Pepites

A DOUBLE-BLIND, PLACEBO-CONTROLLED, RANDOMIZED PHASE III PIVOTAL TRIAL TO ASSESS THE EFFICACY AND SAFETY OF PEANUT EPICUTANEOUS IMMUNOTHERAPY WITH VIASKIN PEANUT IN PEANUT-ALLERGIC CHILDREN (PEPITES STUDY)

Clinical Research Organization:

Sponsor Protocol No.:

DBV TECHNOLOGIES S.A.

PEPITES

SIGNATURE PAGE

Declaration of Sponsor or Responsible Medical Officer

Title: A Double-blind, Placebo-controlled, Randomized Phase III Pivotal Trial to Assess the Efficacy and Safety of Peanut Epicutaneous Immunotherapy with Viaskin Peanut in Peanut-allergic children (PEPITES Study)
This study protocol was subjected to critical review. The information it contains is consistent with current knowledge of the risks and benefits of the investigational product, as well as with the moral, ethical, and scientific principles governing clinical research as set out in the Declaration of Helsinki, [2013] (APPENDIX 1), and the guidelines on Good Clinical Practice.

PROTOCOL SYNOPSIS

• During the first week (from Day 1 through Day 7), the patches will be applied for 6 hours every day;
• During the second week (from Day 8 through Day 14), the patches will be applied for 12 hours every day;
• From the third week onwards (Day 15), the patches will be applied for the entire 24 hours daily.
  It is planned to screen approximately 470 subjects to achieve 330 subjects randomized in a 2:1 ratio ( 220 subjects in the Viaskin Peanut group and 110 subjects in the placebo group) in this study. Assuming that the drop-out rate might be up to , this will allow ensuring that approximately 280 subjects complete the study.
  Throughout the screening and randomization process, and to guarantee an adequate and sufficient representation of subjects of 4, 5 and 11 years of age (the youngest and the oldest of the age range), a minimum of 25 subjects of each of these 3 ages must be randomized. Each of these ages will thus represent a minimum of of the overall number of randomized subjects.

Population

Criteria for Evaluation of Efficacy

Primary efficacy endpoint:

• The initial ED was peanut protein and the ED is peanut protein at the post-treatment DBPCFC at Month 12, or;
• The initial ED was and the ED is peanut protein at the post-treatment DBPCFC at Month 12.

Secondary efficacy endpoints:

• Percentage of treatment responders at Month 12 in the active Viaskin Peanut group compared to the placebo group in each of the 2 screening ED strata.
• Percentage of treatment responders at Month 12 in the active Viaskin Peanut group compared to the placebo group in each of the 2 age subgroups: 4 to 5 years-old; 6 to 11 years-old.
• Mean and median cumulative reactive dose of peanut protein and change from baseline at Month 12 in the active Viaskin Peanut group versus the placebo group, overall as well as in each of the 2 screening ED strata;
• Mean and median ED of peanut protein and change from baseline at Month 12 in the active Viaskin Peanut group versus the placebo group, overall as well as in each of the 2 screening ED strata;
• Percentage of subjects responsive (those showing objective symptoms leading to DBPCFC stop) to a cumulative dose peanut protein at the post-treatment DBPCFC at Month 12 in the active Viaskin Peanut group versus the placebo group, overall as well as in each of the 2 screening ED strata;
• Percentage of subjects unresponsive (those showing no objective symptoms leading to DBPCFC stop) to a cumulative dose peanut protein at the post-treatment DBPCFC at

• Percentage of subjects unresponsive (those showing no objective symptoms leading to DBPCFC stop) to the highest dose of peanut protein, which is the percentage of subjects who pass the post-treatment DBPCFC at Month 12 in the active Viaskin Peanut group versus the placebo group, overall as well as in each of the 2 screening ED strata.

Other efficacy endpoints:

• Change from baseline in peanut-specific IgE and IgG4 at months 3, 6 and 12 in the active Viaskin Peanut group versus the placebo group, overall as well as in each of the 2 screening ED strata;
• Change from baseline in peanut skin prick testing maximum average wheal diameters at months 3,6 and 12 in the active Viaskin Peanut group versus the placebo group, in the overall population;
• Description of the quality of life questionnaires (Food Allergy Quality of Life Questionnaire [FAQLQ]/Food Allergy Independent Measure [FAIM]) and change from baseline in FAQLQ score at Month 12 in the overall population (for those countries where the translated and validated questionnaires are available and used).
  The following safety criteria will be evaluated:
• AEs and treatment-emergent adverse events (TEAEs) by System Organ Class (SOC) and Preferred Terms (PTs);
• TEAEs by maximum severity and relatedness to Viaskin Peanut ;
• Incidence, duration and maximum severity of local cutaneous Viaskin Peanut -induced AEs as assessed by the subject;
• Severity of local cutaneous Viaskin Peanut -induced AEs as assessed by the Investigator;
• Adverse events of special interest (AESI) including grade 4 local cutaneous reactions and systemic allergic AEs considered related to Viaskin Peanut ;
• Serious adverse events (SAEs) by SOC and PTs, and relatedness to Viaskin Peanut ;
• Laboratory data, physical examinations and vital signs;
• Spirometry results or PEF results.

• Objective symptoms elicited during the entry/screening DBPCFC and post-treatment DBPCFC at Month 12 by severity;
• Change in severity of objective symptoms elicited during the DBPCFC from baseline to Month 12 in the active Viaskin Peanut group versus the placebo group;
• SAEs elicited during the entry/screening DBPCFC and post-treatment DBPCFC at Month 12.
  A Data and Safety Monitoring Board (DSMB) composed of experts in food allergy and in the methodology of clinical studies will review study safety data at specific intervals during the study and on an ad hoc basis. A specific DSMB meeting will be held when the first 15 subjects 4 to 5 years of age have been randomized and treated for at least 4 weeks (that is, have
  completed the Month 1 visit). This is to assess very early in the study that the safety of Viaskin Peanut is acceptable in the youngest subjects.

Exploratory endpoints

• Change from baseline in IgE and IgG4 specific to peanut protein components at months 3,6 and 12 in the active Viaskin Peanut group versus the placebo group;
• Enumeration and characterization of reactions triggered by accidental consumption of peanut during the study;
• Analysis of "risk-taking behavior" of subjects (voluntary peanut consumption) during the study;
• Epigenetic modifications of the promoters of some specific genes;
• Safety sub-analysis in subjects with mutations in the filaggrin gene versus wild type subjects;
• Sensitization status to some other allergies and their evolution over the study period;
• SCORAD evolution over time.

Statistical Methods

Analysis sets:

Safety population:

Statistical methods:

Primary efficacy analysis:

Sensitivity analyses of primary efficacy endpoint:

Secondary efficacy analysis:

Other efficacy analyses:

Multiplicity issues:

Sample size calculations:

• A response rate for the active Viaskin Peanut group and response rate for the placebo group in the overall population, with a 2 -sided type-I error rate set to ;
• A lower bound of the CI of the difference between active
  treatment and placebo response rates in the overall population and in each stratum;
• A response rate for the active Viaskin Peanut g group and response rate for the placebo group in Stratum 1, with a 2 -sided type-I error rate set to ;
• A response rate for the active Viaskin Peanut group and response rate for the placebo group in Stratum 2, with a 2 -sided type-I error rate set to and a power set to ;
• The following expected distribution of the screening ED strata:
• of children having a screening ED from 1 mg to 10 mg ;
• of children having a screening ED from 30 mg to 300 mg .
• A ratio 2:1 to maximize the number of subjects treated in the active Viaskin Peanut group.
  Therefore, the sample size calculated for Stratum 2 is 185 subjects (approximately 123 subjects in the active Viaskin Peanut group and 62 subjects in the placebo group). Hence, if 185 children with a screening ED from 30 mg to 300 mg are required in the study, then, according to the expected distribution of the screening ED strata, approximately 95 children having a screening ED from 1 mg to 10 mg should be randomized, resulting in a total of 280 subjects evaluable for the primary efficacy endpoint in the analysis.
  This number of subjects leads to a power of in the overall population and in the Stratum 1.
  This is summarized in the following Table:

Summary of Sample Size Calculations

LIST OF STUDY PERSONNEL

Sponsor	PPD
	Chief Clinical Trial Officer DBV Technologies S.A. Green Square - Bâtiment D 80/84, rue des Meuniers 92220 Bagneux, France PPD
	PPD Director, Regulatory Affairs & Quality DBV Technologies S.A. (same address as above) PPD
	PPD Medical Director DBV Technologies S.A. (same address as above) PPD
	PPD Biostatistician DBV Technologies S.A. (same address as above) PPD
Contract Research Organization	PAREXEL International (IRL) Limited ("PAREXEL") 70 Sir John Rogerson's Quay Dublin 2 Ireland
Central Laboratory

TABLE OF CONTENTS
PROTOCOL SYNOPSIS ..... 4
LIST OF STUDY PERSONNEL ..... 14
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..... 22
1 INTRODUCTION. ..... 24
1.1 Background ..... 24
1.1.1 Summary of Findings from Non-clinical and Clinical Studies ..... 25
1.1.1.1 Non-clinical Studies ..... 25
1.1.1.2 Clinical Studies ..... 26
1.2 Rationale ..... 35
1.3 Risk-Benefit Assessment ..... 35
2 STUDY OBJECTIVES ..... 37
3 OVERALL DESIGN AND PLAN OF THE STUDY ..... 38
3.1 Overview ..... 38
3.2 Criteria for Evaluation of the Study ..... 40
3.2.1 Efficacy Criteria ..... 40
3.2.1.1 Primary Efficacy Endpoint ..... 40
3.2.1.2 Secondary Efficacy Endpoint ..... 40
3.2.1.3 Other Efficacy Endpoints ..... 41
3.2.2 Safety Criteria ..... 41
3.2.3 Exploratory Criteria ..... 42
3.3 Justification of the Study Design ..... 43
4 STUDY POPULATION ..... 44
4.1 Inclusion Criteria ..... 44
4.2 Exclusion Criteria ..... 45
4.3 Patient Withdrawal and Replacement ..... 47
4.3.1 Criteria for Withdrawal from Study Treatment and Study ..... 47
4.3.2 Study Stopping Rules ..... 48
4.3.3 Replacement of Withdrawn Subjects ..... 48
4.3.4 Data Collection and Follow-up after Withdrawal. ..... 48
4.4 Planned Sample Size and Number of Study Centers ..... 48
4.5 Patient Identification and Randomization ..... 49
4.5.1 Patient Identification ..... 49
4.5.2 Randomization Scheme ..... 49
4.5.3 Allocation/Randomization of Patients to Treatment ..... 49
5 STUDY DRUG ..... 50
5.1 Identity ..... 50
5.2 Administration ..... 50
5.2.1 Adjustment of Viaskin Patch Application in Case of Local or Systemic Reactions ..... 52
5.2.2 Safety Precaution Information ..... 53
5.3 Packaging, Labeling and Storage ..... 53
5.4 Blinding and Breaking the Blind ..... 54
5.5 Drug Accountability ..... 55
5.6 Compliance ..... 55
5.7 Viaskin Patch Adhesion ..... 55
5.8 Prior and Concomitant Medication ..... 56
5.8.1 Permitted Concomitant Medication ..... 56
5.8.2 Prohibited Prior and Concomitant Medication ..... 57
6 VARIABLES AND METHODS OF ASSESSMENT ..... 58
6.1 Efficacy Variables ..... 58
6.1.1 Response to Treatment - DBPCFC to Peanut ..... 58
6.1.1.1 Preparation of Peanut and Placebo Formulas ..... 59
6.1.1.2 Time Interval and Doses ..... 59
6.1.1.3 Entry/screening DBPCFC to Peanut ..... 59
6.1.1.4 Post-treatment DBPCFC to Peanut at Month 12 ..... 62
6.2 Safety Variables ..... 63
6.2.1 Adverse Events ..... 63
6.2.1.1 Collection of Adverse Events ..... 63
6.2.1.2 Definitions ..... 63
6.2.1.3 Assessment of Adverse Events ..... 63
6.2.1.4 Recording Adverse Events ..... 67
6.2.1.5 Reporting Serious Adverse Events ..... 67
6.2.1.6 Follow-up of Adverse Events ..... 68
6.2.1.7 Pregnancy ..... 68
6.2.1.8 Treatment of Overdose of Study Medication ..... 68
6.2.2 Laboratory Variables ..... 69
6.2.3 Vital Signs ..... 69
6.2.4 Physical Examinations ..... 70
6.2.5 Spirometry Test ..... 70
6.2.6 Peak Expiratory Flow ..... 70
6.2.7 Subject Diaries ..... 71
6.2.8 Skin Reaction and Photography ..... 71
6.2.9 Viaskin Patch Adhesion ..... 72
6.3 Demographics and Baseline Characteristics ..... 73
6.3.1 Patient Demography ..... 74
6.3.2 Disease History and Medical History ..... 74
6.3.3 Prior and Concomitant Medications ..... 74
6.4 Exploratory Variables ..... 74
6.4.1 Immunological Markers ..... 74
6.4.2 Skin Prick Test ..... 74
6.4.3 Food Allergy Quality of Life Questionnaire /Food Allergy Independent Measure ..... 75
6.4.4 Accidental Consumption of Peanuts ..... 75
6.4.5 Epigenetic analyses ..... 75
6.4.6 Genetic Screening ..... 75
6.4.7 Scoring Atopic Dermatitis ..... 76

9 ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS ....................... 106
9.1 Data Quality Assurance ........................................................................... 106
9.1.1 Database Management and Quality Control.................................... 106
9.2 Case Report Forms and Source Documentation ...................................... 106
9.2.1 Data Collection ............................................................................. 107
9.3 Access to Source Data ................................................................................ 107
9.3.1 Routine Monitoring.......................................................................... 107
9.3.2 Inspections and Auditing Procedures.............................................. 107
9.4 Data Processing ........................................................................................... 108
9.5 Archiving Study Records........................................................................... 108
9.6 Good Clinical Practice ............................................................................... 109
9.7 Informed Consent...................................................................................... 109
9.8 Protocol Approval and Amendment......................................................... 110
9.9 Data and Safety Monitoring Board ........................................................... 110

9.11 Premature Termination of the Study ...................................................... 111
9.12 Confidentiality ........................................................................................... 111
9.13 Contractual and Financial Details ............................................................. 112
9.14 Liability and Insurance.............................................................................. 112
9.15 Publication Policy ....................................................................................... 112
9.16 Study Center File Management ................................................................. 112
9.17 Clinical Study Report ................................................................................ 113
10 REFERENCE LIST ..... 114
APPENDICES ..... 117
APPENDIX 1 ..... 118
APPENDIX 2 ..... 125
APPENDIX 3 ..... 127
APPENDIX 4 ..... 128
APPENDIX 5 ..... 129
APPENDIX 6 ..... 130
APPENDIX 7 ..... 132
APPENDIX 8 ..... 142

Tables in Text

Table 2: Summary of Occurrence of Dosing Symptoms Per Applied Dose and Per Age Group in the CoFAR6 Study
30

List of Appendices

LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS

1 INTRODUCTION

1.1 Background

1.1.1 Summary of Findings from Non-clinical and Clinical Studies

1.1.1.1 Non-clinical Studies

1.1.1.2 Clinical Studies

1.1.1.2.2 ARACHILD Study: Phase II Pilot Efficacy and Safety Study (Completed)

1.1.1.2.3 VIPES Study: Phase IIb Efficacy and Safety Study (Completed)

1.1.1.2.4 OLFUS-VIPES Study: Open-label Follow-up Study of the VIPES Study (Ongoing)

1.1.1.2.5 CoFAR6 Study: Phase II Efficacy and Safety Study (Ongoing)

1.2 Rationale

1.3 Risk-Benefit Assessment

2 STUDY OBJECTIVES

3 OVERALL DESIGN AND PLAN OF THE STUDY

3.1 Overview

• Stratum 1: Children with a screening ED of or 10 mg ;
• Stratum 2: Children with a screening ED of or 300 mg .

• of children with a screening ED from 1 mg to 10 mg ;
• of children with a screening ED from 30 mg to 300 mg .

Figure 1: Study Design

3.2 Criteria for Evaluation of the Study

3.2.1 Efficacy Criteria

3.2.1.1 Primary Efficacy Endpoint

• The initial ED was peanut protein and the ED is peanut protein at the post-treatment DBPCFC at Month 12; or
• The initial ED was peanut protein and the ED is peanut protein at the post-treatment DBPCFC at Month 12.

3.2.1.2 Secondary Efficacy Endpoint

• The percentage of treatment responders at Month 12 in the active Viaskin Peanut group compared to the placebo group in each of the 2 screening ED strata;
• The percentage of treatment responders at Month 12 in the active Viaskin Peanut group compared to the placebo group in each of the 2 age subgroups (4 to 5 years-old; 6 to 11 years-old);
• The mean and median cumulative reactive dose of peanut protein and change from baseline at Month 12 in the active Viaskin Peanut group versus the placebo group, overall and for each screening ED stratum;
• The mean and median ED of peanut protein and change from baseline at Month 12 in the active Viaskin Peanut group versus the placebo group, overall as well as in each of the 2 screening ED strata;
• The percentage of subjects responsive (those showing objective symptoms leading to DBPCFC stop) to a cumulative dose peanut protein at the post-treatment DBPCFC at Month 12 in the active Viaskin Peanut group versus the placebo group, overall as well as in each of the 2 screening ED strata;
• The percentage of subjects unresponsive (those showing no objective symptoms leading to DBPCFC stop) to a cumulative dose peanut protein at the post-treatment DBPCFC at Month 12 in the active Viaskin Peanut group versus the placebo group, overall as well as in each of the 2 screening ED strata;
• The percentage of subjects unresponsive (those showing no objective symptoms leading to DBPCFC stop) to the highest dose of peanut protein, which is the percentage of subjects who pass the post-treatment DBPCFC at Month 12 in the active Viaskin Peanut group versus the placebo group, overall as well as in each of the 2 screening ED strata.

3.2.1.3 Other Efficacy Endpoints

• The change from baseline in peanut-specific IgE and immunoglobulin G4 subtype (IgG4) at months 3,6 and 12 in the active Viaskin Peanut group versus the placebo group, overall as well as in each of the 2 screening ED strata;
• The change from baseline in peanut skin prick testing maximum average wheal diameters at months 3,6 and 12 in the active Viaskin Peanut group versus the placebo group, in the overall population;
• Description of the quality of life questionnaires (Food Allergy Quality of Life Questionnaire [FAQLQ]/Food Allergy Independent Measure [FAIM]) and change from baseline in FAQLQ score at Month 12 in the overall population (for those countries where the translated and validated questionnaires are available and used).

3.2.2 Safety Criteria

• AEs and treatment-emergent adverse events (TEAEs) by System Organ Class (SOC) and Preferred Terms (PTs);
• TEAEs by maximum severity and relatedness to Viaskin Peanut ;
• Incidence, duration and maximum severity of local cutaneous Viaskin Peanut -induced AEs as assessed by the subject;
• Severity of local cutaneous Viaskin Peanut -induced AEs as assessed by the Investigator;
• Adverse events of special interest (AESI) including grade 4 local cutaneous reactions and systemic allergic AEs considered related to Viaskin Peanut ;
• Serious adverse events (SAEs) by SOC and PTs, and relatedness to Viaskin Peanut ;
• Laboratory data, physical examinations and vital signs;
• Spirometry results or Peak Expiratory Flow (PEF) results.

• Objective symptoms elicited during the entry/screening DBPCFC and post-treatment DBPCFC at Month 12 by severity;
• Change in severity of objective symptoms elicited during the DBPCFC from baseline to Month 12 in the active Viaskin Peanut group versus the placebo group;
• SAEs elicited during the entry/screening DBPCFC and post-treatment DBPCFC at Month 12.

3.2.3 Exploratory Criteria

• The change from baseline in IgE and IgG4 specific to peanut protein components at months 3,6 and 12 in the active Viaskin Peanut group versus the placebo group;
• Enumeration and characterization of reactions triggered by accidental consumption of peanut during the study;
• Analysis of "risk-taking behavior" of subjects (voluntary peanut consumption) during the study;
• Epigenetic modifications of the promoters of some specific genes;
• Safety sub-analysis in subjects with mutations in the filaggrin gene versus wild type subjects;
• Sensitization status to some other allergies and their evolution over the study period;
• Scoring atopic dermatitis (SCORAD) evolution over time.

3.3 Justification of the Study Design

4 STUDY POPULATION

4.1 Inclusion Criteria

1. Male or female children aged 4 through 11 years at Visit 1;
2. Physician-diagnosis of peanut allergy or children with a well-documented medical history of IgE-mediated symptoms after ingestion of peanut and currently following a strict peanut-free diet, but without a physician diagnosis;
3. Signed informed consent of parents/guardians of the child and child's assent (for children years of age or as per the country-specific regulations);
4. Negative urine pregnancy test for female subjects of childbearing potential. Female subjects of childbearing potential must agree and commit to use effective medical methods of contraception for the entire duration of their participation in the study. Sexual abstinence will be accepted as an effective method of contraception;
5. Peanut-specific IgE level (ImmunoCAP system) ;
6. Positive peanut SPT with a largest wheal diameter:
   a. for children 4 through 5 years of age at Visit 1,
   b. for children 6 years and above at Visit 1;
7. Positive DBPCFC at peanut protein: the ED of peanut protein during the entry/screening DBPCFC is capped to 300 mg , as in subjects must have objective IgE-mediated symptoms to peanut leading to stopping the challenge at peanut protein;
8. Ability to perform spirometry in accordance with the American Thoracic Society (ATS) guidelines 2007 (39) for subjects years of age. Ability to perform peak expiratory flow (PEF) measurements for subjects years of age. Subjects from 6 to 8 years of age who have documented inability to adequately perform spirometry can perform the PEF measurement instead. Subjects 4 years of age can be enrolled if they had no clinical features of moderate or severe persistent asthma within 1 year prior to visit 1 .

4.2 Exclusion Criteria

1. History of severe anaphylaxis to peanut with any of the following symptoms: hypotension, hypoxia, neurological compromise (collapse, loss of consciousness or incontinence);
2. Pregnancy or lactation;
3. Severe reaction during the entry/screening DBPCFC, defined as need for intubation, hypotension persisting after epinephrine administration, and/or the need for doses of epinephrine;
4. Objective IgE-mediated symptoms to the placebo formula during the entry/screening DBPCFC and leading to stopping the challenge;
5. Viral upper respiratory infection or gastroenteritis within 7 days of a food challenge (challenge must be rescheduled to occur at least 7 days after recovery);
6. Any clinically significant abnormality identified at the time of screening such as major infectious diseases (for example chicken pox, measles) which in the judgment of the Investigator may preclude safe participation or strict compliance with the protocol procedures (subjects can be considered for the study after recovery from these diseases);
7. Generalized dermatologic disease (for example active atopic dermatitis, uncontrolled generalized active eczema, ichthyosis vulgaris) extending widely on the skin and especially on the back with no intact zones to apply the Viaskin patches;
8. Symptomatic seasonal allergies that may interfere with the conduct of a DBPCFC. Subjects should be screened at a time when such allergies are asymptomatic (for example outside of the culprit season);
9. Known hypersensitivity to any of the Viaskin patch components (except peanut), including the adhesive film;
10. Known hypersensitivity to any component of the food challenge formula (except peanut);
11. Inability to discontinue short-acting antihistamines or long-acting antihistamines for the minimum wash-out periods as specified in the table in APPENDIX 4) prior to the skin prick testings or the food challenges;
12. Spirometry forced expiratory volume in 1 second of the predicted value at screening (visit 1) for subjects years of age and able to perform the spirometry, or PEF < 80% of predicted value at screening (visit 1) for subjects performing only the PEF measurements.
13. Diagnosis of asthma that fulfills any of the following criteria:
    a. Uncontrolled persistent asthma as defined by National Asthma Education and Prevention Program Asthma guidelines 2007 (40) or by Global Initiative for Asthma guidelines 2015 (41),
    b. Asthma treated with either a high daily dose of inhaled corticosteroid or with a combination therapy of a medium daily dose of inhaled corticosteroid with a long-acting inhaled -agonist or with a combination therapy of a high daily dose of inhaled corticosteroid with a long-acting inhaled -agonist (a list of daily dosages of inhaled corticosteroid is provided in APPENDIX 2). Asthmatic subjects treated with a medium daily dose of inhaled corticosteroids are eligible. Intermittent asthmatic subjects who require intermittent use of inhaled corticosteroids for rescue are also eligible,
    c. Two or more systemic corticosteroid courses for asthma in the past year or 1 oral corticosteroid course for asthma within 3 months prior to Visit 1, or during screening period (unless used to treat symptoms triggered by the DBPCFC),
    d. Prior intubation/mechanical ventilation for asthma within 1 year prior to Visit 1, or during screening;
14. Receiving -blocking agents, angiotensin-converting enzyme inhibitors, angiotensinreceptor blockers, calcium channel blockers or tricyclic antidepressant therapy;
15. Received anti-tumor necrosis factor drugs or anti-IgE drugs (such as omalizumab) or any biologic immunomodulatory therapy within 1 year prior to Visit 1, during screening period or during study participation;
16. Use of systemic long-acting corticosteroids within 12 weeks prior to Visit 1 and/or use of systemic short-acting corticosteroids within 4 weeks prior to Visit 1 or during screening (unless used for DBPCFC symptoms) (see APPENDIX 3);
17. Prior or concomitant history of any immunotherapy to any food allergy (for example EPIT, OIT, SLIT, or specific oral tolerance induction);
18. Receiving or planning to receive any aeroallergen immunotherapy during their participation in the study. Aeroallergen immunotherapy must be discontinued at the time of Visit 1;
19. Subject or parents/guardians of subjects with obvious excessive anxiety and unlikely to cope with the conditions of a food challenge;
20. Past or currently active disease(s) which, in the opinion of the Investigator or the Sponsor, may affect the subject's participation in this study or place the subject at increased risk during participation in the study, including but not limited to eosinophilic gastrointestinal disorders, autoimmune disorders, immunodeficiency, malignancy, uncontrolled diseases (for example hypertension, psychiatric illness, cardiac disease), or other disorders (for example liver, gastrointestinal, kidney, cardiovascular, pulmonary disease, or blood disorders);
21. Any disorder in which epinephrine is contraindicated such as coronary artery disease, uncontrolled hypertension, or serious ventricular arrhythmias;
22. Subjects unable to follow the protocol requirements;
23. Current participation in another clinical trial or participation in another clinical trial in the last 3 months prior to visit 1;
24. Diagnosis of mast cell disorders including mastocytosis or urticaria pigmentosa as well as hereditary or idiopathic angioedema;
25. Subjects receiving cyclosporine or other immunosuppressive agents within 1 year prior to Visit 1, or during the screening period or during study participation. Topical calcineurin inhibitors are permitted;
26. Subjects with severe psychiatric, psychological or neurological disorders;
27. Subjects being in any relationship or dependency with the sponsor and/or the investigator or the study staff.

4.3 Patient Withdrawal and Replacement

4.3.1 Criteria for Withdrawal from Study Treatment and Study

• Pregnancy (see Section 6.2.1.7);
• Severe "maculo-papular rash" or severe "dermatitis" failed to be controlled by adequate corrective treatments (including topical corticosteroids) and in spite of several study treatment interruptions;
• Severe anaphylaxis (or stage 3 anaphylaxis) (see APPENDIX 5) related to Viaskin Peanut patch application;
• More than 1 epinephrine injection for an AE related to Viaskin Peanut patch application (and not occurring during the DBPCFC).

• AE(s);
• At the discretion of the Investigator, if she/he decides that it is in the subject's best interest to be withdrawn from the study;
• The subject is unwilling to continue in the study (consent withdrawal);
• Lack of compliance with protocol requirements and procedures;
• The Sponsor, Regulatory Authorities, or Independent Ethics Committees (IECs)/Institutional Review Boards (IRBs) for any reason, stop the study;
• The subject fails to return to the clinic for scheduled visits and does not respond to telephone or written attempts at contact (lost to follow-up);
• Premature termination of the entire study as described in Section 9.11.

4.3.2 Study Stopping Rules

1. Any death related to Viaskin patch dosing;
2. More than one case of severe anaphylaxis (or stage 3 anaphylaxis) (see APPENDIX 5) related to Viaskin® Peanut patch application (not occurring during the DBPCFC);
3. More than 3 subjects requiring more than 1 injection of epinephrine for an AE related to the Viaskin Peanut patch application (and not occurring during the DBPCFC).
   Upon safety review, 1 of the following outcomes will be determined:

• Accrual to the study may continue without modification;
• Accrual to the study may continue with modifications as prescribed by the DSMB;
• Accrual to the study should be discontinued.

4.3.3 Replacement of Withdrawn Subjects

4.3.4 Data Collection and Follow-up after Withdrawal

4.4 Planned Sample Size and Number of Study Centers

4.5 Patient Identification and Randomization

4.5.1 Patient Identification

4.5.2 Randomization Scheme

• of children with a screening ED from 1 mg to 10 mg ;
• of children with a screening ED from 30 mg to 300 mg .

4.5.3 Allocation/Randomization of Patients to Treatment

5 STUDY DRUG

5.1 Identity

5.2 Administration

Figure 2: Schematic Representation of Viaskin Patch Application on the Back of the Subjects

• During the first week (from Day 1 through Day 7), the patches will be applied for 6 hours every day;
• During the second week (from Day 8 through Day 14), the patches will be applied for 12 hours every day;
• From the third week onwards (Day 15), the patches will be applied for the entire 24 hours.
  If possible, the subjects should take advantage of their shower/bath time to change the patch. The previous Viaskin patch should be removed just before the shower/bath, and the new Viaskin patch should be applied a few minutes after the shower/bath and after drying the skin. Application of the Viaskin patch at a similar time for each daily application (morning or evening) is recommended. If the subject does not bathe or shower daily or at the same time daily, it is recommended that the zone to which the patch will be applied be cleaned with a moist disposable napkin or tissue and dried prior to application.
  A Viaskin patch must not be re-applied. In case the Viaskin patch comes off, it should be immediately discarded.
  A new patch can be applied the same day to replace the previous patch that came off only if that patch came off within 2 hours after being applied. However, no new patch should be applied the same day if the previous patch came off more than 2 hours after being applied. In that case, a new patch will be applied once 24 hours have passed since the previous patch (the one that came off) was applied. After the Viaskin patch comes off,
  or after removing a Viaskin patch to apply a new one, it is recommended that the subject's parents/guardians wipes the zone with a moist disposable napkin or a moist disposable tissue and then washes her/his hands to prevent accidental manual transmission of peanut protein.
  After the first application of the Viaskin patch at the study site, all subjects will be observed for 3 hours before being discharged in order to check and grade any reactions under or around the patch.
  Because the study includes children aged 4 through 5 years, additional safety measures have been adopted and generalized to all ages. On Day 4 and on Day 22, specific phone contacts will be made to the parents/guardians to assess the safety of patch applications on the back. If required, the subjects may come to the site sooner than planned to be seen and evaluated by the Investigator.
  Of note, the recommended duration of daily Viaskin patch application is 24 hours of application per day. However, any daily duration of Viaskin patch application of 24 hours hours will be allowed.

5.2.1 Adjustment of Viaskin Patch Application in Case of Local or Systemic Reactions

5.2.2 Safety Precaution Information

1. Instructions and procedures to apply the patch safely and correctly in the back of the subject;
2. Necessity to call the investigative site staff in case of intense or severe local reactions lasting for more than 1 day or any unexpected reactions during the treatment period, in particular any appearance of vesicles/blisters under the patch or close to the area of patch application and a recommendation to take photos of the site of application to document such a situation;
3. Necessity to call the investigative site staff in case of occurrence of chicken pox or measles. At the same time, interruption of patch application until recovery;
4. In case of active eczema extending on the back of the child: stop applying the patch until recovery from the active eczema on the back;
5. Anaphylaxis Emergency Action Plan in case of a suspected anaphylactic reaction and how to administer the epinephrine auto-injector to rapidly treat the reaction;
6. Subject stopping rules (subject are consequently withdrawn):
   a. Severe "maculo-papular rash" or severe "dermatitis" at sites of patch application not controlled by topical corticosteroids,
   b. Severe anaphylaxis related to Viaskin Peanut patch application confirmed by an expedited safety review.
   c. More than 1 epinephrine injection in relation to Viaskin Peanut patch application (and not occurring during DBPCFC).

5.3 Packaging, Labeling and Storage

5.4 Blinding and Breaking the Blind

5.5 Drug Accountability

5.6 Compliance

5.7 Viaskin Patch Adhesion

5.8 Prior and Concomitant Medication

5.8.1 Permitted Concomitant Medication

5.8.2 Prohibited Prior and Concomitant Medication

• Short-acting antihistamines or long-acting antihistamines taken must be washed out for the minimum period of time specified in the table in APPENDIX 4 prior to the skin prick testing or to the food challenges;
• Treatment with a high daily dose of inhaled corticosteroid or treatment with a combination therapy of a medium daily dose of inhaled corticosteroid with a long-acting inhaled -agonist or treatment with a combination therapy of a high daily dose of inhaled corticosteroid with a long-acting inhaled -agonist (a list of dosages of inhaled corticosteroids is provided in APPENDIX 2.
• Two or more systemic corticosteroid courses for asthma taken in the year prior to Visit 1 or 1 oral corticosteroid course for asthma taken within 3 months prior to Visit 1, or during screening period (unless used to treat symptoms triggered by the DBPCFC);
• -blocking agents, angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, calcium channel blockers or tricyclic antidepressant therapy, during the screening period or during study participation;
• Anti-tumor necrosis factor drugs or anti-IgE drugs (such as omalizumab) or any biologic immunomodulatory therapy taken within 1 year prior to Visit 1, during screening period or during study participation;
• Cyclosporine or other immunosuppressive agents used within 1 year prior to Visit 1, during the screening period or during the study participation. Topical calcineurin inhibitors are permitted,
• Systemic long-acting corticosteroids used within 12 weeks prior to Visit 1 and/or systemic short-acting corticosteroids used within 4 weeks prior to Visit 1 or during screening (unless used for DBPCFC symptoms);
• Any prior or concomitant immunotherapy administered to any food (for example EPIT or OIT or SLIT or specific oral tolerance induction);
• Any aeroallergen immunotherapy administered during study participation.

6 VARIABLES AND METHODS OF ASSESSMENT

6.1 Efficacy Variables

6.1.1 Response to Treatment - DBPCFC to Peanut

6.1.1.1 Preparation of Peanut and Placebo Formulas

6.1.1.2 Time Interval and Doses