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Safety of epicutaneous immunotherapy for the treatment of peanut allergy: A phase 1 study using the Viaskin patch

2016; Elsevier BV; Volume: 137; Issue: 4 Linguagem: Inglês

10.1016/j.jaci.2016.01.008

1097-6825

Stacie M. Jones, Wence Agbotounou, David M. Fleischer, A. Wesley Burks, Robert D. Pesek, M. Harris, Laurent Martin, Claude Thébault, Charles Ruban, Pierre‐Henri Benhamou,

Contact Dermatitis and Allergies

Peanut allergy (PA) affects approximately 1% to 1.5% of children and adults living in westernized society1Sicherer S.H. Munoz-Furlong A. Godbold J.H. Sampson H.A. US prevalence of self-reported peanut, tree nut, and sesame allergy: 11-year follow-up.J Allergy Clin Immunol. 2010; 125: 1322-1326Abstract Full Text Full Text PDF PubMed Scopus (744) Google Scholar and is considered a life-long allergy in the vast majority of subjects.2Boyce J.A. Assa'ad A. Burks A.W. Jones S.M. Sampson H.A. Wood R.A. et al.NIAID-Sponsored Expert PanelGuidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-sponsored expert panel.J Allergy Clin Immunol. 2010; 126: S1-S58PubMed Scopus (768) Google Scholar, 3Fleischer D.M. Conover-Walker M.K. Christie L. Burks A.W. Wood R.A. The natural progression of peanut allergy: resolution and the possibility of recurrence.J Allergy Clin Immunol. 2003; 112: 183-189Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar Additionally, peanuts and tree nuts account for 90% of all cases of fatal and near-fatal anaphylaxis to foods.4Bock S.A. Munoz-Furlong A. Sampson H.A. Further fatalities caused by anaphylactic reactions to food, 2001-2006.J Allergy Clin Immunol. 2007; 119: 1016-1018Abstract Full Text Full Text PDF PubMed Scopus (782) Google Scholar Strict dietary avoidance and availability of injectable epinephrine are key management tools in the current food allergy guidelines,2Boyce J.A. Assa'ad A. Burks A.W. Jones S.M. Sampson H.A. Wood R.A. et al.NIAID-Sponsored Expert PanelGuidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-sponsored expert panel.J Allergy Clin Immunol. 2010; 126: S1-S58PubMed Scopus (768) Google Scholar and the quest for effective allergen immunotherapy for PA is ongoing.5Jones S.M. Burks A.W. Dupont C. State of the art on food allergen immunotherapy: oral, sublingual, and epicutaneous.J Allergy Clin Immunol. 2014; 133: 318-323Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar Epicutaneous immunotherapy (EPIT) has shown promise in animal studies6Dioszeghy V. Mondoulet L. Dhelft V. Ligouis M. Puteaux E. Dupont C. et al.The regulatory T cells induction by epicutaneous immunotherapy is sustained and mediates long-term protection from eosinophilic disorders in peanut-sensitized mice.Clin Exp Allergy. 2014; 44: 867-881Crossref PubMed Scopus (52) Google Scholar, 7Mondoulet L. Dioszeghy V. Ligouis M. Dhelft V. Dupont C. Benhamou P.H. Epicutaneous immunotherapy on intact skin using a new delivery system in a murine model of allergy.Clin Exp Allergy. 2010; 40: 659-667Crossref PubMed Scopus (123) Google Scholar, 8Mondoulet L. Dioszeghy V. Vanoirbeek J.A. Nemery B. Dupont C. Benhamou P.H. Epicutaneous immunotherapy using a new epicutaneous delivery system in mice sensitized to peanuts.Int Arch Allergy Immunol. 2011; 154: 299-309Crossref PubMed Scopus (91) Google Scholar and in a single pilot study9Dupont C. Kalach N. Soulaines P. Legoue-Morillon S. Piloquet H. Benhamou P.H. Cow's milk epicutaneous immunotherapy in children: a pilot trial of safety, acceptability, and impact on allergic reactivity.J Allergy Clin Immunol. 2010; 125: 1165-1167Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar as a novel future treatment for food allergy. Preclinical studies indicate that allergen applied through EPIT to intact skin does not cross into the circulation but rather activates dendritic cells in the dermal layer of the skin to affect immune activation.5Jones S.M. Burks A.W. Dupont C. State of the art on food allergen immunotherapy: oral, sublingual, and epicutaneous.J Allergy Clin Immunol. 2014; 133: 318-323Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar The findings presented in this letter expand the data presented in abstract form10Agbotounou W. Martin L. Dupont B. Pascal I. Vauleon C. Benhanou P.H. Epicutaneous immunotherapy (EPIT) is safe for the treatment of peanut allergy in allergic patients.J Allergy Clin Immunol. 2012; 131 ([abstract]): AB91Google Scholar to include a comprehensive analysis of the phase 1 study. The purpose of this study was to evaluate the safety and tolerability of peanut EPIT when the new Viaskin Peanut patch (DBV Technologies, Bagneux, France) is applied on intact skin of subjects with PA. One hundred subjects (n = 80 receiving active treatment; n = 20 receiving placebo treatment) aged 6 to 50 years, including 70 subjects with nonsevere PA (adults: n = 40, age range, 18-50 years; adolescents: n = 20; age range, 12-17 years; and children: n = 10; age range, 6-11 years) and 30 adults with severe PA, were enrolled in a randomized, double-blind, placebo-controlled phase 1b study at 5 clinical sites in the United States (see Table E1 for study sites, Table E2 for inclusion/exclusion criteria, and Table E3 for nonsevere/severe definitions in this article's Online Repository at www.jacionline.org). Subjects were randomized 4:1 (peanut/placebo) to receive Viaskin Peanut treatment in dosing cohorts at doses of 20, 100, 250, and 500 μg or placebo applied to intact skin of the upper arm or interscapular space of the back at either 24- or 48-hour intervals during a 2-week dosing period with a 1-week follow-up. Subjects were enrolled sequentially, starting with the low-dose Viaskin Peanut patch in the nonsevere adult cohort and then progressing on to the next dose escalation in the nonsevere adult cohorts by using an interactive Web-based response system. Data and Safety Monitoring Board (DSMB) review occurred before progression of dosing at all stages. The nonsevere adult cohorts were completed before progressing to the adolescent and then child dosing cohorts. The adult cohorts with severe PA were enrolled after DSMB review of the nonsevere adult cohorts. The child cohort did not receive the 500-μg dose after DSMB review (see Fig E1 in this article's Online Repository at www.jacionline.org). Study visits were scheduled on days 1, 2, 3, 8, and 15 of dosing and on day 22 (7 days after completion of dosing) to assess the safety and tolerability of the study product. Subjects recorded Viaskin application/removal and any patch site symptoms (pruritus, erythema, edema, and urticaria) and severity by using daily diary assessments. Viaskin patch site and atopic dermatitis (AD) scores were assessed by the investigative team at study visits. The safety and tolerability of peanut EPIT were assessed by means of evaluation for the presence and severity of treatment-emergent adverse events (TEAEs; reactions not at the Viaskin site only) and local treatment-emergent adverse events (L-TEAEs; local Viaskin site only), the severity of those events, any treatment required, and adherence to therapy. Adverse events were coded according to the Medical Dictionary for Regulatory Activities, version 13.0. Data were pooled and summarized by cohort dosing group and analyzed by using χ2 or Fisher exact tests to compare the proportion of events between treatment groups. Table E4 in this article's Online Repository at www.jacionline.org shows the clinical characteristics of the study population. The majority of subjects were male, non-Hispanic white subjects with a median age of 22 years (range, 6-49 years) and with other atopic diseases, including asthma (63%), allergic rhinitis (45%), and AD/eczema (37%). The mean baseline peanut IgE level was 25.47 kilounits of antibody per liter (kUA/L; range, 0.71->100 kUA/L). Overall, TEAEs were mostly mild and transient, with no differences between treatment groups (Fig 1 and see Fig E2 and Tables E5 and E6 in this article's Online Repository at www.jacionline.org). For subjects who received Viaskin Peanut, 42 (52.5%) of 80 reported at least 1 TEAE, 41.3% of mild severity and 11.3% of moderate severity. For subjects who received placebo, 9 (45%) of 20 reported at least 1 TEAE, 30% of mild severity and 15% of moderate severity. No severe TEAEs were reported, and 47.5% of Viaskin Peanut–treated subjects and 55% of placebo-treated subjects reported no TEAEs. No reports of severe adverse events or epinephrine use occurred. There were no statistically significant differences in the proportion of subjects reporting TEAEs when comparing the placebo and Viaskin Peanut treatment groups and between subjects with nonsevere and those with severe PA. Overall, 4 (4%) of 100 subjects discontinued from the study; 1 withdrew consent, and 3 discontinued because of TEAEs. One (1.25%) subject receiving active treatment (child, 250 μg of Viaskin Peanut/48 h) was discontinued because of several nonsevere TEAEs involving moderate vomiting, mild ocular pruritus, mild nasal congestion, and mild throat irritation. One (1.25%) subject (severe adult, 100 μg of Viaskin Peanut/48 h) was discontinued because of report of a moderate L-TEAE (local severe pruritus, erythema, edema, and urticaria). One (5%) subject (nonsevere adult, placebo/24 h) discontinued because of protocol noncompliance after failure to use epinephrine after a moderate anaphylactic reaction considered related to study treatment by the investigator. Adherence to treatment was documented by diary records and Viaskin accountability: compliance of greater than 96% for each cohort and for active treatment (mean, 100.2% ± 4.6%) and placebo (mean, 101.1% ± 3.5%) subjects (see Table E7 in this article's Online Repository at www.jacionline.org). At least 1 L-TEAE was experienced in 84% of Viaskin Peanut–treated subjects versus 60% of placebo-treated subjects based on self-report (see Table E8 in this article's Online Repository at www.jacionline.org). Viaskin Peanut triggered more L-TEAEs than placebo treatment (P = .021; relative risk, 1.4; 95% CI, 0.99-2.08), the majority of which were mild to moderate and lasted longer than placebo-triggered L-TEAEs (Fig 2 and see Tables E6 and E8). Moderate L-TEAEs were described more frequently in Viaskin Peanut–treated subjects than in placebo-treated subjects. When assessed by investigators, the majority of Viaskin-induced site reactions were grade 0 or 1. Grade 2 reactions were recorded for 3 subjects at day 2, 6 subjects at day 3, 10 subjects at days 8 and 9, and 9 subjects at day 15. Grade 3 reactions were recorded in 2 subjects at day 3 and in 1 subject at days 2, 8, and 15. No grade 4 reactions were recorded. All L-TEAEs reverted to grade 0 or 1 within 1 week of Viaskin discontinuation (day 22). Grade 2 and 3 L-TEAEs were described in more subjects with nonsevere than severe PA treated with Viaskin Peanut, indicating that severity of PA did not affect the L-TEAEs. The 24-hour regimen had a slightly improved safety profile, with less L-TEAEs noted when compared with the 48-hour regimen. The use of topical 1% hydrocortisone and oral antihistamines increased from 46% at baseline to 93% during the study for Viaskin Peanut–treated subjects and from 50% at baseline to 100% during the study for placebo-treated subjects. Safety parameters, including vital signs, physical findings, AD severity scores, change in peak expiratory flow/FEV1, and clinical laboratory parameters remained unchanged throughout the study among all treatment cohorts. Additionally, there were no significant changes in peanut sensitization in any treatment group, as measured based on comparison of baseline and end-of-study peanut-specific IgE measurements and SPT responses during the study. In conclusion, peanut EPIT administered through the novel Viaskin delivery system on intact skin is safe and well tolerated, with high adherence by study participants. Two participants receiving active dosing had systemic symptoms during the study, findings most likely related to transfer of allergen from the patch to mucosal surfaces (eg, eyes, nose, and mouth) during application rather than systemic absorption of microgram quantities of allergen through intact skin. This rationale is supported by preclinical studies, but findings highlight the need for further investigation in phase 2 clinical trials. Application of Viaskin Peanut for 24 hours demonstrated the optimal safety profile in all ages, with no differences in systemic or local reactions among different ages or PA severity cohorts. All tested Viaskin Peanut doses were considered safe for each age group and were recommended by the DSMB for forthcoming studies as follows: 250 μg for children with nonsevere allergy (6-11 years), 500 μg for adolescents with nonsevere allergy (12-17 years), and 500 μg for adults with nonsevere and severe allergy (≥18 years). The safety profile and adherence parameters reported here provide a benchmark for comparison for phase 2 clinical trials using the Viaskin Peanut device. Fig E2Incidence of non–L-TEAEs by system organ class and severity of PA. The proportion of subjects reporting non–L-TEAEs grouped by system organ classification and severity of PA is shown.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table E1Clinical study sitesClinical siteCity, stateArkansas Children's Hospital Research InstituteLittle Rock, ArkansasNational Jewish HealthDenver, ColoradoDuke University Medical CenterDurham, NCAspen Clinical ResearchOrem, UtahCRI WorldwideWillingboro, NJ Open table in a new tab Table E2Study inclusion and exclusion criteriaInclusion criteria 1. Male and female subjects aged 6-50 years at enrollment, any race, any ethnicity. 2. Physician-diagnosed PA or convincing history of PA regardless of the degree of the reaction provided that it was grade ≤3 anaphylaxis (or nonsevere anaphylaxis); subjects with history of severe anaphylaxis to peanut (defined as grades 4 or 5 with dyspnea, cyanosis, hypoxia, hypotension, or neurological compromise). 3. Peanut-specific IgE level, as measured by means of ImmunoCAP >0.7 kUA/L for all subjects AND a positive skin prick test response to peanut allergen with a wheal diameter ≥8 mm for all subjects with nonsevere allergy. A skin prick test for severe subjects will be conducted only if judged to be necessary by the investigator. 4. Use of an effective method of contraception by female subjects of childbearing potential and agreement to continue to practice an acceptable method of contraception for the duration of their participation in the study. Acceptable methods of contraception include oral, injectable, or implantable contraceptives; intrauterine device; diaphragm plus spermicide; or any double-barrier method. Women who have had a hysterectomy or tubal ligation ≥6 months before visit 1 or who have been postmenopausal for at least 1 year before visit 1 are not considered to be of childbearing potential. 5. Ability to perform spirometric maneuvers in accordance with the American Thoracic Society guidelines (1994) 6. Able to understand the protocol and willing to comply with all study requirements during participation in the study. 7. Provide signed informed consent and assent, as appropriate.Exclusion criteria 1. Participation in a study using an investigational new drug in the last 30 days before visit 1. 2. Participation in any interventional study for the treatment of food allergy in the past 6 months before visit 1. 3. Pregnancy or lactation. 4. Allergy or known hypersensitivity to the Viaskin disk or adhesives. 5. Severe or poorly controlled AD or generalized eczema. 6. FEV1 1 month during the past year, burst oral steroid course in the past 6 months, or >1 burst oral steroid course in the past year before visit 1. Use of oral steroids as described above after visit 1 and before randomization (visit 2) will render the subject ineligible for randomization. 8. Asthma requiring ≥1 hospitalization in the past year or >1 emergency department visit in the past 6 months before visit 1. Occurrence of asthma in these conditions after visit 1 and before randomization (visit 2) will render the subject ineligible for randomization. 9. Use of omalizumab or immunomodulatory or biologic therapy in the past year before visit 1. 10. Use of other nontraditional forms of allergen immunotherapy (eg, oral immunotherapy or sublingual allergen immunotherapy) in the past year before visit 1. 11. Use of subcutaneous immunotherapy other than a stable maintenance dose for less than a year before visit 1. 12. Use of β-blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers. 13. Inability to discontinue antihistamines for at least 1 week to allow skin testing at visit 1. 14. History of alcohol or drug abuse. 15. Uncontrolled hypertension. 16. History of cardiovascular disease, arrhythmias, chronic lung disease, active eosinophilic gastrointestinal disease, malignancy, psychiatric illness, or any other medical or surgical conditions, which, in the opinion of the investigator, place the subject at increased risk for participation in this study. 17. Inability or unwillingness to sign informed consent forms or provide assent (where age appropriate). 18. Inability to speak English, including caretakers of participants when the participant is a child. Open table in a new tab Table E3Grading of food-induced anaphylaxis according to severity of clinical symptomsGradeSkinGastrointestinal tractRespiratory tractCardiovascularNeurological1Localized pruritus, flushing, urticaria, angioedemaOral pruritus, oral "tingling," mild lip swelling2Generalized pruritus, flushing, urticaria, angioedemaAny of the above, nausea and/or emesis x's 1Nasal congestion and/or sneezingChange in activity level3Any of the aboveAny of the above plus repetitive vomitingRhinorrhea, marked congestion, sensation of throat pruritus or tightnessTachycardia (increase >15 beats/min)Change in activity level plus anxiety4Any of the aboveAny of the above plus diarrheaAny of the above, hoarseness, "barky" cough, difficulty swallowing, dyspnea, wheezing, cyanosisAny of the above, dysrhythmia and/or mild hypotension"Light headedness," feeling of "pending doom"5Any of the aboveAny of the above, loss of bowel controlAny of the above, respiratory arrestSevere bradycardia and/or hypotension or cardiac arrestLoss of consciousnessSubjects with nonsevere allergy were defined as children, adolescents, or adults with a positive SPT response (wheal diameter, ≥8 mm), an sIgE level of greater than 0.7 kUA/L, and a history of clinical allergy to peanut with anaphylaxis of grade 3 or less. Subjects with severe allergy were defined as adults with a positive SPT response (wheal diameter, ≥8 mm), an sIgE level of greater than 0.7 kUA/L, and a history of allergy to peanuts with anaphylaxis of grade 4 or 5. No symptoms are mandatory. The severity score should be based on the organ system most affected. For example, if grade 3 respiratory symptoms but only grade 1 gastrointestinal symptoms are present, then the anaphylaxis severity score would be grade 3. Boldface symptoms are absolute indications for the use of epinephrine; use of epinephrine with other symptoms will depend on the patient's history. From Sampson HA. Anaphylaxis and emergency treatment. Pediatrics 2003;111:1601-8. Open table in a new tab Table E4Clinical characteristics of the study populationViaskin Peanut, all subjects (n = 80)Placebo, all subjects (n = 20)Age (y)∗Age at informed consent was calculated as follows: ([Date of informed consent − Date of birth]/365.25). Mean (SD)24.7 (11.56)22.2 (9.18) Median23.022.0 Minimum-maximum6-499-48Sex Male50 (62.5%)10 (50.0%) Female30 (37.5%)10 (50.0%)Race White62 (77.5%)16 (80.0%) Black16 (20.0%)3 (15.0%) Asian1 (1.3%)0 (0.0%) Other1 (1.3%)1 (5.0%)Ethnicity Hispanic4 (5.0%)2 (10.0%) Non-Hispanic76 (95.0%)18 (90.0%)Height (cm) Mean (SD)168.44 (15.79)169.50 (13.51) Median170.85170.35 Minimum-maximum124.5-195.6134.6-188.0Weight (kg) Mean (SD)72.87 (24.39)69.03 (21.16) Median74.4072.11 Minimum-maximum23.40-130.027.12-105.40Peanut-specific IgE, (kUA/L)†Baseline measurement was defined as the last (nearest) predose measurement obtained before the initial Viaskin Peanut application at day 1. Peanut-specific IgE values of greater than the cutoff of 100.00 kUA/L were arbitrarily set to 100.001 kUA/L. Mean (SD)22.73 (29.24)36.50 (38.18) Median9.8921.75 Minimum-maximum0.78->100.000.71->100.00Historical anaphylaxis reaction grade 13 (3.8%)0 (0.0%) 210 (12.5%)4 (20.0%) 343 (53.8%)10 (50.0%) 424 (30.0%)6 (30.0%)Note: Percentages are based on the number of subjects in each dose group.∗ Age at informed consent was calculated as follows: ([Date of informed consent − Date of birth]/365.25).† Baseline measurement was defined as the last (nearest) predose measurement obtained before the initial Viaskin Peanut application at day 1. Peanut-specific IgE values of greater than the cutoff of 100.00 kUA/L were arbitrarily set to 100.001 kUA/L. Open table in a new tab Table E5Summary of adverse events and subject withdrawalsViaskin Peanut (n = 80)Viaskin Placebo (n = 20)SAEs00Dropouts3 (3.75%)1 (5%)Subjects with ≥1 TEAE42 (52.5%)9 (45%) Mild3 (41.3%)6 (30%) Moderate9 (11.2%)3 (15%) Severe0 (0%)0 (0%)Subjects with ≥1 L-TEAE67 (84%)12 (60%) Mild26 (32.5%)10 (50%) Moderate32 (40%)2 (10%) Severe9 (11%)0 (0%)SAEs, Severe adverse events. Open table in a new tab Table E6Incidence of TEAEs∗Includes 4 prespecified symptoms from the diary.: Pooled treatment group P values and relative riskViaskin Peanut, all subjects (n = 80)Placebo, all subjects (n = 20)P value†P value from Fisher exact test comparing proportions of TEAEs between the 2 treatment groups (ie, Viaskin Peanut and placebo) based on comparing the "all subjects" columns corresponding to Viaskin Peanut and placebo.Relative risk‡Relative risk was computed as the presence of adverse events in the Viaskin Peanut treatment group relative to presence of adverse events in the placebo group.95% CI for RRNo. of subjects with ≥1 TEAE75 (93.8%)15 (75.0%).02551.30.96-1.62General disease and administration-site conditions69 (86.3%)12 (60.0%).02121.40.99-2.08 Application-site pruritus66 (82.5%)10 (50.0%) Application-site erythema56 (70.0%)5 (25.0%) Application-site edema38 (47.5%)1 (5.0%) Application-site urticaria40 (50.0%)3 (15.0%) Chest discomfort1 (1.3%)0 Influenza-like illness1 (1.3%)0 Pyrexia1 (1.3%)0 Application-site pain01 (5.0%)Gastrointestinal disorders8 (10.0%)2 (10.0%)1.00001.00.23-4.35 Abdominal discomfort2 (2.5%)0 Vomiting2 (2.5%)0 Abdominal pain, upper1 (1.3%)2 (10.0%) Lip edema1 (1.3%)0 Mouth ulceration1 (1.3%)0 Nausea1 (1.3%)0Nervous system disorders10 (12.5%)6 (30.0%).8400.40.17-1.01 Headache7 (8.8%)6 (30.0%) Migraine2 (2.5%)0 Paraesthesia, mucosal1 (1.3%)0Infections and infestations10 (12.5%)3 (15.0%).72000.80.25-2.75 Nasopharyngitis4 (5.0%)0 Pharyngitis, streptococcal1 (1.3%)0 Viral upper respiratory tract infection1 (1.3%)0 Arthritis, infective01 (5.0%) Oral herpes01 (5.0%) Skin infection01 (5.0%)Skin and subcutaneous tissue disorders7 (8.8%)2 (10.0%)1.0000.90.20-3.89 Dermatitis, atopic1 (1.3%)0 Eczema1 (1.3%)0 Pruritus2 (2.5%)0 Rash2 (2.5%)0 Urticaria2 (2.5%)1 (5.0%) Dermatitis, contact01 (5.0%)Immune system disorders5 (6.3%)1 (5.0%)1.0001.30.15-10.11 Allergy to animals2 (2.5%)0 Food allergy1 (1.3%)0 Injury, poisoning, and procedural complications1 (1.3%)1 (5.0%) Arthropod bite1 (1.3%)2 (10.0%).10110.10.01-1.31 Contusion1 (1.3%)0 Joint sprain01 (5.0%)Percentages are based on the number of subjects in each dose group. Adverse events were coded by using the Medical Dictionary for Regulatory Activities (Version 13.0). At each level of subject summarization, a subject was counted once if that subject experienced the same adverse event more than once.RR, Relative risk.∗ Includes 4 prespecified symptoms from the diary.† P value from Fisher exact test comparing proportions of TEAEs between the 2 treatment groups (ie, Viaskin Peanut and placebo) based on comparing the "all subjects" columns corresponding to Viaskin Peanut and placebo.‡ Relative risk was computed as the presence of adverse events in the Viaskin Peanut treatment group relative to presence of adverse events in the placebo group. Open table in a new tab Table E7Extent of exposure and compliance to study medication: Pooled treatment groupsViaskin Peanut, all subjects (n = 80)Placebo, all subjects (n = 20)Duration of exposure (d)∗Duration is calculated as follows ([Day of last removal of double-blind study medication − Fay of first application of double–blind study medication] + 1). Mean (SD)14.6 (2.23)14.6 (1.57) Median15.015.0 Minimum-maximum1-168-15Cumulative dose received (μg)†The cumulative dose received is the sum of all medication taken across all visits. Mean (SD)2829.8 (2124.91)2856.0 (2304.04) Median2250.01875.0 Minimum-maximum140-7500140-8000Compliance (%)‡For subjects undergoing the 24-hour regimen, compliance is calculated as follows: 100 * (Total number of Viaskin disks used)/(Duration of exposure − 1). For subjects undergoing the 48-hour regimen, compliance is calculated as follows: 100 * 2 * (Total number of Viaskin disks used)/(Duration of exposure − 1).§Compliance for Viaskin Peanut was for 79 subjects. Mean (SD)100.18 (4.568)101.07 (3.494) Median100.00100.00 Minimum-maximum85.7-114.3100.0-114.3∗ Duration is calculated as follows ([Day of last removal of double-blind study medication − Fay of first application of double–blind study medication] + 1).† The cumulative dose received is the sum of all medication taken across all visits.‡ For subjects undergoing the 24-hour regimen, compliance is calculated as follows: 100 * (Total number of Viaskin disks used)/(Duration of exposure − 1). For subjects undergoing the 48-hour regimen, compliance is calculated as follows: 100 * 2 * (Total number of Viaskin disks used)/(Duration of exposure − 1).§ Compliance for Viaskin Peanut was for 79 subjects. Open table in a new tab Table E8Summary of incidence of L-TEAEs reported in the diary section by maximum duration and severity of PA: Safety populationViaskin PeanutPlaceboNonsevere allergy (n = 56)Severe allergy (n = 24)Nonsevere allergy (n = 14)Severe allergy (n = 6)No. of subjects with ≥1 L-TEAE452293 >21 d2 (3.6%)000 15-21 d8 (14.3%)5 (20.8%)00 8-14 d15 (26.8%)8 (33.3%)3 (21.4%)0 1-7 d20 (35.7%)9 (37.5%)6 (42.9%)3 (50.0%)General dis. and administration-site conditions452293 >21 d2 (3.6%)000 15-21 d8 (14.3%)5 (20.8%)00 8-14 d15 (26.8%)8 (33.3%)3 (21.4%)0 1-7 d20 (35.7%)9 (37.5%)6 (42.9%)3 (50.0%)Application-site pruritus442282 15-21 d8 (14.3%)3 (12.5%)00 8-14 d13 (23.2%)7 (29.2%)3 (21.4%)0 1-7 d23 (41.1%)12 (50.0%)5 (35.7%)2 (33.3%)Application-site erythema371841 >21 d2 (3.6%)000 15-21 d2 (3.6%)4 (16.7%)00 8-14 d12 (21.4%)5 (20.8%)00 1-7 d21 (37.5%)9 (37.5%)4 (28.6%)1 (16.7%)Application-site edema281010 15-21 d03 (12.5%)00 8-14 d2 (3.6%)1 (4.2%)00 1-7 d20 (35.7%)7 (29.2%)3 (21.4%)0Application-site urticaria281230 15-21 d4 (7.1%)1 (4.2%)00 8-14 d4 (7.1%)4 (16.7%)00 1-7 d20 (35.7%)7 (29.2%)3 (21.4%)0Note: Percentages are based on numbers of subjects in each severity group. Adverse events were coded by using the Medical Dictionary for Regulatory Activities (Version 13.0). At each level of subject summarization, a subject was counted once if that subject experienced the same adverse event more than once. Subjects were summarized according to the highest duration level within both the system organ class and preferred term. Duration levels were as follows: more than 21 days, 15 to 21 days, 8 to 14 days, and 1 to 7 days. For the diary, an event was defined as 1 day or a sequence of consecutive days for a specific symptom graded 1, 2, or 3.AE, Adverse event. Open table in a new tab Subjects with nonsevere allergy were defined as children, adolescents, or adults with a positive SPT response (wheal diameter, ≥8 mm), an sIgE level of greater than 0.7 kUA/L, and a history of clinical allergy to peanut with anaphylaxis of grade 3 or less. Subjects with severe allergy were defined as adults with a positive SPT response (wheal diameter, ≥8 mm), an sIgE level of greater than 0.7 kUA/L, and a history of allergy to peanuts with anaphylaxis of grade 4 or 5. No symptoms are mandatory. The severity score should be based on the organ system most affected. For example, if grade 3 respiratory symptoms but only grade 1 gastrointestinal symptoms are present, then the anaphylaxis severity score would be grade 3. Boldface symptoms are absolute indications for the use of epinephrine; use of epinephrine with other symptoms will depend on the patient's history. From Sampson HA. Anaphylaxis and emergency treatment. Pediatrics 2003;111:1601-8. Note: Percentages are based on the number of subjects in each dose group. SAEs, Severe adverse events. Percentages are based on the number of subjects in each dose group. Adverse events were coded by using the Medical Dictionary for Regulatory Activities (Version 13.0). At each level of subject summarization, a subject was counted once if that subject experienced the same adverse event more than once. RR, Relative risk. Note: Percentages are based on numbers of subjects in each severity group. Adverse events were coded by using the Medical Dictionary for Regulatory Activities (Version 13.0). At each level of subject summarization, a subject was counted once if that subject experienced the same adverse event more than once. Subjects were summarized according to the highest duration level within both the system organ class and preferred term. Duration levels were as follows: more than 21 days, 15 to 21 days, 8 to 14 days, and 1 to 7 days. For the diary, an event was defined as 1 day or a sequence of consecutive days for a specific symptom graded 1, 2, or 3. AE, Adverse event.