Study to Evaluate the Efficacy, Safety, Tolerability, and Immunogenicity of TEV-45779 Compared to XOLAIR (Omalizumab) in Patients With Chronic Idiopathic/Spontaneous Urticaria Who Remain Symptomatic Despite Antihistamine (H1) Treatment.
Phase: PHASE3
Conditions: Chronic Urticaria
Sponsor: Teva Pharmaceuticals USA

 
 
 
Clinical Study Protocol 
 
 
Multinational, Multicenter, Randomized, Double-Blind Study to Evaluate the 
Efficacy, Pharmacokinetics, Pharmacodynamics, Safety, Tolerability, and 
Immunogenicity of TEV-45779 Compared to Omalizumab (XOLAIR®) in 
Patients With Chronic Idiopathic Urticaria/Chronic Spontaneous Urticaria who 
Remain Symptomatic Despite Antihistamine (H1) Treatment 
 
 
Study Number TV45779-IMB-30086 
 
 
NCT04976192 
 
 
Protocol with Amendment 04 Approval Date: 15 February 2023 

 
Active-Controlled Study–Chronic Idiopathic Urticaria/Chronic Spontaneous Urticaria 
Clinical Study Protocol with Amendment 04 
Study TV45779-IMB-30086 
1 
 
 
Clinical Study Protocol with Amendment 04 
Study Number TV45779-IMB-30086 
A Multinational, Multicenter, Randomized, Double-Blind Study to Evaluate the Efficacy, 
Pharmacokinetics, Pharmacodynamics, Safety, Tolerability, and Immunogenicity of 
TEV-45779 Compared to Omalizumab (XOLAIR®) in Patients With Chronic Idiopathic 
Urticaria/Chronic Spontaneous Urticaria who Remain Symptomatic Despite Antihistamine 
(H1) Treatment 
Short title: A Randomized, Double-Blind Study of Efficacy, Pharmacokinetics, 
Pharmacodynamics, and Safety of TEV-45779 in Adults with Chronic Idiopathic 
Urticaria/Chronic Spontaneous Urticaria 
Title of the protocol for lay people: A Study to Find Out if TEV-45779 Helps to Treat 
Chronic Idiopathic Urticaria/Chronic Spontaneous Urticaria That is Not Helped by 
Antihistamines 
Efficacy and Safety Study (Phase 3) 
IND number: 145915; 
EudraCT number: 2021-001796-17 
EMA Decision number of Pediatric Investigation Plan: Not applicable 
Article 45 or 46 of 1901/2006 does not apply 
Clinical Study Protocol with Amendment 04 Version Date: 15 February 2023 
Sponsor 
Teva Pharmaceuticals, Inc. 
400 Interpace Parkway, Building A,  
Parsippany, NJ 07054, United States of America 
Information regarding clinical laboratories and other departments and institutions is 
found in Appendix A 
This clinical study will be conducted in accordance with current Good Clinical Practice (GCP) as directed 
by the provisions of the International Council for Harmonisation (ICH); United States (US) Code of 
Federal Regulations (CFR), and European Union (EU) Directives and Regulations (as applicable in the 
region of the study); national country legislation; and the sponsor’s Standard Operating Procedures 
(SOPs). 
Confidentiality Statement 
This document contains confidential and proprietary information (including confidential commercial 
information pursuant to 21CFR§20.61) and is a confidential communication of Teva Pharmaceuticals, 
Inc. and its affiliates. The recipient agrees that no information contained herein may be published or 
disclosed without written approval from the sponsor. 
© 2023 Teva Pharmaceuticals, Inc. All rights reserved. 
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Study TV45779-IMB-30086 
2 
AMENDMENT HISTORY 
The protocol for study TV45779-IMB-30086 (original protocol dated 18 April 2021) has been 
revised and reissued as follows: 
Amendment 04 
15 February 2023 
372 patients enrolled as of 6 February 
2023 
Administrative Letter 07 (For 
India) 
19 December 2022 
Administrative Letter 06 (For 
India) 
20 October 2022 
Administrative Letter 05 
01 August 2022 
Amendment 03 
10 May 2022 
36 patients enrolled as of 27 April 2022 
Administrative Letter 04 (For 
S. Korea) 
23 February 2022 
14 patients enrolled to date 
Administrative Letter 03 
28 January 2022 
8 patients enrolled to date 
Amendment 02 
23 November 2021 
0 patients enrolled to date 
Administrative Letter 02 
10 November 2021 
0 patients enrolled to date 
Administrative Letter 01 
26 October 2021 
0 patients enrolled to date 
Amendment 01 
11 June 2021 
0 patients enrolled to date 
The Summary of Changes to the Protocol includes the corresponding reason/justification for 
each change and is provided in Section 16. 
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Active-Controlled Study–Chronic Idiopathic Urticaria/Chronic Spontaneous Urticaria 
Clinical Study Protocol with Amendment 04 
Study TV45779-IMB-30086 
3 
INVESTIGATOR AGREEMENT 
Clinical Study Protocol with Amendment 04 Version Date: 15 February 2023 
Study TV45779-IMB-30086 
A Multinational, Multicenter, Randomized, Double Blind Study to Evaluate the Efficacy, 
Pharmacokinetics, Pharmacodynamics, Safety, Tolerability, and Immunogenicity of 
TEV-45779 Compared to Omalizumab (XOLAIR®) in Patients With Chronic Idiopathic 
Urticaria/Chronic Spontaneous Urticaria who Remain Symptomatic Despite Antihistamine 
(H1) Treatment. 
 
Principal Investigator:   
Title: 
 
Address of Investigational Center: 
 
 
 
 
 
Tel: 
 
I have read the protocol with Amendment 04 and agree that it contains all necessary details for 
carrying out this study. I am qualified by education, experience, and training to conduct this 
clinical research study. The signature below constitutes agreement with this protocol and 
attachments, and provides assurance that this study will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and according to 
national or local legal and regulatory requirements and applicable regulations and guidelines. 
I will make available the protocol and all information on the investigational medicinal product 
(IMP) that were furnished to me by the sponsor to all physicians and other study personnel 
reporting to me who participate in this study and will discuss this material with them to ensure 
that they are fully informed regarding the IMP and the conduct of the study. I agree to keep 
records on all patient information, IMP shipment and return forms, and all other information 
collected during the study, in accordance with national and local Good Clinical Practice (GCP) 
regulations as well as all other national and international laws and regulations. 
Principal Investigator 
Signature 
Date 
Executed signature pages are maintained separately within the Trial Master File 
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Study TV45779-IMB-30086 
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SPONSOR PROTOCOL APPROVAL 
Sponsor’s Authorized 
Representative 
 
 
 
Signature 
Date 
Executed signature pages are maintained separately within the Trial Master File 
VV-00471912 v6.0

 
Active-Controlled Study–Chronic Idiopathic Urticaria/Chronic Spontaneous Urticaria 
Clinical Study Protocol with Amendment 04 
Study TV45779-IMB-30086 
5 
COORDINATING INVESTIGATOR AGREEMENT 
Clinical Study Protocol with Amendment 04 Version Date: 15 February 2023 
Study TV45779-IMB-30086 
A Multinational, Multicenter, Randomized, Double Blind Study to Evaluate the Efficacy, 
Pharmacokinetics, Pharmacodynamics, Safety, Tolerability, and Immunogenicity of 
TEV-45779 Compared to Omalizumab (XOLAIR®) in Patients With Chronic Idiopathic 
Urticaria/Chronic Spontaneous Urticaria who Remain Symptomatic Despite Antihistamine 
(H1) Treatment. 
 
Coordinating Investigator: 
 
Title: 
 
Address of Investigational Center: 
 
 
 
 
 
Tel: 
 
I have read the protocol with Amendment 04 and agree that it contains all necessary details for 
carrying out this study. I am qualified by education, experience, and training to conduct this 
clinical research study. The signature below constitutes agreement with this protocol and 
attachments, and provides assurance that this study will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and according to 
national or local legal and regulatory requirements and applicable regulations and guidelines. 
I will make available the protocol and all information on the investigational medicinal product 
(IMP) that were furnished to me by the sponsor to all physicians and other study personnel 
reporting to me who participate in this study and will discuss this material with them to ensure 
that they are fully informed regarding the IMP and the conduct of the study. I agree to keep 
records on all patient information, IMP shipment and return forms, and all other information 
collected during the study, in accordance with national and local Good Clinical Practice (GCP) 
regulations as well as all other national and international laws and regulations. 
Coordinating Investigator 
 
Signature 
Date 
Executed signature pages are maintained separately within the Trial Master File 
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Study TV45779-IMB-30086 
6 
CLINICAL STUDY PROTOCOL SYNOPSIS 
With Amendment 04 
Study TV45779-IMB-30086 
Title of Study: A Multinational, Multicenter, Randomized, Double Blind Study to Evaluate the 
Efficacy, Pharmacokinetics, Pharmacodynamics, Safety, Tolerability, and Immunogenicity of 
TEV-45779 Compared to Omalizumab (XOLAIR®) in Patients With Chronic Idiopathic 
Urticaria/Chronic Spontaneous Urticaria who Remain Symptomatic Despite Antihistamine (H1) 
Treatment. 
Sponsor: Teva Pharmaceuticals, Inc. 
Investigational New Drug (IND) Number: 145915 
EudraCT Number: 2021-001796-17 
European Medicines Agency (EMA) Decision number of Pediatric Investigation Plan: 
Article 45 or 46 of 1901/2006 does not apply 
Name of Test Investigational Medicinal Product (IMP) or Device: TEV-45779 
Active Substance: Omalizumab solution for injection 
EudraVigilance (EV) code for the IMP, if applicable: Not applicable 
Type of the Study: Phase 3 - Efficacy and Safety 
Indication: Chronic Idiopathic Urticaria (CIU)/Chronic Spontaneous Urticaria (CSU) 
Is this study conducted to investigate the New Use of an approved, marketed product? No 
Number of Investigational Centers Planned: The study is planned to be conducted in 
approximately 140 investigational sites. 
Countries Planned: The study is planned to be conducted in approximately 18 countries in 
North America, Latin America, Europe, and Asia-Pacific. 
Planned Study Period and Duration: Approximately 2 years from quarter (Q)3 2021 to Q2 
2024 
Number of Patients Planned (total): Approximately 600 patients (200:200:100:100 to 
TEV-45779 300 mg, XOLAIR 300 mg, TEV-45779 150 mg and XOLAIR 150 mg) will be 
randomized. 
Study Population: Patients with CIU/CSU who remain symptomatic despite antihistamine (H1) 
treatment. 
Primary and Secondary Objectives and Endpoints: To demonstrate that there are no clinically 
meaningful differences in efficacy, pharmacokinetics, pharmacodynamics, and safety between 
TEV-45779 and XOLAIR administered subcutaneously (sc) in patients with CIU/CSU. The 
primary and secondary study objectives and endpoints are presented below. 
Primary and Secondary Study Objectives and Endpoints 
Objectives 
Endpoints 
The primary objective of the study is to 
demonstrate biosimilar efficacy of 
TEV-45779 300 mg compared to 
XOLAIR 300 mg as determined by 
change in itch severity score of CIU/CSU 
The primary efficacy endpoint is: 
• 
Change from baseline in the weekly itch severity score 
(ISS7; sum of the daily itch severity score for 7 days) at 
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Objectives 
Endpoints 
in patients who remain symptomatic 
despite antihistamine (H1) treatment. 
Week 12, TEV-45779 300 mg compared to XOLAIR 
300 mg 
The co-primary objective (for the FDA 
submission only) of the study is to 
demonstrate relative potency of 
TEV-45779 compared to XOLAIR as 
determined by itch severity score of 
CIU/CSU in patients who remain 
symptomatic despite antihistamine (H1) 
treatment. 
The co-primary efficacy endpoint is: 
• 
Relative potency of 2 dose levels (300 mg and 150 mg) of 
TEV-45779 and XOLAIR as measured by change from 
baseline ISS7 at Week 12 using a 4-point assay, ie, 
TEV-45779 300 mg, TEV-45779 150 mg, XOLAIR 
300 mg, and XOLAIR 150 mg. 
Secondary objectives 
 
To compare further efficacy parameters 
between TEV-45779 and XOLAIR. The 
comparisons will be performed between 
the different doses (150 mg vs. 300 mg) as 
well as between TEV-45779 and XOLAIR 
Secondary efficacy endpoints are as follows.  
• 
Change from baseline in ISS7 at Week 12 
• 
Change from baseline in the ISS7 at Week 4 
• 
Change from baseline in the weekly urticaria activity score 
(UAS7; sum of the daily number of wheals score and itch 
severity score over 7 days) at Week 12 
• 
Percentage of patients with UAS7 ≤6 at Week 12 
• 
Percentage of complete responders (UAS7=0) at Week 12 
• 
Change from baseline in the physician’s (in-clinic) 
assessment of UAS7 at Week 12 
• 
Change from baseline in the weekly number of wheals 
score at Week 12 
• 
Change from baseline in the weekly size of the largest 
wheals score at Week 12 
• 
Time to minimally important difference (MID; reduction 
from baseline in ISS7 of ≥5 points) response up to 
Week 12 
• 
Percentage of ISS7 MID responders at Week 12 
(percentage of patients with reduction of ≥5 points from 
baseline in ISS7 at Week 12). 
• 
Percentage of angioedema-free days from Week 4 to 
Week 12 
• 
Change from baseline in the overall dermatology life 
quality index (DLQI) score at Week 12 
To compare efficacy parameters between 
TEV-45779 and XOLAIR after the switch 
from XOLAIR to TEV-45779. The 
comparisons will be performed between 
the different doses (150 mg vs. 300 mg) as 
well as between TEV-45779 and XOLAIR 
Secondary efficacy endpoints are: 
• 
Change from Week 12 in ISS7 at Week 24 
• 
Change from Week 12 in ISS7 at Week 40 
• 
Change from Week 12 in UAS7 at Week 24 
• 
Change from Week 12 in the physician’s (in-clinic) 
assessment of urticaria activity score (UAS) at Week 24 
• 
Change from Week 12 in the weekly number of wheals 
score at Week 24 
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Objectives 
Endpoints 
• 
Change from Week 12 in the weekly number of wheals 
score at Week 40 
• 
Change from Week 12 in the weekly size of the largest 
wheals score at Week 24 
• 
Change from Week 12 in the weekly size of the largest 
wheals score at Week 40 
• 
Percentage of angioedema-free days from Week 12 to 
Week 24 
• 
Change from Week 12 in the overall DLQI score at 
Week 24 
• 
Change from Week 12 in the overall DLQI score at 
Week 40 
To compare the safety and tolerability 
between TEV-45779 and XOLAIR 
• 
throughout the study 
• 
after the switch from XOLAIR to 
TEV-45779 
The safety/tolerability parameters include: 
• 
Adverse events (and the number of patients who withdraw 
from the study due to adverse events) 
• 
Change from baseline in clinical laboratory measurements 
(serum chemistry, hematology, and urinalysis) and vital 
signs 
• 
Physical examination findings 
• 
Electrocardiogram findings 
• 
Local tolerability at the injection site after each 
investigational medicinal product (IMP) administration 
• 
Use of concomitant medication (including use of rescue 
medication) 
• 
Device-related adverse events and malfunctions 
To compare pharmacokinetics between 
TEV-45779 and XOLAIR after multiple 
doses 
The pharmacokinetic parameter is: 
• 
Omalizumab serum concentration before next dose 
(Ctrough) 
• 
Omalizumab serum concentration following last dose at 
Week 24, 28, 32, 36 and 40 
To compare pharmacodynamics between 
TEV-45779 and XOLAIR after multiple 
doses 
The pharmacodynamic parameters are: 
• 
Free immunoglobulin E (IgE) serum concentration 
• 
Total IgE serum concentration 
To assess the immunogenicity of 
TEV-45779 in comparison with XOLAIR 
• 
throughout the study 
• 
after the switch from XOLAIR to 
TEV-45779 
The immunogenicity parameters are: 
• 
Incidence of patients with a confirmed anti-drug antibody 
(ADA) positive sample 
• 
For confirmed positive samples, the ADA titer and the 
neutralizing potential will be tested 
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Primary Estimand: 
The primary estimand for the primary efficacy endpoint for the Food and Drug Administration 
(FDA) submission is: 
• The difference in mean change from baseline in weekly itch severity score (ISS7; 
sum of the daily itch severity score for 7 days) at Week 12 between 
TEV-45779 300 mg and XOLAIR 300 mg in patients with CIU/CSU who remain 
symptomatic despite antihistamine (H1) treatment, regardless of treatment-related 
adverse events. The treatment policy will be applied to account for the intercurrent 
event of patients discontinuing the treatment early, and patients receiving any 
disallowed concomitant medication between randomization and Week 12 ISS7 
assessment. In order to account for the missing itch severity scores, the following 
strategy will be applied: 
− Daily itch severity score – If either the morning or evening score is missing, the 
available (morning or evening) itch severity score for that day will be used as the 
daily itch severity score, and if both the morning and evening itch severity scores 
are missing, the daily itch severity score will be considered missing. 
− Weekly itch severity score – If 4-7 daily itch severity scores are available for the 
calculation of the weekly score (as defined in “Statistical Considerations” below), 
the ISS7 will be defined as the sum of the available daily itch severity scores in 
that week, divided by the number of days for which a daily itch severity score is 
available, multiplied by 7. If no more than 3 daily itch severity scores are 
available (ie, 4-7 daily scores are missing), the ISS7 will be considered missing 
for that week. 
− Week 12 itch severity score – multiple imputation using the predictive mean 
matching multiple imputation method (Heitjan and Little 1991, Schenker and 
Taylor 1996), under the MAR assumption for each treatment arm separately. 
The primary estimand for the co-primary efficacy endpoint (for the FDA submission) of relative 
potency is: 
• The relative potency of TEV-45779 and XOLAIR as measured by change from 
baseline in ISS7 at Week 12 using a 4-point assay, ie, TEV-45779 300 mg, 
TEV-45779 150 mg, XOLAIR 300 mg, and XOLAIR 150 mg, in patients with 
CIU/CSU who remain symptomatic despite antihistamine (H1) treatment, regardless 
of treatment-related adverse events. The treatment policy will be applied to account 
for the intercurrent event of patients discontinuing the treatment early, and patients 
receiving any disallowed concomitant medication between randomization and 
Week 12 ISS7 assessment. The same rules for the missing daily and weekly itch 
severity score will be applied, as described for the primary endpoint of difference in 
mean change from baseline in weekly ISS7 at Week 12 between TEV-45779 300 mg 
and XOLAIR 300 mg. Missing Week 12 itch severity scores will not be imputed for 
the relative potency analysis. 
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The primary estimand for the primary efficacy endpoint for the EMA submission is: 
• The difference in mean change from baseline in weekly itch severity score (ISS7) at 
Week 12 between TEV-45779 300 mg and XOLAIR 300 mg in patients with 
CIU/CSU who remain symptomatic despite antihistamine (H1) treatment and have a 
baseline ISS7 assessment, regardless of treatment-related adverse events. The 
hypothetical strategy will be applied to account for the intercurrent event of patients 
discontinuing the treatment early, and patients receiving any disallowed concomitant 
medication between randomization and Week 12 ISS7 assessment. Thus, any 
available assessments after the intercurrent event should be excluded and imputed. In 
order to account for the missing or excluded itch severity scores the same imputation 
rules will be applied as described for the primary endpoint for the FDA submission. 
General Study Design: This is a multicenter, randomized, double-blind study to demonstrate 
similar efficacy and safety of TEV-45779 compared to XOLAIR administered sc at doses of 
300 mg or 150 mg every 4 weeks for 24 weeks (6 treatments) in patients with CIU/CSU who 
remain symptomatic despite antihistamine (H1) treatment. This study will consist of a screening 
period (up to 3 weeks), a 24-week treatment period consisting of a 12-week double-blind main 
treatment period and a 12-week double-blind transition period, which is followed by a 16-week 
follow-up period. The total duration of the study is up to 43 weeks.  
During the conduct of this study, an Independent Data Monitoring Committee (IDMC) will 
review accumulating unblinded safety data on a regular basis and also ad hoc if needed, as 
detailed in the IDMC charter, to ensure the continuing safety of the study patients. The specific 
details regarding the IDMC sessions will be outlined in the IDMC charter. 
Standard Treatment 
Throughout the entire study, patients should remain on a single H1 antihistamine at stable and 
fixed doses not exceeding label recommendations as the standard treatment regimen. For the 
duration of the study, all patients will be provided with diphenhydramine hydrochloride (25 mg, 
maximum 3 times/day) as rescue medication for itch relief. 
Disallowed concomitant treatment includes the use of systemic and topical steroids, 
H1 antihistamines at greater than approved doses, H2 antihistamines, leukotriene receptor 
antagonists (LTRAs), hydroxychloroquine, methotrexate, cyclosporine, cyclophosphamide, 
intravenously-given immunoglobulin, and disallowed medications according to the 
contraindications for diphenhydramine hydrochloride. 
Study Treatment 
Patients will receive a total of 6 treatments, each consisting of 2 sc injections resulting in 150 mg 
or 300 mg of IMP (TEV-45779 or XOLAIR) as add-on therapy every 4 weeks; patients will 
receive 3 treatments in the main treatment period and 3 treatments in the transition period. 
Main Treatment Period: Following screening, eligible patients will be randomly assigned to 
treatment with TEV-45779 300 mg, XOLAIR 300 mg, TEV-45779 150 mg or XOLAIR 150 mg 
in a 2:2:1:1 ratio on day 1 of the main treatment period, stratified by baseline ISS7 (<13 vs. ≥13), 
and baseline body weight (<80 kg vs. ≥80 kg). 
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Transition Treatment Period: At the beginning of the transition period (Week 12), patients in the 
XOLAIR 300 mg and XOLAIR 150 mg groups will be re-randomized 1:1 to either continue with 
XOLAIR treatment (at the same dose level as prior to re-randomization) or transition to 
TEV-45779 (at the same dose level prior to re-randomization) to primarily assess the 
immunogenicity and safety after the transition from XOLAIR to TEV-45779. All patients in the 
TEV-45779 group will continue treatment with TEV-45779 at the same dose level as prior to re-
randomization. 
After the End of Treatment visit (Week 24), all patients will be followed for 16 weeks. 
Patients who complete all scheduled visits will have final procedures and assessments performed 
at the End of Study visit at the end of the follow-up (Week 40). Patients who withdraw from the 
study before completing the follow-up will have early termination procedures and assessments 
performed at their final visit. 
Method of Randomization and Blinding: This is a randomized double-blind study. At baseline, 
patients will be randomized in a 2:2:1:1 ratio to receive the first 3 treatments of TEV-45779 
300 mg, XOLAIR 300 mg, TEV-45779 150 mg or XOLAIR 150 mg (main treatment period). At 
Week 12, prior to receiving their fourth dose of study medication, patients in the XOLAIR 
300 mg and the XOLAIR 150 mg treatment groups will be randomized 1:1 to receive 
3 additional doses of XOLAIR (at the same dose level as prior to randomization, or switch to 
3 doses of TEV-45779 (transition period) at the same dose level as prior to randomization. All 
patients in the TEV-45779 groups will continue to receive TEV-45779 at the same dose levels as 
prior to randomization. 
During the main treatment period, the sponsor, investigators (including other site staff involved 
in study assessments) and patients will be blinded to the treatment assignment of all patients. To 
maintain blinding to the treatment assignment, the re-randomization process will be performed 
for all patients, including the patients in the TEV-45779 group (although only patients in the 
XOLAIR arm will actually be re-randomized while patients in the TEV-45779 group will 
continue to receive TEV-45779 in the transition period). Randomization will be implemented 
using the Randomization and Trial Supply Management (RTSM) system. After last patient last 
visit and database lock (DBL) of the main treatment period, the sponsor will unblind the 
treatments for the analysis of the main treatment period. After last patient last visit and DBL of 
the main treatment period, staff responsible for population pharmacokinetics, and/or the 
pharmacokinetics/pharmacodynamics model will receive access to the patient treatment 
randomization. The investigators, patients, and staff responsible for the pharmacokinetic, 
pharmacodynamics, and immunogenicity bioanalysis will remain blinded to the main treatment 
period treatment assignments. 
During the main and transition treatment period, the persons who are involved in receipt, storage, 
distribution, administration, return, and accountability of IMP will be unblinded as the IMPs 
differ in appearance: these persons will not be involved in the conduct of any study procedures or 
assessments. 
Only after completion of the study (after Week 40) and final DBL will the study be fully 
unblinded and analyzed. 
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Investigational Medicinal Products: Dose, Pharmaceutical Form, Route of Administration, 
and Administration Rate 
IMP 
Test 
Reference 
Placebo 
IMP name 
TEV-45779  
(omalizumab) 
XOLAIR® 
(omalizumab) 
Injection 
Placebo (no active) 
to complement 
TEV-45779 
(omalizumab) or 
XOLAIR® 
(omalizumab) 
Trade name or 
company-assigned number 
TEV-45779 
XOLAIR 
Placebo 
Formulation 
Active 
150 mg/mL 
150 mg/mL 
NA 
Histidine 
20 mM 
20 mM 
20 mM 
Arginine 
hydrochloride 
200 mM 
200 mM 
200 mM 
Polysorbate 20 
0.04% 
0.04% 
0.04% 
Unit dose strength(s)/Dosage 
level(s) 
150 mg/mL 
150 mg/dose (single sc 
injection) or 
300 mg/dose (2 sc 
injections) 
150 mg/mL 
150 mg/dose (single sc 
injection) or 
300 mg/dose (2 sc 
injections) 
NA 
Route of administration 
sc injection 
sc injection 
sc injection 
Device 
Automatically activated 
needle safety guard 
Automatically activated 
needle safety guard  
Automatically activated 
needle safety guard  
Storage conditions 
2°C to 8°C (36°F to 
46°F), protected from 
direct light and heat. 
Avoid vigorous 
shaking. Do not freeze 
2°C to 8°C (36°F to 
46°F), protected from 
direct light and heat. 
Avoid vigorous 
shaking. Do not freeze 
2°C to 8°C (36°F to 
46°F), protected from 
direct light and heat. 
Avoid vigorous 
shaking. Do not freeze 
Manufacturer 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP=investigational medicinal product; NA=not applicable; sc=subcutaneous; USA=United States of America. 
The IMP will be prepared in a separate room by the non-blinded person (eg, pharmacist or 
designee) as the IMPs differ in appearance. The blinding will be maintained during the 
transportation from and to the dosing room. Dosing will be performed by a non-blinded staff 
member in the dosing room. The original IMP packaging and syringes should not be visible 
when the patient or any other blinded study team member enters the room. In order to ensure 
additional patient blinding, a blindfold with an additional pillow at chest level (or similar device) 
will be used during the IMP injection as a shield to hide the IMP from the patient. IMP will be 
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Study TV45779-IMB-30086 
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preferably administered in the front and middle of the thigh area (both injections at least 1 inch 
(2.5 cm) apart). Alternatively, if injection in the thigh is not possible, the injection may be given 
in the abdomen, avoiding the 2-inch (5 cm) area directly around the navel. The used injection site 
will be documented. 
Duration of Patient Participation and Maximal Exposure to IMP: The total duration of 
patient participation in the study is planned to be approximately 42 weeks including up to an 
approximately 3-week screening period, approximately 12-week double-blind main treatment 
period, an approximately 12-week transition period, and an approximately 16-week follow-up. 
End of Study: End of study is defined as the last visit of the last patient. 
Plans for Treatment or Care after the Patient Has Ended Participation in the Study: After 
study end, no IMP will be provided as XOLAIR is commercially available. 
Inclusion Criteria: Patients may be randomized/enrolled in this study only if they meet all of 
the following criteria: 
a. Male or female patients aged ≥18 years and ≤75 years. 
b. Diagnosis of CIU/CSU refractory to H1 antihistamines at the time of randomization, 
as defined by all of the following: 
− The presence of itch and wheals for ≥8 consecutive weeks at any time prior to 
enrollment despite current use of H1 antihistamine treatment during this time 
period. 
− Weekly urticaria activity score (UAS7; sum of the daily number of wheals score 
and itch severity score over 7 days) ≥16 (range 0-42) and itch component of 
UAS7 ≥8 (range 0-21) during 7 days prior to randomization.1 
− Urticaria activity score (UAS) ≥4 assessed by a clinician on ≥1 of the screening 
visit days. 
− Patients must have been on an approved dose of an H1 antihistamine for 
CIU/CSU for ≥3 consecutive days immediately prior to the start of screening and 
must document current use on the day of the initial screening visit, OR, have their 
H1 antihistamine for CIU/CSU adjusted to an approved dose during the first 3 
days of screening and have their adjusted use documented at the end of the dose 
adjustment. 
− CIU/CSU diagnosis for ≥3 months.2 
c. Women may be included if they fulfill one of the following criteria: 
− Women of non-childbearing potential who are either surgically (documented 
hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) or congenitally 
sterile as assessed by a physician, or 1-year postmenopausal (no menses for 
12 months without an alternative medical cause plus an increased concentration of 
                                                 
1 Refer to Section 9.3.1 for handling of missing data for daily and weekly scores. 
2 Diagnosis or symptoms leading to this diagnosis have to be present for ≥3◦months. 
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follicle stimulating hormone [FSH] of more than 35 U/L) in women not using 
hormonal contraception or hormonal replacement therapy. 
− Women of childbearing potential whose male partners are potentially fertile (ie, 
no vasectomy) must: 
○ have a negative beta-human chorionic gonadotropin (β-HCG) test result at 
screening (visit 2); and 
○ use highly effective birth control methods for the duration of the study (ie, 
starting at screening) and for 5 half-lives (20 weeks) after last dose of IMP. 
Highly effective birth control methods are methods that can achieve a failure rate of less than 1% 
per year when used consistently and correctly (see such methods in Appendix J).  
d. Male patients (including vasectomized men) with partners who are of childbearing 
potential (whether pregnant or not) must use condoms prior to IMP administration 
and until 20 weeks after last IMP dose. 
e. Must be able to understand the requirements of the study and to provide their written 
informed consent to participate in the study. 
f. Must be willing and able to comply with study requirements and procedures as 
specified in this protocol. In particular, the patient must be willing and able to 
complete a symptom diary twice daily (morning and evening) for the duration of the 
study. The patients must have diary entries during at least 4 of the 7 days prior to 
randomization. 
Exclusion Criteria: Patients will not be randomized/enrolled in this study if they meet any of 
the following criteria: 
a. Body weight <40 kg. 
b. Clearly defined underlying etiology for chronic urticarias other than CIU/CSU. 
c. Evidence of parasitic infection defined as meeting the following 3 criteria: 
− Risk factors for parasitic disease (living in an endemic area, chronic 
gastrointestinal symptoms, travel within the last 6 months to an endemic area 
and/or chronic immunosuppression), and 
− An absolute eosinophil count more >2× the upper limit of normal (ULN), and 
− Evidence of parasitic colonization or infection on stool evaluation for ova and 
parasites. Note that stool ova and parasite evaluation will only be conducted in 
patients with risk factor(s) and an eosinophil count >2× the ULN. 
d. Atopic dermatitis, bullous pemphigoid, dermatitis herpetiformis, senile pruritus, or 
other skin disease associated with itch. 
e. Treatment with an investigational agent within 30 days or longer depending on 
half-life (>5 half-lives) prior to the start of screening. 
f. Previous treatment with omalizumab or other Anti-IgE therapy within a year prior to 
the start of screening. 
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g. Routine (daily or every other day during 5 or more consecutive days) doses of the 
following medications within 30 days prior to screening: Systemic or cutaneous 
(topical) corticosteroids (prescription or over-the-counter), hydroxychloroquine, 
methotrexate, cyclosporine, or cyclophosphamide. 
h. Intravenous immunoglobulin G, or plasmapheresis within 30 days prior to the start of 
screening. 
i. Regular (daily/every other day) doxepin (oral) use within 2 weeks prior to the start of 
screening. 
j. Any H2 antihistamine use within 7 days prior to the start of screening. 
k. Any LTRA (montelukast or zafirlukast) use within 7 days prior to the start of 
screening. 
l. Any H1 antihistamines at greater than approved doses use from 3 days after the start 
of screening. 
m. Current malignancy, history of malignancy within the last 5 years, or currently under 
work-up for suspected malignancy except non-melanoma skin cancer that has been 
treated or excised and is considered resolved. 
n. Hypersensitivity to omalizumab or any component of the formulation. 
o. History of anaphylactic shock. 
p. Contraindications to diphenhydramine hydrochloride. 
q. Pregnant or lactating woman, or plans to become pregnant during the study. 
r. Presence of clinically significant cardiovascular, neurological, psychiatric, metabolic, 
or other pathological conditions that could interfere with the interpretation of the 
study results and or compromise the safety of the patients. 
s. Evidence of current drug or alcohol abuse. 
t. Patients taking either LTRAs or H2 blockers for diseases other than CIU (eg, asthma 
or gastroesophageal reflux disease, respectively) will be permitted to continue their 
use during the study. These diseases must be recorded as part of the medical history 
collected during the screening period. Inhaled asthma controllers, including 
corticosteroids, are also permitted during the study. 
Statistical Considerations 
The statistical analysis of the study is planned to assess the biosimilarity (efficacy and safety) 
between TEV-45779 and XOLAIR, and to support the safety and immunogenicity assessment of 
a single switch from XOLAIR to TEV-45779. 
Sample Size Rationale: A sample size of 600 evaluable patients, randomized 2:2:1:1 to 
TEV-45779 300 mg, XOLAIR 300 mg, TEV-45779 150 mg or XOLAIR 150 mg, will provide: 
• 
 power (marginal, eg, regardless of other endpoints) to demonstrate biosimilarity 
of efficacy based on the difference in change from baseline in ISS7 at Week 12 using 
90% confidence interval (CI) 
between the 
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TEV-45779 and XOLAIR 300 mg arms (200 patients per arm), 
 
 
• 
 power (marginal) to demonstrate biosimilarity of efficacy based on the 
difference in change from baseline in ISS7 at Week 12 using 95% CI 
 
 between the TEV-45779 and XOLAIR 300 mg arms (200 patients 
per arm), 
 
 
 
• 
 power to demonstrate biosimilarity of efficacy based on the difference in change 
from baseline in ISS7 at Week 12 using 90% CI 
 
between the TEV-45779 and XOLAIR 300 mg arms (200 patients per arm), an 
 
 
 
 
• 
 power (
) for the co-primary endpoint of 
relative potency of TEV-45779 and XOLAIR as measured by change from baseline in 
ISS7 at Week 12 using a 4-point assay, 
 
 (TEV-45779 and XOLAIR at 300 mg and 150 mg). 
• 
 
 
Power assessment for the co-primary endpoint of relative potency of TEV-45779 and XOLAIR, 
as measured by change from baseline in ISS7 at Week 12 using a 4-point assay, was performed 
using simulations based on innovator studies data. 
Primary Efficacy Analysis: The primary endpoint is the change from baseline in the ISS7 at 
Week 12 in the TEV-45779 300 mg and XOLAIR 300 mg arms. 
The co primary efficacy endpoint (for the FDA submission only) is the relative potency of 
TEV-45779 and XOLAIR as measured by change from baseline in ISS7 at Week 12 using a 4-
point assay, ie, TEV-45779 300 mg, TEV-45779 150 mg, XOLAIR 300 mg, and XOLAIR 150 
mg. 
Itch severity is recorded twice daily (morning and evening) in the patient's symptom diary, on a 
scale of 0 (none) to 3 (severe). A daily itch severity score is calculated as the average of the 
morning and evening scores. A weekly itch severity (ISS7) score is calculated as the sum of the 
daily itch severity scores over the study days that make up a given study week. If at least 1 daily 
itch severity score is missing or if a given study week is shorter than 7 days (ie, if a treatment 
visit occurs earlier or later, the study week before or after the treatment visit, respectively, would 
be shorter), the approach for handling the missing data will be similar to the one used by the 
originator. Multiple imputation will be used for the missing ISS7 at Week 12 for the analysis of 
change from baseline to Week 12 in ISS7. 
For the EMA Submission: 
The primary analysis of change from baseline in the ISS7 at Week 12 will be an analysis of 
covariance (ANCOVA) with treatment group (2 levels: TEV-45779 300 mg and XOLAIR 
300 mg), baseline itch severity score, baseline weight and region (3 levels planned: Americas, 
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Europe and Asia-Pacific) as covariates. Biosimilarity will be demonstrated if the 95% CI for the 
mean difference between TEV-45779 300 mg and XOLAIR 300 mg falls entirely within the 
equivalence margin of ±2.0. 
The primary analysis will be based on the intent to treat (ITT) analysis set. 
For the FDA Submission: 
The following analyses will be considered co-primary: 
1. The primary analysis of change from baseline in the ISS7 at Week 12 will be an analysis 
of covariance (ANCOVA) with treatment group (2 levels: TEV-45779 300 mg and 
XOLAIR 300 mg), baseline itch severity score, baseline weight and region (3 levels 
planned: Americas, Europe and Asia-Pacific) as covariates. Biosimilarity will be 
demonstrated if the 90% CI for the mean difference between TEV-45779 300 mg and 
XOLAIR 300 mg falls entirely within the asymmetric equivalence margin of (-2.5, +2.0). 
2. The analysis of relative potency of TEV-45779 and XOLAIR as measured by change 
from baseline in ISS7 at Week 12 using a 4-point assay, ie, TEV-45779 300 mg, 
TEV-45779 150 mg, XOLAIR 300 mg and XOLAIR 150 mg using a multi-step process. 
Relative potency will be demonstrated if the 90% CI for relative potency falls entirely 
within the equivalence margins of (0.5, 2). 
Both primary analyses will be based on the ITT analysis set. 
Efficacy Analysis in the Transition Period: 
Descriptive statistics will be presented by the treatment groups and dose level to which the 
patients were assigned in the main treatment and transition periods (TEV-45779/TEV-45779, 
XOLAIR/XOLAIR and XOLAIR/TEV-45779). In addition, the difference and 95% CI for the 
difference between the XOLAIR/XOLAIR and XOLAIR/TEV-45779 groups at both doses will 
be presented. 
The efficacy analyses in the transition period will be based on the transition period modified 
intent-to-treat (TmITT) analysis set. 
All efficacy analyses in the transition period are considered descriptive and no formal hypothesis 
testing is planned. 
Sensitivity/Supplementary Analysis: The main sensitivity/supplementary analyses to assess the 
robustness of the primary efficacy analysis will include: 
• Change from baseline in the ISS7 at Week 12 difference between TEV-45779 300 mg 
and XOLAIR 300 mg: 
− primary model, but with a single factor of treatment group 
− primary analysis using mixed-model-for-repeated-measures, with additional fixed 
effects of week (as a categorical variable with 3 levels: Weeks 4, 8, and 12) and 
treatment-group-by-week interaction as well as patient as a random effect. 
• 4-points relative potency between TEV-45779 300 mg and XOLAIR 300 mg 
− the ANCOVA model in the %RELPOT macro run without baseline covariates 
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• Supplementary analyses for missing data for change from baseline in the ISS7 at 
Week 12 difference between TEV-45779 300 mg and XOLAIR 300 mg 
− tipping point (missing-not-at-random) 
− 2 separate 1-sided tests of alpha=0.05 with missing data imputed under the 
corresponding null using a multiple imputation method 
Secondary Efficacy Analysis: No formal statistical analysis of secondary efficacy endpoints is 
planned; descriptive statistics will be presented. 
Multiple Comparisons and Multiplicity: For the FDA submission, the above efficacy endpoint 
and the relative-potency endpoint of 2 dose levels (300 mg and 150 mg) of TEV-45779 and 
XOLAIR, as measured by change from baseline in ISS7 at Week 12, are considered co-primary. 
The hierarchical approach for the 2 co-primary endpoints will be applied, meaning that the 
relative-potency endpoint will be tested for biosimilarity only if efficacy similarity is 
demonstrated for the endpoint of change from baseline in ISS7 at Week 12 for TEV-45779 
300 mg compared to XOLAIR 300 mg. The secondary efficacy analyses will be descriptive in 
nature. 
Safety Analyses: Safety analyses will be performed on the safety and transition period safety 
analyses sets. 
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Each patient will be counted only once in each preferred term or system organ class 
(SOC) category for the analyses of safety. Summaries will be presented for all adverse events 
(overall and by severity), adverse events determined by the investigator to be related to test IMP 
(ie, reasonable possibility) (defined as related or with missing relationship) (overall and by 
severity), serious adverse events, and adverse events causing withdrawal from the study. 
Summaries for the main treatment period, transition period and overall treatment period will be 
presented as indicated below. Patient listings of serious adverse events and adverse events 
leading to withdrawal will be presented. 
Changes in laboratory and vital signs data will be summarized descriptively by treatment period. 
All values will be compared with predefined criteria to identify potentially clinically significant 
values or changes, and such values will be listed. 
The use of concomitant medications will be summarized by therapeutic class using descriptive 
statistics by treatment period. 
For continuous variables, descriptive statistics (n, mean, SD, median, minimum, and maximum) 
will be provided for actual values and changes from baseline to each time point. For categorical 
variables, patient counts and percentages will be provided. Descriptive summaries of serious 
adverse events, patient withdrawals due to adverse events, and potentially clinically significant 
abnormal values (clinical laboratory or vital signs) based on predefined criteria will be provided 
as well by treatment period. 
If any patient dies during the study, a listing of deaths will be provided and all relevant 
information will be discussed in the patient narrative included in the clinical study report (CSR). 
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Safety Analysis in the Main Treatment Period: 
Safety analyses in the main treatment period will be performed on the safety analysis set. 
Summaries will be presented by treatment group (TEV-45779, XOLAIR, further subdivided by 
dose 150 mg or 300 mg) and for all patients. 
All safety variables at the Week 12 visit that are assessed prior to IMP administration will be 
considered as occurring during the main treatment period. 
Safety Analysis in the Transition Period: 
Safety analyses in the transition period will be performed on the transition period safety analysis 
set. Summaries will be presented by the treatment groups to which the patients were assigned in 
the main treatment and transition periods (TEV-45779/TEV-45779, XOLAIR/XOLAIR and 
XOLAIR/TEV-45779, further subdivided by dose 150 mg or 300 mg) and for all patients. 
Safety Analysis in the Overall Treatment Period: 
Safety analyses in the overall treatment period will be performed on the safety analysis set. The 
analyses will include only patients in the TEV-45779/TEV-45779, XOLAIR/XOLAIR treatment 
groups. 
The analyses will be similar to the analyses of the main treatment period. Summaries will be 
presented by treatment group (TEV-45779, XOLAIR, further subdivided by dose 150 mg or 
300 mg) and for all patients included in the analysis. 
Tolerability Analysis: If more than 10% of the patients withdraw from the study before the end 
of the main treatment period, the number of days until study discontinuation will be analyzed 
using Kaplan-Meier methodology using the ITT analysis set. 
Pharmacokinetic Analysis: Omalizumab serum concentrations will be summarized by 
treatment and time point using descriptive statistics for all patients who have omalizumab serum 
concentration data for ≥1 time point. 
Individual data will be listed. 
Pharmacodynamic Analysis: Free and total IgE will be summarized by treatment and time 
point using descriptive statistics. Individual data will be listed. 
Immunogenicity Analysis: Results of the immunogenicity analysis will be provided by 
immunogenicity incidence (number and percent of treatment-related ADA positive patients by 
treatment group), antibody titration and neutralization potential by treatment group. 
The safety analysis set will be used for immunogenicity analysis. 
Interim Analysis: No interim analysis is planned for this study. 
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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
AMENDMENT HISTORY .............................................................................................................2 
INVESTIGATOR AGREEMENT...................................................................................................3 
SPONSOR PROTOCOL APPROVAL ...........................................................................................4 
COORDINATING INVESTIGATOR AGREEMENT ...................................................................5 
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................6 
LIST OF ABBREVIATIONS ........................................................................................................28 
1. 
INTRODUCTION AND BACKGROUND INFORMATION ..................................32 
1.1. 
Introduction .................................................................................................................32 
1.1.1. 
TEV-45779 .................................................................................................................32 
1.1.2. 
TEV-45779 and Chronic Idiopathic Urticaria/Chronic Spontaneous Urticaria .........32 
1.1.3. 
Purpose of the Study ...................................................................................................34 
1.2. 
Findings from Nonclinical and Clinical Studies .........................................................34 
1.2.1. 
Nonclinical Studies .....................................................................................................34 
1.2.2. 
Clinical Studies ...........................................................................................................35 
1.2.2.1. 
Pharmacokinetics ........................................................................................................35 
1.2.2.2. 
Pharmacodynamics .....................................................................................................36 
1.2.2.3. 
Safety and Immunogenicity ........................................................................................36 
1.3. 
Known and Potential Benefits and Risks to Patients ..................................................37 
1.3.1. 
Known and Potential Benefits and Risks of TEV-45779 ...........................................37 
1.3.2. 
Known and Potential Benefits and Risks of Reference Investigational 
Medicinal Product .......................................................................................................37 
1.3.2.1. 
Important Identified Risks with Omalizumab (XOLAIR)..........................................37 
1.3.2.1.1. 
Anaphylaxis/Anaphylactoid Reactions .......................................................................37 
1.3.2.1.2. 
Churg-Strauss Syndrome/Hypereosinophilic Syndrome ............................................37 
1.3.2.2. 
Important Potential Risks with Omalizumab (XOLAIR) ...........................................38 
1.3.2.2.1. 
Arterial Thromboembolic Events ...............................................................................38 
1.3.2.2.2. 
Malignant Neoplasms in Adults and Adolescents ≥12 Years of Age ........................38 
1.3.3. 
Overall Benefit and Risk Assessment for this Study ..................................................38 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................40 
2.1. 
Primary and Secondary Study Objectives and Endpoints ..........................................40 
2.1.1. 
Primary Estimand: ......................................................................................................42 
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2.1.2. 
Justification of Primary Endpoint and Equivalence Margins .....................................43 
3. 
STUDY DESIGN .......................................................................................................45 
3.1. 
General Study Design and Study Schematic Diagram ...............................................45 
3.2. 
Planned Number of Patients and Countries ................................................................47 
3.3. 
Justification for Study Design and Selection of Population .......................................47 
3.4. 
Stopping Rules for the Study ......................................................................................47 
3.5. 
Schedule of Study Procedures and Assessments ........................................................48 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................53 
4.1. 
Patient Inclusion Criteria ............................................................................................53 
4.2. 
Patient Exclusion Criteria ...........................................................................................54 
4.3. 
Withdrawal Criteria and Procedures for the Patient ...................................................56 
4.4. 
Replacement of Patients .............................................................................................57 
4.5. 
Re-screening ...............................................................................................................57 
4.6. 
Screening Failure ........................................................................................................57 
5. 
TREATMENTS ..........................................................................................................58 
5.1. 
Investigational Medicinal Products Used in the Study ...............................................58 
5.1.1. 
Test Investigational Medicinal Product ......................................................................58 
5.1.2. 
Reference Investigational Medicinal Product .............................................................58 
5.1.3. 
Placebo Investigational Medicinal Product ................................................................58 
5.1.4. 
Medical Devices .........................................................................................................59 
5.2. 
Preparation, Handling, Labeling, Storage, and Accountability for 
Investigational Medicinal Products ............................................................................60 
5.2.1. 
Storage and Security ...................................................................................................60 
5.2.2. 
Labeling ......................................................................................................................60 
5.2.3. 
Accountability .............................................................................................................60 
5.3. 
Justification for Investigational Medicinal Products ..................................................61 
5.3.1. 
Justification for Dose of Test Investigational Medicinal Product ..............................61 
5.3.2. 
Justification for Use of Reference Investigational Medicinal Product .......................61 
5.3.3. 
Justification for Use of Placebo Investigational Medicinal Product ..........................61 
5.4. 
Treatment After the End of the Study .........................................................................61 
5.5. 
Restrictions .................................................................................................................61 
5.5.1. 
Activity .......................................................................................................................61 
5.6. 
Prior and Concomitant Medication or Therapy ..........................................................62 
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5.7. 
Procedures for Monitoring Patient Compliance .........................................................62 
5.8. 
Randomization and Blinding ......................................................................................62 
5.9. 
Maintenance of Randomization and Blinding ............................................................63 
5.9.1. 
Blinding and Unblinding ............................................................................................63 
5.9.2. 
Independent Data Monitoring Committee ..................................................................64 
5.10. 
Total Blood Volume ...................................................................................................64 
6. 
ASSESSMENT OF EFFICACY ................................................................................65 
6.1. 
Patient Symptom Diary ...............................................................................................65 
6.2. 
Physician's Assessment of Urticaria Activity Score ...................................................65 
6.3. 
Dermatology Life Quality Index ................................................................................65 
6.4. 
Timing and Description of Assessments and Procedures ...........................................65 
7. 
ASSESSMENT OF SAFETY .....................................................................................66 
7.1. 
Adverse Events ...........................................................................................................66 
7.1.1. 
Definition of an Adverse Event ..................................................................................66 
7.1.2. 
Recording and Reporting of Adverse Events .............................................................67 
7.1.3. 
Severity of an Adverse Event .....................................................................................67 
7.1.4. 
Relationship of an Adverse Event to the Investigational Medicinal Product .............68 
7.1.5. 
Serious Adverse Events ..............................................................................................69 
7.1.5.1. 
Definition of a Serious Adverse Event .......................................................................69 
7.1.5.2. 
Expectedness ...............................................................................................................70 
7.1.5.3. 
Reporting a Serious Adverse Event ............................................................................70 
7.1.5.3.1. 
Investigator Responsibility .........................................................................................70 
7.1.5.3.2. 
Sponsor Responsibility ...............................................................................................71 
7.1.6. 
Protocol-Defined Adverse Events of Special Interest ................................................72 
7.1.7. 
Protocol Deviations Because of an Adverse Event ....................................................73 
7.2. 
Adverse Device Effects ..............................................................................................73 
7.2.1. 
Adverse Device Effect Reporting ...............................................................................73 
7.2.2. 
Serious Adverse Device Effects .................................................................................73 
7.2.2.1. 
Serious Adverse Device Effect Reporting ..................................................................74 
7.3. 
Pregnancy ...................................................................................................................74 
7.4. 
Medication Error and Special Situations Related to the Investigational 
Medicinal Products .....................................................................................................75 
7.5. 
Clinical Laboratory Tests ...........................................................................................76 
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7.5.1. 
Serum Chemistry, Hematology, and Urinalysis .........................................................76 
7.5.2. 
Other Clinical Laboratory Tests .................................................................................77 
7.5.2.1. 
Human Chorionic Gonadotropin Tests .......................................................................77 
7.5.2.2. 
Follicle Stimulating Hormone ....................................................................................77 
7.5.2.3. 
Coronavirus Disease 2019 Testing .............................................................................78 
7.6. 
Physical Examinations ................................................................................................78 
7.7. 
Height and Weight ......................................................................................................78 
7.8. 
Vital Signs ..................................................................................................................78 
7.9. 
Electrocardiography ....................................................................................................78 
7.10. 
Assessment of Local Tolerability and Pain ................................................................79 
8. 
ASSESSMENT OF PHARMACOKINETICS, PHARMACODYNAMICS, 
AND IMMUNOGENICITY .......................................................................................80 
8.1. 
Pharmacokinetic Assessment ......................................................................................80 
8.2. 
Pharmacodynamics Assessment .................................................................................80 
8.3. 
Immunogenicity Testing .............................................................................................80 
9. 
STATISTICS ..............................................................................................................81 
9.1. 
Sample Size and Power Considerations .....................................................................81 
9.2. 
Analysis Sets ...............................................................................................................82 
9.2.1. 
Intent-to-Treat Analysis Set ........................................................................................82 
9.2.2. 
Modified Intent-to-Treat Analysis Set ........................................................................82 
9.2.3. 
Modified Intent-to-Treat 1 Analysis Set .....................................................................82 
9.2.4. 
Transition Intent-to-Treat Analysis Set ......................................................................82 
9.2.5. 
Transition Period Modified Intent-to-Treat Analysis Set ...........................................82 
9.2.6. 
Transition Period Modified Intent-to-Treat 1 Analysis Set ........................................83 
9.2.7. 
Safety Analysis Set .....................................................................................................83 
9.2.8. 
Transition Period Safety Analysis Set ........................................................................83 
9.2.9. 
Per-Protocol Analysis Set ...........................................................................................83 
9.2.10. 
Pharmacokinetic Analysis Set ....................................................................................83 
9.3. 
Data Handling Conventions ........................................................................................83 
9.3.1. 
Handling Withdrawals and Missing Data ...................................................................83 
9.4. 
Study Population .........................................................................................................84 
9.4.1. 
Patient Disposition ......................................................................................................84 
9.4.2. 
Demographic and Baseline Characteristics ................................................................85 
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9.5. 
Efficacy Analysis ........................................................................................................85 
9.5.1. 
Primary Endpoint ........................................................................................................85 
9.5.1.1. 
Primary Efficacy Analysis ..........................................................................................85 
9.5.1.1.1. 
Relative Potency .........................................................................................................86 
9.5.1.1.2. 
Missing Week 12 Itch Severity Score Multiple Imputation .......................................87 
9.5.1.2. 
Sensitivity Analysis for the Primary Analysis ............................................................87 
9.5.1.3. 
Supplementary Analysis for the Primary Analysis .....................................................88 
9.5.2. 
Secondary Endpoints ..................................................................................................89 
9.5.2.1. 
Secondary Efficacy Endpoints in the Main Treatment Period ...................................89 
9.5.2.2. 
Secondary Efficacy Endpoints in the Transition Period .............................................90 
9.5.2.3. 
Secondary Efficacy Analysis ......................................................................................91 
9.5.2.4. 
Efficacy and Pharmacodynamic Analysis in the Transition Period ...........................91 
9.6. 
Multiple Comparisons and Multiplicity......................................................................91 
9.7. 
Safety Analysis ...........................................................................................................91 
9.7.1. 
Safety Analysis in the Main Treatment Period ...........................................................92 
9.7.2. 
Safety Analysis in the Transition Period ....................................................................92 
9.7.3. 
Safety Analysis in the Overall Treatment Period .......................................................92 
9.8. 
Pharmacokinetic Analysis ..........................................................................................93 
9.9. 
Pharmacodynamic Analysis........................................................................................93 
9.10. 
Immunogenicity Analysis ...........................................................................................93 
9.11. 
Planned Interim Analysis ............................................................................................93 
9.12. 
Reporting Deviations from the Statistical Plan ..........................................................93 
10. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................94 
11. 
COMPLIANCE STATEMENT ..................................................................................95 
12. 
DATA MANAGEMENT AND RECORD KEEPING ..............................................96 
13. 
FINANCING AND INSURANCE .............................................................................97 
14. 
PUBLICATION POLICY ..........................................................................................98 
15. 
REFERENCES ...........................................................................................................99 
16. 
SUMMARY OF CHANGES TO PROTOCOL .......................................................101 
16.1. 
Amendment 04 Dated 15 February 2023 ..................................................................101 
16.2. 
Administrative Letter 07 Dated 19 December 2022 .................................................114 
16.3. 
Administrative Letter 06 Dated 20 October 2022 ....................................................115 
16.4. 
Administrative Letter 05 Dated 01 August 2022 ......................................................117 
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16.5. 
Amendment 03 Dated 10 May 2022 .........................................................................119 
16.6. 
Administrative Letter 04 dated 23 February 2022 ....................................................129 
16.7. 
Administrative Letter 03 Dated 28 January 2022 .....................................................131 
16.8. 
Amendment 02 Dated 23 November 2021 ...............................................................133 
16.9. 
Administrative Letter 02 Dated 10 November 2021 ................................................150 
16.10. 
Administrative Letter 01 Dated 11 June 2021 ..........................................................151 
16.11. 
Amendment 01 Dated 11 June 2021 .........................................................................152 
APPENDIX A. CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND 
INSTITUTIONS .......................................................................................................166 
APPENDIX B. STUDY PROCEDURES AND ASSESSMENTS BY VISIT .........................168 
APPENDIX C. MANAGEMENT OF STUDY ACTIVITIES DURING 
CORONAVIRUS DISEASE 2019 OUTBREAKS ..................................................177 
APPENDIX D. PATIENT DIARY ...........................................................................................180 
APPENDIX E. URTICARIA ACTIVITY SCORE ..................................................................181 
APPENDIX F. IN-CLINIC URTICARIA ACTIVITY SCORE ..............................................182 
APPENDIX G. RELATIVE POTENCY ..................................................................................183 
APPENDIX H. QUALITY CONTROL AND QUALITY ASSURANCE ..............................185 
APPENDIX I. ETHICS .............................................................................................................187 
APPENDIX J. BIRTH CONTROL METHODS AND PREGNANCY TESTING..................188 
APPENDIX K. LOST TO FOLLOW-UP .................................................................................190 
APPENDIX L. LIST OF PROHIBITED MEDICATIONS ......................................................191 
APPENDIX M. PHARMACOKINETICS AND PHARMACODYNAMICS 
SAMPLES ................................................................................................................193 
APPENDIX N. IMMUNOGENICITY SAMPLES ..................................................................194 
APPENDIX O. PRODUCT COMPLAINTS ............................................................................195 
APPENDIX P. DATA MANAGEMENT AND RECORD KEEPING ....................................202 
APPENDIX Q. PUBLICATION POLICY ...............................................................................205 
APPENDIX R. CTCAE GRADING SCALE ...........................................................................206 
APPENDIX S. ADDITIONAL INFORMATION TO THE PROTOCOL FOR SOUTH 
KOREA .....................................................................................................................207 
APPENDIX T. ADDITIONAL INFORMATION TO THE PROTOCOL FOR INDIA .........208 
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LIST OF TABLES 
Table 1: 
Study Procedures and Assessments ............................................................................49 
Table 2: 
Investigational Medicinal Products Used in the Study ...............................................59 
Table 3: 
The Relationship of an Adverse Event to the Investigational Medicinal 
Products ......................................................................................................................68 
Table 4: 
Clinical Laboratory Tests ...........................................................................................77 
Table 5: 
Severity Assessment of Local Tolerability .................................................................79 
Table 6: 
Potential Use-Related Deficiencies That Could Lead to Serious Adverse 
Events .......................................................................................................................198 
Table 7: 
Potential Design Related Deficiencies That Could Lead to Serious Adverse 
Events .......................................................................................................................200 
 
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LIST OF FIGURES 
Figure 1: 
Overall Study Schematic Diagram .............................................................................46 
Figure 2: 
Decision Tree for Adverse Events and Adverse Device Effects Classification .........74 
Figure 3: 
Decision Tree for Device Deficiencies .....................................................................197 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
β-HCG 
beta-human chorionic gonadotropin 
εRI 
epsilon RI 
ADA 
anti-drug antibody 
ADE 
adverse device effect 
ADL 
activities of daily living 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase (SGPT) 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase (SGOT) 
ATE 
arterial thromboembolic events 
AUCext 
area under the concentration-time curve  
BPD 
Biological Product Development 
BUN 
blood urea nitrogen 
CDMS 
clinical data management system 
CFR 
Code of Federal Regulations (USA) 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CIU 
chronic idiopathic urticaria 
CL 
total body clearance  
COVID-19 
Coronavirus disease 2019 
CPK 
creatine phosphokinase 
CRF 
case report form (refers to any media used to collect study data [ie, paper or electronic]) 
CRO 
contract research organization 
CRSwNP 
chronic rhinosinusitis with nasal polyp 
CSR 
clinical study report 
CSU 
chronic spontaneous urticaria 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
omalizumab serum concentration before next dose 
DBL 
database lock 
DLQI 
Dermatology Life Quality Index 
ECG 
electrocardiogram 
eDiary 
electronic Patient Symptom Diary 
EMA 
European Medicines Agency 
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Abbreviation 
Term 
EoS 
end of study 
EoT 
end of treatment 
ePRO 
electronic patient-reported outcome  
EU 
European Union 
EV 
EudraVigilance  
F 
Bioavailability 
Fc 
crystallizable fragment 
FcRn 
neonatal Fc receptor 
FcεRI 
high-affinity IgE receptor 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume in 1 second 
FSH 
follicle stimulating hormone 
GCA 
Global Quality Assurance 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transpeptidase 
GMP 
Good Manufacturing Practice 
GPSP 
Global Patient Safety and Pharmacovigilance 
HDL 
high density lipoprotein 
HEENT 
head, eyes, ears, nose, and throat 
IA 
interim analysis 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
The International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IgE 
immunoglobulin E 
IgG 
immunoglobulin G 
IgG1 
immunoglobulin G1 
IMP 
investigational medicinal product 
INC 
intranasal corticosteroids 
IND 
Investigational New Drug 
INN 
international nonproprietary name 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization  
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Abbreviation 
Term 
ISS7 
weekly itch severity score (sum of the daily itch severity score for 7 days) 
ITT 
intent-to-treat 
LDH 
lactic dehydrogenase 
LDL 
low density lipoprotein 
LSO 
local safety officer 
LTRA 
leukotriene receptor antagonist 
MAA 
Marketing Authorisation Application 
mAb 
monoclonal antibody 
MAR 
missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities  
MFDS 
Ministry for Food and Drug Safety 
MID 
minimally important difference 
mITT 
modified intent to treat 
MMRM 
mixed-model-for-repeated-measures 
MNAR 
missing-not-at-random 
n 
number 
NIAID/FAAN 
National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network  
NRS-11 
11-point pain intensity numerical response scale 
PDAESI 
protocol-defined adverse event of special interest 
PFS 
prefilled syringe 
PP 
per-protocol 
PT 
prothrombin time 
PTT 
partial prothromboplastin time 
Q 
quarter 
RBC 
red blood cell count 
RSI 
reference safety information 
RTSM 
Randomization and Trial Supply Management 
SADE 
serious adverse device effect 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
sc 
subcutaneous/subcutaneously 
SD 
standard deviation 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SmPC 
Summary of Product Characteristics 
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Abbreviation 
Term 
SOC 
system organ class  
SOP 
Standard Operating Procedure 
SUSAR 
suspected unexpected serious adverse reaction 
TITT 
transition intent-to-treat 
tmax 
time to maximum observed drug concentration  
TmITT 
transition modified intent-to-treat 
UAS 
urticaria activity score 
UAS7 
weekly urticaria activity score (sum of the daily number of wheals score and itch severity score 
over 7 days)  
ULN 
upper limit of normal 
US 
United States (of America) 
USPI 
US Prescribing Information  
VC 
videoconference 
Vz 
volume of distribution 
W 
week 
WBC 
white blood cell count 
WHO 
The World Health Organization 
WHO Drug 
World Health Organization Drug Dictionary 
XML 
Extensible Markup Language 
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1. 
INTRODUCTION AND BACKGROUND INFORMATION 
1.1. 
Introduction 
1.1.1. 
TEV-45779 
TEV-45779 is a humanized immunoglobulin G1 (IgG1)/kappa monoclonal antibody (mAb) 
directed against immunoglobulin E (IgE). TEV-45779 is being developed by the sponsor as a 
biosimilar candidate to omalizumab, which is licensed under the trade name XOLAIR® for the 
treatment of allergic asthma and chronic idiopathic urticaria (CIU), and nasal polyps in the 
United States (US) and allergic asthma, chronic spontaneous urticaria (CSU), and chronic 
rhinosinusitis with nasal polyps (CRSwNP) in the European Union (EU). Both XOLAIR and 
TEV-45779 are presented in a prefilled syringe (PFS) with needle safety device for single-use 
subcutaneous (sc) administration. 
Omalizumab is comprised of 2 identical light chains and 2 identical heavy chains. Each light 
chain consists of 218 amino acid residues while each heavy chain is predicted to contain 
451 residues. The molecular weight of omalizumab is 149 kDa. 
Omalizumab binds to IgE at an epitope that IgE requires for its binding to the crystallizable 
fragment (Fc) epsilon RI (εRI) (FcεRI; high-affinity IgE receptor) (Pelaia et al 2011). Thus, it 
inhibits the binding of IgE to the FcεRIs found on mast cells, basophils, and dendritic cells. In 
addition, as omalizumab depletes free IgE, the FcεRIs on basophils, mast cells, and dendritic 
cells are down-regulated. Consequently, the likelihood for mast cells and basophils to release the 
mediators necessary to elicit an inflammatory response is decreased by a reduction of both the 
ligand and the receptor necessary to initiate such a release. 
TEV-45779 drug substance is produced using a Chinese hamster ovary K1SV cell line. The 
analysis for biosimilarity includes structural and functional assessments. The functional assays 
panel includes the assessment of activities associated with the mechanism of action, which is 
binding to IgE and therefore inhibiting IgE binding to FcRI and human neonatal Fc receptor 
(FcRn), and effector functions. The data show overall similarity in these assays between 
TEV-45779 and XOLAIR. 
1.1.2. 
TEV-45779 and Chronic Idiopathic Urticaria/Chronic Spontaneous Urticaria 
CIU, also known as CSU, is defined as the occurrence of daily, or almost daily, wheals and 
frequently intractable pruritus (itching) for ≥6 weeks without an obvious cause. Itch is the most 
concerning symptom for patients and has the greatest impact on their quality of life. Angioedema 
or deep tissue swelling occurs in over 40% of patients with CIU; it is unpredictable and can 
involve swelling anywhere in the body or upper respiratory tract. Swelling of the face, lips, or 
airway is particularly uncomfortable and can be very serious (XOLAIR, European Public 
Assessment Report- Assessment Report EMEA/H/C/000606/II/0048, EMEA 2020). 
The majority of CIU patients achieve symptomatic control with conventional H1 antihistamine 
therapy. Less commonly, a triple regimen of H1 and H2 antihistamines combined with a LTRA 
is used, although H2 antihistamines and LTRAs are not approved for the treatment of CIU 
(Viegas et al 2014). In some patients, CIU can be a debilitating condition and can have a 
profound negative influence on the patient’s quality of life (Maurer et al 2011, Balp et al 2015). 
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Some patients may remain symptomatic despite ongoing H1 antihistamine treatment, and for this 
group of patients, therapies such as immunosuppressants (including cyclosporine, 
corticosteroids, intravenous IgG, and methotrexate) and plasmapheresis have been used (Kozel 
and Sabroe 2004). However, these agents have varying success and may be associated with 
severe adverse effects. 
TEV-45779 is being developed as a biosimilar candidate to XOLAIR.  
In the US, XOLAIR is currently approved for: 
• Moderate to severe persistent asthma in patients 6 years of age and older with a 
positive skin test or in vitro reactivity to a perennial aeroallergen and symptoms that 
are inadequately controlled with inhaled corticosteroids. 
• Nasal polyps in adult patients 18 years of age and older with inadequate response to 
nasal corticosteroids, as add-on maintenance treatment. 
• CSU in adults and adolescents 12 years of age and older who remain symptomatic 
despite H1 antihistamine treatment (XOLAIR Prescribing Information 7/2021). 
In the EU, XOLAIR is currently approved for: 
• Allergic asthma 
− Adults and adolescents (12 years of age and older): XOLAIR is indicated as 
add-on therapy to improve asthma control in patients with severe persistent 
allergic asthma who have a positive skin test or in vitro reactivity to a perennial 
aeroallergen and who have reduced lung function (forced expiratory volume in 
1 second [FEV1] <80%) as well as frequent daytime symptoms or night-time 
awakenings and who have had multiple documented severe asthma exacerbations 
despite daily high-dose inhaled corticosteroids, plus a long-acting inhaled 
beta2-agonist. 
− Children (6 to <12 years of age): XOLAIR is indicated as add-on therapy to 
improve asthma control in patients with severe persistent allergic asthma who 
have a positive skin test or in vitro reactivity to a perennial aeroallergen and 
frequent daytime symptoms or night-time awakenings and who have had multiple 
documented severe asthma exacerbations despite daily high-dose inhaled 
corticosteroids, plus a long-acting inhaled beta2-agonist. 
• CSU: XOLAIR is indicated as add-on therapy for the treatment of CSU in adult and 
adolescent (12 years and above) patients with inadequate response to H1 
antihistamine treatment. 
• CRSwNP: XOLAIR is indicated as an add-on therapy with intranasal corticosteroids 
(INC) for the treatment of adults (18 years and above) with severe CRSwNP for 
whom therapy with INC does not provide adequate disease control (XOLAIR 
Summary of Product Characteristics 25/10/2021). 
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1.1.3. 
Purpose of the Study 
TEV-45779 is a biosimilar candidate for XOLAIR. The purpose of the study is to compare the 
efficacy, pharmacokinetics, pharmacodynamics, safety, tolerability, and immunogenicity of 
TEV-45779 compared to XOLAIR in patients with CIU/CSU who remain symptomatic on H1 
antihistamine treatment. 
1.2. 
Findings from Nonclinical and Clinical Studies 
1.2.1. 
Nonclinical Studies 
Animal studies were not performed with TEV-45779, as agreed with the US FDA, because the 
available physicochemical and biological data from the current biosimilarity assessment did not 
indicate product quality differences that would require such studies to resolve remaining 
uncertainties. 
Information on the nonclinical pharmacology, pharmacokinetics, and toxicology of omalizumab 
is available in the public domain, and is summarized below. 
Omalizumab is a recombinant humanized IgG1 monoclonal anti-IgE antibody that binds to IgE 
at the same epitope as the FcεRI. Thus, omalizumab binding reduces the pool of IgE available to 
interact with mast cells and basophils via the FcεRI, and allergic responses are attenuated. 
Omalizumab binds to Cynomolgus monkey and human IgE with similar affinity but does not 
bind non-primate IgE, therefore, the majority of the nonclinical studies with omalizumab were 
conducted in the Cynomolgus monkey. 
Omalizumab pharmacokinetics in the Cynomolgus monkey were characteristic of a high-affinity 
mAb targeting cellularly expressed targets. Clearance of omalizumab involved IgG clearance 
processes, as well as clearance via specific binding and complex formation with its target ligand, 
IgE. Omalizumab:IgE complexes were eliminated by saturable interactions with Fc gamma 
receptors within the reticuloendothelial system at rates that were generally faster than IgG 
clearance rates. Clearance of omalizumab:IgE complexes was significantly slower than clearance 
of free IgE (XOLAIR Prescribing Information 7/2021). 
No drug-related effects were observed for vital functions such as blood pressure, 
electrocardiograph measurements, heart rate, and respiration rate in Cynomolgus monkey 
toxicology studies. 
Chronic intravenous or sc administration of omalizumab was well tolerated in Cynomolgus 
monkeys, except for a dose-related decrease in blood platelets, with a greater sensitivity in 
juvenile animals. The omalizumab serum concentration required to attain a 50% drop in platelets 
from baseline in adult Cynomolgus monkeys was roughly 4- to 20-fold higher than maximum 
clinical serum concentrations. Other adverse effects were acute hemorrhage and inflammation at 
injection sites. 
There were no effects on fertility, reproductive performance, maternal toxicity, embryotoxicity, 
or teratogenicity in Cynomolgus monkeys that received XOLAIR at sc doses up to 
75 mg/kg/week (approximately 10 times the maximum recommended human dose on a mg/kg 
basis). Omalizumab did not elicit adverse effects on fetal or neonatal growth when administered 
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throughout late gestation, delivery, and nursing (XOLAIR Prescribing Information 7/2021), 
although it crosses the placental barrier and is excreted into non-human primate breast milk. 
Omalizumab was not mutagenic in the Ames test (XOLAIR Product Monograph 1/11/2022) and 
no carcinogenicity studies have been performed in animals with omalizumab (XOLAIR 
Prescribing Information 7/2021). 
Special toxicity studies have demonstrated safety in a Cynomolgus monkey model challenged 
with ragweed allergen, no evidence of in vitro tissue cross-reactivity with Cynomolgus monkey 
and human tissues, no evidence of in vitro hemolysis of human and Cynomolgus monkey 
erythrocytes or incompatibility with human and Cynomolgus monkey serum and plasma, and no 
evidence of irritation in the rabbit (XOLAIR Product Monograph 1/11/2022). 
1.2.2. 
Clinical Studies 
Clinical data for TEV-45779 are available from the pivotal pharmacokinetic/pharmacodynamic 
study TV45779-BE-10160 (report approval date: 25 November 2021). This first-in-human study 
was a phase I, single dose, 3-arm, parallel-group study in subjects with serum IgE levels of <100 
IU/mL to demonstrate pharmacokinetic biosimilarity between TEV-45779 150 mg and XOLAIR 
150 mg sourced from the US (US-licensed XOLAIR) and XOLAIR 150 mg sourced from the 
EU (EU-approved XOLAIR), and to evaluate pharmacodynamics based on total and free IgE. 
A total of 228 healthy subjects were enrolled into the study: 75 subjects were randomized to 
receive a single sc injection of TEV-45779, 76 subjects to XOLAIR EU, and 77 subjects to 
XOLAIR US. 
Blood sampling for PK, PD and anti-drug antibody (ADA) assessment and routine safety visits 
occurred up to 126 days after study drug administration. 
Overall, 218 (96%) subjects completed the study. From the 10 subjects who withdrew from the 
study: 7 subjects were in the TEV-45779 group, 1 subject in the XOLAIR EU group, and 2 
subjects in the XOLAIR US group. The most frequent reason for withdrawal was lost to follow-
up, which occurred in 4 subjects in the TEV-45779 group and 1 subject in the XOLAIR US 
group. A further 3 subjects were withdrawn due to pregnancy (2 in the TEV-45779 group and 1 
subject in the XOLAIR EU group), and 2 subjects withdrew voluntarily (1 subject in each of the 
TEV-45779 and XOLAIR US groups). 
1.2.2.1. 
Pharmacokinetics 
Omalizumab serum concentrations were measured in serum samples for up to 126 days after 
administration of TEV-45779, XOLAIR US, or XOLAIR EU using a validated assay. All 3 
groups had a similar mean omalizumab serum concentration-time profile.  
Pharmacokinetic similarity was demonstrated between TEV-45779 and XOLAIR US, TEV-
45779 and XOLAIR EU, and XOLAIR US and XOLAIR EU: for each of the 2 co-primary 
endpoints (Cmax and AUC0-∞), the 90% CI for the GMRs were fully contained within the pre-
defined limits of 0.8000 to 1.2500. 
Evaluation of the secondary pharmacokinetic parameters (time to maximum observed drug 
concentration [tmax], percentage extrapolated area under the concentration-time curve [%AUCext], 
apparent total body clearance [CL/F], apparent volume of distribution [Vz/F], terminal 
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elimination rate constant [λz] and terminal elimination half-life [t½]) and partial AUCs support 
that the pharmacokinetics of the 3 treatments are similar. 
1.2.2.2. 
Pharmacodynamics 
Pharmacodynamic similarity was evaluated comparing the change of free and total IgE in serum 
following drug administration. TEV-45779, XOLAIR EU, and XOLAIR US had similar mean 
free IgE and total IgE concentration time profiles for both total and free IgE. For each 
pharmacodynamic parameter evaluated (negative AUEC of free IgE change from baseline, 
positive AUEC of total IgE change from baseline, Cmin,IgE,free, and Cmax,IgE,total), the results were 
descriptively similar for each treatment group. 
1.2.2.3. 
Safety and Immunogenicity 
The proportion of subjects reporting adverse events and treatment-related adverse events was 
low and similar between treatment groups. All adverse events were mild or moderate in severity. 
There were no deaths, other serious adverse events, or withdrawals due to adverse events, and no 
protocol defined adverse events of special interest (ie, anaphylaxis) during the study. There were 
5 pregnancy cases reported in the TV45779-BE-10160 study, 3 in the TEV-45779 group, 1 in the 
XOLAIR EU group, and 1 in the XOLAIR US group.  In 2 cases (1 each in the TEV-45779 and 
XOLAIR US groups), the pregnancy outcome was elective termination while in another case in 
the TEV-45779 group, the event of biochemical pregnancy was reported to have no viable 
pregnancy. One case in the TEV-45779 group was considered as lost to follow up. One serious 
adverse event of spontaneous abortion was reported after completion of the study for a subject 
who received XOLAIR EU. There were no findings of clinical importance in any treatment 
group for vital signs, ECGs, or clinical laboratory data. Local tolerability at the injection site was 
good following sc administration of each treatment, with no clinically meaningful differences 
between the groups. 
Anti-drug antibody formation occurred during the study for 30% to 40% of subjects in each 
group, with no substantial difference between TEV-45779, XOLAIR EU, and XOLAIR US. 
ADA had returned to baseline levels at the last sampling point, 126 days post dose. Only a small 
percentage of ADA-positive subjects tested positive for neutralizing ADA during the study 
(1% to 9%), with no marked difference between groups. 
The adverse events and other safety data observed after dosing of 228 healthy subjects are in line 
with the known safety profile of XOLAIR (XOLAIR Prescribing Information 7/2021; XOLAIR 
Summary of Product Characteristics 25/10/2021) and also with events expected in a healthy 
study population. 
Clinical data on omalizumab, the reference product, have been published in the scientific 
literature (Rivière et al 2011) and in the XOLAIR US Prescribing Information (USPI) (XOLAIR 
Prescribing Information 7/2021), EU Summary of Product Characteristics (SmPC) (XOLAIR 
Summary of Product Characteristics 25/10/2021), and Canadian Consumer Information Leaflet 
(XOLAIR Consumer Information 04/2017). Since TEV-45779 is being developed as a biosimilar 
candidate to XOLAIR, the clinical findings for TEV-45779 are expected to be similar to those of 
XOLAIR, particularly the safety, pharmacokinetic, pharmacodynamic, immunogenicity 
response, and efficacy profiles. 
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Further information can be found in the current version of the TEV-45779 Investigator's 
Brochure (IB). 
1.3. 
Known and Potential Benefits and Risks to Patients 
1.3.1. 
Known and Potential Benefits and Risks of TEV-45779 
No safety concerns have been observed in Study TV45779-BE-10160 (Section 1.2.2). Since 
TEV-45779 is being developed as a proposed biosimilar to XOLAIR, treatment risks with 
TEV-45779 are anticipated based on the safety information for the use of XOLAIR in the US 
and EU. 
Additional information regarding risks to patients may be found in the IB. 
1.3.2. 
Known and Potential Benefits and Risks of Reference Investigational Medicinal 
Product 
Information regarding benefits and risks to patients may be found in the current SmPC for 
XOLAIR (XOLAIR Summary of Product Characteristics 25/10/2021), the XOLAIR USPI 
(XOLAIR Prescribing Information 7/2021), and the IB. 
1.3.2.1. 
Important Identified Risks with Omalizumab (XOLAIR) 
1.3.2.1.1. Anaphylaxis/Anaphylactoid Reactions 
Anaphylaxis has been reported to occur after administration of XOLAIR in premarketing clinical 
trials and in post marketing spontaneous reports. Signs and symptoms in these reported cases 
have included bronchospasm, hypotension, syncope, urticaria, and/or angioedema of the throat or 
tongue. Some of these events have been life threatening. In premarketing clinical trials in 
patients with asthma, anaphylaxis was reported in 3 of 3507 (0.1%) patients. Anaphylaxis 
occurred with the first dose of XOLAIR in 2 patients and with the fourth dose in 1 patient. The 
time to onset of anaphylaxis was 90 minutes after administration in 2 patients and 2 hours after 
administration in 1 patient. 
A case control study showed that, among XOLAIR users, patients with a history of anaphylaxis 
to foods, medications, or other causes were at increased risk of anaphylaxis associated with 
XOLAIR, compared to those with no prior history of anaphylaxis. 
1.3.2.1.2. Churg-Strauss Syndrome/Hypereosinophilic Syndrome 
In rare cases, patients with asthma on therapy with XOLAIR may present with serious systemic 
eosinophilia, sometimes presenting with clinical features of vasculitis consistent with 
Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. 
These events usually, but not always, have been associated with the reduction of oral 
corticosteroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening 
pulmonary symptoms, cardiac complications, paranasal sinus abnormalities, and/or neuropathy 
presenting in their patients. A causal association between XOLAIR and these underlying 
conditions has not been established. 
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1.3.2.2. 
Important Potential Risks with Omalizumab (XOLAIR) 
1.3.2.2.1. Arterial Thromboembolic Events 
In controlled clinical trials and during interim analyses of an observational study, a numerical 
imbalance of arterial thromboembolic events (ATE) was observed. The definition of the 
composite endpoint, ATE, included stroke, transient ischemic attack, myocardial infarction, 
unstable angina, and cardiovascular death (including death from unknown cause). In the final 
analysis of the observational study, the rate of ATE per 1,000 patient-years was 7.52 (115/15, 
286 patient-years) for XOLAIR-treated patients and 5.12 (51/9,963 patient-years) for control 
patients. In a multivariate analysis controlling for available baseline cardiovascular risk factors, 
the hazard ratio was 1.32 (95% CI: 0.91-1.91). In a separate analysis of pooled clinical trials, 
which included all randomized double-blind, placebo-controlled clinical trials lasting 8 or more 
weeks, the rate of ATE per 1,000 patient-years was 2.69 (5/1,856 patient-years) for 
XOLAIR-treated patients and 2.38 (4/1,680 patient-years) for placebo patients (rate ratio: 1.13, 
95% CI: 0.24-5.71). 
1.3.2.2.2. Malignant Neoplasms in Adults and Adolescents ≥12 Years of Age 
Malignant neoplasms were observed in 20 of 4127 (0.5%) XOLAIR-treated patients compared 
with 5 of 2236 (0.2%) control patients in clinical studies of adults and adolescents ≥12 years of 
age with asthma and other allergic disorders. The observed malignancies in XOLAIR-treated 
patients were a variety of types, with breast, non-melanoma skin, prostate, melanoma, and 
parotid occurring more than once, and 5 other types occurring once each. The majority of 
patients were observed for less than 1 year. The impact of longer exposure to XOLAIR or use in 
patients at higher risk for malignancy (eg, elderly, current smokers) is not known. 
In a subsequent observational study of 5007 XOLAIR-treated and 2829 non-XOLAIR-treated 
adolescent and adult patients with moderate to severe persistent asthma and a positive skin test 
reaction or in vitro reactivity to a perennial aeroallergen, patients were followed for up to 
5 years. In this study, the incidence rates of primary malignancies (per 1000 patient-years) were 
similar among XOLAIR-treated (12.3) and non-XOLAIR-treated patients (13.0). However, study 
limitations preclude definitively ruling out a malignancy risk with XOLAIR. 
1.3.3. 
Overall Benefit and Risk Assessment for this Study 
TEV-45779 is a proposed biosimilar to XOLAIR and physiochemical and functional 
characterization has shown similarity between both products. 
All patients in the study will receive active urticaria treatment for 24 weeks, either XOLAIR or 
TEV-45779, which is expected to show no relevant clinical difference in efficacy and safety 
compared to XOLAIR. 
The TEV-45779 and XOLAIR dosing schedule, ie, 300 mg or 150 mg administered as a sc 
injection every 4 weeks, reflects the US recommendation for XOLAIR to treat patients with CSU 
who remain symptomatic despite antihistamine (H1) treatment. In the EU, the 300 mg dose is 
recommended with the same schedule. 
Data from the originator studies show differences between the 300 mg and 150 mg dose of about 
2 score points for the sum of the daily itch severity score for 7 days (ISS7) (Maurer et al 2013). It 
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is expected that this difference will not be considered clinically meaningful, as Mathias et al 
(Mathias et al 2010) estimated a minimally important difference (MID) value of 4.5-5.0 for ISS7. 
Furthermore, patients will be provided with rescue medication for itch relief (diphenhydramine 
hydrochloride, 25 mg, maximum 3 times/day) that patients can take if required. Therefore, all 
patients are likely to derive significant benefit from the urticaria treatment in the clinical study. 
Since TEV-45779 is being developed as a proposed biosimilar to XOLAIR, the risks of 
treatment with TEV-45779 are expected to be similar to the known risks of treatment with 
omalizumab. All study interventions are routine clinical practice for patients with CSU. 
The purpose of the development of biosimilars, and TEV-45779 in particular, is to provide high 
quality biological products to patients, that in turn should result in increased patient access to 
treatment. 
Information regarding risks to patients may be found in the EU SmPC (XOLAIR Summary of 
Product Characteristics 25/10/2021), the XOLAIR USPI (XOLAIR Prescribing Information 
7/2021), and the IB. 
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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Primary and Secondary Study Objectives and Endpoints 
The primary and secondary study objectives and endpoints are: 
Objectives 
Endpoints 
The primary objective of the study is to 
demonstrate biosimilar efficacy of 
TEV-45779 300 mg compared to XOLAIR 
300 mg as determined by change in itch 
severity score of CIU/ CSU in patients 
who remain symptomatic despite 
antihistamine (H1) treatment. 
The primary efficacy endpoint is: 
• 
Change from baseline in the weekly itch severity score 
(ISS7; sum of the daily itch severity score for 7 days) at 
Week 12, TEV-45779 300 mg compared to XOLAIR 
300 mg 
The co-primary objective (for the FDA 
submission only) of the study is to 
demonstrate relative potency of 
TEV-45779 compared to XOLAIR as 
determined by change in itch severity score 
of CIU/CSU in patients who remain 
symptomatic despite antihistamine (H1) 
treatment. 
The co-primary efficacy endpoint is: 
• 
Relative potency of 2 dose levels (300 mg and 150 mg) 
of TEV-45779 and XOLAIR as measured by change 
from baseline in ISS7 at Week 12 using a 4-point assay, 
ie, TEV-45779 300 mg, TEV-45779 150 mg, XOLAIR 
300 mg, and XOLAIR 150 mg. 
Secondary objectives 
 
To compare further efficacy parameters 
between TEV-45779 and XOLAIR. The 
comparisons will be performed between 
the different doses (150 mg vs. 300 mg) as 
well as between TEV-45779 and XOLAIR 
Secondary efficacy endpoints are as follows: 
• 
Change from baseline in ISS7 at Week 12 
• 
Change from baseline in ISS7 at Week 4 
• 
Change from baseline in the weekly urticaria activity 
score (UAS7; sum of the daily number of wheals score 
and itch severity score over 7 days) at Week 12 
• 
Percentage of patients with a UAS7 ≤6 at Week 12 
• 
Percentage of complete responders (UAS7=0) at 
Week 12 
• 
Change from baseline in the physician’s (in-clinic) 
assessment of UAS7 at Week 12 
• 
Change from baseline in the weekly number of wheals 
score at Week 12 
• 
Change from baseline in the weekly size of the largest 
wheals score at Week 12 
• 
Time to MID(reduction from baseline in ISS7 of ≥5 
points) response in ISS7 score by Week 12 
• 
Percentage of ISS7 MID responders at Week 12 
(percentage of patients with reduction of ≥5 points from 
baseline in ISS7 at Week 12) 
• 
Percentage of angioedema-free days from Week 4 to 
Week 12 
• 
Change from baseline in the overall dermatology life 
quality index (DLQI) score at Week 12 
To compare efficacy parameters between 
TEV-45779 and XOLAIR after the switch 
Secondary efficacy endpoints are: 
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Objectives 
Endpoints 
from XOLAIR to TEV-45779. The 
comparisons will be performed between 
the different doses (150 mg vs. 300 mg) as 
well as between TEV-45779 and XOLAIR 
• 
Change from Week 12 in ISS7 at Week 24 
• 
Change from Week 12 in ISS7 at Week 40 
• 
Change from Week 12 in UAS7 at Week 24 
• 
Change from Week 12 in the physician’s (in-clinic) 
assessment of UAS at Week 24 
• 
Change from Week 12 in the weekly number of wheals 
score at Week 24 
• 
Change from Week 12 in the weekly number of wheals 
score at Week 40 
• 
Change from Week 12 in the weekly size of the largest 
wheals score at Week 24 
• 
Change from Week 12 in the weekly size of the largest 
wheals score at Week 40 
• 
Percentage of angioedema-free days from Week 12 to 
Week 24 
• 
Change from Week 12 in the overall DLQI score at 
Week 24 
• 
Change from Week 12 in the overall DLQI score at 
Week 40  
To compare the safety and tolerability 
between TEV-45779 and XOLAIR 
• 
throughout the study 
• 
after the switch from XOLAIR to 
TEV-45779 
The safety/tolerability parameters include: 
• 
Adverse events (and the number of patients who 
withdraw from the study due to adverse events) 
• 
Change from baseline in clinical laboratory 
measurements (serum chemistry, hematology, and 
urinalysis) and vital signs 
• 
Physical examination findings 
• 
Electrocardiogram findings 
• 
Local tolerability at the injection site after each IMP 
administration 
• 
Use of concomitant medication (including use of rescue 
medication) 
• 
Device-related adverse events and malfunctions 
To compare pharmacokinetics between 
TEV-45779 and XOLAIR after multiple 
doses 
The pharmacokinetic parameter is: 
• 
Omalizumab serum concentration before next dose 
(Ctrough) 
• 
Omalizumab serum concentration following last dose at 
Week 24, 28, 32, 36 and 40 
To compare pharmacodynamics between 
TEV-45779 and XOLAIR after multiple 
doses 
The pharmacodynamic parameters are: 
• 
Free IgE serum concentration 
• 
Total IgE serum concentration 
To assess the immunogenicity of 
TEV-45779 in comparison with XOLAIR  
• 
throughout the study  
The immunogenicity parameters are: 
• 
Incidence of patients with a confirmed treatment-related 
ADA positive sample 
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Objectives 
Endpoints 
• 
after the switch from XOLAIR to 
TEV-45779 
• 
For confirmed positive samples, the ADA titer and the 
neutralizing potential will be tested 
2.1.1. 
Primary Estimand: 
The primary estimand for the primary efficacy endpoint for the FDA submission is: 
• The difference in mean change from baseline in ISS7 at Week 12 between 
TEV-45779 300 mg and XOLAIR 300 mg in patients with CIU/CSU who remain 
symptomatic despite antihistamine (H1) treatment, regardless of treatment-related 
adverse events. The treatment policy will be applied to account for the intercurrent 
event of patients discontinuing the treatment early, and patients receiving any 
disallowed concomitant medication between randomization and Week 12 ISS7 
assessment. In order to account for the missing itch severity scores, the following 
strategy will be applied: 
− Daily itch severity score – If either the morning or evening score is missing, the 
available (morning or evening) itch severity score for that day will be used as the 
daily itch severity score, and if both the morning and evening itch severity scores 
are missing, the daily itch severity score will be considered missing. 
− Weekly itch severity score – If 4-7 daily itch severity scores are available for the 
calculation of the weekly score (as defined in “Statistical Considerations” below), 
the ISS7 will be defined as the sum of the available daily itch severity scores in 
that week, divided by the number of days for which a daily itch severity score is 
available, multiplied by 7. If no more than 3 daily itch severity scores are 
available (ie, 4-7 daily scores are missing), the ISS7 will be considered missing 
for that week. 
− Week 12 itch severity score – multiple imputation using the predictive mean 
matching multiple imputation method (Heitjan and Little 1991, Schenker and 
Taylor 1996), under the MAR assumption for each treatment arm separately. 
The primary estimand for the co-primary efficacy endpoint (for the FDA submission) of relative 
potency is: 
• The relative potency of TEV-45779 and XOLAIR as measured by change from 
baseline in ISS7 at Week 12 using a 4-point assay, ie, TEV-45779 300 mg, 
TEV-45779 150 mg, XOLAIR 300 mg, and XOLAIR 150 mg, in patients with 
CIU/CSU who remain symptomatic despite antihistamine (H1) treatment, regardless 
of treatment-related adverse events. The treatment policy will be applied to account 
for the intercurrent event of patients discontinuing the treatment early, and patients 
receiving any disallowed concomitant medication between randomization and 
Week 12 ISS7 assessment. The same rules for the missing daily and weekly itch 
severity score will be applied, as described for the primary endpoint of difference in 
mean change from baseline in weekly ISS7 at Week 12 between TEV-45779 300 mg 
and XOLAIR 300 mg. Missing Week 12 itch severity scores will not be imputed for 
the relative potency analysis. 
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The primary estimand for the primary efficacy endpoint for the EMA submission is: 
• The difference in mean change from baseline in ISS7 at Week 12 between 
TEV-45779 300 mg and XOLAIR 300 mg in patients with CIU/CSU who remain 
symptomatic despite antihistamine (H1) treatment and have a baseline ISS7 
assessment, regardless of treatment-related adverse events. The hypothetical strategy 
will be applied to account for the intercurrent event of patients discontinuing the 
treatment early, and patients receiving any disallowed concomitant medication 
between randomization and Week 12 ISS7 assessment. Thus, any available 
assessments after the intercurrent event should be excluded and imputed. In order to 
account for the missing or excluded itch severity scores the same imputation rules 
will be applied as described for the primary endpoint for the FDA submission. 
2.1.2. 
Justification of Primary Endpoint and Equivalence Margins 
The primary endpoint of the study is the change from baseline in the ISS7 at Week 12 after 
3 treatments of 300 mg of TEV-45779 compared to XOLAIR. This primary endpoint was agreed 
with the FDA and the European Medicines Agency (EMA) as being sensitive enough to confirm 
that there is no relevant clinical difference in efficacy between TEV-45779 and XOLAIR. The 
ISS7 is a reliable, clinically well-established, and reproducible measure of urticaria itch 
symptoms and is considered appropriate to detect potential differences in clinical efficacy since 
the results of the originator studies (Asteria I [Saini et al 2015]); Asteria II [Maurer et al 2013]; 
GLACIAL [Kaplan et al 2013]) showed a clear and dose-dependent treatment response for doses 
of 75, 150, and 300 mg at Week 12 in comparison to placebo treatment, leading to FDA and 
EMA approval. Thus, the graduated response of ISS7 should reflect potential differences in 
potency and clinical efficacy between test and reference product. 
The justification for the equivalence margins chosen for the primary efficacy analysis (±2.0 for 
EMA submission; -2.5, +2.0 for FDA submission; Section 9.5.1.1) is based on the following 
reasoning:  
• The equivalence margin of ±2.0 for this endpoint preserves 50% of the treatment 
effect of XOLAIR based on the lower bound of the 95% CI for the pooled XOLAIR 
treatment effect in placebo-controlled studies (Saini et al 2015, Maurer et al 2013, 
Kaplan et al 2013). 
• Mathias et al (Mathias et al 2015) estimated a minimal important difference of 4.5 to 
5.0 for the ISS7 from clinical data of the mentioned above originator studies 
mentioned above. Therefore, demonstration of similarity within a margin of -2.5, +2.0 
(ISS7 score points) for the comparison of TEV-45779 and XOLAIR ensures that no 
clinically important difference may occur between test and reference product. 
Furthermore, the more negative margin of -2.5 covers a more negative (better) 
treatment effect difference. Thus, the test product may be better in 2.5 score points 
and worse in only 2.0 score points than the reference product if similarity could be 
demonstrated. 
Co-primary endpoint 
The co-primary endpoint for the FDA submission is the relative potency of TEV-45779 and 
XOLAIR (using a 4-point assay with a margin of [0.5, 2.0]), as recommended by the FDA in 
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their written response to the Biological Product Development (BPD) Type 2 meeting (BPD 
Type 2 Meeting Written Responses 2021). 
The inclusion of the 150 mg and 300 mg doses of both products allows: 
1. Comparisons of 150 versus 300 mg to support the assay sensitivity of the study. 
2. Comparisons of TEV-45779 and XOLAIR at both approved doses for CIU. 
3. An evaluation of relative potency between TEV-45779 and XOLAIR. 
These additional evaluations are especially important given the range of doses that are approved 
for asthma and could be used as part of the justification to support extrapolation from CIU to 
asthma. 
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3. 
STUDY DESIGN 
3.1. 
General Study Design and Study Schematic Diagram 
This is a multicenter, randomized, double-blind study to demonstrate similar efficacy and safety 
of TEV-45779 compared to XOLAIR administered sc at doses of 300 mg or 150 mg every 
4 weeks for 24 weeks (6 treatments) in patients with CIU/CSU who remain symptomatic despite 
antihistamine (H1) treatment. This study will consist of a screening period (up to 3 weeks), a 
24-week treatment period consisting of a 12-week double-blind main treatment period and a 
12-week double-blind transition period, which is followed by a 16-week follow-up period. 
The total duration of the study is up to 43 weeks. 
Standard Treatment 
Throughout the entire study, patients should remain on a single H1 antihistamine at stable and 
fixed doses not exceeding label recommendations as the standard treatment regimen. For India, 
Cetirizine is to be used as the single H1 antihistamine at stable and fixed doses, not exceeding 
label recommendations, as a uniform standard treatment regimen, throughout the entire study 
(Appendix T). For the duration of the study, all patients will be provided with diphenhydramine 
hydrochloride (25 mg, maximum 3 times/day) as rescue medication for itch relief. 
Disallowed concomitant treatment includes the use of systemic and topical steroids, H1 
antihistamines at greater than approved doses, H2 antihistamines, LTRAs, hydroxychloroquine, 
methotrexate, cyclosporine, cyclophosphamide, and intravenously-given immunoglobulin. 
Study Treatment 
Patients will receive a total of 6 treatments, resulting in 150 mg or 300 mg sc of IMP 
(TEV-45779 or XOLAIR) as add on therapy every 4 weeks; patients will receive 3 treatments in 
the main treatment period and 3 treatments in the transition period. Patients in the 300 mg groups 
will receive 2 sc injections of 150 mg IMP whereas patients in the 150 mg groups will receive 1 
sc injection of 150 mg IMP and an additional placebo injection in order to administer 2 injections 
per dosing in all groups and, thereby, ensure maintaining of the blind to treatment.  
Main Treatment Period: Following screening, eligible patients will be randomly assigned to 
treatment with TEV-45779 300 mg, XOLAIR 300 mg, TEV-45779 150 mg or XOLAIR 150 mg 
in a 2:2:1:1 ratio on Day 1 of the main treatment period, stratified by baseline ISS7 (<13 vs. 
≥13), and baseline body weight (<80 kg vs. ≥80 kg). 
Transition Treatment Period: At the beginning of the transition period (Week 12), patients in the 
XOLAIR 300 mg and XOLAIR 150 mg groups will be re-randomized 1:1 to either continue with 
XOLAIR treatment (at the same dose level as prior to re-randomization) or transition to 
TEV-45779 (at the same dose level prior to re-randomization) to primarily assess the 
immunogenicity and safety after the transition from XOLAIR to TEV-45779. All patients in the 
TEV-45779 group will continue treatment with TEV-45779 at the same dose level as prior to re-
randomization. 
After the End of Treatment visit (Week 24), all patients will be followed for 16 weeks. 
Patients who complete all scheduled visits will have final procedures and assessments performed 
at the End of Study visit at the end of the follow-up (Week 40). Patients who withdraw from the 
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study before completing the follow-up will have early termination procedures and assessments 
performed at their final visit. 
An Independent Data Monitoring Committee (IDMC) will be established to ensure the 
continuing safety of the study patients during the study (Section 5.9.2). 
The end of study (EoS) is defined as the last visit of the last patient. 
The assessments and procedures performed during each study visit are detailed in Table 1 and 
Appendix B. 
The study schematic diagram is presented in Figure 1. 
Figure 1: 
Overall Study Schematic Diagram 
 
BL=baseline; BL TP=baseline transition period; EoMTP=end of main treatment period; EoS=end of study; 
EoT=end of treatment; ET=early termination, N=number; W=week. 
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3.2. 
Planned Number of Patients and Countries 
Approximately 600 patients (200:200:100:100 to TEV-45779 300 mg, XOLAIR 300 mg, 
TEV-45779 150 mg and XOLAIR 150 mg) will be randomized (also see Appendix S). 
Details on the definition of evaluable patients and sample size are given in Section 9. 
The study is planned to be conducted at approximately 140 investigational sites in approximately 
18 countries in North America, Latin America, Europe, and Asia-Pacific. The study is expected 
to start in quarter Q3 2021 and last until approximately Q2 2024. 
3.3. 
Justification for Study Design and Selection of Population 
The design of the current study in patients with CSU/CIU was agreed with the FDA and EMA 
and is regarded as appropriate to show that there is no clinically meaningful difference in 
efficacy, safety and immunogenicity between TEV-45779 and XOLAIR. 
The study population, as defined by the inclusion and exclusion criteria, is a sensitive and 
homogenous population similar to the population of the clinical studies performed for the 
approval of XOLAIR. The EMA confirmed in the Scientific Advice, Question 9: “The selected 
CSU population is a relatively homogenous population, easier to diagnose, with shorter treatment 
periods, higher effect size and less concomitant medication as compared to asthma patients. 
Hence, it is acceptable to test comparability of TEV-45779 safety and efficacy to XOLAIR in the 
selected CSU population.” (Scientific Advice. Procedure No.: EMEA/H/SA/4461/1/2020/II. 
09/2020). 
Patients in the XOLAIR arm will be re-randomized at their Week 12 visit to either continue with 
XOLAIR or transition to TEV-45779 to assess whether a single transition would result in an 
increased risk in terms of hypersensitivity, immunogenicity, or other reactions. 
3.4. 
Stopping Rules for the Study 
During the conduct of the study, serious adverse events will be reviewed (Section 7.1.5) as they 
are reported from the investigational centers to identify safety concerns. 
The study may be terminated by the sponsor for any reason at any time. For example, the 
sponsor should terminate the study in the event of: 
• New toxicological or pharmacological findings or safety issues invalidate the earlier 
positive benefit-risk assessment. 
• Discontinuation of the development of the IMP. 
• Additional criteria for pausing enrollment and review by the IDMC are: 
− A death for which the cause is judged to be related to the study drug by the 
treating investigator. 
− A life-threatening SAE judged to be related to the study drug by the treating 
investigator. 
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− Any combination of 4 occurrences of Grade 3 or higher (per Common 
Terminology Criteria for Adverse Events [CTCAE] grading) toxicities that are 
assessed to be related to the study drug by the investigator. 
− For the same Preferred Term, 2 occurrences of Grade 3 or higher (per CTCAE 
grading) toxicities that are assessed to be related to the study drug by the 
investigator. 
− Any combination of 4 occurrences of a clinically significant Grade 3 or higher 
(per CTCAE grading) laboratory abnormality for different laboratory parameters 
assessed to be related to the study drug by the investigator. 
− Two occurrences of a clinically significant Grade 3 or higher (per CTCAE 
grading) laboratory abnormality for the same laboratory parameter that are 
assessed to be related to the study drug by investigator.” 
If the whole study or arms of the study will be stopped, the patients that are terminated early will 
be followed according to Withdrawal Criteria and Procedures for the Patient (Section 4.3). 
3.5. 
Schedule of Study Procedures and Assessments 
Study procedures and assessments with their time points are presented in Table 1. Detailed 
descriptions of each method of procedures and assessments are provided in Section 6 (efficacy 
assessments), Section 7 (safety assessments), and Section 8 (pharmacokinetics, 
pharmacodynamics, and immunogenicity). Study procedures and assessments by visit are listed 
in Appendix B. 
Medical history: any medical event relevant to eligibility and further participation should be 
collected and reported in source documents and case report form (CRF) (eg, completely cured 
non-melanoma skin malignancy, hysterectomy, allergic diseases or any other significant medical 
event). 
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Table 1: 
Study Procedures and Assessments 
Study period 
Screening 
Main treatment period 
Transition period 
Follow-up period 
BL 
 
EoMTP/
BL TPa 
 
EoT 
 
EoS/ET 
Visit 
V1b 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
Week 
-2 
-1 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
Day 
-14 
-7 
1 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
Allowed time window (days)c 
-7/+2 
-2 
- 
±3 
±3 
+3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Procedures and assessments 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and surgical historyd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medication and treatment 
history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion 
criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Randomization/ 
Re-randomization 
 
 
X 
 
 
Xe 
 
 
 
 
 
 
 
IMP administrationf, g, h, i 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Local tolerability at injection 
sitej 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Adverse events inquiry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
inquiry, including the use of 
rescue medication 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
COVID-19 inquiry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient Symptom Diary 
(eDiary)k including UAS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Table 1: 
Study Procedures and Assessments (Continued) 
Study period 
Screening 
Main treatment period 
Transition period 
Follow-up period 
BL 
 
EoMTP/
BL TPa 
 
EoT 
 
EoS/ET 
Visit 
V1b 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
Week 
-2 
-1 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
Day 
-14 
-7 
1 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
Allowed time window (days)c 
-7/+2 
-2 
- 
±3 
±3 
+3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Procedures and assessments 
Physician’s (in-clinic) 
assessment of UASl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dermatology Life Quality 
Index (DLQI) 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Physical examinationm 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body weight 
X 
 
X 
 
 
X 
 
 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
Vital signs measurement 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Stool ova and parasite 
evaluation 
 
Xn 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for: 
Free IgE  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Total IgE 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetics 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Table 1: 
Study Procedures and Assessments (Continued) 
Study period 
Screening 
Main treatment period 
Transition period 
Follow-up period 
BL 
 
EoMTP/
BL TPa 
 
EoT 
 
EoS/ET 
Visit 
V1b 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
Week 
-2 
-1 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
Day 
-14 
-7 
1 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
Allowed time window (days)c 
-7/+2 
-2 
- 
±3 
±3 
+3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Procedures and assessments 
Clinical laboratory tests 
(serum chemistry, 
hematology, urinalysis, 
COVID-19)o 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Pregnancy testp 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
ADA evaluationq 
 
 
X 
X 
 
X 
 
 
X 
 
 
 
X 
Rescue medication 
dispensationr 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
a The assessments made at visit 6 (Week 12) before the administration of IMP constitute the end of the main treatment period and the baseline for the transition 
period. 
b The interval between V1 and V2 should be at least 5 days; patients that require a 3-day adjustment period to reach an approved dose of their H1 antihistamine 
treatment will need an interval of at least 8 days. 
c In case of an out-of-window visit, the date of the next visit will be calculated based on the baseline date (V3) or will be scheduled at least 21 days apart. 
d Any medical event relevant to eligibility and further participation should be collected and reported in source documents and CRF (eg, completely cured non-
melanoma skin malignancy, hysterectomy, allergic diseases or any other significant medical event).  
e Patients in the XOLAIR treatment group will be re randomized 1:1 to XOLAIR or switch to TEV-45779. Patients who were initially randomized to 
TEV-45779 will continue to receive TEV-45779, however, to maintain blinding, the re randomization process will be performed for all patients (although only 
patients in the XOLAIR treatment group will actually be re randomized) 
f Assessments scheduled on the day of IMP administration should be completed before IMP administration, except for the assessment of local tolerability at the 
injection site. 
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g IMP will be preferably administered in the front and middle of the thigh area (both injections at least 1 inch (2.5 cm) apart). Alternatively, if injection in the 
thigh is not possible, the injection may be given in the abdomen, avoiding the 2-inch (5 cm) area directly around the navel. The used injection site will be 
documented. 
h All device-related adverse events, malfunctions etc will be recorded; their impact relative to the safety and tolerability of the IMP will be evaluated. 
i If during IMP administration or during the 2-hour post-IMP administration observation the patient develops clinical symptoms or signs, vital signs should be 
collected and a physical examination (brief or full, at the discretion of the investigator) performed. The patient should be assessed for 
anaphylaxis/hypersensitivity reactions as detailed in Section 7.1.6. 
j Assessments will be performed at 20, 60 and 120 minutes after IMP administration and include the assessment of erythema, ecchymosis, induration, 
tenderness, warmth, swelling, and pain at the injection site. 
k Patients receive the electronic Patient Symptom Diary (eDiary) during the V1 (on day −14) visit. It includes the twice daily (morning and evening) assessment 
of the number of wheals (hives) and of the itch severity. Patients must have diary entries during at least 4 of the 7 days prior to randomization on day 1. 
l The physician’s (in clinic) assessment is a non−diary based, in clinic assessment of UAS (itch score + number of wheals [hives] score) based on the patient’s 
condition over 12 hours prior to the visit. It should be completed prior to reviewing the diary entries of the patients and must be completed prior to 
administration of IMP on visits 3 to 8. 
m The V1 (day 14) visit physical examination should be comprehensive while subsequent examinations may be abbreviated to detect changes in symptoms of 
CIU/CSU as well as directed by patient complaints regarding adverse events. 
n The stool ova and parasite evaluation should be performed at the V2 (day 7) visit in patients with an eosinophil count >2 times the ULN on day 14 and risk 
factors for parasitic disease. Stool ova and parasite evaluation will be performed by a local laboratory. In case the stool ova and parasite evaluation needs to be 
done by the central laboratory (for some countries), the test can be done at the V1 visit or at an unscheduled visit shortly after the V1 visit and the preceding 
eosinophil count can be done locally. 
o Additional laboratory parameters, such as FSH and β-HCG (see footnote n) or as applicable (see inclusion criterion c, Section 4.1), may be assessed at 
screening and baseline. COVID-19 testing to be performed at V1. In addition, the patient should be tested at any other time point during the study if the patient 
exhibits clinical symptoms that may indicate COVID-19 infection. COVID-19 testing will be performed locally. At V1, serum chemistry sample in non-fasting 
state may be acceptable. 
p Only for women of childbearing potential. Women will have a urine pregnancy test at screening (visit 2), at the start of the transition period (visit 6) and at EoT 
(visit 9). If the urine pregnancy test result is positive a serum pregnancy test should be performed by the central laboratory. Urine pregnancy tests will be 
performed at the site. 
q If any severe hypersensitivity reaction (eg, anaphylaxis) or immunogenicity-related adverse event (serious or non-serious) is observed, additional sample(s) will 
be collected for immunogenicity assessment as close to the onset of the event as possible, at resolution of the event, and 30 days following the event onset, if 
possible. ADA samples should also be collected for analysis of neutralizing antibodies if treatment related ADA positive samples are detected. When a number 
of assessments are to be conducted at the same time point, the immunogenicity blood sample should be taken after other assessments and before drug 
administration. 
r Dispensation of rescue medication must be done at V1 in amount of maximum dose (3 tablets/day) until V2. At subsequent visits, patients have to return all 
unused rescue medication, the consumption from previous visit should be confirmed, and based on it further dispensation should ensure that subject has 
sufficient rescue medication to cover the period till the next subject visit with a maximum dose. 
ADA=anti-drug antibody; BL=baseline; BL TP=baseline transition period; β-HCG=human chorionic gonadotropin; CIU/CSU=chronic idiopathic 
urticaria/chronic spontaneous urticaria; COVID-19=Coronavirus disease 2019; ECG=electrocardiography; eDiary=electronic Patient Symptom Diary; 
EoMTP=end of main treatment period; EoS=end of study; EoT=end of treatment; ET=early termination; FSH=follicle stimulating hormone; 
IgE=immunoglobulin E; UAS=urticaria activity score; ULN=upper limit of normal; V=visit. 
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4. 
SELECTION AND WITHDRAWAL OF PATIENTS 
Prospective waivers (exceptions) from study inclusion and exclusion criteria to allow patients to 
be randomized/enrolled are not granted by Teva. 
Changes to inclusion or exclusion criteria are indicated below and detailed in Section 16. 
4.1. 
Patient Inclusion Criteria 
Patients may be randomized/enrolled in this study only if they meet all of the following criteria: 
a. Male or female patients aged ≥18 years and ≤75 years. 
b. Diagnosis of CIU/CSU refractory to H1 antihistamines at the time of randomization, 
as defined by all of the following: 
− The presence of itch and wheals for ≥8 consecutive weeks at any time prior to 
enrollment despite current use of H1 antihistamine treatment during this time 
period. 
− Weekly urticaria activity score (UAS7; sum of the daily number of wheals score 
and itch severity score over 7 days) ≥16 (range 0-42) and itch component of 
UAS7 ≥8 (range 0-21) during 7 days prior to randomization.3 
− UAS ≥4 assessed by a clinician on ≥1 of the screening visit days. 
− Patients must have been on an approved dose of an H1 antihistamine for 
CIU/CSU for ≥3 consecutive days immediately prior to the start of screening and 
must document current use on the day of the initial screening visit, OR, have their 
H1 antihistamine for CIU/CSU adjusted to an approved dose during the first 3 
days of screening and have their adjusted use documented at the end of the dose 
adjustment. 
− CIU/CSU diagnosis for ≥3 months.4 
c. Women may be included if they fulfill one of the following criteria: 
− Women of non-childbearing potential who are either surgically (documented 
hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) or congenitally 
sterile as assessed by a physician, or 1-year postmenopausal (no menses for 
12 months without an alternative medical cause plus an increased concentration of 
FSH of more than 35 U/L) in women not using hormonal contraception or 
hormonal replacement therapy. 
− Women of childbearing potential whose male partners are potentially fertile (ie, 
no vasectomy) must: 
○ have a negative β-HCG test result at screening (visit 2); and 
                                                 
3 Refer to Section 9.3.1 for handling of missing data for daily and weekly scores. 
4 Diagnosis or symptoms leading to this diagnosis have to be present for ≥3◦months. 
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○ use highly effective birth control methods for the duration of the study (ie, 
starting at screening) and for 5 half-lives (20 weeks) after last dose of IMP. 
Highly effective birth control methods are methods that can achieve a failure rate of 
less than 1% per year when used consistently and correctly (see such methods in 
Appendix J).  
d. [Revision 1] Male patients (including vasectomized men) with partners who are of 
childbearing potential (whether pregnant or not) must use condoms prior to IMP 
administration and until 20 weeks after last IMP dose. 
e. Must be able to understand the requirements of the study and to provide their written 
informed consent to participate in the study. 
f. Must be willing and able to comply with study requirements and procedures as 
specified in this protocol. In particular, the patient must be willing and able to 
complete a symptom diary twice daily (morning and evening) for the duration of the 
study. The patients must have diary entries during at least 4 of the 7 days prior to 
randomization. 
4.2. 
Patient Exclusion Criteria 
Patients will not be randomized/enrolled in this study if they meet any of the following criteria: 
a. Body weight <40 kg. 
b. Clearly defined underlying etiology for chronic urticarias other than CIU/CSU.5 
c. Evidence of parasitic infection defined as meeting the following 3 criteria: 
− Risk factors for parasitic disease (living in an endemic area, chronic 
gastrointestinal symptoms, travel within the last 6 months to an endemic area 
and/or chronic immunosuppression), and 
− An absolute eosinophil count >2× the ULN, and 
− Evidence of parasitic colonization or infection on stool evaluation for ova and 
parasites. Note that stool ova and parasite evaluation will only be conducted in 
patients with risk factor(s) and an eosinophil count >2× the ULN. 
d. Atopic dermatitis, bullous pemphigoid, dermatitis herpetiformis, senile pruritus, or 
other skin disease associated with itch. 
e. Treatment with an investigational agent within 30 days or longer depending on 
half-life (>5 half-lives) prior to the start of screening. 
f. Previous treatment with omalizumab or other Anti-IgE therapy within a year prior to 
the start of screening. 
                                                 
5 Other chronic urticarias include: acute, solar, cholinergic, heat, cold, aquagenic, delayed pressure, or contact. The 
following diseases should be considered for exclusion as they may have symptoms of urticaria or angioedema: 
urticarial vasculitis, urticaria pigmentosa, erythema multiforme, mastocytosis, hereditary or acquired angioedema, 
lymphoma, leukemia, or generalized cancer. 
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g. Routine (daily or every other day during 5 or more consecutive days) doses of the 
following medications within 30 days prior to start of screening: Systemic or 
cutaneous (topical) corticosteroids (prescription or over-the-counter), 
hydroxychloroquine, methotrexate, cyclosporine, or cyclophosphamide. 
h. Intravenous IgG, or plasmapheresis within 30 days prior to the start of screening. 
i. Regular (daily/every other day) doxepin (oral) use within 2 weeks prior to the start of 
screening. 
j. Any H2 antihistamine use within 7 days prior to the start of screening. 
k. Any LTRA (montelukast or zafirlukast) use within 7 days prior to the start of 
screening. 
l. [Revision 1] Any H1 antihistamines at greater than approved doses use from 3 days 
after the start of screening. 
m. [Revision 1] Current malignancy, history of malignancy within the last 5 years, or 
currently under work-up for suspected malignancy except non-melanoma skin cancer 
that has been treated or excised and is considered resolved. 
n. Hypersensitivity to omalizumab or any component of the formulation. 
o. History of anaphylactic shock. 
p. Contraindications to diphenhydramine hydrochloride 6 
q. Pregnant or lactating woman, or plans to become pregnant during the study. 
r. Presence of clinically significant cardiovascular, neurological, psychiatric, metabolic, 
or other pathological conditions that could interfere with the interpretation of the 
study results and or compromise the safety of the patients.7 
s. Evidence of current drug or alcohol abuse. 
t. Patients taking either LTRAs or H2 blockers for diseases other than CIU (eg, asthma 
or gastroesophageal reflux disease, respectively) will be permitted to continue their 
use during the study. These diseases must be recorded as part of the medical history 
collected during the screening period. Inhaled asthma controllers, including 
corticosteroids, are also permitted during the study. 
                                                 
6 To include: over-reactivity against the agent diphenhydramine hydrochloride, other antihistaminic agents, or other 
components of this agent; acute bronchial asthma; acute angle-closure glaucoma; pheochromocytoma; hyperplasia 
of the prostate gland with formation of residual urine; epilepsy; hypokalemia; hypomagnesemia; bradycardia; 
congenital long QT syndrome or other clinically significant cardiac disorders (especially coronary heart disease, 
disturbances in conduction, arrhythmias); simultaneous application of drugs which prolong the QT interval (eg, 
antiarrhythmic drugs class IA or III, antibiotics, cisapride, malaria drugs, antihistaminic drugs, neuroleptic drugs) 
or lead to hypokalemia (eg, certain diuretic drugs); simultaneous application of monoamine inhibitors; 
simultaneous uptake of alcohol. 
7 To include medical examination or laboratory findings that suggest the possibility of decompensation of 
co-existing conditions for the duration of the study. Any findings must be reviewed with the medical monitor. 
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4.3. 
Withdrawal Criteria and Procedures for the Patient 
Each patient is free to withdraw from the study or discontinue from IMP at any time, without 
prejudice to their continued care. Patients must be withdrawn from the study if any of the 
following events occur: 
1. Patient withdraws consent or requests withdrawal from the study or discontinuation from 
IMP for any reason. 
2. Patient develops an illness that would interfere with his/her continued participation. 
3. Patient is noncompliant with the study procedures and assessments in the opinion of the 
investigator. 
4. Patient takes prohibited concomitant medications as defined in this protocol (see 
Appendix L). Under certain circumstances, a patient may be eligible to remain in the 
study when taking prohibited concomitant medications - such cases should be discussed 
with, and approved by, the medical monitor. 
5. The sponsor requests withdrawal of the patient. 
6. Patients experiencing anaphylaxis (Section 7.1.6) have to be discontinued from IMP.  
7. Patient experiences an adverse event or other medical condition which indicates to the 
investigator that continued participation is not in the best interest of the patient. 
8. A female patient has a confirmation of pregnancy during the study from a positive serum 
pregnancy test. 
Patients who discontinue from IMP while remaining in the study are invited to continue safety 
follow-up per study schedule and to complete the remaining study visits and assessments (with 
the exception of administration of IMP) including the EoS visit within the original time frames 
based on date of randomization. The investigator should determine the reason for and the date of 
discontinuation of study treatment and record this information in both the source documentation 
and the CRF. The patient should not be considered withdrawn from the study due to interruption 
or discontinuation of IMP. 
Patients should be treated with standard of care after withdrawal from or termination of the study 
as appropriate. 
Investigators should attempt to obtain information on patients in the case of withdrawal from the 
study. Results of any evaluations and observations, together with a narrative describing the 
reason(s) for withdrawal from the study, must be recorded in the source documents. The CRF 
must document the primary reason for withdrawal from the study. 
If a patient exhibits clinical symptoms that may indicate Coronavirus disease 2019 (COVID-19) 
infection after entering the study, the patient should be tested for active COVID-19. If the patient 
tests positive for active COVID-19, he/she may continue for scheduled visits when recovered (ie, 
tests negative for active COVID-19), assuming he/she has no protocol violations including use of 
disallowed medications. See Appendix C for information regarding study conduct during 
COVID-19 outbreaks. 
See Appendix K for information regarding how the study will define and address lost to 
follow-up patients to help limit the amount and impact of missing data. 
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If the reason for withdrawal from the study is an adverse event and/or clinically significant 
abnormal laboratory test result, monitoring will be continued as applicable (eg, until the event 
has resolved or stabilized, until the patient is referred to the care of a health care professional, or 
until a determination of a cause unrelated to the IMP/device or study procedure is made). The 
specific event or test result (including repeated test results, as applicable) must be recorded both 
on the source documentation and in the CRF; both the adverse events page and the relevant page 
of the CRF will be completed at that time. 
The patient will be monitored as applicable (eg, until the event has resolved or stabilized, until 
the patient is referred to the care of a health care professional, or until a determination of a cause 
unrelated to the test IMP/device or study procedure is made). The investigator must inform the 
sponsor’s medical expert as soon as possible of each patient who is being considered for 
withdrawal due to adverse events. Additional reports must be provided when requested. 
If a patient is withdrawn from the study for multiple reasons that include also adverse events, the 
relevant page of the CRF should indicate that the withdrawal was related to an adverse event. An 
exception to this requirement will be the occurrence of an adverse event that in the opinion of the 
investigator is not severe enough to warrant discontinuation but that requires the use of a 
prohibited medication, thereby requiring discontinuation of the patient. In such a case, the reason 
for discontinuation would be “need to take a prohibited medication”, not the adverse event. 
In the case of patients lost to follow-up, attempts to contact the patient must be made and 
documented in the patient’s medical records and transcribed to the CRF. 
4.4. 
Replacement of Patients 
A patient who is randomized but does not complete all treatment periods will not be replaced. 
4.5. 
Re-screening 
A patient who is screened but not enrolled (eg, because inclusion and exclusion criteria were not 
met or enrollment did not occur within the specified time) may be considered for re-screening 1 
time if there is a change in the patient’s medical background or other relevant change. (Note: the 
medical monitor should approve re-screening after review of the enabling reasons.) 
If the patient is re-screened, a new informed consent form (ICF) will need to be signed and all 
study assessments will need to be repeated. 
4.6. 
Screening Failure 
Screening failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized in the study. 
Selected information about patients who screen-fail will be collected to comply with reporting 
and publishing requirements. This information may include, but is not limited to, demography, 
screening failure details, eligibility criteria, and any serious adverse events. 
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5. 
TREATMENTS 
Investigational medicinal products (IMPs) in this study include TEV-45779 (omalizumab) 
solution for injection 150 mg/mL PFS (test IMP) and XOLAIR (omalizumab) injection 
(reference IMP). Patients will receive a total of 6 treatments, each consisting of 2 sc injections 
resulting in 150 mg or 300 mg of TEV-45779 or XOLAIR as add-on therapy every 4 weeks. 
Patients will receive 3 treatments in the main treatment period and 3 treatments in the transition 
period. 
Detailed information about the composition of the test IMP and reference IMP can be found in 
the following sections. 
5.1. 
Investigational Medicinal Products Used in the Study 
IMPs are defined as the test IMP (TEV-45779) and reference IMP (XOLAIR). 
5.1.1. 
Test Investigational Medicinal Product 
TEV-45779 (omalizumab) is provided as a sterile, preservative-free, clear to slightly opalescent 
and colorless to pale brownish-yellow solution intended for sc injection. It will be supplied in a 
combination product consisting of a PFS with an integrated needle safety guard for single-use 
administration to mirror the XOLAIR configuration. 
Each PFS of TEV-45779 contains 150 mg TEV-45779 in 1 mL of solution. 
Refer to Table 2 for specific details regarding TEV-45779. Additional details may be found in 
the Pharmacy Manual and the IB for TEV-45779. 
5.1.2. 
Reference Investigational Medicinal Product 
XOLAIR (omalizumab) injection is supplied as a single dose PFS. Each PFS of XOLAIR 
contains 150 mg of omalizumab in 1 mL of solution. 
Refer to Table 2 for specific details regarding XOLAIR. 
5.1.3. 
Placebo Investigational Medicinal Product 
Placebo (no active) to complement TEV-45779 (omalizumab) or XOLAIR (omalizumab) is 
supplied as a single dose PFS. Each PFS of placebo contains 1 mL solution of the same 
composition as the TEV-45779 (omalizumab) and XOLAIR (omalizumab) syringes, but without 
active drug substance. 
Refer to Table 2 for specific details regarding placebo. 
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Table 2: 
Investigational Medicinal Products Used in the Study 
IMP 
Test 
Reference 
Placebo 
IMP name 
TEV-45779  
(omalizumab) 
XOLAIR® 
(omalizumab) 
Injection 
Placebo (no active) 
to complement 
TEV-45779 
(omalizumab) or 
XOLAIR® 
(omalizumab) 
Trade name or 
company-assigned number 
TEV-45779 
XOLAIR 
Placebo 
Formulation 
Active 
150 mg/mL 
150 mg/mL 
NA 
Histidine 
20 mM 
20 mM 
20 mM 
Arginine 
hydrochloride 
200 mM 
200 mM 
200 mM 
Polysorbate 20 
0.04% 
0.04% 
0.04% 
Unit dose strength(s)/Dosage 
level(s) 
150 mg/mL 
150 mg/dose (single sc 
injection) or 
300 mg/dose (2 sc 
injections) 
150 mg/mL 
150 mg/dose (single sc 
injection) or 
300 mg/dose (2 sc 
injections) 
NA 
Route of administration 
sc injection 
sc injection 
sc injection 
Device 
Automatically activated 
needle safety guard 
Automatically activated 
needle safety guard  
Automatically activated 
needle safety guard  
Storage conditions 
2°C to 8°C (36°F to 
46°F), protected from 
direct light and heat. 
Avoid vigorous 
shaking. Do not freeze 
2°C to 8°C (36°F to 
46°F), protected from 
direct light and heat. 
Avoid vigorous 
shaking. Do not freeze 
2°C to 8°C (36°F to 
46°F), protected from 
direct light and heat. 
Avoid vigorous 
shaking. Do not freeze 
Manufacturer 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
EU=European Union; IMP=investigational medicinal product; INN=international nonproprietary name; 
PFS=prefilled syringe; sc=subcutaneous; USA=United States of America. 
5.1.4. 
Medical Devices 
The medical device for TEV-45779, manufactured by Teva and provided for use in this study is: 
• a PFS with an automatically activated needle safety guard for single-use 
administration. 
This automatically activated needle safety guard requires no additional actions by the user to 
shield the needle after use, and thus reduces the potential for accidental needle stick injuries. 
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The medical device for XOLAIR provided for use in this study is: 
• a PFS with automatically activated needle safety guard for single-use administration. 
This automatically activated needle safety guard requires no additional actions by the user to 
shield the needle after use, and thus reduces the potential for accidental needle stick injuries. 
Instructions for use of both devices are provided in the Pharmacy Manual. 
All device-related adverse events, malfunctions, etc. will be recorded; their impact relative to the 
safety and tolerability of the IMP will be evaluated (see Section 7.2 and Appendix O). 
5.2. 
Preparation, Handling, Labeling, Storage, and Accountability for 
Investigational Medicinal Products 
5.2.1. 
Storage and Security 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained for all IMP received and any discrepancies are reported and resolved before use of 
the IMP. 
The IMP (TEV-45779, XOLAIR, and placebo) must be stored at a controlled temperature of 2°C 
to 8°C [36°F to 46°F]) in a secure area (eg, locked refrigerator). The site should have a process 
for monitoring the storage temperature of unused IMP. 
5.2.2. 
Labeling 
Supplies of IMP will be labeled according to the current International Council for Harmonisation 
(ICH) guidelines on Good Clinical Practice (GCP) and Good Manufacturing Practice (GMP) and 
will include any locally required statements. If necessary, labels will be translated into the local 
language. 
5.2.3. 
Accountability 
Each IMP shipment will include a packing slip listing the contents of the shipment, return 
instructions, and any applicable forms. 
The investigator is responsible for ensuring that deliveries of IMP and other study materials from 
the sponsor are correctly received, recorded, handled, and stored safely and properly in 
accordance with the Code of Federal Regulations (CFR) or national and local regulations, and 
used in accordance with this protocol. 
Only patients enrolled in the study may receive IMP and only authorized staff at the 
investigational center may supply or administer IMP. All IMP must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions or appropriate instructions with access limited to the unblinded 
authorized staff (eg, unblinded pharmacist, unblinded designee, IMP administrator) at the 
investigational center. 
The unblinded pharmacist, unblinded designee, or IMP administrator is responsible for IMP 
accountability, reconciliation, and record maintenance (eg, receipt, reconciliation, and final 
disposition records). 
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During the main and transition treatment period, the persons who are involved in receipt, storage, 
distribution, administration, return, and accountability of IMP will be unblinded as the IMPs 
differ in appearance: these persons will not be involved in the conduct of any study procedures or 
assessments. 
A record of IMP accountability (ie, IMP and other study materials received, used, retained, 
returned, or destroyed) must be prepared and signed by the pharmacist, designee, or IMP 
administrator, with an account given for any discrepancies. Empty and partially-used IMP will 
be disposed of on site, and unused IMP can be disposed of on site or returned to Teva or its 
designee. 
Further guidance and information are provided in the Pharmacy Manual. 
5.3. 
Justification for Investigational Medicinal Products 
5.3.1. 
Justification for Dose of Test Investigational Medicinal Product 
The dose of IMP to be evaluated for the primary endpoint in this double-blind study (ie, 300 mg) 
was selected to match the approved dose of XOLAIR for CSU in the EU and CIU in the US, 
respectively. The 150 mg dose required for the evaluation of the relative potency as co-primary 
endpoint (for FDA submission) is approved for CIU in the US as well. 
5.3.2. 
Justification for Use of Reference Investigational Medicinal Product 
As TEV-45779 is being developed as a potential biosimilar to XOLAIR, XOLAIR was selected 
as the reference IMP. 
5.3.3. 
Justification for Use of Placebo Investigational Medicinal Product 
Placebo syringes are only required as a complementary injection to the 150 mg doses of 
TEV-45779 or XOLAIR in order to administer 2 injections per dosing in all groups and, thereby, 
maintain the blinding of patients and investigators regarding the strength of the dose. 
5.4. 
Treatment After the End of the Study 
After study end, no IMP will be provided as XOLAIR is commercially available. Patients should 
be further treated with omalizumab as appropriate. 
5.5. 
Restrictions 
Patients will be required to comply with the restrictions detailed below. 
5.5.1. 
Activity 
Patients must remain seated, semi-recumbent, or supine as needed for assessments or other 
procedures, including dosing. 
Patients will fast overnight prior to the morning of blood sampling for lipid profiling (at V1 non-
fasting state before blood sampling may be acceptable).  
Blood donation is forbidden for the duration of the study. 
There are no additional restrictions in this study. 
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5.6. 
Prior and Concomitant Medication or Therapy 
See Section 4.1 and Section 4.2 for patient inclusion and exclusion criteria. 
Any prior or concomitant medication (including prior CIU/CSU medication), or procedure a 
patient has had from 4 weeks before screening through the end of the study will be recorded in 
the source documentation and in the CRF. Also, any prior intake of IMP and omalizumab (and 
any anti-IgE medications) before screening or treatment with an investigational agent within 30 
days or longer depending on half-life (>5 half-lives) before screening needs to be recorded in the 
source documentation and in the CRF. Trade name and international nonproprietary name (INN) 
(if available), indication, dose, and start and end dates of the administered medication or 
treatment will be recorded. The sponsor will encode all medication and treatment according to 
the World Health Organization (WHO) drug dictionary (WHO Drug). 
The list of prohibited medications and guidance rules are located in Appendix L. 
At each visit at the investigational center after the screening visit (visits 1 and 2), the investigator 
will ask patients whether they have taken any medications, including over-the-counter 
medications, vitamins, or herbal or nutritional supplements, since the previous visit. 
Concomitant medication and treatment will be recorded until the EoS visit (visit 13 
[Week 40±3 days]). 
5.7. 
Procedures for Monitoring Patient Compliance 
The investigator will be responsible for monitoring patient compliance with this protocol from 
the start of the screening period through the transition period. If the investigator or the sponsor 
determines that the patient is not in compliance with the study protocol, the investigator and the 
sponsor should determine whether the patient should be withdrawn from the study. The 
Independent Ethics Committee (IEC)/Institutional Review Board (IRB) should be notified if 
required by local regulation. 
5.8. 
Randomization and Blinding 
This is a randomized, double-blind study. Patients and investigators will remain blinded to IMP 
assignment during the study. 
At baseline, patients will be randomized in a 2:2:1:1 ratio to receive the first 3 doses of 
TEV-45779 300 mg, XOLAIR 300 mg, TEV-45779 150 mg, or XOLAIR 150 mg (main 
treatment period). Patients in the 150 mg groups will receive an additional placebo injection in 
order to administer 2 injections per dosing in all groups and, thereby, ensure maintaining of the 
blind to treatment. At Week 12, prior to receiving their fourth dose of study medication, patients 
in the XOLAIR treatment group will be re-randomized 1:1 to receive 3 additional doses of 
XOLAIR (at the same dose level as prior to re-randomization) or switch to 3 doses of 
TEV-45779 (at the same dose level as prior to re-randomization) for the transition period. All 
patients in the TEV-45779 group will continue to receive TEV-45779 during the transition 
period at the same dose level as prior to re-randomization.  
During the main treatment period, the sponsor, investigators (including other site staff involved 
in study assessments) and patients will be blinded to the treatment assignment of all patients. To 
assure continued blinding to the treatment assignments after the main treatment period, 
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re-randomization will be performed for all patients, including patients in the TEV-45779 group 
(although only patients in the XOLAIR arm will actually be re-randomized while patients in the 
TEV-45779 group will continue to receive TEV-45779 in the transition period). The 
randomization will be implemented using a Randomization and Trial Supply Management 
(RTSM) system. Further details on unblinding during the transition and follow-up periods are 
provided in Section 5.9.1. 
5.9. 
Maintenance of Randomization and Blinding 
5.9.1. 
Blinding and Unblinding 
During the main and transition treatment period, the persons who are involved in receipt, storage, 
distribution, administration, return, and accountability of IMP will be unblinded as the IMPs 
differ in appearance: these persons will not be involved in the conduct of any study procedures or 
assessments. The IMP will be prepared in a separate room by the non-blinded person (eg, 
pharmacist or designee). The blinding will be maintained during the transportation from and to 
the dosing room. Dosing will be performed by a non-blinded staff member in the dosing room. 
The original IMP packaging and syringes should not be visible when the patient or any other 
blinded study team member enters the room. In order to ensure additional patient blinding, a 
blindfold with an additional pillow at chest level (or similar device) will be used during the IMP 
injection as a shield to hide the IMP from the patient. IMP will be preferably administered in the 
front and middle of the thigh area (both injections at least 1 inch (2.5 cm) apart). Alternatively, if 
injection in the thigh is not possible, the injection may be given in the abdomen, avoiding the 2-
inch (5 cm) area directly around the navel. The used injection site will be documented. 
During the main treatment period, the staff responsible for population pharmacokinetics, and/or 
the pharmacokinetics/pharmacodynamics model will be blinded. The staff responsible for the 
pharmacokinetic, pharmacodynamics, and immunogenicity bioanalysis, will remain blinded to 
the subject treatment randomization during the main and transition treatment period. 
During the transition period, investigators (and other site staff involved in study assessments) 
and patients will remain blinded to the randomized treatment of patients who received XOLAIR 
in the main treatment period and are re-randomized for the transition period.  
After last patient last visit and DBL of the main treatment period, the sponsor will unblind the 
treatments for the analysis. Staff responsible for population pharmacokinetics, and/or the 
pharmacokinetics/pharmacodynamics model will receive access to the patient treatment 
randomization of the main treatment period (up to and including week 12; not including fourth 
IMP dose and assessments following the fourth dose). A full CSR may be prepared with all data 
up to week 12 (end of main treatment phase procedures).  
Only after completion of the study (after Week 40), final DBL and formal request to unblind 
from the sponsor statistician, will the study be fully unblinded and analyzed. The results will be 
reported separately in a CSR addendum, including any updates to the safety analysis of the main 
treatment period. If a full CSR is not prepared after the main treatment period, then the full study 
results will be analyzed in a single CSR after end of study. 
In case of an emergency, serious adverse event (see Section 7.1.5), or in cases when knowledge 
of the IMP assignment is needed to make treatment decisions, the investigator may unblind the 
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patient’s IMP assignment as deemed necessary, mainly in emergency situations. Individual 
randomization codes, indicating the IMP assignment for each randomized patient, will be 
available to the investigator(s) or pharmacist(s) at the investigational center via the RTSM, both 
via telephone and internet. Breaking of the treatment code can always be performed by the 
investigator without prior approval by the sponsor; however, the sponsor should be notified 
following the breaking of the treatment code. The patient's assignment should not be revealed to 
the sponsor. 
When a blind is broken for safety reasons, the patient will be withdrawn from the study treatment 
and the event will be recorded on the CRF. The patient will be invited to continue safety follow-
up per study schedule. The circumstances leading to the breaking of the code should be fully 
documented in the investigator’s study files and in the patient’s source documentation. 
Assignment of IMP should not be recorded in any study documents or source document. 
In blinded studies, for an adverse event defined as a suspected unexpected serious adverse 
reaction (SUSAR) (ie, reasonable possibility; see Section 7.1.4), Global Patient Safety and 
Pharmacovigilance (GPSP) may independently request that the blind code be broken (on a 
case-by-case basis) to comply with regulatory requirements. The report will be provided in an 
unblinded manner for regulatory submission. If this occurs, blinding will be maintained for the 
investigator and for other personnel involved in the conduct of the study, and analysis and 
reporting of the data. 
5.9.2. 
Independent Data Monitoring Committee 
During the conduct of this study, an IDMC will review accumulating unblinded safety data on a 
regular basis and ad hoc if needed, as detailed in the IDMC charter, to ensure the continuing 
safety of the study patients. The IDMC may request additional data (eg, efficacy data) if deemed 
necessary. The IDMC will perform a safety review if any of the pausing criteria listed in 
Section 3.4 is met. 
The specific details regarding the IDMC sessions will be outlined in the IDMC charter. 
The IDMC will be composed of 2 independent physicians with expertise in the relevant 
therapeutic field and an independent statistician. 
The IDMC chairperson will communicate with the sponsor in regard to issues resulting from the 
conduct and clinical aspects of the study. The sponsor will work closely with the committee to 
provide the necessary data for review. 
The IDMC will provide recommendations about modifying, stopping, or continuing the study. 
The conduct and specific details regarding the IDMC sessions will be outlined in the IDMC 
charter. 
5.10. 
Total Blood Volume 
The total blood volume to be collected for each patient in this study is approximately 250 mL. 
Details on blood volumes to be collected during the study are provided in the ICF and the 
laboratory manual. 
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6. 
ASSESSMENT OF EFFICACY 
6.1. 
Patient Symptom Diary 
The electronic Patient Symptom Diary (eDiary) including UAS will be performed continuously 
during the study according to the time points detailed in Table 1. 
The eDiary questions will consist of UAS (composite of itch severity score and number of 
wheals score), largest wheal size, rescue medication (diphenhydramine hydrochloride) use, 
angioedema episodes, and calls to doctor or nurse practitioner (see Appendix D). 
The eDiary is to be completed twice a day (morning and evening) by the patient for the duration 
of the study. The eDiary will be given to the patient at the day -14 visit (V1). 
The UAS is a composite eDiary-recorded score with numeric severity intensity ratings on a scale 
of 0-3 (0=none to 3=intense/severe) for (1) the number of wheals (hives); and (2) the intensity of 
the itch (see Appendix E), measured twice daily (morning and evening). The daily UAS is the 
average of the morning and evening scores and the UAS7 is the sum of the daily UAS scores 
over 7 days. 
The primary endpoint, ISS7, is obtained from the eDairy based on the itch severity component. A 
daily itch severity score is calculated as the average of the morning and evening scores. The ISS7 
score is calculated as the sum of the daily itch severity scores over the study days that make up a 
given study week. 
6.2. 
Physician's Assessment of Urticaria Activity Score 
Physician's (in-clinic) assessment of UAS score will be performed at the time points detailed in 
Table 1 using the in-clinic UAS (the maximum achievable score is 6; see Appendix F). It should 
be completed prior to reviewing the diary entries of the patients and must be completed prior to 
administration of IMP on visits 3 to 8. 
The physician, or the person he or she designates, will provide the sum of the score of the 
patient’s urticaria lesions (number of wheals [hives]) and pruritus (itch) reflective of the patient's 
condition over the 12 hours prior to the visit using the rating scale detailed in Appendix F. 
6.3. 
Dermatology Life Quality Index  
The DLQI will be performed at the time points detailed in Table 1. The DLQI consists of 10 
questions concerning patients' perception of the impact of skin diseases on different aspects of 
their health-related quality of life over the last week (Finlay and Khan 1994; further information 
is available at: https://www.cardiff.ac.uk/medicine/resources/quality-of-life-
questionnaires/dermatology-life-quality-index). The DLQI is calculated by adding the score of 
each question, resulting in a maximum of 30 and a minimum of 0. The higher the score, the more 
quality of life is impaired. A score higher than 10 indicates that the patient's life is being severely 
affected by their skin disease. 
6.4. 
Timing and Description of Assessments and Procedures 
Refer to Table 1 for the timing of assessments and procedures. See Appendix B for a detailed 
description of assessments and procedures. 
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7. 
ASSESSMENT OF SAFETY 
In this study, safety will be assessed by qualified study personnel by evaluating reported adverse 
events (including adverse device effects), local tolerability at the injection site, clinical 
laboratory test results, vital signs measurements, ECG findings, physical examination findings, 
and use of concomitant medication. Refer to Table 1 for the timing of assessments and 
procedures. 
Adverse events are categorized by ICH guidelines and adverse device effects are categorized and 
classified according to International Organization for Standardization (ISO) standard 
14155:2011(E). Device deficiencies that are not associated with an adverse event as well as those 
that have the potential to cause a serious adverse event are covered in Appendix O. 
7.1. 
Adverse Events 
7.1.1. 
Definition of an Adverse Event 
An adverse event is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. 
In this study, any adverse event occurring after the patient has signed the ICF through the end of 
the study should be recorded and reported as an adverse event. 
An adverse event can, therefore, be any unfavorable and unintended physical sign, symptom, or 
laboratory parameter that develops or worsens in severity during the course of this study, or 
significant worsening of the disease under study, or of any concurrent disease, whether or not 
considered related to IMP. A new condition or the worsening of a pre-existing condition will be 
considered an adverse event. Stable chronic conditions (such as arthritis) that are present before 
study entry and do not worsen during this study will not be considered adverse events. 
Accordingly, an adverse event can include any of the following: 
• intercurrent illnesses 
• physical injuries 
• events possibly related to concomitant medication 
• significant worsening (change in nature, severity, or frequency) of pre-existing 
conditions 
(Note: A condition recorded as pre-existing that is intermittently symptomatic [eg, 
headache] and that occurs during this study should be recorded as an adverse event) 
• drug interactions 
• events occurring during diagnostic procedures or during any washout phase of this 
study 
• laboratory or diagnostic test abnormalities that result in the withdrawal of the patient 
from the study, are associated with clinical signs and symptoms or a serious adverse 
event, require medical treatment or further diagnostic work-up, or are considered by 
the investigator to be clinically significant. 
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(Note: Abnormal laboratory or diagnostic test results at the screening visit that 
preclude a patient from entering the study or receiving study treatment are not 
considered adverse events.) 
7.1.2. 
Recording and Reporting of Adverse Events 
For recording of adverse events, the study period is defined for each patient as the time period 
from signature of the ICF to the end of the study. The period for reporting treatment-emergent 
adverse events is defined as the period after the first dose of IMP is administered and until the 
end of the study. 
All adverse events that occur during the defined study period must be recorded both on the 
source documentation and the CRF, regardless of the severity of the event or judged relationship 
to the IMP. For serious adverse events, the serious adverse event form must be completed and 
the serious adverse event should be reported within 24 hours of when the investigator becomes 
aware of it (Section 7.1.5.3.1). The investigator does not need to actively monitor patients for 
adverse events after the defined study period. 
At each contact with the patient, the investigator or designee must question the patient about 
adverse events by asking an open-ended question such as “Have you had any unusual symptoms 
or medical problems since the last visit? If yes, please describe.” A precise diagnosis should be 
recorded whenever possible. When such a diagnosis is made, all related signs, symptoms, and 
any test findings will be recorded collectively as a single diagnosis on the CRF and, if it is a 
serious adverse event, on the serious adverse event form. Reported or observed signs and 
symptoms that are not manifestations of a known diagnosis should be reported individually. 
The clinical course of each adverse event will be monitored at suitable intervals until resolved, 
stabilized, or returned to baseline; or until the patient is referred for continued care to a health 
care professional; or until a determination of a cause unrelated to the IMP or study procedure is 
made. 
The onset and end dates, duration (in case of adverse event duration of less than 24 hours), action 
taken regarding IMP, treatment administered, and outcome for each adverse event must be 
recorded both on the source documentation and the CRF. 
The relationship of each adverse event to IMP and study procedures, and the severity and 
seriousness of each adverse event, as judged by the investigator, must be recorded as described 
below. 
Further details are given in the Safety Monitoring Plan. 
7.1.3. 
Severity of an Adverse Event 
The severity of each adverse event, including clinical laboratory adverse events, will be graded 
according to the CTCAE grading scale (Appendix R). 
The severity of each adverse event must be recorded as 1 of the following: 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.  
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• Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL). (Instrumental ADL 
refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc).  
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL (Self-care ADL refer to bathing, dressing and undressing, feeding self, 
using the toilet, taking medications, and not bedridden). 
• Grade 4: Life-threatening consequences; urgent intervention indicated.  
• Grade 5: Death related to adverse event.  
7.1.4. 
Relationship of an Adverse Event to the Investigational Medicinal Product 
The relationship of an adverse event to the IMP will be captured separately. Determination of 
this relationship will be made according to the criteria in Table 3. 
Table 3: 
The Relationship of an Adverse Event to the Investigational Medicinal 
Products 
Term 
Definition 
Clarification 
No reasonable 
possibility 
(not related) 
This category applies to adverse 
events that, after careful 
consideration, are clearly due to 
extraneous causes (disease, 
environment, etc.) or to adverse 
events that, after careful medical 
consideration at the time they are 
evaluated, are judged to be unrelated 
to the IMP. 
The relationship of an adverse event may be considered 
“no reasonable possibility” if it is clearly due to 
extraneous causes or if ≥2 of the following apply: 
• 
It does not follow a reasonable temporal sequence 
from the administration of the IMP. 
• 
It could readily have been produced by the patient’s 
clinical state, environmental or toxic factors, or 
other modes of therapy administered to the patient. 
• 
It does not follow a known pattern of response to 
the IMP. 
• 
It does not reappear or worsen when the IMP is 
re-administered. 
Reasonable 
possibility 
(related) 
This category applies to adverse 
events for which, after careful 
medical consideration at the time 
they are evaluated, a connection 
with the administration of IMP 
cannot be ruled out with certainty. 
The relationship of an adverse event may be considered 
“reasonable possibility” if ≥2 of the following apply: 
• 
It follows a reasonable temporal sequence from 
administration of the IMP. 
• 
It cannot be reasonably explained by the known 
characteristics of the patient’s clinical state, 
environmental or toxic factors, or other modes of 
therapy administered to the patient. 
• 
It disappears or decreases on cessation or reduction 
in dose. There are important exceptions when an 
adverse event does not disappear after 
discontinuation of the IMP, yet an IMP relationship 
clearly exists. 
• 
It follows a known pattern of response to the IMP. 
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7.1.5. 
Serious Adverse Events 
For recording of serious adverse event, the study period is defined for each patient as that time 
period from signature of the ICF to the end of the study. Serious adverse events occurring in a 
patient after the end of the study should be reported to the sponsor if the investigator becomes 
aware of them, following the procedures described in Section 7.1.5.3.1. 
7.1.5.1. 
Definition of a Serious Adverse Event 
A serious adverse event is an adverse event occurring at any dose that results in any of the 
following outcomes or actions: 
• Results in death. 
• Is life-threatening adverse event (ie, the patient was at risk of death at the time of the 
event); it does not refer to an event which hypothetically might have caused death if it 
were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization, which 
means that hospital inpatient admission or prolongation of hospital stay were required 
for treatment of an adverse event, or that they occurred as a consequence of the event. 
• Hospitalizations scheduled before the patient signed the ICF will not be considered 
serious adverse events, unless there was worsening of the pre-existing condition 
during the patient’s participation in this study. 
• Results in persistent or significant disability/incapacity (refers to a substantial 
disruption of one’s ability to conduct normal life functions). 
• Is a congenital anomaly/birth defect. 
• An important medical event that may not result in death, be life-threatening, or 
require hospitalization, but may jeopardize the patient and may require medical 
intervention to prevent one of the outcomes listed in this definition.  
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or the development of drug dependency or drug abuse. Note: Any 
suspected transmission of an infectious agent via a medicinal product is considered an 
important medical event. 
• All occurrences of possible drug-induced liver injury that meet Hy’s law criteria, 
defined as all of the below, must be reported by the investigator to the sponsor as a 
serious adverse event: 
− alanine aminotransferase (ALT) or aspartate aminotransferase (AST) increase of 
>3x the ULN 
− total bilirubin increase of >2x ULN 
− absence of initial findings of cholestasis (ie, no substantial increase of alkaline 
phosphatase [ALP]) 
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An adverse event that does not meet any of the criteria for seriousness listed above will be 
regarded as a non-serious adverse event. 
7.1.5.2. 
Expectedness 
In this study, the reference safety information (RSI) for determination of suspected serious 
adverse reaction is included in the IB. A serious adverse reaction that is not included in the 
relevant RSI by its specificity, severity, outcome, or frequency is considered an unexpected 
adverse reaction.  
The sponsor’s GPSP will determine the expectedness for all serious adverse events. 
For the purpose of SUSAR reporting, the version of the IB at the time of occurrence of the 
SUSAR applies. 
7.1.5.3. 
Reporting a Serious Adverse Event 
7.1.5.3.1. Investigator Responsibility 
To satisfy regulatory requirements, all serious adverse events that occur during the study, 
regardless of judged relationship to administration of the IMP, must be reported to the sponsor 
by the investigator. The event must be reported within 24 hours of when the investigator learns 
about it. Completing the serious adverse event form and reporting the event must not be delayed, 
even if not all the information is available. The investigator does not need to actively monitor 
patients for adverse events once this study has ended. 
Serious adverse events occurring to a patient after the last administration of IMP of that patient 
has ended, should be reported to the sponsor if the investigator becomes aware of them. 
The serious adverse event form should be sent to the local safety officer (LSO) or designee, ie, a 
contract research organization (CRO) in a country without a sponsor LSO (the email address will 
be provided on the serious adverse event report form). 
The following information should be provided to record the event accurately and completely: 
• study number 
• investigator and investigational center identification 
• patient number 
• onset date and detailed description of adverse event 
• investigator’s assessment of the relationship of the adverse event to the IMP (no 
reasonable possibility, reasonable possibility, as described in Table 3) 
Additional information includes: 
• age and sex of patient 
• date of first dose of IMP 
• date and amount of last administered dose of IMP 
• action taken 
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• outcome, if known 
• severity 
• explanation of assessment of relatedness 
• concomitant medication (including doses, routes of administration, and regimens) and 
treatment of the event 
• pertinent laboratory or other diagnostic test data 
• medical history 
• results of dechallenge/rechallenge, if known 
• for an adverse event resulting in death 
− cause of death (whether or not the death was related to IMP) 
− autopsy findings (if available) 
Each report of a serious adverse event will be reviewed and evaluated by the investigator and the 
sponsor to assess the nature of the event and the relationship of the event to the IMP, study 
procedures, and to underlying disease. 
Additional information (follow-up) about any serious adverse event unavailable at the initial 
reporting should be forwarded by the investigator within 24 hours of when it becomes known to 
the same address as the initial report. 
For all countries, the sponsor’s GPSP will distribute the Council for International Organizations 
of Medical Sciences (CIOMS) form/Extensible Markup Language (XML) file or MedWatch of 
serious adverse events to the LSO/CRO for submission to the competent authorities, IEC/IRBs, 
and investigators, according to local regulations. The investigator must ensure that the IEC/IRB 
is also informed of the event, in accordance with national and local regulations. 
The sponsor’s GPSP will submit the XML of SUSARs to the EMA in an unblinded manner, 
when applicable and according to local regulations. Submission of SUSARs to the FDA using 
MedWatch forms is done by the Regulatory Affairs department upon receipt from the LSO. 
In the case of a SUSAR, only the LSO/unblinded personnel from the CRO, site, and sponsor will 
receive the unblinded report for regulatory submission; the others will receive a blinded report. 
7.1.5.3.2. Sponsor Responsibility 
If a serious unexpected adverse event is believed to be related to the IMP or study procedures, 
the sponsor will take appropriate steps to notify all investigators participating in sponsored 
clinical studies of TEV-45779 and the appropriate competent authorities (and IEC/IRB, as 
appropriate). 
In addition to notifying the investigators and competent authorities (and IEC/IRB, as 
appropriate), other action may be required, including the following: 
• altering existing research by modifying the protocol 
• discontinuing or suspending the study 
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• modifying the existing consent form and informing all study participants of new 
findings 
• modifying listings of expected toxicities to include adverse events newly identified as 
related to TEV-45779 
7.1.6. 
Protocol-Defined Adverse Events of Special Interest 
Anaphylaxis will be considered a protocol-defined adverse event of special interest (PDAESI). 
Anaphylaxis is described as highly likely when any 1 of the following 3 criteria based on the 
2006 Joint National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network (NIAID/FAAN) Second Symposium on Anaphylaxis are fulfilled (Sampson et al 
2006): 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, or swollen 
lips-tongue-uvula) and at least 1 of the following: 
− Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced 
peak expiratory function, or hypoxemia). 
− Reduced blood pressure or associated symptoms of end-organ dysfunction (eg, 
hypotonia [collapse], syncope, or incontinence). 
2. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours): 
− Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, or 
swollen lips-tongue-uvula). 
− Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced 
peak expiratory function, or hypoxemia). 
− Reduced blood pressure or associated symptoms (eg, hypotonia [collapse], 
syncope, or incontinence). 
− Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting). 
3. Reduced blood pressure after exposure to known allergen for that patient (minutes to 
several hours): 
− Adults: systolic blood pressure of less than 90 mmHg or greater than 30% 
decrease from that person’s baseline. 
The process for reporting this PDAESI is the same as that for reporting a serious adverse event 
(see Section 7.1.5.3). 
In the event of suspected anaphylaxis while the patient is at the site during the 2-hour 
observation period following drug administration, vital signs should be collected and a physical 
examination (brief or full, at the discretion of the investigator) performed. Blood samples to test 
omalizumab serum concentration and ADA formation should be collected if possible. Collection 
of blood samples to test tryptase and/or histamine levels is encouraged if available locally at the 
time of the suspected hypersensitivity event. Other assessments may be performed at the 
discretion of the investigator. As a precaution, each site should have a resuscitation 
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medication/equipment (at a minimum according to local regulations) nearby. Information about 
all suspected anaphylaxis and hypersensitivity events will be recorded on the Suspected 
Anaphylaxis CRF, which is based on the 2006 Joint NIAID/FAAN Second Symposium on 
Anaphylaxis (Sampson et al 2006).  
Patients should be instructed to contact the investigator or seek appropriate medical support (eg, 
in an emergency room) should they experience any signs or symptoms indicative of anaphylaxis 
after leaving the site.  
7.1.7. 
Protocol Deviations Because of an Adverse Event 
If a patient experiences an adverse event or medical emergency, deviations from the protocol 
may be allowed on a case-by-case basis. To ensure patient safety, after the event has stabilized or 
treatment has been administered (or both), the investigator or other physician in attendance must 
contact the CRO medical monitor as soon as possible to discuss the situation. The investigator, in 
consultation with the sponsor, will decide whether the patient should continue to participate in 
the study. 
7.2. 
Adverse Device Effects 
An adverse device effect is an adverse event related to the use of an investigational medical 
device or a combination product. This includes adverse events resulting from insufficient or 
inadequate instructions for use, deployment, implantation, installation, operation, or any 
malfunction of the investigational medical device, including any event resulting from user error 
or from intentional misuse of the investigational medical device.  
Device deficiencies that are not associated with an adverse event as well as those that have the 
potential to cause a serious adverse event are covered in Appendix O. 
7.2.1. 
Adverse Device Effect Reporting 
Adverse device effects (Figure 2) must be recorded both on the source documentation and the 
CRF. 
All adverse device effects shall be reviewed by the investigator, the medical monitor, and the 
sponsor. The investigator and sponsor will record all relevant information regarding every 
adverse device effect/serious adverse device effect and will categorize each as guided in 
Section 7.2.2.1. 
The investigator should make an initial determination if the adverse event may be related to a 
device deficiency.  
Adverse device effects and device deficiencies will be listed in the CSR. 
7.2.2. 
Serious Adverse Device Effects 
A serious adverse device effect is an adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event (Section 7.1.5.1). 
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7.2.2.1. 
Serious Adverse Device Effect Reporting 
The investigator will report to the sponsor, without unjustified delay, all serious adverse device 
effects (within 24 hours); this information shall be promptly followed by detailed written reports 
as described below. 
The process and contact details for serious adverse device effect reporting are the same as for 
serious adverse event reporting provided in Section 7.1.5.3. 
Events shall be reported to the IEC/IRB by the investigator and to the regulatory authorities by 
the sponsor using the appropriate form according to the national and local regulations. 
Figure 2: 
Decision Tree for Adverse Events and Adverse Device Effects Classification 
AE
NO
YES
YES
YES
NO
AE
ADE
• 
Record both on the source documentation and the CRF 
(section 7.2.1)
• 
Report the device deficiency according to Appendix O
SAE
NO
SADE
• 
Notify Teva and IEC/IRB according to the process 
outlined in section 7.2.2.1
• 
Report the device deficiency according to Appendix O
Initial determination 
per Appendix O: Could 
the SAE be related to 
the device?
Initial determination 
per Appendix O: Could 
the AE be related to the 
device?
Does it meet the 
serious criteria? 
 
AE=adverse event; ADE=adverse device effect; CRF=case report form; IEC=Institutional ethics committee; 
IRB=Institutional Review Board; SADE=serious adverse device effect; SAE=serious adverse event. 
7.3. 
Pregnancy 
Any female patient becoming pregnant during the study will discontinue IMP and will be 
discontinued from the study. 
All pregnancies of women participating in the study and female partners of men participating in 
the study, if applicable, that occur during the study, or within 5 half-lives after the last dose or 
30 days after EoS, are to be reported within 24 hours to the physician identified in the Clinical 
Study Personnel Contact Information section of this protocol, and the investigator must provide 
the sponsor (LSO/CRO) with the completed pregnancy form. The process for reporting a 
pregnancy is the same as that for reporting a serious adverse event but using the pregnancy form 
(Section 7.1.5.3). 
The investigator is not required to report patients who are found to be pregnant between 
screening (visit 1) and baseline (visit 3), provided no study drug (IMP) administrations were 
applied. These patients will be considered as screen failures. 
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All female patients (or female partners of men participating in the study) who become pregnant 
will be monitored for the outcome of the pregnancy (including spontaneous, elective, or 
voluntary abortion). Female partners of men participating in the study who become pregnant will 
be asked to sign an ICF. If the pregnancy continues to term, the outcome (health of the infant up 
to 8 weeks of age), including details of birth and presence or absence of any birth defect, 
congenital abnormalities, or maternal and newborn complications, will be reported to the 
sponsor. Any complication of pregnancy during the study and any complication of pregnancy 
that the investigator becomes aware of after withdrawal from the study, will be reported as an 
adverse event or serious adverse event, as appropriate. 
If the pregnancy in a woman participating in the study and/or the female partner of a man 
participating in the study does not continue to term, one of the following actions will be taken: 
• For a spontaneous abortion, report as a serious adverse event. 
• For an elective abortion due to developmental anomalies, report as a serious adverse 
event. 
• For an elective abortion not due to developmental anomalies, report on the pregnancy 
form; do not report as an adverse event. 
7.4. 
Medication Error and Special Situations Related to the 
Investigational Medicinal Products 
Any administration of IMP that is not in accordance with the study protocol should be reported 
in the patient's source documents, regardless of whether or not an adverse event occurs as a 
result. When meeting important protocol deviation criteria, all instances of incorrect IMP 
administration should be categorized as “Non-Compliance to IMP.” 
The following are types of medication errors and special situations: 
• Medication error: Any unintentional error in the prescribing, dispensing, or 
administration of a medicinal product while in the control of the healthcare 
professional, patient, or consumer. 
• Overdose: Administration of a quantity of a medicinal product given per 
administration or cumulatively which is above the maximum recommended dose 
according to the authorized product information. Clinical judgment should always be 
applied. Any dose of IMP (whether the test IMP, reference IMP, or placebo IMP), 
whether taken intentionally or unintentionally, in excess of that prescribed must be 
immediately reported to the sponsor. 
• Misuse: Situations where the IMP is intentionally and inappropriately used not in 
accordance with the authorized product information. 
• Abuse: Persistent or sporadic, intentional excessive use of IMP which is accompanied 
by harmful physical or psychological effects. 
• Occupational exposure: Exposure to an IMP, as a result of one’s professional or 
non-professional occupation. 
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7.5. 
Clinical Laboratory Tests 
All clinical laboratory test results outside of the reference range will be judged by the 
investigator as belonging to one of the following categories: 
• abnormal and not clinically significant 
• abnormal and clinically significant 
A laboratory test result that is judged by the investigator as clinically significant will be recorded 
both on the source documentation and the CRF as an adverse event (except at the initial 
screening visit, which will be captured as medical history), and monitored as described in 
Section 7.1.2. A laboratory or diagnostic test abnormality (once confirmed by repeated testing) 
that results in the withdrawal of the patient from the study, the temporary or permanent 
withdrawal of IMP or medical treatment, or further diagnostic work-up may be considered 
adverse events. If further diagnostic work-up of abnormal laboratory results leads to the 
investigator concluding that the initial abnormality was not clinically significant, it is at the 
investigator's discretion whether or not the result triggering the work-up is an adverse event. 
(Note: Abnormal laboratory or diagnostic test results at the screening visit that preclude a patient 
from entering the study or receiving IMP are not considered adverse events.) 
Details of clinical laboratory tests will be included in the study reference manual. 
7.5.1. 
Serum Chemistry, Hematology, and Urinalysis 
Clinical laboratory tests (serum chemistry, hematology, and urinalysis) will be performed at the 
time points detailed in Table 1. Clinical laboratory tests will be performed using the central 
laboratory (see Appendix A). Specific laboratory tests to be performed are listed in Table 4. 
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Table 4: 
Clinical Laboratory Tests 
Serum chemistry 
Hematology 
Urinalysis 
• 
calcium 
• 
phosphate 
• 
sodium 
• 
potassium 
• 
chloride 
• 
bicarbonate or carbon dioxide 
• 
glucose 
• 
blood urea nitrogen (BUN) 
• 
creatinine 
• 
total cholesterol (low density 
lipoprotein [LDL] and high 
density lipoprotein [HDL]) 
• 
triglycerides (after overnight 
fasting) 
• 
uric acid 
• 
alanine aminotransferase (ALT) 
• 
aspartate aminotransferase 
(AST) 
• 
lactic dehydrogenase (LDH) 
• 
gamma glutamyl transpeptidase 
(GGT) 
• 
alkaline phosphatase (ALP) 
• 
creatine phosphokinase (CPK) 
• 
total protein 
• 
albumin 
• 
total bilirubin 
• hemoglobin 
• hematocrit 
• red blood cell (RBC) count 
• RBC indices 
• platelet count 
• absolute neutrophil count (ANC) 
• white blood cell (WBC) count and 
differential count 
− 
neutrophils 
− 
lymphocytes 
− 
eosinophils 
− 
monocytes 
− 
basophils 
− 
atypical lymphocytes 
• 
coagulation tests 
− 
international normalized ratio 
(INR) 
− 
prothrombin time (PT) 
− partial thromboplastin time 
(PTT) 
• protein 
• glucose 
• ketones 
• blood (hemoglobin) 
• pH 
• nitrates 
• specific gravity 
• microscopic 
− 
bacteria 
− 
RBCs 
− 
WBCs 
− 
casts 
− crystals 
7.5.2. 
Other Clinical Laboratory Tests 
7.5.2.1. 
Human Chorionic Gonadotropin Tests 
Urine β-HCG tests will be performed for all women of childbearing potential at screening 
(visit 2), visit 6 and visit 9. If the urine pregnancy test result is positive a serum pregnancy test 
should be performed by the central laboratory. 
7.5.2.2. 
Follicle Stimulating Hormone 
At screening, women will have a serum FSH assessment, as applicable, to confirm 
postmenopausal status. 
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7.5.2.3. 
Coronavirus Disease 2019 Testing 
COVID-19 testing will be performed at screening (V1). In addition, the patient should be tested 
at any other time point during the study if the patient exhibits clinical symptoms that may 
indicate COVID-19 infection. 
COVID-19 testing will be performed locally and reported in the CRF. 
7.6. 
Physical Examinations 
Physical examinations will be performed at the time points detailed in Table 1. 
A comprehensive physical examination will include, at a minimum, head, eyes, ears, nose, and 
throat (HEENT), chest, cardiovascular, abdominal, and skin examination. An abbreviated 
physical examination will include, at a minimum, chest, cardiovascular, abdomen, and skin 
examinations. 
Any physical examination finding that is judged by the investigator as clinically significant 
(except at the initial screening visit, which will be captured as medical history) may be 
considered an adverse event, recorded on the CRF, and monitored as described in Section 7.1.2. 
7.7. 
Height and Weight 
Height (in centimeters) and weight (in kilograms) will be measured at the time points detailed in 
Table 1. 
7.8. 
Vital Signs 
Vital signs (pulse rate, blood pressure [systolic/diastolic], and respiratory rate) will be measured 
at the time points detailed in Table 1. All vital sign results outside of the reference ranges will be 
judged by the investigator as belonging to one of the following categories: 
• abnormal and not clinically significant 
• abnormal and clinically significant 
Before blood pressure and pulse are measured, the patient must rest in a supine or seated position 
for at least 5 minutes. The same position and arm should be used each time vital signs are 
measured for a given patient. For any abnormal vital sign value, the measurement should be 
repeated as soon as possible. Any vital sign value that is judged by the investigator as clinically 
significant will be recorded both on the source documentation and the CRF as an adverse event, 
and monitored as described in Section 7.1.2. 
7.9. 
Electrocardiography 
A 12-lead ECG will be recorded at the time points detailed in Table 1. 
Standard ECGs parameters will be recorded and the ECG will be interpreted locally by the 
principal investigator (or qualified physician). All ECG results outside of the reference ranges 
will be judged by the investigator (or qualified physician) as belonging to one of the following 
categories: 
• abnormal and not clinically significant 
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• abnormal and clinically significant 
Any ECG finding that is judged by the investigator (or qualified physician) as clinically 
significant (except at the screening visit) will be considered an adverse event, recorded on the 
source documentation and in the CRF, and monitored as described in Section 7.1.2. 
7.10. 
Assessment of Local Tolerability and Pain 
Local tolerability at the injection site (erythema, ecchymosis, induration, tenderness, warmth, 
swelling, and pain) will be assessed using standardized scales. Patient-reported pain at the 
injection site will be reported using a standardized 11-point pain intensity numerical response 
scale (NRS-11) where 0 is “No pain” and 10 is “Worst possible pain”; patients will be asked to 
respond to the following question: “How much pain do you feel at the drug injection site, where 
0 is ‘No pain’ and 10 is ‘Worst possible pain’?”. 
The assessments will be performed at 20, 60, and 120 minutes after dosing (Table 1). 
Severity of local tolerability symptoms should be assessed as described in Table 5. Erythema, 
ecchymosis, and induration will be considered only if they reach a diameter of at least 5 mm. 
The surface diameter in millimeters should be recorded. Induration must be assessed by careful 
superficial palpation avoiding pressuring or squeezing the injection site. 
In the case that symptoms do not resolve, assessments will proceed at each ambulatory visit. 
Appropriate treatment may be provided if necessary, in which case it must be recorded as 
concomitant medication. In case the site(s) of injection need visual representation, in addition to 
comments in the source documents, the injection site(s) may also be photographed along with a 
metric ruler and patient identification number for later review. Any features that could be used to 
identify the patient will not be captured on the photograph. 
Table 5: 
Severity Assessment of Local Tolerability 
Test 
Response 
Erythema 
Absent 
Erythema surface diameter 5 mm to ≤50 mm (mild) 
Erythema surface diameter >50 to ≤100 mm (moderate) 
Erythema surface diameter >100 mm (severe) 
Ecchymosis 
Absent 
Ecchymosis surface diameter 5 mm to ≤50 mm (mild) 
Ecchymosis surface diameter >50 to ≤100 mm (moderate) 
Ecchymosis surface diameter >100 mm (severe) 
Induration 
Absent 
Induration surface diameter 5 mm to ≤50 mm (mild) 
Induration surface diameter >50 to ≤100 mm (moderate) 
Indurations surface diameter >100 mm (severe) 
Tenderness 
Warmth 
Swelling 
None 
Mild 
Moderate 
Severe 
Injection site findings will not be captured as adverse events unless they fulfill characteristics that are beyond those 
in the specified forms/scales (eg, necrosis, abscess, etc) or fulfill seriousness criteria and then they must be recorded 
and reported as specified in Section 7.1. 
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8. 
ASSESSMENT OF PHARMACOKINETICS, 
PHARMACODYNAMICS, AND IMMUNOGENICITY 
8.1. 
Pharmacokinetic Assessment 
Blood samples (4 mL) will be collected via venipuncture before drug administration at the time 
points detailed in Table 1 for measurements of serum concentration of omalizumab. The dates 
and times of IMP administration and the date and time point (24 hour clock time) of each 
pharmacokinetic sample, will be recorded both on the source documentation and the CRF. 
Samples will be analyzed for concentration of TEV-45779 and XOLAIR using validated 
methods. 
Details on sample handling, storage, shipment, and analysis are given in Appendix M. 
8.2. 
Pharmacodynamics Assessment 
Blood samples (4 mL) for assessment of free IgE serum concentration and blood samples (4 mL) 
for assessment of total IgE serum concentration will be taken before drug administration at the 
time points indicated in Table 1. The dates and times of IMP administration and the date and 
timepoint of each pharmacodynamic sample, will be recorded both on the source documentation 
and the CRF. Analysis for the measurement of total IgE and free IgE will be performed by the 
sponsor bioanalytical laboratory (GBT) using validated methods. 
Details on sample handling, storage, shipment, and analysis are given in Appendix M. 
8.3. 
Immunogenicity Testing 
Two blood samples (5 mL each) for assessment of ADA response will be taken before drug 
administration at the time points indicated in Table 1. 
Additionally, if any severe hypersensitivity reaction (eg, anaphylaxis) or immunogenicity-related 
adverse event (serious or non-serious) is observed, additional sample(s) will be collected for 
immunogenicity assessment as close to the onset of the event as possible, at resolution of the 
event, and 30 days following the event onset, if possible. ADA samples should also be collected 
for analysis of neutralizing antibodies if treatment-related ADA-positive samples are detected. 
When a number of assessments are to be conducted at the same time point, the immunogenicity 
blood sample should be taken after other assessments and before drug administration at the 
relevant time point. The dates and times of IMP administration and the date and time point of 
each immunogenicity sample, will be recorded both on the source documentation and the CRF. 
The detection and characterization of antibodies to TEV-45779 and XOLAIR will be performed 
using validated methods by or under the supervision of the sponsor. 
Samples may be stored if permitted by the ICF and local regulations after the last patient’s last 
visit for the study at a facility selected by the sponsor, to enable further analysis of immune 
responses to TEV-45779. 
Details on sample handling, storage, shipment, and analysis are given in Appendix N. 
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9. 
STATISTICS 
This section describes the statistical analysis as foreseen at the time of planning the study. 
Changes, additions, and further details about the analyses will be described in the statistical 
analysis plan (SAP). After finalization of the SAP, any additional analyses or changes to 
analyses that may be required will be fully disclosed in the clinical study report (CSR). 
The statistical analysis of the study is planned to assess the biosimilarity (efficacy and safety) 
between TEV-45779 and XOLAIR, and to support the safety and immunogenicity assessment of 
a single switch from XOLAIR to TEV-45779. 
9.1. 
Sample Size and Power Considerations 
A sample size of 600 evaluable patients, randomized 2:2:1:1 to TEV-45779 300 mg, XOLAIR 
300 mg, TEV-45779 150 mg, or XOLAIR 150 mg, will provide: 
• 
 power (marginal, ie, regardless of other endpoints) to demonstrate biosimilarity 
of efficacy based on the difference in change from baseline in ISS7 at Week 12 using 
90% CI 
between the TEV-45779 and XOLAIR 
300 mg arms (200 patients per arm), 
 
. 
• 
 power (marginal) to demonstrate biosimilarity of efficacy based on the 
difference in change from baseline in ISS7 at Week 12 using 95% CI 
 
between the TEV-45779 and XOLAIR 300 mg arms (200 patients 
per arm), 
 
 
• 
 power to demonstrate biosimilarity of efficacy based on the difference in change 
from baseline in ISS7 score at Week 12 using 90% CI 
 
 between the TEV-45779 and XOLAIR 300 mg arms (200 patients 
per arm), 
 
 
 
 
 
• 
 power (
) for the co-primary endpoint of 
relative potency of TEV-45779 and XOLAIR as measured by change from baseline in 
ISS7 at Week 12 using a 4-point assay, 
 
 (TEV-45779 and XOLAIR at 300 mg and 150 mg). 
• 
 
 
Power assessment for the co-primary endpoint of relative potency of TEV-45779 and XOLAIR, 
as measured by change from baseline in ISS7 at Week 12 using a 4-point assay, was performed 
using the analysis method and the SAS code described in Vezzoli (2011) and simulations based 
on innovator studies data. The method is detailed in Section 9.5.1.1.1. 
For the simulations, the response of change from baseline in ISS7 at Week 12 was assumed to 
be 
 for XOLAIR 150 mg and 
 for XOLAIR 300 mg. 
 
 
 
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9.2. 
Analysis Sets 
9.2.1. 
Intent-to-Treat Analysis Set 
The intent-to-treat (ITT) analysis set will include all randomized patients. 
In the ITT analysis set, treatment will be assigned based on the treatment to which patients were 
randomized, regardless of which treatment they actually received. 
9.2.2. 
Modified Intent-to-Treat Analysis Set 
The modified intent-to-treat (mITT) analysis set will include all randomized patients who 
received at least 1 dose of IMP and have a non-missing baseline ISS7. 
In the mITT analysis set, treatment will be assigned based on the treatment to which patients 
were randomized, regardless of which treatment they actually received. 
9.2.3. 
Modified Intent-to-Treat 1 Analysis Set  
The mITT1 analysis set will include all randomized patients who received at least 1 dose of IMP 
and have a non-missing ISS7 at baseline and Week 12. 
In the mITT1 analysis set, treatment will be assigned based on the treatment to which patients 
were randomized, regardless of which treatment they actually received. 
9.2.4. 
Transition Intent-to-Treat Analysis Set 
The transition intent-to-treat (TITT) analysis set will include all patients randomized in the 
transition period. 
In the TITT analysis set, treatment will be assigned based on the treatment to which patients 
were randomized in the main and transition treatment periods, regardless of which treatment they 
actually received. 
9.2.5. 
Transition Period Modified Intent-to-Treat Analysis Set 
The transition period modified intent to treat (TmITT) analysis set will include all patients from 
the mITT analysis set who received IMP at Week 12, and have a non-missing ISS7 at Week 12. 
In the TmITT analysis set, treatment will be assigned based on the treatment to which patients 
were randomized in the main treatment period and in the transition period, regardless of which 
treatment they actually received. 
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9.2.6. 
Transition Period Modified Intent-to-Treat 1 Analysis Set  
The TmITT1 analysis set will include all patients from the mITT1 analysis set who received IMP 
at Week 12, and have a non-missing ISS7 at Week 24. 
In the TmITT1 analysis set, treatment will be assigned based on the treatment to which patients 
were randomized in the main treatment period and in the transition period, regardless of which 
treatment they actually received. 
9.2.7. 
Safety Analysis Set 
The safety analysis set will include all randomized patients who received at least 1 dose of IMP. 
In the safety analysis set, treatment will be assigned based on the treatment patients actually 
received, regardless of the treatment to which they were randomized, unless otherwise specified. 
Rules for assignment of treatment in case of actual treatment error will be provided in the SAP. 
9.2.8. 
Transition Period Safety Analysis Set 
The transition period safety analysis set will include all patients who received the IMP at 
Week 12. 
In the transition period safety analysis set, treatment will be assigned based upon the treatment 
patients actually received during the main treatment and transition period, regardless of the 
treatment to which they were randomized. 
9.2.9. 
Per-Protocol Analysis Set 
The per protocol (PP) analysis set is a subset of the mITT analysis set that includes only patients 
who remained on treatment up to and including Week 8 (ie, received all 3 doses in the main 
treatment period), did not receive any disallowed concomitant medication after randomization up 
to and including Week 12, had a non-missing ISS7 at Week 12, and completed the main 
treatment period without any major protocol deviations that may impact the itch severity score 
biosimilarity assessments, in particular, received the correct randomized treatment. 
The exclusion of patients from the PP analysis set will be discussed on a case-by-case basis and 
documented prior to DBL and unblinding of the main treatment period for the analysis. 
9.2.10. 
Pharmacokinetic Analysis Set 
The pharmacokinetic analysis set will include those patients from the safety analysis set who 
have omalizumab serum concentration data for at least 1 time point. 
9.3. 
Data Handling Conventions 
For all descriptive statistics, only the observed data from the patients will be used. 
9.3.1. 
Handling Withdrawals and Missing Data 
Data imputation is planned for the primary endpoint analysis, see Section 9.5 for details. The 
missing assessments (either due to withdrawal from the study or for other reasons) are assumed 
to be missing at random (MAR) in this primary analysis. The ITT analysis set will be used for 
the primary analysis. 
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To account for missing itch severity, wheal or urticarial activity scores, the following strategy 
will be applied: 
− Daily score – If either the morning or evening score is missing, the available 
(morning or evening) score for that day will be used as the daily score, and if both 
the morning and evening scores are missing, the daily score will be considered 
missing. 
− Weekly score – If 4-7 daily scores are available for the calculation of the weekly 
score, the ISS7 will be defined as the sum of the available daily scores in that 
week, divided by the number of days for which a daily score is available, 
multiplied by 7. If no more than 3 daily scores are available (ie, 4-7 daily scores 
are missing), the ISS7 will be considered missing for that week. 
Underlying assumptions are that the drop-out rate prior to Week 12 will be similar in both 
treatment groups, and that drop-outs are not related to efficacy. As both treatment groups are 
active, improvement in the underlying disease should be similar between groups and so these 
assumptions are considered reasonable. The assumption that drop-out rates are comparable 
between the treatment groups will be assessed using descriptive statistics (see Section 9.4.1). 
In the primary analysis, missing ISS7 at Week 12 will be imputed based on post-baseline 
assessments using multiple imputation under the MAR assumption (see Section 9.5.1.1); this is a 
conservative approach for similarity testing, as missing data will be imputed within each 
treatment group separately. 
The imputation methodology is reliable as long as the missing ISS7 rate (ie, percentage of 
patients with missing ISS7) at Week 12 is low. Sensitivity and supplementary analyses for 
missing data in the primary analysis are presented in Section 9.5.1.2 and Section 9.5.1.3. 
For all the other variables, only the observed data from the patients will be used in the statistical 
analyses, ie, there is no plan to estimate missing data, unless otherwise specified. 
9.4. 
Study Population 
The ITT analysis set (Section 9.2) will be used for all study population summaries unless 
otherwise specified. Summaries will be presented by treatment group and for all patients. 
9.4.1. 
Patient Disposition 
The number of patients screened, patients screened but not randomized, and patients in the main 
treatment period and the transition period will be summarized using descriptive statistics. 
For the main treatment period, the summary will include: patients randomized (ITT analysis set), 
patients in the mITT, mITT1, safety, PK, and PP analysis sets, patients that withdraw up to 
Week 12, patients that withdraw after Week 12 and patients that complete the main treatment 
period. 
For the transition period, the summary will include: patients randomized (TITT analysis set), 
patients in the TmITT and transition safety analysis sets, patients that withdraw during the 
transition period, and patients that complete the study. 
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Data from patients who withdraw from the study will also be summarized by reason for 
withdrawal as recorded in the disposition CRF using descriptive statistics.  
If more than 10% of the patients withdraw from the study before the end of the main treatment 
period, Kaplan Meier curves for the number of days until study discontinuation will be plotted by 
treatment group. In case of imbalances in withdrawal rates between treatment groups, further 
analysis of any differences with respect to baseline characteristics may be conducted as deemed 
necessary. 
9.4.2. 
Demographic and Baseline Characteristics 
Patient demographic and baseline characteristics, including but not limited to, medical history, 
prior medications and therapies, will be examined by treatment group and will be summarized 
using descriptive statistics based on the ITT, mITT and mITT1 analysis sets, as applicable. 
Generally, for continuous variables, descriptive statistics (number [n], mean, SD, median, 
minimum, and maximum) will be provided. For categorical variables, patient counts and 
percentages will be provided. Categories for missing data will be presented if necessary. 
9.5. 
Efficacy Analysis 
The ITT analysis set will be used as the primary analysis set for efficacy in the main treatment 
period. Supplementary analysis will be carried out using the mITT, mITT1 and PP analysis sets. 
The TITT analysis set will be used as the primary analysis set for efficacy in the transition 
period. The efficacy analyses in the transition period will be based on the TITT, TmITT and 
TmITT1 analysis sets, as applicable. 
9.5.1. 
Primary Endpoint 
The primary endpoint is the change from baseline in the ISS7 at Week 12 in the 
TEV-45779 300 mg and XOLAIR 300 mg arms. 
The co-primary efficacy endpoint (for the FDA submission only) is the relative potency of 
TEV-45779 and XOLAIR as measured by change from baseline in ISS7 at Week 12 using a 
4-point assay, ie, TEV-45779 300 mg, TEV-45779 150 mg, XOLAIR 300 mg, and 
XOLAIR 150 mg. 
9.5.1.1. 
Primary Efficacy Analysis 
Itch severity is recorded twice daily (morning and evening) in the patient's symptom diary, on a 
scale of 0 (none) to 3 (severe). A daily itch severity score is calculated as the average of the 
morning and evening scores. A weekly itch severity (ISS7) score is calculated as the sum of the 
daily itch severity scores over the study days that make up a given study week. If at least 1 daily 
itch severity score is missing or if a given study week is shorter than 7 days (ie, if a treatment 
visit occurs earlier or later, the study week before or after the treatment visit, respectively, would 
be shorter), the approach for handling the missing data will be similar to the one used by the 
originator (see Section 2.1.1). Multiple imputation will be used for the missing ISS7 at Week 12 
for the analysis of change from baseline (see Section 9.5.1.1.2 for details).  
For the FDA submission, the following analyses will be considered co-primary: 
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• The analysis of change from baseline in the ISS7 at Week 12 will be an analysis of 
covariance (ANCOVA) with treatment group (2 levels: TEV-45779 300 mg and 
XOLAIR 300 mg), baseline itch severity score, baseline weight and region (3 levels 
planned: Americas, Europe and Asia-Pacific) as covariates. Biosimilarity will be 
demonstrated if the 90% CI for the mean difference between TEV-45779 300 mg and 
XOLAIR 300 mg falls entirely within the asymmetric equivalence margin of 
(-2.5, +2.0).  
• The analysis of relative potency of TEV-45779 and XOLAIR as measured by change 
from baseline in ISS7 at Week 12 using a 4-point assay, ie, TEV-45779 300 mg, 
TEV-45779 150 mg, XOLAIR 300 mg, and XOLAIR 150 mg using a multi-step 
process. Relative potency will be demonstrated if the 90% CI for relative potency 
estimated as outlined below falls entirely within the equivalence margins of (0.5, 2). 
For the EMA submission, the following analysis will be considered primary: 
• The analysis of change from baseline in the ISS7 at Week 12 will be an ANCOVA 
with treatment group (2 levels: TEV-45779 300 mg and XOLAIR 300 mg), baseline 
itch severity score, baseline weight and region (3 levels planned: Americas, Europe 
and Asia-Pacific) as covariates. Biosimilarity will be demonstrated if the 95% CI for 
the mean difference between TEV-45779 300 mg and XOLAIR 300 mg falls entirely 
within the equivalence margin of (-2.0, +2.0). 
The primary analyses will be based on the ITT analysis set (see Section 9.2.1).  
9.5.1.1.1. Relative Potency 
The relative potency of the test product to the reference product is defined as the dose of the test 
product that produces the same biological response as 1 unit of the dose of the reference product. 
The analysis of relative potency of TEV-45779 and XOLAIR will be performed using a 4-point 
assay, based on the 300 mg and 150 mg dose levels of each product. The methodology will be 
applied as presented in Vezzoli (2011) using the SAS code from the same source. If we define 
𝑋𝑇 and 𝑋𝑅 as the doses of TEV-45779 and XOLAIR producing the same response, then the 
relative potency is given by 𝜌=
𝑋𝑇
𝑋𝑅. Based on this definition, if relative potency is: 
• <1, then a dose of the test produces the same result as does a higher dose of the 
reference (test is more potent). 
• =1, then the 2 products produce the same result at the same dose (test and reference 
are equipotent). 
• >1, then a dose of the test produces the same result as does a lower dose of the 
reference (test is less potent). 
Refer to Appendix G for the technical details regarding relative potency and its CI estimation. 
The estimation of relative potency in a parallel line assay requires the following assumptions to 
hold: 
• Linearity: required but cannot be tested in a 4-point design. 
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• Parallelism: absence of significant deviations from parallelism of dose-response 
curves on the log-dose scale. In case of non-parallel curves a unique value for relative 
potency cannot be assumed. 
• Dose-response relationship: if the slope β is not significantly different from zero, the 
data are consistent with a zero value for β and hence an infinite value for the relative 
potency. 
• No difference between products: the difference between treatments should be 
non-significant. If this assumption does not hold, but relative potency is estimated 
anyway, the estimate obtained is expected to be far from unity. 
The macro to be used for the analysis is described briefly in Appendix G. 
The relative potency 4-point assay will use an ANCOVA model with effect of product (2 levels: 
TEV-45779 and XOLAIR), dose on the log-scale (2 levels: log 150 and log 300), and their 
interaction (4 levels), baseline itch severity score, baseline weight and region (3 levels planned: 
Americas, Europe and Asia-Pacific) as covariates.  
9.5.1.1.2. Missing Week 12 Itch Severity Score Multiple Imputation 
The imputation rules below will be applied according to the region specific estimand. The 
change from baseline in ISS7 at Week 12 will be imputed: 
• per the defined estimand for the FDA submission, for patients having a missing ISS7 at 
Week 12; 
• per the defined estimand for the EMA submission, for patients discontinuing the 
treatment early or using any disallowed concomitant medication between randomization 
and Week 12 ISS7 assessment.  
The change from baseline in ISS7 at Week 12 will be imputed using the predictive mean 
matching multiple imputation method (Heitjan and Little 1991, Schenker and Taylor 1996), 
under the MAR assumption for each treatment arm separately: TEV-45779 300 mg, TEV-45779 
150 mg, XOLAIR 300 mg or XOLAIR 150 mg. The imputation model will include baseline 
ISS7 value, baseline weight and region (3 levels planned: Americas, Europe and Asia-Pacific) as 
covariates. Imputation will use available data from previous post baseline ISS7 scores. The 
resulting complete, imputed datasets will each be analyzed using the same model as the primary 
analysis model, and the resulting statistics combined using methodology provided by Rubin 
(1987) and Little and Rubin (2002). 
Primary analysis of relative potency will use only observed data. 
9.5.1.2. 
Sensitivity Analysis for the Primary Analysis 
To assess the robustness of the primary efficacy analysis using the same estimand (separately for 
each regulatory agency, US and EU), the analyses will include the following sensitivity analyses 
for the statistical model. The analysis of change from baseline in the ISS7 at Week 12 difference 
between TEV-45779 300 mg and XOLAIR 300 mg will use the same predefined confidence 
level and equivalence margins as in the primary analysis, according to region, US or EU: 
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• Change from baseline in the ISS7 at Week 12 difference between TEV-45779 300 mg 
and XOLAIR 300 mg: 
− primary model, but with a single factor of treatment group 
− primary analysis using mixed-model-for-repeated-measures (MMRM), with 
additional fixed effects of week (as a categorical variable with 3 levels: Weeks 4, 
8, and 12) and treatment group by week interaction as well as patient as a random 
effect. The rules for imputation of the missing/excluded ISS7 at each week will be 
applied as defined for Week 12 in the primary analysis 
The following sensitivity analysis will be performed for the 4-points relative potency between 
TEV-45779 and XOLAIR  
− The ANCOVA model in the %RELPOT macro run without baseline covariates 
9.5.1.3. 
Supplementary Analysis for the Primary Analysis 
Analyses for assumptions on missing data: 
• tipping point (missing-not-at-random, MNAR) 
In order to assess the sensitivity of the primary analysis to the MAR assumption on 
missing data, supplementary analysis for the primary analysis will be conducted using 
multiple imputation under different MNAR assumptions. In this sensitivity analysis, 
missing data for change from baseline in the ISS7 at Week 12 will be imputed 
similarly to the primary analysis, except that in step 2 the monotone imputation model 
will be adjusted to different MNAR assumptions:  
− the change from baseline in the ISS7 in patients randomized to TEV-45779 
300 mg with missing ISS7, will be imputed assuming the treatment effect is 
worsened by δ1 compared to the patients who have no missing value (where δ1 = 0 
to 4 or estimated treatment effect of TEV-45779 300 mg group, whichever is 
higher); 
− the change from baseline in the ISS7 in patients randomized to XOLAIR 300 mg 
with missing ISS7, will be imputed assuming the treatment effect is worsened by 
δ2 compared to the patients who have no missing value (where δ1 = 0 to 4 or 
estimated treatment effect of XOLAIR 300 mg group, whichever is higher). 
The resulting complete, imputed datasets will each be analyzed using the same model 
as the primary analysis model, and the resulting statistics combined using 
methodology provided by Rubin (1987) and Little and Rubin (2002). Analysis results 
will be presented for each combination of the worsening factors δ1 and δ2. 
Combinations of the worsening factors that lead to loss of biosimilarity will be 
considered "tipping point". 
• To further alleviate the concern on the uncertainty introduced by missing data, the 
following 2 separate 1-sided tests of alpha=0.05 with missing data imputed under the 
corresponding null using a multiple imputation method will be conducted: 
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− in the first test, missing values for the TEV-45779 300 mg group will be imputed 
assuming the treatment effect has worsened (ie, ISS7 value increased) by the 
upper margin value of 2 compared to the patients who have no missing value, 
while the missing values for the XOLAIR 300 mg group are imputed without 
penalization. Non-inferiority will then be tested by checking that the upper one-
sided 95% confidence limit (equivalently, 2-sided 90% limit) for the mean 
difference TEV-45779 - XOLAIR is less than the margin value of 2;  
− in the second test, missing values for the TEV-45779 300 mg group will be 
imputed assuming the treatment effect improved (ie, ISS7 value decreased) by the 
lower margin value of -2.5 for the FDA submission and -2.0 for the EMA 
submission compared to the patients who have no missing value, while the 
missing values for the XOLAIR 300 mg group are imputed without penalization. 
Non-superiority will then be tested by checking that the lower one-sided 95% 
confidence limit (equivalently, 2-sided 90% limit) for the mean difference TEV-
45779 - XOLAIR is greater than the margin value of -2.5 for the FDA submission 
and -2.0 for the EMA submission.  
The resulting complete, imputed datasets will each be analyzed using the same model 
as the primary analysis model, and the resulting statistics combined using 
methodology provided by Rubin (1987) and Little and Rubin (2002), as in the 
primary analysis. 
• primary analysis repeated on the mITT analysis set. 
Other analyses: 
• primary model repeated for the mITT1 analysis set (see Section 9.2.3) on observed 
data without multiple imputations 
• primary model repeated for the PP analysis set (see Section 9.2.9) on observed data 
without multiple imputations 
• primary model repeated for the ITT analysis set, excluding patients who were 
mistreated by IMP at baseline and/or at later visits till Week 12. 
• primary analysis using MMRM, with additional fixed effects of week (as a 
categorical variable with 3 levels: Weeks 4, 8, and 12) and treatment group by week 
interaction as well as patient as a random effect. No imputation will be carried out for 
this analysis. 
Additional supplementary analyses to address missing data in the relative potency analysis will 
be provided in the SAP. 
9.5.2. 
Secondary Endpoints 
9.5.2.1. 
Secondary Efficacy Endpoints in the Main Treatment Period 
The secondary efficacy endpoints are: 
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• Change from baseline in ISS7 at Week 12 for TEV-45779 150 mg versus 
XOLAIR 150 mg; TEV-45779 300 mg versus TEV-45779 150 mg; XOLAIR 300 mg 
versus XOLAIR 150 mg. 
• Change from baseline in the ISS7 at Week 4, TEV-45779 300 mg vs. XOLAIR 
300 mg. 
• Change from baseline in the UAS7 (sum of the daily number of wheals score and itch 
severity score over 7 days) at Weeks 12. 
• Percentage of patients with a UAS7 ≤6 at Week 12. 
• Percentage of complete responders (UAS7=0) at Week 12. 
• Change from baseline in the physician’s (in-clinic) assessment of UAS7 at Week 12. 
• Change from baseline in the weekly number of wheals score at Week 12. 
• Change from baseline in the weekly size of the largest wheals score at Week 12. 
• Time to MID (reduction from baseline in ISS7 of ≥5 points) response by Week 12. 
• Percentage of ISS7 MID responders at Week 12 (percentage of patients with 
reduction of ≥5 points from baseline in ISS7 at Week 12). 
• Percentage of angioedema-free days from Week 4 to Week 12. 
• Change from baseline in the overall DLQI score at Week 12. 
The comparisons will be made between the different doses used in the study (150 mg vs. 
300 mg) as well as between TEV-45779 and XOLAIR. 
9.5.2.2. 
Secondary Efficacy Endpoints in the Transition Period 
The secondary efficacy endpoints in the transition period are: 
• Change from Week 12 in ISS7 at Week 24. 
• Change from Week 12 in ISS7 at Week 40. 
• Change from Week 12 in UAS7 at Week 24. 
• Change from Week 12 in the physician’s (in-clinic) assessment of UAS at Week 24. 
• Change from Week 12 in the weekly number of wheals score at Week 24. 
• Change from Week 12 in the weekly number of wheals score at Week 40. 
• Change from Week 12 in the weekly size of the largest wheals score at Week 24. 
• Change from Week 12 in the weekly size of the largest wheals score at Week 40. 
• Percentage of angioedema-free days from Week 12 to Week 24. 
• Change from Week 12 in the overall DLQI score at Week 24. 
• Change from Week 12 in the overall DLQI score at Week 40. 
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The comparisons will be made between the different doses used in the study (150 mg vs. 
300 mg) as well as between TEV-45779 and XOLAIR. 
9.5.2.3. 
Secondary Efficacy Analysis 
No formal hypothesis testing is planned for the secondary efficacy and pharmacodynamic 
endpoints. 
Descriptive statistics will be presented by treatment group. For descriptive purposes, 95% CIs for 
the difference in mean (for continuous variables) or proportion (for binary variables) between 
treatment groups will be presented. 
9.5.2.4. 
Efficacy and Pharmacodynamic Analysis in the Transition Period 
Descriptive statistics will be presented by the treatment groups to which the patients were 
assigned in the main treatment and transition periods (TEV-45779/TEV-45779, 
XOLAIR/XOLAIR and XOLAIR/TEV-45779, further subdivided by dose 150 mg or 300 mg). 
In addition, the difference and 95% CI for the difference between the XOLAIR/XOLAIR and 
XOLAIR/TEV-45779 groups at both doses will be presented. 
Free and total IgE will be summarized by treatment and time point using descriptive statistics. 
Individual data will be listed. 
The efficacy analyses in the transition period will be based on the TITT and TmITT analysis sets 
(see Section 9.2.4 and Section 9.2.5), as applicable. 
All efficacy analyses in the transition period are considered descriptive and no formal hypothesis 
testing is planned. 
9.6. 
Multiple Comparisons and Multiplicity 
For the FDA submission, the above efficacy endpoint and the relative-potency endpoint of 
2 dose levels (300 mg and 150 mg) of TEV-45779 and XOLAIR, as measured by change from 
baseline in ISS7 at Week 12, are considered co-primary. The hierarchical approach for the 
2 co-primary endpoints will be applied, meaning that the relative-potency endpoint will be tested 
for biosimilarity only if efficacy similarity is demonstrated for the endpoint of change from 
baseline in ISS7 at Week 12 for TEV-45779 300 mg compared to XOLAIR 300 mg. 
The secondary efficacy analyses will be descriptive in nature, with no predefined control for 
multiplicity. 
9.7. 
Safety Analysis 
Safety analyses will be performed on the safety and transition period safety analyses sets 
(Sections 9.2.7 and 9.2.8, respectively). 
The safety of TEV-45779 and XOLAIR will be assessed throughout the study by evaluating 
adverse events (including device-related adverse events and malfunctions), clinical laboratory 
test results, vital signs measurements, ECG, physical examination results, local tolerability, and 
concomitant medication usage. 
Safety assessments and time points are provided in Table 1. 
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All adverse events will be coded using the MedDRA. Each patient will be counted only once in 
each preferred term or SOC category for the analyses of safety. Summaries will be presented for 
all adverse events (overall and by severity), adverse events determined by the investigator to be 
related to test IMP/device (ie, reasonable possibility) (defined as related or with missing 
relationship) (overall and by severity), serious adverse events, and adverse events causing 
withdrawal from the study. Summaries for the main treatment period, transition period and 
overall treatment period will be presented as indicated below. Patient listings of serious adverse 
events and adverse events leading to withdrawal will be presented. 
Changes in laboratory and vital signs data will be summarized descriptively by treatment period. 
All values will be compared with predefined criteria to identify potentially clinically significant 
values or changes, and such values will be listed. 
The use of concomitant medications will be summarized by therapeutic class using descriptive 
statistics by treatment period. 
For continuous variables, descriptive statistics (n, mean, SD, median, minimum, and maximum) 
will be provided for actual values and changes from baseline to each time point. For categorical 
variables, patient counts and percentages will be provided. Descriptive summaries of serious 
adverse events, patient withdrawals due to adverse events, and potentially clinically significant 
abnormal values (clinical laboratory or vital signs) based on predefined criteria will be provided 
as well by treatment period. 
If any patient dies during the study, a listing of deaths will be provided and all relevant 
information will be discussed in the patient narrative included in the CSR. 
9.7.1. 
Safety Analysis in the Main Treatment Period 
Safety analyses in the main treatment period will be performed on the safety analysis set. 
Summaries will be presented by treatment group (TEV-45779, XOLAIR, further subdivided by 
dose 150 mg or 300 mg) and for all patients. 
All safety variables at the Week 12 visit that are assessed prior to IMP administration will be 
considered as occurring during the main treatment period. 
9.7.2. 
Safety Analysis in the Transition Period 
Safety analyses in the transition period will be performed on the transition period safety analysis 
set (see Section 9.2.8 for definition). Summaries will be presented by the treatment groups to 
which the patients were assigned in the main treatment and transition periods 
(TEV-45779/TEV-45779, XOLAIR/XOLAIR and XOLAIR/TEV-45779, further subdivided by 
dose 150 mg or 300 mg) and for all patients. 
9.7.3. 
Safety Analysis in the Overall Treatment Period 
Safety analyses in the overall treatment period will be performed on the safety analysis set. The 
analyses will include only patients in the TEV-45779/TEV-45779, XOLAIR/XOLAIR treatment 
groups. 
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The analyses will be similar to the analyses of the main treatment period. Summaries will be 
presented by treatment group (TEV-45779, XOLAIR, further subdivided by dose 150 mg or 
300 mg) and for all patients included in the analysis. 
9.8. 
Pharmacokinetic Analysis 
Omalizumab serum concentrations will be summarized by treatment and time point using 
descriptive statistics for all patients who have omalizumab serum concentration data for ≥1 time 
point. 
Individual data will be listed. 
9.9. 
Pharmacodynamic Analysis 
Free and total IgE will be summarized by treatment and time point using descriptive statistics. 
Individual data will be listed. 
9.10. 
Immunogenicity Analysis 
Results of the immunogenicity analysis will be provided by immunogenicity incidence (number 
and percent of ADA positive patients by treatment group), antibody titration and neutralization 
potential by treatment group. 
The safety analysis set will be used for immunogenicity analysis. 
The immunogenicity analysis will be performed after completion of the main treatment period at 
Week 12 for the TEV-45779 and XOLAIR treatment groups, and for TEV-45779 and 
XOLAIR/TEV-45779 treatment groups after the completion of the transition period at Week 24 
and after the follow-up period (EOS) at Week 40. 
Results of immunogenicity assessment will be listed.  
If more than 5 patients develop treatment-related ADA anytime post-baseline, the incidence of 
ADA positive will be summarized by treatment group, and ADA positive/negative, titer level, 
and neutralizing ADA positive/negative will be summarized at each visit using descriptive 
statistics. 
The effect of positive immunogenicity findings on efficacy and safety may be investigated, if 
applicable. 
9.11. 
Planned Interim Analysis 
 No interim analysis is planned for this study.  
9.12. 
Reporting Deviations from the Statistical Plan 
Deviations from the statistical plan, along with the reasons for the deviations, will be described 
in protocol amendments, the SAP, the CSR, or any combination of these, as appropriate, and in 
accordance with applicable national, local, and regional requirements and regulations. 
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10. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Refer to Appendix H for information regarding quality control and quality assurance. This 
includes information about protocol amendments, deviations, responsibilities of the investigator 
to study personnel, study monitoring, and audit and inspection. 
Refer to Appendix O for the definition of a clinical product complaint and investigator 
responsibilities in the management of a clinical product complaint. 
Details are given in the study reference manual. 
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11. 
COMPLIANCE STATEMENT 
This study will be conducted in full accordance with the ICH Harmonised Tripartite Guideline, 
Guideline for GCP E6 and any applicable national and local laws and regulations (eg, Title 21 
Code of Federal Regulations [21CFR] Parts 11, 50, 54, 56, 312, and 314, Directive 2001/20/EC 
of the European Parliament and of the Council on the approximation of the laws, regulations and 
administrative provisions of the Member States relating to the implementation of GCP in the 
conduct of clinical trials on medicinal products for human use). Any episode of noncompliance 
will be documented. 
The investigator is responsible for performing the clinical study in accordance with this protocol 
and the applicable GCP guidelines referenced above for collecting, recording, and reporting the 
data accurately and properly. Agreement of the investigator to conduct and administer this 
clinical study in accordance with the protocol will be documented in separate clinical study 
agreements with the sponsor and other forms as required by national competent authorities in the 
country where each investigational center is located. 
The investigator is responsible for ensuring the privacy, health, and welfare of the patients during 
and after the clinical study; and must ensure that trained personnel are immediately available in 
the event of a medical emergency. The investigator and the involved clinical study personnel 
must be familiar with the background and requirements of the study; and with the properties of 
the IMP as described in the IB or prescribing information. 
The principal investigator at each investigational center has the overall responsibility for the 
conduct and administration of the clinical study at that investigational center and for contacts 
with study management, with the IEC/IRB, and with competent authorities. 
See Appendix I for the ethics expectations of informed consent or assent, competent authorities 
and IEC and IRB, confidentiality regarding study patients, and requirements for registration of 
the clinical study. 
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12. 
DATA MANAGEMENT AND RECORD KEEPING 
See Appendix P for information regarding data management and record keeping. This includes 
direct access to source data and documents, data collection, data quality control, and archiving of 
CRFs and source documents. 
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13. 
FINANCING AND INSURANCE 
A separate clinical study agreement, including a study budget, will be signed between each 
principal investigator and the sponsor (or the CRO designated by the sponsor) before the IMP is 
delivered. 
The patients in this clinical study are insured in accordance with applicable legal provisions. The 
policy coverage is subject to the full policy terms, conditions, extensions, and exclusions. 
Excluded from the insurance coverage are eg, damages to health, and worsening of previous 
existing disease that would have occurred or continued if the patient had not taken part in the 
clinical study. 
The policy of Clinical Trials Insurance will be provided to the investigational centers by the 
sponsor. 
For covered clinical studies (see 21CFR54), the investigator will provide the sponsor with 
financial information required to complete FDA 3454 form. Each investigator will notify the 
sponsor of any relevant changes during the conduct of the study and for 1 year after the study has 
been completed. 
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14. 
PUBLICATION POLICY 
See Appendix Q for information regarding the publication policy. 
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15. 
REFERENCES 
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Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)--a simple practical measure for 
routine clinical use. Clin Exp Dermatol 1994;19(3):210-6. 
Heitjan DF, Little RJA. Multiple Imputation for the Fatal Accident Reporting System. Journal of 
the Royal Statistical Society: Series C (Applied Statistics). 1991;40(1):13–29. 
Kaplan A, Ledford D, Ashby M, Canvin J, Zazzali JL, Conner E, et al. Omalizumab in patients 
with symptomatic chronic idiopathic/spontaneous urticaria despite standard combination therapy. 
J Allergy Clin Immunol 2013;132(1):101-9. 
Kozel MMA, Sabroe RA. Chronic urticaria: Aetiology, management and current and future 
treatment options. Drugs 2004;64(22):2515-36. 
Little RJA, Rubin DB. Statistical Analysis with Missing Data, Second Edition. 2002, New York: 
John Wiley & Sons. 
International Committee of Medical Journal Editors (ICMJE). Recommendations for the 
Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals, 2019. 
Available from: http://www.icmje.org/recommendations/. Accessed 19 November 2020. 
Mathias SD, Dreskin SC, Kaplan A, Saini SS, Spector S, Rosen KE. Development of a daily 
diary for patients with chronic idiopathic urticaria. Ann Allergy Asthma 
Immunol 2010;105(2):142-8. 
Mathias SD, Crosby RD, Rosֳen KE, Zazzali JL. The minimal important difference for measures 
of urticaria disease activity: Updated findings. Allergy Asthma Proc 2015;36(5):394-8. 
Maurer M, Weller K, Bindslev-Jensen C, Giménez-Arnau A, Bousquet PJ, Bousquet J, et al. 
Unmet clinical needs in chronic spontaneous urticaria. A GA2LEN task force report. Allergy. 
2011;66(3):317-30. 
Maurer M, Rosén K, Hsieh H-J, Saini S, Grattan C, Gimenéz-Arnau A, et al. Omalizumab for 
the treatment of chronic idiopathic or spontaneous urticaria. N Engl J Med 2013;368(10):924-35. 
Pelaia G, Gallelli L, Renda T, Romeo P, Busceti MT, Grembiale RD, et al. Update on optimal 
use of omalizumab in management of asthma. J Asthma Allergy 2011;4:49‑59. 
Rivière G, Yeh C, Reynolds C, Brookman L, Kaiser G. Bioequivalence of a novel omalizumab 
solution for injection compared with the standard lyophilized powder formulation. J Bioequiv 
Availab 2011;3(6):144-50. 
Rubin DB. Multiple Imputation for Nonresponse in Surveys. 1987, New York: John Wiley & 
Sons. 
Saini SS, Bindslev-Jensen C, Maurer M, Grob JJ, Baskan EB, Bradley MS, et al. Efficacy and 
safety of omalizumab in patients with chronic idiopathic/spontaneous urticaria who remain 
symptomatic on H1 antihistamines: a randomized, placebo-controlled study. J Invest Dermatol. 
2015;135(1):67-75. 
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100 
Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, 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(2):391-7. 
Scientific Advice Omalizumab (TEV-45779). EMA/CHMP/SAWP/266036/2020. Procedure 
No.: EMEA/H/SA/4461/1/2020/II. Human Medicines Division. 28 May 2020. 
Schenker N, Taylor JMG. Partially Parametric Techniques for Multiple Imputation. 
Computational Statistics & Data Analysis. 1996;22(4):425–46. 
Teva Branded Pharmaceutical Products R&D, Inc. Biosimilar BPD Type 2 Meeting Written 
Responses for TEV-45779. Application Number: 145915. Reference ID: 4654687. 
11 August 2020. 
Teva Branded Pharmaceutical Products R&D, Inc. Biosimilar BPD Type 2 Meeting Written 
Responses for TEV-45779. Application Number: 145915. 19 May 2021. 
Vezzoli S. Estimation of relative potency in a 4-point, parallel line assay. Paper SP01. 
PhUSE 2011. 
Viegas LP, Ferreira MB, Kaplan AP. The maddening itch: an approach to chronic urticaria. 
J Investig Allergol Clin Immunol 2014;24(1):1-5. 
XOLAIR (omalizumab) Injection, for subcutaneous use [US Prescribing Information]; Revised 
7/2021. Jointly marketed by Genentech USA, Inc. and Novartis Pharmaceuticals Corporation. 
XOLAIR Consumer Information. Revised 04/2017. Marketed by Novartis Pharmaceuticals 
Canada Inc. 
XOLAIR Product Monograph. Revised 1/11/2022. Marketed by Novartis Pharmaceuticals 
Canada Inc. 
XOLAIR Summary of Product Characteristics. Revised 25/10/2021. Marketed by Novartis 
Europharm Limited. 
XOLAIR, European Public Assessment Report (EPAR) - Assessment Report 
EMEA/H/C/000606/II/0101, 25 June 2020. Available at: 
https://www.ema.europa.eu/en/documents/variation-report/xolair-h-c-606-ii-0101-epar-
assessment-report-variation_en.pdf. 
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16. 
SUMMARY OF CHANGES TO PROTOCOL 
16.1. 
Amendment 04 Dated 15 February 2023 
The primary reason for this amendment is to clarify details in the Study Protocol; add a method 
for calculating next visit for cases of out-of-window visits, align/clarify inclusion/exclusion 
criteria, and add the information of the Central Clinical Laboratory for India. All major changes 
to the protocol body are listed below in the table and are reflected in the synopsis, as applicable. 
Table 1 (Study Procedures and Assessments) has been revised to reflect changes described 
below. Minor editorial changes (typos, punctuation, etc) have been made to the protocol (and 
protocol synopsis, as appropriate). 
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Original text with changes shown 
New wording 
Reason/Justificat
ion for change 
Sponsor Signature Page - Sponsor’s Authorized Representative 
 
 
 
 
Personnel update 
Section 1.1.2 TEV 45779 and Chronic Idiopathic Urticaria/Chronic Spontaneous Urticaria 
Other sections affected by this change: Section 1.2.2.3 Safety and Immunogenicity, Section 1.3.2 Known and Potential Benefits and Risks of 
Reference Investigational Medicinal Product, Section 1.3.3 Overall Benefit and Risk Assessment for this Study 
XOLAIR Summary of Product Characteristics 
16/12/202125/10/2021 
XOLAIR Summary of Product Characteristics 25/10/2021 
Updated as SmPC 
was revised 
Section 1.2.1 Nonclinical Studies 
Other section affected by this change: Section15 References  
 XOLAIR Product Monograph 8/9/20211/11/2022  
XOLAIR Product Monograph 1/11/2022  
Updated as 
Product 
Monograph was 
revised 
Section 1.2.2 Clinical Studies 
Clinical data for TEV-45779 are available from the pivotal 
pharmacokinetic/pharmacodynamic study TV45779-BE-10160 
(report approval date: 25 November 2021). 
… A blinded interim safety analysis was conducted after 
completion of the Day 29 visit (28 days post dose; cut off date: 19 
April 2021)… 
Clinical data for TEV-45779 are available from the pivotal 
pharmacokinetic/pharmacodynamic study TV45779-BE-10160 
(report approval date: 25 November 2021). 
Clarify study 
report completion 
Section 1.2.2.3 Safety and Immunogenicity 
There were no deaths, other serious adverse events, or withdrawals 
due to adverse events, and no protocol defined adverse events of 
special interest (ie, anaphylaxis) during the study. There were 5 
pregnancy cases reported in the TV45779-BE-10160 study, 3 in the 
TEV-45779 group, 1 in the XOLAIR EU group, and 1 in the 
XOLAIR US group. In 2 cases (1 each in the TEV-45779 and 
XOLAIR US groups), the pregnancy outcome was elective 
termination while in another case in the TEV-45779 group, the 
event of biochemical pregnancy was reported to have no viable 
There were no deaths, other serious adverse events, or withdrawals 
due to adverse events, and no protocol defined adverse events of 
special interest (ie, anaphylaxis) during the study. There were 5 
pregnancy cases reported in the TV45779-BE-10160 study, 3 in 
the TEV-45779 group, 1 in the XOLAIR EU group, and 1 in the 
XOLAIR US group. In 2 cases (1 each in the TEV-45779 and 
XOLAIR US groups), the pregnancy outcome was elective 
termination while in another case in the TEV-45779 group, the 
event of biochemical pregnancy was reported to have no viable 
Update of safety 
information 
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Original text with changes shown 
New wording 
Reason/Justificat
ion for change 
pregnancy. One case in the TEV-45779 group was considered as 
lost to follow up. One serious adverse event of spontaneous 
abortion was reported after completion of the study for a subject 
who received XOLAIR EU.i.e., anaphylaxis). 
 
… Only a small percentage of ADA-positive subjects tested 
positive for neutralizing ADA during the study (1% to 9%), with 
no marked difference between groups. 
pregnancy. One case in the TEV-45779 group was considered as 
lost to follow up. One serious adverse event of spontaneous 
abortion was reported after completion of the study for a subject 
who received XOLAIR EU. 
 
… Only a small percentage of ADA-positive subjects tested 
positive for neutralizing ADA during the study (1% to 9%), with 
no marked difference between groups. 
Section 2.1. Primary and Secondary Study Objectives and Endpoints 
Other sections affected by this change: Section 9.1 Sample Size and Power Considerations, Section 9.5.1 Primary Endpoint, Section 9.5.1.1 Primary 
Efficacy Analysis, Section 9.6 Multiple Comparisons and Multiplicity 
Relative potency of 2 dose levels (300 mg and 150 mg) of 
TEV-45779 and XOLAIR as measured by change from baseline in 
ISS7 at Week 12 using a 4-point assay, ie, TEV-45779 300 mg, 
TEV-45779 150 mg, XOLAIR 300 mg, and XOLAIR 150 mg. 
Relative potency of 2 dose levels (300 mg and 150 mg) of 
TEV-45779 and XOLAIR as measured by change from baseline in 
ISS7 at Week 12 using a 4-point assay, ie, TEV-45779 300 mg, 
TEV-45779 150 mg, XOLAIR 300 mg, and XOLAIR 150 mg 
Clarification 
Section 2.1.1 Primary Estimand 
The relative potency of TEV-45779 and US licensed XOLAIR as 
measured by change from baseline in ISS7 at Week 12 using a 
4-point assay, ie, TEV-45779 300 mg, TEV-45779 150 mg, 
US licensed XOLAIR 300 mg, and US licensed XOLAIR 150 mg, 
in patients with CIU/CSU who remain symptomatic despite 
antihistamine (H1) treatment, regardless of treatment-related 
adverse events… primary endpoint of difference in mean change 
from baseline in weekly ISS7 at Week 12 between TEV-45779 300 
mg and US licensed XOLAIR 300 mg. 
The relative potency of TEV-45779 and XOLAIR as measured by 
change from baseline in ISS7 at Week 12 using a 4-point assay, ie, 
TEV-45779 300 mg, TEV-45779 150 mg, XOLAIR 300 mg, and 
XOLAIR 150 mg, in patients with CIU/CSU who remain 
symptomatic despite antihistamine (H1) treatment, regardless of 
treatment-related adverse events… primary endpoint of difference 
in mean change from baseline in weekly ISS7 at Week 12 between 
TEV-45779 300 mg and XOLAIR 300 mg. 
Deleted as both 
XOLAIR sourced 
from the EU and 
US can be used as 
reference product. 
Section 3.1 General Study Design and Study Schematic Diagram 
Throughout the entire study, patients should remain on a single H1 
antihistamine at stable and fixed doses not exceeding label 
recommendations as the standard treatment regimen. For India, 
Cetirizine is to be used as the single H1 antihistamine at stable and 
fixed doses, not exceeding label recommendations, as a uniform 
standard treatment regimen, throughout the entire study 
(Appendix T). 
Throughout the entire study, patients should remain on a single H1 
antihistamine at stable and fixed doses not exceeding label 
recommendations as the standard treatment regimen. For India, 
Cetirizine is to be used as the single H1 antihistamine at stable and 
fixed doses, not exceeding label recommendations, as a uniform 
standard treatment regimen, throughout the entire study 
(Appendix T). 
Addition of new 
country specific 
information for 
India 
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Original text with changes shown 
New wording 
Reason/Justificat
ion for change 
Section 3.2 Planned Number of Patients and Countries 
Approximately 600 patients (200:200:100:100 to TEV-45779 
300 mg, XOLAIR 300 mg, TEV-45779 150 mg and XOLAIR 
150 mg) will be randomized (also see Appendix S). 
Approximately 600 patients (200:200:100:100 to TEV-45779 
300 mg, XOLAIR 300 mg, TEV-45779 150 mg and XOLAIR 
150 mg) will be randomized (also see Appendix S) 
Cross-link to 
South Korea 
specific study 
information 
The study is expected to start in quarter Q3 2021 and last until 
approximately Q2 2024Q3 2023. 
The study is expected to start in quarter Q3 2021 and last until 
approximately Q2 2024. 
Updated study 
timeline 
according to the 
latest information 
Section 3.5 Schedule of Study Procedures and Assessments 
Other sections affected by this changes: Appendix B Study Procedures and Assessments by Visit 
Table 1 - Rescue medication dispensation 
Rescue 
medication 
dispensati
ons 
X X X X X X X X X X X X  
 
Table 1 - Rescue medication dispensation 
Rescue 
medicatio
n 
dispensati
ont 
X X X X X X X X X X X X  
Corrected table 
information to 
clarify that rescue 
medication is 
dispensed at visits 
1 and visits 2-12 
Table 1 - insert new footnote “c” 
…c  In case of an out-of-window visit, the date of the next visit 
will be calculated based on the baseline date (V3) or will be 
scheduled at least 21 days apart. 
cd Any medical event relevant to eligibility… 
Table 1 - insert new footnote “c” 
… c In case of an out-of-window visit, the date of the next visit 
will be calculated based on the baseline date (V3) or or will be 
scheduled at least 21 days apart. 
d 
Any medical event relevant to eligibility… 
Added method of 
calculating the 
next visit for 
cases of out-of-
window visits.  
Updated footnote 
numbering 
accordingly.  
Table 1 - footnote “o” update 
n o Additional laboratory parameters, such as FSH and β-HCG (see 
footnote kn) or as applicable…performed locally. At V1, serum 
chemistry sample in non-fasting state may be acceptable. 
Table 1 - footnote “o” update 
o Additional laboratory parameters, such as FSH and β-HCG (see 
footnote n) or as applicable… performed locally. At V1, serum 
chemistry sample in non-fasting state may be acceptable. 
Correct incorrect 
footnote reference 
and add 
clarification of 
blood sampling at 
visit 1 
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New wording 
Reason/Justificat
ion for change 
Table 1 - footnote “r” update 
q r Dispensation of rescue medication must be done at V1 in 
amount of maximum dose (3 tablets/day) until V2. At 
subsequentand at other visits, patients have to return all unused 
rescue medication, the consumption from previous visit should be 
confirmed, and based on it further as required; dispensation should 
on other visits will happen as needed to ensure that subject has 
sufficient rescue medication to cover the period till the next subject 
visit at maxwith a maximum dose. 
Table 1 - footnote “r” update 
r 
Dispensation of rescue medication must be done at V1 in 
amount of maximum dose (3 tablets/day) until V2. At subsequent 
visits, patients have to return all unused rescue medication, the 
consumption from previous visit should be confirmed, and based 
on it further dispensation should ensure that subject has sufficient 
rescue medication to cover the period till the next subject visit with 
a maximum dose. 
Clarification on 
dispensation of 
rescue medication 
Section 4 Selection and Withdrawal of Patients 
Not applicable 
Changes to inclusion or exclusion criteria are indicated below and 
detailed in Section 16 
Added to 
emphasize that 
criteria have been 
updated 
Section 4.1 Inclusion Criteria 
Inclusion Criteria “b” 
- CIS/CSU diagnosis for ≥3 months4 
4 Diagnosis or symptoms leading to this diagnosis have to be 
present for ≥3◦months. 
Inclusion Criteria “b” 
- CIS/CSU diagnosis for ≥3 months4 
4 Diagnosis or symptoms leading to this diagnosis have to be 
present for ≥3◦months. 
Added footnote 
for clarification 
on diagnosis 
criteria 
Inclusion Criteria “c” 
Highly effective birth control methods are methods that can 
achieve a failure rate of less than 1% per year when used 
consistently and correctly are considered ( see methods in
Appendix J ). Such methods include: 
○ 
Combined estrogen and progestogen hormonal contraception 
(oral, intravaginal, transdermal) associated with inhibition of 
ovulation; these should be initiated at least 7 days before the first 
dose of IMP. 
○ 
Progestogen only hormonal contraception (oral, injectable, 
implantable) associated with inhibition of ovulation; these should 
be initiated at least 7 days before the first dose of IMP. 
Inclusion Criteria “c” 
Highly effective birth control methods are methods that can 
achieve a failure rate of less than 1% per year when used 
consistently and correctly (see such methods in Appendix J ). 
Referred to 
Appendix J for 
details on birth 
control methods 
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Original text with changes shown 
New wording 
Reason/Justificat
ion for change 
○ 
Intrauterine device and intrauterine hormone releasing system 
need to be in place at least 2 months before the start of screening. 
○ 
Bilateral tubal occlusion or tubal ligation. 
○ 
Vasectomized partner provided he is the sole sexual partner 
and has received medical assessment of the surgical success. 
○ 
Sexual abstinence is only considered a highly effective method 
if defined as refraining from heterosexual intercourse in the defined 
period. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the clinical study and the preferred and 
usual lifestyle of the patient. 
Unacceptable birth control methods: 
○ 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post ovulation methods), and withdrawal are not acceptable 
methods of contraception (according to Medicines and Healthcare 
Products Regulatory Agency). 
Inclusion Criteria “d” 
[Revision 1] Male patients (including vasectomized men) with 
partners who are of childbearing potential (whether pregnant or 
not) must use condoms 
Inclusion Criteria “d” 
[Revision 1] Male patients (including vasectomized men) with 
partners who are of childbearing potential (whether pregnant or 
not) must use condoms 
Clarification that 
criteria was 
revised (ie, “with 
spermicide” 
deleted) during 
protocol 
amendment 3 
Inclusion Criteria “f” 
…In particular, the patient must be willing and able to complete a 
daily symptom diary twice daily (morning and evening) for the 
duration of the study. The patients must have diary entries during 
at least 4 of the 7 days prior to randomization. 
Inclusion Criteria “f” 
…In particular, the patient must be willing and able to complete a 
symptom diary twice daily (morning and evening) for the duration 
of the study. The patients must have diary entries during at least 4 
of the 7 days prior to randomization. 
Clarification on 
eDiary usage  
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Original text with changes shown 
New wording 
Reason/Justificat
ion for change 
Section 4.2 Patient Exclusion Criteria 
Exclusion Criteria “l” 
Revision 1] Any H1 antihistamines at greater than approved doses 
use from 3 days after the start of screening 
Exclusion Criteria “l” 
Revision 1] Any H1 antihistamines at greater than approved doses 
use from 3 days after the start of screening 
Clarification that 
criteria was 
revised (from 
“…within 3 days 
prior…” to 
“…from 3 days 
after…”) during 
protocol 
amendment 3 
Exclusion Criteria “m” 
[Revision 1] Current malignancy, history of malignancy within the 
last 5 years, or currently under work up for suspected malignancy 
except non melanoma skin cancer that has been treated or excised 
and is considered resolved. 
Exclusion Criteria “m” 
[Revision 1] Current malignancy, history of malignancy within the 
last 5 years, or currently under work up for suspected malignancy 
except non melanoma skin cancer that has been treated or excised 
and is considered resolved. 
Clarification of 
exclusion criteria 
to aid with 
enrolment 
Section 4.3 Withdrawal Criteria and Procedures for the Patient 
Patients who discontinue from IMP while remaining in the study 
are invited to continue safety follow-up per study schedule and to 
complete the remaining study visits and assessments encouraged to 
complete end of treatment visit (of the main or transition period as 
applicable) procedures as soon as possible after receiving their last 
dose of IMP and to complete the remaining study visits and 
assessments (with the exception of administration of IMP) 
including the EoS visit within the original time frames based on 
date of randomization. 
Patients who discontinue from IMP while remaining in the study 
are invited to continue safety follow-up per study schedule and to 
complete the remaining study visits and assessments (with the 
exception of administration of IMP) including the EoS visit within 
the original time frames based on date of randomization. 
Clarification for 
patients who 
discontinue from 
IMP 
Section 5.2.3 Accountability 
…area in accordance with the labeled storage conditions or 
appropriate instructions with access limited to the unblinded 
investigator and authorized staff (eg, unblinded pharmacist, 
unblinded designee, IMP administrator) at the investigational 
center. 
The unblinded pharmacist, unblinded designee, or IMP... 
…area in accordance with the labeled storage conditions or 
appropriate instructions with access limited to the unblinded 
authorized staff (eg, unblinded pharmacist, unblinded designee, 
IMP administrator) at the investigational center. 
The unblinded pharmacist, unblinded designee, or IMP... 
Clarification on 
unblinded staff 
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Original text with changes shown 
New wording 
Reason/Justificat
ion for change 
Section 5.5.1 Activity 
Patients will fast overnight prior to the morning of blood sampling 
for lipid profiling (at V1 non-fasting state before blood sampling 
may be acceptable). 
Patients will fast overnight prior to the morning of blood sampling 
for lipid profiling (at V1 non-fasting state before blood sampling 
may be acceptable). 
Clarification of 
blood sampling at 
visit 1 
Section 5.9.1 Blinding and Unblinding 
During the main treatment period, the Sstaff responsible for 
pharmacokinetic and immunogenicity bioanalysis, population 
pharmacokinetics, and/or the pharmacokinetics/pharmacodynamics 
model will be blinded not have access to the patient treatment 
randomization prior to unblinding the study (before final DBL). 
The staff responsible for the pharmacokinetic, pharmacodynamics, 
and immunogenicity bioanalysis, will remain blinded to the subject 
treatment randomization during the main and transition treatment 
period. 
… After last patient last visit and DBL of the main treatment 
period, the sponsor will unblind the treatments for the analysis. 
Staff responsible for population pharmacokinetics, and/or the 
pharmacokinetics/pharmacodynamics model will receive access to 
the patient treatment randomization of the main treatment period 
(up to and including week 12;… 
During the main treatment period, the staff responsible for 
population pharmacokinetics, and/or the 
pharmacokinetics/pharmacodynamics model will be blinded. The 
staff responsible for the pharmacokinetic, pharmacodynamics, and 
immunogenicity bioanalysis, will remain blinded to the subject 
treatment randomization during the main and transition treatment 
period. 
 
…After last patient last visit and DBL of the main treatment 
period, the sponsor will unblind the treatments for the analysis. 
Staff responsible for population pharmacokinetics, and/or the 
pharmacokinetics/pharmacodynamics model will receive access to 
the patient treatment randomization of the main treatment period 
(up to and including week 12;… 
Clarification on 
blinded and 
unblinded staff 
Section 6.1 Patient Symptom Diary 
The eDiary is to be completed twice a day (morning and evening) 
by the patient for the duration of the study. The eDiary will be 
given to the patient at the day -14 visit (V1). 
The eDiary is to be completed twice a day (morning and evening) 
by the patient for the duration of the study. The eDiary will be 
given to the patient at the day -14 visit (V1). 
Clarification on 
eDiary 
distribution and 
usage 
Section 7.3 Pregnancy 
The investigator is not required to report patients who are found to 
be pregnant between screening (visit 1) and baseline (visit 3), 
provided no study drug (IMP) administrations were protocol 
related procedures were applied. These patients will be considered 
as screen failures. 
The investigator is not required to report patients who are found to 
be pregnant between screening (visit 1) and baseline (visit 3), 
provided no study drug (IMP) administrations were applied. These 
patients will be considered as screen failures. 
Clarification on 
reporting of 
patient 
pregnancies 
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Original text with changes shown 
New wording 
Reason/Justificat
ion for change 
Section 7.5 Clinical Laboratory Tests 
A laboratory test result that is judged by the investigator as 
clinically significant will be recorded both on the source 
documentation and the CRF as an adverse event (except at the 
initial screening visit, which will be captured as medical history), 
and monitored as described in Section 7.1.2. 
A laboratory test result that is judged by the investigator as 
clinically significant will be recorded both on the source 
documentation and the CRF as an adverse event (except at the 
initial screening visit, which will be captured as medical history), 
and monitored as described in Section 7.1.2. 
Clarification that 
laboratory tests 
results at initial 
screening visit 
will be recorded 
under medical 
history 
Section 9.5.1.3. Supplementary Analysis for the Primary Analysis 
Section 15 References 
XOLAIR Product Monograph. Revised 1/11/2022. Marketed by 
Novartis Pharmaceuticals Canada Inc. 
XOLAIR Product Monograph. Revised 1/11/2022. Marketed by 
Novartis Pharmaceuticals Canada Inc. 
Updated Product 
Monograph 
information 
Appendix A Clinical Laboratories and Other Departments and Institutions 
Sponsor’s Authorized 
Representative 
  
 
 
  
Teva ratiopharm 
Sponsor’s Authorized 
Representative 
  
 
  
Teva ratiopharm 
 
Update personnel 
information 
Legal Representative of the 
Sponsor in the EU 
Merckle GmbH  
Contact Person: 
 
 
 
  
Merckle GmbH, Teva 
ratiopharm 
Graf-Arco-Strasse 3 
89079 Ulm, Germany 
Tel: 
 
Legal Representative of the 
Sponsor in the EU 
Merckle GmbH  
Contact Person: 
 
 
  
Merckle GmbH, Teva 
ratiopharm 
Graf-Arco-Strasse 3 
89079 Ulm, Germany 
Tel: 
 
 
Update personnel 
information 
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110 
Original text with changes shown 
New wording 
Reason/Justificat
ion for change 
Sponsor’s Medical 
Expert/Contact Point 
Designated by the Sponsor 
for Further Information on 
the Study 
EU Medical Monitor 
 
ICON 
PRA Health Sciences 
Gottlieb-Daimler-Strasse 10 
68165 Mannheim, Germany 
Tel: 
 
Medical monitoring support 
center contact information:  
Americas: 
 
(toll-free) or direct at: 
 
 
EAPA: 
 
 
PRA Health Sciences has 
been acquired by ICON plc, 
creating the world’s most 
advanced healthcare 
intelligence and clinical 
research organization 
 
Sponsor’s Medical 
Expert/Contact Point 
designated by the Sponsor for 
Further Information on the 
Study 
EU Medical Monitor 
 
ICON 
Gottlieb-Daimler-Strasse 10 
68165 Mannheim, Germany 
Tel: 
 
Medical monitoring support 
center contact information:  
Americas: 
 
(toll-free) or direct at: 
 
 
EAPA: 
 
 
 
Update of contact 
information 
Central Clinical Laboratory 
(except India) 
ACM Medical Laboratory, 
Inc. 
160 Elmgrove Park 
Rochester  
New York 14624, USA  
Tel: 
 
Central Clinical Laboratory 
(except India) 
ACM Medical Laboratory, 
Inc. 
160 Elmgrove Park 
Rochester  
New York 14624, USA  
Tel: 
 
Update on 
Clinical 
Laboratory for 
India  
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Study TV45779-IMB-30086 
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Original text with changes shown 
New wording 
Reason/Justificat
ion for change 
Not applicable 
Central Clinical Laboratory 
India 
Metropolis Healthcare Limited 
Plot No. 103 
Road No. 12 
MIDC 
Andheri (E) 
Mumbai – 400 093 
Maharashtra, India 
Addition of 
Central Clinical 
Laboratory for 
India 
Appendix B Study Procedures and Assessments by Visit 
1. Procedures for Screening (Visits 1 and 2, Up to 3-week 
Period) 
a. Visit 1 (Day -14 [ -7/+2 days]) 
• 
dispense and check electronic Patient Symptom Diary 
(eDiary) including UAS 
• 
...clinical laboratory tests: 
− serum chemistry tests (at V1, serum chemistry 
sample in non-fasting state may be acceptable) 
− serum hematology tests… 
1. Procedures for Screening (Visits 1 and 2, Up to 3-week 
Period) 
a. Visit 1 (Day -14 [ -7/+2 days]) 
• 
•dispense electronic Patient Symptom Diary (eDiary) 
• 
…clinical laboratory tests: 
− serum chemistry tests (at V1, serum chemistry 
sample in non-fasting state may be acceptable) 
− serum hematology tests… 
Clarification 
7. Procedures During Follow-up Period (Visits 10 through 13) 
b. Procedures During Visit 13 (day 281 ±3 days) (End of 
Study/Early Termination Visit) 
• 
clinical laboratory tests: 
− 
serum chemistry 
− 
serum hematology 
− 
urinalysis 
• 
obtain blood sample for ADAs 
• 
dispensation of rescue medication (if needed) 
7. Procedures During Follow-up Period (Visits 10 through 13) 
b. Procedures During Visit 13 (day 281 ±3 days) (End of 
Study/Early Termination Visit) 
• 
clinical laboratory tests: 
− 
serum chemistry 
− 
serum hematology 
− 
urinalysis 
• 
obtain blood sample for ADAs 
Updated to be in 
line with Table 1 
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Appendix J Birth Control Methods and Pregnancy Testing 
Highly effective birth control methods in females 
• 
Combined estrogen and progestogen hormonal contraception 
(oral, intravaginal, transdermal) associated with inhibition of 
ovulation; these should be initiated at least 3 months before IMP 
administration 7 days before the first dose of IMP. 
• 
Progestogen-only hormonal contraception (oral, injectable, or 
implantable) associated with inhibition of ovulation; these should 
be initiated at least 3 months before IMP administration 7 days 
before the first dose of IMP. 
• 
Intrauterine device or intrauterine hormone-releasing system 
need to be in place at least 3 months before IMP administration 2 
months before the start of screening. 
• 
Bilateral tubal occlusion (for hysteroscopic "Essure®" a 
hysterosalpingogram is required 3 months post procedure to assess 
surgical success) or tubal ligation. 
• 
Vasectomized partner provided he is the sole sexual partner 
and has received medical assessment of the surgical success. 
Highly effective birth control methods in females 
• 
Combined estrogen and progestogen hormonal contraception 
(oral, intravaginal, transdermal) associated with inhibition of 
ovulation; these should be initiated at least 7 days before the first 
dose of IMP. 
• 
Progestogen-only hormonal contraception (oral, injectable, or 
implantable) associated with inhibition of ovulation; these should 
be initiated at least 7 days before the first dose of IMP. 
• 
Intrauterine device or intrauterine hormone-releasing system 
need to be in place at least 2 months before the start of screening. 
• 
Bilateral tubal occlusion (for hysteroscopic "Essure®" a 
hysterosalpingogram is required 3 months post procedure to assess 
surgical success) or tubal ligation. 
• 
Vasectomized partner provided he is the sole sexual partner 
and has received medical assessment of the surgical success. 
Aligned with 
previous 
information 
included in 
Section 4.1 
Inclusion Criteria 
bullet c. Now 
only refer to 
Appendix J for 
details on birth 
control methods. 
 
Unacceptable birth control methods: 
Periodic abstinence (eg, calendar, symptothermal, post-ovulation 
methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method are not acceptable methods of 
contraception. Female condom and male condom should not be 
used together. 
Male contraception: 
Male patients (including vasectomized men) with if their partners 
are of childbearing potential (whether pregnant or not) must always 
use a condoms prior to IMP administration and until 20 weeks after 
last IMP dose. 
Unacceptable birth control methods: 
Periodic abstinence (eg, calendar, symptothermal, post-ovulation 
methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method are not acceptable methods of 
contraception. Female condom and male condom should not be 
used together. 
Male contraception: 
Male patients (including vasectomized men) with partners of 
childbearing potential (whether pregnant or not) must always use 
condoms prior to IMP administration and until 20 weeks after last 
IMP dose. 
Aligned with 
previous 
information 
included in 
Section 4.1 
Inclusion Criteria 
bullet c. Now 
only refer to 
Appendix J for 
details on birth 
control methods. 
 
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Appendix L List of Prohibited Medications 
…will be discontinued from study treatment; under certain 
circumstances, a patient may be eligible to remain in the study 
when taking prohibited concomitant medications - such cases 
should be discussed with, and approved by, the medical monitor. 
Iif a patient has received… 
…will be discontinued from study treatment; under certain 
circumstances, a patient may be eligible to remain in the study 
when taking prohibited concomitant medications - such cases 
should be discussed with, and approved by, the medical monitor. If 
a patient has received… 
Clarification on 
using concomitant 
medications 
Appendix T Additional Information to the Protocol for India 
Not applicable 
For India, Cetirizine is to be used as the single H1 antihistamine at 
stable and fixed doses, not exceeding label recommendations, as a 
uniform standard treatment regimen, throughout the entire study 
according to Section 3.1. 
New appendix 
added. Country 
specific 
instructions for 
the use of 
H1antihistamine 
in India 
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16.2. 
Administrative Letter 07 Dated 19 December 2022 
 
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16.3. 
Administrative Letter 06 Dated 20 October 2022 
 
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16.4. 
Administrative Letter 05 Dated 01 August 2022 
 
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16.5. 
Amendment 03 Dated 10 May 2022 
The primary reason for this amendment is to clarify details in the Study Protocol: number of 
ADA blood samples, align Inclusion Criterion in the protocol synopsis with those in the 
corresponding section of the protocol (Section 4.1), align Exclusion Criterion l with Inclusion 
Criterion b, clarify that COVID-19 testing at screening is mandatory. In addition, Appendix S 
ADDITIONAL INFORMATION TO THE PROTOCOL FOR SOUTH KOREA was added. All 
major changes to the protocol body are listed below in the table and are reflected in the synopsis, 
as applicable. Table 1 (Study Procedures and Assessments) has been revised to reflect changes 
described below. Minor editorial changes (typos, punctuation, etc) have been made to the 
protocol (and protocol synopsis, as appropriate). 
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CLINICAL STUDY PROTOCOL SYNOPSIS and Section 3.1. General Study Design and Study Schematic Diagram 
The total duration of the study is up to 42 weeks. 
 
The total duration of the study is up to 43 weeks. 
 
Adding: up to 3 weeks 
of Screening period + 
24 weeks of study 
treatment + 16 Follow 
Up 
CLINICAL STUDY PROTOCOL SYNOPSIS. Inclusion criteria. 
f. …The patients must have diary entries during 4 of the 7 days prior to 
randomization. 
f. …The patients must have diary entries during at least 4 
of the 7 days prior to randomization. 
To align Inclusion 
Criterion f in the 
protocol synopsis with 
Inclusion Criterion f in 
protocol section 4.1. 
CLINICAL STUDY PROTOCOL SYNOPSIS, 9.4.2. Demographic and Baseline Characteristics and 9.7. SAFETY ANALYISIS 
CLINICAL STUDY PROTOCOL SYNOPSIS  
Changes in laboratory, electrocardiogram (ECG), and vital signs data 
will be summarized descriptively by treatment period. 
 
Descriptive summaries of serious adverse events, patient withdrawals 
due to adverse events, and potentially clinically significant abnormal 
values (clinical laboratory, ECG or vital signs) based on predefined 
criteria will be provided as well by treatment period. 
 
 
9.4.2. Demographic and Baseline Characteristics 
Patient demographic and baseline characteristics, including but not 
limited to, medical history, prior medications and therapies, and ECG 
findings, will be …. 
 
9.7. SAFETY ANALYISIS 
CLINICAL STUDY PROTOCOL SYNOPSIS  
Changes in laboratory and vital signs data will be 
summarized descriptively by treatment period. 
 
Descriptive summaries of serious adverse events, patient 
withdrawals due to adverse events, and potentially 
clinically significant abnormal values (clinical laboratory 
or vital signs) based on predefined criteria will be 
provided as well by treatment period. 
 
9.4.2. Demographic and Baseline Characteristics 
Patient demographic and baseline characteristics, 
including but not limited to, medical history, prior 
medications and therapies, will be ….. 
 
9.7. SAFETY ANALYISIS 
Changes in laboratory and vital signs data will be 
summarized descriptively by treatment period….. 
No detailed ECG data 
are captured in the 
database; thus, 
references to statistical 
analysis of ECG 
parameters were 
omitted from the 
protocol. 
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Changes in laboratory, ECG and vital signs data will be summarized 
descriptively by treatment period….. 
Descriptive summaries of serious adverse events, patient withdrawals 
due to adverse events, and potentially clinically significant abnormal 
values (clinical laboratory, ECG or vital signs) based on predefined 
criteria will be provided as well by treatment period. 
Descriptive summaries of serious adverse events, patient 
withdrawals due to adverse events, and potentially 
clinically significant abnormal values (clinical laboratory 
or vital signs) based on predefined criteria will be 
provided as well by treatment period. 
3.4 Stopping Rules for the Study 
 
 
• 
Additional criteria for pausing enrollment can be found in the 
IDMC charter. 
• 
Additional criteria for pausing enrollment are: 
− 
A death for which the cause is judged to be 
related to the study drug by the treating 
investigator. 
− 
A life-threatening SAE judged to be related to 
the study drug by the treating investigator. 
− 
Any combination of 4 occurrences of Grade 3 
or higher (per Common Terminology Criteria 
for Adverse Events [CTCAE] grading) 
toxicities that are assessed to be related to the 
study drug by the investigator. 
− 
For the same Preferred Term, 2 occurrences of 
Grade 3 or higher (per CTCAE grading) 
toxicities that are assessed to be related to the 
study drug by the investigator. 
− 
Any combination of 4 occurrences of a 
clinically significant Grade 3 or higher (per 
CTCAE grading) laboratory abnormality for 
different laboratory parameters assessed to be 
related to the study drug by the investigator. 
− 
Two occurrences of a clinically significant 
Grade 3 or higher (per CTCAE grading) 
laboratory abnormality for the same laboratory 
parameter that are assessed to be related to the 
study drug by investigator. 
Reintroduction of 
recruitment stopping 
rules from DMC 
charter, without 
mentioning this 
document, since it 
should not be available 
to PIs. 
3.5 Schedule of Study Procedures and Assessments 
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Added: 
Medical history: any medical event relevant to eligibility 
and further participation should be collected and reported 
in source documents and CRF (eg, completely cured non-
melanoma skin malignancy, hysterectomy, allergic 
diseases or any other significant medical event). 
To clear things to 
report in medical 
history 
4.1 INCLUSION CRITERIA AND APPENDIX J 
4.1 Inclusion criteria 
d. Male patients (including vasectomized) with partners who are of 
childbearing potential (whether pregnant or not) must use condoms with 
spermicide prior to IMP administration and until 20 weeks after last IMP 
dose. 
 
Appendix J 
Male contraception: 
Male patients must always use a condom with spermicide including 
vasectomized men if their partners are of childbearing potential. The 
sponsor will provide condoms and spermicide at each visit to encourage 
further adherence to the contraceptive measures recommended in the 
study. 
Inclusion criteria 
d. Male patients (including vasectomized) with partners 
who are of childbearing potential (whether pregnant or 
not) must use condoms prior to IMP administration and 
until 20 weeks after last IMP dose. 
 
 
Male contraception: 
Male patients must always use a condom including 
vasectomized men if their partners are of childbearing 
potential. 
In light of the new 
knowledge that 
condoms with 
spermicide may not be 
available in all 
countries 
Section 4.2. Exclusion Criterion l 
 
 
Any H1 antihistamines at greater than approved doses use within 3 days 
prior to the start of screening. 
Any H1 antihistamines at greater than approved doses use 
from 3 days after the start of screening. 
To align Exclusion 
Criterion l with 
Inclusion  
Criterion b, 
5.5.1. Activity 
 
Added: 
Blood donation is forbidden for the duration of the study. 
To add this restriction 
where it belongs. 
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5.6. Prior and Concomitant Medication or Therapy 
Any prior or concomitant medication (including prior CIU/CSU 
medication), or procedure a patient has had from 4 weeks before 
screening through the end of the study will be recorded in the source 
documentation and in the CRF. Trade name and international… 
 
Prohibited and restricted medications are listed in Appendix L. 
Any prior or concomitant medication (including prior 
CIU/CSU medication), or procedure a patient has had 
from 4 weeks before screening through the end of the 
study will be recorded in the source documentation and in 
the CRF. Also, any prior intake of IMP and omalizumab 
(and any anti-IgE medications) before screening or 
treatment with an investigational agent within 30 days or 
longer depending on half-life (>5 half-lives) before 
screening needs to be recorded in the source 
documentation and in the CRF. Trade name and 
international... 
The list of prohibited medications and guidance rules are 
located in Appendix L. 
Protocol was updated 
with requirements for 
reporting medical 
history 
 
 
To align with exclusion 
criteria e and f 
7.1.5.2. Expectedness 
In this study, the reference safety information (RSI) for TEV-45779 for 
determination of suspected serious adverse reaction is included in the 
IB… 
The RSI of XOLAIR for this study is the USPI. 
The sponsor’s GPSP will determine the expectedness for all serious 
adverse events. 
In this study, the reference safety information (RSI) for 
determination of suspected serious adverse reaction is 
included in the IB… 
The sponsor’s Global Patient Safety and 
Pharmacovigilance (GPSP) will determine the 
expectedness for all serious adverse events. 
Eventually, the safety 
team might want to 
switch to SmPC as the 
RSI, since it could be 
modified in the IB 
revision without 
making changes to the 
protocol. 
Section 7.5.2.3. (Coronavirus Disease 2019 Testing) 
7.5.2.3. COVID 19 testing will be performed at screening and at any 
other time point during the study if the patient exhibits clinical 
symptoms that may indicate COVID 19 infection. 
COVID 19 testing will be performed locally (if available) or centrally (if 
not available locally) and reported in the CRF. 
7.5.2.3. COVID-19 testing will be performed at screening 
(V1). In addition, the patient should be tested at any other 
time point during the study if the patient exhibits clinical 
symptoms that may indicate COVID-19 infection. 
COVID-19 testing will be performed locally and reported 
in the CRF. 
To clarify that COVID-
19 testing at screening 
(V1) is mandatory and 
that testing will only be 
performed locally. 
8.3 Immunogenicity Testing 
 
 
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Blood samples (5 mL) for assessment of anti-drug antibody (ADA) 
response will be taken before drug administration at the time points 
indicated in Table 1. 
Two blood samples (5 mL each) for assessment of 
anti-drug antibody (ADA) response will be taken before 
drug administration at the time points indicated in 
Table 1. 
The volume of ADA 
blood samples should 
be increased for the 
purpose of possibly 
requested extended 
ADA analyses. This 
would increase the 
total blood volume in 
the 
study to 255 mL. 
Table 1 
 
 
 
Lettering for footnotes was changed from c onwards 
A footnote had to be 
introduced for 
“Medical and surgical 
history” as letter c 
 
Rescue medication dispensationq 
(X added at V1) 
q Dispensation of rescue medication must be done at V1 
and at other visits as required; dispensation on other 
visits will happen as needed to ensure that subject has 
sufficient rescue medication to cover the period till the 
next subject visit at max dose.  
The Protocol is not 
specific about the 
expected timing for 
dispensation of rescue 
medication and it may 
be assumed it must be 
done at the baseline 
visit and also when it is 
required. 
m. COVID-19 testing to be performed at screening, and the patient 
should be tested at any other time point during the study if the patient 
exhibits clinical symptoms that may indicate COVID 19 infection. 
COVID-19 testing will be performed locally (if available) or centrally 
(if not available locally). 
n. COVID-19 testing to be performed at V1. In addition, 
the patient should be tested at any other time point during 
the study if the patient exhibits clinical symptoms that 
may indicate COVID-19 infection. COVID-19 testing will 
be performed locally. 
To clarify that COVID-
19 testing at screening 
(V1) is mandatory and 
that testing will only be 
performed locally. 
Table 5, footnote 
All injection site findings will be captured as adverse events and must be 
recorded and reported as specified in Section 7.1.5. 
Injection site findings will not be captured as adverse 
events unless they fulfill characteristics that are beyond 
those in the specified forms/scales (eg, necrosis, abscess, 
Injection site findings 
don’t need to be 
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etc) or fulfill seriousness criteria and then they must be 
recorded and reported as specified in Section 7.1. 
captured generally as 
adverse events 
APPENDIX M 
Specimen Sampling and Handling 
For serum collection, samples will be collected in vacutainer tubes 
containing no anticoagulant and allowed to set at room temperature for 
between 1 and 1.5 hours to allow for serum separation to occur. Samples 
will then be centrifuged (2000 g, approximately 10 minutes, at 4 to 8°C). 
Separated serum (at least 1 mL) will be transferred in approximately 
equal portions into 2 opaque, labeled, polypropylene tubes 
(Sets A and B). The 2 aliquots (Set A and Set B) will be prepared for 
each analysis purpose i.e. for PK, for Total IgE and for free IgE. 
Labels for samples should include study number, patient randomization 
number, period, nominal collection time, Set A or B, and indication that 
they are PK samples or Total IgE samples or free IgE samples. Samples 
will be stored at a temperature 80°C (nominal) in an upright position 
until they are shipped to the central laboratory. If a 80°C (nominal) 
freezer is not available at the investigational site, serum samples will be 
stored at 20°C and should be transferred to 80°C (nominal) within the 
timeframe that the bioanalytical assays stability data at 20°C supports. 
Shipment and Analysis of Samples 
Serum samples for all patients will be shipped from the investigational 
center to the central laboratory, in dry ice with a temperature data logger. 
The central laboratory will be notified before the shipment of the 
samples and the shipping information will be sent when the samples are 
shipped. Primary and backup samples (Set A and Set B) are not to be 
sent in the same shipment. An electronic file containing sample 
collection dates will be emailed to the central laboratory and the 
sponsor’s representatives from bioanalytical departments for each 
shipment. 
All samples will be stored at 80°C (nominal) in an upright position at 
the central laboratory until they are shipped to the bioanalytical 
laboratory (GBT) for analysis. The bioanalytical laboratory (GBT) will 
be notified before the shipment of the samples and the shipping 
information will be sent when the samples are shipped. All samples 
Instructions for sampling, handling and shipment of the 
pharmacokinetics and pharmacodynamics samples are 
described in the TV45779-IMB-30086 Laboratory 
Manual. 
Samples should not be shipped on a holiday. Samples are 
not to arrive on the Israel weekend or a holiday. 
Samples will be analyzed using an appropriate validated 
method. Timing of the initiation of sample analysis will 
be determined by the management of bioanalytical 
laboratory responsible for the bioanalysis while keeping 
the study blinding, if any, intact. 
Instructions for 
sampling, handling and 
shipment of the 
pharmacokinetics, and 
pharmacodynamics 
samples were modified 
and are described in 
detail in the latest 
version of the 
TV45779-IMB-30086 
Laboratory Manual.  
 
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should be shipped in dry ice with a temperature data logger. Primary and 
backup samples (Set A and Set B) are not to be sent in the same 
shipment. An electronic file containing sample collection dates will be 
emailed to the bioanalytical laboratory representatives for each 
shipment. 
Set A samples will be transported with a temperature data logger and 
frozen with dry ice sufficient for 4 days, by next day courier to the 
bioanalytical laboratory (GBT). 
Set B samples will be sent to the same laboratory as that for Set A 
samples on a subsequent day by next day courier. 
Instructions as to the disposition of the Set B samples will be provided 
by the sponsor. 
Samples should not be shipped on a holiday. Samples are not to arrive 
on the Israel weekend or a holiday. 
Samples will be analyzed using an appropriate validated method. Timing 
of the initiation of sample analysis will be determined by the 
management of bioanalytical laboratory responsible for the bioanalysis 
while keeping the study blinding, if any, intact.  
APPENDIX N 
 
 
For serum collection, samples will be collected in vacutainer tubes 
containing no anticoagulant and allowed to set at room temperature for 
between 1 and 1.5 hours to allow for serum separation to occur. Samples 
will then be centrifuged (2000 g, approximately 10 minutes, at 4 to 8°C). 
Separated serum (at least 1 mL) will be transferred in approximately 
equal portions into 2 opaque, labeled, polypropylene tubes 
(Sets A and B).  
Labels for samples should include study number, patient randomization 
number, period, nominal collection time, Set A or Set B, and indication 
that they are anti drug antibody (ADA) samples. Samples will be stored 
at 80°C (nominal) in an upright position until they are shipped to the 
central laboratory. If a 80°C (nominal) freezer is not available at the 
investigational site, serum samples will be stored at 20°C and should be 
transferred to 80°C (nominal) within the timeframe that the 
bioanalytical assays stability data at 20°C supports. 
Instructions for sampling, handling and shipment of the 
immunogenicity samples are described in the TV45779-
IMB-30086 Laboratory Manual. 
Samples should not be shipped on a holiday. Samples are 
not to arrive on the Israel weekend or a holiday. 
Samples will be analyzed using an appropriate validated 
method. Timing of the initiation of sample analysis will 
be determined by the management of bioanalytical 
laboratory responsible for the bioanalysis while keeping 
the study blinding, if any, intact. 
Instructions for 
sampling, handling and 
shipment of the 
immunogenicity 
samples were modified 
and are described in 
detail in the latest 
version of the 
TV45779-IMB-30086 
Laboratory Manual.  
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Shipment and Analysis of Samples 
Serum samples for all patients will be shipped from the investigational 
center to the central laboratory, in dry ice with a temperature data logger. 
The central laboratory will be notified before the shipment of the 
samples and the shipping information will be sent when the samples are 
shipped. Primary and backup samples (Set A and Set B) are not to be 
sent in the same shipment. An electronic file containing sample 
collection dates will be emailed to the central laboratory and the 
sponsor’s representatives from bioanalytical departments for each 
shipment. 
All samples will be stored at 80°C (nominal) in an upright position at 
central laboratory until they are shipped to the bioanalytical laboratory 
(GBT) for analysis. The bioanalytical laboratory (GBT) will be notified 
before the shipment of the samples and the shipping information will be 
sent when the samples are shipped. All samples to shipped in dry ice 
with temperature data logger. Primary and backup samples (Set A and 
Set B) are not to be sent in the same shipment. An electronic file 
containing sample collection dates will be emailed to the bioanalytical 
laboratory representatives for each shipment. 
Set A samples will be transported with a temperature data logger and 
frozen with dry ice sufficient for 4 days, by next day courier to the 
bioanalytical laboratory (GBT). 
Set B samples will be sent to the same laboratory as that for Set A 
samples on a subsequent day by next day courier. Instructions as to the 
disposition of the Set B samples will be provided by the sponsor. 
Samples should not be shipped on a holiday. Samples are not to arrive 
on the Israel weekend or a holiday. 
Samples will be analyzed using an appropriate validated method. Timing 
of the initiation of sample analysis will be determined by the 
management of bioanalytical laboratory responsible for the bioanalysis 
while keeping the study blinding, if any, intact. 
APPENDIX S (NEW). ADDITIONAL INFORMATION TO THE PROTOCOL FOR SOUTH KOREA 
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The sponsor sought advice for the study protocol 
regarding detailed study design and statistical analysis 
from the FDA (Type 2 meetings, 2020, 2021) and the 
EMA (Scientific Advice Meeting, 2020, SA Follow Up, 
2020). 
The EMA agreed essentially to the study design proposed 
by the sponsor. 
Later, the FDA requested a different study design with at 
least 600 patients, inclusion of arms with 150 mg doses of 
TEV-45779 or XOLAIR and an additional co-primary 
endpoint of relative potency of 2 dose levels.  
Harmonization of study design according to the FDA 
requests was not accepted by the EMA. The sponsor 
incorporated the different requests into the study design. 
Therefore, the study protocol contains two statistical 
approaches for FDA and EMA, respectively.  
In this study, patients will be randomly assigned to 1 of 
the 4 treatment arms and may receive 150 mg or 300 mg 
doses of TEV-45779 or XOLAIR. Thus, patients from a 
specific country will be randomized to all treatment arms.  
Patients from South Korea will be part of the whole study 
population. Their data will be pooled and analyzed with 
the data from all study patients.  
There will be 1 primary analysis according to FDA 
criteria and 1 according to EMA criteria. The results of 
both analyses will be completely reported in the Clinical 
Study Report.  
As this is an investigational medicinal product, Teva has 
not determined at this time if a Marketing Authorization 
Application (MAA) will be submitted to the Ministry for 
Food and Drug Safety (MFDS). In the event that an MAA 
is submitted to the MFSD, Teva will determine the 
successfulness of this study result in South Korea by 
using EMA criteria as specific criteria for South Korea. 
New additional 
information for South 
Korea 
 
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16.6. 
Administrative Letter 04 dated 23 February 2022 
 
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Administrative Letter 03 Dated 28 January 2022 
 
 
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16.8. 
Amendment 02 Dated 23 November 2021 
The primary reason for this amendment is to clarify patient inclusion criteria, blinded statistical 
analysis and safety related activities such as study stop criteria, patient withdrawal criteria, add 
screening visit window and concomitant medication use. All major changes to the protocol body 
are listed below in the table and are reflected in the synopsis, as applicable. Table 1 (Study 
Procedures and Assessments) has been revised to reflect changes described below. Minor 
editorial changes (typos, punctuation, etc) have been made to the protocol (and protocol 
synopsis, as appropriate). 
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Title Page 
 
 
Teva Pharmaceuticals Development, Inc. 
400 Interpace Parkway, Building A,  
Parsippany, NJ 07054, United States of America 
 
Similar changes have been applied to other text in this section 
Teva Pharmaceuticals, Inc. 
400 Interpace Parkway, Building A,  
Parsippany, NJ 07054, United States of America 
Change in Sponsor name 
Section 1.1.2 TEV-45779 and Chronic Idiopathic Urticaria/Chronic Spontaneous Urticaria 
… 
CIUCSU in adults and adolescents 12 years of age and older who 
remain symptomatic despite H1 antihistamine treatment 
(XOLAIR Prescribing Information 11/20207/2021). 
… 
CSU in adults and adolescents 12 years of age and older 
who remain symptomatic despite H1 antihistamine 
treatment (XOLAIR Prescribing Information 7/2021). 
Update of term from 
previously used CIU to 
new term CSU; update of 
the prescribing 
information publication 
date. 
Section 1.1.2 TEV-45779 and Chronic Idiopathic Urticaria/Chronic Spontaneous Urticaria (other sections affected by this change: section 1.2.1, 
1.2.2.3, 1.3.2, 1.3.3, 15) 
… 
(XOLAIR Prescribing Information 11/2020) (XOLAIR 
Prescribing Information 7/2021). 
… 
(XOLAIR Prescribing Information 7/2021). 
Update of the prescribing 
information publication 
date in multiple sections. 
Section 1.2.2 Clinical Studies 
TheClinical data for TEV-45779 are available from the pivotal 
pharmacokinetic/pharmacodynamic study of TEV-45779 (Study 
TV45779-BE-10160) started in December 2020. This first-in-
human study iswas a phase I, single dose, 3-arm, parallel-group 
study in subjects with serum IgE levels of <100 IU/mL to 
demonstrate pharmacokinetic biosimilarity between TEV-45779 
150 mg and XOLAIR 150 mg sourced from the US (US-licensed 
XOLAIR) and XOLAIR 150 mg sourced from the EU (EU-
approved XOLAIR), and to evaluate pharmacodynamics based on 
total and free IgE. All subjects (N=228) have been dosed with 
TEV 45779, XOLAIR (US) or XOLAIR (EU).  
A total of 228 healthy subjects were enrolled into the study: 75 
subjects were randomized to receive a single sc injection of TEV-
Clinical data for TEV-45779 are available from the pivotal 
pharmacokinetic/pharmacodynamic study TV45779-BE-
10160. This first-in-human study was a phase I, single 
dose, 3-arm, parallel-group study in subjects with serum 
IgE levels of <100 IU/mL to demonstrate pharmacokinetic 
biosimilarity between TEV-45779 150 mg and XOLAIR 
150 mg sourced from the US (US-licensed XOLAIR) and 
XOLAIR 150 mg sourced from the EU (EU-approved 
XOLAIR), and to evaluate pharmacodynamics based on 
total and free IgE.  
A total of 228 healthy subjects were enrolled into the study: 
75 subjects were randomized to receive a single sc injection 
Update section with new 
PK/PD information. 
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45779, 76 subjects to XOLAIR EU, and 77 subjects to XOLAIR 
US. 
Blood sampling for PK, PD and ADA assessment and routine 
safety visits occurred up to 126 days after study drug 
administration. 
A blinded interim safety analysis was conducted after completion 
of the Day 29 visit (28 days post-dose; cut-off date: 19 April 
2021). The adverse events and other blinded 
Overall, 218 (96%) subjects completed the study. From the 10 
subjects who withdrew from the study: 7 subjects were in the 
TEV-45779 group, 1 subject in the XOLAIR EU group, and 2 
subjects in the XOLAIR US group. The most frequent reason for 
withdrawal was lost to follow-up, which occurred in 4 subjects in 
the TEV-45779 group and 1 subject in the XOLAIR US group. A 
further 3 subjects were withdrawn due to pregnancy (2 in the 
TEV-45779 group and 1 subject in the XOLAIR EU group), and 
2 subjects withdrew voluntarily (1 subject in each of the TEV-
45779 and XOLAIR US groups). 
1.2.2.1. Pharmacokinetics 
Omalizumab serum concentrations were measured in serum 
samples for up to 126 days after administration of TEV-45779, 
XOLAIR US, or XOLAIR EU using a validated assay. All 3 
groups had a similar mean omalizumab serum concentration-time 
profile.  
Pharmacokinetic similarity was demonstrated between TEV-
45779 and XOLAIR US, TEV-45779 and XOLAIR EU, and 
XOLAIR US and XOLAIR EU: for each of the 2 co-primary 
endpoints (Cmax and AUC0-∞), the 90% confidence intervals 
(CI) for the GMRs were fully contained within the pre-defined 
limits of 0.8000 to 1.2500. 
Evaluation of the secondary pharmacokinetic parameters (time to 
maximum observed drug concentration [tmax], percentage 
extrapolated area under the concentration-time curve [%AUCext], 
apparent total body clearance [CL/F], apparent volume of 
distribution [Vz/F], terminal elimination rate constant [λz] and 
of TEV-45779, 76 subjects to XOLAIR EU, and 77 
subjects to XOLAIR US. 
Blood sampling for PK, PD and ADA assessment and 
routine safety visits occurred up to 126 days after study 
drug administration. 
A blinded interim safety analysis was conducted after 
completion of the Day 29 visit (28 days post-dose; cut-off 
date: 19 April 2021).  
Overall, 218 (96%) subjects completed the study. From the 
10 subjects who withdrew from the study: 7 subjects were 
in the TEV-45779 group, 1 subject in the XOLAIR EU 
group, and 2 subjects in the XOLAIR US group. The most 
frequent reason for withdrawal was lost to follow-up, 
which occurred in 4 subjects in the TEV-45779 group and 1 
subject in the XOLAIR US group. A further 3 subjects 
were withdrawn due to pregnancy (2 in the TEV-45779 
group and 1 subject in the XOLAIR EU group), and 2 
subjects withdrew voluntarily (1 subject in each of the 
TEV-45779 and XOLAIR US groups). 
1.2.2.1. Pharmacokinetics 
Omalizumab serum concentrations were measured in serum 
samples for up to 126 days after administration of TEV-
45779, XOLAIR US, or XOLAIR EU using a validated 
assay. All 3 groups had a similar mean omalizumab serum 
concentration-time profile.  
Pharmacokinetic similarity was demonstrated between 
TEV-45779 and XOLAIR US, TEV-45779 and XOLAIR 
EU, and XOLAIR US and XOLAIR EU: for each of the 2 
co-primary endpoints (Cmax and AUC0-∞), the 90% 
confidence intervals (CI) for the GMRs were fully 
contained within the pre-defined limits of 0.8000 to 1.2500. 
Evaluation of the secondary pharmacokinetic parameters 
(time to maximum observed drug concentration [tmax], 
percentage extrapolated area under the concentration-time 
curve [%AUCext], apparent total body clearance [CL/F], 
apparent volume of distribution [Vz/F], terminal 
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terminal elimination half-life [t½]) and partial AUCs supports that 
the pharmacokinetics of the 3 treatments are similar. 
1.2.2.2. Pharmacodynamics 
Pharmacodynamic similarity was evaluated comparing the change 
of free and total IgE in serum following drug administration. 
TEV-45779, XOLAIR EU, and XOLAIR US had similar mean 
free IgE and total IgE concentration time profiles for both total 
and free IgE. For each pharmacodynamic parameter evaluated 
(negative AUEC of free IgE change from baseline, positive 
AUEC of total IgE change from baseline, Cmin,IgE,free, and 
Cmax,IgE,total), the results were descriptively similar for each 
treatment group. 
1.2.2.3. Safety and immunogenicity 
The proportion of subjects reporting adverse events and 
treatment-related adverse events was low and similar between 
treatment groups. All adverse events were mild or moderate in 
severity. There were no deaths, other serious adverse events, or 
withdrawals due to adverse events, and no protocol defined 
adverse events of special interest (ie, anaphylaxis). There were no 
findings of clinical importance in any treatment group for vital 
signs, ECGs, or clinical laboratory data. Local tolerability at the 
injection site was good following sc administration of each 
treatment, with no clinically meaningful differences between the 
groups. 
Anti-drug antibody formation occurred during the study for 30 to 
40% of subjects in each group, with no substantial difference 
between TEV-45779, XOLAIR EU, and XOLAIR US. ADA had 
returned to baseline levels at the last sampling point, 126 days 
post dose. Only a small percentage of ADA-positive subjects 
tested positive for neutralizing ADA during the study. 
 The adverse events and other safety data observed after dosing of 
228 healthy subjects are in line with the known safety profile of 
XOLAIR (XOLAIR Prescribing Information 11/2020 XOLAIR 
Prescribing Information 7/2021; XOLAIR Summary of Product 
Characteristics 08/2020) and also with events expected in a 
healthy study population. 
elimination rate constant [λz] and terminal elimination half-
life [t½]) and partial AUCs supports that the 
pharmacokinetics of the 3 treatments are similar. 
1.2.2.2. Pharmacodynamics 
Pharmacodynamic similarity was evaluated comparing the 
change of free and total IgE in serum following drug 
administration. TEV-45779, XOLAIR EU, and XOLAIR 
US had similar mean free IgE and total IgE concentration 
time profiles for both total and free IgE. For each 
pharmacodynamic parameter evaluated (negative AUEC of 
free IgE change from baseline, positive AUEC of total IgE 
change from baseline, Cmin,IgE,free, and Cmax,IgE,total), 
the results were descriptively similar for each treatment 
group. 
1.2.2.3. Safety and immunogenicity 
The proportion of subjects reporting adverse events and 
treatment-related adverse events was low and similar 
between treatment groups. All adverse events were mild or 
moderate in severity. There were no deaths, other serious 
adverse events, or withdrawals due to adverse events, and 
no protocol defined adverse events of special interest (ie, 
anaphylaxis). There were no findings of clinical importance 
in any treatment group for vital signs, ECGs, or clinical 
laboratory data. Local tolerability at the injection site was 
good following sc administration of each treatment, with no 
clinically meaningful differences between the groups. 
Anti-drug antibody formation occurred during the study for 
30 to 40% of subjects in each group, with no substantial 
difference between TEV-45779, XOLAIR EU, and 
XOLAIR US. ADA had returned to baseline levels at the 
last sampling point, 126 days post dose. Only a small 
percentage of ADA-positive subjects tested positive for 
neutralizing ADA during the study. 
 The adverse events and other safety data observed after 
dosing of 228 healthy subjects are in line with the known 
safety profile of XOLAIR (XOLAIR Prescribing 
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change 
Clinical data on omalizumab, the reference product, have been 
published in the scientific literature (Rivière et al 2011) and in the 
XOLAIR US Prescribing Information (USPI) (XOLAIR 
Prescribing Information 11/2020),(XOLAIR Prescribing 
Information 7/2021), EU Summary of Product Characteristics 
(SmPC) (XOLAIR Summary of Product Characteristics 08/2020), 
and Canadian Consumer Information Leaflet (XOLAIR 
Consumer Information 04/2017). Since TEV 45779 is being 
developed as a biosimilar candidate to XOLAIR, the clinical 
findings for TEV 45779 are expected to be similar to those of 
XOLAIR, particularly the safety, pharmacokinetic, 
pharmacodynamic, immunogenicity response, and efficacy 
profiles. 
Further information can be found in the current version of the 
TEV-45779 IB. 
Information 7/2021; XOLAIR Summary of Product 
Characteristics 08/2020) and also with events expected in a 
healthy study population. 
Clinical data on omalizumab, the reference product, have 
been published in the scientific literature (Rivière et al 
2011) and in the XOLAIR US Prescribing Information 
(USPI) (XOLAIR Prescribing Information 7/2021), EU 
Summary of Product Characteristics (SmPC) (XOLAIR 
Summary of Product Characteristics 08/2020), and 
Canadian Consumer Information Leaflet (XOLAIR 
Consumer Information 04/2017). Since TEV-45779 is 
being developed as a biosimilar candidate to XOLAIR, the 
clinical findings for TEV-45779 are expected to be similar 
to those of XOLAIR, particularly the safety, 
pharmacokinetic, pharmacodynamic, immunogenicity 
response, and efficacy profiles. 
Further information can be found in the current version of 
the TEV-45779 IB. 
Section 1.3.1 Known and Potential Benefits and Risks of TEV045779 
To date (19 April 2021) noNo safety concerns have been observed 
in Study TV45779-BE-10160 (Section 1.2.2). Since TEV 45779 
is being developed as a proposed biosimilar to XOLAIR, 
treatment risks with TEV 45779 are anticipated based on the 
safety information for the use of XOLAIR in the US and EU. 
No safety concerns have been observed in Study TV45779-
BE-10160 (Section 1.2.2). Since TEV 45779 is being 
developed as a proposed biosimilar to XOLAIR, treatment 
risks with TEV 45779 are anticipated based on the safety 
information for the use of XOLAIR in the US and EU. 
Remove the reference date 
of information as the date 
would always be the 
protocol approval date. 
Section 3.1 General Study Design and Study Schematic Diagram (other sections affected by this change: section 5.8) 
… 
Patients in the 300 mg groups will receive 2 sc injections of 150 
mg IMP whereas patients in the 150 mg groups will receive 1 sc 
injection of 150 mg IMP and an additional placebo injection in 
order to administer 2 injections per dosing in all groups and, 
thereby, ensure patients continue to be blinded maintaining of the 
blind to treatment. 
… 
… 
Patients in the 300 mg groups will receive 2 sc injections of 
150 mg IMP whereas patients in the 150 mg groups will 
receive 1 sc injection of 150 mg IMP and an additional 
placebo injection in order to administer 2 injections per 
dosing in all groups and, thereby, ensure maintaining of the 
blind to treatment. 
… 
Generalize the need to 
maintain the treatment 
blind - not only for the 
patient. Correction of 
reference visit for the 
dosing level  
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Transition Treatment Period: At the beginning of the transition 
period (Week 12), patients in the XOLAIR 300 mg and XOLAIR 
150 mg groups will be re-randomized 1:1 to either continue with 
XOLAIR treatment (at the same dose level as prior to re-
randomization) or transition to TEV-45779 (at the same dose 
level prior to re-randomization) to primarily assess the 
immunogenicity and safety after the transition from XOLAIR to 
TEV-45779. All patients in the TEV-45779 group will continue 
treatment with TEV-45779 at the same dose level as prior to re-
randomization. 
Transition Treatment Period: At the beginning of the 
transition period (Week 12), patients in the XOLAIR 
300 mg and XOLAIR 150 mg groups will be 
re-randomized 1:1 to either continue with XOLAIR 
treatment (at the same dose level as prior to re-
randomization) or transition to TEV-45779 (at the same 
dose level prior to re-randomization) to primarily assess the 
immunogenicity and safety after the transition from 
XOLAIR to TEV-45779. All patients in the TEV-45779 
group will continue treatment with TEV-45779 at the same 
dose level as prior to re-randomization. 
Section 3.4 Stopping Rules for the Study 
During the conduct of the study, serious adverse events will be 
reviewed (Section 7.1.5) as they are reported from the 
investigational centers to identify safety concerns. 
The study may be terminated by the sponsor for any reason at any 
time. For example, the sponsor should terminate the study in the 
event of: 
• 
New toxicological or pharmacological findings or safety 
issues invalidate the earlier positive benefit risk assessment. 
• 
Discontinuation of the development of the IMP. 
• 
Additional criteria for pausing enrollment can be found in the 
IDMC charter. 
If any of the below mentioned criteria are met, enrollment will be 
paused for a safety review by the IDMC (Section 5.9.2): 
• 
A death for which the cause is judged to be related to the 
study drug by the treating investigator; 
• 
A life threatening serious adverse event judged to be related 
to the study drug by the treating investigator; 
• 
2 occurrences of Grade 3 or higher (per Common 
Terminology Criteria for Adverse Events [CTCAE] grading) 
adverse events that are assessed to be related to the study drug by 
the investigator; 
During the conduct of the study, serious adverse events will 
be reviewed (Section 7.1.5) as they are reported from the 
investigational centers to identify safety concerns. 
The study may be terminated by the sponsor for any reason 
at any time. For example, the sponsor should terminate the 
study in the event of: 
• 
New toxicological or pharmacological findings or 
safety issues invalidate the earlier positive benefit risk 
assessment. 
• 
Discontinuation of the development of the IMP. 
• 
Additional criteria for pausing enrollment can be found 
in the IDMC charter. 
If the whole study or arms of the study will be stopped, the 
patients that are terminated early will be followed 
according to Withdrawal Criteria and Procedures for the 
Patient (Section 4.3). 
Remove these stopping 
criteria from the protocol 
and refer the reader to the 
IDMC charter. This will 
allow modifying stopping 
criteria without requiring a 
protocol amendment. 
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• 
2 occurrences of a clinically significant Grade 3 or higher 
(per CTCAE grading) laboratory abnormality assessed to be 
related to the study drug by the investigator. 
If the whole study or arms of the study will be stopped, the 
patients that are terminated early will be followed according to 
Withdrawal Criteria and Procedures for the Patient (Section 4.3). 
Section 3.5 Schedule of Study Procedures and Assessments 
Table 1: Study Procedures and Assessments 
See new wording column  
Table 1 has been revised as described below: 
The visit window for V2 (week -1) was changed from 0 
days to -2 days 
Add a visit window to V2 
for scheduling flexibility 
… 
b The interval between V1 and V2 should be at least 5 days; 
patients that require a 3-day adjustment period to reach an 
approved dose of their H1 antihistamine treatment will need an 
interval of at least 8 days 
… 
d IMP will be preferably administered in the front and middle of 
the thigh area (both injections at least 1 inch (2.5 cm) apart). 
Alternatively, if injection in the thigh is not possible, the injection 
may be given in the abdomen, avoiding the 2-inch (5 cm) area 
directly around the navel. The used injection site will be 
documented. 
… 
gi Patients receive the electronic Patient Symptom Diary (eDiary) 
during the V1 (on day −14) visit. It includes the twice daily 
(morning and evening) assessment of the number of wheals 
(hives) and of the itch severity. Patients must not have any 
missing diary entries during at least 4 of the 7 days prior to 
randomization on day 1. 
… 
b The interval between V1 and V2 should be at least 5 days; 
patients that require a 3-day adjustment period to reach an 
approved dose of their H1 antihistamine treatment will 
need an interval of at least 8 days 
… 
d IMP will be preferably administered in the front and 
middle of the thigh area (both injections at least 1 inch (2.5 
cm) apart). Alternatively, if injection in the thigh is not 
possible, the injection may be given in the abdomen, 
avoiding the 2-inch (5 cm) area directly around the navel. 
The used injection site will be documented. 
… 
i Patients receive the electronic Patient Symptom Diary 
(eDiary) during the V1 (on day −14) visit. It includes the 
twice daily (morning and evening) assessment of the 
number of wheals (hives) and of the itch severity. Patients 
must have diary entries during at least 4 of the 7 days prior 
to randomization on day 1. 
Specify the minimal 
interval between V1 and 
V2 since the windows all 
for a very short interval 
and also clarify the 3 days 
required for patients that 
adjust their H1 
antihistamines during 
screening; IMP injection 
sites to be aligned with the 
pharmacy manual and 
update to new eDiary 
compliance requirements. 
 
Footnotes were relabeled 
to remain consistent with 
the table and the body of 
the protocol 
Section 4.1 Patient Inclusion Criteria 
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See new wording column 
Footnote added to inclusion criteria b (bullet 2): Refer to 
Section 9.3.1 for handling of missing data for daily and 
weekly scores. 
eDiary compliance was 
changed and now allows 
missing data as part of this 
inclusion criteria instead 
of the original full 7 days 
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… 
b. Diagnosis of CIU/CSU refractory to H1 antihistamines at the 
time of randomization, as defined by all of the following: 
- The presence of itch and wheals for ≥8 consecutive weeks at any 
time prior to enrollment despite current use of H1 antihistamine 
treatment during this time period. 
- Weekly urticaria activity score (UAS7; sum of the daily number 
of wheals score and itch severity score over 7 days) ≥16 (range 0 
42) and itch component of UAS7 ≥8 (range 0 21) during 7 days 
prior to randomization.  
- Urticaria activity score (UAS) ≥4 assessed by a clinician on ≥1 
of the screening visit days. 
- Patients must have been on an approved dose of an H1 
antihistamine for CIU/CSU for ≥3 consecutive days immediately 
prior to the start of screening and must document current use on 
the day of the initial screening visit, OR, have their H1 
antihistamine for CIU/CSU adjusted to an approved dose during 
the first 3 days of screening and have their adjusted use 
documented at the end of the dose adjustment. 
- CIU/CSU diagnosis for ≥3 months. 
… 
c. Bilateral tubal occlusion or tubal ligation. 
… 
d. Male patients (including vasectomized) with partners who are 
of childbearing potential (whether pregnant or not) must use 
condoms with spermicide prior to IMP administration and until 20 
weeks after last IMP dose. 
… 
f. 
Must be willing and able to comply with study requirements 
and procedures as specified in this protocol. In particular, the 
patient must be willing and able to complete a daily symptom 
diary for the duration of the study. The patients must not have any 
missing diary entries during at least 4 of the 7 days prior to 
randomization. 
… 
b. Diagnosis of CIU/CSU refractory to H1 antihistamines at 
the time of randomization, as defined by all of the 
following: 
- The presence of itch and wheals for ≥8 consecutive weeks 
at any time prior to enrollment despite current use of H1 
antihistamine treatment during this time period. 
- Weekly urticaria activity score (UAS7; sum of the daily 
number of wheals score and itch severity score over 7 days) 
≥16 (range 0 42) and itch component of UAS7 ≥8 (range 0 
21) during 7 days prior to randomization.  
- Urticaria activity score (UAS) ≥4 assessed by a clinician 
on ≥1 of the screening visit days. 
- Patients must have been on an approved dose of an H1 
antihistamine for CIU/CSU for ≥3 consecutive days 
immediately prior to the start of screening and must 
document current use on the day of the initial screening 
visit, OR, have their H1 antihistamine for CIU/CSU 
adjusted to an approved dose during the first 3 days of 
screening and have their adjusted use documented at the 
end of the dose adjustment. 
- CIU/CSU diagnosis for ≥3 months. 
… 
c. Bilateral tubal occlusion or tubal ligation. 
… 
d. Male patients (including vasectomized) with partners 
who are of childbearing potential (whether pregnant or not) 
must use condoms with spermicide prior to IMP 
administration and until 20 weeks after last IMP dose. 
… 
f. 
Must be willing and able to comply with study 
requirements and procedures as specified in this protocol. 
In particular, the patient must be willing and able to 
complete a daily symptom diary for the duration of the 
study. The patients must have diary entries during at least 4 
of the 7 days prior to randomization. 
Allow H1 histamine 
adjustments during the 
screening period in 
consideration of any 
patients who will be on 
higher that approved 
treatment doses at 
screening; extend the 
highly effective birth 
control methods and align 
type of male condom with 
appendix J ; Adjust eDiary 
Compliance requirements 
for determining patient 
eligibility.  
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Section 4.2. Exclusion Criteria 
… 
f. Previous treatment with omalizumab or other Anti-IgE therapy 
within a year prior to the start of screening. 
… 
… 
f. Previous treatment with omalizumab or other Anti-IgE 
therapy within a year prior to the start of screening. 
… 
Clarify specific exclusion 
criteria, aligned with 
appendix L 
Section 4.3. Withdrawal Criteria and Procedures for the Patient 
… 
4. Patient takes prohibited concomitant medications as defined in 
this protocol (see appendix L). Under certain circumstances, a 
patient may be eligible to remain in the study when taking 
prohibited concomitant medications - such cases should be 
discussed with, and approved by, the medical monitor. 
… 
8. A female patient has a confirmation of pregnancy during the 
study from a positive serum pregnancy test. 
… 
4. Patient takes prohibited concomitant medications as 
defined in this protocol (see appendix L). Under certain 
circumstances, a patient may be eligible to remain in the 
study when taking prohibited concomitant medications - 
such cases should be discussed with, and approved by, the 
medical monitor. 
… 
8. A female patient has a confirmation of pregnancy during 
the study from a positive serum pregnancy test. 
Modify the withdrawal 
criteria due to use of 
conmeds – allowing 
patients to continue is 
study under certain 
circumstances. Specifying 
the withdrawal rule due to 
pregnancy as required by 
the Czech Republic CA. 
Section 4.5. Re-screening 
Patients may not be re screened. A patient who is screened but not 
enrolled (eg, because inclusion and exclusion criteria were not 
met or enrollment did not occur within the specified time) may be 
considered for re-screening 1 time if there is a change in the 
patient’s medical background or other relevant change. (Note: the 
medical monitor should approve re-screening after review of the 
enabling reasons.) 
If the patient is re-screened, a new informed consent form (ICF) 
will need to be signed and all study assessments will need to be 
repeated. 
A patient who is screened but not enrolled (eg, because 
inclusion and exclusion criteria were not met or enrollment 
did not occur within the specified time) may be considered 
for re-screening 1 time if there is a change in the patient’s 
medical background or other relevant change. (Note: the 
medical monitor should approve re-screening after review 
of the enabling reasons.) 
If the patient is re-screened, a new informed consent form 
(ICF) will need to be signed and all study assessments will 
need to be repeated. 
Allow one re-screening of 
a patient who previously 
screen failed and the 
process for obtaining this 
approval. 
Section 5.1. Investigational Medicinal Products Used in the Study 
Table 2: Investigational Medicinal Products Used in the Study 
See new wording column 
Table 2 has been revised as described below: 
Manufacturer of the reference drug XOLAIR was changed  
from Novartis AG Forum 1, Novartis Campus, CH 4056 
Basel, Switzerland 
Update the reference drug 
manufacturer address. 
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change 
to Novartis Pharma GmbH, Roonstrasse 25, D-90429, 
Nuremberg, Germany. 
Section 5.8. Randomization nd Blinding 
At baseline, patients will be randomized in a 2:2:1:1 ratio to 
receive the first 3 doses of TEV 45779 300 mg, XOLAIR 300 mg, 
TEV 45779 150 mg, or XOLAIR 150 mg (main treatment 
period). Patients in the 150 mg groups will receive an additional 
placebo injection in order to administer 2 injections per dosing in 
all groups and, thereby, ensure patients continue to be blinded 
maintaining of the blind to treatment. At Week 12, prior to 
receiving their fourth dose of study medication, patients in the 
XOLAIR treatment group will be re-randomized 1:1 to receive 3 
additional doses of XOLAIR (at the same dose level as prior to re-
randomization) or switch to 3 doses of TEV 45779 (at the same 
dose level as prior to re-randomization) for the transition period. 
All patients in the TEV 45779 group will continue to receive TEV 
45779 during the transition period at the same dose level as prior 
to re-randomization.  
During the study main treatment period, the sponsor, investigators 
(and including other site staff involved in study assessments) and 
patients will be blinded to the treatment assignment of all patients. 
To maintain assure continued blinding to the treatment 
assignment, assignments after the main treatment period, re-
randomization process will be performed for all patients, 
including the patients in the TEV 45779 group (although only 
patients in the XOLAIR arm will actually be re randomized while 
patients in the TEV 45779 group will continue to receive TEV 
45779 in the transition period). The randomization will be 
implemented using a Randomization and Trial Supply 
Management (RTSM) system. Further details on unblinding 
during the transition and follow-up periods are provided in 
Section 5.9.1. 
At baseline, patients will be randomized in a 2:2:1:1 ratio 
to receive the first 3 doses of TEV 45779 300 mg, 
XOLAIR 300 mg, TEV 45779 150 mg, or XOLAIR 150 
mg (main treatment period). Patients in the 150 mg groups 
will receive an additional placebo injection in order to 
administer 2 injections per dosing in all groups and, 
thereby, ensure maintaining of the blind to treatment. At 
Week 12, prior to receiving their fourth dose of study 
medication, patients in the XOLAIR treatment group will 
be re-randomized 1:1 to receive 3 additional doses of 
XOLAIR (at the same dose level as prior to re-
randomization) or switch to 3 doses of TEV 45779 (at the 
same dose level as prior to re-randomization) for the 
transition period. All patients in the TEV 45779 group will 
continue to receive TEV 45779 during the transition period 
at the same dose level as prior to re-randomization.  
During the main treatment period, the sponsor, 
investigators (including other site staff involved in study 
assessments) and patients will be blinded to the treatment 
assignment of all patients. To assure continued blinding to 
the treatment assignments after the main treatment period, 
re-randomization will be performed for all patients, 
including patients in the TEV 45779 group (although only 
patients in the XOLAIR arm will actually be re randomized 
while patients in the TEV 45779 group will continue to 
receive TEV 45779 in the transition period). The 
randomization will be implemented using a Randomization 
and Trial Supply Management (RTSM) system. Further 
details on unblinding during the transition and follow-up 
periods are provided in Section 5.9.1. 
Correct how the blinding 
and randomization is 
performed and 
differentiate between 
sponsor and non-sponsor 
blinding. 
Section 5.9.1 Blinding and Unblinding 
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… 
In order to ensure additional patient blinding, a blindfold with an 
additional pillow at chest level (or similar device) will be used 
during the IMP injection as a shield to hide the IMP from the 
patient. IMP will be preferably administered in the front and 
middle of the thigh area (both injections at least 1 inch (2.5 cm) 
apart). Alternatively, if injection in the thigh is not possible, the 
injection may be given in the abdomen, avoiding the 2-inch (5 
cm) area directly around the navel. The used injection site will be 
documented. 
Staff responsible for pharmacokinetic and immunogenicity 
bioanalysis, population pharmacokinetics, and/or 
pharmacokinetics/pharmacodynamics model will not have access 
to the patient treatment randomization prior to unblinding the 
study (before final DBL). 
During the transition period, the sponsor, investigators (and other 
site staff involved in study assessments) and patients will be 
blinded to the randomized treatment of patients who received 
XOLAIR US in the main treatment period and are re randomized 
for the transition period. 
Before final database lock (DBL), staff responsible for 
pharmacokinetic and immunogenicity bioanalysis will not have 
access to the patient treatment randomization. 
After last patient last visit and DBL of the main treatment period, 
the sponsor will unblind the treatments for the analysis of the 
main treatment period (up to and including week 12; not including 
fourth IMP dose and assessments following the fourth dose). A 
full CSR may be prepared with all data up to week 12 (end of 
main treatment phase procedures).  
Only after completion of the study (after Week 40), final DBL 
and formal request to unblind from the sponsor statistician, will 
the study be fully unblinded and analyzed. The results will be 
reported separately in a CSR addendum, including any updates to 
the safety analysis of the main treatment period. If a full CSR is 
… 
In order to ensure additional patient blinding, a blindfold 
with an additional pillow at chest level (or similar device) 
will be used during the IMP injection as a shield to hide the 
IMP from the patient. IMP will be preferably administered 
in the front and middle of the thigh area (both injections at 
least 1 inch (2.5 cm) apart). Alternatively, if injection in the 
thigh is not possible, the injection may be given in the 
abdomen, avoiding the 2-inch (5 cm) area directly around 
the navel. The used injection site will be documented. 
Staff responsible for pharmacokinetic and immunogenicity 
bioanalysis, population pharmacokinetics, and/or 
pharmacokinetics/pharmacodynamics model will not have 
access to the patient treatment randomization prior to 
unblinding the study (before final DBL). 
During the transition period, investigators (and other site 
staff involved in study assessments) and patients will 
remain blinded to the randomized treatment of patients who 
received XOLAIR in the main treatment period and are re-
randomized for the transition period.  
After last patient last visit and DBL of the main treatment 
period, the sponsor will unblind the treatments for the 
analysis of the main treatment period (up to and including 
week 12; not including fourth IMP dose and assessments 
following the fourth dose). A full CSR may be prepared 
with all data up to week 12 (end of main treatment phase 
procedures). 
Only after completion of the study (after Week 40), final 
DBL and formal request to unblind from the sponsor 
statistician, will the study be fully unblinded and analyzed. 
The results will be reported separately in a CSR addendum, 
including any updates to the safety analysis of the main 
treatment period. If a full CSR is not prepared after the 
main treatment period, then the full study results will be 
analyzed in a single CSR after end of study. 
Clarify the IMP injection 
site. 
Reinstate the analysis of 
the main treatment period 
based on newly available 
FDA input. 
Remove redundant section 
that is already detailed two 
paragraphs above. 
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not prepared after the main treatment period, then the full study 
results will be analyzed in a single CSR after end of study. 
… 
… 
Section 9.2.9. Per-Protocol Analysis Set 
… 
The exclusion of patients from the PP analysis set will be 
discussed on a case by case basis and documented prior to DBL 
and unblinding of the main treatment period for the analysis. of 
the main treatment period. 
… 
The exclusion of patients from the PP analysis set will be 
discussed on a case-by-case basis and documented prior to 
DBL and unblinding of the main treatment period for the 
analysis. 
Clarify the unblinding 
language to refer to the 
main treatment period 
only; as this analysis is 
related to week 12 data. 
Section 9.3.1. Handling Withdrawals and Missing Data 
… 
To account for the missing itch severity, wheal or urticaria 
activity scores, the following strategy will be applied: 
Daily itch severity score – If either the morning or evening score 
is missing, the available (morning or evening) itch severity score 
for that day will be used as the daily itch severity score, and if 
both the morning and evening itch severity scores are missing, the 
daily itch severity score will be considered missing. 
Weekly itch severity score – If 4-7 daily itch severity scores are 
available for the calculation of the weekly score, the ISS7 will be 
defined as the sum of the available daily itch severity scores in 
that week, divided by the number of days for which a daily itch 
severity score is available, multiplied by 7. If no more than 3 daily 
itch severity scores are available (ie, 4-7 daily scores are missing), 
the ISS7 will be considered missing for that week. 
… 
To account for missing itch severity, wheal or urticaria 
activity scores, the following strategy will be applied: 
Daily score – If either the morning or evening score is 
missing, the available (morning or evening) score for that 
day will be used as the daily score, and if both the morning 
and evening scores are missing, the daily score will be 
considered missing. 
Weekly score – If 4-7 daily scores are available for the 
calculation of the weekly score, the ISS7 will be defined as 
the sum of the available daily scores in that week, divided 
by the number of days for which a daily score is available, 
multiplied by 7. If no more than 3 daily scores are available 
(ie, 4-7 daily scores are missing), the ISS7 will be 
considered missing for that week. 
Describe use of this 
strategy beyond the itch 
severity score and also in 
support of the newly 
added footnote to 
inclusion criteria b. 
Section 9.11. Planned Interim Analysis 
An interim analysis (IA) may be conducted after all subjects have 
completed the main treatment period in order to facilitate Teva’s 
decision regarding additional studies in the clinical development 
program for TEV 45779 prior to the completion of the current 
study. If performed, the IA will not have any impact on the 
conduct and analyses of this study. The IA will be conducted by 
an external Independent Statistician while keeping Teva and the 
No interim analysis is planned for this study. 
Remove the interim 
analysis and replace with a 
final analysis for efficacy 
in other sections. 
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study team blinded. No actual numeric results or data will be 
shared with Teva and the study team. The only information that 
will be provided to Teva by the Independent Statistician is the 
Yes/No result for each co primary comparison for FDA and EMA 
biosimilarity assessment (see Section 9.5.1.1 for details). As the 
IA does not introduce any inflation to the Type I error rate of the 
final analysis of the study, no adjustments of the nominal 
significance level are required. No interim analysis is planned for 
this study. 
APPENDIX A. CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND INSTITUTIONS 
 
ICON 
PRA Health Sciences 
Gottlieb-Daimler-Strasse 10 
68165 Mannheim, Germany 
Tel: 
 
Medical monitoring support center contact information:  
Americas: 
 (toll-free) or direct at: 
 
 
EAPA: 
 
 
PRA Health Sciences has been acquired by ICON plc, creating 
the world’s most advanced healthcare intelligence and clinical 
research organization. 
… 
 Coordinating Investigator 
 
 
 
 
 
 
ICON 
PRA Health Sciences 
Gottlieb-Daimler-Strasse 10 
68165 Mannheim, Germany 
Tel: 
 
Medical monitoring support center contact information:  
Americas: 
 (toll-free) or direct at: 
 
 
EAPA: 
 
 
PRA Health Sciences has been acquired by ICON plc, 
creating the world’s most advanced healthcare intelligence 
and clinical research organization. 
… 
Coordinating Investigator 
 
 
 
 
 
Update table in the 
following sections, 
including changes to some 
of the role titles: 
- 
Sponsor’s Medical 
Expert 
- 
 Coordinating 
Investigator 
- 
RTSM 
- 
Trial Supply Vendors 
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change 
 
 
 
 
… 
Interactive Voice Recognition System Randomization and Trial 
Supply Management (RTSM) System 
… 
Non US sites 
Secondary Labeling and Distribution 
Almac Clinical Services 
(Almac Group Limited) 
20 Seagoe Industrial Estate, Craigavon, BT63 
5QD, Northern Ireland, UK 
 
Tel: 
 
US Sites 
 
Secondary Labeling and Distribution 
Actavis Laboratories UT, Inc 
577 Chipeta Way 
Salt Lake City, UT 84108, USA 
 
Tel: 
 
 
 
 
 
… 
Randomization and Trial Supply Management (RTSM) 
System 
… 
Secondary Labeling and Distribution 
Almac Clinical Services 
(Almac Group Limited) 
20 Seagoe Industrial Estate, Craigavon, BT63 
5QD, Northern Ireland, UK 
 
Tel: 
 
 
Secondary Labeling and Distribution 
Actavis Laboratories UT, Inc 
577 Chipeta Way 
Salt Lake City, UT 84108, USA 
 
Tel: 
 
APPENDIX B. STUDY PROCEDURES AND ASSESSMENTS BY VISIT 
1. Procedures for Screening (Visits 1 and 2, Up to 3 week Period) 
The screening visit (visits 1 and 2) will take place not more than 
18 21 days before the baseline visit (visit 3). The interval between 
V1 and V2 should be at least 5 days; patients that require a 3-day 
The screening visit (visits 1 and 2) will take place not more 
than 21 days before the baseline visit (visit 3). The interval 
between V1 and V2 should be at least 5 days; patients that 
require a 3-day adjustment period to reach an approved 
Describe new interval 
requirements between V1 
and V2 and 3-day 
adjustment to normal dose 
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adjustment period to reach an approved dose of their H1 
antihistamine treatment will need an interval of at least 8 days. 
… 
b. Visit 2 (Day -7-2 days) 
… 
dose of their H1 antihistamine treatment will need an 
interval of at least 8 days. 
… 
b. Visit 2 (Day -7-2 days) 
… 
which is now part of the 
screening process. Add a 2 
day window to allow V2 
scheduling flexibility. 
APPENDIX L: LIST OF PROHIBITED MEDICATIONS 
See new wording column 
• First column (Trade Name) was deleted 
• INN / Formulation columns updated as follows: 
- INN: Omalizumab or other Anti-IgE therapies 
- INN: Dupilumab, Benralizumab / Formulation: 
Injection (sc) 
- INN: Dapsone, Sulfasalazine / Formulation: Injection 
(sc) 
- INN: Cyclosporine, Tacrolimus, Mycophenolate / 
Formulation: Systemic or cutaneous (topical) 
The medication trade 
name is not useful 
considering the numerous 
countries and variations.  
Add/update with new 
prohibited medications 
based on current clinical 
understanding. 
… 
Routine (daily or every other day during 5 or more consecutive 
days) doses of the following medications within 30 days prior to 
day 14: systemic or cutaneous (topical) corticosteroids 
(prescription or over the counter), hydroxychloroquine, 
methotrexate, cyclosporine, or cyclophosphamide, Tacrolimus, 
mycophenolate, dapsone, or sulfasalazine. 
… 
Omalizumab or other anti-IgE therapy within 1 year prior to 
screening. 
… 
Any H1 antihistamines at greater than approved doses within 
from 3 days prior after start of screening to day 14. 
… 
… 
Routine (daily or every other day during 5 or more 
consecutive days) doses of the following medications 
within 30 days prior to day 14: systemic or cutaneous 
(topical) corticosteroids (prescription or over the counter), 
hydroxychloroquine, methotrexate, cyclosporine, 
cyclophosphamide, Tacrolimus, mycophenolate, dapsone, 
or sulfasalazine. 
… 
Omalizumab or other anti-IgE therapy within 1 year prior 
to screening. 
… 
Any H1 antihistamines at greater than approved doses from 
3 days after start of screening. 
… 
Add/update with new 
prohibited medications 
based on current clinical 
understanding.  
Clarify when H1 
antihistamines are 
prohibited to be aligned 
with updated inclusion 
criteria b. 
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Reason/Justification for 
change 
APPENDIX R: CTCAE GRADING SCALE 
See new wording column 
The CTCAE Grading Scale will be provided as a separate 
document. 
Eliminate the need to print 
out the entire CTCAE 
grading scale as part of the 
protocol. 
 
 
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16.9. 
Administrative Letter 02 Dated 10 November 2021 
 
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16.10. 
Administrative Letter 01 Dated 11 June 2021 
 
  
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16.11. 
Amendment 01 Dated 11 June 2021 
The primary reason for this amendment is to implement changes based on feedback on the 
protocol received from a BPD Type 2 meeting with the FDA (BPD Type 2 Meeting Written 
Responses 2021). All major changes to the protocol body are listed below in the table and are 
reflected in the synopsis, as applicable. Table 1 (Study Procedures and Assessments) has been 
revised to reflect changes described below. Minor editorial changes (typos, punctuation, etc) 
have been made to the protocol (and protocol synopsis, as appropriate). 
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change 
 
 
 
Coordinating Investigator Agreement 
 
 
Coordinating Investigator: 
 
Title: 
 
Address of Investigational Center:  
 
 
 
  
 
 
 
  
 
 
 
 
Tel:
 
Coordinating Investigator: 
 
Title: 
 
Address of Investigational Center:  
 
 
 
  
 
 
 
  
 
 
 
 
Tel:
 
Added name and contact 
details of Coordinating 
Investigator 
1. INTRODUCTION AND BACKGROUND INFORMATION 
Section 1.2.2; other sections affected by this change: Section 1.3.1 
The pivotal pharmacokinetic/pharmacodynamic study of 
TEV-45779 (Study TV45779-BE-10160) started in 
December 2020. This first-in-human study is a single dose, 3-
arm, parallel-group study in subjects with serum IgE levels of 
<100 IU/mL to demonstrate pharmacokinetic biosimilarity 
between TEV-45779 150 mg and XOLAIR 150 mg sourced 
from the US (US-licensed XOLAIR) and XOLAIR 150 mg 
sourced from the EU (EU-approved XOLAIR), and to 
evaluate pharmacodynamics based on total and free IgE. To 
date (18 April 2021), aAll subjects (N=228) have been dosed 
with TEV-45779, XOLAIR (US) or XOLAIR (EU) and no 
safety concerns have been observed. A blinded interim safety 
analysis was conducted after completion of the Day 29 visit 
(28 days post-dose; cut-off date: 19 April 2021). The adverse 
events and other blinded safety data observed after dosing of 
228 healthy subjects are in line with the known safety profile 
of XOLAIR (XOLAIR Prescribing Information 11/2020; 
XOLAIR Summary of Product Characteristics 08/2020) and 
also with events expected in a healthy study population. 
The pivotal pharmacokinetic/pharmacodynamic study of TEV-
45779 (Study TV45779-BE-10160) started in December 2020. 
This first-in-human study is a single dose, 3-arm, parallel-
group study in subjects with serum IgE levels of <100 IU/mL 
to demonstrate pharmacokinetic biosimilarity between TEV-
45779 150 mg and XOLAIR 150 mg sourced from the US 
(US-licensed XOLAIR) and XOLAIR 150 mg sourced from 
the EU (EU-approved XOLAIR), and to evaluate 
pharmacodynamics based on total and free IgE. All subjects 
(N=228) have been dosed with TEV-45779, XOLAIR (US) or 
XOLAIR (EU). A blinded interim safety analysis was 
conducted after completion of the Day 29 visit (28 days post-
dose; cut-off date: 19 April 2021). The adverse events and 
other blinded safety data observed after dosing of 228 healthy 
subjects are in line with the known safety profile of XOLAIR 
(XOLAIR Prescribing Information 11/2020; XOLAIR 
Summary of Product Characteristics 08/2020) and also with 
events expected in a healthy study population. 
Updated to provide the 
most recent information 
available. 
2. STUDY OBJECTIVES AND ENDPOINTS 
Section 2.1; other sections affected by this change: Sections 3.5 (Table 1), 9.5.2.1, and 9.5.2.2 
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change 
additional secondary efficacy endpoint for the main period:  
• 
Change from baseline in the overall dermatology life 
quality index (DLQI) score at Week 12 
additional secondary efficacy endpoints for the main and 
transition period: 
• 
Change from Week 12 in the overall DLQI score at 
Week 24 
• 
Change from Week 12 in the overall DLQI score at 
Week 40 
additional secondary efficacy endpoint for the main period:  
• 
Change from baseline in the overall dermatology life 
quality index (DLQI) score at Week 12 
additional secondary efficacy endpoints for the main and 
transition period: 
• 
Change from Week 12 in the overall DLQI score at 
Week 24 
• 
Change from Week 12 in the overall DLQI score at 
Week 40 
Added DLQI as an 
additional secondary 
efficacy parameter for the 
main and transition period 
Section 2.1.2 
 
 
2.1.2 
Justification of Primary Endpoint and 
Equivalence Margins 
… 
The justification for the equivalence margins chosen for the 
primary efficacy analysis (±2.0 for EMA submission; -2.5, 
+2.0 for FDA submission; Section 9.5.1.1) is based on the 
following reasoning: 
• 
The equivalence margin of ±2.0 for this 
endpoint preserves 50% of the treatment effect 
of XOLAIR based on the lower bound of the 
95% CI for the pooled XOLAIR treatment effect 
in placebo controlled studies (Saini et al 2015, 
Maurer et al 2013, Kaplan et al 2013). 
• 
Mathias et al (2015) estimated a minimal 
important difference of 4.5 to 5.0 for the ISS7 
from clinical data of the above mentioned 
originator studies. Therefore, demonstration of 
similarity within a margin of -2.5, +2.0 (ISS7 
score points) for the comparison of TEV-45779 
and XOLAIR ensures that no clinically 
important difference may occur between test and 
reference product. Furthermore, the more 
negative margin of -2.5 covers a more negative 
(better) treatment effect difference. Thus, the 
test product may be better in 2.5 score points 
2.1.2 
Justification of Primary Endpoint and 
Equivalence Margins 
… 
The justification for the equivalence margins chosen for the 
primary efficacy analysis (±2.0 for EMA submission; -2.5, 
+2.0 for FDA submission; Section 9.5.1.1) is based on the 
following reasoning: 
• 
The equivalence margin of ±2.0 for this endpoint 
preserves 50% of the treatment effect of 
XOLAIR based on the lower bound of the 95% 
CI for the pooled XOLAIR treatment effect in 
placebo controlled studies (Saini et al 2015, 
Maurer et al 2013, Kaplan et al 2013). 
• 
Mathias et al (2015) estimated a minimal 
important difference of 4.5 to 5.0 for the ISS7 
from clinical data of the above mentioned 
originator studies. Therefore, demonstration of 
similarity within a margin of -2.5, +2.0 (ISS7 
score points) for the comparison of TEV-45779 
and XOLAIR ensures that no clinically 
important difference may occur between test and 
reference product. Furthermore, the more 
negative margin of -2.5 covers a more negative 
(better) treatment effect difference. Thus, the test 
product may be better in 2.5 score points and 
Added justification for 
equivalence margins 
chosen 
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Reason/Justification for 
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and worse in only 2.0 score points than the 
reference product if similarity could be 
demonstrated. 
Co-primary endpoint 
The co-primary endpoint for the FDA submission is the 
relative potency of TEV-45779 and XOLAIR (using a 4-point 
assay with a margin of [0.5, 2.0]), as recommended by the 
FDA in their written response to the Biological Product 
Development (BPD) Type 2 meeting (BPD Type 2 Meeting 
Written Responses 2020). 
… 
worse in only 2.0 score points than the reference 
product if similarity could be demonstrated. 
Co-primary endpoint 
The co-primary endpoint for the FDA submission is the 
relative potency of TEV-45779 and XOLAIR (using a 4-point 
assay with a margin of [0.5, 2.0]), as recommended by the 
FDA in their written response to the Biological Product 
Development (BPD) Type 2 meeting (BPD Type 2 Meeting 
Written Responses 2020). 
… 
3. STUDY DESIGN 
Section 3.1 
… 
Throughout the entire study, patients should remain on a 
stablesingle H1 antihistamine at stable and fixed doses not 
exceeding label recommendations as the standard treatment 
regimen.  
…. 
… 
Throughout the entire study, patients should remain on a 
single H1 antihistamine at stable and fixed doses not 
exceeding label recommendations as the standard treatment 
regimen.  
…. 
Clarified H1 antihistamine 
standard treatment 
Section 3.4 
There are no formal rules for early termination of this study. 
During the conduct of the study, serious adverse events will 
be reviewed (Section 7.1.5) as they are reported from the 
investigational centers to identify safety concerns. 
The study may be terminated by the sponsor for any reason at 
any time. For example, the sponsor should terminate the study 
in the event of: 
• 
New toxicological or pharmacological findings or 
safety issues invalidate the earlier positive 
benefit-risk assessment. 
• 
Discontinuation of the development of the IMP. 
If any of the below mentioned criteria are met, enrollment 
will be paused for a safety review by the IDMC 
(Section 5.9.2): 
During the conduct of the study, serious adverse events will be 
reviewed (Section 7.1.5) as they are reported from the 
investigational centers to identify safety concerns. 
The study may be terminated by the sponsor for any reason at 
any time. For example, the sponsor should terminate the study 
in the event of: 
• 
New toxicological or pharmacological findings or 
safety issues invalidate the earlier positive 
benefit-risk assessment. 
• 
Discontinuation of the development of the IMP. 
If any of the below mentioned criteria are met, enrollment will 
be paused for a safety review by the IDMC (Section 5.9.2): 
• 
A death for which the cause is judged to be related to 
the study drug by the treating investigator; 
Revised to include formal 
rules to pause enrollment 
for a DMC safety review 
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• 
A death for which the cause is judged to be related to 
the study drug by the treating investigator; 
• 
A life-threatening serious adverse event judged to be 
related to the study drug by the treating investigator; 
• 
2 occurrences of Grade 3 or higher (per Common 
Terminology Criteria for Adverse Events [CTCAE] 
grading) adverse events that are assessed to be 
related to the study drug by the investigator; 
• 
2 occurrences of a clinically significant Grade 3 or 
higher (per CTCAE grading) laboratory abnormality 
assessed to be related to the study drug by the 
investigator. 
If the whole study or arms of the study will be stopped, the 
patients that are terminated early will be followed according 
to Withdrawal Criteria and Procedures for the Patient 
(Section 4.3). 
• 
A life-threatening serious adverse event judged to be 
related to the study drug by the treating investigator; 
• 
2 occurrences of Grade 3 or higher (per Common 
Terminology Criteria for Adverse Events [CTCAE] 
grading) adverse events that are assessed to be related 
to the study drug by the investigator; 
• 
2 occurrences of a clinically significant Grade 3 or 
higher (per CTCAE grading) laboratory abnormality 
assessed to be related to the study drug by the 
investigator. 
If the whole study or arms of the study will be stopped, the 
patients that are terminated early will be followed according to 
Withdrawal Criteria and Procedures for the Patient 
(Section 4.3). 
Section 3.5 (Table 1); other sections affected by this change: Appendix B 
Timepoints for DLQI completion: Baseline, Week 12, Week 
24, Week 40  
Additional timepoint for weight measurement: Baseline 
Timepoints for DLQI completion: Baseline, Week 12, Week 
24, Week 40  
Additional timepoint for weight measurement: Baseline 
Added timepoints for DLQI 
completion and additional 
timepoint for weight 
measurement 
e If during IMP administration or during the 2-hour post-IMP 
administration observation the patient develops clinical 
symptoms or signs, vital signs should be collected and a 
physical examination (brief or full, at the discretion of the 
investigator) performed. The patient should be assessed for 
anaphylaxis/hypersensitivity reactions as detailed in 
Section 7.1.6. 
e If during IMP administration or during the 2-hour post-IMP 
administration observation the patient develops clinical 
symptoms or signs, vital signs should be collected and a 
physical examination (brief or full, at the discretion of the 
investigator) performed. The patient should be assessed for 
anaphylaxis/hypersensitivity reactions as detailed in 
Section 7.1.6. 
Added new footnote to 
detail the observation of 
patients after IMP 
administration 
j Note that stool ova and parasite evaluation should be 
performed on day -7 in patients with an eosinophil count >2 
times the ULN on day -14 and risk factors for parasitic 
disease. Stool ova and parasite evaluation will be performed 
by a local laboratory. In case the stool ova and parasite 
evaluation needs to be done by the central laboratory (for 
j Note that stool ova and parasite evaluation should be 
performed on day -7 in patients with an eosinophil count >2 
times the ULN on day -14 and risk factors for parasitic 
disease. Stool ova and parasite evaluation will be performed 
by a local laboratory. In case the stool ova and parasite 
evaluation needs to be done by the central laboratory (for 
Added clarification for 
footnote j 
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some countries), the test can be done at Visit 1 or at an 
unscheduled visit shortly after Visit 1 and the preceding 
eosinophil count can be done locally. 
some countries), the test can be done at Visit 1 or at an 
unscheduled visit shortly after Visit 1 and the preceding 
eosinophil count can be done locally. 
4. SELECTION AND WITHDRAWAL OF PATIENTS 
Section 4.3 
Each patient is free to withdraw from the study or discontinue 
from IMP at any time, without prejudice to their continued 
care. Patients must be withdrawn from the study if any of the 
following events occur: 
1. Patient withdraws consent or requests withdrawal 
from the study or discontinuation from IMP for any 
reason. 
2. Patient develops an illness that would interfere with 
his/her continued participation. 
3. Patient is noncompliant with the study procedures 
and assessments in the opinion of the investigator. 
4. Patient takes prohibited concomitant medications as 
defined in this protocol. 
5. The sponsor requests withdrawal of the patient. 
6. Patients experiencing anaphylaxis (Section 7.1.6) 
have to be discontinued from IMP.  
7. Patient experiences an adverse event or other 
medical condition which indicates to the investigator 
that continued participation is not in the best interest 
of the patient. 
Patients who discontinue from IMP while remaining in the 
study are encouraged to complete end of treatment visit (of 
the main or transition period as applicable) procedures as 
soon as possible after receiving their last dose of IMP and to 
complete the remaining study visits and assessments (with the 
exception of administration of IMP) including the EoS visit 
within the original time frames based on date of 
randomization. The investigator should determine the reason 
for and the date of discontinuation of study treatment and 
record this information in both the source documentation and 
Each patient is free to withdraw from the study or discontinue 
from IMP at any time, without prejudice to their continued 
care. Patients must be withdrawn from the study if any of the 
following events occur: 
1. Patient withdraws consent or requests withdrawal 
from the study or discontinuation from IMP for any 
reason. 
2. Patient develops an illness that would interfere with 
his/her continued participation. 
3. Patient is noncompliant with the study procedures 
and assessments in the opinion of the investigator. 
4. Patient takes prohibited concomitant medications as 
defined in this protocol. 
5. The sponsor requests withdrawal of the patient. 
6. Patients experiencing anaphylaxis (Section 7.1.6) 
have to be discontinued from IMP.  
7. Patient experiences an adverse event or other medical 
condition which indicates to the investigator that 
continued participation is not in the best interest of 
the patient. 
Patients who discontinue from IMP while remaining in the 
study are encouraged to complete end of treatment visit (of the 
main or transition period as applicable) procedures as soon as 
possible after receiving their last dose of IMP and to complete 
the remaining study visits and assessments (with the exception 
of administration of IMP) including the EoS visit within the 
original time frames based on date of randomization. The 
investigator should determine the reason for and the date of 
discontinuation of study treatment and record this information 
in both the source documentation and the CRF. The patient 
Revised withdrawal criteria 
and procedures to include 
IMP discontinuation due to 
anaphylaxis 
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the CRF. The patient should not be considered withdrawn 
from the study due to interruption or discontinuation of IMP. 
Patients should be treated with standard of care after 
withdrawal from or termination of the study as appropriate. 
… 
should not be considered withdrawn from the study due to 
interruption or discontinuation of IMP. 
Patients should be treated with standard of care after 
withdrawal from or termination of the study as appropriate. 
… 
5.  TREATMENT 
Section 5.2.3; other Sections affected by this change: Section 5.9.1 
… 
During the main and transition treatment period, site and 
sponsor representativesthe persons who are involved in 
receipt, storage, distribution, administration, return, and 
accountability of IMP will be unblinded as the IMPs differ in 
appearance: these persons will not be involved in the conduct 
of any study procedures or assessments. 
… 
… 
During the main and transition treatment period, the persons 
who are involved in receipt, storage, distribution, 
administration, return, and accountability of IMP will be 
unblinded as the IMPs differ in appearance: these persons will 
not be involved in the conduct of any study procedures or 
assessments. 
… 
Revised to include reason 
why persons dealing with 
IMP are not blinded 
Sections 5.8 and 5.9.1 
5.8   
Randomization and Blinding 
… 
All patients in the TEV-45779 group will continue to receive 
TEV-45779 during the transition period at the same dose level 
as prior to randomization. During the study main treatment 
period, the sponsor, investigators (and other site staff involved 
in study assessments) and patients will be blinded to the 
treatment assignment of all patients. To maintain blinding of 
the patients and investigators (and other site staff involved in 
study assessments) to the treatment assignment of all patients 
during the entire study, and to maintain blinding of the 
sponsor until the main treatment period is unblinded, the 
re-randomization process will be performed for all patients, 
including the patients in the TEV-45779 group (although only 
patients in the XOLAIR arm will actually be re-randomized 
while patients in the TEV-45779 group will continue to 
receive TEV-45779 in the transition period). The 
5.8   
Randomization and Blinding 
… 
All patients in the TEV-45779 group will continue to receive 
TEV-45779 during the transition period at the same dose level 
as prior to randomization. During the study, the sponsor, 
investigators (and other site staff involved in study 
assessments) and patients will be blinded to the treatment 
assignment of all patients. To maintain blinding to the 
treatment assignment, the re-randomization process will be 
performed for all patients, including the patients in the 
TEV-45779 group (although only patients in the XOLAIR arm 
will actually be re-randomized while patients in the 
TEV-45779 group will continue to receive TEV-45779 in the 
transition period). The randomization will be implemented 
using a Randomization and Trial Supply Management 
(RTSM) system. 
5.9. Maintenance of Randomization and Blinding 
5.9.1. 
Blinding and Unblinding 
Revised to reflect omission 
of unblinded analysis of the 
main treatment period after 
Week 12 
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randomization will be implemented using a Randomization 
and Trial Supply Management (RTSM) system. 
5.9. Maintenance of Randomization and Blinding 
5.9.1. 
Blinding and Unblinding 
… 
Before database lock (DBL), staff responsible for 
pharmacokinetic and immunogenicity bioanalysis will not 
have access to the patient treatment randomization. After the 
last visit of the last patient of the main treatment period and 
DBL for this period and following the formal request of the 
sponsor statistician, the sponsor will unblind the treatments 
for the analysis of the main treatment period (up to and 
including Week 12). 
During the transition period, the sponsor, investigators (and 
other site staff involved in study assessments) and patients 
will be blinded to the randomized treatment and dose of 
patients who received XOLAIR in the main treatment period 
and are re randomized at the beginning of the transition 
period.Only after completion of the study (after Week 40), 
DBL and formal request to unblind from the sponsor 
statistician, will the transition period and the follow upstudy 
be fully unblinded and analyzed. 
… 
… 
Before database lock (DBL), staff responsible for 
pharmacokinetic and immunogenicity bioanalysis will not 
have access to the patient treatment randomization. 
Only after completion of the study (after Week 40), DBL and 
formal request to unblind from the sponsor statistician, will the 
study be fully unblinded and analyzed. 
… 
Section 5.9.1 
… 
The IMP will be prepared in a separate room by the 
non-blinded person (eg, pharmacist or designee). The blinding 
will be maintained during the transportation from and to the 
dosing room. This person will place the respective syringes 
from the original box in a neutral container provided by the 
sponsor to transfer the study medication from the 
pharmacy/storage area to the dosing room. Dosing will be 
performed by a non-blinded staff member in the dosing room. 
Once dosing is complete, the study medication is placed back 
… 
The IMP will be prepared in a separate room by the 
non-blinded person (eg, pharmacist or designee). The blinding 
will be maintained during the transportation from and to the 
dosing room. Dosing will be performed by a non-blinded staff 
member in the dosing room. The original IMP packaging and 
syringes should not be visible when the patient or any other 
blinded study team member enters the room.  
… 
Revised to allow country-
specific procedures for 
maintaining the blinding 
during transportation to and 
from the dosing room 
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into this neutral container to return to the pharmacy/storage 
area for any post dose assessments on the syringes. The 
original IMP packaging and syringes should not be visible 
when the patient or any other blinded study team member 
enters the room. 
… 
Section 5.9.2; other Sections affected by this change: Section 3.1 
There will be no Data Monitoring Committee in this study. 
During the conduct of this study, an IDMC will review 
accumulating unblinded safety data on a regular basis and ad 
hoc if needed, as detailed in the IDMC charter, to ensure the 
continuing safety of the study patients. The IDMC may 
request additional data (eg, efficacy data) if deemed 
necessary. The IDMC will perform a safety review if any of 
the pausing criteria listed in Section 3.4 is met. 
The specific details regarding the IDMC sessions will be 
outlined in the IDMC charter. 
The IDMC will be composed of 2 independent physicians 
with expertise in the relevant therapeutic field and an 
independent statistician. 
The IDMC chairperson will communicate with the sponsor in 
regard to issues resulting from the conduct and clinical 
aspects of the study. The sponsor will work closely with the 
committee to provide the necessary data for review. 
The IDMC will provide recommendations about modifying, 
stopping, or continuing the study. The conduct and specific 
details regarding the IDMC sessions will be outlined in the 
IDMC charter. 
During the conduct of this study, an IDMC will review 
accumulating unblinded safety data on a regular basis and ad 
hoc if needed, as detailed in the IDMC charter, to ensure the 
continuing safety of the study patients. The IDMC may 
request additional data (eg, efficacy data) if deemed necessary. 
The IDMC will perform a safety review if any of the pausing 
criteria listed in Section 3.4 is met. 
The specific details regarding the IDMC sessions will be 
outlined in the IDMC charter. 
The IDMC will be composed of 2 independent physicians with 
expertise in the relevant therapeutic field and an independent 
statistician. 
The IDMC chairperson will communicate with the sponsor in 
regard to issues resulting from the conduct and clinical aspects 
of the study. The sponsor will work closely with the 
committee to provide the necessary data for review. 
The IDMC will provide recommendations about modifying, 
stopping, or continuing the study. The conduct and specific 
details regarding the IDMC sessions will be outlined in the 
IDMC charter. 
Revised to include plans for 
IDMC 
6. ASSESSMENT OF EFFICACY 
Section 6.3 
Added new Section 6.3: 
6.3. Dermatology Life Quality Index  
Added new Section 6.3: 
6.3. Dermatology Life Quality Index  
Added to include 
description of DLQI 
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The Dermatology Life Quality Index (DLQI) will be 
performed at the time points detailed in Table 1. The DLQI 
consists of 10 questions concerning patients' perception of the 
impact of skin diseases on different aspects of their health-
related quality of life over the last week (Finlay and Khan 
1994; further information is available at: 
https://www.cardiff.ac.uk/medicine/resources/quality-of-life-
questionnaires/dermatology-life-quality-index). The DLQI is 
calculated by adding the score of each question, resulting in a 
maximum of 30 and a minimum of 0. The higher the score, 
the more quality of life is impaired. A score higher than 10 
indicates that the patient's life is being severely affected by 
their skin disease. 
The Dermatology Life Quality Index (DLQI) will be 
performed at the time points detailed in Table 1. The DLQI 
consists of 10 questions concerning patients' perception of the 
impact of skin diseases on different aspects of their health-
related quality of life over the last week (Finlay and Khan 
1994; further information is available at: 
https://www.cardiff.ac.uk/medicine/resources/quality-of-life-
questionnaires/dermatology-life-quality-index). The DLQI is 
calculated by adding the score of each question, resulting in a 
maximum of 30 and a minimum of 0. The higher the score, the 
more quality of life is impaired. A score higher than 10 
indicates that the patient's life is being severely affected by 
their skin disease. 
7. ASSESSMENT OF SAFETY 
Section 7.1.3 
The severity of each adverse event must be recorded as 1 of 
the following: 
Mild: 
No limitation of usual activities. 
Moderate: 
Some limitation of usual activities. 
Severe: 
Inability to carry out usual activities. 
The severity of each adverse event, including clinical 
laboratory adverse events, will be graded according to 
CTCAE (Appendix R). 
The severity of each adverse event must be recorded as 1 of 
the following: 
• 
Grade 1: Mild; asymptomatic or mild symptoms; 
clinical or diagnostic observations only; 
intervention not indicated.  
• 
Grade 2: Moderate; minimal, local or 
noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living 
(ADL). (Instrumental ADL refer to preparing 
meals, shopping for groceries or clothes, using 
the telephone, managing money, etc).  
The severity of each adverse event must be recorded as 1 of 
the following: 
Mild: 
No limitation of usual activities. 
Moderate: 
Some limitation of usual activities. 
Severe: 
Inability to carry out usual activities. 
The severity of each adverse event, including clinical 
laboratory adverse events, will be graded according to CTCAE 
(Appendix R). 
The severity of each adverse event must be recorded as 1 of 
the following: 
• 
Grade 1: Mild; asymptomatic or mild symptoms; 
clinical or diagnostic observations only; 
intervention not indicated.  
• 
Grade 2: Moderate; minimal, local or 
noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living 
(ADL). (Instrumental ADL refer to preparing 
meals, shopping for groceries or clothes, using 
the telephone, managing money, etc).  
Revised to include CTCAE 
scale for grading of adverse 
events 
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• 
Grade 3: Severe or medically significant but not 
immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; 
disabling; limiting self care ADL. (Self care 
ADL refer to bathing, dressing and undressing, 
feeding self, using the toilet, taking medications, 
and not bedridden). 
• 
Grade 4: Life-threatening consequences; urgent 
intervention indicated.  
• 
Grade 5: Death related to adverse event. 
• 
Grade 3: Severe or medically significant but not 
immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; 
disabling; limiting self care ADL. (Self care 
ADL refer to bathing, dressing and undressing, 
feeding self, using the toilet, taking medications, 
and not bedridden). 
• 
Grade 4: Life-threatening consequences; urgent 
intervention indicated.  
• 
Grade 5: Death related to adverse event. 
Section 7.1.6 
Anaphylaxis will be considered a protocol-defined adverse 
event of special interest (PDAESI). Anaphylaxis is described 
as highly likely when any 1 of the following 3 criteria based 
on the 2006 Joint National Institute of Allergy and Infectious 
Disease/Food Allergy and Anaphylaxis Network 
(NIAID/FAAN) Second Symposium on Anaphylaxis are 
fulfilled (Sampson et al 2006): 
… 
The process for reporting this PDAESI is the same as that for 
reporting a serious adverse event (see Section 7.1.5.3). 
In the event of suspected anaphylaxis while the patient is at 
the site during the 2-hour observation period following drug 
administration, vital signs should be collected and a physical 
examination (brief or full, at the discretion of the investigator) 
performed. Blood samples to test omalizumab serum 
concentration and ADA formation should be collected if 
possible. Collection of blood samples to test tryptase and/or 
histamine levels are encouraged if available locally at the time 
of the suspected hypersensitivity event. Other assessments 
may be performed at the discretion of the investigator. As a 
precaution, each site should have a resuscitation 
medication/equipment (at a minimum according to local 
regulations) nearby. Information about all suspected 
anaphylaxis and hypersensitivity events will be recorded on 
Anaphylaxis will be considered a protocol-defined adverse 
event of special interest (PDAESI). Anaphylaxis is described 
as highly likely when any 1 of the following 3 criteria based 
on the 2006 Joint National Institute of Allergy and Infectious 
Disease/Food Allergy and Anaphylaxis Network 
(NIAID/FAAN) Second Symposium on Anaphylaxis are 
fulfilled (Sampson et al 2006): 
... 
The process for reporting this PDAESI is the same as that for 
reporting a serious adverse event (see Section 7.1.5.3). 
In the event of suspected anaphylaxis while the patient is at 
the site during the 2-hour observation period following drug 
administration, vital signs should be collected and a physical 
examination (brief or full, at the discretion of the investigator) 
performed. Blood samples to test omalizumab serum 
concentration and ADA formation should be collected if 
possible. Collection of blood samples to test tryptase and/or 
histamine levels are encouraged if available locally at the time 
of the suspected hypersensitivity event. Other assessments 
may be performed at the discretion of the investigator. As a 
precaution, each site should have a resuscitation 
medication/equipment (at a minimum according to local 
regulations) nearby. Information about all suspected 
anaphylaxis and hypersensitivity events will be recorded on 
Added instructions 
regarding the handling of 
potential anaphylaxis cases 
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the Suspected Anaphylaxis CRF, which is based on the 2006 
Joint NIAID/FAAN Second Symposium on Anaphylaxis 
(Sampson et al 2006).  
Patients should be instructed to contact the investigator or 
seek appropriate medical support (eg, in an emergency room) 
should they experience any signs or symptoms indicative of 
anaphylaxis after leaving the site. 
the Suspected Anaphylaxis CRF, which is based on the 2006 
Joint NIAID/FAAN Second Symposium on Anaphylaxis 
(Sampson et al 2006).  
Patients should be instructed to contact the investigator or seek 
appropriate medical support (eg, in an emergency room) 
should they experience any signs or symptoms indicative of 
anaphylaxis after leaving the site. 
Section 7.10; other sections affected by this change: Section 3.5 (Table 1) 
… 
The assessments will be performed at 20, 60 and 120 minutes 
after dosing (Table 1). 
… 
… 
The assessments will be performed at 20, 60 and 120 minutes 
after dosing (Table 1). 
… 
Updated assessment times 
… 
All injection site findings will not be captured as adverse 
events unless they fulfill characteristics that are beyond those 
in the specified forms/scales (eg, necrosis, abscess, etc.) or 
fulfill seriousness criteria and then must be recorded and 
reported as specified in Section 7.1.5. 
… 
All injection site findings will be captured as adverse events 
unless they fulfill characteristics that are beyond those in the 
specified forms/scales (eg, necrosis, abscess, etc.) or fulfill 
seriousness criteria and must be recorded and reported as 
specified in Section 7.1.5. 
Revised to capture all 
injection site findings as 
adverse events 
9. STATISTICS 
Section 9.5.1.1, other Sections affected by this change: Sections 9.5.1.1.1 and 9.5.1.1.2 and Appendix G 
For the FDA submission, the following analyses will be 
considered co-primary: 
• 
The analysis of change from baseline in the ISS7 
at Week 12 will be an ANCOVA with treatment 
group (2 levels: TEV-45779 300 mg and 
XOLAIR 300 mg), baseline itch severity score, 
baseline weight and region (3 levels planned: 
Americas, Europe and Asia-Pacific) as 
covariates. Biosimilarity will be demonstrated if 
the 90% CI for the mean difference between 
TEV-45779 300 mg and XOLAIR 300 mg falls 
entirely within the asymmetric equivalence 
margin of (-2.5, +2.0).  
… 
For the FDA submission, the following analyses will be 
considered co-primary: 
• 
The analysis of change from baseline in the ISS7 
at Week 12 will be an ANCOVA with treatment 
group (2 levels: TEV-45779 300 mg and 
XOLAIR 300 mg), baseline itch severity score, 
baseline weight and region (3 levels planned: 
Americas, Europe and Asia-Pacific) as 
covariates. Biosimilarity will be demonstrated if 
the 90% CI for the mean difference between 
TEV-45779 300 mg and XOLAIR 300 mg falls 
entirely within the asymmetric equivalence 
margin of (-2.5, +2.0).  
… 
Added region as a covariate 
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For the EMA submission, the following analysis will be 
considered primary: 
• 
The analysis of change from baseline in the ISS7 
at Week 12 will be an ANCOVA with treatment 
group (2 levels: TEV-45779 300 mg and 
XOLAIR 300 mg), baseline itch severity score, 
baseline weight and region (3 levels planned: 
Americas, Europe and Asia-Pacific) as 
covariates. Biosimilarity will be demonstrated if 
the 95% CI for the mean difference between 
TEV-45779 300 mg and XOLAIR 300 mg falls 
entirely within the equivalence margin of 
(-2.0, +2.0). 
For the EMA submission, the following analysis will be 
considered primary: 
• 
The analysis of change from baseline in the ISS7 
at Week 12 will be an ANCOVA with treatment 
group (2 levels: TEV-45779 300 mg and 
XOLAIR 300 mg), baseline itch severity score, 
baseline weight and region (3 levels planned: 
Americas, Europe and Asia-Pacific) as 
covariates. Biosimilarity will be demonstrated if 
the 95% CI for the mean difference between 
TEV-45779 300 mg and XOLAIR 300 mg falls 
entirely within the equivalence margin of 
(-2.0, +2.0). 
Section 9.5.1.3 
… 
Additional supplementary analyses to address missing data in 
the relative potency analysis will be provided in SAP. 
… 
Additional supplementary analyses to address missing data in 
the relative potency analysis will be provided in SAP. 
Clarification 
Section 9.11 
9.11 
Planned Interim Analysis 
An interim analysis (IA) may be conducted after all subjects 
have completed the main treatment period in order to 
facilitate Teva’s decision regarding additional studies in the 
clinical development program for TEV-45779 prior to the 
completion of the current study. If performed, the IA will not 
have any impact on the conduct and analyses of this study. 
The IA will be conducted by an external Independent 
Statistician while keeping Teva and the study team blinded. 
No actual numeric results or data will be shared with Teva 
and the study team. The only information that will be 
provided to Teva by the Independent Statistician is the 
Yes/No result for each co-primary comparison for FDA and 
EMA biosimilarity assessment (see Section 9.5.1.1 for 
details). As the IA does not introduce any inflation to the 
9.11 
Planned Interim Analysis 
An interim analysis (IA) may be conducted after all subjects 
have completed the main treatment period in order to facilitate 
Teva’s decision regarding additional studies in the clinical 
development program for TEV-45779 prior to the completion 
of the current study. If performed, the IA will not have any 
impact on the conduct and analyses of this study. The IA will 
be conducted by an external Independent Statistician while 
keeping Teva and the study team blinded. No actual numeric 
results or data will be shared with Teva and the study team. 
The only information that will be provided to Teva by the 
Independent Statistician is the Yes/No result for each co-
primary comparison for FDA and EMA biosimilarity 
assessment (see Section 9.5.1.1 for details). As the IA does not 
introduce any inflation to the Type I error rate of the final 
Deleted previous Section 
9.11 due to omission of 
unblinded analysis of main 
treatment period after Week 
12 and added new Section 
9.11 to present plans 
regarding blinded interim 
analysis 
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Original text with changes shown 
New wording 
Reason/Justification for 
change 
Type I error rate of the final analysis of the study, no 
adjustments of the nominal significance level are required. 
analysis of the study, no adjustments of the nominal 
significance level are required. 
APPENDIX E. URTICARIA ACTIVITY SCORE; same changes made in APPENDIX F. 
IN CLINIC URTICARIA ACTIVITY SCORE 
 
 
Revised format of table 
APPENDIX L. LIST OF PROHIBITED MEDICATIONS 
 
 
Clarification 
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APPENDIX A. CLINICAL LABORATORIES AND OTHER 
DEPARTMENTS AND INSTITUTIONS 
Sponsor’s Authorized Representative 
  
  
Teva ratiopharm 
Legal Representative of the Sponsor in the EU 
Merckle GmbH  
Contact Person: 
 
  
Merckle GmbH, Teva ratiopharm 
Graf-Arco-Strasse 3 
89079 Ulm, Germany 
Tel: 
 
Sponsor’s Medical Expert/Contact Point 
Designated by the Sponsor for Further Information 
on the Study 
EU Medical Monitor 
 
ICON 
Gottlieb-Daimler-Strasse 10 
68165 Mannheim, Germany 
Tel: 
 
Medical monitoring support center contact information:  
Americas: 
 (toll-free) or direct at: 
 
 
EAPA: 
 
 
Coordinating Investigator 
 
 
 
 
 
 
 
 
 
Contract Research Organization 
PHARMACEUTICAL RESEARCH ASSOCIATES 
Inc. 
4130 ParkLake Avenue, Suite 400 
Raleigh, NC 27612, USA  
Central Clinical Laboratory (except India) 
ACM Medical Laboratory, Inc. 
160 Elmgrove Park 
Rochester  
New York 14624, USA  
Tel:
 
Central Clinical Laboratory India 
Metropolis Healthcare Limited 
Plot No. 103 
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Road No. 12 
MIDC 
Andheri (E) 
Mumbai – 400 093 
Maharashtra, India 
Randomization and Trial Supply Management 
(RTSM) System 
Perceptive eClinical Limited d/b/a Calyx with offices at  
Castle Wharf 
4 Canal Street 
Nottingham, United Kingdom 
NG1 7EH 
 
Tel: 
  
Bioanalytical Pharmacokinetics, 
Pharmacodynamics, and Immunogenicity 
Evaluation 
 
Biologics, Assays & Technology (GBT) 
Teva Pharmaceutical Industries, Ltd. 
19 Giborey Israel Street 
Sapir Industrial Zone 
Netanya, Israel 4250419 
Tel: 
 
Trial Supply vendors 
Secondary Labeling and Distribution 
Almac Clinical Services 
(Almac Group Limited) 
20 Seagoe Industrial Estate, Craigavon, BT63 
5QD, Northern Ireland, UK 
 
Tel: 
 
 
Secondary Labeling and Distribution 
Actavis Laboratories UT, Inc 
577 Chipeta Way 
Salt Lake City, UT 84108, USA 
 
Tel:
 
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APPENDIX B. STUDY PROCEDURES AND ASSESSMENTS BY VISIT 
1. Procedures for Screening (Visits 1 and 2, Up to 3-week Period) 
The screening visit (visits 1 and 2) will take place not more than 21 days before the baseline 
visit (visit 3). The interval between V1 and V2 should be at least 5 days; patients that require 
a 3-day adjustment period to reach an approved dose of their H1 antihistamine treatment will 
need an interval of at least 8 days. 
a. Visit 1 (Day -14 [-7/+2 days]) 
The following procedures will be performed: 
• obtain signed and dated informed consent before any study-related procedures are 
performed 
• demographics 
• medical and surgical history 
• document prior medication and treatment history 
• review inclusion and exclusion criteria 
• inquire about adverse events 
• inquire about COVID-19 status 
• complete Physician's (in-clinic) assessment of UAS 
• dispense electronic Patient Symptom Diary (eDiary) 
• comprehensive physical examination 
• height and weight 
•  ECG; 12-lead 
• vital signs measurement 
• obtain blood sample for free and total IgE 
• inform patients of study restrictions and compliance requirements 
• clinical laboratory tests: 
− serum chemistry tests (at V1, serum chemistry sample in non-fasting state may be 
acceptable) 
− serum hematology tests 
− urinalysis 
− COVID-19 testing 
• dispensation of rescue medication 
b. Visit 2 (Day -7 [-2 days]) 
The following procedures will be performed at visit 2: 
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• document prior medication and treatment history 
• review inclusion and exclusion criteria 
• inquire about adverse events 
• inquire about COVID-19 status (if patient exhibits clinical symptoms that may 
indicate COVID-19 infection, COVID-19 testing will be performed locally) 
• complete Physician's (in-clinic) assessment of UAS (it should be completed prior to 
reviewing the diary entries of the patients) 
• check eDiary including UAS 
• stool ova and parasite evaluation (only for patients with an eosinophil count >2× the 
ULN on day -14 and risk factors for parasitic disease) 
• clinical laboratory tests: 
− Urine β-HCG (only for women of childbearing potential). If the urine pregnancy 
test result is positive a serum pregnancy test should be performed by the central 
laboratory. 
• dispensation of rescue medication (if needed) 
2. Procedures During Baseline Visit for Main Treatment Period (Visit 3, Day 1) 
Patients who meet the inclusion and exclusion criteria at visit 2 will continue to visit 3, when 
baseline assessments will be conducted. 
The following procedures will be performed at visit 3, prior to IMP administration: 
• review inclusion and exclusion criteria 
• assign randomization/treatment numbers and enter in CRF 
• weight 
• inquire about adverse events 
• inquire about concomitant medication, including rescue medication 
• inquire about COVID-19 status (if patient exhibits clinical symptoms that may 
indicate COVID-19 infection, COVID-19 testing will be performed locally) 
• complete Physician's (in-clinic) assessment of UAS (it should be completed prior to 
reviewing the diary entries of the patients and must be completed prior to 
administration of IMP) 
• check eDiary including UAS 
• complete DLQI 
• physical examination (abbreviated to detect changes in symptoms of CIU/ CSU) 
• vital signs measurement 
• obtain blood sample for free and total IgE 
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• obtain blood sample for pharmacokinetics 
• clinical laboratory tests: 
− serum chemistry tests 
− serum hematology tests 
− urinalysis 
• obtain blood sample for ADAs 
• dispensation of rescue medication (if needed) 
Patients will have IMP administered by qualified site staff. The following procedure will be 
performed at visit 3, during the 2-hour observation period following IMP administration: 
• local tolerability 
• record device-related adverse events 
3. Procedures During Main Treatment Period (Visits 4 through 5) 
a. Visit 4 (Day 29 ±3 days) 
The following procedures will be performed, prior to IMP administration: 
• inquire about adverse events 
• inquire about concomitant medication, including rescue medication 
• inquire about COVID-19 status (if patient exhibits clinical symptoms that may 
indicate COVID-19 infection, COVID-19 testing will be performed locally) 
• complete Physician's (in-clinic) assessment of UAS (it should be completed prior to 
reviewing the diary entries of the patients and must be completed prior to 
administration of IMP) 
• check eDiary including UAS 
• physical examination (abbreviated to detect changes in symptoms of CIU/CSU) 
• vital signs measurement 
• obtain blood sample for free and total IgE 
• obtain blood sample for pharmacokinetics 
• obtain blood sample for ADAs 
• dispensation of rescue medication (if needed) 
Patients will have IMP administered by qualified site staff. The following procedure will be 
performed at visit 4, during the 2-hour observation period following IMP administration: 
• local tolerability 
• record device-related adverse events 
b. Visit 5 (Day 57 ±3 days) 
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The following procedures will be performed, prior to IMP administration: 
• inquire about adverse events 
• inquire about concomitant medication, including rescue medication 
• inquire about COVID-19 status (if patient exhibits clinical symptoms that may 
indicate COVID-19 infection, COVID-19 testing will be performed locally) 
• complete Physician's (in-clinic) assessment of UAS (it should be completed prior to 
reviewing the diary entries of the patients and must be completed prior to 
administration of IMP) 
• check eDiary including UAS 
• physical examination (abbreviated to detect changes in symptoms of CIU/CSU) 
• vital signs measurement 
• obtain blood sample for free and total IgE 
• obtain blood sample for pharmacokinetics 
• dispensation of rescue medication (if needed) 
Patients will have IMP administered by qualified site staff. The following procedure will be 
performed at visit 5, during the 2-hour observation period following IMP administration: 
• local tolerability 
• record device-related adverse events 
4. Procedures During Visit 6 (Day 85 +3 days) (End of Main Treatment Period 
Visit/Baseline Transition Period) 
The following procedures will be performed at visit 6, prior to IMP administration: 
• randomization for the transition period. Patients in the XOLAIR treatment groups will 
be re-randomized in a 1:1 ratio to receive 3 additional doses of XOLAIR or switch to 
3 doses of TEV-45779 at the same dose, in the transition period. Patients who were 
initially randomized to TEV-45779 will continue to receive TEV-45779 at the same 
dose; however, to maintain blinding, the re-randomization process will be performed 
for all patients (although only patients in the XOLAIR arm will actually be 
re-randomized) 
• inquire about adverse events 
• inquire about concomitant medication, including rescue medication 
• inquire about COVID-19 status (if patient exhibits clinical symptoms that may 
indicate COVID-19 infection, COVID-19 testing will be performed locally) 
• complete Physician's (in-clinic) assessment of UAS (it should be completed prior to 
reviewing the diary entries of the patients and must be completed prior to 
administration of IMP) 
• check eDiary including UAS 
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• complete DLQI 
• physical examination (abbreviated to detect changes in symptoms of CIU/CSU) and 
body weight 
• 12-lead ECG 
• vital signs measurement 
• obtain blood sample for free and total IgE 
• obtain blood sample for pharmacokinetics 
• clinical laboratory tests: 
− serum chemistry tests 
− serum hematology tests 
− urinalysis 
− urine β-HCG (only for women of childbearing potential). If the urine pregnancy 
test result is positive a serum pregnancy test should be performed by the central 
laboratory 
• obtain blood sample for ADAs 
• dispensation of rescue medication (if needed) 
Patients will have IMP administered by qualified site staff. The following procedure will 
be performed at visit 6, during the 2-hour observation period following IMP 
administration: 
• local tolerability 
• record device-related adverse events 
5. Procedures During Transition Period (Visits 7 through 8) 
a. Visit 7 (day 113 ±3 days) 
The following procedures will be performed, prior to IMP administration: 
• inquire about adverse events 
• inquire about concomitant medications, including rescue medication 
• inquire about COVID-19 status (if patient exhibits clinical symptoms that may 
indicate COVID-19 infection, COVID-19 testing will be performed locally) 
• complete Physician's (in-clinic) assessment of UAS (it should be completed prior to 
reviewing the diary entries of the patients and must be completed prior to 
administration of IMP) 
• check eDiary including UAS 
• physical examination (abbreviated to detect changes in symptoms of CIU/CSU) 
• vital signs measurement 
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• obtain blood sample for free and total IgE 
• obtain blood sample for pharmacokinetics 
• dispensation of rescue medication (if needed) 
Patients will have IMP administered by qualified site staff. The following procedure will 
be performed at visit 7, during the 2-hour observation period following IMP 
administration: 
• local tolerability 
• record device-related adverse events 
b. Visit 8 (Day 141 ±3 days) 
The following procedures will be performed, prior to IMP administration: 
• inquire about adverse events 
• inquire about concomitant medications, including rescue medication 
• inquire about COVID-19 status (if patient exhibits clinical symptoms that may 
indicate COVID-19 infection, COVID-19 testing will be performed locally) 
• complete Physician's (in-clinic) assessment of UAS (it should be completed prior to 
reviewing the diary entries of the patients and must be completed prior to 
administration of IMP) 
• check eDiary including UAS 
• physical examination (abbreviated to detect changes in symptoms of CIU/CSU) 
• vital signs measurement 
• obtain blood sample for free and total IgE 
• obtain blood sample for pharmacokinetics 
• dispensation of rescue medication (if needed) 
Patients will have IMP administered by qualified site staff. The following procedure will 
be performed at visit 8, during the 2-hour observation period following IMP 
administration: 
• local tolerability 
• record device-related adverse events 
6. Procedures During Visit 9 (Day 169 ±3 days) (End of Treatment Visit) 
The following procedures will be performed: 
• inquire about adverse events 
• inquire about concomitant medication, including rescue medication 
• inquire about COVID-19 status (if patient exhibits clinical symptoms that may 
indicate COVID-19 infection, COVID-19 testing will be performed locally) 
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• complete Physician's (in-clinic) assessment of UAS (it should be completed prior to 
reviewing the diary entries of the patients) 
• check eDiary including UAS 
• complete DLQI 
• physical examination (abbreviated to detect changes in symptoms of CIU/CSU) 
• 12-lead ECG 
• vital signs measurement 
• obtain blood sample for free and total IgE 
• obtain blood sample for pharmacokinetics 
• clinical laboratory tests: 
− serum chemistry tests 
− serum hematology tests 
− urinalysis 
− urine β-HCG (only for women of childbearing potential). If the urine pregnancy 
test result is positive a serum pregnancy test should be performed by the central 
laboratory 
• obtain blood sample for ADAs 
• dispensation of rescue medication (if needed) 
7. Procedures During Follow-up Period (Visits 10 through 13) 
a. Visit 10 (Day 197 ±3 days), Visit 11 (day 225 ±3 days), and Visit 12 (day 253 
±3 days) 
The following procedures will be performed: 
• inquire about adverse events 
• inquire about concomitant medication, including rescue medication 
• inquire about COVID-19 status (if patient exhibits clinical symptoms that may 
indicate COVID-19 infection, COVID-19 testing will be performed locally) 
• complete Physician's (in-clinic) assessment of UAS (it should be completed prior to 
reviewing the diary entries of the patients) 
• check eDiary including UAS 
• physical examination (abbreviated to detect changes in symptoms of CIU/CSU) 
• vital signs measurement 
• obtain blood sample for free and total IgE 
• obtain blood sample for pharmacokinetics 
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• dispensation of rescue medication (if needed) 
b. Procedures During Visit 13 (day 281 ±3 days) (End of Study/Early Termination 
Visit) 
The following procedures will be performed: 
• inquire about adverse events 
• inquire about concomitant medication, including rescue medication 
• inquire about COVID-19 status (if patient exhibits clinical symptoms that may 
indicate COVID-19 infection, COVID-19 testing will be performed locally) 
• complete Physician's (in-clinic) assessment of UAS (it should be completed prior to 
reviewing the diary entries of the patients) 
• check eDiary including UAS 
• complete DLQI 
• physical examination (abbreviated to detect changes in symptoms of CIU/CSU) and 
body weight 
• 12-lead ECG 
• vital signs measurement 
• obtain blood sample for free and total IgE 
• obtain blood sample for pharmacokinetics 
• clinical laboratory tests: 
− serum chemistry 
− serum hematology 
− urinalysis 
• obtain blood sample for ADAs 
8. Unscheduled Visits 
An unscheduled visit may be performed at any time during the study at the patient’s request 
and as deemed necessary by the investigator. The date and reason for the unscheduled visit 
will be recorded on the CRF as well as any other data obtained from procedures and 
assessments. 
Procedures performed during unscheduled visits include: 
• vital signs measurement 
• inquire about adverse events 
• inquire about COVID-19 status (if patient exhibits clinical symptoms that may 
indicate COVID-19 infection, COVID-19 testing will be performed locally) 
• inquire about concomitant medication 
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• inform patients of study restrictions and compliance requirements 
Other procedures and assessments may be performed at the discretion of the investigator. 
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APPENDIX C. MANAGEMENT OF STUDY ACTIVITIES DURING 
CORONAVIRUS DISEASE 2019 OUTBREAKS 
This appendix addresses the modifications set-up for managing study conduct during 
Coronavirus disease 2019 (COVID-19) outbreaks. 
The changes will be effective in the event of an emergency situation (eg, COVID-19 outbreaks); 
when the situation at specific sites/countries allows the return to regular study activities, this 
appendix will be void for those sites/countries. 
The following sections of the protocol are affected: 
Section 1.3.1 Known and Potential Benefits and Risks of TEV-45779 
In the event of an emergency situation (eg, COVID-19 outbreaks), the sponsor, in close 
collaboration with the investigators, will determine if the benefit-risk assessment remains 
positive as a whole, and will assess any additional risks on a patient-by-patient basis. The 
measures outlined in this appendix are aimed at further mitigating the additional risks in an 
emergency situation. 
Section 3.1 General Study Design and Study Schematic Diagram; Section 3.5 Schedule of 
Study Procedures and Assessments 
In the event of an emergency situation (eg, COVID-19 outbreaks), in case a patient cannot return 
to the clinic for the scheduled visits (eg, due to quarantine, isolation, patient’s concern, active 
COVID-19 infection, or closure of the site clinic) remote assessment of safety via telephone 
and/or videoconference (VC), with VC being the preferred method, may be allowed. 
Modifications to other procedures and assessments (ECG, laboratory sample collection 
[including pharmacokinetics, pharmacodynamics, and immunogenicity] etc.) may be performed 
per implemented contingency measures according to sponsor instructions and the corresponding 
manual. For example, if central laboratory samples cannot be collected for safety assessments, 
sites may have patients visit a local reference laboratory or dispatch a home health nurse to 
perform the assessments, but only after consultation with the sponsor; see Section 7 and 
Section 8 below for details. 
If pharmacokinetics, pharmacodynamics, and immunogenicity samples cannot be collected at 
site, sites may use a home health nurse to collect these blood samples, but only after consultation 
with the sponsor; see Section 7 and Sections 7.5-7.10 below for details. 
If a patient does not continue in the study due to site closure, the patient status should be NOT 
COMPLETED DUE TO: ʽOther’ ʽCOVID-19 logistical reasons prevented patient’s continuation 
in the study’. 
These measures will be implemented on a case-by-case basis, and only when and where they are 
warranted due to the emergency situation. Preferably, the original protocol instructions will be 
followed whenever the new instructions are not required. 
Section 4.3 Withdrawal Criteria and Procedures for the Patient 
If a patient exhibits clinical symptoms that may indicate COVID-19 infection after entering the 
study, the patient should be tested for active COVID-19. If the patient tests positive for active 
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COVID-19, he/she may continue for scheduled visits when recovered (ie, tests negative for 
active COVID-19 infection). 
Section 6 Assessment of Efficacy 
In the event of an emergency situation (eg, COVID-19 outbreaks), in case a patient cannot return 
to the clinic for the scheduled visits (eg, due to quarantine, isolation, patient’s concern, active 
COVID-19 infection, or closure of the site clinic), Physicianʼs Assessment of Urticaria 
Assessment Score should be evaluated if another location might be used after consultation and 
approval by the sponsor. 
These measures will be implemented on a case-by-case basis, and only when and where they are 
warranted due to the emergency situation. Preferably, the full protocol instructions will be 
followed whenever the modified instructions are not required. 
Section 7. Assessment of Safety 
In the event of an emergency situation (eg, COVID-19 outbreaks), in case a patient cannot return 
to the clinic for the scheduled visits (eg, due to quarantine, isolation, patient’s concern, active 
COVID-19 infection, or closure of the site clinic), remote assessment of safety (as well as 
inquiries regarding adverse events and use of concomitant medication) via telephone call and/or 
VC, with VC being the preferred method, may be allowed. The results will be directly entered 
into the CRF per the usual process. 
Modifications to other procedures and assessments (ECG, laboratory sample collection, 
pharmacokinetic sampling, etc.) may be performed per implemented contingency measures 
according to sponsor instructions. For example, if central laboratory samples cannot be collected 
for safety assessments, sites may have patients visit a local reference laboratory or dispatch a 
home health nurse to perform the assessments, but only after consultation with the sponsor. 
These measures will be implemented on a case-by-case basis, and only when and where they are 
warranted due to the emergency situation. These measures will not be implemented for patients 
known to be COVID-19 infectious. Preferably, the original protocol instructions will be followed 
unless the instructions in this appendix are implemented by the sponsor. 
Section 7.5 Clinical Laboratory Tests 
If central laboratory samples cannot be collected for safety assessments, sites may have patients 
visit a local reference laboratory or arrange a home health visit to perform the assessments after 
discussion with and approval by the sponsor. If any patient has clinical laboratory samples 
collected at a local laboratory, the site will be responsible for collection of reference ranges from 
that laboratory. 
Section 7.6 Physical Examinations; Section 7.8 Vital Signs; Section 7.9 
Electrocardiography; Section 7.10 Assessment of Local Tolerability and Pain 
At-home health visits may be used to perform safety assessments such as physical examinations, 
vital signs, ECG, and local tolerability to determine any new adverse events. 
Section 8 Assessment of Pharmacokinetics, Pharmacodynamics, and Immunogenicity 
If pharmacokinetic, pharmacodynamic, and immunogenicity samples cannot be collected due to 
limitations in ability to carry out the procedure or limitations in storage and shipments, the 
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samples will not be collected for those respective visits. Study samples collected from confirmed 
COVID-19 positive patients during the study, with confirmation either before or after the sample 
collection, will be kept at the central laboratory and will not be shipped to Teva bioanalytical 
laboratories nor analyzed. Teva bioanalytical laboratories will be informed within approximately 
1 week of any COVID-19 positive patients confirmed after samples being collected. 
Section 10 Quality Control and Quality Assurance; Appendix H Quality Control and 
Quality Assurance 
Deviations from the study conduct due to emergency situations (eg, COVID-19 outbreaks), 
including implemented contingency measures and their impact (eg, patient discontinuation from 
the study, alternative procedures used to collect critical safety and/or efficacy data, etc.), will be 
described in the appropriate sections of the CSR as applicable. 
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APPENDIX D. PATIENT DIARY 
The patient diary will be provided as a separate document. 
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APPENDIX E. URTICARIA ACTIVITY SCORE 
Wheals (Hives) 
Pruritus (Itch) 
Score 
Criteria 
Score 
Criteria 
0 
None 
0 
None 
1 
Mild (1-6 hives/12 hours) 
1 
Mild 
2 
Moderate (7-12 hives/12 hour) 
2 
Moderate 
3 
Intense (>12 hives/12 hour) 
3 
Severe 
The score is the sum of the wheals (hives) score and pruritus (itch) score. 
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APPENDIX F. IN-CLINIC URTICARIA ACTIVITY SCORE 
Pruritus 
Number of Hives 
Score 
Criteria 
Score 
Criteria 
0 
None 
0 
None 
1 
Mild: minimal awareness, easily 
tolerated 
1 
1= 1-6 
2 
Moderate: definite awareness, 
bothersome but tolerable 
2 
2= 7-12 
3 
Severe: difficult to tolerate 
3 
3= >12 
The score is the sum of the pruritus score and number of hives score. 
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APPENDIX G. RELATIVE POTENCY 
Define 𝑥𝑇= log(𝑋𝑇) and 𝑥𝑅= log(𝑋𝑅) (assume without loss of generality natural logarithm). 
Assume that on the log-dose scale, the horizontal distance between the linear and parallel 
dose-response curves is constant. This condition ensures a unique value for relative potency, 
irrespective of the response level considered. The regression lines for the dose-response curves 
of the treatment (T) and reference (R) products can be expressed respectively as 𝑌𝑇= 𝛼𝑇+ 𝛽∙
𝑥𝑇 and 𝑌𝑅= 𝛼𝑅+ 𝛽∙𝑥𝑅, where 𝑌𝑖 is the response, 𝛼𝑖 is the intercept (𝑖= 𝑇, 𝑅) and 𝛽 is a 
common slope. It can be shown algebraically that log(𝜌) = 𝑥𝑇−𝑥𝑅=
𝛼𝑅−𝛼𝑇
𝛽
, and can be 
estimated by plugging the corresponding estimates 
𝑎𝑅−𝑎𝑇
𝑏
. 
The confidence interval (CI) of the log(𝜌)  
is based on Fieller's theorem. The upper and the lower CI limits are: 
𝑅−𝑔𝑣12
𝑣22 ±𝑡
𝑏[𝑣11−2𝑅𝑣12+𝑅2𝑣22−𝑔(𝑣11−𝑣12
2
𝑣22)]
1
2
1−𝑔
. 
where: 
• R = log(𝜌) =
𝑎𝑅−𝑎𝑇
𝑏
; 
• 𝑔=
𝑡2𝑣22
𝑏2 ; 
• 𝑣11 is the variance of 𝑎𝑅−𝑎𝑇; 
• 𝑣12 is the covariance between 𝑎𝑅−𝑎𝑇 and 𝑏; 
• 𝑣22 is the variance of 𝛽; 
• t is the appropriate percentile of the t-distribution with f degrees of freedom; 
• f are the degrees of freedom on which the residual variance is based. 
Estimates of relative potency and its CI are finally obtained by exponentiating R and the 
confidence limits calculated using Fieller’s theorem. 
The 2-Step Analysis 
The method proposed in Vezzoli (2011) for the analysis of relative potency is based on a 2-step 
approach. 
Step 1 
In the first step an ANCOVA model is estimated in order to verify the required assumptions. The 
treatment effect is decomposed into the effects of product, dose on the log-scale and their 
interaction. 
Baseline itch severity score, baseline weight and region (3 levels planned: Americas, Europe and 
Asia-Pacific) will be used in the model as covariates. 
Based on the estimated model, the assumptions are checked. 
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a. Absence of significant deviations from parallelism: the p-value of the interaction 
product * log(dose) should be ≥0.1. 
b. Significant dose-response relationship: the p-value of the slope for log(dose) should 
be <0.05. 
c. Absence of a significant difference between products: the p-value of the product 
effect should be ≥0.05. 
In absence of evidence against the assumptions, we can proceed to the second step. 
Step 2 
The same model used in Step 1 is estimated excluding the non-significant term for interaction. 
Assumptions B and C may be checked for confirmation. The absence of a significant difference 
between products can now be verified without taking into account particular dose levels, since 
the vertical distance between the dose-response curves is constant due to the exclusion of the 
interaction term from the model. Then log relative potency can be estimated as the ratio between 
the estimated product effect (of note, the difference R-T should be considered instead of the 
usual T-R) and the estimated slope for log(dose): (aR– aT) / b. Its confidence limits can be 
obtained based on the other results from the model. 
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APPENDIX H. QUALITY CONTROL AND QUALITY ASSURANCE 
Protocol Amendments and Protocol Deviations 
Protocol Amendments 
No changes from the final approved (signed) protocol will be initiated without the prior written 
approval or favorable opinion of a written amendment by the IEC/ IRB and national and local 
competent authorities, as applicable, except when necessary to address immediate safety 
concerns to the patients or when the change involves only non-substantial logistics or 
administration. The principal investigator at each investigational center, the coordinating 
investigator (if applicable), and the sponsor will sign the protocol amendment. 
Important Protocol Deviations 
Any deviation from the protocol that affects, to a significant degree, (a) the safety, physical, or 
mental integrity of the patients in the study and/or (b) the scientific value of the study will be 
considered an important protocol deviation. Important protocol deviations may include 
non-adherence on the part of the patient, the investigator, or the sponsor to protocol-specific 
inclusion and exclusion criteria, primary objective variable criteria, or GCP guidelines; 
noncompliance to IMP administration; use of prohibited medications. Important protocol 
deviations will be identified and recorded in the patient's source. All important protocol 
deviations will be reported to the responsible IEC/IRB, as required. 
When an important protocol deviation is reported, the sponsor will determine whether to 
withdraw the patient from the study or permit the patient to continue in the study, with 
documented approval from the medical expert. The decision will be based on ensuring the safety 
of the patient and preserving the integrity of the study. 
Changes in the inclusion and exclusion criteria of the protocol are not prospectively granted by 
the sponsor. If investigational center personnel learn that a patient who did not meet protocol 
inclusion and exclusion criteria was entered in a study, they must immediately inform the 
sponsor of the important protocol deviation. If such patient has already completed the study or 
has withdrawn early, no action will be taken but the deviation will be recorded. 
Information to Study Personnel 
The investigator is responsible for giving information about the study to all personnel members 
involved in the study or in any element of patient management, both before starting the study and 
during the course of the study (eg, when new personnel become involved). The investigator must 
ensure that all study personnel are qualified by education, experience, and training to perform 
their specific task. These study personnel members must be listed on the investigational center 
authorization form, which includes a clear description of each personnel member’s 
responsibilities. This list must be updated throughout the study, as necessary. 
The study monitor is responsible for explaining the protocol to all study personnel, including the 
investigator, and for ensuring they comply with the protocol. 
Study Monitoring 
To ensure compliance with GCP guidelines, the study monitor or representative is responsible 
for ensuring that patients have signed the ICF and the study is conducted according to applicable 
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Standard Operating Procedures (SOP)s, the protocol, and other written instructions and 
regulatory guidelines. 
The study monitor is the primary association between the sponsor and the investigator. The main 
responsibilities of the study monitors are to visit the investigator before, during, and after the 
study to ensure adherence to the protocol, that all data are correctly and completely recorded and 
reported, and that informed consent is obtained and recorded for all patients before they 
participate in the study and when changes to the consent form are warranted, in accordance with 
IEC/IRB approvals. 
The study monitors will contact the investigator and visit the investigational center according to 
the monitoring plan. The study monitor will be permitted to review and verify the various 
records (CRFs and other pertinent source data records, including specific electronic source 
document relating to the study) to verify adherence to the protocol and to ensure the 
completeness, consistency, and accuracy of the data being recorded. 
As part of the supervision of study progress, other sponsor personnel may, on request, 
accompany the study monitor on visits to the investigational center. The investigator and 
assisting personnel must agree to cooperate with the study monitor to resolve any problems, 
errors, or possible misunderstandings concerning the findings detected during the course of these 
monitoring visits or provided in follow-up written communication. 
In case of an emergency situation (eg, the COVID-19 pandemic), where study monitors may not 
be able to access the investigational centers for on-site visits, investigational centers will be 
monitored remotely, where allowed, and in accordance with local regulations. 
Audit and Inspection 
The sponsor may audit the investigational center to evaluate study conduct and compliance with 
protocols, SOPs, GCP guidelines, and applicable regulatory requirements. The sponsor’s Global 
Clinical Quality Assurance, independent of Global Specialty Development, is responsible for 
determining the need for (and timing of) an investigational center audit. 
The investigator must accept that competent authorities and sponsor representatives may conduct 
inspections and audits to verify compliance with GCP guidelines. 
In case of an emergency situation (eg, the COVID-19 pandemic), where auditors may not be able 
to access the investigational centers for on-site visits, investigational centers will be audited 
remotely, where allowed and in accordance with local regulations. 
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APPENDIX I. ETHICS 
Informed Consent 
The investigator, or a qualified person designated by the investigator, should fully inform the 
patient of all pertinent aspects of the study, including the written information approved by the 
IEC/ IRB. All written and oral information about the study will be provided in a language as 
nontechnical as practical to be understood by the patient. The patient should be given ample time 
and opportunity to inquire about details of the study and to decide whether or not to participate in 
the study. The above should be detailed in the source documents. 
Written informed consent will be obtained from each patient before any study specific 
procedures or assessments are done and after the aims, methods, anticipated benefits, and 
potential hazards are explained. The patient’s willingness to participate in the study will be 
documented in the ICF, which will be signed and personally dated by the patient and by the 
person who conducted the informed consent discussion. The investigator will keep the original 
ICFs, and copies will be given to the patients. It will also be explained to the patients that they 
are free to refuse participation in the study and free to withdraw from the study at any time 
without prejudice to future treatment. 
Adult patients with a legally acceptable representative should provide informed consent 
according to national and local requirements. 
Competent Authorities and Independent Ethics Committees/Institutional Review Boards 
Before this study starts, the protocol will be submitted to the national competent authority and to 
the respective IEC/IRB for review. As required, the study will not start at a given investigational 
center before the IEC/IRB and competent authority (as applicable) for the investigational center 
give written approval or a favorable opinion. 
Confidentiality Regarding Study Patients 
The investigator must ensure that the privacy of the patients, including their identity and all 
personal medical information, will be maintained at all times. In CRFs and other documents or 
image material submitted to the sponsor, patients will be identified not by their names, but by an 
identification number. 
Personal medical information may be reviewed for the purpose of patient safety or for verifying 
data in the source and the CRF. This review may be conducted by the study monitor, properly 
authorized persons on behalf of the sponsor, Global Quality Assurance (GCA), or competent 
authorities. Personal medical information will always be treated as confidential. 
Registration of the Clinical Study 
In compliance with national and local regulations and in accordance with Teva standard 
procedures, this clinical study will be registered on trials registry websites. 
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APPENDIX J. BIRTH CONTROL METHODS AND PREGNANCY 
TESTING 
DEFINITIONS 
Women of childbearing potential are defined as: 
• Not surgically (documented hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy) or congenitally sterile nor clinically diagnosed infertile 
(documentation required) as assessed by a physician 
• Not postmenopausal 
Postmenopausal women are defined as: 
• 1 year postmenopausal (no menses for 12 months without an alternative medical 
cause plus an increased concentration of FSH of more than 35 IU/L) in women not 
using hormonal contraception or hormonal replacement therapy 
DESCRIPTION OF DIFFERENT BIRTH CONTROL METHODS 
Highly effective birth control methods in females: 
Highly effective birth control methods that can achieve a failure rate of less than 1% per year 
when used consistently and correctly are considered. Such methods include the following: 
• Combined estrogen and progestogen hormonal contraception (oral, intravaginal, 
transdermal) associated with inhibition of ovulation; these should be initiated at least 
7 days before the first dose of IMP. 
• Progestogen-only hormonal contraception (oral, injectable, or implantable) associated 
with inhibition of ovulation; these should be initiated at least 7 days before the first 
dose of IMP. 
• Intrauterine device or intrauterine hormone-releasing system need to be in place at 
least 2 months before the start of screening. 
• Bilateral tubal occlusion (for hysteroscopic "Essure®" a hysterosalpingogram is 
required 3 months post procedure to assess surgical success) or tubal ligation. 
• Vasectomized partner provided he is the sole sexual partner and has received medical 
assessment of the surgical success. 
• Sexual abstinence is only considered a highly effective method if defined as 
refraining from heterosexual intercourse in the defined period. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the clinical study 
and the preferred and usual lifestyle of the patient. 
Unacceptable birth control methods: 
Periodic abstinence (eg, calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea method are not acceptable methods of 
contraception. Female condom and male condom should not be used together. 
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Male contraception: 
Male patients (including vasectomized men) with partners of childbearing potential (whether 
pregnant or not) must always use condoms prior to IMP administration and until 20 weeks after 
last IMP dose. 
Vasectomy: 
Use of contraceptive methods also applies to vasectomized men. 
Pregnant female partners of male study participants: 
Male study participants must use condoms during intercourse if their female partners are 
pregnant. 
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APPENDIX K. LOST TO FOLLOW-UP 
A patient will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the investigational center. 
The following actions must be taken if a patient fails to return to the investigational center for a 
required study visit: 
• The investigational center must attempt to contact the patient and reschedule the 
missed visit as soon as possible and counsel the patient on the importance of 
maintaining the assigned visit schedule and ascertain whether or not the patient 
wishes to and/or should continue in the study. 
• In cases in which the patient is deemed lost to follow-up, the investigator or designee 
must make every effort to regain contact with the patient (where possible, 3 telephone 
calls and, if necessary, a certified letter to the patient’s last known mailing address or 
local equivalent methods). These contact attempts should be documented in the 
patient’s medical record. 
• Should the patient continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of ‘lost to follow-up’. 
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APPENDIX L. LIST OF PROHIBITED MEDICATIONS 
INN 
Formulation 
Omalizumab or other Anti-IgE therapies 
Injection (sc) 
Dupilumab, Benralizumab  
Injection (sc) 
Corticosteroids 
Systemic or cutaneous (topical) 
Hydroxychloroquine 
Systemic or cutaneous (topical) 
Methotrexate 
Systemic or cutaneous (topical)  
Dapsone, Sulfasalazine 
Systemic or cutaneous (topical) 
Cyclosporine, Tacrolimus, Mycophenolate 
Systemic or cutaneous (topical) 
Cyclophosphamide 
Systemic or cutaneous (topical) 
Doxepin 
Tablet (or other if applicable) 
Leukotriene receptor antagonists (montelukast, zafirlukast, pranlukast) 
Tablet (or other if applicable)  
H2 antagonists (cimetidin, ranitidin, famotidin, nizatidin, roxatidin, 
lafutidin) 
Tablet, granules, suspension, 
injection (iv) 
INN=international nonproprietary name; iv=intravenous; sc=subcutaneous 
Prior to the screening visit (-14 days) and during the study, the following medications and 
treatments will be restricted: 
• Routine (daily or every other day during 5 or more consecutive days) doses of the 
following medications within 30 days prior to day -14: systemic or cutaneous 
(topical) corticosteroids (prescription or over-the-counter), hydroxychloroquine, 
methotrexate, cyclosporine, cyclophosphamide, Tacrolimus, mycophenolate, 
dapsone, or sulfasalazine. 
• Routine (daily or every other day during 5 or more consecutive days) doses of 
doxepin within 14 days prior to day -14. 
• Omalizumab or other anti-IgE therapy within 1 year prior to screening. 
• Any LTRAs (montelukast or zafirlukast) or H2 blockers within 7 days prior to 
day -14. 
• Any H1 antihistamines at greater than approved doses from 3 days after start of 
screening.  
• Either intravenous IgG or plasmapheresis within 30 days prior to day -14. 
• Treatment with an investigational agent within 30 days or longer depending on half-
life (>5 half-lives) prior to the start of screening. 
 
Patients who receive any excluded therapy during screening should be considered a screening 
failure. Patients who receive any excluded therapy after randomization will be discontinued from 
study treatment; under certain circumstances, a patient may be eligible to remain in the study 
when taking prohibited concomitant medications - such cases should be discussed with, and 
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approved by, the medical monitor. If a patient has received at least 1 dose of omalizumab 
following enrollment, the patient should be followed for safety for the remainder of the study. 
Patients taking either LTRAs or H2 blockers for diseases other than CIU (eg, asthma or 
gastroesophageal reflux disease, respectively) will be permitted to continue their use during the 
study. These diseases must be recorded as part of the medical history collected during the 
screening period. Inhaled asthma controllers, including corticosteroids, are also permitted during 
the study. 
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Appendix M. 
PHARMACOKINETICS AND PHARMACODYNAMICS 
SAMPLES 
Instructions for sampling, handling and shipment of the pharmacokinetics and 
pharmacodynamics samples are described in the TV45779-IMB-30086 Laboratory Manual. 
Samples should not be shipped on a holiday. Samples are not to arrive on the Israel weekend or a 
holiday. 
Samples will be analyzed using an appropriate validated method. Timing of the initiation of 
sample analysis will be determined by the management of bioanalytical laboratory responsible 
for the bioanalysis while keeping the study blinding, if any, intact. 
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APPENDIX N. IMMUNOGENICITY SAMPLES 
Instructions for sampling, handling and shipment of the immunogenicity samples are described 
in the TV45779-IMB-30086 Laboratory Manual. 
Samples should not be shipped on a holiday. Samples are not to arrive on the Israel weekend or a 
holiday. 
Samples will be analyzed using an appropriate validated method. Timing of the initiation of 
sample analysis will be determined by the management of bioanalytical laboratory responsible 
for the bioanalysis while keeping the study blinding, if any, intact. 
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APPENDIX O. PRODUCT COMPLAINTS 
I. Clinical Product Complaints/Device Deficiency 
A clinical product complaint is defined as a problem or potential problem with the physical 
quality or characteristics of clinical IMP supplies or clinical device supplies used in a clinical 
research study sponsored by Teva. Examples of a product complaint include but are not limited 
to: 
• suspected contamination 
• questionable stability (eg, color change, flaking, crumbling, etc.) 
• defective components 
• missing or extra units (eg, primary container is received at the investigational center 
with more or less than the designated number of units inside) 
• incorrect packaging, or incorrect or missing labeling/labels 
• unexpected or unanticipated taste or odor, or both 
• device not working correctly or appears defective in some manner 
Each investigational center will be responsible for reporting a possible clinical product complaint 
by completing the product complaint form provided by Teva and emailing it to 
clinical.productcomplaints@tevapharm.com within 48 hours of becoming aware of the issue. 
For complaints involving a device/combination product or other retrievable item, it is required 
that the device/combination product (or item) be sent back to the sponsor for investigative testing 
whenever possible. For complaints involving an IMP, all relevant samples (eg, the remainder of 
the patient’s IMP supply) should be sent back to the sponsor for investigative testing whenever 
possible. 
Product Complaint Information Needed from the Investigational Center 
In the event that the product complaint form cannot be completed, the investigator will provide 
the following information, as available: 
• investigational center number and principal investigator name 
• name, phone number, and address of the source of the complaint 
• clinical protocol number 
• patient identifier (patient study number) and corresponding visit numbers, if 
applicable 
• patient number, bottle, and kit numbers (if applicable) for double-blind or open-label 
studies 
• product available for return Yes/No 
• product was taken or used according to protocol Yes/No 
• description or nature of complaint 
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• device deficiency associated with adverse event Yes/No  
• device deficiency associated serious adverse event Yes/No * 
• device deficiency that could lead to a serious adverse event Yes/No * 
• clinical supplies unblinded (for blinded studies) Yes/No 
• date and name of person receiving the complaint 
Note: Reporting a product complaint must not be delayed even if not all the required information 
can be obtained immediately. Known information must be reported immediately. The sponsor 
will collaborate with the investigator to obtain any outstanding information. 
*Please refer to Table 6 and Table 7. 
Handling of Investigational Medicinal Product(s) at the Investigational Center(s) 
The investigator is responsible for retaining the product in question in a location separate from 
the investigator’s clinical study supplies. The sponsor may request that the investigator returns 
the product for further evaluation and/or analysis. If this is necessary, the clinical study monitor 
or designee will provide the information needed for returning the IMP or device. 
If it is determined that the investigational center must return all IMP or devices, the sponsor will 
provide the information needed to handle the return. 
The integrity of the randomization code and corresponding blinded clinical supplies will be 
maintained whenever possible. A serious adverse event or the potential for a product quality 
problem existing beyond the scope of the complaint may be a reason to unblind the clinical 
supplies for an affected patient, if applicable. 
Adverse Events or Serious Adverse Events Associated with a Product Complaint 
If there is an adverse event or serious adverse event due to product complaint, the protocol 
should be followed for recording and reporting (Section 7.1.2 and Section 7.1.5.3, respectively). 
Documenting a Product Complaint 
The investigator will record in the source documentation a description of the product complaint, 
the initial determination whether the deficiency could have led to a serious adverse event 
(Section II), and any actions taken to resolve the complaint and to preserve the safety of the 
patient. Once the complaint has been investigated by the sponsor and the investigator, if 
necessary, an event closure letter may be sent to the investigational center where the complaint 
originated or to all investigational centers using the product. 
Medical device incidents, including those resulting from malfunctions of the device, must be 
detected, documented, and reported by the investigator throughout the study. 
II. 
Assessment of Device Performance 
Device performance will be assessed by device deficiencies and product complaints.  
A device deficiency is defined as any inadequacy of an investigational medical device or 
combination product with respect to its identity, quality, durability, reliability, usability, safety, 
or performance (Figure 3). This definition includes malfunctions, use errors, inadequate labeling 
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(eg, unintelligible label, incorrect expiry date), and product complaints that are related to the 
IMP.  
The investigator should use Table 6 and Table 7 to help make an initial determination whether 
the device deficiency could have led to a serious adverse event and include this assessment in the 
product complaint form. 
Device deficiencies with potential serious adverse device effect are defined as deficiencies that 
might have led to a serious adverse device effect if (Figure 3): 
• suitable action had not been taken (or) 
• intervention had not been made (or) 
• if circumstances had been less fortunate 
These device deficiencies shall be reported to the IEC/IRB by the investigator and to the 
regulatory authorities by the sponsor according to the national and local regulations. 
Figure 3: 
Decision Tree for Device Deficiencies 
Device Deficiency
Reference 
Appendix O for 
initial device 
deficiency 
determination
YES
NO
• 
Notify IEC/IRB 
• 
Report as product complaint (Appendix O)
Report as product complaint (Appendix O)
Initial determination per 
Appendix O: Could the 
device deficiency have 
led to a SAE?
 
IEC=Independent Ethics Committee; IRB=Institutional Review Board; SAE=serious adverse event 
 
 
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Table 6: 
Potential Use-Related Deficiencies That Could Lead to Serious Adverse 
Events 
Use Step 
Use Error 
Potential Hazard 
Situation 
Potential Harm 
Store the product in the 
appropriate storage 
location 
Failure to store product 
between 2°C and 8°C 
Injection of Degraded or 
Expired Drug 
Injury or impairment 
requiring professional 
medical intervention to 
patient or third party 
Check the product name 
Failure to identify the 
product name 
Injection of Wrong Drug 
Death to patient or third 
party 
Check the product dose 
Failure to identify the 
dose 
Overdose 
Injury or impairment 
requiring professional 
medical intervention to 
patient or third party 
Check the product 
expiration date 
Failure to check the 
expiration date 
Injection of Degraded or 
Expired Drug 
Injury or impairment 
requiring professional 
medical intervention to 
patient or third party 
Allow the product to come 
to room temperature 
Failure to allow the 
product to come to room 
temperature prior to use 
Injection of Degraded or 
Expired Drug 
Injury or impairment 
requiring professional 
medical intervention to 
patient or third party 
Remove the syringe from 
the packaging 
Failure to grasp syringe 
properly when removing 
from packaging. 
Damaged device. 
Injury or impairment 
requiring professional 
medical intervention to 
patient or third party 
Inspect the syringe 
Failure to check the drug 
color and quality.  
Injection of Degraded or 
Expired Drug 
Injury or impairment 
requiring professional 
medical intervention to 
patient or third party 
Choose an injection site 
Failure to select an 
acceptable injection site 
that is consistent with 
subcutaneous injection 
Injection to Wrong Depth 
– Intramuscular or 
Intradermal 
Injury or impairment 
requiring professional 
medical intervention to 
patient or third party 
Clean the injection site 
Failure to clean the 
injection site prior to use 
Improper Aseptic or 
Disinfection Technique 
Permanent impairment or 
life-threatening injury to 
patient or third party 
Pinch the skin 
Failure to pinch the skin 
adequately to achieve the 
intended injection depth 
Injection to Wrong Depth 
– Intramuscular or 
Intradermal 
Injury or impairment 
requiring professional 
medical intervention to 
patient or third party 
Insert the needle into the 
pinched skin 
Failure to manipulate the 
syringe to be at 90 degrees 
Injection to Wrong Depth 
- Intramuscular or 
Intradermal  
Injury or impairment 
requiring professional 
medical intervention to 
patient or third party 
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Table 6: 
Potential Use-Related Deficiencies That Could Lead to Serious Adverse 
Events (Continued) 
Use Step 
Use Error 
Potential Hazard 
Situation 
Potential Harm 
Insert the needle into the 
pinched skin 
Failure to avoid inserting 
the needle through 
clothing. 
Improper Aseptic or 
Disinfection Technique 
Permanent impairment or 
life-threatening injury to 
patient or third party 
Inject the product 
Failure to push the 
plunger rod all the way 
down to activate the 
needle shield. 
Needle Stick Injury - Used 
Needle 
Permanent impairment or 
life-threatening injury to 
patient or third party 
Release the plunger rod 
Failure to release the 
plunger rod to deploy the 
needle shield. 
Needle Stick Injury - Used 
Needle 
Permanent impairment or 
life-threatening injury to 
patient or third party 
Inspect the injection site 
Failure to avoid rubbing 
the injection site. 
Improper Aseptic or 
Disinfection Technique 
Permanent impairment or 
life-threatening injury to 
patient or third party 
Dispose of the used 
product 
Failure to avoid putting 
the cap back on the 
needle. 
Failure to dispose of 
syringe in the intended 
location. 
Needle Stick Injury - Used 
Needle 
Permanent impairment or 
life-threatening injury to 
patient or third party 
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Table 7: 
Potential Design Related Deficiencies That Could Lead to Serious Adverse 
Events 
Device Component 
Failure Mode 
Potential Hazard 
Situation 
Harm 
Syringe assembly 
Cannot push plunger rod to 
deliver drug without an 
extremely forceful push. 
Damaged or inoperable 
device 
Injury or impairment 
requiring professional 
medical intervention to 
patient or third party 
Syringe assembly 
Syringe assembly appears 
damaged and inoperable. 
Damaged or inoperable 
device 
Injury or impairment 
requiring professional 
medical intervention to 
patient or third party 
Syringe assembly  
Drug product leaks. 
Breach of container 
closure integrity or 
other sterile barrier 
Permanent impairment or 
life- threatening injury to 
patient or third party 
Rigid Needle Shield 
The rigid shell detaches from 
the elastomer when user 
removes the RNS. 
Damaged or inoperable 
device 
Injury or impairment 
requiring professional 
medical intervention to 
patient or third party 
Rigid Needle Shield 
The RNS cannot be removed 
from the needle. 
Damaged or inoperable 
device 
Injury or impairment 
requiring professional 
medical intervention to 
patient or third party 
Rigid Needle Shield 
The RNS detaches from the 
needle during shipping and 
storage. 
Breach of container 
closure integrity or 
other sterile barrier 
Permanent impairment or 
life- threatening injury to 
patient or third party 
Rigid Needle Shield 
Needle tip punctures the 
RNS. 
Breach of container 
closure integrity or 
other sterile barrier 
Permanent impairment or 
life- threatening injury to 
patient or third party 
Needle 
Needle has blunted or 
otherwise damaged tip 
Damaged or inoperable 
device 
Injury or impairment 
requiring professional 
medical intervention to 
patient or third party 
Needle 
Needle deforms when 
attempting insertion into 
patient's skin. 
Damaged or inoperable 
device 
Injury or impairment 
requiring professional 
medical intervention to 
patient or third party 
Needle 
Needle clogged 
Damaged or inoperable 
device 
Injury or impairment 
requiring professional 
medical intervention to 
patient or third party 
Needle Safety Device 
The NSD activates 
prematurely. 
Damaged or inoperable 
device 
Injury or impairment 
requiring professional 
medical intervention to 
patient or third party 
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Table 7: 
Potential Design Related Deficiencies That Could Lead to Serious Adverse 
Events (Continued) 
Device Component 
Failure Mode 
Potential Hazard 
Situation 
Harm 
Needle Safety Device 
The NSD does not fully 
shield the needle after 
activation. 
Needle Stick Injury - 
Used Needle 
Permanent impairment or 
life- threatening injury to 
patient or third party 
Needle Safety Device 
The activated NSD is 
overridden to expose a used 
needle. 
Needle Stick Injury - 
Used Needle 
Permanent impairment or 
life- threatening injury to 
patient or third party 
Needle Safety Device 
The NSD does not activate 
post-injection. 
Needle Stick Injury - 
Used Needle 
Permanent impairment or 
life- threatening injury to 
patient or third party 
Tamper Seal 
Carton closure seal is not 
adhered to carton or broken. 
Tampered Product 
Injury or impairment 
requiring professional 
medical intervention to 
patient or third party 
Carton 
Carton is damaged 
Damaged or inoperable 
device 
Injury or impairment 
requiring professional 
medical intervention to 
patient or third party 
Labeling 
Critical information missing 
or incomplete 
Exposure to toxic 
substance or degraded 
drug 
Injury or impairment 
requiring professional 
medical intervention to 
patient or third party 
 
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APPENDIX P. DATA MANAGEMENT AND RECORD KEEPING 
Direct Access to Source Data and Documents 
All patient data must have supportive original source documentation in the medical records, or 
equivalent, before they are transcribed to the CRF. Data may not be recorded directly on the CRF 
and considered as source data unless the sponsor provides written instructions specifying which 
data are permitted to be recorded directly to the CRF. 
If data are processed from other institutions or by other means (eg, clinical laboratory, central 
image center, or electronic diary data) the results will be sent to the investigational center, where 
they will be retained but not transcribed to the CRF, unless otherwise noted in the protocol. 
These data may also be sent electronically to the sponsor (or organization performing data 
management). 
The medical experts, study monitors, auditors, IEC/ IRB, and inspectors from competent 
authority (or their agents) will be given direct access to source data and documents (eg, medical 
charts/records, laboratory test results, printouts, videotapes) for source data verification, provided 
that patient confidentiality is maintained in accordance with national and local requirements. 
The investigator must maintain the original records (ie, source documents) of each patient’s data 
at all times. The investigator must maintain a confidential patient identification list that allows 
the unambiguous identification of each patient. 
Data Collection 
Data will be collected using CRFs that are specifically designed for this study. The data collected 
on the CRFs will be captured in a clinical data management system (CDMS) that meets the 
technical requirements described in 21 Code of Federal Regulations (CFR) Part 11 (USA) and 
documents of other concerned competent authorities. Before using the CDMS, it will be fully 
validated and all users will receive training on the system and study-specific training. After they 
are trained, users will be provided with individual system access rights. 
Data will be collected at the investigational center by appropriately designated and trained 
personnel, and CRFs must be completed for each patient who provided informed consent. Patient 
identity should not be discernible from the data provided on the CRF. 
If data are processed from other sources (eg, central laboratory, bioanalytical laboratory, central 
image center, electronic diary data, electronic patient-reported outcome [ePRO] tablet), these 
data will be sent to the investigational center, where they will be retained but not transcribed to 
the CRF, unless otherwise noted in the protocol. These data may also be sent electronically to the 
sponsor (or organization performing data management). All patient data must have supportive 
original source documentation in the medical records, or equivalent, before they are transcribed 
to the CRF. Data may not be recorded directly on the CRF and considered as source data unless 
the sponsor provides written instructions specifying which data are permitted to be recorded 
directly to the CRF. 
For patients who enter a study but do not meet entry criteria, at a minimum, data for screening 
failure reason, demography, and adverse events from the time of informed consent will be 
entered in the CRF. 
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Data Quality Control 
Data Management is responsible for the accuracy, quality, completeness, and internal 
consistency of the data from this study. Oversight will be carried out as described in the 
sponsor’s SOPs for clinical studies. Day to day data management tasks for this study are 
delegated to a contract organization, and these functions may be carried out as described in the 
SOPs for clinical studies at that organization. These SOPs will be reviewed by the sponsor before 
the start of data management activities. 
Data will be verified by the study monitor, using the data source, and reviewed by data 
management using both automated logical checks and manual review. Data identified as 
erroneous, or data that are missing, will be referred to the investigational center for resolution 
through data queries. Any necessary changes will be made in the clinical database, and data 
review and validation procedures will be repeated as needed. Data from external sources will be 
compared with the information available in the CDMS and any discrepancies will be queried. 
Applicable terms will be coded according to the coding conventions for this study. 
At the conclusion of the study, the CDMS and all other study data will be locked to further 
additions or corrections. Locking the study data represents the acknowledgment that all data have 
been captured and confirmed as accurate. All data collected will be approved by the investigator 
at the investigational center. This approval acknowledges the investigator’s review and 
acceptance of the data as being complete and accurate. 
Archiving of Case Report Forms and Source Documents 
Sponsor Responsibilities 
The original CRFs will be archived by the sponsor. Investigational center-specific CRFs will be 
provided to the respective investigational centers for archiving. 
Investigator Responsibilities 
The investigator must maintain all written and electronic records, accounts, notes, reports, and 
data related to the study and any additional records required to be maintained under country, 
state/province, or national and local laws, including, but not limited to: 
• full case histories 
• signed informed consent forms 
• patient identification lists 
• CRFs for each patient on a per-visit basis 
• data from other sources (eg, central laboratory, bioanalytical laboratory, central image 
center, electronic diary) 
• safety reports 
• financial disclosure reports/forms 
• reports of receipt, use, and disposition of the IMP 
• copies of all correspondence with sponsor, the IEC/IRB, and any competent authority 
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The investigator will retain all records related to the study and any additional records required, as 
indicated by the protocol and according to applicable laws and regulations, until the CRO or 
sponsor notifies the institution in writing that records may be destroyed. If, after 25 years from 
study completion, or earlier in the case of the investigational center closing or going out of 
business, the investigator reasonably determines that study record retention has become unduly 
burdensome, and sponsor has not provided written notification of destruction, then the 
investigator may submit a written request to sponsor at least 60 days before any planned 
disposition of study records. After receipt of such request, the sponsor may make arrangements 
for appropriate archival or disposition, including requiring that the investigator deliver such 
records to the sponsor. The investigator shall notify the sponsor of any accidental loss or 
destruction of study records. 
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APPENDIX Q. PUBLICATION POLICY 
All unpublished information given to the investigator by the sponsor shall not be published or 
disclosed to a third party without the prior written consent of the sponsor. 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission. 
This allows the sponsor to protect proprietary information and to provide comments. 
The sponsor will comply with the requirements for publication of study results: 
“Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in 
Medical Journals” (ICMJE 2019). Publication of the results will occur in a timely manner 
according to applicable regulations. In accordance with standard editorial and ethical practice, 
the sponsor will generally support publication of multicenter studies only in their entirety and not 
as individual investigational center data. In this case, a coordinating investigator will be 
designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements: 
• Substantial contributions to the conception or design of the work; or the acquisition, 
analysis, or interpretation of data for the work. 
• Drafting the work or revising it critically for important intellectual content. 
• Final approval of the version to be published. 
• Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved. 
The publications committee established by the sponsor will oversee this process. Additional 
publications may follow. Policies regarding the publication of the study results are defined in the 
financial agreement. 
No patent applications based on the results of the study may be made by the investigator nor may 
assistance be given to any third party to make such an application without the written 
authorization of the sponsor. 
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APPENDIX R. CTCAE GRADING SCALE 
The CTCAE Grading Scale will be provided as a separate document. 
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APPENDIX S. ADDITIONAL INFORMATION TO THE PROTOCOL 
FOR SOUTH KOREA 
The sponsor sought advice for the study protocol regarding detailed study design and statistical 
analysis from the FDA (Type 2 meetings, 2020, 2021) and the EMA (Scientific Advice Meeting, 
2020, SA Follow Up, 2020). 
The EMA agreed essentially to the study design proposed by the sponsor. 
Later, the FDA requested a different study design with at least 600 patients, inclusion of arms 
with 150 mg doses of TEV-45779 or XOLAIR and an additional co-primary endpoint of relative 
potency of 2 dose levels.  
Harmonization of study design according to the FDA requests was not accepted by the EMA. 
The sponsor incorporated the different requests into the study design. Therefore, the study 
protocol contains two statistical approaches for FDA and EMA, respectively.  
In this study, patients will be randomly assigned to 1 of the 4 treatment arms and may receive 
150 mg or 300 mg doses of TEV-45779 or XOLAIR. Thus, patients from a specific country will 
be randomized to all treatment arms.  
Patients from South Korea will be part of the whole study population. Their data will be pooled 
and analyzed with the data from all study patients.  
There will be 1 primary analysis according to FDA criteria and 1 according to EMA criteria. The 
results of both analyses will be completely reported in the Clinical Study Report.  
As this is an investigational medicinal product, Teva has not determined at this time if a 
Marketing Authorization Application (MAA) will be submitted to the Ministry for Food and 
Drug Safety (MFDS). In the event that an MAA is submitted to the MFSD, Teva will determine 
the successfulness of this study result in South Korea by using EMA criteria as specific criteria 
for South Korea. 
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APPENDIX T. ADDITIONAL INFORMATION TO THE PROTOCOL 
FOR INDIA 
For India, Cetirizine is to be used as the single H1 antihistamine at stable and fixed doses, not 
exceeding label recommendations, as a uniform standard treatment regimen, throughout the 
entire study according to Section 3.1.  
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