No apparent impact of incremental dosing on eliciting dose at double‐blind, placebo‐controlled peanut challenge

Oral food challenges (OFC) are the gold standard diagnostic for food allergy, but not without limitation. Administering incremental doses every 15-30min differs from a real-world exposure where ingestion occurs at a single episode. Blumchen et al. reported a median time to objective symptoms of 55min (range 5-210min)1; if doses are given every 15min, this could significantly overestimate the reaction threshold.1, 2 This could also occur due to incremental dosing causing transient desensitization.3 With OFC increasingly used to determine starting doses for oral immunotherapy and guide dietary avoidance,4 we assessed how clinical thresholds and symptoms at OFC compare to an ingestion more representative of real-world consumption. Seventeen peanut-allergic adults (median age 24 years, range 18–40) underwent initial double-blind, placebo-controlled food challenge (DBPCFC) to peanut, as part of a clinical trial (TRACE Peanut study; ClinicalTrials.gov Identifier: NCT02665793). Detailed methods are described elsewhere.5 Doses were given every 30 minutes (using a water-continuous dessert matrix) according to the following schedule: 3μg, 30μg, 300μg, 3mg, 30mg, 100mg, 300mg and 1000mg of peanut protein (or placebo), until stopping criteria (adapted from PRACTALL consensus criteria) were met.5 Participants returned for two further DBPCFC, at 8–12 week intervals later. The first was an ‘abbreviated’ DBPCFC using the same matrix, with the first active dose equivalent to the maximum tolerated dose at baseline DBPCFC (see Figure 1 and Table S1); this was done as a safety measure. Subjects allocated (by computer randomization) to placebo: had two initial placebo doses, prior to active doses (Figure 1). The third DBPCFC used the same abbreviated protocol, but with the appropriate dose given as peanut butter (Kraft Foods) mixed into a soya-based spread (Wowbutter) and eaten as a small 3cm sandwich (Kingsmill 50/50 bread). For all challenges, the dosing interval was 30 minutes, although this could be doubled if symptoms were progressing. Triangle testing demonstrated the suitability of Wowbutter for blinding, and prior tolerance to this was demonstrated in all participants. The study was approved by the NHS Human Research Authority (reference 15/LO/0286), and written informed consent from all participants. At baseline DBPCFC, the median cumulative eliciting dose (cumED) was 133mg (IQR 83.3–433.3mg) peanut protein; 2/17 patients had anaphylaxis (WAO 2020 criteria). Median cumED at abbreviated challenge was 133mg (IQR 33.3–433.3mg) (Figure 2A). The shift in cumED was not significant (p=0.10, Wilcoxon sign-rank test), and there were no major differences in clinical symptoms observed (Fig S1), with 4/17 having anaphylaxis. Fourteen subjects underwent the third DBPCFC using peanut butter sandwiches (one had too low a cumED for the appropriate dose to be accurately measured, and two declined). Median cumED at this challenge was 433mg (IQR 33.3–1433.3mg), representing a non-significant half-log increase in cumED (p>0.05; Figure 2B); 2/14 had anaphylaxis. In a systematic review and meta-analysis of peanut-DBPCFC, 69% of peanut-allergic individuals show a shift in cumED over time; in 56%, this is limited to a half-log difference, equivalent to 1 dosing interval with a PRACTALL-based semi-log dosing regimen.6 Indeed, Dua et al reported a fall of around 0.5-log (equivalent to 1 dosing increment) at subsequent OFC in these same participants.5 Therefore, the non-significant shift in cumED with an abbreviated challenge protocol is entirely consistent with the inherent ‘noise’ in determining cumED at OFC. We undertook a post hoc power calculation; our sample size would have been sufficient to detect a 1-log difference in cumED with at least 90% power, that is greater than that due to the inherent intraindividual variability. In summary, we did not find a significant difference in either cumED or symptoms following DBPCFC with a 30-minutely incremental dosing protocol, compared to an abbreviated challenge which is more representative of a normal consumption episode. In addition, there was no significant difference in cumED between baseline DBPCFC and a more ‘real-world’ exposure to peanut butter in a sandwich. Therefore, using threshold data from OFC (with 30-minute dosing intervals) is a valid approach to individual allergen risk management. Importantly, the impact of cofactors was minimized due to the nature of the study design. In reality, thresholds will vary due to cofactors among other reasons,6 so appropriate caution should be exercised in extrapolating challenge thresholds into clinical advice at an individual patient level. We thank our study participants, who were recruited through the TRACE Peanut study (funded by the UK Food Standards Agency); we are grateful to the study investigators (Chief investigator A Clark) and the Food Standards Agency for their support; and to the members of our Data Safety Monitoring Board: Professor Stephen Till, Dr Hazel Gowland and Dr Mich Erlewyn-Lajeunesse. We are grateful to Emily Wilson, Louise Cross and staff at the Respiratory Clinical Research Facility at the Royal Brompton Hospital for their clinical support. All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare grants from UK Medical Research Council, NIHR/Imperial BRC and UK Food Standards Agency for the submitted work. MRG is now employed by Laboratorios Leti, this occurred following data lock and completion of study analyses. SRD reports grants from the Immune Tolerance Network, National Institute of Allergy and Infectious Diseases, ALK-Abelló, Regeneron, and Biotech Tools outside the submitted work; personal fees from Anergis, Circassia, Biomay, Merck, Allergy Therapeutics, Med Update GmbH and Food Standards Agency. RJB reports personal fees from Prota Therapeutics, DBV Technologies, Cochrane Collaboration, John Wiley & Sons on behalf of Clinical and Experimental Allergy, personal fees from giving expert testimony, outside the submitted work. ENCM reports grants from the UK Biological and Biotechnological Sciences Research Council, DBV Technologies, Reacta Biotech, the Medical Research Council, the European Union, and the UK Food Standards Agency and has patents pending to Reacta Biotech Ltd (PCT/GB2016/051637 and PCT/GB2016/053829). PJT reports grants from UK Food Standards Agency, JM Charitable Foundation and End Allergies Together, outside the submitted work; personal fees from UK Food Standards Agency, DBV Technologies, Aimmune Therapeutics, Allergenis and ILSI Europe outside the submitted work. All other authors declare no competing interests. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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