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01-03-2017 | Immunotherapy and Immunomodulators (B Vickery, Section Editor)

Allergen Immunotherapy Clinical Trial Outcomes and Design: Working Toward Harmonization of Methods and Principles

Authors: Harold S. Nelson, Moises A. Calderon, David I. Bernstein, Thomas B. Casale, Stephen R. Durham, Jens S. Andersen, Robert Esch, Linda S. Cox, Hendrik Nolte

Published in: Current Allergy and Asthma Reports | Issue 3/2017

Abstract

Progress has been made in the harmonization of efficacy and safety outcome measures for allergen immunotherapy (AIT) trials, but unresolved issues still remain. Furthermore, there are discrepancies in recommendations from professional medical societies and regulatory agencies regarding requirements for AIT trials. In this article, we reviewed published recommendations and current data from recent clinical trials, as well as the criteria applied by regulatory authorities for approval of AIT products, to provide updated considerations for conducting phase 3 AIT trials. Topics discussed include analysis of outcomes and trial designs for pediatric and asthma indications, as well as trial designs for perennial allergic rhinoconjunctivitis. In addition, the need for harmonization of safety reporting is emphasized. Considerations presented in this article may further effort to find common ground among professional medical societies and government agencies in developing future recommendations for AIT trial design.

Casale TB, Canonica GW, Bousquet J, Cox L, Lockey R, Nelson HS, et al. Recommendations for appropriate sublingual immunotherapy clinical trials. J Allergy Clin Immunol. 2009;124(4):665–70. doi:10.1016/j.jaci.2009.07.054.CrossRefPubMed

Guideline on the clinical development of products for specific immunotherapy for the treatment of allergic diseases. CHMP/EWP/18504. London, UK: European Medicines Agency 2008.

Bousquet J, Schunemann HJ, Bousquet PJ, Bachert C, Canonica GW, Casale TB, et al. How to design and evaluate randomized controlled trials in immunotherapy for allergic rhinitis: an ARIA-GA(2) LEN statement. Allergy. 2011;66(6):765–74. doi:10.1111/j.1398-9995.2011.02590.x.CrossRefPubMed

Canonica GW, Baena-Cagnani CE, Bousquet J, Bousquet PJ, Lockey RF, Malling HJ, et al. Recommendations for standardization of clinical trials with allergen specific immunotherapy for respiratory allergy. A statement of a World Allergy Organization (WAO) taskforce. Allergy. 2007;62(3):317–24.CrossRefPubMed

Calderon MA, Bernstein DI, Blaiss M, Andersen JS, Nolte H. A comparative analysis of symptom and medication scoring methods used in clinical trials of sublingual immunotherapy for seasonal allergic rhinitis. Clin Exp Allergy. 2014;44(10):1228–39. doi:10.1111/cea.12331.CrossRefPubMed

• 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(7):854–67. doi:10.1111/all.12383. Describes the advantages and disadvantages of commonly used AIT clinical trial outcomes, and provides consensus recommendations for the definitions and scoring of outcomes CrossRefPubMed

Pfaar O, Kleine-Tebbe J, Hormann K, Klimek L. Allergen-specific immunotherapy: which outcome measures are useful in monitoring clinical trials? Immunol Allergy Clin N Am. 2011;31(2):289–309. x doi:10.1016/j.iac.2011.02.004.CrossRef

Rosner-Friese K, Kaul S, Vieths S, Pfaar O. Environmental exposure chambers in allergen immunotherapy trials: current status and clinical validation needs. J Allergy Clin Immunol. 2015;135(3):636–43. doi:10.1016/j.jaci.2014.10.045.CrossRefPubMed

Devillier P, Chassany O, Vicaut E, de Beaumont O, Robin B, Dreyfus JF, et al. The minimally important difference in the rhinoconjunctivitis total symptom score in grass-pollen-induced allergic rhinoconjunctivitis. Allergy. 2014;69(12):1689–95. doi:10.1111/all.12518.CrossRefPubMed

10.

Massie T. Statistical criteria for establishing safety and efficacy of allergenic products. Allergenics Products Advisory Committee, U.S. Food and Drug Administration. 2011. http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/AllergenicProductsAdvisoryCommittee/ucm263446.htm.

11.

• 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(5):617–23. doi:10.1111/all.12373. Provides evidence that pollen exposure can influence AIT efficacy measurements, which should be considered when interpreting AIT clinical trial outcomes CrossRefPubMedPubMedCentral

12.

Maloney J, Bernstein D, Nelson H, Creticos P, Hebert J, Noonan M, et al. Efficacy and safety of grass sublingual immunotherapy tablet, MK-7243: a large randomized controlled trial. Ann Allergy Asthma Immunol. 2014;112:146–53.e2.CrossRefPubMed

13.

Creticos P, Esch R, Couroux P, Gentile D, D'Angelo P, Whitlow B, et al. Randomized, double-blind, placebo-controlled trial of standardized ragweed sublingual-liquid immunotherapy for allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2013;133(3):751–8.CrossRefPubMed

14.

Cox LS, Casale TB, Nayak AS, Bernstein DI, Creticos PS, Ambroisine L, et al. Clinical efficacy of 300IR 5-grass pollen sublingual tablet in a US study: the importance of allergen-specific serum IgE. J Allergy Clin Immunol. 2012;130(6):1327–34.CrossRefPubMed

15.

Canonica GW, Cox L, Pawankar R, Baena-Cagnani CE, Blaiss M, Bonini S, et al. Sublingual immunotherapy: World Allergy Organization position paper 2013 update. The World Allergy Organization journal. 2014;7(1):6. doi:10.1186/1939-4551-7-6.CrossRefPubMedPubMedCentral

16.

Creticos PS, Maloney J, Bernstein DI, Casale T, Kaur A, Fisher R, et al. Randomized controlled trial of a ragweed allergy immunotherapy tablet in North American and European adults. J Allergy Clin Immunol. 2013;131(5):1342–9. e6 doi:10.1016/j.jaci.2013.03.019.CrossRefPubMed

17.

Pfaar O, Urry Z, Robinson DS, Sager A, Richards D, Hawrylowicz CM, et al. A randomized placebo-controlled trial of rush preseasonal depigmented polymerized grass pollen immunotherapy. Allergy. 2012;67(2):272–9. doi:10.1111/j.1398-9995.2011.02736.x.CrossRefPubMed

18.

Nelson HS, Nolte H, Creticos P, Maloney J, Wu J, Bernstein DI. Efficacy and safety of timothy grass allergy immunotherapy tablet treatment in North American adults. J Allergy Clin Immunol. 2011;127(1):72–80. e2CrossRefPubMed

19.

Guidance for industry: allergic rhinitis: clinical development programs for drug products. Rockville, MD: Food and Drug Administration 2000.

20.

Pfaar O, Gerth van Wijk R. Mite-allergic rhinitis: how to evaluate clinical efficacy in allergen-specific immunotherapy trials? Curr Treat Options Allergy. 2015;2(1):1–9. doi:10.1007/s40521-014-0040-y.

21.

Demoly P, Emminger W, Rehm D, Backer V, Tommerup L, Kleine-Tebbe J. Effective treatment of house dust mite-induced allergic rhinitis with 2 doses of the SQ HDM SLIT-tablet: results from a randomized double-blind, placebo-controlled phase III trial. J Allergy Clin Immunol. 2016;137(2):444–51.CrossRefPubMed

22.

Nolte H, Bernstein DI, Nelson HS, Kleine-Tebbe J, Sussman GL, Seitzberg D, et al. Efficacy of house dust mite SLIT-tablet in North American adolescents and adults in a randomized, placebo-controlled trial. J Allergy Clin Immunol. 2016;138(6):1631–8.CrossRefPubMed

23.

Durham SR, Creticos PS, Nelson HS, Li Z, Kaur A, Meltzer EO, et al. Treatment effect of sublingual immunotherapy tablets and pharmacotherapies for seasonal and perennial allergic rhinitis: pooled analyses. J Allergy Clin Immunol. 2016;138(4):1081–8.CrossRefPubMed

24.

Statistical principles for clinical trials: E9. International Conference on Harmonisation. 1998. http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html. Accessed 09 March 2017.

25.

United States code, 2006 Edition, Supplement 4, Title 21 - Food and Drugs. US. Government 2010.

26.

Regulation (EC) No 1901/2006 on medicinal products for paediatric use.: European Parliament and the Council of the European Union 2006.

27.

Dretzke J, Meadows A, Novielli N, Huissoon A, Fry-Smith A, Meads C. Subcutaneous and sublingual immunotherapy for seasonal allergic rhinitis: a systematic review and indirect comparison. J Allergy Clin Immunol. 2013;131(5):1361–6. doi:10.1016/j.jaci.2013.02.013.CrossRefPubMed

28.

Larenas-Linnemann D, Blaiss M, Van Bever HP, Compalati E, Baena-Cagnani CE. Pediatric sublingual immunotherapy efficacy: evidence analysis, 2009–2012. Ann Allergy Asthma Immunol. 2013;110(6):402–15. e9 doi:10.1016/j.anai.2013.02.017.CrossRefPubMed

29.

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(1):64–71. e4CrossRefPubMed

30.

Bufe A, Eberle P, Tholstrup B, Henmar H, Durham SR. Clinical efficacy and immunological response in children is similar to that of adults after the first treatment season with SQ-standardized grass allergy immunotherapy tablet in two randomized trials. Allergologie. 2013;36(5):238–45.CrossRef

31.

Lai X, Li J, Xiao X, Liu E, Zhang C, Wang H, et al. Specific IgG4 production during house dust mite immunotherapy among age, gender and allergic disease populations. Int Arch Allergy Immunol. 2013;160(1):37–46. doi:10.1159/000339239.CrossRefPubMed

32.

Jacobsen L, Wahn U, Bilo MB. Allergen-specific immunotherapy provides immediate, long-term and preventive clinical effects in children and adults: the effects of immunotherapy can be categorised by level of benefit -the centenary of allergen specific subcutaneous immunotherapy. Clin Transl Allergy. 2012;2:8.

33.

Akdis CA, Blesken T, Akdis M, Wuthrich B, Blaser K. Role of interleukin 10 in specific immunotherapy. J Clin Invest. 1998;102(1):98–106. doi:10.1172/JCI2250.CrossRefPubMedPubMedCentral

34.

Francis JN, Till SJ, Durham SR. Induction of IL-10+CD4+CD25+ T cells by grass pollen immunotherapy. J Allergy Clin Immunol. 2003;111(6):1255–61.CrossRefPubMed

35.

Jutel M, Akdis M, Budak F, Aebischer-Casaulta C, Wrzyszcz M, Blaser K, et al. IL-10 and TGF-beta cooperate in the regulatory T cell response to mucosal allergens in normal immunity and specific immunotherapy. Eur J Immunol. 2003;33(5):1205–14. doi:10.1002/eji.200322919.CrossRefPubMed

36.

Klossek JM, Annesi-Maesano I, Pribil C, Didier A. The burden associated with ocular symptoms in allergic rhinitis. Int Arch Allergy Immunol. 2012;158(4):411–7. doi:10.1159/000334286.CrossRefPubMed

37.

Bergmann KC, Demoly P, Worm M, Fokkens WJ, Carrillo T, Tabar AI, et al. Efficacy and safety of sublingual tablets of house dust mite allergen extracts in adults with allergic rhinitis. J Allergy Clin Immunol. 2014;133(6):1608–14.e6. doi:10.1016/j.jaci.2013.11.012.CrossRefPubMed

38.

Chang H, Han DH, Mo JH, Kim JW, Kim DY, Lee CH, et al. Early compliance and efficacy of sublingual immunotherapy in patients with allergic rhinitis for house dust mites. Clin Exp Otorhinolaryngol. 2009;2(3):136–40. doi:10.3342/ceo.2009.2.3.136.

39.

Busse WW, Morgan WJ, Taggart V, Togias A. Asthma outcomes workshop: overview. J Allergy Clin Immunol. 2012;129(3 Suppl):S1–8. doi:10.1016/j.jaci.2011.12.985.CrossRefPubMedPubMedCentral

40.

Reddel HK, Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW, et al. An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice. Am J Respir Crit Care Med. 2009;180(1):59–99. doi:10.1164/rccm.200801-060ST.CrossRefPubMed

41.

Cappella A, Durham SR. Allergen immunotherapy for allergic respiratory diseases. Human vaccines & immunotherapeutics. 2012;8(10):1499–512. doi:10.4161/hv.21629.CrossRef

42.

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(16):1715–25. doi:10.1001/jama.2016.3964.CrossRefPubMed

43.

Bernstein DI, Epstein T. Systemic reactions to subcutaneous allergen immunotherapy. Immunol Allergy Clin N Am. 2011;31(2):241–9. viii-ix doi:10.1016/j.iac.2011.02.007.CrossRef

44.

Calderon MA, Simons FE, Malling HJ, Lockey RF, Moingeon P, Demoly P. Sublingual allergen immunotherapy: mode of action and its relationship with the safety profile. Allergy. 2012;67(3):302–11. doi:10.1111/j.1398-9995.2011.02761.x.CrossRefPubMed

45.

Maloney J, Durham S, Skoner D, Dahl R, Bufe A, Bernstein DI et al. Safety of sublingual immunotherapy Timothy grass tablet in subjects with allergic rhinitis with or without conjunctivitis and history of asthma. Allergy. 2015;70(3):302-9.

46.

Ragwitek. Short ragweed pollen allergen extract tablet for sublingual use. Whitehouse Station, NJ, USA: Merck Sharp & Dohme Corp.; 2014.

47.

Grastek. Timothy grass pollen allergen extract tablet for sublingual use. Whitehouse Station, NJ, USA: Merck Sharp & Dohme Corp.; 2014.

48.

Oralair. Sweet vernal, Orchard, Perennial Rye, Timothy, and Kentucky Blue Grass mixed pollens allergen extract tablet for sublingual use. Antony, France: Stallergenes S.A.; 2014.

49.

•• Cox L, Larenas-Linnemann D, Lockey RF, Passalacqua G. Speaking the same language: the World Allergy Organization Subcutaneous Immunotherapy Systemic Reaction Grading System. J Allergy Clin Immunol. 2010;125(3):569–74. 74 e1-74 e7 doi:10.1016/j.jaci.2009.10.060. Provides the first standardized definition of a systemic allergic reaction in response to allergy immunotherapy

50.

•• Passalacqua G, Baena-Cagnani CE, Bousquet J, Canonica GW, Casale TB, Cox L, et al. Grading local side effects of sublingual immunotherapy for respiratory allergy: speaking the same language. J Allergy Clin Immunol. 2013;132(1):93–8. doi:10.1016/j.jaci.2013.03.039. Provides the first proposed system for grading the severity of local adverse events associated with SLIT CrossRefPubMed

51.

•• Cox LS, Sanchez-Borges M, Lockey RF. World Allergy Organization Systemic Allergic Reaction Grading System: is a modification needed? J Allergy Clin Immunol: In Practice. 2017;5(1):58–62.e5. doi:10.1016/j.jaip.2016.11.009. Provides an update on the definition of systemic allergic reactions for allergy immunotherapy clarifying that local AEs and gastrointestinal symptoms associated with SLIT should be not be considered evidence of a systemic allergic reaction unless other systemic manifestations also occur

52.

Structure and content of clinical study reports: E3. International Conference on Harmonisation. 1995. http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/structure-and-content-of-clinical-study-reports.html. Accessed 09 March 2017.

53.

Nolte H, Casale TB, Lockey RF, Fogh BS, Kaur A, Lu S, et al. Epinephrine use in clinical trials of sublingual immunotherapy tablets. J Allergy Clin Immunol: In Practice. 2017;5(1):84–9.CrossRef

54.

Wernicke JF, Faries D, Milton D, Weyrauch K. Detecting treatment emergent adverse events in clinical trials: a comparison of spontaneously reported and solicited collection methods. Drug Saf. 2005;28(11):1057–63.CrossRefPubMed

55.

Portnoy JM, Van Osdol T, Williams PB. Evidence-based strategies for treatment of allergic rhinitis. Curr Allergy Asthma Rep. 2004;4(6):439–46.CrossRefPubMed

56.

Malling HJ. Immunotherapy as an effective tool in allergy treatment. Allergy. 1998;53(5):461–72.CrossRefPubMed

57.

Malling HJ. Sublingual immunotherapy: efficacy—methodology and outcome of clinical trials. Allergy. 2006;61(Suppl 81):24–8. doi:10.1111/j.1398-9995.2006.01158.x.CrossRefPubMed

Title: Allergen Immunotherapy Clinical Trial Outcomes and Design: Working Toward Harmonization of Methods and Principles
Authors: Harold S. Nelson
Moises A. Calderon
David I. Bernstein
Thomas B. Casale
Stephen R. Durham
Jens S. Andersen
Robert Esch
Linda S. Cox
Hendrik Nolte
Publication date: 01-03-2017
Publisher: Springer US
Published in: Current Allergy and Asthma Reports / Issue 3/2017
Print ISSN: 1529-7322
Electronic ISSN: 1534-6315
DOI: https://doi.org/10.1007/s11882-017-0687-0

At a glance: The STEP trials

Springer Medicine

Allergen Immunotherapy Clinical Trial Outcomes and Design: Working Toward Harmonization of Methods and Principles

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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