Skip to main content

Advertisement

SpringerLink
Log in

Evolution of Clinical Trials in Inflammatory Bowel Diseases

  • Inflammatory Bowel Diseases (S Hanauer, Section Editor)
  • Published:
Current Gastroenterology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Since the first clinical trial of cortisone in ulcerative colitis in 1955, remarkable progress has been made in the design and conduct of clinical trials in inflammatory bowel diseases (IBD). In this review article, we will discuss evolution of clinical trials in IBD over the last 3–5 years.

Recent Findings

Recognizing limitations intrinsic to clinical disease activity indices in IBD, regulatory authorities have recommended evaluating co-primary endpoints of patient-reported outcomes and endoscopic disease activity in clinical trials. Biomarker-enriched trial enrolment and central endoscopy reading have emerged as critical events in trial recruitment and outcome assessment and have driven placebo response rates down. While trials of novel biologic therapies and advanced small molecules continue at an accelerated pace, pragmatic comparative efficacy trials of treatment strategy aimed at optimizing current therapies (such as early combined immunosuppression [REACT], tight disease control [CALM], therapeutic drug monitoring [TAXIT, TAILORIX]) have directly informed clinical practice. With emphasis on value-based care and population health management, multi-pronged remote monitoring, self-management, and telemedicine approaches in the era of smartphones have re-emerged with promise. Non-conventional therapies such as fecal microbiota transplantation, though still experimental, have provided insight into disease pathogenesis and offered hope for microbial manipulation strategies for treating these complex diseases.

Summary

Clinical trials have rapidly evolved over the last 5 years not only focusing on novel therapies but also optimizing existing treatment approaches and population health management. Over the next decade, these trials will continue to advance the field, and be readily translatable into clinical practice.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Truelove SC, Witts LJ. Cortisone in ulcerative colitis; final report on a therapeutic trial. Br Med J. 1955;2:1041–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Feagan BG, Sandborn WJ, D'Haens G, Panés J, Kaser A, Ferrante M, et al. Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn’s disease: a randomised, double-blind, placebo-controlled phase 2 study. Lancet. 2017;389:1699–709.

    Article  PubMed  CAS  Google Scholar 

  3. Sandborn WJ, Su C, Sands BE, D'Haens GR, Vermeire S, Schreiber S, et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2017;376:1723–36.

    Article  PubMed  CAS  Google Scholar 

  4. Feagan BG, Sandborn WJ, Gasink C, Jacobstein D, Lang Y, Friedman JR, et al. Ustekinumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2016;375:1946–60.

    Article  PubMed  CAS  Google Scholar 

  5. Vermeire S, Sandborn WJ, Danese S, Hébuterne X, Salzberg BA, Klopocka M, et al. Anti-MAdCAM antibody (PF-00547659) for ulcerative colitis (TURANDOT): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet. 2017;390:135–44.

    Article  PubMed  CAS  Google Scholar 

  6. Sandborn WJ, Feagan BG, Wolf DC, D'Haens G, Vermeire S, Hanauer SB, et al. Ozanimod induction and maintenance treatment for ulcerative colitis. N Engl J Med. 2016;374:1754–62.

    Article  PubMed  CAS  Google Scholar 

  7. Vermeire S, O'Byrne S, Keir M, Williams M, Lu TT, Mansfield JC, et al. Etrolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial. Lancet. 2014;384:309–18.

    Article  PubMed  CAS  Google Scholar 

  8. Sands BE, Chen J, Feagan BG, Penney M, Rees WA, Danese S, et al. Efficacy and safety of MEDI2070, an antibody against interleukin 23, in patients with moderate to severe Crohn’s disease: a phase 2a study. Gastroenterology. 2017;153:77–86.e6.

    Article  PubMed  CAS  Google Scholar 

  9. Vermeire S, Schreiber S, Petryka R, Kuehbacher T, Hebuterne X, Roblin X, et al. Clinical remission in patients with moderate-to-severe Crohn’s disease treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, randomised, placebo-controlled trial. Lancet. 2017;389:266–75.

    Article  PubMed  CAS  Google Scholar 

  10. Dulai PS, Sandborn WJ. Next-generation therapeutics for inflammatory bowel disease. Curr Gastroenterol Rep. 2016;18:51.

    Article  PubMed  PubMed Central  Google Scholar 

  11. •• Khanna R, Bressler B, Levesque BG, Zou G, Stitt LW, Greenberg GR, et al. Early combined immunosuppression for the management of Crohn’s disease (REACT): a cluster randomised controlled trial. Lancet. 2015;386:1825–34. This pivotal cluster-randomized trial represents a new type of pragmatic clinical trial evaluating early algorithmic treatment escalation in patients with Crohn’s disease.

    Article  PubMed  Google Scholar 

  12. •• Colombel JF, Panaccione R, Bossuyt P, et al. Effect of tight control management on Crohn’s disease (CALM): a multicentre, randomised, controlled phase 3 trial. Lancet. 2018;390:2779–89. This pivotal strategy trial presents for the first time evidence that treatment escalated based on biomarkers and/or symptoms is superior to treatment based only on symptoms.

    Article  PubMed  Google Scholar 

  13. • Vande Casteele N, Ferrante M, Van Assche G, et al. Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease. Gastroenterology. 2015;148:1320–9.e3. This trial demonstrated that, after initial optimization of infliximab trough levels in patients on maintenance therapy, routine, repeated infliximab trough concentration-guided dosing is not superior to usual care.

    Article  PubMed  CAS  Google Scholar 

  14. • D'Haens G, Vermeire S, Lambrecht G, et al. Increasing infliximab dose based on symptoms, biomarkers, and serum drug concentrations does not increase clinical, endoscopic, and corticosteroid-free remission in patients with active luminal Crohn’s disease. Gastroenterology. 2018;154:1343–51. e1 In this small randomized trial of patients with active CD, investigators observed that increasing infliximab dose based on a combination of symptoms, biomarkers, and serum drug concentrations is not superior to increasing dose based on symptoms alone, in achieving corticosteroid-free clinical remission.

    Article  PubMed  CAS  Google Scholar 

  15. •• de Jong MJ, van der Meulen-de Jong AE, Romberg-Camps MJ, Becx MC, Maljaars JP, Cilissen M, et al. Telemedicine for management of inflammatory bowel disease (myIBDcoach): a pragmatic, multicentre, randomised controlled trial. Lancet. 2017;390:959–68. This pragmatic trial provides solid evidence supporting a comprehensive telehealth program comprising remote monitoring and self-management for improving population health management in patients with IBD.

    Article  PubMed  Google Scholar 

  16. • Paramsothy S, Kamm MA, Kaakoush NO, Walsh AJ, van den Bogaerde J, Samuel D, et al. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet. 2017;389:1218–28. In this trial, investigators demonstrated that intensive-dosing, multidonor, fecal microbiota transplantation induces clinical remission and endoscopic improvement in patients with active ulcerative colitis and is associated with distinct microbial changes that relate to outcome.

    Article  PubMed  Google Scholar 

  17. Moayyedi P, Surette MG, Kim PT, Libertucci J, Wolfe M, Onischi C, et al. Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. Gastroenterology. 2015;149:102–109.e6.

    Article  PubMed  Google Scholar 

  18. Rossen NG, Fuentes S, van der Spek MJ, Tijssen JG, Hartman JHA, Duflou A, et al. Findings from a randomized controlled trial of fecal transplantation for patients with ulcerative colitis. Gastroenterology. 2015;149:110–118 e4.

    Article  PubMed  Google Scholar 

  19. Cellier C, Sahmoud T, Froguel E, Adenis A, Belaiche J, Bretagne JF, et al. Correlations between clinical activity, endoscopic severity, and biological parameters in colonic or ileocolonic Crohn’s disease. A prospective multicentre study of 121 cases. The Groupe d’Etudes Therapeutiques des Affections Inflammatoires Digestives. Gut. 1994;35:231–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Jones J, Loftus EV Jr, Panaccione R, Chen L–S, Peterson S, Mcconnell J, et al. Relationships between disease activity and serum and fecal biomarkers in patients with Crohn’s disease. Clin Gastroenterol Hepatol. 2008;6:1218–24.

    Article  PubMed  Google Scholar 

  21. Ma C, Guizzetti L, Panaccione R, Fedorak RN, Pai RK, Parker CE, et al. Systematic review with meta-analysis: endoscopic and histologic placebo rates in induction and maintenance trials of ulcerative colitis. Aliment Pharmacol Ther. 2018;47:1578–96.

    Article  PubMed  CAS  Google Scholar 

  22. 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.

    PubMed  Google Scholar 

  23. Williet N, Sandborn WJ, Peyrin-Biroulet L. Patient-reported outcomes as primary end points in clinical trials of inflammatory bowel disease. Clin Gastroenterol Hepatol. 2014;12:1246–56 e6.

    Article  PubMed  Google Scholar 

  24. Ma C, Hussein IM, Al-Abbar YJ, et al. Heterogeneity in definitions of efficacy and safety endpoints for clinical trials of Crohn’s disease: a systematic review for development of a core outcome set. Clin Gastroenterol Hepatol. 2018.

  25. Ma C, Panaccione R, Fedorak RN, Parker CE, Nguyen TM, Khanna R, et al. Heterogeneity in definitions of endpoints for clinical trials of ulcerative colitis: a systematic review for development of a core outcome set. Clin Gastroenterol Hepatol. 2018;16:637–647 e13.

    Article  PubMed  Google Scholar 

  26. Singh S. PROMises made, PROMises to be kept: patient-reported outcome measures in inflammatory bowel diseases. Clin Gastroenterol Hepatol. 2018;16:624–6.

    Article  PubMed  Google Scholar 

  27. •• de Jong MJ, Huibregtse R, Masclee AAM, Jonkers DMAE, Pierik MJ. Patient-reported outcome measures for use in clinical trials and clinical practice in inflammatory bowel diseases: a systematic review. Clin Gastroenterol Hepatol. 2018;16:648–663 e3. This comprehensive systematic review provides a detailed evaluation of all available patient-reported outcomes measures and their relevance to clinical trials and clinical practice in IBD.

    Article  PubMed  Google Scholar 

  28. Cohen ER, Melmed GY. Making a case for patient-reported outcomes in clinical inflammatory bowel disease practice. Clin Gastroenterol Hepatol. 2018;16:603–7.

    Article  PubMed  Google Scholar 

  29. Van Deen WK, van der Meulen-de Jong AE, Parekh NK, et al. Development and validation of an inflammatory bowel diseases monitoring index for use with mobile health technologies. Clin Gastroenterol Hepatol. 2016;14:1742–1750 e7.

    Article  PubMed  Google Scholar 

  30. Mohammed Vashist N, Samaan M, Mosli MH, et al. Endoscopic scoring indices for evaluation of disease activity in ulcerative colitis. Cochrane Database Syst Rev. 2018;1:CD011450.

    PubMed  Google Scholar 

  31. Travis SP, Schnell D, Krzeski P, et al. Reliability and initial validation of the ulcerative colitis endoscopic index of severity. Gastroenterology. 2013;145:987–95.

    Article  PubMed  Google Scholar 

  32. Khanna R, Nelson SA, Feagan BG, et al. Endoscopic scoring indices for evaluation of disease activity in Crohn’s disease. Cochrane Database Syst Rev 2016; CD010642.

  33. Panes J, Feagan BG, Hussain F, et al. Central endoscopy reading in inflammatory bowel diseases. J Crohns Colitis. 2016;10(Suppl 2):S542–7.

    Article  PubMed  Google Scholar 

  34. Feagan BG, Sandborn WJ, D'Haens G, Pola S, McDonald JWD, Rutgeerts P, et al. The role of centralized reading of endoscopy in a randomized controlled trial of mesalamine for ulcerative colitis. Gastroenterology. 2013;145:149–157 e2.

    Article  PubMed  CAS  Google Scholar 

  35. •• Khanna R, Jairath V, Vande Casteele N, Mosli MH, Zou G, Parker CE, et al. Efficient early drug development for ulcerative colitis. Gastroenterology. 2016;150:1056–60. This brief review provides a framework for efficient early drug development in ulcerative colitis.

    Article  PubMed  Google Scholar 

  36. Jairath V, Levesque BG, Vande Casteele N, Khanna R, Mosli M, Hindryckx P, et al. Evolving concepts in phases I and II drug development for Crohn’s disease. J Crohns Colitis. 2017;11:246–55.

    Article  PubMed  Google Scholar 

  37. D'Haens G, Baert F, van Assche G, Caenepeel P, Vergauwe P, Tuynman H, et al. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn’s disease: an open randomised trial. Lancet. 2008;371:660–7.

    Article  PubMed  CAS  Google Scholar 

  38. Colombel JF, Sandborn WJ, Reinisch W, Mantzaris GJ, Kornbluth A, Rachmilewitz D, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010;362:1383–95.

    Article  PubMed  CAS  Google Scholar 

  39. Singh S, Loftus EV Jr. Crohn’s disease: REACT to save the gut. Lancet. 2015;386:1800–2.

    Article  PubMed  Google Scholar 

  40. Vande Casteele N, Herfarth H, Katz J, Falck-Ytter Y, Singh S. American Gastroenterological Association Institute technical review on the role of therapeutic drug monitoring in the management of inflammatory bowel diseases. Gastroenterology. 2017;153:835–857 e6.

    Article  PubMed  Google Scholar 

  41. Feuerstein JD, Nguyen GC, Kupfer SS, Falck-Ytter Y, Singh S, Gerson L, et al. American Gastroenterological Association Institute guideline on therapeutic drug monitoring in inflammatory bowel disease. Gastroenterology. 2017;153:827–34.

    Article  PubMed  Google Scholar 

  42. Steenholdt C, Brynskov J, Thomsen OO, Munck LK, Fallingborg J, Christensen LA, et al. Individualised therapy is more cost-effective than dose intensification in patients with Crohn’s disease who lose response to anti-TNF treatment: a randomised, controlled trial. Gut. 2014;63:919–27.

    Article  PubMed  Google Scholar 

  43. Papamichael K, Chachu KA, Vajravelu RK, Vaughn BP, Ni J, Osterman MT, et al. Improved long-term outcomes of patients with inflammatory bowel disease receiving proactive compared with reactive monitoring of serum concentrations of infliximab. Clin Gastroenterol Hepatol. 2017;15:1580–1588 e3.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  44. Papamichael K, Vajravelu RK, Vaughn BP, Osterman MT, Cheifetz AS. Proactive infliximab monitoring following reactive testing is associated with better clinical outcomes than reactive testing alone in patients with inflammatory bowel disease. J Crohns Colitis. 2018;12:804–10.

    Article  PubMed  Google Scholar 

  45. Dulai PS, Singh S, Ohno-Machado L, Sandborn WJ. Population health management for inflammatory bowel disease. Gastroenterology. 2018;154:37–45.

    Article  PubMed  Google Scholar 

  46. Kosinski LR, Brill J, Regueiro M. Making a medical home for IBD patients. Curr Gastroenterol Rep. 2017;19:20.

    Article  PubMed  Google Scholar 

  47. Regueiro M, Click B, Anderson A, Shrank W, Kogan J, McAnallen S, Szigethy E Reduced unplanned care and disease activity and increased quality of life after patient enrollment in an inflammatory bowel disease medical home. Clin Gastroenterol Hepatol 2018.

  48. Regueiro M, Click B, Holder D, Shrank W, McAnallen S, Szigethy E. Constructing an inflammatory bowel disease patient-centered medical home. Clin Gastroenterol Hepatol. 2017;15:1148–1153 e4.

    Article  PubMed  Google Scholar 

  49. Costello SP, Soo W, Bryant RV, Jairath V, Hart AL, Andrews JM. Systematic review with meta-analysis: faecal microbiota transplantation for the induction of remission for active ulcerative colitis. Aliment Pharmacol Ther. 2017;46:213–24.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Gastroenterology, University of California San Diego, 9452 Medical Center Drive, ACTRI 1W 501, La Jolla, CA, 92093, USA

    Siddharth Singh

  2. Division of Biomedical Informatics, University of California San Diego, La Jolla, CA, USA

    Siddharth Singh

Authors
  1. Siddharth Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Siddharth Singh.

Ethics declarations

Conflict of Interest

Siddhartha Singh is supported by the American College of Gastroenterology Junior Faculty Development Award and Crohn’s and Colitis Foundation Career Development Award. Dr. Singh has received research grants from Pfizer and AbbVie and has received consulting fees from AbbVie and AMAG Pharmaceuticals.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Inflammatory Bowel Diseases

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Singh, S. Evolution of Clinical Trials in Inflammatory Bowel Diseases. Curr Gastroenterol Rep 20, 41 (2018). https://doi.org/10.1007/s11894-018-0648-3

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11894-018-0648-3

Keywords

Search

Navigation