, Centocor Inc., Elan/Biogen, UCB Pharma, Bristol-Myers Squibb, Genentech, ActoGenix, and Wyeth Pharmaceuticals Inc.; consulting fees from Millennium Pharmaceuticals, Merck, Centocor Inc., Elan/Biogen, Janssen-Ortho, Teva Pharmaceuticals, Bristol-Myers Squibb, Celgene, UCB Pharma, AbbVie, Astra Zeneca, Serono, Genentech, Tillotts Pharma AG, Unity Pharmaceuticals, Albireo Pharma, Given Imaging Inc., Salix Pharmaceuticals, Novonordisk, GSK, Actogenix, Prometheus Therapeutics and Diagnostics, Athersys, Axcan, Gilead, Pfizer, Shire, Wyeth, Zealand Pharma, Zyngenia, GiCare Pharma Inc., and Sigmoid Pharma; and speakers bureaux fees from UCB, AbbVie, and J&J/Janssen; VJ has received scientific advisory board fees from AbbVie and Sandoz; and speakers bureaux fees from Takeda and Janssen.

Supplementary material

10620_2018_5199_MOESM1_ESM.docx (2.9 mb)
Supplementary material 1 (DOCX 2974 kb)

References

  1. 1.
    Targownik LE, Singh H, Nugent Z, Bernstein CN. The epidemiology of colectomy in ulcerative colitis: results from a population-based cohort. Am J Gastroenterol. 2012;107:1228–1235.CrossRefGoogle Scholar
  2. 2.
    Eriksson C, Cao Y, Rundquist S, et al. Changes in medical management and colectomy rates: a population-based cohort study on the epidemiology and natural history of ulcerative colitis in Orebro, Sweden, 1963-2010. Aliment Pharmacol Ther. 2017;46:748–757.CrossRefGoogle Scholar
  3. 3.
    Solberg IC, Lygren I, Jahnsen J, et al. Clinical course during the first 10 years of ulcerative colitis: results from a population-based inception cohort (IBSEN Study). Scand J Gastroenterol. 2009;44:431–440.CrossRefGoogle Scholar
  4. 4.
    de Silva S, Ma C, Proulx MC, et al. Postoperative complications and mortality following colectomy for ulcerative colitis. Clin Gastroenterol Hepatol. 2011;9:972–980.CrossRefGoogle Scholar
  5. 5.
    Samuel S, Ingle SB, Dhillon S, et al. cumulative incidence and risk factors for hospitalization and surgery in a population-based cohort of ulcerative colitis. Inflamm Bowel Dis. 2013;19:1858–1866.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Farouk R, Pemberton JH, Wolff BG, Dozois RR, Browning S, Larson D. Functional outcomes after ileal pouch-anal anastomosis for chronic ulcerative colitis. Ann Surg. 2000;231:919–926.CrossRefGoogle Scholar
  7. 7.
    Hahnloser D, Pemberton JH, Wolff BG, Larson DR, Crownhart BS, Dozois RR. The effect of ageing on function and quality of life in ileal pouch patients: a single cohort experience of 409 patients with chronic ulcerative colitis. Ann Surg. 2004;240:615–623.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Meagher AP, Farouk R, Dozois RR, Kelly KA, Pemberton JH. J ileal pouch-anal anastomosis for chronic ulcerative colitis: complications and long-term outcome in 1310 patients. Br J Surg. 1998;85:800–803.CrossRefGoogle Scholar
  9. 9.
    Singh S, Stroud AM, Holubar SD, Sandborn WJ, Pardi DS. Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis. Cochrane Database Syst Rev. 2015;11:Cd001176.Google Scholar
  10. 10.
    Pardi DS, Sandborn WJ. Systematic review: the management of pouchitis. Aliment Pharmacol Ther. 2006;23:1087–1096.CrossRefGoogle Scholar
  11. 11.
    Fazio VW, Tekkis PP, Remzi F, et al. Quantification of risk for pouch failure after ileal pouch anal anastomosis surgery. Ann Surg. 2003;238:605–614. (discussion 14-7).PubMedPubMedCentralGoogle Scholar
  12. 12.
    Das P, Smith JJ, Tekkis PP, Heriot AG, Antropoli M, John Nicholls R. Quality of life after indefinite diversion/pouch excision in ileal pouch failure patients. Colorectal Dis Off J Assoc Coloproctol GB Irel. 2007;9:718–724.Google Scholar
  13. 13.
    Gionchetti P, Rizzello F, Helwig U, et al. Prophylaxis of pouchitis onset with probiotic therapy: a double-blind, placebo-controlled trial. Gastroenterology. 2003;124:1202–1209.CrossRefGoogle Scholar
  14. 14.
    Gionchetti P, Rizzello F, Venturi A, et al. Oral bacteriotherapy as maintenance treatment in patients with chronic pouchitis: a double-blind, placebo-controlled trial. Gastroenterology. 2000;119:305–309.CrossRefGoogle Scholar
  15. 15.
    Mimura T, Rizzello F, Helwig U, et al. Once daily high dose probiotic therapy (VSL#3) for maintaining remission in recurrent or refractory pouchitis. Gut. 2004;53:108–114.CrossRefGoogle Scholar
  16. 16.
    Khanna R, Jairath V, Vande Casteele N, et al. Efficient early drug development for ulcerative colitis. Gastroenterology. 2016;150:1056–1060.CrossRefGoogle Scholar
  17. 17.
    Jairath V, Zou GY, Parker CE, et al. Placebo response and remission rates in randomised trials of induction and maintenance therapy for ulcerative colitis. Cochrane Database Syst Rev. 2017;9:CD011572.PubMedGoogle Scholar
  18. 18.
    Higgins JP, Altman DG, Gotzsche PC, et al. The cochrane collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.CrossRefGoogle Scholar
  19. 19.
    Stijnen T, Hamza TH, Ozdemir P. Random effects meta-analysis of event outcome in the framework of the generalized linear mixed model with applications in sparse data. Stat Med. 2010;29:3046–3067.CrossRefGoogle Scholar
  20. 20.
    Murad MHMV, Ioannidis JPA, et al. Fixed-effects and random-effects models. In: Guyatt G, Rennie D, Meade MO, Cook DJ, eds. Users’ guide to the medical literature. A manual for evidence-based clinical practice. 3rd ed. New York: McGraw-Hill; 2015.Google Scholar
  21. 21.
    van Houwelingen HC, Arends LR, Stijnen T. Advanced methods in meta-analysis: multivariate approach and meta-regression. Stat Med. 2002;21:589–624.CrossRefGoogle Scholar
  22. 22.
    Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–1558.CrossRefGoogle Scholar
  23. 23.
    Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–634.CrossRefGoogle Scholar
  24. 24.
    Viechtbauer W. Conducting meta-analyses in R with the metafor Package. J Stat Softw. 2010;36:1–48.CrossRefGoogle Scholar
  25. 25.
    Team RC. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. https://www.R-project.org/.2017.
  26. 26.
    Team R. RStudio: Integrated development for R. RStudio, Inc., Boston, MA. http://www.rstudio.com (2016).
  27. 27.
    Brown SJMJ, Smith S, Matchet D, Elliott R. Bifidobacterium longum BB-536 and prevention of acute pouchitis. Gastroenterology. 2004;126:S465.CrossRefGoogle Scholar
  28. 28.
    Ha CY, Bauer JJ, Lazarev M, et al. Early institution of tinidazole may prevent pouchitis following ileal-pouch anal anastomosis (IPAA) surgery in ulcerative colitis (UC) patients. Gastroenterology. 2010;1:S69.Google Scholar
  29. 29.
    Isaacs KL, Sandler RS, Abreu M, et al. Rifaximin for the treatment of active pouchitis: a randomized, double-blind, placebo-controlled pilot study. Inflamm Bowel Dis. 2007;13:1250–1255.CrossRefGoogle Scholar
  30. 30.
    Joelsson M, Andersson M, Bark T, et al. Allopurinol as prophylaxis against pouchitis following ileal pouch-anal anastomosis for ulcerative colitis: a randomized placebo-controlled double-blind study. Scand J Gastroenterol. 2001;36:1179–1184.CrossRefGoogle Scholar
  31. 31.
    Kjaer MD, Qvist N, Nordgaard-Lassen I, Christensen LA, Kjeldsen J. Adalimumab in the treatment of chronic pouchitis. A Randomized double-blind, placebo-controlled trial. Gastroenterology. 2016;1:S773–S774.CrossRefGoogle Scholar
  32. 32.
    Kuisma J, Mentula S, Jarvinen H, Kahri A, Saxelin M, Farkkila M. Effect of Lactobacillus rhamnosus GG on ileal pouch inflammation and microbial flora. Aliment Pharmacol Ther. 2003;17:509–515.CrossRefGoogle Scholar
  33. 33.
    Madden M, McIntyre A, Nicholls R. Double-blind crossover trial of metronidazole versus placebo in chronic unremitting pouchitis. Digestive diseases and sciences. 1994;39:1193–1196.CrossRefGoogle Scholar
  34. 34.
    Tremaine WJ, Sandborn WJ, Wolff BG, Carpenter HA, Zinsmeister AR, Metzger PP. Bismuth carbomer foam enemas for active chronic pouchitis: a randomized, double-blind, placebo-controlled trial. Aliment Pharmacol Ther. 1997;11:1041–1046.CrossRefGoogle Scholar
  35. 35.
    Yasueda A, Mizushima T, Nezu R, et al. The effect of Clostridium butyricum MIYAIRI on the prevention of pouchitis and alteration of the microbiota profile in patients with ulcerative colitis. Surg Today. 2016;46:939–949.CrossRefGoogle Scholar
  36. 36.
    Sandborn WJ, Tremaine WJ, Batts KP, Pemberton JH, Phillips SF. Pouchitis after ileal pouch-anal anastomosis: a pouchitis disease activity index. Mayo Clin Proc. 1994;69:409–415.CrossRefGoogle Scholar
  37. 37.
    Shen B, Achkar JP, Connor JT, et al. Modified pouchitis disease activity index: a simplified approach to the diagnosis of pouchitis. Dis Colon Rectum. 2003;46:748–753.CrossRefGoogle Scholar
  38. 38.
    Hahnloser D, Pemberton JH, Wolff BG, Larson DR, Crownhart BS, Dozois RR. The effect of ageing on function and quality of life in ileal pouch patients: a single cohort experience of 409 patients with chronic ulcerative colitis. Ann Surg. 2004;240:615–621. (discussion 21-3).PubMedPubMedCentralGoogle Scholar
  39. 39.
    Hurst RD, Molinari M, Chung TP, Rubin M, Michelassi F. Prospective study of the incidence, timing and treatment of pouchitis in 104 consecutive patients after restorative proctocolectomy. Arch Surg. 1996;131:497–500. (discussion 1–2).CrossRefGoogle Scholar
  40. 40.
    Stahlberg D, Gullberg K, Liljeqvist L, Hellers G, Lofberg R. Pouchitis following pelvic pouch operation for ulcerative colitis. Incidence, cumulative risk, and risk factors. Dis Colon Rectum. 1996;39:1012–1018.CrossRefGoogle Scholar
  41. 41.
    Abdelrazeq AS, Kandiyil N, Botterill ID, et al. Predictors for acute and chronic pouchitis following restorative proctocolectomy for ulcerative colitis. Colorectal Dis Off J Assoc Coloproctol GB Irel. 2008;10:805–813.Google Scholar
  42. 42.
    Hashavia E, Dotan I, Rabau M, Klausner JM, Halpern Z, Tulchinsky H. Risk factors for chronic pouchitis after ileal pouch-anal anastomosis: a prospective cohort study. Colorectal Dis Off J Assoc Coloproctol GB Irel. 2012;14:1365–1371.Google Scholar
  43. 43.
    Hata K, Watanabe T, Shinozaki M, Nagawa H. Patients with extraintestinal manifestations have a higher risk of developing pouchitis in ulcerative colitis: multivariate analysis. Scand J Gastroenterol. 2003;38:1055–1058.CrossRefGoogle Scholar
  44. 44.
    Jairath V, Zou G, Parker CE, et al. Systematic review and meta-analysis: placebo rates in induction and maintenance trials of ulcerative colitis. J Crohns Colitis. 2016;10:607–618.CrossRefGoogle Scholar
  45. 45.
    Su C, Lewis JD, Goldberg B, Brensinger C, Lichtenstein GR. A meta-analysis of the placebo rates of remission and response in clinical trials of active ulcerative colitis. Gastroenterology. 2007;132:516–526.CrossRefGoogle Scholar
  46. 46.
    Brook RH. The RAND/UCLA appropriateness method. In: McCormick KA, Moore SR, Siegel RA, eds. Clinical practice guideline development: Methodology practices (AHCPR Publication No 95-0009). Rockville, MD: Agency for Health Care Policy and Research, Public Health Service, U.S. Department of Health and Human Services; 1994.Google Scholar
  47. 47.
    Ma C, Panaccione R, Fedorak RN, et al. Development of a core outcome set for clinical trials in inflammatory bowel disease: study protocol for a systematic review of the literature and identification of a core outcome set using a Delphi survey. BMJ Open. 2017;7:e016146.CrossRefGoogle Scholar
  48. 48.
    Feagan BG, Sandborn WJ, D’Haens G, et al. The role of centralized reading of endoscopy in a randomized controlled trial of mesalamine for ulcerative colitis. Gastroenterology. 2013;145:e2.CrossRefGoogle Scholar
  49. 49.
    Gottlieb K, Travis S, Feagan B, Hussain F, Sandborn WJ, Rutgeerts P. Central reading of endoscopy endpoints in inflammatory bowel disease trials. Inflamm Bowel Dis. 2015;21:2475–2482.PubMedGoogle Scholar
  50. 50.
    Samaan MA, Shen B, Mosli MH, et al. Reliability among central readers in the evaluation of endoscopic disease activity in pouchitis. Gastrointest Endosc. 2018.  https://doi.org/10.1016/j.gie.2018.04.2330.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Jonathan Athayde
    • 1
  • Sarah C. Davies
    • 1
  • Claire E. Parker
    • 2
  • Leonardo Guizzetti
    • 2
  • Christopher Ma
    • 2
    • 4
  • Reena Khanna
    • 1
    • 2
  • Brian G. Feagan
    • 1
    • 2
    • 3
  • Vipul Jairath
    • 2
    • 3
    • 5
  1. 1.Department of MedicineUniversity of Western OntarioLondonCanada
  2. 2.Robarts Clinical Trials Inc.LondonCanada
  3. 3.Department of Epidemiology and BiostatisticsUniversity of Western OntarioLondonCanada
  4. 4.Division of Gastroenterology and HepatologyUniversity of CalgaryCalgaryCanada
  5. 5.Division of Gastroenterology, Departments of MedicineUniversity of Western OntarioLondonCanada

Personalised recommendations