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. 2021 Sep 23;12:742732. doi: 10.3389/fimmu.2021.742732

Table 3.

Overview of clinical studies performed for peanut and tree nut allergy grouped according to the route of administration (OIT, SLIT, EPIT, rectal application).

Allergen Number of participant (age) Study design Protocol summary Clinical outcome Serological outcome Reported side effects Clinical trial number Ref.
OIT
Peanut: peanut flour (50% protein); for additional analysis peanut proteins were extracted from peanut flour, Ara h 2 was purified and protein concentrations were determined by bicinchoninic acid assay 29 subjects (1-16 years) completed the 3 phases of the study and OFC Open-label Initial dose escalation day starting at 0.1 mg peanut protein. Dose was doubled every 30 minutes up to 50 mg. Build-up phase started with highest tolerated dose during initial day escalation. During build-up phase daily ingestion of peanut protein with biweekly dose increases (by 25 mg) until 300 mg reached. For patients that stopped initial escalation dosing below 50 mg, doses were doubled every 2 weeks until 50 mg reached, followed by increases of 25 mg. After reaching a daily tolerated dose of 300 mg peanut protein, dose was maintained until OFC. After OFC, doses were increased until a daily dose of 1800 mg peanut protein was reached, provided that peanut-specific IgE was > 2 kUA/L after 1 year on maintenance dose. Evaluation of subjects every 4 months during maintenance phase (up to total duration of 36 months). OFC up to 3.9 g peanut protein or until objective symptoms appeared.

  • 27 of 29 (93%) reached total peanut dose of 3.9 g in OFC after 36 months without showing more than mild symptoms and were thus considered desensitized. The other 2 stopped OFC after 2.1 g peanut protein.

  • 7 subjects underwent open OFC to peanut protein after 13-22 months of maintenance dosing; 22 underwent OFC after 4-7 months

  • Within 4 months, basophil reactivity at peanut concentration of 10 µg/ml was significantly reduced.

  • Within 3 months, peanut-specific IgE levels increased from an initial median concentration of 85.4 kUA/L to 249.0 kUA/L. For all time points after 18 months (up to 33 months) peanut-specific IgE levels were decreased.

  • An increase of specific IgG levels was observed starting at 3 months of treatment and remained high until 24 months, before it returned to baseline by 33 months.

  • Peanut-specific IgG4 levels reached significance at 3 months and increased until the end of the study.

  • Several inflammatory cytokines/chemokines (IL-1β, IL-5, TNF-α, MIP-1β, G-CSF and GM-CSF) were increased over time (following peanut stimulation).

  • At 6 and 12 months FoxP3 T cells increased 1.5-fold in peanut-stimulated cells before returning to baseline by 20 months.

 Symptoms were reported after 46% of build-up doses.
During maintenance phase, all subjects experienced adverse events at some point, which were mostly mild and affected most commonly the upper respiratory tract and the skin. Two of the participants received epinephrine once during home dosing.		 NCT01074840 (249)
Peanut: whole crushed roasted peanuts; 4 g whole peanut = 1 g peanut protein; dose of individual major allergens not determined 23 initial subjects (3-14 years); 14 finished study protocol (until final DBPCFC) Open-label, randomized Participants underwent DBPCFC with increasing doses of whole peanut (0.03-2 g), equaling 0.0075-0.5 g peanut protein, which were given every 30 minutes (on 2 different days). In absence of objective reaction, patients were challenged on another day with 4 g whole peanut. The day after positive DBPCFC followed a rushed escalation protocol for 1 week during which increasing doses of whole peanuts were given 2-4x a day. The staring dose was approx. 1/100 of the reaction eliciting dose during DBPCFC. In those starting with more than 6 mg whole peanuts, doses were doubled. If starting point was 80 mg, doses were increased by 20%. Subjects that reached at least 500 mg whole peanut during the rushed protocol, continued with a maintenance phase of 8 weeks. Subjects that did not reach a dose of 500 mg peanut continued with individual long-term build-up protocol (0-20 months) during which the individual tolerated dose (24-400 mg peanut) was consumed daily, with dose increases every 2-4 weeks until 500 mg was reached, followed by a maintenance phase of 8 weeks. After 2 weeks of peanut avoidance, final DBPCFC was performed.

  • 5 patients reached 500 mg peanut dose during the rushed protocol.

  • Overall, 14 of 22 patients reached a daily maintenance dose of at least 500 mg whole peanut after a median of 7 months and underwent DBPCFC.

  • At final DBPCFC, a median of 1 g peanut was tolerated. Three patients tolerated 4 g whole peanut. Median tolerated dose before OIT was 0.19 g peanut.

  • In the 14 patients that finished the study protocol, a reduction in the secretion of IL-5, IL-4, and IL-2 at the end of the OIT treatment (before avoidance) was observed and seen to be stable in most, but not all of the patients after avoidance phase.

  • An increase in peanut-specific IgG4 levels was seen in all patients after OIT. However, a drop in the peanut-specific IgG4 level was detected after 2 weeks of avoidance.

  • Patients that reached 500 mg peanut had lower median peanut-specific IgE levels (9.1 kUA/L) that those that tolerated less (212 kUA/L).

 Of 6137 total OIT doses, 2.6% were associated with mild to moderate adverse effects. 4 patients stopped OIT due to adverse reactions. All of them had reported mild to moderate asthma before start of the study. During the rush protocol, objective allergic symptoms were associated with 25 of 317 total OIT doses. No clinical trial number found; study was approved by the local ethics committee (250)
Peanut: Peanut protein extracted from defatted peanut four (50% protein); intact allergen content in soluble extract of roasted peanut flour ∼8% Ara h 1 and ∼7%
Ara h 2		 Initially 28 (1-16 years) participants; 3 withdrew; 16 remained in peanut OIT group, 9 in placebo group Randomized, placebo-controlled Initial day escalation phase starting with 0.1 mg peanut protein (or placebo). Doses were doubled every 30 minutes up to 6 mg. Build-up phase started with highest tolerated dose in initial escalation. During home-dosing, subjects ingested daily doses and attended build-up visits every two weeks for approximately 44 weeks. Doses were increased by 50-100% until 75 mg and 25-33% until daily maintenance dose of 4000 mg was reached. The maintenance dose was consumed daily for one month, followed by an OFC at week 48.

  • 16 of originally 19 participants (84%) in the OIT group reached a maintenance dose of 4000 mg and tolerated a maximum cumulative dose of 5000 mg peanut protein in OFC compared to a median cumulative dose of 280 mg peanut protein in the placebo group.

  • In the peanut OIT group, median peanut-specific IgE increased from baseline level of 104 kUA/L to 308 kUA/L by two months, but was not significantly different to baseline at time of challenge. No difference in the IgE levels were observed in the placebo group.

  • At all time points, peanut OIT subjects showed increase in peanut-specific IgG levels, including IgG4, which were not increased in the placebo group.

  • IL-5 and IL-13 levels significantly decreased in the peanut OIT group from baseline to 9 months and OFC, while there was no change in the placebo group.

  • In the peanut OIT group, an increase in the ratio of FoxP3hi: FoxP3intermediate

  • CD4+CD25+ Treg cells at time of challenge was observed compared to the baseline. This did not apply for subjects in the placebo group.

 During initial dose-escalation, 9 of 19 subjects in the peanut OIT group had clinically-relevant adverse effects and required antihistamine treatment. Of those, 2 additionally required treatment with epinephrine. No clinically-relevant symptoms were reported in the placebo group. Of 407 build-up doses, 1.2% caused clinically-relevant symptoms in the peanut OIT group. During home dosing, none of the peanut OIT subjects required epinephrine. In the placebo group, one subject received epinephrine after reporting symptoms. One patient in the peanut OIT group experienced mild-moderate symptoms after completing OFC and was given antihistamine treatment. In the placebo group, 8 subjects experienced side effects during OFC, 3 required epinephrine treatment. No clinical trial number found; study approved by each institution’s Institutional Review Board (251)
Peanut: peanut flour (50% protein); dose of individual major allergens not determined 22 subjects (4-18 years) Interventional, open-label Gradual build-up phase (56-264 days) with dose increases every 2 weeks up to 800 mg peanut protein per day. After reaching the highest tolerated dose, subjects continued with maintenance for 30 weeks during which dose was ingested on a daily basis. Patients underwent DBPCFCs after 6 weeks of maintenance and at the end of the study (week 30).

  • Primary endpoint was defined by rate of those passing challenge after approx. 6 months.

  • Of 22 subjects, 19 tolerated build-up to a maximum daily dose of 800 mg peanut protein and successfully continued maintenance.

  • After 6 weeks of maintenance, 19 subjects underwent OFC to 2.6 g peanut protein, 18 ingested the full dose. 12 of 19 (63%) had no symptoms during challenge, 7 (37%) showed mild to moderate symptoms.

  • After 30 weeks, 18 subjects underwent final challenge with 6.6 g peanut protein. 14 of 18 subjects tolerated challenge without any symptoms.

  • Median peanut-specific IgE levels increased initially, before decreasing until week 30 (8.35 kUA/L) compared to the baseline (29.7 kUA/L).

  • Median peanut-specific IgE level was significantly lower at baseline in the participants that passed final OFC compared to those that did not.

 At some point during build-up and maintenance phase, 19 of 22 (86%) subjects experienced adverse reactions, most commonly affecting the respiratory or gastrointestinal tract. NCT01259804 (252)
Peanut: peanut flour (50% protein); dose of individual major allergens not determined 99 participants (7-16 years) were randomized: 49 in peanut OIT group (10 did not have DBPCFC after OIT), 50 in the peanut avoiding control group (46 included in primary analysis) Randomized, controlled (crossover) Initial gradual up-dosing phase with biweekly increases until a target protein dose of 800 mg/day was reached. This was followed by a maintenance period with ingestion of the highest tolerated dose on a daily basis to complete 26 weeks of OIT.
During the 26-week long first phase, subjects received peanut OIT or avoided peanut (control group).
During the second phase (crossover), subjects in the control group received peanut OIT, followed by DBPCFC.
Toleration of a cumulative dose of 1400 mg peanut protein during DBPCFC was considered desensitization.

  • Primary endpoint was defined as desensitization. In the first phase, 24 of 39 (62%) participants in the active OIT group compared to 0 of 46 (0%) in the control group tolerated a cumulative dose of 1400 mg peanut protein in OFC.

  • 84% in the active group tolerated a daily dose of 800 mg peanut protein (secondary outcome).

  • In the second phase (control group after OIT), 91% tolerated daily dose of 800 mg protein and 54% tolerated 1400 mg in OFC.

  • Increase in peanut-specific IgE was measured after 24 weeks in the OIT group.

 Adverse reactions were reported to the same extend in both groups during treatment but were mostly mild. Oral itching occurred in 6.3% of all doses. 0.41% of doses in 22% of subjects caused wheezing which was treated either with antihistamines alone or, in one patient, additionally with epinephrine on two occasions. Cutaneous symptoms were reported after 0.16% of doses. ISRCTN62416244 (253)
Peanut: peanut protein from partially defatted peanut flour (50% protein); see (249) Initially 39 subjects (1-16 years) included; 24 completed the protocol Open-label End-of-study results of pilot trial by (249). OIT protocol by (249), which was described above. Extended treatment with a maximum of 4000 mg peanut protein per day for up to 5 years. At the end of the treatment, subjects underwent two DBPCFCs to 5 g peanut protein, 4 weeks apart. During these 4 weeks OIT was not continued in order to evaluate sustained unresponsiveness.

  • 12 of 24 (50%) subjects showed treatment success by reaching 5000 mg peanut protein in the second OFC, 4 weeks after stopping OIT, and achieved sustained unresponsiveness (primary endpoint).

  • In the first OFC, which was performed after a maximum of 5 years of OIT with 4000 mg peanut protein per day, all the subjects successfully ingested 5 g of peanut protein.

  • Patients that passed final OFC had lower median IgE levels specific for peanut allergens Ara h 1 and Ara h 2, than those that did not achieve sustained unresponsiveness.

  • In all OIT subjects, a reduction to below baseline IgE levels specific for major peanut allergens (Ara h 1, 2, 3) was observed.

  • Peanut-specific IgG levels, including IgG4, increased in all participants. However, IgG4 production was not associated with the clinical outcome of the study.

  • Ara h 2-specific IgE levels were the best predictor of sustained unresponsiveness, followed by peanut-specific IgE levels.

 6 of the initial 39 subjects withdrew due to allergic side effects (not further specified). no clinical trial number found; ethics approval obtained through the Institutional Review Boards at Duke University
Medical Center and University of Arkansas for Medical Sciences		 (254)
Peanut: peanut powder used for OIT (protein content not given); dose of individual major allergens not determined; oat flour used for placebo OIT 21 subjects (7-13 years); 10 in active SLIT/placebo OIT group and 11 in active OIT/placebo SLIT group;
16 completed protocol (7 in active OIT group)		 Randomized, double-blinded, placebo-controlled Initial dose escalation starting with 0.1 mg peanut protein up to 6 mg. Dose increases every 1-2 weeks until a maintenance dose of 2000 mg/day reached. Doses were ingested on a daily basis for 16 weeks. The maintenance dose was taken daily for 12 months. OFC with 10 g peanut powder was performed at 6 and 12 months of maintenance. In those, that completed OFC without more than mild symptoms discontinued treatment for 4 weeks and were then rechallenged, all of the others proceeded with unblinding phase for additional 6 months. Subjects that reacted during OFC at 12 months to less than 5 g continued treatment with SLIT added. Subsequently, subjects underwent OFC with 10 g peanut protein. Those that tolerated the challenge discontinued treatment for 4 weeks and were then rechallenged.

  • Primary endpoint, defined as a toleration of at least 10-fold increase in OFC threshold after 12 months of treatment, was achieved by 7 of originally 11 subjects in active OIT group (considered desensitized).

  • In the original active OIT group, 1 subject passed OFC at 12 months to 10 g peanut protein and was rechallenged after 4 weeks of treatment discontinuation. 3 extended the prior treatment for 6 months and another 3 continued OIT with SLIT added, before being rechallenged.

  • 3 of originally 11 subjects in the active OIT group achieved sustained unresponsiveness.

  • In SLIT and OIT group peanut-specific IgE levels increases initially but decreased over the time of the treatment. In the OIT group median peanut-specific IgE was 68 and 53 kUA/L after 6 and 12 months compared to 169 kUA/L at the baseline.

  • Peanut-specific IgG4 increased in both groups during treatment. In the OIT group IgG4 medial levels increased from 1.3 mgA/L at baseline to 76 mgA/L after 12 months.

 2 subjects in the active OIT group discontinued treatment due to adverse reactions (one with gastrointestinal symptoms, one with systemic reaction). 43% of OIT doses were associated with adverse reactions. All subjects in the OIT group had symptoms with dosing. Epinephrine was required by one subject in the active OIT/additional active SLIT group during maintenance. 4 subjects in the OIT group required 5 doses of epinephrine. Overall, adverse reactions were more common in the OIT group. NCT01084174 (255)
Peanut: peanut flour (50% protein); dose of individual major allergens not determined 11 subjects (4-16 years) Open-label Entry dose chosen based on threshold dose of reactivity. Dosing was increased approx. every 2 weeks during build-up phase until a maintenance dose of 2000 mg peanut protein was reached. The median time to maintenance was 41 weeks. After approximately 4 months of maintenance, 5000 mg DBPCFC was performed. Participants received 2000 mg peanut protein maintenance dose per day after DBPCFC.

  • 9 of 11 subjects achieved maintenance dosing of 2000 mg peanut protein per day and passed 5000 mg DBPCFC, with 6 of 9 (66%) not showing symptoms during challenge.

  • Significant changes of peanut-specific IgE, IgG4 and IgE/IgG4 6 weeks after therapy.

 264 of 3265 doses (7.9%) were associated with reported side effects, which were mostly mild. In 2 cases severe reactions were reported. No clinical trial number found; study was approved by the University of Texas Southwestern Institutional Review Board (256)
Peanut: peanut flour (50% protein) together with Lactobacillus rhamnosus CGMCC 1.3724; dose of individual major allergens not determined; placebo group received maltodextrin Initially 62 subjects (1-10 years); 6 withdrew from study; 56 reached end of trial: 28 in OIT group, 28 in placebo control group Randomized, double-blind, placebo-controlled Peanut OIT in combination with probiotic (PPOIT) was given. Initial 1-day rush dose escalation phase starting with 0.1 mg peanut protein up to a final dose of 12 mg. Build-up phase (approx. 8 months) with biweekly dose increases until daily tolerated dose of 2000 mg peanut protein reached, followed by maintenance for 12 months. If maintenance dose reached in more than 12 months, extension of total duration to ensure 6 months of maintenance. DBPCFC performed at last day of treatment (confirmation of desensitization) and repeated challenge 2-5 weeks after stopping treatment (confirmation of sustained unresponsiveness) in those that passed the challenge.

  • Possible sustained unresponsiveness was achieved in 23 of 28 (82.1%) PPOIT subjects and 1 of 28 (3.6%) in the placebo group (primary endpoint).

  • Desensitization was achieved in 26 of 29 (89.7%) PPOIT-treated and 2 of 28 (7.1%) placebo-treated subjects.

  • After treatment, an overall reduction in peanut-specific IgE levels compared to the baseline (median, −4.45 kUA/L) was seen in the PPOIT-treated group together with an increase in peanut-specific IgG4 (median, 3.24 mgA/L). This did not apply for the placebo group.

 At least 1 severe adverse reaction was reported in 45.2% in the PPOIT group and 32.3% subjects in the placebo group. Total number of severe events was greater in PPOIT group than placebo group.
Overall, 6 treatment-related severe adverse events occurred in 3 patients in the PPOIT group, and 4 adverse reactions occurred in 4 placebo-treated patients.		 ACTRN12608000594325 (257)
Peanut: peanut margarine made from roasted defatted peanut flour (50% protein); dose of individual major allergens not determined 60 subjects (6-18 years): 39 active OIT, 21 controls that avoided peanuts Interventional Patients ingested daily doses of peanut protein starting with 0.1 mg and dose escalations every 1-2 weeks. Build-up phase (approx. 8 months) until maintenance daily dose of 800 mg peanut protein (4 peanuts) was reached. DBPCFC was performed 1 month after reaching maintenance dose. Afterwards, subjects ingested 3-7 weekly doses of 4 raw or roasted peanuts. Patients that failed challenge continued with tolerated daily dose. Median follow-up period was 30 months.

  • 33 of 39 (85%) OIT-treated patients reached daily maintenance dose (800 mg peanut protein) in a median of 269 days.

  • 26 patients (67% in intention-to-treat analysis) passed challenge with 1255 mg peanut protein (5 g peanuts) (primary endpoint).

  • None of the 21 controls showed desensitization.

  • Median follow-up duration was 30 months. During the follow-up phase the median weekly peanut protein consumption was 5600 mg.

  • OIT had no significant effect on peanut-specific IgE to Ara h 1, 2, 3, 8, or 9.

  • Specific IgG4 levels to peanut, Ara h 1, 2 and 3 increased significantly during the treatment. No difference was observed in the avoidance group.

  • In 29 subjects that continued OIT (1-year follow-up) peanut-specific IgE levels to major peanut allergens (Ara h 1, 2, 3) decreased significantly.

 30 of 39 (77%) OIT subjects reported adverse symptoms during build-up. 16 of 39 (41%) needed additional antihistamines, 15 of 39 (38%) received prednisolone and 1 of 39 (2.6%) used epinephrine autoinjector. NCT01502878 (258)
Peanut: peanut flour (50% protein), for low dose mixed with oat flour; dose of individual major allergens not determined 37 subjects (9-36 months) eligible for study (5 withdrew); 154 standard-care controls Randomized, double-blind, controlled Initial dose escalation. Buildup-phase for 42 weeks until maintenance dose reached. Patients received either low- or high-dose early OIT (maintenance dose 300 mg or 3000 mg peanut protein/day) and underwent 2 final DBPCFCs after a maintenance phase of up to 36 months. Unresponsiveness 4 weeks after stopping OIT (4-SU) was defined by toleration of 5 g peanut protein (cumulative) during DBPCFC.

  • subjects underwent first DBPCFC to 5 g peanut, which two failed. The others repeated challenge after 4 weeks of peanut avoidance, which was completed by 29 patients. Thus, 29 of 37 (78%) achieved 4-SU (primary endpoint): 17/20 (85%) in low-dose, 12/17 (71%) in high-dose group. 4-SU was achieved over a median of 29 months.

  • 30 of 37 (81%) subjects achieved desensitization by the end of the treatment (intention-to-treat analysis): 17/20 (85%) in low-dose and 13/17 (76%) in high-dose group

  • Over the time of the study, median peanut-specific IgE level declined in OIT treated subjects (1.6 kUA/L), compared to the baseline (14.4 kUA/L), while there was an increase in control subjects (57.4 kUA/L compared to 21.9 kUA/L at baseline).

  • Treatment success correlated with lower peanut-specific IgE and peanut-specific IgE/total IgE ratio at baseline.

 Of the initial 37 eligible study participants, 3 withdrew due to treatment-related adverse reactions. Overall, 95% of the participants were affected by adverse events which occurred more frequently during the build-up phase. Most adverse events were mild (85%), 15% were considered moderate and no severe reaction was reported. NCT00932828 (259)
Peanut: AR101 peanut powder capsules containing 0.5-100 mg peanut protein; relative potency of Ara h 1, 2, and 6 determined to ensure content uniformity together with determination of additional allergen molecules such as Ara h 3 and Ara h 8;
oat flour containing capsules for placebo group		 55 subjects (4-26 years): 29 AR101 treated, 26 in placebo group Randomized, double-blind, placebo-controlled During the initial dose escalation day, doses were increased from 0.5 mg to a maximum of 6 mg. OIT subjects received daily AR101 or placebo with dose increases every 2 weeks to a final daily dose of 300 mg (20-34 weeks). Patients that tolerated daily dose of 300 mg for 2 consecutive weeks were eligible for final DBPCFC.

  • The primary endpoint, defined as the rate of subjects that completed final DBPCFC to a cumulative dose of at least 443 mg peanut protein (cumulative), was achieved by 23 of 29 (79%) in the AR101 group (Intention-to-treat population) and 5 of 26 (19%) in the placebo group.

  • 18 of 29 (62%) in the AR101 group tolerated 1043 mg (cumulative) during DBPCFC compared to 0% in the placebo group.

  • In the AR101 group a significant increase in peanut-specific IgG4 levels was observed while almost no difference was seen in the placebo group.

  • No statistically significant difference in peanut-specific IgE levels was seen between both groups during the treatment.

 28/29 subjects (96.6%) in the AR101 group and 22/26 (84.6%) in the placebo group experienced at least 1 adverse event.
Of the 23 AR101 subjects that passed 443 mg challenge, 3 (13%) had mild symptoms. In the placebo group, 10 subjects (38%) experienced severe symptoms during DBPCFC, 2 occurred at cumulative dose of 43 mg. At cumulative dose of 1043 mg 61% of AR101 subjects and none of the placebo subjects were symptom free. During final DBPCFC 11/26 (42%) placebo subjects and 2/23 (9%) AR1010 subjects received epinephrine.		 NCT01987817 (260)
Peanut: AR101 peanut powder in capsules (doses of 0.5-100 mg) or foil-laminate sachets (300 mg); quantities administered reported as mg of peanut protein; for further information see (260) 496 subjects (4-17 years), 372 in active treatment group, 124 in placebo group Randomized, double-blind, placebo-controlled Initial dose-escalation day with doses from 0.5 to 6 mg.
Doses were ingested on a daily basis and were increased every 2 weeks starting at 3 mg, until 300 mg peanut protein were tolerated. Maintenance dose was ingested for 24 weeks. At the end of the study (approx. 12 months) subjects underwent final DBPCFC.

  • Primary endpoint was proportion of subjects that responded to treatment and were able to ingest a single dose of at least 600 mg peanut protein during final DBPCFC without dose-limiting effects. This was achieved by 250 of 372 (67.2%) participants in the active treatment group, compared to 5 of 124 (4.0%) in the placebo group.

  • 76.6% and 50.3% in the active OIT group tolerated 300 mg and 1000 mg peanut protein dose during DBPCFC. In comparison, 8.1% and 2.4% in the placebo group tolerated 300 mg and 1000 mg dose, respectively.

  • Peanut-specific IgG4 levels increased during treatment in the active OIT group.

  • There was no significant between-group difference in regard to peanut-specific IgE levels from baseline to the trial endpoint.

 During final DBPCFC, 25% in the OIT group and 59% in the placebo group experienced moderate symptoms. Severe symptoms were reported in 5% in the active group compared to 11% in the placebo group. In the active OIT group, 10% of the participants received epinephrine during final food challenge compared to 53% in the placebo group. During the intervention period (excluding final OFC), 98.7% in the OIT group and 95.2% in the placebo group had an adverse event. In the active OIT group, 34.7% and 59.7% experience mild and moderate reactions, respectively. In the placebo group 50% had mild and 44.4% had moderate side effects. Severe adverse events were reported in 4.3% in the OIT group and 0.8% in the placebo group. NCT02635776 (261)
Peanut: peanut powder (protein content not specified); dose of individual major allergens not determined 24 (5-18 years) subjects with history of anaphylaxis in OIT group, 10 historical controls (avoided peanuts) Open-label Subjects ingested peanut powder 2x/day during 5 days of hospitalization. Up to 1 month after discharge, dosing was continued with amount decided at time of discharge. If dose was tolerated for 5 consecutive days after this month, dose was increased gradually until a target dose of 133 mg peanut protein/day was reached. Patients visited hospital every 1-3 months (total duration 12 months). One year after staring the treatment, patients stopped intake for 2 weeks and then underwent 133 mg and 795 mg OFC (on two consecutive days). Patients that passed the challenges continued with weekly ingestion of 795 mg peanut protein. Those without showing symptoms 3 months after OFC were considered having achieved sustained unresponsiveness.

  • After 12 months of treatment, 8 (33%) children in the OIT group achieved sustained unresponsiveness compared to 0% in the control group (primary endpoint).

  • 22 of 24 (92%) participants in the OIT group achieved desensitization within 12 months.

  • After 1 year, 16 (67%) of the OIT-treated children tolerated 133 mg and 14 (58%) tolerated 795 mg in OFC compared to 1 of 10 (10%) and 0 of 10 (0%) in the historical control group.

  • The median peanut- and Ara h 2-specific IgE levels increased significantly during the first month, and then decreased at 3, 6 and 12 months.

  • Median peanut- and Ara h 2-specific IgG and IgG4 levels increased significantly from baseline to 1 month in the OIT group, while no changes were observed in the control group.

  • Baseline Ara h 2-specific IgE levels were predictive for the achievement of sustained unresponsiveness.

 In total, 79 of 119 admission doses (66.4%) caused allergic reactions, but none of them were severe. During home dosing, 9.1% of the subjects experienced adverse symptoms, which were severe in 0.01% of cases. One child required treatment with epinephrine. UMIN000011202 (262)
Peanut: peanut paste made from roasted peanut (protein content approximately 20%); dose of individual major allergens not determined Initially 30 subjects (12-18 years): 21 in peanut OIT group, 9 placebo controls; 2 patients withdrew Randomized, double-blind, placebo-controlled Initial DBPCFC, followed by 24 weeks of build-up phase during which subjects ingested daily doses between 2-400 mg peanut protein. Doses were increased every 2 weeks until subjects reached daily doses of up to 400 mg peanut protein. At the end of the build-up phase, subjects underwent DBPCFC.

  • Primary endpoint was defined by toleration of at least 400 mg (cumulative) peanut protein during DBPCFC, performed 1-3 days after the end of the build-up phase. This was achieved by 17 of 21 (81%) OIT treated subjects compared to 1 of 9 (11%) in the placebo control group (intention-to-treat analysis).

  • 17 of 19 patients in the OIT group that finished the build-up protocol increased their reactivity threshold 4-fold between first and second DBPCFC compared to 2 of 9 in the placebo group.

  • Peanut-specific IgE levels increased significantly in the OIT group compared to the placebo group at second DBPCFC.

  • No significant difference was observed for Ara h 1-, 2- and 3-specific IgE levels between first and second DBPCFC.

  • Peanut-specific IgG4 levels increased significantly during build-up phase. The same applied for IgG4 levels specific for major peanut allergens.

  • Peanut and Ara h 2-specific IgG4/specific IgE ratios increased in the OIT group at the second DBPCFC, and reached significance for Ara h 2.

  • No difference in the peanut-specific IgE/total IgE ratio was observed in either group during the build-up phase.

 Two patients in the OIT group withdrew during the build-up phase. One due to a severe reaction that required epinephrine and the other due to moderate side effects. Overall, only 3 subjects experienced no adverse event during the build-up phase. While there was no difference between the number of patients with adverse events between both groups, the number of events/patients was higher in the OIT group. In 91/1000 doses medication was required in the OIT group, compared to 36/1000 in the placebo group. Five systemic reactions occurred in 4 OIT-treated patients; one was life-threatening. NCT02046083 (263)
Peanut: peanut flour (50% protein) in vehicle of chocolate pudding; dose of individual major allergens not determined; placebo group only received vehicle without peanut flour 62 subjects (3-17 years): 31 in OIT group, 31 placebo controls Randomized, double-blind, placebo-controlled Initial dose escalation phase during which patients received whole crushed roasted peanuts starting with 3 mg peanut protein in 2-hour intervals for a maximum of 3 days until 4500 mg peanut protein was reached or objective symptoms were observed. OIT was started with doses of 0.5-30 mg peanut protein, depending on eliciting dose during initial OFC. Doses were taken on a daily basis and increased approximately every 2 weeks (up to 14 months). Patients with eliciting dose of 3-100 mg during initial OFC had goal maintenance dose of 125 mg, subjects with an eliciting dose of 300-4500 mg should reach a maintenance dose of 250 mg peanut protein. Maintenance dose was continued for 2 months (+/- 2 weeks).

  • Primary endpoint was the proportion of subjects tolerating a single dose of at least 300 mg peanut protein during final OFC, which was achieved by 23/31 (74.2%) in the active OIT group versus 5/31 (16.1%) in the placebo control group.

  • 13 of 31 (41.9%) subjects in the active OIT group compared to 1 of 31 (3.2%) in the placebo group tolerated 4.5 g peanut protein at final challenge.

  • 50% in each group reached the goal maintenance dose (peanut protein or placebo).

  • In the peanut-OIT group a significant reduction in IL-4, IL-5, IL-10 and IL-2 production, a significant increase in median peanut-specific IgG4 levels and a decrease in the peanut-specific IgE/IgG4 ratio were observed after treatment when compared between the randomized arms.

 Two patients in each group withdrew due to experiencing adverse events, which were severe in one of the subjects of each group. All patients experienced adverse events at some point, however, only 1.2% of placebo doses and 4.3% of peanut OIT doses were associated with treatment-related adverse reactions. 40% in the placebo group and 45% in the active OIT group needed at least 1 dose reduction because of reported side effects. DRKS00004553 (264)
Peanut: suspension of peanut flour in Kool-Aid containing 2.5 µg of peanut protein; with increasing doses alternative forms of peanut were provided with equivalent doses of peanut protein; dose of individual major allergens not determined 270 subjects (4-18 years) Retrospective record Retrospective medical record review of OIT treated patients between 2009 and 2017. Initial dose escalation phase with ingestion of tolerated dose 2x/day for at least 1 week before participants returned for another dose increase. Buildup phase until target dose of 3000 mg peanut protein reached (individual duration).
After 6000 mg peanut protein challenge, maintenance dose of 2000 mg was taken once or twice daily for at least 3 years. Sustained unresponsiveness was defined by passing 6 g DBPCFC 30 days after stopping OIT.

  • 214 of 270 (79%) subjects reached target maintenance dose (211 reached target dose of 3000 mg peanut protein, 3 reduced target of 2000 mg) and were challenged with 6000 mg peanut protein, with all except one passing the challenge

  • 14 of 214 (6.5%) patients achieved sustained unresponsiveness.

  • A decrease in peanut-specific IgE levels was observed during the maintenance period.

  • In 54 tested patients, peanut-specific IgG4 level after reaching maintenance was > 80 µg/mL, however, measurement was discontinued afterwards.

 During dose escalation, 63 of 270 (23%) patients required treatment with epinephrine. In total, 157 subjects (58%) reported 330 minor adverse reactions that did not require treatment with epinephrine. No clinical trial number found; study was approved by the North Texas Institutional Review Board (265)
Walnut: doses given as mg of walnut protein (not further specified); dose of individual major allergens not determined 73 subjects (4 years or older), 55 in OIT group, 18 observational controls (dietary exclusion) Prospective Initial dose escalation over 4 days (in in an ambulatory care setting). The highest tolerated dose was consumed daily for 24 days. Each month patients returned for dose escalations followed by daily dose intake until target dose of 4000 mg walnut protein was reached (was considered desensitization). Maintenance of 1200 mg walnut protein/day for 6 months in those patients that were desensitized, followed by OFC to 4000 mg walnut protein. Crossover of control group after observation period (median period 7.1 months).

  • Primary study endpoint was defined as toleration of 4000 mg walnut protein (26 g walnut) by the end of the study (desensitization). Desensitization was achieved in 49 of 55 (89%) patients (intention-to-treat analysis) in the OIT group, compared to 0 of 18 (0%) in the control group.

  • Patients that were co-allergic to pecan (n = 46) also showed desensitization to pecan.

  • 18 of 30 (60%) with co-allergy to hazelnut or cashew and 14 of 15 (93%) with co-allergy to hazelnut alone were considered either fully desensitized or treatment responders.

  • In the walnut OIT group, walnut-specific IgE levels, CD63 expression in BAT and IgE/IgG4 ratio significantly decreased, while walnut-specific IgG4 levels increased during the treatment period (similar results for antibody levels to all walnut-specific components). This did not apply for the control group.

 In total, 47 (85%) of 55 patients in OIT group experienced adverse reactions during in-hospital up-dosing and 40 (73%) during home-dosing. However, reactions were mostly mild and occurred in response to 109 (4%) of in-clinic doses and 244 (2%) of home doses. Epinephrine treatment was required by 11 patients during in-hospital phase and 8 during at home treatment. No clinical trial number found; study was approved by the institutional review board (266)
Peanut: peanut flour; protein content was calculated and confirmed through protein assays (not further specified); oat flour for placebo group used 120 subjects (7-55 years): 60 in peanut-0 group, 35 in peanut-300 group, 25 in placebo group Randomized, double-blind, placebo-controlled Buildup phase until maintenance dose of 4000 mg peanut protein reached (week 104), followed by discontinuation (peanut-0 group), daily intake of 300 mg peanut protein (peanut-300 group) or placebo for 52 weeks. DBPCFC every 3 months if a cumulative dose of 4000 mg peanut protein was tolerated during previous challenge.

  • Primary endpoint was defined of proportion of subjects that tolerated a cumulative dose of 4000 mg peanut protein during DBPCFC at week 104 and week 117. At week 104, 51 of 60 (85%) peanut-0 subjects, 29 of 35 (83%) peanut-300 subjects and 1 of 25 (4%) in the placebo group passed DBPCFC. At week 117, 21 of 60 (35%) peanut-0 subjects, 1 of 25 (4%) in the placebo group and 19 of 35 (54%) peanut-300 subjects passed 4000 mg challenge.

  • In the peanut-0 group, 8 of 60 (13%) participants passed 4000 mg challenge after week 156 compared to 13 of 35 (37%) in the peanut-300 group and 1 of 25 (4%) in the placebo group.

  • Lower peanut- and Ara h 2-specific IgE levels were associated with passing challenge at week 117 in the peanut-0 and the peanut-300 arms.

  • In the peanut-0 group, higher peanut-specific IgG4/peanut-specific IgE ration was associated with week 117 success, however, this did not apply for the peanut-300 group.

  • A higher Ara h 2-specific IgE/peanut-specific IgE ratio was associated with higher risk of treatment failure.

 Two patients withdrew due to severe adverse events. During the first year, 95% in the peanut-0 group, 91% in the peanut-300 group and 64% in the placebo group reported adverse events. In the third year, adverse events were reported by 2% in the peanut-0 group, 20% in the peanut-300 group and 5% in the placebo group. NCT02103270 (267)
Hazelnut: doses given as mg of hazelnut protein; 259 mg hazelnut protein equivalent to 1 whole hazelnut; dose of individual major allergens not determined 100 subjects (3-9 years) Retrospective DBPCFCs were performed at time of diagnosis and 6 months after starting OIT. During challenge doses were increased every 20 minutes up to a cumulative dose of 1635 mg hazelnut protein. Buildup phase started with one-tenth of eliciting dose from initial DBPCFC. Monthly dose increases until tolerated cumulative dose of 1635 mg hazelnut protein (equivalent to 8 whole hazelnuts) during OFC (performed after 6 months) was reached. After passing OFC, subjects continued with maintenance dose of 416 mg hazelnut protein 3x/week. If OFC was failed, schema was repeated until desensitization was achieved.

  • Primary endpoint was defined by proportion of desensitized subjects after 6 months of OIT treatment.

  • 34 of 100 (34%) patients tolerated 1635 mg hazelnut protein during OFC after 6 months and were considered desensitized

  • Patients without desensitization repeated procedure based on eliciting dose from 6-month OFC.

  • Desensitization to hazelnut was associated with lower hazelnut specific- and Cor a 14-specific IgE levels.

 76 patients completed a survey about OIT side effects and 30% reported at least one side effect (non-severe). No serious adverse reactions were reported. NCT03048149 (268)
Peanut: AR101 = drug consisting of peanut flour; see (Bird et al., 2018) 175 subjects (4-17 years): 132 in AR101 group, 43 in placebo group; 106 of the AR101 group and 40 of the placebo group completed the study Randomized, double-blind, placebo-controlled (phase 3) Build-up phase with biweekly dose increases (20-40 weeks) until daily dose of 300 mg peanut protein (AR101) reached, followed by maintenance for 3 months.

  • Primary endpoint was defined by proportion of subjects that could consume 1000 mg (cumulative dose 2043 mg) peanut protein at final DBPCFC (after 9 months) without dose-limiting effects. 77 of originally 132 (58%) subjects in the AR101 group passed challenge compared to 1 of 43 (2%) in the placebo group.

  • In the AR101 group peanut-specific IgG4 levels increased during the study.

  • No significant difference in the change of peanut-specific IgE levels was observed between the active treatment and the placebo group.

  • A reduction in the IgE/IgG4 ratio by the end of the trial in comparison to the initial screening in the AR101 group.

 Adverse reactions were reported by almost all subjects, but were mostly mild to moderate in both, AR101 and placebo group. One severe adverse event was reported in the AR101 group. Gastrointestinal disorders were reported by 91% in the active treatment group and 77% in the placebo group. NCT03201003 (269)
Peanut: PTAH, formerly AR101 = drug consisting of peanut flour; see (261) 358 eligible subjects (4-17 years): 256 in original active treatment group, 102 in original placebo group Open-label, follow-on study to (261) Patients that reached 300-mg dose at the exit DBPCFC in previous study and placebo group entered the follow-on study. Subjects were assigned to 5 dosing cohorts, receiving either daily doses of 300 mg (cohorts 1 and 3A) or non-daily doses (cohorts 2, 3B, 3C). PTAH-naïve subjects (from initial placebo group) underwent buildup to daily dose of 300 mg, followed by maintenance. At the end of the study (approx. 2 years), subjects underwent DBPCFC up to 2000 mg peanut protein (highest dose).

  • Cohort 3A (300 mg daily for approx. 56 weeks) had highest desensitization rates

  • In PTAH-native group, desensitization rates at challenge doses of 2000 mg were 45.8% at maintenance challenge (after 24 weeks of 300 mg daily maintenance) and 51.4% at exit challenge (52 weeks after maintenance challenge).

  • IgG4 levels increased during the study period in daily-dosing cohorts.

  • IgE levels decreased from PALISADE entry to study exit in PTAH-naïve and PTAH-continuing subjects.

 83% of subjects experienced mild to moderate adverse events. 6.1% of subjects in non-daily dosing group had to revert to daily dosing due to adverse events. Severe adverse events occurred in 2.1% of daily-treated and 2.7% of non-daily treated subjects. 7 participants in PTAH-continuing group withdrew due to adverse events. In the PTAH-naïve group, 86% experienced treatment-related adverse events. 5 subjects (from cohorts 1 and 3C) experienced treatment-related anaphylaxis. NCT02993107 (270)
SLIT
Hazelnut: hazelnut extract in glycerosaline solution; dose of individual major allergens not determined;
saline solution used as placebo		 22 subjects (18-60 years): 11 in active treatment group, 11 in placebo group Randomized, double-blind, placebo-controlled Patients kept allergen solution in the mouth for at least 3 minutes before spitting out (sublingual-discharge technique). SLIT was performed with hazelnut extract of 5 strengths (F0, F1, F2, F3, FA). 4-day build-up phase during which doses were given in 15-minute intervals, followed by daily maintenance dose of 5 drops of maximum concentration (vial concentration (FA) 66.25 mg/ml) for 8-12 weeks. Treatment efficacy was assessed by DBPCFC at the end of the study.

  • 5 of 11 (45%) in the SLIT group and 1 of 11 (9%) in the placebo group tolerated the highest level of 20 g raw hazelnuts (15-20 hazelnuts) in OFC.

  • Hazelnut-, Cor a 1- and Cor a 8-specific IgE levels were lower in both groups after treatment (no statistical significance).

  • In the treatment group, increased mean IgG4 levels (7.34 allergen units (AU)/mL to 9.84 AU/mL) were observed. However, no statistical significance regarding hazelnut-specific IgG4 levels was found between the groups.

  • Increase in IL-10 levels (from 1.62 pg/mL to 2.24 pg/mL) was seen in the active SLIT group after treatment.

 • 3 of 1466 total SLIT doses caused systemic reactions, which appeared during build-up phase and were treated with antihistamines.
• Local reactions (mainly oral itching) were observed in 109 of 1466 doses.		 No clinical trial number found; study was approved by the ethics committees of the participating hospitals (271)
Peanut: peanut and placebo sublingual drops; active group received crude peanut extract (1:20 w/v) dissolved in 0.2%
phenol and 50% - 55% glycerinated saline to maximum peanut protein concentration of
5000 µg/ml; Ara h 2 content was approximately 6% of protein concentration; placebo was glycerinated saline solution		 18 subjects (1-11 years): 11 in SLIT group, 7 in placebo group Randomized, double-blind, placebo-controlled Treatment started with 0.25 µg peanut protein (initial visit). Doses were taken on a daily basis after escalation. Patients returned every 2 weeks for dose escalation until maintenance daily dose of 2000 µg peanut protein was reached. Dose-escalation for 6 months was followed by 6 months maintenance. Final DBPCFC up to cumulative dose of 2500 mg peanut protein performed after 12 months of treatment.

  • The primary endpoint was defined as the evaluation of change in the reaction threshold to peanut after SLIT therapy compared to placebo. 11 subjects of the active SLIT group tolerated a cumulative dose of 1710 mg peanut protein in DBPCFC after 12 months of treatment, while 7 subjects in the placebo group tolerated a median cumulative dose of 85 mg.

  • During the first 4 months, peanut-specific IgE increased significantly in the active group (median level 118.5 kUA/L) compared to the baseline (33.5 kUA/L) and over the following 8 months decreased again (median level of 31.4 kUA/L).

  • After 1 years of treatment, peanut-specific IgG4 levels were significant higher in the active SLIT group (1.12 mg/L), compared to the baseline (0.3 mg/L), however, this was not observed in the placebo group.

  • In the active SLIT group, IL-5 levels decreased significantly during the treatment in the active SLIT group (79 pg/ml) compared to the placebo group (368.9 pg/ml).

  • No significant difference in IL-13, IL-10 and IFN-gamma levels were observed between groups.

  • An increase of Tregs was observed in the active group by the end of the treatment, but did not reach significance.

 Adverse events were associated with 11.5% of active SLIT doses and 8.6% of placebo doses. No epinephrine was required any time during the study. NCT00597727 (272)
Peanut: peanut and placebo sublingual drops; allergenic extract from whole non-roasted peanut with 0.5% sodium chloride and 0.54% sodium bicarbonate as aqueous extracts in 50% glycerin; Ara h 2 content = 6% of crude protein; placebo extract was prepared from a glycerinated saline solution with phenol 40 (12-37 years) subjects: 20 in SLIT group, 20 placebo controls Randomized, double-blind, placebo-controlled Escalation dosing started with 0.000165 µg peanut protein. Biweekly escalation through 660 µg with 3 doses given at minimal interval of 30 minutes. If participants failed 3 dose escalations after 3 consecutive (biweekly) attempts, 1-2 dose biweekly escalations were allowed. After each escalation, participants continued with daily dose intake until 660 µg target dose was achieved. Subsequently, single dose increase occurred, followed by a 2-week maintenance phase. Maintenance daily doses of 165-1386 µg peanut protein were taken until subjects underwent DBPCFC with 5 g peanut powder in weeks 44. After unblinding at week 44, placebo controls crossed over to higher-dose peanut SLIT (3696 µg maximum maintenance dose), followed by 5 g peanut powder OFC at week 44. Subjects in the original active treatment group continued with maintenance dose followed by 10 g peanut powder OFC after 12 months of maintenance.

  • After 44 weeks, 14 of 20 (70%) subjects in the SLIT group and 3 of 20 (15%) in the placebo group achieved primary endpoint of tolerating 5 g or at least 10-fold more peanut powder (~2.5 g peanut protein) compared to the baseline in OFC and were considered responders.

  • In the crossover group, 7 of 16 (44%) subjects were considered responders.

  • In the active SLIT group, median peanut-specific IgE levels increased significantly from baseline to week 44, but not between week 44 and week 68. At week 44, no significant differences in peanut-specific IgE levels were seen between active SLIT and placebo group, SLIT responders and non-responders or high-dose crossover and original peanut SLIT subjects.

  • Peanut-specific IgG4 levels increased significantly between baseline and week 44 in the active SLIT group, which was not observed in the placebo group. Between weeks 44 and 68 no increase was observed in the peanut SLIT group.

  • In the crossover subjects an increase in peanut-specific IgG4 levels was observed from baseline to week 44. No difference in peanut-specific IgG4 levels was observed between treatment responders and non-responders.

 In total, 127 of 11854 doses (1.1%) that were given until week 44 required treatment; only one with epinephrine. 59.9% of peanut SLIT doses compared to 99.4% of placebo doses were symptom-free until week 44. In the high-dose crossover group, 66.7% of doses were symptom-free. NCT00580606 (273)
Peanut: peanut extract prepared from the edible part of the peanut with 0.5% sodium chloride and 0.54% sodium bicarbonate as aqueous extracts in 50% glycerin; dose of individual major allergens not determined; glycerinated saline used for placebo 21 (7-13 years) subjects: 10 in active SLIT/placebo OIT group and 11 in active OIT/placebo SLIT group;
16 completed protocol (9 in active SLIT group)		 Randomized, double-blinded, placebo-controlled SLIT treatment started with 0.000165μg of peanut protein with escalation to 0.066μg on the first day. Daily doses were taken for 16 weeks, with dose increase every 1-2 weeks. Build-up phase was continued until maintenance dose of 3.7 mg peanut protein per day (SLIT) reached, followed by 12 months of maintenance and OFC after 6 and 12 months. Subjects that passed OFC (toleration of 5 g peanut powder or at least 10-fold increase) stopped treatment and were rechallenged after 4 weeks. The others continued with 6 months of unblinded treatment. The subjects that reacted during OFC at 12 months to less than 5 g peanut powder continued treatment with OIT added. Finally, subjects underwent OFC with 10 g. Those that passed the challenge, discontinued treatment for 4 weeks and were then rechallenged (sustained unresponsiveness).

  • 7 of originally 10 subjects in active SLIT group achieved 10-fold increase compared to the baseline (primary endpoint)

  • In total, 9 subjects in the SLIT group continued with unblinded phase with active OIT added. Two had to stop OIT build-up due to side effects. The other 7 passed OFC after 6 months of add-on OIT.

  • 1 of 10 in original SLIT group achieved sustained unresponsiveness.

  • Peanut-specific IgE increased at first and then decrease over time in both groups, however decrease was greater in the OIT group at 6 and 12 months. In the SLIT group, the median peanut-specific IgE increased from 163 kUA/L at baseline to 387 kUA/L after 6 months of maintenance before slightly decreasing after 12 months (273 kUA/L).

  • In the SLIT group, peanut-specific median IgG4 levels increased from 0.9 mgA/L at baseline to 8.5 mgA/L after 12 months.

 9% of doses in the SLIT group were associated with adverse reactions. In total, 9 of 10 SLIT subjects had symptoms with dosing. Antihistamines were required in 23.1% of SLIT doses. Epinephrine was required by one subject in the active SLIT/additional OIT group during OIT build-up. NCT01084174 (255)
Peanut: see (273) 40 subjects (12-40 years) Open-label
Follow up study to (273)		 Second phase of study by Fleischer et al. (273). Maintenance of peanut SLIT with daily doses of 165-1386 µg peanut protein for 164 weeks. OFCs were performed at 2 and 3 years of SLIT maintenance. Those subjects that passed 10 g peanut powder (5 g peanut protein) OFC were rechallenged after 8 weeks of treatment discontinuation to evaluate sustained unresponsiveness. Sustained unresponsiveness OFC included challenge to 10 g followed by open feeding of 2 tablespoons peanut butter 1 h later.

  • In higher-dose crossover group, 12 of 17 withdrew prior to final OFC. Of the remaining 5, 2 passed 10 g peanut powder OFC after 3 years and further achieved sustained unresponsiveness.

  • In the initial active peanut SLIT group, 11 of 20 subjects withdrew prior to final OFC. Of the remaining 9, 2 passed OFC after 3 years and further achieved sustained unresponsiveness.

  • Total IgE levels, peanut-specific IgE and IgG4 levels were not statistically different in those defined as treatment responders (passed OFC) at year 2 and those that were non-responders.

  • Percentage of CD63+ basophils was significantly lower in the 2-year responders than in non-responders.

 In the time following the initial 44 weeks, 112 adverse events were reported by 12 high-dose crossover subjects and 83 adverse events were reported by 13 subjects in the original peanut SLIT group. In the peanut SLIT group, 1 life-threatening anaphylactic reaction occurred during year 3 OFC. However, only a mild contact reaction was considered definitely related to the study product. NCT00580606 (274)
Peanut: see study by Kim et al. (272) 48 subjects (1-11 years) initially included: 19 subjects from the initial study, 11 subsequently enrolled subjects and 18 subjects from an additional study cohort that followed identical dosing protocol; 37 subjects completed SLIT therapy Open-label;
extension study of (272)		 Initial study was described above (272). An additional cohort of patients that followed identical protocol were also included in the extension study. During the long-term extension study, subjects received SLIT with maintenance daily dose of 2 mg peanut protein (up to 5 years). After the final day of SLIT, sensitization was assessed by DBPCFC with 5 g peanut protein.

  • 12 of 48 (25%) passed challenge with 5000 mg peanut protein without showing clinical symptoms.

  • The 12 subjects discontinued SLIT for 2-4 weeks, were rechallenged and 10 subjects demonstrated sustained unresponsiveness.

  • Overall, 37 of 48 subjects completed the SLIT treatment (9 after 3 years, 1 after 4 years, 27 after 5 years).

  • 32 of 48 (67%) intention-to-treat subjects tolerated at least 750 mg peanut protein during DBPCFC.

  • The median peanut-specific IgE level decreased significant from baseline (83.9 kUA/L) to study completion (20.0 kUA/L).

  • Median peanut-specific IgG4 level increased significantly from baseline (0.3 mg/L) to study completion (10.9 mg/L).

  • The peanut-specific IgG4/peanut-specific IgE ration increased from 1.45 at baseline to 356.3.

  • Ratio of peanut-specific basophil activation/non-specific activation decreased significantly.

 Of 75,366 total doses, 3599 (4.78%) were associated with side effects affecting 45/48 subjects. During end-of-treatment DBPCFC, 12 subjects required epinephrine. During sustained unresponsiveness DBPCFC no epinephrine treatment was required. No clinical trial number found; protocol and consent forms approved by the local institutional
review board		 (275)
EPIT
Peanut: Viaskin peanut patch containing liquid formulation of peanut protein extract derived from defatted peanut flour; Viaskin peanut 100 µg (VP100) or 250 µg (VP250) used for treatment; dose of individual major allergens not determined; for placebo same device without peanut protein 74 subjects (4-25 years) started dosing: 24 in VP100 group, 25 in VP250 group, 25 placebo controls Randomized, double-blind, placebo-controlled At study entry, subjects underwent OFC with cumulative dose of 1044 mg peanut protein. Participants either received Viaskin Peanut 100 µg or Viaskin Peanut 250 µg. Patch was placed on upper arm (subjects older than 11 years) or the interscapular space (subjects aged 4-11 years). 1-6 application sited were used at 24-h intervals. Doses were increased by extending duration the patch was worn. In the first week, patch was worn 3 h/day, in week 2, 6 h/day and week 3, 12h/day. Patch was applied 24 h/day from day 22 on. At week 52, subjects underwent challenge with cumulative dose of 5044 mg peanut protein.

  • Primary endpoint was defined by passing week-52 OFC with 5044 mg peanut protein (cumulative) or at least 10-fold increase compared to baseline, which was achieved in 11 of 24 (46%) VP100-treated subjects, 12 of 25 (48%) VP250-treated subjects and 3 of 25 (12%) in the placebo group.

  • Higher treatment response was observed in younger children.

  • Subjects that received active treatment had increased peanut-specific IgG4 levels and IgG4/IgE ratios compared to the placebo receiving subjects.

  • No difference between treatments was seen for total IgE levels and percentage of peanut-specific IgE over the time of the study.

  • Median frequencies of T cells producing IL-4 and IL-13 were lower at the VP250 dose compared to placebo, but not at the VP100 dose.

 14.4% of placebo doses caused an adverse reaction in comparison to 79.8% of VP100 and VP250 doses. Most reactions were mild and occurred at patch site. A patch-site reaction of grade 4 was reported by one patient with VP100 dose at day 34. Reactions not limited to patch site were associated with 0.2% of placebo doses, 0.2% of VP100 doses and 0.1% of VP250 doses. No epinephrine was required with dosing. NCT01904604 (276)
Peanut: Viaskin peanut patch containing liquid formulation of peanut protein extract derived from defatted peanut flour; Viaskin patch (VP) with 50 µg, 100 µg or 250 µg peanut protein used for treatment; dose of individual major allergens not determined; for placebo same device without peanut protein 221 (5-66 years) subjects: 53 in VP50 group, 56 in VP100 group, 56 in VP250 group, 56 in placebo group Phase 2 double-blind, placebo-controlled dose-ranging study, followed by open-label extension (for 2 years) Participants received patches containing either 50, 100 or 250 µg peanut protein. The patched were applied daily either on backs (children) or inner upper arms (adolescents and adults). In the first week, patch was worn 3 h/day, in week 2, 6 h/day and week 3, 12h/day. Patch was applied 24 h/day from the third week on. After 12 months, subjects continued with 2-year open-label extension. At 6 months all subjects received 250 µg patch.

  • Primary endpoint was defined as percentage of treatment responders after 12 months of treatment. Responders reached at least 10-times increase in the eliciting dose and/or at least 1000 mg peanut protein in OFC.

  • This applied for 28 of 56 (50%) in the 250-µg group compared to 14 of 56 (25%) in the placebo group.

  • No statistically significant difference in response rate was observed between the 100-µg group and the placebo control.

  • The highest difference in response rate between the 250-µg group and the placebo group was seen in the age group between 6 and 11 years.

  • In patch-treated subjects, the median peanut-specific IgE levels increased over the first 3-6 months compared to the placebo group, followed by a decrease reaching almost baseline levels at 12 months.

  • Peanut-specific IgG4 levels increased over the 12-months treatment period in all patch-treated subjects. After 12 months, mean peanut-specific IgG4 levels were greater for VP250 subjects than placebo subjects.

 Treatment-emergent adverse events occurred primarily during the first months of therapy and twice as often in the peanut-patch groups compared to the placebo group. Most adverse events were local skin reactions. In total, 20 serious adverse events were reported in 17 subjects, but none of them were treatment-related and most occurred during food challenges. NCT01675882 (277)
Peanut: 250 µg peanut protein-containing patch (Viaskin); dose of individual major allergens not determined; for placebo same device without peanut protein 356 subjects (4-11 years): 238 in peanut-patch group, 118 placebo controls Randomized, double-blind, placebo-controlled (phase 3 trial) Daily active treatment with 250 µg peanut protein-containing patch. Treatment responders were defined as those passing OFC after 12 months of treatment by reaching at least 300 mg (for those with baseline eliciting dose of ≤ 10 mg) or at least 1000 mg peanut protein (for those that had baseline eliciting dose of 10-300 mg). On the first day patch was worn 3 h/day, in week 1, 6 h/day (gradually increased) in week 2, 12h/day and thereafter patch was applied 24 h/day.

  • Primary endpoint was defined by differences in the respond rate between patch-treated and placebo-treated subjects determined by OFC after 12 months of treatment. 84 of 238 (35.3%) of peanut-patch treated subjects compared to 16 of 118 (13.6%) in the placebo group were considered responders.

 Not reported Incidence of treatment-emergent adverse events was 95.4%in the peanut-patch group
and 89% in the placebo group. Most adverse reactions occurred at the application site and primarily within the first month. 4 patients in the peanut-patch group experienced adverse events that led to treatment discontinuation. 4.2% of subjects in the peanut-patch group and 5.1% in the placebo group reported serious adverse events at any time during the study (excluding OFC).		 NCT02636699 (278)
Molecular AIT
Peanut: rectally administered vaccine (EMP-123) consisting of recombinant modified Ara h 1, Ara h 2, and Ara h
3, encapsulated within heat/phenol inactivated E.
coli.		 10 peanut-allergic subjects (18-50 years) and 5 healthy subjects Phase 1 trial Rectally administration of EMP-123.
Five healthy control subjects received 4 weekly escalating doses up to a maximum of 3063 µg modified peanut protein.
Peanut-allergic patients received weekly dose escalations for 10 weeks (10-3063 µg), followed by 3 biweekly doses of 3063 µg (maximum dose).

  • Primary endpoint was defined as assessment of safety of EMP-123 in peanut-allergic subjects and healthy controls.

  • 4 of 10 peanut-allergic patients completed dosing without experiencing symptoms. 1 subjects experienced rectal pruritus, but completed treatment and was considered non-reactive.

  • 2 subjects had mild adverse reactions, 3 experienced more severe side effects, including 2 anaphylactic reactions.

  • In the healthy subject group, 2 experienced diarrhea or loose stools after dosing.

  • In healthy subjects no immunological changes were observed.

  • No significant changes in peanut-specific IgE levels from baseline to week 20 were observed for reactive and non-reactive subjects, however, baseline peanut- and Ara h 2-specific IgE levels were higher in the 5 reactive subjects.

  • Peanut-specific IgG4 levels did not change significantly from baseline to week 20.

 See clinical outcome No clinical trial number found; study approved by the NIAID Data Safety Monitoring Board, the investigational review
boards of Mount Sinai and Johns Hopkins, and the NIH Recombinant DNA Advisory
Committee		 (279)

Design of studies, numbers of participants, outcomes, side effects and references are listed.