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

ACKNOWLEDG EMENTS This work was partly funded by the National Research University Project, Office of Higher Education Commission (NRU59003HR), the Center of Excellence on Medical Biotechnology (CEMB), S&T Postgraduate Education and Research Development Office (PERDO), SB6000303), Chulalongkorn Academic Advancement (2nd Century ProjectCUAASC), and a 90th Anniversary of Chulalongkorn University Scholarship.


S U PP O RTI N G I N FO R M ATI O N
Additional supporting information may be found in the online version of the article at the publisher's website. 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).  (Figure 2A).
The shift in cumED was not significant (p=0.10, Wilcoxon signrank 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.

K E Y WO R DS
allergy, eliciting dose, food challenge, lowest observed adverse effect level, peanut

ACK N OWLED G EM ENTS
We thank our study participants, who were recruited through the  & Figure 1a-d). At baseline, CRS was controlled in 0%, partly controlled in 4.2%, and uncontrolled in 95.8%. At 24w and 48w, respectively, 75.7% and 93.8% were partly controlled, and 24.3% and 6.2% were uncontrolled; "controlled CRS" was unachievable with biologicals considered rescue treatment (Table 1 & Table S1).

CO N FLI C T O F I NTE R E S T
Rescue treatment otherwise was applied in two cases (oral corticosteroids and no antibiotics). Four patients ceased treatment, due to non-responsiveness (1); subjective insufficient control (1); persistent hypereosinophilia (1); and possible treatment emergent