Clinical trial NCT04984876
Conditions: Allergy, Peanut
Keywords: Food allergy Peanut allergy Oral food challenge IgE ligelizumab
Sponsor: Novartis Pharmaceuticals
Start date: 2021-12-07; Completion date: 2023-11-27
Enrollment: 211 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a 52-week, Phase 3 multi-center, randomized, double-blind and placebo-controlled study to assess the safety and clinical efficacy of two dosing regimens of ligelizumab (240 mg and 120 mg) SC q4w (subcutaneous injection every 4 weeks) in participants with a medically confirmed diagnosis of Immunoglobulin E (IgE) mediated peanut allergy.

Detailed description:
Participants were randomized to ligelizumab 240 mg, ligelizumab 120 mg, or placebo (5 treatment arms, randomization ratio of 2:2:2:2:1) for the double-blind placebo-controlled treatment period (up to Week 12).

Participants initially assigned to the 8-week placebo arms received the first dose of blinded ligelizumab treatment at the Week 8 visit. Participants initially assigned to the 16-week placebo arm received the last dose of placebo before the Double Blind Placebo Controlled Food Challenge (DBPCFC) at Week 12 and the first dose of blinded ligelizumab treatment at the Week 16 visit.

At the start of the study, recruitment was restricted to 12-55-year-old participants. After approximately 60 adolescent participants (defined as 12-17 yrs of age) had completed all Week 12 assessments, an interim analysis (IA1) on Pharmacokinetics (PK) and selected Pharmacodynamics (PD) data (total IgE and basophil bound High affinity immunoglobulin E receptor 1 (FcƐRI)) was performed (safety was reviewed by a Data Monitoring Committee - DMC). Independent sponsor members who were responsible for PK/ PD data analysis and Modeling \& Simulation were unblinded to the results of this interim analysis. The planned intent of this analysis was to confirm the dosing strategy for the youngest age group, 6-11 yrs and once the dose was to be confirmed, recruitment was supposed to be open for this age group. However, Novartis made a strategic decision to close recruitment in the study CQGE031G12301 and to terminate the study early, once all eligible participants in the study had completed week 12 assessments and the 16-week safety follow-up period. This decision was based on a blinded data review, which showed evidence of efficacy without the detection of any safety signal and that efficacy may be optimized with a different dosing regimen. Due to this decision, the final population size was 211, with only adolescent and adult participants (12 - 17yrs, and 18 - 55yrs) recruited.

Arms: arm 1: ligelizumab 240 mg subcutaneous injection for 52 weeks arm 2: ligelizumab 120 mg subcutaneous injection for 52 weeks arm 3: Placebo subcutaneous injection for first 8 weeks and ligelizumab 120 mg subcutaneous injection for 44 weeks arm 4: Placebo subcutaneous injection for first 16 weeks and ligelizumab 120 mg OR 240 mg subcutaneous injection for 36 weeks arm 5: Placebo subcutaneous injection for first 8 weeks and ligelizumab 240 mg subcutaneous injection for 44 weeks
Interventions: intervention 1: ligelizumab intervention 2: Placebo
Intervention descriptions: intervention 1: Subcutaneous injection once every 4 weeks intervention 2: Subcutaneous injection once every 4 weeks

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development 
QGE031 
Clinical Trial Protocol CQGE031G12301 / NCT04984876
A 52 week, multi-center, randomized, double-blind placebo-
controlled study to assess the clinical efficacy and safety 
of ligelizumab (QGE031) in decreasing the sensitivity to 
peanuts in patients with peanut allergy 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2020-005339-56/ PIP Number: EMEA-001811-PIP03-20 
Version number: 
01 (Clean) 
Clinical Trial Phase: 
III 
Approval date: 
12-Apr-2022 (content final)
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 4.0 dated 15-Feb-2021 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 7 
List of abbreviations ............................................................................................................ 8 
Glossary of terms ............................................................................................................... 12 
Amendment 1 (12-Apr-2022) ............................................................................................ 15 
Protocol summary .............................................................................................................. 19 
1 
Introduction ....................................................................................................................... 22 
1.1 
Background ............................................................................................................ 22 
1.2 
Purpose .................................................................................................................. 23 
2 
Objectives, endpoints and estimands ................................................................................. 24 
2.1 
Primary estimands ................................................................................................. 25 
2.2 
Secondary estimands ............................................................................................. 27 
2.2.1 
Proportion of responders who can tolerate a single dose of ≥1000 
mg of peanut protein at Week 12 .......................................................... 27 
2.2.2 
Proportion of responders who can tolerate a single dose of 3000 mg 
of peanut protein at Week 12 ................................................................ 27 
2.2.3 
Maximum severity of symptoms at any single challenge dose up to 
and including 1000 mg of peanut protein at Week 12 .......................... 27 
2.2.4 
Proportion of responders who can tolerate a single dose of ≥1000 
mg of peanut protein at Week 12 with 8 weeks of placebo followed 
by 4 weeks of ligelizumab..................................................................... 28 
3 
Study design ...................................................................................................................... 29 
4 
Rationale ............................................................................................................................ 31 
4.1 
Rationale for study design ..................................................................................... 31 
4.1.1 
Rationale for choice of background therapy ......................................... 32 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 32 
4.3 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 34 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 34 
4.5 
Risks and benefits .................................................................................................. 35 
4.6 
Rationale for Public Health Emergency mitigation procedures ............................ 39 
5 
Study Population ............................................................................................................... 39 
5.1 
Inclusion criteria .................................................................................................... 39 
5.2 
Exclusion criteria ................................................................................................... 40 
6 
Treatment ........................................................................................................................... 42 
6.1 
Study treatment ...................................................................................................... 42 


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6.1.1 
Investigational and control drugs .......................................................... 42 
6.1.2 
Treatment arms/group ........................................................................... 43 
6.1.3 
Treatment duration ................................................................................ 43 
6.2 
Other treatment(s) .................................................................................................. 43 
6.2.1 
Concomitant therapy ............................................................................. 43 
6.2.2 
Prohibited medication ........................................................................... 44 
6.2.3 
Rescue medication ................................................................................ 45 
6.3 
Preparation and dispensation ................................................................................. 46 
6.3.1 
Handling of study treatment and other treatment .................................. 46 
6.3.2 
Instruction for prescribing and taking study treatment ......................... 47 
6.4 
Participant numbering, treatment assignment, randomization .............................. 48 
6.4.1 
Participant numbering ........................................................................... 48 
6.4.2 
Treatment assignment, randomization .................................................. 48 
6.5 
Treatment blinding ................................................................................................ 49 
6.6 
Dose escalation and dose modification.................................................................. 51 
6.6.1 
Dose modifications ................................................................................ 51 
6.7 
Additional treatment guidance ............................................................................... 51 
6.7.1 
Treatment compliance ........................................................................... 51 
6.7.2 
Recommended treatment of adverse events .......................................... 51 
6.7.3 
Emergency breaking of assigned treatment code .................................. 51 
7 
Informed consent procedures ............................................................................................ 52 
8 
Visit schedule and assessments ......................................................................................... 54 
8.1 
Screening ............................................................................................................... 62 
8.1.1 
Information to be collected on screening failures ................................. 62 
8.2 
Participant demographics/other baseline characteristics ....................................... 62 
8.2.1 
Spirometry ............................................................................................. 63 
8.3 
Efficacy .................................................................................................................. 63 
8.3.1 
Double Blind Placebo Controlled Food Challenge (DBPCFC) ............ 63 
8.3.2 
Appropriateness of efficacy assessments .............................................. 64 
8.4 
Safety ..................................................................................................................... 64 
8.4.1 
Laboratory evaluations .......................................................................... 65 
8.4.2 
Electrocardiogram (ECG) ..................................................................... 66 
8.4.3 
Pregnancy and assessments of fertility ................................................. 67 
8.4.4 
Other safety evaluations ........................................................................ 67 
8.4.5 
Appropriateness of safety measurements .............................................. 68 
8.5 
Additional assessments .......................................................................................... 68 


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8.5.1 
Clinical Outcome Assessments (COAs) ............................................... 68 
 
 71 
 
 71 
8.5.4 
Other Assessments ................................................................................ 72 
9 
Discontinuation and completion ........................................................................................ 73 
9.1 
Discontinuation from study treatment and from study .......................................... 73 
9.1.1 
Discontinuation from study treatment ................................................... 73 
9.1.2 
Discontinuation from study ................................................................... 75 
9.1.3 
Lost to follow-up ................................................................................... 75 
9.2 
Withdrawal of informed consent and exercise of participants’ data privacy 
rights ...................................................................................................................... 75 
9.3 
Study completion and post-study treatment .......................................................... 76 
9.4 
Early study termination by the sponsor ................................................................. 76 
10 Safety monitoring, reporting and committees ................................................................... 77 
10.1 
Definition of adverse events and reporting requirements ...................................... 77 
10.1.1 
Adverse events ...................................................................................... 77 
10.1.2 
Serious adverse events .......................................................................... 78 
10.1.3 
SAE reporting........................................................................................ 79 
10.1.4 
Pregnancy reporting .............................................................................. 80 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 81 
10.2 
Additional Safety Monitoring ................................................................................ 81 
10.2.1 
Liver safety monitoring ......................................................................... 81 
10.2.2 
Renal safety monitoring ........................................................................ 82 
10.3 
Committees ............................................................................................................ 83 
10.3.1 
Data Monitoring Committee ................................................................. 83 
10.3.2 
Adjudication committee ........................................................................ 83 
11 Data Collection and Database management ...................................................................... 83 
11.1 
Data collection ....................................................................................................... 83 
11.2 
Database management and quality control ............................................................ 84 
11.3 
Site monitoring ...................................................................................................... 84 
12 Data analysis and statistical methods ................................................................................ 85 
12.1 
Analysis sets .......................................................................................................... 85 
12.2 
Participant demographics and other baseline characteristics ................................. 85 
12.3 
Treatments ............................................................................................................. 85 
12.4 
Analysis supporting primary objectives ................................................................ 86 
12.4.1 
Definition of primary endpoint(s) ......................................................... 86 


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12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 86 
12.4.3 
Handling of intercurrent events of primary estimand ........................... 87 
12.4.4 
Handling of missing values not related to intercurrent event ............... 87 
12.4.5 
Sensitivity analyses ............................................................................... 88 
12.4.6 
Supplementary analysis ......................................................................... 88 
12.4.7 
Supportive analyses ............................................................................... 88 
12.5 
Analysis supporting secondary objectives ............................................................. 88 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) .................................... 88 
12.5.2 
Safety endpoints .................................................................................... 92 
 
 93 
 
 93 
 
 93 
 
 93 
 
 94 
 
 94 
12.7 
Interim analyses ..................................................................................................... 94 
12.8 
Sample size calculation.......................................................................................... 95 
12.8.1 
Primary endpoint(s) ............................................................................... 95 
12.8.2 
Secondary endpoint(s) ........................................................................... 97 
13 Ethical considerations and administrative procedures .................................................... 100 
13.1 
Regulatory and ethical compliance ...................................................................... 100 
13.2 
Responsibilities of the investigator and IRB/IEC ................................................ 100 
13.3 
Publication of study protocol and results............................................................. 100 
13.4 
Quality Control and Quality Assurance ............................................................... 101 
13.5 
Participant Engagement ....................................................................................... 101 
14 Protocol adherence .......................................................................................................... 101 
14.1 
Protocol amendments........................................................................................... 101 
15 References ....................................................................................................................... 103 
16 Appendices ...................................................................................................................... 108 
16.1 
Appendix 1: Clinically notable laboratory values and vital signs ....................... 108 
16.2 
Appendix 2: Liver event and laboratory trigger definitions & follow-up 
requirements ........................................................................................................ 110 
16.3 
Appendix 3: Specific Renal Alert Criteria and Actions and Event Follow-up .... 113 
16.4 
Double-blind Placebo Controlled Food Challenge .............................................. 114 
16.4.1 
Background ......................................................................................... 114 
16.4.2 
DBPCFC dosing schedule ................................................................... 114 


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16.4.3 
DBPCFC material ............................................................................... 116 
16.4.4 
Preparing for the food challenge ......................................................... 116 
16.4.5 
Evaluation parameters of the DBPCFC .............................................. 117 
16.4.6 
DBPCFC completion .......................................................................... 118 
16.5 
Guidance for skin prick test ................................................................................. 119 
16.5.1 
Background of Skin Prick Test ........................................................... 119 
16.5.2 
Material ............................................................................................... 119 
16.5.3 
Starting the Skin Prick Test................................................................. 120 
16.5.4 
Completion of the Skin Prick Test ...................................................... 121 
16.6 
PRO Measures ..................................................................................................... 122 
16.6.1 
FAQLQ-CF: Food Allergy Quality of Life Questionnaire  Child 
Form .................................................................................................... 122 
16.6.2 
FAIM-CF: Food Allergy Independent Measure  Child Form ............. 124 
16.6.3 
FAQLQ-TF: Food Allergy Quality of Life Questionnaire  Teenager 
Form .................................................................................................... 125 
16.6.4 
FAIM-TF: Food Allergy Independent Measure  Teenager Form ....... 127 
16.6.5 
FAQLQ-AF: Food Allergy Quality of Life Questionnaire  Adult 
Form .................................................................................................... 128 
16.6.6 
FAIM-AF: Food Allergy Independent Measure  Adult Form ............ 131 
16.6.7 
FAQLQ-PF: Food Allergy Quality of Life Questionnaire  Parental 
Form .................................................................................................... 132 
16.6.8 
FAQL-PB: Food Allergy Quality of Life - Parental Burden 
Questionnaire ...................................................................................... 136 
16.6.9 
SF-36v2 Acute Version Short Form 36-Health Survey 
Questionnaire v2 ................................................................................. 139 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 24 
Table 6-1 
Investigational and control drug ............................................................ 42 
Table 6-2 
Medications allowed under certain conditions ...................................... 44 
Table 6-3 
Prohibited medication ........................................................................... 44 
Table 6-4 
Blinding level ........................................................................................ 50 
Table 8-1 
Assessment Schedule ............................................................................ 56 
Table 8-2 
Physical Assessments ............................................................................ 65 
Table 8-3 
Laboratory Evaluations ......................................................................... 66 
Table 8-4 
PROs based on participant’s age ........................................................... 69 
Table 10-1 
Base Renal Monitoring ......................................................................... 82 
Table 12-1 
Sensitivity of the power for each dose for the primary variable ........... 96 


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Table 12-2 
Power of each dose for the analyses of primary and key secondary 
variables in the base case scenario ........................................................ 97 
Table 12-3 
Power of each dose for the analyses of primary and key secondary 
variables in case of only 120 mg dosing for children 6 - 11 years ........ 98 
Table 12-4 
Precision levels (95% CI) for sensitivity of safety incidence rate 
per age group ......................................................................................... 99 
Table 12-5 
Precision levels (95% CI) for sensitivity of safety incidence rate for 
overall population ................................................................................ 100 
Table 16-1 
Notable values for Heart Rate (HR) and Blood Pressure in children 
and adolescents .................................................................................... 108 
Table 16-2 
Liver event and Laboratory trigger definitions ................................... 110 
Table 16-3 
Follow up requirements for liver laboratory triggers .......................... 110 
Table 16-4 
Follow up requirements for liver laboratory triggers .......................... 111 
Table 16-5 
Specific renal alert criteria and actions ............................................... 113 
Table 16-6 
Renal event follow-up ......................................................................... 113 
Table 16-7 
Dry Weight Dosing Table ................................................................... 115 
Table 16-8 
Definition of Dose-Limiting Symptoms (per the CoFAR* grading 
scale, Chinthrajah et al 2022 ) ............................................................. 117 
Table 16-9 
Medications to be washed out prior to SPT ........................................ 120 
List of figures 
Figure 3-1 
Study design .......................................................................................... 29 
Figure 3-2 
Study design for 6-11y with 120 mg only ............................................. 30 
Figure 4-1 
Simulation of PK/PD outcomes ............................................................ 33 
Figure 12-1 
Testing strategy ..................................................................................... 90 
Figure 16-1 
Measurement of skin reaction ............................................................. 121 
 


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List of abbreviations 
AC 
Adjudication Committee 
ACE 
Angiotensin converting enzyme 
ACR 
Albumin-to-creatinine ratio  
 
 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of covariance 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
ATS 
American Thoracic Society 
AUC 
Area under Curve 
AV 
Atrioventricular 
 
 
BM 
Biomarker 
bpm 
Beats per minute 
BUN 
Blood Urea Nitrogen 
CD23 
IgE (low affinity) receptor 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CI 
confidence intervals 
CK 
Creatine Kinase 
cm 
centimeter 
CMO&PS  
Chief Medical Office and Patient Safety 
CO 
Country Organization 
COA 
Clinical Outcome Assessment 
COVID-19 
Corona Virus Disease 2019 
CRA 
Clinical Research Associate 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
CSU 
Chronic Spontaneous Urticaria 
CT 
Computed Tomography 
CV 
coefficient of variation 
DBL 
Database Lock 
DBPCFC 
Double Blind Placebo Controlled Food Challenge 
DDE 
Direct Data Entry  
DIN 
Drug Inducted Nephrotoxicity 
DMC 
Data Monitoring Committee 
 
 
EAACI 
European Academy of Allergy and Clinical Immunology  
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 


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EDC 
Electronic Data Capture 
eSource 
Electronic Source 
EMA 
European Medicines Agency 
EOS 
End of study 
ERS 
European Respiratory Society 
EU 
European Union 
FAIM 
Food Allergy Independent Measure 
Fab 
Fragment antigen binding region 
FAQLQ 
Food Allergy Quality of Life Questionnaire 
FAS 
Full Analysis Set 
FcεRI 
IgE (high affinity) receptor 
FDA 
Food and Drug Administration 
FEV1 
Forced Expiratory Volume during the 1st second 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GCS 
Global Clinical Supply 
eGFR 
Estimated Glomerular Filtration Rate 
GGT 
Gamma-glutamyl transferase 
GINA 
Global Initiative for Asthma 
GLDH 
Glutamate Dehydrogenase 
gMCP 
Graph Based Multiple Comparison Procedures 
HLT 
High Level Term 
HRQoL 
Health-Related Quality of Life 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for Pharmaceuticals for 
Human Use 
ICU 
Intensive Care Unit 
IEC 
Independent Ethics Committee 
IG 
Immunoglobulin 
IgE 
Immunoglobulin E  
IgG 
Immunoglobulin G 
IMP 
Investigational Medicinal Product 
IN 
Investigator Notification 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IU 
International unit 
IUD 
Intrauterine device 
IUS 
Intrauterine system 
KDIGO 
Kidney Disease: Improving Global Outcomes 
L 
liter 
LDH 
lactate dehydrogenase 
LFT 
Liver function test  
LLOQ 
lower limit of quantification 
MAR 
Missing at random 


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MedDRA 
Medical dictionary for regulatory activities  
mg 
milligram(s) 
mL 
milliliter(s) 
mm 
millimeter 
mmHg 
Blood pressure unit millimeters of mercury 
MMRM 
Mixed model with repeated measures 
MRI 
Magnetic Resonance Imaging 
ms 
millisecond 
MTD 
Maximum Tolerated Dose 
NIH 
National Institutes of Health  
NOAEL 
No Observed Adverse Effect level 
NSD 
Needle Safety Device  
NYHA 
New York Heart Association 
OCS 
Oral corticosteroids 
OFC 
Oral Food Challenge 
OIT 
Oral immunotherapy  
PB 
Parental Burden 
PCR 
Protein-creatinine ratio  
PD 
Pharmacodynamic(s) 
PF 
Parental Form 
PFS 
Prefilled Syringe 
PK 
Pharmacokinetic(s) 
PRO 
Patient Reported Outcomes 
PSD 
Premature Subject Discontinuation 
PT 
prothrombin time 
q2w 
every two weeks 
q4w 
Every 4 weeks 
QMS  
Quality Management System 
QTcF 
QT interval corrected by Fridericia’s formula 
RAS 
Randomized Analysis Set  
RBC 
red blood cell(s) 
RR 
Responder rate 
SABA 
short-acting ß-agonist 
SAE 
Serious Adverse Event 
SAF 
Safety analysis set 
SAP 
Statistical Analysis Plan 
SC/ s.c. 
subcutaneous 
SCRN 
Screening 
sCD23 
Soluble (low affinity) IgE receptor  
SCq4W 
Subcutaneous injection every 4 weeks 
SD 
standard deviation 
sIgE 
specific IgE for the study allergen 
SLIT 
Sublingual immunotherapy 
SMQ 
Standardized MedDRA Query  


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SOP 
Standard Operating Procedure 
SPT 
Skin Prick Test 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TBIL 
Total Bilurubin 
TBL 
Total bilirubin 
TFQ 
Trial Feedback Questionnaires  
Total IgE 
Drug-bound and free IgE 
TSPT 
Titration skin prick test 
UK 
United Kingdom 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cell(s) 
WHO 
World Health Organization  
WK 
Week 
WoC 
Withdrawal of Consent 
β-hCG 
Beta-Human Chorionic Gonadotropin 
μL 
microliter 


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Glossary of terms 
Additional treatment 
Medicinal products that may be used during the clinical trial as described in the 
protocol, but not as an investigational medicinal product (e.g. any background 
therapy) 
Assessment 
A procedure used to generate data required by the study 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study participant  
Clinical Trial Team 
A group of people responsible for the planning, execution and reporting of all 
clinical trial activities. Examples of team members include the Study Lead, 
Medical Monitor, Trial Statistician etc. 
Cohort 
 A group of individuals who share a common exposure, experience or 
characteristic, or a group of individuals followed-up or traced over time 
Control drug 
A study drug (active or placebo) used as a comparator to reduce assessment 
bias, preserve blinding of investigational drug, assess internal study validity, 
and/or evaluate comparative effects of the investigational drug 
Discontinuation from 
study 
Point/time when the participant permanently stops receiving the study treatment 
and further protocol required assessments or follow-up, for any reason. No 
specific request is made to stop the use of their samples or data. 
Discontinuation from 
study treatment 
Point/time when the participant permanently stops receiving the study treatment 
for any reason (prior to the planned completion of study drug administration, if 
any). Participant agrees to the other protocol required assessments including 
follow-up. No specific request is made to stop the use of their samples or data. 
Dosage 
Dose of the study treatment given to the participant in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day) 
Electronic Data Capture 
(EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical study data 
using data collection systems, such as Web-based applications, interactive voice 
response systems and clinical laboratory interfaces. EDC includes the use of 
Electronic Case Report Forms (eCRFs) which are used to capture data 
transcribed from source   data/documents used at the point of care 
End of the clinical trial 
The end of the clinical trial is defined as the last visit of the last participant or at a 
later point in time as defined by the protocol  
Enrollment 
Point/time of participant entry into the study at which informed consent must be 
obtained  
eSource (DDE) 
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource Platform/Applications combines 
source documents and case report forms (eCRFs) into one application, allowing 
for the real time collection of clinical trial information to sponsors and other 
oversight authorities, as appropriate 
Estimand  
As defined in the ICH E9(R1) addendum, estimand is a precise description of the 
treatment effect reflecting the clinical question posed by the trial objective. It 
summarizes at a population-level what the outcomes would be in the same 
participants under different treatment conditions being compared. Attributes of an 
estimand include the population, variable (or endpoint) and treatment of interest, 
as well as the specification of how the remaining intercurrent events are 
addressed and a population-level summary for the variable. 
Intercurrent events 
Events occurring after treatment initiation that affect either the interpretation or the 
existence of the measurements associated with the clinical question of interest. 
Investigational drug/ 
treatment 
The drug whose properties are being tested in the study 
Medication number 
A unique identifier on the label of medication kits 
Mis-randomized 
participants 
Mis-randomized participants are those who were not qualified for randomization 
and who did not take study treatment, but have been inadvertently randomized 
into the study or the participant allocated to an invalid stratification factor 


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Other treatment 
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy) 
Part  
A sub-division of a study used to evaluate specific objectives or contain different 
populations. For example, one study could contain a single dose part and a 
multiple dose part, or a part in participants with established disease and in those 
with newly-diagnosed disease 
Participant 
A trial participant (can be a healthy volunteer or a patient)  
Participant number 
A unique number assigned to each participant upon signing the informed consent. 
This number is the definitive, unique identifier for the participant and should be 
used to identify the participant throughout the study for all data collected, sample 
labels, etc. 
Patient-Reported 
Outcome (PRO) 
A measurement based on a report that comes directly from the patient about the 
status of a participant's health condition without amendment or interpretation of 
the patient's report by a clinician or anyone else 
Period 
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) which 
are described in the Protocol. Periods define the study phases and will be used in 
clinical trial database setup and eventually in analysis 
Personal data 
Participant information collected by the Investigator that is coded and transferred 
to Novartis for the purpose of the clinical trial. This data includes participant 
identifier information, study information and biological samples. 
Premature participant 
withdrawal 
Point/time when the participant exits from the study prior to the planned 
completion of all study drug administration and/or assessments; at this time all 
study drug administration is discontinued and no further assessments are planned 
Randomization 
The process of assigning trial participants to investigational drug or 
control/comparator drug using an element of chance to determine the 
assignments in order to reduce bias. 
Randomization number 
A unique identifier assigned to each randomized participant 
Re-screening 
If a participant fails the initial screening and is considered as a Screen Failure, 
he/she can be invited once for a new Screening visit after medical judgment and 
as specified by the protocol 
Remote 
Describes any trial activities performed at a location that is not the investigative 
site where the investigator will conduct the trial, but is for example a home or 
another appropriate location 
Screen Failure 
A participant who did not meet one or more criteria that were required for 
participation in the study 
Source Data/Document 
Source data refers to the initial record, document, or primary location from where 
data comes. The data source can be a database, a dataset, a spreadsheet or 
even hard-coded data, such as paper or eSource 
Start of the clinical trial 
The start of the clinical trial is defined as the signature of the informed consent by 
the first participant 
Study treatment 
Any drug or combination of drugs   or intervention administered to the study 
participants as part of the required study procedures; includes investigational 
drug(s), control(s) or background therapy 
Study treatment 
discontinuation 
When the participant permanently stops taking any of the study drug(s) prior to 
the defined study treatment completion date (if any) for any reason; may or may 
not also be the point/time of study discontinuation  
Treatment arm/group  
A treatment arm/group defines the dose and regimen or the combination, and 
may consist of 1 or more cohorts. 
Treatment of interest 
The treatment of interest and, as appropriate, the alternative treatment to which 
comparison will be made. These might be individual interventions, combinations 
of interventions administered concurrently, e.g. as add-on to standard of care, or 
might consist of an overall regimen involving a complex sequence of 
interventions. This is the treatment of interest used in describing the related 


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clinical question of interest, which might or might not be the same as the study 
treatment. 
Variable (or endpoint) 
The variable (or endpoint) to be obtained for each participant that is required to 
address the clinical question. The specification of the variable might include 
whether the participant experiences an intercurrent event. 
Withdrawal of study 
consent (WoC)  
Withdrawal of consent from the study occurs when the participant explicitly 
requests to stop use of their data and/ or biological samples  AND no longer 
wishes to receive study treatment, AND does not agree to further protocol 
required assessments. This request should be in writing (depending on local 
regulations) and recorded in the source documentation. 
 This request should be distinguished from a request to discontinue the study. 
Other study participant’s privacy rights are described in the corresponding 
informed consent form. 


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Amendment 1 (12-Apr-2022) 
Amendment rationale 
The main purpose of this amendment is to 
• Change the data review mode for the DMC from semi-blinded to unblinded as per request 
of the DMC from 12-Oct-2021.  
• Adjust inclusion criterion number 4: The amended cutoff for positive peanut-specific IgE 
(peanut sIgE) is set at ≥ 0.35 kUA/L at Screening Visit 1 in order to avoid excluding patients 
with otherwise strong evidence supporting the diagnosis of peanut allergy (based on medical 
history and SPT).  
• Clarify and harmonize usage of prohibited medication and medication allowed under certain 
conditions  
 
 
• Reduce the number of stool samples required to determine participant eligibility at screening 
from three to one in asymptomatic participants.  
• Define two entry timepoints for participants who wish to enter the Extension study: at week 
68 (end of follow-up) for the first one third of participants or week 52 (end of treatment) for 
the remaining participants. 
It also includes other clarifications, minor updates and corrections of typographical errors across 
the document. 
Changes to protocol and rationale: 
Changes are shown in the track changes version of the protocol using strike through red font 
for deletions and red underlined for insertions. 
• Cover page: addition of approval date and PIP number 
• List of Abbreviations: Removal of abbreviations that are not required, correction of 
typographical errors, additions of required abbreviations 
• Glossary of terms: Rewording of withdrawal of consent, mis-randomized participants and 
cohort.  
• Protocol summary: rewording of data analysis section, rewording of eligibility criteria: 
positive skin prick test (SPT) for peanut allergen at Screening Visit 1 defined as an average 
diameter (Longest diameter and mid-point orthogonal diameter) ≥ 4 mm wheal compared 
to negative control, positive peanut-specific immunoglobulin E (peanut sIgE), ≥ 0.35 
kUA/L at Screening Visit 1, a positive peanut DBPCFC at baseline (Screening Visit 2, Part 
1 and Part 2 DBPCFC) defined as the occurrence of dose-limiting symptoms at a single dose 
≤ 100 mg of peanut protein. 
 
 
• Section 2.1: Combining two intercurrent events due to operational complications caused by 
public health emergency into one category for simplification, rewording for clarity   
• Section 2.2: Rewording of secondary estimands for clarification and simplification 


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• Section 3: Correction of visit timepoint (week 1), clarification of role of unblinded sponsor 
members in the interim analysis; clarification of timepoint: “baseline” replaced by 
“screening”; Definition of two timepoints for entering the Extension study, at week 52 or 
week 68. 
• Section 4.4: Addition of wording on DMC for clarification 
• Section 4.5: Summary of risk benefit section added; clarification that DMC review is 
unblinded; clarification that no contraception is required for male participants; explanation 
added why a double-blind placebo-controlled food challenge is required; addition of 
statement that most experience with OFC has been collected in children.  
• Section 4.6: Public health emergency language updated. 
• Section 5: typographical errors corrected 
• Section 5.1: Peanut specific IgE cutoff changed to 0.35; symptoms on placebo challenge 
are allowed unless they are dose-limiting symptoms.  
• Section 5.2: Reference for assessing renal values in children added – National Kidney 
Foundation 2002. 
• Section 6.2.1: Addition of usage of stable regimen of controller treatment for asthma 
patients 
• Section 6.2.1.1: Medications allowed under certain conditions: local corticosteroid and 
local anti-histamine usage adjusted; usage of long and short acting anti-histamines aligned. 
• Section 6.2.2: Prohibited medication: Removal of short-term administration of prohibited 
medications; JAK inhibitors added; washout of systemic corticosteroids clarified. 
• Section 6.3.1.1: Clarification added that the investigator must provide accountability for 
locally sourced material used for administration. 
• Section 6.4.2: clarification of timepoint: “baseline” replaced by “screening” 
• Section 6.5: Typographical errors corrected; Removal of sentence that participant needs to 
look away from injection site. Table 6-4: DMC removed from blinding table as they review 
unblinded data. 
• Section 7: Addition of wording on ICF regarding risk/ benefit, voluntary study participation, 
source data documentation, optional consent for additional research and ICF copy for study 
participant 
• Section 8: Emphasizing that original study schedule should be followed in case of a 
rescheduled visit; reconciliation of all dispensed investigational product for final visit needs 
to be done; delegation of investigator responsibility clarified; assessment schedule  
table 8-1: numbering of days corrected; PROs need to be done before physical exam at 
Randomization visit, physical exams need to be done at Day1, body height needs to be 
collected in the clinical database at Screening Visit 1,
, “
 
 
; typographical errors corrected. 
• Section 8.1: Assent added to Informed Consent. 
• Section 8.2: Addition that collection of race and ethnicity data are depending on HA 
feedback. 
• Section 8.3.1: Typographical errors corrected. 


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• Section 8.4: Spirometry added to safety evaluations 
• Section 8.4.1: Clarification that if blood limits are exceeded, the guidance in the 
prioritization table in the flow chart should be followed. 
• Section 8.4.3:  FSH testing is suggested but not required. 
• Section 8.4.4: Reduce the number of stool samples required to determine participant 
eligibility at screening from three to one in asymptomatic participants and three in 
symptomatic patients at screening and throughout the study.  
• Section 8.5.1: References corrected 
 
 
 
.  
 
. 
• Section 8.5.3.3: Double coding of samples is not done anymore. 
• Section 9.1.1: Redundant sentence on emergency code break removed. 
• Section 9.2: Withdrawal of consent/ exercise of participants’ data privacy rights are further 
specified in this section as well as the heading is updated to align with protocol template 
V5.0. 
• Section 9.3: Definition of two entry timepoints for participants who wish to enter the 
Extension study: at week 68 (end of follow-up) for the first one third of participants or 
week 52 (end of treatment) for the remaining participants. 
• Section 10.1.3: SAE reporting language updated; including reference to more stringent 
local regulations. Reporting of SAEs is described with reference to ligelizumab half-life.  
• Section 10.1.4: Pregnancy reporting: clarification added on SAE reporting and timepoints 
• Section 10.1.5: Table on study treatment errors removed; the text from deleted table is 
included in the text of Section 10.1.5.   
• Section 10.3.1: Clarification that the DMC will review unblinded data. 
• Section 11.1: Removal of redundant sentence 
• Section 12.1: Editorial changes were made for clarification  
• Section 12.2: Replacing FAS and Safety set with Randomized set and adding geometric 
mean for non-normal variables 
• Section 12.3 and Section 12.4.2: Editorial changes were made for clarification 
• Section 12.4.3: Combing two intercurrent events due to operational complications caused 
by public health emergency into one category for simplification 
• Section 12.4.7: Clarifying total IgE at Screening Visit 1 for subgroup analysis, and 
removing the method of handling non-convergence issue for simplification 
• Section 12.5.1: Adding the principle of handling intercurrent events and missing data for 
key secondary endpoints; Adding log-transformed total IgE at Screening Visit 1 into 
ANCOVA model for peanut specific IgE and IgG4 endpoints, correcting comparison time 
point for SPT (Week 16 instead of Week 12) and adding details of descriptive analysis for 
FAQLQ and SF-36v2. 
• Section 12.5.2: Adding editorial changes and removing description of listings for simplicity 
as details of listings will be provided in SAP 


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• Section 12.6.1: Removing the description of listings for simplicity; Removing wording of 
handling values below LLOQ as details will be fully specified in SAP  
 
 
• Section 12.6.4: Editorial changes were made for clarification  
• Section 12.6.5: Removing the description of listings for simplicity 
• Section 12.7: Adding DMC analysis for clarification; clarification that a dose-exposure-
Response model to describe the responder rate and the factors impacting the response will 
be developed 
• Section 16: References on CoFAR grading scale, ICF E2D Guideline, National Kidney 
Foundation added. 
• Section 16.4.2: Reference to exceeding 7 day window removed. 
• Section 16.4.2.1: Dry weight information for OFC challenge base material added. 
• Section 16.4.2.3: Dry weight information added to dosing table 
• Section 16.4.3: High and low dose composition corrected. 
• Section 16.4.4: Information on allergen kit assignment added 
• Section 16.4.5: CoFAR reference added 
• Section 16.4.6: Causality assessment added to SAE reporting 
• Section 16.5.2: Syringe added to material used for SPT 
• Section 16.5.3: Prohibited medication for SPT aligned with section 6.2.2 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC and Health Authority 
approval according to local regulations prior to implementation.  
The changes herein affect the trial specific model ICF. 


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Protocol summary 
Protocol number 
CQGE031G12301 
Full Title 
A 52 week, multi-center, randomized, double-blind placebo-controlled study to assess 
the clinical efficacy and safety of ligelizumab (QGE031) in decreasing the sensitivity to 
peanuts in patients with peanut allergy 
Brief title 
Efficacy and safety of QGE031 (ligelizumab) in patients with peanut allergy 
Sponsor and 
Clinical Phase 
Novartis 
Phase 3 
Investigation type 
Biological 
Study type 
Interventional 
Purpose  
The purpose of this study is to evaluate the clinical efficacy and safety of ligelizumab 
240 mg and 120 mg compared to placebo in participants with peanut allergy 
Primary 
Objective(s)  
To evaluate the efficacy of ligelizumab 240 mg and 120 mg (SCq4w) compared to 
placebo, as measured by the proportion of participants who can tolerate a single dose 
of ≥ 600 mg (1044 mg cumulative tolerated dose) of peanut protein without dose-limiting 
symptoms during the DBPCFC at Week 12. 
The primary clinical question of interest is: What is the efficacy of ligelizumab compared 
to placebo as measured by the proportion of participants who can tolerate a single dose 
of ≥ 600 mg (1044 mg cumulative tolerated dose) of peanut protein without dose-limiting 
symptoms during the DBPCFC at Week 12, in the absence of operational complications 
caused by a public health emergency (e.g. the COVID-19 pandemic), regardless of 
intake of rescue medication prior to Week 12? 
Secondary 
Objectives 
Key secondary objectives 
• 
To evaluate the efficacy of ligelizumab 240 mg and 120 mg (SCq4w), compared to 
placebo, as measured by the proportion of participants who can tolerate a single 
dose of  ≥ 1000 mg (2044 mg cumulative tolerated dose) of peanut protein without 
dose-limiting symptoms during the DBPCFC at Week 12 
• 
To evaluate the efficacy of ligelizumab 240 mg and 120 mg (SCq4w), compared to 
placebo, as measured by the proportion of participants who can tolerate a single 
dose of 3000 mg (5044 mg cumulative tolerated dose) of peanut protein without 
dose-limiting symptoms during the DBPCFC at Week 12 
• 
To evaluate the efficacy of ligelizumab 240 mg and 120 mg (SCq4w), compared to 
placebo, as measured by the maximum symptom severity at any single challenge 
dose up to and including 1000 mg of peanut protein during the DBPCFC at week 12 
• 
To evaluate the efficacy of 8 weeks of placebo treatment followed by 4 weeks of 
ligelizumab 120 mg / 240 mg (SCq4w) treatment compared to 12 weeks of placebo 
treatment, as measured by the proportion of participants who can tolerate a single 
dose ≥1000 mg of peanut protein without dose-limiting symptoms during the 
DBPCFC at Week 12 
Other secondary objectives 
• 
To evaluate the efficacy of ligelizumab 240 mg and 120 mg (SCq4w), as measured 
by the proportion of participants who can tolerate a single dose of ≥1000 mg 
(2044 mg cumulative tolerated dose) of peanut protein without dose-limiting 
symptoms during the DBPCFC at Week 52 compared to Week 12 
• 
To evaluate the effects of ligelizumab 240 mg and 120 mg (SCq4w), compared to 
placebo (when applicable), as measured by multiple systemic biomarkers to inform 
on response to treatment or disease severity 
• 
To evaluate the safety and tolerability of ligelizumab 240 mg and 120 mg (SCq4w) 
• 
To assess the ability of IgE suppression to impact skin mast cells through the 
assessment of allergen-specific skin prick test (SPT). 
• 
To evaluate the impact of ligelizumab on the health-related quality of life (HRQoL) of 
patients with peanut allergy. 


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Study design 
This is a 52-week, Phase 3 multi-center, randomized, double-blind and placebo-
controlled study to assess the safety and clinical efficacy of two dosing regimens of 
ligelizumab (240 mg and 120 mg) SCq4w (subcutaneous injection every 4 weeks) in 
participants with a medically confirmed diagnosis of IgE-mediated peanut allergy. 
Rationale 
To demonstrate that ligelizumab 240 mg and 120 mg given subcutaneously (SC) every 
4 weeks (q4w) ensures protection against food allergic reactions by decreasing the 
sensitivity to oral peanut allergen in participants aged 6 to 55 years with peanut allergy. 
Study population 
The study consists of approximately 486 participants (male and female) aged 6 - 55 
years who have been diagnosed with IgE-mediated peanut allergy.  
Key Inclusion 
criteria 
• 
Male or female participants who are ≥ 6 and ≤ 55 years of age at the time of signing 
informed consent/assent. 
• 
Documented medical history of allergy to peanuts or peanut-containing foods. 
• 
Positive peanut-specific immunoglobulin E (peanut sIgE), ≥ 0.35 kUA/L at Screening 
Visit 1.Screening 
• 
Positive skin prick test (SPT) for peanut allergen at Screening Visit 1 defined as an 
average diameter (Longest diameter and mid-point orthogonal diameter) ≥ 4 mm 
wheal compared to negative control. 
• 
A positive peanut DBPCFC at baseline (Screening Visit 2, Part 1 and Part 2 
DBPCFC) defined as the occurrence of dose-limiting symptoms at a single dose ≤ 
100 mg of peanut protein. Eligibility to proceed with the DBPCFC requires fulfillment 
of all other eligibility criteria. 
• 
Participants must weigh ≥ 20 kg at Screening Visit 1. 
Key Exclusion 
criteria 
• 
Total IgE >2000 IU/mL at Screening Visit 1. 
• 
History of severe or life-threatening hypersensitivity event needing an ICU 
admission or intubation within 60 days prior to baseline DBPCFC (Screening Visit 
2). 
• 
Participants with uncontrolled asthma (according to GINA guidelines, GINA 2020) 
who meet any of the following criteria:  
• 
FEV1 <80% of subject’s predicted normal value at Screening Visit 1 
• 
One hospitalization for asthma within 12 months prior to Screening Visit 1 
Study treatment 
QGE031 120 mg/1ml 
QGE031 Placebo/1ml 
Efficacy 
assessments 
Double blind placebo controlled food challenge (DBPCFC) 
Key safety 
assessments 
Adverse event monitoring, physical examinations, monitoring of laboratory markers in 
blood and urine, ECGs, assessment of pregnancy and fertility, assessment of parasitic 
infection, assessment of anaphylactic events, cardiocerebrovascular and neoplastic 
events. 
Data analysis 
The primary endpoint for this study is the proportion of participants tolerating a single 
dose of ≥ 600 mg (1044 mg cumulative tolerated dose) of peanut protein without dose-
limiting symptoms during the DBPCFC conducted at the end of 12 weeks of treatment. 


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Participants with treatment discontinuation or missing more than 1 dose of study drug 
prior to Week 12 due to non-operational public health emergency or reasons unrelated 
to public health emergency will be considered non-responders. 
The null hypotheses for the primary endpoint being tested is any of the ligelizumab 
groups (low or high dose) is not superior to placebo group with respect to the responder 
rate at a single dose of 600 mg peanut protein without dose-limiting symptoms at Week 
12. The primary estimation method is based on a logistic regression model, including 
treatment, age subgroup (6– 11 years, 12–17 years, 18-55 years), region as fixed class 
effects and log-transformed total IgE at Screening Visit 1 as a covariate. 
The key secondary efficacy endpoints included in the testing strategy are: 
• 
Responder status defined as tolerating a single dose of ≥ 1000 mg (2044 mg 
cumulative tolerated dose) peanut protein without dose-limiting symptoms at Week 
12. 
• 
Responder status defined as tolerating a single dose of 3000 mg (5044 mg 
cumulative tolerated dose) peanut protein without dose-limiting symptoms at Week 
12. 
• 
Maximum severity of symptoms occurring at any challenge dose of peanut protein 
up to and including 1000 mg during the DBPCFC conducted at Week 12. Symptom 
severity will be categorized as 4 levels: None, Mild, Moderate, Severe. 
• 
Responder status defined as participants tolerating a single dose of ≥ 1000 mg 
(2044 mg cumulative tolerated dose) peanut protein without dose-limiting 
symptoms at Week 12 (8 weeks of placebo + 4 weeks of ligelizumab treatment vs. 
12 weeks of placebo).  
The familywise type I error rate will be controlled at the one-sided 0.025 level across the 
primary and key secondary null hypotheses in a closed testing procedure 
(Bretz et al 2009). 
The estimands of interest are described in detail in the corresponding sections. 
Key words 
Food allergy, peanut allergy, oral food challenge, IgE, ligelizumab 


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1 
Introduction 
1.1 
Background 
Food allergy affects people of all ages and nations and, giving its prevalence and the costs 
associated to the disease, it represents an emerging population health priority 
(Warren et al 2020). An estimated 11% of US adults and approximately 8% of US children are 
affected by food allergies (Gupta et al 2019). The overall economic cost of food allergy is 
estimated at approximately $24.8 billion annually (Gupta et al 2013). 
The National Institutes of Health (NIH) Food Allergy Expert Panel defines food allergy as a 
specific IgE-mediated adverse reaction to a given food (Boyce et al 2010). A slightly broader 
definition by the European Academy of Allergy and Clinical Immunology (EAACI) regards 
food allergy as an immune mediated adverse reaction to food involving specific IgE-mediated, 
cell-mediated, or combined IgE and cellular mechanisms (Muraro et al 2014). Peanut allergy is 
an IgE-mediated disease and, in peanut allergic individuals, ingestion of small quantities of the 
allergen may lead to severe and potentially life-threatening allergic reactions (Wood 2003). 
The underlying pathogenesis of food allergy involves an immunologic mechanism in which IgE 
is synthesized in response to allergen exposure and binds to high affinity receptors for IgE 
(FcεRI receptors) via its Fc region on the surface membranes of mast cells and basophils 
(Sampson et al 2006). Cross-linking of receptor-bound IgE molecules occurs on re-exposure to 
the allergen and results in cell activation and mediator release (Peavy and Metcalfe 2008). IgE 
also contributes to the intensity of the reaction by enhancing the expression of FcεRI on mast 
cells and basophils. Mast cells and basophils play an important role in initiating and amplifying 
the acute allergic response through the release of preformed chemical mediators of 
inflammation, as well as newly generated mediators leading to the characteristic symptoms of 
allergic reaction and anaphylaxis (Vadas et al 2008). 
Currently the standard of care for food allergy is limited to strict avoidance of the inciting 
food(s), rescue medication in case of unintentional exposure, and community wide interventions 
for schools (i.e., peanut free classrooms) and restaurants (i.e., ingredient alerts) 
(Jones and Burks 2017). Nevertheless, accidental exposures of food-sensitive individuals to the 
very antigen they are striving to avoid are frequent. For example, 58% of young children with 
clinical peanut hypersensitivity followed for up to 5 years experienced adverse reactions from 
accidental peanut exposure despite best efforts at allergen avoidance (Vander Leek et al 2000). 
Recently, a peanut oral immunotherapy (OIT) (Vickery et al 2018) was approved by FDA to 
mitigate allergic reactions during accidental exposure to peanuts (Jan-2020) and by EMA for 
the treatment of peanut allergy (Dec-2020). Yet this treatment is not fundamentally changing 
the unmet medical need in this space as it is only targeting one allergen; is indicated only for a 
subset of age groups and might not be suitable for all peanut allergic patients. 
Due to rising prevalence (including allergy to multiple foods) (Sicherer and Sampson 2018), 
current limited therapeutic options and the lifelong disease burden in many, there is a 
recognized medical need to develop novel therapies for food allergy. Following the 
identification of IgE as a principal player in allergic diseases and the advent of monoclonal 
antibody (mAb) technology in the 1970s, mAbs to IgE were developed to the site on IgE that 
binds the FcεRI receptor (Baniyash et al 1988). These antibodies were identified based on their 


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ability to inhibit the IgE–FcεRI interaction and to block the activation of IgE sensitized cells. It 
was recognized that these antibodies would thereby prevent the initiation of the allergic cascade 
through both the FcεRI and FcεRII (CD23) pathways. Such antibodies are termed “non-
triggering”; in contrast to conventional anti-IgE antibodies that cross-link cell bound IgE thus 
precipitating degranulation and even systemic anaphylaxis. Based on this strategy, the 
development of monoclonal anti-IgE treatment (TNX-901) was shown to be able to 
significantly increase the threshold of sensitivity to peanut antigen, as assessed by an oral food 
challenge (OFC), in a dose dependent manner, to levels that should translate into at least partial 
protection against most unintended ingestions of peanut (Leung et al 2003). 
Ligelizumab (QGE031) is a humanized IgG-type mAb that binds to human IgE (Investigator 
Brochure, 17 Ed.). Upon binding to specific epitopes in the C3 region of IgE, ligelizumab is 
able to block the interaction of IgE with both the high and low affinity IgE receptors (FcεRI 
and CD23, respectively). Ligelizumab does not mediate IgE receptor cross-linking and 
consequent histamine release (i.e. is non-activating). The rationale for its development reflects 
the evidence that a more efficient suppression of IgE than that achieved by omalizumab may be 
associated with improved clinical outcomes in IgE mediated diseases (Lowe et al 2009, 
Ankerst et al 2010). 
When participants are treated with ligelizumab, circulating IgE is rapidly bound by the anti-IgE 
antibody and becomes inaccessible to IgE receptors on mast cells and basophils. Ligelizumab 
has demonstrated dose- and time-dependent suppression of free IgE, reduction in basophil 
FcεRI expression and thus basophil surface IgE, and inhibition of skin prick test (SPT) 
responses to allergens, superior in extent and duration to those observed with omalizumab 
(Arm et al 2014, Gauvreau et al 2016). IgE is necessary for the enhanced expression of the 
FcεRI seen in atopic participants (MacGlashan et al 1997, MacGlashan et al 1998), and thus a 
decrease in FcεRI expression on circulating basophils accompanies ligelizumab treatment. 
Other potentially beneficial effects from anti-IgE therapy include decreased IgE production 
(Lowe and Renard 2011), reduced IgE and B cell numbers (Ota et al 2009) and reduced 
cytokine production by T cells (Coyle et al 1996). 
Consequently, it is hypothesized that the higher level of suppression elicited by ligelizumab 
 will result in a more efficient desensitization against the allergen 
therefore, ensuring protection against food allergic reactions by decreasing the sensitivity to 
oral peanut allergen. 
1.2 
Purpose 
The purpose of this Phase 3 study is to evaluate the safety and clinical efficacy of ligelizumab 
240 mg and 120 mg given subcutaneously (s.c.) every 4 weeks (q4w) to ensure protection 
against allergic reaction by decreasing the sensitivity to oral peanut allergen in participants aged 
6 to 55 years with peanut allergy, compared to placebo.Data from this study, as well as data 
from an additional Phase 3 study assessing two other major food allergens (milk and egg), will 
support the registration of ligelizumab in food allergy to protect participants against allergic 
reactions due to an accidental exposure irrespective of the causative food allergen(s). 


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2 
Objectives, endpoints and estimands 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• To evaluate the efficacy of ligelizumab 240 mg 
and 120 mg (SCq4w) compared to placebo, as 
measured by the proportion of participants who 
can tolerate a single dose of  ≥ 600 mg (1044 mg 
cumulative tolerated dose) of peanut protein 
without dose-limiting symptoms during the 
DBPCFC (Section 16.4, Table 16-7) at Week 12 
• Responder status defined as tolerating a single dose 
of ≥ 600 mg (1044 mg cumulative tolerated dose) of 
peanut protein without dose-limiting symptoms 
during the DBPCFC conducted at Week 12 
(Section 2.1 Primary Estimands). 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
Key secondary objectives 
• 
Key secondary endpoints 
• 
To evaluate the efficacy of ligelizumab 240mg 
and 120mg (SCq4w), compared to placebo, as 
measured by the proportion of participants who 
can tolerate a single dose of  ≥ 1000 mg (2044 
mg cumulative tolerated dose) of peanut protein 
without dose-limiting symptoms during the 
DBPCFC at Week 12 
• 
Responder status defined as tolerating a single 
dose of ≥ 1000 mg (2044 mg cumulative tolerated 
dose) of peanut protein without dose-limiting 
symptoms during the DBPCFC conducted at Week 
12 (Section 2.2 Secondary Estimands). 
• 
To evaluate the efficacy of ligelizumab 240mg 
and 120mg (SCq4w), compared to placebo, as 
measured by the proportion of participants who 
can tolerate a single dose of 3000 mg (5044 mg 
cumulative tolerated dose) of peanut protein 
without dose-limiting symptoms during the 
DBPCFC at Week 12 
• 
Responder status defined as tolerating a single 
dose of 3000 mg (5044 mg cumulative tolerated 
dose) of peanut protein without dose-limiting 
symptoms during the DBPCFC conducted at Week 
12 (Section 2.2 Secondary Estimands). 
• 
To evaluate the efficacy of ligelizumab 240mg 
and 120mg (SCq4w), compared to placebo, as 
measured by the maximum symptom severity 
at any single challenge dose up to and 
including 1000 mg of peanut protein during the 
DBPCFC at week 12  
• 
Maximum severity of symptoms occurring at any 
challenge dose of peanut protein up to and 
including 1000 mg during the DBPCFC conducted 
at Week 12. Symptom severity will be categorized 
as 4 levels: None, Mild, Moderate, Severe 
(Section 2.2 Secondary Estimands).  
• 
To evaluate the efficacy of 8 weeks of placebo 
treatment followed by 4 weeks of ligelizumab 
120 mg and 240 mg (SCq4w) treatment 
compared to 12 weeks of placebo treatment, as 
measured by the proportion of participants who 
can tolerate a single dose ≥1000 mg of peanut 
protein without dose-limiting symptoms during 
the DBPCFC at Week 12  
• 
Responder status defined as tolerating a single 
dose of ≥ 1000 mg (2044 mg cumulative tolerated 
dose) of peanut protein without dose-limiting 
symptoms during the DBPCFC conducted at Week 
12 (8 weeks of placebo + 4 weeks of ligelizumab 
treatment vs. 12 weeks of 
placebo)  (Section 2.2 Secondary Estimands).  
• 
Other secondary objectives 
• 
Other secondary endpoints 
• 
To evaluate the efficacy of ligelizumab 240mg 
and 120mg (SCq4w), as measured by the 
proportion of participants who can tolerate a 
single dose of ≥1000 mg (2044 mg cumulative 
tolerated dose) of peanut protein without dose-
limiting symptoms during the DBPCFC at Week 
52 compared to Week 12 
• 
Proportion of participants tolerating a single dose of 
≥ 1000 mg (2044 mg cumulative tolerated dose) of 
peanut protein without dose-limiting symptoms 
during DBPCFC conducted at Week 52 
• 
Change in maximum tolerated dose (MTD) of 
peanut protein without dose-limiting symptoms 
during the DBPCFC at Week 52 compared to Week 
12 
• 
To evaluate the effects of ligelizumab 240 mg 
and 120 mg (SCq4w), compared to placebo 
(when applicable), as measured by multiple 
• 
Change from baseline at Week 12, 16 and Week 
52 of 
• 
peanut-specific IgE 


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Objective(s) 
Endpoint(s) 
systemic biomarkers to inform on response to 
treatment or disease severity 
• 
peanut-specific IgG4 
• 
To evaluate the safety and tolerability of 
ligelizumab 240 mg and 120 mg (SCq4w) 
• 
Summaries of treatment-emergent adverse events, 
vital signs, ECG, and laboratory values 
• 
To assess the ability of IgE suppression to 
impact skin mast cells through the assessment 
of allergen-specific skin prick test (SPT). 
• 
Change from baseline (screening) in SPT mean 
wheal diameters at Week 16, Week 56 and Week 
68. 
• 
To evaluate the impact of ligelizumab on the 
health-related quality of life (HRQoL) of patients 
with peanut allergy. 
• 
Change from baseline in total and domain scores in 
the FAQLQ, FAIM, and SF-36v2 by age and 
responder (subject and/or caregiver) at various 
points in time.  
2.1 
Primary estimands 
The estimand is the precise description of the treatment effect and reflects strategies to address 
events occurring during trial conduct which could impact the interpretation of the trial results 
(e.g. premature discontinuation of treatment). The primary clinical question of interest is, ‘What 
are the effects of ligelizumab 120mg SCq4w vs. placebo, and ligelizumab 240mg SCq4w vs. 
placebo on the proportion of responders at Week 12 in the absence of operational complications 
caused by a public health emergency (e.g. the COVID-19 pandemic), regardless of intake of 
rescue medication prior to Week 12?’ Responder status is defined as tolerating a single dose of 
≥ 600 mg (1044 mg cumulative tolerated dose*) of peanut protein without dose-limiting 
symptoms** during the DBPCFC conducted at Week 12. 


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The primary estimand will account for two categories of intercurrent events which will be 
treated in different ways. We will distinguish between intercurrent events unrelated to public 
health emergency and intercurrent events that happen due to operational complications caused 
by public health emergency; e.g., participants missed their dose as they are not able to receive 
their study medication due to regional lockdowns. Intercurrent events due to non-operational 
public health emergency related reasons will be classified as intercurrent events unrelated to 
public health emergency. 
The primary estimand is described by the following attributes: 
• Population: participants aged 6 - 55 years who have been diagnosed with IgE-mediated 
peanut allergy and met study inclusion/exclusion criteria. Further details about the 
population are provided in Section 5. 
• Variable: Responder status defined as tolerating a single dose of ≥ 600 mg (1044 mg 
cumulative tolerated dose) of peanut protein without dose-limiting symptoms during the 
DBPCFC conducted at Week 12. 
• Treatment: the randomized treatment^ (ligelizumab 120mg SCq4w, ligelizumab 240mg 
SCq4w, and placebo) plus rescue medication (e.g., epinephrine, SABA, anti-histamines), 
if needed. Further details about the randomized treatment and rescue medication are 
provided in Section 6. 
• Handling of intercurrent events: 
Category 1 - Intercurrent events unrelated to public health emergency (e.g. COVID-19 
pandemic): 
• Discontinuation of treatment prior to Week 12: participants who discontinue treatment 
prior to Week 12 and therefore do not undergo DBPCFC at Week 12 will be considered 
non-responders (composite variable strategy). 
• Missing more than one dose prior to Week 12: participants who miss more than one dose 
and therefore do not undergo DBPCFC at Week 12 will be considered non-responders 
(composite variable strategy).Intake of rescue medication prior to DBPCFC conducted at 
Week 12: ignorable (treatment policy strategy, reflected in the Treatment attribute) 
Category 2 - Intercurrent events related to operational complications caused by public health 
emergency (e.g., regional lockdowns): 
• Discontinuation of treatment or missing more than one dose of study drug prior to Week 
12: the interest lies in the responder status at Week 12 that would be observed if 
participants had not had intercurrent events due to operational complications caused by 
public health emergency prior to Week 12 (hypothetical strategy)  
Intercurrent events due to non-operational public health emergency related reasons (e.g., 
COVID-19 infection) are classified as intercurrent events unrelated to public health emergency. 
• Summary measure: odds ratio comparing the proportion of responders between each 
ligelizumab dose group and placebo group 
*The cumulative tolerated dose is the sum of the tolerated doses, not including the reactive dose 
(Casale et al 2019)  


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** Dose-limiting symptoms indicate a true allergic reaction occurring during administration 
of a single dose of peanut protein at the DBPCFC that should preclude the administration of 
any further doses in the view of the investigator. 
^ The randomized treatment indicates three arms specified in Section 6.1.2 , i.e., ligelizumab 
120 mg arm, ligelizumab 240 mg arm, and placebo 16wk/ligelizumab 120/240 mg arm 
Supplementary estimands to the primary estimand are defined in Section 12. 
2.2 
Secondary estimands 
Only key secondary objectives are considered for estimands below. 
2.2.1 
Proportion of responders who can tolerate a single dose of ≥1000 mg 
of peanut protein at Week 12 
The secondary estimand is the same as the primary estimands except that “a single dose of ≥ 
600 mg (1044 mg cumulative tolerated dose)” is replaced by “a single dose of ≥ 1000 mg (2044 
mg cumulative tolerated dose)”. 
2.2.2 
Proportion of responders who can tolerate a single dose of 3000 mg of 
peanut protein at Week 12 
The secondary estimand is the same as the primary estimands except that “a single dose of ≥ 
600 mg (1044 mg cumulative tolerated dose)” is replaced by “a single dose of  3000 mg (5044 
mg cumulative tolerated dose)”. 
2.2.3 
Maximum severity of symptoms at any single challenge dose up to 
and including 1000 mg of peanut protein at Week 12 
This secondary estimand is described by the following attributes: 
Population:  same as for the primary estimand 
Variable: maximum severity of symptoms occurring at any challenge dose of peanut protein 
up to and including 1000 mg during the DBPCFC conducted at Week 12. According to the 
CoFAR grading scale of dose-limiting symptoms (Section 16.4.5), symptom severity will be 
categorized as Mild, Moderate, and Severe. In addition, symptom severity for participants who 
completed DBPCFC without any symptom will be categorized as "None". 
Treatment: same as for the primary estimand 
Handling of intercurrent events: 
• Category 1 - Intercurrent events unrelated to public health emergency (e.g. COVID-19 
pandemic): 
• Discontinuation of treatment prior to Week 12: participants who discontinue study 
treatment will no longer undergo any DBPCFC. The interest lies in efficacy at week 
12 regardless of study drug compliance (treatment policy strategy)  
• Missing more than one dose prior to Week 12: participants who miss more than one 
dose of study treatment will not undergo the DBPCFC at Week 12. The interest lies in 
efficacy at week 12 regardless of study drug compliance (treatment policy strategy).  


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• Intake of rescue medication prior to DBPCFC conducted at Week 12: ignorable 
(treatment policy strategy, reflected in the 'Treatment' attribute) 
• Category 2 - Intercurrent events related to operational complications caused by public 
health emergency:   
• Discontinuation of treatment or missing more than one dose of study drug prior to 
Week 12: the interest lies in the efficacy at Week 12 that would be observed if 
participants had not had intercurrent events due to operational complications caused 
by public health emergency prior to Week 12 (hypothetical strategy)  
Intercurrent events due to non-operational public health emergency related reasons are 
classified as intercurrent events unrelated to public health emergency. 
Summary measure: odds ratio comparing the odds of developing less severe symptoms 
between each ligelizumab dose group and placebo group 
2.2.4 
Proportion of responders who can tolerate a single dose of ≥1000 mg 
of peanut protein at Week 12 with 8 weeks of placebo followed by 4 
weeks of ligelizumab 
The secondary estimand provides insight into the magnitude of efficacy that might be achieved 
if all participants were able to take one dose of study treatment. The attributes of the secondary 
estimand are described as follows: 
Population: same as for the primary estimand.Variables: Responder status defined as 
tolerating a single dose of ≥ 1000 mg (2044 mg cumulative tolerated dose) of peanut protein 
without dose-limiting symptoms during the DBPCFC conducted at Week 12 
Treatment: the randomized treatment (placebo 8wk/ligelizumab 120 mg SCq4w, placebo 
8wk/ligelizumab 240 mg SCq4w, and placebo 16wk/ligelizumab 120/240 mg SCq4w) plus 
rescue medication, if needed.  
Handling of intercurrent events: 
• Discontinuation of treatment prior to Week 12: the interest lies in the responder status at 
Week 12 that would be observed if participants had not discontinued treatment prior to 
Week 12 (hypothetical strategy). 
• Missing the dose of study treatment at Week 8: the interest lies in the responder status at 
Week 12 that would be observed if participants had not missed the dose of study treatment 
at Week 8 (hypothetical strategy). 
• Intake of rescue medication prior to DBPCFC conducted at Week 12: ignorable (treatment 
policy strategy, reflected in the 'Treatment' attribute). 
The same approach of handling intercurrent events will be used for events related and unrelated 
to public health emergency. 
Summary measure: odds ratio comparing the proportion of responders between each 
ligelizumab dose group and placebo group. 


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3 
Study design 
This is a 52-week, Phase 3 multi-center, randomized, double-blind and placebo-controlled study 
to assess the safety and clinical efficacy of two dosing regimens of ligelizumab (240 mg and 
120 mg) SCq4w (subcutaneous injection every 4 weeks) in participants with a medically 
confirmed diagnosis of IgE-mediated peanut allergy. Approximately 486 participants will be 
randomized to ligelizumab 240 mg, ligelizumab 120 mg, or placebo (5 treatment arms, 
randomization ratio of 2:2:2:2:1; Figure 3-1) for the double-blind placebo-controlled treatment 
period (up to Week 12).  Participants initially assigned to the 8-week placebo arms will receive 
the first dose of blinded ligelizumab treatment at the Week 8 visit. Participants initially assigned 
to the 16-week placebo arm will receive the last dose of placebo before the DBPCFC at week 
12 and the first dose of blinded ligelizumab treatment at the Week 16 visit. 
Participants will be stratified based on region, total IgE at screening (<350 IU/ mL; ≥350 IU/ 
mL at Screening Visit 1) and age (6-11y, 12-17y, and 18-55y). Approximately the same number 
of participants will be randomized into each age group. 
Age groups are defined as follows: 
6-11y corresponds to ≥ 6 to < 12 years of age  
12-17y corresponds to ≥ 12 to < 18 years of age 
18-55y corresponds to ≥ 18 to ≤ 55 years of age 
Figure 3-1 
Study design 
The study will include the following: 
1. Screening period (Duration of 4 weeks): Written informed consent and assent (as 
applicable) will be obtained before any study related assessments or procedures are performed. 
Consented participants will be assessed for study eligibility during the Screening period which 
includes the initial qualifying DBPCFC. 
2.Treatment period (Duration of 52 weeks): The study treatment will be administered in the 
clinic every 4 weeks. 


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• Double-blind placebo controlled treatment period (Duration of 12 weeks): Study 
participants will be seen in the clinic at Day 1, Week 1, Week 4, Week 8 and Week 12. 
The DBPCFC will be performed at Week 12. Participants assigned to the 16 week placebo 
arm will receive the first dose of blinded ligelizumab treatment at the Week 16 visit. 
• Long-term active blinded (no placebo control) treatment period (Duration of 40 weeks/ 
36 weeks for participants on the 16-week placebo arm): Starting at Week 16, all study 
participants will receive blinded ligelizumab study treatment in the clinic every 4 weeks 
until Week 52. A final DBPCFC will be performed at Week 52. 
3. Post-treatment follow-up period (Duration of 16 weeks): There are 4 planned clinic visits 
(every 4 weeks). Study evaluations include safety, 
, 
. Study treatment is not given and there is no DBPCFC. 
An Extension Study will be made available for participants to enter at the completion of the 
treatment period (week 52) or the completion of the follow-up period (week 68)( Section 9.3). 
At the start of the study, recruitment will be restricted to 12 - 55 year old participants. When 
approximately 60 adolescent participants (defined as 12 -17 years of age) have completed all 
Week 12 assessments,
 
 (safety will be reviewed by a Data Monitoring Committee - 
DMC). Independent sponsor members who are responsible for 
 and 
 
 
 
 
 
 
 
 


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4 
Rationale 
4.1 
Rationale for study design 
The randomized, parallel group, double blind, placebo controlled design has been used in the 
past to assess the ability of an anti-IgE treatment to shift the level of reactivity against the peanut 
allergen during a DBPCFC (Leung et al 2003, Sampson et al 2011). Details of the DBPCFC are 
provided in Section 8.3.1. The randomized, double-blind, parallel-group, and placebo-
controlled design supports the assessment of efficacy as well as safety by minimizing bias. 
The choice of peanut as the main food allergen in this study relates to the following key factors: 
• It represents an important unmet medical need as food allergic reactions are most often 
severe with this allergen (Gupta et al 2011), and is a leading cause of fatal and near-fatal 
anaphylaxis in the US (Jones and Burks 2017) 
• Most patients (> 80%) retain their phenotype into adulthood (Byrne et al 2010) which 
enables a study across multiple age groups 
The DBPCFC has demonstrated regulatory significance and will support the main efficacy 
outcome of the study.
 
 
 
The recruitment of an approximately equal amount of participants across the three age groups 
 
 
 
 
 
 
 
 
 
The long-term blinded treatment period will assess the sustainability of the effect of the clinical 
response achieved in the first 12 weeks of treatment through a final DBPCFC. In this study all 
participants assigned to the 16-week placebo arm will receive their last placebo dose before the 
week 12 DBPCFC and the first dose of blinded ligelizumab treatment at the week 16 visit. This 
change to active treatment (120 mg or 240 mg SC4qW pre-assigned at randomization) avoids 
longer-term placebo exposure, which is no longer necessary to support the primary objective. 
At randomization, participants in the 16-week placebo group will be pre-assigned 1:1 to 120 
mg and to 240 mg SC4qW which they will receive after week 12.  
The Follow-up period will ensure that investigational drug has been completely cleared from 
the body before the final visit (EOS). Sixteen weeks of follow-up correspond to five half –lives 
after the last dose of ligelizumab. 


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4.1.1 
Rationale for choice of background therapy 
Strict avoidance of the inciting food(s) and symptomatic treatment of allergic symptoms with 
epinephrine, antihistamines and corticosteroids represent the current standard of care. No other 
anti-IgE medication is currently indicated for the prevention of allergic events in participants 
with peanut allergy. Therefore, the active treatment will be compared to placebo on top of 
standard of care for acute allergic reactions. 
4.2 
Rationale for dose/regimen and duration of treatment 
The two selected dosing regimens (120 mg SCq4w and 240 mg SCq4W) reflect the clinical 
goal to maximize the protection against potentially life-threatening allergic reactions triggered 
by accidental exposure to food allergens. In fact the cascade of events leading to full blown 
anaphylaxis is mediated by the cross-linking of the high affinity IgE receptor (FcεRI) on 
effector cells (basophils and mast cells) that triggers the release of the inflammatory mediators. 
In this pathophysiologic context, a profound blockade of IgE binding to the FcεRI receptors 
with the consequent maximal downregulation of these FcεRIs is required because data suggests 
that basophils can respond maximally to stimulation with only 5000 antigen-specific IgE 
molecules per cell (MacGlashan 1993). Maximal suppression is also desirable considering that 
the IgE system is exposed to external factors like infections that may further increase its 
reactivity as described by Xepapadaki et al 2019. 
The proposed two doses have been selected based on simulations with a model build on atopic 
healthy volunteers and asthmatic participants then adapted in another version with CSU data 
for a sensitivity analysis (QGE031 simulations food allergy, Novartis). The activity of the FcεRI 
(wheal diameter of a skin prick test and PC15 = the dose of allergen required to trigger an acute 
15% decrease of FEV1) and selected critical biomarkers required for its activation (density of 
basophil-bound FcεRI and its occupancy with IgE) Figure 4-1 provides the output from this 
model.   


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of bronchially 
administered allergen required to induce a 15% change in FEV1) were simulated. 
 
 
 
 
 
 
 
 
 
 
 
The decision to include the 120 mg on top of the 240 mg regimen is based on two main 
considerations: 


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• The study population will be characterized by a range of 
 
 These parameters are well known to impact 
 ligelizumab and 
some participants with 
 might sufficiently benefit of the 120 
mg SC4qW regimen. 
• A lower dosing regimen of 120 mg SCq4w is also important to generate a broad range of 
data (exposure/response), supporting robust modeling at the end of the Phase 3 program to 
support the final posology for registration purposes. 
Finally, the two selected dosing regimens are also supported by several key safety aspects, 
which are very important considering the inclusion of participants ≥6y: 
• The maximal dose expected with the proposed 240 mg SCq4w posology in the phase 3 
program in food allergy based on the eligibility criteria is 12 mg/kg body weight/month. 
• 
 
• In the CSU program (currently in Phase 3 studies with 72 and 120 mg SCq4w for up to 12 
months, the completed Phase 2b study evaluated doses up to 240 mg SCq4w), no dose 
related adverse events were identified (with the exception of injection site reactions due to 
the two times higher number of injections required for the 240 mg dose compared with 
lower doses). 
 
 
 
 
4.3 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
Placebo is used in this study for the following reasons: 
• to minimize bias in the evaluation of safety and efficacy assessments and 
• to allow assessment of the change in sensitivity from DBPCFC when comparing 
participants taking ligelizumab 240 mg and ligelizumab 120 mg SCq4W with those 
continuing solely on food avoidance. 
4.4 
Purpose and timing of interim analyses/design adaptations 
An independent DMC (see Section 10.3.1) will conduct periodic monitoring of safety data and 
emerging risk/benefit. Interim reports to the DMC will be generated by an independent 
statistical group not involved in the conduct of the trial. 
There are three planned analyses before the final DBL, in addition to the DMC analyses. In 
order to maintain the integrity of the study data, a limited number of pre-specified sponsor team 
members will be unblinded to the study data for these analyses, and separate blinded sponsor 
team members will continue working on the study until its completion: 


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Interim Analysis: 
At the start of the study recruitment will be restricted to 12 - 55 year old participants. When 
approximately 60 adolescent participants (defined as 12 - 17 years of age) have completed all 
week 12 assessments, an interim analysis on 
 safety 
 data 
 
) will be performed. The intent of this analysis is to confirm the dosing 
strategy for the youngest age cohort. Once confirmed, recruitment will open to participants aged 
6 - 11 years. Dosing of ligelizumab would be either 120 mg only or 120 and 240 mg for this 
age group.  
Primary Analysis at Week 12: 
Once all participants have completed 12 weeks of treatment (or prematurely withdrawn from 
the study), an interim database lock will be conducted to perform the Primary Analysis. The 
Primary Analysis includes primary, key secondary and pre-specified other secondary 
 
 endpoints.   
Analysis at Week 52: 
The study will continue in a blinded manner until EOS (week 68). The analysis at Week 52 will 
be performed on all participants who have either completed Week 52 or prematurely withdrawn 
from the study. 
In terms of reporting, two separate CSRs will be written: 
CSR1 will include the analyses of data after all participants have completed Week 52 or 
prematurely withdrawn from the study prior to Week 52. 
CSR2 will include the final analyses of all data after follow-up, once all participants have 
completed their EOS visit or prematurely withdrawn from the study. 
4.5 
Risks and benefits 
The risks to participants in this trial will be minimized by compliance with all of the eligibility 
criteria and by close clinical monitoring including periodic review of data by an independent 
Data Monitoring Committee (DMC). 
As of the cut-off date of 22-Jan-2021, more than 2000 participants have been or are anticipated 
to have been exposed to ligelizumab across completed, prematurely terminated and ongoing 
studies, covering the indications of CSU, asthma, atopic dermatitis, and bullous pemphigoid. 
The longest exposure to ligelizumab is approximately 17 months (across studies 
CQGE031B2201, CQGE031B2201E1, CQGE031C2201 and CQGE031C2201E1). The 
following doses have been tested in the clinical programs: 12 mg, 24 mg, 36 mg, 72 mg, 180 
mg and 240 mg SC q4w, 280 mg SCq2w and 120 mg SC single dose. To date in the CSU 
program alone, 254 participants have been exposed to ligelizumab at doses up to 240 mg SC 
q4w. [Investigator Brochure, 17 Ed.] 
Overall, no apparent dose-dependent safety signals (except for a trend in injection site reactions, 
which can be easily managed clinically) have been observed to date, although the number of 
participants studied is relatively small, in line with the development phase of the CSU program. 


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In the asthma clinical study CQGE031B2201, there appeared to be a dose dependency of 
injection site reactions between ligelizumab high dose group (28.6% of 199 participants, pooled 
from ligelizumab 240 mg q2w, 240 mg q4w, 180 mg q2w, and 120 mg q2w treatment arms) 
and ligelizumab low dose group (12.5% of 40 participants, pooled from ligelizumab 36 mg q2w, 
and 12 mg q2w treatment arms), which was comparable to omalizumab (14.5% of 131 
participants). The incidence of injection site reactions was higher among all the active treatment 
groups compared to that of placebo (5.2% of 96 participants). Similarly, in the CSU dose-
finding study (CQGE031C2201), the overall safety profile was comparable between different 
doses of ligelizumab (24 mg, 72 mg and 240 mg q4w or 120 mg single dose), omalizumab and 
placebo. The exceptions were AEs related to injection site reactions, where a possible trend of 
dose dependency for ligelizumab was observed. All cases of injection site reactions (except 1 
case of medical significance), regardless of treatment group or doses, were non-serious, mild to 
moderate in severity, reversible, and did not lead to discontinuation of study treatment. 
Regarding Serious Adverse Events (SAEs), the incidence of SAEs was comparable between 
participants treated with ligelizumab and those receiving placebo in both asthma and CSU 
studies. There has been no dose dependency in SAEs observed among participants treated with 
different doses of ligelizumab (CQGE031B2201 in asthma and CQGE031C2201 in CSU). 
Biologics can cause hypersensitivity reactions. Ligelizumab is in the same drug class as 
omalizumab, for which the risk and characteristics of anaphylaxis are well-characterized, and 
theoretically are applicable to the study drug. Investigators should therefore be alert to the 
occurrence of hypersensitivity events, including anaphylaxis, following the administration of 
ligelizumab and be familiar with the information and guidance provided in this protocol and in 
the Investigator Brochure.  
IgE is an antibody that may have an adaptive role in immunity to parasitosis, particularly 
helminthic infections. Thus, blocking the interaction of IgE and its receptors with ligelizumab 
may alter immunologic responsiveness to parasites. Bearing this in mind, monitoring for the 
occurrence of infection and response to therapy is recommended for participants at high risk of 
geohelminth infection who receive ligelizumab. Insufficient data are available to determine the 
length of monitoring required for geohelminth infections after stopping ligelizumab. However, 
it is expected that ligelizumab will not interfere with a polyclonal reaction triggered by exposure 
to parasites. The resulting increase of IgE production would decrease, through target-mediated 
disposition, the half-life of ligelizumab hence restoring normal IgE levels more rapidly. 
Therefore, based on the cumulative data available across all clinical studies in different 
participant populations for ligelizumab, the current evidence demonstrates that ligelizumab is 
safe and well tolerated and thus appropriate for further development. 
The non-clinical safety evaluation for ligelizumab supports a clinical treatment of children 
down to the age of 2 years:
 
 
No new or unexpected safety 
signals were identified in the CQGE031C2201 (CSU dose-ranging) study in adults. 
This study is placebo-controlled design and approximately one-third of participants will receive 
placebo by randomization (Section 4.3), however, the participants who are initially allocated to 
placebo will be switched to the active treatment (ligelizumab 120 or 240 mg SCq4w) at Week 


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8 or Week 16, depending on the treatment arm. (Figure 4-1), therefore these participants are 
also able to receive the benefit of ligelizumab. Throughout the study including the placebo 
period, measures like strict avoidance of the inciting food(s) and symptomatic treatment of 
allergic symptoms with epinephrine, anti-histamines and corticosteroids will be taken to reduce 
the risk for the participant. The inclusion and exclusion criteria are selected to enroll participants 
with IgE-mediated peanut allergy likely to benefit from participating in the study, and to limit 
the presence of concomitant morbidities and medications that might increase the risks 
associated with the oral food challenge. The oral food challenge is the gold standard 
investigation for the objective diagnosis of IgE-mediated food allergy and the use of a double-
blind 
placebo-controlled 
food 
challenge 
is 
recommended 
in 
research 
settings  
(Muraro et al 2014). 
Oral food challenges have inherent risks including acute allergic reactions with potentially life-
threatening anaphylaxis, exacerbation of atopic dermatitis, and emotional distress, particularly 
in older children, teenagers, and adults who may become more anxious about their food allergy 
(Feng and Kim 2019). In participants with cardiovascular disease, anaphylaxis or its treatment 
(e.g., with epinephrine) could result in morbidity due to a cardiovascular event. Also, 
participants with uncontrolled asthma are at higher risk of a dying from anaphylactic event. A 
prior history of a severe allergic event may increase the risk of a severe reaction during the OFC. 
These participants are excluded from participating in the study. To further limit the risks 
associated with this procedure the following measures have been applied: 
• The OFC is based upon the Practall Consensus Meeting Report (Sampson et al 2012) and 
the current CoFAR definition of dose-limiting symptoms. 
• Only highly trained experts representing facilities that are equipped and have the expertise 
to handle potentially life-threatening hypersensitivity events can participate in this study. 
• Three adjudication committees will review all the suspected anaphylactic events, 
cardiovascular events and neoplastic events identified during the study (Section 8.4.4). 
• A Data Monitoring Committee (DMC) will monitor the safety of this study. The DMC 
will review the data generated externally and independently of Novartis in an unblinded 
fashion, according to the charter at predetermined intervals. Based on the safety 
implications of the data, the DMC may recommend modification or termination of the 
study. 
The lower limit of body weight (20 kg) set in the eligibility criteria covers at least 50% of the 
population in the 6-11 year age group according to the CDC growth curves for boys and girls. 
 
 
 
 
 
 
In addition, it has been shown that exposure to viral infections, to which children are 
very prone, might increase the specific IgE levels and consequently the reactivity to food 
allergens (Xepapadaki et al 2019). A high exposure might provide an “efficacy margin” against 
a potentially dangerous external factor of variable reactivity against food allergens. 


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Female participants of child bearing potential must be informed that taking the study treatment 
may involve unknown risks to the fetus if pregnancy were to occur during the study, and agree 
that in order to participate in the study they must adhere to the basic (acceptable effective) 
contraception requirements outlined in the exclusion criteria. If there is any question that the 
participant will not reliably comply, they should not be entered or continued in the study. 
With respect to the ongoing COVID-19 pandemic, IgE suppression is not expected to increase 
the risk of infection (Teach et al 2015). In case of the introduction of a vaccine against COVID-
19, the guidance relative to immunizations summarized in Table 6-2 and Table 6-3 remains 
applicable. 
The key mechanism underlying IgE mediated food allergy is the cross-linking of allergen 
specific IgE molecules bound to the high affinity receptor (FcεRI) on effector cells like 
basophils and mast cells, which triggers the release of inflammatory mediators responsible for 
the final clinical presentation. Therefore, IgE suppression is expected to decrease the probability 
of food allergens to initiate such an acute inflammatory response. Indeed multiple studies have 
supported this therapeutic approach (Leung et al 2003, Savage et al 2012, Schneider et al 2013). 
Recent mechanistic data has shown that ligelizumab is very effective at inhibiting the signaling 
cascade associated with the FcεRI (Gasser et al 2020) hence supporting its use in food allergy 
and anticipating a therapeutic benefit (basophil/ mast cell desensitization). 
Risk and benefit evaluation for adolescents (12-17 yrs) and children (6-11 yrs) 
IgE mediated food allergy affects all ages and upon exposure to the allergen(s) it can result in 
considerable morbidity and life-threatening anaphylaxis. 
The standard of care consists of allergen avoidance and epinephrine administration upon 
accidental exposure. The unmet need, in particular for therapeutic solutions not requiring 
regular allergen administration, is significant in children and adolescents.  
The evaluations specified in this study (including SPT and OFC) are clinically accepted and 
widely used in clinical research that investigates food allergy in adults, adolescents and children. 
With respect to the OFC most of the clinical experience has been collected in children but the 
procedure is also applicable to older patients (Nowak et al 2009). The limited use of placebo 
reflects a consideration for the need to treat this vulnerable population while preserving the 
study's primary objective. The staggered recruitment approach will allow for the determination 
of a suitable dose for children aged 6-11 years. Blood volume for laboratory evaluations for 
children 6-11 years is in line with the “The Hospital for Sick Children (SickKids) Research 
Ethics Board Blood Sampling Guidelines” (Howie 2011)(Section 8.4.1). 
In conclusion, IgE mediated food allergy is a potentially life-threatening condition affecting all 
age groups for which current standard of care still mainly consists of allergen avoidance and 
epinephrine use upon accidental exposure. IgE suppression directly addresses the underlying 
pathophysiology and data from other anti-IgE monoclonal antibodies support this mechanism. 
The proposed ligelizumab regimens aim at an efficient suppression of the FcεRI receptor while 
generating exposures that have been well characterized clinically and that accordingly have not 
been associated with dose-related safety concerns. Residual risks due to hypersensitivity 
reactions related to the investigational drug or to the oral food challenge have been addressed 
by a series of measures that include (but are not limited to) clear eligibility criteria, study drug 


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discontinuation rules, limitations of key risk factors (uncontrolled asthma, selected 
medications), a highly standardized food challenge protocol (and material), adjudication 
committees for event of special interests, and the implementation of a DMC. 
4.6 
Rationale for Public Health Emergency mitigation procedures 
In the event of a Public Health emergency as declared by Local or Regional authorities (i.e. 
pandemic, epidemic or natural disaster), mitigation procedures may be required to ensure 
participant safety and trial integrity and are listed in relevant sections of the study protocol. 
Notification of the Public health emergency should be discussed with Novartis prior to 
implementation of mitigation procedures, and permitted/approved by local or regional health 
authorities and ethics committees as appropriate. 
5 
Study Population 
The study population consists of approximately 486 male and female participants aged 6 - 55 
years who have been diagnosed with IgE-mediated peanut allergy. Participants with multiple 
food allergies will be allowed to enroll as long as an allergy to peanuts exists. A screen failure 
rate of approximately 40% is expected. 
Participants will receive one of three treatments (ligelizumab 240 mg SCq4w, ligelizumab 120 
mg SCq4w, or placebo SCq4w) and will be randomized into five treatment arms with a ratio 
2:2:2:2:1. Participants will be also stratified based on region, total IgE at screening (<350 IU/ 
mL; ≥350 IU/ mL at Screening Visit 1) and age (6 -11 y, 12 - 17 y, and 18 - 55 y). Approximately 
the same number of randomized participants will be recruited into each age group. 
If after the interim analysis it is determined that dosing will be limited to 120 mg for the 
youngest age group, the 240 mg treatment arms will be removed for this age group and 
participants aged 6-11 years will be randomized into the 3 remaining treatment arms 
(randomization ratio of 4:4:1, 1 being the 16 week placebo arm). 
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
1. Signed informed consent and/or assent (where applicable) must be obtained prior to study 
participation. Participant (and parent/legal guardian) must be able to understand and 
provide informed consent and assent, as applicable. If a minor participant providing assent 
reaches the age of legal majority (as defined by local law), he/she must be re-consented 
(ICF) at the next study visit. 
2. Male or female participants who are 6 to 55 years of age at the time of signing informed 
consent/assent. 
3. Documented medical history of allergy to peanuts or peanut-containing foods. 
4. Positive peanut-specific IgE (peanut sIgE), ≥ 0.35  kUA/L at Screening Visit 1. 
5. Positive skin prick test (SPT) for peanut allergen at Screening Visit 1. This is defined as 
the average diameter (longest diameter and mid-point orthogonal diameter) ≥ 4 mm wheal 
compared to the negative control. 


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6. A positive peanut DBPCFC at baseline (Screening Visit 2, Part 1 and Part 2 DBPCFC) 
defined as the occurrence of dose-limiting symptoms at a single dose ≤ 100 mg of peanut 
protein . Eligibility to proceed with the DBPCFC requires presence of all inclusion and 
absence of all exclusion criteria. 
7. Participants must weigh ≥ 20 kg at Screening Visit 1. 
8. Participants must be able to receive injections (study treatment), participate in the 
DBPCFC, and must be willing to continue avoiding exposure to peanuts and any other 
foods that they are allergic to throughout this study. 
5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
1. Use of other investigational drugs within 5 half-lives or within 30 days prior to Screening 
Visit 1, whichever is longer. 
2. History of hypersensitivity to ligelizumab or its excipients, or to other biologics (i.e. to 
murine, chimeric or human antibodies). 
3. Hypersensitivity or intolerance to any of the matrix components used within the material 
for the oral food challenge. (Please refer to the QGE031G12301 Pharmacy Manual for the 
preparation of the DBPCFC and for details on the material components). 
4. Any occurrence of dose-limiting symptoms to placebo allergen at baseline DBPCFC 
(Screening Visit 2). 
5. Inability to comply with study and follow-up procedures. 
6. Total IgE >2000 IU/mL at Screening Visit 1. 
7. History of severe or life-threatening hypersensitivity event needing an ICU (intensive care 
unit) admission or intubation within 60 days prior to baseline DBPCFC (Screening Visit 
2). 
8. Participants with uncontrolled asthma (according to GINA guidelines, GINA 2020) who 
meet any of the following criteria: 
• FEV1 <80% of participant's predicted normal value at Screening Visit 1 
• One hospitalization for asthma within 12 months prior to Screening Visit 1 
9. Current or previous history of a mast cell disorder, including mastocytosis. 
10. Use of prohibited medication (Table 6-3) or medication that is not allowed under certain 
conditions (Table 6-2).  
11. Participants with evidence of helminthic parasitic infection as evidenced by stools being 
positive for a pathogenic organism according to local guidelines at Screening Visit 1 
(before start of Screening Visit 2) (Section 8.1). If stool testing is positive for pathogenic 
organisms, the subject should not be randomized and should not be allowed to be 
rescreened. 
12. History of malignancy of any organ system within the past 5 years (except for basal cell 
carcinoma; actinic keratoses; Bowen disease (carcinoma in situ) that have been treated, 
with no evidence of recurrence in the past 12 weeks; carcinoma in situ of the cervix or 
non-invasive malignant colon polyps that have been removed). 
13. Presence of clinically significant cardiovascular conditions such as but not limited to 
myocardial infarction, unstable ischemic heart disease, NYHA Class III/IV left ventricular 


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failure, arrhythmia and uncontrolled hypertension within 12 months prior to Screening 
Visit 1. 
14. History or current diagnosis of ECG abnormalities indicating significant risk of safety for 
participants participating in the study such as: 
• Concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular 
tachycardia, and clinically significant second or third degree AV block without a 
pacemaker 
• History of familial long QT syndrome or known family history of Torsades de Pointe 
15. Neurological, psychiatric, metabolic or other pathological conditions (such as but not 
limited to cerebrovascular disease, neurodegenerative or other neurological diseases, 
uncontrolled hypo- and hyperthyroidism and other autoimmune diseases, hypokalemia, 
hyperadrenergic state or ophthalmologic disorder) that could interfere with or compromise 
the safety of the participants, interfere with evaluation or interpretation of the study 
results, or preclude completion of the study. 
16. History or evidence of ongoing alcohol or drug abuse, within the last 6 months prior 
to Screening Visit 1. 
17. History of, or current treatment for, hepatic disease including but not limited to acute or 
chronic hepatitis, cirrhosis or hepatic failure or Aspartate Aminotransferase (AST) or 
Alanine Aminotransferase (ALT) levels of more than 1.5 x upper limit of normal (ULN) 
or International Normalized Ratio (INR) of more than 1.5 at Screening Visit 1. 
19. History of renal disease or creatinine level above 1.5x ULN at Screening Visit 1. For 
children (<12y) this criterion is replaced by an eGFR <60cc/min/1.73m2 according to the 
Schwartz formula (National Kidney Foundation 2002) (Schwartz et al 2009).  Platelets < 
100’000/μL at Screening Visit 1. 
20. Pregnant or nursing (lactating) females 
21. Female subjects, including adolescent females of 12 to less than 18 years of age, of child-
bearing potential, defined as all women physiologically capable of becoming pregnant, 
unless they are using basic (acceptable effective) methods of contraception for the 
duration of the study (approx. 4 months, i.e. 5 half-lives, after last dose of ligelizumab). 
Basic (acceptable effective) contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
participant). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable effective methods of 
contraception 
• Female sterilization (surgical bilateral oophorectomy with or without hysterectomy), 
total hysterectomy or bilateral tubal ligation at least six weeks before taking 
investigational drug. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow-up hormone level assessment 
• Male sterilization (at least 6 months prior to screening). For female participants, the 
vasectomized male partner should be confirmed as their sole partner. 
• Barrier methods of contraception: Condom or Occlusive cap (e.g. diaphragm or 
cervical/vault caps). For UK: with spermicidal foam/gel/film/cream/ vaginal 
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• Use of oral (estrogen and progesterone) injected or implanted hormonal methods of 
contraception or other forms of hormonal contraception that have comparable efficacy 
(failure rate < 1%), for example hormone vaginal ring or transdermal hormone 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS) 
Female participants using oral contraception should be on a stable dose for a minimum of 
3 months prior to taking study treatment. 
Female participants are considered post-menopausal and not of child bearing potential if 
they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g. age appropriate history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or bilateral tubal 
ligation at least six weeks ago. In the case of oophorectomy alone, only when the 
reproductive status of the female has been confirmed by follow up hormone level 
assessment is she considered not of child bearing potential. 
If local regulations are more stringent the contraception methods listed above to prevent 
pregnancy, local regulations apply and will be described in the ICF/assent. 
22. Sexually active children below the age of 12 years. 
6 
Treatment 
6.1 
Study treatment 
Study treatment includes investigational drug QGE031 (120 mg/ml) and placebo. Study 
treatment must be administered by an independent drug administrator or unblinded pharmacist 
who is not involved in any of the study assessments. The procedure related to DBPCFC is 
provided in Section 16.4. Information on the food challenge materials and preparation 
instructions are provided separately in the pharmacy manual. 
6.1.1 
Investigational and control drugs 
Novartis will supply ligelizumab (QGE031) 120 mg per 1 mL as prefilled syringe (PFS) with a 
needle safety device (NSD) and placebo. 
Table 6-1 
Investigational and control drug 
Investigational/ 
Control Drug 
(Name and 
Strength) 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Presentation 
Sponsor (global or 
local) 
QGE031 120 
mg/1ml 
Solution for 
injection 
s.c. 
Double-blind 
global 
QGE031 
Placebo/1ml 
Solution for 
injection 
s.c. 
Double-blind 
global 


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6.1.2 
Treatment arms/group 
Participants will be assigned at randomization (Day1) to one of the following five treatment 
arms in a ratio of 2:2:2:2:1. Each participant will receive two (2) s.c. injections every four weeks 
starting at Day1: 
1. ligelizumab 240 mg arm: 2 injections of 1.0 mL ligelizumab from Day1 through Week 52 
2. placebo 8wk/ligelizumab 240 mg arm: 2 injections of 1.0 mL placebo at Day 1 and Week 4; 
2 injections of 1.0 mL ligelizumab from Week 8 through Week 52 
3. ligelizumab 120 mg arm: 1 injection of 1.0 mL ligelizumab and 1 injection of 1.0 mL placebo 
from Day1 through Week 52 
4. placebo 8wk/ligelizumab 120 mg arm: 2 injections of 1.0 mL placebo at Day1 and Week 4; 
1 injection of 1.0 mL ligelizumab and 1 injection of 1.0 mL placebo from Week 8 through Week 
52 
5. placebo 16wk/ligelizumab 120/240 mg arm: 2 injections of 1.0 mL placebo from Day1 
through Week 12; as of week 16 participants will receive either 120 mg or 240 mg ligelizumab 
for the remaining of the treatment phase: 
a. 120 mg: 1 injection of 1.0 mL ligelizumab and 1 injection of 1.0 mL placebo from Week 16 
through Week 52 
b. 240 mg: 2 injections of 1.0 mL ligelizumab from Week 16 through Week 52 
The assignment to receive 120 mg or 240 mg ligelizumab from Week 16 through Week 52 will 
be determined at randomization. 
6.1.3 
Treatment duration 
Treatment duration is 52 weeks. Participants will receive two subcutaneous injections every 4 
weeks (SCq4w) at 14 visits during the double-blind treatment period. Administration of study 
drug must be recorded in the source documents and the corresponding eCRF for each 
administration. The Follow-up period is a non-treatment period of 16 weeks where neither study 
treatment will be administered nor a DBPCFC will be performed. 
6.2 
Other treatment(s) 
6.2.1 
Concomitant therapy 
All medications, procedures, and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the participant was enrolled into the study must be 
recorded on the appropriate Case Report Forms. 
Each concomitant drug must be individually assessed against all exclusion criteria, medication 
allowed under certain conditions (listed in Table 6-2) and prohibited medication (listed in 
Table 6-3). If in doubt, the investigator should contact Novartis before randomizing a 
participant or allowing a new medication to be started. If a participant is already enrolled and 
taking a prohibited medication, contact Novartis to determine if the participant should continue 
to participate in the study. 


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It is recommended that participants with asthma who are eligible for study participation 
maintain a stable regimen of controller treatment throughout the study. 
6.2.1.1 
Permitted concomitant therapy requiring caution and/or action 
The following medications are allowed if taken as per below conditions: 
Table 6-2 
Medications allowed under certain conditions 
Medication 
Condition under which medication is 
permitted 
Topical Corticosteroids and other topical 
immunosuppressants 
In recommended doses and dosage regimens 
Immunotherapy for treatment of allergies in 
maintenance phase (except food allergies) 
In maintenance phase for at least 3 months prior to 
Screening Visit 1 
s.c. (subcutaneous) immunotherapy: time window of 1 
week between DBPCFC/study drug administration 
and immunotherapy shot. 
SLIT (sublingual immunotherapy): Hold SLIT dose on 
the day of DBPCFC  
Inactivated, non-live vaccines 
Not administered within 48 hours prior to a study visit 
Intra-nasal corticosteroids 
in recommended doses and dosage regimens   
Short acting and long acting anti-histamines 
(e.g., chlorpheniramine, promethazine, 
diphenhydramine, loratidine, cetirizine) 
Not administered within 5 half-lives  prior to SPT (skin 
prick test) and DBPCFC 
 
 
Short Acting beta agonist  (SABA) 
Not used within 6h of all spirometry assessments for 
asthma participants and within 6h prior to start of 
DBPCFC 
Anti-Histamine nose spray 
 in recommended doses and dosage regimens   
Oral H2 receptor antagonists: 
e.g., cimetidine, ranitidine, famotidine, nizatidine 
Not administered within 24 hours prior to SPT and 
DBPCFC 
6.2.2 
Prohibited medication 
Use of the treatments displayed below ( Table 6-3) is not allowed after screening (Screening 
Visit 1) to the end of study. The minimum required period without prohibited treatment 
before Screening Visit 1 is also shown. 
If a participant develops a medical condition that requires use of prohibited treatment or if 
participant exhibits a behavior of non-compliance regarding prohibited medications at any 
timepoint from Screening Visit 1 to the end of the study, investigational treatment and DBPCFC 
must be discontinued (see also Section 9.1.1). 
Table 6-3 
Prohibited medication 
Medication 
Minimum required period 
without medications 
Action taken if medication is 
taken during  
study 
Any monoclonal antibody 
treatment (including any Fab 
fragments); e.g. omalizumab 
(Xolair®), dupilumab (Dupixent®), 
benralizumab (Fasenra™), 
6 months before Screening Visit 1 
Discontinue investigational 
treatment 


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mepolizumab (Nucala®), 
reslizumab (Cinqair®), 
Immunotherapy for treatment of 
food allergies 
6 months before Screening Visit 1 
Discontinue investigational 
treatment 
Other systemic 
immunosuppressive medication 
including but not limited to 
methotrexate, cyclosporine A, 
cyclophosphamide, tacrolimus and 
mycophenolate mofetil, Janus 
Kinase inhibitors 
30 days prior to Screening Visit 1 
Discontinue investigational 
treatment 
Systemic corticosteroids (for short-
term burst see footnote*) 
 ≥5 half-lives prior to Screening 
Visit 1 
Discontinue investigational 
treatment 
Beta blockers 
Depending on the compound, to 
be ≥ 5 half-lives prior to Screening 
Visit 1 
Discontinue investigational 
treatment 
ACE inhibitors 
Depending on the compound, to 
be ≥ 5 half-lives prior to Screening 
Visit 1 
Discontinue investigational 
treatment 
Tricyclic antidepressants 
Depending on the compound, to 
be ≥ 5 half-lives prior to Screening 
Visit 1 
 Discontinue investigational 
treatment 
Other investigational drugs 
30 days or 5 half-lives, whichever 
is longer prior to Screening Visit 1 
Discontinue investigational 
treatment 
Live attenuated vaccines 
30 days prior to Screening Visit 1 
Discontinue investigational 
treatment 
* Short-term burst of corticosteroids is allowed (e.g. in case of an allergic reaction); a wash-out period of 5 half-
lives is then required prior to DBPCFC and skin prick testing. The use of long-acting corticosteroids to treat 
allergic reactions during DBPCFC e.g. dexamethasone is not recommended to avoid long wash-out periods 
between two DBPCFCs.  
6.2.3 
Rescue medication 
Any treatment deemed necessary by the investigator can be used to treat adverse events, 
including allergic reactions. Typically, this includes epinephrine, SABA, anti-histamines and 
saline bolus. Any use of rescue medication must be captured on the designated CRF. 
Epinephrine: 
In alignment with treatment guidelines for food allergy, all study participants will be provided 
with rescue medication epinephrine (e.g. EpiPen®) to be used to treat any allergic reactions and 
potential anaphylactic events that occur throughout the study as needed. If the participant is 
treated with epinephrine (e.g. EpiPen®) outside of a study visit, the participant or 
parents/caregiver should contact the study site staff. 
SABA (salbutamol/albuterol): 
Participants with a documented diagnosis of asthma will additionally be provided with SABA 
rescue medication. As listed on Table 6-2, the participant should not use SABA rescue 
medication within 6 hours of a spirometry assessment and/or DBPCFC. 
These two rescue medications are to be provided to the participant locally before the start of the 
DBPCFC (Screening Visit 2). Participants should be instructed to bring them to each visit.  


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The counseling of participants/caregivers on the identification of allergic reactions and 
symptoms of anaphylaxis, as well as proper instruction for the use of rescue medication must 
be documented in source. 
Repeat counseling should be provided as needed to ensure complete understanding. Additional 
supplies of rescue medication should be provided as needed throughout the study. 
Rescue medication can either be provided directly at the study center or prescribed to the 
participant. Please refer to Section 6.3.2 for further information. 
6.3 
Preparation and dispensation 
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section (Section 6.1.1). 
A unique medication number is printed on the study medication label. 
Please refer to the QGE031G12301 Pharmacy Manual for study drug handling and 
administration. 
An independent unblinded administrator will identify the study treatment kits to dispense to the 
participant by contacting the IRT and obtaining the medication number(s). The study treatment 
has a 2-part label (base plus peel-off label). Immediately before preparing study treatment, the 
unblinded pharmacist (or authorized delegate) will detach the outer part of the label from the 
packaging and affix it to the source document. 
6.3.1 
Handling of study treatment and other treatment 
6.3.1.1 
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only designated site personnel has 
access. Upon receipt, all study treatment must be stored according to the instructions specified 
on the labels and in the Investigator's Brochure. 
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis CO Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the participant except for the medication number. 
The designated site personnel must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Monitoring of drug accountability will be 
performed by monitors during site visits or remotely and at the completion of the trial. The  
investigator must also provide accountability for locally sourced materials used for 
administration. 
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the 
investigator folder at each site. 


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6.3.1.2 
Handling of additional treatment 
All rescue medication regardless of dispensation method, must be documented in source and 
closely monitored. Participants should be reminded to bring rescue medication to all study 
visits. This applies to the following: 
• SABA (for participants with a documented diagnosis of asthma) 
• Epinephrine (e.g., EpiPen) 
If rescue medication is provided at the study site it must be handled and stored according to the 
package label, kept in a secured location and dispensed only in accordance with the protocol. 
The investigator must maintain an accurate record of dispensing of the above-mentioned 
treatment in a drug accountability log/inventory log, and source documents. Monitoring of drug 
accountability will be performed by monitors during site visits and at the completion of the 
study. Participants will be asked to return all unused SABA and epinephrine treatments and 
packaging at the end of the study or at the time of discontinuation from the study. 
Any unused epinephrine and SABA stored at the site will be disposed of according to local 
regulation. 
6.3.2 
Instruction for prescribing and taking study treatment 
The independent study drug administrator or unblinded pharmacist will administer the study 
treatment to the participant during the study visit without engaging in any unnecessary 
interactions that may have the potential to unblind the participant or any of the study site 
personnel. 
The s.c. injections can be administered in the deltoid region on the upper right and/or left arm, 
the lower stomach area (but not the area 5 cm around the belly button) and/or into the front of 
the right and/or left thigh, or the abdomen as preferred by the participant and/or site. The 
injections are administered subcutaneously. Do not inject into skin that is tender, bruised, red, 
scaly, hard or into areas with scars or stretch marks. Each injection must be administered at a 
different site (e.g., right arm and left thigh). The guidelines for the preparation and 
administration of study treatment are described in the pharmacy manual (provided separately). 
Participants will remain on-site for observation for a period of 2 h post-dose for the drug 
administrations at the Randomization, Week 4, Week 8, Week 16, Week 20 and Week 24 visits. 
At Week 12 and Week 52 there must be a minimum of 1 hour between administration of 
study drug and performing the DBPCFC. (Section 8.3.1). Study drug must be 
given before the DBPCFC. 
For all remaining drug administrations participants will remain on-site for observation for a 
period of 30 min post-dose.   
These observation periods follow the recommendation suggested by the National Heart, Lung, 
and Blood Institute and by the American Academy of Allergy, Asthma & Immunology and the 
American College of Allergy, Asthma and Immunology Executive Committees Joint Task 
Force (Cox et al 2007) for the anti-IgE therapy currently available (omalizumab). As described 
in the Investigator Brochure, the site needs to ensure readiness to react to anaphylactic events 
(e.g., immediate availability of qualified staff, available injectable epinephrine, antihistamine, 


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corticosteroids, intravenous supplies, oxygen, an oral airway, Ambu bag and the ability to 
transport a participant rapidly to an emergency department/hospital). 
The dose for individual participants will be the same within a treatment arm and will be assigned 
at randomization. 
All study drug dosages prescribed and dispensed to the participant and all dosing errors or 
missed administrations during the study must be recorded on the appropriate eCRF. 
All kits of study treatment assigned by the IRT will be recorded in the IRT. 
The investigator must promote compliance by instructing the participant to ensure scheduled 
visits are made to the site in order to receive the study treatment as per protocol and by stating 
that compliance is necessary for the participant’s safety and the validity of the study. 
6.4 
Participant numbering, treatment assignment, randomization 
6.4.1 
Participant numbering 
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled for screening and is retained for the participant 
throughout his/her participation in the trial. A new Participant No. will be assigned at every 
subsequent enrollment if the participant is re-screened. The Participant No. consists of the 
Center Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential 
participant number suffixed to it, so that each participation is numbered uniquely across the 
entire database. Upon signing the informed consent form, the participant is assigned to the next 
sequential Participant No. available. 
A new ICF will need to be signed if the investigator chooses to re-screen the participant after a 
participant has screen failed. 
6.4.2 
Treatment assignment, randomization 
At the Randomization Visit (Day 1), all eligible participants will be randomized via Interactive 
Response Technology (IRT) to one of the treatment arms. The designated site personnel will 
contact the IRT after confirming that the participant fulfills all the inclusion/exclusion and 
screening criteria. The IRT will assign a randomization number to the participant, which will 
be used to link the participant to a treatment arm and will specify a unique medication number 
for the first study treatment to be dispensed to the participant. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from participants and investigator staff. A 
participant randomization list will be produced by the IRT provider using a validated system 
that automates the random assignment of participant numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the responsibility 
of Novartis Global Clinical Supply (GCS) using a validated system that automates the random 
assignment of medication numbers to packs containing the study treatment. 


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In general, randomization will be stratified by region, total IgE at screening (<350 IU/ mL; ≥350 
IU/ mL at Screening Visit 1) and age (6 - 11y, 12 - 17y, and 18 - 55y). The trial will aim to 
randomize approximately one third of total participants from each defined age cohort. 
Treatment assignment as well as participant stratification is determined by the IRT at 
randomization.  
Randomization will be stratified by patient age at Screening visit 1. 
The randomization scheme for participants will be reviewed and approved by a member of the 
Randomization Office. 
6.4.2.1 
Replacement policy 
Refer to Section 12.8.2. 
6.5 
Treatment blinding 
This is a double-blind study. Participants, investigator study staff and the Novartis Clinical Trial 
Team will remain blinded to the identity of the treatment assignment from the time of 
randomization until clinical database lock. Randomization data are kept strictly confidential 
until the time of unblinding, and will not be accessible by anyone else involved in the study 
with the following exceptions: 
• Bioanalyst 
): to enable identification of samples from the ligelizumab treatment 
arms of the study to facilitate bioanalysis; 
• Specific vendors whose role in trial conduct requires their unblinding (e.g. IRT) 
• Global Clinical Supply (GCS) 
• An independent Data Monitoring Committee (DMC) and the independent statistician & 
programmer supporting the DMC activities 
• Novartis associates who are involved the analysis before final DBL described in 
Section 4.4 
The following measures must be applied by the study site to keep the participant and study site 
personnel blinded to the identity of the treatment: 
• The study drug must be administered by an independent drug administrator or unblinded 
pharmacist who is not involved in the performance of any of the study assessments. 
• Apart from the independent drug administrator or unblinded pharmacist, study site staff 
should NOT handle the Investigational Medicinal Product (IMP) and no information 
regarding the IMP should be discussed with the site study staff 
For the primary analysis at Week 12 ( Section 4.4), a limited number of pre-specified members 
of the program team from Novartis will be unblinded in a phasic manner. After the primary 
analysis at Week 12 and until study completion, the study will be under the management of a 
separate blinded team, replacing pre-specified unblinded team members, who will be 
responsible for study conduct. To maintain the integrity of the study data, the blinded team 
members will not have access to any of the unblinded data. 
Unblinding will occur in the case of participant emergencies and at the conclusion of the study. 
Health authorities will be granted access to unblinded data if needed. Any participant whose 


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treatment code has been broken inadvertently or for any non-emergency reason will be 
discontinued from study treatment. These participants will transition into the follow up period. 
The investigator must maintain an accurate record of the shipment and dispensing of 
investigational treatment in a drug accountability log. 
Table 6-4 
Blinding level 
Role 
Time or Event 
Randomization 
list generated 
Study 
treatment 
and 
allergen 
allocation 
& dosing 
Safety 
event 
(single 
subject 
unblinded) 
Interim analysis: 
60 adolescent 
completers 
Primary 
analysis  
at Week 
12 
Analysis 
at Week 
52 
Participants 
B 
B 
B 
B 
B 
B 
Investigator and 
site staff 
B 
B 
B 
B 
B 
B 
Site staff: 
Pharmacy staff and 
IMP administrator 
B 
UI 
B 
B 
B 
B 
Global Clinical 
Supply and 
Randomization 
Office 
UI 
UI 
UI 
UI 
UI 
UI 
sponsor staff: CRA 
B 
B 
B 
B 
B 
B 
Sponsor staff: 
Pharmacovigilance 
staff 
B 
B 
UI 
B 
B 
B 
Sponsor staff: 
Bioanalysis 
 
B 
UI 
B 
B 
B 
B 
Independent 
statistician and 
programmer 
B 
B 
B 
B 
B 
B 
 
 
 
 
 
 
 
Adjudication 
committee 
B 
B 
B 
B 
B 
B 
All other sponsor 
staff not identified 
above but defined 
in the unblinding 
charter 
B 
B 
B 
UI 
UI 
UI 
B Remains blinded 
UI Allowed to be unblinded on individual participant level. The results of the DBPCFC at screening will be 
unblinded to assess eligibility. 


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6.6 
Dose escalation and dose modification 
Study drug dose adjustments and/or interruptions are not permitted. 
Any interruption of study drug administration should be discussed with Novartis or delegate 
regarding the participant’s eligibility to continue investigational treatment. 
Any missed or altered study drug administration must be recorded on the appropriate eCRF in 
order to reconstruct an accurate dosing history for each participant. 
6.6.1 
Dose modifications 
Not applicable 
6.7 
Additional treatment guidance 
6.7.1 
Treatment compliance 
Participants will receive two injections SCq4w at 14 visits during the treatment period. 
Compliance is assured as long as the participant attends all study visits according to the 
Schedule of Assessments (Table 8-1). Study drug is administered at the site only at designated 
study visits. The administration of study drug must be recorded in the source documents and 
the corresponding eCRF. 
6.7.2 
Recommended treatment of adverse events 
Any treatment deemed necessary by the investigator for the safety of the participant is allowed. 
For treatment of severe allergic reactions including anaphylaxis, epinephrine and SABA are 
typically used.  
Treatments of adverse events should align with prohibited medication (Section 6.2.2,  
Table 6-3) and medications allowed under certain conditions (Section 6.2.1.1, Table 6-2). 
Medication used to treat adverse events (AEs) must be recorded on the appropriate CRF. 
For adverse events associated with the DBPCFC, please consult Section 16.4. 
6.7.3 
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
participant safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study participant who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a participant, he/she must provide 
the requested participant identifying information and confirm the necessity to break the 
treatment code for the participant. The investigator will then receive details of the 
investigational drug treatment for the specified participant and a fax or email confirming this 
information. The system will automatically inform Novartis monitor for the site and the study 
team that the code has been broken. 


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It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The investigator 
will provide: 
• protocol number 
• participant number 
In addition, oral and written information to the participant must be provided on how to contact 
the investigator or his/ her backup in cases of emergency, or when he/she is unavailable, to 
ensure that un-blinding can be performed at any time. 
In case of emergency code breaks, the respective participant is not eligible for joining the 
extension study anymore. 
7 
Informed consent procedures 
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent and assent, if applicable. 
If applicable, in cases where the participants' representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 
possible given his/her understanding. If the participant is capable of doing so, he/she must 
indicate agreement by personally signing and dating the written informed consent or assent 
document. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the participant source documents.  
The Investigator or his/her representative will explain the nature of the study, including the risks 
and benefits, to the participant or their legally authorized representative and answer all questions 
regarding the study. 
Participants must be informed that their participation is voluntary. Participants or their legally 
authorized representatives will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, privacy and data protection 
requirements, where applicable, and the IRB/IEC or study center. 
A copy of the ICF(s) must be provided to the participant or their legally authorized 
representative. 
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
Per Section 4.6 during a Public Health emergency as declared by Local or Regional authorities 
(i.e. pandemic, epidemic or natural disaster), that may challenge the ability to obtain a standard 
written informed consent due to limits that prevent an on-site visit, the investigator may conduct 
the informed consent discussion remotely (e.g. telephone, videoconference) if allowable by 
local Health Authorities. 


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Guidance issued by local regulatory bodies on this aspect prevail and must be implemented and 
appropriately documented (e.g. the presence of an impartial witness, sign/dating separate ICFs 
by trial participant and person obtaining informed consent, etc.).   
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC. Likewise, Novartis 
will also provide to investigators in separate documents proposed age-appropriate child assent 
forms. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the 
participant informed consent and assents and should be discussed with the participant during 
the study as needed. Any new information regarding the safety profile of the investigational 
drug that is identified between IB updates will be communicated as appropriate, for example, 
via an investigator notification or an aggregate safety finding. New information might require 
an update to the informed consent and then must be discussed with the participant. 
This ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional additional research. The Investigator or authorized designee will explain to each 
participant the objectives of the additional research. Participants will be told that they are free 
to refuse to participate and may withdraw their consent at any time and for any reason during 
the storage period. A separate signature will be required to document a participant’s agreement 
to allow any remaining specimens to be used for additional research. Participants who decline 
to participate in this optional additional research will document this. 
• Parent/Guardian study consent including the subsections mentioned above. 
• Child Assent for ages 6-11 years 
• Adolescent Assent for ages 12-17 years 
• As applicable, Pregnancy Outcomes Reporting Consent for female participants who took 
study treatment 
 
 
If a minor participant reaches the age of legal majority in the course of the study, he/she/they 
must be re-consented as an adult. 
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the basic (acceptable effective) contraception 
requirements. 


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A copy of the approved version of all consent/assent forms must be provided to Novartis after 
IRB/IEC approval. 
Participants might be asked to complete an optional questionnaire to provide feedback on their 
clinical trial experience. 
8 
Visit schedule and assessments 
The Assessment Schedule (Table 8-1) lists all of the assessments when they are performed. All 
data obtained from these assessments must be supported in the participant’s source 
documentation. The table indicates which data are entered into the eCRF from the source data 
(X), or remain in the source documents only (S). 
Participants should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-1) or as close to the designated day/time as possible. The participant should be 
instructed to contact the investigator if he/she is unable for any reason to attend the visit as 
planned and the visit should be rescheduled as close as possible to the original date. In case of 
a rescheduled visit, all upcoming visits need to follow the original schedule. Missed or 
rescheduled visits should not lead to automatic treatment or study discontinuation.  
Participants who discontinue from study or withdraw their consent/oppose the use of their 
data/biological samples should be scheduled for a final evaluation visit if they agree, as soon as 
possible, at which time all of the assessments listed for the final visit will be performed. At this 
final visit, all dispensed investigational product should be reconciled and the adverse event and 
concomitant medications not previously reported must be recorded on the CRF. 
All participants who complete the treatment period will be expected to attend all follow-up 
visits (Visit Week 56 to EOS). 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster that limits or prevents on-site study visits, 
alternative methods of providing continuing care may be implemented by the investigator as 
the situation dictates. If allowable by a local Health Authority and depending on operational 
capabilities, phone calls, virtual contacts (e.g. tele consult) or visits by site staff/ home nursing 
staff to the participant´s home, can replace on-site study visits, for the duration of the disruption 
until it is safe for the participant to visit the site again. If the Investigator delegates tasks to any 
on-site or off-site healthcare professional, the Investigator must ensure the individual(s) is/are 
qualified and appropriately trained to perform assigned duties. The Investigator must oversee 
their conduct and remain responsible for the evaluation of the data collected. 


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Please refer to the assessment schedule (Table 8-1) to understand which assessments have to be 
carried out in what order. Assessments at the top of the table have to be done before assessments 
at the bottom of the table. This is especially critical for days on when the DBPCFC is carried 
out: (e.g.: Cellular biomarker blood draw has to be done before SPT.) 
Administration of study drug has to be done before the DBPCFC. There must be a minimum 
of 1 hour between study drug administration and DBPCFC. 
Please make sure the order of assessments is respected consistently. 


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Table 8-1 
Assessment Schedule 
Period 
Screening 
Treatment 
Visit Name 
SCRN1
1 
SCRN
2  Part 
1-OFC 
SCRN
2 Part 
2-OFC 
Day 1 
(Randomizatio
n) 
WK
1 
WK
4 
WK
8 
WK12 
Part 
1-OFC 
WK12 
Part 
2-OFC 
WK1
6 
WK2
0 
WK2
4 
WK2
8 
WK3
2 
WK3
6 
WK4
0 
WK4
4 
WK4
8 
WK52 
Part 
1-OFC 
WK52 
Part 
2-OFC 
Days 
-28 to -1 
1 
8 
29 
57 
85 
87 to 
92 
113 
141 
169 
197 
225 
253 
281 
309 
337 
365 
367 to 
372 
Informed 
consent and 
assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / 
Exclusion 
criteria 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography/ 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications, 
therapies, 
procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient reported 
outcomes 
(PROs) 
 
 
 
X 
 
 
 
appro
x. 10 
days 
before 
the 
OFC 
appro
x. 3 
days 
after 
the 
OFC 
 
 
 
 
 
 
 
 
 
appro
x. 10 
days 
before 
the 
OFC 
 
appro
x. 3 
days 
after 
the 
OFC 
Physical 
Examination 
S 
S 
S 
S 
 
 
 
S 
S 
 
 
 
 
 
 
 
 
 
S 
S 
Body Weight 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Body Height 2 
X 
 
 
S 
 
S 
 
S 
 
 
 
 
 
 
S 
 
 
 
S 
 
Electrocardiogra
m (ECG) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 


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Period 
Screening 
Treatment 
Visit Name 
SCRN1
1 
SCRN
2  Part 
1-OFC 
SCRN
2 Part 
2-OFC 
Day 1 
(Randomizatio
n) 
WK
1 
WK
4 
WK
8 
WK12 
Part 
1-OFC 
WK12 
Part 
2-OFC 
WK1
6 
WK2
0 
WK2
4 
WK2
8 
WK3
2 
WK3
6 
WK4
0 
WK4
4 
WK4
8 
WK52 
Part 
1-OFC 
WK52 
Part 
2-OFC 
Spirometry in 
co-morbid 
asthma only 
X 
X 
X 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
Clinical 
Chemistry 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
Coagulation lab 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Liver Safety 
Monitoring 
S 
 
 
S 
 
S 
 
S 
 
 
 
 
 
 
S 
 
 
 
S 
 
Renal Safety 
Monitoring 
S 
 
 
S 
 
S 
 
S 
 
 
 
 
 
 
S 
 
 
 
S 
 
Urine pregnancy 
test 
 
S 
 
S 
S 
S 
S 
S 
 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
 
Serum 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
dipstick 
S 
 
 
 
 
 
 
S 
 
 
 
 
 
 
S 
 
 
 
S 
 


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Period 
Screening 
Treatment 
Visit Name 
SCRN1
1 
SCRN
2  Part 
1-OFC 
SCRN
2 Part 
2-OFC 
Day 1 
(Randomizatio
n) 
WK
1 
WK
4 
WK
8 
WK12 
Part 
1-OFC 
WK12 
Part 
2-OFC 
WK1
6 
WK2
0 
WK2
4 
WK2
8 
WK3
2 
WK3
6 
WK4
0 
WK4
4 
WK4
8 
WK52 
Part 
1-OFC 
WK52 
Part 
2-OFC 
Stool Sample 
(ova & parasitic 
test) by local lab 
S 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total IgE and 
peanut specific 
IgE (sIgE) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood collection 
for peanut
 
 
specific IgE and 
IgG4 
 
 
 
X 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
Skin Prick Test3 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 


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Period 
Screening 
Treatment 
Visit Name 
SCRN1
1 
SCRN
2  Part 
1-OFC 
SCRN
2 Part 
2-OFC 
Day 1 
(Randomizatio
n) 
WK
1 
WK
4 
WK
8 
WK12 
Part 
1-OFC 
WK12 
Part 
2-OFC 
WK1
6 
WK2
0 
WK2
4 
WK2
8 
WK3
2 
WK3
6 
WK4
0 
WK4
4 
WK4
8 
WK52 
Part 
1-OFC 
WK52 
Part 
2-OFC 
Contact IRT 
S 
S 
S 
S 
 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
Study drug 
administration 
 
 
 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study drug 
Accountability 
 
 
 
S 
 
S 
S 
S 
 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
 
Providing 
rescue 
medication, 
counseling, 
training & 
accountability 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
DBPCFC4 
 
X 
X 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Trial Feedback 
Questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
S 
Extension Study 
participation 
discussion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
S 
 
 
Study 
disposition 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Period 
Follow- up 
Visit Name 
WK56 
WK60 
WK64 
EOS/PSD 
Days 
393 
421 
449 
477 
Informed consent and assent 
 
 
 
 
Inclusion / Exclusion criteria 
 
 
 
 
Demography/ Medical history 
 
 
 
 


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Period 
Follow- up 
Visit Name 
WK56 
WK60 
WK64 
EOS/PSD 
Days 
393 
421 
449 
477 
Concomitant medications, therapies, procedures 
X 
X 
X 
X 
Patient reported outcomes (PROs) 
 
 
 
 
Physical Examination 
 
 
 
S 
Body Weight 
 
 
 
 
Body Height 2 
 
 
 
S 
Electrocardiogram (ECG) 
 
 
 
X 
Spirometry in co-morbid asthma only 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
Hematology 
 
 
 
X 
Clinical Chemistry 
 
 
 
X 
Coagulation lab 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
Liver Safety Monitoring 
 
 
 
S 
Renal Safety Monitoring 
 
 
 
S 
Urine pregnancy test 
S 
S 
S 
S 
Serum Pregnancy test 
 
 
 
 
Urinalysis dipstick 
 
 
 
S 
Stool Sample (ova & parasitic test) by local lab 
 
 
 
S 
Total IgE and peanut specific IgE (sIgE) 
 
 
 
 
Blood collection for peanut 
 specific IgE and 
IgG4 
X 
X 
X 
X 
Skin Prick Test3 
X 
 
 
X 


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Period 
Follow- up 
Visit Name 
WK56 
WK60 
WK64 
EOS/PSD 
Days 
393 
421 
449 
477 
Contact IRT 
 
 
 
S 
Study drug administration 
 
 
 
 
Study drug Accountability 
 
 
 
 
Providing rescue medication, counseling, training & 
accountability 
S 
S 
S 
S 
DBPCFC4 
 
 
 
 
Trial Feedback Questionnaire 
 
 
 
 
Extension Study participation discussion 
 
 
 
 
Study disposition 
 
 
 
X 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
1 Re-screening may be allowed for participants who failed initial screening; only 1 re-screening will be allowed (See Section 8.1) 
2 Body Height needs to be measured for children and adolescents at all visits where clinical chemistry is analyzed. The results need to be captured in source data. Body 
height only needs to be captured at SCR1 for adults (18 years and older). 
3 Please check the medications prior to skin prick test.  
4 The DBPCFC will be done on two separate days and within a window of one to seven days (See Section 8.3.1) 


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8.1 
Screening 
Screening 
In order to enroll in the study, participants must meet inclusion and none of the exclusion criteria 
(Section 5.1 and Section 5.2). Participants will have up to a 4 week screening period to establish 
study eligibility. During the screening period participants will be required to attend two visits; 
Screening Visit 1 and Screening Visit 2 (Part 1 and Part 2). Prior to the Screening Visit 2 Part 
1 (DBPCFC) screening can be extended one additional week if any information concerning 
eligibility to proceed to the DBPCFC is outstanding.  
Rescreening will be allowed only once for participants who failed initial screening (Screening 
Visit 1) and still fulfill ALL the study eligibility criteria (Section 5). If a participant rescreens 
for the study, the participant must sign a new informed consent (and assent if applicable) and 
will be issued a new participant number. Informed consent (and assent if applicable) for a 
rescreened participant must be obtained prior to performing any study-related assessments or 
collecting any data for the Screening visit. 
8.1.1 
Information to be collected on screening failures 
Participants who sign an informed consent form and are subsequently found to be ineligible 
prior to randomization will be considered as a screen failure. The reason for screen failure 
should be recorded on the appropriate CRF. The demographic information, informed consent, 
inclusion/exclusion pages, disposition, total IgE and peanut specific IgE, medical history, 
DBPCFC and SPT must also be collected for screen failure participants. No further data will be 
entered into the clinical database for participants who are screen failures, unless the participant 
experienced a serious adverse event during the screening phase (Section 10.1.3). Adverse 
events that are not SAEs will be followed by the investigator and collected only in the source 
data. If the participant fails to be randomized, the IRT must be notified within 2 days of the 
screen fail that the participant was not randomized. Participants who are randomized and fail to 
start treatment, e.g. participants randomized in error, will be considered an early terminator. 
The reason for early termination should be recorded on the appropriate CRF. 
8.2 
Participant demographics/other baseline characteristics 
Participant demographics and baseline characteristics will be collected at Screening (Screening 
Visit 1), as specified in the assessment schedule (Table 8-1). 
Data collected will include age; sex; race; ethnicity; height and weight; relevant medical history, 
and prior and concomitant medications. A detailed medical history (including family medical 
history) and current medical conditions present before signing of informed consent will be 
recorded. Investigators will have the discretion to record abnormal test findings on the CRF 
capturing medical history whenever in their judgment, the test abnormality occurred prior to 
the informed consent signature. Participant race and ethnicity are collected and analyzed to 
identify variations in safety or efficacy due to these factors as well as to assess the diversity of 
the study population as required by Health Authorities. 


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8.2.1 
Spirometry 
For participants with a documented diagnosis of asthma, spirometry testing should be 
performed at screening (Screening Visit 1) to assess the participant’s eligibility for study 
participation. Per Section 5.2, exclusion criterion 8, participants with uncontrolled asthma 
defined as FEV1 < 80% of predicted normal value and/or the history of one hospitalization for 
asthma within 12 months, are excluded. 
Furthermore, spirometry is performed prior to the DBPCFCs at Screening Visit 2 - parts 1 and 
2, week 12 parts 1 and 2, and at week 52 parts 1 and 2. If the FEV1 % predicted normal value 
is below 80% (< 80%) before the DBPCFC at any of the beforementioned visits, the DBPCFC 
should not be performed and rescheduled as appropriate. 
For each spirometry measurement, the accurate participant data (e.g., age, gender and height) 
should be used for the calculation of FEV1 predicted normal value at the site. 
The spirometry assessment should be performed in accordance with the standard practice at the 
site including the quality check. It is recommended to follow the ATS/ERS standard (ATS/ERS 
Task Force: Standardization of Lung Function Testing, Graham et al 2019) if possible. 
8.3 
Efficacy 
8.3.1 
Double Blind Placebo Controlled Food Challenge (DBPCFC) 
The DBPCFC is the critical assessment needed to evaluate the primary objective. It is performed 
at baseline (Screening Visit 2), Week 12 and Week 52. Details of this procedure are outlined in 
Section 16.4 and preparation of the allergen is outlined in the QGE031G12301 Pharmacy 
Manual. 
Conducting the food challenge requires the physical facility to prepare material as well as an 
unblinded and independent study nurse or staff to execute preparation. The assessment itself is 
conducted under medical supervision by blinded study personnel. Sites should be equipped with 
supplies to treat allergic reactions (including severe anaphylaxis) (Section 16.4), as well as 
access to emergency care units. 
To ensure participant safety, on study visits where the DBPCFC is conducted, it is critical to 
follow the order of assessments as outlined in Table 8-1., i.e. concomitant medication check, 
physical examination, ECG, vital signs, spirometry (for asthma participants only), urine 
pregnancy (if applicable), laboratory evaluations and study drug administration (Weeks 12 and 
52) must be performed prior to the start of the DBPCFC.  
The site should be prepared react to immediate and late hypersensitivity reactions, including 
anaphylaxis. At the completion of the DBPCFC participants must remain under observation at 
the site for a minimum of 2 hours after the last OFC dose (or for a positive challenge at least 
for 1 hour after all allergic symptoms have improved). After the observation period, discharge 
from the study site is at the discretion of the investigator. Prior to discharge, all participants 
should be briefed about the signs and symptoms of anaphylaxis and provided with an 
epinephrine auto-injector. 
DBPCFC data will be captured on a designated electronic case report form (eCRF). 


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If a participant fails to receive study medication for any reason AT the week 12 visit, do not 
proceed with the DBPCFC. Additionally, if a participant misses more than one dose of study 
treatment BEFORE week 12, they should not undergo the DBPCFC at the week 12 visit. 
8.3.2 
Appropriateness of efficacy assessments 
The procedures of oral food challenge have been endorsed in principle by the Adverse Reactions 
to Foods Committee of the American Academy of Allergy and Immunology, and there are well 
established guidelines such as the PRACTALL protocol (Cox et al (2017), Sampson et al 2012) 
and the CoFAR definition of dose-limiting symptoms (Table 16-8). The DBPCFC is the state-
of-the-art technique to confirm or refute histories of adverse reactions to foods. It is the “gold 
standard” by which all studies of food allergy should be judged (Bock et al 1988). 
Threshold doses can only be determined using DBPCFCs with low doses of the offending food. 
This approach has been previously used in a clinical study to determine the ability of an anti-
IgE monoclonal to shift the dose-response curve of a peanut DBPCFC (Leung et al 2003). 
Although the average amount of peanut consumed in an accidental exposure has not been 
accurately quantified, it is generally believed to be no more than one or two peanuts, or the 
equivalent of approximately 160 to 325 mg of peanut protein. Therefore, as proposed in this 
study, an increase in the threshold of peanut flour required to provoke symptoms should serve 
as a proxy to estimate the level of protection against unintended ingestion. 
8.4 
Safety 
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed. 
For details on AE collection and reporting, refer to AE section: 
• AEs and SAEs, including AEs leading to treatment discontinuation and events of interest 
such as injection site reactions, anaphylaxis, pre-malignancy/malignancy, cardio-
cerebrovascular events 
• Physical examination 
• Vital signs 
• Laboratory evaluations 
• Spirometry (for asthma participants only, Section 8.2.1) 
• ECG (Electrocardiogram) 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
regular phone or virtual calls can occur for safety monitoring and discussion of the participant´s 
health status until it is safe for the participant to visit the site again. 


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Table 8-2 
Physical Assessments 
Assessment 
Specification 
Physical examination 
A complete physical examination will be performed as specified in the Table 8-1, 
and includes the examination of general appearance, skin, neck (including 
thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular and neurological. If indicated based on medical history 
and/or symptoms, rectal, external genitalia, breast, and pelvic exams will be 
performed. Information for all physical examinations must be included in the 
source documentation at the study site. Clinically relevant findings that are 
present prior to signing informed consent must be recorded on the appropriate 
eCRF that captures medical history. Significant findings made after signing the 
informed consent which meet the definition of an AE must be recorded as an 
AE. 
Vital signs 
Vital signs include blood pressure and pulse measurements. After the participant 
has been sitting for 5 minutes, with back supported and both feet placed on the 
floor, systolic and diastolic blood pressure will be measured using an automated 
validated device e.g. OMRON, with an appropriately sized cuff. In case the cuff 
sizes available are not large enough for the participant’s arm circumference, a 
sphygmomanometer with an appropriately sized cuff may be used. 
Clinically notable vital signs are defined in Section 16.1. 
Height and weight 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg) in 
indoor clothing, but without shoes) will be measured as specified in the  
Table 8-1. 
8.4.1 
Laboratory evaluations 
A central laboratory will be used for analysis of all specimens detailed in this section unless 
noted otherwise. Details on the collections, shipment of samples and reporting of results by the 
central laboratory are provided to investigators in the laboratory manual. The blood volume 
collected for pediatric participants aligns with “The Hospital for Sick Children (SickKids) 
Research Ethics Board Blood Sampling Guidelines” (Howie 2011) and is outlined in detail in 
the QGE031G12301 Laboratory Manual. If local regulatory requirements stipulate more 
stringent limits for blood volumes for pediatric participants, the Novartis Clinical Team should 
be consulted for implementation of prioritization of lab evaluations. 
If health authorities require additional testing on biological samples, such tests will be done, 
wherever possible. 
Clinically notable laboratory findings are defined in Section 16.1. In case of lab abnormalities, 
an additional re-draw for central laboratory assessment is allowed during the screening period 
to confirm eligibility criteria. 
Clinically significant abnormalities must be recorded on the relevant section of the CRFs (Case 
report/Record Forms) capturing medical history/Current medical conditions/AEs. 
A serum β-hCG will be collected at screening (Screening Visit 1) for all after menarche and 
pre-menopausal women who are not surgically sterile. 


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Table 8-3 
Laboratory Evaluations 
 
Test Category 
Test Name 
Hematology 
Hemoglobin, hematocrit, red blood cell count, white blood cell count with 
differential and platelet count 
Coagulation 
International Normalized Ratio (INR), Activated partial thromboplastin time 
(APTT).  
Chemistry 
Albumin, total bilirubin, direct bilirubin, alkaline phosphatase, AST, ALT, LDH, 
GGT, chloride, sodium, potassium, magnesium, calcium, phosphate, 
creatinine, urea/BUN, uric acid, amylase, lipase, and glucose. If the total 
bilirubin concentration is increased above 1.5 times the upper limit of normal, 
direct and indirect reacting bilirubin should be differentiated. 
Urinalysis 
A midstream urine sample (approximately 30 mL) will be obtained, in order to 
avoid contamination with epithelial cells and sediments, and allow proper 
assessments. Semi-quantitative “dipstick” evaluation for specific gravity, 
glucose, protein, bilirubin, ketones, leukocyte esterase and blood will be 
performed at site. When a dipstick evaluation is abnormal, e.g., positive for 
WBC and/or blood, a urine sample must be sent to the Central Lab for 
microscopic examination including RBC and WBC. (Details on collection of 
urine for analysis by central laboratory are provided to investigators in the 
laboratory manual.) 
Parasite screening 
Assessment of stool samples for parasitic infections is done by the local 
laboratory (refer to Assessment of parasitic infections Section 8.4.3) 
Pregnancy Test 
Serum / Urine pregnancy test (refer to Pregnancy and assessments of fertility 
Section 8.4. 4) 
8.4.2 
Electrocardiogram (ECG) 
ECGs will be measured at Screening Visit 1 (for eligibility), week 12, week 52 and EOS visits 
Table 8-1. ECGs must be recorded after 10 minutes rest in the supine position to ensure a stable 
baseline/according to the ECG investigator manual. The preferred sequence of cardiovascular 
data collection during study visits is ECG collection first, followed by vital signs, and blood 
sampling. The Fridericia QT correction formula (QTcF) should be used for clinical decisions. 
Single 12 lead ECGs are collected, and the original trace should be printed on non-heat sensitive 
paper. Each ECG will be sent electronically for central review directly from the ECG machine. 
One print-out will be generated and kept at the investigator site as source documentation and 
will be dated and signed. The subject's number, the date, actual time of the tracing, and Study 
Code must appear on each page. 
Additional unscheduled ECGs may be repeated at the discretion of the investigator at any time 
during the study as clinically indicated. For any ECGs with participant safety concerns, two 
additional ECGs must be performed to confirm the safety finding. ECG safety monitoring or a 
review process should be in place for clinically significant ECG findings at baseline before 
administration of study treatment and during the study. 
Clinically significant abnormalities must be recorded on the CRF as either medical 
history/current medical conditions or adverse events as appropriate. 


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8.4.3 
Pregnancy and assessments of fertility 
All pre-menopausal female participants, including adolescent females of 12 to less than 18 years 
of age, who are not surgically sterile will have pregnancy testing. Post-menopausal status should 
be recorded in the Medical History CRF. 
At Screening Visit 1, all pre-menopausal female participants who are not surgically sterile will 
have serum β-hCG collected. 
At Screening Visit 2 Part 1 and subsequent study visits until Visit EOS, all pre-menopausal 
female participants who are not surgically sterile will have urine pregnancy testing performed 
BEFORE administration of the study treatment. A positive urine test needs to be confirmed 
with a central lab serum test prior to study drug administration. If positive, the participant must 
be discontinued from study treatment. 
Additional pregnancy testing might be performed if requested by local regulatory/ethics 
committee requirements. 
Assessments of fertility 
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the female participants not 
of child-bearing potential must also be available as source documentation in the following cases: 
1. Surgical bilateral oophorectomy without a hysterectomy 
2. Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile. 
In the absence of the above medical documentation, FSH testing is suggested of any female 
participant regardless of reported reproductive/menopausal status at Screening Visit 1. 
8.4.4 
Other safety evaluations 
Assessment of parasitic infection 
Reduction in IgE levels may confer increased susceptibility to parasitic infections. The risk of 
acquiring or activating infections with helminths during or after treatment with anti-IgE therapy 
such as ligelizumab is suspected to be low. Data from the Phase II study in the CSU indication 
(QGE031C2201) in this regard was unremarkable, but limited due to study sample size. 
All participants with no symptoms suggestive of parasitic infection will be given a stool sample 
collection kit at Screening Visit 1 and EOS visit by the site or the site's local laboratory. 
Participants will take the stool sample kit home and collect a stool samples within seven days 
of Screening Visit 1 and in the week prior to EOS visit. Participants will return the stool sample 
to the site or local laboratory as soon as possible after Screening Visit 1 (in order to allow 
processing within the screening period) and EOS visit.  
All participants with symptoms suggestive of parasitic infection at Screening Visit 1 and/ or 
EOS visit will be given three stool sample collection kits. These participants have to collect 
stool samples from three different days, ideally on three different days, within seven days of 
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The stool samples for parasitic disease will be examined for ova and parasites by the local 
laboratory. The identification of organisms in positive stools will be made by local laboratory. 
If stool testing is positive for pathogenic organisms (pathogenic as defined by the local 
laboratory), the result must be recorded in the source data and the participant will not be 
randomized and will not be allowed to rescreen. Stool samples negative for pathogenic 
organisms must be recorded in the source data. 
Participants must be advised that if diarrhea, or any other symptoms suggestive of parasitic 
infection, develops at any time before the end of study, three additional stool samples must be 
collected at the next visit or sooner and sent to local laboratory for analysis. 
Assessment of anaphylactic events 
An adjudication committee (AC) will be put in place to determine whether cases of 
hypersensitivity identified through a search algorithm based on the Standardized MedDRA 
Queries may represent cases of anaphylaxis. Further details regarding the AC will be 
documented in an AC charter. 
Assessment of cardio-cerebrovascular events 
An AC will be put in place to review all cases identified through a search algorithm based on 
the Standardized MedDRA Queries of cardio-cerebrovascular events. The clinical presentation 
and association of these events with pre-existing risk factors will be part of the assessment. See 
Section 10.3.2 for details 
Assessment of neoplastic events 
An AC will be put in place to review all cases identified through a search algorithm based on 
the Standardized MedDRA Queries of neoplastic events. The clinical presentation and 
association of these events with pre-existing risk factors will be part of the assessment. See 
Section 10.3.2 for details. 
8.4.5 
Appropriateness of safety measurements 
In addition to safety assessments that are standard in this population, participants are not eligible 
to join the study if they have a history of a severe or life-threatening hypersensitivity event 
needing an ICU admission or intubation within 60 days prior to baseline DBPCFC (Screening  
Visit 2) or uncontrolled asthma at Screening Visit 1. 
Also, study treatment will be discontinued if the participant experiences a life-threatening 
hypersensitivity event needing an ICU admission or intubation OR a serious hypersensitivity 
event suspected to be related to study treatment. 
8.5 
Additional assessments 
8.5.1 
Clinical Outcome Assessments (COAs) 
Patient reported outcomes (PRO) 


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The impact of ligelizumab on the health-related quality of life (HRQoL) of participants with a 
food allergy will be assessed by the following measures based on age group and responder type: 
• FAQLQ-CF: Food Allergy Quality of Life Questionnaire – Child Form 
• FAIM-CF: Food Allergy Independent Measure – Child Form 
• FAQLQ-TF: Food Allergy Quality of Life Questionnaire – Teenager Form 
• FAIM-TF: Food Allergy Independent Measure – Teenager Form 
• FAQLQ-AF: Food Allergy Quality of Life Questionnaire – Adult Form 
• FAIM-AF: Food Allergy Independent Measure – Adult Form 
• FAQLQ-PF: Food Allergy Quality of Life Questionnaire – Parental Form 
• FAQL-PB: Food Allergy Quality of Life - Parental Burden Questionnaire 
• SF-36v2 Acute Version – Medical Outcomes Study 36-Item Short Form Version 2 Acute 
Version (recall period is past week) 
Table 8-4 
PROs based on participant’s age 
Age Group/ 
Respondent Type 
Day 1 
Randomization 
Week 12 
10 days 
Before D1 
OFC 
Week 12 
3 days After 
D2 OFC 
Week 52 
10 days 
Before D1 
OFC 
Week 52 
3 days After 
D2 OFC 
Children aged 6-7 
Children aged 6-7 will NOT be completing any PRO measures.  
Parents/Caregivers of children aged 6-17 will complete specific PROs designed for 
Parents/Caregivers. 
Note: Children aged 8-12 will self-complete PROs (next row) and their 
parents/caregivers will also complete PROs. 
Children aged 8-12 
FAQLQ-CF 
FAIM-CF 
FAQLQ-CF 
FAIM-CF 
FAQLQ-CF 
FAIM-CF 
FAQLQ-CF 
FAIM-CF 
FAQLQ-CF 
FAIM-CF 
Adolescents aged 
13-17 
FAQLQ-TF 
FAIM-TF 
FAQLQ-TF 
FAIM-TF 
FAQLQ-TF 
FAIM-TF 
FAQLQ-TF 
FAIM-TF 
FAQLQ-TF 
FAIM-TF 
Adults aged 18+ 
FAQLQ-AF 
FAIM-AF 
SF-36v2 
FAQLQ-AF 
FAIM-AF 
FAQLQ-AF 
FAIM-AF 
SF-36v2 
FAQLQ-AF 
FAIM-AF 
FAQLQ-AF 
FAIM-AF 
SF-36v2 
Parents/Caregivers 
of Children 6-12 
FAQLQ-PF 
FAQL-PB 
FAQLQ-PF 
FAQLQ-PF 
FAQL-PB 
FAQLQ-PF 
FAQLQ-PF 
FAQL-PB 
Parents/Caregivers 
of Adolescents13-
17 
FAQL-PB 
  
FAQL-PB 
  
FAQL-PB 
The Food Allergy Quality of Life Questionnaire (FAQLQ) is a self-reported instrument 
intended to assess the effect of food allergy on the particpant’s HRQoL (i.e., domains consist 
of risk of accidental exposure, emotional impact, allergen avoidance and dietary restrictions). 
The FAQLQ- Child Form (aged 8-12) (Flokstra-de Blok et al 2009 a), FAQLQ-Teenager Form 
(aged 13-17) Flokstra-de Blok et al 2008) and FAQLQ-Adult Form (≥18 years of age) 
(Flokstra-de Blok et al 2009 b), are self-administered, validated, food allergy-specific HRQoL 
questionnaires. The FAQLQ-parental form (FAQLQ-PF) is completed by parents of children 
aged 0-12 with food allergy (DunnGalvin et al 2008) 


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The number of items and domains varies by FAQLQ instrument administered. Each question is 
scored on a seven-point scale from 1 to 7 (i.e., from ‘no’ to ‘maximal’ impairment in HRQoL, 
respectively). The total score is the arithmetic average of all non-missing items. Domain scores 
are calculated similarly. 
The Food Allergy Independent Measure (FAIM) reflects the participant’s perceived food 
allergy severity and food allergy-related risk. The total score for the FAIM ranges from 1 to 7 
(i.e., from ‘limited’ to ‘the greatest’ severity perception). If less than 80% of the items are 
complete, then the total score will not be calculated. Similarly, if less than 80% of the items 
within a domain are complete, then the domain score will not be calculated. 
(van der Velde et al 2010) 
The Food Allergy Quality of Life-Parental Burden (FAQL-PB) Questionnaire is a self-
administered, disease-specific instrument developed to measure the effect of pediatric food 
allergy on HRQoL among caregivers. The instrument includes 17 items investigating the effect 
of having a child with food allergy on family/social activities, school, meal preparation, health 
concerns and emotional issues, using a 7-point Likert scale (Cohen et al 2004). 
The SF-36v2® Health Survey is a 36-item instrument for measuring health status and outcomes 
via participant self-report. It is designed for use in surveys of general and specific populations, 
health 
policy 
evaluations, 
and 
clinical 
practice 
and 
research. 
The 
SF-
6Dv2 (Brazier et al 2020) will be derived from the SF-36v2 (Maruish  2011) for health 
economic evaluations. The SF-6Dv2 captures the impacts of food allergy on social activities 
and depression/nervousness. 
All questionnaires will be completed in the language most familiar to the respondent. The same 
parent/caregiver should complete the assessments throughout the study. 
The participant should be given sufficient instruction, space, time and privacy to complete the 
questionnaire during the Randomization visit. The study coordinator should encourage the 
participants to complete all of the available questionnaires. 
All participants will complete the PRO questions via a handheld electronic device (note: 
children aged 6-7 will NOT be completing any PRO measures). Participants will take the device 
home and should complete them 10 days before Day 1 of the OFC and 3 days after Day 2 of the 
OFC at 12 weeks and at 52 weeks. If participants experience any difficulties with submission 
after completing the PROs, they should contact the study staff for assistance. Available training 
materials related to the administrative procedures of the questionnaires will be provided to the 
sites. 
Participant refusal to complete study PROs are not protocol deviations. The participant should 
be made aware that completed measure(s) are not reviewed by the investigator/ study personnel. 
Trial Feedback Questionnaire 
This study includes an optional questionnaire for trial participants (18-55 years) to provide 
feedback on their clinical trial experience. Individual trial participant responses will not be 
reviewed by investigators. Responses may be used by the sponsor to understand where 
improvements can be made in the clinical trial process. This questionnaire does not ask 


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questions about the trial participant's disease, symptoms, treatment effect, or adverse events, 
and, therefore is not considered as trial data. 


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8.5.4 
Other Assessments 
8.5.4.1 
Skin prick testing (SPT) 
An allergen specific SPT is a commonly used diagnostic tool. In this study a titration SPT using 
peanut allergen will provide additional information on the impact of IgE suppression on skin 
mast cells. Milk and/or egg allergens will also be tested based on the participant's medical 
history. 
In performing the test, the skin of the participant's back is the preferred site of testing, 
alternatively the forearm may be used. For consistency it is important to perform the skin prick 
test at the same location throughout the study. Skin reactions are to be recorded after 15 minutes 
of applying allergen to the pricked location. Medications to be washed out prior to the SPT are 
listed in Table 16-9. 


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This study specifies the use of BOTH a titration SPT (TSPT) and non-TSPT. All patients will 
perform a TSPT to peanut. In addition, all patients should perform a non-titration SPT 
(undiluted) to milk and/or egg according to medical history.  
Skin prick testing is scheduled at Screening Visit 1, Week 16, Week 56 and EOS. At Week 16, 
skin prick testing should be performed before dosing of study treatment. 
The size of the wheal and flare (the longest diameter and the midpoint orthogonal diameter) at 
each site will be recorded in the eCRFs. 
The SPT may rarely cause serious allergic reactions, including anaphylaxis, and the site should 
be prepared to provide immediate treatment should that occur. If the participant experiences a 
systemic allergic reaction and/or an event which is judged by the investigator as an adverse 
reaction, it should be reported on the designated CRF. 
The SPT procedure is summarized separately in Appendix Section 16.5. 
 
 
8.5.4.3 
Additional research using coded data 
For participants who consent for additional research, their coded data including biological 
samples may be used for additional research. The purpose of the additional research would be 
limited to: 
• help better understand how the study treatment works; 
• learn more about the disease; 
• help develop ways to detect, monitor, and treat related human diseases; 
• improve the way clinical studies are conducted 
9 
Discontinuation and completion 
9.1 
Discontinuation from study treatment and from study 
9.1.1 
Discontinuation from study treatment 
Discontinuation of study treatment for a participant occurs when study treatment is stopped 
earlier than the protocol planned duration and can be initiated by either the participant or the 
investigator. 


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The investigator must discontinue study treatment for a given participant if he/she believes that 
continuation would negatively impact the participant's well-being. 
Study treatment must be discontinued under the following circumstances: 
• Participant/guardian decision 
• AEs for which continued exposure to the study drug would be detrimental 
• Abnormal renal laboratory results requiring discontinuation (see Section 16.3) 
• Abnormal liver laboratory results requiring discontinuation (see Section 16.2) 
• Platelets < 75000/µL 
• Pregnancy (see Section 5 and Section 8.4.3) 
• Participant develops a medical condition that requires use of prohibited treatment as per 
Section 6.2.2 or if participant exhibits a behavior of non-compliance regarding prohibited 
medications 
• Participant experiences a life-threatening hypersensitivity event due to any reason needing 
an ICU admission or intubation 
• Participant experiences a serious hypersensitivity event suspected to be related to study 
treatment 
• Any other protocol deviation that results in a significant risk to the participant’s safety 
• Any situation in which study participation might result in a safety risk to the participant 
• Following emergency unblinding 
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the participant’s premature discontinuation of study 
treatment and record this information. The investigator must also contact the IRT to register the 
participant’s discontinuation from study treatment. 
Participants who discontinue from study treatment should be encouraged to return for all 
upcoming visits indicated in the Assessment Schedule (Table 8-1).  
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the participant. 
This telephone contact should preferably be done according to the study visit schedule and at a 
minimum information on new/ concomitant treatments and adverse events /serious adverse 
events should be obtained. 
Participants who discontinue study treatment will no longer undergo any DBPCFC that 
may be planned on the remaining visit(s). 
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact: 
• New/concomitant treatments 
• Adverse Events/Serious Adverse Events 
If discontinuation occurs because treatment code has been broken, please refer to Section 6.7.3. 


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9.1.2 
Discontinuation from study 
Discontinuation from study is when the participant permanently stops receiving the study 
treatment, and further protocol-required assessments or follow-up, for any reason. 
If the participant agrees, a final evaluation at the time of the participant’s study discontinuation 
should be made as detailed in the assessment table ( Table 8-1). 
9.1.3 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue from study treatment or discontinue from study or withdraw 
consent/oppose to the use of their data/biological samples, the investigator must show "due 
diligence" by documenting in the source documents steps taken to contact the participant, e.g. 
dates of telephone calls, registered letters, etc. A participant should not be considered as lost to 
follow-up until due diligence has been completed or until end of the study. 
9.2 
 Withdrawal of informed consent and exercise of participants’ 
data privacy rights 
Withdrawal of consent/opposition to use of data and/ or biological samples occurs in countries 
where the legal justification to collect and process the data is consent and when a participant: 
Explicitly requests to stop use of their data and 
• No longer wishes to receive study treatment 
and 
• Does not want any further visits or assessments (including further study-related contacts) 
This request should be as per local regulations (e.g. in writing) and recorded in the source 
documentation. 
Withdrawal of consent impacts the ability to further contact the participant, collect follow-up 
data (e.g. to respond to data queries) and potentially other country-specific restrictions. It is 
therefore very important to ensure accurate recording of withdrawal vs. discontinuation based 
on the protocol definitions of these terms. 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw their 
consent/exercise data privacy rights and record this information. The Investigator shall clearly 
document if the participant has withdrawn his/her consent for the use of data in addition to a 
study discontinuation. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up. 
If the participant agrees, a final evaluation at the time of the participant’s withdrawal of consent/ 
exercise data privacy rights should be made as detailed in the assessment table (refer to 


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Section 8).  Further details on withdrawal of consent or the exercise of participants' data privacy 
rights are included in the corresponding informed consent form. 
9.3 
Study completion and post-study treatment 
Study completion is defined as when the last participant finishes the End of Study (EOS) visit 
(Week 68). This includes any repeat assessments associated with this visit with full 
documentation and follow-up by the Investigator or, in the event of an early study termination 
decision, the date of that decision.  
An Extension Study is planned. Participants who would like to join the Extension study will 
transition at one of the following timepoints:  
1. Approximately the first one third of participants will join the Extension study after 
completion of the follow-up period at week 68. For those participants, the week 68 Visit is the 
Study Completion Visit in study QGE031G12301.  
2. The remaining participants will join the Extension study after completion of the treatment 
period at week 52. For those participants, the week 52 Visit is the Study Completion Visit in 
study QGE031G12301.  
Participation in the Extension Study will be optional.  
Participants not entering the Extension Study will complete the 16 weeks follow-up period. 
Their Study Completion Visit is at Week 68. 
9.4 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time. Reasons for early termination 
• Unexpected, significant, or unacceptable safety risk to participants enrolled in the study 
• Decision based on recommendations from applicable board(s) or regulatory authorities 
after review of safety and efficacy data 
• Discontinuation of study drug development 
• Practical reasons (including slow enrollment) 
• Medical reasons 
In taking the decision to terminate, Novartis will always consider the participant’s welfare and 
safety. Should early termination be necessary, participants must be seen as soon as possible and 
treated as a prematurely withdrawn participant. The investigator may be informed of additional 
procedures to be followed in order to ensure that adequate consideration is given to the 
protection of the participant’s interests. The investigator or sponsor, depending on the local 
regulation, will be responsible for informing IRBs/IECs of the early termination of the trial. For 
more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 


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10 
Safety monitoring, reporting and committees 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical 
investigation participant after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The investigator has the responsibility for managing the safety of individual participant and 
identifying adverse events. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
The occurrence of adverse events must be sought by non-directive questioning of the participant 
at each visit during the study. Additionally, the investigator should proactively query the 
participants about the occurrence of specific adverse events suggestive of hypersensitivity 
reactions during and after the DBPCFC, the administration of study drug, and in the event of 
accidental food ingestion. Adverse events also may be detected when they are volunteered by 
the participant during or between visits or through physical examination findings, laboratory 
test findings, or other assessments. 
Adverse events must be recorded with the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2): 
1. The severity grade  
• mild: usually transient in nature and generally not interfering with normal activities 
• moderate: sufficiently discomforting to interfere with normal activities 
• severe: prevents normal activities 
2. Its relationship to the study treatment. If the event is due to lack of efficacy the assessment 
of causality will usually be ‘Not suspected.’ The rationale for this guidance is that the 
symptoms of a lack of efficacy are not caused by the trial drug, they happen in spite of its 
administration and/or both lack of efficacy can only be evaluated meaningfully by an 
analysis of cohorts, not on a single participant; 
3. Its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported; 
4. Whether it constitutes a SAE (Section 10.1.2 for definition of SAE) and which seriousness 
criteria have been met; 
5. Action taken regarding with study treatment. All adverse events must be treated 
appropriately. Treatment may include one or more of the following: 
• Dose not changed, 
• Drug interrupted/permanently discontinued. 


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• Dose increases or reductions are not permitted. 
6. Its outcome: not recovered/ not resolved; recovered/ resolved; recovering/ 
resolving; recovered/ resolved with sequelae; fatal or unknown 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Adverse event monitoring should be continued until the end of study visit or for at least 30 days 
or 5 half-lives following the last dose of study treatment, whichever is longer. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome. 
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB). 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participant 
with the underlying disease. Alert ranges for laboratory and other test abnormalities are included 
in Section 16.1. 
Please refer to Section 16.4 for the assessment, reporting and management of hypersensitivity 
reactions observed during the DBPCFC and the post-DBPCFC observation period. 
10.1.2 
Serious adverse events 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria: 
• fatal 
• life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 


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• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the participant’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, e.g. defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life-threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines). 
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred. 
10.1.3 
SAE reporting 
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 30 days after the last study visit (EOS visit week 68) 
must be reported to Novartis safety immediately, without undue delay, but under no 
circumstances later than within 24 hours of obtaining knowledge of the events (Note: If more 
stringent, local regulations regarding reporting timelines prevail, those need to be followed) 
Any SAEs experienced after the 30 day period should only be reported to Novartis Safety if the 
investigator suspects a causal relationship to study treatment, unless otherwise specified in local 
regulations. Any SAEs reported up to the participant's last visit will be reported in the eCRF. 
SAEs beyond that date will only be recorded in the Novartis Safety database. Detailed 
instructions regarding the submission process and requirements are to be found in the 
investigator folder provided to each site. 
Information about all SAEs is collected and recorded on the electronic Serious Adverse Event 
Report Form; all applicable sections of the form must be completed in order to provide a 
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All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay, but under no circumstances later than within 24 hours of the 
investigator receiving the follow-up information (Note: If more stringent, local regulations 
regarding reporting timelines prevail, those need to be followed). An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event. 
If the SAE is not previously documented in the Investigator’s Brochure (new occurrence) and 
is thought to be related to the investigational treatment, a Chief Medical Office and Patient 
Safety (CMO&PS) Department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same investigational 
treatment that this SAE has been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 
Screen Failures: SAEs occurring after the participant has signed the ICF until the time the 
participant is deemed a Screen Failure must be reported to Novartis. 
Randomized or treated participants: SAEs occurring after the participant has signed the ICF 
until 120 days (5 half-lives of ligelizumab) after the participant has withdrawn consent or 
discontinued study must be reported to Novartis.  
Please refer to Section 16.4 for the assessment, reporting and management of serious 
hypersensitivity reactions observed during the DBPCFC and the post-DBPCFC observation 
period. 
10.1.4 
Pregnancy reporting 
Details of all pregnancies in female participants will be collected after the start of study 
treatment and until 5 half-lives, after last dose of ligelizumab. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
Abnormal pregnancy outcomes (e.g. spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. 
Any post study pregnancy-related SAE considered reasonably related to the study treatment by 
the Investigator will be reported to Novartis. While the Investigator is not obligated to actively 
seek this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 
Pregnancies 
If a female trial participant becomes pregnant, the study treatment should be stopped, which 
should be documented on the respective CRF. The pregnancy consent form should be presented 
to the trial participant. The participant must be given adequate time to read, review and sign the 


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pregnancy consent form. This consent form is necessary to allow the investigator to collect and 
report information regarding the pregnancy. To ensure participant safety, each pregnancy 
occurring after signing the informed consent must be reported to Novartis within 24 hours of 
learning of its occurrence. The pregnancy should be followed up to determine outcome, 
including spontaneous or voluntary termination, details of the birth, and the presence or absence 
of any birth defects, congenital abnormalities, or maternal and/or newborn complications. 
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship of the study treatment to any 
pregnancy outcome. After providing consent, the follow-up should take place during the 
pregnancy and up to 12 months following the expected delivery date. Any SAE experienced 
during pregnancy must also be reported. 
10.1.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE. Study treatment 
errors and uses outside of what is foreseen in the protocol, misuse or abuse will be collected 
and reported in the safety database irrespective of it being associated with an AE/SAE within 
24 hours of Investigator’s awareness.  For more information on AE and SAE definition and 
reporting requirements, please see the respective sections. 
10.2 
Additional Safety Monitoring 
10.2.1 
Liver safety monitoring 
To ensure participant safety and enhance reliability in determining the hepatotoxic potential of 
an investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
The following 2 categories of abnormalities / AEs have to be considered during the course of 
the study (irrespective of whether classified/reported as AE/SAE): 
·Liver laboratory triggers, which will require repeated assessments of the abnormal laboratory 
parameter 
·Liver events, which will require close observation, follow-up monitoring and contributing 
factors are recorded on the appropriate CRFs 


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Please refer to Table 16-2 in Section 16.2 for complete definitions of liver laboratory triggers 
and liver events. 
Every liver event defined in Table 16-2 should be followed up by the investigator or designated 
personnel at the trial site, as summarized below. Additional details on actions required in case 
of liver events are outlined in Table 16-3 and Table 16-4. Repeat liver chemistry tests (i.e. ALT, 
AST, TBL, PT/INR, ALP and G-GT) to confirm elevation. 
• These liver chemistry repeats will be performed using the central laboratory. If results will 
not be available from the central laboratory, then the repeats can also be performed at a 
local laboratory to monitor the safety of the participant. If a liver event is subsequently 
reported, any local liver chemistry tests previously conducted that are associated with this 
event should have results recorded on the appropriate CRF. 
• If the initial elevation is confirmed, close observation of the participant will be initiated, 
including consideration of  
• Treatment interruption if deemed appropriate 
• Discontinuation of the investigational drug (refer to Section 9.1.1), if appropriate 
• Hospitalization of the participant if appropriate 
• Causality assessment of the liver event should include:  
• A thorough follow-up of the liver event should include (based on investigator’s 
discretion) serology tests, imaging and pathology assessments, gastroenterologist 
or hepatologist’s consultancy, obtaining more detailed history of symptoms and 
prior or concurrent diseases, history of concomitant drug use, exclusion of 
underlying liver disease, imaging such as abdominal ultrasound, CT or MRI 
scans and obtaining a history of exposure to environmental chemical agents 
All follow-up information and procedures performed must be recorded as appropriate in the 
CRF. 
10.2.2 
Renal safety monitoring 
The following base monitoring for renal laboratory values, as per the Novartis Drug-Induced 
Nephrotoxicity Guidelines (Nov 2017; Table 10-1 below) of abnormal renal laboratory values, 
will be carried out as part of the assessment schedule (Table 8-1) during the course of the study 
Table 10-1 
Base Renal Monitoring 
Assessment  
Assessment Frequency 
Serum 
1. Single baseline 
Creatinine, Electrolytes (Na, Ca, K)  
2. Steady State assessment 
Urine  
3. 6-monthly during study  
Dipstick (Spot urine sample) 
4. Final visit ≥ 48h after last dose  
• Every renal laboratory trigger or renal event as defined in Table 16-5 should be followed 
up by the investigator or designated personnel at the trial site as summarized in  
Table 16-6. 


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10.3 
Committees 
10.3.1 
Data Monitoring Committee 
This study will include a data monitoring committee (DMC) which will function independently 
of all other individuals associated with the conduct of this clinical trial, including the site 
investigators participating in the study. The DMC will assess at defined intervals the progress 
of a clinical trial, safety data, and efficacy variables and recommend to the sponsor whether to 
continue, modify, or terminate a trial. The DMC will review unblinded data. 
Specific details regarding composition, responsibilities, data monitoring, and meeting 
frequency, and documentation of DMC reports, minutes, and recommendations will be 
described in a separate charter that is established between the sponsor and the DMC. 
10.3.2 
Adjudication committee 
The role of the Adjudication Committee (AC) is to ensure that all treatment outcomes are judged 
uniformly, using standard criteria and processes. The AC will be composed of clinical experts 
to evaluate disease progression and harmonize endpoint assessment criteria using data provided 
by the sponsor (Section 8.4.4). 
All personnel involved in the adjudication process will remain blinded to treatment allocation 
throughout the trial. Specific details regarding endpoint definitions can be found in the 
adjudication charter. 
11 
Data Collection and Database management 
11.1 
Data collection 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff. 
The investigator/designee is responsible for assuring that the data entered/ recorded on eCRFs 
is complete, accurate, and that entry and updates are performed in a timely manner. The 
Investigator must certify that the data entered are complete and accurate. 
After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site. 


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11.2 
Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
Dates of screenings, randomizations, screen failures and study completion, as well as 
randomization codes and data about all study treatment (s) dispensed to the participant and all 
dosage changes will be tracked using an Interactive Response Technology (IRT). The system 
will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis (or a designated CRO) at specific timelines. 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of Novartis. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis. Any changes to the database after that time can only be made after 
written agreement by Novartis development management. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eSource DDE or 
eCRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of participant records, the 
accuracy of data capture / data entry, the adherence to the protocol and to Good Clinical Practice, 
the progress of enrollment, and to ensure that study treatment is being stored, dispensed, and 
accounted for according to specifications. Key study personnel must be available to assist the 
field monitor during these visits. 
The investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
participant's file.  The investigator must also keep the original informed consent form signed 
and dated by the participant (a signed copy is given to the participant). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 


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documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed. 
12 
Data analysis and statistical methods 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.  
12.1 
Analysis sets 
The Randomized Analysis Set (RAS) consists of all randomized participants, regardless of 
whether or not they receive a dose of study drug. Participants will be analyzed according to the 
treatment they are assigned to. 
The Full Analysis Set (FAS) comprises all participants to whom study treatment has been 
assigned and who received at least one dose of study treatment. According to the intent to treat 
principle, participants will be analyzed according to the treatment they have been assigned to 
during the randomization procedure. FAS will be used for all efficacy variables, unless 
otherwise stated. 
The Safety Analysis Set (SAF) includes all participants who received at least one dose of study 
treatment. Participants will be analyzed according to the treatment they received, where 
treatment received is defined as the randomized/assigned treatment if the participant took at 
least one dose of that treatment or the first treatment received if the randomized/assigned 
treatment was never received. The safety set will be used in the analysis of all safety variables. 
12.2 
Participant demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be summarized 
descriptively by treatment group for the RAS. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean 
(geometric mean for non-normal variables), standard deviation, median, minimum, and 
maximum will be presented. 
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term, by treatment group. 
12.3 
Treatments 
The Safety analysis set will be used for the analyses below. The duration of exposure (in weeks) 
to study treatment will be summarized by treatment group. In addition, the number of doses, 
total cumulative dose, and number of missed doses will be presented. Categorical data will be 
summarized as frequencies and percentages. For continuous data, mean, standard deviation, 
median, 25th and 75th percentiles, minimum, and maximum will be presented. 


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Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized according to the Anatomical Therapeutic Chemical (ATC) 
classification system, and preferred term by treatment group. 
12.4 
Analysis supporting primary objectives 
This section will detail the statistical analysis of the primary estimand. Details of the hypothesis 
testing strategy including primary and key secondary endpoints to handle multiplicity are 
provided in Section 12.5.1. 
12.4.1 
Definition of primary endpoint(s) 
Definition of primary estimand is provided in Section 2.1. 
12.4.2 
Statistical model, hypothesis, and method of analysis 
The trial will be considered positive, if at least one of the two ligelizumab doses demonstrate a 
statistically significant result in comparing the proportion of responders as described below. 
The two doses will be tested in parallel for 12 weeks treatment on the primary endpoint. 
Let pj denote the responder rate for treatment regimens j, j=0, 1 or 2 where 
• 0 corresponds to placebo 
• 1 corresponds to ligelizumab 120 mg treated for 12 weeks 
• 2 corresponds to ligelizumab 240 mg treated for 12 weeks 
Responder rate is defined as the proportion of participants tolerating a single dose of ≥ 600 mg 
(1044 mg cumulative tolerated dose) of peanut protein without dose-limiting symptoms during 
the DBPCFC conducted at Week 12. For participants with treatment discontinuation or missing 
more than 1 doses of study drug prior to Week 12 due to reasons other than operational 
complications caused by public health emergency, they will be considered non-responders. 
The following hypotheses will be tested: 
H0 120 RR600 : p1 / (1- p1) ≤ p0 / (1- p0) versus HA 120 RR600 : p1 / (1- p1) > p0 / (1- p0)  
H0 240 RR600 : p2 / (1- p2) ≤ p0 / (1- p0) , HA 240 RR600 : p2 / (1- p2) > p0 / (1- p0) 
H0 120 RR600 : ligelizumab 120mg is not superior to placebo with respect to the responder rate at 
a level of 600 mg peanut protein (1044 mg cumulative tolerated dose) without dose-limiting 
symptoms at Week 12 
H0 240 RR600 :ligelizumab 240mg is not superior to placebo with respect to the responder rate at a 
level of 600 mg peanut protein (cumulative tolerated dose 1044 mg) without dose-limiting 
symptoms at Week 12 
The primary endpoint will be analyzed based on a logistic regression model, including treatment, 
age subgroup (6 – 11 years, 12 –17 years, 18 - 55 years), region as fixed class effects and log-
transformed total IgE at Screening Visit 1 as a covariate. Odds ratio and 95% confidence 
intervals (CI) will be presented comparing each Ligelizumab dose to Placebo with respect to 
the proportions of responders. 


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The detailed testing strategy for primary and key secondary endpoints is provided in 
Section 12.5.1. 
12.4.3 
Handling of intercurrent events of primary estimand 
The analysis will account for different intercurrent events as explained in the following: 
Intercurrent events unrelated to public health emergency (e.g. COVID-19 pandemic)  
• Discontinuation of treatment prior to Week 12 : a composite variable strategy will be used 
to handle these intercurrent events. Participants who discontinue treatment prior to Week 
12 due to reasons unrelated to public health emergency will be considered non-responder 
to reflect potential treatment failure at Week 12 in clinical practice. 
• Missing more than one dose of study drug prior to Week 12 : participants who miss more 
than 1 treatment doses prior to Week 12 due to reasons unrelated to public health 
emergency will be considered non-responders to reflect potential treatment failure at 
Week 12 in clinical practice. 
• Intake of rescue medication before starting DBPCFC assessment at Week 12 : 
epinephrine, SABA, anti-histamines and saline bolus are typically used as rescue 
medication to treat allergic reactions. Considering participants must be in good health and 
only minimal or no symptomatic medications are allowed before starting the DBPCFC, 
DBPCFC collected after intake of rescue medication will be used for the primary analysis. 
Intercurrent events related to operational complications caused by public health 
emergency (hypothetical strategy) 
• Discontinuation of treatment or missing more than one dose of study drug prior to Week 
12 : the interest lies in DBPCFC data at Week 12 that would be observed if the participant 
had completed 12 week of randomized treatment without the impact of operational 
complications caused by public health emergency. The responder status at Week 12 will 
be multiply imputed using the missing at random (MAR) assumption for all treatment 
arms included in the primary analysis. 
The multiple imputation model will be built based on similar participants (i.e. with the same 
covariates and observed measurement history) in the same treatment arm. More details on the 
imputation model will be pre-specified in the Statistical Analysis Plan (SAP). 
Intercurrent events due to non-operational public health emergency related reasons will be 
classified as intercurrent events unrelated to public health emergency. 
12.4.4 
Handling of missing values not related to intercurrent event 
Missing DBPCFC data at Week 12 not related to aforementioned intercurrent events are 
assumed to be unrelated to response or compliance status, hence their missing data will be 
handled with a missing at random approach and imputed consequently.  
The full specification will be provided in the SAP.  


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12.4.5 
Sensitivity analyses 
The following sensitivity analysis will be performed for the primary estimand, to assess the 
robustness of the estimation in the presence of deviations from the assumptions specified in the 
primary analysis. 
A two-dimensional tipping point analysis will be conducted to identify the points at which 
conclusions from primary analysis will be overturn, in a stepwise manner for both arms 
independently.  After such tipping points are determined, clinical judgment can be applied as 
to the plausibility of the assumptions underlying these tipping points. 
12.4.6 
Supplementary analysis 
The target population, the primary variable and handling of intercurrent events for the 
supplementary estimand are the same as for the primary estimand. Differently from the primary 
estimand, the summary measure for this supplementary estimand is the relative risk that would 
provide additional insights for clinical interpretation of a treatment effect. 
The estimation method is the same as for the primary estimand except that a marginal 
standardization method will be used to calculate the relative risk of being a responder and its 
95% confidence interval. This method uses the same fitted logistic model as for the primary 
estimand, but involves averaging predictions for each treatment group. 
12.4.7 
Supportive analyses 
As supportive analyses to the primary analyses, subgroups for primary efficacy endpoint will 
be analyzed but not be limited to the following: 
• By age group (6 – 11 years, 12 – 17 years, 18-55 years) 
• By total IgE at Screening Visit 1 (<350 IU/ mL; ≥350 IU/ mL) 
• By age group and total IgE at Screening Visit 1 
• By allergy status (mono- vs poly-sensitized participants) 
Mono-sensitized participants are only sensitized to peanut protein. Poly-sensitized 
participants are sensitized to peanut protein and at least one of the other proteins in the 
panel. Poly-sensitization is defined as sIgE ≥0.35 kUA/L for a food allergen in the panel 
other than peanut. 
The subgroup analyses for primary endpoint will be conducted using the same model as for the 
main analysis but with additional model terms for the subgroup (if not already included in the 
model), and subgroup-by-treatment interaction terms.  
12.5 
Analysis supporting secondary objectives 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) 
Key secondary endpoints 
Definitions of secondary estimands for key secondary objectives are provided in Section 2.2. 
The key secondary efficacy endpoints are: 


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• Responder status defined as tolerating a single dose of ≥ 1000 mg (2044 mg cumulative 
tolerated dose) peanut protein without dose-limiting symptoms at Week 12. The proportion 
of responders will be analyzed using the logistic regression model in a similar fashion as 
the primary estimand. Intercurrent events and missing data will be handled following the 
same principle as for the primary estimand.  
• Responder status defined as tolerating a single dose of 3000 mg (5044 mg cumulative 
tolerated dose) peanut protein without dose-limiting symptoms at Week 12. The proportion 
of responders will be analyzed using the logistic regression model in a similar fashion as 
the primary estimand. Intercurrent events and missing data will be handled following the 
same principle as for the primary estimand. 
• Maximum severity of symptoms occurring at any challenge dose of peanut protein up to 
and including 1000 mg during the DBPCFC conducted at Week 12. Symptom severity will 
be categorized as 4 levels: None, Mild, Moderate, Severe. The odds of developing less 
severe level of symptoms will be analyzed with a proportional odds model, including 
treatment, age group (6 – 11years, 12 – 17 years, 18 - 55 years), region as fixed class effects 
and log-transformed total IgE at Screening Visit 1 as a covariate. Missing data at Week 12 
corresponding to the intercurrent events of category 1 as described in Section 2.2.3 will be 
multiply imputed in line with the treatment policy strategy. For participants in the active 
treatment arms, missing data will be imputed based on placebo data. For participants in the 
placebo arm, missing data will be imputed based on the observed placebo arm data under a 
missing at random (MAR) assumption (treatment policy strategy). Other intercurrent events 
and missing data will be handled with a similar hypothetical strategy as for the primary 
estimand.  
• Responder status defined as participants tolerating a single dose of ≥ 1000 mg (2044 mg 
cumulative tolerated dose) peanut protein without dose-limiting symptoms at Week 12 (8 
weeks of placebo + 4 weeks of ligelizumab treatment vs. 12 weeks of placebo). The 
proportion of responders will be analyzed using the logistic regression model in a similar 
fashion as the primary estimand. Intercurrent events will be handled with a hypothetical 
strategy as described in Section 2.2.4 and missing data will be imputed under a MAR 
assumption. The familywise type I error rate will be controlled at the one-sided 0.025 
level across the primary and key secondary null hypotheses in a closed testing procedure 
(Bretz et al 2009). 
Key secondary null hypotheses: 
H0 120 RR1000: ligelizumab 120 mg is not superior to placebo with respect to the responder rate at 
a level of 1000 mg peanut protein (cumulative tolerated dose 2044 mg) at Week 12 
H0 240 RR1000: ligelizumab 240 mg is not superior to placebo with respect to the responder rate at 
a level of 1000 mg peanut protein (cumulative tolerated dose 2044 mg) at Week 12 
H0 120 RR3000: ligelizumab 120 mg is not superior to placebo with respect to the responder rate at 
a level of 3000 mg peanut protein (cumulative tolerated dose 5044 mg) at Week 12 
H0 240 RR3000: ligelizumab 240 mg is not superior to placebo with respect to the responder rate at 
a level of 3000 mg peanut protein (cumulative tolerated dose 5044 mg) at Week 12 


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H0 120 severity: ligelizumab 120 mg is not superior to placebo with respect to the odds of 
developing less severe level of symptoms evaluated by maximum severity of symptoms at any 
challenge dose of peanut protein up to and including 1000 mg during the DBPCFC conducted 
at Week 12 
H0 240 severity: ligelizumab 240 mg is not superior to placebo with respect to the odds of 
developing less severe level of symptoms evaluated by maximum severity of symptoms at any 
challenge dose of peanut protein up to and including 1000 mg during the DBPCFC conducted 
at Week 12 
The following secondary hypotheses will be used to evaluate onset of action of ligelizumab (8 
weeks of placebo + 4 weeks of ligelizumab treatment): 
H0 120 wk4 RR1000: ligelizumab 120 mg (8 weeks of placebo + 4 weeks of ligelizumab treatment) 
is not superior to placebo with respect to the responder rate at a level of 1000 mg peanut protein 
(cumulative 2044 mg) at Week 12 
H0 240 wk4 RR1000: ligelizumab 240 mg (8 weeks of placebo + 4 weeks of ligelizumab treatment) 
is not superior to placebo with respect to the responder rate at a level of 1000 mg peanut protein 
(cumulative 2044 mg) at Week 12 
The graphical approach of Bretz et al 2009 for sequentially rejecting testing procedures is used 
to illustrate the testing strategy in Figure 12-1. 
Figure 12-1 
Testing strategy 
 
• The hypotheses will be tested in two branches constituting ligelizumab 120 mg versus 
placebo (left branch) and ligelizumab 240 mg versus placebo (right branch). Initially, the 
full alpha level of 0.025 (one-sided) is equally split across the primary hypotheses for the 
two branches. 
• Once this first primary null hypothesis H0 120 RR600 or H0 240 RR600 for a dose has been 
rejected at the initial alpha level of 0.0125 (one-sided), the alpha will be fully distributed 
to H0 120 RR1000 or H0 240 RR1000 for the same dose. 


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• If H0 120 RR1000 or H0 240 RR1000 is rejected for a dose, then 50% of its local significance level 
is reassigned to the primary null hypothesis for the other dose, and 50% of its local 
significance level is reassigned to H0 120 RR3000 or H0 240 RR3000 for the same dose. 
• If H0 120 RR3000 or H0 240 RR3000 is rejected for a dose, 50% of its local significance level is 
reassigned to the primary null hypothesis for the other dose, and 50% of its local 
significance level is reassigned to H0 120 severity or H0 240 severity for the same dose. 
• If H0 120 severity or H0 240 severity is rejected for a dose, (100-ε)% of its local significance level 
is reassigned to the primary null hypothesis for the other dose. ε is set to a very small 
number in practice, e.g., 10-10. The dotted dashed edges with a weight of ε indicate the 
local significance level will only be reassigned to H0 120 wk4 RR1000 or H0 240 wk4 RR1000 , once 
both H0 120 severity and H0 240 severity are rejected. 
• If H0 120 wk4 RR1000 or H0 240 wk4 RR1000 is rejected for a dose, 100% of its local significance 
level is reassigned to the primary null hypothesis for the other dose. 
Other secondary endpoints 
Other secondary endpoints which are not part of testing strategy include: 
• Proportion of participants tolerating a single dose of ≥ 1000 mg (2044 mg cumulative 
tolerated dose) of peanut protein without dose-limiting symptoms during DBPCFC 
conducted at Week 52 : number and percentage of responders will be summarized by 
treatment group. In addition, the responder rate at Week 52 will be compared to the 
responder rate at Week 12 in ligelizumab 120 mg arm and 240 mg arm with a non-
inferiority test, respectively. The choice of non-inferiority margin and detailed analysis 
will be pre-specified in SAP. 
• Change in maximum tolerated dose (MTD) of peanut protein without dose-limiting 
symptoms during the DBPCFC at Week 52 compared to Week 12 : MTD (log-
transformed scale) at Week 52 along with changes from baseline and changes from Week 
12 will be summarized descriptively. 
• Change from baseline in peanut-specific IgE and IgG4 at Week 12, Week 16 and Week 
52: Summary statistics, including geometric means and geometric standard deviations, 
will be presented for peanut-specific IgE and IgG4 along with changes from baseline by 
time point and treatment group. Change from baseline in log-transformed levels of peanut 
specific-IgE and peanut specific-IgG4 at Week 12 and Week 16 will be analyzed using an 
ANCOVA model with terms for treatment group, age group, region, log-transformed total 
IgE at Screening Visit 1 and log-transformed baseline peanut specific-IgE or peanut 
specific-IgG4. 
• Change from baseline (screening) in mean wheal diameters by SPT at Week 16, Week 56 
and Week 68: Summary statistics for the SPT mean wheal diameter and changes from 
baseline will be presented at each visit by treatment group. Change from baseline in SPT 
mean wheal diameter at Week 16 will be analyzed using an ANCOVA model with terms 
for treatment group, age group, region, log-transformed total IgE at Screening Visit 1, and 
baseline SPT mean wheal diameter. 
• Change from baseline in total and domain scores in the FAQLQ at various timepoints by 
age and responder (subject or caregiver): The scores along with change from baseline will 
be summarized descriptively at Day 1, before and after the DBPCFC at Week 12 and 


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Week 52 by treatment arm. Comparative statistical analyses will be performed to evaluate 
differences between treatment groups. 
• Change from baseline in total and domain scores in the FAIM at various timepoints by age 
and responder (subject or caregiver): similar analysis will be performed as for FAQLQ. 
• Change from baseline in total and domain scores in the SF-36v2 at various timepoints: 
The scores along with change from baseline will be summarized descriptively at Day 1, 
before and after the DBPCFC at Week 12 and Week 52 by treatment.  
Further details of analysis for other secondary endpoints will be provided in the SAP. 
12.5.2 
Safety endpoints 
All safety endpoints (i.e. AEs, laboratory data, vital signs, and ECG) will be summarized by 
treatment for all participants on the safety set. In addition, subgroup analysis by age (6-11 years, 
12-17 years, 18-55 years) will be evaluated for all the safety endpoints listed in this section. 
Adverse events 
Treatment emergent adverse events are defined as events started after the first dose of study 
treatment or events present prior to the first dose of study treatment but increased in severity 
based on preferred term. All events that the investigator classifies as reactions associated to the 
DBPCFC or SPT will not be included in reporting of treatment-emergent AEs. The number 
(and percentage) of participants with treatment emergent adverse events will be summarized in 
the following ways: 
• by treatment, primary system organ class and preferred term. 
• by treatment, primary system organ class, preferred term and maximum severity. 
• by treatment, Standardized MedDRA Query (SMQ) and preferred term. 
Separate summaries will be provided for study treatment related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation. If a participant 
reported more than one AE with the same preferred term, the AE with the greatest severity will 
be presented. If a participant reported more than one AE within the same primary system organ 
class, the participant will be counted only once with the greatest severity at the system organ 
class level, where applicable. 
All AEs with onset in the follow-up period will also be considered as treatment emergent. Data 
from the placebo arm after switching to ligelizumab will be summarized separately. The number 
and percentage of participants with treatment emergent adverse events of special interest will 
be summarized by risk category, preferred term and treatment. 
 In addition, summaries will be provided by subgroups of age and allergy status (mono-
sensitized and poly-sensitized). 
Vital signs 
Summary statistics will be provided by vital sign, treatment group and visit/time as appropriate. 
Change from baseline will only be summarized for participants with both baseline and post-
baseline values. Participants with notable vital signs as defined below will be listed. 


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For adults: 
• Hypertension (systolic blood pressure of ≥ 140 mmHg and/or diastolic blood pressure of ≥ 
90 mmHg) or hypotension (systolic blood pressure of < 90 mmHg and/or diastolic blood 
pressure of < 60 mmHg). 
• Pulse rate below 60 bpm (bradycardia) or above 100 bpm (tachycardia) 
For adolescents and children aged 6-11 years: 
• See Section 16.1 for upper and lower limits for vital signs. 
12-lead ECG 
Summary statistics will be provided by treatment and visit/time. 
Clinical laboratory evaluations 
Summary statistics will be provided by treatment and visit/time. 


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12.7 
Interim analyses 
As previously noted in Section 4.4, there will be three analyses before the final database lock, 
in addition to the DMC analyses. 
Interim Analysis: 
At the start or the study, recruitment will be restricted to 12-55 year old participants. When 
approximately 60 adolescent participants (defined as 12-17 years of age) have completed all 
week 12 assessments, an interim analysis on 
, safety 
 data (
 
) will be performed. The intent of this analysis is to confirm the dosing 
strategy for the youngest age cohort. Once confirmed, recruitment will open to participants aged 
6-11 years. Dosing would be either only 120 mg or 120 mg and 240 mg for this age cohort. 
Primary Analysis at Week 12: 
The Primary Analysis will be performed once all participants have reached Week 12 in the 
study and completed its assessments or prematurely withdrawn from the study prior to Week 
12. Formal testing of primary and key secondary endpoints will be performed according to 
testing strategy specified in Figure 12-1 with full alpha. Since the primary and key secondary 
objectives will be performed only for the Primary Analysis, adjustment to the overall type I 
error rate is not required. In addition, a Dose-Exposure-Response model to describe the 
responder rate and the factors impacting the response will be developed. This model will be 
used to select the dose for registration in the participants 6 years and older, and select the dose 
for pediatric trial in younger population.   
Analysis at Week 52: 
The study will subsequently continue as planned in a blinded manner for the full 52 weeks 
treatment period and 16 weeks follow up. A final analysis will be performed after all 
participants have completed Week 52 or prematurely withdrawn from the study prior to Week 
52. 


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DMC analyses 
The DMC will assess, at defined intervals, the progress of a clinical trial, safety data, and critical 
efficacy variables and recommend to the sponsor whether to continue, modify, or terminate a 
trial, as defined in the DMC charter. Analysis of selected efficacy variables will be provided 
only for the purpose of helping for safety evaluation. Such assessments do not inflate the type 
I error for the primary efficacy hypothesis testing and thus no adjustment for multiplicity is 
required. 
12.8 
Sample size calculation 
A total sample size of approximately 486 randomized participants is targeted to achieve 
sufficient power for the primary and key secondary endpoints and provide adequate precision 
in estimating AE rates in this study. 
Participants will receive one of three treatments (ligelizumab 240mg SCq4w, ligelizumab 
120mg SCq4w, or placebo SCq4w) and will be randomized into five treatment arms with a ratio 
2:2:2:2:1. At the start of the study, recruitment is restricted to 12-55 years old participants and 
children 6-11 years will be recruited upon confirmation of the dosing strategy (120 mg and 240 
mg, or 120 mg only).  
 
 
 
 
 
 
 
 
 
 
 
 
  
12.8.1 
Primary endpoint(s) 
The primary objective is to demonstrate that ligelizumab doses are superior to placebo in 
responder rate at a level of 600 mg peanut protein (1044 mg cumulative tolerated dose) after 12 
weeks of treatment. 
The responder rate at 600 mg dose of peanut protein in placebo and ligelizumab groups have 
been assumed approximately 20% and at least 80%, respectively for participants with evaluable 
DBPCFC at Week 12. These assumptions are considered highly clinically relevant based on the 
PALISADE trial conducted in similar populations (Vickery et al 2018). In the PALISADE trial , 
the responder rate at 600 mg single challenge dose of peanut protein in placebo and AR101 
were 4.3% (95% CI: 1.9% , 9.7%) and 84.5% (95% CI: 79.9, 88.1), respectively. Approximately 
15% of participants were assumed to discontinue treatment before week 12 and will be 


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considered non-responders in power calculations. Therefore, the responder rate at 600 mg single 
dose of peanut protein in placebo and ligelizumab were assumed 17% and 68%, respectively 
for randomized participants. For the purpose of evaluating the power for the primary trial 
objectives, it was assumed that none of the secondary null hypotheses would be rejected and 
the full alpha level of 0.025 (one-sided) would be equally split across the primary hypotheses 
for each dose (i.e., 0.0125 one-sided for each testing). Under the outlined assumptions, a two 
group Fisher’s exact test with a 0.0125 one-sided significance level will have above 99% power 
to detect the difference of responder rate between each ligelizumab group and placebo, when 
the sample size is 108 participants on each ligelizumab dose and 54 participants on placebo. In 
case the dosing will only be limited to 120 mg for children, the anticipated sample size also 
provides greater than 99% power to detect the difference of responder rate between each 
ligelizumab group and placebo at a 0.0125 one-sided significance level. These power 
calculations are an approximation of the power achieved with the logistic regression approach. 
The table below shows the sensitivity of the power to deviations from the assumptions.   
Table 12-1 
Sensitivity of the power for each dose for the primary variable 
RR in 
each 
QGE031 
group 
with 
evaluable 
DBPCFC 
at Week 
12 
RR in 
placebo 
group 
with 
evaluable 
DBPCFC 
at Week 
12 
Dropout 
rate 
RR in 
each 
QGE031 
group 
RR in 
placebo 
group 
Sample 
size in 
each 
QGE031 
group 
Sample 
size in 
placebo 
Power 
80% 
20% 
15% 
68% 
17% 
108 
54 
>99.9% 
80% 
20% 
15% 
68% 
17% 
144 
54 
>99.9% 
80% 
20% 
15% 
68% 
17% 
72 
36 
>99.9% 
70% 
20% 
15% 
59.5% 
17% 
108 
54 
99.8% 
70% 
20% 
15% 
59.5% 
17% 
144 
54 
>99.9% 
70% 
20% 
15% 
59.5% 
17% 
72 
36 
98.6% 
RR = responder rate. Approximately 15% of participants were assumed to discontinue treatment before week 
12 and be considered as non-responders in power calculations. 
Power results were calculated with East 6 version 6.4. 
The consistency trend of treatment effect on primary endpoint will be evaluated in age 
subgroups. Participants will be stratified based on region, total IgE at screening and by age at 
screening (6-11 years, 12-17 years, and 18-55 years) in randomization. Approximately one third 
of randomized participants are expected in each age subgroup. This yields approximately 36 
participants in each ligelizumab group per age subgroup and 18 participants in placebo group 
per age subgroup in the base case scenario. In case the dosing will only be limited to 120 mg 
for children, approximately 72 children will be allocated to each of the two ligelizumab 120 mg 
arms. The number of participants per age subgroup may be varied in actual recruitment. To 
ensure a high probability (90%) of observing the point estimates of odds ratio for the treatment 
effect greater than 1 in all age subgroups, the sample size for the smallest age subgroup should 
be at least 9.4% of the number of participants included for primary analysis based on an 
approach to partition sample size in a multiregional trial (Kawai et al 2008). In practice, the 
estimation of responder rate based on this limited sample size may be easily affected by a few 


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extreme random observations. Therefore, it is suggested to enlarge the sample size for the 
smallest age subgroup whenever feasible. Additional consideration from safety aspects for 
number of participants in age subgroups are provided in Section 12.8.2.1. 
12.8.2 
Secondary endpoint(s) 
If statistical significance is achieved in the primary test, the tests for the key secondary variables 
included in the testing strategy will be performed. The local significance level for each key 
secondary null hypothesis will be determined based on the closed testing procedure shown in 
Figure 12-1. 
Assuming a treatment discontinuation rate of 15% before week 12 and responder rates in each 
treatment group as shown in the table below, the local power (unconditional) of each hypothesis 
was estimated using 10,000 simulations with package gMCP in R 3.6.1. 
 
 
 
 
 
 
 
 
 
 
 
Table 12-2 
Power of each dose for the analyses of primary and key secondary 
variables in the base case scenario 
Variable 
Assumptions of treatment effect 
Local power 
(unconditional) 
 
QGE031 240 
mg 
QGE031 120 
mg 
Pbo 
QGE031 240 
mg 
QGE031 120 
mg 
RR of 
tolerating 
600 mg 
peanut 
protein 
RR* (RR in 
rand) 
80% 
(68%) 
80% 
(68%) 
20% 
(17%) 
>99.9% 
>99.9% 
RR of 
tolerating 
1000 mg 
peanut 
protein 
RR* (RR in 
rand) 
70% 
(59.5%) 
70% 
(59.5%) 
20% 
(17%) 
>99.9% 
>99.9% 
RR of 
tolerating 
3000 mg 
peanut 
protein 
RR* (RR in 
rand) 
60% 
(51%) 
60% 
(51%) 
15% 
(12.75%) 
>99.9% 
>99.9% 
Maximum 
severity of 
symptoms at 
% None 
38% 
38% 
2% 
>99.9% 
>99.9% 
% Mild 
32% 
32% 
28% 
% Moderate 
25% 
25% 
59% 


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any 
challenge 
dose up to 
and including 
1000 mg# 
% Severe 
5% 
5% 
11% 
RR of 
tolerating 
1000 mg 
peanut 
protein with 4 
weeks of 
ligelizumab 
treatment 
RR^ 
50% 
45% 
20% 
98.3% 
93.0% 
RR=responder rate; Pbo=placebo; The proposed number of participants for comparisons between ligelizumab 
and placebo are 108 in each ligelizumab arm and 54 in placebo arm. 
*RR is based on the anticipated proportion of responders in participants with evaluable DBPCFC at Week 12. 
Approximately 15% of participants are assumed to discontinue treatment before week 12 and considered non-
responders for randomized population in power calculation (RR in rand).#For maximum severity of symptoms, 
the assumed proportion of participants in each category is based on randomized population. 
Power calculations were performed in R 3.6.1 with package gMCP. 
^RR is based on the anticipated proportion of responders in participants with evaluable DBPCFC at Week 
12. Same treatment effect is expected for randomized population in power calculation, assuming participants 
had taken study treatment at Week 8 and conducted DBPCFC at Week 12. 
 
 


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12.8.2.1 Precision for adverse events 
All participants will have the opportunity of receiving treatment for ligelizumab 120 mg or 240 
mg in the 52 weeks of treatment period with a ratio of 50%: 50% (n=243 for each group). For 
each ligelizumab dose group, approximately one third of randomized participants are in each 
age subgroup (6-11 years, 12-17 years and 18-55 years). This yields approximately 81 
participants per age group exposed with each ligelizumab dose for at least 9 months in the base 
case scenario.
 
 
 
 
 
 
 
The table below shows the sensitivity of the precision level (95% CI) 
based on the assumptions of different incidence rates and number of participants per age group. 
Table 12-4 
Precision levels (95% CI) for sensitivity of safety incidence rate per 
age group 
Event rate (proportion of 
participants with an event) 
Number of participants 
95% CI 
0% 
81 
(0, 4.5%) 
1% 
81 
(0, 6.3%) 
2% 
81 
(0.2%, 7.9%) 
0% 
162 
(0, 2.3%) 
1% 
162 
(0.1%, 4%) 
2% 
162 
(0.4%, 5.5%) 


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Meanwhile, all the participants (486 participants) randomized in the study would be exposed 
with ligelizumab treatment for at least 9 months. For any adverse event with 1% incidence rate, 
the exact 95% Clopper-Pearson CI for the proportion of participants would be (0.3%, 2.3%). 
Table 12-4 shows the sensitivity of the precision (95% CI) based on the assumptions of different 
incidence rates and total number of participants. 
Table 12-5 
Precision levels (95% CI) for sensitivity of safety incidence rate for 
overall population 
Event rate (proportion of 
participants with an event) 
Number of participants 
95% CI 
0% 
486 
(0, 0.8%) 
1% 
486 
(0.3%, 2.3%) 
2% 
486 
(1%, 3.7%) 
13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, participant recruitment procedures (e.g., 
advertisements) and any other written information to be provided to participants. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last participant last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.). 


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For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 
13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
13.5 
Participant Engagement 
Participant engagement initiatives are included in this study and will be provided, for 
distribution to study participants. If compliance is impacted by cultural norms or local laws and 
regulations, sites may discuss modifications to these requirements with Novartis. 
• Thank You letter 
• Plain language trial summary - after CSR publication 
• Trial Feedback Questionnaires (TFQ) 
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and Health Authorities, where required, it cannot be implemented. 
14.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 


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Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 


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15 
References 
References are available upon request 
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validation of the self-administered Food Allergy Quality of Life Questionnaire for 
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the therapeutic anti-IgE antibody ligelizumab differs from omalizumab. Nat Commun 11(1): 
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asthmatic responses. J. Allergy Clinical Immunology; 138(4):1051-1059 
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Gupta RS, Springston EE, Warrier MR, et al (2011) The prevalence, severity, and distribution 
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Teach SJ, Gill MA, Togias A, et al (2015) Preseasonal treatment with either omalizumab or 
an inhaled corticosteroid boost to prevent fall asthma exacerbations. J. Allergy Clinical 
Immunology; 136(6):1476-1485 
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and severe anaphylaxis. N. Engl. J. Med.; 358(1):28-35 
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young children and its association with serum peanut-specific IgE. J. Pediatr.; 137(6):749-55 
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upper respiratory infections on IgE reactivity to food allergens. Pediatr Allergy Immunol; 
30(1):127-130 


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16 
Appendices 
16.1 
Appendix 1: Clinically notable laboratory values and vital signs 
Laboratory assessments 
Refer to Section 16.2 for clinically notable laboratory values for hepatotoxicity. 
Refer to Section 16.3 for clinically notable laboratory values for nephrotoxicity 
The following other specific criteria have been identified for this study: 
• Platelets < 75 000/μL 
• Any participant who has platelets < 75 000/μL after being randomized should discontinue 
study treatment. 
For all other laboratory assessments, the Central Laboratory will flag laboratory values falling 
outside of the normal ranges on the Central Laboratory Report (which the investigator should 
review and sign-off) and the investigator will report any values considered clinically significant 
in the CRF. 
Vital signs 
Notable values for vital signs for adults are: 
• heart rate of < 60 and > 100 bpm 
• systolic blood pressure of < 90 and ≥ 140 mmHg 
• diastolic blood pressure of < 60 and ≥ 90 mmHg 
For children (6-11years) and adolescents, the notable values are described in Table 16-1: 
Table 16-1 
Notable values for Heart Rate (HR) and Blood Pressure in children and 
adolescents 
  
HR (bpm) 
Age range 
Low 
High 
6-8 years 
<74 
>111 
8-12 years 
<67 
>103 
12-15 years 
<62 
>96 
≥ 15 years 
<58 
>92 
  
Age (years) 
Blood pressure (mmHg) 
Boys 
Girls 
6 
105 
66 
105 
67 
7 
106 
68 
106 
68 
8 
107 
69 
107 
69 
9 
107 
70 
108 
71 
10 
108 
72 
109 
72 
11 
110 
74 
111 
74 
12 
113 
75 
114 
75 
13 
120 
80 
120 
80 
Heart Rate (HR) Adapted from Fleming et al 2011; Blood Pressure (BP) adapted from Flynn et al 2017 


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ECG 
For adults, a notable QTc value is defined as a QTcF (Fridericia’s) interval of greater than 450 
ms for males or greater than 460 ms for females – all such ECGs will be flagged by the 
Central CRO’s cardiologist and require assessment for clinical relevance by the investigator. 
For children, a QTc ≤450 ms is recommended as the upper limit of normal for children up to 
12 years of age. In children older than 12 years, the same thresholds apply as for adults i.e. QTc 
<450 ms in males and QTc <460 ms in females (Novartis ECG and QTc Clinical Development 
Safety Guideline, 2017) 


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16.2 
Appendix 2: Liver event and laboratory trigger definitions & 
follow-up requirements 
Table 16-2 
Liver event and Laboratory trigger definitions 
  
Definition/ threshold 
Liver laboratory triggers 
If ALT, AST and total bilirubin normal at baseline: 
· ALT or AST > 5 × ULN 
· ALP > 2 × ULN (in the absence of known bone 
pathology) 
· Total bilirubin > 3 × ULN (in the absence of known 
Gilbert syndrome) 
· ALT or AST > 3 × ULN and INR > 1.5 
· Potential Hy’s Law cases (defined as ALT or AST > 
3 × ULN and Total bilirubin > 2 × ULN [mainly 
conjugated fraction] without notable increase in ALP 
to > 2 × ULN) 
· Any clinical event of jaundice (or equivalent term) 
· ALT or AST > 3 × ULN accompanied by (general) 
malaise, fatigue, abdominal pain, nausea, or vomiting, 
or rash with eosinophilia 
· Any adverse event potentially indicative of a liver 
toxicity* 
If ALT or AST abnormal at baseline: 
· ALT or AST > 2x baseline or > 300 U/L (whichever 
occurs first) 
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-related 
conditions; non-infectious hepatitis; benign, malignant and unspecified liver neoplasms ULN: upper limit of 
normal 
Table 16-3 
Follow up requirements for liver laboratory triggers  
  
ALT 
TBL 
Liver Symptoms 
Action 
ALT increase without bilirubin increase: 
  
  
If normal at 
baseline: 
ALT > 3 x ULN 
Normal 
For participants 
with Gilbert’s 
syndrome: No 
change in baseline 
TBL 
None 
• No change to 
study treatment 
• Measure ALT, 
AST, ALP, GGT, 
TBIL, INR, 
albumin, CK, and 
GLDH in 48-72 
hours. 
• Follow-up for 
symptoms. 
If elevated at 
baseline: 
ALT > 2 x baseline 
or > 300 U/L 
(whichever occurs 
ﬁrst) 
  
If normal at 
baseline: 
ALT > 5 x ULN for 
more than two 
weeks 
Normal 
For participants 
with Gilbert’s 
syndrome: No 
change in baseline 
TBL 
None 
• Interrupt 
study drug 
• Measure ALT, 
AST, ALP, 
GGT, TBIL, 
INR, albumin, 
CK, and GLDH 
in 48-72 hours. 
If elevated at 
baseline: 
ALT > 3 x baseline 
or > 300 U/L 
(whichever occurs 


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ALT 
TBL 
Liver Symptoms 
Action 
ﬁrst) for more than 
two weeks 
• 
Follow-up for 
symptoms. 
• 
Initiate close 
monitoring and 
workup for 
competing 
etiologies. 
• 
Study drug can 
be restarted 
only if another 
etiology is 
identiﬁed and 
liver enzymes 
return to 
baseline. 
  
If normal at 
baseline: 
ALT > 8 x ULN 
Normal 
None 
ALT increase with bilirubin increase: 
  
If normal at 
baseline: 
ALT > 3 x ULN 
TBL > 2 x ULN (or 
INR > 1.5) 
For participants 
with Gilbert’s 
syndrome: 
Doubling of direct 
bilirubin 
None 
If elevated at 
baseline: 
ALT > 2 x baseline 
or > 300 U/L 
(whichever occurs 
ﬁrst) 
  
If normal at 
baseline: 
ALT > 3 x ULN 
Normal or elevated 
Severe fatigue, 
nausea, vomiting, 
right upper 
quadrant pain 
If elevated at 
baseline: 
ALT > 2 x baseline 
or > 300 U/L 
(whichever occurs 
ﬁrst) 
Table 16-4 
Follow up requirements for liver laboratory triggers  
Criteria 
Actions required 
Follow-up monitoring 
Total Bilirubin (isolated) 
  
  
>1.5 – 3.0 ULN 
• 
Maintain treatment 
• 
Repeat LFTs within 48-72 
hours 
Monitor LFTs weekly until 
resolutionc to ≤ Grade 1 or to 
baseline 
> 3 - 10 × ULN (in the absence of 
known Gilbert syndrome) 
• 
Interrupt treatment  
• 
Repeat LFT within 48-72 
hours 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in the 
appropriate CRF 
Monitor LFTs weekly until 
resolutionc to ≤ Grade 1 or to 
baseline (ALT, AST, total bilirubin, 
Alb, PT/INR, ALP and GGT)  
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] bilirubin) 
> 10 x ULN 
• 
Discontinue the study 
treatment immediately  
• 
Hospitalize the participant 
• 
Establish causality 
• 
Record 
the 
AE 
and 
contributing 
factors(e.g. 
conmeds, med hx, lab)in the 
appropriate CRF 
ALT, AST, total bilirubin, Alb, 
PT/INR, ALP and GGT until 
resolutionc (frequency at 
investigator discretion) 


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Criteria 
Actions required 
Follow-up monitoring 
Any AE potentially indicative of a 
liver toxicity* 
• 
Consider study treatment 
interruption or discontinuation 
• 
Hospitalization 
if 
clinically 
appropriate 
• 
Establish causality 
• 
Record 
the 
AE 
and 
contributing 
factors(e.g., 
conmeds, med hx, lab)in the 
appropriate CRF 
Investigator discretion 
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable values at 
three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level after a maximum of 6 
months, (4) liver transplantation, and (5) death. 
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver 
damage – related conditions; non-infectious hepatitis; the benign, malignant and 
unspecified liver neoplasms. 
Based on investigator’s discretion investigation(s) for contributing factors for the liver event 
can include: Serology tests, imaging and pathology assessments, hepatologist’s consultancy; 
obtaining more detailed history of symptoms and prior or concurrent diseases, history of 
concomitant drug use, exclusion of underlying liver disease. 


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16.3 
Appendix 3: Specific Renal Alert Criteria and Actions and Event 
Follow-up 
Table 16-5 
Specific renal alert criteria and actions 
Renal Event 
Actions 
Confirmed serum creatinine increase 25% – 49% 
• Consider causes and possible interventions 
• Follow up within 2-5 days 
Serum creatinine increase ≥ 50% + OR if <18 years 
old, eGFR ≤ 35mL/min/1.73 m2 
• Consider causes and possible interventions 
• Repeat assessment within 24-48h if possible 
• Consider drug interruption or discontinuation unless 
other causes are diagnosed and corrected 
• Consider participant hospitalization and specialized 
treatment 
New onset dipstick proteinuria ≥ 3+ 
OR 
Protein-creatinine ratio (PCR) ≥ 1g/g 
Cr (or mg/mmol equivalent as 
converted by the measuring 
laboratory) 
• Consider causes and possible interventions 
• Assess serum albumin & serum protein 
• Repeat assessment to confirm 
• Consider drug interruption or discontinuation unless 
other causes are diagnosed and corrected 
New onset hematuria ≥ 3+ on urine 
dipstick 
Assess & document 
• Repeat assessment to confirm 
• Distinguish hemoglobinuria from hematuria 
• Urine sediment microscopy 
• Assess sCr 
• Exclude infection, trauma, bleeding from the 
distal urinary tract/bladder, menstruation 
• Consider bleeding disorder 
+ Corresponds to KDIGO criteria for Acute Kidney Injury 
(Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work 2013) 
Whenever a renal event is identified, a detailed participant history and examination are indicated to identify and 
potentially eliminate risk factors that may have initiated or contributed to the event:  
· Blood pressure assessment (after 5-minute rest, with an appropriate cuff size)  
· Signs and symptoms like fever, headache, shortness of breath, back or abdominal pain, dysuria or hematuria, 
dependent or periorbital edema  
· Changes in blood pressure, body weight, fluid intake, voiding pattern, or urine output  
· Concomitant events or procedures such as trauma, surgical procedures, cardiac or hepatic failure, contrast 
media or other known nephrotoxin administration, or other diseases or causes, e.g., dehydration due to 
delirium, tumor lysis 
Table 16-6 
Renal event follow-up 
FOLLOW-UP OF RENAL EVENTS 
Assess+, document and record in CRF • Urine dipstick and sediment microscopy evidence of DIN: crystals, red 
blood cells (dysmorphic/glomerular vs. non-dysmorphic/non-glomerular), white blood cells, tubular epithelial 
cells • Blood pressure and body weight • Serum creatinine, BUN, electrolytes (sodium, potassium, phosphate, 
calcium), bicarbonate and uric acid • Urine output 
Review and record possible contributing factors to the renal event (co-medications, other co-morbid conditions) 
and additional diagnostic procedures (MRI etc) in the CRF 
Monitor participant regularly (frequency at investigator’s discretion) until - • Event resolution: (sCr within 10% of 
baseline or protein-creatinine ratio < 1 g/g Cr, or ACR <300 mg/g Cr of baseline) or • Event stabilization: sCr 


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FOLLOW-UP OF RENAL EVENTS 
level with ±10% variability over last 6 months or protein-creatinine ratio stabilization at a new level with ±50% 
variability over last 6 months 
Analysis of urine markers in samples collected over the course of the DIN event 
16.4 
Double-blind Placebo Controlled Food Challenge 
16.4.1 
Background 
The DBPCFC, also referred to as the oral food challenge (OFC), represents the gold standard 
to diagnose food allergy. It is also the most objective method to clinically estimate threshold 
doses for allergenic foods in highly sensitive individuals (Taylor et al 2004). In this study the 
OFC is based upon several available guidelines, PRACTALL (Sampson et al 2012) and the 
CoFAR Grading Definition of Dose-Limiting Symptoms. The double-blind aspect of the 
OFC markedly reduces any potential bias of participant and/or supervising health care 
professionals that could interfere with its appropriate interpretation. The test itself corresponds 
most closely to the natural ingestion of food. 
In general, the OFC is to be strictly performed under medical supervision to document the dose 
of allergen that provokes a reaction and, if needed, to administer symptomatic treatment which 
could potentially require the management of anaphylaxis. Participants must be in good health 
before proceeding with the food challenge and should be advised to avoid physical exercise at 
least one hour prior to the start of the procedure. A light breakfast is optional on the day of the 
OFC, in line with local practice. Additionally, participants should be on minimal or no 
symptomatic medication before starting the OFC (Table 6-2 and Table 6-3). Due to the inherent 
risk of a severe reaction, participants who have experienced a severe or life-threatening 
hypersensitivity event needing an ICU admission or intubation within 60 days prior to baseline 
DBPCFC (at Screening 2 visit) are excluded from study participation.   
Intravenous access may be set up before the DBPCFC at the investigator’s discretion (e.g., 
participant at high risk of reaction or severe reaction based upon prior history and medical 
history). 
At the start of the OFC a small dose of peanut allergen is administered. This dose is intentionally 
lower than any dose expected to induce a reaction (Niggemann and Beyer 2007). While 
monitoring the participant for any allergic symptoms, the allergen dose is gradually increased 
until a cumulative dose at least equivalent to the portion of allergen as defined in the objectives 
(Section 2)  is ingested (refer to the QGE031G12301 Pharmacy Manual). 
16.4.2 
DBPCFC dosing schedule 
This study includes three DBPCFCs: the first at Screening Visit 2, the second at 12 weeks, and 
the third at 52 weeks (end of treatment). 
Each DBPCFC consists of two parts, active allergen (peanut) challenge and placebo challenge. 
Each challenge is to be performed on a separate day (Part 1 and Part 2). The active allergen 
challenge is either given on the first day or the second day. To ensure and preserve the double-
blind nature of the challenge, independent (unblinded) study site staff need to prepare the 
material for each challenge prior to administration. Study staff/investigator administering the 
challenge and participants undergoing the challenge remain blinded to the identity of the 


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challenge on the two test days (i.e. if peanut allergen or placebo is tested on the first or the 
second day). The time interval between each challenge part is approximately one to seven days; 
there must be a minimum of one full day between Part 1 and Part 2 and maximum of 7 days. 
There must be at least 24 hours between the completion of the OFC Part 2 and the first 
administration of study treatment at the Randomization visit. 
At Part 1 (the first challenge day) of week 12 and week 52 visits, study treatment must be 
administered at least 1 hour before the DBPCFC.  
16.4.2.1 Allergen dose escalation 
At each DBPCFC, participants will be exposed to increasing amounts of allergen, either peanut 
protein or corresponding placebo in a randomized fashion, with each dose administration 
separated by at least 15 minutes (Table 16-7). 
At screening the dry weight amounts of 1 mg, 3 mg, 10 mg, 30 mg and 100 mg of peanut protein 
and corresponding placebo will be tested. 
At 12 weeks and at 52 weeks, the dry weight amounts of 1mg, 3 mg, 10 mg, 30 mg, 100 mg, 
300 mg, 600 mg, 1000 mg and 3000 mg of peanut protein and corresponding placebo will be 
tested. 
16.4.2.2 Maximum dose 
Within the OFC, incremental allergen (or placebo) dose increases continue until the highest 
dose for the challenge has been reached (100 mg at screening and 3000 mg at 12 weeks and 52 
weeks), or until the participant displays (a) dose-limiting symptom(s) (Section 16.4.5). 
Three hundred (300) mg peanut protein is estimated to correspond to the amount of allergen 
generally associated with accidental exposure, while 3000 mg corresponds to the highest peanut 
protein dose used within this protocol. 
The DBPCFC allergen doses are indicated by dry weight (mg) in Table 16-7. The allergen 
granules are to be reconstituted for administration and given to the participant in portions 
measured by volume (mL). Refer to the Pharmacy Manual.  
16.4.2.3 DBPCFC allergen dose administration instruction 
Table 16-7 
Dry Weight Dosing Table 
Dose No. 
Peanut Protein/Placebo (mg) 
Cumulative Dose (mg) 
1 
1 
1 
2 
3 
4 
3 
10 
14 
4 
30 
44 
5 
100 
144 
6 
300 
444 
7 
600 
1044 
8 
1000 
2044 
9 
3000 
5044 


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After each administered dose of reconstituted allergen (or placebo) participants are to be 
monitored for any reaction. In the presence of an allergic reaction, and at the investigator's 
discretion, the interval between escalating doses can be increased or the challenge can be 
stopped. (Section 16.4.5). 
The minimum observation time between doses is 15 minutes, the maximum observation time is 
30 minutes. If needed, an additional 30 minutes of observation is permitted for further 
evaluation of symptoms. If continuation of the OFC is still in question after 1 hour of 
observation, the challenge should be considered positive and should be stopped. 
During and up to at least one hour after the completion of the DBPCFC, vital signs should be 
monitored approximately every 15 minutes and documented in source.   
In the event of an allergen dosing error, the site should contact Novartis. 
16.4.3 
DBPCFC material 
Novartis will supply the Oral Food Allergen Peanut Flour Chocolate Meal Base and its placebo 
globally in an open-label fashion. 
• high dose: 20%w/w Peanut Flour Chocolate Flavour Challenge Meal Base (20%w/w 
Peanut Choc)  
• low dose: 0.67%w/w Peanut Flour Chocolate Flavour Challenge Meal Base (0.67%w/w 
Peanut Choc)  
• Placebo: 0%w/w Peanut Flour Chocolate Flavour Challenge Meal Base (0%w/w Peanut 
Choc) 
Pharmaceutical Dosage Form: Granules for oral suspension 
Route of Administration: Oral 
The food challenge material and preparation instructions are described in detail in the 
QGE031G12301 Pharmacy Manual provided separately. 
As previously noted, there should be an independent (unblinded) nurse, or other appropriately 
trained study site staff to prepare (i.e. NOT TO ADMINISTER) the unblinded material for the 
DBPCFC after obtaining the randomly assigned test sequence through the IRT system 
(Section 16.4.2) 
16.4.4 
Preparing for the food challenge 
Prior to DBPCFC material preparation, independent unblinded study site personnel need to 
access the IRT system to obtain the allergen kit number to be used (corresponding to peanut 
allergen or placebo). 
IMPORTANT NOTE: After completion of the 2nd day of the DBPCFC at Screening Visit 
2 ONLY, the BLINDED site staff will access the IRT system to unblind the test and evaluate 
eligibility for randomization.  
This unblinding step is only applicable for the first DBPCFC at Screening and does 
NOT apply to the DBPCFC at weeks 12 and 52.  


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16.4.5 
Evaluation parameters of the DBPCFC 
Objective symptoms exhibited by participants should be evaluated through physical 
examination. Complaints arising from the participant without observable changes will be 
classified as subjective. 
The DBPCFC will be considered positive with the occurrence of any dose-limiting symptom(s). 
Dose-limiting symptoms indicate a true allergic reaction occurring during administration of a 
single dose that should preclude the administration of any further doses in the view of the 
investigator. Investigators should refer to Table 16-8 (CoFAR grading scale) for definition of 
dose-limiting symptoms. Symptoms can be mild, moderate or severe. Mild symptoms are not 
usually considered dose-limiting, although a combination of mild symptoms during a single 
dose might lead to the cessation of the OFC at the discretion of the investigator. All moderate 
and severe symptoms as defined in Table 16-8 are considered dose-limiting.  
Symptoms that require administration of any rescue medication (e.g. SABA, epinephrine or 
other) are considered dose-limiting symptoms. In this case, the challenge has to be stopped and 
the challenge is considered positive.  
All findings that the investigator classifies as reactions to the DBPCFC should be recorded in 
source documentation and on a designated eCRF. These events should not be reported on the 
Adverse Event eCRF unless they constitute an SAE according to the investigator’s judgement.  
The details and start time of any treatment and/or medication provided to treat DBPCFC-related 
allergic reactions should be recorded on the respective eCRF. The DBPCFC will be considered 
negative if a participant does not exhibit (a) dose-limiting symptom(s) (= positive challenge) 
at the end of the challenge. 
Table 16-8 
Definition of Dose-Limiting Symptoms (per the CoFAR* grading scale, 
Chinthrajah et al 2022 )   
MILD (not typically dose limiting) 
MODERATE (dose limiting) 
SEVERE (dose limiting) 
• 
Skin – limited (few) or 
localized hives, swelling (e.g., 
mild lip edema), skin flushing 
(e.g., few areas of faint 
erythema) or mild pruritus 
(e.g., occasional scratching) 
 
• 
Respiratory – rhinorrhea (e.g., 
occasional sniffling or 
sneezing), nasal congestion, 
occasional cough, throat 
discomfort 
 
• 
GI – mild abdominal 
discomfort (including mild 
nausea with or without 
decreased activity), isolated 
emesis thought to be 
secondary to gag 
• 
Skin – systemic hives (e.g., 
numerous or widespread 
hives), swelling (e.g., 
significant lip or face edema), 
pruritus causing protracted 
scratching, more than a few 
areas of erythema or 
pronounced erythema 
 
• 
Respiratory – throat tightness 
without hoarseness, persistent 
cough, wheezing without 
dyspnea 
 
• 
GI – persistent moderate 
abdominal 
pain/cramping/nausea with 
decreased activity, vomiting 
• 
Skin – severe generalized 
urticaria/angioedema/erythema 
 
• 
Respiratory – laryngeal 
edema, throat tightness with 
hoarseness, wheezing with 
dyspnea, stridor 
 
• 
GI – severe abdominal 
pain/cramping/repetitive 
vomiting 
• 
 
• 
Neurological – change in 
mental status 
• 
 
• 
Circulatory – clinically 
significant hypotension 


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16.4.6 
DBPCFC completion 
At the completion of the DBPCFC (post-administration of the last dose of allergen), participants 
must remain under observation at the study site for a minimum of 2 hours to confirm a negative 
challenge. In the event of a positive challenge participants must remain under observation at the 
study site for a minimum of 1 hour after allergic symptoms have improved to a level compatible 
with safe discharge. Observation beyond this timepoint remains at the Investigator's discretion 
and could potentially include hospital overnight observation. 
Treatment of positive reactions 
Epinephrine, SABA, anti-histamines and saline bolus are typically used to treat allergic 
reactions. Treatment in line with local clinic provisions/ guidelines is at the investigator's 
discretion. All treatment must be documented in the corresponding eCRF. 
Discharge procedures 
Upon discharge from the study site post-DBPCFC participants should be provided with a 24-
hour emergency telephone contact. Furthermore, participants should be advised to avoid 
physical exercise within 2 hours after having received the last dose of the DBPCFC. 
Delayed or late-onset reactions to the DBPCFC are defined as reactions occurring after the 
participant was discharged from the clinic. Since a delayed reaction to the DBPCFC cannot be 
predicted prior to discharge, all participants should be briefed about the signs and symptoms of 
anaphylaxis and provided with rescue medication (epinephrine auto-injector and short acting 
beta-agonists [asthma participants only]). Participants should also receive specific information 
on how to recognize a late reaction and on how and when to use rescue medication.  Delayed 
or late- onset reactions will not be considered dose-limiting and will be captured on a designated 
CRF.  
Post-discharge, participants who need to use epinephrine due to a suspected reaction should 
immediately go to the closest emergency room for additional assessment and contact the 
investigative site.  
Adverse event reporting 
If the participant experiences an allergic reaction associated with the DBPCFC (immediate, 
delayed or late-onset) that meets the criteria for a serious adverse event in the investigator's 
judgment, it should be captured on the designated CFR and reported as described in 
Section 10.1.3 SAE Reporting. 
The administration of study medication will precede the DBPCFC at weeks 12 and 52. 
Investigators should apply their medical judgement when assessing if reactions occurring 
during the DBPCFC or during the post-DBPCFC observation period are symptoms caused by 
the food challenge or whether they are adverse events suspected to be related to the study 
treatment. Both adverse events suspected to be related to study treatment and allergic reactions 
due to the DBPCFC should be captured on the designated CRFs, and if serious, be reported as 
described in Section 10.1.3 SAE Reporting. For such SAEs, a causality assessment to either 


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study treatment or DBPCFC must be provided and documented together with its medical 
rationale.  
16.5 
Guidance for skin prick test 
16.5.1 
Background of Skin Prick Test 
This study includes a Skin Prick Test (SPT) targeting peanut allergen as well as milk and/or egg 
allergens (if indicated by medical history). SPTs are performed at Screening Visit 1, Week 16 
(before study drug dosing), Week 56 and End of Study. The Screening Visit 1 SPT will confirm 
the eligibility of all participants to peanut allergen and to assess the level of sensitivity to milk 
and/or egg if medical history indicates that the participant is allergic to milk and/or egg. A 
positive SPT for peanut allergen is defined as an average diameter of the longest diameter and 
mid-point orthogonal diameter ≥ 4 mm wheal compared to negative control. 
This study specifies the use of BOTH a titration SPT (TSPT) and non-TSPT. All participants 
will receive the TSPT to peanut. In addition, all participants should receive the non-titration 
SPT (undiluted) to milk and/or egg based on medical history. 
The TSPT will be conducted to the peanut allergen only; undiluted extract, five 10-fold dilutions 
(1:10, 1:100, 1:1’000, 1:10’000, and 1:100’000).  
In addition to peanut, milk stock and egg stock will be tested (if indicated). 
Positive and negative control should be tested together. 
16.5.2 
Material 
Preparation for the reagent of titration SPT. 
• ~ 5ml Vials (can be purchased from any supplier) 
• Diluent (saline) (also purchased from any supplier) 
• Pipette with disposable pipette tip or syringe (able to measure 0.1 to 0.9 ml) 
• Add 0.9 mL of diluent to each of 5 vials (~ 5 mL in size). Label them from 1:10, 1:100, 
1:1’000, 1:10’000, 1:100’000; and include the name of the allergen, the lot number, and 
the date on which the dilutions were made. 
• Take 0.1 mL of the undiluted peanut stock and add to vial 1:10. Mix well. 
• Take 0.1 mL from the 1:10 vial and add to vial 1:100. Mix well. 
• Take 0.1 mL from the 1:100 vial and add to vial 1:1’000. Mix well. 
• Take 0.1 mL from the 1:1,000 vial and add to vial 1:10’000. Mix well. 
• Take 0.1 mL from the 1:10,000 vial and add to vial 1:100’000. Mix well. 
Only a very small volume of allergen is needed per test – one “drop”. The prepared dilutions 
should not be used for more than one week after reconstitution. 
The non-TSPT will be conducted using the stock (undiluted) of milk and egg if medical history 
indicates allergy to these foods at Screening 1, 
Positive and negative control always need to be tested together. 


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16.5.3 
Starting the Skin Prick Test 
• Location of SPT: The skin of the participant's back is the preferred site of testing, 
alternatively the forearm may be used. For consistency purposes it is important for 
individual participants to perform the SPT at the same site during the study. 
EXAMPLE: 
TSPT: if the participant had a positive medical history of milk and egg in addition to peanut, 
total 10 pricks are needed; positive control, negative control, peanut (extract), peanut (1:10), 
peanut (1:100), peanut (1:1’000), peanut (1:10’000), peanut (1:100’000), milk, and egg  
• Test time: Skin reactions should be recorded after 15 minutes of dropping allergen to the 
pricked location. 
• Positive/negative control: The SPT should be repeated if the valid positive (≥ 3  mm 
wheal) and negative (no response) control results were not obtained. 
• Prohibited/washout medications prior to SPT 
Table 16-9 
Medications to be washed out prior to SPT 
Medication 
Prohibited period 
Short acting and long acting anti histamines (e.g., 
chlorpheniramine, prometazine, diphenhydramine, 
loratadine, cetirizine) 
≥5 half-lives  
Antihistamine nose spray 
12 hours 
Oral H2-receptor antagonist (e.g., cimetidine, 
ranitidine, famotidine, roxatidine, lafutidine) 
24 hours 
Systemic corticosteroids (including short-term burst of 
OCS) 
≥5 half-lives  
16.5.3.1 Performing the Skin Prick Test 
Clean the area of skin with 70% alcohol and allow to dry 
1. Use a pen (which can be washed off with an alcohol wipe) to mark the skin with the sites 
where SPT will be performed. Put a mark beside the area where a particular solution will 
be placed; or draw boxes on the skin  
• Label allergen: peanut stock, milk stock (if positive Medical History), egg stock (if 
positive Medical History), and diluted peanut stock for TSPT (from 1:10 to 100’000) 
• Label histamine (positive control) and diluent-saline (negative control) 
2. Place one drop of test solution at the appropriate labelled site as above and “prick” the 
skin with an appropriate SPT device: 1) Start from saline, positive control, then allergen 
(for TSPT, from the lowest concentration), 2) Use difference lancet for other allergen 
3. Start a time (record it) 
4. After pricking the skin, immediately blot the skin with tissue paper to absorb excess 
liquid; avoid letting the liquid run from one site to another 
5. After 15 minutes measure the size of the wheal at each site: 1) Start with the site you first 
pricked and then work your way in the same order in which the pricks were applied. The 
time taken to do this will be approximately the time it took to apply the solutions and prick 


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them, 2) Measure and record the longest diameter at each site (record in eCRF), 3) 
Measure and record the midpoint orthogonal diameter (record in eCRF). 
For the eligibility check, the average of longest wheal diameter and the corresponding midpoint 
orthogonal diameter will be used, e.g. 11.5 mm = (15+8)/2 
Figure 16-1 
Measurement of skin reaction 
 
16.5.4 
Completion of the Skin Prick Test 
After measurement of skin reaction and recorded them in the source document, clean the skin 
with alcohol to remove the ink from marker pen on the skin. 
Rarely, SPT can cause a generalized allergic reaction (e.g., hives itchy, runny nose, asthma) or 
even anaphylaxis. Therefore, at the completion of SPT, the participants should remain under 
observation at the site as per the investigator's discretion. 
Adverse event reporting 
If the participant experiences a systemic allergic reaction suspected to be triggered by the SPT, 
the event should be captured in the designated CRF. Adverse events meeting the criteria for a 
SAE should be reported as described in Section 10.1.3 SAE Reporting.  


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16.6 
PRO Measures 
16.6.1 
FAQLQ-CF: Food Allergy Quality of Life Questionnaire  Child Form 
 


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16.6.2 
FAIM-CF: Food Allergy Independent Measure  Child Form 
 


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16.6.3 
FAQLQ-TF: Food Allergy Quality of Life Questionnaire  Teenager Form 
 


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16.6.4 
FAIM-TF: Food Allergy Independent Measure  Teenager Form 
 


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16.6.5 
FAQLQ-AF: Food Allergy Quality of Life Questionnaire  Adult Form 
 


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16.6.6 
FAIM-AF: Food Allergy Independent Measure  Adult Form 
 


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16.6.7 
FAQLQ-PF: Food Allergy Quality of Life Questionnaire  Parental Form 
 


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16.6.8 
FAQL-PB: Food Allergy Quality of Life - Parental Burden 
Questionnaire 
 


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16.6.9 
SF-36v2 Acute Version Short Form 36-Health Survey Questionnaire v2 
 


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SAP_001.pdf: 
Clinical Development 
QGE031/Ligelizumab 
CQGE031G12301 / NCT04984876
A 52 week, multi-center, randomized, double-blind placebo-
controlled study to assess the clinical efficacy and safety 
of ligelizumab (QGE031) in decreasing the sensitivity to 
peanuts in patients with peanut allergy 
Statistical Analysis Plan (SAP) 
Document type: 
SAP Documentation Amendment 3 
Release date: 
11-September-2023
Number of pages: 
48 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
Template Version 4.0, Effective from 23-Apr-2021 


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SAP 
 
Study No. CQGE031G12301 
 
Document History – Changes compared to previous final version of SAP 
Date 
Time point 
Reason for 
update 
Outcome for update 
Section and 
title impacted 
(Current) 
13 
July 
2021 
Prior to DB 
lock 
Creation of 
final version 
N/A - First version 
NA 
 
 
28 
July 
2023 
After 
Protocol 
Amendment 
1 and 
before Dry 
run 
Recruitment 
halt with the 
intention to 
terminate 
study early. 
Aligned with 
protocol 
amendment 1.  
Analyses 
changed. 
Removed references to the second CSR  
Section 1 
 
 
 
Described changes from early study termination and 
recruitment halt. 
Section 1.1 
 
 
 
Removed analysis concerning sustainability of effect 
at Week 52. 
Section 2.6.4 
 
 
 
Analysis of children under 12 years old removed, 
due to recruitment halt. Specific output to be 
presented at Primary Analysis listed. Analysis at 
Week 52 removed. DMC information added. 
Section 2.13 
 
 
 
Due to halt of recruitment, sentences about children 
6-11 years old removed.  
Section 3 
 
 
 
 
 
 
 
 
 
Handling of intercurrent events was simplified, with 
COVID-19 no longer being an intercurrent event and 
composite variable strategy being used consistently 
across endpoints. (Section 2.7.3 on 'Handling of 
Intercurrent Events' was deleted). 
Section 1.2.1 
and Section 
1.2.2 
 
 
 
 
 the independent DMC is 
described. 
 
 
 
 
Treatment group labels are described. 
Section 2.1.1.1 
 
 
 
The maximum tolerated dose is defined. 
Section 2.1.1.5 
 
 
 
Described how mis-randomized patients are 
analyzed. PRO data collected removed and 
described elsewhere. 
Section 2.2 
 
 
 
Potential subgroup analysis to split data according to 
notification of recruitment halt was added. Removed 
separate analysis for Japanese patients 
Section 2.2.1 
 
 
 
Changes to how the number of patients will be 
summarized for patient disposition and included 12-
week timepoint.  
Section 2.3.1 
 
 
 
Added additional categories of baseline 
characteristics for summary. 
Section 2.3.2 


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Study No. CQGE031G12301 
 
 
 
 
Added information about prior medications, 
concomitant medications, and epinephrine use. 
Replaced summaries by ATC classification by 
primary system organ class and MedDRA preferred 
term. 
Section 2.4.2 
 
 
 
Added log-transformed MTD (Maximum Tolerated 
Dose) at screening DBPCFC    as covariate in 
logistic regression model. Added P-value will be 
generated with a likelihood ratio test. 
Section 2.5.2 
 
 
 
Removed tipping point analyses as missing data due 
to intercurrent events will be handled with relative 
conservative strategy (i.e., composite variable 
strategy)  
Section 2.5.3 
 
 
 
Added Kaplan-Meier plot and modified marginal 
standardization analysis.  
Section 2.5.4 
 
 
 
Maximum tolerated dose analyses and skin prick 
test described in more detail. 
Section 2.6.4 
 
 
 
Pooling periods for safety analyses described 
elsewhere (Section 2.1.1.1).  
Section 2.7 
 
 
 
Added details on treatment-emergent adverse 
events. 
Section 2.7.1 
 
 
 
Added exposure-adjusted incidence rate. 
Section 2.7.1.1 
 
 
 
Added details for summarizing injection site 
reactions. 
Section 2.7.1.2 
 
 
 
Imputation methods described for values that are 
abnormal or outside the level of quantification.  
Section 2.7.3 
and Section 
2.8 
 
 
 
Details on ECG parameters provided. 
Section 2.7.4.1 
 
 
 
 
. 
 
 
 
 
IgE levels specified as at screening. 
Section 2.9 
 
 
 
Age groups and scoring of PRO instruments 
clarified, including SF-6Dv2.  
Section 2.10.1 
 
 
 
Analysis for PRO scores described. 
Section 
2.10.1.1 
 
 
 
. 
 
 
 
 
Power calculations updated using PASS Version 11.  
Paragraph on consistency trend across age groups 
removed. 
Section 3.1 
 
 
 
Sentence about potentially increasing sample size 
for covid impact was removed. Power table for 
children 6-11 removed.  
Section 3.2 
 
 
 
Table on precision levels for safety incidence rate 
per age group removed.  
Section 3.2.1 
 
 
 
Changes to protocol specified analyses noted. 
Section 4 
 
 
 
Details for multiple imputation added, for maximum 
tolerated dose, binary endpoints involving logistic 
regression, and marginal standardization. Tipping 
point analysis for primary estimand removed.  
Section 5.4.1 
 
 
 
For maximum severity of symptoms, covariates were 
specified and details on imputation strategy added. 
Section 5.4.2 
 
 
 
IgE specified as being measured at screening. 
Section 5.4.2.1 


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11 
Sep 
2023 
Before 
database 
lock 
Clarification of 
analyses 
Specified calculation of negative control for skin 
prick test mean diameters.  
Section 2.6.4 
 
 
 
Removed SF-36 output from Table 2-2 and specified 
missing data approach for additional analysis 
 
Section 2.13 
 
 
 
Labelled systolic and diastolic blood pressure values 
Section 5.3 


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Table of contents 
Table of contents ................................................................................................................. 5 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 7 
List of abbreviations ............................................................................................................ 8 
1 
Introduction ....................................................................................................................... 10 
1.1 
Study design .......................................................................................................... 10 
1.2 
Study objectives, endpoints and estimands ........................................................... 12 
1.2.1 
Primary estimand(s) .............................................................................. 14 
1.2.2 
Secondary estimand(s) .......................................................................... 15 
2 
Statistical methods ............................................................................................................. 16 
2.1 
Data analysis general information ......................................................................... 16 
2.1.1 
General definitions ................................................................................ 16 
2.2 
Analysis sets .......................................................................................................... 18 
2.2.1 
Subgroups of interest............................................................................. 18 
2.3 
Patient disposition, demographics, and other baseline characteristics .................. 19 
2.3.1 
Patient disposition ................................................................................. 19 
2.3.2 
Demographics and other baseline characteristics ................................. 19 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................ 20 
2.4.1 
Study treatment / compliance ................................................................ 20 
2.4.2 
Prior, concomitant and post therapies ................................................... 20 
2.5 
Analysis supporting primary objective(s) .............................................................. 21 
2.5.1 
Primary endpoint(s) ............................................................................... 21 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 21 
2.5.3 
Handling of missing values not related to intercurrent event ............... 22 
2.5.4 
Supplementary analyses ........................................................................ 22 
2.6 
Analysis supporting secondary objectives ............................................................. 22 
2.6.1 
Key secondary endpoint(s) .................................................................... 22 
2.6.2 
Statistical hypothesis, model, and method of analysis .......................... 23 
2.6.3 
Handling of missing values not related to intercurrent events .............. 25 
2.6.4 
Other secondary endpoint analyses ....................................................... 25 
2.7 
Safety analyses....................................................................................................... 26 
2.7.1 
Adverse events (AEs) ............................................................................ 26 
2.7.2 
Deaths .................................................................................................... 29 
2.7.3 
Laboratory data ..................................................................................... 29 
2.7.4 
Other safety data ................................................................................... 29 


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 32 
 
 32 
2.10 
Patient-reported outcomes ..................................................................................... 32 
2.10.1 
Patient-reported outcome assessments .................................................. 32 
 
 35 
 
 35 
2.13 
Interim analysis ...................................................................................................... 35 
3 
Sample size calculation ..................................................................................................... 38 
3.1 
Primary endpoint(s) ............................................................................................... 38 
3.2 
Secondary endpoint(s) ........................................................................................... 39 
3.2.1 
Precision for adverse events .................................................................. 40 
4 
Change to protocol specified analyses .............................................................................. 40 
5 
Appendix ........................................................................................................................... 42 
5.1 
Imputation rules ..................................................................................................... 42 
5.1.1 
Study drug ............................................................................................. 42 
5.1.2 
AE date imputation ............................................................................... 42 
5.1.3 
Concomitant medication date imputation ............................................. 43 
5.2 
AEs coding/grading ............................................................................................... 44 
5.3 
Laboratory parameters derivations ........................................................................ 44 
 
 45 
 
 45 
 
 46 
5.5 
Rule of exclusion criteria of analysis sets.............................................................. 47 
6 
Reference ........................................................................................................................... 47 
 
List of tables 
Table 1-1 
Objectives and related endpoints .......................................................... 12 
Table 2-1 
Administration of questionnaires according to participant age. ............ 33 
Table 2-2 
Results presented at the Primary Analysis ............................................ 36 
Table 3-1 
Sensitivity of the power for each dose for the primary variable ........... 39 
Table 3-2 
Power of each dose for the analyses of primary and key secondary 
variables in the base case scenario ........................................................ 40 
Table 3-3 
Precision levels (95% CI) for sensitivity of safety incidence rate for 
overall population .................................................................................. 40 
Table 5-1 
Notable values requiring further evaluation for Heart Rate (HR) 
and Blood Pressure in children and adolescents ................................... 44 


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Table 5-2 
Criteria leading to exclusion ................................................................. 47 
 
List of figures 
Figure 1-1 
Study design .......................................................................................... 11 
Figure 2-1 
Testing strategy ..................................................................................... 24 
 


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List of abbreviations 
 
 
AE 
Adverse Event 
ANCOVA 
Analysis of covariance 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under Curve 
bpm 
Beats per minute 
CD23 
IgE (low affinity) receptor 
CI 
confidence intervals 
CM 
Concomitant Medication 
Covid-19 
Corona Virus Disease 2019 
CRF 
Case Report/Record Form (paper or electronic) 
CSR 
Clinical study report 
CV 
Coefficient of variation 
DBL 
Database Lock 
DBPCFC 
Double Blind Placebo Controlled Food Challenge 
DMC 
Data Monitoring Committee 
 
 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EOS 
End of study 
FAIM 
Food Allergy Independent Measure 
FAQLQ 
Food Allergy Quality of Life Questionnaire 
FAS 
Full Analysis Set 
FcεRI 
IgE (high affinity) receptor 
gMCP 
Graph Based Multiple Comparison Procedures 
h 
Hour 
HRQoL 
Health-Related Quality of Life 
IgE 
Immunoglobulin E (specific and un-specific for the study allergen) 
IgG 
Immunoglobulin G 
L 
Liter 
LLOQ 
Lower limit of quantification 
MAR 
Missing at random 
MedDRA 
Medical dictionary for regulatory activities  
mg 
Milligram(s) 
mL 
Milliliter(s) 
mm 
Millimeter 
mmHg 
Blood pressure unit millimeters of mercury 
MRI 
Magnetic Resonance Imaging 
ms 
Millisecond 
MTD 
Maximum Tolerated Dose 
OFC 
Oral Food Challenge 
 
 
 
 
PRO 
Patient Reported Outcomes 
q4W 
Every 4 weeks 


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RAS 
Randomized Analysis Set  
RR 
Responder rate 
SABA 
Short-acting ß-agonist 
SAE 
Serious Adverse Event 
SAF 
Safety analysis set 
SC 
Subcutaneous 
SCq4W 
Subcutaneous injection every 4 weeks 
SD 
Standard deviation 
sIgE 
Specific IgE for the study allergen 
SMQ 
Standardized MedDRA Query  
SPT 
Skin Prick Test 
Total IgE 
Drug-bound and free IgE 
μL 
Microliter 
ULOQ 
Upper limit of quantification 
 


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1 
Introduction 
The purpose of this document is to describe the statistical analyses mentioned in version 01 
(amendment 1) of the Phase 3 study CQGE031G12301 protocol.  
This document covers statistical and analytical plans for the primary endpoint analysis (i.e., 
after all participants have completed the visit at Week 12) and the final analysis (i.e., after all 
participants have completed the follow-up visit or prematurely withdrawn from the study). 
1.1 
Study design 
This is a 52-week, Phase 3 multi-center, randomized, double-blind and placebo-controlled study 
to assess the safety and clinical efficacy of ligelizumab (QGE031) in participants with a 
medically confirmed diagnosis of IgE-mediated peanut allergy. The primary objective of the 
study is to evaluate the efficacy of ligelizumab 240 mg and 120 mg (SCq4w) compared to 
placebo at Week 12, as measured by the proportion of participants who can tolerate a single 
dose of  ≥ 600 mg (1044 mg cumulative tolerated dose) of peanut protein without dose-limiting 
symptoms during the double-blind, placebo controlled, food challenge (DBPCFC). 
A total sample size of approximately 486 randomized participants aged 6 to 55 years was 
initially planned. Due to the decision of halt recruitment and terminate the study early  
(Section 4), the final size is 211, with only adolescent and adult participants being recruited. 
Participants were randomized at a 2:2:2:2:1 ratio to one of five treatment arms at the time of 
randomization visit as follows: 
• Ligelizumab 240 mg SC q4w 
• Ligelizumab 120 mg SC q4w 
• Placebo 8 weeks to Ligelizumab 240 mg SC q4w 
• Placebo 8 weeks to Ligelizumab 120 mg SC q4w 
• Placebo 16 weeks to Ligelizumab 240 or 120 mg SC q4w (with a ratio of 0.5 : 0.5 for 
switched treatment) 
Participants will be stratified based on region, total IgE at screening (<350 IU/ mL; ≥350 IU/ 
mL) and age (12 - 17y, and 18 - 55y).  


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Figure 1-1 
Study design 
 
The study will include the following: 
1. Screening period (Duration of 4 weeks) 
2. Treatment period (Duration of 52 weeks) 
• Double-blind placebo-controlled treatment period (Duration of 12 weeks): Study 
participants will be seen in the clinic at Day 1, Week 1, Week 4, Week 8 and Week 
12. The DBPCFC will be performed at Week 12. Participants assigned to the 8-week 
placebo arms will receive the first dose of blinded ligelizumab treatment at the Week 
8 visit. Participants assigned to the 16-week placebo arm will receive the first dose of 
blinded ligelizumab treatment at the Week 16 visit. 
• Long-term active blinded (no placebo control) treatment period (Duration of 40 
weeks/ 36 weeks for participants on the 16-week placebo arm): Starting at Week 
16, all study participants will receive blinded ligelizumab study treatment in the clinic 
every 4 weeks until Week 52. A final DBPCFC will be performed at Week 52. 
3. Post-treatment follow-up period (Duration of 16 weeks): There are 4 planned clinic visits 
(every 4 weeks). Study evaluations include safety, 
, post-treatment 
biomarkers. Study treatment is not given and there is no DBPCFC. 
At the start of the study, recruitment was restricted to 12 - 55 year old participants. When 
approximately 60 adolescent participants (defined as 12 -17 years of age) would have completed 
all Week 12 assessments, an interim analysis
 
 was to be performed for confirmation of the pediatric dose (safety will be 
reviewed by a Data Monitoring Committee - DMC). Independent sponsor members who are 
responsible for 
 Modeling & Simulation will be unblinded to the 
results of this interim analysis.  
As Novartis decided  to halt recruitment (Date of issuing halt notification: 05 Apr 2023) with 
the intention to terminate the study early, there will be no recruitment of children under age 12.  


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Patients who are already in the study (i.e., signed informed consent) at the time of the halt 
notification will be managed according to their individual progress within the study as described 
in the table below. 
 
Group 
1 
Already completed 
Week 52 Visit 
assessments 
Complete the 16-week safety follow up period as per protocol 
Group 
2 
Already completed 
Week 12 Part 2 
Visit 
Attend the next scheduled visit (as per schedule of events), which will now 
correspond to the end of treatment visit (Week 52 Part 1). Patients will be 
informed at that visit that the treatment is stopped (no drug administration at 
that visit) and that they will enter the 16-week follow up period as per protocol. 
Notably, no oral food challenge will be done at this end of treatment visit 
Group 
3 
Randomized but 
have not yet 
reached the Week 
12 Part 2 Visit 
At their next visit, investigators should inform the patient of the study status 
and provide them with the opportunity to continue and perform the 
assessments until week 12 Part 2. The week 12 Part 2 visit will now be 
considered end of treatment (Week 52 Part 2) so that afterwards patients will 
then enter the 16-week safety follow up period as per protocol. In this 
situation, there is no need to fill out the “Trial Feedback Questionnaire.” 
Group 
4 
Reached the 
Screening Visit 2 
Part 1 
Allowed to complete the Screening Visit 2 Part 2 (i.e., complete both parts of 
the baseline Oral Food Challenge) and, pending final eligibility, to be 
randomized and continue as patients in Group 3.  
Group 
5 
In screening period 
but have not 
reached the 
Screening Visit 2 
Part 1 
Screening failed and patients will be eligible for future pivotal studies 
 
1.2 
Study objectives, endpoints and estimands  
Table 1-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To evaluate the efficacy of ligelizumab 240 mg and 
120 mg (SCq4w), compared to placebo, as 
measured by the proportion of participants who can 
tolerate a single dose of  ≥ 600 mg (1044 mg 
cumulative tolerated dose) of peanut protein 
without dose-limiting symptoms during the 
DBPCFC at Week 12 
• 
Responder status defined as tolerating a single 
dose of ≥ 600 mg (1044 mg cumulative 
tolerated dose) of peanut protein without dose-
limiting symptoms during the DBPCFC 
conducted at Week 12. 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
Key secondary objectives 
• 
Key secondary endpoints 
• 
To evaluate the efficacy of ligelizumab 240mg and 
120mg (SCq4w), compared to placebo, as 
measured by the proportion of participants who can 
tolerate a single dose of  ≥ 1000 mg (2044 mg 
cumulative tolerated dose) of peanut protein 
without dose-limiting symptoms during the 
DBPCFC at Week 12 
• 
Responder status defined as tolerating a single 
dose of ≥ 1000 mg (2044 mg cumulative 
tolerated dose) of peanut protein without dose-
limiting 
symptoms 
during 
the 
DBPCFC 
conducted at Week 12. 
• 
To evaluate the efficacy of ligelizumab 240mg and 
120mg (SCq4w), compared to placebo, as 
• 
Responder status defined as tolerating a single 
dose of 3000 mg (5044 mg cumulative tolerated 


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Objective(s) 
Endpoint(s) 
measured by the proportion of participants who can 
tolerate a single dose of 3000 mg (5044 mg 
cumulative tolerated dose) of peanut protein 
without dose-limiting symptoms during the 
DBPCFC at Week 12 
dose) of peanut protein without dose-limiting 
symptoms during the DBPCFC conducted at 
Week 12. 
• 
To evaluate the efficacy of ligelizumab 240mg and 
120mg (SCq4w), compared to placebo, as 
measured by the maximum symptom severity at 
any single challenge dose up to and including 1000 
mg of peanut protein during the DBPCFC at Week 
12  
• 
Maximum severity of symptoms occurring at 
any challenge dose of peanut protein up to and 
including 1000 mg during the DBPCFC 
conducted at Week 12. Symptom severity will 
be categorized as 4 levels: None, Mild, 
Moderate, Severe.  
• 
To evaluate the efficacy of 8 weeks of placebo 
treatment followed by 4 weeks of ligelizumab 120 
mg / 240 mg (SCq4w) treatment compared to 12 
weeks of placebo treatment, as measured by the 
proportion of participants who can tolerate a single 
dose ≥1000 mg of peanut protein without dose-
limiting symptoms during the DBPCFC at Week 12  
• 
Responder status defined as participants 
tolerating a single dose of ≥ 1000 mg (2044 mg 
cumulative tolerated dose) of peanut protein 
without dose-limiting symptoms during the 
DBPCFC conducted at Week 12 (8 weeks of 
placebo + 4 weeks of ligelizumab treatment vs. 
12 weeks of placebo).  
• 
Other secondary objectives 
• 
Other secondary endpoints 
• 
To evaluate the efficacy of ligelizumab 240mg and 
120mg (SCq4w), as measured by the proportion of 
participants who can tolerate a single dose of 
≥1000 mg (2044 mg cumulative tolerated dose) of 
peanut protein without dose-limiting symptoms 
during the DBPCFC at Week 52 compared to Week 
12 
• 
Proportion of participants tolerating a single 
dose of ≥ 1000 mg (2044 mg cumulative 
tolerated dose) of peanut protein without dose-
limiting symptoms during DBPCFC conducted 
at Week 52  
• 
Change in maximum tolerated dose (MTD) of 
peanut protein without dose-limiting symptoms 
during the DBPCFC at Week 52 compared to 
Week 12  
• 
To evaluate the effects of ligelizumab 240 mg and 
120 mg (SCq4w), compared to placebo (when 
applicable), as measured by multiple systemic 
biomarkers to inform on response to treatment or 
disease severity 
• 
Change from baseline at Week 12, 16 and 
Week 52 of 
•peanut-specific IgE 
•peanut-specific IgG4 
• 
To evaluate the safety and tolerability of 
ligelizumab 240 mg and 120 mg (SCq4w) 
• 
Summaries of treatment-emergent adverse 
events, vital signs, ECG, and laboratory values 
• 
To assess the ability of IgE suppression to impact 
skin mast cells through the assessment of allergen-
specific skin prick test (SPT). 
• 
Change from baseline (screening) in SPT mean 
wheal diameters at Week 16, Week 56 and 
Week 68. 
• 
To evaluate the impact of ligelizumab on the 
health-related quality of life (HRQoL) of patients 
with peanut allergy. 
• 
Change from baseline in total and domain 
scores in the FAQLQ, FAIM, and SF-36v2 by 
age and responder (subject and/or caregiver) at 
various points in time.  


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Objective(s) 
Endpoint(s) 
1.2.1 
Primary estimand(s)  
The primary estimand quantifies the effects of ligelizumab 120mg and 240mg SCq4w as 
compared to placebo on the proportion of responders at Week 12 regardless of intake of rescue 
medication prior to Week 12.  
The primary estimand is described by the following attributes: 
• Population: participants who have been diagnosed with IgE-mediated peanut allergy and 
met study inclusion/exclusion criteria. 
• Variable: Responder status defined as tolerating a single dose of ≥ 600 mg (1044 mg 
cumulative tolerated dose*) of peanut protein without dose-limiting symptoms **during 
the DBPCFC conducted at Week 12. 
• Treatment: the randomized treatment^ (ligelizumab 120mg SCq4w, ligelizumab 240mg 
SCq4w, and placebo) plus rescue medication (e.g., epinephrine, SABA, anti-histamines), 
if needed.  
• Handling of intercurrent events: 
• Discontinuation of treatment or missing more than one dose prior to Week 12: 
participants who discontinue treatment or miss more than one dose prior to Week 12 
will not undergo any DBPCFC. They will be considered non-responders (composite 
variable strategy). 
• Intake of rescue medication prior to DBPCFC conducted at Week 12: ignorable 
(treatment policy strategy, reflected in the Treatment attribute) 
Epinephrine, SABA, anti-histamines and saline bolus are typically used as rescue 
medication to treat allergic reactions. Participants who experience allergic reactions 
due to accidental exposure or other reasons may need to take rescue medications prior 
to Week 12. However, participants must be in good health before proceeding with the 
food challenge and meet the washout requirement of permitted medications as 
described in Protocol Table 6-2.  Therefore, to reflect clinical practice, all observed 
values after this intercurrent event will be used in the statistical analyses whenever 
the treatment effect is estimated.  


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• Summary measure: odds ratio comparing the proportion of responders between each 
ligelizumab dose group and placebo group 
• *The cumulative tolerated dose is the sum of the tolerated doses, not including the reactive 
dose (Casale et al 2019)  
• **Dose-limiting 
symptoms 
indicate 
a 
true 
allergic 
reaction 
occurring 
during administration of a single dose of peanut protein at the DBPCFC that should 
preclude the administration of any further doses in the view of the investigator. Symptoms 
that require administration of any rescue medication are considered dose-limiting 
symptoms. 
• ^ The randomized treatment indicates ligelizumab 120 mg arm, ligelizumab 240 mg arm, 
and placebo 16wk to ligelizumab 120/240 mg arm (labelled as placebo for efficacy 
estimands).  
1.2.2 
Secondary estimand(s) 
The four key secondary endpoints defined in the protocol are considered for estimands as below. 
1.2.2.1 Secondary estimand 1 : Proportion of responders who can tolerate a 
single dose of ≥1000 mg of peanut protein at Week 12 
The secondary estimand 1 is the same as the primary estimand except that “a single dose of ≥ 
600 mg (1044 mg cumulative tolerated dose)” is replaced by “a single dose of ≥ 1000 mg (2044 
mg cumulative tolerated dose)”. 
1.2.2.2 Secondary estimand 2: Proportion of responders who can tolerate a 
single dose of 3000 mg of peanut protein at Week 12 
The secondary estimand 2 is the same as the primary estimand except that “a single dose of ≥ 
600 mg (1044 mg cumulative tolerated dose)” is replaced by “a single dose of ≥ 3000 mg (5044 
mg cumulative tolerated dose)”. 
1.2.2.3 Secondary estimand 3: Maximum severity of symptoms up to and 
including 1000 mg of peanut protein 
This secondary estimand 3 is described by the following attributes: 
• Population: same as for the primary estimand. 
• Variable: maximum severity of symptoms occurring at any challenge dose of peanut 
protein up to and including 1000 mg during the DBPCFC conducted at Week 12. 
According to CoFAR grading scale of dose-limiting symptoms, symptom severity will be 
categorized as Mild, Moderate and Severe. Symptom severity for participants who 
completed DBPCFC without any symptoms will be categorized as “None”.  
• Treatment: same as for the primary estimand. 
• Handling of intercurrent events: 
• Discontinuation of treatment or missing more than one dose prior to Week 12: 
Missing data at Week 12 will replaced by the maximum severity of symptoms at 
screening (composite variable strategy).  


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• Intake of rescue medication prior to DBPCFC conducted at Week 12: ignorable 
(treatment policy strategy, reflected in the “Treatment” attribute). 
• Summary measure: odds ratio comparing the odds of developing less severe symptoms 
between each ligelizumab dose group and placebo group. 
1.2.2.4 Secondary estimand 4: Proportion of responders who can tolerate a 
single dose of 1000 mg of peanut protein at Week 12 with 8 weeks of 
placebo followed by 4 weeks of ligelizumab 
The secondary estimand 4 provides insight into the treatment effect after one dose of 
ligelizumab. This secondary estimand is the same as the primary estimand except the following 
attributes : 
• Variable: Responder status defined as tolerating a single dose of ≥ 1000 mg (2044 mg 
cumulative tolerated dose) of peanut protein without dose-limiting symptoms during the 
DBPCFC conducted at Week 12. 
• Treatment: the randomized treatment (placebo 8 weeks to ligelizumab 240 mg SCq4w,  
placebo 8 weeks to ligelizumab 120 mg SCq4w and placebo 16 weeks to ligelizumab 
240/120 mg SCq4w) plus rescue medication, if needed. 
2 
Statistical methods 
2.1 
Data analysis general information 
The statistical analysis of the study will be performed by 
 a designated Contract Research 
Organization (CRO) following this document. SAS version 9.4 will be used to perform all 
analyses.  
There are two planned analyses before the final database lock, in addition to the DMC analyses. 
The details of these analyses are provided in the Section 2.13 below.  
An independent DMC will conduct periodic monitoring of safety data and emerging risk/benefit. 
Interim reports to the DMC will be generated by an independent statistical group not involved 
in the conduct of the trial. Statistical Analysis Plan for the DMC analyses will be prepared 
separately.   
Categorical data will be summarized as frequencies and percentages. For continuous data, mean 
(geometric mean for non-normal distributed variables), standard deviation, median, 25th and 
75th percentiles, minimum and maximum will be presented.   
2.1.1 
General definitions  
2.1.1.1 Study treatment 
The study treatment includes investigational drug QGE031 and placebo. The following 
abbreviated treatment groups will be used as the headers in the tables.  
• QGE031 240 mg q4w 
• QGE031 120 mg q4w 
• Placebo 8 wks – QGE031 240 mg 


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• Placebo 8 wks – QGE031 120 mg 
• Placebo 16 wks – QGE120 or 240 mg q4w* 
* In the efficacy analysis outputs, placebo 16 wks switch will be labelled as “placebo group” 
for simplicity. 
In addition, for most of safety summaries, the following abbreviated treatment groups under 
different pooling period will be used as the headers in the tables.  
• Placebo-controlled pool up to Week 8 (QGE031 240 mg vs. QGE031 120 mg vs. three 
Placebo arms combined) 
• Placebo-controlled pool up to Week 16 (QGE031 240 mg vs. QGE031 120 mg vs. 
Placebo 16 wks – QGE120 or 240 mg) 
• Entire study period up to Week 68 (combined three arms with QGE031 240 mg vs. 
combined three arms with QGE 120 mg) 
2.1.1.2 Study day 
Study day will be defined as the number of days since the date of first dose of study treatment. 
The date of first dose of study treatment will be defined as Day 1 and the day before the first 
dose of study treatment will be defined as Day -1. 
Therefore, for a particular date, study day will be calculated as follows: 
For dates on or after the first dose date of study treatment, study day will be calculated as  
[Assessment date – Date of first dose of study treatment + 1]. For dates prior to the first dose 
date of study treatment, study day will be calculated as [Assessment date – Date of first dose of 
study treatment]. 
2.1.1.3 Baseline definition 
In general, baseline is defined as the last measurement before the first dose of study treatment. 
Details on calculation of baseline for PRO measures is provided in Section 2.10. 
2.1.1.4 Post-baseline definition 
Post-baseline measurements are defined as the assessments after the first dose of study 
treatment. When change from baseline of raw or log-transformed data is of interest, the 
following formula will be used to calculate the change from baseline, provided, both baseline 
and post-baseline values are available: 
Change from baseline = post-baseline value – baseline value. 
2.1.1.5 Maximum tolerated dose in DBPCFC 
Maximum tolerated dose (MTD) is defined as the maximum tolerated single dose without any 
dose limiting symptoms in peanut challenge part. If the MTD at any visit is 0mg, it will be 
imputed as 0.3 mg and reported as “< 1 mg.”  


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2.2 
Analysis sets  
The Randomized Analysis Set (RAS) consists of all randomized participants, regardless of 
whether or not they receive a dose of study drug. Participants will be analyzed according to the 
treatment they are assigned to. 
The Full Analysis Set (FAS) comprises all participants who received at least one dose of study 
treatment. According to the intent to treat principle, participants will be analyzed according to 
the treatment they have been assigned to during the randomization procedure. Mis-randomized 
patients (mis-randomized in IRT) will be excluded. Mis-randomized patients are defined as 
cases where IRT contacts were made by the site either prematurely or inappropriately prior to 
confirmation of the patient’s final randomization eligibility and no study medication was 
administered to the patient. FAS will be used for all efficacy variables, unless otherwise stated. 
The Safety Set (SAF) includes all participants who received at least one dose of study treatment 
whether or not being randomized. Participants will be analyzed according to the treatment they 
received, where treatment received is defined as the randomized/assigned treatment if the 
participant took at least one dose of that treatment or the first treatment received if the 
randomized/assigned treatment was never received. The safety set will be used in the analysis 
of all safety variables. 
 
 
2.2.1 
Subgroups of interest 
Subgroup analyses will be performed for primary endpoint and selected secondary endpoints 
using the same models mentioned in Section 2.6 and Section 2.7 but with additional model 
terms for the subgroup (if not already included in the model) and subgroup-by-treatment 
interaction terms. Due to the reduced number of participants who completed the study, models 
for subgroup analyses may fail to converge after dropping factors, then only descriptive 
subgroup analyses will be provided instead. The subgroup variables are listed below: 
• By age group (12 – 17 years, 18 – 55 years) 
• By total IgE at screening (<350 IU/ mL; ≥350 IU/ mL) 
• By age group and total IgE at screening 
• By maximum tolerated dose of allergen at screening OFC (< 30 mg; ≥ 30 mg) 
• By allergy status (mono- vs poly-sensitized participants) 
Mono-sensitized participants are only sensitized to peanut protein. Poly-sensitized participants 
are sensitized to peanut protein and at least one of the other proteins in the panel. Poly-
sensitization is defined as sIgE ≥ 0.35 kUA/L for a food allergen in the panel other than peanut 
and confirmed in the medical history. 
The following subgroup analysis may be conducted to evaluate potential impact of temporary 
halt on primary and key secondary efficacy endpoints, if participants who have not reached 


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Week 12 upon receiving the notification of temporary halt (Date of issuing temporary halt 
notification : 05 Apr 2023) have a dropout rate greater than or equal to 25%:  
• By Week 12 completion date (or date of study discontinuation if study discontinuation 
occurred prior to Week 12) before or after the notification of the halt. 
In addition, subgroup analyses by age (12-17 years and 18-55 years) for selected safety 
endpoints, 
 will also be provided. 
2.3 
Patient disposition, demographics, and other baseline 
characteristics 
2.3.1 
Patient disposition 
For each study epoch (i.e., screening, treatment phase and post treatment follow-up), the overall 
number of participants who entered, completed and discontinued that phase will be summarized 
including the primary reasons for discontinuation of that phase. 
The number of participants who completed the 12-week and 52-week study treatment and who 
discontinued prematurely will be shown including the reasons for discontinuation of treatment.  
Number of participants with protocol deviations will be summarized by category and deviation. 
2.3.2 
Demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be summarized 
descriptively by treatment group for the RAS.  
Demographics 
• Age 
• Age group (12-17 years and 18-55 years) 
• Sex 
• Race 
• Ethnicity 
• Region [Japan; US and Canada (North America); Australia; Denmark, France, Germany, 
Italy, Spain, the Netherlands (EU)] 
• Weight 
• Height 
• Body Mass Index – calculated as weight (kg)/(height (m))2 
• BMI group (< 25, 25 - < 30, ≥ 30 kg/ m2) 
Baseline characteristics 
• Peanut sIgE 
• Peanut specific IgG4 
• SPT mean wheal diameter  
• MTD (maximum tolerated dose) of peanut protein at screening DBPCFC (<1< 1, 1, 3, 10, 
30 mg)   


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• Poly-allergic to food 
• History of anaphylactic reaction to food (Yes, No) 
• Number of Use of Epinephrine auto-injector in the last two years 
• Duration of peanut allergy (months since peanut allergy diagnosis) 
• History of desensitization therapy to peanut allergy (Yes, No) 
Categorical data will be presented as frequencies and percentages. For continuous data, mean 
(geometric mean for non-normal distributed variables), standard deviation, median, minimum, 
and maximum will be presented. 
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term, by treatment group. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
The duration of exposure in weeks to each treatment group will be summarized using 
descriptive statistics. 
Duration of exposure to study treatment will be calculated as the number of weeks between the 
first dose date and the last dose date exposed to that treatment over the specified period 
(Duration of exposure = (date of last known study treatment – date of first known study 
treatment + 28)/7). 
In addition, the number of doses, total cumulative dose and number of missed doses will be 
presented. Categorical data will be summarized as frequencies and percentages. For continuous 
data, mean, standard deviation, median, 25th and 75th percentiles, minimum and maximum will 
be presented. 
2.4.2 
Prior, concomitant and post therapies 
Prior medications are defined as treatment taken and stopped prior to first dose or study 
treatment. Prior medications will be summarized by Anatomical Therapeutic Chemical (ATC) 
code, preferred term and treatment group on RAN set, separately for peanut allergy treatment 
(other than the ones taken during screening DBPCFC) and non-peanut allergy treatment 
(including ones taken during screening DBPCFC). For peanut allergy treatment, reason for 
discontinuation will be summarized as well.  
Concomitant medications are defined as any medication given at least once between the day of 
first dose of study treatment and the date of the last study visit. Concomitant medications will 
be summarized by ATC code, preferred term and treatment group for safety set.  
Rescue medications will be summarized by ATC code, preferred term and treatment group for 
safety set. 
Use of epinephrine during and outside of OFC will be summarized separately. Epinephrine used 
during the OFC are reported by the Investigator, on the concomitant medication eCRF page 


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after choosing Yes to the question on OFC signs and symptoms eCRF page: Was any treatment 
provided for these sign/symptoms? 
Significant prior and concomitant surgeries and procedures will be summarized by primary 
system organ class and MedDRA preferred term.  
2.5 
Analysis supporting primary objective(s) 
This section will describe the statistical analysis of the primary estimand. Details of the 
hypothesis testing strategy including primary and key secondary endpoints to handle 
multiplicity are provided in Section 2.6.2. 
2.5.1 
Primary endpoint(s) 
Definition of primary estimand is provided in Section 1.2.1. 
2.5.2 
Statistical hypothesis, model, and method of analysis  
The trial will be considered positive, if at least one of the two ligelizumab doses demonstrates 
a statistically significant result in comparing the proportion of responders as described below. 
The two doses will be tested in parallel for 12 weeks treatment on the primary endpoint. 
Let pj denote the responder rate for treatment regimens j, j=0, 1 or 2 where 
• 0 corresponds to placebo 
• 1 corresponds to ligelizumab 120 mg treated for 12 weeks 
• 2 corresponds to ligelizumab 240 mg treated for 12 weeks 
Responder rate is defined as the proportion of participants tolerating a single dose of ≥ 600 mg 
(1044 mg cumulative tolerated dose) of peanut protein without dose-limiting symptoms during 
the DBPCFC conducted at Week 12. For participants with treatment discontinuation or missing 
more than 1 doses of study drug prior to Week 12 due to reasons other than operational 
complications caused by public health emergency, they will be considered non-responders. 
The following hypotheses will be tested: 
H0 120 RR600 : p1 / (1- p1) ≤ p0 / (1- p0) versus HA 120 RR600 : p1 / (1- p1) > p0 / (1- p0)  
H0 240 RR600 : p2 / (1- p2) ≤ p0 / (1- p0) , HA 240 RR600 : p2 / (1- p2) > p0 / (1- p0) 
H0 120 RR600 : ligelizumab 120mg is not superior to placebo with respect to the responder rate at 
a level of 600 mg peanut protein (1044 mg cumulative tolerated dose) without dose-limiting 
symptoms at Week 12 
H0 240 RR600 :ligelizumab 240mg is not superior to placebo with respect to the responder rate at a 
level of 600 mg peanut protein (cumulative tolerated dose 1044 mg) without dose-limiting 
symptoms at Week 12 
The primary endpoint will be analyzed based on a logistic regression model, including treatment, 
age subgroup (12 – 17 years, 18 – 55 years), region as fixed class effects, as well as log-
transformed total IgE at screening and log-transformed MTD (Maximum Tolerated Dose) at 
screening DBPCFC as covariates. P-value will be generated with a likelihood ratio test. Odds 


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ratio and 95% profile likelihood confidence intervals (CI) will be presented comparing each 
ligelizumab dose to placebo with respect to the proportions of responders. 
The detailed testing strategy for primary and key secondary endpoints is provided in 
Section 2.6.2. 
2.5.3 
Handling of missing values not related to intercurrent event 
Handling of intercurrent events associated with key secondary objectives are described in the 
Section 1.2.1. Missing data not related to intercurrent events will be imputed for primary 
endpoint using multiple imputation under the missing at random (MAR) assumption. Details of 
the imputation method are mentioned in the Section 5.4.1. 
2.5.4 
Supplementary analyses 
Two supplementary analyses will be performed for the primary endpoint.  
Marginal Standardization 
The first supplementary estimand is the same as for the primary estimand except that the 
summary measure is the risk difference for marginal proportions of responders . The risk 
difference will be derived from the predicted risks for every patient as if they had received each 
treatment using a logistic regression model (Ge et al 2011). The model will include the same 
terms as in the primary analysis. The estimated treatment group risks, risk difference and 95% 
CI will be presented. Details are provided in Section 5.4.1. 
Kaplan-Meier plot 
A Kaplan-Meier plot will show the probability of experiencing a dose-limiting symptom during 
dose escalation of DBPCFC at Week 12 by treatment group. The dose of peanut protein at 
which dose-limiting symptom occurs during the DBPCFC at Week 12 will be treated as the 
time variable. There will be two separate plots showing those who completed DBPCFC at Week 
12: the first will show the results for the overall population; the second will be stratified by the 
highest tolerated dose of peanut protein at baseline (< 30 mg or >= 30mg). Participants’ 
maximum tolerated dose may be censored if they: 
• tolerated 3000mg of peanut protein; or 
• completed a certain level of challenge dose without experiencing dose-limiting-symptoms 
and chose to stop the DBPCFC before beginning or finishing a higher challenge dose (for 
example, due to the taste of the challenge material). 
2.6 
Analysis supporting secondary objectives  
This section describes the analyses of key secondary and other secondary endpoints. The details 
of the analyses are described below. 
2.6.1 
Key secondary endpoint(s) 
Definition of key secondary endpoints is provided in Section 1.2.2. 
The other secondary endpoints and corresponding analyses are defined in the Section 2.6.5 
below. 


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2.6.2 
Statistical hypothesis, model, and method of analysis 
Key secondary endpoint analyses 
The key secondary null hypotheses are as defined below. The familywise type I error rate will 
be controlled at the one-sided 0.025 level across the primary and key secondary null hypotheses 
in a closed testing procedure (Bretz et al 2009). 
H0 120 RR1000: ligelizumab 120 mg is not superior to placebo with respect to the responder rate at 
a level of 1000 mg peanut protein (cumulative tolerated dose 2044 mg) at Week 12 
H0 240 RR1000: ligelizumab 240 mg is not superior to placebo with respect to the responder rate at 
a level of 1000 mg peanut protein (cumulative tolerated dose 2044 mg) at Week 12 
H0 120 RR3000: ligelizumab 120 mg is not superior to placebo with respect to the responder rate at 
a level of 3000 mg peanut protein (cumulative tolerated dose 5044 mg) at Week 12 
H0 240 RR3000: ligelizumab 240 mg is not superior to placebo with respect to the responder rate at 
a level of 3000 mg peanut protein (cumulative tolerated dose 5044 mg) at Week 12 
H0 120 severity: ligelizumab 120 mg is not superior to placebo with respect to the odds of 
developing less severe level of symptoms evaluated by maximum severity of symptoms at any 
challenge dose of peanut protein up to and including 1000 mg during the DBPCFC conducted 
at Week 12 
H0 240 severity: ligelizumab 240 mg is not superior to placebo with respect to the odds of 
developing less severe level of symptoms evaluated by maximum severity of symptoms at any 
challenge dose of peanut protein up to and including 1000 mg during the DBPCFC conducted 
at Week 12 
The following secondary hypotheses will be used to evaluate onset of action of ligelizumab (8 
weeks of placebo + 4 weeks of ligelizumab treatment): 
H0 120 wk4 RR1000: ligelizumab 120 mg (8 weeks of placebo + 4 weeks of ligelizumab treatment) 
is not superior to placebo with respect to the responder rate at a level of 1000 mg peanut protein 
(cumulative tolerated dose 2044 mg) at Week 12 
H0 240 wk4 RR1000 : ligelizumab 240 mg (8 weeks of placebo + 4 weeks of ligelizumab treatment) 
is not superior to placebo with respect to the responder rate at a level of 1000 mg peanut protein 
(cumulative tolerated dose 2044 mg) at Week 12 
The graphical approach of Bretz et al 2009 for sequentially rejecting testing procedures is used 
to illustrate the testing strategy in Figure 2-1 below. 


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Figure 2-1 
Testing strategy 
 
• The hypotheses will be tested in two branches constituting ligelizumab 120 mg versus 
placebo (left branch) and ligelizumab 240 mg versus placebo (right branch). Initially, the 
full alpha level of 0.025 (one-sided) is equally split across the primary hypotheses for the 
two branches. 
• Once this first primary null hypothesis H0 120 RR600 or H0 240 RR600 for a dose has been 
rejected at the initial alpha level of 0.0125 (one-sided), the alpha will be fully distributed 
to H0 120 RR1000 or H0 240 RR1000 for the same dose. 
• If H0 120 RR1000 or H0 240 RR1000 is rejected for a dose, then 50% of its local significance level 
is reassigned to the primary null hypothesis for the other dose, and 50% of its local 
significance level is reassigned to H0 120 RR3000 or H0 240 RR3000 for the same dose. 
• If H0 120 RR3000 or H0 240 RR3000 is rejected for a dose, then 50% of its local significance level 
is reassigned to the primary null hypothesis for the other dose, and 50% of its local 
significance level is reassigned to H0 120 severity or H0 240 severity for the same dose. 
• If H0 120 severity or H0 240 severity is rejected for a dose, (100-ε)% of its local significance level 
is reassigned to the primary null hypothesis for the other dose. ε is set to a very small 
number in practice, e.g., 10-10. The dotted dashed edges with a weight of ε indicate the 
local significance level will only be reassigned to H0 120 wk4 RR1000 or        H0 240 wk4 RR1000, 
once both H0 120 severity and H0 240 severity are rejected. 
• If H0 120 wk4 RR1000 or H0 240 wk4 RR1000 is rejected for a dose, 100% of its local significance 
level is reassigned to the primary null hypotheses for the other dose. 
The proportion of responders for the endpoints as stated below will be analyzed using a logistic 
regression model in a similar fashion as the primary estimand (see Section 5.4.1 for details). 
• Responder status defined as tolerating a single dose of 1000 mg (2044 mg cumulative 
tolerated dose) peanut protein without dose-limiting symptoms as Week 12. 
• Responder status defined as tolerating a single dose of 3000 mg (5044 mg cumulative 
tolerated dose) peanut protein without dose-limiting symptoms at Week 12. 


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• Responder status defined as participants tolerating a single dose of ≥ 1000 mg (2044 mg 
cumulative tolerated dose) peanut protein without dose-limiting symptoms at Week 12 (8 
weeks of placebo + 4 weeks of ligelizumab treatment vs. 12 weeks of placebo). 
The odds of developing less severe level of symptoms for the endpoint, defined as maximum 
severity of symptoms occurring at any challenge dose of peanut protein up to and including 
1000 mg during the DBPCFC conducted at Week 12, will be analyzed with a proportional odds 
model, including treatment, age subgroup (6-11 years, 12-17 years, 18-55 years), region as fixed 
class effects and log-transformed baseline total IgE at screening as a covariate. 
2.6.3 
Handling of missing values not related to intercurrent events 
Handling of intercurrent events associated with key secondary objectives are described in the 
Section 1.2.2. The missing data not related to intercurrent events for key secondary will be 
imputed based on the missing at random (MAR) assumption. The details of the imputation 
method are mentioned in Section 5.4.1. 
2.6.4 
Other secondary endpoint analyses 
Secondary endpoints which are not part of the testing strategy include: 
• Proportion of participants tolerating a single dose of ≥ 1000 mg (2044 mg cumulative 
tolerated dose) of peanut protein without dose-limiting symptoms during DBPCFC 
conducted at Week 52 
Number and percentage of responders at Week 52 will be summarized by treatment group in 
overall population. Number and percentage of responders at Week 52 may also be summarized 
by treatment group in the subset of responders at Week 12. Missing data of DBPCFC at Week 
52 will not be imputed. The summary statistics will be provided for observed data. 
• Change in maximum tolerated dose (MTD) of peanut protein without dose-limiting 
symptoms during the DBPCFC at Week 52 compared to Week 12 
MTD  at Week 52 along with changes from baseline and changes from Week 12 will be 
summarized descriptively. Missing data will not be imputed. The summary statistics will be 
provided for observed data. 
• Change from baseline in MTD of peanut protein without dose-limiting symptoms during 
the DBPCFC at Week 12 
An analysis of covariance (ANCOVA) model of change from baseline in log transformed MTD 
at Week 12 DBPCFC will be fit with terms for treatment group, age subgroup (12-17 years, 18-
55 years), log-transformed total IgE at Screening Visit 1, region, and log-transformed MTD at 
baseline. Missing MTD at Week 12 values due to intercurrent events will be imputed by 
screening MTD, and other missing data will be multiply imputed under MAR assumption. If 
model assumptions of homoscedasticity and normality are not met, then the Wilcoxon rank-
sum test may be performed. 
• Change from baseline in peanut-specific IgE and IgG4 at Week 12, Week 16 and Week 52 
Summary statistics, including geometric means and standard deviations, will be presented for 
peanut-specific IgE and IgG4 along with changes from baseline by time point and treatment 
group. The summary statistics will be provided for observed data. Change from baseline in log-


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transformed levels of peanut specific-IgE and peanut specific-IgG4  at Week 12 and Week 16 
will be analyzed using an ANCOVA model with terms for treatment group, age group, region, 
log-transformed total IgE at Screening Visit 1, and log-transformed baseline peanut specific-
IgE or peanut specific-IgG4. Values below the LLOQ or above the ULOQ will be imputed as 
half the LLOQ or as the ULOQ, respectively. 
• Change from baseline (screening) in mean wheal diameters by SPT to peanut at Week 16, 
Week 56 and Week 68 
The mean is the average of wheal orthogonal diameter and wheal longest diameter minus the 
average of the non-missing negative control diameters. In most instances, the negative control 
diameters are 0mm.   
Summary statistics will be presented by treatment group at each visit for: 
• Undiluted peanut SPT 
• Change from baseline in undiluted peanut SPT (mm) 
• Percent change from baseline in undiluted peanut SPT 
• Average across all dilutions 
• Change from baseline across average of all dilutions (mm) 
• Percent change from baseline across average of all dilutions   
The summary statistics will be provided for observed data.  Change from baseline in SPT mean 
wheal diameter at Week 16 will be analyzed using an ANCOVA model with terms for treatment 
group, age subgroup, region, log-transformed total IgE at screening, and baseline mean wheal 
diameter. This analysis will be performed for undiluted peanut SPT and the average across all 
dilutions (i.e. 1/100000, 1/10000, 1/1000, 1/100, 1/10, and undiluted). Note that the undiluted 
values are included in the average across all dilutions.  
The analyses of PRO endpoints are described in Section 2.10. 
2.7 
Safety analyses 
All safety endpoints (i.e. AEs, laboratory data, vital signs, and ECG) will be summarized by 
treatment for all participants on the safety set. In addition, subgroup analysis by age (12-17 
years, 18-55 years) will be evaluated for most of the safety endpoints listed in this section. The 
safety analyses will be performed by the treatment groups for the three pooling periods as 
described in Section 2.1.1.1, unless otherwise specified. 
2.7.1 
Adverse events (AEs) 
Unless otherwise specified, summaries will include treatment-emergent adverse events (TEAEs) 
only. Treatment emergent adverse events are defined as events started after the first dose of 
study treatment and within 16 weeks after the last study treatment, or events present prior to the 
first dose of study treatment but increased in severity based on preferred term within 16 weeks 
after the last study treatment. All events that the investigator classifies as reactions associated 
to the DBPCFC or SPT will not be included in reporting of treatment-emergent AEs and may 
be reported separately. The number and percentage (with exact binomial 95% CIs) of 
participants with TEAEs will be summarized in the following ways: 


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• by treatment, primary system organ class and preferred term. 
• by treatment, primary system organ class, preferred term and maximum severity. 
• by treatment, Standardized MedDRA Query (SMQ) and preferred term. 
Separate summaries will be provided for study treatment-related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation and TEAEs with 
potential cause of accidental exposure or ingestion. If a participant reported more than one AE 
with the same preferred term, the AE with the greatest severity will be presented. If a participant 
reported more than one AE within the same primary system organ class, the participant will be 
counted only once with the greatest severity at the system organ class level, where applicable. 
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on TEAEs 
which are not SAEs with an incidence greater than a certain threshold based on the final 
database and on TESAEs and SAEs suspected to be related to study treatment will be provided 
by system organ class and PT on the safety set population. 
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT: 
a. a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE 
b. more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE 
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non-SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE. 
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. 
2.7.1.1 
Exposure-Adjusted Incidence Rate 
The crude incidence rate is defined as the percentage of participants with a specific adverse 
event divided by the total number of participants in each study group. 
Due to expected differences in exposure and follow-up due to varied duration of study 
participation between participants, adverse event incidence rates will be provided as “exposure 
adjusted AE incidence rates” in addition to the crude incidence.  
The EAIR is defined as the number of participants with a specific event divided by the total 
exposure-time among the participants in the study group. That is, the EAIR is calculated as: 
𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸= n / 𝛴𝛴 ti , where n is the number of participants having the ith type event, and ti is a 
participant's exposure time and defined as the shortest of the following: 
1. time to the first episode of the ith type event (if the event occurs), 
2. time to the end of observation period, or 
3. duration of study treatment plus the 16-week washout period (approximately 
corresponding to five half-lives) after last treatment dose 


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The total exposure time of all participants in a treatment group is 𝛴𝛴 ti. The EAIR is interpreted 
as the number of events occurring in a population per unit time. The exact Poisson 95% 
confidence interval for the EAIR will be provided as well, where an exact 100*(1-α)% 
confidence interval will be derived as follows (Garwood 1936, Sahai and Khurshid 1993): 
• 
Lower confidence limit 𝐿𝐿=
0.5𝐶𝐶𝛼𝛼/2,2𝑛𝑛
∑𝑡𝑡𝑖𝑖
  for n>0, 0 otherwise,  
• 
Upper confidence limit 𝑈𝑈=
0.5𝐶𝐶1−𝛼𝛼/2,2𝑛𝑛+2
∑𝑡𝑡𝑖𝑖
, 
where 𝐶𝐶𝛼𝛼,𝑘𝑘 is the αth quantile of the Chi-square distribution with k degrees of freedom. 
Whenever applicable, exposure adjusted incidence rates will be provided for the type as below: 
1. 
TEAE: Primary SOC level, PT level 
2.7.1.2 
Adverse events of special interest / grouping of AEs 
AEs of special interest (AESI) are defined in the latest version of the compound electronic Case 
Retrieval Strategy (eCRS). The classification reflects the safety topics of interest identified in 
the current version of the QGE031 Development Safety Profiling Plan and may be updated 
based on review of accumulating data. The number and percentage of participants with 
treatment emergent AEs of special interest will be summarized by risk category, PT and 
treatment. The search criteria in the latest eCRS corresponding the MedDRA version at the 
database lock will be used and reported in the CSR: 
• Hypersensitivity reactions (including anaphylaxis) 
• Cardiovascular and Cerebrovascular (CCV) events 
• Neoplastic conditions 
• Injection site reactions 
• Serum Sickness 
• Eosinophilic Conditions / Churg-Strauss Syndrome 
• Parasitic (Helminthic) infections 
• Thrombocytopenia 
Injection Site Reactions 
For treatment emergent injection site reactions (ISR), besides the overall summary table for 
AESI, number of participants with recurrence of ISR (single ISR, 2-3 ISRs, > 3 ISRs) will be 
summarized by treatment. 
Adjudicated AEs 
From the AESIs listed above, the following AEs will be adjudicated by the independent 
committee. The adjudicated events will be listed, and a summary table may be provided 
following the adjudication. 
• Anaphylaxis 
• Cardiovascular and Cerebrovascular (CCV) events 
• Neoplastic conditions 


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In addition, summaries will be provided by subgroups of age and allergy status (mono-
sensitized and poly-sensitized).  
2.7.2 
Deaths 
The number of deaths resulting from TEAEs will be summarized by SOC and PT. All the deaths 
in the clinical database including those occurring during screening will be listed. 
2.7.3 
Laboratory data 
The descriptive summary statistics (mean (95% CI), median, first and third quartiles, minimum 
and maximum) for change from baseline to each study visit and maximum/minimum value will 
be presented. These descriptive summaries will be presented by test group, laboratory test and 
treatment group. Change from baseline will only be summarized for participants with both 
baseline and post baseline values for quantitative parameters, and the maximum/minimum 
value could come from post-baseline scheduled, unscheduled or premature discontinuation 
visits. For categorical parameters, frequencies by categories at each visit will be summarized. 
The laboratory values below Lower Level of Quantification (LLOQ) or above Upper Level 
of  Quantification (ULOQ)  will be imputed as LLOQ or ULOQ in the summary tables, 
respectively. The numerical part of the reported result will be treated as the actual LLOQ or 
ULOQ. These laboratory values will be displayed in listings using the standard unit with the 
reported sign (“<” or “>”).  
For selected laboratory parameters, abnormalities occurring at any time-point from scheduled, 
unscheduled and premature discontinuation visits considering all post-baseline on-treatment 
data will be summarized. Where normal ranges are available, abnormalities in laboratory data 
may be listed by, participant, and visit/time. 
The number of participants with worsening abnormality during the study will be summarized 
by treatment. A case is considered as worsening abnormality if the value at baseline and at least 
one post-baseline value during the study is worse than baseline.  
2.7.4 
Other safety data 
2.7.4.1 
ECG  
Summary statistics (absolute values and change from baseline) for all ECG parameters will be 
provided by treatment and time point; Participants with notable abnormalities in ECG data will 
be listed by treatment group and visit/time. The following will be considered as notable values 
for adults: QT > 500 msec; QTcF > 450 msec (males), QTcF > 460 msec (females); PR > 250 
msec. The following will be considered as notable ECG values for adolescents: QTcF >450 
msec (males), QTcF >460 msec (females); PR >250 msec. 
For ECG parameters, the number and percentage of patients with worsening abnormalities 
occurring post-baseline will be summarized using shift table by treatment group. The definition 
worsening is the same as laboratory values.  


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2.7.4.2 
Vital signs 
Summary statistics will be provided by vital sign, treatment group and visit/time as appropriate. 
Change from baseline will only be summarized for participants with both baseline and post-
baseline values. Participants with notable vital signs as defined below will be listed. 
For adults: 
• Hypertension (systolic blood pressure of ≥ 140 mmHg and/or diastolic blood pressure of ≥ 
90 mmHg) or hypotension (systolic blood pressure of < 90 mmHg and/or diastolic blood 
pressure of < 60 mmHg) 
• Pulse rate below 60 bpm (bradycardia) or above 100 bpm (tachycardia) 
For adolescents: 
See Section 5.3 for upper and lower limits for vital signs. 
 
 


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2.10 
Patient-reported outcomes 
2.10.1 
Patient-reported outcome assessments 
PRO data will be analyzed in accordance with the secondary endpoint described in Section 1.2. 
The following measures are being administered based on age group and responder type: 
• FAQLQ-CF: Food Allergy Quality of Life Questionnaire – Child Form (completed by 
children aged 8-12) 
• FAIM-CF: Food Allergy Independent Measure – Child Form (completed by children aged 
8-12) 
• FAQLQ-TF: Food Allergy Quality of Life Questionnaire – Teenager Form (completed by 
adolescents aged 13-17) 
• FAIM-TF: Food Allergy Independent Measure – Teenager Form (completed by 
adolescents aged 13-17) 
• FAQLQ-AF: Food Allergy Quality of Life Questionnaire – Adult Form (completed by 
adults aged 18-55) 
• FAIM-AF: Food Allergy Independent Measure – Adult Form (completed by adults aged 
18-55) 
• FAQLQ-PF: Food Allergy Quality of Life Questionnaire – Parental Form (completed by 
same parent/caregiver of children aged 0-12) 
• FAQL-PB: Food Allergy Quality of Life – Parental Burden Questionnaire (completed by 
same parent/caregiver of children aged 0-17) 


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• SF-36v2 Acute Version – Medical Outcomes Study 36-Item Short Form Version 2 Acute 
Version (recall period is past week) (completed by adults aged 18-55) 
Table 2-1 
Administration of questionnaires according to participant age. 
Age Group / 
Respondent 
Type 
Questionnaire 
Day 1 
Randomization 
Week 12 
(10 Days 
Before D1 
OFC) 
Week 12 
(3 Days 
After D2 
OFC) 
Week 52 
(10 Days 
Before D1 
OFC) 
Week 52 
(3 Days 
After D2 
OFC) 
Children aged 
12 
FAQLQ-CF 
x 
x 
x 
x 
x 
FAIM-CF 
x 
x 
x 
x 
x 
Teenagers 
aged 13-17 
FAQLQ-TF 
x 
x 
x 
x 
x 
FAIM-TF 
x 
x 
x 
x 
x 
Adults aged 
18+ 
FAQLQ-AF 
x 
x 
x 
x 
x 
FAIM-AF 
x 
x 
x 
x 
x 
SF-36v2 
x 
 
x 
 
x 
Parents/ 
Caregivers of 
Children aged 
13-17   
FAQL-PB 
x 
x 
x 
x 
x 
Parents/ 
Caregivers of 
Children aged 
12 
FAQLQ-PF 
x 
x 
x 
x 
x 
The Food Allergy Quality of Life Questionnaire (FAQLQ) is a self-reported instrument 
intended to assess the effect of food allergy on the participant’s health-related quality of life 
(HRQoL. The FAQLQ-CF (aged 8-12) (Flokstra – de Blok, DunnGalvin et al. 2009), FAQLQ-
TF (aged 13-17) (Flokstra – de Blok, DunnGalvin et al. 2008) and FAQLQ-AF (≥18 years of 
age) (Flokstra-de Blok, van der Meulen et al. 2009) are self-administered, validated food 
allergy-specifc HRQoL questionnaires. The FAQLQ-PF is completed by parents of children 
aged 0 - 12 with food allergy (DunnGalvin, de BlokFlokstra et al. 2008).  
Scoring of PRO Instruments 
The number of items and domains varies by FAQLQ instrument administered. Each question is 
scored on a 7-point scale (coded as 1-7 in analysis, with a higher level indicating greater 
impairment in HRQoL). The total score is the arithmetic average of all completed items. 
Domain scores are calculated similarly for each form as following: 
FAQLQ-CF: Emotional impact (EI) (item no. 19-24), Allergen avoidance (AA) (item no. 4, 6-
10, 15), Risk of accidental exposure (RAE) (item no. 11, 13, 14, 16, 17), Dietary restriction 
(DR) (item no. 1-3, 5, 12, 18) 
FAQLQ-TF: Emotional impact (EI) (item no. 5, 12, 19-23), Allergen avoidance and dietary 
restrictions (AADR) (item no. 1-4, 6-10, 16), Risk of accidental exposure (RAE) (item no. 11, 
13-15, 17, 18) 
FAQLQ-AF: Emotional impact (EI) (item no. 5, 24-29), Allergen avoidance and dietary 
restrictions (AADR) (item no. 1-4, 6, 8-12, 20), Risk of Accidental Exposure (RAE) (item no. 
7, 13-18, 21), Food allergy related health (FAH) (item no. 19, 22, 23) 


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FAQLQ-PF: Emotional impact (EI) (item no. 2, 6, 7, 9-11, 23-28, 30), Food anxiety (FA) (item 
no. 1, 4, 5, 16, 17, 20, 21, 29), Social and dietary limitations (SDL) (item no. 3, 8, 12-15, 18, 
19, 22).  
If more than one item in any domain is missing, a domain score should not be calculated for 
that case.  A total score can still be calculated if 20% or fewer of the items are missing.  
The FAIM reflects the participant’s perceived food allergy severity and food allergy-related 
risk (van der Velde, Flokstra-de Blok et al. 2010). Each question is scored on a 7-point scale 
(coded as 1-7 in analysis, with a greater score indicating a higher level of perceived risk or 
chance of adverse events occurring). The total score is the arithmetic average of all completed 
items. If less than 80% of the items within the score are complete, it will not be calculated. 
Questions 4 and 5 (effectively managing a reaction, receiving sufficient help from others) must 
be reverse coded. 
A threshold of 0.45 points has been suggested and used as a minimal important difference (MID) 
to interpret clinical relevance (Dunn Galvin, Cullinane et al. 2010). For FAQLQ and FAIM 
forms, the 0.45 threshold will be used to interpret the clinical relevance of group-level 
differences and changes, in addition to within-patient changes. 
The FAQL-PB is a self-administered, disease-specific instrument developed to measure the 
effect of pediatric food allergy on HRQoL for caregivers (Cohen, Noone et al. 2004). The 
instrument includes 17 items (assessing social, dietary and emotional impacts) on the impact of 
having a child with food allergy on the parents themselves  using a 7-point Likert scale ranging 
from 0 (not limited/troubled) to 6 (extremely limited/troubled). The total score is the arithmetic 
average of all completed items. 
The SF-36v2® Health Survey is a 36-item instrument that measures generic health-related 
quality of life. It is designed for use in surveys of general and specific populations, health policy 
evaluations and clinical practice and research.  Two forms of this instrument are available and 
this study will use the one-week recall (acute) form. The SF-36v2 contains 8 scales and 2 
component summary indices evaluating physical, social and emotional functioning in addition 
to general health perceptions and mental health.. Responses to items allow for direct calculation 
of scale scores, while the physical component summary (PCS) and mental component summary 
(MCS) scores are computed from weighted scale scores. The SF-36v2 scale and composite 
scores can be converted to a T-score metric, allowing for norm-based scores derived from 
responses to a 2009 survey conducted by QualityMetric.4 For all scales and summary measures, 
higher scores indicate better health outcomes.  
The SF-6Dv2 will be derived from the SF-36v2 for health economic evaluations (Brazier, 
Mulhern et al. 2020). The SF-6Dv2 captures the impact of diseases and conditions on social 
activities and depression/nervousness. The SF-6Dv2 questionnaire uses a standardized health 
state descriptive system consisting of 6 dimensions, including social limitations, which was 
deemed essential to cover in food allergy. All dimensions are expressed over 5 levels, except 
for pain, which uses 6 levels, allowing for the description of 18,750 different health states. 
Health states are described using a combination of 6 digits each expressing the level for a 
dimension. For example, state “111111” indicates perfect health and state “555655” indicates 
the worst possible health status. The resulting SF-6Dv2 index, scored from 0.0 (worst health 


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state) to 1.0 (best health state), can be used in the assessment of the quality adjusted life years 
(QALYs) and the cost-effectiveness of various health care interventions. 
2.10.1.1 
Patient-reported outcome analysis 
All PRO scores will be summarized descriptively at Day 1, before and after the DBPCFC at 
Week 12 and Week 52 by treatment. Tabular summaries will present continuous PRO total and 
domain scores, plus change from baseline scores, as per Section 2.11.1. Summaries for change 
from baseline in FAQLQ and FAIM domain and total scores at Week 12 (before and after the 
DBPCFC) will also be provided by response status and treatment during DBPCFC at Week 12 
(Responder/Non-responder at 600 mg of peanut protein). Change from baseline in SF-6Dv2 
social function and mental health dimensions at Week 12 will be summarized by response status 
and treatment.   
Change from baseline after Week 12 OFC Day 2 in FAQLQ and FAIM total scores will be 
analyzed using ANCOVA models with treatment group and region as fixed effects, and log-
transformed total IgE at screening as well as respective PRO baseline value as covariates. Least 
Squares Mean differences, corresponding 95% CIs and p-values will be presented. All p-values 
presented from PRO inferential analyses are unadjusted and should be used to aid interpretation 
of the data only. Change from baseline before Week 12 OFC Day 1 in FAQLQ and FAIM total 
scores will be analyzed in a similar fashion. 
All analyses will be performed on the FAS using observed data with no imputation of missing 
data.  
2.11 
Biomarkers  
Peanut-specific IgE and IgG4 and SPT are analyzed as other secondary endpoints and 
described in Section 2.6.2.
 
 
 
 
Additional details will be provided in a separate analysis plan targeting the analyses of 
biomarkers. 
 
 
 
 
 
2.13 
Interim analysis 
There will be two analyses before the final database lock, in addition to the DMC analyses as 
described below. 
Interim Analysis: 


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At the start of the study, recruitment will be restricted to 12-55 year old participants. When 
approximately 60 adolescent participants (defined as 12 -17 years of age) have completed all 
week 12 assessments, an interim analysis on 
safety 
 data 
 
 will be performed (Section 2.9). Safety data (semi-blinded or unblinded) 
will only be generated for DMC review. 
 
 
 
Primary Analysis at Week 12: 
The Primary Analysis will be performed once all participants have reached Week 12 in the 
study and completed its assessments or prematurely withdrawn from the study prior to Week 
12. Formal testing of primary and key secondary endpoints will be performed according to 
testing strategy specified in Figure 2-1 with full alpha. Since the primary and key secondary 
objectives will be performed only for the Primary Analysis, adjustment to the overall type I 
error rate is not required. In addition, a Dose-Exposure-Response model to describe the 
responder rate and the factors impacting the response will be developed. 
Table 2-2 provides the list of results that may be presented for the Primary Analysis at Week 
12.  
Table 2-2 
Results presented at the Primary Analysis  
Category 
Analysis Description 
OFC 
Effect of 12 weeks of Ligelizumab: Analysis of the Proportion of Participants who 
Tolerated a Single Dose of >= 600 mg of Peanut Protein without Dose-Limiting Symptoms 
during DBPCFC at Week 12 using Logistic Regression Model (Full Analysis Set) 
OFC 
Effect of 12 weeks of Ligelizumab: Analysis of the Proportion of Participants who 
Tolerated a Single Dose of >= 1000 mg of Peanut Protein without Dose-Limiting 
Symptoms during DBPCFC at Week 12 using Logistic Regression Model (Full Analysis 
Set) 
OFC 
Effect of 12 weeks of Ligelizumab: Analysis of the Proportion of Participants who 
Tolerated a Single Dose of 3000 mg of Peanut Protein without Dose-Limiting Symptoms 
during DBPCFC at Week 12 using Logistic Regression Model (Full Analysis Set) 
OFC 
Effect of 4 weeks of Ligelizumab: Analysis of the Proportion of Participants who Tolerated 
a Single Dose of >= 1000 mg of Peanut Protein without Dose-Limiting Symptoms during 
DBPCFC at Week 12 (Full Analysis Set) 
OFC 
Summary of Proportion of Participants who Tolerated at Least the Single Dose of >=600 
mg Peanut Protein without Dose-Limiting Symptoms during DBPCFC at Week 12 (Full 
Analysis Set) 
OFC 
Proportion of Participants who Tolerated a Single Dose of >= 600 mg of Peanut Protein 
without Dose-Limiting Symptoms during DBPCFC at Week 12 by Timing of Study 
Termination Notice (Full Analysis Set) 
OFC 
Marginal Proportion of Participants who Tolerated a Single Dose of >= 600 mg of Peanut 
Protein without Dose-Limiting Symptoms during DBPCFC at Week 12 (Full Analysis Set) 
OFC 
Odds of Participants Developing Less Severe Level of Symptoms Evaluated by Maximum 
Severity of Symptoms at Any Challenge Dose of Peanut Protein up to and including 1000 
mg during the DBPCFC Conducted at Week 12 (Full Analysis Set) 


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SPT 
Summary of Skin Prick Test (undiluted peanut protein) and change from baseline by 
treatment group and across visits 
SPT 
Summary of Skin Prick Test (average dilutions peanut protein) and change from baseline 
by treatment group and across visits 
PRO 
FAQLQ-PF: Food Allergy Quality of Life Questionnaire – Parental Form (completed by 
parents of children aged 12) 
PRO 
FAQLQ-TF: Food Allergy Quality of Life Questionnaire – Teenager Form (completed by 
adolescents aged 13-17) 
PRO 
FAIM-TF: Food Allergy Independent Measure – Teenage Form (completed by 
adolescents aged 13-17)) 
PRO 
FAQLQ-AF: Food Allergy Quality of Life Questionnaire – Adult Form (completed by adults 
aged 18-55) 
PRO 
FAIM-AF: Food Allergy Independent Measure – Adult Form (completed by adults aged 
18-55) 
Adverse Event 
Number of adverse events due to Accidental Exposure (plus respective listing) 
Event 
Use of Epinephrine During and Outside of OFC 
Safety 
Overview of Treatment Emergent Adverse Events (Safety Set) 
Safety 
Exposure-adjusted TEAE tables for the entire population (Safety Set) 
Listing 
Deaths and SAEs by system organ class and preferred term (plus respective listing) 
Safety 
Treatment-emergent SAEs by primary system organ class 
Safety 
Treatment-emergent SAEs by preferred term (plus respective listing) 
Safety 
TEAEs by primary system organ class 
Safety 
TEAEs, by preferred term (plus respective listing) 
Safety 
TEAEs by preferred term and maximum severity  
Safety 
TEAEs leading to discontinuation by primary system organ class 
Safety 
TEAEs leading to discontinuation by preferred term (plus respective listing) 
Safety 
Treatment-emergent Adverse Events of Special Interest (AESI), by standardized 
MedDRA term  (plus respective listing) 
Safety 
Number of AEs (n, %) 
Safety 
Newly occurring or worsening chemistry and hematology abnormalities (plus respective 
listing) 
Safety 
Newly occurring or worsening vital sign abnormalities (plus respective listing) 
Safety 
Adverse events for screen failures 
Safety 
Number of Subjects with Adjudicated Anaphylaxis Events (Safety Set) (plus respective 
listing) 
Safety 
Number of Subjects with Adjudicated CCV Events (Safety Set) (plus respective listing) 
Safety 
Number of Subjects with Adjudicated Neoplastic Events (Safety Set) (plus respective 
listing) 
Safety 
Number of AEs requiring Epinephrine treatment (n, %) 
Disposition 
Participant Disposition at Treatment Period (Randomized Set) 
Set 
Analysis Sets (Randomized Set) 
Baseline 
Subject Demographics (Randomized Set) 
Baseline 
Subject Baseline Characteristics (Randomized Set) 
 


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In addition, the following analyses will be presented.  
 
DMC analyses: 
The DMC will assess, at defined intervals, the progress of a clinical trial, safety data, and critical 
efficacy variables and recommend to the sponsor whether to continue, modify, or terminate a 
trial, as defined in the DMC charter. Analysis of selected efficacy variables will be provided 
only for the purpose of helping for safety evaluation. Such assessments do not inflate the Type 
I error for the primary efficacy hypothesis testing and thus no adjustment for multiplicity is 
required. 
3 
Sample size calculation 
A total sample size of approximately 486 randomized participants is originally planned to 
achieve sufficient power for the primary and key secondary endpoints, and it provides adequate 
precision in estimating AE rates in this study. Due to the halt of recruitment, the sample size is 
now 211. This reduced sample size provides sufficient power for the primary endpoint.  
Participants will receive one of three treatments (ligelizumab 240mg SCq4w, ligelizumab 
120mg SCq4w, or placebo SCq4w) and will be randomized into five treatment arms with a ratio 
2:2:2:2:1. At the start of the study, recruitment was restricted to participants 12-55 years 
old. Due to the recruitment halt, no other age groups were recruited. 
3.1 
Primary endpoint(s) 
The primary objective is to demonstrate that ligelizumab doses are superior to placebo in 
responder rate at a level of 600 mg peanut protein (1044 mg cumulative tolerated dose) after 12 
weeks of treatment. 
The responder rate at 600 mg dose of peanut protein in placebo and ligelizumab groups have 
been assumed approximately 20% and at least 80%, respectively, for participants with evaluable 
DBPCFC at Week 12. These assumptions are considered highly clinically relevant based on the 
PALISADE trial conducted in similar populations (Vickery et al 2018). In the PALISADE trial, 
the responder rate at 600 mg single challenge dose of peanut protein in placebo and AR101 
were 4.3% (95% CI: 1.9%, 9.7%) and 84.5% (95% CI: 79.9%, 88.1%), respectively. 
Approximately 15% of participants were assumed to discontinue treatment before week 12 and 
will be considered non-responders in power calculations. Therefore, the responder rate at 600 
mg single dose of peanut protein in placebo and ligelizumab were assumed 17% and 68%, 
respectively, for randomized participants. For the purpose of evaluating the power for the 
primary trial objectives, it was assumed that none of the secondary null hypotheses would be 
rejected and the full alpha level of 0.025 (one-sided) would be equally split across the primary 


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hypotheses for each dose (i.e., 0.0125 one-sided for each testing). Under the outlined 
assumptions, a two group Fisher’s exact test with a 0.0125 one-sided significance level will 
have above 99% power to detect the difference of responder rate between each ligelizumab 
group and placebo, when the sample size is 108 participants on each ligelizumab dose and 54 
participants on placebo. Due to halt of recruitment, the sample size is expected to be around 
211 (around 46 participants on each ligelizumab dose and 23 participants on placebo). This 
reduced sample size provides 96% power to detect the difference of responder rate between 
each ligelizumab group and placebo at a 0.0125 one-sided significance level. These power 
calculations are an approximation of the power achieved with the logistic regression approach. 
The table below shows the sensitivity of the power to deviations from the assumptions.   
Table 3-1 
Sensitivity of the power for each dose for the primary variable 
RR in each 
QGE031 
group with 
evaluable 
DBPCFC at 
Week 12 
RR in placebo 
group with 
evaluable 
DBPCFC at 
Week 12 
Drop-
out 
rate 
RR in 
each 
QGE031 
group 
RR in 
placebo 
group 
Sample 
size in 
each 
QGE031 
group 
Sample 
size in 
placebo 
Power 
80% 
20% 
15% 
68% 
17% 
108 
54 
>99.9% 
80% 
20% 
15% 
68% 
17% 
46 
23 
96% 
70% 
20% 
15% 
59.5% 
17% 
108 
54 
99.8% 
70% 
20% 
15% 
59.5% 
17% 
46 
23 
86% 
RR = responder rate. Approximately 15% of participants were assumed to discontinue treatment 
before week 12 and be considered as non-responders in power calculations. 
Power results were calculated with PASS version 11. 
3.2 
Secondary endpoint(s) 
If statistical significance is achieved in the primary test, the tests for the key secondary variables 
included in the testing strategy will be performed. The local significance level for each key 
secondary null hypothesis will be determined based on the closed testing procedure shown in 
Figure 2-1. 
Assuming a treatment discontinuation rate of 15% before week 12 and responder rates in each 
treatment group as shown in the table below, the local power (unconditional) of each hypothesis 
was estimated using 10,000 simulations with package gMCP in R 3.6.1. The assumption for 
maximum severity of symptoms is based on the PALISADE trial conducted in similar 
populations (Vickery et al 2018). The hypothesized response to 4 weeks of ligelizumab is 
supported by results reported in Savage et al 2012 
 
. According to Savage et al 2012, omalizumab 
increased the median tolerated threshold dose of peanut protein from 80 mg at baseline to 6500 
mg at Week 5 approximately. The underlying distribution of difference in responder rate 
between ligelizumab and placebo is assumed to be multivariate normal in power simulations. 
To be conservative, correlation between endpoints was ignored for power simulation. The 
originally proposed sample size of 486 ensured sufficient power for primary and key secondary 
endpoints.  


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Table 3-2 
Power of each dose for the analyses of primary and key secondary 
variables in the base case scenario 
Variable 
Assumptions of treatment effect 
Local power 
(unconditional) 
  
QGE031 
240 mg 
QGE031 
120 mg  
Pbo 
QGE031 240 
mg 
QGE031 120 
mg  
RR of tolerating 600 mg 
peanut protein 
RR* (RR in 
rand) 
80% 
(68%) 
80% 
(68%) 
20% 
(17%) 
>99.9% 
>99.9% 
RR of tolerating 1000 mg 
peanut protein 
RR* (RR in 
rand) 
70% 
(59.5%) 
70% 
(59.5%) 
20% 
(17%) 
>99.9% 
>99.9% 
RR of tolerating 3000 mg 
peanut protein 
RR* (RR in 
rand) 
60% 
(51%) 
60% 
(51%) 
15% 
(12.75%) 
>99.9% 
>99.9% 
Maximum severity of 
symptoms at any 
challenge dose up to and 
including 1000 mg# 
% None 
38% 
38% 
2% 
>99.9% 
>99.9% 
% Mild 
32% 
32% 
28% 
% Moderate 
25% 
25% 
59% 
% Severe 
5% 
5% 
11% 
RR of tolerating 1000 mg 
peanut protein with 4 
weeks of ligelizumab 
treatment 
RR^ 
50% 
45% 
20% 
98.3% 
93.0% 
RR=responder rate; Pbo=placebo; The proposed number of participants for comparisons between ligelizumab 
and placebo are 108 in each ligelizumab arm and 54 in placebo arm. 
*RR is based on the anticipated proportion of responders in participants with evaluable DBPCFC at Week 12. 
Approximately 15% of participants are assumed to discontinue treatment before week 12 and considered non-
responders for randomized population in power calculation (RR in rand). #For maximum severity of symptoms, 
the assumed proportion of participants in each category is based on randomized population. Power 
calculations were performed in R 3.6.1 with package gMCP. 
^RR is based on the anticipated proportion of responders in participants with evaluable DBPCFC at Week 
12. Same treatment effect is expected for randomized population in power calculation, assuming participants 
had taken study treatment at Week 8 and conducted DBPCFC at Week 12. 
3.2.1 
Precision for adverse events 
Table 3-3 
Precision levels (95% CI) for sensitivity of safety incidence rate for 
overall population 
Event rate (proportion of participants with an event) 
Number of participants 
95% CI 
0% 
486 
(0%, 0.8%) 
1% 
486 
(0.3%, 2.3%) 
2% 
486 
(1%, 3.7%) 
0% 
211 
(0%, 1.7%) 
1% 
211 
(0.1%, 3.5%) 
2% 
211 
(0.6%, 4.9%) 
4 
Change to protocol specified analyses 
On 31 March 2023, Novartis made a strategic decision to close recruitment in study 
CQGE031G12301 and terminate the study early. As a result, there are several changes to the 
specified analyses in the protocol, namely: 
• Instead of 486 participants, the sample size is 211. 


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• There will be no recruitment of children under age 12, and the age-groups of interest are 
now 12-17 and 18-55.  
• For participants who have reached Screening Visit 2 Part 1 and not completed Week 52 visit 
at the time of halt recruitment will need to complete Screening Visit 2 Part 2 to determine 
eligibility. If they are eligible, they will either continue treatment and perform assessments 
until Week 12 Part 2 or will stop treatment at the next scheduled visit if they have already 
completed Week 12 Part 2.  This leads to limited number of participants reaching Week 52. 
Hence, non-inferiority test for sustainability of treatment effect at Week 52 compared to 
Week 12 is removed.  
• Week 52 interim analysis will not be conducted.  
There are also some changes made to simplify the analyses: 
• Since the number of COVID-19 related intercurrent events is expected to be minimal, 
references to COVID-19 related intercurrent events were removed. 
• Handling of intercurrent events for the secondary estimands were changed to be consistent 
with the primary estimand strategy. 
• The two-dimensional tipping point analysis for the primary estimand was removed. 
In analysis for primary estimand and secondary estimands( 1, 2 and 4), log-transformed MTD 
at screening DBPCFC was added as covariate in logistic regression models.  
The protocol mentions the summary measure of supplementary estimand is relative risk 
generated with a marginal standardization method. In SAP, relative risk is changed to risk 
difference to facilitate clinical interpretation. 


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5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Study drug 
No imputation of missing/partial start or end study drug date. If missing, the time of study end 
date will be imputed to 00:00:00. 
5.1.2 
AE date imputation 
Rules for imputing the AE end date: 
• If the AE end date month is missing, then the imputed end date should be set to the earliest 
of the study end date, 31DECYYYY or date of death. 
• If the AE end date day is missing, then the imputed end date should be set to the earliest of 
the study end date, last day of the month or date of death. 
• If AE year is missing or AE is ongoing, then the end date will not be imputed. 
Rules for imputing the AE start date: 
1. If imputing end dates, then this should be done prior to calculating imputed start dates. 
Before imputing AE start date, find the AE start reference date.  
• If the (imputed) AE end date is complete and the (imputed) AE end date < treatment start 
date, then AE start reference date = min(informed consent date, earliest visit date). 
• Otherwise, AE start reference date = treatment start date. 
Impute AE start date:  
• If the AE start date year value is missing, then the date uncertainty is too high to impute a 
rational date.  Therefore, if the AE year value is missing, then the imputed AE start date is 
set to NULL. 
• If the AE start date year value is less than the treatment start date year value, then the AE 
started before treatment.  Therefore: 
• If AE month is missing, then the imputed AE start date is set to the mid-year point 
(01JulYYYY). 
• Otherwise, if AE month is not missing, then the imputed AE start date is set to the 
mid-month point (15MONYYYY). 
• If the AE start date year value is greater than the treatment start date year value, then the 
AE started after treatment.  Therefore: 
• If the AE month is missing, then the imputed AE start date is set to the year start point 
(01JanYYYY). 
• Otherwise, if the AE month is not missing, then the imputed AE start date is set to the 
later of month start point (01MONYYYY) or AE start reference date + 1 day. 
• If the AE start date year value is equal to the treatment start date year value: 


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• If the AE month is missing, then the imputed AE start date is set to the AE reference 
start date + 1 day. 
• If the AE month is less than the treatment start month, then the imputed AE start date 
is set to the mid-month point (15MONYYYY). 
• Otherwise, if the AE month is equal to the treatment start date month or greater than 
the treatment start date month, then the imputed AE start date is set to the later of 
(month start point (01MONYYYY), AE start reference date + 1 day). 
If complete (imputed) AE end date is available and the imputed AE start date is greater than the 
(imputed) AE end date, then imputed AE start date should be set to the (imputed) AE end date. 
5.1.3 
Concomitant medication date imputation 
Rules for imputing the CM end date (including on-going records): 
a. If imputing end dates, this should be done prior to calculating imputed start dates. 
b. When the medication is ongoing at the end of the study, no numeric end date is derived. 
c. If the end date is completely missing no numeric end date is derived.  
1. If CM end day is missing and CM month/year are non-missing, then impute CM date as 
the minimum of study end date and the last day of the month. 
2. If CM end day/month are missing and CM year is non-missing, then impute CM date as 
the minimum of study end date and the end of the year (31DECYYYY). 
3. If imputed CM end date is less than the complete CM start date, use the complete CM start 
date as the imputed CM end date. 
Rules for imputing the CM start date:  
1. If imputing end dates, then this should be done prior to calculating imputed start dates.  
• If the CM start date year value is missing, then the imputed CM start date is set to one day 
prior to Treatment start date (TR01SDT).  
• If the CM start date year value is less than the Treatment start date (TR01SDT) year value, 
then the CM started before treatment.  Therefore; 
• If the CM month is missing, then the imputed CM start date is set to the mid-year 
point (01JulYYYY). 
• Else if the CM month is not missing, then the imputed CM start date is set to the mid-
month point (15MONYYYY). 
• If the CM start date year value is greater than the Treatment start date (TR01SDT) year 
value, the CM started after treatment. Therefore; 
• If the CM month is missing, then the imputed CM start date is set to the year start 
point (01JanYYYY). 
• Else if the CM month is not missing, then the imputed CM start date is set to the 
month start point (01MONYYYY). 
• If the CM start date year value is equal to the Treatment start date (TR01SDT) year value; 
• And the CM month is missing or the CM month is equal to the Treatment start date 
(TR01SDT) month, then the imputed CM start date is set to one day prior  Treatment 
start date (TR01SDT). 


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• Else if the CM month is less than the Treatment start date (TR01SDT) month, then the 
imputed CM start date is set to the mid-month point (15MONYYYY). 
• Else if the CM month is greater than the Treatment start date (TR01SDT) month, then 
the imputed CM start date is set to the month start point (01MONYYYY). 
If complete (imputed) CM end date is available and the imputed CM start date is greater than 
the complete (imputed) CM end date, then imputed CM start date should be set to the complete 
(imputed) CM end date. 
If there is no end date and ongoing check is not ticked, the CM will be considered as ongoing 
and included in the summary table. 
5.2 
AEs coding/grading 
The MedDRA version which will be available at the time of database lock, will be used for the 
coding purpose of the adverse events. 
5.3 
Laboratory parameters derivations 
Refer to Section 16.2 of the protocol for clinically notable laboratory values for hepatotoxicity. 
Refer to Section 16.3 of the protocol for clinically notable laboratory values for nephrotoxicity 
The following other specific criteria have been identified for this study: 
• Platelets < 75 000/μL 
• Any participant who has platelets < 75 000/μL after being randomized should discontinue 
study treatment. 
For all other laboratory assessments, the Central Laboratory will flag laboratory values falling 
outside of the normal ranges on the Central Laboratory Report (which the investigator should 
review and sign-off) and the investigator will report any values considered clinically significant 
in the CRF. 
Vital signs 
Notable values for vital signs for adults are: 
• heart rate of < 60 and > 100 bpm 
• systolic blood pressure of < 90 and ≥ 140 mmHg 
• diastolic blood pressure of < 60 and ≥ 90 mmHg 
For participants aged 12 and older, the notable values are described in Table 5-1: 
Table 5-1 
Notable values requiring further evaluation for Heart Rate (HR) and 
Blood Pressure in children and adolescents 
Age (years) 
HR (bpm) 
Blood Pressure (mmHg) 
Low 
High 
Systolic 
Diastolic 
12 
< 67 
> 103 
>= 114 for girls (>= 113 for boys) 
>= 75 
13 or 14 
< 62 
> 96 
>= 120 
>= 80 
15 to 17 
< 58 
> 92 
>= 120 
>= 80 


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Heart Rate (HR) Adapted from Fleming et al 2011; Blood Pressure (BP) adapted from 
Flynn 2017 
 
 


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5.5 
Rule of exclusion criteria of analysis sets  
Table 5-2 
Criteria leading to exclusion 
Analysis Set 
Criteria that cause subjects to be excluded 
RAN 
Not randomized 
FAS 
Not in RAN; 
Mistakenly randomized and no double-blind study drug taken 
SAF 
No double-blind study drug taken 
6 
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