Available studies
The available studies on EPIT for FA are summarized in Table
2. All the studies were performed with whole extract.
Table 2
Summary of the epicutaneous immunotherapy (EPIT) for food allergy clinical trials
Proof of concept trial: Dupont et al. [ 21] | 19 children | Cow’s milk | 1 mg | 48 | Local AE: TG: 4 subjects PG: 2 subjects Systemic AE: TG: 24 times PG: 8 times | OFC: increase in cumulative tolerate dose from baseline (< 10 ml) after 3 months | None |
Safety and tolerability trial: Jones et al. [ 22] | 100 mixed populationa | Peanuts | 20 μg 100 μg 250 μg 500 μg | 24 48 | TEAE: TG: 52.5% PG: 45% L-TEAEs: TG: 84% PG: 64% | | |
Efficacy, safety and dose-ranging trial: Sampson et al. [ 23] | 221 mixed populationa | Peanuts | 50 μg 100 μg 250 μg | 24 | TEAE: 50 μg: 96.2% 100 μg: 94.6% 250 μg: 96.4% PG: 48.2% 1 moderate anaphylaxis | OFC after 12 months (1000 mg or tenfold increase)b | Overall response rate 250 μg-placebo: 50–25% (p = 0.01) 6–11 year stratum 250 μg placebo: 53.6–19.4% (p = 0.008) |
171 mixed population | Peanuts | 50 μg 100 μg 250 μg | 24 | TEAEs: 93% in year 1 of extension 62% in year 2 of extension | OFC after 12 and 24 months | Overall response rate 12 months: 59.7% 24 months: 64.5% |
Efficacy, safety and immune-response trial: Jones et al. [ 24] | 74 mixed populationc | Peanuts | 100 μg 250 μg | 24 | Patch site AE: 100 μg: 79.8% 250 μg: 79.8% PG: 14.4% Non-patch site AE: 100 μg: 0.2% 250 μg: 0.1% PG: 0.2% 1 systemic hives | OFC after 52 weeks (5044 mg or tenfold increase)d | 100 μg-placebo: 45.8% (p = 0.005) 250 μg-placebo: 48% (p = 0.003) |
There is a particular interest in the development of new food allergy immunotherapy routes for the lack of successful desensitization procedures in this field [
3]. Recently, four double-blind, placebo-controlled EPIT trials have been performed using the Viaskin patch system on intact skin. The evaluation of the safety and efficacy by EPIT was performed by an oral food challenge (OFC) to define the threshold of reaction to the allergen at baseline and after treatment, according to the EAACI guidelines [
3].
The first trial [
21] tested EPIT safety and tolerability in 19 children with a history of cow milk allergy. The cumulative dose of skimmed cow’s milk powder (36 mg) was administered for 3 months. The results of this study showed an increase in the cumulative tolerated dose (CTD) in the treated group, although the comparison with placebo did not reach statistical significance. The results of the epicutaneous delivery system were that it was well-tolerated and without severe adverse events. Local reactions were more frequent, but not significantly more frequent, in the active group. Only gastrointestinal side effects were significantly more frequent in the active group compared to the placebo group (16/470 vs. 0/316, p < 0.001).
A second trial [
22] was performed to assess the clinical safety and tolerability of EPIT in peanut allergies. One hundred patients aged from 6 to 50 years with peanut allergies were randomized to four dosing cohorts, which received 20 μg, 100 μg, 250 μg, or 500 μg of peanut protein. The patches were applied for 24 or 48 h, and the entire treatment was 2 weeks long. In this study, EPIT by Viaskin resulted in being safe and well-tolerated in all of the ages. No significant difference in systemic adverse events versus the placebo group were reported. Only three subjects in the treated group dropped out. In addition, in the 24 h regimen, fewer local adverse events were reported compared with the 48 h regimen. There were no differences in the safety profiles of the different ages or in the cohorts with different peanut allergy severities. The IgE levels and SPT did not change at the end of the study. The efficacy was not evaluated.
In the third double-blind study [
23], 221 people with peanut allergies, aged from 6 to 55 years, received different doses of allergen (50 μg, 100 μg or 250 μg) using Viaskin patches, which were applied daily for 12 months. For the patients < 12 years of age, it was applied to the upper central back area, and for those 12 years of age and older, it was applied to the inside of the upper arm. The food challenge-eliciting dose at baseline was equal to or inferior to 300 mg of peanut protein. The primary endpoints were the tolerance of 1000 mg or more at 52 weeks or a tenfold increase in the food challenge dose compared to baseline. At 12 months, a significant difference in the response rates was observed only between the high dose group and the placebo group (50% vs. 25%, p = 0.01). Additionally, the patient subgroup of age < 12 years treated with the same dose (250 mg) showed a more significant response rate compared to that of the placebo group (53.6% vs. 19.4%, p = 0.008). The median cumulative dose increased from 30 mg to 400 mg of peanut protein. The increase in specific IgE in the first 3–6 months was followed by a decrease at 12 months and by a fivefold increase in peanut IgG4 in all of the active treated groups. Mild or moderate local skin reactions were the most frequently occurring adverse event. Systemic severe adverse events were not reported. Adverse reactions were recorded in 48.2% of patients in the placebo group, while they were two times more frequent in the treated group (94.6–96.4%). After the first year, in an open-label extension period, 171 subjects were enrolled and randomized to initially receive patches with 50 μg, 100 μg or 250 μg of peanut, and after 6 months, all of them were switched to a 250 μg treatment. Food challenge, which was performed in 171/221 of the patients, showed an increase in the response rate from 59.7% at month 12 to 64.5% at month 24 (in patients of age < 12 years, it was from 63.3 to 68.4%). The mean cumulative reactive dose (CRD) increased from 44 to 440 mg, 1440 mg and 1440 mg after 1, 2 and 3 years, respectively, and 61% of the children treated with 250 µg achieved a CRD > 1000 mg. A reduction of adverse events to 62%, compared to 96% in the first year, was observed.
A last double-blind, placebo-controlled, multicentre trial [
24] was performed in 74 people with peanut allergy aged 4–25 years. The treated group received 100 μg or 250 μg of peanut for a period of 52 weeks. In this study, the eligible dose of the double-blind, placebo-controlled challenge was less than or equal to 1044 mg, and the primary endpoint was a 5044 mg or a tenfold increase from baseline at 52 weeks. A significant dose increase was observed in 45.8% and 48% of the patients treated with the 100 µg and 250 µg doses, respectively (p = 0.005 and p = 0.003), which is compared to 12% in the placebo group. As for safety, local and systemic reactions occurred more frequently in the treated group, but this was without a statistically significant difference from the placebo group.
Critical analysis of the results
In the cow milk pilot study by Dupon et al. [
21], a suggestive increase in tolerance in ten treated children was reported, but this increase was not significant compared to the placebo. The low number of patients and low cumulative dose (36 mg) given for only 3 months may be responsible for this nonsignificant result. Local adverse events were more frequent in patients treated with cow milk, but the difference compared to those of the placebo was not significant. Systemic adverse events were not reported.
The first EPIT peanut study [
22] confirmed the safety data of the previous study on cow milk allergies. This study was performed in a non-homogeneous population of children and adults using three different doses in a short period of 2 weeks. It showed that adverse events were more frequent with the high doses, but the differences were not significant.
The second peanut multinational double-blind study [
23] was performed in a large population. The patients were randomized into four groups, and a significant difference in the response rate versus the placebo was shown in only the 250 µg treated group and was more evident in patients aged < 12 years, who achieved a > tenfold increase in the eliciting dose. As reported by the authors, these significant results are affected by some limitations: the small number of patients included when the division into the subgroups was performed, which evidences a possible relation with age; the primary endpoint not being stringent enough in the definition of clinical improvement; the exclusion of patients with severe anaphylaxis; and the different cutaneous sites of patch application, which might condition the allergen diffusion into the epidermidis. Additionally, the age, sex and race of the patients varied [
20].
Despite these limits, in the following 2 years of this open study, the response rate increased to 63.3% after 12 months in < 12 years old patients and to 68.4% after 24 months, showing the progressive increase in efficacy, which is correlated with the duration of treatment and is associated with a significant reduction of adverse events. In the last EPIT study [
24], in accordance with the previous trial, the authors underlined that EPIT is safe in children and that its efficacy is more evident in younger people. A decrease in specific IgE and a significant increase in IgG4 supports these encouraging clinical results. In the last two studies [
23,
24], local adverse events were more frequently shown in the 250 µg treated patients, but this difference compared to the placebo was not significant. Systemic adverse events were rare, and a high rate of adherence was observed.