May 2, 2023

Placebo-controlled clinical trials are the gold standard in drug development, in part to ensure that the efficacy of a new therapy exceeds the placebo response in the indication being studied. The placebo response is a measured improvement in clinical signs or symptoms that occurs in patients receiving a sham (or “dummy”) treatment. The placebo response is a complex psychological, biological and sociological phenomenon that confounds clinical data analysis, particularly for subjective patient-reported outcomes. The placebo response is widely known to compromise evaluation of pain endpoints and has been suggested to contribute to as much as ~2/3 of the measured treatment effect in pain from various etiologies1, contributing to the high rate of Phase II and III clinical trial failure in this indication2. The placebo response is, however, not limited to pain trials. In fact, the understanding of the impact of this phenomenon in a wide variety of therapeutic areas is growing steadily – from rheumatoid arthritis and osteoarthritis to Parkinson’s disease and irritable bowel disease. This article is part of a series that will examine the impact of the placebo response in drug development in areas beyond pain.

Immunology is the study of how the immune system functions to protect the body from infection3. This indication encompasses many aspects of the immune response, including how the system recognizes and responds to allergens like pollen, house dust mite, food and others. Allergies are a result of an abnormal immune response to otherwise harmless substances in the environment, in which the immune system overreacts to what it would normally ignore4

Allergies are a very common health condition that affects millions of people across all ages, races, genders and socioeconomic statuses. In the United States, up to 25% of the population suffer from allergic conditions (such as rhinitis, urticaria, conjunctivitis, asthma, and food allergies); and approximately 40 million people suffer from allergic rhinitis, many of which remain underdiagnosed and undertreated5. These conditions can have a significant impact on an individual’s quality of life, from as mild as a running nose to as extreme as life-threatening anaphylaxis.

Allergies are characterized by variable clinical responses, involving a complex interplay of environmental factors, patient immune system health, age, personal sensitivities to allergens, inconsistent exposures, and the subjective nature of symptom assessment6,7. This variability introduces challenges in allergen immunotherapy (AIT) clinical trials, which is why international guidelines recommend double-blind, placebo-controlled trials (DBPC)7

In a Position Paper, the European Academy of Allergy and Clinical Immunology (EAACI) Task Force investigates placebo effects in participants as described in systematic reviews or press releases7. A 2018 sublingual allergen immunotherapy (SLIT) study, in which the allergen extract is administered under the patient’s tongue, saw an average placebo effect of 68% in adults. In the same review, the largest placebo effect was 77% in a subcutaneous allergen immunotherapy (SCIT) trial, in which the allergen extract is injected into the patient’s skin.  

Several factors have been identified related to the placebo response in allergy immunotherapy, including neuroimmune and psychological mechanisms, study design and others. A house dust mite allergy study concluded that placebo responses in type 1 allergy, the most common type of allergic reaction, seem to be induced by cognitive factors, like patient expectations8. Another study detected a stronger placebo effect in SCIT trials (maximum 40.5%) compared to SLIT (1.3% or less)6. These differences in magnitude of placebo effects may be explained by the treatment method, or the ingredients of the SCIT placebos that are required to meet regulatory standards or maintain binding. Traditional design features, including cross-over designs, a higher number of arms, and a higher randomization ratio of the active drug, as well as the use of patient reported outcomes and efforts to improve medication adherence, are associated with increased placebo response9

The power of the placebo in AIT clinical trials is twofold: first, presenting an opportunity for expectation-based interventions, and second, making it difficult to assess the true effectiveness and safety of the treatment. A 2021 study hypothesized that a placebo’s immune modulation would be proportional to endogenous opioid activity in certain brain regions relating to immune processes10. While this emerging evidence suggests placebo-responsive neurotransmitter systems can regulate immune function, more research is required. 

Thus, our focus is on minimizing the impact of the placebo effect in AIT trials to deliver better therapies to patients that reduce drug-dose while maintaining therapeutic efficacy11. At Cognivia, we have developed a solution, Placebell©™, which generates a prediction of each patient’s placebo responsiveness following a sophisticated evaluation of patient characteristics. Applying Placebell©™ in a clinical trial statistical analysis leads to increased study power, improved p-values and a reduced risk of trial failure. Placebell©™ has been successfully applied in areas like pain, osteoarthritis and Parkinson’s disease and can be applied to virtually any disease, especially those with subjective assessments and variable factors, like allergies and broader immunology indication like Crohn’s disease. To learn more about how Placebell©™ could be applied in immunology, contact us.


1. Häuser W, Bartram-Wunn E, Bartram C, Reinecke H, Tölle T. Systematic review: Placebo response in drug trials of fibromyalgia syndrome and painful peripheral diabetic neuropathy – Magnitude and patient-related predictors. Pain. 2011;152(8):1709-1717. doi:10.1016/j.pain.2011.01.050

2. Dumitrescu TP, McCune J, Schmith V. Is Placebo Response Responsible for Many Phase III Failures? Clin Pharmacol Ther. 2019;106(6):1151-1154. doi:10.1002/cpt.1632

3. Marshall JS, Warrington R, Watson W, Kim HL. An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol. 2018 Sep 12;14(Suppl 2):49. doi: 10.1186/s13223-018-0278-1. PMID: 30263032; PMCID: PMC6156898.

4. Simon D. Recent Advances in Clinical Allergy and Immunology 2019. Int Arch Allergy Immunol. 2019;180(4):291-305. doi: 10.1159/000504364. Epub 2019 Nov 6. PMID: 31694018.

5. Emanuel IA, Parker MJ, Traub O. Undertreatment of allergy: exploring the utility of sublingual immunotherapy. Otolaryngol Head Neck Surg. 2009 May;140(5):615-21. doi: 10.1016/j.otohns.2009.01.023. PMID: 19393398.

6 Narkus A, Lehnigk U, Haefner D, Klinger R, Pfaar O, Worm M. The placebo effect in allergen-specific immunotherapy trials. Clin Transl Allergy. 2013 Dec 21;3(1):42. doi: 10.1186/2045-7022-3-42. PMID: 24360060; PMCID: PMC3878370.

7. Pfaar O, Agache I, Bergmann KC, et al. Placebo effects in allergen immunotherapy—An EAACI Task Force Position Paper. Allergy. 2021;76:629–647.

8. Vits S, Cesko E, Benson S, Rueckert A, Hillen U, et al. (2013) Cognitive Factors Mediate Placebo Responses in Patients with House Dust Mite Allergy. PLoS ONE 8(11): e79576. doi:10.1371/journal.pone.0079576

9. Jairath V, Zou GY, Parker CE, MacDonald JK, Mosli MH, AlAmeel T, Al Beshir M, Almadi MA, Al-Taweel T, Atkinson NSS, Biswas S, Chapman T, Dulai PS, Glaire MA, Hoekman DR, Kherad O, Koutsoumpas A, Minas E, Restellini S, Samaan M, Khanna R, Levesque BG, D’Haens G, Travis S, Sandborn WJ, Feagan BG. Placebo response and remission rates in randomised trials of induction and maintenance therapy for Crohn’s disease. Cochrane Database of Systematic Reviews 2016, Issue 7. Art. No.: CD012288. DOI:10.1002/14651858.CD012288.

10. Prossin A, Koch A, Campbell P, Laumet G, Stohler CS, Dantzer R, Zubieta JK. Effects of placebo administration on immune mechanisms and relationships with central endogenous opioid neurotransmission. Mol Psychiatry. 2022 Feb;27(2):831-839. doi: 10.1038/s41380-021-01365-x. Epub 2021 Oct 29. PMID: 34716408; PMCID: PMC9054677.

11. Hadamitzky M, Sondermann W, Benson S, Schedlowski M. Placebo Effects in the Immune System. Int Rev Neurobiol. 2018;138:39-59. doi: 10.1016/bs.irn.2018.01.001. Epub 2018 Mar 2. PMID: 29681334.


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