Conditions: Chronic Spontaneous Urticaria
Keywords: Chronic Spontaneous Urticaria Chronic Urticaria Urticaria Chronic Idiopathic Urticaria Chronic Autoimmune Urticaria Idiopathic Chronic Urticaria Autoimmune Urticaria
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 127
Healthy volunteers: no

Brief summary:
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of subcutaneous lirentelimab (AK002) in adult subjects with H-1 antihistamine refractory chronic spontaneous urticaria. Subjects who complete the randomized, double-blind, placebo-controlled treatment period may have the option to enroll in an open-label extension period and receive up to 6 doses of subcutaneous lirentelimab.

Detailed description:

Arms:
arm 1: Subjects in this arm will receive lirentelimab (AK002) administered subcutaneously. arm 2: Placebo

Interventions: intervention 1: Lirentelimab (AK002) intervention 2: Placebo
Intervention descriptions: intervention 1: Lirentelimab (AK002) is a humanized non-fucosylated immunoglobulin G1 (IgG1) monoclonal antibody directed against Siglec-8 intervention 2: Placebo

Protocol document:
Prot_000.pdf: 
A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of Lirentelimab in Adult Subjects with H-1 Antihistamine Refractory 
Chronic Spontaneous Urticaria 
NCT Number: NCT05528861 
Document Date: 22 September 2023 
IRB Approval Date: 22 September 2023 




Protocol AK002-027
Amendment 4
Date: 22 September 2023 
Allakos Inc.
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Confidential
Medical Monitor for 
Germany and Poland
Name:
, MD, PhD
Phone:
Email:
Approval:
, MD, 
Date
Confidentiality Statement
This confidential information about an investigational product is provided for the exclusive use 
of Investigators of this product and is subject to recall at any time. The information in this 
document may not be disclosed unless federal or state law or regulations require such disclosure. 
Subject to the foregoing, this information may be disclosed only to those persons involved in the 
study who have a need to know, with the obligation not to further disseminate this information. 


Protocol AK002-027 
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Date: 22 September 2023  
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Investigator Protocol Agreement
I have read the protocol specified below. In my formal capacity as Principal Investigator, my 
duties include ensuring the safety of the study subjects enrolled under my supervision and 
providing Allakos Inc. with complete and timely information, as outlined in the protocol. It is 
understood that all information pertaining to the study will be held strictly confidential and that 
this confidentiality requirement applies to all study staff at this site. Furthermore, on behalf of 
the study staff and myself, I agree to maintain the procedures required to carry out the study in 
accordance with accepted Good Clinical Practice (GCP) principles, the Declaration of Helsinki 
in the applicable version, and the applicable legal and regulatory requirements, as well as to 
abide by the terms of this protocol. 
Protocol Number:
AK002-027 
IND Number:
137491 
EudraCT Number: 
2022-001847-26 
Protocol Title:
A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled 
Study to Evaluate the Efficacy and Safety of Lirentelimab in Adult Subjects with H-1 
Antihistamine Refractory Chronic Spontaneous Urticaria 
Protocol Amendment 4: 
22 September 2023  
 
 
 
Investigator Printed Name:
Investigator Signature: 
 
Date: 
 


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Table of Contents 
Clinical Research Protocol AK002-027 ........................................................................................1
Investigator Protocol Agreement..................................................................................................3
Table of Contents ...........................................................................................................................4
List of Figures ........................................................................................................................12
List of Tables .........................................................................................................................12
List of Abbreviations .............................................................................................................13
1.
Protocol Synopsis .................................................................................................................17
2.
Background ..........................................................................................................................31
2.1 
Siglec-8 and Lirentelimab .........................................................................................31
2.2 
Overview of Nonclinical Studies ...............................................................................31
2.3 
Overview of Clinical Studies .....................................................................................33
2.4 
Chronic Urticaria .......................................................................................................34
2.5 
Benefit–Risk Assessment ..........................................................................................37
3.
Rationale for Study and Dose Selection .............................................................................38
3.1 
Rationale for Study Design .......................................................................................38
3.2 
Rationale for Dose Selection .....................................................................................39
4.
Study Objectives ..................................................................................................................40
4.1 
Primary Objective and Endpoint ...............................................................................40
4.2 
Secondary Objectives and Endpoints ........................................................................40
4.3 
Exploratory Objectives and Endpoints ......................................................................41
4.4 
Safety Objectives .......................................................................................................41
5.
Study Design .........................................................................................................................42
5.1 
Study Overview .........................................................................................................42
5.2 
Schedule of Events and Study Diagram ....................................................................44


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6.
Estimand Considerations ....................................................................................................50
7.
Criteria for Evaluation ........................................................................................................50
7.1 
Safety Endpoints ........................................................................................................50
7.2 
Pharmacokinetic Endpoints .......................................................................................51
7.2.1 
Primary Efficacy Endpoints ........................................................................51
7.2.2 
Secondary Efficacy Endpoints ....................................................................51
7.2.3 
Exploratory Efficacy Endpoints ..................................................................52
8.
Subject Selection ..................................................................................................................52
8.1 
Number of Subjects ...................................................................................................52
8.2 
Number of Sites .........................................................................................................52
8.3 
Study Population .......................................................................................................53
8.4 
Inclusion Criteria .......................................................................................................53
8.5 
Exclusion Criteria ......................................................................................................54
8.6 
Safety Evaluations .....................................................................................................57
9.
Prior and Concurrent Medications ....................................................................................57
9.1 
Prohibited Medications ..............................................................................................58
9.2
Allowed Medications .................................................................................................59
9.3 
Rescue Medications ...................................................................................................59
10.
Study Treatment ..................................................................................................................60
10.1 
Formulation of Test Product and Placebo .................................................................60
10.2 
Study Drug Packaging and Labeling .........................................................................61
10.3 
Supply of Study Drug to the Investigational Site ......................................................61
10.4 
Study Drug Dosage and Dosage Regimen ................................................................62
10.5 
Preparation of Study Drug .........................................................................................62
10.6 
Study Drug Administration .......................................................................................62


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10.7
Study Drug Storage ...................................................................................................62
10.8 
Study Drug Accountability ........................................................................................63
11.
Subject Numbering, Stratification, Randomization, and Blinding .................................63
11.1 
Subject Numbering ....................................................................................................63
11.2
Stratification and Randomization ..............................................................................64
11.3
Blinding .....................................................................................................................65
11.4 
Breaking the Blind .....................................................................................................65
12.
Study Procedures and Guidelines ......................................................................................66
12.1 
Pharmacodynamic/Efficacy-Related Procedures ......................................................66
12.1.1 
Urticaria Patient Daily Diary ......................................................................66
12.1.2 
Weekly Urticaria Activity Score .................................................................66
12.1.3 
Hives Severity Score ...................................................................................66
12.1.4 
Itch Severity Score ......................................................................................67
12.1.5 
 .................................................................................67
12.1.6 
 .................................................................68
12.1.7 
 ........................................................................68
12.1.8 
Atopic Conditions Questionnaire ................................................................68
12.1.9 
Photographs .................................................................................................68
12.1.10 Complete Blood Count with Differential ....................................................68
12.1.11 Fresh biopsies ..............................................................................................69
12.2 
Safety-Related Procedures .........................................................................................69
12.2.1 
Concomitant Medications ...........................................................................69
12.2.2 
Complete Physical Examination .................................................................70
12.2.3 
Body Weight and Height .............................................................................70
12.2.4 
Symptom-Directed Physical Examination ..................................................70
12.2.5 
Electrocardiogram .......................................................................................70


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12.2.6
Previous CSU Diagnosis and Treatments Review ......................................71
12.2.7
Vital Signs ...................................................................................................71
12.3
Clinical Laboratory Measurements ...........................................................................72
12.3.1
Blood Chemistry Profile .............................................................................73
12.3.2
Pregnancy Test and Follicle-Stimulating Hormone ....................................73
12.3.3 
Effective Methods of Contraception for Allakos Studies ...........................74
12.3.4 
Urinalysis ....................................................................................................76
12.3.5 
Serology ......................................................................................................76
12.3.6 
Anti-Lirentelimab Antibodies .....................................................................76
12.3.7 
Blood for Pharmacokinetics ........................................................................76
12.3.8 
Blood for IgE ..............................................................................................77
12.3.9 
COVID-19 Testing ......................................................................................77
13.
Evaluations and Procedures by Visit .................................................................................77
13.1 
Screening Day for H1-AH Dose Stabilization – Screening Period ...........................78
13.2 
Screening Day or Post H1-A1 Stabilization – Screening Period ~Day -14 ..............79
13.3 
Day -7 (±3) – Screening Period/Baseline ..................................................................80
13.4 
Day 1 (±3) – Randomization/Day 1/Baseline/Dose 1 ...............................................80
13.5
Day 8 (±3) ..................................................................................................................81
13.6 
Day 15 (±5) – Dose 2 ................................................................................................82
13.7 
Day 29 (±5) – Dose 3 ................................................................................................82
13.8 
Day 43 (±5) – Dose 4 ................................................................................................83
13.9 
Day 57 (±5) – Dose 5 ................................................................................................84
13.10 Day 71 (±5) – Dose 6 ................................................................................................85
13.11 Day 85 (±5) or 14 Days Post-Dose – Follow-up Visit 1 ...........................................86
13.12 Day 127 (±5) or 56 Days Post-Dose – Follow-up Visit 2 .........................................87
13.13 Day 155 (±5) or 84 Days Post-Dose – Follow-up Visit 3 .........................................87


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13.14 End of Study Definition .............................................................................................88
14.
Adverse Event Reporting and Documentation .................................................................88
14.1 
Adverse Events ..........................................................................................................88
14.2 
Serious Adverse Events .............................................................................................89
14.3
Adverse Events of Special Interest ............................................................................90
14.4
Injection-Related Reactions .......................................................................................90
14.5 
Injection Site Reactions .............................................................................................91
14.6 
Anaphylaxis ...............................................................................................................91
14.7 
Evaluating Adverse Events and Serious Adverse Events ..........................................92
14.7.1 
Establishing Diagnosis ................................................................................92
14.7.2 
Assessment of Intensity ..............................................................................92
14.7.3 
Assessment of Causality to Study Drug ......................................................93
14.7.4 
Assessment of Causality to Study Procedure ..............................................93
14.7.5 
Action Taken ...............................................................................................94
14.7.6 
Assessment of Outcome ..............................................................................94
14.8 
Adverse Event Reporting Procedures ........................................................................94
14.8.1 
All Adverse Events .....................................................................................94
14.8.2 
Serious Adverse Event Reporting ...............................................................95
14.8.3 
Pregnancy Reporting ...................................................................................96
14.8.4 
AESI Reporting ...........................................................................................97
14.9 
Medical Monitoring ...................................................................................................97
14.10 Independent Data Monitoring Committee .................................................................97
14.11 Study Withdrawal Criteria .........................................................................................98
14.12 Study Stopping Rules ................................................................................................98
14.12.1 General ........................................................................................................98
14.12.2 Additional Regional Stopping Rules ...........................................................99


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15.
Discontinuation and Replacement of Subjects ..................................................................99
15.1 
Definition of Study Completion ................................................................................99
15.2 
Early Discontinuation of Study Drug ........................................................................99
16.
Statistical Methods and General Considerations ...........................................................100
16.1
Sample Size .............................................................................................................100
16.2
Analysis Populations ...............................................................................................101
16.3 
Subject Disposition ..................................................................................................101
16.4 
Demographic and Baseline Characteristics .............................................................101
16.5 
Study Drug Exposure ..............................................................................................102
16.6 
Efficacy Analysis .....................................................................................................102
16.6.1 
Primary Efficacy Endpoint Analysis .........................................................102
16.6.2 
Secondary Efficacy Endpoint Analysis .....................................................102
16.6.3 
Exploratory Analysis .................................................................................103
16.7 
Safety Analysis ........................................................................................................103
16.7.1 
Treatment Emergent Adverse Events........................................................103
16.7.2 
Anti-Drug Antibodies ...............................................................................104
16.7.3
Clinical Laboratory Assessments ..............................................................104
16.7.4
Vital Signs .................................................................................................104
16.7.5 
ECG ...........................................................................................................104
16.7.6 
Physical Exam ...........................................................................................104
16.7.7 
Concomitant Medications .........................................................................104
16.8 
Subject Confidentiality ............................................................................................105
17.
Data Collection, Retention, and Monitoring ...................................................................105
17.1 
Data Collection Instruments ....................................................................................105
17.2 
Data Management Procedures .................................................................................105
17.3 
Data Quality Control and Reporting ........................................................................105


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17.4
Database Lock/Disclosure of Randomization Code ................................................106
17.5 
Archiving of Data ....................................................................................................106
17.6 
Availability and Retention of Investigational Records ...........................................106
17.7 
Monitoring ...............................................................................................................107
18.
Administrative, Ethical, and Regulatory Considerations ..............................................107
18.1
Protocol Amendments .............................................................................................108
18.2 
Independent Ethics Committees/Institutional Review Boards ................................108
18.3 
Informed Consent Form ..........................................................................................109
18.4 
Publications .............................................................................................................109
18.5 
Clinical Study Registration ......................................................................................109
18.6 
Payment to Subjects ................................................................................................109
18.7 
Investigator Responsibilities ...................................................................................110
19.
References ..........................................................................................................................111
20.
Appendices .........................................................................................................................114
20.1 
Appendix 1: Urticaria Patient Daily Diary – PRO for Itch and Hives Severity ......115
20.2 
Appendix 2: 
 ................................................................119
20.3
Appendix 3: 
 .........................................................................123
20.4 
Appendix 4: 
 ........................................................124
20.5 
Appendix 5: Atopic Conditions Questionnaire .......................................................125
20.6 
Appendix 6: Common Terminology Criteria for Adverse Events v. 5.0 ................126
20.7 
Appendix 7: Sampson’s Criteria of Anaphylaxis ....................................................128
20.8 
Appendix 8: Hepatitis B and Hepatitis C Serologic Testing Details .......................129
20.9 
Appendix 9: Open Label Extension Period (Optional) ...........................................130
20.9.1 
Summary of the Open-Label Extended Dosing Period .............................130
20.9.2 
OLE Objective ..........................................................................................131


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20.9.3
OLE Eligibility Criteria.............................................................................131
20.9.4
OLE Inclusion Criteria ..............................................................................131
20.9.5 
OLE Exclusion Criteria .............................................................................132
20.9.6 
OLE Treatment..........................................................................................132
20.9.7 
OLE Procedures and Guidelines ...............................................................132


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List of Figures
Figure 1 
Classification of Chronic Urticaria ............................................................................36
Figure 2 
Subject with Chronic Urticaria: Spontaneous Wheal, Flare, and Itch .......................36
Figure 3 
Study Diagram ...........................................................................................................49
Figure 4 
Example of Grading for General Disorders and Administration Site Conditions ...126
Figure 5 
Example of Grading for Laboratory Abnormalities (Investigations) ......................127 
List of Tables 
Table 1
Study AK002-027 Schedule of Assessments: Double-Blind Period .........................45
Table 2
Study Drug Administration .......................................................................................62
Table 3
Hives Severity Score .................................................................................................67
Table 4
Itch Severity Score ....................................................................................................67
Table 5
Adverse Event Severity per CTCAE .........................................................................92
Table 6
Adverse Event Relationship to Study Drug ...............................................................93
Table 7
Adverse Event Relationship to Study Procedure .......................................................94
Table 8
Hepatitis B Testing ..................................................................................................129
Table 9
Hepatitis C Testing ..................................................................................................129
Table 10
Study AK002-027 Schedule of Assessments: Open-Label Extension Period .........133


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List of Abbreviations 
AC 
Allergic conjunctivitis 
ACS 
Allergic Conjunctivitis Symptom(s) 
ADA 
Anti-drug-antibody 
ADCC
Antibody-dependent cellular cytotoxicity
ADL
Activities of daily living
AE 
Adverse event(s) 
AESI 
Adverse event(s) of special interest 
AKC 
ALT 
Atopic keratoconjunctivitis 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
Anti-HBc 
Antibody to Hepatitis B core antigen 
Anti-HCV 
Hepatitis C virus antibody 
AST
Aspartate aminotransferase
CBC 
Complete blood count 
CFR 
Code of Federal Regulation 
CHOLUAS7 
Cholinergic urticaria assessment score 
CI 
Confidence interval
cm 
Centimeter 
CMH 
Cochran-Mantel-Haenszel (test) 
COVID-19 
Coronavirus disease 2019 
CS 
Clinically significant 
CSU
Chronic spontaneous urticaria
CTA 
Clinical Trial Application  
CTCAE 
Common Terminology Criteria for Adverse Events 
CTFG 
Clinical Trials Facilitation and Coordination Group 
CU 
Chronic urticaria
 
 
EAACI 
European Academy of Allergy and Clinical Immunology  
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDF
European Dermatology Forum 


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EG 
Eosinophilic gastritis 
ELISA 
Enzyme-linked immunosorbent assay 
EoD 
Eosinophilic duodenitis (formerly referred to as eosinophilic gastroenteritis) 
EoE
Eosinophilic esophagitis 
EOS
End of Study
ET 
Early Termination 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
FUP 
Follow-up 
GA2LEN 
Global Allergy and Asthma European Network 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation (European Union) 
GGT
Gamma-glutamyl transferase
GLP 
Good Laboratory Practice 
H1-AH 
H1-antihistamine 
H2-AH 
H2-antihistamine 
HBsAg 
Hepatitis B surface antigen 
HIPAA 
Health Insurance Portability and Accountability Act
HIV 
Human immunodeficiency virus 
hCG 
human chorionic gonadotropin  
HSS 
Hives Severity Score 
ICE
Intercurrent event(s)
ICF 
Informed consent form 
ICH 
International Council on Harmonisation 
iDMC 
Independent Data Monitoring Committee 
IEC
Independent Ethics Committee
IgE 
Immunoglobulin E 
IgG 
Immunoglobulin G 
IgG1 
Immunoglobulin G1 
IND 
Investigational New Drug (application) 
IP
Investigational product
IRB 
Institutional Review Board 


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IRR 
Infusion-related reaction (intravenous infusion) 
Injection-related reaction (subcutaneous injection) 
IRT 
Interactive Response Technology (system) 
ISM
Indolent systemic mastocytosis 
ISR
Injection site reaction 
ISS 
Itch Severity Scale 
ITIM 
Immunoreceptor tyrosine-based inhibitory motif 
ITT 
Intent to treat 
IUD
Intrauterine device
IUS 
Intrauterine hormone-releasing system 
IV 
Intravenous 
IVIG 
Intravenous immunoglobulin  
JAK 
Janus kinase(s)
kg 
Kilogram 
LARC 
Long-Acting Reversible Contraceptives  
LLN 
Lower limit of normal 
LS 
Least square (mean)
LTRA 
Leukotriene receptor antagonist(s) 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mITT 
Modified Intention-to-Treat 
mIU 
Milli-international units 
mL 
Milliliter 
mM 
Millimolar 
mTOR
mammalian Target of Rapamycin 
NCI 
National Cancer Institute 
NCS 
Not clinically significant  
NOAEL 
No-observed-adverse-effect level 
NOEL 
No-observed effect level 
PD
Pharmacodynamics 
PEF 
Peak expiratory flow  
PID 
Patient identification number 


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PK 
Pharmacokinetic(s) 
PP 
Per Protocol 
PRO  
Patient reported outcome 
 
 
SAE
Serious adverse event(s)
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SE 
Standard error 
Siglec 
Sialic acid-binding, immunoglobulin-like lectin
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event(s)  
TEAESI 
Treatment-emergent adverse event(s) of special interest  
TNF
Tumor necrosis factor 
µL 
Microliter 
UAS7 
Urticaria Assessment Score 
 
 
ULN
Upper limit of normal
UPDD 
Urticaria Patient Daily Diary
USP 
United States Pharmacopeia 
VKC 
Vernal conjunctivitis 
w/v 
Weight/Volume 
WAO
World Allergy Organization 
WOCBP 
Women of childbearing potential 
 


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1.
Protocol Synopsis 
Title:
A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study 
to Evaluate the Efficacy and Safety of Lirentelimab in Adult Subjects with 
H-1 Antihistamine Refractory Chronic Spontaneous Urticaria. 
Sponsor:
Allakos Inc., 825 Industrial Road, Suite 500, San Carlos, CA 94070.
Number of Sites:  
Up to 70 clinical centers in the United States, Germany, and Poland 
Number of Subjects: Approximately 130 
Nonclinical Background 
Lirentelimab (AK002) is a humanized non-fucosylated immunoglobulin G1 (IgG1) monoclonal 
antibody directed against Siglec-8, a member of the CD33-related family of sialic acid-binding, 
immunoglobulin-like lectins (Siglecs). Siglec-8 has a restricted tissue distribution, expressed selectively 
on the surface of mature eosinophils and mast cells, but not in early precursors of these cell populations. 
In blood, binding of lirentelimab to Siglec-8 induces antibody-dependent cellular cytotoxicity (ADCC) 
against eosinophils, leading to rapid and sustained depletion of these cells from the circulation. In tissue, 
lirentelimab induces direct apoptosis of eosinophils and inhibition of mast cells. 
Lirentelimab has been produced in 2 formulations: 1 for intravenous infusion (lirentelimab IV) and 1 for 
subcutaneous injection (lirentelimab SC) (see Test Product, Dose, and Administration). 
Clinical Background 
Lirentelimab IV, administered every 4 weeks, has previously been tested in over 700 healthy volunteers 
and in subjects with indolent systemic mastocytosis (ISM), chronic urticaria (CU), severe allergic 
conjunctivitis (AC), mast cell gastritis, eosinophilic gastritis (EG) and/or eosinophilic duodenitis (EoD), 
and eosinophilic esophagitis (EoE). Multiple monthly doses of 3 mg/kg have been given to subjects 
with ISM, chronic urticaria, severe AC, EG and/or EoD, and EoE.  
In general, lirentelimab IV has been well tolerated. The most common treatment-emergent adverse 
events (TEAE) observed with IV infusion were mild to moderate infusion-related reactions (IRR). The 
IRR were mostly mild to moderate and occurred most often during the first infusion. IRR that were 
deemed more serious typically resolved within 24 hours, and additional corticosteroids and/or 
antihistamines were used in cases when slowing the rate of infusion and additional supportive care 
alone did not resolve the issue. Common symptoms of IRR were headache, nausea, sweating, flushing, 
and redness. Most IRR that occurred during the infusion could be managed by slowing or temporary 
interruption of the infusion, with minimal intervention. The risk of IRR has been substantially reduced 
by administration of a single dose of corticosteroid (e.g., prednisone 60 mg) given orally 12–24 hours 
prior to the first dose of lirentelimab IV.  
Study AK002-017 evaluated the pharmacokinetics (PK) and pharmacokinetics (PD) of lirentelimab IV 
and SC in healthy volunteers. Subjects received 0.3, 1, 3, or 5 mg/kg or a fixed dose of 300 mg or 
450 mg lirentelimab SC, or 1 mg/kg or 3 mg/kg lirentelimab IV. In each of the SC cohorts, 8 subjects 
were randomized to lirentelimab (6 per group) or placebo (2 per group) in a double-blind manner; 
12 subjects received lirentelimab IV (6 subjects per group) in an open-label manner. 




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Target Disease Background and Rationale cont. 
Subjects with CU are often severely impaired in their quality of life (Mlynek, 2009), with negative 
effects on sleep, daily activities, school/work life, and social interactions, and psychiatric comorbidity 
being frequent. The duration of the disease is generally several years but is likely to be longer in more 
severe cases, cases with concurrent angioedema, in combination with physical urticaria, or with a 
positive autologous serum skin test (autoreactivity). It also has a large impact on society in terms of 
direct and indirect health care costs, as well as reduced performance at work and in private life 
(Maurer, 2011). In many subjects, an underlying cause of CSU cannot be identified, making a causal 
and/or curative treatment difficult. 
The European EAACI/GA2LEN/EDF/WAO Guideline states that the aim of treatment for all types of 
urticaria is to achieve complete symptom relief (Zuberbier, 2014). However, most subjects with CSU 
and all subjects with inducible urticaria require symptomatic treatment for effective symptom control. 
The current treatment guidelines for the management of all forms of urticaria recommend the use of 
non-sedating oral H1-AH as first-line therapy. In more than 50% of subjects, symptoms persist despite 
dosing of antihistamines up to 4 times the licensed dose (Maurer, 2011). In antihistamine-refractory 
subjects with CSU, the only currently licensed treatment is omalizumab, a monoclonal anti-IgE 
antibody. In subjects with inducible urticaria, including CU, no other licensed drugs are available and 
subjects often need to be treated with omalizumab, cyclosporin, or other off-label drugs (Metz, 2014a; 
Metz, 2014b). 
In double-blind placebo-controlled studies in selected H1-AH refractory subjects, omalizumab has been 
shown to be effective in the treatment of CSU and is recommended as third-line therapy if symptoms 
persist with 4-fold antihistamines. However, a substantial number of CSU subjects continue to have 
symptoms despite omalizumab treatment or do not respond at all to omalizumab treatment. Therefore, 
there is a significant unmet need for new targeted therapeutic options for subjects with CSU.  
As described above, lirentelimab was studied in various forms of spontaneous and inducible urticaria in 
an open-label study. The results of that study provide a strong rationale for conducting a randomized, 
double-blind study in CSU. 
This study will evaluate the safety, tolerability, and PD of repeat doses of lirentelimab SC in subjects 
with moderate-to-severe CSU and provide evidence of efficacy as assessed by symptomatology and 
need for rescue medications. In this study, subjects with moderate-to-severe disease, which is defined 
using the following criteria, will be included: 
 
Chronic CSU that has been diagnosed and present for at least 6 months at the time of screening. 
 
Subjects who are refractory to treatment with H1-AH, either omalizumab-exposed or omalizumab 
naïve.  
 
At the screening visit the subject must have presence of hives and itch for at least 6 consecutive 
weeks. 
 
At the time of randomization the subject must have a UAS7 score of at least 16 (range 0–42) and a 
HSS7 score of at least 8 (range 0–21) during the 7 days prior to randomization. 


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Target Disease Background and Rationale cont.
These well-established measures will objectively define the severity of the disease at the time of entry 
into the study.  
Rationale for Dose Selection 
A dosing regimen of 300 mg lirentelimab SC administered every 2 weeks for 6 doses is proposed. This 
regimen is based on PK modeling for Study AK002-017, comparing dose regimens of the IV infusion 
doses vs. the SC injection doses administered every 28 days. These simulations showed that a dose of 
300 mg lirentelimab SC provided a substantially lower Cmax and slightly lower 1-month trough level 
than 3 mg/kg lirentelimab IV. Discussion with experts participating in dermatologic trials with biologics 
and reports of external data from other compounds targeting other type 2 dermatological conditions 
such as atopic dermatitis support the use of higher or more frequent dosing in cutaneous diseases than in 
other allergic conditions (i.e., asthma). Dose-response relationships and results across multiple 
endpoints show trends toward improved efficacy with increasing dose and duration and suggest that 
further increases in dose or treatment duration might improve efficacy. In CSU, clinical response to 
omalizumab has been demonstrated to be dose dependent across multiple clinical trials (Metz, 2020; 
Zhao, 2015). 
Furthermore, reports of omalizumab updosing beyond licensed doses in the real-world treatment setting 
of CSU demonstrate success in clinical response that exceeds those reported in clinical trials, with a 
safety profile similar to that reported in clinical trials. The use of doses higher than the licensed dose of 
omalizumab 300 mg provides support to recommend the use of higher doses of other immuno-
modulating therapies, especially for subjects who are partial responders or non-responders and 
refractory to treatment. Consequently, increasing the frequency of the 300 mg lirentelimab SC dose 
from every 4 weeks to every 2 weeks is proposed for the AK002-027 study. 
Simulations using AK002-017 study data indicate that a fixed dose of lirentelimab SC 300 mg every 
2 weeks is expected to provide greater exposure than 300 mg administered monthly without an 
increased Cmax, in contrast to the 3 mg/kg IV dose. The proposed SC dose and frequency of 
administration is expected to provide higher steady state levels as supported by the safety and 
tolerability profile of lirentelimab IV in subjects with other eosinophilic and mast cell diseases. The 
concentration of 150 mg/mL lirentelimab SC is consistent with an injection volume of 2 mL for the 
300 mg dose, which was well tolerated without injection site reactions in Study AK002-017. When 
proof of concept is established, other lirentelimab SC doses and schedules may be explored.
Study Design 
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled study to evaluate the 
efficacy and safety of lirentelimab in omalizumab-naïve or exposed adult subjects with H1-AH 
refractory CSU. Subjects enrolled in the study will receive 6 doses of lirentelimab SC or placebo SC 
administered every 2 weeks followed by the option to enroll in the open-label extension (OLE) period, 
contingent on defined selection criteria, to receive 6 doses of 300 mg lirentelimab SC every 2 weeks. 
Subjects will be observed for a post-treatment period of 12 weeks. 
 


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Study Design cont.
Based on the feedback from chronic spontaneous urticaria experts and completed feasibility 
assessments, it is expected that each site will be able to screen three subjects and enroll two of them in 
the duration of the enrollment period. Enrollment is considered to be competitive. To ensure the 
enrollment goal is achieved in a timely manner, up to 70 sites (approximately 55 in the US, and 15 in 
Germany and Poland) will be initiated. If study enrollment rate can be achieved with fewer sites in order 
to meet the study timeline, then fewer sites may be needed. 
Subjects will be consented and then screened for up to 3 weeks. Subjects who have been on a stable, 
approved dose regimen of 2nd generation or later H1-AH prior to screening will undergo a 2-week 
eligibility screening period. Subjects who are not on a stable approved dose regimen of 2nd generation or 
later H1-AH will be allowed an additional 1 week during the screening period during which they must 
reach a stable approved dosing regimen before entering the 2-week eligibility screening period. 
Stable approved doses of H1-AH for study purposes is defined as a H1-AH regimen between 1x and 4x 
of the licensed dose and at the licensed frequency of dosing for the treatment of CSU for at least 1 week 
prior to screening. 
Baseline H1-AH dosing regimen must be established by Day -14 (14 days prior to randomization) for 
purposes of the screening eligibility period. Baseline disease activity data will be collected with daily 
assessment of itch and hive severity, both of which will be used to calculate a weekly urticaria activity 
score (UAS7). Subjects who meet eligibility criteria at both Day -7 and Day 1 can be enrolled into the 
study. The baseline UAS7 score for efficacy analysis calculations will be defined by the 7-day period 
prior to randomization.  
Eligible subjects will receive the first dose of lirentelimab SC or placebo SC on Day 1. If the study drug 
is well tolerated (no stopping rules being met), subjects will continue to receive subsequent doses on 
Days 15, 29, 43, 57, and 71, for a total of 6 doses. Subjects will remain in the clinic for at least 1 hour of 
observation (or longer, as per Investigator’s discretion) following the end of dose administration after 
each dose. In the event of an IRR, the subject may require prolonged observation (>1 hour or until the 
symptoms resolve), as per Investigator’s discretion. Subjects will also be instructed to immediately 
contact the study team if any reactions occur after discharge. 
During the treatment period, subjects will return to the site for study visits as described in the Schedule 
of Events. Subjects will have the option to enter an open-label extension (OLE) period of the study to 
receive 6 doses of 300 mg lirentelimab SC contingent on meeting defined study selection criteria. All 
subjects will be followed for another 12 weeks after the last dose in the randomized double-blind period 
or OLE period.  
The primary endpoint will be assessed at Week 12, i.e., 2 weeks after the last dose in the double-blind 
period of the study. Subjects will be stratified at randomization based on omalizumab experience for the 
treatment of CSU (exposed/naïve) and UAS7 score (16–27 or 28–42). 
 






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will also be required to have a negative urine dipstick pregnancy test prior to dosing and at each 
study visit. 
9)
Male subjects with female partners of childbearing potential must agree to use a highly effective 
method of contraception as defined in this protocol or abstain from sexual activity from screening 
until the end of the study or for 120 days following the last dose of study drug, whichever is longer. 
All fertile men with female partners of childbearing potential should be instructed to contact the 
Investigator immediately if they suspect their partner might be pregnant (e.g., missed or late 
menstrual period) at any time during study participation. 
Exclusion Criteria: Subjects will be excluded from the study if they meet any of the following criteria. 
1) 
History of hypersensitivity to the study drugs or their excipients or to drugs of similar chemical 
classes (i.e., murine, chimeric or human antibodies). 
2) 
Current use of biologics for any indication. 
3) 
Demonstrated lack of primary response to treatment with a biologic therapy (e.g., omalizumab) for 
the treatment of CSU, defined as no response to treatment despite complete adherence to a 
prescribed regimen (e.g., 
) for at least 3 months, 
based on interview at screening. 
4) 
Use of any of the following treatments within 4 weeks prior to the baseline visit or any condition 
that in the opinion of the Investigator is likely to require such treatment(s) during the first 4 weeks 
of study treatment. 
–
Immunosuppressive or immunomodulatory drugs, including but not limited to systemic 
calcineurin inhibitors (e.g., cyclosporin, tacrolimus), mTOR inhibitors (e.g., sirolimus, 
everolimus), anti-metabolites (e.g., azathioprine, methotrexate, 6-mercaptopurine, leflunomide, 
mycophenolate mofetil), alkylating agents (e.g., cyclophosphamide), and eosinophil-depleting 
drugs (e.g., benralizumab, pramipexole) 
–
Routine (daily or every other day during 5 or more consecutive days) doses of systemic 
hydroxychloroquine 
–
Plasmapheresis 
5) 
Use of oral Janus kinase (JAK) inhibitors within 8 weeks of the baseline visit (requires discussion 
with Medical Monitor prior to subject enrolling in study). 
6) 
Use of any of the following treatments within 3 weeks prior to the baseline visit: 
–
H2 Antihistamines (H2-AH) 
–
Routine (daily or every other day during 5 or more consecutive days) doses of systemic 
corticosteroids 
–
Regular (daily or every other day) doxepin (oral) 
–
Leukotriene Receptor Antagonists (LTRA) (e.g., montelukast, zafirlukast) 
7) 
H1-AH use at greater than approved doses or greater than local CSU guideline recommended doses 
after Screening Visit 1. 


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Subject Selection Criteria – Exclusion Criteria cont.
8) 
Previous Treatment with biologics or intravenous immunoglobulin: 
–
Any cell-depleting agents including but not limited to rituximab within 6 months prior to the 
baseline visit or until lymphocyte count returns to normal, whichever is longer. 
–
Other biologics, including investigational biologics (e.g., dupilumab, omalizumab, 
benralizumab, etc.) and TNF inhibitors (e.g., infliximab, adalimumab), within 5 half-lives if 
known or 8 weeks prior to the baseline visit, whichever is longer. 
–
Intravenous immunoglobulin (IVIG) within 5 half-lives
9) 
Planned or anticipated use of any prohibited medication. 
10) Subjects having causes other than CSU for their urticaria including symptomatic dermographism, 
cholinergic urticaria, or any inducible urticaria. 
11) Diseases other than chronic urticaria with urticarial or angioedema symptoms, including chronic 
itching, that in the Investigator’s opinion might influence study evaluations and results. 
12) Subjects with known or suspected urticarial vasculitis. 
13) Subjects with known or suspected hereditary angioedema. 
14) Any other skin disease associated with chronic itch, including atopic dermatitis, that in the 
Investigator’s opinion might influence study outcome and subject’s interpretation of symptoms 
caused by CSU. 
15) A helminth parasitic infection diagnosed within 6 months prior to the date that informed consent is 
obtained and has not been treated with or has failed to respond to standard-of-care therapy.  
16) Evidence of active HIV infection at screening based on serology or evidence of active hepatitis B 
or C at screening based on serology. 
17) Presence of an abnormal screening laboratory value considered to be clinically significant by the 
Investigator. 
18) Known or suspected history of alcohol, drug, or other substance abuse or dependence that in the 
opinion of the Investigator may interfere with study participation or assessments. 
19) Treatment with chemotherapy or radiotherapy in the preceding 6 months. 
20) History of malignancy except carcinoma in situ in the cervix, early-stage prostate cancer, or non-
melanoma skin cancers. 
21) Women who are pregnant, breastfeeding, or planning to become pregnant while participating in the 
study. 
22) Participation in a concurrent interventional study with the last intervention occurring within 
30 days prior to study drug administration (or 90 days or 5 half-lives, whichever is longer, for 
biologic products). 


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Subject Selection Criteria – Exclusion Criteria cont.
23) Subjects who weigh <40 kg at screening. 
24) Any other reason that in the opinion of the Investigator or the Medical Monitor makes the subject 
unsuitable for enrollment. 
25) Vaccination with live attenuated vaccines within 30 days prior to initiation of treatment in the 
study, during the treatment period, or vaccination expected within 5 half-lives (4 months) of study 
drug administration.  
Note: This exclusion criterion does not apply to all types and formulations of vaccines (including 
live attenuated vaccines) currently authorized/approved by FDA or other regulatory 
authority for the prevention of COVID-19, which may be administered before, during, or 
after the study.  
The vaccine should not be administered within 3 days before and within 3 days after the 
administration of lirentelimab so that any side effects caused by either of the 2 medications 
can be more easily determined. 
26) Employees or relatives of the Sponsor or the Investigator, or other persons dependent on the 
Sponsor or the Investigator. 
27) Commitment to an institution by order issued either by the judicial or the administrative 
authorities. 
28)  Presence of a SARS-CoV-2 infection and/or have not completed an authorized/approved COVID-
19 primary immunization series as per national recommendations at the time of screening. 
Acceptable and required documentation to confirm inclusion and exclusion criteria is further explained 
in the Study Reference Manual and listed in the eCRF. 
Test Product, Dose, and Administration 
Lirentelimab SC Drug Product: The lirentelimab drug product is supplied in 2R Type I clear glass 
vials, securely sealed with a fluoropolymer-coated bromobutyl stopper and aluminum flip-off cap. It is 
intended for SC injection. Each drug product vial contains a nominal volume of 1 mL. It is a sterile, 
preservative-free solution that contains 
 
, pH 6.0 in Water for 
Injection (WFI). The solution is visually characterized as clear to slightly opalescent, appearing 
colorless to slightly yellow. 
Placebo SC Product: The placebo is supplied in 2R Type I clear glass vials, securely sealed with a 
fluoropolymer-coated bromobutyl stopper and aluminum flip-off cap. It is intended for SC injection. 
Each placebo vial contains a nominal volume of 1 mL. It is a sterile, preservative-free solution that 
contains 
 
, pH 6.0 in WFI. The solution is visually characterized as clear to slightly 
opalescent, appearing colorless to slightly yellow. 






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Statistical Analysis
All subjects who receive study medication will be included in the Safety population for safety analysis. 
Subjects who are randomized and have received at least 1 dose of study medication will be included in 
the modified Intent-to-Treat (mITT) population for efficacy analysis. mITT subjects who have received 
all 6 injections of study drug and do not have major protocol deviations possibly interfering with the 
interpretation of efficacy and safety assessment will be included in the Per Protocol (PP) population. 
When appropriate, summary statistics of number of non-missing values, mean, median, standard 
deviation, minimum, and maximum will be computed for continuous variables and summary statistics 
of number and proportion will be computed for categorical variables.  
Two-sided 95% confidence intervals (CI) will be provided for the mean and proportion. No formal 
statistical inferences will be made for safety parameters. Safety data will be summarized for each 
treatment group.  
Baseline for safety analysis is defined as the last observation before administration of the first dose of 
study drug. Baseline for efficacy endpoints derived from daily diary assessments will be based on the 
7 days before administration of the first dose of study drug. 
Subjects will be stratified at randomization based on omalizumab experience for the treatment of CSU 
(exposed/naïve) and UAS7 score (16–27 or 28–42).  
The primary endpoint will be analyzed by analysis of covariance (ANCOVA). The least square (LS) 
mean, standard error (SE), and 95% CI for each treatment group, and the between group difference will 
be derived from ANCOVA with treatment as a factor, baseline UAS7 (continuous), and omalizumab 
experience for the treatment of CSU (exposed or naïve) as covariates. Data on subjects who experience 
an intercurrent event (ICE, i.e., exit the study prematurely or initiate prohibited or rescue medications) 
prior to the end of Week 12 will be set to missing. Missing UAS7 will be imputed using the Markov 
Chain Monte Carlo (MCMC) method. Detailed specifications for the missing data imputation will be 
provided in the Statistical Analysis Plan (SAP).  
Binary data will be analyzed using the Cochran-Mantel-Haenszel (CMH) test, stratified by the 
randomization stratification factors (omalizumab experience for the treatment of CSU, exposed or 
naïve, and UAS7 score [16–27 or 28–42]). Data on subjects who experience an ICE prior to the end of 
Week 12 will be set to non-response status.  
Change from baseline in continuous secondary outcomes measured at multiple post-baseline time points 
will be analyzed longitudinally using a mixed model. The model will include fixed effects for baseline 
value, randomization stratification factor, treatment, week, treatment by week interaction, baseline value 
by week interaction, and allow for random subject effects. The model variance-covariance matrix will 
be unstructured. However, if computation does not converge, the variance-covariance matrix will take 
the form of Toeplitz, AR (1), and compound symmetry, whichever converges first. The Kenward-
Rogers approach for computing denominator degrees of freedom will be used to account appropriately 
for pooling of within-subject and between-subject variance estimates. Least square means and the 95% 
CI for the between-group difference will be estimated for each week.  


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Statistical Analysis cont.
Subject incidence of TEAE will be tabulated by MedDRA System Organ Class and Preferred Term and 
by severity and treatment relationship. Serious TEAE and TEAE leading to study discontinuation will 
be listed with pertinent information. Change from baseline in laboratory tests will be summarized with 
descriptive statistics. Details will be provided in the SAP. 
 


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2.
Background 
2.1
Siglec-8 and Lirentelimab 
Siglec-8, a member of the CD33-related family of sialic acid-binding, immunoglobulin-like 
lectins (Siglecs), is a transmembrane cell surface protein with restricted tissue distribution, 
expressed selectively on the surface of mature eosinophils and mast cells, but not in early 
precursors of these cell populations. Siglec-8 contains 3 extracellular immunoglobulin-like 
domains, a transmembrane region, and a cytoplasmic tail containing 2 tyrosine-based signaling 
motifs including an immunoreceptor tyrosine-based inhibitory motif (ITIM) with inhibitory 
function. Engagement of Siglec-8 in mast cells can result in inhibition of mediator release, and in 
eosinophils can induce apoptosis (Bochner, 2009). Lirentelimab also shows potent antibody-
dependent cellular cytotoxicity (ADCC) against eosinophils in vivo and in vitro.  
2.2
Overview of Nonclinical Studies 
Lirentelimab is a humanized non-fucosylated immunoglobulin G1 (IgG1) monoclonal antibody 
directed against Siglec-8, a member of the CD33-related family of sialic acid-binding, 
immunoglobulin-like lectins (Siglecs). Siglec-8 has a restricted tissue distribution, expressed 
selectively on the surface of mature eosinophils and mast cells, but not in early precursors of 
these cell populations. In blood, binding of lirentelimab to Siglec-8 induces ADCC against 
eosinophils, leading to rapid and sustained depletion of these cells from the circulation. In the 
tissue, lirentelimab induces direct apoptosis of eosinophils and inhibition of mast cells.  
Lirentelimab has been produced in 2 formulations: 1 for intravenous infusion (lirentelimab IV) 
and 1 for subcutaneous injection (lirentelimab SC) (see Section 10. Study Treatment). 
Siglec-8 is not expressed in species other than humans and high-order primates, and therefore, 
2 novel mouse models have been developed for in vivo testing of lirentelimab. Lirentelimab has 
been studied in Siglec-8 humanized and transgenic mouse models and with human blood and 
tissue cells. The first model uses immunodeficient mice capable of generating human immune 
cells including mast cells and eosinophils when engrafted with human hematopoietic stem cells. 
The ability of anti-Siglec-8 antibodies to inhibit mast cell-mediated reactions has been evaluated 
in this model. The second rodent model is a transgenic mouse line that expresses human 
Siglec-8. The expression of Siglec-8 on the cell surface in these mice is restricted to eosinophils, 
mast cells, and basophils, a pattern of surface expression equivalent to that in humans. 
Anti-Siglec-8 antibodies can prevent IgE-mediated anaphylaxis in this transgenic mouse line, 
indicating that Siglec-8 is pharmacologically active in the model. The ability of lirentelimab to 
affect mast cells and eosinophils has been evaluated in this model.  


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Lirentelimab inhibits IgE-mediated mast cell degranulation and release of the newly formed 
mediator prostaglandin D2 in vitro without affecting mast cell viability. In peripheral blood 
preparations from normal human donors, lirentelimab shows selective depletion of eosinophils. 
Importantly, in a whole-blood cytokine-release assay using immobilized lirentelimab to enhance 
the potential for antibody crosslinking, lirentelimab did not lead to dose-dependent release of 
pro-inflammatory cytokines. 
To evaluate the in vivo activity of anti-Siglec-8 antibodies in an immunocompetent rodent 
model, a transgenic mouse strain has been developed that selectively expresses human Siglec-8 
on the surface of mouse mast cells, eosinophils, and basophils. In single-dose and repeat-dose 
studies in Siglec-8 transgenic mice, lirentelimab demonstrated selective depletion of peritoneal 
mast cells and circulating and tissue (spleen) eosinophils and basophils.  
In the 1-month and 6-month Good Laboratory Practice (GLP) toxicity and toxicokinetic studies, 
lirentelimab IV was well tolerated at doses of 50 mg/kg and 100 mg/kg, 5-fold and 10-fold, 
respectively, the level of the highest dose proposed to be studied in humans. Lirentelimab 
showed sustained systemic exposure in Siglec-8 transgenic mice with an extended terminal 
half-life estimated as 272 hours or 337 hours following single IV administration of 50 mg/kg or 
100 mg/kg, respectively. There was no evidence of anti-drug antibodies (ADA) in either study. 
Decreases in eosinophil counts in both sexes were observed, which reflect the expected 
pharmacology of lirentelimab. The no-observed-adverse-effect-level (NOAEL) following 
intravenous administration of lirentelimab to transgenic mice was 100 mg/kg.  
A GLP toxicology study was conducted to characterize the local tolerance and bioavailability of 
lirentelimab SC in transgenic mice to support human clinical studies. The dose, 60 mg/kg, was 
selected to represent a dose level 6-fold higher than the highest human dose level (10 mg/kg), 
to identify a NOAEL/no observed effect level (NOEL) and was representative of the IV 
lirentelimab doses previously studied (50 mg/kg and 100 mg/kg). There were no lirentelimab-
related clinical observations following SC or IV administration, and there were no 
lirentelimab-related skin reactions noted following SC or IV administration.  
A GLP study of lirentelimab SC was conducted using C57Bl/6 male breeder mice and F0 
generation Siglec-8 transgenic female mice to evaluate the effects of 60 mg/kg lirentelimab SC 
on fertility, development, and perinatal/postnatal reproduction, including postnatal 
behavior/function. Observations were continued through sexual maturity of the F1 generation 
mice. There were no lirentelimab-related effects on fertility, development, or perinatal/postnatal 
reproduction, or on the postnatal behavioral assessments. Based on these results, the NOAEL of 
lirentelimab SC is 60 mg/kg.  


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2.3
Overview of Clinical Studies
Lirentelimab IV, administered as a monthly intravenous infusion, has previously been tested in 
over 700 healthy volunteers and in subjects with indolent systemic mastocytosis (ISM), chronic 
urticaria (CU), severe allergic conjunctivitis (AC), mast cell gastritis, eosinophilic gastritis (EG) 
and/or eosinophilic duodenitis (EoD), and eosinophilic esophagitis (EoE). Multiple monthly 
doses of 3 mg/kg have been given to subjects with ISM, CU, severe AC, EG and/or EoD, and 
EoE. 
In general, lirentelimab IV has been well tolerated. The most common treatment-emergent 
adverse events (TEAE) observed with IV infusion were mild to moderate infusion-related 
reactions (IRR). The IRR were mostly mild to moderate, and occurred most often during the first 
infusion. IRR that were deemed more serious typically resolved within 24 hours, and additional 
corticosteroids and/or antihistamines were used in cases when slowing the rate of infusion and 
additional supportive care alone did not resolve the issue. Common symptoms of IRR were 
headache, nausea, sweating, flushing, and redness. Most IRR that occurred during the infusion 
could be managed by slowing or temporary interruption of the infusion, with minimal 
intervention. In subjects with ISM, CU, severe AC, and EG/EoD, fewer adverse events (AE) 
including IRR were reported during the second and subsequent infusions when compared to the 
first infusion. The risk of IRR has been substantially reduced by administration of a single dose 
of oral corticosteroid (e.g., prednisone 60 mg) given orally 12 to 24 hours prior to the first dose 
of lirentelimab IV.
Study AK002-017 evaluated the PK and PD of lirentelimab IV and SC in healthy volunteers. 
Subjects received 0.3, 1, 3, or 5 mg/kg or a fixed dose of 300 mg or 450 mg lirentelimab SC, or 
1 mg/kg or 3 mg/kg lirentelimab IV. In each of the SC cohorts, 8 subjects were randomized to 
lirentelimab (6 per group) or placebo (2 per group) in a double-blind manner; 12 subjects 
received lirentelimab IV (6 subjects per group) in an open-label manner.  
The study showed that the PD effect (depletion of blood eosinophils) occurred within 1 hour of 
dosing and lasted for at least 1 month at IV and SC doses of 1 mg/kg and for 3 months at all 
higher IV and SC doses. The SC injections were well tolerated, and no injection site reactions or 
general injection reactions were noted at any dose demonstrating suitability for further 
evaluation. 
Lirentelimab IV was previously studied in an open-label study in subjects with CU, who were 
omalizumab-naïve and refractory to treatment with non-sedating H1-antihistamines (H1-AH), 
and in some subjects with chronic spontaneous urticaria (CSU) refractory to omalizumab. The 


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design was intended to assess the efficacy and safety of lirentelimab in both CSU and chronic 
inducible urticaria (cholinergic and dermatographic subtypes) refractory to standard treatment.  
Efficacy was assessed by subject reported outcome assessment, using the urticaria control test 
(UCT), urticaria assessment score (UAS7), cholinergic urticaria assessment score (CHOLUAS7), 
as well as various quality of life measures. The primary efficacy endpoint was change in UCT 
from baseline at Week 22. At baseline, all subjects had uncontrolled CU as determined using 
UCT <12. At Week 22, UCT increased in all subject cohorts. Within each disease cohort, the 
95% confidence intervals (CI) for the mean changes signified significant improvement in moving 
subjects from an initial state of poorly controlled disease to well-controlled disease.
UAS7 was assessed in CSU subjects only. At Week 22, the mean reductions in UAS7 from 
baseline (% change) were statistically significant: 
 
CSU (omalizumab-naïve, XN) group: mean = -13.9, 95% CI = -19.5 to -8.4 
(% change = -73.2, 95% CI = -94.9 to -51.4) 
 
CSU (omalizumab-failure, XF) group: mean = -14.0, 95% CI = -21.0 to -7.0 
(% change = -46.6, 95% CI = -71.0 to -22.2)  
Supplementary analysis of UAS7 evaluated complete response (
eduction 
from baseline) and clinical response (
). Clinical response was met by over 60% of 
subjects in the CSU-XN disease cohort and 55% in the omalizumab failure group. In addition, 
complete responses were observed in 53.8% of subjects in CSU-XN and 9.1% in CSU-XF group. 
Lirentelimab IV was well tolerated, with IRR being the only significant adverse event (AE) 
related to the intravenous formulation.  
Taken together, these efficacy and safety data suggest that lirentelimab may have a role in the 
treatment of various subtypes of antihistamine-resistant urticaria, including subjects who have 
failed omalizumab. 
2.4 
Chronic Urticaria 
Chronic spontaneous urticaria (CSU) is a skin condition, which is characterized by transient and 
unpredictable pruritic wheal and flare type skin reactions and, in some subjects, the occurrence 
of angioedema. There are >500,000 people estimated to have CU in the US, most of whom are 
age (Wertenteil, 2019). In Europe, more than 5 million subjects 
are thought to suffer from persisting urticarial symptoms (Maurer, 2011), which either occurs 
spontaneously (i.e., spontaneous urticaria), or can be induced as a result of environmental 


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physical stimuli such as pressure, ultraviolet irradiation, heat or cold (physical urticaria), or by 
other means (Metz, 2012).  
Subjects with CU are often severely impaired in their quality of life (Mlynek, 2009), with 
negative effects on sleep, daily activities, school/work life, and social interactions, and 
psychiatric comorbidity being frequent. The duration of the disease is generally several years but 
is likely to be longer in cases that are more severe, cases with concurrent angioedema, in 
combination with physical urticaria, or with a positive autologous serum skin test 
(autoreactivity). It also has a large impact on society in terms of direct and indirect health care 
costs, as well as reduced performance at work and in private life (Maurer, 2011). In many 
subjects, an underlying cause of CSU cannot be identified making a causal and/or curative 
treatment difficult. Figure 1 provides a classification of chronic urticaria subtypes 
(Zuberbier, 2014), and Figure 2 presents an example of CU.  
The European EAACI/GA2LEN/EDF/WAO Guideline states that the aim of treatment for all 
types of urticaria is to achieve complete symptom relief (Zuberbier, 2014). However, most 
subjects with CSU and all subjects with inducible urticaria require symptomatic treatment for 
effective symptom control. 
The current treatment guidelines for the management of all forms of urticaria recommend the use 
of non-sedating oral H1-AH as first-line therapy. In more than 50% of the subjects, symptoms 
persist despite dosing of antihistamines up to 4 times the licensed dose (Maurer, 2011). In 
antihistamine-refractory subjects with CSU, the only currently licensed treatment is omalizumab, 
a monoclonal anti-IgE antibody. In subjects with inducible urticaria, including CU, no other 
licensed drugs are available, and subjects often need to be treated with omalizumab, cyclosporin, 
or other off-label drugs (Metz, 2014a; Metz, 2014b).
In double-blind placebo-controlled studies in selected H1-AH refractory subjects, omalizumab 
has been shown to be effective in the treatment of CSU and is recommended as third-line therapy 
if symptoms persist with 4-fold antihistamines. However, a substantial number of CSU subjects 
continue to have symptoms despite omalizumab treatment or do not respond at all to omalizumab 
treatment. Therefore, there is a significant unmet need for new targeted therapeutic options for 
subjects with CSU.
As described above, lirentelimab was studied in various forms of spontaneous and inducible 
urticaria in an open-label study. The results of that study provide a strong rationale for 
conducting a randomized, double-blind study in CSU. 
 




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2.5
Benefit–Risk Assessment 
In the treatment of CSU, there remains an unmet medical need for more effective and safe 
therapies. The goal of therapy, as outlined in current treatment guidelines, is to achieve complete 
control of the disease, but despite this some patients continue to have symptoms that remain 
bothersome. Standard first-line treatment of CSU consists of the use of nonsedating H1-
antihistamines (H1-AH) at locally approved doses, with escalation up to four times the approved 
dose used off-label as second-line treatment. For those patients that have uncontrolled disease 
despite optimized H1-AH therapy, current guidelines recommend omalizumab as third-line 
therapy to be used in addition to H1-AH (Zuberbier, 2014). However, the treatment of H1-AH 
refractory patients cannot be fully met by omalizumab as more than half of subjects with CSU in 
registrational studies continued to experience symptoms despite omalizumab treatment (Maurer, 
2013). In addition, other biologics tested in controlled clinical trials have failed to demonstrate 
benefit in omalizumab refractory subjects leaving a population in particular need of a safe and 
effective therapy (Sanofi, 2022). 
Results from nonclinical studies demonstrate that lirentelimab has the potential to provide 
clinical benefit to patients with diseases in which eosinophils and mast cells play a pathogenic 
role, particularly CSU. In vitro, in vivo, and human ex vivo studies have shown that lirentelimab 
binds specifically to Siglec-8-positive cells (eosinophils, mast cells, and to a lesser degree 
basophils), reduces the number of blood and tissue eosinophils, inhibits the activation of mast 
cells, and decreases the release of eosinophil-derived and mast cell-derived inflammatory 
mediators, offering an attractive and unique therapeutic approach for difficult-to-treat diseases 
such as CSU, atopic dermatitis, and others. In clinical studies of lirentelimab conducted in more 
than 700 subjects (healthy volunteers and patients with eosinophilic diseases), the maximum 
tolerated dose (MTD) for lirentelimab in humans has not been reached. Lirentelimab is generally 
well tolerated, with mild to moderate IRR as the most common AE. A total of five related cases 
of IRR SAEs have been reported to date, all of which resolved within 24 hours without sequelae 
or fatalities. Of note, all IRR AEs and SAEs occurred when lirentelimab was administered 
intravenously and most often occurred in association with the first infusion.  
Preliminary evidence of clinical activity in CU (including CSU) has been obtained in a phase 2 
open-label study with lirentelimab IV in subjects who were omalizumab-naïve and refractory to 
treatment with non-sedating H1-AH, as well as some subjects with chronic spontaneous urticaria 
(CSU) refractory to omalizumab (Altrichter, 2022). In this study, a total of 45 patients were 
enrolled in 4 cohorts (n=13 omalizumab-naive CSU, n=11 omalizumab-refractory CSU, n=11 
CholU, n=10 symptomatic dermographism). Urticaria Control Test scores were noted to increase 
with lirentelimab across the cohorts, with mean changes at week 22 of 11.1 ± 4.1, 4.8 ± 7.0, 6.5 ± 


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6.2, and 3.4 ± 4.1 and complete response rates (Urticaria Control Test score  12) of 92%, 36%, 
82%, and 40%, respectively. In omalizumab-naive and omalizumab-refractory patients with 
CSU, disease activity decreased at week 22 (mean UAS7 change, -73% and -47%, respectively), 
with UAS7 response rates (
50% reduction) of 77% and 45%, respectively. Most commonly 
reported adverse events included infusion-related reactions (43%; all mild/moderate and 
transient), nasopharyngitis (21%), and headache (19%) and no treatment-related serious adverse 
events were reported during this study. The results of the study supported evidence of efficacy 
based on significant improvement of subject reported outcome assessments, using the urticaria 
control test (UCT), and urticaria activity score (UAS7), as well as various quality of life 
measures across both omalizumab naïve and omalizumab refractory patients.
The Sponsor has developed a lirentelimab formulation that can be administered subcutaneously 
(lirentelimab SC). A Phase 1 study of lirentelimab SC in 36 healthy volunteers demonstrated that 
lirentelimab SC was also well tolerated and achieved eosinophil depletion at a level comparable 
to that of lirentelimab IV. In this study, no lirentelimab SC-treated subjects reported local or 
systemic injection-related reactions were reported. This subcutaneous formulation is currently 
being used in a Phase 2 atopic dermatitis clinical trial and will be used for the current CSU study. 
The overall benefit-risk assessment of lirentelimab appears to be positive. Clinical safety data 
observed from over 700 exposed subjects suggest that lirentelimab is generally well tolerated and 
presents an acceptable safety profile to date. There is a significant unmet need for additional 
treatment options for patients with CSU refractory to H1-antihistamines, and particularly those 
whose symptoms are also refractory to omalizumab as no effective therapeutic options currently 
exist. Results from the Phase 2a lirentelimab study in CU suggest that lirentelimab may be an 
effective treatment for CSU patients, for both omalizumab naïve and omalizumab refractory 
subjects. Adequately powered double-blind, placebo-controlled randomized studies are 
warranted to further characterize lirentelimab as a potential treatment option for H1-AH 
refractory CSU. 
3. 
Rationale for Study and Dose Selection 
3.1 
Rationale for Study Design 
The approach utilized in this study is consistent with current international 
EAACI/GA2LEN/EuroGuiDerm/APAAACI guidelines that recommend add-on therapy with a 
biologic (e.g., anti-IgE biologic therapy) for H1-AH refractory CSU patients after trying 
therapeutic options such as guideline-recommended H1-AH dose escalation up to 4x the licensed 
dose (Zuberbier, 2022). Nevertheless, the use of sustained, higher than licensed doses of H1-AH 
varies in practice between countries and may not be feasible or tolerated in some subjects. For 


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example, higher than licensed doses of newer H1-AHs were reported to be associated with 
dystonia and psychoactive effects (Garg, 2018; Tashiro, 2004).  
The flexibility provided in the current international guidelines allows for addition of other 
treatments such as omalizumab prior to maximizing H1-AH dosage to 4x. The omalizumab
indication for CSU sets no minimum, required dose titration of H1-AH before starting the 
therapy (EMA, 2023). 
The study design includes the continuous use of stable doses of H1-AH treatment throughout the 
study. To qualify for study entry, the investigator must ensure that subjects with CSU remain 
symptomatic while receiving stable doses of H1-AH, i.e., ‘refractory’ to 1-4x the licensed dose 
of H1-AH. This would avoid excluding subjects that may benefit from biologic treatment due to 
H1-AH drug intolerance to above labeled doses. Furthermore, the use of stable doses of H1-AH 
ranging at 1-4x the licensed dose as background therapy for CSU clinical trials is consistent with 
industry standard for studies evaluating novel pharmacological therapies for the treatment of H1-
AH refractory CSU subjects.
3.2
Rationale for Dose Selection 
A dosing regimen of 300 mg lirentelimab SC administered every 2 weeks for 6 doses is 
proposed. This regimen is based on pharmacokinetic (PK) modeling for Study AK002-017, 
comparing dose regimens for the IV infusion doses vs. the SC injection doses administered every 
28 days. These simulations showed that a dose of 300 mg lirentelimab SC provided a 
substantially lower Cmax and slightly lower 1-month trough level than 3 mg/kg lirentelimab IV.  
Discussion with experts participating in dermatologic trials with biologics and reports of external 
data from other compounds targeting other type 2 dermatological conditions such as atopic 
dermatitis support the use of higher or more frequent dosing in cutaneous diseases than in other 
allergic conditions (i.e., asthma). Dose-response relationships and results across multiple 
endpoints show trends toward improved efficacy with increasing dose and duration and suggest 
that further increases in dose or treatment duration might improve efficacy. In CSU, clinical 
response to omalizumab has been demonstrated to be dose-dependent across multiple clinical 
trials (Metz, 2020; Zhao, 2015).
Furthermore, reports of omalizumab up-dosing beyond licensed doses in the real-world treatment 
setting of CSU demonstrate success in clinical response that exceeds those reported in clinical 
trials, with a safety profile similar to that reported in clinical trials. The use of doses higher than 
the licensed dose of omalizumab 300 mg provides support to recommend the use of higher doses 
of other immunomodulating therapies, especially for subjects who are partial responders or non-


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responders and refractory to treatment. Consequently, increasing the frequency of the 300 mg 
lirentelimab SC dose from every 4 weeks to every 2 weeks is proposed for the AK002-027 study.  
Simulations using AK002-017 study data indicate that a fixed dose of lirentelimab SC 300 mg 
every 2 weeks is expected to provide greater exposure than 300 mg administered monthly 
without an increased Cmax, in contrast to the lirentelimab IV 3 mg/kg dose. The proposed SC
dose and frequency of administration is expected to provide higher steady state levels, as
supported by the safety and tolerability profile of lirentelimab IV in subjects with other 
eosinophilic and mast cell diseases. 
The concentration of lirentelimab SC of 150 mg/mL is consistent with an injection volume of 
2 mL for the 300 mg dose, which was well tolerated without injection site reactions in Study 
AK002-017. When proof of concept is established, other lirentelimab SC doses and schedules 
may be explored.
4.
Study Objectives
4.1
Primary Objective and Endpoint
The primary objective of the study will be to characterize the efficacy of lirentelimab SC in 
omalizumab-naïve and omalizumab-exposed adult subjects with H1-AH refractory CSU as 
assessed by the absolute change from baseline in UAS7 at Week 12.  
4.2 
Secondary Objectives and Endpoints 
To further characterize the efficacy of lirentelimab SC in adult subjects with CSU as measured 
by the following: 
1)
Improvement of severity of hives assessed as absolute change from baseline in Hives 
Severity Score (HSS7) at Weeks 12.
2) 
Improvement of severity of itch assessed as absolute change from baseline in Itch Severity 
Scale (ISS7) at Weeks 12. 
3) 
Complete absence of hives and itch at Weeks 12, assessed as proportion of subjects 
achieving UAS7=0. 
4) 
Occurrence of treatment-emergent adverse events (TEAE) and serious adverse events 
(SAE), laboratory values, vital signs, and physical examinations during the study. 


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4.3
Exploratory Objectives and Endpoints
The exploratory objectives of the study are to better characterize the timing and nature of the 
clinical response to lirentelimab SC in adult subjects as measured by the following exploratory 
efficacy endpoints: 
1)
Impact on subject’s
 based on absolute change in 
 at Week 12 
compared with baseline.
2)
Impact on subject's 
 at Week 12 and Week 22 assessed as proportion of 
subjects achieving 
.
3) 
Impact on 
 at Week 12 and Week 22 assessed as proportion of subjects 
achieving 
. 
4) 
Impact on 
 at Week 12 and Week 22 assessed as proportion of 
subjects achieving 
4.4 
Safety Objectives 
To evaluate the safety and tolerability of lirentelimab in adult subjects with H1-AH refractory 
CSU by determining AE incidence and severity, study withdrawals due to AE, changes in vital 
signs and laboratory tests including immunogenicity, changes in concomitant medication 
beginning on or after the first injection of study drug, and other safety parameters. 
Safety and tolerability will be assessed throughout the study by monitoring and evaluating AE, 
including any reactions to the SC injection. All TEAE will be collected from the start of study 
drug administration through Day 155 (±5 days) or Early Termination (ET) during the double-
blind period of the study.  
Severity will be assessed using the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) tables and toxicity grading scale (version 5 or the current 
version). All AE will be assigned a severity grade and will be assessed to determine whether they 
are clinically significant and related to study drug.  
Additional safety evaluations include clinical laboratory tests comprising anti-drug antibody 
(ADA) to lirentelimab SC, complete blood counts, chemistries, and urinalyses; physical exams; 
and vital sign measurements.  
The Medical Monitor will review blinded safety data throughout the study. Certain safety data 
(post-treatment cell differentials) collected during the double-blind period of the study will not 
be provided to study sites or to the Sponsor as it may cause bias. The designated Safety Monitor 


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will review blinded safety data as well as post-treatment cell counts and will escalate to the 
Medical Monitor, as needed, in a manner that does not cause bias. 
An independent Data Monitoring Committee (iDMC) has been convened and will meet in 
accordance with the iDMC charter.
5.
Study Design
5.1
Study Overview
This is a Phase 2, proof-of-concept, multicenter, randomized, double-blind, placebo-controlled 
study to evaluate the efficacy and safety of lirentelimab in adult subjects with moderate-to-severe 
H1-AH refractory CSU. Subjects enrolled in the study will receive 6 doses of 300 mg 
lirentelimab SC or placebo SC administered every 2 weeks, followed by the option to enroll in 
the open-label extension (OLE) period, contingent on defined selection criteria, to receive 
6 doses of 300 mg lirentelimab SC. Subjects will be observed for a post-treatment period of 
12 weeks.
Based on the feedback from chronic spontaneous urticaria experts and completed feasibility 
assessments, it is expected that each site will be able to screen three subjects and enroll two of 
them in the duration of the enrollment period. Enrollment is considered to be competitive. To 
ensure the enrollment goal is achieved in a timely manner, up to 70 sites (approximately 55 in 
the US, and 15 in Germany and Poland) will be initiated. If study enrollment rate can be 
achieved with fewer sites in order to meet the study timeline, then fewer sites may be needed.
Subjects will be consented and then screened for up to 3 weeks. Subjects who have been on a 
stable, approved dose regimen of 2nd generation or later H1-AH prior to screening will undergo a 
2-week eligibility screening period. Subjects who are not on a stable approved 2nd generation or 
later H1-AH dose regimen will be allowed an additional 1 week during the screening period 
during which they must reach a stable approved dosing regimen before entering the 2-week 
eligibility screening period. 
Stable approved doses of H1-AH for study purposes is defined as an H1-AH regimen between 
1× and 4× of the licensed dose and at the licensed frequency of dosing for the treatment of CSU, 
for at least 1 week prior to screening. 
Baseline H1-AH dosing regimen must be established by Day -14 (14 days prior to 
randomization) for purposes of the screening eligibility period. Baseline disease activity data will 
be collected with daily assessment of itch and hives severity, both of which will be used to 


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calculate a weekly UAS7. Subjects who meet eligibility criteria at both Day -7 and Day 1 can be 
enrolled in the study.  
The baseline UAS7 score for efficacy analysis calculations will be defined by the 7-day period 
prior to randomization. To ensure there is sufficient patient-reported outcome (PRO) data at 
baseline, a subject should complete at least four daily PRO questionnaires per week for a 
minimum period of the seven days prior to Day 1.
Subjects who meet eligibility criteria at Day -7 and Day 1 can be enrolled into the study. 
Subjects will not be allowed to rescreen for inadequate PRO compliance or PRO scores not 
meeting the minimum requirements (UAS7 16, or HSS7 8).
Aside from the exclusion noted above, subjects may be allowed to be rescreened once after 
consultation and agreement with the Medical Monitor. Subjects rescreened within 30 days of 
signing initial consent will not need to reconsent if there are no changes to the ICF. 
Eligible subjects who meet selection criteria at screening and baseline will receive the first dose 
of lirentelimab SC or placebo SC on Day 1. If the study drug is well tolerated (no stopping rules 
being met), subjects will continue to receive subsequent doses on Days 15, 29, 43, 57, and 71 for 
a total of 6 doses. Subjects will remain in the clinic for at least 1 hour of observation (or longer
as per Investigator’s discretion) following the end of dose administration after each dose. In the 
event of an injection-related reaction (IRR), the subject may require prolonged observation 
(>1 hour or until the symptoms resolve), as per Investigator’s discretion. Subjects will also be 
instructed to immediately contact the study team if any reactions occur after discharge. 
During the treatment period, subjects will return to the site for study visits as described in the 
Schedule of Events. Subjects will have the option to enter an OLE period of the study to receive 
6 doses of lirentelimab contingent on meeting defined study selection criteria. Subjects will be 
followed for another 12 weeks after the last dose. Subjects not entering the OLE period will be 
followed for 12 weeks after the last dose of study drug in the double-blind period.  
The primary endpoint will be assessed at Week 12, i.e., 2 weeks after the last dose in the double-
blind period of the study. Subjects will be stratified at randomization based on omalizumab 
experience for the treatment of CSU (exposed/naïve) and UAS7 score (16–27 or 28–42). 
At selected US sites, fresh biopsies of lesional (if available) and nonlesional skin may be 
collected from subjects predose and post-dose. Providing biopsies is optional. 


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5.2
Schedule of Events and Study Diagram
The overall schedule of assessments and procedures is described in Table 1. The study diagram 
is presented in Figure 3. 
 






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ADA: Anti-lirentelimab antibody 
FSH: Follicle-Stimulating Hormone 
IRT: Interactive Response Technology 
CBC: Complete Blood Count 
FUP: Follow-up 
UAS7: Weekly Urticaria Activity Score 
 
hCG: Human Chorionic Gonadotropin  
 
EOS: End of Study 
IP: Investigational Product 
UPDD: Urticaria Patient Daily Diary  
Table 1 Notes 
1) 
Documentation of CSU diagnosis and previous treatments should be noted in detail. This can be subject reported and/or based on medical records (see details in 
Section 12.2.6). 
2) 
At screening, height (in cm) and weight (in kg) will be recorded. Body weight only will be measured at every visit. 
3) 
Vital signs will be measured at every visit and will 
. On all dosing days: 30 (±5) minutes predose, 15 (±5) minutes 
after administration of study drug SC injection, and just prior to discharge. Additional vital sign measurements may be collected at the Investigator’s discretion if an IRR 
occurs. Vital signs including systolic and diastolic blood pressure, pulse, body temperature, and respiratory rate will be measured after the subject has been at rest for 
 minutes and before any blood draws have been obtained (unless collected for an IRR). 
4) 
A 10-lead or 12-lead ECG will be obtained at screening before any blood is drawn and after the subject has been in the resting 
 
5) 
A complete physical examination will be performed by either the Investigator or designee and include the following body system or organ assessments: skin; head, eyes, ears, 
nose, and throat; thyroid; lungs; cardiovascular; abdomen; extremities; lymph nodes; and a brief neurological examination. 
6) 
A symptom-directed physical exam (including assessment of possible injection site reactions) will be performed by the Investigator or designee, as needed, if any symptoms 
are reported. 
7) 
All subjects will be provided with the UPDD. Subjects will receive clear instructions on the completion of the diary. UPDD includes UAS7 (itch and hives) for CSU subjects 
for clinical symptoms, and activity interference. Activate daily PRO and have subject complete first PRO (UPDD) in the clinic at Screening. To ensure there is sufficient 
PRO data at baseline, subject should complete at least four daily PRO questionnaires during the seven days prior to Day 1. 
8) 
The UAS7 is the sum for 7 days of the daily Hives Severity Score (HSS) and the daily Itch Severity Scale (ISS) based on information collected in the UPDD and will be 
assessed weekly. 
9) 
The 
is a 
 questionnaire for assessing 
 and will be administered to the subject when in clinic. 
10) The 
 be completed by those subjects that also have a history of 
 
11) Subjects will be prompted to answer additional questions about symptoms related to asthma, allergic rhinitis, and allergic conjunctivitis. 
12) Blood samples for total serum IgE will be collected during screening, predose on Days 43 and 71, on follow-up Days 85, 127, and 155 or 14, 56, and 84 (±5) days after the 
last dose of study drug if early termination (ET). 


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13) Female subjects of childbearing potential are required to have serum hCG measured during the screening period. Postmenopausal women are required to have serum FSH 
measured. If FSH level is 30 mIU/mL, a negative serum hCG will be required in order for subject to proceed to randomization. Blood for chemistry will be obtained predose 
on dosing days and on follow-up days (14, 56, and 84 [±5] days after the last dose of study drug if ET).  
14) Blood for CBC with differential, including absolute blood eosinophil count, will be obtained at screening, just prior to each SC injection, 1 hour (±15 minutes) after the end 
of each SC injection, and on all follow-up days (14, 56, and 84 [±5] days after last dose if ET). All differential blood counts from Day 1 (post-dose) through the end of the 
subject’s participation in the double-blind period will be blinded to the Sponsor and the site. An unscheduled CBC may be collected at the request of the Safety Monitor. 
15) Blood for PK will be obtained predose on all dosing days as well as on Day 8 (±3) and on follow-up days (14, 56 and 84 [±5] days after last dose of study drug if ET).
16) Blood for ADA will be collected predose on dosing Days 1, 29, and 43, as well as on Day 8 (±3), and on follow-up Days 85 and 155 (14 and 84 [±5] days after last dose of 
study drug if ET). The ADA sample will also be collected any time an immunogenicity-related AE occurs. 
17) Urine will be collected for dipstick pregnancy test on all dosing days, Day 8, and all follow-up days (14, 56, and 84 [±5] days after last dose of study drug if ET) for all 
subjects of childbearing potential. Test kits will be supplied by the central laboratory. Tests will be completed on site and evaluated prior to each SC injection. 
18) Urine for standard urinalysis will be obtained at screening and on follow-up Days 85 and 155 (14 and 84 [±5] days if ET), and symptom-based, as necessary. 
19) Randomization will be conducted through the IRT system. Subjects will be randomized 1:1, 300 mg lirentelimab SC or placebo SC. They will be stratified based on biologic 
status and UAS7 score at baseline. 
20) The capture of non-serious AE and adverse events of special interest (AESI) will begin after the first dose of study drug has occurred. 
21) The reporting of serious adverse events (SAE) occurring after signing the ICF and prior to the first SC injection will be limited to those that relate to screening procedures. 
The capture of all SAE and AE that are not related to screening procedures will begin at the time of first SC injection of study drug. 
22) Lesional (if available) and nonlesional skin biopsies will be collected at selected US sites and is optional for subjects. Biopsies may be collected at baseline/predose on Day 1 
and post-dose on either Day 57, Day 71, or Day 85. See Section 12.1.11. 
23) Open-label extension dosing may start on Day 85 after all Day 85 procedures are conducted or within 7 days after the Day 85 visit. Subjects who decide to enter the OLE 
period and meet the selection criteria for the OLE period will follow the schedule of events in Appendix 9. 
24) The diary eligibility period will be 3 weeks for subjects that are screened but not on stable approved doses of H1-AH for at least a week prior to screening. They will enter 
screening at Day -21 and be stabilized on H1-AH. Subjects will start completing the UPDD the day they start screening. The diary eligibility period will be 2 weeks for 
subjects that are screened and on stable approved doses of H1-AH for at least a week prior to screening. These subjects will enter screening at Day -14. Subjects will have to 
meet the UAS7 and HSS7 criteria at Day -7 and again at Day 1, along with other entry criteria in order to qualify for the study. 
25) Subjects will either have a 3-week screening period (subjects who are not on a stable dose of H1-AH) or a 2-week screening period (subjects who are on a stable dose of 
H1-AH) depending on H1-AH usage at the time of screening (refer to Table Note #24). 
26) If assessment was performed at Day -21, it is not required to repeat at Day -14. 




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6.
Estimand Considerations 
The estimand for the AK002-027 study estimates the effect of treatment, while considering 
treatment adherence and response. The estimand will provide an answer to the question that is 
crucial to individual subjects: “If I take this study medication as part of my treatment regimen, 
without adding any further drugs that may impact the underlying disease or exit the study 
prematurely, what improvement in CSU might be anticipated after 12 weeks?”
Target of Estimation 
Consistent with the ICH E9 Addendum (FDA, 2021b), definition of the attributes of the estimand 
(target of estimation) is provided in this section.
Population Targeted by the Scientific Question
The population targeted by the scientific question is defined by the inclusion and exclusion 
criteria as part of the study protocol. Subjects may be male or female and must have a clinical 
diagnosis of CSU as defined by the study inclusion criteria. 
Variable (or Endpoint) to be Obtained for Each Subject that is Required to Address the 
Scientific Question 
The primary endpoint to be obtained for each subject in this study to address the scientific 
question is the UAS7 score at Week 12.  
Specification of How to Account for Intercurrent Events to Reflect the Scientific Question
of Interest
The following intercurrent events (ICE) will be anticipated and addressed: 
Premature discontinuation from the study  
Use of prohibited medications or rescue therapy during the study 
For the analysis of the estimand, UAS7 scores will be set to missing from the point when an ICE 
occurs.  
7.
Criteria for Evaluation 
7.1
Safety Endpoints
The safety and tolerability of lirentelimab SC will be assessed by determining the incidence, 
relationship to study drug, and severity of TEAE, withdrawals due to AE, and changes in vital 


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signs, laboratory tests, changes in concomitant medication use due to AE, immunogenicity, and 
other safety parameters. These endpoints will be based on the following:  
 
Adverse events (Section 14.1) including severity, withdrawals due to AE, and other safety 
parameters. 
 
Adverse events of special interest (AESI), injection-related reactions (IRR), malignancy, 
parasitic infections, and opportunistic infections (Section 14.3) 
 
Anti-drug antibodies (Section 12.3.6): Blood (serum) will be collected for assessment of 
ADA using a validated assay method.  
 
Blood chemistry (Section 12.3.1) 
 
Hematology (Section 12.3.1) 
 
Urinalysis (Section 12.3.4) 
 
Physical examination (Section 12.2.2 and Section 12.2.4) 
 
Changes in vital signs (Section 12.2.7) 
 
Changes in concomitant medication use due to AE (Section 12.2.1) 
7.2 
Pharmacokinetic Endpoints  
Blood (serum) will be collected for assessment of lirentelimab concentrations using a validated 
enzyme-linked immunosorbent assay (ELISA) method. Pharmacokinetic blood samples will be 
obtained predose on Days 1, 15, 29, 43, 57, 71, 85, 127, and 155 (or ET) and on Day 8 between 
Dose 1 and Dose 2. Additional PK samples will be collected in the OLE period of the study. 
Blood (serum) will be collected for assessment of lirentelimab anti-drug antibodies (ADA) using 
a validated assay method. ADA blood samples will be obtained predose on Days 1, 29, and 43, 
on follow-up days 85 and 155 (or ET), on Day 8 between Dose 1 and Dose 2, and in the event of 
a suspected immunogenicity-related AE. Additional ADA samples will be collected in the OLE 
period of the study. 
7.2.1 
Primary Efficacy Endpoints 
The primary endpoint will be the absolute change from baseline in UAS7 at Week 12 (Day 85).  
7.2.2 
Secondary Efficacy Endpoints  
Secondary endpoints will be: 
1) 
Improvement of severity of hives assessed as absolute change from baseline in HSS7 at 
Week 12.  


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2)
Improvement of severity of itch assessed as absolute change from baseline in ISS7 at 
Week 12. 
3)
Complete absence of hives and itch at Weeks 12 assessed as proportion of subjects 
achieving UAS7 = 0.
4) 
Occurrence of TEAE and SAE, laboratory values, vital signs, and physical examinations 
during the study.
7.2.3 
Exploratory Efficacy Endpoints 
1)
Impact on subject’s
 based on change in
 at Week 12 vs baseline.
2) 
Impact on subject's 
 at Week 12 and Week 22 assessed as proportion of 
subjects achieving 
.
3) 
Impact on 
 at Week 12 and Week 22 assessed as proportion of subjects 
achieving 
 
4) 
Impact on 
 at Week 12 and Week 22 assessed as proportion of 
subjects achieving
8. 
Subject Selection 
8.1 
Number of Subjects
Approximately 130 subjects with H1-AH refractory urticaria are expected to be randomized in 
this study. Subjects will be randomized 1:1 in double-blind manner to receive:  
 
6 doses of 300 mg lirentelimab SC every 2 weeks
6 doses of placebo SC every 2 weeks
8.2
Number of Sites
Up to 70 clinical centers in the United States, Germany, and Poland.
Based on the feedback from chronic spontaneous urticaria experts and completed feasibility 
assessments, it is expected that each site will be able to screen three subjects and enroll two of
them in the duration of the enrollment period. Enrollment is considered to be competitive. To 
ensure the enrollment goal is achieved in a timely manner, up to 70 sites (approximately 55 in 
the US, and 15 in Germany and Poland) will be initiated. If study enrollment rate can be 
achieved with fewer sites in order to meet the study timeline, then fewer sites may be needed.


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8.3
Study Population
Approximately 130 male and female subjects with H1-AH refractory urticaria will be enrolled in
the study. Subjects will be either biologic-naïve or biologic-exposed. Biologic-exposed subjects 
include those who have demonstrated secondary loss of response, intolerance, or lack of access 
to biologics due to economic reasons. 
8.4
Inclusion Criteria
Subjects with CSU are eligible to enroll in the study if they meet all of the following criteria.
1)
Subject is able to understand the information on the study, has the capacity to consent, and 
has provided written informed consent.
2) 
Male and female sub
 
3) 
 
4) 
Diagnosis of moderate-severe CSU refractory to H1-AH at a minimum of the licensed dose 
at the licensed frequency at the time of randomization as defined by the following: 
 P
Screening Visit 1. 
 UAS7 score (range 0–
–
consecutive days prior to screening Day -7 Phone Visit and during the 7 consecutive 
days prior to randomization (Day 1).  
5) 
Subjects that are omalizumab-naïve or omalizumab-exposed. Omalizumab-exposed 
subjects are those that have demonstrated secondary loss of response, intolerance, or lack of 
access to biologics due to economic reasons. 
6)
Subjects must be on a stable dose of H1-AH, between 1× and 4× of the licensed dose and at 
the licensed dosing frequency, for treatment of CSU for at least 1 week prior to screening 
and willing to remain on a stable dose throughout the study.
7)
Able and compliant with completing a daily symptom eDiary for the duration of the study 
and adherent to the study visit schedules.
8)
Female subjects must be either postmenopausal (defined as no menses for 12 months 
without an alternative medical cause) with FSH level >30 mIU/mL at screening or surgically 
sterile (tubal ligation, hysterectomy, or bilateral oophorectomy) for at least 3 months or, if 
of childbearing potential, have a negative serum pregnancy test and agree to use a highly 
effective method of contraception as defined in this protocol or abstain from sexual activity, 


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if compliant with preferred and usual lifestyle of the subject, from screening until the end of 
the study or for 120 days following the last dose of study drug, whichever is longer. 
the subject will be required to have a negative serum pregnancy test during the screening 
period and will also be required to have a negative urine dipstick pregnancy test prior to 
dosing and at each study visit.
9) 
Male subjects with female partners of childbearing potential must agree to use a highly 
effective method of contraception as defined in this protocol or abstain from sexual activity 
from screening until the end of the study or for 120 days following the last dose of study 
drug, whichever is longer. All fertile men with female partners of childbearing potential 
should be instructed to contact the Investigator immediately if they suspect their partner 
might be pregnant (e.g., missed or late menstrual period) at any time during study 
participation. 
8.5 
Exclusion Criteria 
Subjects will be excluded from the study if they meet any of the following criteria:
1) 
History of hypersensitivity to the study drugs or their excipients or to drugs of similar 
chemical classes (i.e., murine, chimeric or human antibodies).
2) 
Current use of biologics for any indication.
3) 
Demonstrated lack of primary response to treatment with a biologic therapy (e.g., 
omalizumab) for the treatment of CSU, defined as no response to treatment despite 
complete adherence to a prescribed regimen (e.g., 
mg 
per month) for at least 3 months, based on interview at screening. 
4) 
Use of any of the following treatments within 4 weeks prior to the baseline visit or any 
condition that in the opinion of the Investigator is likely to require such treatment(s) during 
the first 4 weeks of study treatment: 
 Immunosuppressive or immunomodulatory drugs, including but not limited to systemic 
calcineurin inhibitors (e.g., cyclosporin, tacrolimus), mTOR inhibitors (e.g., sirolimus, 
everolimus), anti-metabolites (e.g., azathioprine, methotrexate, 6-mercaptopurine, 
leflunomide, mycophenolate mofetil), alkylating agents (e.g., cyclophosphamide), and 
eosinophil-depleting drugs (e.g., pramipexole). 
 Routine (daily or every other day during 5 or more consecutive days) doses of systemic 
hydroxychloroquine 


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 Plasmapheresis 
5) 
Use of oral Janus kinase (JAK) inhibitors within 8 weeks of the baseline visit (requires 
discussion with Medical Monitor prior to subject enrolling in study). 
6) 
Use of any of the following treatments within 3 weeks prior to the baseline visit: 
 H2-AH 
 Routine (daily or every other day during 5 or more consecutive days) doses of systemic 
corticosteroids 
 Regular (daily or every other day) doxepin (oral) 
 Leukotriene Receptor Antagonists (LTRA) (e.g., montelukast, zafirlukast) 
7) 
H1-AH use at greater than approved doses or greater than local CSU guideline 
recommended doses after Screening Visit 1. 
8) 
Previous treatment with biologics or intravenous immunoglobulin: 
 Any cell-depleting agents including but not limited to rituximab; within 6 months prior 
to the baseline visit or until lymphocyte count returns to normal, whichever is longer. 
 Other biologics, including investigational biologics (e.g., dupilumab, omalizumab, 
benralizumab, etc.) and TNF inhibitors (e.g., infliximab, adalimumab) within 5 half-
lives if known or 8 weeks prior to baseline visit, whichever is longer.
 Intravenous immunoglobulin (IVIG) within 5 half-lives 
9) 
Planned or anticipated use of any prohibited medication. 
10) Subjects having causes other than CSU for their urticaria including symptomatic 
dermographism, cholinergic urticaria, or any inducible urticaria. 
11) Diseases other than chronic urticaria with urticarial or angioedema symptoms, including 
chronic itching, that in the Investigator’s opinion might influence study evaluations and 
results. 
12) Subjects with known or suspected urticarial vasculitis. 
13) Subjects with known or suspected hereditary angioedema. 
14) Any other skin disease associated with chronic itch, including atopic dermatitis, that in the 
Investigator’s opinion might influence study outcome and subject’s interpretation of 
symptoms caused by CSU. 


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15) A helminth parasitic infection diagnosed within 6 months prior to the date that informed 
consent is obtained and has not been treated with or has failed to respond to standard-of-
care therapy.
16) Evidence of active HIV infection at screening based on serology or evidence of active 
hepatitis B or C at screening based on serology. 
17) Presence of an abnormal screening laboratory value considered to be clinically significant 
by the Investigator. 
18) Known or suspected history of alcohol, drug, or other substance abuse or dependence that 
in the opinion of the Investigator may interfere with study participation or assessments. 
19) Treatment with chemotherapy or radiotherapy in the preceding 6 months. 
20) History of malignancy except carcinoma in situ in the cervix, early-stage prostate cancer, or 
non-melanoma skin cancers. 
21) Women who are pregnant, breastfeeding, or planning to become pregnant while 
participating in the study. 
22) Participation in a concurrent interventional study with the last intervention occurring within 
30 days prior to study drug administration (or 90 days or 5 half-lives, whichever is longer, 
for biologic products). 
23) Subjects who weigh <40 kg at screening. 
24) Any other reason that in the opinion of the Investigator or the Medical Monitor makes the 
subject unsuitable for enrollment. 
25) Vaccination with live attenuated vaccines within 30 days prior to initiation of treatment in 
the study, during the treatment period, or vaccination expected within 5 half-lives 
(4 months) of study drug administration.  
Note: This exclusion criterion does not apply to all types and formulations of vaccines 
(including live attenuated vaccines) currently authorized/approved by FDA or other 
regulatory authority for the prevention of COVID-19, which may be administered 
before, during, or after the study.  
 
The vaccine should not be administered within 3 days before and within 3 days after 
the administration of lirentelimab so that any side effects caused by either of the 
2 medications can be more easily determined. 


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26) Employees or relatives of the Sponsor or the Investigator, or other persons dependent on the 
Sponsor or the Investigator. 
27) Commitment to an institution by order issued either by the judicial or the administrative 
authorities.
28) Presence of a SARS-CoV-2 infection and/or have not completed an authorized/approved 
COVID-19 primary immunization series as per national recommendations at the time of 
screening.
Acceptable and required documentation to confirm inclusion and exclusion criteria is further 
explained in the Study Reference Manual and listed in the eCRF.
8.6
Safety Evaluations 
Safety and tolerability will be assessed throughout the study by monitoring and evaluating AE, 
including any reactions to the SC injection. All TEAE will be collected from the start of study 
drug administration through Day 155 (±5 days) or ET for both the double-blind period and OLE 
period.  
Severity will be assessed using the NCI CTCAE, version 5.0 or most current version. All AE 
will be assigned a severity grade and will be assessed to determine whether they are clinically 
significant and related to study drug.  
Additional safety evaluations include clinical laboratory tests comprising ADA to lirentelimab, 
complete blood counts, chemistries, and urinalyses; physical exams; and vital sign 
measurements.  
The Medical Monitor will review blinded safety data throughout the study. Certain safety data 
(post-treatment cell differentials as well as tissue eosinophil and mast cell counts) will not be 
provided to study sites or to the Sponsor as it may cause bias. The Safety Monitor will review 
blinded safety data as well as unblinded cell counts and will escalate to the Medical Monitor as 
needed in a manner that does not cause bias. 
9.
Prior and Concurrent Medications 
Prior and concomitant medications include both prescribed and over-the-counter medications 
taken 30 days prior to the screening visit and will be recorded in the electronic Case Report 
Forms (eCRF). Prior medications and therapies taken for the treatment of CSU, even if taken 
>30 days before the screening visit, will be documented in the eCRF.  


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Any medications that are exclusionary should be discontinued or handled as outlined in 
Section 9.1 of the protocol. 
Subjects should be advised against taking any new medications, both prescribed and over-the-
counter, without consulting the Investigator, unless it is required for emergency use, or it is a 
COVID-19 vaccine. 
Immediately prior to the first SC injection, study site personnel should ensure that the subject 
continues to meet the inclusion criteria and none of the exclusion criteria (including use of 
prohibited medications). 
All medications taken for the treatment of CSU and any other medications taken during the 
30 days prior to screening and during the study must be documented on the eCRF. All 
medications used to treat IRR or AE during the study must be documented.  
9.1
Prohibited Medications 
The introduction of medications or therapies for other medical conditions known to affect CSU 
(e.g., systemic corticosteroids, H2-AH, immunosuppressive or immunomodulatory drugs, 
biologics, hydroxychloroquine, oral doxepin, intravenous IgG, plasmapheresis) are not permitted 
during the study and during the interval prior to entry into the study as defined in Section 8.5 
Exclusion Criteria with the exception of use as rescue therapy. 
Topical corticosteroids applied to the skin to manage CSU are prohibited within 7 days prior to 
baseline visit.
The list of prohibited medications is not considered all inclusive. Medication should be assessed 
for adherence to the indication and other inclusion/exclusion criteria. The Investigator should 
instruct the subject to notify the study site about any new medications he/she takes subsequent to 
receiving the study drug. All medications and significant non-drug therapies (including physical 
therapy and blood transfusions) administered following initial study drug treatment must be 
listed on the concomitant medications/significant non-drug therapies CRF. Planned or 
anticipated major medical procedures or surgeries should be avoided during the clinical study.  
Any biologics or medications that may interfere with the study efficacy or safety assessments 
such as systemic immunosuppressive or immunomodulatory drugs or biologics, including but 
not limited to IL-5 modulators (e.g., benralizumab, reslizumab, mepolizumab), IL-4 and IL-13 
antagonists (e.g. dupilumab), systemic calcineurin inhibitors (e.g., cyclosporin, tacrolimus), 
mTOR inhibitors (e.g., sirolimus, everolimus), anti-metabolites (e.g., azathioprine, 
methotrexate, 6-mercaptopurine, leflunomide, mycophenolate mofetil), alkylating agents (e.g., 


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cyclophosphamide), TNF inhibitors (e.g., infliximab, adalimumab), anti-IgE antibodies (e.g., 
omalizumab), eosinophil-depleting drugs (e.g., pramipexole), and systemic corticosteroids are 
prohibited throughout the study.  
Subjects can be omalizumab-naïve or omalizumab-exposed for the treatment of their CSU. 
Biologic-exposed subjects include those who have demonstrated secondary loss of response, 
intolerance, or lack of access to biologics due to economic reasons.  
Subjects who have demonstrated lack of primary response to treatment with a biologic for their 
CSU for at least 3 months will not be allowed to participate.  
9.2 
Allowed Medications 
Medications taken for the treatment of CSU, such as 2nd generation or later H1-AH, are allowed 
during the study, unless prohibited (Section 9.1), and total daily doses are to remain stable during 
the entire course of the study unless change is required for unforeseen medical necessity. 
Increases in the dose of H1-AH for CSU symptom management (or other reasons) will be 
considered rescue therapy, and the subject will be considered a non-responder at the time of the 
increase in dosage. Subjects should also not decrease the dosage of their H1-AH over the course 
of the study to prevent confounding of the study results. 
Only one H1-AH medication should be used during the study. If more than one H1-AH 
medications are used prior to screening, subject must reduce to only one stable 2nd generation or 
later H1-AH and follow the appropriate washout before eligibility screening. All CSU 
medications used during the screening period and throughout the study will be documented in 
the CRF. Any allowed medications that are taken must remain stable throughout the study.  
All types and formulations of vaccines (including live attenuated vaccines) currently authorized 
by FDA or other regulatory authority for the prevention of COVID-19 may be administered 
before, during, or after the study.  
The vaccine should not be administered within 3 days before and within 3 days after the 
administration of lirentelimab so that any side effects caused by either of the 2 medications can 
be more easily determined. 
9.3 
Rescue Medications 
The use or initiation of any new H1-AH, increase in the total daily dose of an H1-AH, or the 
use of systemic or topical corticosteroids for the purpose of treating CSU at any point in the 
study, as compared to baseline, will be considered rescue therapy. Rescue medications are not 
allowed during the study unless deemed medically necessary at the discretion of the Investigator 


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(i.e., to treat flare-ups of CSU symptoms) and while subjects will be encouraged to remain in the 
study following the use of any of these rescue therapies, they will be deemed as treatment 
non-responders for data evaluation purposes.  
Subjects initiating rescue therapy for CSU symptoms or for the treatment of any other medical 
condition with any of the prohibited medications listed in Section 9.1 that could pose a potential 
safety risk to the subject (e.g. immunomodulators or other biologic therapies) at any point during 
the double-blind period of the study will be discontinued from the study but will be followed for 
the 12-week follow-up period. 
The use of systemic corticosteroids at any point during the study for conditions other than CSU 
is discouraged, and alternative treatments should be considered when possible. If the use of 
systemic corticosteroids is deemed medically necessary for periods of less than 5 consecutive 
days to treat conditions other than CSU, the subject may remain in the study at the discretion of 
the Medical Monitor, and the doses of systemic corticosteroids and reason for administration 
must be documented as concomitant medications. 
10. Study Treatment
10.1 
Formulation of Test Product and Placebo 
Lirentelimab SC Drug Product: The lirentelimab drug product is intended for SC injection. 
Each drug product vial contains a nominal volume of 1 mL. It is a sterile, preservative-free 
solution that contains 
 lirentelimab in 
 
, pH 6.0 in Water for Injection 
(WFI). The solution is visually characterized as clear to slightly opalescent, appearing colorless 
to slightly yellow.
Placebo SC Product: The placebo is intended for SC injection. Each placebo vial contains a 
nominal volume of 1 mL. It is a sterile, preservative-free solution that contains 
 
, pH 6.0 in WFI. The solution is visually characterized as clear to slightly 
opalescent, appearing colorless to slightly yellow. 
Note: Lirentelimab SC and placebo SC will be referred to as “study drug.”  
Each dose (lirentelimab SC or placebo SC) will comprise 1 SC injection of 2 mL of study drug 
administered in the front of the thigh with a 27-gauge SC needle. Maximum volume 
administered will be 2 mL. Lirentelimab SC or placebo SC (based on randomization assignment) 


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will be administered on Day 1 (±3), Dose 1; Day 15 (±5), Dose 2; Day 29 (±5), Dose 3; Day 43 
(±5), Dose 4; Day 57 (±5), Dose 5; and Day 71 (±5), Dose 6. 
Subjects will have the option to enroll in an OLE period to receive 6 doses of 300 mg 
lirentelimab SC. Subjects will be observed for at least 1 hour after each injection.
Dosing visits must be conducted within the ± windows stipulated in the protocol with the 
following requirements: 
The interval between dosing visits must be at least 7 days and no more than 21 days from 
the previous dosing visit unless directed otherwise by Allakos. The interval count starts the 
day after the visit and includes the day of the next visit. 
The interval between the final dosing visit and the efficacy visit (Day 85) must be at least 
11 days and no more than 17 days from the final dosing visit unless directed otherwise by 
Allakos. The interval count starts the day after the visit and includes the day of the next 
visit. 
10.2
Study Drug Packaging and Labeling
Study drug is supplied as a sterile liquid in 2R Type I clear glass vials, securely sealed with a 
fluoropolymer-coated bromobutyl stopper and aluminum flip-off cap. It is intended for SC 
injection. The vials are packed in cartons, and each carton contains 1 vial. 
Each vial and each carton will be labeled with all required details as per the applicable local 
regulations. The labels will include, among other details, an investigational use statement, lot 
number, kit number, Sponsor name, and directions for storage. Each vial will also contain a tear-
off label with kit number and space to document Subject ID and dispensing/administration date. 
This tear-off label should be applied to the IP Injection Dispensing Worksheet and maintained 
with the source documents. 
10.3
Supply of Study Drug to the Investigational Site
The Sponsor (or designee) will ship study drug to the investigational sites. The initial study drug 
shipment will be shipped after all required regulatory documentation and approvals have been 
received by the Sponsor, the contract has been executed, and the first screened subject is entered 
into the IRT system. Subsequent study drug shipments will be triggered automatically based on 
predetermined supply levels and enrollment activity at the site. 


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10.4
Study Drug Dosage and Dosage Regimen
Subjects will be randomly assigned through the IRT system to an active dose group of 6 doses of 
lirentelimab SC or placebo SC (Table 2).
Study drug will comprise 1 SC injection of 2 mL administered in the front of the thigh with a 
27-gauge needle. Injection sites should be alternated between each thigh for subsequent 
injections. Maximum volume administered per SC injection will be 2 mL as indicated in the 
study Pharmacy Manual on Day 1 (±3), Dose 1; Day 15 (±5), Dose 2; Day 29 (±5), Dose 3; 
Day 43 (±5), Dose 4; Day 57 (±5), Dose 5; and Day 71 (±5), Dose 6. 
Table 2 
Study Drug Administration
Route 
Dose (6 Doses Biweekly Over 10 Weeks) 
Total Injection Volume 
Subcutaneous
300 mg lirentelimab SC or Placebo SC
2 mL
10.5
Preparation of Study Drug 
A study pharmacist or designee will prepare the study drug for the SC injection. On the day of 
dosing, the designated study pharmacist will prepare lirentelimab or placebo for SC injection. 
Appropriate aseptic technique will be used, and the drug will be dispensed according to the 
Pharmacy Manual for AK002-027. Refer to the Pharmacy Manual for additional details.  
Lirentelimab does not meet the definition of a “hazardous drug” and therefore is not required to 
be classified according to the USP Hazardous Drug Grouping. A drug is considered to be 
hazardous if it exhibits one or more of the following characteristics in humans or animals: 
carcinogenicity, teratogenicity or developmental toxicity, reproductive toxicity, organ toxicity at 
low doses, genotoxicity, or structure and toxicity profiles of new drugs that mimic existing 
hazardous drugs (USP, 2019). Since lirentelimab is not considered to be a hazardous drug,
special precautions do not need to be taken when handling or preparing the study drug.  
10.6 
Study Drug Administration 
Specific instructions on administration and supplies required for administration are detailed in 
the Pharmacy Manual. In general, study drug will comprise 1 SC injection administered in the 
front of the thigh with a 27-gauge needle. Injection sites should be alternated between each thigh 
for subsequent injections. Subjects will be observed for at least 1 hour after the SC injection and 
per the Investigator’s discretion.  
10.7 
Study Drug Storage 
Study drug will be stored by the study sites at 2°C to 8ºC under lock at the designated pharmacy 
location. Access will be restricted to designated clinic/pharmacy staff. If the temperature of study 


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drug storage in the clinic/pharmacy exceeds or falls below this range, the study drug will be 
quarantined, and the temperature excursion will be reported to the Sponsor or designee. The 
Sponsor will notify the site if the study drug can to be released from quarantine. Refer to the 
Pharmacy Manual for additional details.
10.8
Study Drug Accountability
The site’s study pharmacist/designee is responsible for maintaining accurate and current records 
accounting for the receipt, dispensing, preparation, use, return (or destruction), and final 
disposition of all investigational product (IP). All kit assignments and dispensations will be 
documented on the source documents. The Master IP Accountability Log should be used to 
capture receipt, dispensing, and return (or destruction). Electronic IP accountability systems may 
be used, depending on site preference, as long as the same information is captured. The study 
monitor will verify entries on these documents throughout the course of the study. Study drug 
will be labeled with kit numbers but will not reveal whether the kit contains active drug or 
placebo. 
11.
Subject Numbering, Stratification, Randomization, and Blinding 
11.1 
Subject Numbering  
Each subject who provides informed consent will be assigned a patient identification number 
(PID) that uniquely identifies them as a subject in the study. The PID will consist of a 9-digit 
number: 
 
The first 3 digits designate the study number. For this study, the number is 227. 
The second 3 digits designate the site number.
The last 3 digits designate the order of consent at the site (the first subject who provides 
consent is 001, the second subject is 002, etc.).
Subjects will not be allowed to rescreen for inadequate PRO compliance or PRO scores not 
meeting the minimum requirements (UAS7 16, or HSS7 8).
Aside from the exclusion noted above, subjects may be allowed to be rescreened once after 
consultation and agreement with the Medical Monitor. Subjects rescreened within 30 days of 
signing the initial consent will not need to sign a new ICF providing no changes have been made 
to the ICF. A new PID will be assigned at the time of rescreening, and the subject will maintain 
the same PID throughout the study.


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11.2
Stratification and Randomization
To be randomized into the study, the subject 
refractory to HI-AH. The diagnosis of moderate-to-severe CSU refractory to approved doses of 
H1-AH at the time of randomization is defined by the 
consecutive weeks prior to Screening Visit 1 and UAS7 score (range 0–
(range 0–
randomization. The subject must also meet all other 
applicable inclusion criteria and none of the exclusion criteria.
If the subject qualifies for the study after completing all of the screening procedures, on the day 
of the first SC injection (Dosing Day 1), the site will access the IRT system in order to stratify 
and randomize the subject into the study. The IRT system will then randomly assign the subject 
at an allocation ratio to lirentelimab SC 300 mg or placebo SC for 12 weeks (6 doses) in a 
double-blind manner and will send an email to the pharmacist and/or designee detailing the kit 
number(s) to use to prepare the SC injection.  
The subject will be stratified based on: 
 
UAS7 score: 16–27 vs. 28–42. 
 
Omalizumab experience for the treatment of CSU: omalizumab-exposed vs. 
omalizumab-naïve. 
Approximately 130 subjects (65 per arm) will be randomized to treatment with lirentelimab SC 
or placebo SC. A subject is considered enrolled in the study when the subject receives the first 
dose of study drug. For subsequent SC injections the coordinator will access the IRT system on 
the day of SC injection and enter the PID; the system will assign the subject the dose according 
to the subject’s randomization number. The pharmacist and/or designee will then receive an 
email detailing the kit number(s) to prepare.
Prior to each SC injection, the Investigator or designee will confirm the PID recorded on the SC 
syringe provided by the pharmacist matches the subject. The subject identification should be 
confirmed and documented by a second party prior to administering the SC injection, whenever 
possible. There will not be any unblinding information on the IRT notification to the pharmacist 
or on the vials provided to the site.
The assignment of treatment to lirentelimab SC or placebo SC will be securely retained in the 
IRT system until such time as designated by the Statistical Analysis Plan (SAP). 


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11.3
Blinding
The identity of test and control treatments will not be known to Investigators, Sponsor, research 
staff, subjects, or the study monitor. The following study procedures will be in place to ensure 
double-blind administration of study treatments: 
 
Access to the randomization codes will be strictly controlled by the IRT system. 
 
Throughout the double-blind study, the blind should remain unbroken except for an 
emergency when knowledge of the subject’s study medication is necessary for further 
management or if required for regulatory reporting. The Medical Monitor approves any 
emergency blind break, if at all possible, prior to the unblinding.  
 
The lirentelimab SC and placebo SC administered by SC injection will be identical in 
appearance.  
 
Results from the analysis of blood samples for PK and ADA will not be provided to the 
Investigator and Sponsor until after final database lock of the double-blind study.  
 
Results from the analysis of blood samples for histamine/tryptase tests (collected in case of 
possible anaphylaxis) will not be provided to the Investigator and Sponsor until after final 
database lock of the double-blind study, unless required for immediate safety reasons.  
 
Results of the assessments noted below will not be provided to the Investigator and Sponsor 
until after final database lock of the double-blind study to avoid bias. The results will be 
reviewed on an ongoing basis by the Safety Monitor and escalated as appropriate.  
 Differential cell counts including neutrophils, eosinophils, basophils, monocytes, and 
lymphocytes.  
Other than under the conditions described above, the study blind will be revealed on completion 
of the study as noted in Section 17.4. 
11.4 
Breaking the Blind 
Breaking the blind in a clinical study on an emergency basis by the site should only occur when 
knowledge of the treatment to which a subject was allocated would have implications for the 
emergency medical management of the subject, if required for regulatory reporting, or if there is 
a pregnancy during the pregnancy reporting period. 
If necessary, emergency breaking of the blind can be conducted through the IRT by the 
Investigator or other registered site users and/or the Medical Monitor. Whenever possible, the 
Investigator should contact the Medical Monitor before an emergency unblinding. Reason for 


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unblinding, person conducting the unblinding, personnel who know the unblinded treatment, and 
date/time of unblinding will be recorded. 
12.
Study Procedures and Guidelines
Table 1 provides the schedule of assessments depicting the required testing procedures to be 
performed for the duration of the study. When multiple evaluations are scheduled at the same 
time point, the priority for each will be as follows: 
At home: The subject should complete the UPDD at home daily. Subjects who have a 
history of 
 should also complete the 
. 
At the clinic: 
1) UAS7, 
 forms, and Atopic Conditions Questionnaire. 
2) Vital signs will be obtained after the subject has been 
 
3) Physical examinations can be performed, and urine samples can be collected either 
before or after other evaluations, unless otherwise specified.  
12.1 
Pharmacodynamic/Efficacy-Related Procedures 
12.1.1 
Urticaria Patient Daily Diary 
All subjects will be provided with an Urticaria Patient Daily Diary (UPDD) (Appendix 1). The 
subjects will receive clear instructions on the completion of the diary. UPDD includes UAS7 
(itch and hives) for CSU subjects for clinical symptoms and activity interference. Sub-
investigators and subjects will receive appropriate training and guidance on the use of the 
UPDD. 
12.1.2 
Weekly Urticaria Activity Score 
The UAS7 is the sum for 7 days of the daily Hives Severity Score (HSS) and the daily Itch 
Severity Scale (ISS) score. The possible range of the weekly UAS7 score is 0–42. Complete 
UAS7 response is defined as UAS7 = 
 from baseline. 
12.1.3 
Hives Severity Score 
The severity of hives will be recorded by all subjects once daily in their UPDD, on a scale of 
0 (none) to 3 (>50 hives) (Table 3). A weekly HSS7 is derived by adding the average daily 
scores of the 7 days preceding the visit. Therefore, the possible range of the weekly score is 0-21. 
A complete hives response is defined as HSS7 = 0. When one or more of the daily scores are 
missing, the following principles will be applied to handle the missing data: 


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At baseline and post-baseline time points, if a subject has at least 4 non-missing daily 
scores within a given week, the weekly score is calculated as the sum of the available 
scores in that week, divided by the number of days that have a non-missing diary score, 
multiplied by 7.   
 
At post-baseline time points, if there are less than 4 non-missing daily scores within a given 
week, then the weekly score is set to missing for the week.  Missing data will be imputed 
using methods outlined in the SAP. It is worth remarking that missing data imputation is 
not required at baseline since a minimum of 4 daily scores per week are required to 
determine subject eligibility for the study.
Table 3 
Hives Severity Score 
Score 
Number of Hives per 24 Hours 
0 
None 
1
< 20 
2 
20-50 
3 
> 50 
12.1.4 
Itch Severity Score 
The severity of itching will be recorded by all subjects once daily in their UPDD, on a scale of 
0 (none) to 3 (severe) (Table 4). A weekly ISS7 is derived by adding the average daily scores of 
the 7 days preceding the visit. Therefore, the possible range of the weekly score is 0-21. A 
complete itch response is defined as ISS7 = 0. Partially missing diary entries will be handled in 
the same way described for the hives severity score. 
Table 4 
Itch Severity Score 
Score
Pruritus (Itch) over the Last 24 Hours
0 
None 
1
Mild (present but not annoying or troublesome)
2 
Moderate (troublesome but does not interfere with normal daily activity or sleep) 
3 
Severe (severe itching, which is sufficiently troublesome to interfere with normal 
daily activity or sleep) 
12.1.5 
 
The 
 is a 
 questionnaire for assessing 
 
 and will be administered to the subject when in the clinic (Appendix 3). Each 


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item is rated on a scale of 
 and a total score is calculated (range, 
). Higher scores 
indicate 
. 
12.1.6
 
The 
 is a 
 questionnaire used to measure the 
 
 of an affected person (Appendix 4). The format is a simple response 
 
 that assess 
 over the past week with an 
overall scoring system of 
 a high score is indicative of a 
 is a 
self-administered questionnaire. Subjects will complete this during screening, Day 8 visit, 
predose on Days 1, 15, 29, 43, 57, and 71, and during follow-up on Days 85, 127, and 155 or ET.
12.1.7
Subjects that have a history of 
 will have to complete the 
 daily. The 
 is a 
, self-administered, daily questionnaire that records 
 in subjects with 
 (Appendix 2). The format provides 
 for each item (scored 
), with a minimum score of  and a maximum score of 
 per day. Lower scores reflect 
 
 and higher scores reflects 
. The 
 describes the 
 
 of 7 consecutive days for a score range from 
. Subjects will complete this 
during screening, Day 8 visit, predose on Days 1, 15, 29, 43, 57, and 71, and during follow-up on 
Days 85, 127, and 155 or ET. 
12.1.8
Atopic Conditions Questionnaire
On Day 1 and Day 85, subjects will be prompted to answer additional questions about severity of 
symptoms related to asthma, allergic rhinitis, and allergic conjunctivitis (Appendix 5).
12.1.9
Photographs 
The site staff may take photographs of subjects’ CSU disease to track study drug response and 
disease progression. This will depend on the sites’ standard operating procedures regarding 
photography. Subjects will be consented before the Sponsor will have access to any images.
12.1.10 Complete Blood Count with Differential
Blood for CBC with differential, including absolute blood eosinophil count, will be obtained at 
screening, just prior to each SC injection, and 1 hour (±15 minutes) after the end of each SC 
injection, as well as on all follow-up days 85, 127, and 155 (±5) or 14, 56, and 84 (±5) days after 
last dose, if ET. The blood sample will be processed and shipped in accordance with the 
Laboratory Manual and lab kit instructions. A central laboratory will analyze the blood sample 
and provide results for CBC with differential including hemoglobin, hematocrit, platelet count, 


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red blood cell count, white blood cell count, and absolute differential count (neutrophils, 
lymphocytes, monocytes, eosinophils, and basophils).  
During the double-blind period, all differential blood counts from Day 1 (post-dose) through the 
end of the subject’s participation will be blinded to the Sponsor and the site. An unscheduled 
CBC may be collected at the request of the Safety Monitor. The blood differential test results 
(neutrophils, eosinophils, basophils, monocytes, and lymphocytes) will be blinded from the 
Investigator and Sponsor from post-dose Day 1 through Day 155 or ET and until database lock 
has occurred. If a subject continues to the OLE period of the study, all differential blood counts 
will be blinded for the first (OLE Day 1) predose assessments and will be unblinded after the 
subject has received the first dose of the study drug. 
As described in the Investigator’s Brochure, changes in certain lab results are a part of the 
expected effects of lirentelimab and could potentially introduce bias in blinded members of the 
study. The Safety Monitor will have real-time access to these laboratory results and will review 
and escalate any concerns/issues to the Medical Monitor and/or the site as appropriate. An 
unscheduled CBC with differential may be collected if requested by the Safety Monitor. All 
panic alerts for blinded values will be sent to the Safety Monitor and evaluated in real time.  
12.1.11 Fresh biopsies 
At selected US sites only: Optional lesional (if available) and nonlesional skin biopsy samples 
will be collected at selected sites for exploratory analysis at baseline/predose on Day 1 and post-
dose at either Day 57, Day 71, or Day 85 during the double-blind period. These fresh biopsies 
will be shipped overnight to the Sponsor for additional cell phenotyping and other exploratory 
analysis. Once the Sponsor receives the biopsies, they will be dissociated into single cells and 
immunophenotyped for immune cell populations (lymphocytes, eosinophils, basophils, mast 
cells, neutrophils, and macrophages) and other exploratory analysis. Detailed instructions on 
collection, packaging and shipping will be included in the lab manual. All materials required for 
shipment of the additional samples will be provided to the site by the Central Laboratory.
12.2
Safety-Related Procedures
12.2.1 
Concomitant Medications
All concomitant medication and concurrent therapies will be documented at screening and at 
study visits if changes are made. Dose, route, unit, frequency of administration, indication for 
administration, and dates of medication will be captured. Any prior medication received within 
30 days before screening and during the study through Day 155 or 84 (±5) days after last dose of 


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study drug, if ET, or through the first dose of study drug if the subject enters the OLE period of 
the study will be recorded.
For subjects participating in the OLE period, concomitant medications should be recorded in the 
AK002-027 double-blind treatment period database up until the first OLE dose is administered 
after the Day 85 (OLE Dose 1) visit. Rescue medications and procedures must be documented as 
rescue treatment in the source documents and on the Prior and Concomitant Medications eCRF.
Any medications taken for CSU or CSU-related symptoms at any time (even if longer than 
30 days before screening) should be listed as concomitant medications, even if the medication 
was discontinued prior to study participation. 
12.2.2 
Complete Physical Examination 
A complete physical exam will be performed by either the Investigator or a qualified designee 
during the screening visit. A complete physical exam will include the following body system or 
organ assessments: skin; head, eyes, ears, nose, and throat; thyroid; lungs; cardiovascular; 
abdomen; extremities; lymph nodes; and a brief neurological examination.  
12.2.3 
Body Weight and Height 
At screening, height (in cm) and weight (in kg) will be measured by the site and recorded. The 
site cannot use values stated by the subject. Body weight will also be measured on all dosing and 
follow-up days or 14, 56, and 84 days after last dose if ET.  
12.2.4 
Symptom-Directed Physical Examination 
A symptom-directed physical exam of reported or observed subject symptoms warranting 
examination in the opinion of the Investigator, including assessments of possible injection site 
reactions and IRR, will be performed by either the Investigator or a qualified designee at all 
study visits during the treatment period and follow-up period. New, abnormal physical exam 
findings must be documented and will be followed by the Investigator or Subinvestigator at the 
next scheduled visit or sooner if clinically indicated or referred to a non-study physician.  
12.2.5 
Electrocardiogram 
An ECG will be obtained during screening after the subject has been in the resting position for 
 minutes and before any blood draw. The Investigator or Subinvestigator will review and 
assess any abnormalities on the ECG in terms of clinical significance. The ECG (without 
intensive QT analysis) will be used to identify diseases or conditions that would put the subject 
at increased risk if participating in a clinical study, so this should be taken into consideration 
when evaluating eligibility for entry into the study. 


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12.2.6
Previous CSU Diagnosis and Treatments Review
During the screening visit the Investigator or designee will collect documentation supporting the 
CSU diagnosis and ask the subject about the various treatments or methods of symptom control 
that they have tried in relation to their CSU symptoms. The treatments may include medications 
(prescription or over-the-counter) or adaptive behaviors as well as alternative medicine (i.e., 
acupuncture or hypnotic therapy). Any previous therapies and medications as related to subjects’ 
CSU disease will be recorded in the study CRF.
Required specific source documentation supporting the assessment of inclusion and exclusion 
criteria regarding history of CSU diagnosis and treatments will be the following: 
 
For Inclusion Criteria #3, documentation of duration and a confirmed diagnosis of CSU 
should be supported by medical records and/or current documentation by the treating/study 
dermatologist (or allergist/immunologist) that the subject has a diagnosis of CSU which has 
been present for at least 6 months before screening based on patient interview. 
 
For Inclusion Criteria #4, the diagnosis of moderate-severe CSU refractory to H1-AH at a 
minimum of the licensed dose and at licensed frequency should be supported by 
treating/study dermatologist’s (or allergist/immunologist) documented assessment at 
screening based on medical records or discussion with a referring physician. 
 
For Inclusion Criteria #6, the required stable dose of H1-AH between 1x and 4x of the 
licensed dose and at licensed frequency for treatment of CSU at least 1 week prior to 
screening needs to be confirmed by medical records and/or treating/study dermatologist’s 
(or allergist/immunologist) notes. 
For Exclusion Criteria #3, the demonstrated lack of primary response to treatment with a 
biologic therapy (e.g. omalizumab) for the treatment of CSU should be confirmed by 
medical records and/or notes from the treating/study dermatologist (or 
allergist/immunologist).
More details are provided in the instructions on the eCRF pages and Study Reference Manual.
12.2.7
Vital Signs
Vital signs including systolic and diastolic blood pressure, pulse, body temperature, and 
respiratory rate will be taken after the subject
blood draw (except for post-SC injection when vital signs will be obtained as described below). 


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Vital signs will be measured at screening, on Day 8 (±3), on all follow-up days or 14, 56, and 
84 (±5) days after last dose if ET, and on all dosing days within 30 (±5) minutes predose, 
15 (±5) minutes after completion of the SC injection, and just prior to discharge.  
Additional vital signs measurements may be collected at the Investigator’s discretion if an IRR 
occurs. Vital signs including systolic and diastolic blood pressure, pulse, body temperature, and 
respiratory rate will be measured after the subject
blood draws have been obtained (unless collected for an IRR). Please refer to the schedule of 
assessments in Table 1.  
12.3
Clinical Laboratory Measurements  
Blood and urine samples for clinical safety laboratory tests will be collected at the time points 
described below. Investigators may have additional laboratory tests performed for the purpose of 
planning treatment administration or following AE or abnormal laboratory values. 
The site will process and ship blood and urine samples per central laboratory instructions. 
A central laboratory or designee will analyze blood and urine samples and provide results for the 
following clinical safety laboratory tests. 
Clinical laboratory testing may be performed locally, if necessary, with prior approval from 
Allakos. The site will strive to use the central laboratory whenever possible. 
For any laboratory test value outside the reference range, the Investigator will determine clinical 
significance: Not Clinically Significant (NCS) or Clinically Significant (CS). An abnormal 
laboratory value should be deemed CS if any of the following conditions are met: 
 
The abnormality suggests a disease and/or organ toxicity that is new or has worsened from 
baseline. 
 
The abnormality is of a degree that requires additional active management, e.g., change of 
study drug dose, discontinuation of the study drug, close observation, more frequent 
follow-up assessments, or further diagnostic investigation. 
Therefore, a clinically significant lab value is one that indicates a new disease process, an 
exacerbation or worsening of an existing condition, or requires further action to be taken. For 
any laboratory test value outside the reference range that the Investigator considers clinically 
significant, the Investigator will: 
 
Repeat the test to verify the out-of-range value. 
 
Follow the out-of-range value to a satisfactory clinical resolution. 


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Record as an AE any laboratory test value after start of study drug that: 
 The Investigator considers clinically significant. 
 Requires a subject to be discontinued from the study. 
 Requires a subject to receive treatment.
Blood will be obtained for CBC with differential as described in Section 12.1.10. 
12.3.1 
Blood Chemistry Profile 
Blood for chemistry, including hCG and FSH (only for screening), will be collected. Subjects of 
childbearing potential and postmenopausal women are required to undergo serum hCG or FSH 
testing (as described in Section 12.3.2). Blood for chemistry will be obtained during screening, 
predose on all dosing days, as well as on follow-up days 85, 127, and 155 or 14, 56, and 84 (±5) 
days after last dose if ET. 
The blood sample will be processed and shipped in accordance with the Laboratory Manual and 
laboratory kit instructions. A central laboratory will analyze the serum sample and provide 
results for chemistry tests including sodium, potassium, chloride, bicarbonate, glucose, blood 
urea nitrogen, creatinine, creatine kinase, calcium, phosphorus, magnesium, total and direct 
bilirubin, total protein, albumin, aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), alkaline phosphatase, gamma-glutamyl transferase (GGT), and lactate dehydrogenase. 
12.3.2 
Pregnancy Test and Follicle-Stimulating Hormone 
A serum pregnancy test (hCG level) will be completed for all female subjects of childbearing 
potential. Women who are surgically sterile (tubal ligation, partial or total hysterectomy, or 
bilateral oophorectomy) for at least 3 months or those who are postmenopausal for at least 1 year 
with FSH level >30 mIU/mL are not considered to be of childbearing potential. At screening, 
FSH levels will be tested on female subjects to confirm postmenopausal status. Both FSH and 
hCG samples will be processed by the central laboratory. 
Subjects with FSH le
mIU/mL will be considered to be of childbearing potential. Blood 
will be collected for serum pregnancy test at screening. Urine will be collected for dipstick 
pregnancy test on all dosing days, Day 8, and all follow-up days (or 14, 56, and 84 (±5) days 
after last dose of study drug if ET) for all subjects of childbearing potential. Test kits will be 
supplied by the central laboratory. Tests will be completed on site and evaluated prior to each SC 
injection. If a subject has a positive pregnancy test, dosing will immediately be discontinued. 


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To ensure subject safety, each pregnancy in a subject that received study drug must be reported 
within 24 hours of learning of its occurrence. If the subject received lirentelimab SC, the 
pregnancy should be followed to determine outcome, including spontaneous or voluntary 
termination, details of the birth, and the presence of absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications. If the subject received 
lirentelimab SC, any SAE experienced during pregnancy must be reported on the SAE Report 
Form.  
12.3.3 
Effective Methods of Contraception for Allakos Studies 
This section applies to study subjects who are women of childbearing potential (WOCBP), and 
male study subjects whose sexual partners are WOCBP.  
Applicable for Study Sites in the United States:  
Abstinence is the only birth control method that is 100% effective in preventing pregnancy. For 
subjects who do not practice abstinence, Allakos requires that study subjects use highly effective 
methods of contraception, which include:  
 
Permanent Sterilization: Tubal ligation, vasectomy – 99% effective  
 
Long-Acting Reversible Contraceptives (LARC):  
 IUD – 99% effective  
 Implantable rod (matchstick sized rod that contains progestin hormone implanted under 
the skin of the upper arm; prevents ovulation) – 99% effective  
 
Contraceptive Injection:  
Intramuscular or SC injection of progestin hormone every 3 months – 96% effective 
Short-Acting Hormonal Methods:  
 Oral contraceptives or patch – 91% effective  
Vaginal contraceptive ring (releases 2 hormones, progestin and estrogen, to prevent 
ovulation) – 91% effective 
Note: Effectiveness rates obtained from the Birth Control Guide on the FDA web site 
(FDA, 2021a).
Barrier and other methods not listed above when used together as dual methods such as a 
condom + diaphragm or condom + spermicide are less effective methods. Therefore, these dual 
methods are not recommended as they could increase the risk of becoming pregnant during the 


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study or follow-up period. When using dual methods, at least 1 of the methods should be a 
highly effective method of contraception.  
Applicable for Study Sites in Germany and Poland: 
Methods that can achieve a failure rate of less than 1% per year when used consistently and 
correctly are considered as highly effective birth control methods. Allakos requires that study 
subjects use highly effective methods of contraception, which include: 
 
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation1: Oral, intravaginal or transdermal
 
Progestogen-only hormonal contraception associated with inhibition of ovulation1: Oral, 
injectable, or implantable2
 
Intrauterine device (IUD)2  
 
Intrauterine hormone-releasing system (IUS)2  
 
Bilateral tubal occlusion2
 
Vasectomised partner2,3  
 
Sexual abstinence4 
1) 
Hormonal contraception may be susceptible to interaction with the study drug, which may 
reduce the efficacy of the contraception method. 
2) 
Contraception methods that in the context of this guidance are considered to have low user 
dependency.  
3) 
Vasectomised partner is a highly effective birth control method provided that partner is the 
sole sexual partner of the WOCBP trial participant and that the vasectomised partner has 
received medical assessment of the surgical success.  
4) 
In the context of this guidance sexual abstinence is considered a highly effective method 
only if defined as refraining from heterosexual intercourse during the entire period of risk 
associated with the study treatments. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle 
of the subject. 
Note: Recommendations related to contraception and pregnancy testing in clinical trials 
(version 1.1) by the Clinical Trials Facilitation and Coordination Group (CTFG, 2020). 


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12.3.4
Urinalysis
Urine will be obtained for urinalysis at screening and on follow-up Days 85 and 155 (14 and 
84 [±5] days after last dose if ET), and symptom-based, as necessary. The urine sample will be 
processed and shipped in accordance with the Laboratory Manual and laboratory kit instructions. 
A central laboratory will analyze the urine sample for specific gravity, pH, protein, glucose, 
ketones, blood, and leukocyte esterase.  
12.3.5
Serology 
Blood will be obtained at screening for serology tests including hepatitis B surface antigen 
(HBsAG), hepatitis C antibody, hepatitis B core antibody (anti-HBc), and human 
immunodeficiency virus (HIV). The blood sample will be processed and shipped to the central 
laboratory in accordance with the Laboratory Manual and lab kit instructions. A positive result, if 
clinically significant (and not due to previous vaccination or resolved disease or exposure), will 
exclude the subject from enrollment (Appendix 8).
12.3.6 
Anti-Lirentelimab Antibodies
Blood for determination of ADA will be collected predose on dosing Days 1, 29, and 43, and on 
follow-up Days 85 and 155 (14 and 84 [±5] days after last dose of study drug if ET) and on 
Day 8, between Dose 1 and Dose 2. The ADA sample will also be collected any time an 
immunogenicity-related AE occurs. Additional ADA samples will be collected at each dosing 
visit during the OLE period.  
An unscheduled blood sample for ADA may also be obtained if a related AE suspected of being 
associated with immunogenicity occurs. The serum sample will be collected predose and 
processed and shipped in accordance with the Laboratory Manual and lab kit instructions. A 
central laboratory will analyze the sample for ADA using a validated assay method. 
Additionally, the serum samples collected for ADA will be retained for future testing in the event 
that any new potential safety or immunogenicity issues are identified.
12.3.7
Blood for Pharmacokinetics 
Blood samples for serum PK assessments will be collected predose on dosing Days 1, 15, 29, 43, 
57, 71, and 85 (±5), on Day 8 (±3) between Dose 1 and Dose 2, and during follow-up on 
Days 85, 127, and 155 (±5) or 14, 56, and 84 (±5) days after last dose of study drug if ET. The 
serum samples will be collected predose and processed and shipped frozen in accordance with 
the study Laboratory Manual and lab kit instructions.  


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Lirentelimab concentrations will be determined by the central laboratory or designee using a 
validated ELISA method. Specific information on PK sample collection, processing, storage, and 
shipment will be provided in the laboratory manual.  
12.3.8
Blood for IgE 
Blood will be collected for determination of serum IgE levels and sent to the central laboratory 
for processing. Blood will be collected during screening, predose on Day 43 and Day 71, and on 
follow-up Days 85, 127, and 155 or 14, 56, and 85 (±5) days after last dose of study drug if ET.  
12.3.9
COVID-19 Testing 
Testing for COVID-19 is not required for this study but may be implemented by the study site at 
any time during the study due to safety regulations or procedures. Testing for COVID-19 may be 
individually mandated by facilities or by state or country (e.g. Germany) regulation, and if 
required, this will be consented through the site and not listed in the AK002-027 ICF. Testing for 
COVID-19 may be performed according to the trial site standard procedures and safety 
regulations. 
The risk assessment related to ongoing COVID-19 pandemic will be reviewed on a continuous 
basis, and measures required for reducing the risk of infection with the novel coronavirus will be 
taken, as appropriate.   
13. Evaluations and Procedures by Visit 
Evaluations and procedures by visit are shown in Table 1. 
General Information: 
All recorded clock times should utilize a 24-hour clock. 
Procedures for screening may be performed over the course of multiple visits prior to the 
first SC injection.
Dose 1 is the day of the first SC injection. Dose 1/Day 1 can occur within a ±3 day window, 
i.e., the screening period can be a maximum of 17 days and a minimum of 11 days. Dosing 
visits must be conducted within the ± windows stipulated in the protocol with the following 
requirements:
The interval between dosing visits must be at least 7 days and no more than 21 days 
from the previous dosing visit unless directed otherwise by Allakos. The interval count 
starts the day after the visit and includes the day of the next visit. 


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 The interval between the final dosing visit and the efficacy visit (Day 85) must be at 
least 11 days and no more than 17 days from the final dosing visit unless directed 
otherwise by Allakos. The interval count starts the day after the visit and includes the 
day of the next visit. 
 
For Day 8, the visit can occur within a ±3 day window. 
13.1
Screening Day for H1-AH Dose Stabilization – Screening Period 
~Day -21: For subjects entering screening without prior medication history of using a stable, 
approved dose of H1-AH for at least 7 days prior to Screening Day.  
Day -14: For subjects meeting the definition of having a stable, approved dose of H1-AH, 
Screening Day will be Day -14.  
1) 
Obtain written informed consent. 
2) 
Assign the participant a PID. 
3) 
Collect demographics. 
4) 
Obtain medical history.
5) 
Gather and review CSU diagnosis and detailed previous treatment history and concomitant 
medications (Section 12.2.6). 
6) 
Confirm H1-AH usage.
7) 
Collect body weight (in kg) and height (in cm) 
8) 
Vital signs.
9) 
Perform ECG.
10) Conduct complete physical examination. 
11) Administer 
.
12) Activate daily PRO and have subject complete first PRO (UPDD) in the clinic and have 
subject complete the 
 if subject has a history of 
. 
13) Have subject complete the 
.
14) Collect blood for serology, serum IgE, chemistry (including hCG and FSH, if applicable), 
and CBC. Female subjects of childbearing potential are required to have serum hCG 
measured. Postmenopausal subjects are required to have serum FSH measured and if FSH 
level is 
measurement will be required during the screening 
period. 


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15) Collect urine for urinalysis. 
16) Conduct eligibility assessment and confirm subject is eligible to move forward with 
screening.
13.2
Screening Day or Post H1-A1 Stabilization – Screening Period ~Day -14 
1) 
Obtain written informed consent. 
2) 
Assign the participant a PID. 
3) 
Collect demographics. 
4) 
Obtain medical history. 
5) 
Gather and review CSU diagnosis and detailed previous treatment history and concomitant 
medications (Section 12.2.6). 
6) 
Confirm H1-AH usage. 
7) 
Collect body weight (in kg) and height (in cm) 
8) 
Vital signs. 
9) 
Perform ECG. 
10) Conduct complete physical examination. 
11) Administer 
. 
12) Activate daily PRO and have subject complete first PRO (UPDD) in the clinic and have 
subject complete the 
 if subject has a history of 
. 
13) Have subject complete the 
. 
14) Collect blood for serology, serum IgE, chemistry (including hCG and FSH, if applicable), 
and CBC. 
15) Collect urine for urinalysis. 
16) Conduct eligibility assessment and confirm subject is eligible to move forward with 
screening. 
17) SAE review, reporting of SAE occurring after signing the ICF and prior to the first SC 
injection, will be limited to those that relate to screening procedures. The capture of all 
SAE and AE that are not related to screening procedures will begin at the time of first SC 
injection of study drug. 


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13.3
Day -7 (±3) – Screening Period/Baseline
Phone Visit:
1) 
Assess the subject for SAE related to screening procedures. 
2) 
Assess UPDD and 
 (if applicable) compliance.
3)
Confirm continuing eligibility.
4)
Document any changes to medical history and concomitant medications.
5)
Confirm H1-AH usage.
6)
Perform UAS7 assessment.
7) 
Complete 
.
13.4 
Day 1 (±3) – Randomization/Day 1/Baseline/Dose 1 
1) 
Prior to SC Injection: 
a) Assess the subject for SAE related to screening procedures.
b) Confirm continuing eligibility.
c) Assess UPDD and 
 (if applicable) compliance. Subject should complete at least 
four daily PRO questionnaires during the seven days prior to Day 1.
d) Document any changes to health status.
e) Document any changes to medical history and concomitant medications. 
f) 
Perform urine dipstick pregnancy test if subject is of childbearing potential.
g)
Collect body weight (in kg).
h)
Perform symptom-directed physical exam, if needed.
i)
Complete UAS7 and
.
j)
Have subject complete the 
and Atopic Conditions Questionnaire.
k)
Collect blood for chemistry, PK, and ADA.
l) 
Optional: collect skin biopsies (applicable for select US sites only).
2)
Randomization:
a)
Prior to randomizing the subject in the IRT system, the Investigator will determine 
subject’s UAS7 score and biologic-naïve vs biologic-exposed status. The study 
coordinator or designee will enter UAS7 score and biologic status into the IRT on 
Study Day 1 to stratify the subject. 


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b)
The IRT system will then randomly assign the subject to lirentelimab SC 300 mg or 
placebo SC in a double-blind manner and will send an email to the pharmacist and/or 
designee detailing the kit number(s) to use to prepare the injection. See Pharmacy 
Manual for detailed SC injection preparations.
3)
Collect vital signs within 30 minutes of the start of the injection.
4)
SC Injection of Study Drug: Subcutaneous dosing (lirentelimab SC or placebo SC) 
comprises 1 SC injection administered in the front of the thigh with a 27-gauge needle. 
Maximum volume administered will be 2 mL. See the Pharmacy Manual for SC injection 
instructions. 
5) 
Post-SC Injection: 
a) Collect vital signs within 15 minutes of the end of the injection. 
b) Collect blood for CBC with differential 1 hour (±15 minutes) after the end of the 
injection. 
c) Observe the subject for at least 1 hour after study drug administration. 
d) Collect vital signs just prior to discharge.
If anaphylaxis is suspected, a sample of blood should be obtained for plasma histamine 
level and tryptase within 1–2 hours of the onset of symptoms. Also, an unscheduled ADA 
blood sample may be obtained if an immunogenicity-related AE is suspected. 
13.5 
Day 8 (±3) 
1) 
Assess the subject for AE and SAE. 
2) 
Document any changes to concomitant medications. 
3) 
Assess UPDD and 
 (if applicable) compliance. 
4) 
Collect vital signs and body weight (in kg). 
5) 
Complete UAS7 assessment. 
6) 
Have subject complete the 
. 
7) 
Collect blood for PK and ADA. 
8) 
Perform urine dipstick pregnancy test if subject is of childbearing potential. 
9) 
Perform symptom-directed physical exam, as needed. 


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13.6
Day 15 (±5) – Dose 2
1) 
Prior to SC Injection:
a)
Assess the subject for AE and SAE.
b)
Document any changes to concomitant medications.
c)
Assess UPDD and 
 (if applicable) compliance.
d)
Complete UAS7 assessment.
e)
Have subject complete 
.
f)
Collect body weight (in kg).
g) Perform urine pregnancy test if subject is of childbearing potential. 
h) Collect vital signs 30 (±5) minutes prior to the start of the SC injection. 
i) 
Perform symptom-directed physical exam, as needed. 
j) 
Collect blood for CBC, chemistry, and PK. 
k) The study pharmacist will prepare study drug using dosage and kit number(s) provided 
by the IRT. See the Pharmacy Manual for detailed SC injection preparations. 
2) 
SC Injection of Study Drug: Subcutaneous dosing (lirentelimab SC or placebo SC) 
comprises 1 SC injection administered in the front of the thigh with a 27-gauge needle. 
Maximum volume administered will be 2 mL. See the Pharmacy Manual for SC injection 
instructions. 
3) 
Post-SC Injection: 
a) Collect vital signs within 15 minutes of the end of the SC injection. 
b) Collect CBC with differential 1 hour (±15 minutes) after the SC injection. 
c) Observe the subject for at least 1 hour after the SC injection. Collect vital signs just 
prior to discharge. 
 
If anaphylaxis is suspected, a sample of blood should be obtained for plasma histamine 
level and tryptase within 1–2 hours of the onset of symptoms. Also, an unscheduled ADA 
blood sample may be obtained if an immunogenicity-related AE is suspected. 
13.7 
Day 29 (±5) – Dose 3 
1) 
Prior to SC Injection: 
a) Assess the subject for AE and SAE. 
b) Document any changes to concomitant medications. 


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c)
Assess UPDD and 
 (if applicable) compliance.
d) Complete UAS7 and 
 assessments. 
e)
Have subject complete 
.
f)
Collect body weight (in kg).
g) Perform urine pregnancy test if subject is of childbearing potential. 
h)
Collect vital signs 30 (±5) minutes prior to the start of the SC injection.
i) 
Perform symptom-directed physical exam, as needed.
j) 
Collect blood for CBC, chemistry, PK, and ADA.
k) The study pharmacist will prepare study drug using dosage and kit number(s) provided 
by the IRT. See the Pharmacy Manual for detailed SC injection preparations.
2) 
SC Injection of Study Drug: Subcutaneous dosing (lirentelimab SC or placebo SC) 
comprises 1 SC injection administered in the front of the thigh with a 27-gauge needle. 
Maximum volume administered will be 2 mL. See the Pharmacy Manual for SC injection 
instructions. 
3) 
Post-SC Injection: 
a) Collect vital signs within 15 minutes of the end of the SC injection.
b) Collect CBC with differential 1 hour (±15 minutes) after the SC injection.
c) Observe the subject for at least 1 hour after the SC injection. Collect vital signs just 
prior to discharge. 
 
If anaphylaxis is suspected, a sample of blood should be obtained for plasma histamine 
level and tryptase within 1–2 hours of the onset of symptoms. Also, an unscheduled ADA 
blood sample may be obtained if an immunogenicity-related AE is suspected. 
13.8 
Day 43 (±5) – Dose 4 
1) 
Prior to SC Injection:
a)
Assess the subject for AE and SAE. 
b)
Document any changes to concomitant medications. 
c) Assess UPDD and 
 (if applicable) compliance.
d) Complete UAS7 assessment.
e) Have subject complete 
.


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f)
Collect body weight (in kg).
g) Perform urine pregnancy test if subject is of childbearing potential. 
h)
Collect vital signs 30 (±5) minutes prior to the start of the SC injection.
i)
Perform symptom-directed physical exam, as needed.
j) 
Collect blood for CBC, chemistry, PK, and ADA. 
k)
Collect blood for total serum IgE.
l) 
The study pharmacist will prepare study drug using dosage and kit number(s) provided 
by the IRT. 
2) 
SC Injection of Study Drug: Subcutaneous dosing (lirentelimab SC or placebo SC) 
comprises 1 SC injection administered in the front of the thigh with a 27-gauge needle. 
Maximum volume administered will be 2 mL. See the Pharmacy Manual for SC injection 
instructions. 
3) 
Post-SC Injection: 
a) Collect vital signs within 15 minutes of the end of the SC injection. 
b) Collect CBC with differential 1 hour (±15 minutes) after the SC injection. 
c) Observe the subject for at least 1 hour after the SC injection. Collect vital signs just 
prior to discharge. 
If anaphylaxis is suspected, a sample of blood should be obtained for plasma histamine 
level and tryptase within 1–2 hours of the onset of symptoms.  Also, an unscheduled ADA 
blood sample may be obtained if an immunogenicity-related AE is suspected. 
13.9 
Day 57 (±5) – Dose 5 
1) 
Prior to SC Injection: 
a) Assess the subject for AE and SAE. 
b) Document any changes to concomitant medications. 
c) Assess UPDD and 
 (if applicable) compliance. 
d) Complete UAS7 and 
 assessments. 
e) Have subject complete 
. 
f) 
Collect body weight (in kg). 
g) Perform urine pregnancy test if subject is of childbearing potential. 


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h)
Collect vital signs 30 (±5) minutes prior to the start of the SC injection.
i) 
Perform symptom-directed physical exam, as needed. 
j)
Collect blood for CBC, chemistry, PK, and ADA.
k)
The study pharmacist will prepare study drug using dosage and kit number(s) provided 
by the IRT. 
l)
Optional: collect skin biopsies on either Day 57, Day 71, or Day 85 (applicable for 
select US sites only). 
2) 
SC Injection of Study Drug: Subcutaneous dosing (lirentelimab SC or placebo SC) 
comprises 1 SC injection administered in the front of the thigh with a 27-gauge needle. 
Maximum volume administered will be 2 mL. See the Pharmacy Manual for SC injection 
instructions. 
3) 
Post-SC Injection: 
a) Collect vital signs within 15 minutes of the end of the SC injection. 
b) Collect CBC with differential 1 hour (±15 minutes) after the SC injection. 
c) Observe the subject for at least 1 hour after the SC injection. Collect vital signs just 
prior to discharge. 
If anaphylaxis is suspected, a sample of blood should be obtained for plasma histamine 
level and tryptase within 1–2 hours of the onset of symptoms. Also, an unscheduled ADA 
blood sample may be obtained if an immunogenicity-related AE is suspected. 
13.10 Day 71 (±5) – Dose 6 
1) 
Prior to SC Injection: 
a) Assess the subject for AE and SAE. 
b) Document any changes to concomitant medications. 
c) Assess UPDD and 
 (if applicable) compliance. 
d) Complete UAS7 assessment. 
e) Have subject complete 
. 
f) 
Collect body weight (in kg). 
g) Perform urine pregnancy test if subject is of childbearing potential. 
h) Collect vital signs 30 (±5) minutes prior to the start of the SC injection. 


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i)
Perform symptom-directed physical exam, as needed.
j) 
Collect blood for CBC, chemistry and PK. 
k)
Collect blood for total serum IgE.
l)
The study pharmacist will prepare study drug using dosage and kit number(s) provided 
by the IRT. 
m) Optional: collect skin biopsies on either Day 57, Day 71, or Day 85 (applicable for 
select US sites only). 
2) 
SC Injection of Study Drug: Subcutaneous dosing (lirentelimab SC or placebo SC) 
comprises 1 SC injection administered in the front of the thigh with a 27-gauge needle. 
Maximum volume administered will be 2 mL. See the Pharmacy Manual for SC injection 
instructions. 
3) 
Post-SC Injection: 
a) Collect vital signs within 15 minutes of the end of the SC injection. 
b) Collect CBC with differential 1 hour (±15 minutes) after the SC injection. 
c) Observe the subject for at least 1 hour after the SC injection. Collect vital signs just 
prior to discharge. 
 
If anaphylaxis is suspected, a sample of blood should be obtained for plasma histamine 
level and tryptase within 1–2 hours of the onset of symptoms. Also, an unscheduled ADA 
blood sample may be obtained if an immunogenicity-related AE is suspected. 
13.11 Day 85 (±5) or 14 Days Post-Dose – Follow-up Visit 1 
1) 
Assess the subject for AE and SAE. 
2) 
Document any changes to concomitant medications. 
3) 
Assess UPDD and 
 (if applicable) compliance. 
4) 
Perform UAS7 and 
 assessments. 
5) 
Have subject complete 
 and Atopic Conditions Questionnaire. 
6) 
Collect body weight (in kg). 
7) 
Collect urine for urinalysis. 
8) 
Perform urine pregnancy test if subject is of childbearing potential. 
9) 
Collect vital signs. 
10) Perform symptom-directed physical exam, as needed. 


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11) Collect blood for CBC, chemistry, PK, and ADA.
12) Collect blood for total serum IgE.
13) Optional: collect skin biopsies on either Day 57, Day 71, or Day 85 (applicable for select 
US sites only).
If the subject elects to receive OLE dosing, the OLE period of the study may begin after all 
Day 85 assessments of the double-blind period have been completed. The start of OLE dosing 
may be delayed for up to 7 days after completion of the Day 85 visit. The subject is in the 
double-blind period of the study until the first OLE dose of lirentelimab is administered.
13.12 Day 127 (±5) or 56 Days Post-Dose – Follow-up Visit 2
1)
Assess the subject for AE and SAE.
2)
Document any changes to concomitant medications.
3)
Assess UPDD and 
 (if applicable) compliance.
4)
Perform UAS7 and 
assessments.
5) 
Have subject complete 
. 
6) 
Collect body weight (in kg). 
7) 
Perform urine pregnancy test if subject is of childbearing potential. 
8) 
Collect vital signs. 
9) 
Perform symptom-directed physical exam, as needed. 
10) Collect blood for CBC, chemistry, and PK. 
11) Collect blood for total serum IgE. 
13.13 Day 155 (±5) or 84 Days Post-Dose – Follow-up Visit 3 
1) 
Assess the subject for AE and SAE.
2) 
Document any changes to concomitant medications. 
3) 
Assess UPDD and 
 (if applicable) compliance. 
4) 
Perform UAS7 and 
 assessments. 
5) 
Have subject complete 
. 
6) 
Collect body weight (in kg). 
7) 
Collect urine for urinalysis. 
8) 
Perform urine pregnancy test if subject is of childbearing potential. 


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9) 
Collect vital signs.
10) Perform symptom-directed physical exam, as needed. 
11) Collect blood for CBC, chemistry, PK, and ADA. 
12) Collect blood for total serum IgE. 
For Early Termination: Perform the visit 14, 56, or 84 (±5) days after the last dose of study 
drug or prior to this, if necessary, to ensure compliance with the visit. 
13.14 End of Study Definition
The end of the double-blind, placebo-controlled period of the study is defined as the completion 
of the last follow-up visit of the last enrolled subject who elects not to participate in the OLE 
period of the study. 
For subjects electing to enter the OLE period of the study, the end of the OLE period of the study 
is defined as the completion of the last follow-up visit for the last subject.
The enrollment of the last subject in the double-blind period of the study is anticipated to occur 
in 2023. The last subject’s last follow up visit will be approximately 24 weeks after the date of 
enrollment if OLE is not elected, or up to 36 weeks after the date of enrollment if the OLE is 
elected. 
Please refer to Section 14.12 for the study ending prematurely.  
14. Adverse Event Reporting and Documentation
14.1
Adverse Events 
In accordance with 21 Code of Federal Regulation (CFR) 312.32(b) and International 
Conference on Harmonization (ICH) Guidance E2A, an AE is any untoward medical occurrence 
in a clinical investigation of a subject administered a pharmaceutical product and that does not 
necessarily have a causal relationship with the treatment.  
An AE is therefore any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the administration of an investigational 
product, whether or not related to that investigational product. An unexpected AE is one of a 
type not identified in nature, severity, or frequency in the current Investigator’s Brochure or of 
greater severity or frequency than expected based on the information in the Investigator’s 
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Examples of an AE include:
Significant worsening or exacerbation of underlying medical condition.
 
Significant abnormal findings from physical exams, vital signs, or laboratory tests. 
The following examples are not considered AE: 
 
Medical or surgical procedure, although the condition leading to the procedure is usually 
an AE. 
 
Anticipated day-to-day fluctuations of preexisting medical conditions (including laboratory 
values) as long as significant worsening from baseline does not occur. 
 
Signs or symptoms of the disorder being studied unless they become more severe or occur 
with greater frequency than occurring at baseline.
All AE, whether elicited by questions from study staff, volunteered, or noted on physical 
examination/laboratory testing, and regardless of causality or severity, will be assessed and 
recorded in the eCRF beginning after the first administration of study drug in the double-blind 
period of the study and ending at the time of study completion or ET of the double-blind period 
or the OLE period, whichever is later.
For subjects participating in the OLE period, AE will be recorded in the CRF of the AK002-027
double-blind treatment period database up until the first administration of lirentelimab in the 
OLE period and recorded in the CRF of the AK002-027 OLE period database beginning from 
the time of first administration of lirentelimab ending at the time of study completion or ET of 
the OLE period. 
14.2 
Serious Adverse Events 
A SAE is defined as an AE that meets that one of the following criteria: 
 
Death 
 
A life-threatening AE that places the subject at risk of death at the time of the event. It does 
not refer to an event that hypothetically might cause death if it were more severe.  
 
Inpatient hospitalization or prolongation of existing hospitalization. 
 
A persistent or significant disability/incapacity.
 
A congenital anomaly/birth defect occurring in the offspring of a study subject. 


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Other important medical events may also be considered a SAE when, based on appropriate 
medical judgment, they jeopardize the subject or require intervention to prevent any of the 
outcomes listed above. 
Serious adverse events will be assessed and recorded beginning after the first administration of 
study drug and ending at Day 155 (±5) or 84 (±5) days after last dose, unless the SAE is related 
to a screening procedure, in which case it will be captured from the date of informed consent.  
14.3
Adverse Events of Special Interest 
Adverse Events of Special Interest (AESI) for this study include: 
Malignancies confirmed by histopathological report. (Mast cells and eosinophils are part of 
the normal immune response. By decreasing their function, lirentelimab could theoretically 
increase the risk of malignancy.)
Parasitic infections confirmed by positive clinical laboratory test. (Eosinophils are believed 
to be involved in protecting the body from parasitic infections. Decreasing their function 
could theoretically increase the risk of parasitic and opportunistic infections.)
Opportunistic infections (infections known to be more severe or occur more frequently in 
immunosuppressed populations) as confirmed by positive clinical laboratory test.
Injection-related reactions and hypersensitivity reactions, including anaphylaxis.
Adverse Events of Special Interest will be assessed beginning after the time of first 
administration of study drug and ending on Day 155 (±5) or 84 (±5) days after last dose. Any 
new AESI (or new information related to a previously reported AESI) must be recorded in the 
AE eCRF and designated as an “AE of special interest.”
14.4
Injection-Related Reactions
All AE considered by the Investigator to be related to the biological substance and occurring 
within 24 hours of the start of the SC injection of study drug should be captured as 1 IRR. 
Common symptoms of IRR may include but are not exclusive to: 
Flushing
Nausea
Chills
Vomiting
Back or abdominal pain
Sweating
Chest discomfort or tightness
Fever
Dizziness
Urticaria


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Shortness of breath 
Pruritus
 
Headache 
 
Bronchospasm 
 
Hypotension or hypertension 
 
All symptoms experienced by a subject during an IRR will be listed in the eCRF under 1 IRR, 
unless the Investigator believes a symptom is not part of the IRR, in which case it will be 
recorded separately. The start time of the IRR will be captured as the start time of the first 
symptom, and the end time of the IRR will be captured as the end time of the last symptom. 
14.5
Injection Site Reactions
All AE considered by the Investigator to be related to the SC administration of the biological 
substance at the injection site and occurring within 24 hours of the start of the injection should be 
captured as 1 injection site reaction (ISR).
Common symptoms of ISR include, but are not exclusive to: 
Redness at the injection site
Bruising at the injection site
Itching at the injection site
Burning at the injection site
Swelling at the injection site (beyond the 
bump caused by the volume of the drug 
injected under the skin) 
Pain at the injection site
All symptoms experienced by the subject during an ISR will be listed in the eCRF under 1 ISR, 
unless the Investigator believes a symptom is not part of the ISR, in which case it will be 
recorded separately. The start time of the ISR will be captured as the start time of the first 
symptom, and the end time of the ISR will be captured as the end time of the last symptom. 
14.6
Anaphylaxis 
A suspicion of anaphylaxis will be carefully monitored and treated according to standard of care. 
Emergency crash cart equipment and medications, including multiple doses of epinephrine, 
vasopressors, and bronchodilators, will be available at all times during the conduct of the study. 
To define anaphylactic reactions in a consistent and objective manner, all AE of suspected 
anaphylaxis will be evaluated using Sampson’s Criteria for Anaphylaxis (Appendix 7). The
assessment of an AE will be done pursuant to definitions set forth by ICH Good Clinical Practice 
(GCP) guidelines and applicable regulatory requirements.  


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If a subject experiences signs or symptoms of anaphylaxis, they should be treated with standard 
of care, such as epinephrine, diphenhydramine, acetaminophen, methylprednisolone, and other 
supportive measures along with cessation of the SC injection. A sample of blood should be 
obtained for plasma histamine level and tryptase within 1–2 hours of the onset of symptoms. 
Also, an unscheduled ADA blood sample may be obtained if an immunogenicity-related AE is 
suspected.
14.7 
Evaluating Adverse Events and Serious Adverse Events 
14.7.1
Establishing Diagnosis 
Whenever possible, diagnoses should be given when signs and symptoms are due to a common 
etiology (e.g., dysuria, urinary nitrites should be reported as a urinary tract infection). If the 
diagnosis is not known, individual signs and symptoms should be assessed and recorded in the 
AE eCRF as separate AE.  
The Investigator (or qualified Subinvestigator) must assign the AE attributes listed in Table 5 
(AE severity), Table 6 (relationship to study drug), and Table 7 (relationship to study procedure) 
and is responsible for ensuring this information is recorded in the source documentation. 
14.7.2 
Assessment of Intensity 
Investigators will use their clinical judgment as well as the guidelines laid out in the NCI 
CTCAE (version 5.0 or most current version) tables to assess the intensity of each AE and SAE 
(Table 5 and Appendix 6). 
Table 5 
Adverse Event Severity per CTCAE 
Grade
CTCAE Description* 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.
2 
Moderate; minimal, local, or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living (ADL). 
3 
Severe or medically significant but not immediately life-threatening, hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL. 
4 
Life-threatening consequences, urgent intervention indicated. 
5 
Death related to AE. 
* CTCAE v. 5.0: Grade refers to the severity of the AE. The CTCAE displays Grades 1–5 with unique clinical 
descriptions of severity for each AE based on this general guideline. 
The term “severe” is a measure of intensity, and a severe AE is not necessarily a SAE. When the 
intensity of an AE changes more than once a day, the maximum severity for the event should be 


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entered into the AE eCRF. If the intensity changes over a number of days, these changes should 
be recorded separately (i.e., as having distinct onset dates). 
14.7.3
Assessment of Causality to Study Drug 
The Investigator should use their clinical judgment as well as the guidelines in Table 6 to assess 
the relationship between study drug and AE. 
Table 6 
Adverse Event Relationship to Study Drug 
Relationship to 
Study Drug 
Comment 
Related
There is clear evidence that the event is related to the use of study drug (e.g., confirmation 
by positive rechallenge test, if possible). Another etiology is considerably less likely. 
Possible 
The event cannot be explained by the subject’s medical condition, concomitant therapy, 
or other causes, and there is a plausible temporal relationship between the event and study 
drug administration.  
Unlikely/Remote 
An event for which an alternative explanation is more likely (e.g., concomitant 
medications or ongoing medical conditions) or the temporal relationship to study drug 
administration and/or exposure suggests that a causal relationship is unlikely. 
(For reporting purposes, Unlikely/Remote will be grouped together with Not Related.)  
Not Related 
The event can be readily explained by the subject’s underlying medical condition, 
concomitant therapy, or other causes, and therefore, the Investigator believes no 
relationship exists between the event and study drug.  
14.7.4 
Assessment of Causality to Study Procedure 
The Investigator should use their clinical judgment as well as the guidelines in Table 7 to assess 
the relationship between study procedure and AE. Assessment of causality to study procedure 
should include causality to such items as blood draw (as appropriate), or other.  
 


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Table 7
Adverse Event Relationship to Study Procedure
Relationship to 
Study Procedure 
Comment 
Related 
There is clear evidence that the event is related to a study procedure. 
Possible
The event cannot be explained by the subject’s medical condition, concomitant therapy, 
or other causes, and there is a plausible temporal relationship between the event and a 
study procedure.  
Unlikely/Remote 
An event for which an alternative explanation is more likely (e.g., concomitant 
medications or ongoing medical conditions) or the temporal relationship to any study 
procedure suggests that a causal relationship is unlikely (For reporting purposes, 
Unlikely/Remote will be grouped together with Not Related).  
Not Related 
The event can be readily explained by the subject’s underlying medical condition, 
concomitant therapy, or other causes, and therefore, the Investigator believes no 
relationship exists between the event and a study procedure.  
14.7.5 
Action Taken 
Action taken with respect to study drug will be categorized as none, study drug permanently 
discontinued, study drug temporarily withdrawn, or other (specify).
Action taken with respect to study participation will be categorized as none, withdrawal from 
study participation, or other (specify).  
Action taken with respect to treatment of an AE will be categorized as none, concomitant 
medication, concomitant procedure, or other (specify).  
14.7.6 
Assessment of Outcome 
Event outcome at resolution or time of last follow-up will be recorded as: recovered, recovering, 
not recovered, recovered with sequelae, fatal, or unknown.  
14.8 
Adverse Event Reporting Procedures  
14.8.1 
All Adverse Events  
Any clinically significant AE that is ongoing at the time of study completion or ET will be 
followed by the Investigator until event resolution, the AE is otherwise explained, not considered 
clinically significant by the Investigator, or the subject is lost to follow-up. 
All AE identified, whether serious or non-serious, will be recorded in the AE eCRF beginning 
from the first administration of study drug in the double-blind period of the study and ending at 
the time of study completion or ET of the double-blind period or the OLE period, whichever is 


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later. Serious adverse events considered related to screening procedures will be recorded in the 
AE eCRF starting on the date of informed consent. Whenever appropriate, the CTCAE (version 
5.0 or most current version) should be utilized for naming common AE (Appendix 6).
For subjects participating in the OLE period, AE will be recorded in the CRF of the AK002-027 
double-blind treatment period database until the first administration of lirentelimab in the OLE 
period and recorded in the CRF of the AK002-027 OLE period database beginning at the time of 
the first administration of lirentelimab. 
14.8.2 
Serious Adverse Event Reporting  
In the event of any SAE reported or observed during the study, whether or not attributable to the 
study drug, site personnel must report it immediately (within 24 hours of becoming aware of 
the SAE) by fax or email to the Sponsor, Allakos Inc.  
The SAE report forms will be provided to the investigational site to assist in collecting, 
organizing, and reporting SAE, and forms must be completed with as much information as is 
available and should be submitted to the Sponsor within 24 hours of becoming aware of the 
SAE. Serious adverse events must also be recorded on the AE eCRF and designated as “serious.”  
Even when only minimal information is available for the initial SAE report, the Investigator 
should try to make a causality assessment, as the causality is used to determine the timing of 
regulatory reporting requirements. If the Investigator or designee is not available to sign the SAE 
report on initial submission, they should be contacted and their assessment documented on the 
SAE form (with a note stating signature is forthcoming). The Investigator may change their 
causality assessment based on follow-up information and submit an amended SAE report form.  
All efforts will be made to obtain accurate and complete medical records for the SAE. All efforts 
to obtain information should be documented in the subject’s source documents. 
The site will notify the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
according to its guidelines.  
The subject’s condition will be followed by the Investigator or designated Subinvestigator until 
resolution of the condition or a return to baseline levels. If additional visits are required, the 
subject will be asked to return to the study site for further follow up. If the condition is still 
ongoing at the time the subject exits the study, every effort will be made to continue to follow up 
with the subject for a reasonable period of time, as determined by the Investigator or until there 
is a return to baseline or stabilization of the condition. As additional information becomes 


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available, such as hospital discharge notes and subject medical records, the Investigator will be 
notified and provided with all relevant information.  
All SAE that have not resolved by the end of the study or that have not resolved on
discontinuation of the subject’s participation in the study must be followed until any of the 
following occurs: 
 
The event resolves.  
The event stabilizes.
The event returns to baseline if a baseline value is available. 
The event can be attributed to agents other than the investigational product or to factors 
unrelated to study conduct. 
It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts). 
SAE must be reported within 24 hours to:
Fax:
+1-888-237-7475
 
Email: SAE@allakos.com 
14.8.3 
Pregnancy Reporting 
Pregnancies are captured if they occur in female subjects or in the sexual partners of male 
subjects from the time the subject is first exposed to the investigational product through the time 
of study completion or ET of the double-blind period or the OLE period, whichever is longer.
Female subjects must be instructed to discontinue all study drugs and inform the Investigator 
immediately if they become pregnant during the study. Male subjects must inform the 
Investigator immediately if their partner becomes pregnant during the study.
The Investigator must report any pregnancy to Allakos within 24 hours of becoming aware of it 
using the provided pregnancy reporting forms. Female subjects must be immediately 
discontinued from study drug. An uncomplicated pregnancy will not be considered an AE or 
SAE, but all pregnancies in subjects who received lirentelimab will be followed through term. 
For male subjects with female partners who become pregnant, the site will ask the father (the 
study subject) to provide information about the outcome of the pregnancy and information about 
the baby. If detailed health information about the mother is requested by Allakos, a Pregnant 
Partner Information Release Form will be provided to the site for the mother to sign.


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Any congenital abnormalities noted at birth in the offspring of a subject who received 
lirentelimab will be reported as a SAE. If the subject received lirentelimab, the outcome of any 
pregnancy and the presence or absence of any congenital abnormality will be recorded in the 
source documentation and reported to the Medical Monitor and Sponsor via the pregnancy 
reporting form.  
14.8.4 
AESI Reporting 
Beginning from the time of first SC injection of study drug and ending at the time of study 
completion or ET of the double-blind period or the OLE period, whichever is later, any new 
AESI (or new information related to a previously reported AESI) must be recorded in the AE 
eCRF and designated as an “AE of special interest.”  
For subjects participating in the OLE period, AESI will be assessed and recorded in the CRF of 
the AK002-027 double-blind treatment period database up until the start of the first OLE 
injection after the Day 85 visit and recorded in the CRF of the AK002-027 OLE period database 
beginning from the start of the first OLE injection after the Day 99 visit. 
An AESI that also qualifies as a SAE (per Section 14.2) must also be reported as a SAE in 
accordance with Section 14.8.2. Adverse events of special interest that are also SAE must be 
recorded in the AE eCRF and designated as both “serious” and as an “AE of special interest.” 
These will be reported on the Sponsor-provided SAE forms and should be reported to the 
Sponsor within 24 hours of site awareness. 
14.9 
Medical Monitoring 
Medical Monitoring is provided by the Sponsor for medically related questions. 
14.10 Independent Data Monitoring Committee 
An independent Data Monitoring Committee (iDMC) has been convened for this study. The 
iDMC will meet at established intervals (per the iDMC Charter) throughout the study and will 
also convene as necessitated by data and/or safety reviews.  
At the sole discretion of the Sponsor, a separate independent statistical review committee may be 
convened and tasked to assess if there is evidence of a beneficial clinical effect prior to 
unblinding of the double-blind portion of the AK002-027 study. The primary and relevant 
secondary endpoints will be evaluated for this purpose. The statistical review committee will not 
be tasked with any determination as to stopping the study early for efficacy or futility. Greater 
detail concerning the statistical review committee will be provided in a separate charter. 


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14.11 Study Withdrawal Criteria
Participation of a subject will be discontinued in the event that: 
 
Occurrence of an exclusion criterion, which is clinically relevant and affects the subject’s 
safety, if discontinuation is considered necessary by the Investigator and/or Sponsor.
Rebounding of eosinophil counts to >1500/mL in subjects who entered the study with 
eosinophil levels >1500/mL and whose eosinophil counts were initially suppressed after 
study drug, as assessed by the Safety Monitor, may be withdrawn from the study at the 
instruction of the Medical Monitor. 
Serum transaminases (ALT and/or AST) >3 × ULN and total bilirubin >2 × ULN 
(confirmed by subsequent repeat) without an alternative explanation.  
 
Elevation of ALT or AST >3 × ULN (confirmed by repeat) with the appearance or 
worsening of symptoms felt by the Investigator to be potentially related to hepatic 
inflammation, such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever, and rash. 
14.12 Study Stopping Rules 
14.12.1 General 
The study will be temporarily or permanently discontinued, and the DMC will convene for 
discussion of the case and for providing advice on study restart in the event of any of the 
following: 
 
An unexpected life-threatening AE that is confirmed to be related to treatment.  
 
A fatal AE that is confirmed to be related to treatment.  
 
Sponsor obtains new information leading to unfavorable risk-benefit judgment of the study 
drug. 
 
Sponsor’s decision that continuation of the trial is unjustifiable for medical or 
ethical reasons.  
 
Discontinuation of development of the Sponsor’s study drug.  
The Sponsor reserves the right to close a trial site or terminate the trial at any time for any reason 
at the sole discretion of the Sponsor. 
The Sponsor will notify all principal investigators outlining the reasons for the termination of the 
clinical trial. The Sponsor will provide principal investigators with instructions if assessments 
beyond the regular per protocol procedures should be necessary.   


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14.12.2 Additional Regional Stopping Rules
The study must be discontinued in the affected region in the event of any of the following events: 
 
Approval of the national competent authority or the Favorable Opinion/Approval of 
IEC/IRB for the conduct of the clinical trial is withdrawn. 
 
The required modification of the maximum insured sum is not possible following a 
negative change in the assessment of the benefit-risk ratio, if applicable. 
Health Authorities and IEC/IRB will be informed about the discontinuation of the study in 
accordance with applicable regulations.  
Study stopping for an individual site or investigator may occur in the event of noncompliance 
with the protocol or lapse of good clinical practice. 
15. Discontinuation and Replacement of Subjects 
15.1 
Definition of Study Completion 
A subject who completes visits through the Day 155 visit will be categorized as having 
completed the double-blind period of the study. 
A subject who completes visits through the Day 85 visit and enters the OLE period of the study
will be categorized as having completed the double-blind period of the study. 
A subject who completes visits through the OLE Day 155 visit will be categorized as having 
completed the OLE period of the study. 
The study is considered completed when the last subject completes the last study visit. 
15.2 
Early Discontinuation of Study Drug  
A subject may be discontinued from study treatment at any time if the subject, the Investigator, 
or the Sponsor feels that it is not in the subject’s best interest to continue. The following is a list 
of possible reasons for study treatment discontinuation: 
 
Subject withdraws consent.  
 
An AE that in the opinion of the Investigator results in it being in the best interest of the 
subject to discontinue study treatment.  
Protocol deviation requiring discontinuation of study treatment.  
 
Participation in any other study during the duration of this study.  


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Use of a non-permitted concomitant drug, which may adversely affect data interpretation in 
the opinion of the Medical Monitor. 
 
Loss of ability to freely provide consent through imprisonment or involuntary incarceration 
or treatment of either a psychiatric or physical (e.g., infectious disease) illness.  
If a subject is withdrawn from treatment due to an AE, the subject will be followed and treated 
by the Investigator until the abnormal parameter or symptom has resolved or stabilized.  
All subjects who discontinue study drug treatment should be encouraged to continue on study 
and complete assessments and procedures according to the 12-week follow-up period in Table 1, 
if possible.  
Reasonable attempts will be made by the Investigator to provide reasons for subject withdrawals. 
The reason for the subject’s withdrawal from the study or all attempts to acquire such will be 
specified in the source documents.  
16. Statistical Methods and General Considerations 
This section outlines the statistical methods to be used for the analysis of the data from the study. 
A separate SAP, which must be documented as completed prior to unblinding the study, will 
describe data handling and statistical techniques in full detail.  
When appropriate, summary statistics of number of non-missing values, mean, median, standard 
deviation, minimum, and maximum will be computed for continuous variables and summary 
statistics of number and proportion will be computed for categorical variables.  
Two-sided 95% CI will be provided for the mean and proportion. No formal statistical inferences 
will be made for safety parameters. Safety data will be summarized for each treatment group 
unless otherwise specified.  
Baseline for all safety and efficacy endpoints is defined as the last observations before 
administration of the first dose of study drug, unless otherwise specified. 
Subjects will be stratified at randomization based on omalizumab experience for the treatment of 
CSU (exposed vs. naïve) and UAS7 score (16–27 vs. 28–42). 
16.1 
Sample Size 
A sample size of approximately 55 subjects per treatment group will provide >90% power to 
demonstrate a statistically significant difference between lirentelimab and placebo in achieving a 
reduction in UAS7. We hypothesized a mean difference of at least 8 between lirentelimab SC 


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and placebo SC, and a pooled standard deviation of 11. This calculation is based on results 
derived from the AK002-006 study and expected placebo response rates reported in previously 
published data in H1-AH refractory CSU. 
Randomization of up to 130 subjects (approximately 65 subjects per treatment group) is driven 
by the powering calculations, the likely dropout rate of up to approximately 10%, and will
further support the evaluation of the safety and tolerability of lirentelimab SC.
16.2 
Analysis Populations 
The Safety population is defined as all subjects who received study medication.
The primary efficacy analysis population is the modified Intent-to-Treat (mITT) population, 
defined as all randomized subjects who have received at least 1 SC injection of study medication.
The Per Protocol (PP) population is defined as mITT subjects who have received all 6 
injections of study drug and do not have major protocol deviations possibly interfering with the 
interpretation of efficacy and safety assessment. The study statistician and study team will 
review protocol deviations to identify subjects to be excluded from the PP population analysis.
The mITT population will be used for all efficacy analysis, and the PP population will be used to 
evaluate sensitivity of the primary endpoint and secondary endpoints. 
16.3
Subject Disposition 
Subject disposition and reason for early discontinuation will be tabulated. Subject demographics, 
baseline characteristics, and treatment exposure will be summarized.
16.4
Demographic and Baseline Characteristics
The following demographic and baseline variables will be summarized:
Demographics
Medical history
Complete physical exam
ECG at screening
Screening vital signs and laboratory tests
Neither the subject’s initials nor the full date of birth will be documented in the CRF or in the 
questionnaires.


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16.5
Study Drug Exposure
Number and percent (n and %) of subjects who have received 1, 2, 3, 4, 5, or 6 SC injections will 
be presented.
16.6
Efficacy Analysis
16.6.1 
Primary Efficacy Endpoint Analysis 
The primary endpoint will be analyzed by analysis of covariance (ANCOVA). The least square 
(LS) mean, standard error (SE), and 95% CI for each treatment group and for the between group 
difference will be derived from ANCOVA with treatment as a factor, baseline UAS7 
(continuous), and omalizumab experience for the treatment of CSU (exposed vs. naïve) as
covariates. Data on subjects who experience an ICE (i.e., exit the study prematurely or initiate 
prohibited or rescue medications) prior to the end of Week 12 will be set to missing. Missing
data imputation method will be provided in the SAP.
Handling of missing PRO data for less than four data entries per week, other than during 
Screening, will be addressed in SAP.
16.6.2
Secondary Efficacy Endpoint Analysis
Binary data will be carried out using the Cochran-Mantel-Haenszel (CMH) test stratified by the 
randomization stratification factors (omalizumab experience for the treatment of CSU [exposed 
vs. naïve] and UAS7 score [16–27 vs. 28–42]). Data on subjects who experience an ICE prior to 
the end of Week 12 will be set to non-response status. 
Change from baseline in continuous secondary outcomes measured at multiple post-baseline 
time points will be analyzed longitudinally using a mixed model. The model will include fixed 
effects for baseline value, randomization stratification factor, treatment, week, the treatment by 
week interaction, baseline value by week interaction, and allow for random subject effects. The 
model variance-covariance matrix will be unstructured. However, if computation does not 
converge, the variance-covariance matrix will take the form of Toeplitz, AR(1), and compound 
symmetry, whichever converges first. The Kenward-Rogers approach for computing 
denominator degrees of freedom will be used to account appropriately for pooling of within-
subject and between-subject variance estimates. The LS means and the 95% CI for the between-
group difference will be estimated for each week.


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16.6.3
Exploratory Analysis
The binary exploratory efficacy endpoints will be analyzed using the Cochran-Mantel-Haenszel 
test adjusted by the randomization stratification factors. All exploratory efficacy endpoints of 
continuous nature will utilize MMRM procedure as described above. 
The following exploratory endpoints will be analyzed:
Impact on subject’s
 based on change in 
 at Week 12 compared 
with baseline. 
 
Impact on subject's 
 at Week 12 and Week 22 assessed as proportion of 
subjects achieving 
.
 
Impact on 
 at Week 12 and Week 22 assessed as proportion of subjects 
achieving 
.
 
Impact on 
 at Week 12 and Week 22 assessed as proportion of 
subjects achieving
16.7 
Safety Analysis 
Subject incidence of TEAE will be tabulated by the Medical Dictionary for Regulatory Activities 
(MedDRA) system organ class (SOC) and preferred term, and by severity and treatment 
relationship. Serious TEAE and TEAE leading to study discontinuation will be listed with 
pertinent information. Change from baseline in laboratory tests will be summarized with 
descriptive statistics. Details will be provided in the SAP. 
Adverse Events: All AE will be coded using MedDRA and will be classified by MedDRA SOC 
and preferred term. Listings will include all AE collected on study. The summaries of AE will be 
based on TEAE, defined as an AE reported in the clinical database with a date of onset (or 
worsening) on or after the start date of the first SC injection of study drug.  
16.7.1 
Treatment Emergent Adverse Events 
Subject incidence (N and %) of TEAE will be summarized as follows:  
 
Overview of TEAE to include 
 Number (%) of subjects who reported at least 1 TEAE overall, by severity and 
by relationship 
 Number (%) of subjects who reported at least 1 serious TEAE  
 Number (%) of subjects who reported at least 1 TEAE leading to treatment 
discontinuation  


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 Number (%) of subjects who reported at least 1 TEAE of special interest (TEAESI) 
TEAE by preferred term 
 
TEAE by SOC and preferred term  
 
TEAE by maximum severity, SOC, and preferred term  
 
TEAE by SOC and preferred term and relationship to study drug 
 
TEAE leading to withdrawal by SOC and preferred term  
 
Serious TEAE by SOC and preferred term  
 
TEAESI by SOC and preferred term
16.7.2 
Anti-Drug Antibodies
Samples will be obtained for testing of ADA at times identified in Section 12.3.6.  
16.7.3 
Clinical Laboratory Assessments 
Samples will be obtained for the clinical laboratory tests identified in Section 12.3, and 
laboratory tests to be summarized include chemistry, hematology, urinalysis, and lirentelimab 
ADA. Descriptive statistics will be used to summarize laboratory results at baseline, each visit, 
and the change from baseline for each visit. In addition, shift tables will summarize the 
laboratory results relative to normal reference ranges at baseline and each post-baseline 
time point.  
16.7.4 
Vital Signs
Vital signs will be summarized at baseline, each visit, and change from baseline at each visit.  
16.7.5 
ECG 
Subject incidence of the Investigator’s overall assessment (normal, abnormal – not clinically 
significant, and abnormal – clinically significant) will be summarized.
16.7.6 
Physical Exam 
New or worsening symptoms in the symptom-directed physical exams will be included in the 
by-subject data listing.  
16.7.7 
Concomitant Medications 
All medications (prior and concomitant) will be coded using the most current World Health 
Organization Drug Dictionary. Concomitant medications will be summarized by Anatomical 
Therapeutic Chemical class and preferred term.  


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16.8
Subject Confidentiality
Only the PID, and demographics will be recorded in the eCRF. If the subject’s name or other 
identifiers (e.g., medical record number or address) appear on any source document collected 
(e.g., hospital discharge summary), it must be removed from the document if the document will 
be viewed by the Sponsor, or a sponsor-contracted study vendor not permitted access to subject-
identifying information. All study findings will be stored in electronic databases. The subjects 
will give explicit written permission for representatives of the Sponsor, regulatory authorities, 
and the IEC/IRB to inspect their medical records to verify the information collected. Subjects 
will be informed that all personal information made available for inspection will be kept 
confidential to the extent permitted by all applicable state, local, and federal data 
protection/privacy laws and/or regulations and will not be made publicly available. If the results 
of the study are published, the subject’s identity will remain confidential.  
At study check-in to the study site, subjects will be advised not to share their study information 
with other subjects or on social media.  
17. Data Collection, Retention, and Monitoring  
17.1 
Data Collection Instruments  
All staff at participating clinical sites will adhere to good documentation practices. Data will be 
entered into the eCRF using source document data. Source documents may include but are not 
limited to laboratory data, recorded data from automated instruments, medical progress notes, 
and email correspondence.  
17.2
Data Management Procedures 
The data will be entered into a validated database. The data management group will be 
responsible for data processing in accordance with procedural documentation. Database lock will 
occur once quality assurance procedures have been completed. 
All procedures for handling and analysis of data will be conducted using good computing 
practices meeting FDA guidelines for handling and analysis of data for clinical studies. 
17.3
Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized data validation 
checks will be implemented and applied to the database on a regular basis. Queries are entered, 
tracked, and resolved through the electronic data capture system directly. The study database will 
be updated in accordance with the resolved queries. All changes to the study database will be 
documented.


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17.4
Database Lock/Disclosure of Randomization Code
There will be 2 database locks for the double-blind treatment period of the study:  
 
A provisional database lock after all subjects complete the Day 85 visit to allow for the 
analysis of safety and efficacy through Day 85. 
 
A final database lock after all subjects complete the study to allow for the analysis of any 
safety data collected after Day 85.  
For each database lock, applicable EDC data will be locked in order to protect write access after 
the following preconditions are fulfilled:
 
All records are entered in the database. 
 
All AE are coded to the satisfaction of the Chief Medical Officer or designee. 
 
All medications are coded to the satisfaction of the Chief Medical Officer or designee. 
 
All data queries have been resolved.  
 
All decisions have been made regarding all protocol violations and ITT population 
exclusions. 
 
Written authorizations to lock the database are obtained from Allakos Clinical Data 
Management and the Chief Medical Officer.  
The randomization code for this study will not be revealed until the previous preconditions are 
fulfilled, and documentation of the database lock is complete. After the database lock, the 
randomization code will be made available to individuals at Allakos who are involved in the data 
analysis. Data analysis will commence after the data lock. In addition, the PK and ADA data 
may be locked and assessed separately. 
17.5 
Archiving of Data 
The database is safeguarded against unauthorized access by established security procedures; 
appropriate backup copies of the database and related software files will be maintained. 
Databases are backed up by the database administrator in conjunction with any updates or 
changes to the database. At critical junctures of the protocol (e.g., production of interim reports 
and final reports), data for analysis is locked and cleaned per established procedures.  
17.6 
Availability and Retention of Investigational Records 
In accordance with 21 CFR 312.62(c), GCP-V § 13 (10), ICH GCP E6 (R2), and all other 
applicable regulatory requirements, all essential documents at the study site, the Sponsor’s 


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organization, or the Sponsor’s designee should be retained until at least 2 years after the last 
approval of an application for a marketing authorization in an ICH region, until there are no 
pending or contemplated applications for marketing authorization in an ICH region, and until at 
least 2 years have elapsed since the formal discontinuation of clinical development of the tested 
IMP and at least 10 years after the end of the clinical study, whichever period is longer. 
Furthermore, the essential documents should be retained for a longer period if required by the 
applicable regulatory requirements or by an agreement with the Sponsor. The trial master file 
will be created during the implementation period of a study, maintained on an ongoing basis 
throughout the duration of the project, and collated at the end of the study. The files will contain 
folders that may include but are not limited to the following subcategories: 
 
Financial agreements 
 
Regulatory documents 
 
Independent Ethics Committee (IEC)/IRB documents 
 
Drug Accountability documents 
 
Correspondence 
 
Medical Reports 
 
Subject Data 
 
Monitoring Visit Reports 
Sample CRF and CRF Guidelines 
17.7 
Monitoring 
Monitoring visits will be conducted by representatives of the Sponsor according to 21 CFR 
Parts 50, 56, and 312 and/or ICH GCP Guideline E6. By signing this protocol, the Investigator 
grants permission to the Sponsor (or designee) and appropriate regulatory authorities to conduct 
on-site monitoring and/or auditing, IRB/IEC review, and regulatory inspections of all appropriate 
study documentation, providing direct access to source data and documents. Monitoring of all 
appropriate study documentation may occur off-site, with remote access to study documents, if 
allowed by local regulation, as permitted by individual study site requirements.  
18. Administrative, Ethical, and Regulatory Considerations 
The study will be conducted in a manner consistent with this protocol, the Declaration of 
Helsinki (1996 version), IRB/IEC (21 CFR 56 and/or ICH E6), and Obligations of Clinical 
Investigators (21 CFR 312 and/or ICH E6), Directive 2001/20/EC (April 4, 2001) as well as 
other applicable local and national regulations. The Sponsor, the Investigators, and all 


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subcontracted organizations involved in the study conduct must also comply with all applicable 
privacy regulations (e.g., HIPAA, GDPR). The study can be initiated only after obtaining 
competent authority approval and IRB and/or IEC favorable opinion. If the competent authority 
withdraws the CTA approval or if the IRB withdraws the favorable opinion on the CTA, the 
conduct of the study will be terminated immediately. 
18.1
Protocol Amendments 
An amendment must be agreed to in writing by Allakos Inc. and submitted to the health authority 
as an Investigational New Drug (IND) amendment. An amendment which is considered 
substantial according to the EC CT-1 guidelines, must be submitted for review to the competent 
authority and the responsible IEC/IRB and cannot be implemented without prior written 
competent authority approval and the IEC/IRB favorable opinion. Written approval of a protocol 
amendment is not required prior to implementation of changes to the protocol that eliminate 
immediate hazard to the subject; however, approval must be obtained as soon as possible 
thereafter. Each protocol amendment must also be signed by the Investigator.  
18.2 
Independent Ethics Committees/Institutional Review Boards 
The protocol and ICF will be reviewed and approved by the IEC/IRB of each participating study 
site prior to study initiation. A central IRB may be used if permitted by the participating study 
site. All SAE, regardless of causality, will be reported to the IEC/IRB in accordance with the 
standard operating procedures and policies of the IEC/IRB, and the Investigator will keep the 
IEC/IRB informed as to the progress of the study. The Investigator or designee will obtain 
assurance of IEC/IRB compliance with regulations.  
Any documents that the IEC/IRB may need to fulfill its responsibilities (such as protocol, 
protocol amendments, Investigator’s Brochure, ICF, information concerning subject recruitment, 
payment or compensation procedures, or other pertinent information) will be submitted to the 
IEC/IRB. The IEC/IRB’s written unconditional approval of the study protocol and the ICF will 
be in the possession of the Investigator before the study is initiated. The IEC/IRB’s approval of 
the investigational site must be available to Allakos prior to shipment of study supplies to the 
site. This approval must refer to the study by exact protocol title and number and should identify 
the documents reviewed and the date of review. 
The IEC/IRB must be informed of revisions to other documents originally submitted for review; 
serious and/or unexpected adverse experiences occurring during the study in accordance with the 
standard operating procedures and policies of the IEC/IRB; new information that may adversely 
affect the safety of subjects or the conduct of the study; an annual update and/or request for 
reapproval; and when the study has been completed. 


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18.3
Informed Consent Form
Prior to study enrollment, all subjects must consent to participate in writing. The process of 
obtaining the informed consent will comply with all federal regulations, ICH requirements, and 
local laws.  
In accordance with ICH GCP Guideline E6 Section 4.3.3, subjects should be asked whether they 
would like their primary care physician notified of their study participation. If yes, the primary 
care physician should be notified in writing. Otherwise, the subject should sign a form stating 
that he/she does not wish to disclose such information. 
The Investigator or designee will review the study and the ICF with each potential subject. The 
review will include the nature, scope, procedures, and possible consequences of participation in 
the study. The consent and review must be in a form understandable to the potential subject. The 
Investigator or designee and the subject must both sign and date the ICF after review and before 
the subject can participate in the study, i.e., before any study-specific procedures are conducted. 
The subject will receive a copy of the signed and dated form, and the original will be retained in 
the site’s study files. The Investigator or designee must emphasize to the subject that study 
participation is entirely voluntary and that consent regarding study participation may be 
withdrawn at any time without penalty or loss of benefits to which the subject is otherwise 
entitled.  
18.4 
Publications 
The preparation and submittal for publication of manuscripts containing the study results will be 
in accordance with a process determined by mutual written agreement among the study Sponsor 
and respective site(s). The publication or presentation of any study results will comply with all 
applicable privacy laws including but not limited to the Health Insurance Portability and 
Accountability Act of 1996 and the EU General Data Protection Regulation (GDPR). 
18.5 
Clinical Study Registration 
This clinical study will be registered on the Clinical Trial Registry Websites, 
www.ClinicalTrials.gov and www.clinicaltrialsregister.eu  
18.6 
Payment to Subjects 
All subjects may be compensated for participating in this study in accordance with the payment 
amounts per study day stated in the subject’s signed ICF approved by the IEC/IRB. In 
accordance with Section 4.8.3 ICH E6 (R2), financial compensation from the sponsor to 
participating subjects shall be limited to the reimbursement of any travel expenses incurred 
(Germany only). In Poland, no incentives of financial rewards may be given, except for 


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compensation for costs incurred. If the subject is discontinued from the study prior to the last 
study visit, the subject will be compensated for each completed study visit on a pro rata basis as 
stated in the subject’s ICF. 
Beginning with Dosing Day 1, subjects will be compensated for each completed week of daily 
questionnaires as long as at least 4 questionnaires per week are completed. Subjects may be 
reimbursed for expenses associated with attending study visits. 
No additional compensation beyond what is stated in the ICF is permitted.  
18.7 
Investigator Responsibilities  
By signing the Investigator Protocol Agreement page, the Investigator agrees to:  
1) 
Conduct the study in accordance with the protocol and only make changes after notifying 
the Sponsor (or designee), except when to protect the safety, rights, or welfare of subjects.  
2) 
Personally conduct or supervise the study.  
3) 
Ensure that the requirements relating to obtaining informed consent and IEC/IRB review 
and approval meet country requirements.  
4) 
Report to the Sponsor or designee any AE that occurs in the course of the study, in 
accordance with 21 CFR Part 312.64 and/or ICH Guideline E2A.  
5) 
Ensure that all associates, colleagues, and employees assisting in the conduct of the study 
are informed about their obligations in meeting the above commitments.  
6) 
Maintain adequate and accurate records in accordance with 21 CFR Part 312.62 and ICH 
Guideline E6 and to make those records available for inspection with the Sponsor (or 
designee).  
7) 
Ensure that an IEC/IRB that complies with the requirements of 21 CFR Part 56 and ICH 
Guideline E6 as applicable will be responsible for initial and continuing review and 
approval of the clinical study.  
8) 
Promptly report to the IEC/IRB and the Sponsor (or designee) all changes in the research 
activity and all unanticipated problems involving risks to subjects or others (to include 
amendments and IND safety reports).  
9) 
Seek IEC/IRB approval before any changes are made in the research study, except when 
necessary to eliminate hazards to the subjects.  


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10) Comply with all other requirements regarding the obligations of clinical Investigators and 
all other pertinent requirements listed in 21 CFR Part 312 and/or ICH Guideline E6.  
19.
References 
Altrichter S, Staubach P, Pasha M, Singh B, Chang, A, Bernstein J, Rasmussen H, Siebenhaar F, 
Maurer M. An open-label, proof-of-concept study of lirentelimab for antihistamine-
resistant chronic spontaneous and inducible urticaria. J Allergy Clin Immunol, 
2022;149:1683-90.
Bochner B. Siglec-8 on human eosinophils and mast cells, and Siglec-F on murine eosinophils, 
are functionally related inhibitory receptors. Clin Exp Allergy 2009;39:317–24. 
Clinical Trials Facilitation and Coordination Group (CTFG). Recommendations related to 
contraception and pregnancy testing in clinical trials, version 1.1. 21 Sep 2020, accessed 
28 Jun 2022, https://legemiddelverket.no/Documents/Godkjenning/Klinisk%20utpr% 
C3%B8ving/2014_09_HMA_CTFG_Contraception_guidance%20Version%201.1.pdf.  
European Medicine Agency. 31/01/2023 Xolair – EMEA/H/C/00606 – N/0117. Xolair: EPAR – 
Product Information. 01 Feb 2023, accessed 15 Feb 2023, 
https://www.ema.europa.eu/en/medicines/human/EPAR/xolair. 
Food and Drug Administration. Birth Control Chart from FDA.gov/consumers/free-publications-
women/birth-control. 18 Jun 2021a, accessed 27 Feb 2022,
https://www.fda.gov/consumers/free-publications-women/birth-control. 
Food and Drug Administration. E9 (R1) Statistical Principles for clinical trials: addendum: 
estimands and sensitivity analysis in clinical trials. Guidance for industry, ICH, 
May 2021b. 
Garg A, Cranwell A, Chan D. Cetirizine – how much is too much? J Pharmacy Practice and 
Research. 2018;48:170-172. 
Maurer M, Weller K, Bindslev-Jensen C, Gimenez-Arnau A, Bousquet P, Bousquet J, et al. 
Unmet clinical needs in chronic spontaneous urticaria. A GA2LEN task force report. 
Allergy, 2011;66:317–30. 
Maurer M, Rosén K, Hsieh HJ, Saini S, Grattan C, Gimenéz-Arnau A, Agarwal S, Doyle R, 
Canvin J, Kaplan A, Casale T. Omalizumab for the treatment of chronic idiopathic or 
spontaneous urticaria. N Engl J Med. 2013;368:924-35. 


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Metz M, Maurer M. Omalizumab in chronic urticaria. Curr Opin Allergy Clin Immunol, 
2012;12:406–11.
Metz M, Ohanyan T, Church M, Maurer M. Omalizumab is an effective and rapidly acting 
therapy in difficult-to-treat chronic urticaria: a retrospective clinical analysis. J Dermatol 
Sci, 2014a;73:57–62. 
Metz M, Ohanyan T, Church M, Maurer M. Retreatment with omalizumab results in rapid 
remission in chronic spontaneous and inducible urticaria. JAMA Dermatol, 
2014b;150(3):288–90. 
Metz M, Vadasz Z, Kocatürk E, Giménez-Arnau A. Omalizumab updosing in chronic 
spontaneous urticaria: an overview of real-world evidence. Clin Rev Allergy Immunol,
2020;59:38–45. 
Mlynek A, Magerl M, Hanna M, Lhachimi S, Baiardini I, Canonica G, et al. The German version 
of the Chronic Urticaria Quality-of-Life Questionnaire: factor analysis, validation, and 
initial clinical findings. Allergy, 2009;64:927–36. 
Sampson H, Munoz-Furlong A, Campbell R, Adkinson Jr N, Bock S, Branum A, et al. Second 
symposium on the definition and management of anaphylaxis: summary report – Second 
National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol 2006;117:391–7. 
Sanofi. Update on ongoing Dupixent
 (dupilumab) chronic spontaneous urticaria Phase 3 
program. 18 Feb 2022, accessed 16 Nov 2022, https://www.sanofi.com/en/media-
room/press-releases/2022/2022-02-18-06-00-00-2387700. 
Tashiro M, Sakurada Y, Iwabuchi K, Mochizuki H, Kato M, Aoki M, et al. Central effect of 
fexofenadine and cetirizine: measurement of psychomotor performance, subjective 
sleepiness, and brain histamine H1-receptor occupancy using 11C-doxepin positron 
emission tomography. J Clin Pharmacol, 2004;44:890-900. 
Wertenteil S, Strunk A, Garg A. Prevalence estimates for chronic urticaria in the United States: 
A sex- and age-adjusted population analysis. J Am Acad Dermatol, 2019;81:152–56. 
Zhao Z, Ji C, Yu W, Meng L, Hawro T, Wei J, Maurer M. Omalizumab for the treatment of 
chronic spontaneous urticaria: A meta-analysis of randomized clinical trials. J Allergy 
Clin Immunol, 2016;137:1742–50.e4.


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Zuberbier T, Aberer W, Asero R, Bindslev-Jensen C, Brzoza Z, Canonica G, et al. The 
EAACI/GA2LEN/EDF/WAO Guideline for the definition, classification, diagnosis, and 
management of urticaria: the 2013 revision and update. Allergy, 2014;69:868–87.
Zuberbier T, Abdul Latiff AH, Abuzakouk M, Aquilina S, Asero R, Baker D, et al. The 
international EAACI/GA²LEN/EuroGuiDerm/APAAACI guideline for the definition, 
classification, diagnosis, and management of urticaria. Allergy, 2022;77:734-766.
 


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20.
Appendices
20.1 
Appendix 1: Urticaria Patient Daily Diary – PRO for Itch and Hives Severity 
20.2
Appendix 2: 
20.3
Appendix 3: 
 
20.4
Appendix 4: 
20.5
Appendix 5: Atopic Conditions Questionnaire
20.6
Appendix 6: Common Terminology Criteria for Adverse Events v. 5.0
20.7
Appendix 7: Sampson’s Criteria of Anaphylaxis
20.8
Appendix 8: Hepatitis B and Hepatitis C Serologic Testing Details
20.9
Appendix 9: Open Label Extension Period (Optional)


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20.1
Appendix 1: Urticaria Patient Daily Diary – PRO for Itch and Hives Severity


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20.1
Appendix 1: Urticaria Patient Daily Diary – PRO for Itch and Hives Severity cont.


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20.1
Appendix 1: Urticaria Patient Daily Diary – PRO for Itch and Hives Severity cont.


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20.1
Appendix 1: Urticaria Patient Daily Diary – PRO for Itch and Hives Severity cont.


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20.2
Appendix 2:
 




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20.2
Appendix 2:


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20.2
Appendix 2:


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20.3
Appendix 3:


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20.4
Appendix 4: 


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20.5
Appendix 5: Atopic Conditions Questionnaire


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20.6
Appendix 6: Common Terminology Criteria for Adverse Events v. 5.0  
The CTCAE (version 5) for download can be found at: 
 
http:\\ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_ 
Quick_Reference_5x7.pdf 
Examples for grading of terms are shown below in Figure 4 Example of Grading for General 
Disorders and Administration Site Conditions and Figure 5 Example of Grading for Laboratory 
Abnormalities (Investigations). 
Figure 4 
Example of Grading for General Disorders and Administration Site Conditions


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20.6
Appendix 6: Common Terminology Criteria for Adverse Events v. 5.0 cont.
Figure 5
Example of Grading for Laboratory Abnormalities (Investigations)
 


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20.7
Appendix 7: Sampson’s Criteria of Anaphylaxis  
ANAPHYLAXIS: Sampson’s definition of anaphylaxis (clinical definition) is the acute onset of 
illness (minutes to several hours) which involves SKIN, MUCOSAL TISSUE, or BOTH (e.g., 
generalized hives, pruritus or flushing, swollen lips-tongue uvula) with 1 OR more of the 
following (Sampson, 2006): 
RESPIRATORY: Airway compromise (e.g., dyspnea, wheeze, or bronchospasm, stridor, 
reduced PEF, hypoxemia) 
 
CIRCULATORY: Reduced blood pressure or associated symptoms of end-organ 
dysfunction (e.g., hypotonia, syncope) 
OR
2 or MORE of the following that occur rapidly after exposure: 
 
SKIN, MUCOSAL TISSUE: e.g., generalized hives, itch-flush, swollen lips-tongue-uvula 
 
RESPIRATORY: Airway compromise (e.g., dyspnea, wheeze, or bronchospasm, stridor 
and reduced PEF) 
 
CIRCULATORY: Reduced blood pressure or associated symptoms of end-organ 
dysfunction (e.g., hypotonia, syncope) 
 
GASTROINTESTINAL: Persistent gastrointestinal symptoms (e.g., crampy abdominal 
pain, vomiting, nausea, diarrhea) 
 


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20.8
Appendix 8: Hepatitis B and Hepatitis C Serologic Testing Details 
Hepatitis B Testing Details 
HBsAg positive subjects are excluded. However, in case of past infections/vaccinations in order 
to qualify, the subject’s testing status needs to align with the information in Table 8. 
Table 8
Hepatitis B Testing
Past Infection (Resolved) 
Or 
Vaccinated 
HBsAg 
Negative 
HBsAg 
Negative 
Anti-HBc
Positive
Anti-HBc
Negative
Anti-HBs
Positive
Anti-HBs
Positive
Hepatitis C Testing Details 
Anti-HCV positive and HCV-RNA positive are excluded. In order to qualify for enrollment, the 
subject’s testing status needs to align with the information in Table 9. 
Table 9 
Hepatitis C Testing 
Non-Reactive 
Or 
Past Infection (Resolved)
Anti- HCV 
Negative 
Anti- HCV 
Positive 
HCV RNA 
Negative 
 


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20.9
Appendix 9: Open Label Extension Period (Optional)
20.9.1 
Summary of the Open-Label Extended Dosing Period 
Subjects who complete the double-blind, placebo-controlled treatment period (including the 
Day 85 study visit) and meet the open-label extended dosing eligibility criteria will be given the 
option to receive 6 doses of 300 mg lirentelimab SC through the open-label extension (OLE) 
dosing period. 
On Day 85 (±5 days) of the double-blind period, eligible subjects participating in the OLE period 
will begin following the OLE Schedule of Assessments (Table 10) and will no longer follow the 
Double-Blind Period Schedule of Assessments (Table 1). The subjects starting the OLE period 
on Day 85 of the double-blind period do not need to repeat any assessments that overlap with 
Day 85 from the double-blind period. 
The OLE dosing period is summarized as follows: 
 
The Investigator will evaluate whether the subject is eligible for OLE. If eligible, the 
subject will be given the option to participate in the OLE period and receive 6 doses of 
open-label 300 mg lirentelimab SC administered every 2 weeks starting on Day 85 of the 
double-blind period, which will be considered Day 1 of the OLE period. OLE dosing may 
be delayed for up to 7 days after completion of the Day 85 visit.
 
On Day 85, eligible subjects who choose to participate in the OLE period will begin 
following the OLE Schedule of Events (Table 10). Subjects starting the OLE period on 
Day 85 of the double-blind period do not need to repeat any assessments that overlap with 
Day 85 from the double-blind period. 
Day 1 of the OLE can occur up to 7 days following Day 85 of the double-blind period. In 
case Day 1 of the OLE is not the same as Day 85 of the double-blind period, applicable 
subjects (women of childbearing potential) will have to take a urine dipstick pregnancy test. 
Subsequent doses will be given on OLE Days 15, 29, 43, 57, and 71 (±5 days).  
All differential blood counts will be blinded to the Sponsor and the site until after OLE Day 
1 dosing. 
Subjects will remain at the site for at least 1 hour of observation after each dose. In the 
event of an IRR, the subject may require prolonged observation (>1 hour or until the 
symptoms resolve), as per Investigator discretion.  


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Subjects will be followed for approximately 12 weeks after the last dose. Follow-up visits 
will occur on OLE Days 85, 127, and 155 (14, 56, and 84 [±5] days) after the last dose of 
open-label study drug. 
 
If absolute lymphocyte and/or eosinophil counts have not recovered by the OLE Day 155 
visit (last follow-up visit), subjects will return approximately every 28 days for extended 
follow-up until counts have recovered.  
 
If extended follow-up is required, data collection will be limited to hematology, SAE, 
and AESI. 
20.9.2 
OLE Objective 
The objective of the OLE period is to evaluate long-term safety and tolerability of up to 6 doses 
of open-label lirentelimab in subjects with CSU. The Medical Monitor will review data from the 
OLE period relating to safety and tolerability throughout the course of OLE dosing. 
20.9.3 
OLE Eligibility Criteria 
Following completion of the randomized, double-blind, placebo-controlled treatment period 
(including the Day 85 visit), eligible subjects will have the option to receive 6 doses of 
open-label 300 mg lirentelimab SC through participation in the OLE period. 
Subjects who are not eligible or who choose not to participate in the OLE period will remain in 
the double-blind study and continue to follow the double-blind period Schedule of Events 
(Table 1). 
20.9.4 
OLE Inclusion Criteria 
Subjects are eligible to participate in the OLE period if all the following criteria are met:
1) 
Subject completed the randomized, double-blind, placebo-controlled treatment period and 
the Day 85 visit procedures. 
2) 
Subject is willing and able to comply with the OLE period Schedule of Events (Table 10), 
including receiving the first open-label 300 mg lirentelimab SC at the Day 85 visit which is 
14 days following the last dose of study drug in the double-blind period. OLE dosing may 
be delayed for up to 7 days after completion of the Day 85 visit. 
3) 
Subject demonstrates continued eligibility per applicable inclusion criteria (Section 8.4) and 
exclusion criteria (Section 8.5) of the protocol. “Screening” in Section 13.1 and 
Section 13.2. refers only to the screening period completed prior to enrollment in the 
double-blind treatment period of the study and is not applicable to the OLE period. 


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20.9.5
OLE Exclusion Criteria
Subjects are not permitted to participate in the OLE period if any of the following criteria are 
met:
1) 
Previous administration of the study drug (lirentelimab or placebo) was poorly tolerated by 
the subject, in the opinion of the Investigator. 
2) 
Any other reason that in the opinion of the Investigator or Medical Monitor makes the 
subject unsuitable for participation in the OLE period. 
Acceptable documentation required to confirm inclusion and exclusion criteria will be further 
explained in the Study Reference Manual. 
20.9.6 
OLE Treatment 
Formulation, storage, preparation, and administration of the open-label lirentelimab SC for the 
OLE will be consistent with Section 10 of the protocol and the AK002-027 Pharmacy Manual. 
The first OLE study drug administration of open-label 300 mg lirentelimab SC will be done on 
Day 85 of the double-blind period. This will be considered Day 1 of the OLE period. OLE 
dosing may be delayed for up to 7 days after the completion of the Day 85 visit. The subsequent 
injections will occur on OLE Days 15, 29, 43, 57, and 71 (±5 days). 
The subject will be observed for at least 1 hour (or longer as per Investigator’s discretion) after 
the end of the injection. In the event of an IRR, the subject may require prolonged observation 
(>1 hour or until symptoms resolve), as per Investigator’s discretion. Subjects will also be 
instructed to immediately contact the study doctor if any reactions occur after discharge. 
20.9.7
OLE Procedures and Guidelines
The OLE period will be conducted in accordance with Table 10 (Schedule of Assessments: 
Open-Label Extension Period) and the protocol. This includes prohibited medications, dietary 
and lifestyle restrictions, study drug preparation and administration, study assessment and 
procedure guidelines, AE reporting, withdrawal criteria and stopping rules, data collection and 
management, and ethical and regulatory requirements.
The Investigator will evaluate whether the subject is eligible for the OLE period. On Day 85, 
eligible subjects that choose to participate in the OLE period will begin following the OLE 
Schedule of Assessments (Table 10) and will receive the first open-label dose of lirentelimab.






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Table 10 Notes cont. 
6) 
The 
 will be completed by those subjects that also have a history of 
 at screening. 
7) 
Subjects will be prompted to answer additional questions about symptoms related to asthma, allergic rhinitis, and allergic conjunctivitis. 
8) 
Blood samples for total serum IgE will be collected predose on OLE Days 1, 43, and 71, on follow-up OLE Days 85, 127, and 155, or 14, 56, and 84 (±5) days after the last 
dose of study drug if ET. 
9) 
Blood for chemistry, including hCG, will be collected. Only subjects of childbearing potential and postmenopausal women are required to have hCG testing completed. 
Blood for chemistry will be obtained predose on all dosing days and on all follow-up days (14, 56, and 84 [±5] days after the last dose of study drug if ET).  
10) Blood for CBC with differential, including absolute blood eosinophil count, will be obtained just prior to each SC injection, 1 hour (±15 minutes) after the end of each 
SC injection, and on all follow-up days (14, 56, and 84 [±5] days after last dose if ET). An unscheduled CBC may be collected at the request of the Safety Monitor. 
11) Blood for PK will be obtained predose on all dosing days and on all follow-up days (14, 56 and 84 [±5] days after last dose of study drug if ET). 
12) Blood for ADA will be collected predose on Days 1 and 43 and on follow-up Days 85 and 155 (14 and 84 [±5] days after last dose of study drug if ET). The ADA sample 
will also be collected any time an immunogenicity-related AE occurs. 
13) Urine will be collected for dipstick pregnancy test on all dosing days and all follow-up days (14, 56, and 84 days after last dose of study drug if ET) for all subjects of 
childbearing potential. Test kits will be supplied by the central laboratory. Tests will be completed on site and evaluated prior to each SC injection. 
14) Urine for standard urinalysis will be obtained at OLE Dose 1 and on follow-up OLE Days 85 and 155 (14 and 84 days [±5] if ET), and symptom-based, as necessary. 
15) The capture of non-serious AE, SAE, and AESI will continue throughout the open-label period. 
16) If OLE Day 1 takes place the same day as Day 85, the following assessments should only be done under Day 85 and not duplicated under OLE Day 1: prior/concomitant 
medications, body weight, symptom-directed physical exam (if applicable), UPDD, USA7, 
 Atopic Conditions Questionnaire, blood for IgE, chemistry, 
CBC, PK, and ADA, urine for dipstick pregnancy test (if applicable), and non-serious and serious adverse events. Blood draw and vital sign assessments must follow OLE 
Schedule of Events (as per above table notes). 

SAP_001.pdf: 
A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of Lirentelimab in Adult Subjects with H-1 Antihistamine Refractory 
Chronic Spontaneous Urticaria 
NCT Number: NCT05528861 
Document Date: 03 November 2023 






 
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Table of Contents 
Statistical Analysis Plan for Protocol AK002-027.......................................................................1 
Signature Page ................................................................................................................................2 
Table of Contents ...........................................................................................................................3 
List of In-Text Tables ..............................................................................................................6 
List of Abbreviations ...............................................................................................................7 
Revision History .............................................................................................................................9 
1. 
Introduction .........................................................................................................................10 
2. 
Study Objectives ..................................................................................................................10 
2.1 
Primary Objective and Endpoint ...............................................................................10 
2.1.1 Weekly Urticaria Assessment Score (UAS7) ................................................10 
2.2 
Secondary Objectives and Endpoints ........................................................................12 
2.3 
Exploratory Objectives and Endpoints ......................................................................12 
2.3.1 
 ....................................................................................12 
2.3.2 
 ...................................................................12 
2.3.3 
 ..........................................................................14 
2.4 
Safety Objectives and Endpoints ...............................................................................14 
3. 
Study Design .........................................................................................................................15 
3.1 
General Description ...................................................................................................15 
3.2 
Methods of Assigning Subjects to Treatment Groups ...............................................21 
3.3 
Treatment Blinding ....................................................................................................21 
3.4 
Determination of Sample Size ...................................................................................21 
4. 
Definitions ............................................................................................................................21 
4.1 
Terminology and Definitions ....................................................................................21 
4.2 
Target of Estimation ..................................................................................................22 


 
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4.2.1 Population Targeted by the Scientific Question ............................................22 
4.2.2 Variables of Interest (or Endpoint) to be Obtained for Each Subject 
that is Required to Address the Scientific Question ......................................23 
4.2.3 Treatment .......................................................................................................23 
4.2.4 Intercurrent Events ........................................................................................23 
4.2.5 Strategy for Handling Intercurrent Events ....................................................23 
4.2.6 Summary Measure of the Estimand ..............................................................24 
5. 
Statistical Methods ..............................................................................................................24 
5.1 
General Methodology ................................................................................................24 
5.2 
Visit Window and Unscheduled Assessments ..........................................................25 
5.3 
Adjustment for Covariates .........................................................................................27 
5.4 
Data Handling Conventions ......................................................................................27 
5.5 
Independent Safety Monitoring Committee ..............................................................27 
5.6 
Timing of Data Analyses ...........................................................................................27 
5.7 
Interim Analysis ........................................................................................................28 
5.8 
Multicenter Study ......................................................................................................28 
5.9 
Multiple Comparisons/Multiplicity Adjustment .......................................................28 
5.10 
Examination of Subgroups ........................................................................................28 
6. 
Statistical Analysis ...............................................................................................................29 
6.1 
Analysis Populations .................................................................................................29 
6.1.1 Safety Population ...........................................................................................29 
6.1.2 Intent-to-Treat Population .............................................................................29 
6.1.3 Modified Intent-to-Treat Population .............................................................29 
6.2 
Disposition of Subjects ..............................................................................................30 
6.3 
Protocol Deviations and Violations ...........................................................................30 
6.4 
Demographics and Baseline Disease Characteristics ................................................31 


 
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6.5 
Medical History .........................................................................................................31 
6.6 
Electrocardiogram .....................................................................................................31 
6.7 
Pregnancy Test ..........................................................................................................31 
6.8 
Treatments .................................................................................................................31 
6.8.1 Treatment Compliance ..................................................................................31 
6.8.2 Prior, Concomitant, and Newly Initiated Medications ..................................32 
6.9 
Analyses of Efficacy Endpoints ................................................................................32 
6.9.1 Analysis of Primary Efficacy Endpoint .........................................................32 
6.9.2 Analysis of Secondary and Exploratory Efficacy Endpoints ........................35 
6.10 
Analysis of Pharmacokinetic Endpoint .....................................................................37 
6.11 
Safety Analyses .........................................................................................................38 
6.11.1 Adverse Events ..............................................................................................38 
6.11.2 Laboratory Test .............................................................................................39 
6.11.3 Vital Signs, Height and Weight, and Other Safety Measures .......................39 
6.11.4 Electrocardiogram .........................................................................................39 
6.11.5 Physical Examination ....................................................................................39 
6.11.6 Analysis of Anti-Drug Antibodies .................................................................39 
7. 
Validation .............................................................................................................................40 
8. 
References ............................................................................................................................40 
9. 
Appendices ...........................................................................................................................41 
9.1 
Appendix 1: Intercurrent Events and Listing of Prohibited Medication/Treatments 
and Potential Rescue Medications for CSU ..............................................................42 
9.2 
Appendix 2: List of Tables, Figures, and Listings ....................................................44 
 


 
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List of In-Text Tables 
Table 1 
Hives Severity Score ..............................................................................................11 
Table 2 
Itch Severity Score .................................................................................................11 
Table 3 
 ..............................................................13 
Table 4 
Meaning of 
 ............................................13 
Table 5 
Detailed Analysis of 
 ..........................................13 
Table 6 
Study AK002-027 Schedule of Assessments: Double-Blind Period .....................17 
Table 7 
Terminology and Definitions .................................................................................22 
Table 8 
Analysis Week Definitions Based on Scheduled Visits ........................................26 
 


 
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List of Abbreviations 
AD 
Atopic dermatitis 
ADA 
Anti-drug antibody 
ADaM 
Analysis Data Model  
AE 
Adverse event 
ANCOVA 
Analysis of covariance 
ATC 
Anatomical Therapeutic Chemical (Classification System) 
BLOQ 
Below limit of quantification 
BMI 
Body mass index  
CBC 
Complete blood count 
CDISC 
Clinical Data Interchange Standards Consortium 
CMH 
Cochran-Mantel-Haenszel 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
DM 
Data management  
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
Electronic Data Capture (system) 
ET 
Early Termination 
FDA 
Food and Drug Administration 
HSS 
Hive Severity Score 
ICE 
Intercurrent events  
ICH 
International Conference on Harmonization 
ICF 
Informed Consent Form 
IRT 
Interactive Response Technology 
ISS 
Itch Severity Score 
ITT 
Intent-to-treat (population) 
LLN 
Lower limit of normal 
LLOQ 
Lower limit of quantification 
LSM 
Least squares mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified intent-to-treat (population) 


 
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MMRM 
Mixed Model for Repeated Measures 
NRI 
Nonresponder Imputation 
OLE 
Open-label extension 
p-value 
Probability value 
PD 
Pharmacodynamics 
PE 
Physical examination 
PK 
Pharmacokinetic(s) 
PP 
Per protocol population 
PT 
Preferred term 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical analysis system 
SC 
Subcutaneous 
SD 
Standard deviation 
SE 
Standard error 
SDTM 
Study Data Tabulation Model 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event(s) 
TEAESI 
Treatment-emergent adverse event(s) of special interest 
TESAE 
Treatment-emergent serious adverse event(s) 
TLF 
Tables, listings, and figures 
 
 
ULN 
Upper limit of normal 
UPDD 
Urticaria Patient Daily Diary 
WHO 
World Health Organization 
WHODD 
World Health Organization Drug Dictionary 
 


 
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Revision History 
Version Date 
Version Number 
Brief Summary of Changes 
03 November 
2023 
 Version 1 
Original document 
 
 


 
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1. 
Introduction 
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled study to evaluate 
the efficacy and safety of lirentelimab administered via subcutaneous injection (SC) in 
omalizumab-naïve or exposed adult subjects with H1-antihistamine (H1-AH) refractory chronic 
spontaneous urticaria (CSU). 
The statistical analysis plan (SAP) describes a priori the data and variables to be summarized or 
analyzed, including specifications of the analytical methods to be performed. This SAP 
supersedes the statistical analysis methods described in the clinical protocol except for the 
standard pharmacokinetic (PK) data analyses. Significant deviations/changes from the planned 
analyses described in this SAP will be identified, with justification, in the appropriate section of 
the clinical study report (CSR). The SAP is based on Clinical Study Protocol AK002-027 
Amendment 3, dated 07 September 2023 (Global), Clinical Study Protocol AK002-027 
Amendment 4, dated 23 September 2023 (US Only), and the associated electronic case report 
form (eCRF).  
2. 
Study Objectives  
2.1 
Primary Objective and Endpoint 
The primary objective of the study is to assess the efficacy of lirentelimab SC in adult subjects 
with CSU.  
The associated estimand for this objective is the effect of therapy with lirentelimab SC as 
assessed by the absolute change in weekly Urticaria Assessment Score (UAS7) from baseline to 
Week 12.  
2.1.1 
Weekly Urticaria Assessment Score (UAS7) 
The UAS7 is the sum for 7 days of the daily Hives Severity Score (HSS) and the daily Itch 
Severity Score (ISS). The possible range of the weekly UAS7 score is 0–42. Complete UAS7 
response is defined as UAS7 = 0 or by reduction of ≥90% from baseline. 
The severity of hives will be recorded by all subjects once daily in their Urticaria Patient Daily 
Diary (UPDD), on a scale of 0 (none) to 3 (> 50 hives) (see Table 1). A weekly HSS score 
(HSS7) is derived by adding the average daily scores of the 7 days preceding the visit. Therefore, 
the possible range of the weekly score is 0 - 21. A complete hives response is defined as HSS7 = 
0. When one or more of the daily scores are missing, the following principles will be applied to 
handle the missing data: 


 
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x 
At baseline and post-baseline time points, if a subject has at least 4 non-missing daily 
scores within a given week, the weekly score is calculated as the sum of the available 
scores in that week, divided by the number of days that have a non-missing diary score, 
multiplied by 7.  
x 
At post-baseline time points, if there are less than 4 non-missing daily scores within a given 
week, then the weekly score is set to missing. Missing data will be imputed using methods 
outlined in Section 6.9.1. It is worth remarking that missing data imputation is not required 
at baseline since a minimum of 4 daily scores per week are required to determine subject 
eligibility for the study. 
Table 1 
Hives Severity Score 
Score 
Number of Hives per 24 Hours 
0 
None 
1 
< 20 
2 
20 – 50 
3 
> 50 
 
The severity of itching will be recorded by all subjects once daily in their UPDD, on a scale of 0 
(none) to 3 (severe) (see Table 2). A weekly ISS score (ISS7) is derived by adding the average 
daily scores of the 7 days preceding the visit. Therefore, the possible range of the weekly score is 
0 – 21. Partially missing diary entries will be handled in the same way described for the hives 
severity score. 
A complete itch response is defined as ISS7 = 0. 
Table 2 
Itch Severity Score 
Score 
Pruritus (Itch) over the last 24 Hours 
0 
None 
1 
Mild (present but not annoying or troublesome) 
2 
Moderate (troublesome but does not interfere with normal daily 
activity or sleep) 
3 
Severe (severe itching, which is sufficiently troublesome to 
interfere with normal daily activity or sleep) 
 




 
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 that assess 
 over the past week 
with an overall scoring system of 
; a high score is indicative of a 
 is 
a self-administered questionnaire. The scoring of each question is defined in Table 3.  
Table 3 
 Scoring 
Response Per Question 
Score 
The 
is calculated by summing the score of each question resulting in a maximum of 
 
and a minimum of
 The higher the score, the more 
 (Table 4).  
Table 4 
Meaning of 
 Scores 
Score 
Definition 
The 
 can be analyzed under six headings as shown in Table 5. 
Table 5 
Detailed Analysis of 
 
Heading 
Question Number(s) 
Score Maximum 


 
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Heading 
Question Number(s) 
Score Maximum 
Interpretation of incorrectly completed 
 questionnaires: 
x 
If one question is left unanswered this is scored 0 and the scores are summed and expressed 
as usual out of a maximum of 
. 
x 
If two or more questions are left unanswered the questionnaire is not scored. 
x 
If question 7 is answered 'yes' this is scored . If question 7 is answered 'no' or 'not relevant' 
but then either 'a lot' or 'a little' is ticked this is then scored 
 If it is answered 'no', but 
the second half is left incomplete, the score will remain 0. 
2.3.3 
 
Subjects that have a history of 
 will have to complete the 
 daily. The 
 is a 
, self-administered, daily questionnaire that records 
 in subjects with 
. The format provides 
 for each item (scored 
), with a 
minimum score of  and a maximum score of 
 per day. Lower scores reflect 
 
 and higher scores reflects 
. The 
 describes the 
 
of 7 consecutive days for a score range from 
 points.  
2.4 
Safety Objectives and Endpoints 
The safety objective of the study is to evaluate the study drug safety profile using the following 
safety endpoints:  
x 
Treatment emergent adverse events (TEAE) including severity, relationship to study 
treatment, serious adverse events (SAE), and adverse events (AE) leading to study drug 
withdrawal 
x 
Anti-drug (lirentelimab) antibody (ADA)  
x 
Changes in Laboratory tests 
x 
Changes in Physical examination  
x 
Changes in vital signs  


 
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3. 
Study Design 
3.1 
General Description 
This is a Phase 2, proof-of-concept, multicenter, randomized, double-blind, placebo-controlled 
study to evaluate the efficacy and safety of lirentelimab in adult subjects with moderate-to-severe 
H1-AH refractory CSU. Subjects enrolled in the study will receive 6 doses of 300 mg 
lirentelimab SC or placebo SC administered every 2 weeks, followed by the option to enroll in 
the open-label extension (OLE) period, contingent on defined selection criteria, to receive 
6 doses of 300 mg lirentelimab SC. Subjects will be observed for a post-treatment period of 
12 weeks. 
Based on the feedback from chronic spontaneous urticaria experts and completed feasibility 
assessments, it is expected that each site will be able to screen three subjects and enroll two of 
them during the duration of the enrollment period. Enrollment is considered to be competitive. 
To ensure the enrollment goal is achieved in a timely manner, up to 70 sites (approximately 55 in 
the US, and 15 in Germany and Poland) will be initiated. If study enrollment goal can be 
achieved with fewer sites and meet the study timeline, then fewer sites may be needed. 
Subjects will be consented and then screened for up to 3 weeks. Subjects who have been on a 
stable, approved dose regimen of H1-AH prior to screening will undergo a 2-week eligibility 
screening period. Subjects who are not on a stable approved H1-AH dose regimen will be 
allowed an additional 1 week during the screening period during which they must reach a stable 
approved dosing regimen before entering the 2-week eligibility screening period. 
Stable approved doses of H1-AH for study purposes is defined as an H1-AH regimen between 1x 
and 4x of the licensed dose and at the licensed frequency of dosing for the treatment of CSU, for 
at least 1 week prior to screening. 
Baseline H1-AH dosing regimen must be established by Day -14 (14 days prior to 
randomization) for purposes of the screening eligibility period. Baseline disease activity data will 
be collected with daily assessment of itch and hives severity, both of which will be used to 
calculate a weekly UAS7. Subjects who meet eligibility criteria at both Day -7 and Day 1 can be 
enrolled in the study.  
The baseline UAS7 score for efficacy analysis calculations will be defined by the 7-day period 
prior to randomization. To ensure there is sufficient patient-reported outcome (PRO) data at 
baseline, a subject should complete at least four daily PRO questionnaires per week for a 
minimum period of the seven days prior to Day 1. 


 
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Subjects who meet eligibility criteria at Day -7 and Day 1 can be enrolled into the study. 
Subjects will not be allowed to rescreen for inadequate PRO compliance or PRO scores not 
meeting the minimum requirements (UAS7 ≥16, or HSS7 ≥8).  
Aside from the exclusion noted above, subjects may be allowed to be rescreened once after 
consultation and agreement with the Medical Monitor. Subjects rescreened within 30 days of 
signing initial consent will not need to reconsent if there are no changes to the ICF. 
Eligible subjects who meet selection criteria at screening and baseline will receive the first dose 
of lirentelimab SC or placebo SC on Day 1. If the study drug is well tolerated (no stopping rules 
being met), subjects will continue to receive subsequent doses on Days 15, 29, 43, 57, and 71 for 
a total of 6 doses. Subjects will remain in the clinic for at least 1 hour of observation (or longer 
as per Investigator’s discretion) following the end of dose administration after each dose. In the 
event of an injection-related reaction (IRR), the subject may require prolonged observation 
(>1 hour or until the symptoms resolve), as per Investigator’s discretion. Subjects will also be 
instructed to immediately contact the study team if any reactions occur after discharge. 
During the treatment period, subjects will return to the site for study visits as described in the 
Schedule of Events. Subjects will have the option to enter an open-label extension (OLE) period 
of the study to receive 6 doses of lirentelimab SC, contingent on meeting defined study selection 
criteria. Subjects will be followed for another 12 weeks after the last dose. Subjects not entering 
the OLE period will be followed for 12 weeks after the last dose of study drug in the double-
blind period.  
The primary endpoint will be assessed at Week 12, i.e., 2 weeks after the last dose in the double-
blind period of the study. Subjects will be stratified at randomization based on omalizumab 
experience for the treatment of CSU (exposed/naïve) and UAS7 score (16–27 or 28–42).  
At selected US sites, fresh biopsies of lesional (if available) and nonlesional skin may be 
collected from subjects predose and post-dose. Providing biopsies is optional. 
The overall schedule of procedures and assessments is presented in Table 6. 
 


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Table 6 
Study AK002-027 Schedule of Assessments: Double-Blind Period 
Assessment/Procedure 
Description 
Screening 
Double-Blind Treatment Period 
(10 weeks) 
Double-Blind Follow-Up 
Period (12 weeks) 
Day -2125 
~Day -1426 
Day -7 
(±3) 
Baseline 
Day 1 (±3)  
Baseline 
Day 8 
(±3) 
Day 15 
(±5) 
Day 29 
(±5) 
Day 43 
(±5) 
Day 57 
(±5) 
Day 71 
(±5) 
Day 85 
(±5) 
Day 127 
(±5) 
Day 155 
(±5) 
Dose 1 
 
Dose 2 
Dose 3 
Dose 4 
Dose 5 
Dose 6 
Week -3 
Week -2 
Week -1 
Phone Visit 
Week 0 
Week 1 
Visit 
Week 2 
Week 4 
Week 6 
Week 8 
Week 10 
Week 12 
FUP-1 
Week 18 
FUP-2 
Week 22 
FUP-3/EOS 
<--------Diary Eligibility Phase24-- -----------> 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
X26 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
X26 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X26 
X 
X 
 
 
 
 
 
 
 
 
 
Detailed previous diagnosis and 
treatments review1 
X 
X26 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Confirm H1-AH usage 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Body weight and height2 
X 
X26 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs3 
X 
X26 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
10-lead or 12-lead ECG4 
X 
X26 
 
 
 
 
 
 
 
 
 
 
 
Complete physical exam5 
X 
X26 
 
 
 
 
 
 
 
 
 
 
 
Symptom-directed physical exam6 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
UPDD7 
<---------------------------------------Complete daily from Screening through Day 155 or 84 days post last dose-------------------------------------> 
UAS78 
 
X 
X 
X  
X  
X 
X 
X 
X 
X 
X 
X 
X 
9 
X 
X 
 
X 
  
 
X 
 
X 
 
X 
X 
X 
10 
X 
X 
X 
X  
X  
X  
X  
X  
X  
X  
X 
X 
X 
 
X 
X 
X 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Blood for serology 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Atopic Conditions Questionnaire11 
 
 
 
X 
 
 
 
 
 
 
X 
 
 




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EOS: End of Study 
IP: Investigational Product 
UPDD: Urticaria Patient Daily Diary  
Table 6 Notes 
1) 
Documentation of CSU diagnosis and previous treatments should be noted in detail. This can be subject reported and/or based on medical records (see details in Section 
12.2.6 of the protocol). 
2) 
At screening, height (in cm) and weight (in kg) will be recorded. Body weight only will be measured at every visit. 
3) 
Vital signs will be measured at every visit and will be obtained after the subject has been at rest for ≥5 minutes. On all dosing days: 30 (±5) minutes predose, 15 (±5) minutes 
after administration of study drug SC injection, and just prior to discharge. Additional vital sign measurements may be collected at the Investigator’s discretion if an IRR 
occurs. Vital signs including systolic and diastolic blood pressure, pulse, body temperature, and respiratory rate will be measured after the subject has been at rest for 
≥5 minutes and before any blood draws have been obtained (unless collected for an IRR). 
4) 
A 10-lead or 12-lead ECG will be obtained at screening before any blood is drawn and after the subject has been in the resting position for ≥5 minutes. 
5) 
A complete physical examination will be performed by either the Investigator or designee and include the following body system or organ assessments: skin; head, eyes, ears, 
nose, and throat; thyroid; lungs; cardiovascular; abdomen; extremities; lymph nodes; and a brief neurological examination. 
6) 
A symptom-directed physical exam (including assessment of possible injection site reactions) will be performed by the Investigator or designee, as needed, if any symptoms 
are reported. 
7) 
All subjects will be provided with the UPDD. Subjects will receive clear instructions on the completion of the diary. UPDD includes UAS7 (itch and hives) for CSU subjects 
for clinical symptoms, and activity interference. Activate daily PRO and have subject complete first PRO (UPDD) in the clinic at Screening. To ensure there is sufficient 
PRO data at baseline, subject should complete at least four daily PRO questionnaires during the seven days prior to Day 1. 
8) 
The UAS7 is the sum for 7 days of the daily Hives Severity Score (HSS) and the daily Itch Severity Score (ISS) based on information collected in the UPDD and will be 
assessed weekly. 
9) 
The 
is a 
 questionnaire for assessing 
 and will be administered to the subject when in clinic. 
10) The 
 will be completed by those subjects that also have a history of 
. 
11) Subjects will be prompted to answer additional questions about symptoms related to asthma, allergic rhinitis, and allergic conjunctivitis. 
12) Blood samples for total serum IgE will be collected during screening, predose on Days 43 and 71, on follow-up Days 85, 127, and 155 or 14, 56, and 84 (±5) days after the 
last dose of study drug if early termination (ET). 
13) Female subjects of childbearing potential are required to have serum hCG measured during the screening period. Postmenopausal women are required to have serum FSH 
measured. If FSH level is ≤30 mIU/mL, a negative serum hCG will be required in order for subject to proceed to randomization. Blood for chemistry will be obtained predose 
on dosing days and on follow-up days (14, 56, and 84 [±5] days after the last dose of study drug if ET).  
 


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Table 6 Notes cont. 
14) Blood for CBC with differential, including absolute blood eosinophil count, will be obtained at screening, just prior to each SC injection, 1 hour (±15 minutes) after the end 
of each SC injection, and on all follow-up days (14, 56, and 84 [±5] days after last dose if ET). All differential blood counts from Day 1 (post-dose) through the end of the 
subject’s participation in the double-blind period will be blinded to the Sponsor and the site. An unscheduled CBC may be collected at the request of the Safety Monitor. 
15) Blood for PK will be obtained predose on all dosing days as well as on Day 8 (±3) and on follow-up days (14, 56 and 84 [±5] days after last dose of study drug if ET). 
16) Blood for ADA will be collected predose on dosing Days 1, 29, and 43, as well as on Day 8 (±3), and on follow-up Days 85 and 155 (14 and 84 [±5] days after last dose of 
study drug if ET). The ADA sample will also be collected any time an immunogenicity-related AE occurs. 
17) Urine will be collected for dipstick pregnancy test on all dosing days, Day 8, and all follow-up days (14, 56, and 84 [±5] days after last dose of study drug if ET) for all 
subjects of childbearing potential. Test kits will be supplied by the central laboratory. Tests will be completed on site and evaluated prior to each SC injection. 
18) Urine for standard urinalysis will be obtained at screening and on follow-up Days 85 and 155 (14 and 84 [±5] days if ET), and symptom-based, as necessary. 
19) Randomization will be conducted through the IRT system. Subjects will be randomized 1:1, 300 mg lirentelimab SC or placebo SC. They will be stratified based on biologic 
status and UAS7 score at baseline. 
20) The capture of non-serious AE and adverse events of special interest (AESI) will begin after the first dose of study drug has occurred. 
21) The reporting of serious adverse events (SAE) occurring after signing the ICF and prior to the first SC injection will be limited to those that relate to screening procedures. 
The capture of all SAE and AE that are not related to screening procedures will begin at the time of first SC injection of study drug. 
22) Lesional (if available) and nonlesional skin biopsies will be collected at selected US sites and is optional for subjects. Biopsies may be collected at baseline/predose on Day 1 
and post-dose on either Day 57, Day 71, or Day 85. See Section 12.1.11 of the study protocol. 
23) Open-label extension dosing may start on Day 85 after all Day 85 procedures are conducted or within 7 days after the Day 85 visit. Subjects who decide to enter the OLE 
period and meet the selection criteria for the OLE period will follow the schedule of events in Appendix 9 of the study protocol. 
24) The diary eligibility period will be 3 weeks for subjects that are screened but not on stable approved doses of H1-AH for at least a week prior to screening. They will enter 
screening at Day -21 and be stabilized on H1-AH. Subjects will start completing the UPDD the day they start screening. The diary eligibility period will be 2 weeks for 
subjects that are screened and on stable approved doses of H1-AH for at least a week prior to screening. These subjects will enter screening at Day -14. Subjects will have to 
meet the UAS7 and HSS7 criteria at Day -7 and again at Day 1, along with other entry criteria in order to qualify for the study. 
25) Subjects will either have a 3-week screening period (subjects who are not on a stable dose of H1-AH) or a 2-week screening period (subjects who are on a stable dose of 
H1-AH) depending on H1-AH usage at the time of screening (refer to Table Note #24). 
26) If assessment was performed at Day -21, it is not required to repeat at Day -14. 
 


 
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3.2 
Methods of Assigning Subjects to Treatment Groups 
Approximately 130 subjects (65 per arm) will be randomized to treatment with lirentelimab SC or 
placebo SC in a 1:1 ratio. Stratified permuted block randomization will be used. Randomization will 
be stratified based on UAS7 score (16–27 vs. 28–42) and on Omalizumab experience for the 
treatment of CSU (omalizumab-exposed vs. omalizumab-naïve). An Interactive Response 
Technology System (IRT) will be used to perform the randomization. 
3.3 
Treatment Blinding 
This is a double-blind study. The identity of active and placebo treatments will not be known to 
Investigators, Sponsor (including safety monitor), research staff (including pharmacy), subjects, or 
the study monitor.  
3.4 
Determination of Sample Size 
A sample size of 55 subjects per treatment group will provide >90% power to demonstrate a 
statistically significant difference between lirentelimab and placebo in achieving a reduction in 
UAS7. We hypothesized a mean difference of at least 8 between lirentelimab SC and placebo SC, and 
a pooled standard deviation of 11. This calculation is based on results derived from the AK002-006 
study and expected placebo response rates reported in previously published data in H1-AH refractory 
CSU.  
Randomization of up to 130 subjects (approximately 65 subjects per treatment group) is driven by the 
powering calculations, the likely dropout rate of up to approximately 10%, and will further support 
the evaluation of the safety and tolerability of lirentelimab SC. 
4. 
Definitions  
4.1 
Terminology and Definitions 
 


 
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Table 7 
Terminology and Definitions 
 
Terminology 
Definition 
Baseline 
Baseline for non-daily assessment (e.g., laboratory tests) is defined as the 
non-missing value collected most recently to and before the time of the 
very first dose of study drug. Baseline Patient Reported Outcome (PRO) 
data will be the average or the sum of the weekly PRO data collected in 
the last 7 days prior to Day 1 depending on the outcome under 
consideration. 
Concomitant 
Medications and 
Procedures 
Medications and procedures with a stop date before the treatment dosing 
date will be considered prior medications/procedures. Medications and 
procedures with a start or stop date on or after the treatment dosing date 
will be considered concomitant. All medications/procedures marked as 
ongoing are concomitant. 
Study Day  
Study Day 1 is defined as the date on which a subject received the first 
dose of study drug. For visits prior to the first dose of study drug, Study 
Day is calculated as Visit Date – Day 1 Date. For visits after the first 
dose, Study Day is calculated as Visit Date – Day 1 Date +1. 
Study Week 
Study Week for PRO analysis is defined as 7 days a week starting from 
the day of first dose (Day 1). Details are provided in Section 5.2.  
 
4.2 
Target of Estimation 
The estimand for the AK002-027 study estimates the effect of treatment, while considering treatment 
adherence and response. The estimand will provide an answer to the question that is crucial to 
individual subjects: “If I take this study medication as part of my treatment regimen, without adding 
any further drugs that may impact the underlying disease or exit the study prematurely, what 
improvement in CSU might be anticipated after 12 weeks?” 
The sections below describe the attributes of the estimand consistent with the ICH E9 (R1) 
Addendum (FDA, 2021). 
4.2.1 
Population Targeted by the Scientific Question 
The population targeted by the scientific question is defined via the inclusion and exclusion criteria as 
part of the study protocol. Subjects may be male or female and must have a clinical diagnosis of CSU 
as defined by the study inclusion criteria. 


 
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4.2.2 
Variables of Interest (or Endpoint) to be Obtained for Each Subject 
that is Required to Address the Scientific Question 
The primary endpoint to be obtained for each subject in this study to address the scientific question is 
change from baseline in UAS7 score at Week 12.  
4.2.3 
Treatment 
Lirentelimab SC or placebo SC administered to subjects on Days 1, 15, 29, 43, 57, and 71 for a total of 6 
doses. 
4.2.4 
Intercurrent Events 
The events below are considered intercurrent events (ICE) potentially confounding with the efficacy 
outcomes. 
x 
Premature discontinuation from the double-blind portion of the study  
x 
Use of prohibited medications during the study 
x 
Use of rescue medication for symptoms of CSU during the study 
4.2.5 
Strategy for Handling Intercurrent Events 
For subjects who experienced an ICE of premature discontinuation from the double-blind portion of 
the study, efficacy outcome will be defined as “non-responder”, referred to as non-response 
imputation, for binary endpoints and will be set to missing for continuous endpoints from the point 
when that ICE occurs. An appropriate method for handling missing data through statistical modeling 
(e.g., multiple imputation [MI]) will be used. 
During the double-blind portion of the study, use of the following prohibited medications for reasons 
unrelated to CSU or rescue medications for the purposes of alleviating symptoms of CSU (see 
Appendix 1) will be deemed an ICE and efficacy data for the affected subject will be handled as 
follows: 
x 
Antihistamines – Use of any new H1-AH or additional doses of an H1-AH above the stable 
baseline dose are prohibited. Subject-entered data for the day after the prohibited medication 
was used will be set to missing and this will apply for each day of prohibited medication use. 
x 
Systemic corticosteroids – Use of systemic corticosteroids at any dose and for a duration of less 
than 3 consecutive days will result in the subject’s efficacy data for a period of 7 calendar days 
will be set to missing beginning with the first day of systemic corticosteroid use and extending 
to a 7 day period following the last dose. Use of systemic corticosteroids for 3 or more days will 
result in censoring of all efficacy data from the first day of corticosteroid treatment, i.e., this 


 
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censoring rule is equivalent to using all the data up to first day of corticosteroid treatment. An 
appropriate method for handling missing data through statistical modeling (e.g., multiple 
imputation [MI]) will be used for continuous endpoints. For binary endpoints, efficacy outcome 
will be set to non-responder status. 
x 
Immunosuppressants, Immunomodulators and Biologics – Use of any immunomodulator, 
immunosuppressant or biologic will result in the premature withdrawal of the subject from the 
study and the censoring of all efficacy from the initiation of that therapy, i.e., this censoring rule 
is equivalent to using all the data up to first day of the prohibited therapy. An appropriate 
method for handling missing data through statistical modeling (e.g., multiple imputation [MI]) 
will be used for continuous endpoints. For binary endpoints, efficacy outcome will be set to 
non-responder status. 
Blinded adjudication of prohibited medication uses for rescue or for reasons unrelated to symptoms 
of CSU will be implemented before database lock. 
4.2.6 
Summary Measure of the Estimand 
Least squares mean (LSM) (and standard error [SE]) of change from baseline in UAS7 to Week 12 
and the between treatment difference in the lirentelimab SC and placebo SC groups LSM. 
5. 
Statistical Methods 
5.1 
General Methodology  
All statistical analyses will be conducted using SAS v9.4 or later version on the Microsoft Windows 
Operating System.  
All eCRF data (raw data) will be converted into SDTM (Study Data Tabulation Model) datasets, 
which will be used to create ADaM (Analysis Data Model) data sets. The creation of the SDTM and 
ADaM data sets will follow the CDISC (Clinical Data Interchange Standards Consortium) standards 
and the FDA Study Data Technical Conformance Guide. All analysis tables and listings will be 
created from the ADaM data sets. 
Continuous data will be summarized using “n” (number of subjects with non-missing observations), 
mean, median, standard deviation (SD), minimum value, and maximum value. Categorical data will 
be summarized using the frequency count and percentage (n, %) of subjects in each category. 
Number of subjects with non-missing values or number of subjects with missing values (e.g., Not 
Done) will be presented, where appropriate. Subjects with missing values will not contribute to the 
denominator for percentage calculations, unless specified otherwise. Counts of 0 in any category will 
be presented without percentage. All summaries will be presented for individual treatment groups. In 


 
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addition, for summary of disposition and subject baseline characteristics, the presentation will include 
both treatment groups combined.  
The precision rules for the presentation of summary statistics will be: 
x 
Sample size (n, N) and number of missing responses (if displayed): Integer 
x 
Mean, confidence interval, and median: Same number of decimal places as reported/collected 
x 
Standard deviation: Same number of decimal places as reported/collected 
x 
Percentiles, minimum, maximum: Same number of decimal places as reported/collected 
x 
Odds Ratio: 2 decimal places 
x 
Percentage: 1 decimal place generally, or 2 decimal places for <0.1%, or no decimal places for 
0% and ≥100% 
x 
P-value: 4 decimal places 
x 
WBC: 2 decimal places as 0.01 × 109/L 
x 
Height/Weight/BMI: 1 decimal place 
The data summaries will be accompanied by individual subject data listings. All data available from 
questionnaires, eCRF, and external transfer (labs) will be listed and will include relevant subject 
information, e.g., treatment group and study day. The listings will be sorted in the order of treatment 
group, subject ID, assessment name and date/time.  
Dates will be presented in the ISO-8601 format YYYY-MM-DD. Times will be displayed in 24-hour 
clock format. Numbering for tables, figures and listings will follow ICH E3 Guideline (ICH, 1996). 
Alternative methods of analysis of the data may be considered prior to database lock, and reason for 
departure from the planned methods will be documented in an amendment to the SAP or in the CSR. 
5.2 
Visit Window and Unscheduled Assessments 
Data collected for study assessments provide information on the status of the subject at a given time 
point. For all the non-daily, by-visit assessments, no analysis window will be defined. The by-visit 
summaries will be performed based on their associated visits.  
In the event of multiple values from unscheduled or early termination assessments associated with a 
single visit, the value closest to the scheduled visit target study day will be used for analyses. If 2 
values tie as closest to the time point (for example, 1 value is before and the other value is after the 


 
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time point), then the later value will be selected. Data collected at all visits will be included in the 
data listings with visit presented as reported by the site. 
Post-baseline weekly diary endpoints will be derived from subject daily diary windows anchored on 
day of first dose (Study Day 1) and day of last dose. Weeks 1 through 9 are defined in Table 8. 
 
Table 8 
Analysis Week Definitions Based on Scheduled Visits 
Analysis Week 
Study Days 
1 
1 – 7 
2 
8 – 14 
3 
15 – 21 
4 
22 – 28 
5 
29 – 35 
6 
36 – 42 
7 
43 – 49 
8 
50 – 56 
9 
57 - 63 
The diary window of Week 12 is the 7 days prior to the earlier of a) 14 days after Day 71 dose; or b) 
Open Label Extension Day 1 dose. In the case of diary non-compliance (fewer than 4 completed daily 
diaries in the Week 12 diary window), the start of the window can be extended back one day at a time 
until 4 completed daily diaries are obtained, or up to the day of Day 71 dose, whichever is reached 
first. If the Week 12 diary window still has fewer than 4 daily diaries after extending the start of 
Week 12 diary window to the day of Day 71 dose, the Week 12 diary window is defined as 7 days 
and the value of the window is set to missing. 
The Week 11 diary window begins on the day of Day 71 dose and ends on the earlier of a) six days 
after Day 71 dose; or b) 1 day prior to the start of the Week 12 diary window. 
The diary window of Week 10 begins on the latter of a) 7 days prior to Day 71 dose; or b) Study Day 
64 and ends on the day before Day 71 dose. 
If after constructing the diary windows there are fewer than 4 completed daily diaries for any week, 
the value of that week is set to missing and subject to imputation rules. 


 
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5.3 
Adjustment for Covariates 
Efficacy analyses will be adjusted for baseline values and randomization strata using ANCOVA, 
MMRM, or Cochran-Mantel-Haenszel tests, where applicable.  
5.4 
Data Handling Conventions 
This section includes the methods for missing data imputation for some summary analyses, if 
necessary. 
Adverse events with incomplete start or stop dates (i.e., either day or month is missing) will be 
considered treatment-emergent adverse events (TEAE) unless the partial start date or the stop date 
confirms the AE started or ended prior to Study Day 1 (e.g., the day of the AE start date is unknown 
but the month and year indicate that the AE starts prior to Study Day 1). Adverse events with missing 
relationship to study drug will be included in the “Related” category for the summary tables and 
footnoted. Adverse events with missing severity will not be included in the by-severity summary 
table but will be footnoted in the table. 
When there is incomplete information regarding dosing dates for prior and concomitant medication, 
the medication will be considered as a concomitant medication unless it contradicts with the stop 
date. For example, a medication will be considered a prior medication if the month and year of the 
end date indicates a date before Study Day 1 even though the start date could be missing.  
5.5 
Independent Safety Monitoring Committee 
An independent Data Monitoring Committee (iDMC) has been convened for this study for purposes 
of safety monitoring. The iDMC will meet at established intervals (as per the iDMC charter) 
throughout the study and will also convene as necessitated by data and/or safety reviews. The iDMC 
will not be tasked with any efficacy analyses. 
5.6 
Timing of Data Analyses 
The database lock will occur after all subjects complete participation in the double-blind period of the 
study.  
For the database lock, applicable EDC data will be locked to protect write access after the following 
preconditions are fulfilled: 
x 
All records are entered in the database. 
x 
All AE are coded to the satisfaction of the Chief Medical Officer. 
x 
All medications are coded to the satisfaction of the Chief Medical Officer. 


 
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x 
All data queries have been resolved.  
x 
All decisions have been made regarding all protocol violations and ITT population exclusions. 
x 
Written authorizations to lock the database are obtained from Allakos Clinical Data 
Management and the Chief Medical Officer.  
The randomization code for this study will not be revealed until the previous preconditions are 
fulfilled, and documentation of the database lock is complete. After the database lock, the 
randomization code will be made available to individuals at Allakos who are involved in the data 
analysis. Data analysis will commence after the data lock. In addition, the PK and ADA data may be 
locked and assessed separately. 
5.7 
Interim Analysis 
No interim analysis will be conducted for this study. 
5.8 
Multicenter Study 
The study will have approximately 70 sites in the US, Germany, and Poland. For efficacy analysis, 
sites within countries will be pooled together. 
5.9 
Multiple Comparisons/Multiplicity Adjustment 
To control for the family-wise type-I error rate, the following testing procedures will be 
implemented: 
Test primary efficacy endpoint at 2-sided α=0.05 level.  
x 
If p≤0.05 for primary endpoint, then reject the null hypothesis that lirentelimab SC is no different 
from placebo SC and accept the alternative hypothesis that lirentelimab SC is superior to placebo 
SC in improving UAS7 score.  
x 
If p≤0.05 for primary endpoint, the hypothesis tests for the secondary endpoints will proceed in 
the prespecified order (see Section 2.2). If at any point during the analysis of the secondary 
endpoints, the statistical test is not significant at 2-sided α=0.05 level, the hypothesis testing 
procedure will stop. Lirentelimab SC will be deemed superior to placebo SC for all endpoints 
prior to the stop. 
5.10 
Examination of Subgroups 
Key endpoints will be summarized by subgroup to assess the consistency of the treatment effect 
across each of these subgroups. For any subgroup, if there are zero subjects within a stratification 


 
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stratum in any treatment group, the statistical model will not be adjusted by the stratification factors. 
Subgroups to be considered are: 
x 
Sex (Male, Female) 
x 
Age group (<65, ≥65) 
x 
Race (White, Non-White) 
x 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
x 
Region (U.S., non-U.S.) 
x 
Baseline weekly itch severity score (<13, ≥13) 
x 
History of angioedema at screening (Yes, No) 
x 
Prior omalizumab experience for the treatment of CSU (exposed, naïve) 
x 
Baseline UAS7 score (16–27, 28–42) 
x 
Duration of disease prior to baseline (<2, 2-10, >10 years) 
x 
Screening IgE (≥43 kU/L, <43 kU/L) 
6. 
Statistical Analysis 
6.1 
Analysis Populations 
The population of “all screened subjects” comprises subjects who signed the informed consent (ICF). 
6.1.1 
Safety Population 
The safety population comprises randomized subjects who have received at least 1 dose of the study 
drug.  
6.1.2 
Intent-to-Treat Population 
The intent-to-treat (ITT) population is defined as subjects who were randomized to treatment. 
6.1.3 
Modified Intent-to-Treat Population 
The modified intent-to-treat (mITT) population will be defined as all randomized subjects who 
received at least one dose of study drug and had no major protocol violations based on key inclusion 
and exclusion criteria defining the population of interest (i.e., defined as not meeting inclusion 
criteria number 3, 4, 5, or 6). 
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any major protocol deviations or violations and have received all 6 doses of study medication (see 
Section 6.3 for list of protocol deviations and violations).  
6.2 
Disposition of Subjects 
Subject demographics and reasons for screening failure will be summarized for screen-failed 
subjects. Subjects (n and %) who completed or discontinued from the study will be tabulated by 
treatment group and for both treatment groups combined. The primary reasons for study 
discontinuation will be included in the tabulation. The primary reasons may include, but are not 
limited to, any of the following: 
x 
Subject withdrew consent 
x 
Lost to follow-up 
x 
Administrative reason 
x 
Adverse event  
x 
Investigator decision 
x 
Failure to follow required study procedures 
x 
Other 
Subject disposition will be summarized for the ITT population. Subject counts for the Safety, mITT, 
and PP populations will be included in the table. A data listing for subject disposition will be 
presented for the ITT population.  
6.3 
Protocol Deviations and Violations 
Protocol deviations will include, but are not limited to 
x 
Non-compliance with scheduled study visit  
x 
Non-compliance with study treatment  
x 
Received prohibited medications (see Protocol Section 9.1) 
x 
Any major violations of efficacy-related entry inclusion or exclusion criteria (defined as not 
meeting inclusion criteria number 3, 4, 5, or 6)  
x 
Non-compliance with study assessment procedures  
Subjects with major protocol deviations will be listed. The listing will include a brief description of 
the deviation, deviation category, and if applicable, study day when deviation occurred along with 
other pertinent information. If warranted by the sample size, subjects (n and %) with major protocol 


 
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deviations will be tabulated by treatment group and by deviation category. 
Subjects who are excluded from the PP population will be listed with reasons for exclusion.  
6.4 
Demographics and Baseline Disease Characteristics 
The demographic and baseline characteristics variables are described in Section 5.10. 
Descriptive statistics for these variables will be presented for all populations, by treatment group, and 
both treatment groups combined. Continuous variables will be summarized with n, mean, SD, and 
median. Categorical variables will be summarized with n and % of subjects for each category for the 
mITT, and PP populations.  
6.5 
Medical History 
Subject incidence (n and %) of medical history (and current medical condition before signing the 
informed consent document) will be tabulated by the Medical Dictionary for Regulatory Activities 
(MedDRA), version 21.0) System Organ Class (SOC) and Preferred Term (PT). 
6.6 
Electrocardiogram 
A listing of electrocardiogram (ECG) overall interpretations at screening visit will be provided. 
6.7 
Pregnancy Test 
A listing of pregnancy test results will be provided. 
6.8 
Treatments 
6.8.1 
Treatment Compliance  
Summaries of treatment compliance will be based on the safety population. 
The compliance with study treatment will be calculated as follows: 
Treatment Compliance = (Number of study drug injections during exposure period) / (Number of 
planned study drug injections during exposure period) x 100%. 
The treatment compliance will be presented by the following specific ranges for each treatment 
group: <80% and ≥80%. 
In addition, an overall compliance that includes adherence to treatment administration schedule and 
any interruptions will be included in the data listing. 


 
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6.8.2 
Prior, Concomitant, and Newly Initiated Medications  
Prior medications and concomitant medications will be extracted from the Prior/Concomitant 
Medication CRF. Medications taken prior to Study Day 1 will be considered as prior medications, 
medications taken on or after Study Day 1 will be considered as concomitant medications, and newly 
initiated medication refers to any medication with a start date ≥ Study Day 1. Note that a Prior 
Medication may also be a Concomitant Medication if the start date is prior to Study Day 1 and the 
end date is on/after Study Day 1. Medications will be coded using the WHO Drug Dictionary 
(WHODRUG GLOBAL September 2022 release) for preferred term (PT) and Anatomical 
Therapeutic Chemical (ATC) classification.  
Medications will be tabulated separately based on the Safety population. The number (n and %) of 
subjects taking at least 1 medication and the number (%) of subjects taking each medication at the 
preferred term level will be tabulated by ATC4, and PT. Subjects taking the same PT medication 
twice will only be counted once. 
A subject data listing will be provided to include the reported medication name, the WHODD PT, 
ATC4, study day and pertinent subject information.  
6.9 
Analyses of Efficacy Endpoints 
For all efficacy variables, the analysis will be comparison of lirentelimab SC and placebo SC groups. 
The following null and alternative hypotheses for the primary endpoint will be tested for lirentelimab 
SC group and placebo SC group: 
H0: No treatment difference between lirentelimab SC and placebo SC 
H1: There is a treatment difference between lirentelimab SC and placebo SC 
Omalizumab experience for the treatment of CSU (exposed, naïve) and UAS7 score (16–27, 28–42) 
will be the 2 stratification factors for subject randomization and will be accounted for in the statistical 
modeling for efficacy. In addition, if it is evident that the primary endpoint is confounded by baseline 
disease characteristics at study entry, then the primary efficacy analysis will be adjusted for the 
effects of these variables.  
6.9.1 
Analysis of Primary Efficacy Endpoint 
The primary endpoint will be analyzed using analysis of covariance (ANCOVA) using the imputed 
data set described below. The synthesizing method will be used to combine the results from multiple 
imputations. The least square (LS) mean, standard error (SE), and 95% confidence interval (CI) for 
each treatment group and for the between group difference will be derived from the ANCOVA model 


 
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with treatment as factor, and baseline UAS7 score and omalizumab experience for the treatment of 
CSU (exposed, naïve) as covariates. The hypothesis test for the treatment effect will be carried out by 
the F-test.  
For the analysis described above, missing data from subjects who prematurely discontinue the 
randomized treatment, initiate any treatment adjustments as outlined in Section 4.2.5 (e.g., use of 
prohibited or rescue medication), or missing daily PRO scores as described in Section 2.1 will be 
imputed using multiple imputation (MI) techniques. There are five steps in the MI process. 
1) 
Check missing data patterns. 
2) 
Impute non-monotonic or intermittent data until only monotone missing data remains. 
3) 
Use monotone regression to impute monotone missing data and create multiply imputed data 
sets. 
4) 
Run the primary efficacy analysis (ANCOVA using SAS PROC MIXED) on the multiply 
imputed data sets. 
5) 
Use SAS PROC MIANALYZE to combine the efficacy output to get a single estimate from all 
the imputed data sets. 
6.9.1.1 
Step 1. Checking missing data patterns  
For this study, the missing data patterns will be checked by treatment and visits (baseline to Week 
12). There are 3 steps to this process:  
Create dataset for efficacy measure including visits from baseline to Week 12  
data mi_chk1; set datax;  
where paramcd="UAS7" and baseline <= visit <=Week 12;  
run;  
Transpose dataset to display each visit as one column:  
proc sort data = mi_chk1; by treatment  id;  
proc transpose data=mi_chk1 out=mi_chk2 prefix=’’;  
by treatment   id;  
id avisitn; 
var aval;  
run;  
Use PROC MI with the NIMPUTE=0 option to create the "Missing Data Patterns" table for the 
specified variables:  
ods output MissPattern=missp;  
proc mi data=mi_chk2 NIMPUTE=0; 


 
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   by treatment; 
   var visit0(i.e., baseline) – visit12 (i.e., Week 12); 
run; 
6.9.1.2 
Step 2. Impute non-monotonic/intermittent data until only monotone missing data 
remains. 
Fill in the intermittent missing data using the following code. 
proc sort data = mi_chk2; by treatment; 
proc mi data=mi_chk2 seed=12345 NIMPUTE=50 out=MI; 
   by treatment; 
   mcmc impute=monotone; 
   var Visit0 – Visit12; 
   run; 
6.9.1.3 
Step 3. Use monotone regression to impute monotone missing data and create 
multiply imputed data sets. 
 
proc sort data = mi; by _Imputation_; 
proc mi data=mi out=mi_reg seed=54321 nimpute=1; 
by _Imputation_; 
var treatment Visit0 – Visit12; 
class treatment; 
monotone regression; 
run; 
6.9.1.4 Step 4. Run the efficacy analyses (PROC MIXED) on the multiply imputed data sets. 
 
/** Recalculate change from baseline at Week 12**/ 
data UAS7_imputed; 
   set mi_reg; 
   chg=Visit12 – Visit0; 
run; 
 
proc sort data=UAS7_imputed out=UAS7_imputed1; 
   by _imputation_; 
run; 
 
/** ANCOVA by imputation **/ 
ods output diffs=diffs lsmeans=lsm; 
proc mixed data=UAS7_imputed1 method=reml; 
   by _imputation_; 
   class region omalizumab experience TREATMENT; 
   model CHG= region omalizumab experience Visit0 TREATTMENT; 
   lsmeans TREATMENT / diff; 
quit; 


 
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ods output close; 
6.9.1.5 
Step 5. Combine estimates of the 50 PROC MIXED models to create an overall 
estimate and a relative efficacy score. 
   
/** Combine LS Means (by treatment and difference) **/ 
data lsmdiff; 
   set lsm diffs(in=d); 
   if d then treattment='DIFF'; 
run;  
proc sort;by TREATMENT;run; 
 
/** Synthesized results **/ 
ods output ParameterEstimates=SYNDIF; 
proc mianalyze data=LSMDIFF alpha=0.05; 
    by TREATMENT; 
    modeleffects ESTIMATE; 
    stderr stderr; 
run ; 
ods output close; 
The primary efficacy analysis will be performed on the mITT population. The PP population will be 
analysed as a supporting analysis.  
6.9.2 
Analysis of Secondary and Exploratory Efficacy Endpoints 
The binary secondary and exploratory efficacy endpoints will be analyzed using the Cochran-Mantel-
Haenszel test adjusted by omalizumab experience for the treatment of CSU (exposed, naïve), UAS7 
score (16–27, 28–42), and region (U.S., non-U.S.) at Week 12. A sample SAS code is as follows: 
 
* COMPUTES CMH P-VALUE AND NEWCOMBE COMMON RISK DIFFERENCE ; 
ods output CMH=PVAL(where=(althypothesis='Row Mean Scores Differ')) 
CommonPdiff=DIFF; 
proc freq data=ADEF ; 
 
tables UAS7*OMALIZUMAB_EXPERIENCE*REGION*TRTP*RESP / cmh(MF) 
commonriskdiff  
(cl=NEWCOMBE) ; 
run ; 
The Mantel-Fleiss (MF) criterion will be performed, and if it is not met while using the option CMH 
(MF) in SAS procedure PROC FREQ, analyses including each factor separately in CMH test will be 
conducted. Should assumption per the MF criterion not be satisfied, the comparison will be based on 
a Fisher’s exact test after collapsing across levels of the stratification factor and country. 
Below is an example of the SAS code for the Fisher’s exact test: 
 


 
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* COMPUTE 95% EXACT CONFIDENCE INTERVAL FOR %RESPONSE FOR INDIVIDUAL 
TREATMENT ; 
ods output BinomialCLs=CL ; 
proc freq data=ADEF ; 
 
table RESP / out=CNTS bin(cl=midp) ; 
 
by TRTP ; 
run; 
* COMPUTE 95% EXACT CONFIDENCE INTERVAL AND FISHERS EXACT P-VALUE FOR 
BETWEEN TREATMENT DIFFERENCE ; 
ods output FishersExact=PVAL(where=(name1='XP2_FISH')) 
RiskDiffCol2=DIFF(where=(row='Difference') ; 
proc freq data=ADEF ; 
      table TRTP*RESP / riskdiff(cl=exact) exact  ; 
run ; 
 
For the analysis described above, missing data from subjects who prematurely discontinue the 
randomized treatment, initiate any treatment adjustments as outlined in Section 4.2.5 (e.g., use of 
prohibited or rescue medication), or missing daily PRO scores as described in Section 2.1 will be 
imputed using non-response imputation. 
To assess the impact of the above “non-responder” rule, the missing data strategy will employ mixed 
model for repeated measures (MMRM) technique. This approach assumes missing observations are 
missing at random and borrows information from subjects in the same treatment group considering 
the missingness of data through the correlation of the repeated measurements. The SAS procedure 
PROC GLIMMIX will be used for this purpose. The model will include treatment, region, 
omalizumab experience for the treatment of CSU (exposed, naïve), UAS7 score (16–27, 28–42), visit, 
and treatment-by-visit-interaction as fixed categorical effects, and baseline and baseline-by-visit-
interaction as fixed continuous effects. The model will provide odds ratio, standard error, two-sided 
95% confidence interval for odds ratio and p-values at time points of interest. 
All secondary and exploratory efficacy endpoints of continuous nature will utilize MMRM procedure 
after applying the primary censoring rule, i.e., the rule will censor data after permanent study drug 
discontinuation or after rescue therapy that applies the censoring rule as described in Section 4.2.5. 
This censoring rule is equivalent to using all the data up to discontinuation or rescue. 
The MMRM model will include fixed effects for baseline value, omalizumab experience for the 
treatment of CSU (exposed, naïve), UAS7 score (16–27, 28–42), country, treatment, study week, the 
treatment-by-week interaction, and the baseline-by-week interaction and allow for random subject 
effects. Treatment and week will each be fitted as categorical variables. The model will assume 
unstructured covariance structure. If the model with unstructured covariance does not converge, then 
other covariance structures will be considered to model the within-subject errors. The Kenward-


 
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Rogers approach for computing denominator degrees of freedom will be used to account 
appropriately for pooling of within-subject and between-subject variance estimates. The LS and 95% 
CI for the difference between groups will be estimated using the simple contrast at each time point. 
Below is an example of the SAS code for the MMRM: 
proc mixed data=CONTINUOS method=reml; 
   class TREATMENT USUBJID AVISITN REGION USA7_SCORE (16–27, 28–42) 
OMALIZUMAB_EXPERIENCE; 
   model CHANGE= BASELINE_OF_OUTCOME USA7_SCORE (16–27, 28–42) 
OMALIZUMAB_EXPERIENCE TREATMENT AVISITN REGION 
TREATMENT*AVISITN BASELINE_OF_OUTCOME *AVISITN / DDFM=KR; 
REPEATED AVISITN / SUBJECT=USUBJID (TREATMENT) TYPE=UN; 
RANDOM REGION; 
LSMEANS TREATMENT*AVISITN / PDIFF CL; 
RUN; 
Where TREATMENT = planned treatment group in numeric (1 = placebo SC, 2 = lirentelimab SC); 
AVISITN = time point in Weeks. 
6.10 
Analysis of Pharmacokinetic Endpoint 
The analysis of the PK concentration will be based on the Safety population. Lirentelimab SC 
concentrations will be listed by treatment, subject, nominal time, and actual time. Concentrations that 
are below limit of quantification (BLOQ) will be indicated in the listing.  
Plasma concentrations will be summarized at each nominal time point separately for each treatment. 
The following descriptive statistics will be presented: n, arithmetic mean, SD, geometric mean, 
% CV, median, minimum, and maximum.  
Individual plasma concentration vs. actual times will be plotted for each subject in linear and semi-
logarithmic scales, placed on the same page. Mean plasma concentration at the scheduled time points 
will be plotted for each treatment in linear and semi-logarithmic scale, with the associated standard 
errors (for linear scale only) at each scheduled time point. 
In the plot, concentrations that are BLOQ will be assigned a value of 0 if they are collected predose 
or assigned a value of 1/2 the lower limit of quantification (LLOQ) if they are collected postdose.  
Analysis of PK parameters are specified separately in a PK analysis plan. 


 
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6.11 
Safety Analyses 
6.11.1 
Adverse Events 
Safety assessments will be based mainly on the nature, frequency, relationship, and severity of 
adverse events (AE). The AE will be coded by primary System Organ Class (SOC) and Preferred 
Term (PT) according to MedDRA (version 21.0). The treatment-emergent adverse events (TEAE) 
will be summarized by the number and percentage (n and %) of subjects in each SOC and PT.  
For summaries by relationship to study drug, “possibly related” will be combined with “related”, and 
“unlikely/remotely related” will be combined with “not related.” When multiple AE are reported with 
the same PT, the AE of the strongest relation to study drug will be included in the summary by 
relationship, and the AE of the most severe grade will be included in the summary by severity table. 
The following AE incidence tables will be presented.  
x 
Overview of TEAE to include 
 Number (%) of subjects who reported at least 1 TEAE  
 Number (%) of subjects who reported at least 1 treatment related TEAE 
 Number (%) of subjects who reported at least 1 severe TEAE 
 Number (%) of subjects who reported at least 1 serious TEAE  
 Number (%) of subjects who reported at least 1 TEAE leading to treatment discontinuation  
 Number (%) of subjects who reported at least 1 TEAE leading to study discontinuation  
 Number (%) of subjects who reported at least 1 TEAE of special interest (TEAESI) 
x 
TEAE by PT sorted by decreasing order of subject incidence in the combined treatment group 
x 
TEAE by SOC and PT in alphabetical order 
x 
TEAE by SOC, PT, and maximum severity 
x 
TEAE by SOC, PT, and strongest relationship to study drug  
x 
TEAE leading to treatment discontinuation by SOC and PT, if warranted by sample size 
x 
TEAE leading to study discontinuation by SOC and PT, if warranted by sample size 
x 
Serious TEAE by SOC and PT, if warranted by sample size 
x 
TEAESI by SOC and PT 


 
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All AE will be listed with onset/stop day, relationship to study drug, severity, action taken, and 
outcome. Pertinent subject information including treatment group and demographics will also be 
included.  
Separate listings will be provided for TEAE leading to study discontinuation, TEAE of special 
interest, and treatment-emergent serious AE (TESAE).  
6.11.2 
Laboratory Test 
Laboratory data will be summarized by presenting summary statistics of raw data and change from 
baseline values (means, medians, standard deviations, ranges). For quantitative laboratory 
parameters, both actual values and change from baseline values will be summarized at each visit. 
Shift tables will be presented, in which, lab test results at baseline and post-baseline visit will be 
classified into below (<LLN), within (≥LLN and ≤ULN), and above (>ULN) normal ranges. Subject 
incidences (n and %) will be presented for the shift from baseline to the post-baseline visits. 
Note that the analysis window will be applied for the visits. 
A complete laboratory data listing, including hematology, biochemistry, and urinalysis will be 
provided for all subjects.  
6.11.3 
Vital Signs, Height and Weight, and Other Safety Measures 
Vital signs will be summarized by presenting summary statistics of raw data and change from 
baseline values (means, medians, standard deviations, ranges) for each visit (per analysis window) 
and time point. A data listing will include vital signs from all visits.  
6.11.4 
Electrocardiogram 
Incidence of the Investigator’s overall assessment (normal, abnormal – not clinically significant, and 
abnormal – clinically significant) will be summarized. 
6.11.5 
Physical Examination 
New or worsening symptoms in the symptom-directed physical exams will be included in the 
by -subject data listing. 
6.11.6 
Analysis of Anti-Drug Antibodies 
A data listing of anti-drug-antibodies (ADA) results will be provided for all subjects. Number (%) of 
subjects who are confirmed ADA-positive at any time after receiving study drug and number (%) of 


 
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subjects who are confirmed ADA-positive at the end of study will be cross-tabulated by their ADA 
status and titers at predose. 
7. 
Validation  
The Clinical Operations and Data Management at Allakos will work with the EDC/Data Management 
(DM) vendor to ensure that the data collected for the study is of the highest quality possible. The 
study monitor will be responsible for reviewing and verifying the accuracy of the data recorded on 
the eCRF directly from source documents at the investigative site. The DM vendor will be 
responsible for performing edit checks and reviewing all data entered into the electronic database to 
identify discrepant and/or inconsistent values and to send queries to the clinical sites. The 
Investigator will be responsible for answering queries about discrepant data and providing electronic 
signatures to confirm data integrity.  
The programming of tables, listings, and figures (TLF) based on the clinical data is outsourced. 
Allakos seeks to ensure the quality of the reports provided by the CRO in the form of TLF passing a 
rigorous validation process as follows:  
x 
Derived datasets will be independently reprogrammed by a second programmer. The separate 
datasets produced by the 2 programmers must match 100%.  
x 
Tables will be independently reprogrammed by a second programmer, and the results from both 
programs must match.  
x 
Figures will be checked for consistency against corresponding tables and listings or 
independently reprogrammed if there are no corresponding tables or listings.  
x 
Listings will be checked for consistency against corresponding tables, figures, and derived 
datasets.  
All post-hoc analysis, if accepted for inclusion in the study report, will follow the same quality 
process as stated above. The entire set of TLF will be checked for completeness and consistency prior 
to delivery to Allakos.  
8. 
References 
Food and Drug Administration. E9 (R1) Statistical Principles for clinical trials: addendum: estimands 
and sensitivity analysis in clinical trials. Guidance for industry, ICH, May 2021. 
International Council for Harmonisation (ICH). Guideline for industry E3, structure and content of 
clinical study reports, July 1996.  


 
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9. 
Appendices 
9.1 
Appendix 1: Intercurrent Events and Listing of Prohibited Medication/Treatments and 
Potential Rescue Medications for CSU 
9.2 
Appendix 2: List of Tables, Figures, and Listings 
 


 
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9.1 
Appendix 1: Intercurrent Events and Listing of Prohibited Medication/Treatments and 
Potential Rescue Medications for CSU 
Prohibited medications are defined as therapies that should not be taken during the course of the 
study either because of a potential impact on the assessment of efficacy and/or subject safety. Rescue 
medications/treatments are defined as any therapy or treatment taken during the course of the study 
for the specific purpose of alleviating CSU symptoms that may have an impact on the assessment of 
efficacy and includes: systemic medications such as systemic corticosteroids, increased daily dose or 
addition of a new H1-AHs, immunosuppressants, immunomodulatory medications, and biologics. 
Detailed definitions of ICE and data handling strategy for ICE are described in section 4.2.5.  
The following provides the details of the prohibited medications/therapies for this study: 
1) 
The use or initiation of any new H1-AH or increase in the total daily dose, as compared to 
baseline, of an H1-AH for the purpose of treating CSU at any point in the study will be 
considered rescue therapy H1-AH: ATC code is R06A 
2) 
The use or initiation of topical corticosteroids for the purpose of treating skin conditions other 
than CSU at any point in the study will be not be considered rescue therapy but should be 
avoided if possible. If unavoidable, lower potency topical steroids over the least surface area 
possible and for the shortest duration should be utilized: ATC code is D07A 
High Potency TCS: ATC codes D07AC or D07AD 
Low or moderate potency TCS: ATC code D07, excluding D07AC or D07AD 
3) 
Prohibited systemic medications (including systemic corticosteroids, H2-AH, 
immunosuppressants, immunomodulators, hydroxychloroquine, oral doxepin, IV 
immunoglobulins, and biologics) 
 
Systemic corticosteroids: ATC code is H02 
H2-AHs: ATC code is A02BA 
Immunosuppressants or immunomodulators: ATC code is L04  
Mycophenolate: ATC code is L04AA06 
Methotrexate: ATC code is L04AX 
Interferons: gamma: ATC code is L03AB where Preferred Terms include interferon gamma, 
interferonalfa-2b 
Leukotriene inhibitors: ATC code is R03DC where Preferred Term includes Ibudilast, 
Montelukast, Pranlukast, and Zafirlukast 
Oral calcineurin inhibitors: ATC code is L04AD where Preferred Term includes Ciclosporin, 
Cyclosporin, Tacforius, Tacrolimus, Voclosporin 
Hydroxychloroquine: ATC code is P01BA02  
Oral doxepin: ATC code is N06AA12 
IV immunoglobulins: ATC code is J06B 


 
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Janus Kinase inhibitors (JAKi): ATC code is L01EJ where Preferred Term includes 
Delgocitinib, Fedratinib, Pacritinib, Ruxolitinib and ATC code is D11AH with Preferred 
Term Abrocitinib 
TNF inhibitors: ATC code is L04AB where Preferred Term includes Adalimumab, 
Afelimomab, Certolizumab, Etanercept, Golimumab, Infliximab, Opinercept, Ozoralizumab 
 
Biologics:  
Agents For CSU, Excluding Corticosteroids: ATC code is D11A where preferred terms 
include Dupilumab, Tralokinumab 
CD20 inhibitors: ATC code is L01F where preferred terms include Obinutuzumab, 
Ofatumumab  
Selective Immunosuppressants: ATC code is L04AA where preferred terms include 
Abatacept, Abetimus, Alemtuzumab, Anifrolumab, Apremilast, Baricitinib, Begelomab, 
Belatacept, Belimumab, Belumosudil, Deucravacitinib, Eculizumab, Efalizumab, 
Emapalumab, Filgotinib, Fingolimod, Inebilizumab, Itacitinib, Natalizumab, Ocrelizumab, 
Ofatumumab, Ozanimod, Peficitinib, Pegcetacoplan, Ponesimod, Ravulizumab, Sutimlimab, 
Teprotumumab, Teriflunomide, Tofacitinib, Upadacitinib, Vedolizumab 
Interleukin Inhibitors: ATC code is L04AC where preferred terms include Anakinra, 
Basiliximab, Bimekizumab, Briakinumab, Brodalumab, Canakinumab, Daclizumab, 
Guselkumab, Ixekizumab, Netakimab, Olokizumab, Rilonacept, Risankizumab, Sarilumab, 
Satralizumab, Secukinumab, Siltuximab, Sirukumab, Spesolimab, Tildrakizumab, 
Tocilizumab, Ustekinumab 
Unspecified Immunosuppressants: No ATC code with Preferred Term including 
Barzolvolimab, Fezakinumab, Fletikumab, Gevokizumab, Gusacitinib, Ladarixin, 
Lebrikizumab, Ligelizumab, Mirikizumab, Nemolizumab, Olamkicept, Tabalumab, 
Tregalizumab 
Biologics for Airway Disease and other indications: ATC code R03D with Preferred Term 
including Benralizumab, Mepolizumab, Omalizumab, Reslizumab, Roflumilast, Tezepelumab 
and ATC code is R03DX with Preferred Term including Rituximab 
 
Other potential treatments for CSU:  
The use of plasmapheresis, ultraviolet A or B (UVA or UVB), psoralen + UVA (PUVA), 
other phototherapy is not permitted during the study. The use of a tanning bed will not be 
considered rescue therapy or an ICE. 
 


 
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9.2 
Appendix 2: List of Tables, Figures, and Listings 
Tables 
Table 14.1.1a 
Subject Disposition and Reason for Discontinuation (All Screened Subjects) 
Table 14.1.1b  
Subject Disposition and Reason for Discontinuation (mITT Population) 
Table 14.1.1c  
Subject Disposition and Reason for Discontinuation (Safety Population) 
Table 14.1.1d 
Subject Disposition and Reason for Discontinuation (Per Protocol Population) 
Table 14.1.2 
Major Protocol Deviations and Violations During the Study (All Randomized 
Subjects) 
Table 14.1.3 
Analysis Population: Subject Count (All Randomized Subjects) 
Table 14.1.4 
Per Protocol Population Exclusion (All Randomized Subjects) 
Table 14.1.5a 
Demographics and Baseline Characteristics (mITT Population) 
Table 14.1.5b 
Demographics and Baseline Characteristics (Safety Population) 
Table 14.1.5c 
Demographics and Baseline Characteristics (Per Protocol Population) 
Table 14.1.6 
Medical History by System Organ Class and Preferred Term (Safety Population) 
Table 14.1.7.1 
Study Drug Exposure (mITT Population) 
Table 14.1.7.2 
Duration of Treatment Exposure and Compliance (mITT Population) 
Table 14.1.8.1 
Prior Medications by Anatomic Therapeutic Chemical Classification and 
Preferred Term: Subject Incidence (mITT Population) 
Table 14.1.8.2 
Prior Medications by Anatomic Therapeutic Chemical Classification and 
Preferred Term: Subject Incidence (Safety Population) 
Table 14.1.8.3  
Concomitant Medications by Anatomic Therapeutic Chemical Classification and 
Preferred Term: Subject Incidence (mITT Population) 
Table 14.1.8.4  
Concomitant Medications by Anatomic Therapeutic Chemical Classification and 
Preferred Term: Subject Incidence (Safety Population) 
Table 14.1.9 
12-Lead ECG Evaluation at Baseline (Safety Population) 
Table 14.1.10 
Baseline Vital Signs (mITT Population) 


 
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Table 14.1.11 
Subject Incidence of Intercurrent Events (mITT Population) 
Table 14.2.1.1a 
Change from Baseline in Urticaria Assessment Score (UAS7) at Week 12 – 
Primary Analysis (mITT Population) 
Table 14.2.1.1b 
Change from Baseline in Urticaria Assessment Score (UAS7) at Week 12 – 
Supportive Analysis of Primary Endpoint (PP Population) 
Table 14.2.1.2.1 
Change from Baseline in Urticaria Assessment Score at Week 12 by Sex (mITT 
Population) 
Table 14.2.1.2.2 
Change from Baseline in Urticaria Assessment Score at Week 12 by Age Group 
(mITT Population) 
Table 14.2.1.2.3 
Change from Baseline in Urticaria Assessment Score at Week 12 by Race 
(mITT Population) 
Table 14.2.1.2.4 
Change from Baseline in Urticaria Assessment Score at Week 12 by Ethnicity 
(mITT Population) 
Table 14.2.1.2.4 
Change from Baseline in Urticaria Assessment Score at Week 12 by Region 
(mITT Population) 
Table 14.2.1.2.5 
Change from Baseline in Urticaria Assessment Score at Week 12 by Baseline 
Itch Severity Score (mITT Population) 
Table 14.2.1.2.6 
Change from Baseline in Urticaria Assessment Score at Week 12 by History of 
Angioedema at Screening (mITT Population) 
Table 14.2.1.2.7 
Change from Baseline in Urticaria Assessment Score at Week 12 by Prior 
Omalizumab Experience for the Treatment of CSU (mITT Population) 
Table 14.2.1.2.8 
Change from Baseline in Urticaria Assessment Score at Week 12 by Baseline 
UAS7 Score (mITT Population) 
Table 14.2.1.2.9 
Change from Baseline in Urticaria Assessment Score at Week 12 by Duration of 
Disease Prior to Baseline (mITT Population) 
Table 14.2.1.2.9 
Change from Baseline in Urticaria Assessment Score at Week 12 by Screening 
IgE level (mITT Population) 
Table 14.2.2.1a 
Change from Baseline in Urticaria Severity Score (mITT Population) 


 
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Table 14.2.2.1b 
Change from Baseline in Urticaria Severity Score (PP Population) 
Table 14.2.2.1a 
Change from Baseline in Hives Severity Score (mITT Population) 
Table 14.2.2.1b 
Change from Baseline in Hives Severity Score (PP Population) 
Table 14.2.2.2a 
Change from Baseline in Itch Severity Score (mITT Population) 
Table 14.2.2.2b 
Change from Baseline in Itch Severity Score (PP Population) 
Table 14.2.2.3a 
Proportion of Subjects Achieving Urticaria Assessment Score (UAS7) = 0 at 
Week 12 (mITT Population) 
Table 14.2.2.3b 
Proportion of Subjects Achieving Urticaria Assessment Score (UAS7) = 0 at 
Week 12 (PP Population) 
Table 14.2.3.1 
Change from Baseline in 
 Score at Week 12 (mITT 
Population) 
Table 14.2.4 
Proportion of Subjects Achieving 
 = 0 
or 1 at Week 12 (mITT Population) 
Table 14.2.5 
Proportion of Subjects Achieving 
 = 0 at 
Week 12 (mITT Population) 
Table 14.2.6.1 
Proportion of Subjects Achieving 
 ≤ 6 at 
Week 12 (mITT Population) 
Table 14.2.6.3 
Proportion of Subjects Achieving Hive Severity Score (HSS7) = 0 at Week 12 
(mITT Population) 
Table 14.2.6.4  
Proportion of Subjects Achieving Itch Severity Score (ISS7) = 0 at Week 12 
(mITT Population) 
Table 14.2.8.1 
 (mITT Population) 
Table 14.2.8.2 
 (mITT Population) 
Table 14.2.8.3 
 (mITT Population) 
Table 14.2.9 
Weekly 
 (mITT Population) 
Table 14.2.10 
Change from Baseline in Total Serum IgE Concentration (mITT Population) 


 
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Table 14.2.11 
Subject Incidence of Positive Anti-Drug (AK002) Antibody (ADA) Test (Safety 
Population) 
Table 14.3.1.1 
Overview of Treatment-Emergent Adverse Events (Safety Population) 
Table 14.3.1.2 
Treatment-Emergent Adverse Events by Preferred Term: Subject Incidence 
(Safety Population) 
Table 14.3.1.3 
Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term: Subject Incidence (Safety Population) 
Table 14.3.1.4 
Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, 
and Maximum Severity: Subject Incidence (Safety Population) 
Table 14.3.1.5 
Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, 
and Relationship to Study Drug: Subject Incidence (Safety Population) 
Table 14.3.1.6 
Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation by 
System Organ Class and Preferred Term: Subject Incidence (Safety Population) 
Table 14.3.1.7 
Treatment-Emergent Serious Adverse Events by System Organ Class and 
Preferred Term: Subject Incidence (Safety Population) 
Table 14.3.1.8 
Treatment-Emergent Adverse Events of Special Interest by System Organ Class 
and Preferred Term: Subject Incidence (Safety Population) 
Table 14.3.2.1 
Hematology: Change from Baseline by Visit (Safety Population) 
Table 14.3.2.2 
Blood Chemistry: Change from Baseline by Visit (Safety Population) 
Table 14.3.2.3 
Hematology: Shift from Baseline Classification by Visit (Safety Population) 
Table 14.3.2.4 
Blood Chemistry: Shift from Baseline Classification by Visit 
(Safety Population) 
Table 14.3.2.5 
Urinalysis: Change from Baseline by Visit (Safety Population) 
Table 14.3.3.1 
Summary of Vital Signs by Visit (Safety Population) 
 
Figures 
Figure 1 
Change from Baseline in Weekly Urticaria Assessment Score (UAS7) Over 
Time (mITT Population) 


 
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Figure 2 
Change from Baseline in Weekly Hives Severity Score (HSS7) Over Time 
(mITT Population) 
Figure 3 
Change from Baseline in Weekly Itch Severity Score (ISS7) Over Time (mITT 
Population) 
 
Listings 
Listing 16.1.7 
Subject Randomization Schedule (Randomized Population) 
Listing 16.2.1.1 
Subjects Disposition and Reason for Disposition (Randomized Population) 
Listing 16.2.1.2 
Subjects Who had Major Protocol Deviations (Randomized Population) 
Listing 16.2.1.3 
Subjects Inclusion and the Reason for Exclusion from Analysis Populations 
(Randomized Population) 
Listing 16.2.1.4.1 
Demographic and Baseline Characteristics (Safety Population) 
Listing 16.2.1.4.2 
Demographic and Baseline Characteristics – History of Disease 
(Safety Population) 
Listing 16.2.1.5 
Medical History (Safety Population) 
Listing 16.2.1.6 
Atopic Conditions Questionnaire (Safety Population) 
Listing 16.2.1.7.1  
Prior Medications (Safety Population) 
Listing 16.2.1.7.2 
Concomitant Medications (Safety Population) 
Listing 16.2.1.8 
Intercurrent Events (Safety Population) 
Listing 16.2.2.1 
 (mITT Population) 
Listing 16.2.2.2 
Patient Diary of Chronic Spontaneous Urticaria (mITT Population) 
Listing 16.2.2.3 
Weekly Urticaria Activity Score (UAS7), Hive Severity Score (HSS7), and Itch 
Severity Score (ISS7) (mITT Population) 
Listing 16.2.2.4 
 (mITT Population) 
Listing 16.2.2.5  
 (mITT Population) 
Listing 16.2.2.5  
Weekly 
 (mITT Population) 
Listing 16.2.3.1.1 
All Adverse Events (Safety Population) 


 
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Listing 16.2.3.1.2 
Serious Adverse Events (Safety Population) 
Listing 16.2.3.1.3 
Adverse Events with Outcome of Death (Safety Population) 
Listing 16.2.3.1.4 
Adverse Events Leading to Study Drug Discontinuation (Safety Population) 
Listing 16.2.3.1.5 
Adverse Events of Special Interest (Safety Population) 
Listing 16.2.3.2.1 
Clinical Laboratory Tests-Hematology (Safety Population) 
Listing 16.2.3.2.2 
Clinical Laboratory Tests – Blood Chemistry (Safety Population) 
Listing 16.2.3.2.3 
Clinical Laboratory Tests – Urinalysis (Safety Population) 
Listing 16.2.3.2.4 
Clinical Laboratory Tests – Diagnostic Immunology/Molecular Biology (Safety 
Population) 
Listing 16.2.3.2.5 
Clinical Laboratory Tests – Endocrinology (Safety Population) 
Listing 16.2.3.2.6 
Clinical Laboratory Tests – Parasitology (Safety Population) 
Listing 16.2.3.3 
Urine Pregnancy Test (Safety Population) 
Listing 16.2.3.4.1 
Study Drug Administration (Safety Population) 
Listing 16.2.3.4.2 
Study Drug Accountability (Safety Population) 
Listing 16.2.3.5 
Vital Signs (Safety Population) 
Listing 16.2.3.6 
Subject Body Size (Safety Population) 
Listing 16.2.3.7.1 
12-Lead ECG Intervals at Baseline (Safety Population) 
Listing 16.2.3.7.2 
12-Lead ECG Overall Interpretation (Safety Population) 
Listing 16.2.3.8 
Physical Examination (Safety Population) 
Listing 16.2.3.9 
Antidrug (AK002) Antibody (ADA) Test (Safety Population) 
Listing 16.2.3.11 
Serum Concentrations of IgE (Safety Population)