{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T09:56:22Z","timestamp":1790934982144,"version":"4.1.0"},"reference-count":23,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:00Z","timestamp":1790899200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Inmunotek S.L., Spain"},{"id":[{"id":"https:\/\/ror.org\/01e2spe61","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Clin. Med.","JCM"],"abstract":"<jats:p>Background\/Objectives: Placebo responses can complicate the interpretation of allergen immunotherapy (AIT) trials because symptom- and medication-based outcomes may be influenced by the trial context in addition to treatment-specific effects. Injection-free comparison cohorts are rarely available in conventional double-blind, placebo-controlled AIT trials. We therefore conducted an exploratory post hoc cross-study comparison of clinical outcomes in two placebo-injection cohorts and an injection-free cohort of birch pollen-allergic participants. Methods: Data from three prospective clinical studies evaluating the mannan-conjugated birch pollen allergoid EP-088-T502\u2014T502-SIT-020, T502-SIT-045, and T502-SIT-068\u2014were assembled for this cross-study comparison. Placebo-injection cohorts from studies T502-SIT-020 and T502-SIT-045 were compared with the injection-free cohort from study T502-SIT-068. Clinical outcomes included the Combined Symptom and Medication Score (CSMS), daily Symptom Score (dSS), and daily Medication Score (dMS). Results: The primary peak-period analysis included 60, 93, and 160 participants from T502-SIT-020, T502-SIT-045, and T502-SIT-068, respectively. During the site-specific 14-day peak birch pollen periods, median CSMS was 2.14 in the injection-free cohort compared with 1.34 and 1.07 in the T502-SIT-020 and T502-SIT-045 placebo-injection cohorts, respectively. These values corresponded descriptively to approximately 37% and 50% lower cohort medians, respectively, relative to the injection-free cohort. Median dSS, which was defined consistently across the three source studies, was 1.22 in the injection-free cohort compared with 0.78 and 0.70 in the two placebo-injection cohorts. Median dMS was 0.93 compared with 0.39 and 0.36, respectively. The same between-cohort pattern was observed in the secondary fixed 1\u201330 April analysis. Conclusions: Both placebo-injection cohorts showed lower CSMS and dSS values than the injection-free cohort. Because the cohorts were non-concurrent and derived from separate studies, the observed differences do not establish a causal effect of placebo injections.<\/jats:p>","DOI":"10.3390\/jcm15197637","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T09:10:48Z","timestamp":1790932248000},"page":"7637","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical Outcomes in Placebo-Injection and Injection-Free Cohorts in Birch Pollen Allergy: An Exploratory Cross-Study Comparison"],"prefix":"10.3390","volume":"15","author":[{"given":"Esther","family":"Raskopf","sequence":"first","affiliation":[{"name":"ClinCompetence Cologne GmbH, 50933 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen Fierro","family":"Ballester","sequence":"additional","affiliation":[{"name":"Institute of Medical Statistics and Computational Biology, Faculty of Medicine, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hacer","family":"Sahin","sequence":"additional","affiliation":[{"name":"ClinCompetence Cologne GmbH, 50933 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadine","family":"Katzke","sequence":"additional","affiliation":[{"name":"ClinCompetence Cologne GmbH, 50933 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9323-6887","authenticated-orcid":false,"given":"Christian","family":"Neuhof","sequence":"additional","affiliation":[{"name":"ClinCompetence Cologne GmbH, 50933 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Day","sequence":"additional","affiliation":[{"name":"ClinCompetence Cologne GmbH, 50933 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5306-5412","authenticated-orcid":false,"given":"Anna","family":"Rybachuk","sequence":"additional","affiliation":[{"name":"ClinCompetence Cologne GmbH, 50933 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silke","family":"Allekotte","sequence":"additional","affiliation":[{"name":"ClinCompetence Cologne GmbH, 50933 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2330-3963","authenticated-orcid":false,"given":"Miguel","family":"Casanovas","sequence":"additional","affiliation":[{"name":"Inmunotek S.L., 28805 Alcal\u00e1 de Henares, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0134-5321","authenticated-orcid":false,"given":"Jos\u00e9 Luis","family":"Subiza","sequence":"additional","affiliation":[{"name":"Inmunotek S.L., 28805 Alcal\u00e1 de Henares, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5205-4105","authenticated-orcid":false,"given":"Sandra","family":"del Pozo","sequence":"additional","affiliation":[{"name":"Inmunotek S.L., 28805 Alcal\u00e1 de Henares, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,10,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1111\/all.14331","article-title":"Placebo effects in allergen immunotherapy-An EAACI Task Force Position Paper","volume":"76","author":"Pfaar","year":"2021","journal-title":"Allergy"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1146\/annurev.psych.59.113006.095941","article-title":"A comprehensive review of the placebo effect: Recent advances and current thought","volume":"59","author":"Price","year":"2008","journal-title":"Annu. Rev. Psychol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1186\/2045-7022-3-42","article-title":"The placebo effect in allergen-specific immunotherapy trials","volume":"3","author":"Narkus","year":"2013","journal-title":"Clin. Transl. Allergy"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1111\/all.12383","article-title":"Recommendations for the standardization of clinical outcomes used in allergen immunotherapy trials for allergic rhinoconjunctivitis: An EAACI Position Paper","volume":"69","author":"Pfaar","year":"2014","journal-title":"Allergy"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1111\/all.13758","article-title":"Birch pollen allergy in Europe","volume":"74","author":"Biedermann","year":"2019","journal-title":"Allergy"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1111\/j.1398-9995.2007.01393.x","article-title":"Allergenic pollen and pollen allergy in Europe","volume":"62","author":"Cecchi","year":"2007","journal-title":"Allergy"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"S147","DOI":"10.1067\/mai.2001.118891","article-title":"Allergic rhinitis and its impact on asthma","volume":"108","author":"Bousquet","year":"2001","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1016\/j.jaci.2010.06.047","article-title":"Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines: 2010 revision","volume":"126","author":"Brozek","year":"2010","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1111\/j.1398-9995.2007.01620.x","article-title":"Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen)","volume":"63","author":"Bousquet","year":"2008","journal-title":"Allergy"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1111\/all.13317","article-title":"EAACI Guidelines on Allergen Immunotherapy: Allergic rhinoconjunctivitis","volume":"73","author":"Roberts","year":"2018","journal-title":"Allergy"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1111\/all.15910","article-title":"A randomized, double-blind, placebo-controlled trial with mannan-conjugated birch pollen allergoids","volume":"79","author":"Zeyen","year":"2024","journal-title":"Allergy"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1111\/all.16387","article-title":"Short-course subcutaneous treatment with birch pollen allergoids greatly improves symptom and medication scores in birch allergy","volume":"80","author":"Raskopf","year":"2025","journal-title":"Allergy"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1111\/j.1365-2222.1991.tb00807.x","article-title":"Development and testing of a new measure of health status for clinical trials in rhinoconjunctivitis","volume":"21","author":"Juniper","year":"1991","journal-title":"Clin. Exp. Allergy"},{"key":"ref_14","first-page":"72","article-title":"Quality of life in allergic rhinitis: Standardisation of a self assessment questionnaire","volume":"47","author":"Neumann","year":"1992","journal-title":"Allergy"},{"key":"ref_15","unstructured":"M\u00f6sges, R., and Schl\u00f6ndorff, G. (1993). Gesundheitsbezogene Lebensqualit\u00e4t: Methodik und Profil bei der saisonalen und perennialen Rhinokonjunktivitis. Symposium Topische Therapie der Allergischen Rhinitis: Referate und Vortr\u00e4ge der Aachener Gespr\u00e4che zur Allergologie 1993, Biermann Verlag GmbH."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"World Medical Association (2013). World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. JAMA, 310, 2191\u20132194.","DOI":"10.1001\/jama.2013.281053"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"620","DOI":"10.5114\/ada.2018.77614","article-title":"Evaluation of the placebo effect in the trials of allergen immunotherapy effectiveness: Meta-analysis of randomized and placebo-controlled trials","volume":"35","author":"Abramowicz","year":"2018","journal-title":"Postep. Dermatol. Alergol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1097\/ACI.0000000000001110","article-title":"Patients\u2019 perspective on allergen immunotherapy for respiratory allergy","volume":"25","author":"Barbaglia","year":"2025","journal-title":"Curr. Opin. Allergy Clin. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Li, Y., Xiong, Y., Fan, W., Wang, K., Yu, Q., Si, L., van der Smagt, P., Tang, J., and Chen, N. (2024). Sequential model for predicting patient adherence in subcutaneous immunotherapy for allergic rhinitis. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1371504"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1016\/j.neuron.2014.10.023","article-title":"Placebo effects: From the neurobiological paradigm to translational implications","volume":"84","author":"Benedetti","year":"2014","journal-title":"Neuron"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Niazi, S.K. (2024). Placebo Effects: Neurological Mechanisms Inducing Physiological, Organic, and Belief Responses-A Prospective Analysis. Healthcare, 12.","DOI":"10.3390\/healthcare12222314"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.jaip.2014.01.003","article-title":"The special challenge of nonadherence with sublingual immunotherapy","volume":"2","author":"Bender","year":"2014","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.drudis.2015.07.010","article-title":"Allergy immunotherapy: The future of allergy treatment","volume":"21","author":"Larsen","year":"2016","journal-title":"Drug Discov. 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