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Does 2 years of grass pollen sublingual immunotherapy reduce symptoms after nasal allergen challenge at 3-year follow-up (1 year after discontinuation of treatment)?
In this randomized clinical trial of 106 adults, 2 years of treatment with sublingual immunotherapy, compared with placebo, did not significantly reduce total nasal symptom scores after challenge at 3 years.
Among patients with moderate to severe seasonal allergic rhinitis, 2 years of sublingual grass pollen immunotherapy was not significantly different than placebo in improving the nasal response to allergen challenge at 3-year follow-up.
Sublingual immunotherapy and subcutaneous immunotherapy are effective in seasonal allergic rhinitis. Three years of continuous treatment with subcutaneous immunotherapy and sublingual immunotherapy has been shown to improve symptoms for at least 2 years following discontinuation of treatment.
To assess whether 2 years of treatment with grass pollen sublingual immunotherapy, compared with placebo, provides improved nasal response to allergen challenge at 3-year follow-up.
Design, Setting, and Participants
A randomized double-blind, placebo-controlled, 3–parallel-group study performed in a single academic center, Imperial College London, of adult patients with moderate to severe seasonal allergic rhinitis (interfering with usual daily activities or sleep). First enrollment was March 2011, last follow-up was February 2015.
Thirty-six participants received 2 years of sublingual immunotherapy (daily tablets containing 15 µg of major allergen Phleum p 5 and monthly placebo injections), 36 received subcutaneous immunotherapy (monthly injections containing 20 µg of Phleum p 5 and daily placebo tablets) and 34 received matched double-placebo. Nasal allergen challenge was performed before treatment, at 1 and 2 years of treatment, and at 3 years (1 year after treatment discontinuation).
Main Outcomes and Measures
Total nasal symptom scores (TNSS; range; 0 [best] to 12 [worst]) were recorded between 0 and 10 hours after challenge. The minimum clinically important difference for change in TNSS within an individual is 1.08. The primary outcome was TNSS comparing sublingual immunotherapy vs placebo at year 3. Subcutaneous immunotherapy was included as a positive control. The study was not powered to compare sublingual immunotherapy with subcutaneous immunotherapy.
Among 106 randomized participants (mean age, 33.5 years; 34 women [32.1%]), 92 completed the study at 3 years. In the intent-to-treat population, mean TNSS score for the sublingual immunotherapy group was 6.36 (95% CI, 5.76 to 6.96) at pretreatment and 4.73 (95% CI, 3.97 to 5.48) at 3 years, and for the placebo group, the score was 6.06 (95% CI, 5.23 to 6.88) at pretreatment and 4.81 (95% CI, 3.97 to 5.65) at 3 years. The between-group difference (adjusted for baseline) was −0.18 (95% CI, −1.25 to 0.90; [P = .75]).
Conclusions and Relevance
Among patients with moderate to severe seasonal allergic rhinitis, 2 years of sublingual grass pollen immunotherapy was not significantly different from placebo in improving the nasal response to allergen challenge at 3-year follow-up.
clinicaltrials.gov Identifier: NCT01335139; EudraCT Number: 2010-023536-16
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Corresponding Author: Stephen R. Durham, MD, Allergy and Clinical Immunology, Section of Inflammation, Repair, and Development, National Heart and Lung Institute, Imperial College London, Dovehouse St, London, UK SW3 6LY (firstname.lastname@example.org).
Author Contributions: Drs Durham and Togias had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Scadding, Calderon-Zapata, and Shamji contributed equally to the work.
Concept and design: Calderon-Zapata, Bahnson, Laurienzo Panza, Togias, Durham.
Acquisition, analysis, or interpretation of data: Scadding, Calderon-Zapata, Shamji, Eifan, Penagos, Dumitru, Sever, Bahnson, Lawson, Harris, Plough, Qin, Lim, Togias, Durham.
Drafting of the manuscript: Calderon-Zapata, Eifan, Penagos, Dumitru, Sever, Bahnson, Plough, Qin, Durham.
Critical revision of the manuscript for important intellectual content: Scadding, Calderon-Zapata, Shamji, Eifan, Dumitru, Sever, Bahnson, Lawson, Harris, Plough, Laurienzo Panza, Lim, Togias, Durham.
Statistical analysis: Sever, Bahnson, Lawson, Qin, Lim.
Administrative, technical, or material support: Scadding, Calderon-Zapata, Shamji, Eifan, Penagos, Dumitru, Sever, Bahnson, Plough, Laurienzo Panza.Other - mechanistic assessments: Harris.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Calderon reports receipt of personal fees for advisory board participation from ALK and Hal Allergy and for lectures from ALK, Merck, and Stallergenes-Greer. Dr Penagos reports receipt of grants from the US Department of Health and Human Services (HHS), the National Institutes of Health (NIH), the National Institute of Allergy and Infectious Diseases (NIAID), and the Immune Tolerance Network (ITN); nonfinancial support from ALK-Abello A/S Hørsholm during the conduct of the study; and personal fees for the development of educational presentations from ALK-Abello and Stallergenes outside the submitted work. Dr Dumitru reports receipt of grants to cover conference attendance from Allergy Therapeutics and Stallergenes outside the submitted work. Dr Durham reports receipt of grants from the ITN and NIAID, and nonfinancial support from ALK during the conduct of the study; and grants from Regeneron, Biotech Tools, ALK, personal fees from Anergis, Circassia, Biomay, Merck, Allergy Therapeutics, ALK, and med Update GmbH outside the submitted work. No other disclosures were reported.
GRASS Study Contributors: Andrea Goldstone, RN, MS, Fotini Rozakeas, RN, MS, and Rachel Yan, RN, MS, Imperial College Nursing Staff; Natalia Klimowska-Nassar, MA, and Mimi Poon, MSc, Imperial College Study Management and Administration; Delica Kit Cheung, MSc, Constance Ito, MSc, Janice Layhadi, PhD, Elisabeth Lemm, BSc, Ellen Macfarlane, BSc, Orla MacMahon, BSc, Tomokasu Matsuoka, MD, PhD, Rebecca Parkin, BSc, and Amy Switzer, MSc, Imperial College Laboratory Projects; Adam Asare, PhD (past), Eduard Chani, PhD, Judith Evind, Deborah Phippard PhD (past), Peter Sayre MD, PhD, Maureen Sharkey, MA (past), and Don Whitehouse, MS, ITN staff; Steven Adah, PhD (past), Theresa Allio, PhD, Christine Czarniecki, PhD, and Jui Shah, PhD (past), Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases (DAIT-NIAID) Staff; and Travis Mason, BS, Ann Nguyen, BSN, Shayala Gibbs, MPH, and Spencer Childress, BS, Rho Federal Systems Staff.
Funding/Support: The trial was conducted by the ITN with financial support from the DAIT-NIAID, National Institutes of Health (NIH) under award numbers NO1-AI-15416, UM1AI109565, and UM2AI117870; the following DAIT-NIAID–funded groups: Statistical and Clinical Coordinating Centers (contract HHSN272200800029C and grant UM2AI117870), Clinical Site Monitoring Center (contract HHSN272201200004C), and Regulatory Management Center (contract HHSN272201200002C); ALK-Abello A/S Horsholm, Denmark supplied Alutard SQ Grass Pollen, and Grazax, and matching placebos used for the GRASS clinical trial to DAIT-NIAID without charge. Dr Durham served as the sponsor of the Medicines and Healthcare Products Regulatory Agency Clinical Trial Application.
Role of the Funder/Sponsor: The sponsor for the study was the ITN under a contract from the NIAID. The ITN clinical trial physician and administrative team and ITN scientists liaised closely concerning all aspects of the trial with the principal investigator (protocol chair) and the site team at Imperial College London. Similarly, the medical monitor from NIAID and the regulatory team at NIAID worked closely with ITN and the protocol chair and study team concerning all aspects of the study. ALK Denmark supplied the allergy vaccines, matched placebos, and allergen extracts for skin testing and nasal allergen provocation for the study free of charge. ALK had no input to the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript or decision to submit the manuscript for publication.
Disclaimer: The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Additional Contributions: We thank the patients for their participation in this study.
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