Clinical trial NCT04545385
Conditions: Asthma
Keywords: T2 low, non-T2 asthma
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Start date: 2020-10-07; Completion date: 2022-01-17
Enrollment: 65 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the study is to evaluate the effect of TEV-48574 compared with placebo on loss of asthma control (LoAC) in adult participants with T2-low and non-T2 severe asthma uncontrolled on inhaled corticosteroids plus long-acting beta-agonists (ICS+LABA).

The secondary efficacy objective is to evaluate the effect of TEV-48574 compared with placebo on a range of clinical measures of asthma control.

The duration of participant participation in the study is planned to be up to approximately 30 weeks.

Detailed description:

Arms: arm 1: Participants will receive the investigational medicinal product (IMP) loading doses on the day of randomization and the subsequent corresponding IMP maintenance doses every 2 weeks for a total of 8 doses (1 loading dose and 7 maintenance doses). arm 2: Participants will receive placebo matching to TEV-48574 SC every 2 weeks for a total of 8 doses.
Interventions: intervention 1: TEV-48574 intervention 2: Placebo
Intervention descriptions: intervention 1: subcutaneous infusion intervention 2: Matching Placebo

Protocol documents:
Prot_000.pdf: 
 
 
 
Clinical Study Protocol 
 
 
A 16-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, 
Proof-of-Concept Study to Evaluate the Efficacy and Safety of TEV-48574 in 
Adults with T2-low/non-T2 Severe Uncontrolled Asthma 
 
 
Study Number TV48574-AS-20031 
 
 
NCT04545385 
 
 
Protocol with Amendment 02 Approval Date: 28 April 2021 


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Clinical Study Protocol with Amendment 02
Study TV48574-AS-20031
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Clinical Study Protocol with Amendment 02
Study Number TV48574-AS-20031
A 16-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, 
Proof-of-Concept Study to Evaluate the Efficacy and Safety of TEV-48574 in Adults with 
T2-low/non-T2 Severe Uncontrolled Asthma
Short title: A Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of 
TEV-48574 in Adults with Severe Uncontrolled Asthma
Title of the protocol for lay people: A Study to Test if TEV-48574 is Effective in Relieving 
Asthma
Proof of Concept Study (Phase 2a)
IND number: 133677;
NDA number: NA;
BLA number: NA;
EudraCT number: 2020-001927-15
EMA Decision number of Pediatric Investigation Plan: NA 
Article 45 or 46 of 1901/2006 does not apply 
Original Protocol Approval Date: 28 May 2020
Protocol with Amendment 01 Approval Date: 09 November 2020
Protocol with Amendment 02 Approval Date: 28 April 2021
Sponsor
Teva Branded Pharmaceutical
Products R&D, Inc.
145 Brandywine Parkway,
West Chester, Pennsylvania 19380
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 and/or its affiliates. The recipient agrees 
that no information contained herein may be published or disclosed without written approval from the sponsor.
© 2020 Teva Branded Pharmaceutical Products R&D, Inc. All rights reserved.


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AMENDMENT HISTORY
The protocol for Study TV48574-AS-20031 (original protocol dated 28 May 2020) has been 
amended and reissued as follows:
Amendment 02
28 April 2021
12 patients randomized to date
Administrative Letter 02
02 December 2020
7 patients randomized to date
Amendment 01
09 November 2020
6 patients randomized to date
Administrative Letter 01
13 October 2020
2 patients randomized to date
The Summary of Changes to the Protocol includes the corresponding reason/justification for 
each change and is provided in Section 15.


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INVESTIGATOR AGREEMENT
Clinical Study Protocol with Amendment 02 Dated 28 April 2021
Clinical Study Protocol with Amendment 01 Dated 09 November 2020
Original Protocol Dated 28 May 2020
IND number: 133677;
NDA number: NA;
BLA number: NA; 
EudraCT number: 2020-001927-15
EMA Decision number of Pediatric Investigation Plan: NA
Article 45 or 46 of 1901/2006 does not apply
A 16-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, 
Proof-of-Concept Study to Evaluate the Efficacy and Safety of TEV-48574 in Adults with 
T2-low/non-T2 Severe Uncontrolled Asthma
Principal Investigator: 
Title:
Address of Investigational Center:
Tel:
I have read the protocol 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, investigational medicinal products (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


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SPONSOR PROTOCOL APPROVAL
Sponsor’s Authorized 
Representative
 
 
Signature
Date
Executed signature pages are maintained separately within the Trial Master File.


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COORDINATING INVESTIGATOR AGREEMENT
Clinical Study Protocol with Amendment 02 Dated 28 April 2021
Clinical Study Protocol with Amendment 01 Dated 09 November 2020
Original Protocol Dated 28 May 2020
IND number: 133677;
NDA number: NA;
BLA number: NA;
EudraCT number: 2020-001927-15
EMA Decision number of Pediatric Investigation Plan: NA
Article 45 or 46 of 1901/2006 does not apply
A 16-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, 
Proof-of-Concept Study to Evaluate the Efficacy and Safety of TEV-48574 in Adults with 
T2-low/non-T2 Severe Uncontrolled Asthma
I have read the protocol 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 and 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 patient information, IMPs shipment and return forms, and other information collected 
during the study, in accordance with my responsibilities under the function of the coordinating 
investigator and in accordance with national and local Good Clinical Practice (GCP) regulations 
as well as all other national and international laws and regulations. In addition I will assume the 
responsibility of the coordinating investigator according to a separate contract.
Coordinating Investigator
Title:
Address of Investigational Center:
Tel:
Coordinating Investigator
Signature
Date
Executed signature pages are maintained within the Investigator Site File and Trial Master File.


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CLINICAL STUDY PROTOCOL SYNOPSIS
With Amendment 02
Study TV48574-AS-20031
Title of Study: A 16-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Proof-of-Concept 
Study to Evaluate the Efficacy and Safety of TEV-48574 in Adults with T2-low/non-T2 Severe Uncontrolled 
Asthma
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc 
IND Number: 133677
EudraCT Number: 2020-001927-15
Name of Active Ingredient: TEV-48574
Name of Investigational Medicinal Product: Fully human monoclonal antibody to tumor necrosis factor (ligand) 
1A (TL1A)
Type of Study: Proof of Concept, Phase 2a
Indication: T2-low/non-T2 Severe Uncontrolled Asthma
Is this study conducted to investigate the New Use of an approved, marketed product? 
No
Number of Investigational Centers Planned: ~75
Countries Planned: United States and the European Union, ~5 countries
Planned Study Period: Q3 2020 to Q3 2022
Number of Patients Planned: Approximately 124 to 174 patients; the final number may be determined based on an 
interim analysis.
Study Population: Adult patients aged 18 years and older with T2-low and non-T2 uncontrolled severe asthma.
Primary Objective: The primary objective of the study is to evaluate the effect of TEV-48574 compared with 
placebo on loss of asthma control (LoAC) in adult patients with T2-low and non-T2 severe asthma uncontrolled on 
inhaled corticosteroids plus long-acting beta-agonists (ICS+LABA).
Secondary Objectives: The secondary efficacy objective is to evaluate the effect of TEV-48574 compared with 
placebo on a range of clinical measures of asthma control. 
Other Objectives: Other objectives include the evaluation of the safety and tolerability, device-related events, 
pharmacokinetics, and immunogenicity of TEV-48574.
Exploratory Objectives:
 
Study Endpoints:
Primary Efficacy Endpoint: 
The primary efficacy endpoint is the proportion of patients who experience LoAC during the treatment period.
LoAC is defined as any one of the following during the treatment period:

Morning peak expiratory flow (PEF) decrease ≥30% from baseline on 2 consecutive days or morning 
handheld forced expiratory volume in the first second of exhalation (FEV1) decrease ≥20% from 
baseline on 2 consecutive days 

Increase in short-acting beta agonist (SABA)/quick-relief medication ≥6 puffs over baseline use in 
24 hours on 2 consecutive days

Increase in ICS dose ≥4x most recent dose

Systemic corticosteroid use


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
Asthma ER visit or hospitalization
Key Secondary Efficacy Endpoints: 
The key secondary efficacy endpoints are as follows:

Time from randomization to LoAC during the treatment period

Asthma Control Questionnaire 6-question version (ACQ-6) at end-of-treatment (EOT) and throughout 
the study 

FEV1 (% predicted, L) at EOT and throughout the study

Use of SABA quick relief medication at EOT and throughout the study
Other Secondary Efficacy Endpoints:
The other efficacy endpoints are as follows:

Proportion of patients who have a clinical asthma exacerbation (CAE) during the treatment period
CAE is defined as a worsening of asthma symptoms resulting in any of the following: 

The use of systemic corticosteroids (oral or injectable)

An emergency department visit due to asthma treated with systemic corticosteroids

An inpatient hospitalization due to asthma. 
Note: CAEs are a subset of LoACs

Time from randomization to first CAE during the treatment period

Number of nighttime awakenings due to asthma during the treatment period

Percent decrease in ICS dose during the treatment period

Other lung function parameters as assessed by hand-held spirometry at end of treatment (EOT) and 
throughout the study

Fractional exhaled nitric oxide (FeNO) throughout the study
Safety Endpoints
The safety endpoints for this study are as follows:

Frequency of adverse events

Change from baseline in clinical laboratory test results (serum chemistry, hematology, and urinalysis) 
throughout the study

Change from baseline in vital signs throughout the study

Change from baseline in 12-lead electrocardiogram (ECG) findings throughout the study

Use of concomitant medication

Local tolerability

Number (%) of patients who did not complete the study due to adverse events
Device-Related Events

All device-related adverse events, malfunctions etc. will be recorded and evaluated for their impact 
relative to the safety and efficacy of the investigational medicinal product.  
Pharmacokinetic Endpoints
The pharmacokinetic endpoints for this study are as follows:

Trough serum TEV-48574 concentrations throughout the study (sparse sampling)

Population pharmacokinetic analysis of pharmacokinetic data


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Immunogenicity endpoints
The immunogenicity endpoints for this study are as follows:

Assessment of treatment-emergent anti-drug-antibody (ADA) results and responses: change from 
baseline and throughout the study 

Impact of the presence of ADAs on pharmacokinetics and clinical safety (if possible) 

Assessment of neutralizing ADA in ADA positive patients throughout the study
Exploratory analyses
General Design: This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 
proof-of-concept (POC) study to evaluate the efficacy and safety of TEV-48574 administered subcutaneously (sc) 
every 2 weeks in adult patients aged 18 years and older with T2-low and non-T2 uncontrolled severe asthma. The 
primary efficacy endpoint is the proportion of patients who experience LoAC during the treatment period. 
Eligibility requirements include: peripheral blood eosinophil counts of <250 cells/μL (at least 2 out of 3 
measurements both <250 cells/μL separated by 2 weeks [± 3 days]); an ACQ-6 score ≥1.5 despite daily treatment 
with medium/high dose ICS+LABA for at least 3 months with a stable dose for at least 1 month prior to screening, 
with or without other asthma controller medications, and at least one clinical asthma exacerbation (worsening of 
asthma requiring systemic corticosteroids [oral or injected], or an emergency department visit due to asthma, or an 
inpatient hospitalization due to asthma, or a 2-fold or higher increase from the subject's usual maintenance ICS dose 
during the exacerbation period documented in the patient’s medical or pharmacy records in the 18 months prior to 
(but not within 30 days of) the initial screening visit (Visit S1). Patients with asthma controller medications 
(excluding systemic corticosteroids and systemic immunomodulatory therapies) in addition to ICS+LABA may be 
eligible provided all eligibility criteria are met. 
The study will consist of an approximate 4- to 5-week screening/run-in period, a 16-week treatment period, and an 
8-week follow-up period. The initial 5-week period consisting of screening plus run-in may be extended for up to 
14 days if needed for the shipment of investigational medicinal product (IMP) to the investigational site or to 
complete assessment of eosinophil counts. All inclusion and exclusion criteria, with the exception of the second 
eosinophil count, should be assessed within the first 2 weeks of Visit S1. If a patient contracted and recovered from 
coronavirus disease 2019 (COVID-19) more than 6 weeks prior to screening, and the patient was not admitted to a 
hospital’s ICU during that COVID-19 infection, and if the patient’s symptoms from COVID-19 completely resolved 
back to pre-COVID-19 status (no lingering anosmia, weakness, persistent dyslogia or feelings of dysphoria for many 
months after the infection resolved), then the patient may enroll in the trial. The principal investigator should 
determine whether or not the subject has truly recovered back to his/her usual pre-COVID-19 status and is eligible 
for enrollment in the study. 
A hand-held spirometer and an e-diary will be dispensed at the second screening visit (Visit S2), 2 weeks (± 3 days) 
after the initial S1 screening visit, and will be trained on their use. Patients who meet all inclusion criteria (except 
for eosinophil counts if assessment is incomplete) and none of the exclusion criteria are eligible to enter the run-in 
and have their ICS+LABA standardized with study-provided ICS+LABA (background asthma controller therapy) at 
Visit S2; this should start at least 2 weeks prior to randomization and marks the start the of run-in. At the end of run-
in, patients who continue to meet all of the inclusion criteria, none of the exclusion criteria, and all of the 
randomization criteria will be eligible to be randomized to TEV-48574 (
 
 For patients who are 
randomized, the standardized ICS+LABA dose must be maintained and the patient held stable on that dose for the 
first 4 weeks of the treatment period, followed by a structured decrease in background asthma controller therapies 
for patients not meeting criteria for LoAC. Patients will be monitored via hand-held spirometry and e-diary daily, 
including between visits, throughout the study. Patients who experience an event of LoAC will be treated by the 
investigator, discontinue IMP, restart (or increase) background asthma controller therapies, and remain in the study 
and complete all remaining visits, procedures and assessments, except for IMP administration. The total duration of 
patient participation in the study is planned to be up to approximately 30 weeks.
Brief Summary of Study Design for the Trial Registry(ies): The main purpose of this study is to test if 
TEV-48574 is effective in preventing loss of asthma control when background therapies are decreased in a 
structured manner. Researchers will look at 2 different groups of patients: 1 group of patients who are administered 
the study drug and 1 group of patients who are administered a placebo. The study is “double-blind,” which means 


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patients and researchers will not know who takes TEV-48574 or placebo. In addition to testing the efficacy of 
TEV-48574, the safety, pharmacokinetics, and immunogenicity of TEV-48574 will also be assessed.
Method of Blinding and Randomization: This is a randomized, double-blind, placebo-controlled study. Patients 
who meet all inclusion criteria, none of the exclusion criteria and all of the randomization criteria will be randomly 
assigned to receive TEV-48574 or placebo to match TEV-48574, in a 1:1 ratio. Patients will be randomly assigned 
to the treatment groups by means of a computer-generated randomization list using interactive response technology 
after confirmation of all eligibility criteria. The study patients and the clinical team at the site will be blinded to 
treatment assignment until the database is locked for analysis. Individuals who may not be blinded include (but are 
not limited to) the bioanalytical scientists, pharmacokineticists, and biostatisticians who are not directly involved in 
study conduct. 
Study Drug Dose, Mode of Administration, and Administration Rate: TEV-48574 for sc injection is provided as 
a liquid solution with a concentration of 100 mg/mL. Placebo IMP is provided as a liquid solution in the same 
formulation as TEV-48574, except for absence of active protein. 
 


Placebo to match TEV-48574
 
Investigational Medicinal Product (IMP): TEV-48574
Reference IMP: 
Placebo: matching placebo
Comparison Drug: None
Duration of Patient Participation: Approximately 30 weeks, including an approximate 4- to 5-week screening/ 
run-in period (that can be extended by 2 weeks where required), 16-week treatment period, and 8-week follow-up 
period. 
End of Study: End of study (EOS) is defined as the last visit of the last patient at the follow-up visit (V11 EOS). 
Plans for Treatment or Care after the Patient Has Ended Participation in the Study: The investigator will 
discuss with the patient the return to appropriate medical care and medication as part of standard of care provided by 
the patient’s primary physician and specialists.
Inclusion Criteria: Patients may be included in the study only if they meet all of the following criteria:
a.
The patient is a man or woman of any ethnic origin, at least 18 years of age at the time of signature of 
the informed consent form (ICF). 
b.
The patient has a diagnosis of asthma for at least 12 months prior to the initial screening visit. 
c.
The patient must have an absolute eosinophil count <250 cells/μL (at least 2 measurements both 
<250 cells/μL separated by 14 days [± 3 days]). If one of the results is ≥250 cells/µL, samples may be 
collected at a third time point (Visit S3) provided that the third time point is 14 days (± 3 days) after 
the sample collected at Visit S2. If the value at a third time point is used to meet the eligibility criteria, 
2 out of the 3 values should be <250 cells/µL 
d.
The patient has an ACQ-6 score ≥1.5.
e.
The patient has demonstrated ≥12% and ≥200 mL response to a bronchodilator from baseline FEV1
within 30 minutes after 4 inhalations of albuterol/salbutamol HFA MDI (90 mcg ex‑actuator) or 
equivalent (eg, Ventolin) at screening.


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f.
The patient has asthma with a FEV1 ≥30% and <80% of the value predicted for age, height, sex, and 
race at screening. FEV1 must be performed using the office-based spirometer provided for the study.
One pulmonary function test retest during the screening visit(s) period (up to 2 weeks) is allowed to 
fulfill this criterion.
g.
The patient is able to perform technically acceptable and repeatable spirometry, including with a 
hand-held spirometer, after training (applicable to FEV1, not PEF).
h.
The patient’s background asthma therapy includes daily medium- or high-dose ICS plus LABA for at 
least 3 months prior to the initial screening visit with or without other asthma controller medications. 
The dose of ICS may vary during these 3 months, but must remain at a stable daily dose for at least 
1 month prior to Visit S1. Medium- and high-dose ICS classification will be based on the Global 
Initiative for Asthma Global Strategy for Asthma Management and Prevention (2019 
update, Appendix C). Patients with asthma controller medications (excluding systemic corticosteroids 
and systemic immunomodulatory therapies) in addition to ICS+LABA may be eligible provided all 
eligibility criteria are met.
i.
The patient has had at least one clinical asthma exacerbation (worsening of asthma requiring systemic 
corticosteroids [oral or injected], or an emergency department visit due to asthma, or an inpatient 
hospitalization due to asthma, or a 2-fold or greater increase from the subject's usual maintenance ICS 
dose during the exacerbation period documented in the patient’s medical or pharmacy records in the 18 
months prior to (but not within 30 days of) the initial screening visit. Only clinical asthma 
exacerbations with historical documentation in the patient’s medical or pharmacy records may count 
towards this criterion. 
j.
Patients must be able to replace their pre-study ICS+LABA with study-provided ICS+LABA
k.
The patient is a non-smoker for ≥6 months with lifetime history ≤10 pack-years, with no current 
e-cigarette use. The patient must have a negative urine cotinine test at the screening visit. 
l.
The patient is able to communicate satisfactorily with the investigator and to participate in, and comply 
with, the requirements of the study.
m. The patient is able to understand the nature of the study and any potential hazards associated with 
participating in the study.
n.
The patient must be willing and able to comply with study restrictions and to remain at the 
investigational center for the required duration during the study period, and willing to return to the 
investigational center for further visits, as applicable, and the follow up procedures and assessments as 
specified in this protocol.
o.
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 at least 12 months without an alternative medical cause plus an 
increased concentration of follicle stimulating hormone [FSH] of more than 35 U/L in women not 
using hormonal contraception or hormonal replacement therapy).
Women of childbearing potential must have a negative β-HCG test result and practice a highly 
effective method of birth control (methods that can achieve a failure rate of less than 1% per year when 
used consistently and correctly, see Section 5.9) prior to IMP administration and until the EOS visit or 
10 weeks after last IMP dose, whichever is longer.
Male patients (including vasectomized) with women of childbearing potential (WOCBP) partners 


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(whether pregnant or not) must use condoms prior to IMP administration and until the EOS visit or 
10 weeks after last IMP dose, whichever is longer.
Exclusion Criteria: Patients will be excluded from participating in this study if they meet any of the following 
criteria: 
a.
The patient has any other pulmonary diagnosis that in the opinion of the investigator and/or the clinical 
study physician could adversely affect patient safety or interpretation of study results. Examples 
include but are not limited to: chronic obstructive pulmonary disease, chronic bronchitis or any 
respiratory condition that requires any chronic antibiotic use (some antibiotics can be 
immunomodulatory such as macrolides [eg, erythromycin, azithromycin, and clarithromycin]), 
bronchiectasis, cystic fibrosis, bronchopulmonary dysplasia, and interstitial lung disease (including 
eosinophilic granulomatosis with polyangiitis [EGPA] which is expressly prohibited), obstructive sleep 
apnea (sometimes referred to as sleep apnea or Pickwickian Syndrome), and gastroesophageal reflux 
disease that is not treated with a proton pump inhibitor on a scheduled treatment regimen (not as 
needed).
b.
The patient has any concomitant conditions or treatments that could interfere with study conduct, 
influence the interpretation of study observations/results, or put the patient at increased risk during the 
study as judged by the investigator and/or the clinical study physician.
c.
The patient has any of the following medical conditions: 
-
Conditions that may mimic asthma (eg, vocal cord dysfunction, hyperventilation, panic 
attacks, cardiac asthma, uncontrolled gastroesophageal reflux disease [gastroesophageal 
reflux disease controlled on a stable proton pump inhibitor regimen for at least 1 month 
may be allowed]) 
-
Conditions of immunodeficiency, immunocompromise, and/or conditions requiring 
immunomodulatory therapy
-
A history of malignancy within 5 years before screening (exception: basal cell carcinoma or 
in situ carcinoma of the cervix if successful curative therapy occurred at least 12 months 
prior to screening)
-
Tested positive for tuberculosis (TB) at screening by the QuantiFERON® TB Gold Test, or 
had a history of untreated latent or active TB. If the QuantiFERON® TB Gold Test is 
deemed by the principal investigator to be a false positive, a repeat specimen shall be 
submitted; if the second test is also positive, the patient screen fails; if the second test is 
negative, a third test shall be submitted; if the third test agrees with the first test, the patient 
screen fails; if the third test agrees with second test, the patient is considered to be negative 
for TB; see Section 7.5.2 for details.
-
Known history of, or a positive test result for, hepatitis B surface antigen (HBsAg), 
hepatitis C virus (HCV), or human immunodeficiency virus (HIV) types 1 or 2 at screening
-
A history of more than one herpes zoster episode or multimetameric herpes zoster
-
A history of an opportunistic infection (eg, cytomegalovirus retinitis, Pneumocystis carinii, 
aspergillosis, Clostridium difficile)
-
A history of or ongoing chronic or recurrent infectious disease (eg, infected indwelling 
prosthesis, osteomyelitis, chronic sinusitis)


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-
A suspected bacterial or viral infection of the upper or lower respiratory tract, sinus, or 
middle ear that has not resolved at least 2 weeks before the initial screening visit. Note: 
Patients who develop an upper respiratory infection/lower respiratory infection (URI/LRI) 
during the screening period may rescreen 2 weeks after symptoms resolve subject to local 
or regional public health directives.
-
Patients with clinical symptoms that may indicate COVID-19 infection, and/or patients who 
in the investigator’s opinion were at high risk of exposure to COVID-19 within 6 weeks 
before screening or during screening/run-in, will be tested for active COVID-19 infection 
and will only be included if they test negative for COVID-19. Patients who were admitted 
to an ICU during a prior COVID-19 infection; or patients who contracted or recovered from  
COVID-19 less than 6 weeks prior to screening, or patients with COVID-19 symptoms 
(lingering anosmia, weakness, persistent dyslogia or feelings of dysphoria for many 
months) from a pre-study COVID-19 infection that have not completely resolved back to 
their pre-COVID-19 infection health status are excluded from the study.
d.
The patient has taken any systemic corticosteroids within 30 days of screening, including but not 
limited to oral corticosteroids as maintenance therapy for asthma, and/or treatment for clinical asthma 
exacerbation (CAE) within 30 days of screening.
e.
Intensive care unit (ICU) admission or intubation within the 3 months prior to screening.
f.
CAE as defined by this protocol (see Section 6.1.2) within the 30 days prior to screening.
g.
The patient is currently using any systemic immunosuppressive or immunomodulatory biologic or non-
biologic. Note: Previous use of such agents that occurred ≥5 half-lives from the initial screening visit 
may be allowed, if approved by the clinical study physician. 
h.
The patient participated in a clinical trial within 30 days or 5 half-lives of the investigational drug 
before screening.
i.
The patient has received investigational drugs targeted against TL1A.
j.
Abnormality in laboratory values during screening that is considered clinically significant by the 
investigator, or could interfere with the objective of the study as determined by the sponsor. Any such 
laboratory abnormality may be retested at the investigator’s clinical discretion and if within normal 
limits, accepted. 
k.
The patient is currently pregnant or lactating or is planning to become pregnant during the study or for 
at least 10 weeks after administration of the last dose of IMP in case of early withdrawal. Any woman 
becoming pregnant during the study will be withdrawn from the study.
l.
The patient has a known hypersensitivity to the IMP and/or excipients.
m. Live and attenuated vaccines should be excluded 14 days before IMP dosing and throughout the study. 
Inactivated vaccines (including approved inactivated COVID 19 vaccines) should preferably be 
completed 14 days before first IMP dosing. If administered during the study it is recommended to be at 
least 3 days before and after IMP administration, or as required by local country regulations. 
n.
The patient has a positive urine drug test during screening for compounds of abuse, or for cotinine, the 
relevant metabolite from cigarette smoking, the use of which would make the patient ineligible. Repeat 
testing will not be permitted. A positive urine test for tetrahydrocannabinol, the psychoactive 
ingredient in marijuana, is permitted during the trial.


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o.
The patient has a history of alcohol or drug abuse within 2 years preceding the initial screening visit.
p.
Initiation or dose escalation of allergen immunotherapy (administered by any route) is planned during 
the study period. However, patients who initiated immunotherapy 90 days or more before the initial 
screening visit and have been on a stable (maintenance) dose for 30 days or more before the initial 
screening visit may be considered for inclusion. 
q.
The patient is either an employee or an immediate relative of an employee of the sponsor or of any of 
the clinical investigational centers participating in the study.
Randomization criteria: The patients must meet the following randomization criteria prior to randomization:
a.
The patient continues to meet all of the inclusion criteria (including ACQ-6 ≥1.5) and none of the 
exclusion criteria.
b.
The patient has not had a clinical asthma exacerbation (worsening of asthma requiring systemic 
corticosteroids [oral or injected], or an emergency department visit due to asthma treated with systemic 
corticosteroids, or an inpatient hospitalization due to asthma, or a 2-fold or greater increase from the 
subject’s usual maintenance ICS dose during the exacerbation period documented in the patient’s 
medical or pharmacy records in the 18 months prior to (but not within 30 days of) the initial screening 
visit, or other need for systemic corticosteroids during the screening period. 
c.
The patient has at least 57% adherence (4 out of the 7 days prior to randomization) to hand-held 
spirometry and e-diary assessments.
Statistical Considerations:
Sample Size Rationale:
The primary efficacy analysis for this study will be the comparison between treatment groups of the proportion of 
patients experiencing a LoAC event during the 16-week treatment period. The study will be considered positive if 
the primary efficacy test indicates a statistically significant treatment effect versus placebo at the predefined 
significance level.
Sample size calculations were performed based on the following considerations:
In the Phase 2a study results for dupilumab, the observed LoAC rate in the placebo group was 44% (Wenzel et al 
2013). The patients in that study had elevated peripheral blood eosinophil counts (≥300 cells/µL). To estimate the 
LoAC rate that would have been observed in patients with peripheral blood eosinophil counts <300 cells/µL the 
ratio of exacerbation rates observed between eosinophil count strata in the placebo groups of the dupilumab Phase 3 
study were used (Castro et al 2018). This resulted in an estimated LoAC rate of 27% for the patients meeting the 
entrance criteria for the current study. 
This study is designed to detect a 60% reduction in LoAC rate versus placebo; ie, a placebo group rate of 27% and a 
TEV-48574 group rate of 10.8%.
Based on the assumptions above, and assuming a 15% dropout rate during the study, 62 randomized patients per 
treatment group will provide 80% power to detect a treatment effect of 60% reduction in LoAC rate in the 
TEV-48574 group using a Chi-square test with one-sided alpha (Type I error rate) of 0.1.
An unblinded interim analysis is planned to re-assess the sample size and conduct a futility analysis as described in 
Section 9.13. If the sample size increases as a result of the interim analysis, the number of evaluable patients would 
be expected to increase proportionately.


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Analysis of Primary Endpoint: The primary analysis will compare rates of LoAC between treatment groups using 
logistic regression with fixed effect for treatment, baseline FEV1, baseline weight, age group (<65 years vs ≥65 
years), and gender as covariates. The primary analysis will be performed on the intent-to-treat (ITT) analysis set. 
Patients who withdraw from the study or discontinue treatment due to lack of efficacy or due to an asthma-related 
adverse event will be analyzed as having experienced LoAC. Patients who withdraw from the study for other 
reasons will be analyzed as not experiencing a LoAC. The treatment effect will be tested at a one-sided alpha of 0.1.
Analysis of Secondary Efficacy Endpoints: All efficacy variables will be summarized by treatment group. For 
continuous variables, the summary statistics will include n, mean, standard deviation (SD), standard error (SE), 
median, minimum, and maximum. For categorical variables, patient counts and percentages will be provided.
LoAC rates, 90% and 95% CIs for LoAC rates, estimated treatment effects (ie, the odds ratio of TEV-48574 versus 
placebo), and 90% and 95% CIs of the odds ratio will be provided.
The key secondary efficacy analysis of time to LoAC will use a one-sided log-rank test to compare the hazard rates 
between the TEV-48574 and placebo groups. The analysis will be performed on the ITT analysis set. Patients who 
withdraw from the study or discontinue treatment due to lack of efficacy or due to an asthma-related adverse event 
will be analyzed as having experienced LoAC at the time of the withdrawal or treatment discontinuation. Patients 
who withdraw from the study for other reasons will be analyzed as being right-censored at the time of withdrawal.
The Kaplan-Meier (KM) method will be used to estimate and compare the distributions of time to LoAC between 
treatment groups. 
Analysis of ACQ-6 will use the mixed model repeated measures model with treatment group, baseline value, visit, 
treatment and visit interaction, and baseline value as fixed effects and patient as a random effect.
The on-site morning trough FEV1 throughout study will be analyzed using similar mixed model repeated measures 
(MMRM) method, as described for the analysis of ACQ-6. 
Use of SABA quick relief medication will be derived from the e-diary data in monthly analysis intervals and will be 
analyzed using a similar MMRM method.
The efficacy endpoints defined at end-of-treatment (EOT) will take the last available assessment value in the 
treatment period, and will be analyzed using appropriate analysis of covariance models.
Additional covariates or factors may be added to the statistical models. These will be detailed in the SAP. 
Multiple Comparisons and Multiplicity: As there are only 2 treatment groups and one primary analysis test in this 
study, no multiplicity correction is necessary. Secondary endpoints will be considered as hypothesis-generating, and 
multiple testing adjustment will not be made.
Planned Interim Analyses: An unblinded interim analysis is planned after the first 40 to 52 randomized patients 
have completed the treatment period, experienced LoAC, or withdrawn from the study completely. The main 
purposes of the interim analysis include sample size re-assessment and futility analysis.
Safety/Tolerability, PK, and Immunogenicity Analyses: Safety/tolerability, PK, and immunogenicity results will 
be summarized using descriptive statistics by treatment group. 
 may be addressed in a 
separate statistical analysis plan and report.


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TABLE OF CONTENTS
TITLE PAGE...................................................................................................................................1
AMENDMENT HISTORY .............................................................................................................2
INVESTIGATOR AGREEMENT...................................................................................................3
COORDINATING INVESTIGATOR AGREEMENT...................................................................5
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................6
LIST OF ABBREVIATIONS........................................................................................................23
1.
INTRODUCTION AND BACKGROUND INFORMATION ..................................27
1.1.
Introduction.................................................................................................................27
1.1.1.
Asthma Background ...................................................................................................27
1.1.2.
T2 and Non-T2 Asthma..............................................................................................27
1.1.3.
TL1A as a Target........................................................................................................28
1.1.4.
TEV-48574 .................................................................................................................29
1.2.
Findings from Nonclinical and Clinical Studies.........................................................29
1.2.1.
Nonclinical Studies.....................................................................................................29
1.2.2.
First-in-Human Clinical Study ...................................................................................30
1.3.
Known and Potential Benefits and Risks of the Test Investigational 
Medicinal Product.......................................................................................................33
2.
STUDY OBJECTIVES AND ENDPOINTS..............................................................34
2.1.
Primary, Secondary, and Other Study Objectives and Endpoints ..............................34
2.1.1.
Justification of Primary Endpoint...............................................................................35
2.2.
Exploratory 
 and PK/PD ..........................................................................35
2.2.1.
Exploratory 
..............................................................................................35
2.2.2.
Exploratory 
.....................................................................................................36
3.
STUDY DESIGN .......................................................................................................37
3.1.
General Study Design and Study Schematic Diagram ...............................................37
3.2.
Planned Number of Patients and Countries................................................................42
3.3.
Justification for Study Design and Selection of Population.......................................42
3.4.
Stopping Rules for the Study......................................................................................43
3.5.
Joint Data Monitoring Committee..............................................................................43
3.6.
Schedule of Study Procedures and Assessments........................................................43
3.6.1.
Study Procedures and Assessments By Visit..............................................................52
3.6.1.1.
Assessments and Procedures for Screening and Run-in.............................................52


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3.6.1.2.
Assessments and Procedures During the Treatment Period .......................................55
3.6.1.3.
Assessments and Procedures During Follow-up ........................................................65
3.6.1.4.
Unscheduled Visits .....................................................................................................66
4.
SELECTION AND WITHDRAWAL OF PATIENTS..............................................68
4.1.
Patient Inclusion Criteria ............................................................................................68
4.2.
Patient Exclusion Criteria...........................................................................................69
4.3.
Randomization Criteria...............................................................................................72
4.4.
Withdrawal Criteria and Procedures for the Patient...................................................72
4.4.1.
Withdrawal Criteria ....................................................................................................72
4.4.2.
Discontinuation of IMP ..............................................................................................73
4.4.3.
Withdrawal from the Study ........................................................................................73
4.4.4.
Lost to follow-up ........................................................................................................74
4.5.
Replacement of Patients .............................................................................................74
4.6.
Rescreening.................................................................................................................74
4.7.
Screen Failure .............................................................................................................74
5.
TREATMENTS..........................................................................................................75
5.1.
Test Investigational Medicinal Product......................................................................75
5.2.
Placebo Investigational Medicinal Product ................................................................75
5.3.
Test and Placebo Investigational Medicinal Product Administration ........................75
5.4.
Preparation, Handling, Labeling, Storage, and Accountability for IMPs...................76
5.4.1.
Storage and Security...................................................................................................76
5.4.2.
Labeling......................................................................................................................76
5.4.3.
Accountability.............................................................................................................77
5.5.
Justification for Investigational Medicinal Products..................................................77
5.5.1.
Justification for Dose of Test Investigational Medicinal Product ..............................77
5.5.2.
Justification for Use of Placebo Investigational Medicinal Product ..........................78
5.6.
Other Medicinal Products...........................................................................................78
5.7.
Treatment after the End of the Study..........................................................................78
5.8.
Restrictions .................................................................................................................78
5.8.1.
Activity .......................................................................................................................78
5.8.2.
Tobacco and illicit drugs ............................................................................................79
5.8.3.
Blood Donation...........................................................................................................79
5.9.
Effective Methods of Birth Control............................................................................79


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5.10.
Prior and Concomitant Medication or Therapy..........................................................79
5.11.
Procedures for Monitoring Patient Compliance .........................................................80
5.12.
Randomization and Blinding......................................................................................81
5.13.
Maintenance of Randomization and Blinding............................................................81
5.13.1.
Maintenance of Randomization..................................................................................81
5.13.2.
Blinding and Unblinding ............................................................................................81
5.14.
Total Blood Volume ...................................................................................................82
6.
ASSESSMENT OF EFFICACY ................................................................................83
6.1.
Assessments of Efficacy.............................................................................................83
6.1.1.
Loss of Asthma Control (Primary Efficacy Endpoint)...............................................83
6.1.2.
Clinical Asthma Exacerbation....................................................................................83
6.1.3.
e-Diary........................................................................................................................84
6.1.4.
Asthma Control Questionnaire (ACQ-6)....................................................................84
6.1.5.
Spirometry/FEV1 ........................................................................................................84
6.1.6.
Asthma Rescue Medication Use.................................................................................85
6.1.7.
Nighttime Awakenings...............................................................................................85
6.1.8.
Fractional Exhaled Nitric Oxide.................................................................................85
7.
ASSESSMENT OF SAFETY.....................................................................................86
7.1.
Adverse Events and Adverse Device Effects .............................................................86
7.1.1.
Definition of an Adverse Event..................................................................................86
7.1.2.
Recording and Reporting of Adverse Events .............................................................87
7.1.3.
Severity of an Adverse Event .....................................................................................87
7.1.4.
Relationship of an Adverse Event to the Investigational Medicinal Product.............87
7.1.5.
Serious Adverse Events..............................................................................................88
7.1.5.1.
Definition of a Serious Adverse Event .......................................................................88
7.1.5.2.
Expectedness...............................................................................................................89
7.1.5.3.
Reporting a Serious Adverse Event............................................................................89
7.1.6.
Protocol-Defined Adverse Events of Special Interest ................................................91
7.1.7.
Protocol Deviations Because of an Adverse Event ....................................................92
7.2.
Adverse Device Effects ..............................................................................................92
7.2.1.
Adverse Device Effect Reporting...............................................................................92
7.2.2.
Serious Adverse Device Effects .................................................................................93
7.2.2.1.
Serious Adverse Device Effect Reporting..................................................................93


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7.3.
Pregnancy ...................................................................................................................94
7.4.
Medication Error and Special Situations Related to the Investigational 
Medicinal Products.....................................................................................................94
7.5.
Clinical Laboratory Tests ...........................................................................................95
7.5.1.
Serum Chemistry, Hematology, and Urinalysis .........................................................96
7.5.2.
Other Clinical Laboratory Tests .................................................................................96
7.5.2.1.
Human Chorionic Gonadotropin Tests.......................................................................97
7.5.2.2.
Follicle Stimulating Hormone ....................................................................................97
7.6.
Local Tolerability .......................................................................................................97
7.7.
Physical Examinations................................................................................................98
7.8.
Vital Signs ..................................................................................................................99
7.9.
Electrocardiography....................................................................................................99
8.
ASSESSMENT OF PHARMACOKINETICS, PHARMACOGENOMICS, 
IMMUNOGENICITY AND 
..................................100
8.1.
Pharmacokinetic Assessment....................................................................................100
8.2.
Immunogenicity Testing...........................................................................................100
8.3.
 (Exploratory) .................................................101
8.4.
Pharmacogenomics Assessment (Optional) .............................................................101
9.
STATISTICS ............................................................................................................102
9.1.
Sample Size and Power Considerations ...................................................................102
9.2.
Analysis Sets.............................................................................................................102
9.2.1.
Intent-to-Treat Analysis Set......................................................................................102
9.2.2.
Safety Analysis Set...................................................................................................103
9.2.3.
Per-Protocol Analysis Set.........................................................................................103
9.2.4.
Additional Analyses Sets..........................................................................................103
9.3.
Data Handling Conventions......................................................................................103
9.3.1.
Handling Withdrawals and Missing Data.................................................................103
9.4.
Study Population.......................................................................................................103
9.4.1.
Patient Disposition....................................................................................................104
9.4.2.
Demographic and Baseline Characteristics ..............................................................104
9.5.
Endpoints..................................................................................................................104
9.5.1.
Primary Endpoint......................................................................................................104
9.5.2.
Secondary Endpoints ................................................................................................104


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9.5.3.
Other endpoints.........................................................................................................105
9.5.4.
Exploratory ...............................................................................................................105
9.6.
Efficacy Analysis......................................................................................................106
9.6.1.
Planned Method of Analysis.....................................................................................106
9.6.1.1.
Primary Efficacy Analysis........................................................................................106
9.6.1.2.
Sensitivity Analysis ..................................................................................................106
9.6.1.3.
Secondary Efficacy Analysis....................................................................................106
9.6.1.4.
Other Efficacy Analysis............................................................................................107
9.7.
Multiple Comparisons and Multiplicity....................................................................107
9.8.
Safety Analysis .........................................................................................................107
9.9.
Population Pharmacokinetic, Pharmacodynamic, and 
Pharmacokinetic/Pharmacodynamic Analysis..........................................................108
9.9.1.
Population Pharmacokinetics....................................................................................108
9.9.2.
Pharmacokinetics/Pharmacodynamics (PK/PD) ......................................................109
9.10.
Immunogenicity Analysis.........................................................................................109
9.11.
 Analysis ..................................................................................................109
9.12.
Pharmacogenomics Analysis....................................................................................109
9.13.
Planned Interim Analyses.........................................................................................109
9.14.
Reporting Deviations from the Statistical Plan ........................................................110
10.
QUALITY CONTROL AND QUALITY ASSURANCE .......................................111
11.
COMPLIANCE STATEMENT................................................................................111
12.
DATA MANAGEMENT AND RECORD KEEPING ............................................111
13.
FINANCING AND INSURANCE...........................................................................112
14.
REFERENCES .........................................................................................................113
15.
SUMMARY OF CHANGES TO PROTOCOL .......................................................116
15.1.
Amendment 02 Dated 28 April 2021........................................................................116
15.2.
Administrative Letter Dated 02 December 2020......................................................142
15.3.
Amendment 01 Dated 09 November 2020 ...............................................................144
15.4.
Administrative Letter 01 Dated 13 October 2020 ....................................................161
APPENDIX A.
STUDY REPRESENTATIVES, CLINICAL LABORATORIES AND 
OTHER DEPARTMENTS AND INSTITUTIONS.................................................163
APPENDIX B.
JOINT DATA MONITORING COMMITTEE...............................................166
APPENDIX C.
CLASSIFICATION OF INHALED CORTICOSTEROIDS ..........................167


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APPENDIX D.
QUALITY CONTROL AND QUALITY ASSURANCE ..............................168
APPENDIX E.
ETHICS............................................................................................................170
APPENDIX F.
ASTHMA CONTROL QUESTIONNAIRE....................................................171
APPENDIX G.
PRODUCT COMPLAINTS............................................................................174
APPENDIX H.
DATA MANAGEMENT AND RECORD KEEPING ...................................177
APPENDIX I.
LIST OF EXAMPLES OF OPPORTUNISTIC INFECTIONS .......................180
APPENDIX J.
MANAGEMENT OF STUDY ACTIVITIES DURING COVID-19 
OUTBREAKS ..........................................................................................................182
APPENDIX K.
RULES FOR PULMONARY FUNCTION TESTING ..................................186


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LIST OF TABLES
Table 1:
Examples of Schedule of Withdrawal of Background Asthma Controller 
Therapies.....................................................................................................................40
Table 2:
Study Procedures and Assessments: Screening and Run-In.......................................44
Table 3:
Study Procedures and Assessments: Treatment Period (Visits 1 – 10)......................47
Table 4:
Study Procedures and Assessments: Follow-up Period..............................................51
Table 5:
Investigational Medicinal Products Used in the Study...............................................76
Table 6:
The Relationship of an Adverse Event to the IMP and/or Device Suspects ..............88
Table 7:
Clinical Laboratory Tests ...........................................................................................96
Table 8:
Administration Site Finding Severity Assessment .....................................................98
Table 9:
Classification of ICS into low/medium/high dose....................................................167


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LIST OF FIGURES
Figure 1:
Overall Study Schematic Diagram .............................................................................38
Figure 2:
Decision Tree for Adverse Events and Adverse Device Effects Classification .........93


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LIST OF ABBREVIATIONS
Abbreviation
Term
-HCG
beta-human chorionic gonadotropin
ACQ-6
Asthma Control Questionnaire (6-question)
ADA
anti-drug antibody
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the serum concentration-time curve
AUC0–t
area under the serum concentration-time curve from time 0 to the time of the last measurable 
drug concentration
AUC0-∞
area under the serum concentration-time curve from time 0 to infinity
AUC
AUC over one dosing interval
AUC,ss
AUC during dosing interval at steady state
CAE
clinical asthma exacerbation
CFR
code of federal regulations
CI
confidence interval
CL/F
apparent total clearance of the drug from serum after extravascular administration
Cmax
maximum observed serum drug concentration
CMV
cytomegalovirus
COVID-19
coronavirus disease 2019
CRF
case report form
CSR
clinical study report
DcR3
Decoy Receptor 3
DoR
day of randomization
DR3
Death Receptor 3
ECG
electrocardiography, electrocardiogram
EGPA
eosinophilic granulomatosis with polyangiitis
EOS
end-of-study
EOT
end-of-treatment
ER
emergency room
ET
early termination
FAAN
Food Allergy and Anaphylaxis Network
FDA
Food and Drug Administration


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Abbreviation
Term
FEF25%-75%
forced expiratory flow at 25-75% of the pulmonary volume
FeNO
fractional exhaled nitric oxide
FEV1
forced expiratory volume in the first second of exhalation
FSH
follicle-stimulating hormone
FVC
forced vital capacity
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GINA
Global Initiative for Asthma
GPSP
Global Patient Safety and Pharmacovigilance
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HFA
hydrofluoroalkanes
HIV
human immunodeficiency virus
IB
investigator's brochure
HSP
hysterosalpingogram
ICF
informed consent form
ICH
International Council for Harmonisation
ICS
inhaled corticosteroid
ICU
intensive care unit
IEC
Independent Ethics Committee
IL
interleukin
ILC2
innate lymphoid cells, type 2
IMP
investigational medicinal product
IRB
Institutional Review Board
IRT
interactive response technology
ITT
intention-to-treat
JDMC
Joint Data Monitoring Committee
KM
Kaplan-Meier
LABA
long-acting beta agonist
LoAC
Loss of asthma control
LRI
lower respiratory infection
MAD
multiple ascending dose
MDI
metered-dose inhaler
MedDRA
Medical Dictionary for Regulatory Activities


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Abbreviation
Term
NF-κB
nuclear factor kappa-light chain enhancer of activated B cells
NIAID
National Institute of Allergy and Infectious Diseases
NOAEL
no observed adverse effect level
NRS
numerical response scale
PAR
pharmacometrics analysis report
PDAESI
protocol-defined adverse events of special interest
PEF
peak expiratory flow
PK/PD
pharmacokinetic/pharmacodynamic
POC
proof-of concept
PP
per-protocol
QSP
quantitative systems pharmacology
SABA
short-acting beta agonist
SAD
single ascending dose
SAE
serious adverse event
SAP
statistical analysis plan
sc
subcutaneous
SD
standard deviation
SE
standard error
SOC
system organ class
SUSAR
suspected unexpected serious adverse reaction
t½
elimination half-life
tmax
time to maximum observed drug concentration
TB
tuberculosis
TC
teleconference
TL1A
tumor necrosis factor ligand 1A
TNF
tumor necrosis factor
TNFSF15
TNF superfamily member 15
Treg
regulatory T cell
ULN
upper limit of the normal range
URI
upper respiratory infection
USA
United States of America
VC
videoconference
Vz/F
apparent volume of distribution after extravascular administration
WHO-DD
World Health Organization Drug Dictionary


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Abbreviation
Term
WOCBP
women of childbearing potential


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1.
INTRODUCTION AND BACKGROUND INFORMATION
1.1.
Introduction
1.1.1.
Asthma Background
Asthma is a common chronic lung disorder characterized by inflammation and narrowing of the 
airways. Symptoms of asthma include cough, breathlessness, and wheezing. Recent estimates 
suggest that as many as 339 million people in the world have asthma (Global Asthma Network 
2018). 
Until recently, inhaled corticosteroids (ICS) have been considered the most effective treatment 
agents for the long-term control of asthma (see EPR-3 2007 and GINA 2014). For patients whose 
asthma was not adequately controlled on daily ICS alone, the addition of long-acting beta-
agonists (LABAs) and/or other controller therapies was recommended to provide additional 
control. For some severely affected patients with asthma, daily oral corticosteroid or currently 
approved biologics help maintain asthma control. However, it has been observed that the 
aforementioned treatment paradigm is not effective for all asthma subpopulations and there is a 
growing understanding that efficacy is often associated with the underlying pathophysiological 
pathways driving patients’ asthma. Currently there are no approved effective therapies for 
patients whose asthma is not well controlled by the above therapies.
1.1.2.
T2 and Non-T2 Asthma
It is now generally acknowledged that a number of underlying pathophysiological processes can 
lead to asthma, and a number of phenotypes and endotypes have been characterized (Fajit and 
Wenzel 2014; Robinson et al 2017). Asthma has been dichotomized according to the presence 
and level of type 2 (T2) inflammation in the airways (Fahy 2016; Samitas et al 2017). T2 
inflammation refers to inflammation driven by a particular set of cytokines including IL-4, IL-5 
and IL-13. Originally described in relation to T helper 2 (Th2) cells and initially referred to as 
Th2 inflammation, it is now recognized that other types of cells also play a role and so the more 
general designation of T2 has come into use (Th2 inflammation represents a subset of T2 
inflammation driven by Th2 cells). Cells (other than Th2 cells) that have been described as 
secreting T2 type cytokines include: type 2 innate lymphoid cells (ILC2); natural killer cells; 
other types of T cells and eosinophil-basophil progenitors.
T2 asthma has been divided into T2-high and T2-low subtypes based upon a variety of criteria 
including cytokine profiles and/or eosinophil counts. Non-T2 asthma is generally thought of as 
not driven by T2 inflammation and is often described relative to the absence of evidence of T2 
inflammation. Non T2-asthma is poorly understood (Fajt and Wenzel 2014; Samitas et al 2017). 
The underlying causes of some T2-low asthma and non-T2 asthma might be attributable to 
several cellular signaling pathways, including: oxidative stress; neutrophilic inflammation caused 
by dysregulation of the Th17 pathway; Th1-related processes; and potentially Th2 components 
as well (Robinson et al 2017; Samitas et al 2017). Lack of responsiveness to corticosteroids has 
been described in patients with T2-low and non-T2 asthma (Pavord et al 1999; Fahy 2016; 
Schleich et al 2013). In addition, currently approved asthma biologics are only for the treatment 
of T2 asthma and often show increased efficacy for T2 high asthma (FitzGerald et al 2018, 
Castro et al 2018). 


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For practical purposes, T2-high, T2-low, and non-T2 status is often identified by peripheral 
blood eosinophil counts. Some investigators recommend adding fractional exhaled nitric oxide 
(FeNO) to peripheral blood eosinophil counts for categorization. Even though peripheral 
eosinophil counts are used to identify T2 patients, T2 asthma is not identical to the phenotype of 
eosinophilic asthma (although there is probably substantial overlap between the two 
populations).
While there is some debate as to what threshold(s) distinguishes T2-high from T2-low asthma, 
most studies have used a cutoff between 250 cells/μL and 300 cells/mL (Coverstone et al 2020). 
Examples of absolute eosinophil counts used to define T2-high, T2-low, and non-T2 include:

T2-high ≥250 cells/μL

T2-low ≥150 cells/μL to <250 cells/μL

Non-T2 <150 cells/μL

Non-T2-high refers to T2-low and non-T2 combined, i.e., patients with absolute 
eosinophil counts <250 cells/μL
1.1.3.
TL1A as a Target
Tumor necrosis factor (TNF) (ligand) 1A (TL1A, also known as TNF [ligand]) superfamily 
member 15 [TNFSF15], VEGI) is a member of the TNF ligand superfamily and has a trimeric 
structure consisting of 3 noncovalently associated TL1A protein subunits. It is a single-pass 
type II membrane protein that can be cleaved by endogenous proteases to produce a soluble 
form. Both the membrane-bound and soluble forms are active. TL1A has been reported to be 
expressed by a number of cells including endothelial cells (Migone et al 2002), tissue 
macrophages, lamina propria lymphocytes, and CD11chigh dendritic cells (Bamias et al 2003; 
Bamias et al 2006).
TL1A expression has also been reported to differ between steady state and inflammatory 
conditions and between healthy and diseased states (Migone et al 2002; Bamias et al 2003; 
Bamias et al 2006; Riley et al 2018; Schofield et al 2019; Pavlidis et al 2019).
TL1A has 2 identified receptors: Death Receptor 3 (DR3, TNFRSF25, APO-3, TRAMP, LARD, 
WSL-1) and Decoy Receptor 3 (DcR3,TNFRSF6B). DR3 is the cognate signaling receptor for 
TL1A and a member of the tumor necrosis factor receptor superfamily (TNFRSF25). DR3 
expression by a number of cells including lymphocytes (eg, NK cells, T cells) has been reported 
(Pappu et al 2008). DcR3 is a soluble decoy receptor that is also bound by other TNF 
superfamily members FASL and LIGHT (Zhan et al 2011; Migone et al 2002). DcR3 binding of 
TL1A competes with DR3 binding thereby competitively inhibiting the results of TL1A-DR3 
signaling (Migone et al 2002).
Under most circumstances, TL1A signaling through DR3 activates the NF-κB signaling pathway 
and has both costimulatory and anti-apoptotic effects on T cells (Migone et al 2002). 
Additionally, DR3 contains a canonical TNF receptor family death domain and may be 
pro-apoptotic in cells lacking the NF-κB signaling pathway or under conditions where this 
pathway is not activated, eg, under cellular stress (Wen et al 2003).


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TL1A signaling is not a primary driver of immune responses but rather amplifies responses 
under certain conditions. It has been reported as amplifying type 1 helper T-cell (Th1) responses 
by synergizing with interleukin 12 (IL-12) (Bamias et al 2003; Papadakis et al 2004), Th17 
responses by synergizing with IL-23 (Pappu et al 2008; Takedatsu et al 2008), and Th2 responses 
by both amplifying response to antigen (Kayamuro et al 2009) and inhibiting the production of 
inducible regulatory T cells (Tregs) and the function of natural Tregs (Meylan et al 2011). TL1A 
signaling through DR3 also enhances Th9 cell pathogenicity in allergic responses (Richard et al 
2015), and is associated with type 2 innate lymphoid cells (ILC2) expansion and survival 
including in a murine model of asthma (Meylan et al 2014; Yu et al 2014). TL1A is an attractive 
target for therapeutic intervention because targeting TL1A should mitigate over-activation of 
immune responses while leaving baseline immunity intact.
1.1.4.
TEV-48574
TEV-48574 is a highly potent, fully human immunoglobulin G (IgG) subclass 1 (IgG1) (lambda) 
monoclonal antibody (mAb) that targets TL1A. TEV-48574 is a blocking antibody that inhibits 
the binding of TL1A to its cognate signaling receptor, DR3. By competitively inhibiting TL1A 
binding to DR3, the antibody prevents activation of the DR3 signaling pathway. TEV-48574 also 
inhibits the binding of TL1A to DcR3 although TEV-48574 preferentially inhibits the TL1A-
DR3 interaction over the TL1A-DcR3 interaction. TEV-48574 has shown efficacy in nonclinical 
studies (Section 1.2.1) and was safe and well tolerated in the Phase 1 study TV48574-SAD-
10126 (Section 1.2.2).
The purpose of this study is to establish proof-of concept (POC) through the evaluation of 
efficacy of TEV-48574, as well as to further evaluate safety, in patients with T2-low and non-T2 
severe asthma that is uncontrolled on standard of care therapies (ICS+LABA). 
1.2.
Findings from Nonclinical and Clinical Studies
Brief summaries of nonclinical pharmacology, pharmacokinetics, and toxicology studies and the 
first in human study 
 are provided in the following sections. More detailed 
information is provided in the Investigator’s Brochure (IB).
1.2.1.
Nonclinical Studies
 
 
 
 
 
A comprehensive set of in vitro and in vivo nonclinical studies was conducted to support 
TEV-48574 long-term therapeutic use in humans.
 
 


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The nonclinical safety program conducted with TEV-48574 consisted of a 
 
 
 
 
 
 
 
 
The nonclinical safety program revealed no safety concerns. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.2.2.
First-in-Human Clinical Study
The first-in-human study 
was a Phase 1, randomized, double-blind, 
placebo-controlled, parallel-group study to determine the safety, tolerability, PK, and 
immunogenicity of TEV-48574 after: 

 
 
 
 


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High level summaries of data are provided below. Details can be found in the IB.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Safety 
No deaths, serious adverse events, protocol-defined adverse events of special interest (severe 
hypersensitivity reactions or anaphylaxis) or withdrawals due to adverse events were reported 
during the study.
No adverse events consistent with immunosuppression (including opportunistic or unusual 
infections or malignancies), cytopenias, cytokine release syndrome, or systemic reactions were 
reported and no safety signal was observed with treatment-emergent ADA responses. The nature 
and incidence of the adverse events (AEs) were similar between doses and comparable to 
placebo. There were no dose-related trends and no clinically meaningful differences observed 
between the treatment groups for laboratory tests, vital signs, electrocardiogram (ECG), and 
physical examination findings. 
 
 


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Immunogenicity
Immunogenicity is considered a risk for all biologics including TEV-48574 and ADA responses 
are expected. 
 
 
 No safety signal with 
treatment-emergent ADA responses was observed. Details can be found in the IB.
1.3.
Known and Potential Benefits and Risks of the Test Investigational 
Medicinal Product
 
 
 
 
 
 
 
 
 
 
This Proof of Concept study will investigate the efficacy of TEV-48574 in patients with T2-low 
and non-T2 severe asthma uncontrolled on standard of care (ICS+LABA). As described in 
Section 1.1.2, such patients may benefit from the development of further therapy options.
Management of the patients' safety during the study, including their asthma control, is detailed in 
Section 3 (study design), Section 7 (assessment of safety), and Appendix B (Joint Data 
Monitoring Committee [JDMC]).
Management of study activities during coronavirus disease 2019 (COVID-19) outbreaks is 
detailed in Appendix J.
Additional information regarding benefits and risks to patients may be found in the IB.
In summary, the benefit and risk assessment for TEV-48574 in this POC study is considered 
favorable following review of data from the completed Phase 1 clinical study. 


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2.
STUDY OBJECTIVES AND ENDPOINTS
2.1.
Primary, Secondary, and Other Study Objectives and Endpoints
The primary, secondary, and other study objectives and endpoints are:
Objectives
Endpoints
The primary objective of the study 
is to evaluate the effect of TEV-
48574 compared with placebo on 
loss of asthma control (LoAC) in 
adult patients with T2-low and non-
T2 severe asthma uncontrolled on 
inhaled corticosteroids plus long-
acting beta-agonists (ICS+LABA).
Primary efficacy endpoint:
Proportion of patients who experience loss of asthma control (LoAC) 
during the treatment period.
LoAC is defined as any one of the following during the treatment period: 

Morning PEF decrease ≥30% from baseline on 2 consecutive 
days or morning handheld FEV1 decrease ≥20% from baseline 
on 2 consecutive days 

Increase in SABA/quick-relief medication ≥6 puffs over baseline 
use in 24 hours on 2 consecutive days

Increase in ICS dose ≥4x most recent dose

Systemic corticosteroid use

Asthma ER visit or hospitalization 
The secondary efficacy objective is 
to evaluate the effect of TEV-48574 
compared with placebo on a range of 
clinical measures of asthma control
Key secondary efficacy endpoints:

Time from randomization to LoAC during the treatment period

Asthma Control Questionnaire 6-question version (ACQ-6) at 
end of treatment (EOT) and throughout the study 

Forced expiratory volume in the first second of exhalation 
(FEV1) (% predicted, L) at EOT and throughout the study

Use of SABA quick relief medication at EOT and throughout the 
study
Other secondary efficacy endpoints:

Proportion of patients who have a CAE during the treatment 
period

Time from randomization to first CAE during the treatment 
period

Number of nighttime awakenings due to asthma during the 
treatment period

Percent decrease in ICS dose during the treatment period

Other lung function parameters as assessed by hand-held 
spirometry at end of treatment (EOT) and throughout the study

Fractional exhaled nitric oxide (FeNO) throughout the study


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Objectives
Endpoints
Other objectives include the 
evaluation of the safety and 
tolerability, device-related events, 
pharmacokinetics, and 
immunogenicity of TEV-48574
Safety and tolerability endpoints:

Frequency of adverse events

Change from baseline in clinical laboratory test results (serum 
chemistry, hematology, and urinalysis) throughout the study

Change from baseline in vital signs throughout the study

Change from baseline in 12-lead electrocardiogram (ECG) 
findings throughout the study

Use of concomitant medication

Local tolerability

Number (%) of patients who did not complete the study due to 
adverse events 
Device-Related Events

All device-related adverse events, malfunctions etc. will be 
recorded and evaluated for their impact relative to the safety and 
efficacy of the investigational medicinal product.  
Pharmacokinetic endpoints: 

Trough serum TEV-48574 concentrations throughout the study 
(sparse sampling)

Population pharmacokinetic analysis of pharmacokinetic data
Immunogenicity endpoints:

Assessment of treatment-emergent ADA responses: change from 
baseline and throughout the study 

Impact of the presence of ADAs on pharmacokinetics and 
clinical safety (if possible). 

Assessment of neutralizing ADA in ADA positive patients 
throughout the study
2.1.1.
Justification of Primary Endpoint
LoAC is a clinically relevant endpoint suited to proof of concept and shorter clinical trials that is
related to annualized exacerbation rate, a well-established endpoint used to assess efficacy of 
asthma therapies, including in registration trials. In the past, LoAC has been referred to as 
asthma exacerbation (without requiring systemic corticosteroids): for clarification purposes and 
to distinguish this endpoint from clinical asthma exacerbations, the term LoAC will be employed 
for this clinical trial. Proof-of-concept will be evaluated by investigating the effect of 
TEV-48574 on the proportion of patients who experience a LoAC event in a population of 
patients with severe uncontrolled T2-low and non-T2 asthma who will undergo withdrawal of 
background asthma controller therapies.
2.2.
Exploratory 
2.2.1.
Exploratory 
 
 


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2.2.2.
Exploratory 
 


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3.
STUDY DESIGN
3.1.
General Study Design and Study Schematic Diagram
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group POC study to 
evaluate the efficacy and safety of TEV-48574 administered sc every 2 weeks in adult patients 
aged 18 years and older with T2-low and non-T2 uncontrolled severe asthma. The primary 
efficacy endpoint is the proportion of patients who experience loss of asthma control (LoAC) 
during the treatment period. 
Eligibility requirements include: peripheral blood eosinophil counts of <250 cells/μL (at least 
2 out of 3 measurements both <250 cells/μL separated by 2 weeks [± 3 days]); an ACQ-6 score 
≥1.5 despite daily treatment with medium/high dose ICS+LABA for at least 3 months with a 
stable dose for at least 1 month prior to screening, with or without other asthma controller 
medications, and at least one clinical asthma exacerbation (worsening of asthma requiring 
systemic corticosteroids [oral or injected], or an emergency department visit due to asthma, or an 
inpatient hospitalization due to asthma, or a 2-fold or higher increase from the subject’s usual 
maintenance ICS dose during the exacerbation period, documented in the patient’s medical or 
pharmacy records in the 18 months prior to (but not within 30 days of) the initial screening visit 
(Visit S1). Patients with asthma controller medications (excluding systemic corticosteroids and 
systemic immunomodulatory therapies) in addition to ICS+LABA may be eligible provided all 
eligibility criteria are met. Detailed inclusion and exclusion criteria can be found in Section 4.1
and Section 4.2.
The study will consist of an approximate 4- to 5-week screening/run-in period, a 16-week 
treatment period, and an 8-week follow-up period. The initial 5-week period consisting of 
screening plus run-in may be extended for up to 14 days if needed for the shipment of 
investigational medicinal product (IMP) to the investigational site or to complete assessment of 
eosinophil counts. All inclusion and exclusion criteria, with the exception of the second 
eosinophil count, should be assessed within the first 2 weeks of Visit S1. 
If a patient contracted and recovered from COVID-19 more than 6 weeks prior to screening, and 
the patient was not admitted to a hospital's ICU during that COVID-19 infection, and if the 
patient’s symptoms from COVID-19 completely resolved back to pre-COVID-19 status (no 
lingering anosmia, weakness, persistent dyslogia or feelings of dysphoria for many months after 
the infection resolved), then the patient may enroll in the trial. The principal investigator should
determine whether or not the subject has truly recovered back to his/her usual pre-COVID -19 
status and is eligible for enrollment in the study.
An e-diary will be dispensed at the second screening visit (Visit S2), 2 weeks (± 3 days) after the 
initial S1 screening visit. Patients who meet all inclusion criteria (except for eosinophil counts if 
assessment is incomplete) and none of the exclusion criteria are eligible to enter the run-in and 
have their ICS+LABA standardized with study-provided ICS+LABA (background asthma 
controller therapy) at Visit S2; this should start at least 2 weeks prior to randomization and marks 
the start the of run-in. At the end of run-in, patients who continue to meet all of the inclusion 
criteria, none of the exclusion criteria, and all of the randomization criteria will be eligible to be 
randomized to TEV-48574 (
 
. For patients who are randomized, the standardized 


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ICS+LABA dose must be maintained and the patient held stable on that dose for the first 4 
weeks of the treatment period, followed by a structured decrease in background asthma 
controller therapies for patients not meeting criteria for LoAC. Patients will be monitored via 
hand-held spirometry and e-diary daily, including between visits, throughout the study. Patients 
who experience an event of LoAC will be treated by the investigator, discontinue IMP, restart (or 
increase) background asthma controller therapies, and remain in the study and complete all 
remaining visits, procedures and assessments, except for IMP administration. The total duration 
of patient participation in the study is planned to be up to approximately 30 weeks. 
The screening and run-in, treatment, and follow-up periods are described below; the study 
schematic diagram is presented in Figure 1.
Figure 1:
Overall Study Schematic Diagram
ACQ-6 = 6-question Asthma Control Questionnaire; CBC = complete blood count; DoR = day of randomization; 
EOS = end of study; EOT = end of treatment; F/U = follow up; IMP = investigational medicinal product.
Screening and Run-in (4- to 5- weeks)
Screening starts with the initial screening visit and will be followed by a run-in that proceeds 
through the day prior to the day of randomization. The duration of the screening and run-in 
period will be approximately 5 weeks and may be extended by up to 14 days to allow for IMP 
shipping and to complete assessments of peripheral blood eosinophil count. Screening 
assessments and procedures will be completed over at least 2 visits, including the initial 
screening visit, and may be completed over more than 2 visits. An effort should be made to 
complete screening assessments and procedures in the first 2 weeks following Visit S1, with the 
exception of obtaining the samples for the second (and if applicable third) peripheral blood 
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Samples for peripheral blood eosinophil counts should be collected at 2 time points. The first 
time point should be at Visit S1, if possible, and the second (Visit S2) 14 days (± 3 days) after 
the first sample collected at Visit S1. To meet eligibility criteria, the peripheral blood eosinophil 
counts from both time points should be <250 cells/µL. If one of the results is ≥250 cells/µL, 
samples may be collected at a third time point (Visit S3) provided that the third time point is 
14 days (± 3 days) after Visit S2. If the value at a third time point is used to meet the eligibility 
criteria, 2 out of the 3 values should be <250 cells/µL.
Patients will receive a hand-held spirometer and an e-diary at Visit S2 (14 days ± 3 days) after 
the initial screening Visit S1, and will be trained on their use. Patients will record spirometry and 
e-diary results daily throughout the study (screening and run-in through the end of the follow-up 
period/EOS). 
Reversibility testing may be performed on another day if the patient has not withheld LABA and 
SABA for the requisite number of hours: reversibility testing should only be attempted after 
withholding short-acting bronchodilators (ie, inhaled short-acting beta-adrenergic agonists and/or 
short-acting anticholinergics) for at least 6 hours and long-acting bronchodilators (ie, inhaled 
long-acting beta-adrenergic agonists and long-acting anticholinergic agents) for at least 12 or 
24 hours, according to their labeled dose schedule. Patients may only be asked to hold 
bronchodilators for reversibility once informed consent has been signed. However, if of their 
own volition, without being asked, patients have not taken any of the aforementioned 
bronchodilators for the requisite amount of time prior to the initial screening visit, reversibility 
may be performed at the initial screening visit.
When the e-diary is dispensed, or when reversibility is performed during screening (whichever 
comes first), the patient’s pre-study quick relief rescue medication will be converted to 
study-provided albuterol/salbutamol inhalers. The subject’s pre-study quick relief rescue 
medication will be converted to study-provided albuterol/salbutamol inhalers at Visit S1. At 
Visit S2, once all eligibility criteria (inclusion and exclusion) have been confirmed, with the 
exception of the second peripheral blood eosinophil count, eligible patients will have their 
ICS+LABA converted to study-provided ICS+LABA inhalers and commence run-in; this should 
be completed at least 2 weeks prior to randomization.
All patients will be provided with the strength of inhaled fluticasone propionate plus salmeterol 
closest to the equivalent of the patient’s pre-screening ICS+LABA. This will include fixed-dose 
combination ICS+LABA and any additional ICS dose. Patients on additional asthma controller 
medication(s) except those excluded by the eligibility criteria (see Section 4.2) will continue 
those medications throughout the run-in period and will discontinue them at 4 weeks after 
randomization (Visit 3). 
Treatment Period (16 weeks)
The treatment period begins with randomization and ends with the EOT visit (week 16). After 
the end of the screening period, patients who meet all of the inclusion criteria (Section 4.1), none 
of the exclusion criteria (Section 4.2), and all of the randomization criteria (Section 4.3) will be 
randomized in a 1:1 ratio to the following regimens administered sc every 2 weeks: 

TEV-48574 

Placebo to match TEV-48574 


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With randomization, patients enter the 16-week treatment period. The patients will receive the 
IMP loading dose on the day of randomization and the subsequent corresponding IMP 
maintenance dose every 2 weeks for a total of 8 doses (1 loading dose and 7 maintenance doses). 
 
 
Patients qualifying for randomization will continue the same background asthma controller 
regimen as used during run-in without change for the first 4 weeks of the treatment period; this 
regimen includes study-provided controller inhalers (ICS+LABA and additional ICS), plus any 
additional controller medications that met the eligibility criteria. After week 4, background 
asthma controller therapies will be decreased in a structured manner in patients not experiencing 
LoAC (see Section 6.1.1 for LoAC definition) (the patient will be aware of the dose decreases). 
The first step is implemented after the first 4 weeks of the treatment period and includes 
discontinuing LABA and any additional asthma controller medications, with the exception of 
study-provided additional ICS. The second step will be made 2 weeks later. The second and 
subsequent steps will consist of decreasing the ICS dose step-wise weekly, by ~50%. For 
patients on ICS doses greater than the high dose ICS+LABA twice a day, the total ICS dose 
should also be decreased step-wise weekly, by ~50%. Excluding patients who meet LoAC 
criteria during the structured withdrawal of background asthma controller therapies, the duration 
of treatment with IMP only will be approximately 8 or 9 weeks. Since study-provided asthma 
controller formulations may vary locally, Table 1 shows an example of the step-wise structured 
withdrawal. Eligibility assessment for structured withdrawal of background asthma controller 
therapies (between scheduled in-person visits) may be done by phone; if it is suspected that a 
patient meets the criteria for LoAC, the investigator may ask the patient to attend the site for an 
unscheduled visit.
Table 1:
Examples of Schedule of Withdrawal of Background Asthma Controller 
Therapies
Dose at start of treatment period
Time point:
Weeks after 
randomization (visit 
number)
Action
Fluticasone/salmeterol 
500/50 µg BID
Fluticasone/salmeterol 
250/50 µg BID
4 weeks (V3)
Discontinue LABA and 
other non-ICS asthma 
controllers*
FP 500 BID
FP 250 BID
6 weeks (V4)
First ICS decrease
500 decreased to 250 BID
250 decreased to 100 BID
7 weeks (Telephone, V5)
Second ICS decrease
250 decreased to 100 BID
100 BID decreased to 0
8 weeks (V6)
Third ICS decrease
100 BID decreased to 0
0
*Other asthma controllers (eg, LAMA, leukotriene antagonists) will also be discontinued.
Note: Last IMP administration 14 weeks after randomization (visit 9); end-of-treatment visit (EOT) 16 weeks after 
randomization
BID=twice daily; FP=fluticasone propionate; ICS=inhaled corticosteroids; LABA=long-acting beta-agonists; 
LAMA= long-acting muscarinic antagonist; V = visit. 


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Patients will be monitored for worsening of asthma and potential LoAC (and CAE) both at 
scheduled visits and in between visits via hand-held spirometry and e-diary. Asthma specific 
alerts will be sent for the following: 

Decrease in morning FEV1 ≥20% from baseline on 2 consecutive days OR decrease in 
morning PEF ≥30% from baseline on 2 consecutive days

Increase in rescue medication use/SABA of 4 or more puffs over baseline for 2 or more 
consecutive days OR ≥12 puffs in any single day

Increase of 2 nighttime awakenings due to asthma over baseline on 2 consecutive days
In the event of an alert, the site will follow-up with the patient. An alert does not mean that the 
patient’s medications need to be changed or that study drug should be discontinued, only that the 
patient should be contacted and evaluated by phone or at an unscheduled visit according to 
investigator judgment. If, in the investigator's judgment, LoAC is suspected, every effort to have 
the patient evaluated at an unscheduled visit should be made.
Definitions of LoAC and Clinical Asthma Exacerbation (CAE) are presented in Section 6.1.1
and Section 6.1.2. LoAC events and CAEs will be treated by the investigator according to local 
standard of care. In the event of a LoAC or CAE, IMP will be discontinued and background 
asthma controller therapy will be restarted or increased per investigator judgment. Patients who 
experience LoAC or CAE will remain in the study for assessments. (Note: CAEs are a subset of 
LoAC events; see Section 6.1.1 and Section 6.1.2 for definitions). 
Study procedures and assessments are described in detail Section 3.6. 
The last dose will be administered 14 weeks after the start of the treatment period 
(randomization). The EOT visit that takes place 2 weeks after the last dose (ie, 16 weeks after the 
start of the treatment period) marks the end of the treatment period. After EOT, patients may 
restart the background asthma controller therapy regimen that they started at randomization. 
Patients have the right to withdraw from the study completely or to discontinue treatment with 
IMP while remaining in the study at any time. Patients who withdraw from the study before 
completing the treatment period are encouraged to complete EOT/early termination (ET) visit as 
soon as possible after receiving their last dose of IMP (Section 4.4.3). Patients who discontinue 
treatment with IMP for reasons other than a protocol defined LoAC or CAE while remaining in 
the study are encouraged to complete ET visit procedures as soon as possible after receiving their 
last dose of IMP (Section 4.4.2) and to complete the remaining study visits and assessments 
(with the exception of administration of IMP). 
Follow-up Period (8 weeks)
After the end of the 16-week treatment period, the patient will enter the 8-week follow-up period 
for continued assessments. During the follow-up period, patients may resume their 
study-provided background controller therapies. This follow-up visit marks the end of study 
(EOS). Patients who complete the EOS visit will be considered to have completed the study.
The end of trial for notification purposes will be the last patient last EOS visit.
The study duration will be approximately 18 months. The study is expected to start in Q3 2020 
and last until approximately Q1 2022. The expected duration of the study may also be extended 
dependent on enrollment, sample size adjustment, and other factors. 


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The principal investigator is the main investigator at each site; the responsibilities of the 
principal investigator are outlined in Section 11.
Detailed information about study procedures and assessments are presented in Section 6
(efficacy), Section 7 (safety), and Section 8 (pharmacokinetics, immunogenicity, exploratory 
measures including 
). 
Details about the timing of study procedures and assessments are presented in Table 2 (screening 
and run-in), Table 3 (treatment period), and Table 4 (follow-up). 
Management of study activities during COVID-19 outbreaks is detailed in Appendix J.
3.2.
Planned Number of Patients and Countries
Approximately 310 patients will be screened to achieve approximately 62 randomized patients 
per arm (124 in total). An unblinded interim analysis (described in Section 9.12) is planned, 
which could result in a sample size increase, from the initially planned 124 to up to 174 total 
randomized patients (87 per arm), which would require up to 435 patients screened. 
Assuming a dropout rate of approximately 15%, the number of evaluable patients is planned to 
be approximately 52 per arm (104 in total). If the sample size increases as a result of the interim 
analysis, the number of evaluable patients would be expected to increase proportionately (eg, 
approximately 148 evaluable patients for a sample size of 174 patients randomized). Details on 
definition of evaluable patients and sample size are given in Section 8.4.
The study is planned to be conducted in the United States and the European Union across 
approximately 75 investigational centers in approximately 5 countries. Additional geographic 
locations and investigational centers may be added, if needed. 
3.3.
Justification for Study Design and Selection of Population
This is a placebo-controlled POC study to evaluate the efficacy and safety of TEV-48574 in 
adult patients with uncontrolled severe asthma of the T2-low and non-T2 type. As is typical after 
Phase 1, the efficacy of TEV-48574 has not yet been established. The purpose of this POC study 
is to investigate the efficacy and safety of TEV-48574 in patients with T2-low and non-T2 severe 
asthma uncontrolled on standard of care (ICS+LABA). The primary and secondary efficacy 
objectives have been designed to test POC with a TEV-48574 loading dose of 
sc 
followed by maintenance doses of
 sc every 2 weeks over a treatment period of 
16 weeks (with structured decreases in background asthma controller therapies starting 4 weeks 
after randomization). The study has also been designed to protect the safety of the participating 
patients. The results of this study may support the development of TEV-48574, with potential 
benefits for patients with uncontrolled severe asthma, especially with T2-low and non-T2 
endotypes.
 
 
To mitigate other potential risks to patients, in addition to every-two-weeks in-person 
evaluations, daily measures of asthma control including FEV1 and rescue medication use will be 


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collected between visits and decreases in background asthma controller therapies will be 
structured. Patients who experience loss of asthma control, as defined by this protocol 
(Section 6.1.1), will stop the IMP, receive appropriate treatment by the investigator and resume 
background asthma controller therapy.
The sample size calculation is provided in Section 9.1. The TEV-48574 dose to be evaluated in 
this study was selected 
 
(Section 5.5.1). A placebo control arm will be used to establish efficacy and safety 
(Section 5.5.2). Randomized treatment allocation (Section 5.13.1) and double-blinding 
(Section 5.13.2) will be used to prevent bias in the assessment of efficacy and safety. 
3.4.
Stopping Rules for the Study
The study may be terminated by the sponsor for any reason at any time. For example, the 
sponsor may terminate the study in the event of:

new toxicological or pharmacological findings or safety issues that invalidate the 
earlier positive benefit-risk assessment

discontinuation of the development of TEV–48574 for treatment of asthma
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 4.4).
3.5.
Joint Data Monitoring Committee
There will be a JDMC in this study. The data will be reviewed in a blinded fashion. The JMDC
will recommend whether to continue the study as designed, conduct protocol/informed consent 
form (ICF) modifications, temporarily suspend enrollment and/or study intervention until some 
uncertainty is resolved, or discontinue the study. Details for the JDMC are given in Appendix B.
3.6.
Schedule of Study Procedures and Assessments
Study procedures and assessments with their time points are presented in Table 2 (screening and 
run-in), Table 3 (treatment period), and Table 4 (follow-up). Detailed descriptions of procedures 
and assessments are provided in Section 6 (efficacy assessments), Section 7 (safety assessments), 
and Section 8 (pharmacokinetics, immunogenicity, and exploratory measures including 
). Study procedures and assessments by visit are listed in Section 3.6.1.


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Table 2:
Study Procedures and Assessments: Screening and Run-In
Note: Screening will include at least 2 visits and may be completed over more than 2 visits. The screening 
assessments and procedures for the first screening visit may be completed over more than one visit: sites should 
make every effort to complete the screening assessments and procedures in the first 2 weeks following the initial 
screening visit, with the exception of the second eosinophil count. If the screening assessments and procedures are 
divided over more than one visit, each additional screening visit should include the following: prior/concomitant 
medication inquiry; adverse event inquiry, LoAC/CAE inquiry, daily e-diary and handheld spirometry review 
including adherence, vital signs, and brief physical exam. Once all inclusion and exclusion criteria have been 
assessed, with the exception of the second eosinophil count, and it has been confirmed that patients meet all of the 
inclusion criteria and none of the exclusion criteria (with the exception of incomplete assessment of eosinophil 
count), the run-in will commence at Visit S2 with the provision of study-provided ICS+LABA.
Samples for peripheral blood eosinophil counts will be collected at a minimum of 2 time points. The first time point 
should be at the initial screening visit (Visit S1), if possible, and the second (Visit S2) 14 days (± 3 days) after the 
first sample collected at Visit S1. To meet eligibility criteria, the peripheral blood eosinophil counts from both time 
points should be <250 cells/µL. If one of the results is ≥250 cells/µL, samples may be collected at a third time point 
(Visit S3) provided that the third time point is 14 days (± 3 days) after the sample collected at Visit S2. If the value 
at a third time point is used to meet the eligibility criteria, 2 out of the 3 values should be <250 cells/µL.
Study period
Screening and Run-In
Visit number 
S1
Screening
(may be completed over 
more than one visit)
S2/3 
At least 1 other visit for 
peripheral eosinophil 
count (blood draw)
Procedures and assessments, weeks before 
randomization
-5a
Informed consent
X
Inclusion and exclusion criteria
X
X
Demography
X
Medical history
X
Asthma and allergy history
X
Prior/concomitant medication inquiry
X
X
Adverse events inquiry
X
X
Perform COVID-19 symptoms inquiryb
X
X
LoAC and CAE inquiry
X
X
ACQ-6
X
ECGc
X
Vital signs measurementd
X
X
Full physical examination, including height and 
weighte
X
Brief physical examinatione
X


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Study period
Screening and Run-In
Visit number 
S1
Screening
(may be completed over 
more than one visit)
S2/3 
At least 1 other visit for 
peripheral eosinophil 
count (blood draw)
Procedures and assessments, weeks before 
randomization
-5a
FeNOf
X
Distribute e-diary and handheld spirometer
X
Review e-diary for SABA/quick-relief medication 
usage, and nighttime awakenings/asthma symptoms, 
including adherence
X (S3)
Review hand-held spirometry, including for 
adherence
X (S3)
Spirometry with reversibility testingg
X
X (if not completed prior 
to this visit)
Distribute albuterol/quick-relief medication
X
Infectious serologiesh
X
TB screeningi
X
X (at S3 if needed)
Urine drug screen including cotinine
X
Hormone testing (FSH, for confirmation in females 
reporting postmenopausal status)
X
Serum pregnancy test (women of childbearing 
potential)
X
Urine pregnancy test (women of childbearing 
potential) 
X
Serum Chemistry
X
CBC with differential count
X
Peripheral eosinophil count
X
X (at S3 if needed)
Coagulation
X
Urinalysis
X
Run-in
Distribute study-provided 
controller inhalers at S2 
and commence run-in 
once all inclusion and 
exclusion criteria, with the 
exception of the second 
eosinophil count, have 
been fulfilled (see text in 
Section 3.6.1.1)
a Run-in may be extended for up to 14 days if needed for the shipment of IMP to the investigational site or to 
complete assessment of eosinophil counts.


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b Patients with clinical symptoms that may indicate COVID-19 infection, and/or patients who in the 
investigator’s opinion were at high risk of exposure to COVID-19 within 6 weeks before screening or during 
screening/run-in, will be tested for active COVID-19 infection. Patients who were hospitalized in the intensive 
care unit for COVID-19 are excluded. 
c ECGs should be performed before scheduled blood draws and after the subject has been in a supine position for 
5 minutes. 
d Vital signs measurements include blood pressure, pulse, body temperature, and respiratory rate. Patients are to 
remain in a supine position for at least 5 minutes prior to measuring blood pressure and pulse. If possible, blood 
pressure measurements should be completed on the same arm at each visit. Vital signs should be measured 
before scheduled blood draws.
e For details on full/brief physical examinations, see Section 7.7.
f FeNO should be completed before reversibility testing.
g Patients need to have signed the ICF before being asked to hold medications for reversibility testing. Therefore, 
initial reversibility testing may take place at a visit after the initial screening visit (see Section 3.6.1.1 for 
additional details). Reversibility testing should only be attempted after withholding short acting bronchodilators 
(ie, inhaled short-acting beta-adrenergic agonists and/or short-acting anticholinergics) for at least 6 hours and 
long-acting bronchodilators (ie, inhaled long-acting beta-adrenergic agonists and long-acting anticholinergic 
agents) for at least 12 or 24 hours, according to their labeled dose schedule. Patients who do not meet 
reversibility criteria (≥12% and ≥200 mL), may be re-tested once during the initial 2 weeks (±3 days) of the 
screening period.
h Serology includes hepatitis B surface antigen (HBsAg), antibodies to hepatitis C virus (HCV), and human 
immunodeficiency virus (HIV) types 1 or 2.
i QuantiFERON® TB Gold Test (If the QuantiFERON® TB Gold Test is deemed by the principal investigator to 
be a false positive, additional samples will be tested to confirm diagnosis; see Section 7.5.2 for details.)
ACQ-6=Asthma Control Questionnaire 6-question version; CAE=clinical asthma exacerbation; COVID-19= 
coronavirus disease 2019; ECG=electrocardiogram; FSH=follicle-stimulating hormone; ICF=informed consent 
form; ICS+LABA=inhaled corticosteroids + long acting beta-agonists; IMP=investigational medical product; 
LoAC=loss of asthma control; SABA=short-acting beta agonist; TB=tuberculosis
.


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Table 3:
Study Procedures and Assessments: Treatment Period (Visits 1 – 10)
Study period
Treatment Period – Visits 1 – 10
Visit number
V1
DoR
V2
V3
V4
V5
Phonea
V6
V7
V8
V9
V10
EOTb
Procedures and 
assessments
weeks after random.
       study day
0
-
2
15 
4
29
6
43
7
50
8
57
10
71
12
85
14
99
16
113
Allowed time windows, 
±days  
-
3
3
3
3
3
3
3
3
3
Inclusion and exclusion 
criteria
X
Randomization criteria
X
LoAC and CAE inquiryc
X
X
X
X
X
X
X
X
X
X
Review e-diary for 
SABA/quick-relief 
medication usaged and 
nighttime awakenings, 
including for adherence
X
X
X
X
X
X
X
X
X
X
Review hand-held 
spirometry, including for 
adherence
X
X
X
X
X
X
X
X
X
X
ACQ-6
X
X
X
X
X
X
X
X
X
Check supply and, if 
required, dispense study-
provided controller 
therapies. Collect returned 
inhalers.
X
X
X
X
X
X
X
X
X
Check supply of study-
provided SABA. Collect 
returned inhalers.
X
X
X
X
X
X
X
X
X


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Study period
Treatment Period – Visits 1 – 10
Visit number
V1
DoR
V2
V3
V4
V5
Phonea
V6
V7
V8
V9
V10
EOTb
Procedures and 
assessments
weeks after random.
       study day
0
-
2
15 
4
29
6
43
7
50
8
57
10
71
12
85
14
99
16
113
Allowed time windows, 
±days  
-
3
3
3
3
3
3
3
3
3
Concomitant medication 
inquiry
X
X
X
X
X
X
X
X
X
X
Adverse events inquiry
X
X
X
X
X
X
X
X
X
X
Perform COVID-19 
symptoms inquirye
X
X
X
X
X
X
X
X
X
X
ECGf
X
X
X
X
X
Vital signs measurementg
X
X
X
X
X
X
X
X
X
Full physical examination, 
including weighth
X
X
Brief physical 
examination
X
X
X
X
X
X
X
FeNOi
X
X
X
X
X
X
X
X
X
Background asthma 
controller therapies 
withdrawal (other than 
ICS/LABA)
X
Background asthma 
ICS/LABA controller 
therapies withdrawal 
evaluationj
X
X
X
X
X
X
X


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Study period
Treatment Period – Visits 1 – 10
Visit number
V1
DoR
V2
V3
V4
V5
Phonea
V6
V7
V8
V9
V10
EOTb
Procedures and 
assessments
weeks after random.
       study day
0
-
2
15 
4
29
6
43
7
50
8
57
10
71
12
85
14
99
16
113
Allowed time windows, 
±days  
-
3
3
3
3
3
3
3
3
3
In-office spirometry (full 
flow-volume loop)
X
X
X
X
X
X
X
X
X
Urine pregnancy testk
X
X
X
X
X
X
X
X
X
Serum chemistry
X
X
X
X
X
CBC with differential 
count
X
X
X
X
X
Urinalysisl
X
X
Serum drug 
concentrationm
X
X
X
X
X
X
ADAm
X
X
X
X
X
X
 
(exploratory)m
X
X
X
X
Pharmacogenomics –
Blood in PaxGene DNA 
tube (optional)n
X
IMP administrationop
X
X
X
X
X
X
X
X
Local tolerability 
assessmentq
X
X
X
X
X
X
X
X
a For patients who have not withdrawn completely from their background asthma controller therapies due to the patient entering the study on higher background 
asthma controller therapy doses, further phone visits will be performed between in-person visits after V6, V7 etc. (see Section 3.6.1.2.7)


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b In case of early termination the procedures outlined in Section 3.6.1.2.9 should be followed. 
c If, in the investigator's judgment, LoAC is suspected, every effort to have the patient evaluated at an unscheduled visit should be made. Procedures and 
assessments to be performed if an unscheduled visit occurs are described in Section 3.6.1.4. An effort should be made to collect blood samples for TEV-48574 
serum concentration and ADA testing at (or as close to) the time of LoAC as possible in addition to the scheduled assessments.
d At the visits it should be determined if the patient has adequate rescue medication remaining.
e If a patient exhibits clinical symptoms during the study that may indicate COVID-19 infection, the patient will be tested for active COVID-19 infection. If the 
patient tests positive, the patient will be discontinued from IMP and will need to visit the clinical site again for an early termination visit. Remote assessment of 
safety via teleconference and/or videoconference, with videoconference being the preferred method, is recommended until the patient is able to visit the clinical 
site for the early termination visit.   
f ECG assessments should precede vital sign assessments. ECGs should be performed in a supine position after 5 minutes rest. At DoR, ECG will be performed 
in triplicate, with each ECG taken within 1 to 5 minutes of the previous one.
g Vital signs measurements include blood pressure, pulse, body temperature, and respiratory rate. Patients are to remain in a supine position for at least 5 minutes 
prior to measuring blood pressure and pulse. If possible, blood pressure measurements should be completed on the same arm at each visit. Vital signs should be 
measured before scheduled blood draws and after the ECG assessment when applicable. 
h For details on full/brief physical examinations, see Section 7.7.
i FeNO should be completed before in-office spirometry. 
j A structured decrease in background asthma controller therapies will performed as described in Section 3.1 in patients without LoAC. Further details can be 
found in the pharmacy manual. 
k Only for women of childbearing potential.
l When sampling urine, menstruation status should be recorded for women of childbearing potential.
m In cases of a suspected severe systemic hypersensitivity reaction (eg, anaphylaxis), CAE, LoAC, serious adverse event or immunogenicity-related adverse 
event, efforts should be made to collect additional sample(s) for immunogenicity, serum total and free TL1A and serum concentration of TEV-48574. In cases 
of suspected or confirmed anaphylaxis, efforts should be made to collect samples for ADA determination as close to the onset of the event as possible, at 
resolution, and 30 days after onset of the event. 
n On signing the appropriate ICF, an optional blood sample may be collected for pharmacogenomics analysis.
o If during administration or during post-IMP administration observation the patient develops clinical symptoms or signs, vital signs should be collected and a 
physical exam (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. IMP will be discontinued in patients who experience LoAC and background therapy will be restarted/increased; these patients will 
stay in the study.
p All device-related adverse events, malfunctions etc. will be recorded and evaluated for their impact relative to the safety and efficacy of the IMP.
q Administration site findings and pain will be assessed 1 hour after the completion of IMP administration. Additionally after the loading dose and first 
maintenance dose, assessments will also be performed 2 hours after the completion of administration. Allowed time windows for the local tolerability 
assessments are ±15 minutes. 
ADA=anti-drug antibody; ACQ-6=Asthma Control Questionnaire 6-question version; β-HCG=beta human chorionic gonadotropin; CAE=clinical asthma 
exacerbation; COVID-19=coronavirus disease 2019; DoR=day of randomization; ECG=electrocardiogram; EOT=End of Treatment; FeNO=fractional exhaled 
nitric oxide; ICF=informed consent form; ICS+LABA=inhaled corticosteroids + long acting beta-agonists; IMP=investigational medicinal product; LoAC=loss 
of asthma control; PK=Pharmacokinetic; random=randomization; SABA=short-acting beta agonist; V=visit.


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Table 4:
Study Procedures and Assessments: Follow-up Period
Study period
Follow-up
Visit number
V11
EOS
Procedures and assessments 
                        week after randomization -
                        study day
24
169
Allowed time window, ±days
7
Concomitant medication inquiry
X
Adverse events inquiry
X
Perform COVID-19 symptoms inquirya
X
LoAC and CAE inquiry
X
Review e-diary for SABA/quick-relief medication usage and nighttime 
awakenings, including for adherence
X
Review hand-held spirometry, including for adherence
X
Collect e-diary and hand-held spirometer
X
ACQ-6
X
Collect any study-provided inhalers
X
ECGb
X
Vital signs measurementc
X
Full physical examination, including weightd
X
FeNO
X
Urine pregnancy test (women of childbearing potential)
X
Serum chemistry
X
CBC with differential count
X
Urinalysise
X
Serum drug concentration
X
ADA
X
 (exploratory)
X
a If a patient exhibits clinical symptoms during the study that may indicate COVID-19 infection, the patient will be 
tested for active COVID-19 infection.
b ECG assessments should precede vital sign assessments. ECGs should be performed in a supine position after 5 
minutes rest.
c Vital signs measurements include blood pressure, pulse, body temperature, and respiratory rate. Patients are to 
remain in a supine position for at least 5 minutes prior to measuring blood pressure and pulse. If possible, blood 
pressure measurements should be completed on the same arm at each visit. Vital signs should be measured before 
scheduled blood draws and after the ECG assessment when applicable. 
d For details on full physical examinations, see Section 7.7.
e When sampling urine, menstruation status should be recorded for women of childbearing potential.
ACQ-6=Asthma Control Questionnaire 6-question version; ADA=anti-drug antibody; CAE=clinical asthma 
exacerbation; COVID-19=coronavirus disease 2019; ECG=electrocardiogram; EOS=End-of-study; FeNO=fractional 
exhaled nitric oxide; LoAC=loss of asthma control; V=visit.


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3.6.1.
Study Procedures and Assessments By Visit
3.6.1.1.
Assessments and Procedures for Screening and Run-in
A signed and dated ICF will be obtained from all patients before screening assessments and 
procedures commence. 
After informed consent is obtained, patients who are screened will be assigned a permanent 
identification number such that all patients from each investigational center are given 
consecutive identification numbers in successive order of inclusion. 
Note: Screening will include at least 2 visits and may be completed over more than 2 visits. The 
screening assessments and procedures for the first screening visit may be completed over more 
than one visit: sites should make every effort to complete the screening assessments and 
procedures in the first 2 weeks following the initial screening visit, with the exception of the 
second eosinophil count. It is recommended that the site consider consenting the subject and 
completing the first peripheral eosinophil count at the initial S1 screening visit in order to 
determine if the subject meets the eosinophil criteria for enrollment. If the subject is eligible, the 
remaining S1 assessments and procedures may be performed within two weeks of the initial S1 
screening visit. However, sites may elect to conduct the entire S1 screening assessments and 
procedures at one visit only.  
If the screening assessments and procedures are divided over more than one visit, each additional 
screening visit should include the following: review inclusion/exclusion criteria, 
prior/concomitant medication inquiry; adverse event inquiry, COVID-19 symptoms inquiry, 
LoAC/CAE inquiry, vital signs, and brief physical exam. Once all inclusion and exclusion 
criteria have been assessed, with the exception of the second eosinophil count (see below), and it 
has been confirmed that patients meet all of the inclusion criteria and none of the exclusion 
criteria (with the exception of incomplete assessment of eosinophil count), the run-in will 
commence with the provision of study-provided ICS+LABA at Visit S2.
Samples for peripheral blood eosinophil counts should be collected at 2 time points. The first 
time point should be at Visit S1, if possible, and the second (Visit S2) 14 days (± 3 days) after 
the first sample collected at Visit S1. To meet eligibility criteria, the peripheral blood eosinophil 
counts from both time points should be <250 cells/µL. If one of the results is ≥250 cells/µL, 
samples may be collected at Visit S3 provided that the third time point is 14 days (± 3 days) after 
the sample collected at Visit S2. If the value at a third time point is used to meet the eligibility 
criteria, 2 out of the 3 values should be <250 cells/µL. 
Efforts to perform the following assessments and procedures in the order listed should be made 
and may be divided over more than one visit:
3.6.1.1.1. Visit S1

Obtain written informed consent before any other study-related assessments or 
procedures are performed.

Review inclusion/exclusion criteria.

Document demography and review medical history, including asthma and allergy 
history.


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
Perform prior/concomitant medication inquiry.

Perform adverse event inquiry.

Perform COVID-19 symptoms inquiry. 

Perform LoAC and CAE inquiry.

Complete the ACQ-6.

Perform ECG.

Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, body temperature, and respiratory rate).

Perform full physical examination, and measure height and weight.

Measure FeNO.

Perform reversibility testing

Patients need to have signed the ICF before being asked to hold medications for 
reversibility testing. Reversibility testing should only be attempted after 
withholding short acting bronchodilators (ie, inhaled short-acting beta-adrenergic 
agonists and/or short-acting anticholinergics) for at least 6 hours and long-acting 
bronchodilators (ie, inhaled long-acting beta-adrenergic agonists and long-acting 
anticholinergic agents) for at least 12 or 24 hours, according to their labeled dose 
schedule. Therefore, initial reversibility testing may take place at a visit after the 
first screening visit. 
Perform reversibility testing if long-acting and short-acting inhaled 
bronchodilators were held for the specified time; if not, the patient should be 
brought back on another day to complete. If of their own volition, without being 
asked, patients have not taken any of the aforementioned bronchodilators for the 
requisite amount of time prior to the initial screening visit, reversibility may be 
performed at the initial screening visit. If the inclusion criterion for reversibility is 
not met, testing may be repeated once within the initial 2-weeks (±3 days) of the 
screening period. SABAs, such as salbutamol or albuterol, administered via a 
metered dose inhaler should be used for reversibility testing. Four separate puffs 
(eg, albuterol 90 μg or salbutamol 100 μg ex-valve, or equivalent) should be given 
by metered dose inhaler, as tolerated. Post-bronchodilator spirometry should be 
performed a minimum of 15 minutes after SABA is taken and within 30 minutes 
after SABA. 

Distribute albuterol/quick-relief medication at Visit S1.

Obtain sample for infectious serologies.

Perform tuberculosis screen.

Perform urine drug screen.

Perform hormone testing (FSH, for confirmation in females reporting postmenopausal 
status) and serum pregnancy testing (women of childbearing potential).


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
Collect samples for clinical laboratory tests (serum chemistry, CBC with differential 
count, coagulation, urinalysis), including peripheral blood eosinophil counts. As 
described below, a second peripheral blood eosinophil count will be required to fulfil 
the inclusion criteria.
3.6.1.1.2. Visit S2 (14 days [± 3 days] after Visit S1)

Review inclusion/exclusion criteria.

Perform prior/concomitant medication inquiry.

Perform adverse event inquiry.

Perform COVID-19 symptoms inquiry.

Perform LoAC and CAE inquiry.

Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, body temperature, and respiratory rate).

Perform brief physical examination.

Distribute e-diary, instruct the patient on how to perform the respective assessments, 
and perform first assessments.

Distribute hand-held spirometer.

Perform reversibility testing (if not completed prior to this visit).

Perform urine pregnancy testing (women of childbearing potential).

Repeat testing of peripheral blood eosinophil counts.

If all inclusion and exclusion criteria, with the exception of the second eosinophil 
count, are fulfilled within the first 2 weeks, distribute study-provided controller 
inhalers to standardize the patient’s ICS+LABA and commence run-in. This should 
start at least 2 weeks prior to randomization.
3.6.1.1.3. Visit S3 (14 days [± 3 days] after Visit S2) (if required)
If required, to meet the eosinophil count inclusion criterion, efforts should be made to perform 
the following assessments and procedures in the order listed: 

Perform prior/concomitant medication inquiry.

Perform adverse event inquiry.

Perform COVID-19 symptoms inquiry.

Perform LoAC and CAE inquiry.

Review daily e-diary for SABA/quick-relief medication usage and nighttime 
awakenings, including for adherence.

Review daily hand-held spirometry, including for adherence.


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
Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, body temperature, and respiratory rate).

Perform brief physical examination.

Repeat testing of peripheral blood eosinophil counts.

Perform urine pregnancy testing (women of childbearing potential).

Review inclusion/exclusion criteria.

If the patient has not already started run-in and all inclusion and exclusion criteria are 
now fulfilled, distribute study-provided controller inhalers to standardize the patient’s 
ICS+LABA and commence run-in. This should start at least 2 weeks prior to 
randomization.
3.6.1.2.
Assessments and Procedures During the Treatment Period
3.6.1.2.1. Assessments and Procedures for the Day of Randomization (Visit 1): Pre-Study 
Drug Administration; Randomization, and Administration of the Loading Dose
Patients who have been on study-provided controller inhalers for at least 2 weeks and who meet 
all of the inclusion criteria, none of the exclusion criteria, and all of the randomization criteria 
proceed to the Day of Randomization (DoR) visit (Visit 1). 
Efforts should be made to perform the following procedures in the order listed, at the Day of 
Randomization visit before IMP administration:

Review inclusion/exclusion criteria.

Review randomization criteria. 

Review daily e-diary for SABA/quick-relief medication usage and nighttime 
awakenings, including for adherence.

Review daily hand-held spirometry, including for adherence.

Perform LoAC and CAE inquiry.

Complete the ACQ-6.

Check supply and, if required, dispense study-provided controller therapies. Collect 
returned inhalers.

Check supply of study-provided SABA. Collect returned inhalers.

Perform concomitant medication inquiry.

Perform adverse event inquiry.

Perform COVID-19 symptoms inquiry.

Perform ECG in triplicate.

Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, body temperature, and respiratory rate).


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
Perform full physical examination and document body weight.

Measure FeNO.

Perform in-office spirometry (full flow-volume loop).

Perform urine pregnancy testing (women of childbearing potential).

Collect samples for clinical laboratory tests (serum chemistry, CBC with differential 
count, peripheral eosinophil count, urinalysis).

Collect blood sample for serum TEV-48574 concentration determination (PK 
assessment) from all patients before IMP administration.

Collect blood sample for immunogenicity (ADA) assessment.

Collect blood for 
 assessment.

Collect optional blood sample in PaxGene DNA tube for pharmacogenomics analysis.

Withdraw all controller medications with the exception of ICS/LABA.
Patients who continue to meet all of the inclusion criteria, none of the exclusion criteria, and all 
of the randomization criteria will be assigned a permanent unique randomization number and a 
treatment number generated by interactive response technology (IRT). These two newly assigned 
numbers will be entered into the CRF, and study drug will be dispensed. During the double-blind 
treatment period, patients will return to the study center every 2 weeks for administration of 
IMP, assessments and procedures.
The following procedures/assessments will be performed during and after administration of 
study drug:

Administer IMP 
 using the 
 

 

Evaluation of local tolerability at the administration site at 1- and 2-hours 
post-administration.

If, during administration or during post-IMP administration observation the patient 
develops clinical symptoms or signs, vital signs should be collected and a physical 
exam (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.
3.6.1.2.2. Treatment Visit 2 (Week 2) 
At this visit, background asthma controller therapies remain unchanged.
Efforts should be made to perform the following assessments and procedures in the order listed, 
before administration of study drug:

Perform concomitant medication inquiry.

Perform adverse event inquiry.

Perform COVID-19 symptoms inquiry.


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
Review daily e-diary for SABA/quick-relief medication usage and nighttime 
awakenings, including for adherence.

Review daily hand-held spirometry, including for adherence.

Perform LoAC and CAE inquiry.

Complete the ACQ-6.

Check supply and, if required, dispense study-provided controller therapies. Collect 
returned inhalers.

Check supply of study-provided SABA. Collect returned inhalers.

Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, body temperature, and respiratory rate).

Perform brief physical examination.

Measure FeNO.

Perform in-office spirometry (full flow-volume loop).

Perform urine pregnancy testing (women of childbearing potential).

Collect blood for serum TEV-48574 concentration determination (PK assessment) 
from all patients.

Collect blood sample for immunogenicity (ADA) assessment.
The following procedures/assessments will be performed during and after administration of 
study drug:

Administer IMP 
 using the 
 

 

Evaluation of local tolerability at the administration site at 1- and 2-hours post-
administration.

If, during administration or during post-IMP administration observation the patient 
develops clinical symptoms or signs, vital signs should be collected and a physical 
exam (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.
3.6.1.2.3. Treatment Visit 3 (Week 4) 
At this study visit, patients who have not had LoAC will begin the structured withdrawal of their 
background asthma controller therapies.
Efforts should be made to perform the following assessments and procedures in the order listed:

Perform concomitant medication inquiry.

Perform adverse event inquiry.

Perform COVID-19 symptoms inquiry.


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
Review daily e-diary for SABA/quick-relief medication usage and nighttime 
awakenings, including for adherence.

Review daily hand-held spirometry, including for adherence.

Perform LoAC and CAE inquiry.

Patients who have not had LoAC will commence the structured withdrawal of their 
background asthma controller therapies (see Section 3.1).

Complete the ACQ-6.

Check supply and, if required, dispense study-provided controller therapies. Collect 
returned inhalers.

Check supply of study-provided SABA. Collect returned inhalers.

Perform ECG.

Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, body temperature, and respiratory rate).

Perform brief physical examination.

Measure FeNO.

Perform in-office spirometry (full flow-volume loop).

Perform urine pregnancy testing (women of childbearing potential).

Collect samples for clinical laboratory tests (serum chemistry, CBC with differential 
count, peripheral eosinophil count).

Collect blood for serum TEV-48574 concentration determination (PK assessment) 
from all patients.

Collect blood sample for immunogenicity (ADA) assessment.

Collect blood sample for 
 assessment.
The following procedures/assessments will be performed during and after administration of 
study drug:

Administer IMP 
 using the 
 

 

Evaluation of local tolerability at 1-hour post-administration.

If, during administration or during post-IMP administration observation the patient 
develops clinical symptoms or signs, vital signs should be collected and a physical 
exam (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.


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3.6.1.2.4. Treatment Visit 4 (Week 6) 
At this study visit, patients who have not had LoAC will continue the structured withdrawal of 
their background asthma controller therapies.
Efforts should be made to perform the following assessments and procedures in the order listed:

Perform concomitant medication inquiry.

Perform adverse event inquiry.

Perform COVID-19 symptoms inquiry.

Review daily e-diary for SABA/quick-relief medication usage and nighttime 
awakenings, including for adherence.

Review daily hand-held spirometry, including for adherence.

Perform LoAC and CAE inquiry.

Patients who have not had LoAC will continue the structured withdrawal of their 
background asthma controller therapies (see Section 3.1).

Complete the ACQ-6.

Check supply and, if required, dispense study-provided controller therapies. Collect 
returned inhalers.

Check supply of study-provided SABA. Collect returned inhalers.

Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, body temperature, and respiratory rate).

Perform brief physical examination.

Measure FeNO.

Perform in-office spirometry (full flow-volume loop).

Perform urine pregnancy testing (women of childbearing potential).
The following procedures/assessments will be performed during and after administration of 
study drug:

Administer IMP 
 using the 
 

 

Evaluation of local tolerability at the administration site at 1-hour post-
administration.

If, during administration or during post-IMP administration observation the patient 
develops clinical symptoms or signs, vital signs should be collected and a physical 
exam (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.


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3.6.1.2.5. Telephone Enquiry, Visit 5 (Week 7)
The patient will be contacted by telephone. The following assessments will be performed:

Perform prior/concomitant medication inquiry.

Perform adverse event inquiry.

Perform COVID-19 symptoms inquiry.

Review uploaded daily e-diary for SABA/quick-relief medication usage and 
nighttime awakenings, including for adherence.

Review uploaded daily hand-held spirometry, including for adherence.

Perform LoAC and CAE inquiry.

Patients who have not had LoAC will continue the structured withdrawal of their 
background asthma controller therapies (see Section 3.1).
If, in the investigator's judgment, LoAC is suspected, every effort to have the patient evaluated at 
an unscheduled visit should be made.
For patients who have not withdrawn completely from their background asthma controller 
therapies by visit 5, additional phone visits (P1, P2 etc) should be performed between in-person 
visits until the withdrawal of background therapies is complete or the patient experiences a 
LoAC. 
As noted Section 3.3, daily measures of asthma control including FEV1 and rescue medication 
use will be collected between visits and decreases in background asthma controller therapies will 
be structured. Patients who experience loss of asthma control at any time, as defined by this 
protocol, will stop the IMP, receive appropriate treatment by the investigator, and resume 
background asthma controller therapy.
3.6.1.2.6. Treatment Visit 6 (Week 8) 
At this study visit, patients who have not had LoAC will continue the structured withdrawal of 
their background asthma controller therapies, or IMP only if that had already been reached.
Efforts should be made to perform the following assessments and procedures in the order listed:

Perform concomitant medication inquiry.

Perform adverse event inquiry.

Perform COVID-19 symptoms inquiry.

Confirm that structured withdrawal of background asthma controller therapy 
occurred, as discussed during visit 5 (telephone enquiry) (if applicable).

Review daily e-diary for SABA/quick-relief medication usage and nighttime 
awakenings, including for adherence.

Review daily hand-held spirometry, including for adherence.

Perform LoAC and CAE inquiry.


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
Patients who have not had LoAC will continue the structured withdrawal of their 
background asthma controller therapies if not already fully withdrawn (see 
Section 3.1).

Complete the ACQ-6.

Check supply and, if required, dispense study-provided controller therapies. Collect 
returned inhalers.

Check supply of study-provided SABA. Collect returned inhalers.

Perform ECG.

Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, body temperature, and respiratory rate).

Perform brief physical examination.

Measure FeNO.

Perform in-office spirometry (full flow-volume loop)

Perform urine pregnancy testing (women of childbearing potential).

Collect samples for clinical laboratory tests (serum chemistry, CBC with differential 
count, peripheral eosinophil count).

Collect blood for serum TEV-48574 concentration determination (PK assessment) 
from all patients.

Collect blood sample for immunogenicity (ADA) assessment.

Collect blood sample for 
 assessment.
The following procedures/assessments will be performed during and after administration of 
study drug:

Administer IMP 
 using the
 

 

Evaluation of local tolerability at the administration site at 1-hour 
post-administration.

If, during administration or during post-IMP administration observation the patient 
develops clinical symptoms or signs, vital signs should be collected and a physical 
exam (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.
3.6.1.2.7. Further Telephone Enquiries, Phone 1, 2 etc. 
For patients who have not withdrawn completely from their background asthma controller 
therapies by visit 5, additional phone visits (P1, P2 etc) should be performed between in-person 
visits until the withdrawal of background therapies is complete or the patient experiences a 
LoAC.


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The patient will be contacted by telephone. The following assessments will be performed:

Perform prior/concomitant medication inquiry.

Perform adverse event inquiry.

Perform COVID-19 symptoms inquiry.

Review uploaded daily e-diary for SABA/quick-relief medication usage and 
nighttime awakenings, including for adherence.

Review uploaded daily hand-held spirometry, including for adherence.

Perform LoAC and CAE inquiry.

Patients who have not had LoAC will continue the structured withdrawal of their 
background asthma controller therapies (see Section 3.1).
If, in the investigator's judgment, LoAC is suspected, every effort to have the patient evaluated at 
an unscheduled visit should be made.
3.6.1.2.8. Treatment Visits 7 (Week 10), 8 (Week 12) and 9 (Week 14)
At these study visits, most patients who have not had LoAC will have fully withdrawn their 
background asthma controller therapies and will continue on IMP only.
Patients who have not had LoAC and are not yet on IMP only (due to the initial ICS dose) will 
continue the structured withdrawal of their background asthma controller therapies. 
Efforts should be made to perform the following assessments and procedures in the order listed 
at each of these visits, unless otherwise indicated:

Perform concomitant medication inquiry.

Perform adverse event inquiry.

Perform COVID-19 symptoms inquiry.

Confirm that all background asthma controller therapies have been discontinued, as 
scheduled.

Review daily e-diary for SABA/quick-relief medication usage and nighttime 
awakenings, including for adherence.

Review daily hand-held spirometry, including for adherence.

Perform LoAC and CAE inquiry.

Patients who have not had LoAC will continue either on IMP only (Section 3.1) or 
with structured withdrawal of their background asthma controller therapies.

Complete the ACQ-6.

Check supply and, if required, dispense study-provided controller therapies. Collect 
returned inhalers.

Check supply of study-provided SABA. Collect returned inhalers.

Perform ECG (visit 8 only).


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
Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, body temperature, and respiratory rate).

Perform brief physical examination.

Measure FeNO.

Perform in-office spirometry (full flow-volume loop).

Perform urine pregnancy testing (women of childbearing potential).

Collect samples for clinical laboratory tests (serum chemistry, CBC with differential 
count, peripheral eosinophil count; visit 8 only).

Collect blood for serum TEV-48574 concentration determination (PK assessment) 
from all patients (visit 8 only).

Collect blood sample for immunogenicity (ADA) assessment (visit 8 only).
The following procedures/assessments will be performed during and after administration of 
study drug:

Administer IMP 
 using the KORU
 

 

Evaluation of local tolerability at the administration site at 1-hour 
post-administration.

If, during administration or during post-IMP administration observation the patient 
develops clinical symptoms or signs, vital signs should be collected and a physical 
exam (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.
3.6.1.2.9. Early Termination (ET) Visit 
Patients who discontinue treatment with IMP for reasons other than the occurrence of 
LoAC/CAE in the study are encouraged to complete early termination (ET visit) 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 EOT and EOS within 
the original time frames based on day of randomization (DoR). These patients are not considered 
to have withdrawn from the study.
Patients who decide to withdraw completely from the study are encouraged to complete early 
termination (ET visit) procedures as soon as possible after receiving their last dose of IMP.
At the ET visit the following procedures/assessments will be performed: 

Perform concomitant medication inquiry.

Perform adverse event inquiry.

Perform COVID-19 symptoms inquiry.

Review daily e-diary for SABA/quick-relief medication usage and nighttime 
awakenings, including for adherence.


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
Review daily hand-held spirometry, including for adherence.

Perform LoAC and CAE inquiry.

Complete the ACQ-6.

Check supply and, if required, dispense study-provided controller therapies (for 
patients who remaining in the study). Collect returned inhalers.

Check supply of study-provided SABA (for patients who are remaining in the study). 
Collect returned inhalers.

Perform ECG.

Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, body temperature, and respiratory rate).

Perform full physical examination.

Measure FeNO.

Perform in-office spirometry (full flow-volume loop).

Perform urine pregnancy testing (women of childbearing potential).

Collect samples for clinical laboratory tests (serum chemistry, CBC with differential 
count, peripheral eosinophil count, urinalysis).

Collect blood for serum TEV-48574 concentration determination (PK assessment) 
from all patients.

Collect blood sample for immunogenicity (ADA) assessment.

Collect blood sample for 
 assessment.
3.6.1.2.10. End of Treatment (EOT) Visit (Visit 10, Week 16)
Two weeks after the final administration of IMP in the double-blind treatment period, patients 
will return to the study center for the EOT visit and efforts should be made to perform the 
following assessments and procedures in the order listed:

Perform concomitant medication inquiry.

Perform adverse event inquiry.

Perform COVID-19 symptoms inquiry.

Review daily e-diary for SABA/quick-relief medication usage and nighttime 
awakenings, including for adherence.

Review daily hand-held spirometry, including for adherence.

Perform LoAC and CAE inquiry.

Complete the ACQ-6.

Review background asthma controller therapies to be restarted after EOT visit.


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
Check supply and, if required, dispense study-provided controller therapies. Collect 
returned inhalers.

Check supply of study-provided SABA. Collect returned inhalers.

Perform ECG.

Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, body temperature, and respiratory rate).

Perform full physical examination.

Measure FeNO.

Perform in-office spirometry (full flow-volume loop)

Perform urine pregnancy testing (women of childbearing potential).

Collect samples for clinical laboratory tests (serum chemistry, CBC with differential 
count, peripheral eosinophil count, urinalysis).

Collect blood for serum TEV-48574 concentration determination (PK assessment) 
from all patients.

Collect blood sample for immunogenicity (ADA) assessment.

Collect blood sample for 
 assessment.
The follow-up period starts after the EOT visit. Patients will restart background asthma 
controller therapy after this visit.
3.6.1.3.
Assessments and Procedures During Follow-up
3.6.1.3.1. Assessments and Procedures at the End of Study Visit
At 24 weeks after randomization (±7 days), patients will return to the study center for the EOS 
visit. 
All patients, including those who discontinued treatment whether for protocol-defined LoAC or 
other reasons, should complete the End of Study (EOS) visit. Patients who complete the EOS 
visit are considered to have completed the study.
The monitoring of patients with ongoing adverse events or clinically significant abnormal 
laboratory test results (as interpreted by the investigator) at the EOS is described in Section 7.1.2. 
Efforts should be made to perform the following assessments and procedures in the order listed 
at the EOS visit (week 24):

Perform concomitant medication inquiry.

Perform adverse event inquiry.

Perform COVID-19 symptoms inquiry.

Review daily e-diary for SABA/quick-relief medication usage and nighttime 
awakenings, including for adherence.

Review daily hand-held spirometry, including for adherence.


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
Collect e-diary and hand-held spirometer

Perform LoAC and CAE inquiry.

Complete the ACQ-6.

Collect any study-provided inhalers.

Perform ECG.

Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, body temperature, and respiratory rate).

Perform full physical examination and document body weight.

Measure FeNO.

Perform urine pregnancy testing (women of childbearing potential).

Collect samples for clinical laboratory tests (serum chemistry, CBC with differential 
count, peripheral eosinophil count, urinalysis).

Collect blood for serum TEV-48574 concentration determination (PK assessment) 
from all patients.

Collect blood sample for immunogenicity (ADA) assessment.

Collect blood sample for 
 assessment.
3.6.1.4.
Unscheduled Visits
An unscheduled visit may be performed at any time during the study at the patient’s request or as 
deemed necessary by the investigator. If, in the investigator's judgment, LoAC is suspected, 
every effort to have the patient evaluated at an unscheduled visit should be made. The date and 
reason for the unscheduled visit, as well as any other data obtained (eg, adverse events, 
concomitant medications and treatments, and results from procedures or tests), should be 
documented in the patient's source records and be recorded on the CRF.
Assessments and procedures performed during unscheduled visits include, but are not limited to, 
the following: 

Perform concomitant medication inquiry.

Perform adverse event inquiry.

Perform COVID-19 symptoms inquiry.

Review e-diary for SABA/quick-relief medication usage and nighttime awakenings, 
including for adherence.

Review hand-held spirometry, including for adherence.

Perform LoAC and CAE inquiry.

Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, body temperature, and respiratory rate).

Perform physical exam (brief or full, at the discretion of the investigator).


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Other procedures may be performed at the discretion of the investigator. Details for ET visits for 
patients who withdraw completely from the study and for patients who discontinue treatment for 
reasons other than per protocol for LoAC events (including CAEs) and remain in the study may 
be found in Section 4.4.


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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 (Appendix D). To be eligible for the study, 
patients must meet all of the inclusion criteria and none of the exclusion criteria. To be eligible 
for randomization, patients must continue to meet all of the inclusion criteria, none of the 
exclusion criteria, and all of the randomization criteria.
4.1.
Patient Inclusion Criteria
Inclusion Criteria: Patients may be included in the study only if they meet all of the following 
criteria: 
a.
The patient is a man or woman of any ethnic origin, at least 18 years of age at the 
time of signature of the ICF. 
b. The patient has a diagnosis of asthma for at least 12 months prior to the initial 
screening visit. 
c.
The patient must have an absolute eosinophil count <250 cells/μL (at least 
2 measurements both <250 cells/μL separated by 14 days [± 3 days]). If one of the 
results is ≥250 cells/µL, samples may be collected at a third time point (Visit S3) 
provided that the third time point is 14 days (± 3 days) after the sample collected at 
Visit S2. If the value at a third time point is used to meet the eligibility criteria, 2 out 
of the 3 values should be <250 cells/µL.
d. The patient has an ACQ-6 score ≥1.5.
e.
The patient has demonstrated ≥12% and ≥200 mL response to a bronchodilator from 
baseline FEV1 within 30 minutes after 4 inhalations of albuterol/salbutamol HFA 
MDI (90 mcg ex-actuator) or equivalent (eg, Ventolin) at screening.
f.
The patient has asthma with a FEV1 ≥30% and <80% of the value predicted for age, 
height, sex, and race at screening. FEV1 must be performed using the office-based 
spirometer provided for the study. One pulmonary function test retest during the 
screening visit(s) period (up to 2 weeks) is allowed to fulfill this criterion.  
g. The patient is able to perform technically acceptable and repeatable spirometry, 
including with a hand-held spirometer, after training (applicable to FEV1, not PEF).
h. The patient’s background asthma therapy includes daily medium- or high-dose ICS 
plus LABA for at least 3 months prior to the initial screening visit with or without 
other asthma controller medications. The dose of ICS may vary during these 3 
months, but must remain at a stable daily dose for at least 1 month prior to Visit S1. 
Medium- and high-dose ICS classification will be based on the Global Initiative for 
Asthma (GINA) Global Strategy for Asthma Management and Prevention (2019 
update, Appendix C). Patients with asthma controller medications (excluding 
systemic corticosteroids and systemic immunomodulatory therapies) in addition to 
ICS+LABA may be eligible provided all eligibility criteria are met.
i.
The patient has had at least one clinical asthma exacerbation (worsening of asthma 
requiring systemic corticosteroids [oral or injected], or an emergency department visit 


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due to asthma, or an inpatient hospitalization due to asthma, or a 2-fold or greater 
increase from the subject’s usual maintenance ICS dose during the exacerbation 
period documented in the patient’s medical or pharmacy records in the 18 months 
prior to (but not within 30 days of) the initial screening visit. Only clinical asthma 
exacerbations with historical documentation in the patient’s medical or pharmacy 
records may count towards this criterion.  
j.
Patients must be able to replace their pre-study ICS+LABA with study-provided 
ICS+LABA
k. The patient is a non-smoker for ≥6 months with lifetime history ≤10 pack-years, with 
no current e-cigarette use. The patient must have a negative urine cotinine test at the 
screening visit. 
l.
The patient is able to communicate satisfactorily with the investigator and to 
participate in, and comply with, the requirements of the study.
m. The patient is able to understand the nature of the study and any potential hazards 
associated with participating in the study.
n. The patient must be willing and able to comply with study restrictions and to remain 
at the investigational center for the required duration during the study period, and 
willing to return to the investigational center for further visits, as applicable, and the 
follow up procedures and assessments as specified in this protocol.
o. 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 at least 
12 months without an alternative medical cause plus an increased concentration of 
follicle stimulating hormone [FSH] of more than 35 U/L in women not using 
hormonal contraception or hormonal replacement therapy).
Women of childbearing potential must have a negative β-HCG test result and practice 
a highly effective method of birth control (methods that can achieve a failure rate of 
less than 1% per year when used consistently and correctly, see Section 5.9) prior to 
IMP administration and until the EOS visit or 10 weeks after last IMP dose, 
whichever is longer.
Male patients (including vasectomized) with WOCBP partners (whether pregnant or 
not) must use condoms prior to IMP administration and until the EOS visit or 
10 weeks after last IMP dose, whichever is longer.
4.2.
Patient Exclusion Criteria
Patients will be excluded from participating in this study if they meet any of the following 
criteria:
a.
The patient has any other pulmonary diagnosis that in the opinion of the investigator 
and/or the clinical study physician could adversely affect patient safety or 
interpretation of study results. Examples include but are not limited to: chronic 
obstructive pulmonary disease, chronic bronchitis or any respiratory condition that 
requires any chronic antibiotic use (some antibiotics can be immunomodulatory such 


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as macrolides [eg, erythromycin, azithromycin, and clarithromycin]), bronchiectasis, 
cystic fibrosis, bronchopulmonary dysplasia, and interstitial lung disease (including 
eosinophilic granulomatosis with polyangiitis [EGPA] which is expressly prohibited), 
obstructive sleep apnea (sometimes referred to as sleep apnea or Pickwickian 
Syndrome), and gastroesophageal reflux disease that is not treated with a proton 
pump inhibitor on a scheduled treatment regimen (not PRN).
b. The patient has any concomitant conditions or treatments that could interfere with 
study conduct, influence the interpretation of study observations/results, or put the 
patient at increased risk during the study as judged by the investigator and/or the 
clinical study physician. 
c.
The patient has any of the following medical conditions: 
-
Conditions that may mimic asthma (eg, vocal cord dysfunction, 
hyperventilation, panic attacks, cardiac asthma, uncontrolled 
gastroesophageal reflux disease [gastroesophageal reflux disease controlled 
on a stable proton pump inhibitor regimen for at least 1 month may be 
allowed]) 
-
Conditions of immunodeficiency, immunocompromise, and/or conditions 
requiring immunomodulatory therapy
-
A history of malignancy within 5 years before screening (exception: basal 
cell carcinoma or in situ carcinoma of the cervix if successful curative 
therapy occurred at least 12 months prior to screening)
-
Tested positive for tuberculosis (TB) at screening by the QuantiFERON®
TB Gold Test, or had a history of untreated latent or active TB. If the 
QuantiFERON® TB Gold Test is deemed by the principal investigator to be 
a false positive, a repeat specimen shall be submitted; if the second test is 
also positive, the patient screen fails; if the second test is negative, a third 
test shall be submitted; if the third test agrees with the first test, the patient 
screen fails; if the third test agrees with second test, the patient is considered 
to be negative for TB; see Section 7.5.2 for details.
-
Known history of, or a positive test result for, hepatitis B surface antigen 
(HBsAg), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) 
types 1 or 2 at screening
-
A history of more than one herpes zoster episode or multimetameric herpes 
zoster
-
A history of an opportunistic infection (eg, cytomegalovirus retinitis, 
Pneumocystis carinii, aspergillosis, Clostridium difficile)
-
A history of or ongoing chronic or recurrent infectious disease (eg, infected 
indwelling prosthesis, osteomyelitis, chronic sinusitis)
-
A suspected bacterial or viral infection of the upper or lower respiratory 
tract, sinus, or middle ear that has not resolved at least 2 weeks before the 
initial screening visit. Note: Patients who develop an upper respiratory 


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infection/lower respiratory infection (URI/LRI) during the screening period 
may rescreen 2 weeks after symptoms resolve subject to local or regional 
public health directives.
-
Patients with clinical symptoms that may indicate COVID-19 infection, 
and/or patients who in the investigator’s opinion were at high risk of 
exposure to COVID-19 within 6 weeks before screening or during 
screening/run-in, will be tested for active COVID-19 infection and will only 
be included if they test negative for COVID-19. Patients who were admitted 
to an ICU during a prior COVID-19 infection; or patients who contracted or 
recovered from  COVID-19 less than 6 weeks prior to screening, or patients 
with COVID-19 symptoms (lingering anosmia, weakness, persistent 
dyslogia or feelings of dysphoria for many months) from a pre-study 
COVID-19 infection that have not completely resolved back to their 
pre-COVID-19 infection health status are excluded from the study.
d. The patient has taken any systemic corticosteroids within 30 days of screening, 
including but not limited to oral corticosteroids as maintenance therapy for asthma, 
and/or treatment for clinical asthma exacerbation (CAE) within 30 days of screening.
e.
Intensive care unit (ICU) admission or intubation within the 3 months prior to 
screening.
f.
CAE as defined by this protocol (see Section 6.1.2) within the 30 days prior to 
screening.
g. The patient is currently using any systemic immunosuppressive or 
immunomodulatory biologic or non-biologic. Note: Previous use of such agents that 
occurred ≥5 half-lives from the initial screening visit may be allowed, if approved by 
the clinical study physician. 
h. The patient participated in a clinical trial within 30 days or 5 half-lives of the 
investigational drug before screening.
i.
The patient has received investigational drugs targeted against TL1A.
j.
Abnormality in laboratory values during screening that is considered clinically 
significant by the investigator, or could interfere with the objective of the study as 
determined by the sponsor. Any such laboratory abnormality may be retested at the 
investigator’s clinical discretion and if within normal limits, accepted. 
k. The patient is currently pregnant or lactating or is planning to become pregnant 
during the study or for at least 10 weeks after administration of the last dose of IMP 
in case of early withdrawal. Any woman becoming pregnant during the study will be 
withdrawn from the study.
l.
The patient has a known hypersensitivity to the IMP and/or excipients.
m. Live and attenuated vaccines should be excluded 14 days before IMP dosing and 
throughout the study. Inactivated vaccines (including approved inactivated COVID 
19 vaccines) should preferably be completed 14 days before first IMP dosing. If 


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administered during the study it is recommended to be at least 3 days before and after 
IMP administration, or as required by local country regulations. 
n. The patient has a positive urine drug test during screening for compounds of abuse, or 
for cotinine, the relevant metabolite of tobacco abuse, the use of which would make 
the patient ineligible. Repeat testing will not be permitted. A positive urine test for 
tetrahydrocannabinol, the psychoactive ingredient in marijuana, is permitted during 
the trial. 
o. The patient has a history of alcohol or drug abuse within 2 years preceding the initial 
screening visit.
p. Initiation or dose escalation of allergen immunotherapy (administered by any route) is 
planned during the study period. However, patients who initiated immunotherapy 
90 days or more before the initial screening visit and have been on a stable 
(maintenance) dose for 30 days or more before the initial screening visit may be 
considered for inclusion. 
q. The patient is either an employee or an immediate relative of an employee of the 
sponsor or of any of the clinical investigational centers participating in the study.
4.3.
Randomization Criteria
The patients must meet the following randomization criteria prior to randomization:
a.
The patient continues to meet all of the inclusion criteria (including ACQ-6 ≥1.5) and 
none of the exclusion criteria.
b. The patient has not had a clinical asthma exacerbation (worsening of asthma requiring 
systemic corticosteroids [oral or injected], or an emergency department visit due to 
asthma treated with systemic corticosteroids, or an inpatient hospitalization due to 
asthma, or a 2-fold or greater increase from the subject’s usual maintenance ICS dose 
during the exacerbation period  documented in the patient’s medical or pharmacy 
records in the 18 months prior to (but within 30 days of) the initial screening visit, or 
other need for systemic corticosteroids during the screening period. 
c.
The patient has at least 57% adherence (complete and acceptable data for 4 out of the 
7 days prior to randomization) to hand-held spirometry and e-diary assessments.
4.4.
Withdrawal Criteria and Procedures for the Patient
4.4.1.
Withdrawal Criteria
In accordance with the Declaration of Helsinki (in accordance with the applicable country’s 
acceptance) patients may completely withdraw from the study (ie, with no further study 
participation or contact) at any time for any reason. Patients may also voluntarily discontinue 
IMP and remain in the study for assessments. The investigator and/or sponsor may also 
discontinue a patient from IMP and/or withdraw a patient from the study, eg, 

in the event of intercurrent illness, adverse events, pregnancy, or any other reason 
concerning the health or well-being of the patient that indicates to the investigator 
that continued participation is not in the best interest of the patient, or 


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
if the patient is noncompliant with the study procedures and assessments or 
protocol-defined study restrictions or prohibited concomitant medication
Investigators are to discuss patients who may be considering discontinuing IMP or withdrawing 
completely from the study with the sponsor as soon as the site becomes aware of the situation. 
Investigators should attempt to obtain information on patients in the case of withdrawal from the 
study or discontinuation from IMP. Results of any evaluations and observations, together with a 
narrative describing the reason(s) for withdrawal from the study or discontinuation from IMP, 
should be recorded in the source documents. The case report form (CRF) should document the 
primary reason for withdrawal from the study or discontinuation from IMP. 
Discontinuation of IMP as described above and below does not include patients who discontinue 
IMP due to a LoAC event, as LoAC events are part of the planned conduct of the study.
If an adverse event is the primary reason for discontinuation of IMP or withdrawal from the 
study, this should be documented in the source and in the CRF including test results if 
applicable. Under these circumstances, monitoring should be continued until the event has 
resolved or stabilized, or until the patient is referred to the care of a health care professional, or 
until a determination of a cause unrelated to the study drug or study procedure is made. 
The investigator should inform the sponsor as soon as possible of each patient who is being 
considered for withdrawal due to adverse events. Additional reports should be provided when 
requested.
If a patient exhibits clinical symptoms during the study that may indicate COVID-19 infection, 
the patient will be tested for active COVID-19 infection. If the patient tests positive, the patient 
will be discontinued from IMP and will attend for an ET visit. Remote assessment of safety via 
teleconference (TC) and/or videoconference (VC), with VC being the preferred method, is 
recommended until the patient attends for the ET visit. 
4.4.2.
Discontinuation of IMP 
Patients who discontinue treatment with IMP while remaining in the study are encouraged to 
complete early termination (ET visit) 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 EOT and EOS within the original time frames based on date of 
randomization (DoR). 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. 
4.4.3.
Withdrawal from the Study
If a patient decides to completely withdraw from the study (ie, refuses any further study 
participation or contact), all study participation for that patient will cease and all data to be 
collected at subsequent visits will be considered missing. If a patient decides to completely 
withdraw from the study, the patient should be encouraged return to the clinic as soon as possible 
to complete EOT/ET visit procedures. A complete final evaluation at the time of the patient’s 
withdrawal should be made, including an explanation of why the patient is withdrawing from the 


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study. The reason for and date of withdrawal from the study should be recorded in the source 
documentation and the CRF.
4.4.4.
Lost to follow-up
For patients who are lost to follow-up (ie, patients whose status is unclear because they fail to 
appear for study visits without stating an intention to withdraw), the investigator should make 
appropriate efforts to re-establish contact with the patient; attempts to contact the patient should 
be documented in the source documents. The investigator should attempt to 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. Efforts should still be made to locate the patient and obtain information regarding 
serious adverse events, asthma exacerbation events, and survival status at the end of the 16-week 
treatment period. Whether or not contact is reestablished with the patient, every effort should be 
made to ascertain survival status at the end of the treatment period. 
4.5.
Replacement of Patients
A patient who is randomized but does not complete the treatment period will not be replaced.
4.6.
Rescreening
A subject may be rescreened up to 2 times in the study. Rescreening for urine test found positive 
for illicit drugs or cotinine, or failure to meet inclusion criterion “e” (ACQ-6 score ≥1.5, 
Section 4.1) will not be allowed. A subject may be rescreened for all other inclusion and 
exclusion criteria that are not fulfilled.  
4.7.
Screen Failure
Screen failure occurs when a patient who consents to participate in the clinical study is not 
subsequently randomized into the study because that patient did not meet inclusion criteria, did 
meet exclusion criteria, and/or did not meet randomization criteria. Patients will be allowed to
screen fail twice before no longer being considered for enrollment in the clinical 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, 
detailed reasons for screening failure, eligibility criteria, and any serious adverse events.


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5.
TREATMENTS
Investigational Medicinal Products in this study include TEV-48574 (test IMP) and matching 
placebo (placebo IMP).
 
 

TEV-48574 

Placebo to match TEV-48574 
Detailed information about the composition of the test IMP and placebo IMP can be found in the 
following sections. 
Other study-provided medications (ICS+LABA, ICS and short-acting bronchodilators) are not 
considered IMPs in this study (see Section 5.6 for details). 
5.1.
Test Investigational Medicinal Product
TEV-48574 for subcutaneous administration is provided as a liquid solution with a nominal 
concentration of 100 mg/mL. Refer to Table 5 for specific details regarding TEV-48574. 
Additional details may be found in the Pharmacy Manual and in the IB for TEV-48574. 
5.2.
Placebo Investigational Medicinal Product
Placebo IMP for subcutaneous administration is provided as a liquid solution in the same 
formulation as TEV-48574, except for absence of active protein. Refer to Table 5 for specific 
details regarding placebo IMP. 
5.3.
Test and Placebo Investigational Medicinal Product Administration
TEV-48574 or placebo IMP will be administered sc using the 
 
 
 
 
 
 
 
 
 
 
 
 
The test and placebo IMP administration procedures are outlined in the Pharmacy Manual. 


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Table 5:
Investigational Medicinal Products Used in the Study
Test IMP
Placebo IMP
Trade name and INN, if applicable, 
or company-assigned number
TEV-48574
-
Formulation
 
 
Unit dose strength(s)/Dosage level(s)
 
-
Route of Administration
Subcutaneous administration
Subcutaneous administration
Dosing instructions
Refer to details in the Pharmacy 
Manual
Refer to details in the Pharmacy 
Manual
Packaging
 
 
 
 
 
Manufacturer
 
 
 
 
 
 
 
 
IMP=Investigational Medicinal Product.
5.4.
Preparation, Handling, Labeling, Storage, and Accountability for 
IMPs
5.4.1.
Storage and Security
The investigator or designee must confirm appropriate temperature conditions have been 
maintained for all IMPs received and any discrepancies are reported and resolved before use of 
the IMPs.
 
 The site should have a process for monitoring the storage temperature or 
unused IMP.
5.4.2.
Labeling
Supplies of IMPs will be labeled according to the current International Council for 
Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and Good Manufacturing 
Practice and will include any locally required statements. If necessary, labels will be translated 
into the local language.


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5.4.3.
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 IMPs and other study materials 
from the sponsor are correctly received, recorded, handled, and stored safely and properly in 
accordance with the CFR or national and local regulations, and used in accordance with this 
protocol.
Only patients enrolled (ie, randomized) in the study may receive IMPs and only authorized staff 
at the investigational center may supply or administer IMPs. All IMPs 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 investigator and 
authorized staff at the investigational center.
The investigator is responsible for IMP accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
A record of IMP accountability (ie, IMP and other study materials received, used, retained, 
returned, or destroyed) must be prepared and signed by the principal investigator or designee, 
with an account given for any discrepancies. 
Further guidance and information are provided in the Pharmacy Manual.
5.5.
Justification for Investigational Medicinal Products
5.5.1.
Justification for Dose of Test Investigational Medicinal Product
The TEV-48574 dose to be evaluated in this study is a 
 loading dose sc followed every 
2 weeks by a 
 maintenance dose sc (7 maintenance doses in total).
This dose was selected on the basis of pharmacokinetic and safety data from the Phase 1 Study 
 (Section 1.2.2),
 
 
 
 
 
 
 
 
 


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5.5.2.
Justification for Use of Placebo Investigational Medicinal Product
A placebo-controlled design is scientifically appropriate as the use of a placebo-controlled design 
in this POC study will allow robust evaluation of any treatment effect of TEV-48574 and 
characterization of any potential adverse drug reactions.
Patients will have close medical observation throughout the study and will be provided with 
rescue medication. In addition, only patients for whom it is considered safe to participate in the 
study, in the opinion of the investigator, will be permitted to participate.
5.6.
Other Medicinal Products
Note that other medicinal product is mandated for use in this study; however, for the purposes of 
this study it is not considered an IMP.
The study-provided ICS+LABA and ICS will consist of fluticasone propionate plus salmeterol 
and fluticasone propionate with strengths closest to the equivalent of the patient’s pre-study 
ICS+LABA, plus additional ICS if applicable initially and per the structured withdrawal (see 
Section 3.1) subsequently. Locally approved formulations of fluticasone propionate plus 
salmeterol and fluticasone propionate will be used if available. Any other controller medications 
will not be study-provided.
The study-provided SABA/quick-relief bronchodilator medication will be albuterol/salbutamol. 
5.7.
Treatment after the End of the Study
No additional extension or compassionate use of TEV-48574 is planned after completion of this 
study. At the EOS visit, the investigator will discuss with the patient the return to appropriate 
medical care and medication as part of standard of care provided by the patient’s primary 
physician and specialists.
5.8.
Restrictions
Patients will be required to comply with the following restrictions:
5.8.1.
Activity
Patients should avoid strenuous exercise for at least 4 hours prior to any clinic visit and for at 
least 4 hours after IMP administration.


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5.8.2.
Tobacco and illicit drugs
Smoking or use of tobacco products (eg, cigarettes, e-cigarettes, cigars, chewing tobacco, pipe 
tobacco), and use of illicit drugs is strictly forbidden in this study, and objective tests that 
indicate the use of and/or exposure to these drugs will be administered at the screening visit. 
Positive tests will result in an irrevocable screen failure of the subject, and retesting is not 
permitted. In addition, these drugs may not be used or taken at any time during the trial (from 
Screening Visit S1 through EOS visit). A positive urine test for tetrahydrocannabinol, the 
psychoactive ingredient in marijuana, is however, permitted during the trial. 
5.8.3.
Blood Donation
Patients may not donate blood during the study.
5.9.
Effective Methods of Birth Control
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. 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

Intrauterine device (IUD) and intrauterine hormone-releasing system (IUS) need to be 
in place at least 2 months before screening

Bilateral tubal occlusion/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 study period. 
5.10.
Prior and Concomitant Medication or Therapy
Any prior or concomitant therapy, medication, or procedure a patient has had 4 weeks before 
screening through the end of the study will be recorded in the source documentation and in the
CRF. Generic or trade name, indication, and dosage will be recorded. The sponsor will encode 
all therapy and medication according to the World Health Organization drug dictionary (WHO 
Drug). In addition, prior biologics and immunomodulatory therapies (biologics and non-
biologics should also be recorded in the source documents and in the CRF even if the end date 
was greater than 4 weeks prior to the initial screening visit. 
The following medications will not be allowed during this study:

Any systemic immunosuppressive or immunomodulatory agents (biological and 
non-biological excluding systemic maintenance allergen immunotherapy and 


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systemic corticosteroids for the treatment of LoAC events including clinical asthma 
exacerbations). 
Examples include but are not limited to:

systemic corticosteroids (except for the treatment of LoAC/CAE during the study)

methotrexate

cyclosporine

interferon

omalizumab 

dupilumab

mepolizumab

benralizumab

reslizumab

anti-tumor necrosis factor monoclonal antibodies

Non-protocol specified ICS+LABA

Any investigational drug (biologic or non-biologic) 

Investigational drugs targeted against TL1A

Live and attenuated vaccines
Note:

Stable maintenance allergen immunotherapy will be allowed. Starting or build-up phase 
allergen immunotherapy will not be allowed.

Completion of inactivated vaccination (including available inactivated COVID-19 
vaccinations) is preferable at least 14 days before the first IMP dose, if possible. Inactivated 
vaccination during the study is recommended to be at least 3 days before and after IMP 
administration, if possible, or as required by local country regulations.
5.11.
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 EOS visit.
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 (Section 4.4). The IEC/IRB/competent authorities should be notified if 
required by local regulation.


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5.12.
Randomization and Blinding
This is a randomized, double-blind study. Patients who meet all inclusion criteria, none of the 
exclusion criteria, and all of the randomization criteria will be randomly assigned to receive 
TEV-48574 or placebo to match TEV-48574 in a 1:1 ratio. 
Patients will be randomly assigned to treatment groups by means of a computer-generated 
randomization list. The specifications for randomization will be under the responsibility and 
oversight of Teva Global Statistics.
The study patients and the clinical team at the site will be blinded to treatment assignment until 
the database is locked for analysis. Individuals who may not be blinded include (but are not 
limited to) the bioanalytical scientists, pharmacokineticists, and biostatisticians who are not 
directly involved in study conduct. 
The randomization list will be assigned to the relevant treatment groups through a qualified 
service provider, eg, via the Randomization and Trial Supply Management (RTSM) system. The 
generation of the randomization list and management of the RTSM system will be done by a 
qualified service provider under the oversight of the responsible function at Teva.
5.13.
Maintenance of Randomization and Blinding
5.13.1.
Maintenance of Randomization
Patient randomization codes will be maintained in a secure location at the service provider 
contracted to generate the codes. At the time of analysis (after the end of study), after receiving 
unblinding request from Teva statistician, the service provider will provide the unblinded IMP 
assignment according to the processes defined in the relevant Standard Operating Procedure 
(SOP).
5.13.2.
Blinding and Unblinding
Blinded pharmacokinetic and immunogenicity data may be assessed during the study. For 
patients who have pharmacokinetic or immunogenicity sample bioanalysis or data analysis 
conducted, the individuals responsible for sample bioanalysis and other responsible personnel 
will know who received test IMP and who received placebo IMP during the study (of those 
patients only). Personnel responsible for bioanalysis will be provided with the randomization 
code to facilitate the analysis. However, the personnel responsible for bioanalysis and 
pharmacokinetic data analysis will not have access to clinical safety and efficacy data, and will 
provide concentration data to other personnel in a manner that will not identify individual 
patients (ie, a dummy patient identifier will be linked to the concentration data of an individual 
patient).
Pharmacokinetic sample analysis by the bioanalytical laboratory and pharmacokinetic parameter 
calculations by pharmacokineticists will be performed during the course of the study. The 
population pharmacokinetic model for TEV-48574 may be updated with new pharmacokinetic 
data emerging from the ongoing study. The process to ensure study integrity, maintenance of the 
double blind, and the responsibilities of the relevant study personnel will be described in a 
pharmacokinetic analysis plan that will be approved prior to any data transfer, per the sponsor's 
relevant SOP(s) (eg, GBP-RD-502 [Performing Pharmacokinetic Analyses While Maintaining 


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the Blind]). A similar process could be implemented for the pharmacokinetic/pharmacodynamic 
model with updated pharmacokinetic and pharmacodynamic data, based on availability of the 
appropriate SOP.
In case of a serious adverse event, pregnancy, or in cases when knowledge of the IMP 
assignment is needed to make treatment decisions, the investigator may unblind the 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 IMP assignment should not be revealed to the sponsor.
When a blind is broken, the patient will be withdrawn from the study and the event will be 
recorded on the CRF. 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.
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. 
The JDMC will review data in a blinded fashion, as outlined in Appendix B.
An interim analysis (Section 9.12) will be conducted by an independent, unblinded statistician 
who is not a part of the study team. A group of the sponsor’s management team who are not a 
part of the study team may have access to the unblinded interim analysis results. A 
communication plan to ensure the maintenance of the study blind among the blinded personnel 
involved in the conduct of the study will be put in place prior to the interim analysis.
5.14.
Total Blood Volume
The estimated maximum blood volume to be collected for each patient in this study is 
approximately 23 mL per visit. With a maximum number of 6 scheduled visits during any 
8-week period of the study, the maximum volume within such a period would be 138 mL. 
Details on blood volumes to be collected during the study are provided in the ICF and 
Laboratory Manual.


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6.
ASSESSMENT OF EFFICACY
6.1.
Assessments of Efficacy
Refer to Table 2 (screening and run-in), Table 3 (treatment period), and Table 4 (follow-up) for 
the timing of assessments and procedures. See Section 3.6 for a detailed description of 
assessments and procedures.
6.1.1.
Loss of Asthma Control (Primary Efficacy Endpoint)
The primary efficacy endpoint is the proportion of patients who experience LoAC during the 
treatment period.
LoAC is defined as any one of the following during the treatment period: 

Morning PEF decrease ≥30% from baseline on 2 consecutive days or morning 
handheld FEV1 decrease ≥20% from baseline on 2 consecutive days 

Increase in SABA/quick-relief medication ≥6 puffs over baseline use in 24 hours on 
2 consecutive days*

Increase in ICS dose ≥4x most recent dose*

Systemic corticosteroid use

Asthma ER visit or hospitalization
A patient who meets criteria for LoAC will discontinue IMP, and resume or increase background 
asthma controller therapies, but will remain in the study. LoAC events will be treated by the 
investigator according to local standard of care. An effort should be made to collect blood 
samples for TEV-48574 serum concentration and ADA testing at (or as close to) the time of 
LoAC as possible in addition to the scheduled assessments (see Table 3 [treatment period] and 
Table 4 [follow-up]). 
In addition to the primary efficacy endpoint of the proportion of patients who experience LoAC, 
time to LoAC will be a key secondary endpoint (see Section 9.5.2). 
*Once background asthma controller therapy has been standardized per protocol, the asthma 
controller regimen is to remain stable throughout the treatment period until the structured 
withdrawal per protocol or treatment of LoAC/CAE (Section 6.1.2). Patients who experience 
LoAC, including CAEs, during the treatment period will discontinue IMP and resume/increase 
background asthma controller therapy for the remainder of the study.
6.1.2.
Clinical Asthma Exacerbation 
CAEs are a subset of LoAC events (Section 6.1.1).
Asthma exacerbation during the study is defined as a worsening of asthma symptoms (examples 
are described below) resulting in any of the following: 

The use of systemic corticosteroids (oral or injectable).

An emergency department visit due to asthma treated with systemic corticosteroids

An inpatient hospitalization due to asthma. 


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Worsening asthma includes new or increased symptoms or signs that either worry the patient, or 
are related to an asthma-specific alert (if available through the e-diary/hand-held spirometer [see 
Section 3.1]).
A patient who meets criteria for a CAE will be treated per the local standard of care. Additional 
medication and/or medical intervention that would satisfy the definition of CAE occurring within 
7 days of the last day of a prior CAE event will be considered as part of the same event for 
analysis purposes.
CAEs will be assessed at the time points specified in Table 2 (screening and run-in), Table 3
(treatment period) and Table 4 (follow-up).
6.1.3.
e-Diary
Patients will be trained in using the e-diary to ensure proper use and to ensure rigorous data is 
collected throughout the study.  
6.1.4.
Asthma Control Questionnaire (ACQ-6)
The ACQ-6 is a validated asthma assessment tool that has been widely used (Juniper et al, 1999). 
Six questions are self-assessments (completed by the patient). Each item on the ACQ-6 has a 
possible score ranging from 0 to 6, and the total score is the mean of all responses (Appendix F). 
ACQ-6 results at screening and at DoR are part of the study inclusion criteria and randomization 
criteria respectively.
ACQ-6 will be administered at the sites at the time points in Table 2 (screening and run-in), 
Table 3 (treatment period) and Table 4 (follow-up).
6.1.5.
Spirometry/FEV1 
Spirometry will be performed both at the site and by hand-held spirometer. On-site spirometry 
will include full-flow volume loops (FVC, FEV1, FEV1/FVC, FEF25%-75% and PEF) and 
reversibility testing at the time points in Table 2 (screening and run-in), Table 3 (treatment 
period) and Table 4 (follow-up). On site spirometry will be done according to American 
Thoracic Society/European Respiratory Society procedural guidelines (Graham, 2019). The 
National Health and Nutrition Survey (NHANES) III reference equations will be used.
Hand-held spirometry (FEV1, PEF) will be performed daily. Every effort should be made to 
complete hand-held spirometry at approximately the same time each day, preferably in the 
morning. Patients will be trained in appropriate hand-held spirometry technique prior to 
dispensing the hand held spirometer. FEV1 and PEF values will be monitored for data quality.
Reversibility testing will involve pre- and post-bronchodilator spirometry. For reversibility 
testing, SABAs, ie, salbutamol or albuterol, administered via a metered dose inhaler should be 
used. Four separate puffs (eg, albuterol 90 μg/puff or salbutamol 100 μg ex-valve/puff, or 
equivalent) should be given by metered-dose inhaler, as tolerated. Post-bronchodilator 
spirometry should be completed a minimum of 15 minutes after dosing of SABA and within 
30 minutes after SABA.
FEV1 is the volume of air that can be forcibly exhaled from the lungs in the first second, 
measured in liters. FVC is the volume of air that can be forcibly blown out after full inspiration, 


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measured in liters. The FEF25%-75% is the forced expiratory flow from 25% to 75% of forced vital 
capacity.
6.1.6.
Asthma Rescue Medication Use
The number of inhalations/puffs of SABA/quick-relief inhaler will be recorded in the e-diary 
daily. Note: SABA therapy used for exercise pretreatment or for reversibility testing as described 
in Section 3.6.1.1 should not be recorded in the e-diary. Study sites should monitor rescue 
medication use during the study visits at the time points in Table 2 (screening and run-in), 
Table 3 (treatment period), and Table 4 (follow-up). Study sites are also responsible for 
responding to asthma specific alert criteria related to SABA/quick-relief inhaler use (see 
Section 3.1).
6.1.7.
Nighttime Awakenings
Patients will record nighttime awakenings due to asthma in the e-diary daily, in the morning. 
Sites should check the records of nighttime awakenings during the study visits at the time points 
in Table 2 (screening and run-in), Table 3 (treatment period), and Table 4 (follow-up). Study 
sites are also responsible for responding to asthma specific alert criteria related to nighttime 
awakenings (see Section 3.1).
6.1.8.
Fractional Exhaled Nitric Oxide 
The concentration of NO in exhaled breath (FeNO) will be measured at the time points detailed 
in Table 2 (screening and run-in), Table 3 (treatment period), and Table 4 (follow-up). FeNO 
should be performed prior to spirometry (if spirometry is performed during the visit).


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7.
ASSESSMENT OF SAFETY
In this study, safety will be assessed by qualified study personnel by evaluating reported adverse 
events, clinical laboratory test results, vital signs measurements, ECG findings, physical 
examination findings, and use of concomitant medication. Refer to Table 2 (screening and 
run-in), Table 3 (treatment period), Table 4 (follow-up) for the timing of assessments and 
procedures, and Appendix B (JDMC).
7.1.
Adverse Events and Adverse Device Effects
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: adverse events do not necessarily have to have a 
causal relationship with this treatment.
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. 
Development of a new condition or the worsening of a pre-existing condition will be considered 
an adverse event, whether or not considered related to TEV-48574. 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

drug or drug/device or device/device 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. 
(Note: Abnormal laboratory or diagnostic test results at the screening visit(s) that 
preclude a patient from entering the study or receiving study treatment are not 
considered adverse events.)
LoAC and CAEs are efficacy variables for this study and should be captured on the relevant 
specific CRF; accordingly, neither LoAC events nor CAEs should be recorded as adverse events 
unless assessed as more severe than the patient's usual disease course. LoAC events, including 
CAEs that are more severe than the patient’s usual course of disease and meet the criteria for a 
serious adverse event should be reported as a serious adverse event.


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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 through the EOS visit. The period for reporting treatment-emergent 
adverse events is defined as the period after the first dose of IMP is administered and until the 
EOS visit.
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. Serious adverse events (Section 7.1.5) and/or PDAESI requiring reporting to GPSP 
(Section 7.1.6) must be reported within 24 hours from the investigator's awareness, using the 
SAE/PDAESI form (Section 7.1.5.3.1). The investigator does not need to actively monitor 
patients for new adverse events after the study period defined above.
All device-related adverse events, malfunctions etc. will be recorded and evaluated for their 
impact relative to the safety and efficacy of the IMP.
At each contact with the patient, the investigator or designee must question the patient about 
adverse events by asking open-ended questions 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 the IMP and to the device, as well as the severity and 
seriousness of each adverse event, as judged by the investigator, must be recorded as described 
below. 
7.1.3.
Severity of an Adverse Event
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
7.1.4.
Relationship of an Adverse Event to the Investigational Medicinal Product
The relationship of adverse events will be captured separately for the relationship to the IMP 
and/or to the device. The relationship of an adverse event to the IMP and/or to the device will be 
determined according to the criteria in Table 6. 


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Table 6:
The Relationship of an Adverse Event to the IMP and/or Device Suspects
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/device.
The relationship of an adverse event may be considered 
“no reasonable possibility” if it is clearly due to 
extraneous causes or if at least 2 of the following apply:

It does not follow a reasonable temporal sequence 
from the administration of the IMP/device.

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/device.

It does not reappear or worsen when the IMP/device
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/device cannot be ruled out with 
certainty.
The relationship of an adverse event may be considered 
“reasonable possibility” if at least 2 of the following 
apply:

It follows a reasonable temporal sequence from 
administration of the IMP/device.

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/device, yet an
IMP/device relationship clearly exists.

It follows a known pattern of response to the
IMP/device.
7.1.5.
Serious Adverse Events
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 preexisting condition during 


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the patient’s participation in this study. Hospitalization due to asthma exacerbation 
that is consistent with the patient’s known course of asthma should not be reported as 
an adverse event/serious adverse event.

results in persistent or significant disability/incapacity (refers to a substantial 
disruption of one’s ability to conduct normal life functions)

results in 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 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 upper limit of normal (ULN)

total bilirubin increase of >2x ULN

absence of initial findings of cholestasis (ie, no substantial increase of alkaline 
phosphatase [ALP])
An adverse event that does not meet any of the criteria for seriousness listed above will be 
regarded as a nonserious adverse event.
7.1.5.2.
Expectedness
A serious adverse event that is not included in the Adverse Reaction section of the relevant 
reference safety information (RSI) by its specificity, severity, outcome, or frequency is 
considered an unexpected adverse event. The RSI for this study is included in the IB.
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. This applies also to Protocol Defined Adverse Events of Special Interests (PDAESI) 
requiring reporting to GPSP (Section 7.1.6). Completing the SAE/PDAESI form and reporting 
the event must not be delayed, even if not all the information is available. If any of the 


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information listed below is not immediately available, it should be provided to the sponsor as 
soon as possible but the initial reporting to the Sponsor must not be delayed. 
Serious adverse events occurring to a patient after the end of the study should be reported to the 
sponsor if the investigator becomes aware of them.
The SAE/PDAESI form should be sent to the Local Safety Officer (LSO) or designee (a CRO in 
a country without a sponsor LSO) (contact information is in the Clinical Study Personnel Contact 
Information section); the LSO will forward the report to the sponsor’s GPSP.
The following information should be provided on the SAE/PDAESI form:

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 6)

age and sex of patient

date of first dose of IMP

date and amount of last administered dose of IMP

action taken

outcome, if known

severity

explanation of assessment of relatedness

concomitant medication (including study-provided inhalers, doses, routes of 
administration, dates, and regimens)

treatment for 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 both the investigator 
and the sponsor to assess the nature of the event and the relationship of the event to the IMP.


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In addition, the investigator will assess whether the etiology of the event is associated with the 
patient's primary condition, concomitant medications (including study-provided inhalers), or any
other condition.
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 
SAEs to the LSO/CRO for submission to the competent authorities, IEC/IRBs, and investigators, 
according to regulations. The investigator must ensure that the IEC/IRB is also informed of the 
event, in accordance with national and local regulations. Submission of MedWatch forms to 
FDA is made by Regulatory Affairs upon receipt from the LSO.
The sponsor's GPSP will submit the XML of SUSARs to the EMA in an unblinded manner, 
when applicable and according to local regulations.
Blinding will be maintained for all study site personnel. Therefore, in case of a SUSAR, only the 
LSO/unblinded personnel from the CRO will receive the unblinded report for regulatory 
submission; the others will receive a blinded report.
Further details regarding reporting of SAE/PDAESI will be given in the SAE management plan 
(SMP).
7.1.5.3.2. Sponsor Responsibility
If a serious unexpected adverse event is suspected 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-48754 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

modifying the existing ICF and informing all study participants of new findings

modifying listings of expected toxicities to include adverse events newly identified as 
related to TEV-48574
7.1.6.
Protocol-Defined Adverse Events of Special Interest
For purposes of this protocol, the following are considered protocol-defined adverse events of 
special interest: 

systemic severe reactions (including anaphylaxis)

opportunistic infections

malignancies (including non-melanoma skin cancer)


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
administration site reactions 
The process of reporting the above mentioned adverse events, except for administration site 
reactions, is the same as that for reporting serious adverse events (Section 7.1.5.3). Protocol-
defined adverse events of special interest should be reported to GPSP regardless of seriousness 
or causality assessment, according to the criteria outlined in Section 7.1.5.1.
Administration site reactions will be evaluated and reported as described in Section 7.6.
In the event of suspected anaphylaxis while the patient is at the site, vital signs, including blood 
pressure, oxygen saturation, and respiration rate, should be measured. FEV1 and PEF 
measurements should be obtained if it is safe to do so in the investigator’s opinion. Blood 
samples to test TEV-48574 serum concentration, ADA, and free and total serum TL1A levels 
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 nearby. In addition, 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).
A list of opportunistic infections is included in Appendix I.
7.1.7.
Protocol Deviations Because of an Adverse Event
If a patient experiences an adverse event or medical emergency, the investigator should take the 
actions necessary to ensure patient safety. After the event has stabilized; treatment has been 
administered or both, the investigator or other physician in attendance must contact the physician 
identified in the Clinical Study Personnel Contact Information section of this protocol 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. 
7.2.1.
Adverse Device Effect Reporting
Adverse device effects (Figure 2) must be recorded on both 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 device deficiency and will categorize 
each as guided in Section 7.2.


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The investigator should make an initial determination whether the adverse event may be related 
to a device deficiency (Section 7.1.4).
Adverse device effects and device deficiencies will be listed in the clinical study report (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).
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 national and local regulations.
The investigator should make an initial determination whether the serious adverse event may be 
related to a device deficiency.
Figure 2:
Decision Tree for Adverse Events and Adverse Device Effects Classification
AE=adverse event; ADE=adverse device effect; CRF=case report form; IEC=Independent Ethics Committee; 
IRB=Institutional Review Board; SADE=serious adverse device effect; SAE=serious adverse event.


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7.3.
Pregnancy
Any female patient becoming pregnant during the screening period will be considered a screen 
failure and will not be allowed to rescreen. 
Any female patient becoming pregnant during the study will discontinue IMP.
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 (~10 weeks) of the last 
IMP administration, are to be reported immediately to the individual 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).
All female patients and female partners of men participating in the study (female partners of men 
participating in the study who become pregnant will be asked to sign an ICF) who become 
pregnant will be monitored for the outcome of the pregnancy (including spontaneous, elective, or 
voluntary abortion). 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 the woman participating in the study and/or the female partners of men 
participating in the study does not continue to term, 1 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 patients’ source documents, regardless of whether or not an adverse event occurs as a 
result.
The following are types of medication errors and special situations:
2. 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.
3. 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/study protocol. Clinical judgment should always be 


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applied. Any dose of IMP (whether the test IMP or placebo IMP), whether taken 
intentionally or unintentionally, in excess of that prescribed must be immediately 
reported to the sponsor.
4. Misuse: Situations where the IMP is intentionally and inappropriately used not in 
accordance with the authorized product information/study protocol.
5. Abuse: Persistent or sporadic, intentional excessive use of IMP which is accompanied by 
harmful physical or psychological effects.
6. Off-label use: Situations where an IMP is intentionally used for a medical purpose not in 
accordance with the authorized product information/study protocol.
7. Occupational exposure: Exposure to an IMP, as a result of one’s professional or non-
professional occupation.
8. Breastfeeding: Suspected adverse reactions which occur in infants following exposure to 
a medicinal product from breast milk.
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, 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 result leads to the 
investigator concluding that the initial abnormality was not clinically significant, it is at the 
investigator's discretion whether or not the laboratory result triggering the work-up is an adverse 
event. (Note: Abnormal laboratory or diagnostic test results at the screening visit(s) that preclude 
a patient from entering the study or receiving IMP are not considered adverse events.)


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Table 7:
Clinical Laboratory Tests
Serum Chemistry
Hematology and Coagulation
Urinalysis
Calcium
Phosphate
Sodium
Potassium
Chloride
Creatinine
Glucose
Blood urea nitrogen (BUN)
Urate
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Lactate dehydrogenase (LDH)
Gamma-glutamyl transpeptidase (GGT)
Alkaline phosphatase
Protein
Albumin
Bilirubin
Direct bilirubin
Hemoglobin
Hematocrit
Erythrocytes
Platelets
Leucocytes (including differential count, 
presented in absolute values and 
percentages)
Neutrophils
Lymphocytes
Eosinophils
Monocytes
Basophils
Lymphocytes atypical
Prothrombin International Normalized 
Ratio (INR)
Protein
Glucose
Ketones
Hemoglobin
pH
Specific gravity
Microscopic tests
Bacteria
Erythrocytes
Leucocytes
Crystals
Casts
7.5.1.
Serum Chemistry, Hematology, and Urinalysis
Clinical laboratory tests (serum chemistry, hematology and coagulation, urinalysis) will be 
performed at the time points detailed in Table 2 (screening and run-in), Table 3 (treatment 
period), and Table 4 (follow-up). Tests can be performed in either a fasting or non-fasting state. 
Clinical laboratory tests will be performed using the central laboratory. Details of laboratories to 
be used in the study are provided in Appendix A.
7.5.2.
Other Clinical Laboratory Tests
At screening, patients will be tested for hepatitis B surface antigen (HBsAg), antibodies to 
hepatitis C virus (HCV), human immunodeficiency virus (HIV) types 1 or 2, and TB test 
(QuantiFERON® TB Gold Test). Patients with confirmed positive results will not be eligible to 
participate in the study.
If the QuantiFERON® TB Gold Test is negative at screening, then the patient may proceed in the 
screening period. However, if the QuantiFERON® TB Gold Test is deemed by the principal 
investigator to be a false positive at screening, then a second sample should be drawn and the 
following steps taken:

If the second QuantiFERON® TB Gold Test is positive (ie, results match the first 
test), then the patient will be a screen failure.

If the second QuantiFERON® TB Gold Test is negative (ie, results do not match the 
first test), then a third sample should be drawn.


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
If the third QuantiFERON® TB Gold Test is positive (ie, results match the first 
test), then the patient will be a screen failure.

If the third QuantiFERON® TB Gold Test is negative (ie, results match the second 
test), then the patient may proceed in the screening period.

Note that sites may choose to split the second and third samples and send one to the 
central laboratory and one to a local laboratory. However, the local laboratory result 
may not be used for decision making.
COVID-19 testing will be available at the central laboratory. Locally performed COVID-19 
testing results will also be accepted. 
7.5.2.1.
Human Chorionic Gonadotropin Tests
Human chorionic gonadotropin (HCG) tests in serum and in urine will be performed for women 
of childbearing potential at the time points detailed in Table 2 (screening and run-in), Table 3
(treatment period), and Table 4 (follow-up).
7.5.2.2.
Follicle Stimulating Hormone
At screening, women who have been amenorrheic for at least 1 year without an alternative 
medical cause will have a serum follicle stimulating hormone (FSH) assessment to confirm 
postmenopausal status (an increased concentration of FSH of more than 35 IU/L in women not 
using hormonal contraception or hormonal replacement therapy).
7.6.
Local Tolerability
Local tolerability assessments should be performed after each administration of IMP (Table 3) 
and include administration site findings and pain. Administration site findings (erythema, 
ecchymosis, induration, tenderness, warmth, and swelling) will be assessed using the scales 
provided in Table 8. Pain at the administration 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?”
Both administration site findings and pain will be assessed 1 hour after the completion of IMP 
administration. Additionally after the loading dose and first maintenance dose, assessments will 
also be performed 2 hours after the completion of administration. Allowed time windows for the 
local tolerability assessments are ±15 minutes. 
Severity of local tolerability symptoms should be assessed as described in Table 8. The surface 
diameter in millimeters should be recorded and erythema, induration, and ecchymosis at the 
administration site will be graded according to the diameter measurements: Absent, 5 mm to 
≤50 mm (mild), >50 to ≤100 mm (moderate), and >100 mm (severe). Erythema, ecchymosis, and 
induration under 5 mm in diameter should be assessed as absent. Care should be taken to avoid 
pressuring or squeezing the administration site while assessing induration via careful superficial 
palpation.
In the case that findings do not resolve while the patient remains at the study center, additional 
evaluation should take place thereafter at each visit until resolution occurs. Administration sites 


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may be photographed, including between visits to the study center, to provide visual 
representation in addition to comments in the source documents. Any features that could be used 
to identify the patient will not be captured on the photograph. Appropriate treatment for 
administration site finding or pain may be provided if necessary, in which case such treatments 
must be recorded as concomitant medication(s). 
Table 8:
Administration Site Finding Severity Assessment
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)
- Induration surface diameter >100 mm (severe)
Tenderness
Warmth
Swelling
- None
- Mild
- Moderate
- Severe
Administration site findings described in Table 8 and administration site pain will not be 
captured as adverse events. Administration site findings with characteristics that are not 
described in Table 8 or this section (eg, lipoatrophy, necrosis, abscess) or fulfill seriousness 
criteria must be recorded and reported as specified in Section 7.1.2 and Section 7.1.5.
7.7.
Physical Examinations
Physical examinations, will be performed at the time points detailed in Table 2 (screening and 
run-in), Table 3 (treatment period), and Table 4 (follow-up). 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. Physical exam findings that are attributable to 
another adverse event or to LoAC/CAEs would not be reported as separate adverse events.
A full physical examination will include at a minimum the following organ systems:

General appearance;

Head, eyes, ears, nose, mouth, and throat;

Chest and lungs;

Heart;


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
Abdomen; 

Musculoskeletal;

Skin;

Extremities;

Lymph nodes;

Neurological
Height and weight will be obtained at the at the time points detailed in Table 2 (screening and 
run-in), Table 3 (treatment period), and Table 4 (follow-up).
A brief physical examination will include at a minimum general appearance; head, eyes, ears, 
nose, mouth and throat; chest and lung; heart and extremities (including pulses). 
7.8.
Vital Signs
Vital signs (blood pressure [systolic/diastolic], respiratory rate, body temperature, and pulse) will 
be measured at the time points detailed in Table 2 (screening and run-in), Table 3 (treatment 
period), and Table 4 (follow-up). Patients are to remain in a supine position for at least 5 minutes 
prior to measuring blood pressure and pulse. If possible, blood pressure measurements should be 
completed on the same arm at each visit. All vital signs 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
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 2 (screening and run-in), 
Table 3 (treatment period), and Table 4 (follow-up). ECGs should be performed in a supine 
position after 5 minutes rest.
All ECG 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
Any ECG finding that is judged by the investigator as clinically significant (except at the 
screening visit[s]) will be considered an adverse event, recorded on the source documentation 
and in the CRF, and monitored as described in Section 7.1.2.
Where triplicate measurements are required (DoR), each ECG will be taken within 1 to 
5 minutes of the previous one.


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8.
ASSESSMENT OF PHARMACOKINETICS, 
PHARMACOGENOMICS, IMMUNOGENICITY AND 
8.1.
Pharmacokinetic Assessment
Blood samples will be collected via venipuncture at the time points detailed in Table 3 (treatment 
period), and Table 4 (follow-up) for measurements of serum concentration of TEV-48574. 
Additionally, efforts should be made to determine serum concentration of TEV-48574 in cases of 
suspected severe, systemic hypersensitivity reaction or anaphylaxis; LoAC or CAE; serious 
adverse event; or immunogenicity-related adverse events.
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-48574 using an appropriate validated 
method. 
Incurred sample reanalysis may be performed. Blood samples from patients who received 
placebo will not be analyzed.
Blood volumes are provided in the ICF and Laboratory Manual. Details on sample handling, 
storage, shipment, and analysis are provided in the Laboratory Manual.
8.2.
Immunogenicity Testing
Blood samples for ADA testing will be collected via venipuncture at the time points detailed in 
Table 3 (treatment period), and Table 4 (follow-up). Details on sample handling, storage, 
shipment, and analysis are provided in the Laboratory Manual. 
Additionally, efforts should be made to collect ADA samples in cases of suspected severe, 
systemic hypersensitivity reaction or anaphylaxis; LoAC or CAE; serious adverse event; or 
immunogenicity-related adverse events. In cases of suspected or confirmed anaphylaxis, efforts 
should be made to collect samples as close to the onset of the event as possible, at resolution, and 
30 days after onset of the event. Antibodies to TEV-48574 will be evaluated in serum samples. 
All samples collected for detection of antibodies to TEV-48574 may also be evaluated for 
TEV-48574 serum concentration to facilitate interpretation of the antibody data. Confirmed 
ADA positive samples may be further evaluated for TEV-48574 neutralizing antibodies. 
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-48574 will be performed using 
validated assay methods. Blood samples from patients who received placebo will not be analyzed 
by the ADA assay.
A patient will be classified as having a treatment-emergent ADA response if either: 1) the patient 
had a positive sample at any of the time points after first dose of IMP, but not at the time point 
before first dose of IMP, or 2) the patient had positive samples before first dose of IMP and 1 or 
more time points after first dose of IMP, with at least a 4-fold increase in titers after first dose 
relative to the sample ADA titers before first dose. 


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Where possible, the impact of the presence of ADAs on pharmacokinetics and clinical safety will 
be evaluated.
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-48574. 
8.3.
 (Exploratory)
 
 
 
 
 
 
 
 
 
 
 
 
8.4.
Pharmacogenomics Assessment (Optional)
Pharmacogenomics is the study of how a person’s genetic makeup influences how he or she 
responds to a drug. Pharmacogenomics testing can contribute to a better understanding of the 
variation of drug responses seen during development of an investigational drug. A separate ICF 
is required for pharmacogenomics testing. An optional blood sample for pharmacogenomics 
testing will be collected (following signing of the ICF) via venipuncture into a PaxGene DNA 
tube at the time point detailed in Table 3.  


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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 CSR. In case of discrepancy between 
the descriptions in the protocol and the SAP, the SAP will take precedence.
Exploratory analyses, 
 may be described in a 
separate analysis plan and may be reported separately from the CSR.
9.1.
Sample Size and Power Considerations
The primary efficacy analysis for this study will be the comparison between treatment groups of 
the proportion of patients experiencing a LoAC event during the 16-week treatment period. The 
study will be considered positive if the primary efficacy test indicates a statistically significant 
treatment effect versus placebo at the predefined significance level.
Sample size calculations were performed based on the following considerations:
In the Phase 2a study results for dupilumab, the observed LoAC rate in the placebo group was 
44% (Wenzel et al 2013). The patients in that study had elevated peripheral blood eosinophil 
counts (≥300 cells/µL). To estimate the LoAC rate that would have been observed in patients 
with peripheral blood eosinophil counts <300 cells/µL, the ratio of exacerbation rates observed
between eosinophil count strata in the placebo groups of the dupilumab Phase 3 study were used 
(Castro et al 2018). This resulted in an estimated LoAC rate of 27% for the patients meeting the 
entrance criteria for the current study. 
This study is designed to detect a 60% reduction in LoAC rate versus placebo; ie, a placebo 
group rate of 27% and a TEV-48574 group rate of 10.8%.
Based on the assumptions above, and assuming a 15% dropout rate during the study, 
62 randomized patients per treatment group will provide 80% power to detect a treatment effect 
of 60% reduction in LoAC rate in the TEV-48574 group using a Chi-square test with one-sided 
alpha (Type I error rate) of 0.1.
An unblinded interim analysis is planned to re-assess the sample size and conduct a futility 
analysis as described in Section 9.13. If the sample size increases as a result of the interim 
analysis, the number of evaluable patients would be expected to increase proportionately.
9.2.
Analysis Sets
9.2.1.
Intent-to-Treat Analysis Set
The intent-to-treat (ITT) analysis set will include all randomized patients and will be used as the 
population for the primary efficacy analysis.
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.
Data collected from patients after treatment discontinuation will be included in the ITT analysis 
set.


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9.2.2.
Safety Analysis Set
The safety analysis set will include all randomized patients who receive 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.
9.2.3.
Per-Protocol Analysis Set
The per-protocol (PP) analysis set is a subset of the ITT analysis set including only patients that 
did not experience any important protocol deviation prior to LoAC (if any) or the end of the 
treatment period, whichever comes first. The SAP will present a list of important deviations 
prospectively identified as having the potential to influence and/or bias the primary efficacy 
results. A complete list of important deviations resulting in exclusion of patients from the PP 
analysis will be determined at the end of the study based on a team review of accumulated 
blinded study data.
9.2.4.
Additional Analyses Sets
Population Pharmacokinetic Analysis Set
The population pharmacokinetic analysis set will include those patients in the safety analysis set 
who have at least 1 measurable concentration of TEV-48574.
Patients with important protocol deviations affecting pharmacokinetics may be excluded from 
the population pharmacokinetic analysis set at the discretion of the pharmacometrician. 
Important protocol deviations will be identified before database lock.
Analysis methods may be detailed in a separate population pharmacokinetic analysis plan. 
Pharmacokinetic data from the current study will be pooled with previous data, and a 
population-pharmacokinetic analysis and, if data allows, a population 
pharmacokinetic-pharmacodynamic analysis, will be completed and reported separately.
Immunogenicity Analysis Set
The immunogenicity analysis set will include all patients in the safety set who receive 
TEV-48574, who undergo immunogenicity testing, and who have at least 1 reportable 
immunogenicity result. Patients with important protocol deviations affecting immunogenicity 
analysis may be excluded from the analysis set at the discretion of the Sponsor's clinical study 
physician or delegate. Important protocol deviations will be identified before database lock.
9.3.
Data Handling Conventions
9.3.1.
Handling Withdrawals and Missing Data
For all 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. Detailed data imputation 
rules will be described in the SAP.
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.


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9.4.1.
Patient Disposition
Data from patients screened, patients screened but not randomized, patients randomized to 
treatment in the study, patients randomized but not treated, patients in the safety analysis set, 
patients in the per-protocol analysis set, patients who completed the treatment period (week 16), 
patients who completed the study (see Section 3.1 for definition of study completion), and 
patients who did not complete treatment but were followed up until end of study will be 
summarized. Data from patients who withdrew from the study will also be summarized by 
reason for withdrawal using descriptive statistics, and the number of patients who discontinued 
treatment for reasons other than LoAC/CAE but continued to attend study visits will be 
tabulated.
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 examined to assess the comparability 
of the treatment groups and will be summarized using descriptive statistics. For continuous 
variables, descriptive statistics (number [n], mean, standard deviation [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.
Endpoints
9.5.1.
Primary Endpoint
The primary efficacy endpoint of this study is the proportion of patients who experience LoAC 
during the treatment period. For a definition of LoAC, see Section 6.1.1.
9.5.2.
Secondary Endpoints
Key secondary efficacy endpoints:

Time from randomization to LoAC during the treatment period

Asthma Control Questionnaire 6-question version (ACQ-6) at EOT and throughout 
the study 

FEV1 (% predicted, L) at end of treatment EOT and throughout the study

Use of SABA quick relief medication at EOT and throughout the study
Other efficacy endpoints:

Proportion of patients who have a CAE during the treatment period

Time from randomization to first CAE during the treatment period

Number of nighttime awakenings due to asthma during the treatment period

Percent decrease in ICS dose during the treatment period

Other lung function parameters as assessed by hand-held spirometry at EOT and 
throughout the study


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
Fractional exhaled nitric oxide (FeNO) throughout the study
9.5.3.
Other endpoints
Safety and tolerability endpoints:

Frequency of adverse events

Change from baseline in clinical laboratory test results (serum chemistry, 
hematology, and urinalysis) throughout the study

Change from baseline in vital signs throughout the study

Change from baseline in 12-lead electrocardiogram (ECG) findings throughout the 
study

Use of concomitant medication

Local tolerability

Number (%) of patients who did not complete the study due to adverse events 
Device-Related Events

All device-related adverse events, malfunctions etc. will be recorded and evaluated 
for their impact relative to the safety and efficacy of the investigational medicinal 
product.  
Pharmacokinetic endpoints: 

Trough serum TEV-48574 concentrations throughout the study (sparse sampling)

Population pharmacokinetic analysis of pharmacokinetic data  
Immunogenicity endpoints:

Assessment of treatment-emergent ADA responses: change from baseline and 
throughout the study 

Impact of the presence of ADAs on pharmacokinetics and clinical safety (if possible). 
Efforts will be made to collect ADA samples in cases of suspected severe, systemic 
hypersensitivity reaction or anaphylaxis; LoAC or CAE; serious adverse event; or 
immunogenicity-related adverse events.

Assessment of neutralizing ADA in ADA positive patients throughout the study
9.5.4.
Exploratory
 
 
 


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9.6.
Efficacy Analysis
9.6.1.
Planned Method of Analysis
The ITT analysis set (Sections 9.2.1) will be used for all efficacy analyses unless otherwise 
noted. Summaries will be presented by treatment group. The per-protocol analysis set will be 
used as sensitivity analysis for the primary analysis.
The baseline for spirometry parameters and e-diary variables will be the average of the values 
over the 7 days preceding day of randomization. The baseline for clinic visit variables will be the 
last observed value before the first dose of study drug. The baseline for absolute eosinophil count 
will be the average of all values obtained prior to the administration of the first IMP.
9.6.1.1.
Primary Efficacy Analysis
The primary analysis will compare rates of LoAC between treatment groups using logistic 
regression with fixed effect for treatment, baseline FEV1, weight, age group (<65 years vs ≥65 
years), and gender as covariates. The primary analysis will be performed on the ITT analysis set. 
Patients who withdraw from the study or discontinue treatment due to lack of efficacy or due to 
an asthma-related adverse event will be analyzed as having experienced LoAC. Patients who 
withdraw from the study for other reasons will be analyzed as not experiencing LoAC. The 
treatment effect will be tested at a one-sided alpha of 0.1.
Subgroup analyses may be performed. These will be described and detailed in the SAP.
9.6.1.2.
Sensitivity Analysis
Sensitivity analyses will include repeating the primary analysis on the per-protocol analysis set.
Additional sensitivity analyses may be detailed in the SAP.
9.6.1.3.
Secondary Efficacy Analysis
All efficacy variables will be summarized by treatment group. For continuous variables, the 
summary statistics will include n, mean, SD, standard error (SE), median, minimum, and 
maximum. For categorical variables, patient counts and percentages will be provided.
LoAC rates, 90% and 95% CIs for LoAC rates, estimated treatment effects (ie, the odds ratio of 
TEV-48574 versus placebo), and 90% and 95% CIs of the odds ratio will be provided.
The key secondary efficacy analysis of time to LoAC will use a one-sided log-rank test to 
compare the hazard rates between the TEV-48574 and placebo groups. The analysis will be 
performed on the ITT analysis set. Patients who withdraw from the study or discontinue 
treatment due to lack of efficacy or due to an asthma-related adverse event will be analyzed as 
having experienced LoAC at the time of the withdrawal or treatment discontinuation. Patients 
who withdraw from the study for other reasons will be analyzed as being right-censored at the 
time of withdrawal.
The Kaplan-Meier (KM) method will be used to estimate and compare the distributions of time 
to LoAC between treatment groups. 


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Analysis of ACQ-6 will use the mixed model repeated measures model with treatment group, 
weight, age group (<65 years vs ≥65 years), gender, visit, and treatment and visit interaction, as 
fixed effects and patient as a random effect.
The on-site morning trough FEV1 throughout study will be analyzed using similar MMRM 
method, as described for the analysis ACQ-6. 
Use of SABA quick relief medication will be derived from the e-diary data in monthly analysis 
intervals and will be analyzed using a similar MMRM method.
The efficacy endpoints defined at end-of-treatment (EOT) will take the last available assessment 
value in the treatment period, and will be analyzed using appropriate analysis of covariance 
models.
Additional covariates or factors may be added to the statistical models. These will be detailed in 
the SAP.  
9.6.1.4.
Other Efficacy Analysis
Statistical modeling to be used for other efficacy endpoints will be described and detailed in the 
SAP.
9.7.
Multiple Comparisons and Multiplicity
As there are only 2 treatment groups and one primary analysis test in this study, no multiplicity 
correction is necessary. Secondary endpoints will be considered as hypothesis-generating, and 
multiple testing adjustment will not be made.
9.8.
Safety Analysis
Safety analyses will be performed on the safety analysis set (Section 9.2.2).
Safety assessments and time points are provided in Table 2, Table 3, and Table 4.
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 treatment-emergent adverse events (overall and by severity) (as defined in 
Section 7.1.2 and Section 7.1.3)

Adverse events determined by the investigator to be related to test IMP (ie, 
reasonable possibility; see Section 7.1.4) (defined as related or with missing 
relationship) (overall and by severity), 

Serious adverse events (Section 7.1.5.1)

Protocol-defined adverse events of special interest (Section 7.1.6)

Adverse events causing withdrawal from the study. 


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Summaries will be presented by treatment group and for all patients. Patient listings of all 
adverse events (from signature of the ICF), serious adverse events, and adverse events leading to 
withdrawal will be presented.
Values and change from baseline in laboratory, ECG, and vital signs measurements data 
(including the incidence of abnormalities) will be summarized descriptively.
Local tolerability: administration site findings (erythema, ecchymosis, induration, tenderness, 
warmth, and swelling) and administration site pain will be assessed as described in Section 7.6
and summarized descriptively.
The use of concomitant medications will be summarized by therapeutic class using descriptive 
statistics.
Physical examination data will be listed and may be summarized descriptively. 
For continuous variables, descriptive statistics (n, mean, standard deviation, 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.
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.
9.9.
Population Pharmacokinetic, Pharmacodynamic, and 
Pharmacokinetic/Pharmacodynamic Analysis
A population pharmacokinetic analysis will be performed, and, if feasible, a 
pharmacokinetic/pharmacodynamic analysis of relevant pharmacodynamic variables may be 
performed and reported in a separate Pharmacometrics Analysis Report (PAR). This section 
describes the possible population pharmacokinetic and pharmacokinetic/pharmacodynamic 
analyses foreseen at the time of the preparation of this protocol. Changes, additions, and further 
details about the analysis will be described in the Modeling Analysis Plan. After finalization of 
the Modeling Analysis Plan, any additional analyses or changes to the analyses that may be 
required will be described in the PAR.
9.9.1.
Population Pharmacokinetics
All patients in the safety analysis set who have at least 1 measurable concentration of 
TEV-48574 will be included in the analysis of pharmacokinetic data. Serum concentrations will 
be expressed in mass per volume units. All concentrations below the limit of quantification or 
missing data will be labeled as such in the concentration data listings. TEV-48574 concentration 
data will be summarized by visit and treatment group. In addition to mean, standard deviation, 
coefficient of variation, median and quartiles, the geometric mean and geometric coefficient of 
variation and n(log) will be presented. Pharmacokinetic data per TEV-48574 study treatment 
may be analyzed with a population-pharmacokinetic mixed effects model. The analysis will be
based on a pooled data set, including pharmacokinetic data from previous studies and will be 
reported in the PAR.


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9.9.2.
Pharmacokinetics/Pharmacodynamics (PK/PD)
Based on graphical exploration of the observed data, an appropriate PK/PD modeling approach 
may be used to characterize the time course of efficacy response. Further details of the modeling 
approach, if performed, may be specified in a detailed Modeling Analysis Plan. The PK/PD 
analysis may be reported in the Pharmacometrics Analysis Report.
9.10.
Immunogenicity Analysis
Immunogenicity analyses will be performed on the immunogenicity analysis set. Listing(s) of 
patients with positive ADA sample(s) will be provided. Summaries may be provided if 
appropriate.
Treatment-emergent ADA responses and the impact of the presence of ADAs on 
pharmacokinetics and clinical safety may be assessed. Confirmed ADA positive samples may be 
further characterized (eg, assessment of neutralizing ADA) as needed.
9.11.
 
 
 
 
 
 
9.12.
 
9.13.
Planned Interim Analyses
An unblinded interim analysis is planned after the first 40 to 52 randomized patients have 
completed the treatment period, experienced LoAC, or withdrawn from the study completely. 
The main purposes of the interim analysis include sample size re-assessment and futility 
analysis, as described below.
The assumed LoAC event rate in the placebo group is 0.270. If the actual placebo event rate is 
lower than expected, the study will be underpowered to detect a 60% reduction in event rate. 
At the interim analysis, if the observed placebo event rate is lower than expected, and the 
observed treatment effect is at least a 40% reduction (event rate ratio ≤0.6), the sample size may 


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be increased by up to 50 additional randomized patients, from the initially planned 124 to up to 
174. This procedure corresponds to a Promising Zone methodology and does not increase the 
Type I error rate (Mehta and Pocock, 2011).
The interim futility analysis comprises a statistical comparison between treatment group versus 
placebo in LoAC rate using logistic regression with fixed effect for treatment among 
the randomized patients who have completed the treatment period, experienced LoAC, or 
withdrawn from the study completely at the interim analysis. A p-value above 0.5 will be 
declared as treatment efficacy futility, which could potentially result in early termination of the 
trial. According to simulation analyses, this cutoff value yields correct early termination rates 
under the null hypothesis of 0.43 (40 patients) and 0.44 (52 patients) and controls incorrect early 
termination rate under the alternative hypothesis at approximately 0.06 (40 patients) and 0.04
(52 patients). More details will be provided in a separate Interim Statistical Analysis Plan that 
will be finalized prior to the interim analysis.
The interim analysis will be conducted by an independent, unblinded statistician who is not a 
part of the study team. A group of the sponsor’s management team who are not a part of the 
study team may have access to the unblinded interim analysis results. A communication plan to 
ensure the maintenance of the study blind among the blinded personnel involved in the conduct 
of the study will be put in place prior to the interim analysis.
9.14.
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 D 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 G for the definition of a clinical product complaint and investigator 
responsibilities in the management of a clinical product complaint.
Details are given in a Study Manual.
11.
COMPLIANCE STATEMENT
This study will be conducted in full accordance with the ICH Harmonised Tripartite Guideline, 
Guideline for Good Clinical Practice 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 good clinical practice 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 IMPs 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 Independent Ethics Committee/Institutional Review Board 
(IEC/IRB), and with competent authorities.
See Appendix E for the ethics expectations of informed consent or assent, competent authorities 
and independent ethics committee and institutional review board, confidentiality regarding study 
patients, and requirements for registration of the clinical study.
12.
DATA MANAGEMENT AND RECORD KEEPING
See Appendix H 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 Food and Drug Administration (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.
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localization, and functional activity of TL1A, a novel Th1-polarizing cytokine in inflammatory 
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Bamias G, Mishina M, Nyce M, Ross WG, Kollias G, Rivera-Nieves J, et al. Role of TL1A and 
its receptor DR3 in two models of chronic murine ileitis. Proc Natl Acad Sci USA 
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Castro M, Corren J, Pavord ID, Maspero J, Wenzel S, Rabe KF et al. Dupilumab Efficacy and 
Safety in Moderate-to-Severe Uncontrolled Asthma. N Engl J Med 2018;378(26):2486-2496. 
Coverstone AM, Seibold MA, Peters MC. Diagnosis and Management of T2-High Asthma. 
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Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma —
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Fahy JV. Asthma Was Talking, But We Weren't Listening. Missed or Ignored Signals That Have 
Slowed Treatment Progress. Ann Am Thorac Soc. 2016;13 Suppl 1:S78-82.
Fajt ML, Wenzel SE. Asthma phenotypes and the use of biologic medications in asthma and 
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FitzGerald JM, Bleecker ER, Menzies-Gow A, Zangrilli JG, Hirsch I, Metcalfe P, et al. 
Predictors of enhanced response with benralizumab for patients with severe asthma: pooled 
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applications in multiple sclerosis. Stat Med 2010;29(10):1145-56.
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Graham B, Steenbruggen I, Miller M, Barjaktarevic I, Cooper B, Hall G, et al. Standardization of 
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questionnaire to measure asthma control. Eur Respir J 1999;14(4):902-7.
Kayamuro H, Yoshioka Y, Abe Y, Katayama K, Yoshida T, Yamashita K, et al. TNF 
superfamily member, TL1A, is a potential mucosal vaccine adjuvant. Biochem Biophys Res 
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Mehta CR, Pocock SJ. Adaptive increase in sample size when interim results are promising: a 
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Meylan F, Hawley ET, Barron L, Barlow JL, Penumetcha P, Pelletier M, et al. The TNF-family 
cytokine TL1A promotes allergic immunopathology through group 2 innate lymphoid cells. 
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TL1A drives IL-13-dependent small intestinal inflammation. Mucosal Immunol 
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and TR6/DcR3 and functions as a T cell costimulator. Immunity 2002;16 (3):479-92.
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and IL-18 to enhance IFN-gamma production in human T cells and NK cells. J Immunol 
2004;172 (11):7002-7.
Pappu BP, Borodovsky A, Zheng TS, Yang X, Wu P, Dong X, et al. TL1A-DR3 interaction 
regulates Th17 cell function and Th17-mediated autoimmune disease. J Exp Med 
2008;205(5):1049-62.
Pavlidis S, Takahashi K, Ng Kee Kwong F, Xie J, Hoda U, Sun K, et al."T2-high" in severe 
asthma related to blood eosinophil, exhaled nitric oxide and serum periostin. Eur Respir J. 2019; 
3;53(1).
Pavord ID, Brightling CE, Woltmann G, Wardlaw AJ. Non-eosinophilic corticosteroid 
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Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and 
activity impairment instrument. PharmacoEconomics 1993;4(5):353-65.
Richard AC, Tan C, Hawley ET, Gomez-Rodriguez J, Goswami R, Yang XP, et al. The TNF-
family ligand TL1A and its receptor DR3 promote T cell-mediated allergic immunopathology by 
enhancing differentiation and pathogenicity of IL-9-producing T cells. J Immunol 
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U-BIOPRED: evaluation of the value of a public-private partnership to industry. Drug Discov 
Today. 2018;23(9):1622-1634.
Robinson D, Humbert M, Buhl R, Cruz AA, Inoue H, Korom S et al. Revisiting Type 2-high and 
Type 2-low airway inflammation in asthma: current knowledge and therapeutic implications. 
Clin Exp Allergy 2017;47(2):161-175.
Samitas K, Zervas E, Gaga M. T2-low asthma: current approach to diagnosis and therapy. Curr 
Opin Pulm Med 2017 Jan;23(1):48-55.
Sampson H, Muñoz-Furlong A, Campbell R, Thomas S, Wood J, Decker W. Food Allergy, 
Derm Dis, and Anaphylaxis. 2006;117(2):391-397.
Schleich FN, Manise M, Sele J, Henket M, Seidel L, Louis R. Distribution of sputum cellular 
phenotype in a large asthma cohort: predicting factors for eosinophilic vs neutrophilic 
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Schofield JPR, Burg D, Nicholas B, Strazzeri F, Brandsma J, Staykova D, et al. Stratification of 
asthma phenotypes by airway proteomic signatures. J Allergy Clin Immunol. 2019; 
144(1):70-82. 
Shapiro GS, Klinger NM, Ekholm BP, Colice GL. Comparable bronchodilation with 
hydrofluoroalkane-134a (HFA) albuterol and chlorofluorocarbons-11/12 (CFC) albuterol in 
children with asthma. J Asthma 2000;37(8):667-75.
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European Respiratory Society Technical Statement. American J of Respiratory and Critical Care 
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regulates the development of chronic colitis by modulating both T-helper 1 and T-helper 17 
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TL1A elicits type 2 innate lymphoid cells at mucosal barriers. Mucosal Immunol 
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15.
SUMMARY OF CHANGES TO PROTOCOL
15.1.
Amendment 02 Dated 28 April 2021
The primary reasons for this amendment are to make changes to the inclusion and exclusion 
criteria, as well as other changes in order to increase enrollment to the study. This includes 
changes that address enrollment of subjects with prior COVID-19 infection, as well as 
COVID-19 vaccination. All major changes to the protocol body are listed below in the table and 
are reflected in the synopsis, as applicable. 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/Justification for change
1.2.2. First-in-Human Clinical Study
No adverse events consistent with 
immunosuppression (including opportunistic or 
unusual infections or malignancies), cytopenias, 
cytokine release syndrome, or systemic reactions 
were reported and no safety signal was observed 
with treatment-emergent ADA responses.
No adverse events consistent with immunosuppression 
(including opportunistic or unusual infections or 
malignancies), cytopenias, cytokine release syndrome, or 
systemic reactions were reported and no safety signal was 
observed with treatment-emergent ADA responses.
Malignancies added to 
immunosuppression risk to align with 
ICF
1.3. Know and Potential Benefits and Risks of the Test Investigational Medicinal Product
Given the targeted action of TEV-48574 on TL1A, 
and considering that the product is a mAb, 
immunosuppression (e.g. higher risk for infections 
and malignancies, incomplete response to vaccines, 
etc.), cytokine release syndrome, systemic 
hypersensitivity, and immunogenicity may be 
considered potential risks of TEV-48574.
Given the targeted action of TEV-48574 on TL1A, and 
considering that the product is a mAb, immunosuppression 
(e.g. higher risk for infections and malignancies, 
incomplete response to vaccines, etc.), cytokine release 
syndrome, systemic hypersensitivity, and immunogenicity 
may be considered potential risks of TEV-48574.
Added to immunosuppression risk to 
align with ICF
Management of study activities during coronavirus 
disease 2019 (COVID-19) outbreaks is detailed in 
Appendix J.
Management of study activities during coronavirus disease 
2019 (COVID-19) outbreaks is detailed in Appendix J.
Added definition for the abbreviation 
COVID-19
2.1. Primary, Secondary, and Other Study Objectives and Endpoints
Forced expiratory volume in the first second of 
exhalation (FEV1) (% predicted, L) at EOT and 
throughout the study
Forced expiratory volume in the first second of 
exhalation (FEV1) (% predicted, L) at EOT and 
throughout the study
Added to the definition of FEV1
2.2.1.  Exploratory 
 (Other sections affected by this change: 8.3, 9.5.4)
 
 
 
 
 


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Original text with changes shown
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Reason/Justification for change
3.1.  General Study Design and Study Schematic Diagram (Other sections affected by these changes: 3.6.1.1., 3.6.1.2.9, 3.6.1.2.10) 
A subset of patients at selected sites will have 
sputum collected during screening and at EOT.
Not applicable
Sputum collection removed due to lack of 
experienced staff at sites in collecting 
sputum samples correctly
At selected sites, a subset of patients will undergo 
induced sputum collection during the screening 
period and at EOT. Patients who are scheduled to 
undergo sputum induction collection must be tested 
for active COVID 19 infection within no later than 
5 business days from the planned date of the 
sputum induction prior to the sputum collection. 
Only patients who are confirmed to not have active 
COVID 19 will be deemed safe to undergo sputum 
induction. Patients who are considered to have a 
high probability of being exposed to COVID 19 
infection during the study duration should not be 
included in the sputum collection cohort.
Not applicable
Sputum collection removed due to lack of 
experienced staff at sites in collecting 
sputum samples correctly
The subset of patients who had sputum collected 
during the screening period (approximately 40 
patients in total) will have sputum collected again at 
EOT.
Not applicable
Sputum collection removed due to lack of 
experienced staff at sites in collecting 
sputum samples correctly
3.1.  General Study Design and Study Schematic Diagram 
Eligibility requirements include: peripheral blood 
eosinophil counts of <250 cells/μL (at least 2 out of
3 measurements both <250 cells/μL separated by 3
4 2 weeks ± 3 days); FeNO <25 ppb;
Eligibility requirements include: peripheral blood 
eosinophil counts of <250 cells/μL (at least 2 out of 3 
measurements both <250 cells/μL separated by 2 weeks ± 
3 days) 
Simplified and clarified eosinophil 
measurements during screening; 
eosinophil measurements now to be taken 
at Visit S1 and Visit S2 (14 days apart), 
and at Visit S3 (14 days from Visit S2) if 
needed. No guidelines exist establishing 
whether or not any particular level of 
FeNO truly characterizes T2-low/Non-T2 
asthma.  Thus, FeNo levels will be 
measured during the trial, but will no 
longer be used as an entrance criterion for 
the trial.


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Original text with changes shown
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Reason/Justification for change
3.1 General Study Design and Study Schematic Diagram 
…an ACQ-6 score ≥1.5 despite daily treatment with 
medium/high dose ICS+LABA for at least 3 months 
with a stable dose for at least 1 month prior to 
screening, with or without other asthma controller 
medications, and at least one clinical asthma 
exacerbation (worsening of asthma requiring 
systemic corticosteroids [oral or injected], or an 
emergency department visit due to asthma treated 
with systemic corticosteroids, or an inpatient 
hospitalization due to asthma, or a 2-fold or higher 
increase from the subject’s usual maintenance ICS 
dose during the exacerbation period, documented in 
the patient’s medical or pharmacy records in the 
18 months prior to (but not within 30 days of) the 
initial screening visit (Visit S1).
an ACQ-6 score ≥1.5 despite daily treatment with 
medium/high dose ICS+LABA for at least 3 months with a 
stable dose for at least 1 month prior to screening, with or 
without other asthma controller medications, and at least 
one clinical asthma exacerbation (worsening of asthma 
requiring systemic corticosteroids [oral or injected], or an 
emergency department visit due to asthma treated with 
systemic corticosteroids, or an inpatient hospitalization 
due to asthma, or a 2-fold or higher increase from the 
subject’s usual maintenance ICS dose during the 
exacerbation period, documented in the patient’s medical 
or pharmacy records 18 months prior to (but not within 30 
days of) the initial screening visit (Visit S1).
Follows current standard of care 
regarding asthma exacerbations that now 
includes an increase in the subject’s 
maintenance inhaled corticosteroids (with 
or without LABAs) by at least 2-fold, for 
at least 5 days or more until exacerbation 
symptoms begin to subside. The dose of 
the inhaled medication can then be 
tapered back to pre-exacerbation levels.
3.1 General Study Design and Study Schematic Diagram 
The study will consist of an approximate 5 week 4-
to 5-week screening/run-in period consisting of 
screening followed by a run-in, a 16 week treatment 
period, and an 8 week follow-up period.
The study will consist of an approximate 4- to 5-week 
screening/run-in period consisting of screening followed 
by a run-in, a 16 week treatment period, and an 8 week 
follow-up period.
Simplified text for screening period for 
clarity
All inclusion and exclusion criteria, with the 
exception of the second eosinophil count, should be 
assessed within the first 2 weeks of the initial 
screening visit S1.
All inclusion and exclusion criteria, with the exception of 
the second eosinophil count, should be assessed within the 
first 2 weeks of Visit S1. 
Simplified text for screening period for 
clarity
See New wording column
If a patient contracted and recovered from COVID-19 
more than 6 weeks prior to screening, and the patient was 
not admitted to a hospital's ICU during that COVID-19 
infection, and if the patient’s symptoms from COVID-19 
completely resolved back to pre-COVID-19 status (no 
lingering anosmia, weakness, persistent dyslogia or 
feelings of dysphoria for many months after the infection 
resolved), then the patient may enroll in the trial. The 
principal investigator should determine whether or not the 
subject has truly recovered back to his/her usual pre-
COVID-19 status and is eligible for enrollment in the 
study.
Text to clarify eligibility criteria for 
COVID-19 patients


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Reason/Justification for change
An e-diary will be dispensed within the first week 
of the initial screening visit at the second screening 
visit (Visit S2), 2 weeks (± 3 days) after the initial 
S1 screening visit.
An e-diary will be dispensed at the second screening visit 
(Visit S2), 2 weeks (± 3 days) after the initial S1 screening 
visit.
Simplified text for screening period for 
clarity
Patients who meet all inclusion criteria (except for 
eosinophil counts if assessment is incomplete) and 
none of the exclusion criteria are eligible to enter 
the run-in and have their ICS+LABA standardized 
with study-provided ICS+LABA (background 
asthma controller therapy) at the Visit S2.
Patients who meet all inclusion criteria (except for 
eosinophil counts if assessment is incomplete) and none of 
the exclusion criteria are eligible to enter the run-in and 
have their ICS+LABA standardized with study-provided 
ICS+LABA (background asthma controller therapy) at the 
Visit S2.
Simplified text for screening period for 
clarity
Figure 1, FeNO removed from figure
Figure 1, FeNO removed from figure
No guidelines exist establishing whether 
or not any particular level of FeNO truly 
characterizes T2-low/Non-T2 asthma.  
Thus, FeNo levels will be measured 
during the trial, but will no longer be used 
as an entrance criterion for the trial.
Screening and Run-in (5 weeks)
An effort should be made to complete screening 
assessments and procedures in the first 2 weeks 
following Visit S1, with the exception of obtaining
the samples for the second (and if applicable third) 
peripheral blood eosinophil counts.
An effort should be made to complete screening 
assessments and procedures in the first 2 weeks following 
Visit S1, with the exception of obtaining the samples for 
the second (and if applicable third) peripheral blood 
eosinophil counts.
Simplified text for screening period for
clarity
Samples for peripheral blood eosinophil counts 
should be collected at 2 time points. The first time 
point should be at the initial screening visit S1, if 
possible, and the second approximately 3 4 weeks 
after the first (ie, samples collected at least 21 days 
apart from each other) and the second (Visit S2) 14 
days (± 3 days) after the first sample collected at 
Visit S1. To meet eligibility criteria, the peripheral 
blood eosinophil counts from both time points 
should be <250 cells/µL. If one of the results is 
≥250 cells/µL, samples may be collected at a third 
time point (Visit S3) provided that the third time 
point is 14 days (± 3 days) after the second time 
point Visit S2. If the value at a third time point is 
Samples for peripheral blood eosinophil counts should be 
collected at 2 time points. The first time point should be at 
Visit S1, if possible, and the second (Visit S2) 14 days (± 
3 days) after the first sample collected at Visit S1. To meet 
eligibility criteria, the peripheral blood eosinophil counts 
from both time points should be <250 cells/µL. If one of 
the results is ≥250 cells/µL, samples may be collected at a 
third time point (Visit S3) provided that the third time 
point is 14 days (± 3 days) after Visit S2. If the value at a 
third time point is used to meet the eligibility criteria, 2 out 
of the 3 values should be <250 cells/µL.
The major criterion for defining a subject 
as having T2-low/Non-T2 asthma is 
having eosinophil count of <250 cells/μL
of blood.  It is possible that this level may 
transiently increase to above 250 cells/μL. 
If one measurement exceeds  250 
cells/μL, it is now felt that having 2 other 
measurements below 250 will satisfy the 
definition of T2-low/non-T2 asthma


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Reason/Justification for change
used to meet the eligibility criteria, 2 out of the 3 
values should be <250 cells/µL.
Patients will receive a hand-held spirometer at the 
initial screening visit and an e-diary within the first 
2 weeks of the initial screening visit at Visit S2 (14 
± 3 days) after the initial screening Visit S1, and 
will be trained on their use.
Patients will receive a hand-held spirometer and an e-diary 
at Visit S2 (14 ± 3 days) after the initial screening Visit 
S1, and will be trained on their use.
To align with the screening period of up 
to 2 weeks
At the initial screening visit,When the e-diary is 
dispensed….
When the e-diary is dispensed….
To align with the screening period of up 
to 2 weeks
Once all eligibility criteria (inclusion and exclusion) 
have been confirmed, with the exception of the 
second peripheral blood eosinophil count, eligible 
patients will have their ICS+LABA converted to 
study provided ICS+LABA inhalers and commence 
run in;
The subject’s pre-study quick relief rescue medication will 
be converted to study-provided albuterol/salbutamol 
inhalers at Visit S1. At Visit S2, once all eligibility criteria 
(inclusion and exclusion) have been confirmed, with the 
exception of the second peripheral blood eosinophil count, 
eligible patients will have their ICS+LABA converted to 
study-provided ICS+LABA inhalers and commence run-in
Simplified text for screening period for 
clarity
Patients on additional asthma controller 
medication(s) except those excluded by the 
eligibility criteria (see Section 4.2) will continue 
those medications throughout the run-in period and 
will discontinue them at randomization 4 weeks 
after randomization (Visit 3).
Patients on additional asthma controller medication(s) 
except those excluded by the eligibility criteria (see 
Section 4.2) will continue those medications throughout 
the run-in period and will discontinue them at 4 weeks 
after randomization (Visit 3).
Original text incorrect
3.4. Stopping Rules for the Study

discontinuation of the development of TEV–
48574 for the treatment of asthma
discontinuation of the development of TEV–48574 for the 
treatment of asthma
For clarification
3.5. Joint Safety Review Committee
See New wording column 
Joint Safety Review Committee changed to Joint Data 
Monitoring Committee (change made throughout 
document)
Correction
3.6. Schedule of Study procedures and Assessments
Table 2. Study Procedures and Assessments:  Screening and Run-In
Samples for peripheral blood eosinophil counts will 
should be collected at a minimum of 2 time points. 
The first time point should be at the initial 
screening visit (Visit S1), if possible, and the 
Samples for peripheral blood eosinophil counts will be 
collected at a minimum of 2 time points. The first time 
point should be at the initial screening visit (Visit S1), if 
possible, and the second (Visit S2) 14 days (± 3 days) after 
The major criterion for defining a subject 
as having T2-low/Non-T2 asthma is 
having eosinophil count of <250 cells/μL
of blood.  It is possible that this level may 


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second (Visit S2) 14 days (± 3 days) approximately 
3 4 weeks after the first with the samples collected 
at least 21 days apart from each other.after after the 
first sample collected at Visit S1. To meet 
eligibility criteria, the peripheral blood eosinophil 
counts from both time points should be <250 
cells/µL. If one of the results is ≥250 cells/µL, 
samples may be collected at a third time point (Visit 
S3) provided that third time point is at least 14 days 
(± 3 days) after the second time point sample 
collected at Visit S2. If the value at a third time 
point is used to meet the eligibility criteria, 2 out of 
the 3 values should be <250 cells/µL and the mean 
of the 3 values should also be <250 cells/µL.
the first sample collected at Visit S1. To meet eligibility 
criteria, the peripheral blood eosinophil counts from both 
time points should be <250 cells/µL. If one of the results is 
≥250 cells/µL, samples may be collected at a third time 
point (Visit S3) provided that the third time point is 14 
days (± 3 days) after the sample collected at Visit S2. If 
the value at a third time point is used to meet the eligibility 
criteria, 2 out of the 3 values should be <250 cells/µL.
transiently increase to above 250 
cells/μL. If one measurement exceeds  
250 cells/μL, it is now felt that having 2 
other measurements below 250 will 
satisfy the definition of T2-low/non-T2 
asthma.
Review e-diary for SABA/quick-relief medication 
usage, and nighttime awakenings/asthma
symptoms, including for adherence
Review e-diary for SABA/quick-relief medication usage, 
and nighttime awakenings/asthma symptoms, including 
adherence
For clarification
See New wording column
X (S3)
Review of e-diary and spirometry now 
performed at S3 if applicable
Spirometry with reversibility testingg
Spirometry with reversibility testingg
To ensure spirometry is included as part 
of reversibility testing
See New wording column
TB test added to S2/S3 column (at S3 if needed)
Adds additional TB test to be done at S3 
if needed 
Distribute albuterol/SABA quick-relief medicationj
Distribute albuterol/quick-relief medicationj
Albuterol is the SABA being used in the 
study; SABA redundant
 (exploratory) 
Not applicable
 
a Screening and Rrun-in may be extended for up to 
14 days if needed for the shipment of IMP to the 
investigational site or to complete assessment of 
eosinophil counts.
Run-in may be extended for up to 14 days if needed for the 
shipment of IMP to the investigational site or to complete 
assessment of eosinophil counts.
Simplified text for screening period for 
clarity
b Patients with clinical symptoms that may indicate 
COVID-19 infection, and/or patients who in the 
investigator’s opinion were at high risk of exposure 
to COVID-19 within 6 weeks before screening or 
b Patients with clinical symptoms that may indicate 
COVID-19 infection, and/or patients who in the 
investigator’s opinion were at high risk of exposure to 
COVID-19 within 6 weeks before screening or during 
Additional text added to ensure patients 
who were hospitalized in the intensive 
care unit are ineligible and not enrolled


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during screening/run-in, will be tested for active 
COVID-19 infection. Patients who were 
hospitalized in the intensive care unit for COVID-
19 will be excluded.
screening/run-in, will be tested for active COVID-19 
infection. Patients who were hospitalized in the intensive 
care unit for COVID-19 will be excluded.
f FeNO should be completed before reversibility 
testing. Patients can repeat the FeNO assessment 
once to meet inclusion criterion “d” at a second 
time point during screening (within approximately 2 
weeks of the initial screening visit), if the first 
assessment is not <25 ppb.
f FeNO should be completed before reversibility testing. 
FeNO no longer used as inclusion criteria
g The e-diary will be dispensed within the first  
week of the initial screening visit at Visit S2.
i The e-diary will be dispensed at Visit S2
To align with the new description of 
screening period
l Patients who are scheduled to undergo sputum 
induction collection must be tested for active 
COVID 19 infection within no later than 5 business 
days from the planned date of the sputum induction 
prior to the sputum collection. Only patients who 
are confirmed to not have active COVID 19 will be 
deemed safe to undergo sputum induction. Patients 
who are considered to have a high probability of 
being exposed to COVID 19 infection during the 
study duration should not be included in the sputum 
collection cohort.
Not applicable
Sputum collection removed due to lack of 
experienced staff at sites in collecting 
sputum samples correctly; OLINK 
platform not being used
Table 3: Study Procedures and Assessments: Treatment Period (Visits 1 – 10)
See New wording column
Reversibility testing deleted, in-office spirometry (full 
flow-volume loop)  added to V2, V4, V7, and V9. 
To align with other asthma studies that 
evaluate the pre-BD PFTs as an objective 
sign of improvement during the study; 
pre-BD PFTs will be performed at each 
visit during the active treatment phase 
(visits 1- 10), done routinely at every 2 
week interval throughout treatment.
Peripheral eosinophil count
Not applicable
Redundant with “CBC with differential 
count” since eosinophil count is included 
with CBC


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Reversibility testing should only be attempted after 
withholding short acting bronchodilators (ie, 
inhaled short acting beta adrenergic agonists and/or 
short acting anticholinergics) for at least 6 hours 
and long acting bronchodilators (ie, inhaled long
acting beta adrenergic agonists and long acting 
anticholinergic agents) for at least 12 or 24 hours, 
according to their labeled dose schedule.
Not applicable
To align with other asthma studies that 
evaluate the pre-BD PFTs as an objective 
sign of improvement during the study; 
pre-BD PFTs will be performed at each 
visit during the active treatment phase 
(visits 1- 10), done routinely at every 2 
week interval throughout treatment.
If a patient exhibits clinical symptoms during the 
study that may indicate COVID-19 infection, the 
patient will be tested for active COVID-19 
infection. If the patient tests positive, the patient 
will be discontinued from IMP and will need to 
visit the clinical site again for an early termination 
visit. Remote assessment of safety via 
teleconference and/or videoconference, with 
videoconference being the preferred method, is 
recommended until the patient is able to visit the 
clinical site for the early termination visit.   
If a patient exhibits clinical symptoms during the study 
that may indicate COVID-19 infection, the patient will be 
tested for active COVID-19 infection. If the patient tests 
positive, the patient will be discontinued from IMP and 
will need to visit the clinical site again for an early 
termination visit. Remote assessment of safety via 
teleconference and/or videoconference, with 
videoconference being the preferred method, is 
recommended until the patient is able to visit the clinical 
site for the early termination visit.   
Additional text added ensuring patients 
who test positive for COVID-19 infection 
will be discontinued from IMP 
i FeNo should be completed before reversibility 
testing in-office spirometry.
i FeNo should be completed before in-office spirometry.
Reversibility testing no longer included in 
Table 3
(exploratory)
 (exploratory)m
 
See New wording column
Pharmacogenomics – Blood in PaxGene DNA tube 
(optional)n
Clarification that pharmacogenomics 
testing and the additional blood sample 
collected for this testing is optional. 
See New wording column
n On the signing the appropriate ICF, an optional blood 
sample may be collected for pharmacogenomics analysis.
Clarification that pharmacogenomics 
testing and the additional blood sample 
collected for this testing is optional. 
Table 4: Study Procedures and Assessments: Follow-up Period
i FeNO should be completed before reversibility 
testing.
Requirement for reversibility testing removed
Not needed, requirement for reversibility 
testing removed
Reversibility testing
Not applicable
To align with other asthma studies that 
evaluate the pre-BD PFTs as an objective 


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sign of improvement during the study; 
pre-BD PFTs will be performed at each 
visit during the active treatment phase 
(visits 1- 10), done routinely at every 2 
week interval throughout treatment.
Peripheral eosinophil count
Not applicable
Redundant since this is done with CBC 
differential.
f Reversibility testing should only be attempted after 
withholding short acting bronchodilators (ie, 
inhaled short acting beta adrenergic agonists and/or 
short acting anticholinergics) for at least 6 hours 
and long acting bronchodilators (ie, inhaled long
acting beta adrenergic agonists and long acting 
anticholinergic agents) for at least 12 or 24 hours, 
according to their labeled dose schedule.
Not applicable
To align with other asthma studies that 
evaluate the pre-BD PFTs as an objective 
sign of improvement during the study; 
pre-BD PFTs will be performed at each 
visit during the active treatment phase 
(visits 1- 10), done routinely at every 2 
week interval throughout treatment.
3.6.1.1 Assessments and Procedures for Screening and Run-in
Note: Screening will include at least 2 visits 
and may be completed over more than 2 visits. 
The screening assessments and procedures for 
the first screening visit may be completed over 
more than one visit: sites should make every 
effort to complete the screening assessments 
and procedures in the first 2 weeks following 
the initial screening visit, with the exception of 
the second eosinophil count. If the screening 
assessments and procedures are divided over 
more than one visit, each additional screening 
visit should include the following: 
prior/concomitant medication inquiry; adverse 
event inquiry, LoAC/CAE inquiry, daily e
diary and handheld spirometry review including 
adherence, vital signs, and brief physical exam. 
Once all inclusion and exclusion criteria have 
been assessed, with the exception of the second 
eosinophil count, and it has been confirmed that 
patients meet all of the inclusion criteria and 
none of the exclusion criteria (with the 
exception of incomplete assessment of 
Note: Screening will include at least 2 visits and may be 
completed over more than 2 visits. The screening 
assessments and procedures for the first screening visit 
may be completed over more than one visit: sites should 
make every effort to complete the screening assessments 
and procedures in the first 2 weeks following the initial 
screening visit, with the exception of the second 
eosinophil count. It is recommended that the site consider 
consenting the subject and completing the first peripheral 
eosinophil count at the initial S1 screening visit in order to 
determine if the subject meets the eosinophil criteria for 
enrollment.  If the subject is eligible, the remaining S1 
assessments and procedures may be performed within two 
weeks of the initial  S1 screening visit. However, sites may 
elect to conduct the entire S1 screening assessments and 
procedures at one visit only.  
Section is redundant with text that is 
before Table 2 and additional text added 
for clarification indicating S1 screening 
assessments may occur at one visit only 


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eosinophil count), the run in will commence 
with the provision of study provided 
ICS+LABA. It is recommended that the site 
consider consenting the subject and completing 
the first peripheral eosinophil count at the 
initial S1 screening visit in order to determine if 
the subject meets the eosinophil criteria for 
enrollment.  If the subject is eligible, the 
remaining S1 assessments and procedures may 
be performed within two weeks of the initial  
S1 screening visit. However, sites may elect to 
conduct the entire S1 screening assessments 
and procedures at one visit only.  
If the aforementioned screening assessments and 
procedures are completed over more than one visit, 
each additional screening visit should include the 
followingthe following assessments should be 
completed at each additional visit:

Review inclusion/exclusion criteria.

Perform prior/concomitant medication inquiry.

Perform adverse event inquiry.

Perform COVID 19 symptoms inquiry.

Review daily e diary for SABA/quick relief 
medication usage and nighttime awakenings, 
including for adherence.

Review daily hand held spirometry, including 
for adherence.

Perform LoAC and CAE inquiry.

Perform vital signs measurements (includes 
systolic and diastolic blood pressure, pulse, 
body temperature, and respiratory rate).

Perform brief physical examination.
If the screening assessments and procedures are divided 
over more than one visit, each additional screening visit 
should include the following: review inclusion/exclusion 
criteria, prior/concomitant medication inquiry; adverse 
event inquiry, COVID-19 symptoms inquiry, LoAC/CAE 
inquiry, vital signs, and brief physical exam. Once all 
inclusion and exclusion criteria have been assessed, with 
the exception of the second eosinophil count, and it has 
been confirmed that patients meet all of the inclusion 
criteria and none of the exclusion criteria (with the 
exception of incomplete assessment of eosinophil count), 
the run-in will commence with the provision of study-
provided ICS+LABA at Visit S2.
Bullets removed to simplify and review of 
e-diary and hand-held spirometry now to 
be done only at S3 if applicable and 
section added before Visit S1 section
Efforts to perform the following assessments and 
procedures in the order listed should be made and 
may be divided over more than one visit:
Not applicable
To streamline and simply section 3.6.1.1


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Reason/Justification for change
See New wording column
Subheadings 3.6.1.1.1 Visit S1, 3.6.1.1.2 Visit S2, and 
3.6.1.1.3 Visit S3 added 
Reorganized Section 3.6.1.1 to simply 
and match Table 2

Distribute e diary and handheld spirometer 
within 1 week of the initial screening visit, 
instruct the patient on how to perform the 
respective assessments, and perform first 
assessments.
Not applicable
Now being done at  Visit S2

Distribute albuterol SABA/quick-relief 
medication when the e diary is dispensed or 
when reversibility is performed (whichever 
comes first) at Visit S1.

Distribute albuterol/quick-relief medication at Visit 
S1.
To simplify screening procedures and 
assessments
Samples for peripheral blood eosinophil counts
should be collected at 2 time points. The first time 
point should be at the initial screening visit, if 
possible, and the second approximately 3 4 weeks 
after the first with the samples collected at least 21 
days apart from each other. To meet eligibility
criteria, the peripheral blood eosinophil counts from 
both time points should be <250 cells/µL. If one of 
the results is ≥250 cells/µL, samples may be 
collected at a third time point provided that third 
time point is at least 14 days after the second time
point. If the value at a third time point is used to 
meet the eligibility criteria, 2 of the 3 values should 
be <250 cells/µL and the mean of the 3 values 
should also be <250 cells/µL.
Not applicable
Deleted because text is redundant with 
test before Table 2
At Visit S2 (approximately 3 4 weeks after the first 
peripheral blood eosinophil sample, with the 
samples collected at least 21 days apart from each 
other), efforts should be made to perform the 
following assessments and procedures in the order 
listed:
Not applicable; new subheading for Visit S2 added
To be consistent with new screening 
timeframe 

At selected sites, confirm that the screening 
sputum sample for 
 was obtained in 
a subset of patients. If not, obtain at this visit.
Not applicable
Sputum collection removed due to lack of 
experienced staff at sites in collecting 
sputum samples correctly


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Reason/Justification for change
The FeNO assessment can be repeated once to meet 
inclusion criterion “d” at a second time point during 
screening (within approximately 2 weeks of the 
initial screening visit), if the first assessment is not 
<25 ppb.
Not applicable
No guidelines exist establishing whether 
or not any particular level of FeNO truly 
characterizes T2-low/Non-T2 asthma.  
Thus, FeNo levels will be measured 
during the trial, but will no longer be used 
as an entrance criterion for the trial.
3.6.1.1 Assessments and Procedures for Screening and Run-in 

Distribute e-diary and handheld spirometer 
within 1 2 weeks of the initial screening visit, 
instruct the patient on how to perform the 
respective assessments, and perform first 
assessments.

Distribute e-diary and handheld spirometer within 2
weeks of the initial screening visit, instruct the patient 
on how to perform the respective assessments, and 
perform first assessments.
To align with the screening period of up 
to 2 weeks
The first time point should be at the initial 
screening visit S1, if possible, and the second 
approximately 3 4 weeks after the first with the 
samples collected at least 21 days apart from each 
other at Visit S2 14 days (± 3 days) after the first 
sample collected at Visit S1. To meet eligibility 
criteria, the peripheral blood eosinophil counts from 
both time points should be <250 cells/µL. If one of 
the results is ≥250 cells/µL, samples may be 
collected at a third time point Visit S3 provided that 
the third time point is at least 14 days (± 3 days) 
after the second time point the sample collected at 
Visit S2. If the value at a third time point is used to 
meet the eligibility criteria, 2 out of the 3 values 
should be <250 cells/µLand the mean of the 3 
values should also be <250 cells/µL.
The first time point should be at Visit S1, if possible, and 
the second at Visit S2 14 days (± 3 days) after the first 
sample collected at Visit S1. To meet eligibility criteria, 
the peripheral blood eosinophil counts from both time 
points should be <250 cells/µL. If one of the results is 
≥250 cells/µL, samples may be collected at Visit S3 
provided that the third time point is 14 days (± 3 days) 
after the sample collected at Visit S2. If the value at a third 
time point is used to meet the eligibility criteria, 2 out of 
the 3 values should be <250 cells/µL.
The major criterion for defining a subject 
as having T2-low/Non-T2 asthma is 
having eosinophil count of <250 cells/μL
of blood.  It is possible that this level may 
transiently increase to above 250 
cells/μL. If one measurement exceeds  
250 cells/μL, it is now felt that having 2 
other measurements below 250 will 
satisfy the definition of T2-low/non-T2 
asthma.
At Visit S2 (14 days [± 3 days] after the first 
peripheral blood eosinophil sample, with the 
samples collected at least 21 days apart from each 
other),…
At Visit S2 (14 days [± 3 days] after the first peripheral 
blood eosinophil sample,
Visit S2 now occurs 14 days [± 3 days] 
after Visit S1


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Original text with changes shown
New wording
Reason/Justification for change
If required, to meet the eosinophil count inclusion 
criterion, at Visit S3 (14 days [± 3 days] after Visit 
S2) efforts should be made to perform the following 
assessments and procedures in the order listed
If required, to meet the eosinophil count inclusion 
criterion, at Visit S3 (14 days [± 3 days] after Visit S2) 
efforts should be made to perform the following 
assessments and procedures in the order listed
Visit S3 now occurs 14 days [± 3 days] 
after Visit S2
3.6.1.1 Assessments and Procedures for Screening and Run-in
See New wording column
Collect optional blood sample for pharmacogenomics 
analysis
Clarification that pharmacogenomics 
testing and the blood sample collected for 
this testing is optional.
3.6.1.2.1 Assessments and Procedures for the Day of Randomization (Visit 1): Pre-Study Drug Administration; Randomization, and Administration 
of the Loading Dose (Other sections affected by this change: 3.6.1.2.10)

Perform reversibility testing (includes in office 
spirometry (full flow volume loop)

Perform in-office spirometry (full flow-volume loop)
To align with other asthma studies that 
evaluate the pre-BD PFTs as an objective 
sign of improvement during the study; 
pre-BD PFTs will be performed at each 
visit during the active treatment phase 
(visits 1- 10), done routinely at every 2 
week interval throughout treatment.
See New wording column
• Collect optional blood sample in PaxGene DNA tube for 
pharmacogenomics analysis.
Blood sample for pharmacogenomics 
being collected at Day of Randomization
3.6.1.2.2. Treatment Visit 2 (Week 2) (Other sections affected by this change: 3.6.1.2.3, 3.6.1.2.4, 3.6.1.2.8, 3.6.1.2.9)   
See New wording column

Perform in-office spirometry (full flow-volume loop)
To align with other asthma studies that 
evaluate the pre-BD PFTs as an objective 
sign of improvement during the study; 
pre-BD PFTs will be performed at each 
visit during the active treatment phase 
(visits 1- 10), done routinely at every 2 
week interval throughout treatment.
3.6.1.2.9. ET Visit

Perform reversibility testing in-office 
spirometry(full-volume loop)

Perform in office spirometry (includes full-volume 
loop)
To align with rest of PFTs


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Reason/Justification for change
3.6.1.3.1 Assessments and Procedures at the End of Study Visit

Perform reversibility testing.
Not applicable
To align with other asthma studies that 
evaluate the pre-BD PFTs as an objective 
sign of improvement during the study; 
pre-BD PFTs will be performed at each 
visit during the active treatment phase 
(visits 1- 10), done routinely at every 2 
week interval throughout treatment.
3.6.1.3.1 Assessments and Procedures at the End of Study Visit

At selected sites, in a subset of patients, obtain 
sputum sample for 
 in a subset of 
patients following procedures described in the 
Lab Manual. 
Not applicable
Sputum collection removed due to lack of 
experienced staff at sites in collecting 
sputum samples correctly
4.1 Patient Inclusion Criteria
c. The patient must have an absolute eosinophil 
count <250 cells/μL (at least 2 measurements both 
<250 cells/μL separated by 3 4 weeks 14 days [± 3 
days]). If one of the results is ≥250 cells/µL, 
samples may be collected at a third time point(Visit 
S3)  provided that third time point is at least 14 
days (± 3 days) after the second time point sample 
collected at Visit S2. If the value at a third time 
point is used to meet the eligibility criteria, 2 out of 
the 3 values should be <250 cells/µL and the mean 
of the 3 values should also be <250 cells/µL.
c. The patient must have an absolute eosinophil count 
<250 cells/μL (at least 2 measurements both <250 cells/μL 
separated by 14 days [± 3 days]). If one of the results is 
≥250 cells/µL, samples may be collected at a third time 
point (Visit S3)  provided that third time point is at least 
14 days (± 3 days) after the sample collected at Visit S2. If 
the value at a third time point is used to meet the eligibility 
criteria, 2 out of the 3 values should be <250 cells/µL.
Visit S2 now occurs 14 days [± 3 days] 
after Visit S1 and Visit S3 now occurs 14 
days [± 3 days] after Visit S2
d. The patient has fractional exhaled nitric oxide 
(FeNO) level <25 ppb.
Not applicable
No guidelines exist establishing whether 
or not any particular level of FeNO truly 
characterizes T2-low/Non-T2 asthma.  
Thus, FeNo levels will be measured 
during the trial, but will no longer be used 
as an entrance criterion for the trial.
g. f.  The patient has asthma with a FEV1 ≥4030%
and <80% of the value predicted for age, height, 
sex, and race at screening. FEV1 must be performed 
f. The patient has asthma with a FEV1 ≥30% and <80% of 
the value predicted for age, height, sex, and race at 
screening. FEV1 must be performed using the office-based 
The lower floor is being reduced to 
include eligible subjects who are at a 
lower threshold of pulmonary function, 


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Reason/Justification for change
using the office-based spirometer provided for the 
study. One pulmonary function test during the 
screening visit(s) period (up to 2 weeks) is allowed 
to fulfill this criterion.  
spirometer provided for the study. One pulmonary 
function test retest during the screening visit(s) period (up 
to 2 weeks) is allowed to fulfill this criterion.  
but will be deemed safe for the study 
since their pulmonary function will be 
monitored on a daily basis with the peak 
flow meter.
h.g. The patient is able to perform technically 
acceptable and repeatable spirometry, including 
with a hand-held spirometer, after training 
(applicable to FEV1, not PEF).
g. The patient is able to perform technically acceptable and 
repeatable spirometry, including with a hand-held 
spirometer, after training (applicable to FEV1, not PEF).
Most asthma trials have FEV1 as the 
primary endpoint.  In this trial, both 
FEV1 and PEF are measured, but it is not 
mandated that PEF be in a tight 40 
liter/min range, as this parameter is 
usually more effort-dependent and more 
variable than FEV1.  Thus, the reliance in 
this trial on FEV1 is consistent with most 
other asthma trials.
i. h. The patient’s background asthma therapy 
includes daily medium- or high-dose ICS plus 
LABA for at least 3 months prior to the initial 
screening visit with or without other asthma 
controller medications. The dose of ICS may vary 
during these 3 months, but must remain at a stable 
daily dose for at least 1 month prior to Visit S1.
h. The patient’s background asthma therapy includes daily 
medium- or high-dose ICS plus LABA for at least 3 
months prior to the initial screening visit with or without 
other asthma controller medications. The dose of ICS may 
vary during these 3 months, but must remain at a stable 
daily dose for at least 1 month prior to Visit S1.
The requirement for a stable dose of 
inhaled medication is now reduced to 30 
days (i.e. the dosage may have changed in 
the 2 preceding months, but has to be 
steady for the last month before 
screening).  This requirement is in 
concert with medication treatment 
requirement that is commonly used in 
other asthma trials.
i. The patient has had at least one clinical asthma 
exacerbation (worsening of asthma requiring 
systemic corticosteroids [oral or injected], or an 
emergency department visit due to asthma treated 
with systemic corticosteroids, or an inpatient 
hospitalization due to asthma, or a 2-fold or greater 
increase from the subject’s usual maintenance ICS 
dose during the exacerbation period documented in 
the patient’s medical or pharmacy records in the 
18 months prior to (but not within 30 days of) the 
initial screening visit.
i. The patient has had at least one clinical asthma 
exacerbation (worsening of asthma requiring systemic 
corticosteroids [oral or injected], or an emergency 
department visit due to asthma, or an inpatient 
hospitalization due to asthma, or a 2-fold or greater 
increase from the subject’s usual maintenance ICS dose 
during the exacerbation period documented in the patient’s 
medical or pharmacy records in the 18 months prior to (but 
not within 30 days of) the initial screening visit.
Follows current standard of care 
regarding asthma exacerbations that now 
includes an increase in the subject’s 
maintenance inhaled corticosteroids (with 
or without LABAs) by at least 2-fold, for 
at least 5 days or more until exacerbation 
symptoms begin to subside. The dose of 
the inhaled medication can then be 
tapered back to pre-exacerbation levels.


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Reason/Justification for change
4.2. Patient Exclusion Criteria
a. The patient has any other pulmonary diagnosis 
that in the opinion of the investigator and/or the 
clinical study physician could adversely affect 
patient safety or interpretation of study results. 
Examples include but are not limited to: chronic 
obstructive pulmonary disease, chronic bronchitis 
or any respiratory condition that requires any 
chronic antibiotic use (some antibiotics can be 
immunomodulatory such as macrolides [eg, 
erythromycin, azithromycin, and clarithromycin]),
bronchiectasis, cystic fibrosis, bronchopulmonary 
dysplasia, and interstitial lung disease (including 
eosinophilic granulomatosis with polyangiitis 
[EGPA] which is expressly prohibited), obstructive 
sleep apnea (sometimes referred to as Pickwickian 
syndrome), and gastroesophageal reflux disease that 
is not treated with a proton pump inhibitor on a 
scheduled treatment regimen (not as needed).
a. The patient has any other pulmonary diagnosis that in 
the opinion of the investigator and/or the clinical study 
physician could adversely affect patient safety or 
interpretation of study results. Examples include but are 
not limited to: chronic obstructive pulmonary disease, 
chronic bronchitis or any respiratory condition that 
requires any chronic antibiotic use (some antibiotics can 
be immunomodulatory such as macrolides [eg, 
erythromycin, azithromycin, and clarithromycin]), 
bronchiectasis, cystic fibrosis, bronchopulmonary 
dysplasia, and interstitial lung disease (including 
eosinophilic granulomatosis with polyangiitis [EGPA] 
which is expressly prohibited), obstructive sleep apnea 
(sometimes referred to as Pickwickian syndrome), and 
gastroesophageal reflux disease that is not treated with a 
proton pump inhibitor on a scheduled treatment regimen 
(not as needed).
Clarification of Sponsor’s intention to 
NOT include subjects into the trial who 
may have any pulmonary disease that 
may confound the integrity of the study 
data, or if their underlying condition 
would interfere with the interpretation 
and potential impact of the study 
investigational medicinal product on the 
subject’s underlying asthma condition.
-  Patients with clinical symptoms that may indicate 
COVID-19 infection, and/or patients who in the 
investigator’s opinion were at high risk of exposure 
to COVID-19 within 6 weeks before screening or 
during screening/run-in, will be tested for active 
COVID-19 infection and will only be included if 
they test negative for COVID-19. Patients who 
were admitted to an ICU during a prior COVID-19 
infection; or patients who contracted or recovered 
from  COVID-19 less than 6 weeks prior to 
screening, or patients with COVID-19 symptoms 
(lingering anosmia, weakness, persistent dyslogia or 
feelings of dysphoria for many months) from a pre-
study COVID-19 infection that have not completely 
resolved back to their pre-COVID-19 infection 
health status are excluded from the study.
-  Patients with clinical symptoms that may indicate 
COVID-19 infection, and/or patients who in the 
investigator’s opinion were at high risk of exposure to 
COVID-19 within 6 weeks before screening or during 
screening/run-in, will be tested for active COVID-19 
infection and will only be included if they test negative for 
COVID-19. Patients who were admitted to an ICU during 
a prior COVID-19 infection; or patients who contracted or 
recovered from  COVID-19 less than 6 weeks prior to 
screening, or patients with COVID-19 symptoms 
(lingering anosmia, weakness, persistent dyslogia or 
feelings of dysphoria for many months) from a pre-study 
COVID-19 infection that have not completely resolved 
back to their pre-COVID-19 infection health status are 
excluded from the study.
To specify criteria for patients with 
COVID-19 infections pre-study
m. The patient has received any live or attenuated 
vaccine within 15 days of the initial screening visit. 
n. Live and attenuated vaccines should be excluded 14 
days before IMP dosing and throughout the study. 
Further clarification text added around 
vaccination with live or attenuated 


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Original text with changes shown
New wording
Reason/Justification for change
(Note: live and attenuated vaccines are also 
prohibited during the study [screening through 
EOS].)
Inactivated vaccines (including approved inactivated 
COVID 19 vaccines) should preferably be completed 14 
days before first IMP dosing. If administered during the 
study it is recommended to be at least 3 days before and 
after IMP administration, or as required by local country 
regulations.
vaccines and COVID-19 vaccine; 
vaccinations now allowed
n. The patient has a positive urine drug test during 
screening for compounds of abuse, or for cotinine, 
the relevant metabolite of tobacco abuse, the use of 
which would make the patient ineligible. Repeat 
testing will not be permitted. A positive urine test 
for tetrahydrocannabinol, the psychoactive 
ingredient in marijuana, is permitted during the 
trial.
n. The patient has a positive urine drug test during 
screening for  compounds of abuse, or for cotinine, the 
relevant metabolite of tobacco abuse, the use of which 
would make the patient ineligible. Repeat testing will not 
be permitted. A positive urine test for 
tetrahydrocannabinol, the psychoactive ingredient in 
marijuana, is permitted during the trial. 
Positive urine test for THC now permitted
4.3. Randomization Criteria
b. The patient has not had a clinical asthma 
exacerbation (worsening of asthma requiring 
systemic corticosteroids [oral or injected], or an 
emergency department visit due to asthma treated 
with systemic corticosteroids, or an inpatient 
hospitalization due to asthma, or a 2-fold or greater 
increase from the subject’s usual maintenance ICS 
dose during the exacerbation period  documented in 
the patient’s medical or pharmacy records in the 18 
months prior to (but within 30 days of) the initial 
screening visit, or other need for systemic 
corticosteroids during the screening period. 
b. The patient has not had a clinical asthma exacerbation 
(worsening of asthma requiring systemic corticosteroids 
[oral or injected], or an emergency department visit due to 
asthma treated with systemic corticosteroids, or an 
inpatient hospitalization due to asthma, or a 2-fold or 
greater increase from the subject’s usual maintenance ICS 
dose during the exacerbation period  documented in the 
patient’s medical or pharmacy records in the 18 months 
prior to (but within 30 days of) the initial screening visit, 
or other need for systemic corticosteroids during the 
screening period. 
Follows current standard of care 
regarding asthma exacerbations that now 
includes an increase in the subject’s 
maintenance inhaled corticosteroids (with 
or without LABAs) by at least 2-fold, for 
at least 5 days or more until exacerbation 
symptoms begin to subside. The dose of 
the inhaled medication can then be 
tapered back to pre-exacerbation levels.
a. The patient has at least 57% adherence (complete 
and acceptable data for 4 out of the 7 days prior to 
randomization) to hand-held spirometry and e-
diary assessments.
a. The patient has at least 57% adherence (complete and 
acceptable data for 4 out of the 7 days prior to 
randomization) to hand-held spirometry and e-diary 
assessments.
Added definition for 57% adherence
4.6. Rescreening
Specific rescreening criteria for reversibility, FeNO, 
and peripheral blood eosinophil count are described 
A subject may be rescreened up to 2 times in the study. 
Rescreening for urine test found positive for illicit drugs or 
cotinine, or failure to meet inclusion criterion “e” (ACQ-6 
Establishes more clearly rescreening 
criteria and removes FeNO which is no 
longer being used as a screening criteria. 


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Original text with changes shown
New wording
Reason/Justification for change
in Section 3.6.1.1. A subject may be rescreened up 
to 2 times in the study. 
Rescreening for urine test found positive for illicit 
drugs or cotinine, or failure to meet inclusion 
criterion “e” (ACQ-6 score ≥1.5, Section 4.1) will 
not be allowed. A patient who screen fails for 
reasons other than the 3 aforementioned reasons 
may be permitted to rescreen once if there is a 
reasonable expectation that this patient will become 
eligible for the study. The sponsor may grant 
permission to rescreen more than once under 
extenuating circumstances and only with the 
approval of the sponsor’s. A subject may be 
rescreened for all other inclusion and exclusion 
criteria that are not fulfilled.
score ≥1.5, Section 4.1) will not be allowed. A subject may 
be rescreened for all other inclusion and exclusion criteria 
that are not fulfilled.
4.7. Screen Failure
See New wording column
Patients will be allowed to screen fail twice before no 
longer being considered for enrollment in the clinical 
study.
Now allows subjects 2 screen failures; 
subjects who previously failed to 
randomize with the Protocol Amendment 
1 version may be eligible with the new 
inclusion/exclusion criteria   
5.8.2. Tobacco and Illicit Drugs
Smoking or use of tobacco products (eg, cigarettes, 
e-cigarettes, cigars, chewing tobacco, pipe tobacco), 
or smoking or use of inhaled marijuana products,
and use of illicit drugs is strictly forbidden in this 
study, and objective tests that indicate the use of 
and/or exposure to these drugs will be administered 
at the screening visit. Positive tests will result in an 
irrevocable screen failure of the subject, and 
retesting is not permitted.  In addition, these drugs 
may not be used or taken at any time during the trial 
(from Screening Visit S1 through EOS visit). will 
not be allowed from screening until the EOS visit. 
A positive urine test for tetrahydrocannabinol, the 
psychoactive ingredient in marijuana, is however, 
permitted during the trial. 
Smoking or use of tobacco products (eg, cigarettes, e-
cigarettes, cigars, chewing tobacco, pipe tobacco), and use 
of illicit drugs is strictly forbidden in this study, and 
objective tests that indicate the use of and/or exposure to 
these drugs will be administered at the screening visit. 
Positive tests will result in an irrevocable screen failure of 
the subject, and retesting is not permitted.  In addition, 
these drugs may not be used or taken at any time during 
the trial (from Screening Visit S1 through EOS visit). A 
positive urine test for tetrahydrocannabinol, the 
psychoactive ingredient in marijuana, is however, 
permitted during the trial. 
Since there are now many states in the US 
that have legalized use of marijuana in 
several forms, the presence of 
tetrahydrocannabinol in urine is no longer 
included as an exclusion criteria.


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Original text with changes shown
New wording
Reason/Justification for change
5.10 Prior and Concomitant Medication or Therapy
See New wording column

Live and attenuated vaccines
Live and attenuated vaccines should be 
excluded 14 days before IMP and are 
now not allowed during the study.
Note:
- Stable maintenance allergen immunotherapy will 
be allowed. Starting or build-up phase allergen
immunotherapy will not be allowed.
- Completion of inactivate vaccination (including 
available inactivated COVID-19 vaccinations) is 
preferable at least 14 days before the first IMP dose, 
if possible. Inactivated vaccination during the study 
is recommended to be at least 3 days before and 
after IMP administration, if possible, or as required 
by local country regulations.
Note:
- Stable maintenance allergen immunotherapy will be 
allowed. Starting or build-up phase allergen 
immunotherapy will not be allowed.
- Completion of inactivate vaccination (including available 
inactivated COVID-19 vaccinations) is preferable at least 
14 days before the first IMP dose, if possible. Inactivated 
vaccination during the study is recommended to be at least 
3 days before and after IMP administration, if possible, or 
as required by local country regulations.
Further clarification text added around 
vaccination with live or attenuated 
vaccines and COVID-19 vaccine; 
vaccinations now allowed
5.13.2. Blinding and Unblinding
See New wording column
In addition, unblinding may occur if a review of data of 
COVID-19 patients per the JDMC or medical monitor is 
required.
To allow for review of safety data of 
COVID-19 patients if needed
6.1.2. Clinical Asthma Exacerbation
For this study, asthma exacerbation during the study
is defined as a worsening of asthma symptoms 
(examples are described below) resulting in any of 
the following:
Asthma exacerbation during the study is defined as a 
worsening of asthma symptoms (examples are described 
below) resulting in any of the following:
Simplified text for clarity
6.1.3 e-Diary
See New wording column
New Section 6.1.3 added:
Patients will be trained in using the e-diary to ensure 
proper use and to ensure rigorous data is collected 
throughout the study.  
To ensure proper training of patients on 
use of the e-diary and compliance with e-
diary standards
7.1 Adverse Events
7.1 Adverse Events and Adverse Device Effects
Adverse Events and Adverse Device Effects
To make consistent with section since 
section now contains device text


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Original text with changes shown
New wording
Reason/Justification for change
drug or drug/device or device/device interactions
drug or drug/device or device/device interactions
To make more inclusive to include 
drug/device or device/device interactions
Section 8. ASSESSMENT OF PHARMACOKINETICS, PHARMACOGENOMICS, IMMUNOGENICITY AND 
Section 8. ASSESSMENT OF 
PHARMACOKINETICS, 
PHARMACOGENOMICS, 
IMMUNOGENICITY AND 
 
Section 8. ASSESSMENT OF 
PHARMACOKINETICS, PHARMACOGENOMICS, 
IMMUNOGENICITY AND 
 
To align with new pharmacogenomics 
sections added in previous sections
If pharmacokinetic, pharmacogenomics,
immunogenicity, and/or 
 cannot 
be collected due to limitations in ability to carry out 
the procedure or limitations in storage and 
shipments, the samples will not be collected for 
those respective visits.
If pharmacokinetic, pharmacogenomics, immunogenicity, 
and/or 
 cannot be collected due to 
limitations in ability to carry out the procedure or 
limitations in storage and shipments, the samples will not 
be collected for those respective visits.
To align with new pharmacogenomics 
sections added in previous sections
8.3 
 (Exploratory)
 
 
 
 
ing
8.4 Pharmacogenomics Assessment (Optional) (New section)
See New wording column
Pharmacogenomics is the study of how a person’s genetic 
makeup influences how he or she responds to a drug. 
Pharmacogenomics testing can contribute to a better 
understanding of the variation of drug responses seen 
during development of an investigational drug. A separate 
ICF is required for pharmacogenomics testing. An optional 
blood sample for pharmacogenomics testing will be 
collected (following signing of the ICF) via venipuncture 
into a PaxGene DNA tube at the time point detailed in 
Table 3.  
Clarification that pharmacogenomics 
testing and the blood sample collected for 
this testing is optional.


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Original text with changes shown
New wording
Reason/Justification for change
9.6.1. Planned Method of Analysis
The baseline for absolute eosinophil count will be 
the average of all the values obtained prior to the 
administration of the first IMP in screening.
The baseline for absolute eosinophil count will be the 
average of all values obtained prior to the administration 
of the first IMP.
For clarification that all values will be 
used for the average
9.6.1.1. Primary Efficacy Analysis
The primary analysis will compare rates of LoAC 
between treatment groups using logistic regression 
with fixed effect for treatment, baseline FEV1, 
weight, age group (<65 years vs ≥65 years), and 
gender as covariates.
The primary analysis will compare rates of LoAC between 
treatment groups using logistic regression with fixed effect 
for treatment, baseline FEV1, weight, age group (<65 years 
vs ≥65 years), and gender as covariates.
More detail added for the primary 
efficacy analysis
9.6.1.3. Secondary Efficacy Analysis
Analysis of ACQ-6 will use the mixed model 
repeated measures model with treatment group, 
weight, age group (<65 years vs ≥65 years), gender, 
visit, and treatment and visit interaction, and 
baseline value as fixed effects and patient as a 
random effect.
Analysis of ACQ-6 will use the mixed model repeated 
measures model with treatment group, weight, age group 
(<65 years vs ≥65 years), gender, visit, and treatment and 
visit interaction, as fixed effects and patient as a random 
effect.
More detail added for the secondary 
efficacy analysis
See New wording column
The on-site morning trough FEV1 throughout study will
be analyzed using similar MMRM method, as described 
for the analysis ACQ-6. 
Use of SABA quick relief medication will be derived from 
the e-diary data in monthly analysis intervals and will be 
analyzed using a similar MMRM method.
The efficacy endpoints defined at end-of-treatment (EOT) 
will take the last available assessment value in the 
treatment period, and will be analyzed using appropriate 
analysis of covariance models. 
More detail added for the secondary 
efficacy analysis
9.7. Multiple Comparisons and Multiplicity
As there are only 2 treatment groups and one 
primary analysis test in this study, no multiplicity 
correction is necessary. Secondary endpoints will 
be considered as hypothesis-generating, and 
multiple testing adjustment will not be made.
As there are only 2 treatment groups and one primary 
analysis test in this study, no multiplicity correction is 
necessary. Secondary endpoints will be considered as 
hypothesis-generating, and multiple testing adjustment 
will not be made.
For clarification that multiple testing 
adjustment will not be done


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Original text with changes shown
New wording
Reason/Justification for change
9. Statistics
See New wording column
Section 9.11 changed to Section 9.10 and Section 9.10 
changed to Section 9.11
To align with order in Section 8
9.12. 
 (New section)
See New wording column
 
 
 
9.13. Planned Interim Analyses (Changed from Section 9.12)
An unblinded interim analysis is planned after the 
first 40 to 52 randomized patients have completed 
the treatment period, experienced LoAC, or 
withdrawn from the study completely.
An unblinded interim analysis is planned after the first 40 
to 52 randomized patients have completed the treatment 
period, experienced LoAC, or withdrawn from the study 
completely.
Relaxes the timing of the interim analysis 
to after 40 to 52 patients have completed 
the treatment period, experienced LoAC, 
or withdrawn from the study 
The interim futility analysis comprises a statistical 
comparison between treatment group versus 
placebo in LoAC rate using logistic regression with 
fixed effect for treatment among the 52 randomized 
patients who have completed the treatment period, 
experienced LoAC, or withdrawn from the study 
completely at the interim analysis.
The interim futility analysis comprises a statistical 
comparison between treatment group versus placebo in 
LoAC rate using logistic regression with fixed effect for 
treatment among the randomized patients who have 
completed the treatment period, experienced LoAC, or 
withdrawn from the study completely at the interim 
analysis.
Text updated for consistency with first 
paragraph of section
According to simulation analyses, this cutoff value 
yields a correct early termination rates under the 
null hypothesis of 0.43 (40 patients) and 0.44 
(under the null hypothesis 52 patients) and controls 
incorrect early termination rate under the alternative 
hypothesis at approximately 0.06 (40 patients) and 
0.04 (under the alternative hypothesis of true risk 
ratio 0.4 52 patients).
According to simulation analyses, this cutoff value yields 
correct early termination rates under the null hypothesis of 
0.43 (40 patients) and 0.44 (52 patients) and controls
incorrect early termination rates under the alternative 
hypothesis at approximately 0.06 (40 patients) and 0.04 
(52 patients).
Text updated to provide more detail of 
the interim futility analyses


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Original text with changes shown
New wording
Reason/Justification for change
14. REFERENCES
See New wording column
New reference: Graham B, Steenbruggen I, Miller M, 
Barjaktarevic  I, Cooper B, Hall G, et al. Standardization 
of Spirometry 2019 Update. An Official American 
Thoracic Society and European Respiratory Society 
Technical Statement. Amer J Respir and Crit Care Med 
2019; 200(8):e70-e88.
Added as cross-reference to Section 6.1.4 
See New wording column
New reference: GUIDANCE ON THE MANAGEMENT 
OF CLINICAL TRIALS DURING THE COVID-19 
(CORONAVIRUS) PANDEMIC Version 4, 04/02/2021. 
Available at: 
https://ec.europa.eu/health/sites/health/files/files/eudralex/
vol-
Added as cross-reference to Appendix J
APPENDIX A. STUDY REPRESENTATIVES, CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND INSTITUTIONS
Sputum Supernatant and Sputum Cell Pellet
Biomarker & Metabolism Analytics
Teva Branded Pharmaceutical Products R&D, Inc.
145 Brandywine Parkway
West Chester, Pennsylvania 19380 4245
Not applicable
Sputum collection removed in Protocol 
Amendment #2
APPENDIX J. MANAGEMENT OF STUDY ACTIVITIES DURING COVID-19 OUTBREAKS
Section 1.3. Known and Potential Benefits and Risks of the Test Investigational Medicinal Product
It should be noted that patients diagnosed with 
active or residual COVID-19 or were hospitalized 
in ICU during COVID-19 infection, would not be 
included in the study as they would meet exclusion 
criterion “a” and “c” which exclude patients with 
“any other pulmonary diagnosis that in the opinion 
of the investigator and/or the clinical study 
physician could adversely affect patient safety or 
interpretation of study results” and “a suspected 
bacterial or viral infection of the upper or lower 
respiratory tract, sinus, or middle ear that has not 
It should be noted that patients diagnosed with active or 
residual COVID-19 or were hospitalized in ICU during 
COVID-19 infection, would not be included in the study 
as they would meet exclusion criterion “a” and “c”.
To shorten text and to add clarification; 
additional text not needed.


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Original text with changes shown
New wording
Reason/Justification for change
resolved at least 2 weeks before the initial screening 
visit.” Furthermore, exclusion criterion “c” 
stipulates that: 
Patients with clinical symptoms that may 
indicate COVID 19 infection, and/or patients 
who in the investigator’s opinion were at high 
risk of exposure to COVID 19 within 6 weeks 
before screening or during screening/run in, 
will be tested for active COVID 19 infection 
and will only be included if they test negative 
for COVID 19. 
Not applicable
To shorten text; additional text not 
needed
Patients who are scheduled to undergo sputum 
induction collection must be tested for active 
COVID 19 infection within no later than 5 
business days from the planned date of the 
sputum induction prior to the sputum 
collection. Only patients who are confirmed to 
not have active COVID 19 will be deemed safe 
to undergo sputum induction. Patients who are 
considered to have a high probability of being 
exposed to COVID 19 infection during the 
study duration should not be included in the 
sputum collection cohort.
Sputum collection removed in Protocol 
Amendment #2
See New wording column
The effect of TEV 48574 on the response to vaccines in 
general and specifically to COVID-19 vaccines is 
unknown. All live/attenuated vaccines are disallowed 14 
days prior to IMP administration and throughout the study. 
The completion of planned inactivated vaccinations 
(including approved COVID-19 inactivated vaccinations) 
is preferable at least 14 days before first IMP dose, if 
possible. Inactivated vaccination during the study is 
recommended to be at least 3 days before and after IMP 
administration, if possible.
To add additional text around timing of 
COVID-19 vaccination relative to IMP 
administration.


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Original text with changes shown
New wording
Reason/Justification for change
Section 4.2. Patient Exclusion Criteria; Section 5.10. Prior and Concomitant Medication or Therapy
See New wording column
The eligibility criteria and list of prohibited medications 
can be updated to reflect new data on COVID-19 therapies 
or vaccines  If a patient receives new COVID-19 therapies 
or vaccines not in compliance with the eligibility criteria 
and list of prohibited medications at the time of the 
patient’s participation in the study, the investigator and 
sponsor will discuss how to proceed on a case-by-case 
basis.
Updated text added for future data and/or 
vaccinations for COVID-19
Study Monitoring
See New wording column
(GUIDANCE 2021)
Provide reference for most recent 
guidance on monitoring during 
COVID-19 pandemic
Appendix K. Rules for Pulmonary Function Testing
See New wording column
Appendix K. Rules for Pulmonary Function Testing
Appendix K added to provide 
clarification on pulmonary function 
testing


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15.2.
Administrative Letter Dated 02 December 2020
ADMINISTRATIVE LETTER 02
Study number: TV48574-AS-20031
Clinical Study Protocol with Amendment 01
A 16-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Proof-of-Concept 
Study to Evaluate the Efficacy and Safety of TEV-48574 in Adults with T2-low/non-T2 Severe 
Uncontrolled Asthma, version dated 09 November 2020
IND number: 133677; EudraCT number: 2020-001927-15
02 December 2020
Dear Investigator:
The purpose of this letter is to provide additional clarification related to exclusion criteria “a” 
(Section 4.2 of the protocol). Although the exclusion criteria itself remains the same (ie, the 
patient has any other pulmonary diagnosis that in the opinion of the investigator and/or the 
clinical study physician could adversely affect patient safety or interpretation of study results), 
additional examples are provided in the subsequent statement to provide further context for the 
investigators. Changes are noted below using track changes.
From:
a.
The patient has any other pulmonary diagnosis that in the opinion of the investigator 
and/or the clinical study physician could adversely affect patient safety or 
interpretation of study results. Examples include but are not limited to: chronic 
obstructive pulmonary disease, chronic bronchitis, bronchiectasis, cystic fibrosis, 
bronchopulmonary dysplasia, and interstitial lung disease (including eosinophilic 
granulomatosis with polyangiitis [EGPA] which is expressly prohibited).
To:
b. The patient has any other pulmonary diagnosis that in the opinion of the investigator 
and/or the clinical study physician could adversely affect patient safety or 
interpretation of study results. Examples include but are not limited to: chronic 
obstructive pulmonary disease, chronic bronchitis or any respiratory condition 
requiring chronic antibiotic use (antibiotics can be immunomodulatory such as 
macrolides [eg, erythromycin, azithromycin, and clarithromycin]), bronchiectasis, 
cystic fibrosis, bronchopulmonary dysplasia, and interstitial lung disease (including 
eosinophilic granulomatosis with polyangiitis [EGPA] which is expressly prohibited), 
obstructive sleep apnea, sleep apnea, Pickwickian syndrome, and gastroesophageal 


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reflux disease that is not treated with a proton pump inhibitor on a scheduled 
treatment regimen (not PRN).
This change will be incorporated into the protocol during the next amendment, as applicable. 
Please ensure that this letter is maintained with the study protocol. Also, please provide a copy of 
this letter to your Institutional Review Board/Independent Ethics Committee for review and 
acknowledgement.
Please feel free to contact 
 if you have 
any questions or concerns regarding this letter.
Sincerely,
___________________________________
Clinical Development
Teva Pharmaceuticals


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15.3.
Amendment 01 Dated 09 November 2020
The primary reasons for this amendment are the addition of a JSRC to monitor safety of the 
patients and the addition of a planned futility analysis. All major changes to the protocol body 
are listed below in the table and are reflected in the synopsis, as applicable. 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/Justification for change
1.3. Known and Potential Benefits and Risks of the Test Investigational Medicinal Product
None of these risks were observed in either portion of
the 
study, except for 
immunogenicity, predominantly in the low-dose level 
cohorts up to and including 
 in single and repeat 
dose settings.
None of these risks were observed in the 
study, except for immunogenicity,
predominantly in the low-dose level cohorts up to and 
including 
 mg in single and repeat dose settings.
Minor editorial clarification
See New wording column
Management of the patients' safety during the study, 
including their asthma control, is detailed in Section 3 
(study design), Section 7 (assessment of safety), and 
Appendix B (joint safety review committee [JSRC]).
Addition of JSRC
2.2. Exploratory 
See New wording column
Section 2.2.1.1 changed to Section 2.2.1 and 
Section 2.2.1.2 changed to Section 2.2.2
Correction for previously skipped 
heading level
2.2.1. Exploratory 
 (Other sections affected by this change: 8.3)
 
 
 
3.1. General Study Design and Study Schematic Diagram
Eligibility requirements include: peripheral blood 
eosinophil counts of <250 cells/μL (at least 2 
measurements both <250 cells/μL separated by 3-4 
weeks); FeNO <25 ppb; an ACQ-6 score ≥1.5 despite 
daily treatment with medium/high dose ICS+LABA for 
at least 3 months with or without other asthma 
controller medications, and at least one documented
clinical asthma exacerbation (worsening of asthma 
requiring systemic corticosteroids [oral or injected], or 
an emergency department visit due to asthma treated 
with systemic corticosteroids, or an inpatient 
hospitalization due to asthma) documented in the 18 
months prior to (but not within 30 days of) the initial 
screening visit.
Eligibility requirements include: peripheral blood 
eosinophil counts of <250 cells/μL (at least 2 
measurements both <250 cells/μL separated by 3-4 
weeks); FeNO <25 ppb; an ACQ-6 score ≥1.5 despite 
daily treatment with medium/high dose ICS+LABA for 
at least 3 months with or without other asthma controller 
medications, and at least one clinical asthma 
exacerbation (worsening of asthma requiring systemic 
corticosteroids [oral or injected], or an emergency 
department visit due to asthma treated with systemic 
corticosteroids, or an inpatient hospitalization due to 
asthma) documented in the 18 months prior to (but not 
within 30 days of) the initial screening visit.
Clarification regarding background 
asthma therapy


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Original text with changes shown
New wording
Reason/Justification for change
The study will consist of an approximate 5-week period 
consisting of screening followed by a run-in, a 16 week 
treatment period, and an 8 week follow-up period.
The study will consist of an approximate 5-week period 
consisting of screening followed by a run-in, a 16 week 
treatment period, and an 8 week follow-up period.
Clarification added since the window of 
for the screening and run-in period 
could also be 4 weeks
Screening and Run-in (5 weeks)
The duration of the screening and run-in period will be 
approximately 5 weeks and may be extended by up to 
14 days to allow for IMP shipping and to complete 
assessments of peripheral blood eosinophil count.
The duration of the screening and run-in period will be 
approximately 5 weeks and may be extended by up to 
14 days to allow for IMP shipping and to complete 
assessments of peripheral blood eosinophil count.
Clarification added since the window of 
for the screening and run-in period 
could also be 4 weeks
The FeNO assessment can be repeated once to meet 
inclusion criterion “d” at a second time point during 
screening (within approximately 2 weeks of the initial 
screening visit), if the first assessment is not <25 ppb.
The FeNO assessment can be repeated once to meet 
inclusion criterion “d” at a second time point during 
screening (within approximately 2 weeks of the initial 
screening visit), if the first assessment is not <25 ppb.
Clarification regarding timing of FeNO 
assessments
Treatment Period (16 weeks)
The subset of patients who had sputum collected during 
the screening period (up to approximately 40 patients 
in total) will have sputum collected again at EOT.
The subset of patients who had sputum collected during 
the screening period (approximately 40 patients in total) 
will have sputum collected again at EOT.
Clarification that there is no cap to be 
placed on the subset of patients who 
have sputum collected
3.2. Planned Number of Patients and Countries
An unblinded interim analysis (described in Section 
9.12) may be performed is planned, which could result 
in a sample size increase, from the initially planned 124 
to up to 174 total randomized patients (87 per arm), 
which would require up to 435 patients screened.
An unblinded interim analysis (described in Section 
9.12) is planned, which could result in a sample size 
increase, from the initially planned 124 to up to 174 total 
randomized patients (87 per arm), which would require 
up to 435 patients screened.
Addition of futility analysis
3.5. Joint Safety Review Committee (New section)
See New wording column
There will be a JSRC in this study. The data will be 
reviewed in a blinded fashion. The JSRC will 
recommend whether to continue the study as designed, 
conduct protocol/informed consent form (ICF) 
modifications, temporarily suspend enrollment and/or 
study intervention until some uncertainty is resolved, or 
discontinue the study. Details for the JSRC are given in 
Appendix B.
Addition of JSRC


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Original text with changes shown
New wording
Reason/Justification for change
3.6. Schedule of Study Procedures and Assessments
Table 2: Study Procedures and Assessments: Screening and Run-In
See New wording column
Footnote “m” added to the table cell for FeNO (row) and 
S2/3 (column)
Clarification that FeNO assessment at 
this time point is not required
f FeNO should be completed before reversibility 
testing. Patients can repeat the FeNO assessment once 
to meet inclusion criterion “d” at a second time point 
during screening (within approximately 2 weeks of the 
initial screening visit), if the first assessment is not 
<25 ppb.
f FeNO should be completed before reversibility testing. 
Patients can repeat the FeNO assessment once to meet 
inclusion criterion “d” at a second time point during 
screening (within approximately 2 weeks of the initial 
screening visit), if the first assessment is not <25 ppb.
Clarification regarding timing of FeNO 
assessments
h Patients need to have signed the ICF before being 
asked to hold medications for reversibility testing. 
Therefore, initial reversibility testing may take place at 
a visit after the initial screening visit (see Section 
3.6.1.1 for additional details). Reversibility testing 
should only be attempted after withholding short acting 
bronchodilators (ie, inhaled short-acting beta-
adrenergic agonists and/or short-acting 
anticholinergics) for at least 6 hours and long-acting 
bronchodilators (ie, inhaled long-acting beta-adrenergic 
agonists and long-acting anticholinergic agents) for at 
least 12 or 24 hours, according to their labeled dose 
schedule. Patients who do not meet reversibility criteria 
(≥12% and ≥200 mL), may be re-tested once during the 
initial 2 weeks (±3 days) of the screening period.
h Patients need to have signed the ICF before being 
asked to hold medications for reversibility testing. 
Therefore, initial reversibility testing may take place at a 
visit after the initial screening visit (see Section 3.6.1.1
for additional details). Reversibility testing should only 
be attempted after withholding short acting 
bronchodilators (ie, inhaled short-acting beta-adrenergic 
agonists and/or short-acting anticholinergics) for at least 
6 hours and long-acting bronchodilators (ie, inhaled 
long-acting beta-adrenergic agonists and long-acting 
anticholinergic agents) for at least 12 or 24 hours, 
according to their labeled dose schedule. Patients who do 
not meet reversibility criteria (≥12% and ≥200 mL), may 
be re-tested once during the initial 2 weeks (±3 days) of 
the screening period.
Revised reversibility criteria 
k QuantiFERON® TB Gold Test (If the 
QuantiFERON® TB Gold Test is deemed by the 
principal investigator to be a false positive, additional 
samples will be tested to confirm diagnosis; see Section 
7.5.2 for details.)
k QuantiFERON® TB Gold Test (If the QuantiFERON®
TB Gold Test is deemed by the principal investigator to 
be a false positive, additional samples will be tested to 
confirm diagnosis; see Section 7.5.2 for details.)
Additional procedures to confirm TB 
diagnosis, if the QuantiFERON® TB 
Gold Test is suspected to be a false 
positive at screening


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Reason/Justification for change
3.6.1.1. Assessments and Procedures for Screening and Run-in
• Measure FeNO. The FeNO assessment can be 
repeated once to meet inclusion criterion “d” at a 
second time point during screening (within 
approximately 2 weeks of the initial screening visit), if 
the first assessment is not <25 ppb.
• Measure FeNO. The FeNO assessment can be 
repeated once to meet inclusion criterion “d” at a second 
time point during screening (within approximately 
2 weeks of the initial screening visit), if the first 
assessment is not <25 ppb.
Clarification regarding timing of FeNO 
assessments
4.1. Patient Inclusion Criteria
f. The patient has demonstrated ≥12% and ≥200 mL
response to a bronchodilator from baseline FEV1 
within 30 minutes after 4 inhalations of 
albuterol/salbutamol HFA MDI (90 mcg ex-actuator) 
or equivalent (eg, Ventolin) at screening.
f. The patient has demonstrated ≥12% and ≥200 mL 
response to a bronchodilator from baseline FEV1 within 
30 minutes after 4 inhalations of albuterol/salbutamol 
HFA MDI (90 mcg ex-actuator) or equivalent (eg, 
Ventolin) at screening.
Revised reversibility criteria 
g. The patient has asthma with a FEV1 ≥40% and 
<80% of the value predicted for age, height, sex, and 
race at screening. FEV1 must be performed using the 
office-based spirometer provided for the study.
g. The patient has asthma with a FEV1 ≥40% and <80% 
of the value predicted for age, height, sex, and race at 
screening. FEV1 must be performed using the office-
based spirometer provided for the study.
Clarification that handheld spirometers 
should not be used for FEV1 testing at 
screening
i. The patient’s background asthma therapy includes 
daily medium- or high-dose ICS plus LABA for at least 
3 months prior to the initial screening visit with or 
without other asthma controller medications. Medium-
and high-dose ICS classification will be based on the 
GINA Global Strategy for Asthma Management and 
Prevention (2019 update, Appendix C). Patients with 
asthma controller medications (excluding systemic 
corticosteroids and systemic immunomodulatory 
therapies) in addition to ICS+LABA may be eligible 
provided all eligibility criteria are met.
i. The patient’s background asthma therapy includes 
daily medium- or high-dose ICS plus LABA for at least 
3 months prior to the initial screening visit with or 
without other asthma controller medications. Medium-
and high-dose ICS classification will be based on the 
GINA Global Strategy for Asthma Management and 
Prevention (2019 update, Appendix C). Patients with 
asthma controller medications (excluding systemic 
corticosteroids and systemic immunomodulatory 
therapies) in addition to ICS+LABA may be eligible 
provided all eligibility criteria are met.
Clarification regarding background 
asthma therapy
j. The patient has had at least one documented clinical 
asthma exacerbation (worsening of asthma requiring 
systemic corticosteroids [oral or injected], or an 
emergency department visit due to asthma treated with 
systemic corticosteroids, or an inpatient hospitalization 
due to asthma) documented in the patient’s medical or 
pharmacy records in the 18 months prior to (but not 
within 30 days of) the initial screening visit. Only 
j. The patient has had at least one clinical asthma 
exacerbation (worsening of asthma requiring systemic 
corticosteroids [oral or injected], or an emergency 
department visit due to asthma treated with systemic 
corticosteroids, or an inpatient hospitalization due to 
asthma) documented in the patient’s medical or 
pharmacy records in the 18 months prior to (but not 
within 30 days of) the initial screening visit. Only 
Clarification that retrospective 
documentation of the patient's medical 
or pharmacy records is not acceptable


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clinical asthma exacerbations with historical
documentation in the patient’s medical or pharmacy 
records may count towards this criterion.
clinical asthma exacerbations with historical 
documentation in the patient’s medical or pharmacy 
records may count towards this criterion.
l. The patient is a non-smoker for ≥6 months with 
lifetime history ≤10 pack-years, with no current e-
cigarette or marijuana use. The patient must have a 
negative urine cotinine test at the screening visit.
l. The patient is a non-smoker for ≥6 months with 
lifetime history ≤10 pack-years, with no current e-
cigarette or marijuana use. The patient must have a 
negative urine cotinine test at the screening visit.
Clarification added to confirm patient is 
a non-smoker, with no current 
e-cigarette or marijuana use
p. ...Women of childbearing potential must have a 
negative β-HCG test result and practice a highly 
effective method of birth control (methods that can 
achieve a failure rate of less than 1% per year when 
used consistently and correctly, see Section 5.9) prior 
to IMP administration and until the EOS visit or 10 
weeks after last IMP dose, whichever is longer.
Male patients (including vasectomized) with WOCBP 
partners (whether pregnant or not) must use condoms 
prior to IMP administration and until the EOS visit or 
10 weeks after last IMP dose, whichever is longer.
p. ...Women of childbearing potential must have a 
negative β-HCG test result and practice a highly 
effective method of birth control (methods that can 
achieve a failure rate of less than 1% per year when used 
consistently and correctly, see Section 5.9) prior to IMP 
administration and until the EOS visit or 10 weeks after 
last IMP dose, whichever is longer.
Male patients (including vasectomized) with WOCBP 
partners (whether pregnant or not) must use condoms 
prior to IMP administration and until the EOS visit or 
10 weeks after last IMP dose, whichever is longer.
Minor editorial clarification
4.2. Patient Exclusion Criteria
c. The patient has any of the following medical conditions:
Tested positive for tuberculosis (TB) at screening by 
the QuantiFERON® TB Gold Test, or had a history of 
untreated latent or active TB. If the QuantiFERON®
TB Gold Test is deemed by the principal investigator to 
be a false positive, a repeat specimen shall be 
submitted; if the second test is also positive, the patient 
screen fails; if the second test is negative, a third test 
shall be submitted; if the third test agrees with the first 
test, the patient screen fails; if the third test agrees with 
second test, the patient is considered to be negative for 
TB; see Section 7.5.2 for details.
Tested positive for tuberculosis (TB) at screening by the 
QuantiFERON® TB Gold Test, or had a history of 
untreated latent or active TB. If the QuantiFERON® TB 
Gold Test is deemed by the principal investigator to be a 
false positive, a repeat specimen shall be submitted; if 
the second test is also positive, the patient screen fails; if 
the second test is negative, a third test shall be 
submitted; if the third test agrees with the first test, the 
patient screen fails; if the third test agrees with second 
test, the patient is considered to be negative for TB; see 
Section 7.5.2 for details.
Additional procedures to confirm TB 
diagnosis, if the QuantiFERON® TB 
Gold Test is suspected to be a false 
positive at screening


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5.6. Other Medicinal Products
5.6. Other Medicinal Products/Non Investigational 
Medicinal Products
5.6. Other Medicinal Products
All references to non-IMP were 
removed (deemed unnecessary for the 
study-provided inhalers)
Note that other medicinal product is mandated for use 
in this study; however, for the purposes of this study it 
is not considered an IMP but is termed “non IMP”.
Note that other medicinal product is mandated for use in 
this study; however, for the purposes of this study it is 
not considered an IMP.
All references to non-IMP were 
removed (deemed unnecessary for the 
study-provided inhalers)
5.9. Effective Methods of Birth Control
Bilateral tubal occlusion/ligation
Bilateral tubal occlusion/ligation
Bilateral tubal ligation added to list of 
effective birth control methods
5.10. Prior and Concomitant Medication or Therapy
See New wording column
Reslizumab
Reslizumab added to list of examples of 
systemic immunosuppressive or 
immunomodulatory agents
5.13.2. Blinding and Unblinding
See New wording column
Pharmacokinetic sample analysis by the bioanalytical 
laboratory and pharmacokinetic parameter calculations 
by pharmacokineticists will be performed during the 
course of the study. The population pharmacokinetic 
model for TEV-48574 may be updated with new 
pharmacokinetic data emerging from the ongoing study. 
The process to ensure study integrity, maintenance of the 
double blind, and the responsibilities of the relevant 
study personnel will be described in a pharmacokinetic 
analysis plan that will be approved prior to any data 
transfer, per the sponsor's relevant SOP(s) (eg, GBP-RD-
502 [Performing Pharmacokinetic Analyses While 
Maintaining the Blind]). A similar process could be 
implemented for the pharmacokinetic/pharmacodynamic 
model with updated pharmacokinetic and 
pharmacodynamic data, based on availability of the 
appropriate SOP.
Clarification that the population 
pharmacokinetic model (and potentially 
the pharmacokinetic/pharmacodynamic 
model, if appropriate) will be updated 
with emerging data during the study


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Reason/Justification for change
See New wording column
The JSRC will review data in a blinded fashion, as 
outlined in Appendix B.
An interim analysis (Section 9.12) will be conducted by 
an independent, unblinded statistician who is not a part 
of the study team. A group of the sponsor’s management 
team who are not a part of the study team may have 
access to the unblinded interim analysis results. A 
communication plan to ensure the maintenance of the 
study blind among the blinded personnel involved in the 
conduct of the study will be put in place prior to the 
interim analysis.
Addition of JSRC and interim analysis
7. ASSESSMENT OF SAFETY
Refer to Table 2 (screening and run-in), Table 3 
(treatment period), and Table 4 (follow-up) for the 
timing of assessments and procedures, and Appendix B 
(JSRC).
Refer to Table 2 (screening and run-in), Table 3 
(treatment period), Table 4 (follow-up) for the timing of 
assessments and procedures, and Appendix B (JSRC).
Addition of JSRC
7.1.2. Recording and Reporting of Adverse Events
The relationship of each adverse event to the IMP and 
non IMP to the device, as well as the severity and 
seriousness of each adverse event, as judged by the 
investigator, must be recorded as described below.
The relationship of each adverse event to the IMP and to 
the device, as well as the severity and seriousness of 
each adverse event, as judged by the investigator, must 
be recorded as described below.
All references to non-IMP were 
removed (deemed unnecessary for the 
study-provided inhalers)
7.1.4. Relationship of an Adverse Event to the Investigational Medicinal Product
The relationship of adverse events will be captured 
separately for the relationship to the IMP and/or the 
relationship to the non IMP and/or device. The 
relationship of an adverse event to the IMP and/or non
IMP and/or to the device will be determined according 
to the criteria in Table 6.
The relationship of adverse events will be captured 
separately for the relationship to the IMP and/or to the 
device. The relationship of an adverse event to the IMP 
and/or to the device will be determined according to the 
criteria in Table 6.
All references to non-IMP were 
removed (deemed unnecessary for the 
study-provided inhalers)


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Reason/Justification for change
Table 6: The Relationship of an Adverse Event to the IMP and/or Device Suspects
See New wording column
Table 6 has been revised as described below:

Table title updated from “The Relationship of an 
Adverse Event to the IMP and non-IMP Device 
suspects“ to ‘The Relationship of an Adverse Event 
to the IMP and/or Device Suspects”

All references to “IMP/non-IMP/device” have been 
replaced with “IMP/device”
All references to non-IMP were 
removed (deemed unnecessary for the 
study-provided inhalers)
7.1.5.3.1. Investigator Responsibility
The following information should be provided on the 
SAE/PDAESI form:

additional suspects that are not considered IMP (as 
applicable), including: dose and unit, frequency, 
route and form, start and stop date, indication and 
investigator’s assessment of the relationship of the 
adverse event to the suspect drug 

concomitant medication (including study-provided 
inhalers, doses, routes of administration, dates, and 
regimens) and

treatment of for the event.
The following information should be provided on the 
SAE/PDAESI form:

concomitant medication (including study-provided 
inhalers, doses, routes of administration, dates, and 
regimens)

treatment for the event
Clarification for concomitant 
medications including study-provided 
inhalers
Each report of a serious adverse event will be reviewed 
and evaluated by both the investigator and the sponsor 
to assess the nature of the event and the relationship of 
the event to the IMP and to underlying disease.
In addition, the investigator will assess whether the 
etiology of the event is associated with the patient's 
primary condition, concomitant medications (including 
study-provided inhalers), or any other condition.
Each report of a serious adverse event will be reviewed 
and evaluated by both the investigator and the sponsor to 
assess the nature of the event and the relationship of the 
event to the IMP.
In addition, the investigator will assess whether the 
etiology of the event is associated with the patient's 
primary condition, concomitant medications (including 
study-provided inhalers), or any other condition.
Clarification for concomitant 
medications including study-provided 
inhalers
7.2. Adverse Device Effects (New section)
See New wording column
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 
Text updated for consistency with the 
protocol template.


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Reason/Justification for change
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.
7.2.1. Adverse Device Effect Reporting (New section)
See New wording column
Adverse device effects (Figure 2) must be recorded on 
both 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 device 
deficiency and will categorize each as guided in Section 
7.2.
The investigator should make an initial determination 
whether the adverse event may be related to a device 
deficiency (Section 7.1.4).
Adverse device effects and device deficiencies will be 
listed in the clinical study report (CSR).
Text updated for consistency with the 
protocol template.
7.2.2. Serious Adverse Device Effects (New section)
See New wording column
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).
Text updated for consistency with the 
protocol template.
7.2.2.1. Serious Adverse Device Effect Reporting (New section)
See New wording column
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 
Text updated for consistency with the 
protocol template.


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New wording
Reason/Justification for change
sponsor using the appropriate form according to national 
and local regulations.
The investigator should make an initial determination 
whether the serious adverse event may be related to a 
device deficiency.
See New wording column
New Figure 2 (Decision Tree for Adverse Events and 
Adverse Device Effects Classification) was added
Text updated for consistency with the 
protocol template.
7.5.2. Other Clinical Laboratory Tests
See New wording column
If the QuantiFERON® TB Gold Test is negative at 
screening, then the patient may proceed in the screening 
period. However, if the QuantiFERON® TB Gold Test is 
deemed by the principal investigator to be a false 
positive at screening, then a second sample should be 
drawn and the following steps taken:

If the second QuantiFERON® TB Gold Test is 
positive (ie, results match the first test), then the 
patient will be a screen failure.

If the second QuantiFERON® TB Gold Test is 
negative (ie, results do not match the first test), 
then a third sample should be drawn.

If the third QuantiFERON® TB Gold Test is 
positive (ie, results match the first test), then 
the patient will be a screen failure.

If the third QuantiFERON® TB Gold Test is 
negative (ie, results match the second test), 
then the patient may proceed in the 
screening period.

Note that sites may choose to split the second 
and third samples and send one to the central 
laboratory and one to a local laboratory. 
Additional procedures to confirm TB 
diagnosis, if the QuantiFERON® TB 
Gold Test is suspected to be a false 
positive at screening


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Reason/Justification for change
However, the local lab result may not be used for 
decision making.
9.1. Sample Size and Power Considerations
Based on the assumptions above, and assuming a 15% 
dropout rate during the study, 62 randomized patients 
per treatment group will provide 80% power to detect a 
treatment effect of 60% reduction in LoAC rate in the 
TEV-48574 group using a Chi-square test with one-
sided alpha (Type I error rate) of 0.1.
Based on the assumptions above, and assuming a 15% 
dropout rate during the study, 62 randomized patients 
per treatment group will provide 80% power to detect a 
treatment effect of 60% reduction in LoAC rate in the 
TEV-48574 group using a Chi-square test with one-sided 
alpha (Type I error rate) of 0.1.
Type of statistical test used in the 
sample size calculation was added
An unblinded interim analysis may be performed is 
planned to re-assess the sample size and conduct a 
futility analysis as described in Section 9.13.
An unblinded interim analysis is planned to re-assess the 
sample size and conduct a futility analysis as described 
in Section 9.13.
Addition of futility analysis
9.12. Planned Interim Analyses
An unblinded interim analysis is planned after the first 
52 randomized patients have completed the treatment 
period, experienced LoAC, or withdrawn from the 
study completely, an interim analysis may be 
performed on the unblinded data. The main purposes of 
the interim analysis include sample size re-assessment 
and futility analysis, as described below.
The assumed LoAC event rate in the placebo group is 
0.270. If the actual placebo event rate is lower than 
expected, the study will be underpowered to detect a
60% reduction in event rate. At the interim analysis, if 
the observed placebo event rate is lower than expected, 
and the observed treatment effect is at least a 40% 
reduction (event rate ratio ≤0.6), the sample size may 
be increased by up to 50 additional randomized 
patients, from the initially planned 124 to up to 174. 
This procedure corresponds to a Promising Zone 
methodology and does not increase the Type I error 
rate (Mehta and Pocock 2011). Details will be provided 
in a separate Interim Analysis Statistical Analysis Plan.
The interim futility analysis comprises a statistical 
comparison between treatment group versus placebo in 
An unblinded interim analysis is planned after the first 
52 randomized patients have completed the treatment 
period, experienced LoAC, or withdrawn from the study 
completely. The main purposes of the interim analysis 
include sample size re-assessment and futility analysis, 
as described below.
The assumed LoAC event rate in the placebo group is 
0.270. If the actual placebo event rate is lower than 
expected, the study will be underpowered to detect a 
60% reduction in event rate. At the interim analysis, if 
the observed placebo event rate is lower than expected, 
and the observed treatment effect is at least a 40% 
reduction (event rate ratio ≤0.6), the sample size may be 
increased by up to 50 additional randomized patients, 
from the initially planned 124 to up to 174. This 
procedure corresponds to a Promising Zone 
methodology and does not increase the Type I error rate 
(Mehta and Pocock 2011).
The interim futility analysis comprises a statistical 
comparison between treatment group versus placebo in 
LoAC rate using logistic regression with fixed effect for 
treatment among the 52 randomized patients who have 
Addition of futility analysis


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Reason/Justification for change
LoAC rate using logistic regression with fixed effect 
for treatment among the 52 randomized patients who 
have completed the treatment period, experienced 
LoAC, or withdrawn from the study completely. A p-
value above 0.5 will be declared as treatment efficacy 
futility, which could potentially result in early 
termination of the trial. According to simulation 
analyses, this cutoff value yields a correct early 
termination rate of 0.44 (under the null hypothesis) and 
controls incorrect early termination rate at 
approximately 0.04 (under the alternative hypothesis of 
true risk ratio=0.4). More details will be provided in a 
separate Interim Analysis Statistical Analysis Plan that 
will be finalized prior to the interim analysis.
If performed, The interim analysis will be conducted 
by an independent, unblinded statistician who is not a 
part of the study team, and the final sample size will be 
reported. A group of the sponsor’s management team 
who are not a part of the study team may have access to 
the unblinded interim analysis results. A 
communication plan to ensure the maintenance of the 
study blind among the blinded personnel involved in 
the conduct of the study will be put in place prior to the 
interim analysis.
completed the treatment period, experienced LoAC, or 
withdrawn from the study completely. A p-value above 
0.5 will be declared as treatment efficacy futility, which 
could potentially result in early termination of the trial. 
According to simulation analyses, this cutoff value 
yields a correct early termination rate of 0.44 (under the 
null hypothesis) and controls incorrect early termination 
rate at approximately 0.04 (under the alternative 
hypothesis of true risk ratio=0.4). More details will be 
provided in a separate Interim Statistical Analysis Plan 
that will be finalized prior to the interim analysis.
The interim analysis will be conducted by an 
independent, unblinded statistician who is not a part of 
the study team. A group of the sponsor’s management 
team who are not a part of the study team may have 
access to the unblinded interim analysis results. A 
communication plan to ensure the maintenance of the 
study blind among the blinded personnel involved in the 
conduct of the study will be put in place prior to the 
interim analysis.
14. REFERENCES
See New wording column
Mehta CR, Pocock SJ. Adaptive increase in sample size 
when interim results are promising: a practical guide 
with examples. Stat Med 2011;30(28):3267-84.
Reference added
APPENDIX A. STUDY REPRESENTATIVES, CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND INSTITUTIONS
Updated the Legal Representative of the 
Sponsor in the EU


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New wording
Reason/Justification for change
Teva Specialty R&D
Phone: 
Email: 
Teva Specialty R&D
 
Phone: 
Email: 
 
Phone: 
Cell: 
Email: 
 Clinical Development, 
Teva Pharmaceuticals
Cell: 
Email: 
 Clinical Development, 
Teva Pharmaceuticals
Cell: 
Email: 
Updated the Sponsor’s Medical Expert


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Original text with changes shown
New wording
Reason/Justification for change
APPENDIX B. JOINT SAFETY REVIEW COMMITTEE (New appendix)
See New wording column
During the conduct of this study, a JSRC will review 
accumulating safety data in a blinded manner at 2 
scheduled time points, as described below, to ensure the 
continuing safety of the study patients and to monitor 
study conduct issues.
The JSRC will be composed (at a minimum) of ≥1 of the 
study principal investigators, the study medical monitor 
or designee, the sponsor’s clinical lead, and the 
sponsor’s responsible pharmacovigilance physician. 
External consultants with relevant expertise may also be 
engaged as part of the JSRC, as applicable.
The JSRC will convene and review all available safety 
data after 20 patients (approximately 10 patients on IMP 
and 10 patients on placebo) have completed 8 weeks of 
treatment. A subsequent review will be convened after 
50% of randomized patients (approximately 31 patients 
on IMP and 31 patients on placebo) have completed 
8 weeks of treatment. A summary of the data will be 
reviewed in a blinded fashion. The JSRC will 
recommend whether to continue the study as designed, 
conduct protocol/ICF modifications, temporarily 
suspend enrollment and/or study intervention until some 
uncertainty is resolved, or discontinue the study.
The JSRC may also convene at any time during the 
study at the discretion of any of the JSRC members if 
new and pertinent safety issues arise.
The JSRC will document its recommendations with 
rationale and inform the study team as appropriate.
Additional details on the conduct of the JSRC sessions 
are outlined in the JSRC charter.
Addition of JSRC
APPENDIX G. PRODUCT COMPLAINTS
I. Clinical Product Complaints/Device Deficiency
I. Clinical Product Complaints/Device Deficiency
Text updated for consistency with the 
protocol template.


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Reason/Justification for change
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 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.
Text updated for consistency with the 
protocol template.
Handling of Investigational Medicinal Product(s) and 
Devices at the Investigational Center(s)
Handling of Investigational Medicinal Product(s) and 
Devices at the Investigational Center(s)
Text updated for consistency with the 
protocol template.
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.
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.
Text updated for consistency with the 
protocol template.
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.
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.
Text updated for consistency with the 
protocol template.
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.
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.
Text updated for consistency with the 
protocol template.


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Original text with changes shown
New wording
Reason/Justification for change
See New wording column
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 with respect to its 
identity, quality, durability, reliability, safety, or 
performance (Appendix Figure 1). This definition 
includes malfunctions, use errors, inadequate labeling 
(eg, unintelligible label, incorrect expiry date), and 
product complaints that are related to the device.
The investigator should make an initial determination 
whether the device deficiency could have led to a serious 
adverse event and notify the sponsor by completing the 
product complaint form provided by Teva and emailing
it to clinical.productcomplaints@tevapharm.com.
Device deficiencies with potential serious adverse device 
effect are defined as deficiencies that might have led to a 
serious adverse device effect if (Appendix Figure 1):

suitable action had not been taken (or)

intervention had not been made (or)

circumstances had been less fortunate
Text updated for consistency with the 
protocol template.
See New wording column
New Appendix Figure 1 (Decision Tree for Device 
Deficiencies) was added
Text updated for consistency with the 
protocol template.


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15.4.
Administrative Letter 01 Dated 13 October 2020
ADMINISTRATIVE LETTER 01
Study number: TV48574-AS-20031
Clinical Study Protocol
A 16-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Proof-of-Concept 
Study to Evaluate the Efficacy and Safety of TEV-48574 in Adults with T2-low/non-T2 Severe 
Uncontrolled Asthma, version dated 28 May 2020
IND number: 133677; EudraCT number: 2020-001927-15
13 October 2020
Dear Investigator:
The purpose of this letter is to clarify the procedures for the QuantiFERON® tuberculosis (TB) 
testing at screening. As per patient exclusion criteria (c), described in Section 4.2 of the protocol, 
a patient would be excluded if they tested positive for TB at screening by the QuantiFERON®
TB Gold Test or had a history of latent or active TB. In order to protect against false positives, 
the steps outlined below should be followed when the QuantiFERON® TB Gold Test is drawn at 
screening and sent to the central laboratory:

If the first QuantiFERON® TB Gold Test is negative, then the patient may proceed in 
the screening period.

If the first QuantiFERON® TB Gold Test is positive, then a second sample should be 
drawn and sent to the central laboratory.

If the second QuantiFERON® TB Gold Test is positive (ie, results match the first 
test), then the patient will be a screen failure.

If the second QuantiFERON® TB Gold Test is negative (ie, results do not match 
the first test), then a third sample should be drawn and sent to the central 
laboratory.
○
If the third QuantiFERON® TB Gold Test is positive (ie, results match the 
first test), then the patient will be a screen failure.
○
If the third QuantiFERON® TB Gold Test is negative (ie, results match the 
second test), then the patient may proceed in the screening period.

Note that sites may choose to split the second and third samples and send one to 
the central laboratory and one to a local laboratory. However, the local laboratory 
result may not be used for decision making.


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This change will be incorporated into the protocol during the next amendment, as applicable. 
Please ensure that this letter is maintained with the study protocol. Also, please provide a copy of 
this letter to your Institutional Review Board/Independent Ethics Committee for review and 
acknowledgement.
Please feel free to contact 
 if you have 
any questions or concerns regarding this letter.
Sincerely,
___________________________________
Clinical Development
Teva Pharmaceuticals


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APPENDIX A. STUDY REPRESENTATIVES, CLINICAL 
LABORATORIES AND OTHER DEPARTMENTS AND 
INSTITUTIONS
Sponsor’s Authorized Representative
 
Teva Pharmaceuticals
Legal Representative of the Sponsor in the EU
Teva Specialty R&D
Sponsor’s Medical Expert/Contact Point 
designated by the Sponsor for Further 
Information on the Study
For serious adverse events:
Send by email to the local safety officer/contract 
research organization (LSO/CRO). The email address 
will be provided in the serious adverse event report 
form. In the event of difficulty transmitting the form, 
an email address will be provided in the SAE 
management plan.
 Clinical Development, 
Teva Pharmaceuticals 
Contract Research Organization
ICON Clinical Research
South County Business Park
Leopardstown
Dublin 18, Ireland
Phone: +353 (1) 291 2000
Electronic Data Capture
Medidata Solutions, Inc.
350 Hudson Street
9th Floor
New York, New York 10014 USA


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212-918-1800 
www.mdsol.com
Central Clinical Laboratory
ICON PLC
South County Business Park
Leopardstown
Dublin 18, Ireland
Phone: +353 (1) 291 2000
Spirometry Evaluation
Vitalograph Ltd
Vitalograph Business Park 
Maids Moreton 
Buckingham 
MK18 1SW
England
Phone: +44(0) 1280 827110
Central Electrocardiogram Evaluation
Vitalograph Ltd
Vitalograph Business Park 
Maids Moreton 
Buckingham 
MK18 1SW
England
Phone: +44(0) 1280 827110
E-Diary 
Vitalograph Ltd
Vitalograph Business Park 
Maids Moreton 
Buckingham 
MK18 1SW
England
Phone: +44(0) 1280 827110
Bioanalytical Pharmacokinetics Evaluation
Bioanalytical Immunogenicity Evaluation


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Pharmacogenomics Evaluation 
Serum TL1a Samples
Randomization and Trial Supply Management 
(RTSM) vendor
Parexel International Corporation


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APPENDIX B. JOINT DATA MONITORING COMMITTEE
During the conduct of this study, a JDMC will review accumulating safety data in a blinded 
manner at 2 scheduled time points, as described below, to ensure the continuing safety of the 
study patients and to monitor study conduct issues.
The JDMC will be composed (at a minimum) of ≥1 of the study principal investigators, the study 
medical monitor or designee, the sponsor’s clinical lead, and the sponsor’s responsible
pharmacovigilance physician. External consultants with relevant expertise may also be engaged 
as part of the JDMC, as applicable.
The JDMC will convene and review all available safety data after 20 patients (approximately 
10 patients on IMP and 10 patients on placebo) have completed 8 weeks of treatment. A 
subsequent review will be convened after 50% of randomized patients (approximately 
31 patients on IMP and 31 patients on placebo) have completed 8 weeks of treatment. A 
summary of the data will be reviewed in a blinded fashion. The JDMC will recommend whether 
to continue the study as designed, conduct protocol/ICF modifications, temporarily suspend 
enrollment and/or study intervention until some uncertainty is resolved, or discontinue the study.
The JDMC may also convene at any time during the study at the discretion of any of the JDMC 
members if new and pertinent safety issues arise.
The JDMC will document its recommendations with rationale and inform the study team as 
appropriate.
Additional details on the conduct of the JDMC sessions are outlined in the JDMC charter.


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APPENDIX C. CLASSIFICATION OF INHALED CORTICOSTEROIDS
Classification of ICS into low-, medium- and high-dose will be performed using the 
classification provided in GINA Global Strategy for Asthma Management and Prevention (2019 
update), summarized in the following table.
Table 9:
Classification of ICS into low/medium/high dose
Drug
Daily dose (µg)
Low
Medium
High
Beclomethasone dipropionate (CFC)*
200–500
>500–1000
>1000
Beclomethasone dipropionate (HFA)
100–200
>200–400
>400
Budesonide (DPI)
200–400
>400–800
>800
Ciclesonide (HFA)
80–160
>160–320
>320
Fluticasone furoate (DPI)
100
Not applicable
200
Fluticasone propionate (DPI)
100–250
>250–500
>500
Fluticasone propionate (HFA)
100–250
>250–500
>500
Mometasone furoate
110–220
>220–440
>440
Triamcinolone acetonide
400–1000
>1000–2000
>2000
CFC=chlorofluorocarbon propellant; DPI=dry powder inhaler; HFA=hydrofluoroalkane propellant
*Beclometasone dipropionate CFC is included for comparison with older literature


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APPENDIX D. 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 nonsubstantial 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.


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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 
SOPs, 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 monitor(s) 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 ICF are warranted, in accordance with IEC/IRB 
approvals.
The study monitor(s) 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.
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.


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APPENDIX E. 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 the 
patient is free to refuse participation in the study and free to withdraw from the study at any time 
without prejudice to future treatment.
A separate informed consent will be obtained for pharmacogenomic testing.
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 F.
ASTHMA CONTROL QUESTIONNAIRE
(Sample provided in this appendix is provided as an example only.)


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APPENDIX G. 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

product name and strength for open-label studies

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


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
description or nature of complaint

associated 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.
Handling of Investigational Medicinal Product(s) and Devices 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 return 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.
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 with 
respect to its identity, quality, durability, reliability, safety, or performance (Appendix Figure 1). 
This definition includes malfunctions, use errors, inadequate labeling (eg, unintelligible label, 
incorrect expiry date), and product complaints that are related to the device.


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The investigator should make an initial determination whether the device deficiency could have 
led to a serious adverse event and notify the sponsor by completing the product complaint form 
provided by Teva and emailing it to clinical.productcomplaints@tevapharm.com.
Device deficiencies with potential serious adverse device effect are defined as deficiencies that 
might have led to a serious adverse device effect if (Appendix Figure 1):

suitable action had not been taken (or)

intervention had not been made (or)

circumstances had been less fortunate
Appendix Figure 1: Decision Tree for Device Deficiencies
IEC=Independent Ethics Committee; IRB=Institutional Review Board; SAE=serious adverse event.


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APPENDIX H. 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 21CFR 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 acknowledgement 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 ICFs

patient identification lists

case report forms 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 IMPs

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 I.
LIST OF EXAMPLES OF OPPORTUNISTIC 
INFECTIONS

Bacterial enteric infections

Bartonellosis

Candidiasis (excluding vulvovaginal candidiasis)

Chagas disease

Coccidioidomycosis

Cryptococcosis

Cryptosporidiosis

Cystoisosporiasis (Formerly Isosporiasis)

Cytomegalovirus Disease

Hepatitis B Virus Infection

Hepatitis C Virus Infection

Herpes Simplex Virus

Histoplasmosis

Human Herpesvirus-8

Human Papillomavirus

Leishmaniasis

Malaria

Microsporidiosis

Mycobacterium avium 

Mycobacterium tuberculosis

Pneumocystis Pneumonia

Progressive Multifocal Leukoencephalopathy/JC Virus Infection

Syphilis

Talaromycosis (Formerly Penicilliosis)

Toxoplasma gondii

Varicella-Zoster Virus
Any suspected opportunistic infections (ie, infections that occur more frequently and are more 
severe than expected) are to be reported.
Further details are available in “Guidelines for Prevention and Treatment of Opportunistic 
Infections in HIV-Infected Adults and Adolescents”. Available at: 


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https://aidsinfo.nih.gov/guidelines/html/4/adult-and-adolescent-opportunistic-infection/0). 
Accessed 20-May-2020. Community-acquired pneumonia and vulvovaginal candidiasis were 
removed from the list above as they may be expected in the study patient population.


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Appendix J.
MANAGEMENT OF STUDY ACTIVITIES DURING 
COVID-19 OUTBREAKS
This appendix is to address the modifications set-up in study conduct during coronavirus disease 
2019 (COVID-19) outbreaks.
The changes will be effective for the period of the COVID-19 outbreaks and will be 
implemented exclusively at the sites impacted by COVID-19. When the situation at specific 
sites/countries allows the return to regular study activities, the full protocol will govern the study 
for all sites including those impacted by COVID-19. 
The following sections of the protocol are affected:
Section 1.3.
Known and Potential Benefits and Risks of the Test Investigational 
Medicinal Product
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. 
It should be noted that patients diagnosed with active or residual COVID-19 or were hospitalized 
in ICU during COVID 19 infection would not be included in the study as they would meet 
exclusion criterion “a” and “c”.
The effect of TEV 48574 on the response to vaccines in general and specifically to COVID-19 
vaccines is unknown. All live/attenuated vaccines are disallowed 14 days prior to IMP 
administration and throughout the study. The completion of planned inactivated vaccinations 
(including approved COVID-19 inactivated vaccinations) is preferable at least 14 days before 
first IMP dose, if possible. Inactivated vaccination during the study is recommended to be at 
least 3 days before and after IMP administration, if possible.
If a patient exhibits clinical symptoms during the study that may indicate COVID-19 infection, 
the patient will be tested for active COVID-19 infection. If the patient tests positive, the patient 
will be discontinued from IMP and will attend for an ET visit. Remote assessment of safety via 
teleconference (TC) and/or videoconference (VC), with VC being the preferred method, is 
recommended until the patient attends for the ET visit.
Section 3.1. General Study Design and Study Schematic Diagram; Section 3.6. 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), the patient will be discontinued from IMP, 
will continue with daily hand-held spirometry and e-diary completion, scheduled adverse event 
and concomitant medication monitoring will be continued, and the patient will attend for an ET 
visit when that becomes possible. Remote assessment of safety via teleconference (TC) and/or 
videoconference (VC), with VC being the preferred method, is recommended until the patient 
attends for the ET visit. All other tests (including safety labs, pharmacokinetics, ADA, and 


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 [if applicable and only in patients who do not have active COVID-19 infection]) are 
to be conducted once the patient can return to the study center for the ET visit.
In the event that a patient completes the run-in but cannot come to the site for the DoR visit for 
randomization (eg, due to quarantine, isolation, patient's concern, or closure of the site clinic), it 
may be possible to extend the duration of run-in on a case-by-case basis, following discussion 
between the investigator and the sponsor study physician. Re-screening of the patient will also be 
allowed.
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 4.2 Patient Exclusion Criteria; Section 5.10. Prior and Concomitant Medication or 
Therapy
The eligibility criteria and list of prohibited medications can be updated to reflect new data on 
COVID-19 therapies or vaccines. If a patient receives new COVID-19 therapies or vaccines not 
in compliance with the eligibility criteria and list of prohibited medications at the time of the 
patient’s participation in the study, the investigator and sponsor will discuss how to proceed on a 
case-by-case basis.
Section 4.5 Replacement of Patients
In the event of an emergency situation (eg, COVID-19 outbreaks), in case the proportion of 
patients who terminate the study early due to reasons other than loss of asthma control exceeds 
the anticipated 15%, the number of patients to be randomized may be increased to ensure the 
targeted number of completers per arm. 
Section 5.13. Maintenance of Randomization and Blinding
Unblinded data review of COVID-19 patients by the JDMC may be conducted upon JDMC 
recommendations and Teva’s discretion. 
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), the patient will be discontinued from IMP, 
will continue with daily hand-held spirometry and e-diary completion, remote monitoring for 
asthma-specific alerts will continue, and the patient will attend for an ET visit when that
becomes possible.
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 (ie, inquiries 
regarding adverse events and use of concomitant medication) via TC and/or VC, with VC being 


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the preferred method, may be allowed. The results will be directly entered into the eCRF per the 
usual process.
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 7.4. Clinical Laboratory Tests
For ET patients (patients who cannot be administered the IMP), all required samples scheduled 
for ET will be collected once the patient can return to the study center.  
Section 8. ASSESSMENT OF PHARMACOKINETICS, PHARMACOGENOMICS, 
IMMUNOGENICITY AND 
If pharmacokinetic, pharmacogenomics, immunogenicity, and/or 
 samples cannot be 
collected due to limitations in ability to carry out the procedure or limitations in storage and 
shipments, the 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 lab and will not be shipped to Teva 
bioanalytical laboratories nor analyzed. Teva bioanalytical laboratories will be informed within a 
week of any COVID-19 positive patients confirmed after samples being collected. 
Section 9.6.1.2. Sensitivity Analysis
Sensitivity and supplementary analyses will be conducted to evaluate the impact of the change to 
remote monitoring (TC/VC visits) and the impact of COVID-19 on LoAC rates. The analysis 
will include subgroup analysis (eg, pre, during, and post-COVID-19 outbreak, where each 
patient will be classified into one of the levels), a multivariate model (eg, Cox regression with 
time dependent covariates for COVID-19 and/or use of remote monitoring), and/or imputation 
methodology for patients' attrition due to the COVID-19, as appropriate and if data permit. 
Details of the supplementary and sensitivity analyses will be presented in the statistical analysis 
plan or addendum thereof, following a blinded review meeting prior to database lock.
Section 10. 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 
treatment with investigational medicinal product and/or study, alternative procedures used to 
collect critical safety and/or efficacy data, etc), will be described in the appropriate sections of 
the Clinical Study Report (CSR), as applicable.
Appendix D. Quality Control and Quality Assurance
Important Protocol Deviations
Deviations from the study conduct due to emergency situations (eg, COVID-19 outbreaks), 
including implemented contingency measures and their impact (eg, patient discontinuation from 
treatment with investigational medicinal product and/or 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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Study Monitoring
In case of an emergency situation (eg, COVID-19 outbreaks), monitors may not be able to access 
the investigational centers for on-site visits in a timely manner. A remote monitoring risk 
mitigation plan will be utilized for sites where on-site monitoring visits are not permitted due to 
an increased public health risk, in accordance with IRB/EC approval and current guidance 
(GUIDANCE, 2021). Details are provided in the monitoring plan.


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Appendix K.
Rules for Pulmonary Function Testing 
PFTs – When should you continue to test your subjects? 
The protocol and pulmonary function testing equipment indicates when it is okay to continue 
testing your subjects for the TEV-48574 trial. Here are some guidelines for you to follow with 
your subjects: 
1. Pulmonary function testing MUST follow ATS (American Thoracic Society) 
Standards (Graham 2019)
This means: 
a) At least 3 good quality spirometry efforts must be done for every spirometry session. 
b) You can do up to 8 efforts to achieve this 3 good quality effort requirement 
c) The values from the top 2 spirometry efforts MUST BE WITHIN 150 mLs of each 
other. This applies to both FEV1 and FVC. 
d) When you are done with the Pre-BD spirometry, the Spirotrac will give you an alert IF 
the Pre-BD efforts did NOT meet the ATS standards.  STOP TESTING. You should not 
perform post-BD spirometry 
2. Protocol Criteria 
a) The best FEV1 obtained at the screening visit, and at the Day of Randomization visit, 
MUST BE WITHIN 30% and 80%. Values outside of this range means the subject 
should stop testing. 
b) If this out of range PFT testing occurs at screening, the PFT testing must stop, and the 
subject can return within 2 weeks to try again to meet the spirometry entrance criteria.  
c) If this excursion of PFTs occurs on the Day of Randomization, the subject is a 
Randomization Failure, but may come back once again to rescreen for the study.
3. Retesting for Reversibility 
a) If the subject has done acceptable and repeatable spirometry for the Pre-BD testing at 
visit S1, and the subject cannot reverse at least 12% after bronchodilator 
administration at this S1 visit, then the subject is allowed to return to the office within 
two weeks after initial Screening visit, to try again to meet the spirometry criteria. 
b) Again, spirometry must also meet the ATS standards and the Protocol standards 
identified above.

SAP_001.pdf: 
 
 
 
 
Statistical Analysis Plan 
 
 
A 16-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, 
Proof-of-Concept Study to Evaluate the Efficacy and Safety of TEV-48574 in 
Adults with T2-low/non-T2 Severe Uncontrolled Asthma 
 
 
Study Number TV48574-AS-20031 
 
 
NCT04545385 
 
 
SAP Approval Date: 22 November 2021 


Placebo-Controlled–Asthma
Statistical Analysis Plan
Study TV48574-AS-20031
1
Statistical Analysis Plan
 
Study Number TV48574-AS-20031
A 16-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Proof-of-
Concept Study to Evaluate the Efficacy and Safety of TEV-48574 in Adults with T2-
low/non-T2 Severe Uncontrolled Asthma
Proof of Concept Study (Phase 2a)
IND number: 133677;
EudraCT number: 2020-001927-15
Approval Date: 22 November 2021
Sponsor
Teva Branded Pharmaceutical
Products R&D, Inc. 
145 Brandywine Parkway
West Chester, Pennsylvania 19380
United States of America
Prepared by:
and 
Teva Global Statistics


Placebo-Controlled–Asthma
Statistical Analysis Plan
Study TV48574-AS-20031
2
STATISTICAL ANALYSIS PLAN APPROVAL
Study No.:
TV48574-AS-20031
Study Title:
A 16-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, 
Proof-of-Concept Study to Evaluate the Efficacy and Safety of TEV-48574 in Adults with 
T2-low/non-T2 Severe Uncontrolled Asthma
Statistical Analysis Plan for:
Interim Analysis
Integrated Summary of Efficacy
Final Analysis
Integrated Summary of Safety
Amendment: 0
Authors:
, Teva Global Statistics 
, Teva Global Statistics 
______________________________________________________________________________
Approver:
, 
     
                        Date
                       
 
                       
, Global Statistics
____________
__
_
______________________________________
Approver:  
, 
, 
     
Date                     
                        
, Global Specialty R&D,
                        
 
______________________________________________________________________________


Placebo-Controlled–Asthma
Statistical Analysis Plan
Study TV48574-AS-20031
3
TABLE OF CONTENTS
TITLE PAGE...................................................................................................................................1
STATISTICAL ANALYSIS PLAN APPROVAL..........................................................................2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................................7
INTRODUCTION ...........................................................................................................................9
1.
STUDY ENDPOINTS................................................................................................10
1.1.
Primary Efficacy Endpoints........................................................................................10
1.2.
Secondary Efficacy Endpoints....................................................................................10
1.3.
Safety Endpoints.........................................................................................................10
1.4.
Device-Related Events................................................................................................11
1.5.
Pharmacokinetic Assessment......................................................................................11
1.6.
Immunogenicity Assessment Endpoints.....................................................................11
1.7.
Estimand for Primary Efficacy Endpoint ...................................................................11
2.
STUDY DESIGN .......................................................................................................13
2.1.
General Design ...........................................................................................................13
2.2.
Randomization and Blinding......................................................................................14
2.3.
Joint Safety Review Committee .................................................................................15
2.4.
Sample Size and Power Considerations .....................................................................15
2.5.
Sequence of Planned Analyses ...................................................................................16
2.5.1.
Planned Interim Analyses...........................................................................................16
2.5.2.
Final Analyses and Reporting.....................................................................................16
3.
ANALYSIS SETS ......................................................................................................17
3.1.
Intent-to-Treat Analysis Set........................................................................................17
3.2.
Modified Intent-to-Treat Analysis Set........................................................................17
3.3.
Safety Analysis Set.....................................................................................................17
3.4.
Per-Protocol Analysis Set...........................................................................................17
3.5.
Pharmacokinetic Analysis Set ....................................................................................18
4.
GENERAL ISSUES FOR DATA ANALYSIS..........................................................19
4.1.
General........................................................................................................................19
4.2.
Specification of Baseline Values................................................................................19
4.3.
Handling Withdrawals and Missing Data...................................................................19
4.4.
Study Days and Visits.................................................................................................19


Placebo-Controlled–Asthma
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Study TV48574-AS-20031
4
5.
STUDY POPULATION.............................................................................................21
5.1.
General........................................................................................................................21
5.2.
Patient Disposition......................................................................................................21
5.3.
Demographics and Baseline Characteristics...............................................................21
5.4.
Medical History ..........................................................................................................22
5.5.
Prior Therapy and Medication....................................................................................22
5.6.
Childbearing Potential and Methods of Contraception ..............................................22
5.7.
Physical Examinations................................................................................................22
5.8.
Study Protocol Deviations..........................................................................................22
6.
EFFICACY ANALYSIS ............................................................................................23
6.1.
General........................................................................................................................23
6.1.1.
Analysis Windows for E-diary Data...........................................................................23
6.2.
Primary Efficacy Endpoint and Analysis ...................................................................24
6.2.1.
Definition....................................................................................................................24
6.2.2.
Primary Efficacy Analysis..........................................................................................24
6.2.3.
Subgroup Analysis......................................................................................................25
6.2.4.
Sensitivity Analysis for the Primary Efficacy Endpoint.............................................25
6.2.4.1.
Sensitivity Analysis Using Multiple Imputations.......................................................25
6.3.
Key Secondary Efficacy Endpoints and Analyses......................................................26
6.3.1.
Time from Randomization to LoAC During Treatment Period .................................26
6.3.2.
Asthma Control Questionnaire 6-Question Version (ACQ-6) at End of 
Treatment (EOT) and Throughout Study ...................................................................27
6.3.3.
Forced Expiratory Volume in First Second (FEV1) (% Predicted, L) at EOT 
and Throughout Study ................................................................................................28
6.3.4.
Use of SABA Quick Relief Medication at EOT and Throughout Study....................29
6.4.
Other Secondary Efficacy Endpoints and Analyses ...................................................29
6.4.1.
Proportion of Patients Who Have a CAE During Treatment Period..........................30
6.4.2.
Time from Randomization to First CAE During Treatment Period...........................30
6.4.3.
Number of Nighttime Awakenings Due to Asthma During Treatment Period ..........30
6.4.4.
Percent Decrease in ICS Dose During Treatment Period...........................................31
6.4.5.
Other Lung Function Parameters as Assessed by Hand-Held Spirometry at 
End of Treatment and Throughout the Study .............................................................32
6.4.6.
Fractional Exhaled Nitric Oxide Throughout the Study.............................................33


Placebo-Controlled–Asthma
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7.
MULTIPLE COMPARISONS AND MULTIPLICITY ............................................34
8.
SAFETY ANALYSIS ................................................................................................35
8.1.
General........................................................................................................................35
8.2.
Duration of Exposure to Study Drug..........................................................................35
8.3.
Adverse Events ...........................................................................................................35
8.4.
Hypersensitivity/Anaphylaxis.....................................................................................37
8.5.
Deaths .........................................................................................................................37
8.6.
Clinical Laboratory Tests ...........................................................................................37
8.6.1.
Other Clinical Laboratory Tests .................................................................................38
8.6.2.
Laboratory Values Meeting Hy’s Law Criteria..........................................................38
8.7.
Physical Examinations................................................................................................39
8.8.
Vital Signs ..................................................................................................................39
8.9.
Electrocardiography....................................................................................................40
8.10.
Concomitant Medications or Therapies......................................................................40
9.
TOLERABILITY VARIABLES AND ANALYSIS..................................................42
10.
PHARMACOKINETICS/PHARMACODYNAMICS (PK/PD) ANALYSIS...........43
11.
BIOMARKER ANALYSIS........................................................................................44
12.
IMMUNOGENICITY ANALYSIS............................................................................45
13.
PLANNED INTERIM ANALYSIS ...........................................................................46
13.1.
Sample Size Re-Assessment.......................................................................................46
13.2.
Futility Analysis..........................................................................................................47
14.
STATISTICAL SOFTWARE ....................................................................................48
15.
CHANGES TO ANALYSES SPECIFIED IN THE STUDY PROTOCOL..............49
16.
REFERENCES ...........................................................................................................50


Placebo-Controlled–Asthma
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Study TV48574-AS-20031
6
LIST OF TABLES
Table 1:
Study Visits.................................................................................................................20
Table 2:
Administration Site Finding Severity Assessment .....................................................36
Table 3:
Criteria for Potentially Clinically Significant Laboratory Values..............................37
Table 4:
Criteria for Potentially Clinically Significant Vital Signs..........................................39
Table 5:
Calculated Type 1 Error Rates with or without Sample Size Re-assessment.............46
Table 6:
Correct and Incorrect Early Termination Rates..........................................................47


Placebo-Controlled–Asthma
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7
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
ACQ-6
Asthma Control Questionnaire 6-question version 
ADA
antidrug antibodies
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
BMI
body mass index
CAE
clinical asthma exacerbation
CRF
case report form
CI
Confidence interval
COVID-19
coronavirus disease 2019
CV
coefficient of variation
DoR
Day of randomization
e-diary 
electronic diary
ECG
electrocardiogram/electrocardiography
EOS
end of study
EOT
end of treatment
ER
emergency room
ET
early termination 
mITT
modified intent-to-treat 
PEF
Morning peak expiratory flow
FeNO
Fractional exhaled nitric oxide
FEV1
forced expiratory volume in the first second 
FSH
follicle stimulating hormone
HBsAg
hepatitis B surface antigen 
HCG
Human chorionic gonadotropin
HIV
human immunodeficiency virus 
HCV
hepatitis C virus
ICE
intercurrent events
ICS
inhaled corticosteroid
IMP
investigational medicinal product


Placebo-Controlled–Asthma
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8
Abbreviation
Term
ITT
intent-to-treat
JSRC
joint safety review committee
KM
Kaplan-Meier 
LABA
Long-acting beta agonist
LoAC
loss of asthma control 
LS
least square
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed model for repeated measures
NRS
numerical response scale
PDAESI
protocol-defined adverse events of special interest
PP
per-protocol
Proof of concept
POC
R&D
Research and Development
RTSM
Trial Supply Management
SABA
short-acting beta agonist 
SAP
statistical analysis plan
sc
subcutaneous(ly)
SD
standard deviation
SE
standard error
SI
standard international
SOC
system organ class
SOP
standard operating procedure
ULN
upper limit of normal
UN
unstructured covariance
WHO Drug
World Health Organization Drug Dictionary


Placebo-Controlled–Asthma
Statistical Analysis Plan
Study TV48574-AS-20031
9
INTRODUCTION
This Statistical Analysis Plan describes the planned analysis and reporting for Teva Branded 
Pharmaceutical Products R&D, Inc. study TV48574-AS-20031, [A 16-Week, Randomized, 
Double-Blind, Placebo-Controlled, Parallel-Group, Proof-of-Concept Study to Evaluate the 
Efficacy and Safety of TEV-48574 in Adults with T2-low/non-T2 Severe Uncontrolled Asthma], 
and was written in accordance with
 (Statistical Analysis Plan).
The reader of this SAP is encouraged to read the study protocol (Protocol with Amendment 02
Approval Date: 28 April 2021) for details on the conduct of this study, the operational aspects of 
clinical assessments, and the timing for completing the participation of a patient in this study.
The SAP is intended to be in agreement with the protocol, especially with regard to the primary 
and all secondary endpoints and their respective analyses. However, the SAP may contain more 
details regarding these particular points of interest, or other types of analyses (eg, other 
endpoints). When differences exist in descriptions or explanations provided in the study protocol 
and this SAP, the SAP prevails; the differences will be explained in the clinical study report.


Placebo-Controlled–Asthma
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1.
STUDY ENDPOINTS
1.1.
Primary Efficacy Endpoints
The primary efficacy endpoint is the proportion of patients who experience loss of asthma 
control (LoAC) during the treatment period.
LoAC is defined as any one of the following during the treatment period: 

Morning PEF decrease ≥30% from baseline on 2 consecutive days or morning handheld 
FEV1 decrease ≥20% from baseline on 2 consecutive days 

Increase in SABA/quick-relief medication ≥6 puffs over baseline use in 24 hours on 
2 consecutive days

Increase in ICS dose ≥4x most recent dose

Systemic corticosteroid use

Asthma ER visit or hospitalization
1.2.
Secondary Efficacy Endpoints
Key secondary efficacy endpoints:

Time from randomization to LoAC during the treatment period

Asthma Control Questionnaire 6-question version (ACQ-6) at end of treatment (EOT) 
and throughout the study 

Forced expiratory volume in the first second (FEV1) (% predicted, L) at EOT and 
throughout the study

Use of SABA quick relief medication at EOT and throughout the study
Other secondary efficacy endpoints:

Proportion of patients who have a CAE during the treatment period

Time from randomization to first CAE during the treatment period

Number of nighttime awakenings due to asthma during the treatment period

Percent decrease in ICS dose during the treatment period

Other lung function parameters as assessed by hand-held spirometry at end of treatment 
(EOT) and throughout the study

Fractional exhaled nitric oxide (FeNO) throughout the study
1.3.
Safety Endpoints
Safety and tolerability endpoints:

Frequency of adverse events

Change from baseline in clinical laboratory test results (serum chemistry, hematology, 
and urinalysis) throughout the study

Change from baseline in vital signs throughout the study

Change from baseline in 12-lead electrocardiogram (ECG) findings throughout the study


Placebo-Controlled–Asthma
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
Use of concomitant medication

Local tolerability

Number (%) of patients who did not complete the study due to adverse events 
1.4.
Device-Related Events
All device-related adverse events, malfunctions etc. will be recorded and evaluated for their 
impact relative to the safety and efficacy of the investigational medicinal product.
1.5.
Pharmacokinetic Assessment
Pharmacokinetic endpoints are
Trough serum TEV-48574 concentrations throughout the study (sparse sampling)
Population pharmacokinetic analysis of pharmacokinetic data 
1.6.
Immunogenicity Assessment Endpoints
Immunogenicity endpoints are
Assessment of treatment-emergent anti-drug antibody (ADA) responses: change from baseline 
and throughout the study 
Impact of the presence of ADAs on pharmacokinetics and clinical safety (if possible). 
Assessment of neutralizing ADA in ADA positive patients throughout the study
1.7.
Estimand for Primary Efficacy Endpoint
An estimand, in general, includes 5 inter-related attributes – treatment condition, population of 
interest, variable (endpoint) of interest, intercurrent events (ICE) along with the strategy for 
handling ICE, and population-level summary for the endpoint. The four attributes of the 
estimand are defined as follows: 
Treatment condition: TEV-48574
 
 vs. placebo administered bi-weekly in patients on stable background inhaled 
corticosteroids (ICS) / long-acting best agonist (LABA) in the first four weeks but with 
background asthma controllers withdrawn in a structured manner from week 4 to week 8.  
Population: The patients with T2-low and non-T2 uncontrolled severe asthma met all inclusion 
criteria and met none of the exclusion criteria. 
The intent-to-treat (ITT) analysis set as defined in Section 3.1 will be the primary analysis set for 
efficacy. In the data analyses, the treatment will be assigned based on the treatment to which 
patients were randomized, regardless of which treatment they actually received. 
Variable: The proportion of patients who experience LoAC during the 16-week treatment period
due to the initially randomized treatment as actually taken (Mallinckrodt, 2013).
Intercurrent events: Early treatment discontinuation will result in a lack of exposure to the 
initially randomized treatment and the patient being put on alternative medications. Observations 
after IMP discontinuations may not reflect the treatment effects of the initially randomized 


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treatment. In addition, an early discontinuation prior to week 16 without LoAC will result in a 
missing observation of the primary efficacy endpoint altogether. 
As the strategy to handle the ICEs for the primary analysis, each patient’s treatment period is 
defined as from the first dose to the last dose + 14 days. Patients who withdraw from the study 
prior to week 16 without LoAC or early terminated the study treatment without experiencing 
LoAC during the patient’s treatment period will be analyzed as having experienced LoAC, if the 
assessed reason of discontinuation is lack of efficacy or due to an asthma-related adverse event. 
Patients who withdraw from the study without LoAC or early terminated treatments without 
experiencing LoAC during the patient’s treatment period for other reasons will be analyzed as 
having not experienced LoAC.
Population-level summary: Numbers and proportions of patients who experience LoAC during 
the treatment period, adjusted proportions estimated from the logistic regression analysis in the 
treatment groups, as well as odds ratios between the two treatment groups estimated from the 
logistic regression analysis.


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2.
STUDY DESIGN
2.1.
General Design
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group proof-of-
concept study to evaluate the efficacy and safety of TEV-48574 administered sc every 2 weeks 
in adult patients aged 18 years and older with T2-low and non-T2 uncontrolled severe asthma. 
The primary efficacy endpoint is the proportion of patients who experience loss of asthma 
control (LoAC) during the treatment period. 
The study will consist of a 5-week period consisting of screening followed by a run-in, a 
16-week treatment period, and an 8-week follow-up period.
Screening and run-in (5 weeks)
Screening starts with the initial screening visit and will be followed by a run-in that proceeds 
through the day prior to the day of randomization. The duration of the screening and run-in 
period will be 5 weeks and may be extended by up to 14 days to allow for IMP shipping and to 
complete assessments of peripheral blood eosinophil count. Screening assessments and 
procedures will be completed over at least 2 visits, including the initial screening visit, and may 
be completed over more than 2 visits. An effort should be made to complete screening 
assessments and procedures in the first 2 weeks following the initial screening visit, with the 
exception of the samples for the second (and if applicable third) peripheral blood eosinophil 
counts. 
Treatment Period (16 weeks)
The treatment period begins with randomization and ends with the EOT visit (week 16). After 
the end of the screening period, patients who meet all of the inclusion criteria, none of the 
exclusion criteria, and all of the randomization criteria will be randomized in a 1:1 ratio to the 
following regimens administered sc every 2 weeks: 

TEV-48574 

Placebo to match TEV-48574 
With randomization, patients enter the 16-week treatment period. The patients will receive the 
IMP 
 
 
Patients should be observed for 2 hours after the end of the first (loading dose) and second (first 
maintenance dose) administration of IMP and for 1 hour after the subsequent IMP 
administrations. 
Follow-up Period (8 weeks)
After the end of the 16-week treatment period, the patient will enter the 8-week follow-up period 
for continued assessments. During the follow-up period, patients may resume their 
study-provided background controller therapies. This follow-up visit marks the end of study 
(EOS). Patients who complete the EOS visit will be considered to have completed the study.


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The study duration will be approximately 18 months. The study is expected to start in Q3 2020 
and last until approximately Q1 2022. The expected duration of the study may also be extended 
dependent on enrollment, sample size adjustment, and other factors. 
The screening and run-in, treatment, and follow-up periods are described below; the study 
schematic diagram is presented in Figure 1.
Figure 1:
Overall Study Schematic Diagram
ACQ-6 = 6-question Asthma Control Questionnaire; CBC = complete blood count; DoR = day of randomization; 
EOS = end of study; EOT = end of treatment; FeNO = fractional exhaled nitric oxide; F/U = follow up; 
IMP = investigational medicinal product.
2.2.
Randomization and Blinding
This is a randomized, double-blind study. Patients who meet all inclusion criteria, none of the 
exclusion criteria, and all of the randomization criteria will be randomly assigned to receive 
TEV-48574 or placebo to match TEV-48574 in a 1:1 ratio to the following regimens 
administered sc every 2 weeks:

TEV-48574 

Placebo to match TEV-48574 
Patients will be randomly assigned to treatment groups by means of a computer-generated 
randomization list. The specifications for randomization will be under the responsibility and 
oversight of Teva Global Statistics.
The study patients and the clinical team at the site will be blinded to treatment assignment until 
the database is locked for analysis. Individuals who may not be blinded include (but are not 
Screen → Run-in
DoR
TEV-48574
Placebo
Eosinophils <250/uL
Reversibility ≥12%
ACQ-6 ≥1.5
FeNO <25 ppb
+ 8 weeks F/U (including CBC, 
immunogenicity and safety
assessments) 
-5
0                       4
14
16
24  Week
S1        S2/S3
V1                    V3
V9
V10                            11  Visit
Final IMP
EOS
Decrease
background
therapy
Standardize background
asthma therapy
IMP 
only
Reintroduce background
asthma therapy
Week 4
Discontinue
LABA and other 
non-ICS asthma 
controllers
Week 6
First ICS 
decrease
Week 7
Second 
ICS 
decrease
Week 8
Third ICS 
decrease


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limited to) the bioanalytical scientists, pharmacokineticists, and biostatisticians who are not 
directly involved in study conduct. 
The randomization list will be assigned to the relevant treatment groups through a qualified 
service provider, eg, via the Randomization and Trial Supply Management (RTSM) system. The 
generation of the randomization list and management of the RTSM system will be done by a 
qualified service provider under the oversight of the responsible function at Teva.
2.3.
Joint Safety Review Committee
A Joint Safety Review Committee (JSRC) will convene and review all available safety data at 
specific stages of the study and will recommend proceeding with the study as planned, 
performing modifications, suspending study until further notice, or prematurely terminating the 
study.
Details are in JSRC Charter.
2.4.
Sample Size and Power Considerations
The primary efficacy analysis for this study will be the comparison between treatment groups of 
the proportion of patients experiencing a LoAC event during the 16-week treatment period. The 
study will be considered positive if the primary efficacy test indicates a statistically significant 
treatment effect versus placebo at the predefined significance level.
Sample size calculations were performed based on the following considerations:
In the Phase 2a study results for dupilumab, the observed LoAC rate in the placebo group was 
44% (Wenzel et al 2013). The patients in that study had elevated peripheral blood eosinophil 
counts (≥300 cells/µL). To estimate the LoAC rate that would have been observed in patients 
with peripheral blood eosinophil counts <300 cells/µL, the ratio of exacerbation rates observed 
between eosinophil count strata in the placebo groups of the dupilumab Phase 3 study were used 
(Castro et al 2018). This resulted in an estimated LoAC rate of 27% for the patients meeting the 
entrance criteria for the current study. 
This study is designed to detect a 60% reduction in LoAC rate versus placebo; ie, a placebo 
group rate of 27% and a TEV-48574 group rate of 10.8%.
Based on the assumptions above, and assuming a 15% dropout rate during the study, 
62 randomized patients per treatment group will provide 80% power to detect a treatment effect 
of 60% reduction in LoAC rate in the TEV-48574 group with one-sided alpha (Type I error rate) 
of 0.1 with a Fisher’s exact test.
An unblinded interim analysis is planned to re-assess the sample size and conduct a futility 
analysis as described in Section 13. If the sample size increases as a result of the interim 
analysis, the number of evaluable patients would be expected to increase proportionately.


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2.5.
Sequence of Planned Analyses
2.5.1.
Planned Interim Analyses
An unblinded interim analysis is planned after the first 40-52 randomized patients have 
completed the treatment period, experienced LoAC, or withdrawn from the study completely. 
The main purposes of the interim analysis include sample size re-assessment and futility 
analysis. The details are in Section 13 and the Interim Analysis Charter.
2.5.2.
Final Analyses and Reporting
All final analyses identified in this SAP will be performed after the final database lock.


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3.
ANALYSIS SETS
3.1.
Intent-to-Treat Analysis Set
The intent-to-treat (ITT) analysis set will include all randomized patients and will be used as the 
population for the primary efficacy analysis.
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.
Data collected from patients after treatment discontinuation will be included in the ITT analysis 
set.
3.2.
Modified Intent-to-Treat Analysis Set
The modified intent-to-treat (mITT) analysis set is a subset of the ITT analysis set including only 
patients who receive at least 1 dose of IMP.
The mITT analysis set will serve as the sensitive analysis.
3.3.
Safety Analysis Set
The safety analysis set will include all randomized patients who receive 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.
For the actual treatment assignment, a patient is assigned to the placebo group if the patient only 
received placebo doses. If a patient received at least one dose of active IMP, the actual treatment 
received for the patient will be the active
IMP treatment group.
3.4.
Per-Protocol Analysis Set
The per-protocol (PP) analysis set is a subset of the ITT analysis set including only patients that 
did not experience any important protocol deviation prior to LoAC (if any) or the end of the 
treatment period, whichever comes first. The list of important deviations identified as having the 
potential to influence and/or bias the primary efficacy results are:

Receive any dose of study drug by error, eg. randomized to receive test IMP but 
received dose(s) from placebo IMP, versa vise

Did not complete planed study treatments (8 doses in total) for reason other than 
LoAC related

Use of prohibited medications
A complete list of important deviations resulting in exclusion of patients from the PP analysis 
will be determined and documented at the end of the study based on a team review of 
accumulated blinded study data.


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3.5.
Pharmacokinetic Analysis Set
The pharmacokinetic analysis set will include those patients in the safety analysis set who have 
at least 1 measurable concentration of TEV-48574.


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4.
GENERAL ISSUES FOR DATA ANALYSIS
4.1.
General
Descriptive statistics for continuous variables include count (n), mean, SD, standard error (SE),
median, minimum, and maximum. In addition, for TEV-48574 concentration, percentage 
coefficient of variation (%CV) and geometric mean will also be calculated. Descriptive statistics 
for categorical variables include patient counts and percentages, and a missing category will be 
displayed as appropriate.
Summaries of potentially clinically significant abnormal values for clinical laboratory tests and 
vital signs values will include all postbaseline values (including scheduled, unscheduled, and 
early withdrawal visits).
4.2.
Specification of Baseline Values
Unless otherwise noted, the baseline for clinic visit variables will be the last observed value 
before the first dose of study drug. The baseline for absolute eosinophil count will be the average 
of measurements prior to the administration of the first IMP.
The baseline for hand-held spirometry parameters and e-diary variables will be the average of the 
values over the 7 days preceding day of randomization. 
4.3.
Handling Withdrawals and Missing Data
For all safety 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.
Dates that have incomplete information (the month and year or just the year is available) will be 
estimated for the purpose of calculating variables that are dependent on time if necessary. Day 
will be estimated as the first day (01) of the month (if month and year of partial date are 
available) or middle (July 1) of the year (if only year is available), unless otherwise noted. The 
imputations for partial dates are only for calculation purpose. Original date variables will not be 
modified. Listings will list dates as collected.
4.4.
Study Days and Visits
For by-visit summaries, if there are multiple assessments at a postbaseline visit then the last 
non-missing assessment at that visit will be used for the summary (this includes scheduled and 
unscheduled assessments), except for triplicate ECG assessments (see Section 8.9 for further 
details).
Study visits are in Table 1. See the study protocol Table 2 to 4 for details.


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Table 1:
Study Visits
Study 
Period
Screening 
& Run-in
Treatment Period (Visits 1 -10)
Follow
-up
Visit #
S1
S2/3
V1
DoR
V2
V3
V4
V5
Phone
V6
V7
V8
V9
V10
EOT
V11
EOS
Week
-5
0
2
4
6
7
8
10
12
14
16
24
Study 
Day 
-
1
15
29
43
50
57
71
85
99
113
169
DoR=Day of Randomization; EOT=End of Treatment; EOS=End of Study.
‘Last Assessment’ may be derived for analysis purpose and is defined as the last observed 
postbaseline data during the treatment period. For patients who withdraw from the study early, 
their data at the early withdrawal visit will be excluded from the by-visit summaries but will be 
included in the Last Assessment summaries.
Study days are numbered relative to the first day of the IMP administration. The start of 
treatment (day 1) is defined as the date on which a patient takes the first dose of the IMP, as 
recorded on the case report form (CRF). Days will be numbered relative to treatment start (ie, ..., 
–2, –1, 1, 2, ...; with day 1 being the first day of the IMP administration and day –1 being the day 
before the first day of the IMP administration).


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5.
STUDY POPULATION
5.1.
General
The ITT analysis set (see Section 3.1) will be used for all study population summaries unless 
otherwise specified. Summaries will be presented by treatment group and all patients. All data 
will be listed and sorted by treatment group and subject identifying number.
5.2.
Patient Disposition
Data from patients screened, patients screened but not randomized, patients randomized to 
treatment in the study, patients randomized but not treated, patients in the safety analysis set, 
patients in the per-protocol analysis set, patients who completed the treatment period (week 16), 
patients who completed the study (see Section 2.1 for definition of study completion), and 
patients who did not complete treatment but were followed up until end of study will be 
summarized. Data from screen failures, patients who did not complete the treatment period and
patients who did not complete the study will also be summarized by reason for withdrawal using 
descriptive statistics.
This summary will include all patients.
5.3.
Demographics and Baseline Characteristics
The demographic data will be collected at the screening visit after the patient signs the informed 
consent form. Patient demographic data including age, age group (<65 years vs ≥65 years), 
gender, race, race group (white or other), ethnicity, baseline weight (kg), baseline weight group 
(<75 kg vs ≥75 kg), baseline height (cm), baseline body mass index (BMI; kg/m2), and baseline 
BMI group (<30 vs ≥30) will be summarized using descriptive statistics for the ITT, safety and 
PP analysis sets. 
Baseline characteristics including asthma history and ECG findings at screening will be 
summarized for the ITT analysis set using descriptive statistics. No inferential analyses will be 
performed.
Asthma history includes

Months since asthma diagnosis

The duration of asthma

The number of inpatient hospitalization due to asthma over the past 12 months

Months since most recent inpatient event

The number of emergency department visit due to asthma over the past 12 months

Months since most recent emergency department visit

the number of times oral corticosteroids were prescribed for asthma in the last 18 months

Months since last prescription of corticosteroids


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The month will be calculated as (date of informed consent - the date of the event + 1)/30.44.
Rules for handling partial dates are in Section 4.3.
5.4.
Medical History
All medical history abnormalities will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). The incidence of medical history abnormalities will be summarized using 
descriptive statistics by system organ class (SOC) and preferred term. Patients are counted only 
once in each SOC and only once in each preferred term.
5.5.
Prior Therapy and Medication
All prior medications or therapy will be coded using the World Health Organization Drug
Dictionary of medical codes (WHO Drug). The incidence of prior medications or therapy will be 
summarized by therapeutic class and preferred term using descriptive statistics. Patients are 
counted only once in each therapeutic class category, and only once in each preferred term
category. Prior medications will include all medications taken prior to the administration of the 
first dose of the IMP.
5.6.
Childbearing Potential and Methods of Contraception
Information related to reproductive system findings will be collected at the screening visit. Data 
will be listed.
5.7.
Physical Examinations
Patients with at least 1 abnormal finding (overall) and abnormal findings for each category at the 
baseline will be summarized and listed.
5.8.
Study Protocol Deviations
Data from patients with any important protocol deviations during the study will be summarized 
overall and for each category using descriptive statistics. All study protocol deviations will be 
listed.


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6.
EFFICACY ANALYSIS
6.1.
General
The ITT analysis set (Section 3.1) will be used for all efficacy analyses unless otherwise noted. 
Summaries will be presented by treatment group. The mITT and per-protocol analysis sets
(Section 3.4) will be used as supplementary analysis for the primary analysis. All efficacy related 
data will be listed using ITT analysis set unless otherwise specified.
The baseline for clinic visit variables will be the last observed value before the first dose of study 
drug.
The baseline for spirometry parameters and e-diary variables will be based on the daily average 
of the values over the 7 days preceding day of randomization.
6.1.1.
Analysis Windows for E-diary Data
For the purpose of analysis, the analysis windows for the treatment period will be derived for 
data collected on e-diary and with hand-held spirometry daily if applicable.
Postbaseline monthly (4-week) analysis windows during the treatment period will be 
determined based on the actual dosing day as follows:

Month 1/Weeks 1 to 4: from the day of 1st IMP administration to the day before 3rd
IMP administration (visit 3/week 4 dosing); 

Month 2/Weeks 5 to 8: from the 3rd IMP administration (visit 3/week 4 dosing) to the 
day before the 5th IMP administration (visit 6/week 8); 
Note, Visit 5/Week 7 is a non-dosing visit.

Month 3/Weeks 9 to 12: from the 5th IMP administration (visit 6/week 8) to the day 
before the 8th MP administration (visit 8/week 12); 

Month 4/Weeks 12 to 16: from the 8th IMP administration (visit 8/week 12) to the day 
of the EOT visit (visit 10/week 16);
Notes: 
There will be no IMP administration at visit 10; for patients who withdraw from the study 
early, the end day for the last window will be the day before EOT/early termination (ET); 
a 4-week analysis window may contain <28, 28, or >28 days.
Postbaseline weekly analysis windows during the treatment period will be derived based on the 
study days as follows: 
Week x: day (x-1)*7 + 1 to day x*7
Eg. Week 1 is study days 1 to 7; Week 2 is study days 8 to 14, etc.
A post-treatment analysis window will be from the day after the EOT visit to the day of the 
EOS visit (visit 11/week 24).


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6.2.
Primary Efficacy Endpoint and Analysis
6.2.1.
Definition
The primary efficacy endpoint is the proportion of patients who experience loss of asthma 
control (LoAC) during the treatment period.
LoAC is defined as any one of the following during the treatment period: 

Morning PEF decrease ≥30% from baseline on 2 consecutive days or morning handheld 
FEV1 decrease ≥20% from baseline on 2 consecutive days 

Increase in SABA/quick-relief medication ≥6 puffs over baseline use in 24 hours on 
2 consecutive days

Increase in ICS dose ≥4x most recent dose

Systemic corticosteroid use

Asthma ER visit or hospitalization
LoAC will be determined and recorded by investigator from study sites. A patient who meets 
criteria for LoAC will discontinue IMP, and resume or increase background asthma controller 
therapies, but will remain in the study. LoAC events will be treated by the investigator according 
to local standard of care.
6.2.2.
Primary Efficacy Analysis
The primary analysis will compare rates of LoAC between treatment groups using logistic 
regression with fixed effect for treatment, age group (<65 years vs ≥65 years) and gender, as well 
as baseline FEV1 and baseline weight as covariates. Patients who withdraw from the study before 
the week 16 or early terminated the study treatment due to lack of efficacy, LoAC, or an 
asthma-related adverse event will be analyzed as having experienced LoAC. Patients who 
withdraw from the study before the week 16 without LoAC or early terminated from the study 
treatment without experiencing LoAC during the patient’s treatment period (Section 1.7) for 
other reasons will be analyzed as not experiencing LoAC. Asthma-related adverse events will be 
determined by blinded data reviews prior to the final database lock.
The treatment effect will be tested at a one-sided alpha of 0.1.
The primary analysis will be performed on the ITT analysis set. The rates of LoAC for each 
treatment group, confidence intervals, and p-value will be displayed. 
Example SAS code for Logistic Regression
PROC GENMOD DATA =name;
       CLASS TRTP AGEGR1 SEX;
       MODEL AVALC = TRTP FEV1 WEIGHT AGEGR1 SEX / DIST=BIN TYPE3;
RUN;
Where AVALC denotes the responses with ‘yes’ for LoAC and ‘no’ for not having LoAC; TRTP 
denotes the planned treatment group; AGEGR1 denotes age group; in bold are the SAS key 
words.


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6.2.3.
Subgroup Analysis
Sub-group analyses will be performed on the primary endpoint and key secondary endpoints for 
gender, baseline BMI (<30 vs ≥30), baseline weight (<75 kg vs ≥75 kg) and age group (<65
years vs ≥65 years).
Sub-group analysis will be based on ITT and PP analysis sets.
6.2.4.
Sensitivity Analysis for the Primary Efficacy Endpoint
As a supplementary analysis, the primary analysis will be repeated on mITT analysis set and the 
per-protocol analysis set as defined in Section 3.4. In addition, a sensitivity analysis will be 
performed using multiple imputations method, when there are more than 5% early 
discontinuations from the study before week 16 due to reasons other than lack of efficacy or 
asthma-related AEs in either treatment group.
6.2.4.1.
Sensitivity Analysis Using Multiple Imputations
Patients who discontinued the treatment or the study before week 16 without LoAC due to lack 
of efficacy or asthma-related AEs will be considered as having experienced an LoAC, the same
imputation method as used in the primary efficacy analysis.
For patients who discontinued the study before week 16 without LoAC for reasons other than 
lack of efficacy or due to asthma-related AEs, multiple imputations will be used from a Bernoulli 
distribution with the probability estimated from a logistic regression model from the observed 
LoAC data given the treatment group, sex, age group (<65 years vs ≥65 years), baseline FEV1, 
and baseline weight. A total of 100 datasets will be imputed and each will be analyzed with the 
logistic regression model the way as for the primary analysis. The final estimates will be 
obtained using Rubin’s method. The details are as follows:
Step 1: Estimate the probabilities for Bernoulli distribution
The SAS procedure in Section 6.2.2 will be used to obtain the probability estimates from a 
logistic regression model. The following statement will be added to SAS procedure:
ODS OUTUT ParameterEstimates=pest;
Estimates from PROC GENMOD along with patients’ data will be used to calculate the 
probability, the p used for Bernoulli distribution, for each patient.
Observed data will be duplicated 100 times creating 100 sets of data. In each dataset, the SAS 
function RAND(“Bernoulli”, p) will be used to determine LoAC status (1=having LoAC, 0=not 
having LoAC) for patients with missing data due to reasons other than lack of efficacy or due to 
asthma-related AEs. 
Step 2: Analysis
The 100 sets of data will be analyzed in a manner analogous to the analysis as described in 
Section 6.2.2 adding a by-statement for imputation to the SAS procedure.
The results from the 100 analyses will be combined using Rubin’s formulae in the following 
SAS procedure.
PROC MIANALYZE DATA=diff;


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  MODELEFFECTS estimate;
   STDERR stderr;
RUN;
6.3.
Key Secondary Efficacy Endpoints and Analyses
The key secondary efficacy endpoints are listed in Section 1.2. Analyses will be based on the 
ITT analysis set.
6.3.1.
Time from Randomization to LoAC During Treatment Period
The time (days) from randomization to LoAC during the treatment period is the interval from the 
randomization to the occurrence of the LoAC. 
The observation for each patient is the interval from randomization to the occurrence of the 
LoAC, or censoring, whichever occurs earlier and an indicator whether or not the observation is 
for a LoAC case or censoring. 
The observations are derived as:
1. Time to event or censoring:  the date of censoring or the date of LoAC, whichever occurs 
earlier - the date of randomization + 1.
2. Indicator variable: 1 if a LoAC case is observed; 0 otherwise.
Patients who withdraw from the study before the week 16 or discontinue treatment due to lack of 
efficacy, LoAC, or an asthma-related adverse event will be analyzed as having experienced 
LoAC at the time of the withdrawal or treatment discontinuation. 
Patients who withdraw from the study before week 16 without LoAC or early withdraw from 
treatment without LoAC during the treatment period (section 1.7) for other reasons will be 
analyzed as being right-censored at the time of withdrawal.
Patients who completed treatment without experiencing LoAC will be right-censored at the time 
of treatment completion. 
The Kaplan-Meier (KM) method will be used to estimate and compare the distributions of time 
to LoAC between treatment groups. A one-sided log-rank test will be provided to compare the 
hazard ratio (TEV-48574/placebo) between the TEV-48574 and placebo groups. 
Example SAS code for hazard ratio
ODS OUTPUT PARAMETERESTIMATES=name;
PROC PHREG DATA= NAME;
   MODEL AVALN*CENSOR(1)= TRTPN/RISKLIMITS; 
RUN; 
Notes, for the hazard ratio of active/placebo, the TRTPN should have a value 2 for active and 1 
for placebo.
Example SAS code for log-rank test
  ODS OUTPUT HOMTESTS=name (WHERE=(UPCASE(TEST) = "LOG-RANK"));


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  PROC LIFETEST DATA=name;
   TIME AVALN*CENSOR(1);
   STRATA TRTP;
RUN;
Example SAS code for KM estimates
ODS OUTPUT PRODUCTLIMITESTIMATES=name QUARTILES=name 
CENSOREDSUMMARY = name;
PROC LIFETEST DATA=name OUTSURV=name TIMELIST=x TO y BY n ;
   TIME AVALN*CENSOR(1);
  BY TRTP;
RUN;
Where AVALN denotes the time-to-event (days); CENSOR denotes censoring (1= censoring and 
0=event); TRTP/TRTN denote the planned treatment group.
6.3.2.
Asthma Control Questionnaire 6-Question Version (ACQ-6) at End of 
Treatment (EOT) and Throughout Study
The ACQ-6 is a validated asthma assessment tool that has been widely used. Six questions are 
self-assessments (completed by the patient). Each item on the ACQ-6 has a possible score 
ranging from 0 to 6, and the total score is the mean of all responses (See Appendix E of the study 
protocol). ACQ-6 will be administered at the sites at screening, run-in, all on-site visits during 
treatment period (visits 1, 2, 3, 4, 6, 7, 8, 9, and 10), and follow-up visit (visit 11).
The analysis will be based on ITT and PP analysis sets.
The changes from baseline in ACQ-6 total score at EOT will be analyzed using an analysis of 
covariance (ANCOVA) method. The model will include treatment as the fixed effect and 
baseline weight, age group (<65 years vs ≥65 years), gender, and baseline value of ACQ-6 total 
score as covariates. LS mean and SE for each treatment group, LS means and corresponding 
95% confidence intervals for the treatment differences (TEV-48574 - placebo), and the 
associated p-values from the overall results for treatment comparisons. 
For patients who did not complete the treatment period, data from the early termination (ET)
visit will be used for the analysis. For patients who are lost-to-follow-up (no ET assessment) 
prior completion of the treatment period, the last assessment during the treatment period will be 
used for the analysis.
Example SAS code for ANCOVA
PROC MIXED DATA=<name>; 
     CLASS TRTP AGEGR1 SEX; 
     MODEL CHG= BASE TRTP WEIGHT AGEGR1 SEX /S; 
     LSMEANS TRTP /DIFF=CONTROL (“Placebo”) CL ALPHA=0.05; 
     ODS OUTPUT LSMEANS= <name>  DIFFS= < name> ;
RUN;


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Where TRTP denotes the planned treatment group; CHG denotes the change from baseline at 
EOT; BASE denotes the baseline ACQ-6 total score;
The changes from baseline in ACQ-6 total score throughout the study will be analyzed using 
the mixed model for repeated measures (MMRM) with treatment group, visit, treatment and visit 
interaction, and baseline value of ACQ-6 total score as fixed effects and patient as a random 
effect. The unstructured covariance structure (UN) will be used to model intra-subject 
correlation. LS mean and SE for each treatment group, LS means and corresponding 95% 
confidence intervals for the treatment differences (TEV-48574 - placebo), and the associated p-
values from the overall results for treatment comparisons.
Notes, if UN dose not converge, compound symmetry (CS) will be used.
Data from visits 2 to 10 except visit 5 (phone contact, no data will be collected) will be included 
in the analysis model.
Per the ICE handling strategy, for patients who did not complete the treatment period,
observations after the end of the treatment period will be discarded and treated as missing 
obseravtions.
The overall and by-visit results will be presented. The endpoint will be measured by the overall 
results. Descriptive statistics from each visit will be provided.
Example SAS codes for MMRM analysis:
PROC MIXED DATA=<name> METHOD=REML;
      CLASS USUBJID TRTP AVISIT AGEGR1 SEX; 
      MODEL CHG=BASE TRTP WEIGHT AGEGR1 SEX AVISIT TRTP*AVISIT/S;
      REPEATED AVISIT/ SUB=USUBJID TYPE=UN;
      LSMEANS TRTP TRTP*AVISIT/ DIFF CL DDFM=KR ALPHA=0.05;
      ODS OUTPUT LSMEANS= <name> DIFFS= < name> ;
RUN;
Where TRTP denotes the planned treatment group; AVISIT denotes the visits; BASE denotes the 
baseline ACQ-6 total score; CHG denotes the change from baseline at each visit.
6.3.3.
Forced Expiratory Volume in First Second (FEV1) (% Predicted, L) at EOT and 
Throughout Study
Spirometry will be performed both at the site and by hand-held spirometer. On-site spirometry 
will include full-flow volume loops (FVC, FEV1, FEV1/FVC, FEF25%-75% and PEF) and 
reversibility testing at all visits during treatment period except the phone visit. Hand-held 
spirometry (FEV1, PEF) will be performed daily. 
Analyses will be based on-site FEV1.
The change from baseline in FEV1 at EOT will be analysis using ANCOVA in a manner 
analogous to the analysis as described in Section 6.3.2 using the same algorithm for patients who 
did not complete the treatment period or patients who are lost-to-follow-up (no ET assessment) 
prior completion of the treatment period.


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The changes from baseline in FEV1 throughout study will be analyzed using analyzed using 
MMRM in a manner analogous to the analysis as described in Section 6.3.2. Per the ICE 
handling strategy, for patients who did not complete the treatment period, observations after the 
end of the treatment period will be discarded and treated as missing observations.
The baseline FEV1 will be used in the analysis models.
6.3.4.
Use of SABA Quick Relief Medication at EOT and Throughout Study
The number of inhalations/puffs of SABA/quick-relief inhaler will be recorded in the e-diary 
daily. Study sites will monitor rescue medication use during the study visits screening and run-in 
visit, all visits during treatment period, and follow-up visit. Study sites are also responsible for 
responding to asthma specific alert criteria related to SABA/quick-relief inhaler use.
Analysis windows throughout the study for during the treatment period and post-treatment 
(follow-up period) will be derived for each patient using algorithm detailed in Section 6.1.1.
The daily average of the inhalations/puffs of SABA/quick-relief inhaler in each monthly analysis 
window will be calculated using formula below:
∑ℎ	
/   	 
     	 
The baseline daily average of use of SABAs will be calculated based on the data from 7 days
preceding day of randomization similarly.
The change from baseline in the daily average of the uses of SABA quick relief medication at 
EOT will be analysis using ANCOCA in a manner analogous to the analysis as described in 
Section 6.3.2. For patients who did not complete the treatment period, the last analysis window 
during the treatment period will be used. For patients who are lost-to-follow-up (no ET 
assessment) prior completion of the treatment period, the last analysis window during the 
treatment period will be used for the analysis.
The change from baseline in the daily average of the use of SABA quick relief medication 
throughout study will be analyzed using MMRM in a manner analogous to the analysis as 
described in Section 6.3.2. Per the ICE handling strategy, for patients who did not complete the 
treatment period, observations after the end of the treatment period will be discarded and treated 
as missing observations.
The baseline daily average of use of SABAs will be included in the analysis models.
In additional, weekly analysis windows (weeks 1 to 8) will be derived for each patient using 
algorithm detailed in Section 6.1.1. The daily average of the inhalations/puffs of SABA/quick-
relief inhaler in each weekly analysis window will be calculated similarly using formula above. 
The change from baseline in the daily average of the use of SABA quick relief medication during 
weeks 1 to 8 will be analyzed using MMRM similarly.
6.4.
Other Secondary Efficacy Endpoints and Analyses
The other secondary efficacy endpoints are listed in Section 1.2. Analyses will be based on the 
ITT analysis set.


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6.4.1.
Proportion of Patients Who Have a CAE During Treatment Period
A clinical asthma exacerbation (CAE) during the treatment period CAE is defined as a 
worsening of asthma symptoms resulting in any of the following: 

The use of systemic corticosteroids (oral or injectable)

An emergency department visit due to asthma treated with systemic corticosteroids

An inpatient hospitalization due to asthma. 
Worsening asthma includes new or increased symptoms or signs that either worry the patient, or 
are related to an asthma-specific alert (if available through the e-diary/hand-held spirometer.
A patient who meets criteria for a CAE will be treated per the local standard of care. Additional 
medication and/or medical intervention that would satisfy the definition of CAE occurring within 
7 days of the last day of a prior CAE event will be considered as part of the same event for 
analysis purposes.
CAEs will be assessed at visits (screening and run-in, visits during treatment period, follow-up).
Proportion of patients who have a CAE during the treatment period will be analyzed in a manner 
analogous to the analysis for LoAC as described in Section 6.2.2. Similar approach for handling 
ICEs will be applied.
6.4.2.
Time from Randomization to First CAE During Treatment Period
CAEs are a subset of LoAC events. Asthma exacerbation is defined as a worsening of asthma 
symptoms (examples are described below) resulting in any of the following: 

The use of systemic corticosteroids (oral or injectable)

An emergency department visit due to asthma treated with systemic corticosteroids

An inpatient hospitalization due to asthma. 
CAEs will be assessed at screening and run-in visit, all visits during treatment period, and
follow-up visit.
Time from randomization to first CAE during the treatment period will be analyzed in a manner 
analogous to the analysis of the time to LoAC as described in Section 6.3.1. Patients who early 
terminated from the study or treatment due to lack of efficacy or asthma-related AEs will be also 
treated as CAE. Patients who withdraw from the study before week 16 without LoAC or early 
withdraw from treatment without LoAC during the treatment period for other reasons will be 
analyzed as being right-censored at the time of withdrawal. Patients without CAE will be right-
censored at the time of treatment completion.
6.4.3.
Number of Nighttime Awakenings Due to Asthma During Treatment Period
Patients will record nighttime awakenings due to asthma in the e-diary daily. Sites will check the 
records of nighttime awakenings during the all study visits (screening and run-in), treatment 
period and follow-up visit.


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Monthly analysis windows during the treatment period will be derived for each patient using 
algorithm detailed in Section 6.1.1. The monthly number of nighttime awakenings due to asthma 
during the treatment period will be calculated and normalized to 28 using the formula below. 
∑ ℎ

    	 
 
ℎ
   
ℎ    	  × 28
The baseline will be calculated based on the data from 7 days preceding day of randomization 
and be normalized to 28 days similarly.
The change from baseline in the monthly numbers of nighttime awakenings due to asthma during 
treatment period will be analyzed using MMRM in a manner analogous to the analysis as 
described in Section 6.3.2. Baseline monthly number of nighttime awakenings due to asthma will 
be included in the analysis model.
In additional, weekly analysis windows (weeks 1 to 8) will be derived for each patient using 
algorithm detailed in Section 6.1.1. The weekly number of nighttime awakenings due to asthma 
during weeks 1 to 8 will be calculated using the formula below:
∑ ℎ

    	 
 
ℎ
   
ℎ    	  × 7
The baseline will be calculated based on the data from 7 days preceding day of randomization 
similarly. The change from baseline in the weekly numbers of nighttime awakenings due to 
asthma during weeks 1 to 8 will be analyzed using MMRM similarly. Per the ICE handling 
strategy, for patients who did not complete the treatment period, observations after the end of the 
treatment period will be discarded and treated as missing observations.
6.4.4.
Percent Decrease in ICS Dose During Treatment Period
Inhaled corticosteroid (ICS) use will be recorded as one of asthma medications in the prior and 
concomitant medication data on the CRF.
Monthly analysis windows during the treatment period will be derived for each patient using 
algorithm detailed in Section 6.1.1. The monthly ICS usage in an analysis window will be the 
summation of reported usages in the analysis window.
The baseline will be the summation of reported usage from 28 days preceding day of 
randomization.
The percent decrease in ICS usage in an analysis window will be calculated using the formula 
below:
	  	 −
	  	
	  	
× 100%
The percent decreases and changes from baseline in monthly ICS usage during the treatment 
period will be analyzed using MMRM in a manner analogous to the analysis as described in 
Section 6.3.2. Baseline daily ICS usage will be used in the analysis model.
In additional, weekly analysis windows (weeks 1 to 8) will be derived for each patient using 
algorithm detailed in Section 6.1.1. The weekly ICS usage in each weekly analysis window will 
be the summation of reported usages in the analysis window. The baseline will be the summation 


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of reported usage from 7 days preceding day of randomization. The percent decrease in ICS 
usage in a weekly analysis window will be calculated similarly using formulas above. The 
percent decreases and changes from baseline in monthly ICS usage during weeks 1 to 8 will be 
analyzed using MMRM similarly. Per the ICE handling strategy, for patients who did not 
complete the treatment period, observations after the end of the treatment period will be 
discarded and treated as missing observations.
6.4.5.
Other Lung Function Parameters as Assessed by Hand-Held Spirometry at End 
of Treatment and Throughout the Study
Spirometry will be performed both at the site and by hand-held spirometer. 
On-site spirometry will include full-flow volume loops (FVC, FEV1, FEV1/FVC, FEF25%-75% and 
PEF) and reversibility testing at visit 1 (DoR), visit 3, visit 6, visit 8, and visit 10 during the 
treatment period. Changes from baseline in these parameters at EOT and throughout the study 
will be analyzed in a manner analogous to the analysis as for FEV1 described in Section 6.3.3.
Hand-held spirometry (FEV1, PEF) will be performed daily. Monthly analysis windows during 
the treatment period and post-treatment (follow-up period) will be derived for each patient using 
algorithm detailed in Section 6.1.1. The monthly average of FEV1 and PEF during each analysis 
window will be calculated using the formula below:
∑   	   	 
%    
ℎ 	 
The baseline will be calculated based on the data from 28 days preceding day of randomization 
similarly.
The change from baseline in the monthly averages of hand-held spirometry FEV1 and PEF values
at EOT will be analysis using ANCOVA in a manner analogous to the analysis as described in 
Section 6.3.2. For patients who did not complete the treatment period, the last analysis window 
during the treatment period will be used. For patients who are lost-to-follow-up (no ET 
assessment) prior completion of the treatment period, the last analysis window during the 
treatment period will be used for the analysis.
The changes from baseline in monthly averages of hand-held spirometry FEV1 and PEF values 
throughout study will be analyzed using analyzed using MMRM in a manner analogous to the 
analysis as described in Section 6.3.2. The corresponding baseline value will be included in the 
analysis models. Per the ICE handling strategy, for patients who did not complete the treatment 
period, observations after the end of the treatment period will be discarded and treated as missing 
observations.
In additional, weekly analysis windows (weeks 1 to 8) will be derived for each patient using 
algorithm detailed in Section 6.1.1. The weekly average of FEV1 and PEF during each analysis 
window will be calculated similarly using the formula above. The baseline will be the 
summation of reported usage from 7 days preceding day of randomization. The changes from 
baseline in weekly averages of hand-held spirometry FEV1 and PEF values during week 1 to 8
will be analyzed using analyzed using MMRM similarly.


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6.4.6.
Fractional Exhaled Nitric Oxide Throughout the Study
The concentration of nitric oxide in exhaled breath (FeNO) will be measured at screening, run-in,
all on-site visits during treatment period (visits 1, 2, 3, 4, 6, 7, 8, 9, and 10), and follow-up visit 
(visit 11).
The changes from baseline in FeNO throughout study will be analyzed using analyzed using 
MMRM in a manner analogous to the analysis as described in Section 6.3.2. The baseline FeNo
will be used in the analysis model. Per the ICE handling strategy, for patients who did not 
complete the treatment period, observations after the end of the treatment period will be 
discarded and treated as missing observations.


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7.
MULTIPLE COMPARISONS AND MULTIPLICITY
As there are only 2 treatment groups and one primary analysis test in this study, no multiplicity 
correction is necessary. Secondary endpoints will be considered as hypothesis-generating.


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8.
SAFETY ANALYSIS
8.1.
General
The safety analysis set (Section 3.3) will be used for all safety analyses. Summaries will be 
presented using descriptive statistics by treatment group as actually received unless otherwise 
stated. All data will be listed using ITT analysis set unless otherwise specified.
8.2.
Duration of Exposure to Study Drug
The patients will receive the IMP loading dose on the day of randomization (visit 1) and the 
subsequent corresponding IMP maintenance dose every 2 weeks (visits 2 to 4 and visits 6 to 9) 
for a total of 8 doses (
).
Duration of the treatment period (days), the number of doses received, and reasons for IMP not 
administrated (adverse event or other) will be summarized using descriptive statistics.
Duration of the treatment period (days) for a patient is defined as the number of days a patient is 
in the treatment period and calculated as the date of last IMP administration – the date of first 
IMP administration + 14.
IMP administration, IMP accountability data, and medical device malfunction data will be listed
using safety analysis set.
8.3.
Adverse Events
Adverse events will be recorded from time informed consent is obtained through the end of study 
participation.
All adverse events will be coded using MedDRA. Each patient will be counted only once in each 
preferred term or SOC category for the analyses of safety. Summaries will include 
treatment-emergent adverse events which are defined as adverse events occurring at or after the 
first dose of the IMP through the end of the follow-up visit. Listings will include all adverse 
events recorded.
Summaries will be presented for all adverse events (overall and by severity), adverse events 
determined by the investigator to be related to test IMP (defined as related or with missing 
relationship) (overall and by severity), adverse events determined by the investigator to be 
related to the medical device, or the study inhaler (defined as related or with missing 
relationship), serious adverse events, and adverse events causing drug withdrawal or 
discontinuation from the study. Adverse events with the missing flag indicating serious will be 
excluded from the summary of serious adverse events but included in the summary of non-
serious adverse events.
Summaries for clinical asthma exacerbation related adverse events, loss of asthma control related 
adverse events, injection site reaction adverse events, protocol-defined adverse events of special 
interest (PDAESI), PDAESI require completion of suspected anaphylaxis will also be presented.
Listings for deaths, serious adverse events, adverse events leading to drug withdrawn or the 
study discontinuation, clinical asthma exacerbation related adverse events, loss of asthma control 


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related adverse events, injection site reaction adverse events, PDAESI, and PDAESI require 
completion of suspected anaphylaxis, adverse event required concomitant or additional treatment
will be presented. In addition, listings for MedDRA dictionary terms for adverse event
descriptions and adverse event preferred terms by patient number and treatment group will be 
presented.
Adverse events for patients who did not meet screening criteria will be listed.
In additional, adverse events and serious adverse events occurred during the 10 weeks period
after the last dose of IMP will be summarized using descriptive statistics. These adverse events 
will be presented in a patient listing as well. Injection Site Assessments
Local tolerability assessments will be performed after each administration of IMP (visits 1 to 4 
and visits 6 to 9) and include administration site findings and pain. Administration site findings 
(erythema, ecchymosis, induration, tenderness, warmth, and swelling) will be assessed using the 
scales provided in Table 2. Pain at the administration site will be reported using 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?”
Table 2:
Administration Site Finding Severity Assessment
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)
- Induration surface diameter >100 mm (severe)
Tenderness
Warmth
Swelling
- None
- Mild
- Moderate
- Severe
The injection site assessments (erythema, ecchymosis, induration, tenderness, warmth, and 
swelling) at each visit will be summarized using descriptive statistics. For NRS-11 scale, the 
worst pain score overall and the pain score at each visit will be summarized descriptively. The 
data will be listed using safety analysis set.


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8.4.
Hypersensitivity/Anaphylaxis 
The event of anaphylaxis is considered as a PDAESI. The information about all suspected 
anaphylaxis and hypersensitivity events will be recorded on the Suspected Anaphylaxis CRF. 
PDAESI will be summaries (Section 8.3).
Suspected anaphylaxis data will be listed.
8.5.
Deaths
If any patient dies during the study, all relevant information will be discussed in the patient 
narrative included in the clinical study report.
8.6.
Clinical Laboratory Tests
Clinical laboratory tests (serum chemistry, hematology, coagulation, and urinalysis) will be 
performed at the time points detailed in Table 2 (screening and run-in), Table 3 (treatment 
period), and Table 4 (follow-up) of the study protocol. Clinical laboratory tests will be performed 
using the central laboratory. 
Laboratory test results will be presented in standard international (SI) units in summaries.
Laboratory values and changes from baseline to each visit and Last Assessment will be 
summarized using descriptive statistics. Shifts (below [low], within [normal], and above [high] 
the normal range) from baseline to each postbaseline visit and the Last Assessment will be 
summarized using patient counts. Baseline is defined as the last observed data before the 
administration of the first dose of the IMP (also see Section 4.2).
The potentially clinically significant abnormal values will be derived using criteria specified in 
Table 3 based on all postbaseline values (including scheduled, unscheduled, and withdrawal 
visits). The overall incidence of potentially clinically significant abnormal values will be 
summarized for laboratory variables using descriptive statistics by treatment group. Listings for 
patients who have potentially clinically significant abnormal laboratory data will be presented.
Table 3:
Criteria for Potentially Clinically Significant Laboratory Values
Test
Criterion value
Serum chemistry
  Alanine aminotransferase (ALT)
3x ULN
  Aspartate aminotransferase (AST)
3x ULN
Alkaline phosphatase (ALP)
3x ULN
  Gamma-glutamyl transpeptidase (GGT)
3x ULN
  Lactate dehydrogenase (LDH)
3x ULN
  Blood urea nitrogen (BUN)
10.71 mmol/L
  Creatinine
177 mol/L
  Bilirubin (total)
34.2 mol/L
Hematology


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Test
Criterion value
Hematocrit
Men
<0.37 L/L
Women
<0.32 L/L
Hemoglobin
Men
115 g/L
Women
95 g/L
WBC counts
3 x 109/L 
20 x 109/L
Eosinophils
10%
Absolute neutrophil count (ANC)
1 x 109/L
Platelet counts
75 x 109/L 
700 x 109/L
Urinalysis
   Hemoglobin
2 unit increase from baseline
Glucose
2 unit increase from baseline
Ketones
2 unit increase from baseline
Total protein
2 unit increase from baseline
ULN=upper limit of normal range; WBC=white blood cell
8.6.1.
Other Clinical Laboratory Tests
At screening, patients will be tested for hepatitis B surface antigen (HBsAg), antibodies to 
hepatitis C virus (HCV), human immunodeficiency virus (HIV) types 1 or 2, and Tuberculosis 
test.
COVID-19 testing will be available at the central laboratory. Locally performed COVID-19 
testing results will also be accepted.
Human chorionic gonadotropin (HCG) tests in serum and in urine will be performed for women 
of childbearing potential at the time points detailed in Table 2 (screening and run-in), Table 3
(treatment period), and Table 4 (follow-up) of the study protocol.
At screening, women who have been amenorrheic for at least 1 year without an alternative 
medical cause will have a serum follicle stimulating hormone (FSH) assessment to confirm 
postmenopausal status.
Other clinical laboratory tests results will be listed.
8.6.2.
Laboratory Values Meeting Hy’s Law Criteria
All occurrences of possible drug-induced liver injury that meet Hy’s law criteria as defined in the
Section 7.1.5.1 of the study protocol will be included in serious adverse events reporting.


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8.7.
Physical Examinations
Physical examinations will be performed at the time points detailed in Table 2 (screening and 
run-in), Table 3 (treatment period), and Table 4 (follow-up) of the study protocol. 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 of the study protocol. 
Physical exam findings that are attributable to another adverse event or to LoAC/CAEs would 
not be reported as separate adverse events.
Abnormal physical examination findings will be listed and summarized descriptively.
Height and weight will be obtained at the at the time points detailed in Table 2 (screening and 
run-in), Table 3 (treatment period), and Table 4 (follow-up) of the study protocol. Data will be 
summarized and listed with vital signs data.
8.8.
Vital Signs
Vital signs (blood pressure [systolic/diastolic], respiratory rate, body temperature, and pulse) will 
be measured at the time points detailed in Table 2 (screening and run-in), Table 3 (treatment 
period), and Table 4 (follow-up) of the study protocol. 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 of the protocol.
Vital signs (including weight) values and changes from baseline to each visit and the Last 
Assessment will be summarized using descriptive statistics. The incidence of potentially 
clinically significant abnormal values will be summarized for selected vital signs using 
descriptive statistics. Baseline is defined as the last observed data before the administration of 
the first dose of the IMP (also see Section 4.2).
Table 4 specifies the criteria for identifying vital signs as potentially clinically significant 
abnormal values. Note that in order to qualify as potentially clinically significant abnormal, a 
value needs to meet both criteria below: ie, have a value beyond the criterion value and a change 
of at least the magnitude specified in the change relative to baseline column. The potentially 
clinically significant abnormal vital signs values will include all postbaseline values (including 
scheduled, unscheduled, and early withdrawal visits) for the summaries.
Table 4:
Criteria for Potentially Clinically Significant Vital Signs
Vital Sign
Criterion value
Change relative to baseline
Pulse
120 bpm
Increase of 15 bpm
50 bpm
Decrease of 15 bpm
Systolic blood pressure
180 mm Hg
Increase of 20 mm Hg
90 mm Hg
Decrease of 20 mm Hg
Diastolic blood pressure
105 mm Hg
Increase of 15 mm Hg
50 mm Hg
Decrease of 15 mm Hg


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Table 4:
Criteria for Potentially Clinically Significant Vital Signs
Vital Sign
Criterion value
Change relative to baseline
Temperature
≥38.3C
Change of 1.1C
Bpm=beats per minute
Height will be measured at screening visit, and data will be listed in the vital sign listing.
8.9.
Electrocardiography
A 12-lead ECG will be recorded at the time points detailed in Table 2 (screening and run-in), 
Table 3 (treatment period), and Table 4 (follow-up) of the study protocol. ECGs should be 
performed in a supine position after 5 minutes rest.
All ECG 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
Any ECG finding that is judged by the investigator as clinically significant (except at the 
screening visit[s]) will be considered an adverse event, recorded on the source documentation 
and in the CRF, and monitored as described in Section 7.1.2 of the study protocol.
At DoR visit, triplicate measurements are required, each ECG will be taken within 1 to 5 minutes 
of the previous one. For analysis purpose, the mean of recorded results from the 3 measurements 
will be calculated and used for the analysis.
Baseline is defined as the last observed data before the administration of the first dose of the 
IMP. If the last observed data is at DoR visit, the mean of the 3 measurements will be used as the 
baseline ECG results and the worst value of the 3 recorded findings will be used as the baseline 
ECG finding.
ECG variable results and changes from baseline to each visit and the Last Assessment will be 
summarized using descriptive statistics. 
Baseline ECG findings and shifts (normal, abnormal not clinically significant, and abnormal 
clinically significant) from baseline to each visit, overall (worst value for a patient), and the Last 
Assessment will be summarized using patient counts.
8.10.
Concomitant Medications or Therapies 
Concomitant medications, treatments, or procedures will be collected up to the end of study.
All concomitant medications will be coded using the WHO Drug. The incidence of concomitant 
medications will be summarized using descriptive statistics by therapeutic class and preferred 
term. Patients are counted only once in each therapeutic class category, and only once in each 
preferred term category. The concomitant medications will include all medications taken after 
administration of the first IMP.


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Asthma medications will be summarized by the medication class separately.


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9.
TOLERABILITY VARIABLES AND ANALYSIS
Number (%) of patients who did not complete the study due to adverse events will be 
summarized descriptively.


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10.
PHARMACOKINETICS/PHARMACODYNAMICS (PK/PD)
ANALYSIS
Pharmacokinetic serum concentration results for TEV-48574 will be tabulated descriptively and 
listed at each planned sampling time point using pharmacokinetic analysis set.
PK/PD analyses are outside of the scope of this SAP.


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11.
BIOMARKER ANALYSIS
Biomarker analysis is outside of the scope of this SAP.
Listing of patients’ biomarker data may be provided if applicable.


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12.
IMMUNOGENICITY ANALYSIS
Immunogenicity analyses are outside of the scope of this SAP. 
Listing(s) of patients with positive ADA sample(s) and patient ADA status will be provided if 
applicable. 


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13.
PLANNED INTERIM ANALYSIS
An unblinded interim analysis is planned after the first 40-52 randomized patients have 
completed the treatment period, experienced LoAC, or withdrawn from the study completely. 
The main purposes of the interim analysis include a sample size re-assessment and a futility 
analysis, which will be described in sections 13.1 and 13.2 below.
The interim analysis will be conducted by an independent, unblinded statistician who is not a 
part of the study team. A group of the sponsor’s management team who are not a part of the 
study team may have access to the unblinded interim analysis results. A communication plan to 
ensure the maintenance of the study blind among the blinded personnel involved in the conduct 
of the study will specified in an interim analysis charter prior to the interim analysis.
13.1.
Sample Size Re-Assessment
The assumed LoAC event rate in the placebo group is 0.270. If the actual placebo event rate is 
lower than expected, the study will be underpowered to detect a 60% reduction in event rate. 
At the interim analysis, if the observed placebo event rate is lower than expected, and the 
observed treatment effect is at least a 40% reduction (event rate ratio ≤0.6), the sample size may 
be increased by up to 50 additional randomized patients, from the initially planned 124 to up to 
174. This procedure corresponds to a Promising Zone methodology and does not increase the 
Type I error rate (Mehta and Pocock 2011). Using an exhaustive enumeration of all possible trial 
outcomes, it is verified that the type I error rate is preserved when the interim unblinded sample 
size re-assessment is implemented:
Table 5:
Calculated Type 1 Error Rates with or without Sample Size Re-assessment
True Placebo 
Event Rate
Fixed Sample Size 
Design
Adaptive Sample Size 
Design
0.12
10.5%
9.5%
0.15
10.3%
9.7%
0.18
10.3%
10.0%
0.21
10.4%
10.2%
0.24
10.2%
10.1%
0.27
10.1%
10.0%
0.30
10.3%
10.3%
0.33
10.6%
10.6%
0.36
10.7%
10.7%
0.39
10.3%
10.3%
0.42
9.7%
9.7%
0.45
9.2%
9.2%


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13.2.
Futility Analysis
The interim futility analysis comprises a statistical comparison between treatment group versus 
placebo in LoAC rate using logistic regression among the randomized patients who have 
completed the treatment period, experienced LoAC, or withdrawn from the study completely at 
time of the interim analysis. The logistic regression model will include fixed effect for treatment,
age group (<65 years vs ≥65 years) and gender, as well as baseline FEV1 and baseline weight as 
covariates. A one-sided p-value above 0.5 will be declared as treatment efficacy futility, which 
could potentially result in early termination of the trial. According to simulation analyses, this 
cutoff value yields a correct early termination rates under the null hypothesis of 0.43 (40 
patients) and 0.44 (52 patients) and controls incorrect early termination rate under the alternative 
hypothesis at approximately and 0.06 (40 patients) and 0.04 (52 patients). The following table 
provides the correct early termination rates (under the alternative hypothesis) and the incorrect 
early termination rates (under the null hypothesis) at different interim analysis time points and 
using different p-value cut-offs, calibrated through simulations. The placebo LoAC rate is 
assumed to be 0.27.
Table 6:
Correct and Incorrect Early Termination Rates   
Interim Analysis 
Sample Size
(Total)
P-Value Cut-Off
Correct Early 
Termination Rate
Incorrect Early 
Termination Rate
20
>0.5
0.40
0.12
20
>0.33*
0.60
0.25
30
>0.5
0.42
0.08
30
>0.33
0.58
0.18
40
>0.5
0.43
0.06
40
>0.33
0.57
0.13
52
>0.5
0.44
0.04
52
>0.33
0.56
0.09
*0.33 cut-off shown for comparison purposes only; the actual futility cut-off is p > 0.5


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14.
STATISTICAL SOFTWARE
All data listings, summaries, and statistical analyses will be generated using SAS® version 9.4 or 
later.


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15.
CHANGES TO ANALYSES SPECIFIED IN THE STUDY 
PROTOCOL
None.


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16.
REFERENCES
1. Mallinckrodt C. Choosing primary estimands and analyses. In: Preventing and treating 
missing data in longitudinal clinical trials: A practical guide. New York: Cambridge 
University Press, 2013;103-10.
2. Wenzel S, Ford L, Pearlman D, Spector S, Sher L, Skobieranda, F et al. Dupilumab in 
persistent asthma with elevated eosinophil levels. N Engl J Med. 2013;368(26):2455-66.
3. Castro M, Corren J, Pavord ID, Maspero J, Wenzel S, Rabe KF et al. Dupilumab Efficacy 
and Safety in Moderate-to-Severe Uncontrolled Asthma. N Engl J Med 
2018;378(26):2486-2496. 
4. Mehta CR, Pocock SJ. Adaptive increase in sample size when interim results are 
promising: a practical guide with examples. Stat Med 2011;30(28):3267-84.