Placebo effects in allergen immunotherapy-An EAACI Task Force Position Paper.

Oliver Pfaar ,Carsten Bindslev‐Jensen ,Carmen Vidal ,Glenis Scadding ,Peter S Creticos ,Stephen R Durham ,Bettina Wedi ,Susanne Kaul ,Winfried Rief ,Antonella Muraro ,Gunter J Sturm ,Lars Jacobsen ,Ludger Klimek ,Jean Bousquet ,Peter Hellings ,Roy Gerth Van Wijk ,Marek Jutel ,Ronald Van Ree ,Manfred Schedlowski ,Ioana Agache ,Nikolaos G Papadopoulos ,Karl‐Christian Bergmann ,Mohamed H Shamji ,Stefan Vieths ,Jörg Kleine‐Tebbe ,Philippe Devillier ,Anthony J Frew

doi:10.1111/all.14331

Abstract

The placebo (Latin "I will please") effect commonly occurs in clinical trials. The psychological and physiological factors associated with patients' expectations about a treatment's positive and negative effects have yet to be well characterized, although a functional prefrontal cortex and intense bidirectional communication between the central nervous system and the immune system appear to be prerequisites for a placebo effect. The use of placebo raises certain ethical issues, especially if patients in a placebo group are denied an effective treatment for a long period of time. The placebo effect appears to be relatively large (up to 77%, relative to pretreatment scores) in controlled clinical trials of allergen immunotherapy (AIT), such as the pivotal, double-blind, placebo-controlled (DBPC) randomized clinical trials currently required by regulatory authorities worldwide. The European Academy of Allergy and Clinical Immunology (EAACI) therefore initiated a Task Force, in order to better understand the placebo effect in AIT and its specific role in comorbidities, blinding issues, adherence, measurement time points, variability and the natural course of the disease. In this Position Paper, the EAACI Task Force highlights several important topics regarding the placebo effect in AIT such as a) regulatory aspects, b) neuroimmunological and psychological mechanisms, c) placebo effect sizes in AIT trials, d) methodological limitations in AIT trial design and e) potential solutions in future AIT trial design. In conclusion, this Position Paper aims to examine the methodological problem of placebo in AIT from different aspects and also to highlight unmet needs and possible solutions for future trials.

Highlights

The placebo effect is a common phenomenon in medicine [1]
699 Almost 20 years ago, Frew & Smith emphasized the need for large DBPC randomized clinical trials (RCTs) with 700 carefully balanced groups of patients with moderate-to-severe disease and well701 defined sensitivity to the target allergen
A proportion of correct guesses substantially greater than 50% may suggest that blinding was imperfect but might reflect the patients’ experiences in the trial: a good outcome or a major adverse event will tend to be attributed to a verum, and a poor outcome will tend to be attributed to a placebo [101]

Summary

15 Article type : EAACI Position Paper

Placebo effects in allergen immunotherapy – an EAACI Task Force Position Paper. 5 MACVIA-France, Montpellier, France, and University Hospital Montpellier, Montpellier, France 6 Division of Allergy & Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; and Creticos Research Group, Crownsville, MD, USA 7 Department of Airway Diseases, Exhalomics, Hôpital Foch, Université Paris-Saclay, Suresnes, France 8 Allergy and Clinical Immunology, National Heart and Lung Institute, Imperial College London, London, UK 9 Department of Otorhinolaryngology, University Hospitals of Leuven, Leuven, Belgium Department of Otorhinolaryngology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Department of Neuroscience, University of Ghent, Ghent, Belgium Paul-Ehrlich-Institut, Federal Institute for Vaccines and Biomedicines, Langen, Germany Allergy & Asthma Center Westend, Outpatient Clinic and Clinical Research Center, Berlin, Germany Center for Rhinology and Allergology, Wiesbaden, Germany ALC, Allergy Learning and Consulting, Copenhagen, Denmark Department of Clinical Immunology, Wroclaw Medical University, Wroclaw, Poland All-Med Medical Research Institute, Wroclaw, Poland 52 18 Food Allergy Referral Centre, Padua University Hospital Padua , Italy Division of Infection, Immunity & Respiratory Medicine, University of Manchester, Manchester, UK Allergy Department, 2nd Pediatric Clinic, University of Athens, Athens, Greece Department of Clinical Psychology and Psychotherapy, Philipps-University of Marburg, Marburg, Germany.

98 CSMS combined symptom medication score

144 Introduction

Methods

821 Conclusion

Findings

935 References