Skip to main content
SpringerLink
Log in

Positive and negative AIT trials: What makes the difference?

  • Mini-Review
  • Published:
Allergo Journal Aims and scope Submit manuscript

Abstract

Background

Allergen immunotherapy has proven to be efficacious in allergic rhinitis and asthma. However, results from randomised clinical trials may vary substantially. Clinical trials may unexpectedly fail. The purpose of this review is to discuss the possible factors that may contribute to a successful or unsuccessful study.

Methods

Descriptive review exploring the possible causes of negative outcomes in allergen immunotherapy trials.

Results

A series of factors may lead to negative results. Among of these are underpowering of the study, low allergen content in tested extracts, insufficient allergen exposure during monitoring and recruitment of inappropriate patients. In addition, the choice of the primary endpoint may be critical.

Discussion

A clinical trial aims to evaluate the efficacy of an agent. However, studies with potential effective compounds may fail because of methodical issues. Sometimes, they are the cause of discrepancies between successful phase II and unsuccessful phase III trials. To understand more about failure of studies, investigators and editors should be encouraged to publish negative trials.

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

Abbreviations

AIT:

Allergen immunotherapy

CI:

Confidence interval

CONSORT:

Consolidated standards of reporting trials

GAP:

Grass SLIT tablet asthma prevention

HDM:

House dust mite

ITT:

Intention-to-treat

OR:

Odds ratio

PAT:

Preventive allergy treatment

RCT:

Randomised clinical trial

RCT:

Randomised controlled trial

SCIT:

Subcutaneous immunotherapy

SLIT:

Sublingual immunotherapy

TCS:

Total combined symptom score

References

  1. Noon LA. Prophylactic inoculation against hay fever. Lancet 1911;1:1572–3

    Article  Google Scholar 

  2. Frankland AW, Augustin R. Prophylaxis of summer hay-fever and asthma: a controlled trial comparing crude grass-pollen extracts with the isolated main protein component. Lancet 1954;266:1055–7

    Article  CAS  Google Scholar 

  3. Scadding GK, Brostoff J. Low dose sublingual therapy in patients with allergic rhinitis due to house dust mite. Clin Allergy 1986;16:483–91

    Article  CAS  Google Scholar 

  4. Dhami S, Nurmatov U, Arasi S, Khan T, Asaria M, Zaman H, et al. Allergen immunotherapy for allergic rhinoconjunctivitis: a systematic review and meta-analysis. Allergy 2017;72:1597–631

    Article  CAS  Google Scholar 

  5. Dhami S, Kakourou A, Asamoah F, Agache I, Lau S, Jutel M, et al. Allergen immunotherapy for allergic asthma: a systematic review and meta-analysis. Allergy 2017;72:1825–48

    Article  CAS  Google Scholar 

  6. Calderon MA, Alves B, Jacobson M, Hurwitz B, Sheikh A, Durham S. Allergen injection immunotherapy for seasonal allergic rhinitis. Cochrane Database Syst Rev 2007;https://doi.org/10.1002/14651858.cd001936.pub2

    Google Scholar 

  7. Radulovic S, Wilson D, Calderon M, Durham S. Systematic reviews of sublingual immunotherapy (SLIT). Allergy 2011;66:740–52

    Article  CAS  Google Scholar 

  8. Slovick A, Douiri A, Muir R, Guerra A, Tsioulos K, Hay E, et al. Intradermal grass pollen immunotherapy increases TH2 and IgE responses and worsens respiratory allergic symptoms. J Allergy Clin Immunol 2017;139:1830–1839.e13

    Article  CAS  Google Scholar 

  9. Bousquet PJ, Calderon MA, Demoly P, Larenas D, Passalacqua G, Bachert C, et al. The Consolidated Standards of Reporting Trials (CONSORT) Statement applied to allergen-specific immunotherapy with inhalant allergens: a Global Allergy and Asthma European Network (GA(2)LEN) article. J Allergy Clin Immunol 2011;127:49–56.e11

    Article  Google Scholar 

  10. Pham-Thi N, Scheinmann P, Fadel R, Combebias A, Andre C. Assessment of sublingual immunotherapy efficacy in children with house dust mite-induced allergic asthma optimally controlled by pharmacologic treatment and mite-avoidance measures. Pediatr Allergy Immunol 2007;18:47–57

    Article  Google Scholar 

  11. Khinchi MS, Poulsen LK, Carat F, Andre C, Hansen AB, Malling HJ. Clinical efficacy of sublingual and subcutaneous birch pollen allergen-specific immunotherapy: a randomized, placebo-controlled, double-blind, double-dummy study. Allergy. 2004;59:45–53

    Article  CAS  Google Scholar 

  12. Sander I, Fleischer C, Meurer U, Bruning T, Raulf-Heimsoth M. Allergen content of grass pollen preparations for skin prick testing and sublingual immunotherapy. Allergy. 2009;64:1486–92

    Article  CAS  Google Scholar 

  13. Smith H, White P, Annila I, Poole J, Andre C, Frew A. Randomized controlled trial of high-dose sublingual immunotherapy to treat seasonal allergic rhinitis. J Allergy Clin Immunol 2004;114:831–7

    Article  CAS  Google Scholar 

  14. Roder E, Berger MY, Hop WC, Bernsen RM, de Groot H, Gerth van Wijk R. Sublingual immunotherapy with grass pollen is not effective in symptomatic youngsters in primary care. J Allergy Clin Immunol 2007;119:892–8

    Article  Google Scholar 

  15. Kleine-Tebbe J, Walmar M, Bitsch-Jensen K, Decot E, Pfaar O, de Rojas DH, et al. Negative clinical results from a randomised, double-blind, placebo-controlled trial evaluating the efficacy of two doses of immunologically enhanced, grass subcutaneous immunotherapy despite dose-dependent immunological response. Clin Drug Investig 2014;34:577–86

    Article  CAS  Google Scholar 

  16. Durham SR, Nelson HS, Nolte H, Bernstein DI, Creticos PS, Li Z, et al. Magnitude of efficacy measurements in grass allergy immunotherapy trials is highly dependent on pollen exposure. Allergy. 2014;69:617–23

    Article  CAS  Google Scholar 

  17. van der Heide S, de Monchy JG, de Vries K, Bruggink TM, Kauffman HF. Seasonal variation in airway hyperresponsiveness and natural exposure to house dust mite allergens in patients with asthma. J Allergy Clin Immunol 1994;93:470–5

    Article  CAS  Google Scholar 

  18. Calderon MA, Casale TB, Nelson HS, Demoly P. An evidence-based analysis of house dust mite allergen immunotherapy: a call for more rigorous clinical studies. J Allergy Clin Immunol 2013;132:1322–36

    Article  CAS  Google Scholar 

  19. Dahl R, Kapp A, Colombo G, de Monchy JG, Rak S, Emminger W, et al. Efficacy and safety of sublingual immunotherapy with grass allergen tablets for seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol 2006;118:434–40

    Article  CAS  Google Scholar 

  20. Durham SR, Walker SM, Varga EM, Jacobson MR, O'Brien F, Noble W, et al. Long-term clinical efficacy of grass-pollen immunotherapy. N Engl J Med. 1999;341:468–75

    Article  CAS  Google Scholar 

  21. Frew AJ, Powell RJ, Corrigan CJ, Durham SR, Group UKIS. Efficacy and safety of specific immunotherapy with SQ allergen extract in treatment-resistant seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol 2006;117:319–25

    Article  CAS  Google Scholar 

  22. Varney VA, Gaga M, Frew AJ, Aber VR, Kay AB, Durham SR. Usefulness of immunotherapy in patients with severe summer hay fever uncontrolled by antiallergic drugs. BMJ. 1991;302:265–9

    Article  CAS  Google Scholar 

  23. Varney VA, Tabbah K, Mavroleon G, Frew AJ. Usefulness of specific immunotherapy in patients with severe perennial allergic rhinitis induced by house dust mite: a double-blind, randomized, placebo-controlled trial. Clin Exp Allergy 2003;33:1076–82

    Article  CAS  Google Scholar 

  24. Didier A, Worm M, Horak F, Sussman G, de Beaumont O, Le Gall M, et al. Sustained 3 year efficacy of pre- and coseasonal 5 grass-pollen sublingual immunotherapy tablets in patients with grass pollen-induced rhinoconjunctivitis. J Allergy Clin Immunol 2011;128:559–66

    Article  CAS  Google Scholar 

  25. Blaiss M, Maloney J, Nolte H, Gawchik S, Yao R, Skoner DP. Efficacy and safety of timothy grass allergy immunotherapy tablets in North American children and adolescents. J Allergy Clin Immunol 2011;127:64–71.e4

    Article  CAS  Google Scholar 

  26. Wahn U, Klimek L, Ploszczuk A, Adelt T, Sandner B, Trebas-Pietras E, et al. High-dose sublingual immunotherapy with single-dose aqueous grass pollen extract in children is effective and safe: a double-blind, placebo-controlled study. J Allergy Clin Immunol 2012;130:886–893.e5

    Article  CAS  Google Scholar 

  27. Howarth P, Malling HJ, Molimard M, Devillier P. Analysis of allergen immunotherapy studies shows increased clinical efficacy in highly symptomatic patients. Allergy 2012;67:321–7

    Article  CAS  Google Scholar 

  28. Pfaar O, Demoly P, Gerth van Wijk R, Bonini S, Bousquet J, Canonica GW, et al. Recommendations for the standardization of clinical outcomes used in allergen immunotherapy trials for allergic rhinoconjunctivitis: an EAACI position paper. Allergy 2014;69:854–67

    Article  CAS  Google Scholar 

  29. Normansell R, Kew KM, Bridgman AL. Sublingual immunotherapy for asthma. Cochrane Database Syst Rev 2015; https://doi.org/10.1002/14651858.cd011293.pub2

    Google Scholar 

  30. Virchow JC, Backer V, Kuna P, Prieto L, Nolte H, Villesen HH, et al. Efficacy of a house dust mite sublingual allergen immunotherapy tablet in adults with allergic asthma: a randomized clinical trial. JAMA 2016;315:1715–25

    Article  CAS  Google Scholar 

  31. Moller C, Dreborg S, Ferdousi HA, Halken S, Host A, Jacobsen L, et al. Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study). J Allergy Clin Immunol 2002;109:251–6

    Article  Google Scholar 

  32. Valovirta E, Petersen TH, Piotrowska T, Laursen MK, Andersen JS, Sorensen HF, et al. Results from the 5 year SQ grass sublingual immunotherapy tablet asthma prevention (GAP) trial in children with grass pollen allergy. J Allergy Clin Immunol 2018;141:529–538.e13

    Article  CAS  Google Scholar 

  33. Jacobsen L, Niggemann B, Dreborg S, Ferdousi HA, Halken S, Host A, et al. Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study. Allergy 2007;62:943–8

    Article  CAS  Google Scholar 

  34. Creticos PS, Schroeder JT, Hamilton RG, Balcer-Whaley SL, Khattignavong AP, Lindblad R, et al. Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis. N Engl J Med 2006;355:1445–55

    Article  CAS  Google Scholar 

  35. Niederberger V, Neubauer A, Gevaert P, Zidarn M, Worm M, Aberer W, et al. Safety and efficacy of immunotherapy with the recombinant B cell epitope-based grass pollen vaccine BM32. J Allergy Clin Immunol 2018; https://doi.org/10.1016/j.jaci.2017.09.052

    Google Scholar 

  36. Sampson HA, Shreffler WG, Yang WH, Sussman GL, Brown-Whitehorn TF, Nadeau KC, et al. Effect of varying doses of epicutaneous immunotherapy vs placebo on reaction to peanut protein exposure among patients with peanut sensitivity: a randomized clinical trial. JAMA 2017;318:1798–809

    Article  Google Scholar 

  37. Technologies D. Results of phase III clinicical trial in peanut allergic children four to 11 years of age. 2017. https://media.dbv-technologies.com/d286/ressources/_pdf/5/4257-PR-PEPITES-topline-results-FINAL.pdf. Accessed 25 Feb 2018

    Google Scholar 

  38. Narkus A, Lehnigk U, Haefner D, Klinger R, Pfaar O, Worm M. The placebo effect in allergen-specific immunotherapy trials. Clin Transl Allergy 2013;3:42

    Article  Google Scholar 

  39. Circassia. Cat allergy phase III study June 2016 final. 2016. http://www.circassia.com/wp/wp-content/uploads/2016/06/CIR_Cat-allergy-phase-III-results_June-2016-final.pdf. Accessed 25 Feb 2018

  40. Patel D, Couroux P, Hickey P, Salapatek AM, Laidler P, Larche M, et al. Fel d 1 derived peptide antigen desensitization shows a persistent treatment effect 1 year after the start of dosing: a randomized, placebo-controlled study. J Allergy Clin Immunol. 2013;131:103–109.e7

    Article  CAS  Google Scholar 

  41. Circassia. Circassia announces top-line results from house dust mite allergy field study. 2017. http://www.circassia.com/media/press-releases/circassia-announces-top-line-results-from-house-dust-mite-allergy-field-study/. Accessed 25 Feb 2018

  42. Dynavax. Dynavax reports interim TOLAMBA TM ragweed allergy results from DARTT trial 2007. 2007. http://investors.dynavax.com/releasedetail.cfm?releaseid=230979 (Created 23 Feb 2007). Accessed 25 Feb 2018

Download references

Author information

Authors and Affiliations

  1. Section of Allergology, Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands

    Roy Gerth van Wijk

Authors
  1. Roy Gerth van Wijk
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Roy Gerth van Wijk.

Additional information

Conflict of interest

R.G. van Wijk declares the following relations: consultancy for ALK Abello, Allergopharma, Circassia; lectures for ALK Abello, Allergopharma.

Cite this as

Gerth van Wijk R. Positive and negative AIT trials: What makes the difference? Allergo J Int 2018;27:167–72

https://doi.org/10.1007/s40629-018-0058-y

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

van Wijk, R.G. Positive and negative AIT trials: What makes the difference?. Allergo J 27, 36–41 (2018). https://doi.org/10.1007/s15007-018-1690-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s15007-018-1690-z

Schlüsselwörter

Search

Navigation