Clinical trial NCT05288504
Conditions: Non-Eosinophilic Asthma
Keywords: Non-Eosinophilic Asthma AVTX-002
Sponsor: Avalo Therapeutics, Inc.
Start date: 2022-02-24; Completion date: 2023-05-11
Enrollment: 91 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to evaluate the efficacy of AVTX-002 compared with placebo in patients with poorly controlled non-eosinophilic asthma (NEA).

Detailed description:

Arms: arm 1: Approximately 40 subjects will receive AVTX-002 at a dose of 600 mg three times during the study. arm 2: Approximately 40 subjects will receive placebo sourced as normal saline three times during the study.
Interventions: intervention 1: AVTX-002 intervention 2: Placebo
Intervention descriptions: intervention 1: Dose of 600 mg administered subcutaneously three times during the study. intervention 2: Placebo sourced as normal saline administered subcutaneously three times during the study.

Protocol documents:
Prot_000.pdf: 
PROTOCOL 
 
PRODUCT NAME: 
AVTX-002 
PROTOCOL NUMBER: 
AVTX-002-NEA-201 
IND NUMBER: 
 
DEVELOPMENT PHASE: 
Phase 2 
 
PROTOCOL TITLE: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 
Parallel Group Study to Evaluate the Safety and Efficacy of 
AVTX-002 for the Treatment of Poorly Controlled Non- 
Eosinophilic Asthma 
 
PROTOCOL VERSION AND 
DATE: 
 
COORDINATING/PRINCIPAL 
INVESTIGATOR: 
Version 5.0, 17 October 2022 
 
 
 
SPONSOR: 
Avalo Therapeutics, Inc. 
1500 Liberty Ridge Drive, Suite 321 
Wayne, PA 19087 
Phone: 610-254-4201 
Fax: 
443-304-8001 
 
CONTRACT RESEARCH 
ORGANIZATION: 
 
 
 
 
 
This study will be performed in compliance with Good Clinical Practices (GCP) and applicable regulatory 
requirements, including the archiving of essential documents. 
 
CONFIDENTIAL 
 
Information contained in this protocol is confidential in nature, and may not be used, divulged, published, 
or otherwise disclosed to others except to the extent necessary to obtain approval of the Institutional 
Review Board or Independent Ethics Committee, or as required by law. Persons to whom this information 
is disclosed should be informed that this information is confidential and may not be further disclosed 
without the express permission of Avalo Therapeutics, Inc. 


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1 
APPROVAL SIGNATURES 
 
PROTOCOL NUMBER: 
AVTX-002-NEA-201 
 
PROTOCOL TITLE: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 
Parallel Group Study to Evaluate the Safety and Efficacy of AVTX- 
002 for the Treatment of Poorly Controlled Non-Eosinophilic 
Asthma 
FINAL PROTOCOL: 
17 October 2022 
 
I, the undersigned, have read this protocol and confirm that to the best of my knowledge it 
accurately describes the planned conduct of the study. 
 
 
 


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2 
EMERGENCY CONTACT INFORMATION 
In the event of a serious adverse event (SAE), the investigator must e-mail the Serious Adverse 
Event Form within 24 hours to the CRO Pharmacovigilance Department using the email address 
noted below. For questions on SAE reporting, contact the drug safety mailbox noted below. 
• 
 
 
In the event of an SAE, the Investigator should also notify the Medical Monitor. All medical 
personnel and their contact details can be found in the site study documentation (study binder). 
For protocol safety-related issues, please first contact the Medical Monitor using the contact 
information below: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3 
Protocol Version History 
 
Document 
Date 
Original, Version 1.0 
28 September 2021 
Amendment 1, Version 2.0 
08 November 2021 
Amendment 2, Version 3.0 
05 January 2022 
Amendment 3, Version 4.0 
05 May 2022 
Amendment 4, Version 5.0 
17 October 2022 
 
 
Note: Administrative changes to the protocol have been made throughout the document to reflect change in 
version number and date of issue. Corrections of minor typographical errors and inconsistencies, grammar, 
improvement for comprehension, or corrections of abbreviations are not listed within the summary of 
changes. Major changes are reflected below: 
 
Summary of Changes, Amendment 4, Version 5.0 (17 October 2022): 
 
Section Number and Name 
Description of Change 
Brief Rationale 
4 SYNOPSIS, 
ENDPOINTS, Primary 
Endpoints 
 
7.2.1 Primary Endpoints 
 
10.2.2.1 Asthma Related 
Events 
 
 
Added text in bold:  
o 
Baseline SABA use (defined as the 
number of individual puffs or 
inhalations taken by the subject) will 
be determined by the average use in the 
7 days preceding Visit 2, 
o 
An asthma exacerbation requiring use 
of systemic corticosteroids (tablets, 
suspension, or injection) for at least 3 
days 
o 
a hospitalization or emergency 
room visit because of an asthma 
exacerbation 
 Additions made based upon a prior 
protocol clarification letter as well 
as to align the definition of an 
asthma related event with the 
American Thoracic 
Society/European Respiratory 
Society statement: asthma control 
and exacerbations: standardizing 
endpoints for clinical asthma trials 
and clinical practice (Reddel, 2009). 
4 SYNOPSIS, Study 
Entry Criteria 
 
8.5.1 Inclusion Criteria 
 
Added text in bold: 
5. Subjects must have had at least one asthma 
exacerbation in the last 24 months prior to 
Screening 
An asthma exacerbation is defined as 
follows:  
o 
a course of oral 
corticosteroids because of 
worsening asthma symptoms, 
and/or 
o 
at least a doubling of the 
subject’s inhaled 
corticosteroids for at least 14 
days because of worsening 
asthma symptoms.  
If a subject’s medical experience 
satisfies either or both statements, the 
Additions made based upon a prior 
protocol clarification letter. 


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subject has experienced an asthma 
exacerbation.   
 
SYNOPSIS, Study Entry 
Criteria 
 
8.5.2 Exclusion Criteria 
Added text in bold: 
3. Subjects who: 
• 
Are current smokers, users of inhaled 
cannabis and/or e-cigarettes/vaping 
devices or, 
Wording updated to clarify that 
inhaled cannabis and e-
cigarettes/vaping are also under the 
umbrella of smoking and are 
prohibited during study based on 
their ability to be an airway irritant. 
Table 1.  Schedule of 
Assessments 
Added: 
• 
Footnote 17: Site regular assessment of 
diary completion for compliance  
• 
Footnote 18: SABA use is defined as the 
number of individual puffs or inhalations 
taken by the subject. 
• 
Requirement for AVTX-002 Plasma (PK 
blood draw) at the Early Termination 
Visit.  This has been added to the table 
as well as Footnote 16. 
 
Additional footnotes made based 
upon a prior protocol clarification 
letter as well as to ensure regular 
review of diary data by sites. 
 
PK blood draw added as part of 
Early Termination visit in order to 
ensure information is available on 
AVTX-002 drug levels post last 
dose in subjects who discontinue 
from study early.  
Table 1.  Schedule of 
Assessments 
Updated (change noted in bold): 
Footnote 1  
If confirmation of eligibility is not available 
within 7 days from the date of Screening, the 
study Sponsor should provide approval for the 
subject to continue.  
TO 
If confirmation of eligibility is not available 
within 14 days from the date of Screening, the 
study Sponsor should provide approval for the 
subject to continue.  
 
Widened window for confirmation 
of eligibility to allow time to 
receive and review all screening 
visit data. 
Table 1.  Schedule of 
Assessments 
 
8.2 Discussion of Study 
Design  
 
 
Clarified that: 
Visit 1a may be completed either by 
telephone or as an in-clinic visit, depending 
upon the needs of the site or subject.  
Additions made based upon a prior 
protocol clarification letter. 
8.5 Study Entry Criteria  
 
Added: 
Subjects are to be enrolled based on the 
inclusion 
and 
exclusion 
criteria 
below.  The diagnosis of NEA is 
determined at Screening Visit 1 based 
upon Inclusion Criteria 2 through 5. At 
Baseline Visit 2, a review of all 
Inclusion/Exclusion criteria should be 
done to ensure continued eligibility prior 
to randomization and dosing the subject. 
As long as the subject qualifies as having 
NEA per protocol at the Screening Visit, 
there is no expectation that their 
diagnosis be re-confirmed at Baseline 
Visit 2, and therefore changes in 
eosinophil count and/or ACQ score 
within the period of time between 
Screening Visit 1 and Baseline Visit 2 
Additions made based upon a prior 
protocol clarification letter. 


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would not reverse their diagnosis and 
would not disqualify the subject.   
 
Although chemistry and hematology labs 
must be drawn as part of Baseline Visit 2 
procedures, there is not an expectation 
that these test results be available during 
the 
visit 
to 
re-confirm 
eligibility 
(Exclusion Criteria 12 and 13).   
 
Per the schedule of assessments, a urine 
pregnancy test must be completed and 
show negative results at Baseline Visit 2 
prior to randomization and dosing. 
Subjects with a positive urine pregnancy 
test should NOT be randomized and 
dosed with AVTX-002.   
 
8.7 Premature Subject 
Withdrawal  
12.3.1.1 Disposition and 
Withdrawals 
 
Added: 
Any subject who receives three doses of 
AVTX-002 or placebo by definition is 
considered as completing study therapy.  
 
Subjects who require systemic corticosteroids 
or other non-study drug for treatment of their 
asthma should be considered to have lack of 
efficacy and withdrawn from study drug.  
 
Subjects who meet one of the other protocol 
definitions of an asthma related event should 
also be considered to have lack of efficacy and 
be considered for withdraw from study drug.  
Instances where the Investigator feels that a 
subject meeting these criteria should continue 
receiving study drug should be discussed on a 
case-by-case basis with the medical monitor.  
 
Subjects who are prematurely withdrawn from 
study drug should be followed up as instructed 
in the schedule of assessments. 
 
 Given each dose of study drug 
equates to 4 weeks of therapy, 
clarified that subjects who receive 
all 3 doses are considered as 
completing study therapy.  
 
Also provided requirements for 
study drug discontinuation based 
upon meeting criteria for an asthma 
related event. 
9.11.4 Prohibited 
Therapies 
Added: 
Subjects 
who 
require 
systemic 
corticosteroids or another non-study 
asthma medication to treat an asthma 
exacerbation should be withdrawn from 
the study.  If a subject receives a systemic 
corticosteroid for another reason (e.g., 
bee sting), the Medical Monitor should 
be consulted regarding the subject’s 
continuation in the study. 
Additions made for clarification of 
withdrawal criteria previously 
omitted. 
10 STUDY 
PROCEDURES 
Added: 
In the event a subject cannot be in-clinic 
for a study visit after randomization due 
to pandemic, natural disaster, or other 
kinds of unforeseeable situations, sites 
should attempt to complete as many visit 
procedures as possible that can be done 
remotely, by phone or telehealth/video, 
on time and per protocol windows. This 
Additions made based upon a prior 
protocol clarification letter. 


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includes completion of study-required 
questionnaires which should be provided 
to the subject or reviewed via phone prior 
to the visit, if possible, so that the subject 
can 
be 
prepared 
with 
appropriate 
responses.   
The medical monitor should be consulted 
for 
decisions 
regarding 
dosing, 
laboratory testing, and other protocol 
procedures which are unable to be done 
remotely.   
If a visit is done remotely, it should be 
documented as such in subject source 
records.   
  
 
10.2.2.4 Peak Flow 
Meter 
 
10.2.2.7 Asthma 
Symptom Diary 
 
10.2.2.11 Short-Acting 
Beta Agonist Use 
Added: 
The site will monitor the diary entries 
closely to assess subject compliance. 
Subjects who are not compliant with the 
diary will be counseled by the site and 
will be considered protocol deviations if 
an overall compliance rate of less than 
80% is reached.    
Additions made for clarification of 
diary compliance previously 
omitted. 
11.1.1 Adverse Event 
Collection  
Updated: 
Previous 
wording: 
Lack 
of 
effect, 
including worsening of symptoms, disease 
progression, or lack of improvement, 
should not be recorded as an AE unless it 
meets the definition of the criteria for an 
SAE.  
 
 
New Wording: Events that meet the 
protocol definition of an asthma related 
event are captured as part of the primary 
efficacy endpoint for the study, and 
therefore need not be recorded as an AE 
unless they meet the definition of an 
SAE.  Asthma exacerbations that do not 
meet the protocol definition of an asthma 
related event should be captured as AEs. 
Clarifications of AE capture related 
to primary endpoint events.   
16 REFERENCES 
Added: 
Reddel HK, Taylor DR, Bateman ED, 
Boulet LP, Boushey HA, Busse WW, 
Casale TB, Chanez P, Enright PL, Gibson 
PG, Jongste JC, Kerstjens HAM, Lazarus 
SC, Levy ML, O’Byrne PM, Partridge 
MR, Pavord ID, Sears MR, Sterk PJ, 
Stoloff SW, Sullivan SD, Szefler SJ, 
Thomas MD, Wenzel SE. An official 
American 
Thoracic 
Society/European 
Respiratory Society statement: asthma 
control and exacerbations: standardizing 
endpoints for clinical asthma trials and 
clinical practice. Am J Respir Crit Care 
Med. 2009;180:59–99.  
Addition made to add American 
Thoracic Society/European 
Respiratory Society statement to 
references. 
 


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4 
SYNOPSIS 
 
PRODUCT NAME 
AVTX-002 (formerly known as MDGN-002, SAR252067) 
PROTOCOL NUMBER 
AVTX-002-NEA-201 
DEVELOPMENT 
PHASE 
Phase 2 
PROTOCOL TITLE 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to 
Evaluate the Safety and Efficacy of AVTX-002 for the Treatment of Poorly Controlled 
Non-Eosinophilic Asthma 
OBJECTIVES 
Primary Objective: 
• 
To assess the ability of AVTX-002 to improve asthma control in subjects with 
poorly controlled non-eosinophilic asthma (NEA). 
Secondary Objectives: 
• 
To assess the safety and tolerability of AVTX-002. 
• 
To evaluate biomarkers of pharmacodynamic (PD) activity and mechanism of 
action of AVTX-002. 
• 
To evaluate the immunogenicity of AVTX-002. 
Exploratory Objectives: 
• 
To assess the ability of AVTX-002 to improve asthma control in subjects with 
poorly controlled NEA who also have <150 eosinophils/ µL 
• 
To assess sputum soluble LIGHT levels and gene expression in a select subset of 
subjects 
• 
To evaluate inflammatory proteins including but not limited to: interleukin (IL)-6, 
interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α)  
• 
To evaluate the PK/PD relationship 
ENDPOINTS 
Primary Endpoint: 
• Proportion of patients who experience any of the following asthma-related events: 
o 
≥6 additional reliever puffs of SABA (compared to baseline) in a 24-hour 
period on 2 consecutive days or, 
• 
Baseline SABA use (defined as the number of individual puffs or 
inhalations taken by the subject) will be determined by the 
average use in the 7 days preceding Visit 2, 
o 
increase in ICS dose ≥4 times than the dose at baseline or, 
• 
Baseline ICS dose is defined as the dosage the subject received 
during the 30-day run-in period, 
o 
a decrease in peak flow of 30% or more (compared to baseline) on 2 
consecutive days of treatment or, 
• 
Baseline peak flow will be determined by the average of 
measurements in the 7 days preceding Visit 2 
o 
An asthma exacerbation requiring the use of systemic corticosteroids 
(tablets, suspension, or injection) for at least 3 days or, 
o 
a hospitalization or emergency room visit because of an asthma 
exacerbation. 
Secondary Endpoints: 
• 
Change from baseline in forced expiratory volume in 1 second (FEV1) at Weeks 2, 
4, 6, 8, 12, and 14. 
• 
Time to asthma related event 
• 
Change from baseline in fractional exhaled nitric oxide (FeNO) at Weeks 2, 4, 6, 
8, 12, and 14. 
• 
Change from baseline in Asthma Control Questionnaire (ACQ) at Weeks 2, 4, 6,     
8, 12, and 14. 


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• 
Change from baseline in Standardized Asthma Quality of Life Questionnaire for 
12 years and older (AQLQ(S)+12) at Weeks 2, 4, 6,  8, 12, and 14. 
• 
Change from baseline in Asthma Symptom Diary Score at Weeks 2, 4, 6,  8, 12, 
and 14. 
• 
Change from baseline in European Quality of Life – 5 Dimension 5 level 
Questionnaire at Weeks 2, 4, 6,  8, 12, and 14. 
• 
Change from baseline in Patient Global Impression of Change/Severity at Weeks 2, 
4, 6, 8, 12, and 14. 
• 
Change from baseline in Clinician Global Impression of Improvement/Severity at 
Weeks 2, 4, 6,  8, 12, and 14. 
• 
Incidence of SABA use at Weeks 2, 4, 6,  8, 12, and 14. 
• 
Change from baseline in serum soluble LIGHT (Lymphotoxin like, exhibits 
Inducible expression, and competes with Herpes Virus Glycoprotein D for 
Herpesvirus Entry Mediator) levels at Weeks 2, 4, 6,  8, 12, and 14. 
• 
Incidence of adverse events (AE), and changes from baseline in clinical laboratory 
tests, vital signs measurements, and physical examinations at Weeks 2, 4, 6,  8, 12, 
and 14. 
• 
Incidence of anti-drug antibodies (ADAs) at Weeks 2, 4, 6,  8, 12, and 14. 
 
Exploratory Endpoints: 
• 
Occurrence of asthma related events in subjects with <150 eosinophils/µL 
• 
Change from baseline in sputum soluble LIGHT and gene expression (select subset 
of sites/subjects only) 
• 
Change from baseline in inflammatory proteins including but not limited to: 
interleukin (IL)-6, interferon gamma (IFN-γ) and tumor necrosis factor alpha 
(TNF-α) 
• 
PK/PD assessments 
STUDY DESIGN 
Subjects will be screened for the study and complete a 30-day, stable therapy, run-in 
period with a long-acting beta agonist (LABA) (salmeterol 50 mcg twice daily) and an 
inhaled corticosteroid (ICS) (fluticasone starting dose at investigator discretion). After 
the 30-day run-in is complete, at the Baseline Visit (Day 0), subjects will be randomly 
assigned (1:1) to AVTX-002 or placebo. Fourteen days after randomization, subjects in 
each treatment group will discontinue salmeterol therapy at Visit 4 (Day 14). After an 
additional 14 days, at Visit 5 (Day 28), all subjects will taper fluticasone dose to 50%. 
At Visit 6 (Day 42), all subjects will discontinue the use of fluticasone therapy 
completely. AVTX-002 or placebo will be administered at Visit 2 (Day 0), Visit 5 (Day 
28) and Visit 7 (Day 56). AVTX-002 will be administered at a dose of 600 mg. The final  
visit will be on Day 98. 
PLANNED NUMBER 
OF SUBJECTS 
Approximately 80 completed subjects 
PLANNED NUMBER 
OF STUDY SITES 
Approximately 25 sites from the United States will participate 
STUDY ENTRY 
CRITERIA 
Inclusion criteria: 
1. Subject is ≥18 years of age at the time of informed consent. 
2. Documented non-eosinophilic asthma diagnosis (<300 eosinophils/µL). 
3. Symptoms consistent with a diagnosis of asthma that is poorly controlled as 
determined by an ACQ score ≥ 1.5. 
4. Poorly controlled asthma despite the use of a LABA and ICS for at least 3 
consecutive months immediately prior to screening. 
5. Subjects must have had at least one asthma exacerbation in the last 24 months 
prior to Screening.  An asthma exacerbation is defined as follows:  
o 
a course of oral corticosteroids because of worsening asthma symptoms, 
and/or 
o 
at least a doubling of the subject’s inhaled corticosteroids for at least 14 
days because of worsening asthma symptoms.  


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If a subject’s medical experience satisfies either or both statements, the subject has 
experienced an asthma exacerbation.   
6. Non-pregnant, non-lactating female subjects of childbearing potential who are 
heterosexually active and non-sterile male subjects with female sexual partners of 
childbearing potential agree to use a highly effective method of contraception 
during the treatment period and for 28 days following the last dose of study 
medication. A highly effective method of birth control is defined as one that results 
in a low failure rate (i.e., <1% per year) when used consistently and correctly, such 
as oral/injectable/inserted/implanted/transdermal contraceptives, condom with 
diaphragm, condom with spermicide, diaphragm with spermicide, intrauterine 
hormone-releasing system, or intrauterine device (IUD), or sexual abstinence. 
Contraception is not required where at least 6 weeks have passed since sterilization, 
defined as females having undergone one of the following surgeries: hysterectomy, 
bilateral tubal ligation or occlusion, bilateral oophorectomy, or bilateral 
salpingectomy; and males who are vasectomized. Contraception is not required 
where females are postmenopausal (defined as 12 consecutive months of 
spontaneous amenorrhea and age ≥51 years). Females of childbearing potential 
must have a negative pregnancy test as part of the screening assessment. 
7. Subject can understand and provide informed consent to participate in this study. 
 
Exclusion criteria: 
1. Pulmonary disease other than asthma. 
2. Currently on biologic therapy. Previous biologic therapy is permitted with 
adequate washout (12 weeks or 5 half-lives, whichever is longer). 
3. Subjects who:  
o 
Are current smokers, users of inhaled cannabis and/or e-cigarettes/vaping 
devices or 
o 
Have a history of smoking >/=10 pack years or 
o 
Have a history of inhaled cannabis >4 days/week for the most recent 3 
months prior to screening or 
o 
Use e-cigarettes or vaping devices >4 days/week for the most recent 3 
months prior to screening. 
4. Current suspected drug or alcohol abuse. 
5. Use of systemic immunosuppressants within the last 6 months. 
6. Use of systemic corticosteroids within 6 weeks prior to Screening or use of 
antibiotics within 4 weeks prior to Screening. 
7. Subjects that are pregnant or breastfeeding. 
8. Subject has a history of neoplasia (except for a curatively treated non-
melanoma skin tumor or carcinoma of the cervix treated in situ with no 
indication of recurrence) within the 10 years prior to Visit 1. 
9. Subject has a chronic, active infection or another disease, which entails a 
tendency towards infection. 
10. Subject has a chronic severe or uncontrolled medical disorder that might 
confound the results of safety assessments conducted in this study. 
11. Subject has a history of unresolved latent tuberculosis. 
12. Subject has alanine aminotransferase (ALT)/ aspartate aminotransferase (AST) 
>5 upper limit of   normal (ULN) and/or serum creatinine   concentration 
>1.5 mg/dL. 
13. Subject has hemoglobin ≤10 g/dL, neutrophils ≤1,500/µl, and/or platelets 
≤75,000/µl. 
14. Subject has received a live vaccine within 12 weeks prior to Visit 2. 
15. Subject has used an investigational product, including Emergency Use 
Authorization (EUA) vaccines, within 30 days of Visit 1. 
16. Subject has known or suspected intolerance or hypersensitivity to the 
investigational product(s), closely related compounds, or any ingredients of the 
investigational product. 
17. There is any concern on the part of the investigator regarding the subject’s 
safety, compliance, or suitability with respect to his/her participation in the 
study. 


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CONCOMITANT 
TREATMENT 
During the study, new initiation of investigational compounds or concomitant treatment 
with other asthma therapy is not permitted.  
INVESTIGATIONAL 
PRODUCT, DOSE 
AND MODE OF 
ADMINISTRATION 
AVTX-002   will   be   supplied   in single-use vials containing 300-mg AVTX- 002 
(concentration 150 mg/mL). AVTX-002 will be administered by a subcutaneous (SC) 
injection in the abdomen in a zone of 4 to 10 cm from the umbilicus with the injection 
site rotated based on the number of syringes used. 
REFERENCE 
PRODUCT 
Placebo will be sourced locally and provided as volume matched normal saline for 
injection and will be administered by an SC injection in the abdomen in a zone of 4 to 
10 cm from the umbilicus with the injection site rotated based on the number of syringes 
used. 
TREATMENT 
REGIMEN AND 
DURATION 
600 mg of AVTX-002 or placebo will be administered at Visit 2 (Day 0), Visit 5 (Day 
28), and Visit 7 (Day 56). A subject must be dosed with the Week 8 dose no 
later than Day 56. The investigational product will be prepared by an unblinded 
pharmacist or appropriately qualified individual. 
Fourteen days after randomization (Day 0), subjects in each treatment group will 
discontinue salmeterol therapy at Visit 4 (Day 14). After an additional 14 days, at Visit 
5 (Day 28), all subjects will taper fluticasone dose to 50%. At Visit 6 (Day 42), all 
subjects will discontinue the use of fluticasone therapy completely. 
COORDINATING 
PRINCIPAL 
INVESTIGATOR / 
PRINCIPAL 
INVESTIGATOR 
 
 
 
 
CRITERIA FOR 
EVALUATION 
Efficacy: 
• 
The efficacy of AVTX-002 will be determined by the occurrence of asthma  related 
events (primary endpoint), time to asthma related events, and change from baseline 
in the following parameters: FEV1; FeNO; ACQ; AQLQ(S)+12; Asthma 
Symptom Diary Score; European Quality of Life – 5 Dimension 5 level 
Questionnaire; Patient Global Impression of Change/Severity (PGI-C/S); Clinician 
Global Impression of Improvement/Severity (CGI-I/S); and incidence of short-
acting beta agonist (SABA) use. 
Safety: 
The safety of AVTX-002 will be determined by monitoring of AEs, clinical laboratory 
tests, vital signs measurements, and physical examinations. 
Pharmacodynamics: 
The PD of AVTX-002 will be determined by measuring the serum levels of LIGHT 
biomarker patterns. 
Immunogenicity: 
The immunogenicity of AVTX-002 will be determined by measuring ADA levels. 
Exploratory: 
• 
Evaluation of the primary endpoint in subjects with <150 eosinophils/µL 
• 
Sputum soluble LIGHT and gene expression (select subset of sites/subjects only) 
• 
Inflammatory proteins including but not limited to: IL-6, INF-γ, and TNF-α 
• 
AVTX-002 plasma concentrations at select timepoints 


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STATISTICAL 
METHODS 
For the primary variable, comparison of the proportions of subjects that had an 
asthma-related event will be via a Wald Z-test (continuity corrected).  Summary 
statistics will be provided via a 2x2 table showing the number and percentage with 
and without asthma-related events in each treatment group. The test statistic, its 
associated p-value and a 95% confidence interval for the treatment difference will 
also be provided. 
All other efficacy variables will be summarized using descriptive statistics. 
Descriptive statistics for continuous data will include number of subjects (n), mean, 
standard deviation, median, minimum, and maximum. Summaries of change from 
baseline variables will include only subjects who have both a baseline value and 
corresponding value at the timepoint of interest. Descriptive statistics for categorical 
data will include frequencies and percentages. 
 
AE data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The overall incidence of subjects having at least one AE will be 
summarized. The incidence of treatment-emergent adverse events (TEAEs) will be 
summarized by treatment group, system organ class (SOC), and preferred term (PT). 
Each subject will be counted only once per SOC and PT. For all continuous safety 
variables (e.g., laboratory and vital sign measures), descriptive statistics for all reported 
values and change from baseline values will be summarized by treatment group. 
SAMPLE SIZE 
DETERMINATION 
The sample size in this study will be approximately 80 with 40 subjects per 
treatment arm, randomized in a 1:1 ratio. The sample size estimate was based on 
the estimated proportions of patients in the two treatment groups expected to have 
an asthma related event as defined by the primary endpoint. In a study with another 
product, rates of 6% in the active group and 44% in the placebo group were 
observed (Wenzel, 2013). If these estimates were used as is, then a study with 40 
subjects per group would have over 95% power.  Considering likely variations from 
the cited study, estimates of sample were assessed assuming a Type I error of 5% 
and the proportion of subjects with an asthma related event ranging from 30% to 
50% in the placebo group and 5% to 8% in the active group. In the 20 such scenarios 
examined, only in the cases in which the difference between treatments gets below 
23% does the power fall slightly below 80%. In the vast majority of cases examined 
the power is greater than 90%. 
STUDY AND 
TREATMENT 
DURATION 
After the Screening visit, subjects will complete a 30-day, stable therapy, run-in until 
randomization at the Baseline Visit (Day 0). AVTX-002 or placebo will be 
administered at Visit 2 (Day 0), Visit 5 (Day 28), and Visit 7 (Day 56). The final visit 
will be on Day 98. 
The overall study duration will be up to approximately 135 days. 


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Table 1: 
Schedule of Assessments 
 
Procedure 
Screening 
30-Day  
Run-In Period 
Baseline 
Double-Blind Treatment Period 
Visit 
Visit 1 
 
Visit 1a 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit  9 / ET2 
Assessment Week 
-4 
 
-1 
0 
1 
2 
4 
6 
8 
12 
14 
Assessment Day 
Approxi- 
mately 
-371 
-30 
through 
-1 
-7 
0 
7 
14 
28 
42 
No later 
than 563 
84 
98 
Visit Window4 
NA 
 
-2 days 
+3 days5 
±1 day 
±1 day 
±3 days 
±3 days 
-3 days 
±3 days 
±3 days 
Phone Visit 
 
 
X6 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion review 
X 
 
 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Prior medications 
X 
X 
X 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
 
 
 
 
Concomitant medications 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X8 
 
 
X7 
 
X 
X7 
X 
X7 
X 
X 
Physical examination 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
FEV1 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
FeNO 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Peak Flow Test (Daily)9, 17 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ACQ 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
AQLQ(S)+12 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Asthma Symptom Diary (2xDaily)17 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record SABA Use (2xDaily)18 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EQ-5D-5L 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Patient Global Impression of 
Change/Severity 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Clinician Global Impression of 
Improvement/Severity 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
ADA10 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Serum: soluble LIGHT 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Inflammatory proteins 
X 
 
 
 
 
 
X 
 
X 
X 
X 


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Procedure 
Screening 
30-Day  
Run-In Period 
Baseline 
Double-Blind Treatment Period 
Visit 
Visit 1 
 
Visit 1a 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit  9 / ET2 
Assessment Week 
-4 
 
-1 
0 
1 
2 
4 
6 
8 
12 
14 
Assessment Day 
Approxi- 
mately 
-371 
-30 
through 
-1 
-7 
0 
7 
14 
28 
42 
No later 
than 563 
84 
98 
Visit Window4 
NA 
 
-2 days 
+3 days5 
±1 day 
±1 day 
±3 days 
±3 days 
-3 days 
±3 days 
±3 days 
Immunophenotyping of circulating 
immune cells 
 
 
 
X 
 
 
 
 
 
X 
X16 
Sputum: soluble LIGHT and 
gene expression11 
 
 
 
X 
 
 
 
 
 
X 
 
Plasma: AVTX-002 level 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X16 
Clinical laboratory tests 
(hematology, clinical chemistries) 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
 
X 
 
X 
 
 
X 
X 
X 
Serum pregnancy test12 
X 
 
 
 
 
 
 
 
 
X 
X 
Urine pregnancy test12 
 
 
 
X 
 
 
X 
 
X 
 
 
Study drug administration (onsite)13,14, 15 
 
 
 
X 
 
 
X 
 
X 
 
 
Salmeterol/Fluticasone Run-In 
 
X 
X 
 
 
 
 
 
 
 
 
Discontinue salmeterol 
 
 
 
 
 
X 
 
 
 
 
 
Taper/discontinue fluticasone 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
Abbreviations: ACQ=Asthma Control Questionnaire; ADA=anti-drug antibody; AQLQ(S)+12=Standardized Asthma Quality of Life Questionnaire for 12 years and older; 
ECG=electrocardiogram; European Quality of Life – 5 Dimension 5 Level; Questionnaire ET=early termination; FeNO=fractional exhaled nitric oxide; FEV1=forced expiratory volume 
in 1 second; LIGHT= Lymphotoxin like, exhibits Inducible expression, and competes with Herpes Virus Glycoprotein D for Herpesvirus Entry Mediator. 
 
1. Documentation of eligibility on all Inclusion and Exclusion Criteria is required before a subject can enter the study 30-day run-in period prior to Visit 2 (Randomization) when the subject 
is switched to stand alone Salmeterol and Fluticasone. Confirmation of eligibility should take place within a reasonable amount of time after the Screening Visit. If confirmation of eligibility 
is not available within 14 days from the date of Screening, the study Sponsor should provide approval for the subject to continue. 
2. If a subject discontinues from the study/study drug, the Visit 9/ET procedures will be performed 4 weeks post last dose (+3 days). 
3. A subject must be dosed with the Visit 7 (Week 8) dose no later than Day 56. 
4. After Visit 2 (Day 0), visits should be scheduled relative to Visit 2 (Day 0).  Visit 7 (Week 8) must not be performed later than Day 56. 
5.  Baseline visit to occur the day following completion of the 30-day run-in period with a window of an additional 3 days. 
6. Visit 1a (Day -7) may be completed either by telephone or may be completed as an in-clinic visit, depending on the needs of the site and/or each individual subject. Visit 1a should occur 
with 7 days remaining in the 30-Day Run-In (-2 Day window for Visit 1a). During this phone call/onsite visit, the subject should be reminded to begin daily peak flow testing, and daily 
completion of their diary to capture asthma symptoms, SABA use and daily peak flow values.   
7. At Visit 2 (Day 0), Visit 5 (Day 28), and Visit 7 (Day 56), pre- and post-dose vital signs will be measured: Pre-dose vital signs should be taken within 60 minutes before dosing. Post-dose 
vital signs should be taken at least 60 minutes after dosing, prior to discharge. 
8. Height will only be recorded at the Screening Visit. 


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9.  Subjects should record the best result of 3 attempts daily at home. Subjects should perform daily peak flow at approximately the same time each day between 10:00 AM and 2:00 PM. 
Subject should also bring peak flow meter to clinic visits. If peak flow has not been completed at home by the subject on the day of a clinic visit it should be completed at the clinic during 
the visit. 
10. In addition to ADA collection timepoints per the schedule of events, an ADA sample will be collected if an immunologically related adverse event is reported (e.g., a skin reaction, lupus-
like syndrome, unexplained thrombocytopenia). 
11. Select subset of sites/subjects only. 
12. For females of childbearing potential. A subject is not considered to be of childbearing potential if at least 6 weeks have passed since sterilization, defined as females having undergone 
one of the following surgeries: hysterectomy, bilateral tubal ligation or occlusion, bilateral oophorectomy, or bilateral salpingectomy; and males who are vasectomized. Contraception is 
not required where females are postmenopausal (defined as 12 consecutive months of spontaneous amenorrhea and age ≥51 years). 
13. On the day of Randomization when the first IP administration is required (Visit 2/Day 0), all visit procedures should be completed prior to IP administration. At the other IP administration 
Visit dates (Visit 5/Day 28 and Visit 7/Day 56), only the pharmacokinetic (PK), anti-drug antibody (ADA), Serum soluble LIGHT, inflammatory proteins and immunophenotyping samples 
must be collected prior to dosing. Other procedures can be performed as needed in the clinic on the visit day. 
14. Subjects will be required to remain in the clinic for at least 60 minutes after study drug administration for adverse event monitoring. 
15. Investigational product will be prepared by an unblinded pharmacist or appropriately qualified individual. 
16. Immunophenotyping and PK only required if an Early Termination visit is completed. Immunophenotyping and PK not required at Visit 9/Day 98. 
17. Site regular assessment of diary completion for compliance. 
18. SABA use is defined as the number of individual puffs or inhalations taken by the subject. 


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5 
TABLE OF CONTENTS 
 
PROTOCOL ...................................................................................................................................................... 1 
1 
APPROVAL SIGNATURES ........................................................................................................................... 2 
2 
EMERGENCY CONTACT INFORMATION ...................................................................................................... 3 
3 
PROTOCOL VERSION HISTORY .................................................................................................................................. 4 
4 
SYNOPSIS .................................................................................................................................................. 8 
TABLE 1: 
SCHEDULE OF ASSESSMENTS ................................................................................................................ 13 
5 
TABLE OF CONTENTS ............................................................................................................................... 16 
LIST OF TABLES .............................................................................................................................................. 19 
LIST OF ABBREVIATIONS ............................................................................................................................... 20 
6 
INTRODUCTION ...................................................................................................................................... 22 
6.1 
BACKGROUND AND RATIONALE IN NON-EOSINOPHILIC ASTHMA ............................................................................... 22 
6.2 
NONCLINICAL EXPERIENCE .................................................................................................................................. 22 
6.3 
CLINICAL EXPERIENCE ........................................................................................................................................ 24 
6.4 
SUMMARY OF POTENTIAL RISKS AND BENEFITS ...................................................................................................... 25 
7 
STUDY OBJECTIVES AND ENDPOINTS ....................................................................................................... 25 
7.1 
STUDY OBJECTIVES ............................................................................................................................................ 25 
7.1.1 
PRIMARY OBJECTIVE ....................................................................................................................................... 25 
7.1.2 
SECONDARY OBJECTIVES ................................................................................................................................. 25 
7.1.3 
EXPLORATORY OBJECTIVES .............................................................................................................................. 25 
7.2 
STUDY ENDPOINTS ............................................................................................................................................ 25 
7.2.1 
PRIMARY ENDPOINTS ..................................................................................................................................... 25 
7.2.2 
SECONDARY ENDPOINTS ................................................................................................................................. 26 
7.2.3 
EXPLORATORY ENDPOINTS ............................................................................................................................... 26 
8 
STUDY DESIGN ........................................................................................................................................ 27 
8.1 
OVERALL STUDY DESIGN AND PLAN ...................................................................................................................... 27 
FIGURE 1:      STUDY SCHEMA ....................................................................................................................................... 27 
8.2 
DISCUSSION OF STUDY DESIGN ............................................................................................................................ 27 
8.3 
STUDY SITES ..................................................................................................................................................... 28 
8.4 
SELECTION OF STUDY POPULATION ...................................................................................................................... 28 
8.5 
STUDY ENTRY CRITERIA ...................................................................................................................................... 28 
8.5.1 
INCLUSION CRITERIA ....................................................................................................................................... 29 
8.5.2 
EXCLUSION CRITERIA ...................................................................................................................................... 29 
8.6 
SCREEN FAILURES ............................................................................................................................................. 30 
8.7 
PREMATURE SUBJECT WITHDRAWAL .................................................................................................................... 30 
9 
TREATMENTS .......................................................................................................................................... 32 
9.1 
IDENTIFICATION OF INVESTIGATIONAL PRODUCT(S), DOSE AND MODE OF ADMINISTRATION .......................................... 32 
9.2 
LABELING AND PACKAGING ................................................................................................................................. 32 
9.2.1 
LABELING ..................................................................................................................................................... 32 
9.2.2 
PACKAGING .................................................................................................................................................. 32 
9.3 
TREATMENT PREPARATION ................................................................................................................................. 32 


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9.4 
TREATMENTS ADMINISTERED .............................................................................................................................. 32 
9.5 
DISPENSING AND STORAGE ................................................................................................................................. 33 
9.6 
BLINDING AND UNBLINDING TREATMENT ASSIGNMENT ........................................................................................... 33 
9.7 
SELECTION OF DOSES IN THE STUDY ..................................................................................................................... 33 
9.8 
DOSE ADJUSTMENT CRITERIA .............................................................................................................................. 34 
9.9 
DRUG ACCOUNTABILITY ..................................................................................................................................... 34 
9.10 
HANDLING AND DISPOSAL ................................................................................................................................ 34 
9.11 
PERMITTED AND PROHIBITED THERAPIES ............................................................................................................. 34 
9.11.1 
PRIOR THERAPIES ......................................................................................................................................... 34 
9.11.2 
CONCOMITANT THERAPIES ............................................................................................................................ 34 
9.11.3 
PERMITTED THERAPIES ................................................................................................................................. 35 
9.11.4 
PROHIBITED THERAPIES ................................................................................................................................. 35 
9.12 
TREATMENT AFTER END OF STUDY ..................................................................................................................... 35 
10 
STUDY PROCEDURES ............................................................................................................................. 35 
10.1 
STUDY DURATION ........................................................................................................................................... 36 
10.2 
ASSESSMENTS ................................................................................................................................................ 36 
10.2.1 
MEDICAL HISTORY ....................................................................................................................................... 36 
10.2.2 
EFFICACY .................................................................................................................................................... 36 
10.2.2.1 
ASTHMA RELATED EVENTS .......................................................................................................................... 36 
10.2.2.2 
FORCED EXPIRATORY VOLUME IN 1 SECOND (FEV1) ....................................................................................... 37 
10.2.2.3 
FRACTIONAL EXHALED NITRIC OXIDE (FENO) ................................................................................................ 37 
10.2.2.4 
PEAK FLOW METER ................................................................................................................................... 37 
10.2.2.5 
ASTHMA CONTROL QUESTIONNAIRE (ACQ) .................................................................................................. 37 
10.2.2.6 
STANDARDIZED ASTHMA QUALITY OF LIFE QUESTIONNAIRE FOR 12 YEARS AND OLDER (AQLQ(S)+12) ................... 37 
10.2.2.7 
ASTHMA SYMPTOM DIARY ......................................................................................................................... 37 
10.2.2.8 
EUROPEAN QUALITY OF LIFE – 5 DIMENSION 5 LEVEL QUESTIONNAIRE (EQ-5D-5L) ............................................ 37 
10.2.2.9 
PATIENT GLOBAL IMPRESSION OF CHANGE/SEVERITY ...................................................................................... 38 
10.2.2.10 
CLINICIAN GLOBAL IMPRESSION OF IMPROVEMENT/SEVERITY ......................................................................... 38 
10.2.2.11 
SHORT-ACTING BETA AGONIST USE ........................................................................................................... 38 
10.2.3 
SAFETY ....................................................................................................................................................... 38 
10.2.3.1 
CLINICAL LABORATORY SAFETY ASSESSMENTS ................................................................................................ 38 
10.2.3.1.2 
SAMPLED BLOOD VOLUME ...................................................................................................................... 39 
TABLE 2:         SAMPLED BLOOD VOLUME PER SUBJECT ..................................................................................................... 39 
10.2.3.1.3 
SPECIMEN HANDLING REQUIREMENTS ....................................................................................................... 39 
10.2.3.1.4 
EVALUATION OF LABORATORY VALUES ...................................................................................................... 40 
10.2.3.2 
CLINICAL EXAMINATIONS ............................................................................................................................ 40 
10.2.3.2.2 
ELECTROCARDIOGRAM ............................................................................................................................ 40 
10.2.3.2.3 
PHYSICAL EXAMINATION, WEIGHT, AND HEIGHT ......................................................................................... 40 
10.2.3.3 
ADVERSE EVENTS ...................................................................................................................................... 40 
10.2.4 
IMMUNOGENICITY ANALYSES ......................................................................................................................... 41 
10.2.5 
PHARMACOKINETIC, PHARMACODYNAMIC AND BIOMARKER ASSESSMENTS ............................................................ 41 
11 
ADVERSE EVENTS .................................................................................................................................. 41 
11.1 
DEFINITION OF ADVERSE EVENTS, PERIOD OF OBSERVATION, RECORDING OF ADVERSE EVENTS .................................... 41 
11.2 
SEVERITY OF ADVERSE EVENTS .......................................................................................................................... 42 
11.2.1 
RELATIONSHIP CATEGORIZATION .................................................................................................................... 43 
11.2.1.1 
OUTCOME AT THE TIME OF LAST OBSERVATION ............................................................................................. 43 
11.2.2 
SERIOUS ADVERSE EVENTS ............................................................................................................................. 43 
11.2.2.2 
REPORTING OF SERIOUS ADVERSE EVENTS ..................................................................................................... 43 
11.2.2.3 
SERIOUS ADVERSE EVENT DEFINITION .......................................................................................................... 44 
11.2.2.4 
SERIOUS ADVERSE EVENT COLLECTION TIME FRAME ....................................................................................... 44 
11.2.2.5 
SERIOUS ADVERSE EVENT ONSET AND RESOLUTION DATES .............................................................................. 44 


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11.2.3 
FATAL OUTCOME ......................................................................................................................................... 45 
11.3 
SPECIAL CONSIDERATIONS ................................................................................................................................ 45 
11.3.1 
PREGNANCY ................................................................................................................................................ 45 
11.3.2 
REPORTING TO REGULATORY AGENCY, INSTITUTIONAL REVIEW BOARD/ETHICS COMMITTEE (EC) AND SITE ................. 46 
12 
STATISTICS ............................................................................................................................................ 46 
12.1 
SAMPLE SIZE DETERMINATION .......................................................................................................................... 46 
12.2 
ANALYSIS POPULATIONS ................................................................................................................................... 46 
12.3 
STATISTICAL ANALYSES ..................................................................................................................................... 47 
12.3.1 
STUDY SUBJECTS AND DEMOGRAPHICS ............................................................................................................ 47 
12.3.1.2 
PROTOCOL DEVIATIONS ............................................................................................................................. 47 
12.3.1.3 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ................................................................................ 47 
12.3.2 
PRIOR AND CONCOMITANT MEDICATIONS ........................................................................................................ 47 
12.3.3 
EXPOSURE AND COMPLIANCE ......................................................................................................................... 47 
12.3.4 
SAFETY AND TOLERABILITY ANALYSES .............................................................................................................. 47 
12.3.4.1 
ADVERSE EVENTS ...................................................................................................................................... 48 
12.3.4.2 
CLINICAL LABORATORY EVALUATIONS ........................................................................................................... 48 
12.3.4.3 
VITAL SIGNS ............................................................................................................................................. 48 
12.3.5 
EFFICACY ANALYSES ..................................................................................................................................... 48 
12.3.6 
PHARMACOKINETIC, PHARMACODYNAMIC AND BIOMARKER ANALYSES ................................................................. 48 
12.3.7 
IMMUNOGENICITY ANALYSES ......................................................................................................................... 48 
12.3.8 
INTERIM ANALYSIS ....................................................................................................................................... 48 
13 
STUDY CONDUCT .................................................................................................................................. 49 
13.1 
SPONSOR AND INVESTIGATOR RESPONSIBILITIES .................................................................................................... 49 
13.1.1 
SPONSOR RESPONSIBILITIES ........................................................................................................................... 49 
13.1.2 
INVESTIGATOR RESPONSIBILITIES, PROTOCOL ADHERENCE, AND INVESTIGATOR AGREEMENT ..................................... 49 
13.2 
STUDY DOCUMENTS ........................................................................................................................................ 49 
13.2.1 
CASE REPORT FORMS ................................................................................................................................... 49 
13.2.2 
RECORDING AND RETENTION OF SOURCE DATA AND STUDY DOCUMENTS .............................................................. 50 
13.3 
DATA QUALITY CONTROL ................................................................................................................................. 50 
13.3.1 
ACCESS TO STUDY AND SOURCE DOCUMENTS ................................................................................................... 50 
13.3.2 
DATA MANAGEMENT ................................................................................................................................... 51 
13.3.3 
QUALITY ASSURANCE AUDIT / INSPECTION ....................................................................................................... 51 
13.4 
STUDY TERMINATION ...................................................................................................................................... 51 
13.5 
STUDY SITE CLOSURE ....................................................................................................................................... 51 
13.5.1 
RECORD RETENTION ..................................................................................................................................... 51 
13.5.2 
SAMPLE RETENTION ..................................................................................................................................... 52 
13.6 
CHANGES TO THE PROTOCOL ............................................................................................................................ 52 
13.7 
USE OF INFORMATION AND PUBLICATION ........................................................................................................... 52 
14 
PUBLIC POSTING OF STUDY INFORMATION ........................................................................................... 53 
15 
ETHICAL AND LEGAL CONSIDERATIONS ................................................................................................. 53 
15.1 
DECLARATION OF HELSINKI AND GOOD CLINICAL PRACTICE .................................................................................... 53 
15.2 
SUBJECT INFORMATION AND INFORMED CONSENT ................................................................................................ 53 
15.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEES ....................................................................................... 53 
15.4 
FINANCIAL DISCLOSURE ................................................................................................................................... 54 
15.5 
PRIVACY AND CONFIDENTIALITY ......................................................................................................................... 54 
16 
REFERENCES ......................................................................................................................................... 56 
INVESTIGATOR’S AGREEMENT ....................................................................................................................... 58 
 


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LIST OF TABLES 
Table 1: 
Schedule of Assessments ................................................................................. 9 
Table 2: 
Sampled Blood Volume per Subject .............................................................. 36 
Table 3: 
Assessment of Relationship to Investigational Product ................................. 40 


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LIST OF ABBREVIATIONS 
 
ACQ 
asthma control questionnaire 
ADA 
anti-drug antibody 
AE 
adverse event 
ALT 
alanine aminotransferase 
AQLQ (S)+12 
standardized asthma quality of life questionnaire for 12 years and older 
ARDS 
acute respiratory distress syndrome 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AUClast 
area under the serum concentration versus time curve from time zero to the 
last observed concentration 
AUC0-t 
area under the plasma concentration time curve from time zero to the 
last observed concentration 
AUC0-tau 
area under the curve from time zero to the time of the end of dosing 
interval 
CGI-I 
clinician global impression of improvement 
CGI-S 
clinician global impression of severity 
COVID-19 
coronavirus disease 2019 
Cmax 
maximum observed concentration 
CRA 
clinical research associate 
CRO 
contract research organization 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EC 
Ethics committee 
ET 
early termination 
EU 
European Union 
EUA 
Emergency Use Authorization 
FeNO 
fractional exhaled nitric oxide 
FEV1 
forced expiratory volume in 1 second 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICS 
inhaled corticosteroid 
IC50 
50% inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonization 


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IFN 
interferon 
IFN-γ  
Interferon gamma 
IgG4 
immunoglobulin G subclass 4 
IL 
interleukin 
IL- 6 
Interleukin 6 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
LABA 
long-acting beta agonist 
LIGHT 
Lymphotoxin-like, exhibits Inducible expression, and competes with 
Herpes Virus Glycoprotein D for Herpesvirus Entry Mediator, a 
receptor expressed by T lymphocytes 
Mab 
monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Affairs 
NEA 
non-eosinophilic asthma 
PGI-C 
patient global impression of change 
PGI-S 
patient global impression of severity 
PBMC 
peripheral blood mononuclear cells 
PK 
pharmacokinetic 
PD 
pharmacodynamic 
PT 
preferred term 
SABA 
short-acting beta agonist 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SD 
standard deviation 
SOC 
system organ class 
SOP 
standard operating procedure 
TEAE 
treatment emergent adverse event 
TNF 
tumor necrosis factor 
TNF-α 
tumor necrosis factor alpha 
t1/2 
terminal half-life 
tmax 
time to maximum observed concentration 
ULN 
upper limit of normal 
US 
United States 
VAS 
visual analog scale 
 
WHO 
World Health Organization 


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6 
INTRODUCTION 
6.1 
Background and Rationale in Non-Eosinophilic Asthma 
Asthma is a chronic disease of the lungs characterized by airway inflammation causing swelling 
and excess mucous production, and as a result, patients experience difficulty breathing which can 
be life threatening in severe cases (Boulet et al. 2000). Asthma affects approximately 25 million 
patients in the US and over 300 million globally (Centers for Disease Control, 2021, IHME, 
2019). There are classifications of asthma based on the inciting factors (allergic versus non- 
allergic) and the nature of the immune-inflammatory response (Th2 or low/no Th2) (Ray and 
Kolls 2017, Wenzel et al., 1999, Woodruff et al., 2009). An allergic or Th2 biased response is 
associated with eosinophilic classifications and related to type 2 cytokines IL-4, IL-5, and IL-13 
(Lambrecht, Hammad, and Fahy 2019). Non-allergic or low/absent Th2 response is associated 
with neutrophilic and pauci-granulocytic classifications, which as a group are called non- 
eosinophilic asthma and account for 40% - 50% of all asthma patients (Douwes et al. 2002, 
Stokes et al., 2016). 
 
The long-term control of asthma is typically accomplished through the use of long-acting 
bronchodilators in combination with inhaled corticosteroids as needed. For patients specifically 
with severe allergic asthma, biologic agents have been approved for treatment which target IgE 
(omalizumab) or the Th2-related cytokine pathways of IL-4 and IL-5 (mepolizumab, 
resilizumab, benralizumab, and dupilumab). The cytokine pathways identified as contributing to 
NEA include IL-6, IL-8, IL-17, IFNγ, TNFα, and G-CSF (Lambrecht, Hammad, and Fahy 2019). 
For NEA patients with severe disease, there are no approved agents related to these pathways 
and, as such, there remains a significant unmet medical need for these patients. Previously it was 
demonstrated that human bronchial epithelial cells express receptors for LIGHT (LTbR) and 
upon LIGHT stimulation of BEC there is a resulting broad gene expression of proinflammatory 
mediators, with these proinflammatory changes in gene expression being resistant to 
corticosteroid treatment; consistent with the clinical presentation of NEA (da Silva Antunes et al. 
2015). 
 
Human BEC cells express receptors for LIGHT (LTβR) and upon LIGHT stimulation of BECs 
in vitro there is a resulting broad gene expression of proinflammatory mediators (da Silva 
Antunes et al. 2015), which are resistant to corticosteroid treatment, consistent with the clinical 
presentation of NEA. Soluble proinflammatory mediators such as IL-6, IL-8, OSM, and MCP- 
1 were also detected in this in vitro system. In the clinic, administration of an oral CXCR2 
antagonist resulted in lowered sputum neutrophil counts and fewer mild exacerbations (Nair et 
al. 2012). Separately, sputum levels of soluble LIGHT positively correlated with increased 
sputum Th1 cytokine levels and neutrophil counts and negatively correlated with lung function 
(Romeo 2013). Along with soluble LIGHT detected in sputum, others have observed elevated 
serum levels of DcR3 in asthma patients, which are even greater during asthma exacerbations 
suggesting a response to elevated LIGHT levels in relation to asthma and disease activity 
(Kowal et al., 2019). 
 
6.2 
Nonclinical Experience 
 
 
 
 
 


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6.3 
Clinical Experience 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.4 
Summary of Potential Risks and Benefits 
 
 
 
 
 
 
 
 
 
7 
STUDY OBJECTIVES AND ENDPOINTS 
7.1 
Study Objectives 
 
7.1.1 Primary Objective 
• To assess the ability of AVTX-002 to improve asthma control in subjects with poorly 
controlled NEA 
7.1.2 Secondary Objectives 
• To assess the safety and tolerability of AVTX-002 
• To evaluate biomarkers of pharmacodynamic (PD) activity and mechanism of action of 
AVTX-002 
• To evaluate the immunogenicity of AVTX-002 
 
7.1.3 Exploratory Objectives 
• To assess the ability of AVTX-002 to improve asthma control in subjects with poorly 
controlled NEA who also have <150 eosinophils/ µL 
• To assess sputum soluble LIGHT levels and gene expression in a select subset of subjects 
• To evaluate inflammatory proteins including but not limited to: interleukin (IL)-6, 
interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) 
• To evaluate the PK/PD relationship 
7.2 
Study Endpoints 
 
7.2.1 Primary Endpoints 
• Proportion of patients who experience any of the following asthma related events: 
o  ≥6 additional reliever puffs of SABA (compared to baseline) in a 24-hour period on 2 
consecutive days or, 
• 
Baseline SABA use (defined as the number of individual puffs or inhalations 


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taken by the subject) will be determined by the average use in the 7 days 
preceding Visit 2, 
o increase in ICS dose ≥4 times than the dose at baseline or, 
• 
Baseline ICS dose is defined as the dosage the subject received during the 30-
day run-in period, 
o a decrease in peak flow of 30% or more (compared to baseline) on 2 consecutive days of 
treatment or, 
• 
Baseline peak flow will be determined by the average of measurements in the 
7 days preceding Visit 2 
o 
an asthma exacerbation requiring the use of systemic corticosteroids (tablets, suspension, 
or injection) for at least 3 days or, 
o a hospitalization or emergency room visit because of an asthma exacerbation. 
7.2.2 Secondary Endpoints 
• Change from baseline in forced expiratory volume in 1 second (FEV1) at Weeks 2, 4, 6, 8, 
12, and 14. 
• Time to asthma related event. 
• Change from baseline in fractional exhaled nitric oxide (FeNO) at Weeks 2, 4, 6, 8, 12, and 
14. 
• Change from baseline in Asthma Control Questionnaire (ACQ) at Weeks 2, 4, 6, 8, 12, 
and 14. 
• Change from baseline in Standardized Asthma Quality of Life Questionnaire for 12 years 
and older (AQLQ(S)+12) at Weeks 2, 4, 6, 8, 12, and 14. 
• Change from baseline in Asthma Symptom Diary Score at Weeks 2, 4, 6, 8, 12, and 14. 
• Change from baseline in European Quality of Life – 5 Dimension 5 level Questionnaire at 
Weeks 2, 4, 6, 8, 12, and 14. 
• Change from baseline in Patient Global Impression of Change/Severity at Weeks 2, 4, 6, 8, 12, 
and 14. 
• Change from baseline in Clinician Global Impression of Improvement/Severity at Weeks 2, 4, 
6, 8, 12, and 14. 
• Incidence of short-acting beta agonist (SABA) use at Weeks 2, 4, 6, 8, 12, and 14. 
• Change from baseline in serum soluble LIGHT levels at Weeks 2, 4, 6, 8, 12, and 14. 
• Incidence of adverse events (AEs), and changes from baseline in clinical 
laboratory tests, vital signs measurements, and  physical examinations at Weeks 2, 4, 6, 
8, 12, and 14. 
• Incidence of ADAs at Weeks 2, 4, 6, 8, 12, and 14. 
7.2.3 Exploratory Endpoints 
• Occurrence of asthma related events in subjects with <150 eosinophils/µL 
• Change from baseline in sputum soluble LIGHT and gene expression (select subset of 
site/subjects only) 
• Change from baseline in inflammatory proteins including but not limited to: IL-6, IFN-γ, 
and tumor necrosis factor alpha (TNF-α) 
• 
 PK/PD assessments 


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8 
STUDY DESIGN 
8.1 
Overall Study Design and Plan 
This is a randomized, double-blind, placebo-controlled, Phase 2 study to evaluate the safety and 
efficacy of AVTX-002 for the treatment of poorly controlled NEA. Upon confirmation of 
eligibility, subjects will complete a 30-day, salmeterol and fluticasone stable dose, run-in prior to 
randomization. At Baseline subjects will be randomized to receive either three doses of AVTX- 
002 at 600 mg (Days 0, 28 and 56) or they will receive 3 doses of placebo at the same time points.  
Subjects will then begin a withdrawal of salmeterol and fluticasone therapies. Subjects will 
discontinue salmeterol at Day 14 and then taper fluticasone use to 50% dose at Day 28. Fluticasone 
use will be completely discontinued at Day 42.  Subjects will be followed until Day 98. 
An adequate number of subjects will be enrolled to ensure approximately 80 subjects complete the 
study. 
All subjects will undergo efficacy, safety, PK/PD, and immunogenicity assessments. The efficacy  
of AVTX-002 will be determined by the occurrence of an asthma related event (primary endpoint), 
time to asthma related event, and change from baseline in the following parameters: FEV1; FeNO; 
ACQ; AQLQ(S)+12); Asthma Symptom Diary Score; European Quality of Life – 5 Dimension 5 
level Questionnaire; Patient Global Impression of Change/Severity (PGI-C/S); Clinician Global 
Impression of Improvement/Severity (CGI-I/S); and Incidence of short-acting beta agonist 
(SABA) use. All subjects will be monitored for AEs and will undergo physical exams, vital signs, 
and routine safety laboratory tests. The PK/PD of AVTX-002 will be determined by measuring 
the levels of AVTX-002 and LIGHT in addition to other biomarkers of NEA. Finally, the 
immunogenicity of AVTX-002 will be determined by measuring ADA levels. 
The study schema is displayed in Figure 1. 
 
Figure 1:      Study Schema 
 
 
 
 
8.2 
Discussion of Study Design 
This study will assess safety and efficacy of AVTX-002 in subjects with poorly controlled non- 
eosinophilic asthma. 
Subjects will be evaluated for enrollment at the Screening visit. If considered eligible for enrollment, 
subjects will undergo a 30-day, stable dose, run-in period with a LABA (salmeterol) and an ICS 


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(fluticasone). Documentation of eligibility on all Inclusion and Exclusion Criteria is required before 
a subject can enter the study 30-day run-in period prior to Visit 2 (Randomization) when the subject 
is switched to stand alone Salmeterol and Fluticasone. Confirmation of eligibility should take place 
within a reasonable amount of time after the Screening Visit. If confirmation of eligibility is not 
available within 14 days from the date of Screening, the study Sponsor should provide approval for 
the subject to continue. 
During the 30-day run-in, a visit (Visit 1a) should occur 7 days prior to Baseline, at Day  
-7 (-2 day window).  Visit 1a may be completed either by telephone or as an in-clinic visit, 
depending upon the needs of the site or subject.  During this visit, the subject should be reminded to 
begin daily peak flow measurements as well as completion of the daily diary to capture ASD, SABA 
use and daily peak flow values.   
After the run-in period, subjects will be randomized at the Baseline Visit (Day 0) to either AVTX-
002 administered at 600 mg or placebo. Subjects will receive AVTX-002 or placebo at Visit 2 (Day 
0), Visit 5 (Day 28) and Visit 7 (Day 56). Over the course of the first 42 days after randomization 
subjects will taper or discontinue use of products administered during their run-in period. Salmeterol 
will be discontinued at Visit 4 (Day 14), fluticasone use will be tapered to 50% dose at Visit 5 (Day 
28) and fluticasone will be discontinued completely at Visit 6 (Day 42). All subjects will proceed on 
AVTX-002 or placebo monotherapy until Visit 9 (Day 98), which is also the end of study visit. 
Efficacy will be assessed from Baseline Visit (Day 0) through Visit 9 (Day 98) per the schedule 
outlined in schedule of assessments (Table 1). 
The run-in period after Screening and before Baseline must be completed with a stand-alone 
LABA (salmeterol) and an ICS (fluticasone). Principal investigators will ensure subjects are 
transitioned to these stand-alone products at Run-In if the subject is not already on these products. 
If a subject must discontinue the study prior to Visit 9 (Day 98) for any reason, the subject will be 
required to complete an Early Termination Visit (Day 98 procedures). 
8.3 
Study Sites 
The study will take place at approximately 25 study sites in the US. 
 
8.4 
Selection of Study Population 
Subjects diagnosed with NEA (<300 eosinophils/µL) will be randomized into the study. An 
adequate number of subjects will be enrolled to ensure approximately 80 subjects complete the 
study. 
A screening log of study candidates will be maintained at each study site. 
 
8.5 
Study Entry Criteria 
Subjects are to be enrolled based on the inclusion and exclusion criteria below.  The diagnosis of 
NEA is determined at Screening Visit 1 based upon Inclusion Criteria 2 through 5. At Baseline 
Visit 2, a review of all Inclusion/Exclusion criteria should be done to ensure continued eligibility 
prior to randomization and dosing the subject. As long as the subject qualifies as having NEA per 
protocol at the Screening Visit, there is no expectation that their diagnosis be re-confirmed at 
Baseline Visit 2, and therefore changes in eosinophil count and/or ACQ score within the period of 
time between Screening Visit 1 and Baseline Visit 2 would not reverse their diagnosis and would 
not disqualify the subject.  
Although chemistry and hematology labs must be drawn as part of Baseline Visit 2 procedures, 


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there is not an expectation that these test results be available during the visit to re-confirm 
eligibility (Exclusion Criteria 12 and 13).  
Per the schedule of assessments, a urine pregnancy test must be completed and show negative 
results at Baseline Visit 2 prior to randomization and dosing. Subjects with a positive urine 
pregnancy test should NOT be randomized and dosed with AVTX-002.  
 
 
8.5.1 Inclusion Criteria 
Subjects must fulfill the following requirements to be randomized into the study: 
1. Subject is ≥18 years of age at the time of informed consent. 
2. Documented non-eosinophilic asthma diagnosis (<300 eosinophils/µL). 
3. Symptoms consistent with a diagnosis of asthma that is poorly controlled as determined 
by an ACQ score ≥ 1.5. 
4. Poorly controlled asthma despite the use of a LABA and ICS for at least 3 consecutive months 
immediately prior to the Screening Visit. 
5. Subjects must have had at least one asthma exacerbation in the last 24 months prior to Screening.  
An asthma exacerbation is defined as follows:  
• 
a course of oral corticosteroids because of worsening asthma symptoms, and/or 
• 
at least a doubling of the subject’s inhaled corticosteroids for at least 14 days because 
of worsening asthma symptoms.  
If a subject’s medical experience satisfies either or both statements, the subject has experienced 
an asthma exacerbation.   
6. Non-pregnant, non-lactating female subjects of childbearing potential who are heterosexually 
active and non-sterile male subjects with female sexual partners of childbearing potential agree 
to use a highly effective method of contraception during the treatment period and for 28 days 
following the last dose of study medication. A highly effective method of birth control is 
defined as one that results in a low failure rate (i.e., <1% per year) when used consistently and 
correctly, such as oral/injectable/inserted/implanted/transdermal contraceptives, condom with 
diaphragm, condom with spermicide, diaphragm with spermicide, intrauterine hormone- 
releasing system, or intrauterine device (IUD), or sexual abstinence. Contraception is not 
required where at least 6 weeks have passed since sterilization, defined as females having 
undergone one of the following surgeries: hysterectomy, bilateral tubal ligation or occlusion, 
bilateral oophorectomy, or bilateral salpingectomy; and males who are vasectomized. 
Contraception is not required where females are postmenopausal (defined as 12 consecutive 
months of spontaneous amenorrhea and age ≥51 years). Females of childbearing potential must 
have a negative pregnancy test as part of the screening assessment. 
7. Subject can understand and provide informed consent to participate in this study. 
 
8.5.2 Exclusion Criteria 
The presence of any of the following criteria excludes a subject from the study: 
1. Pulmonary disease other than asthma. 
2. Currently on biologic therapy. Previous biologic therapy is permitted with adequate washout (12 
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3. Subjects who:  
• 
Are current smokers, users of inhaled cannabis and/or e-cigarettes/vaping devices or, 
• 
Have a history of smoking >/=10 pack years or, 
• 
Have a history of inhaled cannabis >4 days/week for the most recent 3 months prior to 
screening or, 
• 
Use e-cigarettes or vaping devices >4 days/week for the most recent 3 months prior to 
screening. 
4. Current suspected drug or alcohol abuse. 
5. Use of systemic immunosuppressants within the last 6 months. 
6. Use of systemic corticosteroids within 6 weeks prior to Screening or use of antibiotics within 
4 weeks prior to Screening. 
7. Subjects that are pregnant or breastfeeding. 
8. Subject has a history of neoplasia (except for a curatively treated non-melanoma skin tumor or 
carcinoma of the cervix treated in situ with no indication of recurrence) within the10 years 
prior to Visit 1. 
9. Subject has a chronic, active infection or another disease, which entails a tendency towards 
infection. 
10. Subject has a chronic severe or uncontrolled medical disorder that might confound the results 
of safety assessments conducted in this study. 
11. Subject has a history of unresolved latent tuberculosis. 
12. Subject has alanine aminotransferase (ALT)/ aspartate aminotransferase (AST) >5 upper limit 
of normal (ULN) and/or serum creatinine concentration >1.5 mg/dL. 
13. Subject has hemoglobin ≤10 g/dL, neutrophils ≤1,500/µl, and/or platelets ≤75,000/µl. 
14. Subject has received a live vaccine within 12 weeks prior to Visit 2. 
15. Subject has used an investigational product, including Emergency Use Authorization (EUA) 
vaccines, within 30 days of Visit 1. 
16. Subject has known or suspected intolerance or hypersensitivity to the investigational 
product(s), closely related compounds, or any ingredients of the investigational product. 
17. There is any concern on the part of the investigator regarding the subject’s safety, compliance, 
or suitability with respect to his/her participation in the study. 
 
8.6 
Screen Failures 
Subjects who fail inclusion and/or exclusion criteria may be rescreened for the study with Sponsor 
approval. 
8.7 
Premature Subject Withdrawal 
All subjects will be advised that they are free to withdraw from participation in this study at any 
time, for any reason, and without prejudice. Every reasonable attempt should be made by the 
investigator to keep subjects in the study; however, subjects must be withdrawn from the study if 
they withdraw consent to participate. Investigators must attempt to contact subjects who fail to 
attend scheduled visits by telephone or other means to exclude the possibility of an AE being the 
cause of withdrawal. Should this be the cause, the AE must be documented, reported, and followed 
as described in Section 11.1.1. 


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Subjects can decline to continue receiving study drug at any time during the study. If this occurs, 
the investigator is to discuss with the subject the completion of the Early Termination Visit to 
occur 4 weeks (±3 days) post last dose. If the subject refuses this visit/procedures associated with 
this visit, data on concomitant medications and AEs will be collected if the subject agrees.    Data on 
concomitant medications and AEs can be collected via a telephone call if the subject refuses an in-
person visit. 
Withdrawal of consent for a study means the subject does not wish to receive further protocol- 
required treatment or procedures, and the subject does not wish to or is unable to continue further 
study participation. Subject data up to withdrawal of consent will be included in the analysis of the 
study, and where permitted, publicly available data can be included after withdrawal of consent.   
Any subject who receives three doses of AVTX-002 or placebo by definition is considered as 
completing study therapy. 
The Sponsor reserves the right to request the withdrawal of a subject due to protocol deviations or 
other reasons. 
The investigator also has the right to withdraw subjects from the study at any time for any reason. 
If a subject is withdrawn before completing the study, the subject should be followed-up as 
instructed in the schedule of assessments (Table 1). The reason for withdrawal must be determined 
by the investigator and recorded in the subject’s medical record and on the electronic case report 
form (eCRF) as well as the date of discontinuation. If a subject is withdrawn for more than 1 
reason, each reason should be documented in the source document and the most clinically relevant 
reason should be entered on the eCRF. 
Reasons for discontinuation include but are not limited to: 
• Lack of efficacy 
• Adverse event 
• Death 
• Protocol deviation 
• Physician decision 
• Sponsor request 
• Withdrawal by subject 
• Lost to follow-up 
• Other (specify). For example, pregnancy. 
 
Subjects who require systemic corticosteroids or other non-study drug for treatment of their asthma 
should be considered to have lack of efficacy and withdrawn from study drug.  
 
Subjects who meet one of the other protocol definitions of an asthma related event should also be 
considered to have lack of efficacy and be considered for withdraw from study drug.  Instances where 
the Investigator feels that a subject meeting these criteria should continue receiving study drug should 
be discussed on a case-by-case basis with the medical monitor.  
 
Subjects who are prematurely withdrawn from study drug should be followed up as instructed in the 
schedule of assessments. 
 


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9 
TREATMENTS 
9.1 
Identification of Investigational Product(s), Dose and Mode of Administration 
The following investigational product will be used in this study: 
• AVTX-002 will be supplied in single-use vials containing 300 mg AVTX-002 
(concentration 150 mg/mL). 
• Placebo will be sourced locally and provided as volume-matched normal saline for 
injection. 
• AVTX-002 or placebo will be administered by SC injection in the abdomen in a zone of 
4 to 10 cm from the umbilicus, with the injection site rotated based on the number of 
syringes used. 
• AVTX-002 or placebo will be administered at Visit 2 (Day 0), Visit 5 (Day 28), and Visit 7 
(Day 56). AVTX-002 will be administered at a dose of 600 mg. 
 
9.2 
Labeling and Packaging 
All packaging and labeling operations will be performed by the Sponsor or designee per Good 
Manufacturing Practice (GMP) and Good Clinical Practice (GCP). The investigational product 
will be sent to the study site by the Sponsor or designee. Labeling will be in local language and 
dependent upon local regulations. 
 
9.2.1 Labeling 
The AVTX-002 vials will have affixed a label that meets the applicable regulatory requirements 
and may include the following: name of compound, dosage strength, medication identifier, 
protocol number, caution statement (“New Drug – Limited by Federal (or United States) Law to 
Investigational Use”), storage conditions, and Sponsor identification. 
The investigator will be asked to save all used or unused vials for final disposition by the Sponsor. 
Syringes used for dosing must be treated as biologic waste and disposed of properly. 
 
9.2.2 Packaging 
AVTX-002 will be supplied in single-use, 2.0 mL vials containing 300 mg AVTX-002 
(concentration 150 mg/mL). Vials will be packaged separately into bulk, open-labeled cartons. 
Placebo will be sourced locally and supplied as volume-matched normal saline for injection. 
 
9.3 
Treatment Preparation 
Preparation of syringes will be described in the pharmacy manual. 
 
9.4 
Treatments Administered 
Eligible subjects will receive 600 mg AVTX-002 or placebo SC on Visit 2 (Day 0), Visit 5 (Day 
28), and Visit 7 (Day 56).  


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9.5 
Dispensing and Storage 
AVTX-002 supplied by the Sponsor is to be used exclusively in this clinical study per the 
instructions of this protocol. Placebo will be sourced locally and provided as volume-matched 
injection of normal saline. The investigator is responsible for dispensing the investigational 
product per the dosage scheme and for ensuring proper storage of the investigational product. 
The unblinded pharmacist or appropriately qualified individual must confirm the receipt of the 
investigational product with his/her signature. A copy of this receipt must be kept by the unblinded 
pharmacist or appropriately qualified individual, and another copy will be stored at the Sponsor 
and/or designee. Until the investigational product is dispensed to the subjects, it must be stored at 
2°C to 8°C (35.6 °F to 46.4 °F) and protected from light. Investigators or other authorized persons 
(e.g., pharmacists) are responsible for storing the investigational product provided by the Sponsor 
in a secure and safe place in accordance with local regulations, labeling specifications, institutional 
policies, and procedures. 
Control of storage conditions for the investigational product provided by the Sponsor, especially 
control of temperature (e.g., refrigerated storage) and daily temperature monitoring, and 
information on in-use stability and instructions for handling the investigational product must be 
managed according to the rules provided by the Sponsor in the pharmacy manual. 
9.6 
Blinding and Unblinding Treatment Assignment 
This is a double-blind study. All subjects, investigators, and study personnel involved in the 
conduct of the study will be blinded to treatment assignment except as outlined in study specific 
blind management plans.  
Treatment unblinding is discouraged if knowledge of the treatment assignment will not materially 
change the planned management of a medical emergency. Unblinding is permitted in a medical 
emergency that requires immediate knowledge of the subject’s treatment assignment. Whenever 
possible unblinding should be discussed with the medical monitor. For emergency unblinding, the 
investigator can unblind in the IRT/eCRF. If the investigator is not able to discuss treatment 
unblinding with the medical monitor in advance of the unblinding, then they should notify the 
medical monitor as soon as possible about the unblinding incident without revealing the subject’s 
treatment assignment. The investigator or designee must record the date and reason for study 
discontinuation on the appropriate eCRF for that subject. In all cases that are not emergencies, the 
investigator should discuss the event with the medical monitor prior to unblinding the subject’s 
treatment assignment. 
If the treatment assignment is unblinded for an individual subject, the investigator will be notified 
of that subject’s treatment assignment without unblinding the treatment assignments for the 
remaining subjects in the study. 
 
9.7 
Selection of Doses in the Study 
 
 
 
 
Based on the PK data and favorable 


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safety profile of 
, the AVTX-002 dose in 
AVTX-002-NEA-201 will be 600 mg once monthly for a total of 3 doses. This dosing regimen is 
expected to provide higher serum AVTX-002 concentrations prior to discontinuation of salmeterol 
at study day 14 with the 28-day dosing interval limiting the potential for accumulation with the 2 
subsequent doses. 
 
9.8 
Dose Adjustment Criteria 
No dose adjustments are allowed. 
 
9.9 
Drug Accountability 
The investigator must ensure that adequate records showing the receipt, dispensing, or other 
disposition of the investigational product including the date, lot identifier, dosage, volume 
administered to each subject, and identification of subjects (subject number and initials) who 
received the investigational product are maintained by an unblinded pharmacist. The investigator 
will not supply the investigational product to any person except those named as sub-investigators 
on the US Food and Drug Administration (FDA) Form FDA 1572 and designated study personnel, 
and subjects in this study. The investigator will not dispense the investigational product from any 
study locations other than those listed on Form FDA 1572. If any of the investigational product is 
not dispensed, is lost, stolen, spilled, unusable, or received in a damaged container, this 
information must be documented and reported to the Sponsor and appropriate regulatory agencies, 
as required. 
Upon completion of the study, unused investigational product, partially used investigational 
product and all empty packaging (e.g., vials) must be left in the original packaging for return and 
final disposition by the Sponsor or their designee or destroyed locally per the site’s standard 
practice after receiving approval from the Sponsor. 
 
9.10 Handling and Disposal 
Investigational product reconciliation must be performed at the site by the unblinded pharmacist(s) 
or appropriately qualified individual(s) using treatment log forms or within the IRT system.  After 
reconciliation authorization by the Sponsor, all used, partially used, and unused vials and all 
original packaging will be disposed of by the Sponsor or per the site’s standard practice. This 
process will be provided to the site by the Sponsor’s designee. 
9.11 Permitted and Prohibited Therapies 
All non-study therapies including but not limited to over the counter and non-pharmacological 
treatments from the time of Screening (Visit 1) and through the end of study must be recorded on 
the appropriate eCRF page.  Record of ICS and LABA use should be captured for the three months 
immediately prior to Screening. 
 
9.11.1 Prior Therapies 
Prior therapies include all therapies received from the Screening Visit (Visit 1) to just prior to 1st 
dose of study drug, with the exception of ICS and LABA which should also be recorded for the 3 
months immediately prior to Screening (Visit 1). Prior therapy information must be recorded on 
the appropriate eCRF page. 
9.11.2 Concomitant Therapies 
Concomitant therapies refer to all therapies taken on or after the first dose of study drug through 


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the last visit. Concomitant therapy information must be recorded on the appropriate eCRF page. 
 
9.11.3 Permitted Therapies 
Medications considered necessary for the subject’s welfare, may be administered at the discretion 
of the investigator. The medical monitor should be contacted in the event the site is in a situation 
where further clarity is needed. 
Acceptable methods of birth control considered to be highly effective (e.g., results in a low failure 
rate 
[i.e., 
<1% 
per 
year]) 
when 
used 
consistently 
and 
correctly, 
include 
oral/injectable/inserted/implanted/ transdermal contraceptives, condom with diaphragm, condom 
with spermicide, diaphragm with spermicide, intrauterine hormone-releasing system or IUD, or 
sexual abstinence. 
 
9.11.4 Prohibited Therapies 
During the study, new initiation of investigational compounds or concomitant treatment with other 
asthma therapy is not permitted. The use of systemic corticosteroids, biologics, immunosuppressants 
and inhaled anticholinergics is not permitted.   Subjects who require systemic corticosteroids or 
another non-study asthma medication to treat an asthma exacerbation should be withdrawn from the 
study.  If a subject receives a systemic corticosteroid for another reason (e.g., bee sting), the Medical 
Monitor should be consulted regarding the subject’s continuation in the study. 
Leukotriene inhibitors are not allowed to be added to a subject’s treatment regimen after they are 
screened for the study.  Subjects who are on leukotriene inhibitors as part of their prior therapy at 
Screening (Visit 1) may continue on leukotriene inhibitors during the course of study participation. 
 
9.12 Treatment after End of Study 
Subjects will be treated per standard clinical practice following completion of participation in the 
study. 
10 STUDY PROCEDURES 
Subjects will provide written informed consent before any study-related procedures are initiated. 
For the timing of assessments and procedures throughout the study, refer to the schedule of 
assessments (Table 1). Throughout the study, every reasonable effort should be made by study 
personnel to follow the timing of assessments and procedures in the schedule of events for each 
subject. Visits performed after Visit 2 should be scheduled relative to Visit 2. If a subject misses a 
study visit for any reason, the visit should be rescheduled as soon as possible. Permitted visit 
windows are noted in the schedule of assessments (Table 1). 
In the event a subject cannot be in-clinic for a study visit after randomization due to pandemic, 
natural disaster, or other kinds of unforeseeable situations, sites should attempt to complete as 
many visit procedures as possible that can be done remotely, by phone or telehealth/video, on time 
and per protocol windows. This includes completion of study-required questionnaires which 
should be provided to the subject or reviewed via phone prior to the visit, if possible, so that the 
subject can be prepared with appropriate responses.  
The medical monitor should be consulted for decisions regarding dosing, laboratory testing, and 
other protocol procedures which are unable to be done remotely.  
If a visit is done remotely, it should be documented as such in subject source records.  
 
 


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10.1 Study Duration 
AVTX-002 and placebo treatment will be administered at Visit 2 (Day 0), Visit 5 (Day 28), and 
Visit 7 (Day 56). A subject may not be dosed after Day 56. The duration of the treatment period 
is considered 84 days, with each dose of study drug considered to be 28 days of treatment.  The 
overall study period is approximately 135 days, including Screening and the 30-day, stable dose, run-
in period. 
 
10.2 Assessments 
 
10.2.1 Medical History 
A medical and surgical history will be taken at Screening. All significant medical history findings 
that have been present or active within the 5 years prior to screening will be entered into the eCRF. 
Medical history findings that have not been present within the 5 years prior to screening will be 
recorded if deemed clinically relevant by the investigator to the conduct of the study. 
Additionally, the subject’s overall NEA history will be captured at Screening. This includes but is 
not limited to the approximate date of diagnosis and prior treatment including approximate start 
and stop dates. 
 
10.2.2 Efficacy 
Efficacy response will be assessed by the procedures listed below at the time points mentioned in 
the schedule of assessments (Table 1). 
10.2.2.1 Asthma Related Events 
The proportion of patients who experience any of the following asthma related events and time to the 
asthma related event will be determined: 
 
o  ≥6 additional reliever puffs of SABA (compared to baseline) in a 24-hour period on 2 
consecutive days or, 
• 
Baseline SABA use (defined as the number of individual puffs or inhalations 
taken by the subject) will be determined by the average use in the 7 days 
preceding Visit 2, 
o increase in ICS dose ≥4 times than the dose at baseline or, 
• 
Baseline ICS dose is defined as the dosage the subject received during the 30-
day run-in period, 
o a decrease in peak flow of 30% or more (compared to baseline) on 2 consecutive days of 
treatment or, 
• 
Baseline peak flow will be determined by the average of measurements in the 7 
days preceding Visit 2. 
o 
an asthma exacerbation requiring the use of systemic corticosteroids (tablets, suspension, 
or injection) for at least 3 days or 
o 
a hospitalization or emergency room visit because of an asthma exacerbation. 
 
Time to event will be measured in days using the first day of the event above to denote the day of the 
overall asthma related event occurrence. 
 
Subjects meeting any of the above criteria for an asthma related event will be permitted to restart 
background (pre-study) therapy, or alternate asthma therapy. If background/alternate therapy is 
reinitiated/started, the patient must be withdrawn from the study.  
 


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10.2.2.2 Forced Expiratory Volume in 1 Second (FEV1) 
The FEV1 is the volume of air that can be forcibly exhaled from the lungs in the first second, 
measured in liters by a spirometer and reported as a percent of expected volume. 
10.2.2.3 Fractional Exhaled Nitric Oxide (FeNO) 
A FeNO test measures the levels of nitric oxide during exhalation. A FeNO test will be done by 
breathing into a tube attached to a hand-held monitor. 
10.2.2.4 Peak Flow Meter 
A peak flow meter measures how well lungs are able to expel air. Subjects will measure peak 
flow daily on a device provided by the Sponsor and record the results in their diary. The site 
will monitor the diary entries closely to assess subject compliance. Subjects who are not 
compliant with the diary will be counseled by the site and will be considered protocol 
deviations if an overall compliance rate of less than 80% is reached.   
10.2.2.5 Asthma Control Questionnaire (ACQ) 
This is a simple questionnaire to measure the adequacy of asthma control and change in asthma 
control. ACQ has a multidimensional construct assessing symptoms (5 items, self-administered), 
rescue bronchodilator use (1 item, self-administered), and FEV1 (1 item, completed by study staff). 
Scores range between 0 (totally controlled) and 6 (severely uncontrolled) (Juniper et al, 2005). 
10.2.2.6 Standardized Asthma Quality of Life Questionnaire for 12 years and older 
(AQLQ(S)+12) 
The AQLQ(S)+12 is a modified version of the standardized AQLQ, which was developed to 
measure functional impairments experienced by adults aged ≥17 years. The AQLQ(S)+12 is valid 
for patients aged 12 to 70 years and includes 32 questions in 4 domains (symptoms, activity 
limitation, emotional function, and environmental stimuli) (Juniper et al, 1992; Wyrwich et al, 
2011). 
Subjects will be asked to recall their experiences during the previous 2 weeks and score each of 
the questions on a 7-point scale, where 7=not at all limited and 1=totally limited. The overall score 
of the AQLQ +12 will be derived as the average of the 32 questions; thus, the total score ranges 
from 1 (indicates "total impairment") to 7 (indicates "no impairment"). 
10.2.2.7 Asthma Symptom Diary 
The Asthma Symptom Diary is a 6-item daily measure of asthma symptom severity that 
assesses three core categories of asthma symptoms: breathing symptoms (difficulty 
breathing; wheezing; shortness of breath), chest symptoms (chest tightness; chest pain), and 
cough. The Asthma Symptom Diary is intended for twice daily completion and comprises a 
morning diary (for completion upon waking and referring to asthma symptoms during the 
nighttime) and an evening diary (for completion before going to bed and referring to asthma 
symptoms during the day). Subjects are required to rate the 6 symptoms at their worst during 
the respective timeframes using an 11-point numeric rating scale ranging from 0 (‘None’) to 
10 (‘As bad as you can imagine’) (FDA, n.d.). The site will monitor the diary entries closely 
to assess subject compliance. Subjects who are not compliant with the diary will be 
counseled by the site and will be considered protocol deviations if an overall compliance rate 
of less than 80% is reached.   
10.2.2.8 European Quality of Life – 5 Dimension 5 level Questionnaire (EQ-5D-5L) 
The EQ-5D-5L consists of the EQ-5D descriptive system and the EQ visual analogue scale (EQ 


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VAS). The descriptive system comprises five dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight 
problems, moderate problems, severe problems, and extreme problems. The EQ VAS records the 
subject’s self-rated health on a vertical VAS, where the endpoints are labelled ‘The best health you 
can imagine’ and ‘The worst health you can imagine’ (EuroQol, 2017). 
10.2.2.9 Patient Global Impression of Change/Severity 
The Patient Global Impression of Change or Severity (PGI-C, PGI-S) scale is a global index that 
can be used to rate the severity of a specific condition (a single-state scale) from the patient’s 
perspective. The PGI-C is a single question scale asking the patient to rate the overall status of 
their specific condition on a 7-point scale. The PGI-S is a single question scale asking the 
patient to rate current state of their specific condition on a 7-point scale. 
10.2.2.10 
Clinician Global Impression of Improvement/Severity 
The Clinician Global Impression of Improvement or Severity (CGI-I, CGI-S) is a global 
index that can be used to rate the severity of a specific condition (a single-state scale) from 
the clinician’s perspective. The CGI-I is a single question scale asking clinician to rate the 
overall status of the patient’s specific condition on a 7-point scale since the beginning of the 
research study. The CGI-S is a single question scale asking the clinician to rate current state 
of the patient’s specific condition on a 7-point scale. 
 
10.2.2.11 Short-Acting Beta Agonist Use 
The number of times a short-acting beta agonist (number of inhalations/puffs) is used will be 
assessed by reviewing the diary maintained by the subject. The site will monitor the diary 
entries closely to assess subject compliance. Subjects who are not compliant with the diary 
will be counseled by the site and will be considered protocol deviations if an overall 
compliance rate of less than 80% is reached.   
 
10.2.3 Safety 
Safety and tolerability assessments will include the frequency and severity of AEs as well as the 
evaluation of changes in clinical laboratory values, vital signs, and physical examination findings. 
10.2.3.1 Clinical Laboratory Safety Assessments 
 
10.2.3.1.1 Clinical Laboratory Tests to be Performed 
Samples for the following clinical laboratory tests will be collected at the time points specified in 
the schedule of assessments (Table 1). 
Hematology 
Hemoglobin, hematocrit, red blood cell count, red blood cell indices, 
mean corpuscular hemoglobin, mean corpuscular hemoglobin 
concentration, mean corpuscular volume, platelet count (or estimate), 
and white bloserum od cell count including differential 
 
Serum chemistry 
Sodium, potassium, chloride, bicarbonate, glucose, blood urea 
nitrogen, 
creatine, 
creatinine 
phosphokinase, 
alanine 
aminotransferase, aspartate aminotransferase, gamma-glutamyl 
transferase, alkaline phosphatase, total bilirubin, calcium, magnesium, 
phosphorous, lactate dehydrogenase, uric acid, total protein, albumin, 
C-reactive protein, total cholesterol, high density lipoprotein, LDL, 
and triglycerides 


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Serum/urine pregnancy 
For females of childbearing potential. 
 
Urinalysis 
pH, specific gravity, dipstick determinations of protein, blood, 
glucose, and ketones 
 
Other 
 Anti-drug antibody (ADA), serum: soluble LIGHT, inflammatory 
proteins, immunophenotyping, sputum: soluble LIGHT, Plasma 
AVTX-002 Pharmacokinetics 
 
Fasting is not required for any study-specific lab sample.   
 
Laboratory specimens will be collected and analyzed at the laboratories specified in the study 
Laboratory Manual(s) or guidelines. 
 
10.2.3.1.2 Sampled Blood Volume 
The sampled blood volume for this study is shown in Table 2. 
 
Table 2:         Sampled Blood Volume per Subject 
 
Assessment 
Sample Volume 
(mL) 
Number of 
samples 
Total Volume 
(mL) 
Chemistry 
3.5 
8 
28.0 
Hematology 
2.0 
8 
16.0 
ADA 
4.5 
7 
31.5 
Serum LIGHT 
3.5 
7 
24.5 
Inflammatory proteins 
3.5 
5 
17.5 
Immunophenotyping of circulating immune cells 
10.0 
3 
30.0 
Plasma AVTX-002 
4.5 
7 
31.5 
Total (approximate) 
31.5 
45 
179 
ADA=anti-drug antibody; LIGHT=Lymphotoxin-like, exhibits Inducible expression, and competes with Herpes Virus 
Glycoprotein D for Herpesvirus Entry Mediator, a receptor expressed by T lymphocytes. 
 
10.2.3.1.3 Specimen Handling Requirements 
The transmission of infectious agents may occur through contact with contaminated needles and 
blood or blood products. Consequently, appropriate blood and body fluid precautions should be 
employed by all study personnel involved in the collection of blood and handling of specimens in 
both the clinic and laboratory settings. Refer to current recommendations of the appropriate 
authorities. 
In addition to appropriate handling of subject samples, specific regulations exist regarding the 
shipment of biologic samples. Procedures and regulations for the packaging and shipping of 
infectious samples are outlined in the site and/or study laboratory manual. The investigator is 
responsible for ensuring that all study samples that are to be transported to another location are 
appropriately packed and shipped per the applicable regulations. 
 


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10.2.3.1.4 Evaluation of Laboratory Values 
The normal ranges of values for the central laboratory assessments in this study will be provided 
to each site as part of the lab manual. For assessments performed locally, the normal ranges of 
values for the local laboratory will be provided to the Sponsor’s designee. They will be regarded 
as the reference ranges on which decisions will be made for the specific site. 
If a laboratory value is out of the reference range, it is not necessarily clinically relevant. The 
investigator must evaluate the out-of-range values and record his/her assessment of the clinical 
relevance in the subject’s source documentation. 
All laboratory values which, in the investigator’s opinion, show clinically relevant or pathological 
changes during or after termination of the treatment are to be discussed with the medical monitor, 
as necessary, and reported as AEs and followed, as described in Section 11.1.1. 
All measurements described in this section are recognized standard methods. 
10.2.3.2 Clinical Examinations 
 
10.2.3.2.1 Blood Pressure, Pulse Rate, Respiratory Rate, and Temperature 
Vital signs, including systolic and diastolic blood pressure, temperature, pulse, respiration rate, 
height, and body weight, will be collected as shown in the schedule of assessments (see Table 1). 
Pre-dose vital signs should be taken within 60 minutes before dosing. Post-dose vital signs should 
be taken at least 60 minutes after dosing, prior to discharge. Additional blood pressure and pulse 
measurements may be performed, as determined by the investigator, to ensure appropriate 
monitoring of subject safety and accurate recording of vital sign measurements. Any changes from 
baseline deemed clinically significant by the investigator are to be recorded as AEs. 
 
10.2.3.2.2 Electrocardiogram 
A standard 12 lead ECG will be performed after the subject has been supine for approximately 
5 minutes, at time points shown in the schedule of assessments (see Table 1). All ECG recordings 
will be identified with the subject number, date, and time of the recording and a copy will be 
included with the subject’s source documentation. 
All ECG values which, in the investigator’s opinion, show clinically relevant or pathological 
changes during or after termination of the treatment are to be discussed with the medical monitor 
and reported as AEs and followed, as described in Section 11.1.1. 
10.2.3.2.3 Physical Examination, Weight, and Height 
A complete physical examination, including measurements of height and weight, will be 
conducted by a qualified licensed physician, physician’s assistant, or a nurse practitioner at Visit 1 
through Visit 9/ET (see Table 1). Any clinically significant physical examination findings are to 
be reported as AEs and followed, as described in Section 11.1.1. Height will be measured only at 
Visit 1. 
 
10.2.3.3 Adverse Events 
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE described below. At each visit, the subject will be allowed time to 
spontaneously report any issues since the last visit or evaluation. 
Any clinically relevant observations made during each visit will also be considered AEs. AEs will 


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be collected from the time of informed consent through the last study visit. 
10.2.4 Immunogenicity Analyses 
Blood samples for ADA analysis will be collected at time points shown in the schedule of 
assessments (see Table 1). The Visit 2 sample is to be collected prior to dosing. Additionally, an 
ADA sample will be collected if an immunologically related AE is reported. Samples for ADA will 
be processed according to the methods and directions set forward in the laboratory manual(s) and 
guidance(s). ADA sample analysis will be performed by a laboratory defined in the laboratory 
manual(s) and guidance(s), according to their standard operating procedures (SOPs) using a 
validated method. Assay and analysis details will be described in the method validation and 
bioanalytical information. 
 
10.2.5 Pharmacokinetic, Pharmacodynamic and Biomarker Assessments 
Blood samples will be collected for assessment of PK, PD activity and mechanism of action of 
AVTX- 002 in NEA. 
Blood samples will be used to isolate serum, which will be subjected to analysis of soluble LIGHT 
levels in circulation using a relevant immunoassay for PD activity measures. Additionally, for a 
selected subset of sites or subjects, sputum samples will be analyzed for soluble LIGHT levels and 
gene expression. Biomarkers associated with inflammation such as (including but not limited to) 
IL-6, IFN-y, and TNF-α may be evaluated using relevant immunoassays. Serum may be also used 
for novel biomarkers analyses as the rationale evolves. 
Blood samples collected for PBMC isolation may be used for comprehensive immunophenotyping 
of immune cell subsets in circulation by flow cytometry or CyTOF to study the effects of AVTX- 
002 on these cell types. Furthermore, transcriptomic analysis may be performed in PBMC as 
needed. 
All these exploratory biomarkers as listed in Table 1 will be performed at the laboratories specified 
in the laboratory manual(s) and/or guidance(s). 
 
11 ADVERSE EVENTS 
 
11.1 Definition of Adverse Events, Period of Observation, Recording of Adverse Events 
 
11.1.1 Adverse Event Collection 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal relationship with 
the product. An AE can therefore be any unfavorable and unintended sign (including a new, 
clinically important abnormal laboratory finding), symptom, or disease, temporally associated with 
the product, whether related to the product. An AE will be considered treatment-emergent if it 
occurs after the first dose of investigational product and within 28 days of a subject’s last dose of 
investigational product. Additionally, an AE that occurred prior to dosing with study medication and 
increased in severity after start of dosing and within 28 days of a subject’s last dose of 
investigational product will also be considered treatment emergent. 
All AEs are collected from the time of the informed consent is signed until the end of study (Day 
98/ET). This includes events occurring regardless of whether investigational product is 
administered. Note: Clinically significant observations noted during screening procedures (labs, 
physical examination, vital signs, etc.) should be entered as medical history. Only if the clinically 


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significant observation is clearly related to the performance of a screening procedure should it be 
entered as an AE (e.g., a hematoma because of drawing blood for screening labs). Where possible, 
a diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, 
then each symptom should be listed individually. 
All AEs must be followed to closure, regardless of whether the subject is still participating in the 
study. Closure indicates that an outcome is reached or stabilization achieved (i.e. the investigator 
does not expect any further improvement or worsening of the event). When appropriate, medical 
tests and examinations are performed so that resolution of an event(s) can be documented. 
 
Events that meet the protocol definition of an asthma related event are captured as part of the 
primary efficacy endpoint for the study, and therefore need not be recorded as an AE unless they 
meet the definition of an SAE.  Asthma exacerbations that do not meet the protocol definition of 
an asthma related event should be captured as AEs. 
An AE that changes in severity over time should be recorded in the eCRF once at the highest 
severity with two exceptions: 
• Worsening of non-NEA-related pre-treatment events after initiation of investigational 
product must be recorded as new AEs. E.g., if the subject experiences mild, intermittent 
headaches prior to dosing with investigational product; however, the headache intensity 
increases to moderate after the first dose of investigational product, a new AE of moderate 
intermittent headaches is to be recorded in the source documents and eCRF. 
• An AE which begins as a non-serious event, which later meets the definition of an SAE, 
should be entered once for the non-serious portion of the AE, and then be re-recorded as a 
new event with the start date the day it became serious. 
 
11.2 Severity of Adverse Events 
The medical assessment of clinical severity of an AE will be determined using the definitions 
outlined in Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0 (Published 
November 27, 2017, by the US Department of Health and Human Services, National Institutes of 
Health, National Cancer Institute): 
Grade 1 Mild; asymptomatic or mild symptoms; or clinical or diagnostic observations only; or 
intervention not indicated 
Grade 2 Moderate; or minimal, local or non-invasive intervention indicated; or limiting age- 
appropriate instrumental activities of daily living (ADL) 
Grade 3 Severe or medically significant but not immediately life-threatening; or hospitalization 
or prolongation of hospitalization indicated; or disabling; or limiting self-care ADL 
Grade 4 Life-threatening consequences; or urgent intervention indicated 
Grade 5 Death related to AE 
The above grading guidelines should be used whenever possible. For AEs that cannot be graded 
using CTCAE, the severity should be graded using mild (Grade 1), moderate (Grade 2), severe 
(Grade 3), life threatening (Grade 4), and fatal (Grade 5). 
Please refer to the above-referenced CTCAE document for full description of CTCAE terms and 
instrumental and self-care ADLs. It is important to distinguish between severe AEs and SAEs. 
Severity is a classification of intensity whereas an SAE is an AE that meets serious criteria, as 


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described in Section 11.2.2.3. 
 
11.2.1 Relationship Categorization 
A physician investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If there 
is no valid reason for suggesting a relationship, then the AE should be classified as “not related”. 
Otherwise, the AE should be categorized per the guidelines below. The causality assessment must 
be documented in the source document and the eCRF (Table 3). 
Table 3: 
Assessment of Relationship to Investigational Product 
 
Relationship 
Description 
Not Related 
Exposure to investigational product has not occurred. 
OR 
The administration of investigational product and the occurrence of the AE are not 
reasonably related in time 
OR 
The AE is considered likely to be related to an etiology other than the use of the 
investigational product, that is, there are no facts/evidence or arguments to suggest a causal 
relationship to the investigational product. 
Possibly Related 
The administration of the investigational product and the occurrence of the AE are 
reasonably related in time. 
AND 
The AE could not be explained equally well by factors or causes other than exposure to 
investigational product 
Probably Related 
The administration of investigational product and the occurrence of the AE are reasonably 
related in time. 
AND 
The AE is more likely explained by exposure to investigational product than by other factors 
or causes. 
AE = adverse event. 
11.2.1.1 Outcome at the Time of Last Observation 
The outcome at the time of last observation will be classified as: 
• Recovered/resolved 
• Recovered/resolved with sequelae 
• Recovering/resolving 
• Not recovered/not resolved 
• Fatal* 
• Unknown 
*See Section 11.2.3. 
 
11.2.2 Serious Adverse Events 
11.2.2.1 Investigational Product Safety Information 
The IB is the reference document for safety information pertaining to this study. The IB is provided 
separately. 
 
11.2.2.2 Reporting of Serious Adverse Events 
Initial and follow-up SAE reports must be completed by the investigator or designee and sent to 


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the CRO within 24 hours of the first awareness of an SAE. The investigator or designee must 
complete, sign and date the appropriate SAE form and verify the accuracy of the information 
against corresponding source documents. This information is to be sent to the CRO 
Pharmacovigilance Department by e-mail as noted below. For questions on SAE reporting, please 
e-mail the drug safety mailbox noted below. 
•
 
 
11.2.2.3 Serious Adverse Event Definition 
An SAE is any untoward medical occurrence, whether considered to be related to investigational 
product or not, that at any dose: 
• Results in death. 
• Is life-threatening. 
NOTE: The term “life-threatening” in the definition of “serious” refers to an event in 
which the subject 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. NOTE: 
Inpatient hospitalization is defined as 24 hours in a hospital or an overnight stay. An 
elective hospital admission to treat a condition present before exposure to the test drug, or a 
hospital admission for a diagnostic evaluation of an AE, does not qualify the condition or 
event as an SAE. Further, an overnight stay in the hospital that is only due to 
transportation, organization, or accommodation problems and without medical 
background does not need to be considered an SAE. 
• Results in persistent or significant disability/incapacity. 
• Is a congenital anomaly. 
NOTE: A congenital anomaly in an infant born to a mother who was exposed to the 
investigational product during pregnancy is an SAE. However, a newly diagnosed 
pregnancy in a subject that has received an investigational product is not considered an 
SAE unless it is suspected that the investigational product(s) interacted with a 
contraceptive method and led to the pregnancy. 
• Is an important medical event. 
NOTE: Medical and scientific judgment should be exercised in deciding whether it is 
appropriate to consider other situations serious, such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. Examples of such events are intensive treatment in an emergency room 
or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result 
in hospitalization, or development of drug dependency or drug abuse. 
 
11.2.2.4 Serious Adverse Event Collection Time Frame 
All SAEs, regardless of the relationship to study, are collected from the time the subject signs the 
informed consent until the End of Study/Early Termination Visit. The investigator or designee must 
report all SAEs promptly to CRO within 24 hours of first becoming aware of the event. 
Any SAE(s), regardless of relationship to study, which occurred during the study but is not discovered 
by the site until after the study has been completed must be reported to CRO within 24 hours of the first 
awareness of the event. Please see individual study site documentation (study binder) for forms and 
contact details. 
 
11.2.2.5 Serious Adverse Event Onset and Resolution Dates 


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The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date an outcome is reached or stabilization is achieved (i.e. the investigator does not 
expect any further improvement or worsening of the event).  
Any signs or symptoms experienced by the subject after signing the informed consent form and 
assent form (if applicable) or leading up to the onset date of the SAE or following the resolution 
date of the SAE must be recorded as an AE. 
 
11.2.3 Fatal Outcome 
Fatal should only be selected as an outcome when the AE results in death. If more than 1 AE is 
possibly related to the subject’s death, the outcome of death should be indicated for each such AE. 
Any AE that results in the subject’s death must have fatal checked as an outcome with the date of 
death recorded as the resolution date. AEs resulting in death must be reported within 24 hours as 
a SAE, if not already reported as such. In the event of a subject’s death, data should be collected 
on whether the death occurred after the withdrawal of care and, if so, the reason for the withdrawal 
of care. 
For other AEs, ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded. 
11.3 Special Considerations 
 
11.3.1 Pregnancy 
All females of childbearing potential, and males with female partners of childbearing potential, 
who participate in the study should be counseled on the need to utilize a highly effective method 
of birth control throughout the study and for 28 days following the last dose of study drug, and on 
the importance of avoiding pregnancy during study participation. A highly effective method of 
birth control is defined as one that results in a low failure rate (i.e., <1% per year) when used 
consistently and correctly, such as oral/injectable/inserted/implanted/ transdermal contraceptives, 
condom with diaphragm, condom with spermicide, diaphragm with spermicide, intrauterine 
hormone-releasing system or IUD, or sexual abstinence. Contraception is not required where at 
least 6 weeks have passed since sterilization, defined as females having undergone one of the 
following surgeries: hysterectomy, bilateral tubal ligation or occlusion, bilateral oophorectomy, or 
bilateral salpingectomy; and males who are vasectomized. Contraception is not required where 
females are postmenopausal (12 consecutive months of spontaneous amenorrhea and age 
≥51 years). 
Females and males with female partners should be instructed to contact the investigator or study 
staff immediately if pregnancy occurs or is suspected. 
Pregnancy testing will be conducted on every female as per the schedule of assessments (Table 1). 
A female who is found to be pregnant at screening will be excluded from the study and considered 
to be a screening failure. A female who is found to be pregnant after receiving investigational 
product is required to be discontinued from the study and the end of study visit assessments 
performed as soon as possible after learning of the pregnancy. 
The investigator must report the pregnancy of any female (study participant or female partner of 
male study participant) who becomes pregnant during investigational product treatment or within 
28 days of discontinuing the investigational product (permission must be obtained from the 
pregnant female partner of a male subject to follow the pregnancy to conclusion and report the 
results). The pregnancy must be reported within 24 hours of learning of the pregnancy to the CRO 


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using the Pregnancy Data Collection Form via the same email address as for SAE reporting. The 
investigator should contact the designated individual(s) who receive pregnancy notification and 
record information related to the pregnancy on the Pregnancy Form/other designated form 
provided by the Sponsor or its designee. 
The investigator is also responsible for following the pregnancy until delivery or termination. 
These findings must be reported on the Pregnancy Data Collection Form and forwarded to the 
designated individual(s). The event meets the SAE criterion only if it results in a spontaneous 
abortion or a congenital anomaly. 
 
11.3.2 Reporting to Regulatory Agency, Institutional Review Board/Ethics Committee (EC) 
and Site 
The Sponsor or its designee is responsible for notifying the relevant regulatory authorities and if 
applicable, US central institutional review board (IRB) of related, unexpected SAEs. 
In addition, the Sponsor and the CRO are responsible for notifying active sites of all related, 
unexpected SAEs occurring during all interventional studies across the development program. 
The investigator is responsible for notifying the local IRB, local ethics committee (EC), or the 
relevant local regulatory authority of all SAEs that occur at his/her site, as required. 
 
12 STATISTICS 
 
12.1 Sample Size Determination 
The sample size in this study will be approximately 80 with 40 subjects per treatment arm, 
randomized in a 1:1 ratio.  
The sample size estimate was based on the estimated proportions of patients in the two treatment 
groups expected to have an asthma related event as defined by the primary endpoint. In a study 
with another product, rates of 6% in the active group and 44% in the placebo group were observed 
(Wenzel, 2013). If these estimates were used as is, then a study with 40 subjects per group would 
have over 95% power.  Considering likely variations from the cited study, estimates of sample 
were assessed assuming a Type I error of 5% and the proportion of subjects with an asthma related 
event ranging from 30% to 50% in the placebo group and 5% to 8% in the active group. In the 20 
such scenarios examined, only in the cases in which the difference between treatments gets below 
23% does the power fall slightly below 80%. In the vast majority of cases examined the power is 
greater than 90%. 
A sample size re-estimation may be performed at a point in time when an adequate number of 
subjects has been enrolled to provide meaningful data.  Details will be provided in the statistical 
analysis plan.   
 
 
12.2 Analysis Populations 
This study will have the following populations of interest: 
• The Randomized Analysis Set will include all subjects who are randomized in the study. 
Subjects will be categorized according to their randomized treatment group. The 
Randomized Analysis Set will be used for all disposition, protocol deviations, and 
demographic and other baseline characteristics analyses. 
• The Safety Analysis Set will include all subjects who are randomized in the study and 


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receive at least one dose of investigational product. Subjects will be categorized according 
to their actual treatment group. The Safety Analysis Set will be used for all exposure and 
safety analyses and immunogenicity analysis. 
• The Full Analysis Set will include all subjects who receive at least one dose of 
investigational product and have a baseline and at least one post-baseline efficacy 
assessment. Subjects will be categorized according to their randomized treatment group. 
The Full Analysis Set will be used for all efficacy and pharmacodynamic analyses. 
 
12.3 Statistical Analyses 
This section presents a summary of the planned statistical analyses. Additional details regarding 
data handling, analytical methods, and presentation of results will be described in the Statistical 
Analysis Plan (SAP) for this study. The SAP will be finalized prior to database lock. 
All efficacy, safety, PD, and ADA variables will be summarized using descriptive statistics. 
Descriptive statistics for continuous data will include number of subjects (n), mean, standard 
deviation, median, minimum, and maximum. Summaries of change from baseline variables will 
include only subjects who have both a baseline value and corresponding value at the timepoint of 
interest. Descriptive statistics for categorical data will include frequency and percentage. 
Listings will be provided for all collected study data. 
 
12.3.1 Study Subjects and Demographics 
12.3.1.1 Disposition and Withdrawals 
The study medication and study disposition of all subjects randomized in this study will be 
summarized by treatment group and completion/discontinuation status. Subjects who discontinue 
the study medication and/or study prematurely will be summarized by treatment group and reason 
for discontinuation. The number of subjects in each analysis set will also be summarized by 
treatment group.  Any subject who receives three doses of AVTX-002 or placebo by definition is 
considered as completing therapy. 
12.3.1.2 Protocol Deviations 
All subject data will be reviewed for the occurrence of protocol deviations. Prior to database lock, 
all protocol deviations will be reviewed and classified with respect to the potential to influence 
experimental outcomes. Protocol deviations will be summarized by treatment group. 
12.3.1.3 Demographics and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized by treatment group using 
descriptive statistics. 
12.3.2 Prior and Concomitant Medications 
All prior and concomitant medications will be coded using the WHO Drug Dictionary. Prior and 
concomitant medications will be summarized by treatment group using descriptive statistics. 
 
12.3.3 Exposure and Compliance 
Exposure to investigational product will be summarized by treatment group using descriptive 
statistics. 
12.3.4 Safety and Tolerability Analyses 


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Safety analyses will be conducted using data from the Safety Analysis Set (as defined in Section 
12.2). Safety variables will include TEAEs, clinical laboratory values, vital signs, and ECG 
results. No formal inferential analyses will be conducted for any safety variables, unless otherwise 
noted. 
12.3.4.1 Adverse Events 
Adverse event verbatim terms will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). The overall incidence of subjects having at least one AE will be 
summarized by treatment group. The incidence of TEAEs will be summarized by treatment group, 
system organ class (SOC) and preferred term (PT). Each subject will be counted only once per 
SOC and preferred term. An AE will be considered treatment-emergent if it occurs after the first 
dose of investigational product and within 28 days after a subject’s last dose of investigational 
product. 
12.3.4.2 Clinical Laboratory Evaluations 
For all continuous laboratory test variables, descriptive statistics for all reported values and change 
from baseline values will be summarized by treatment group and visit. 
12.3.4.3 Vital Signs 
For all continuous vital sign variables, descriptive statistics for all reported values and change from 
baseline values will be summarized by treatment group and visit. 
 
12.3.5 Efficacy Analyses 
For the primary variable, comparison of the proportions of subjects that had an asthma related 
event will be via a Wald Z-test (continuity corrected).  Summary statistics will be provided via a 
2x2 table showing the number and percentage with and without events in each treatment group. 
The test statistic, its associated p-value and a 95% confidence interval for the treatment difference 
will also be provided. 
All other efficacy variables will be summarized using descriptive statistics. Descriptive statistics 
for continuous data will include number of subjects (n), mean, standard deviation, median, 
minimum, and maximum. Summaries of change from baseline variables will include only subjects 
who have both a baseline value and corresponding value at the timepoint of interest. Descriptive 
statistics for categorical data will include frequencies and percentages. 
 
Further details regarding all statistical analysis can be found in the study Statistical Analysis Plan 
(SAP). 
 
12.3.6 Pharmacokinetic, Pharmacodynamic and Biomarker Analyses 
For all PK, PD and biomarker variables, descriptive statistics will be presented by treatment group 
and time point. 
12.3.7 Immunogenicity Analyses 
For all immunogenicity variables, descriptive statistics will be presented by treatment group and 
time point. 
 
12.3.8 Interim Analysis 
No formal interim analysis is planned for this study. 
 


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13 STUDY CONDUCT 
Steps to ensure the accuracy and reliability of data include the selection of qualified investigators 
and appropriate study sites, review of protocol procedures with the investigator and associated 
personnel prior to the study, periodic monitoring visits, and meticulous data management. 
13.1 Sponsor and Investigator Responsibilities 
 
13.1.1 Sponsor Responsibilities 
The Sponsor is obligated to conduct the study in accordance with strict ethical principles (Section 
15). The Sponsor reserves the right to withdraw a subject from the study (Section 8.7), to terminate 
participation of a study site at any time (Section 13.5), and/or to discontinue the study (Section 
13.4). 
The Sponsor agrees to provide the investigator with sufficient material and support to permit the 
investigator to conduct the study per the study protocol. 
 
13.1.2 Investigator Responsibilities, Protocol Adherence, and Investigator Agreement 
By signing the Investigator’s Agreement, the investigator indicates that she/he has carefully read 
the protocol, fully understands the requirements, and agrees to adhere to the protocol as detailed 
in this document. 
The investigator also agrees to conduct this study in accordance with all laws, regulations, and 
guidelines of the pertinent regulatory authorities, including and in accordance with the April 1996 
International Council for Harmonisation (ICH) Guidance for Industry E6 GCP and in agreement 
with the 1996 Version of the Declaration of Helsinki. While delegation of certain aspects of the 
study to sub-investigators and study coordinators is appropriate, the investigator will remain 
personally accountable for closely overseeing the study and for ensuring compliance with the 
protocol and all applicable regulations and guidelines. The investigator is responsible for 
maintaining a list of all persons that have been delegated study-related responsibilities (e.g., sub-
investigators and study coordinators) and their specific study-related duties. 
Investigators should ensure that all persons who have been delegated study-related responsibilities 
are adequately qualified and informed about the protocol, investigational products, and their 
specific duties within the context of the study. Investigators are responsible for providing the 
Sponsor with documentation of the qualifications, GCP training, and research experience for 
themselves and their staff as required by the Sponsor and the relevant governing authorities. 
To ensure compliance with the guidelines, the study may be audited by an independent person. 
The investigator agrees, by written consent to this protocol, to cooperate fully with compliance 
checks by allowing access to all study documentation by authorized individuals. 
Per local laws and regulations, the investigator, Sponsor, or designee will communicate with the 
IRB/EC to ensure accurate and timely information is provided throughout the study. 
13.2 Study Documents 
All documentation and material provided by the Sponsor for this study are to be retained in a secure 
location and treated as confidential material. 
 
13.2.1 Case Report Forms 
By signing the Investigator’s Agreement, the investigator agrees to complete the eCRFs and 
maintain source documentation as part of the case histories for all subjects who sign an ICF. 


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Case report forms are considered confidential documents and should be handled and stored 
accordingly. The Sponsor or its designee will provide the necessary training on the use of 
the specific eCRFs used during the study to ensure that the study information is captured 
accurately and appropriately. 
To ensure data accuracy, eCRF data for individual subject visits should be completed as soon as 
possible after the visit. All requested information must be entered in the eCRF per the completion 
guidelines provided by the Sponsor or its designee. All data will have separate source 
documentation; no data will be recorded directly into the eCRF. 
The eCRFs will be signed by the investigator or a sub-investigator to whom this authority has been 
delegated. These signatures serve to attest that the information contained in the eCRF is accurate 
and true. 
 
13.2.2 Recording and Retention of Source Data and Study Documents 
All study information must be recorded in the subject’s medical records and no data will be 
recorded directly onto the eCRF. Data recorded in the eCRF must be supported by corresponding 
source documentation. Examples of acceptable source documentation include, but are not limited 
to, hospital records, clinic and office charts, laboratory reports and notes, and recorded data from 
automated instruments, memoranda, and pharmacy dispensing records. 
 
13.3 Data Quality Control 
The Sponsor and its designees will perform quality control checks on this clinical study. 
 
13.3.1 Access to Study and Source Documents 
The Sponsor and/or designee will conduct site visits to monitor the study and ensure compliance 
with the protocol, GCP, and applicable regulations and guidelines. The consent form includes a 
statement by which the subject agrees to the monitor/auditor from the Sponsor or its 
representatives, national or local authorities, or the IRB/EC, having access to the source data (for 
example, subject’s medical records, appointment books, original laboratory reports, radiographic 
exams, and reports, etc.) 
The assigned CRA(s) will visit the investigator and study site at periodic intervals and maintain 
periodic communication. The investigator agrees to allow the CRA(s) and other authorized Sponsor 
personnel access. The CRA(s) will maintain current personal knowledge of the study through 
observation, review of study records and source documentation, and discussion of the conduct of 
the study with the investigator and staff. While on site, the CRA(s) will review: 
• 
Regulatory documents, directly comparing entries in the eCRF with the source documents. 
• 
Consenting procedures. 
• 
Adverse event procedures. 
• 
Storage and accountability of study materials. 
• 
Storage and accountability of investigational product (performed by the unblinded CRA). 
The CRA will ask for clarification and/or correction of any noted inconsistencies. Procedures for 
correcting eCRFs will be described for the study personnel as part of training. As representatives 
of the Sponsor, CRAs are responsible for notifying project management of any noted protocol 
deviations. 
By signing the Investigator’s Agreement, the investigator agrees to meet with the CRA(s) during 


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study site visits; to ensure that study staff is available to the CRA(s) as needed, to provide the 
CRA(s) access to all study documentation, to the clinical supplies dispensing and storage area, and 
to assist the monitors in their activities, if requested. Further, the investigator agrees to allow the 
Sponsor or designee auditors or inspectors from IRBs/ECs or regulatory agencies to review records 
and to assist the inspectors in their duties, if requested. 
 
13.3.2 Data Management 
The Sponsor or designee will be responsible for activities associated with the data management of 
this study. The standard procedures for handling and processing records will be followed per GCP 
and the designee’s SOPs. Data are to be reviewed and checked for omissions, errors, and values 
requiring further clarification using computerized and manual procedures. A comprehensive data 
management plan will be developed including a data management overview, database contents, 
annotated eCRF, self-evident correction conventions, and consistency checks. 
Study site personnel will be responsible for providing resolutions to all data queries. The 
investigator will be required to document electronic data review to ensure the accuracy of the 
corrected and/or clarified data. Procedures for soliciting and documenting resolution to data 
queries will be described. 
 
13.3.3 Quality Assurance Audit / Inspection 
 
 
 
 
 
 
 
 
 
13.4 Study Termination 
The study may be terminated at the Sponsor’s discretion at any time and for any reason. 
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the Sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will return all investigational product, containers, and other study materials to the 
Sponsor. 
 
13.5 Study Site Closure 
At the end of the study, all study sites will be closed. The Sponsor may terminate participation of 
a study site at any time. Examples of conditions that may require premature termination of a study 
site include, but are not limited to, the following: 
• 
Noncompliance with the protocol and/or applicable regulations and guidelines. 
• 
Inadequate subject enrollment. 
 
13.5.1 Record Retention 


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It is the investigator’s responsibility for maintaining adequate and accurate study and medical 
records. The investigator shall retain and preserve 1 copy of all data generated during the study, 
specifically including, but not limited to, those defined by ICH GCP as essential until: 
• 
At least 2 years after the last marketing authorization for the investigational product has been 
approved or the Sponsor has discontinued its research with the investigational product, or 
• 
At least 2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product. 
These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirement(s) or if needed by the Sponsor. 
At the end of such period, the investigator must notify the Sponsor in writing of her/his intent to 
move and/or destroy any study material. Approval from the Sponsor must be granted prior to any 
action being taken. 
 
13.5.2 Sample Retention 
All samples will be retained according to applicable SOPs and regulations. Blood samples may be 
stored and used for further analysis related to this research. 
13.6 Changes to the Protocol 
This protocol cannot be altered or changed except through a formal protocol amendment, which 
requires the written approval of the Sponsor. The protocol amendment must be signed by the 
investigator and approved by the IRB before it may be implemented. Protocol amendments will 
be filed with the appropriate regulatory agency(ies) having jurisdiction over the conduct of the 
study. 
13.7 Use of Information and Publication 
All information concerning AVTX-002, Sponsor operations, patent applications, formulas, 
manufacturing processes, basic scientific data, and formulation information supplied by of the 
Sponsor or designee to the investigator and not previously published, is considered confidential 
and remains the sole property of the Sponsor. Case report forms also remain the property of the 
Sponsor. The investigator agrees to use this information for purposes of study execution through 
finalization. 
The information developed in this study will be used by the Sponsor in connection with the 
continued development of AVTX-002 and thus may be disclosed as required to other clinical 
investigators or government regulatory agencies. 
The information generated by this study is the property of the Sponsor. Publication or other public 
presentation of AVTX-002 data resulting from this study requires prior review and written 
approval of the Sponsor. Abstracts, manuscripts, and presentation materials should be provided to 
the Sponsor for review at least 30 days prior to the relevant submission deadline. 


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It is agreed that the results of the study will not be submitted for presentation, abstract, poster 
exhibition or publication by the investigator until of the Sponsor has reviewed and commented on 
such a presentation or manuscript for publication. 
 
14 PUBLIC POSTING OF STUDY INFORMATION 
The Sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigator information 
(e.g., site name, investigator name, site location, site contact information). 
 
15 ETHICAL AND LEGAL CONSIDERATIONS 
 
15.1 Declaration of Helsinki and Good Clinical Practice 
This study will be conducted in compliance with the protocol, the April 1996 ICH Guidance for 
Industry E6 GCP (including archiving of essential study documents), the 1996 Version of the 
Declaration of Helsinki, and the applicable regulations of the country(ies) in which the study is 
conducted. 
15.2 Subject Information and Informed Consent 
It is the responsibility of the investigator to ensure that written informed consent is obtained from 
the subjects before any activity or procedure is undertaken that is not part of routine care including 
baseline assessments. All consent documentation must be in accordance with applicable 
regulations and GCP. Each subject is requested to sign and date the subject informed consent or a 
certified translation, if applicable, after the subject has received and read (or been read) the written 
subject information and received an explanation of what the study involves, included but not 
limited to: the objectives, potential benefits and risks, inconveniences, and the subject’s rights and 
responsibilities. A signed copy of the informed consent and assent documentation (if applicable 
[such as a complete set of subject information sheets and fully executed signature pages]) must be 
given to the subject. This document may require translation into local language. Signed 
consent/assent forms must remain in each subject’s study file and must be available for verification 
at any time. 
The principal investigator provides the Sponsor with a copy of the consent and assent (as 
applicable) form which was reviewed by the IRB/EC, and which received favorable 
opinion/approval. A copy of the IRB/EC’s written favorable opinion/approval of these documents 
must be provided to the Sponsor, prior to the start of the study unless it is agreed to and documented 
(abiding by regulatory guidelines and national requirements) prior to the study start that another 
party (such as the Sponsor or coordinating principal investigator) is responsible for this action. If 
the IRB/EC requires modification of the sample subject information and consent document 
provided by the Sponsor, the documentation supporting this requirement must be provided to the 
Sponsor. 
 
15.3 Institutional Review Board or Ethics Committees 
A properly constituted, valid IRB/EC according to local laws and regulations must review and 
approve the protocol, the investigator’s informed consent and assent (as applicable) document, and 
related subject information and any other study materials requiring review (such as recruitment 
information) before the start of the study. 
Until written approval by the IRB has been received by the investigator, no subject may undergo 
any study procedure solely for determining eligibility for this study. Investigational product will 


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not be released until the Sponsor, or its designee has received written IRB/EC approval. 
Prior to implementing changes in the study, the Sponsor and the IRB/EC must approve and provide 
documentation of favorable opinion/approval of any revisions to informed consent documents and 
amendments to the protocol unless there is a subject safety issue. 
Depending on location (outside European Union [EU] or inside EU) the IRB/EC will be apprised 
of the progress of the study and of any changes made to the protocol at least yearly. This may be 
done by the investigator (outside EU and in some cases, inside EU) or the Sponsor (in some cases 
inside EU). These updates include information on any serious or significant AEs. 
Upon study completion, the investigator will provide the IRB/EC with final report/summary as 
required. 
 
15.4 Financial Disclosure 
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after where the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the Sponsor. The following 
information is collected: any significant payments from Sponsor or subsidiaries such as grant to 
fund ongoing research, compensation in the form of equipment, retainer for ongoing consulting or 
honoraria; any proprietary interest in investigational product; any significant equity interest in the 
Sponsor or subsidiaries as defined in 21 CFR 54 (b) (1998). 
 
15.5 Privacy and Confidentiality 
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with Health Insurance Portability and Accountability Act (HIPAA) of 1996. A 
site that is not a covered entity as defined by HIPAA must provide documentation of this fact to 
the Sponsor/CRO. 
The confidentiality of records that may be able to identify subjects will be protected in accordance 
with applicable laws, regulations, and guidelines. 
After subjects have consented to participate in a study, the Sponsor and/or its representatives 
reviews their medical records and data collected as part of the study. These records and data may 
be reviewed by others including the monitor/auditor from the Sponsor or its representatives, 
national or local authorities, or the IRB/EC which gave the approval for the study, third parties 
with whom the Sponsor may develop, register, or market the investigational product. The Sponsor 
and its representatives will take all reasonable precautions in accordance with applicable laws, 
regulations, and guidelines to maintain the confidentiality of subjects’ identities. 
Subjects are assigned a unique identifying number; however, the initials and date of birth may also 
be collected and used to assist the Sponsor to verify the accuracy of data. 
The results of the studies, containing the subjects’ unique identifying number, relevant medical 
records and possibly initials and dates of birth, will be recorded. They may be transferred to and 
used in other countries which may not afford the same level of protection that applies within the 
countries where the study is conducted. The purpose of such transfer would include supporting 


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regulatory submissions, to conduct new data analyses to publish or present the study results or to 
answer questions asked by regulatory or health authorities. 
 
 
 
 
 
 
 
 


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16 
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Nair P, Gaga M, Zervas E, Alagha K, Hargreave FE, O'Byrne PM, Stryszak P, Gann L, Sadeh J, 
Chanez P. Safety and efficacy of a CXCR2 antagonist in patients with severe asthma and sputum 
neutrophils: a randomized, placebo-controlled clinical trial. Clin Exp Allergy. 2012;42(7):1097- 
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INVESTIGATOR’S AGREEMENT 
 
PROTOCOL NUMBER: 
AVTX-002-NEA-201 
PROTOCOL TITLE: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 
Parallel Group Study to Evaluate the Safety and Efficacy of 
AVTX-002 for the Treatment of Poorly Controlled Non- 
Eosinophilic Asthma 
FINAL PROTOCOL: 
17 Oct 2022 
 
I have read this protocol and agree to conduct this clinical trial as outlined herein. I will ensure that 
all subinvestigators and other study staff members have read and understand all aspects of this 
protocol. I agree to cooperate fully with Avalo Therapeutics, Inc., and designee during the study. 
I will adhere to all FDA, ICH, and other applicable regulations and guidelines regarding clinical 
trials on an investigational product during and after study completion. 
Principal Investigator: 
 
Printed Name: 
 
 
 
Signature: 
 
 
 
 
Date: 

SAP_001.pdf: 
Statistical Analysis Plan: AVTX-002-NEA-201 
Avalo Therapeutics, Inc. 
AVTX-002 
Final 4.0, 02 Jun 2023 
 
Confidential 
Page 1 of 52 
 
 
 
 
Statistical Analysis Plan: AVTX-002-NEA-201 
Study Title: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel 
Group Study to Evaluate the Safety and Efficacy of AVTX-002 for 
the Treatment of Poorly Controlled Non-Eosinophilic Asthma 
Study Number: 
AVTX-002-NEA-201 
Study Phase: 
2 
Sponsor: 
Avalo Therapeutics, Inc. 
1500 Liberty Ridge Drive, Suite 321 
Wayne, PA 19087 
NCT #: 
NCT05288504 
Version: 
Final 4.0 
Date: 
02 Jun 2023 
 
Confidentiality Statement 
This document contains confidential and proprietary information, and is not to be distributed 
to any third party. 
 
 


Statistical Analysis Plan: AVTX-002-NEA-201 
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Version History 
Version: Final 1.0 
Initial version 
 
 
Version: Final 2.0 
Updates resulting from Protocol Amendment No. 4 (ie, Protocol Version 5.0, 17 Oct 2022) 
 
Updates made to baseline definitions as well as post-baseline calculations for diary data 
 
Updates made to reflect programmatically determined derivation of the occurrence of 
asthma related events, in addition to the Investigator assessment in the eCRF 
 
Updates made to reflect repeat analysis of the primary endpoint based on different baseline 
values for daily number of SABA puffs/inhalations and peak flow rate. 
 
Updates made to include calculation of an annual asthma related event rate for each 
treatment group 
 
Added production of figures to display results for peak flow rate and number of SABA 
puffs/inhalations recorded by subjects in their diary 
 
Addition of a Per Protocol Analysis Set 
 
Added clarification on handling of clinical laboratory results reported as not fully numeric 
 
Addition of PCI criteria for vital signs 
 
 
Version: Final 3.0 
Addition of statistical comparison between treatment groups for time to first asthma 
related event, as well as addition of a Kaplan-Meier plot of the time to asthma related 
event curves of the two treatment groups. 
 
Addition of repeat of the primary efficacy analysis for subjects with an asthma related 
event in the period of time from date of first administration of study drug through 28 days 
after final dose of study drug 
 
Update to wording for further clarity on the start date of an asthma related event 
 
Addition of clarification of asthma related event criterion related to use of systemic 
corticosteroids 
 
Minor corrections to formatting 
 
 
Version: Final 4.0 
Update to Section 6.2.4 for imputation of missing values and derivation of overall score 
for the Asthma Control Questionnaire 
 
Update to Section 10.3 to add that the screening eosinophil level will be part of the subject 
listing as well as table summary for demographics and baseline characteristics 
 
Update to Section 10.6.1 to add that Wald Ztest will be performed including and without 
continuity correction 
 
Update to Table 4 (Appendix 2) to clarify imputation of missing start date for prior and 
concomitant medications 
 
Update to Table 9 (Appendix 5) to add CTCAE grading for laboratory parameters 
analyzed per protocol 
 
 
 


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1 TABLE OF CONTENTS 
1 
TABLE OF CONTENTS ......................................................................................................... 3 
LIST OF TABLES ........................................................................................................................... 4 
LIST OF FIGURES ......................................................................................................................... 5 
LIST OF APPENDICES ................................................................................................................. 5 
2 
SIGNATURE PAGE ................................................................................................................ 6 
3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .......................................... 7 
4 
INTRODUCTION .................................................................................................................. 10 
5 
STUDY OBJECTIVES AND ENDPOINTS ......................................................................... 11 
6 
STUDY DESIGN CONSIDERATIONS ............................................................................... 13 
6.1 
Study Design ...................................................................................................................... 13 
6.1.1 
Justification of Sample Size ........................................................................................ 14 
6.2 
Efficacy Measures ............................................................................................................. 14 
6.2.1 
Asthma Related Events ................................................................................................ 15 
6.2.2 
Forced Expiratory Volume in 1 second ....................................................................... 17 
6.2.3 
Fractional Exhaled Nitric Oxide .................................................................................. 17 
6.2.4 
Asthma Control Questionnaire .................................................................................... 17 
6.2.5 
Standardized Asthma Quality of Life Questionnaire for Ages 12 to 70 years ............ 19 
6.2.6 
Asthma Symptom Diary .............................................................................................. 20 
6.2.6.1 
Symptom Scores .................................................................................................... 20 
6.2.6.2 
Additional Endpoints from Diary Data ................................................................. 21 
6.2.7 
European Quality of Life – 5 Dimension 5 Level Questionnaire ................................ 22 
6.2.8 
Patient Global Impression of Change/Severity ........................................................... 22 
6.2.9 
Clinician Global Impression of Improvement/Severity ............................................... 22 
6.3 
Safety Measures ................................................................................................................. 22 
6.4 
Pharmacodynamic and Biomarker, and Pharmacokinetic Assessments ........................... 22 
6.4.1 
Pharmacodynamics and Biomarkers ........................................................................... 23 
6.4.2 
Pharmacokinetics ......................................................................................................... 23 
6.5 
Immunogenicity Measures ................................................................................................ 23 
7 
STUDY POPULATIONS ...................................................................................................... 24 
7.1 
Analysis Populations ......................................................................................................... 24 
7.1.1 
Randomized Analysis Set ............................................................................................ 24 
7.1.2 
Safety Analysis Set ...................................................................................................... 24 
7.1.3 
Full Analysis Set .......................................................................................................... 24 
7.1.4 
Per Protocol Analysis Set ............................................................................................ 24 
7.1.5 
Pharmacokinetic Analysis Set ..................................................................................... 24 
7.2 
Subgroups 24 
8 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE PROTOCOL ........ 25 
9 
OVERALL STATISTICAL CONSIDERATIONS ............................................................... 26 
9.1 
General Conventions ......................................................................................................... 26 


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9.2 
Baseline and Related Changes Definition ......................................................................... 26 
9.3 
Handling of Partial Dates .................................................................................................. 29 
9.4 
Interim Analysis ................................................................................................................ 29 
9.5 
Pooling Strategy for Study Sites ........................................................................................ 30 
9.6 
Visit Windows / Unscheduled Visits ................................................................................. 30 
10 STATISTICAL ANALYSIS METHODS .............................................................................. 31 
10.1 
Subject Disposition ............................................................................................................ 31 
10.2 
Protocol Deviations ........................................................................................................... 31 
10.3 
Demographics and Baseline Characteristics ...................................................................... 31 
10.3.1 
Medical History ........................................................................................................... 32 
10.4 
Prior and Concomitant Medications and Procedures ........................................................ 32 
10.4.1 
Salmeterol/Fluticasone Run-in .................................................................................... 33 
10.5 
Treatment Exposure ........................................................................................................... 33 
10.6 
Efficacy 
33 
10.6.1 
Primary Endpoint Analysis .......................................................................................... 34 
10.6.2 
Secondary Endpoints Summaries ................................................................................ 35 
10.6.3 
Exploratory Endpoint Analyses ................................................................................... 36 
10.6.4 
Interim Analysis .......................................................................................................... 36 
10.7 
Safety and Tolerability ...................................................................................................... 36 
10.7.1 
Adverse Events ............................................................................................................ 36 
10.7.2 
Clinical Laboratory Values .......................................................................................... 38 
10.7.3 
Electrocardiograms ...................................................................................................... 39 
10.7.4 
Vital Signs ................................................................................................................... 39 
10.7.5 
Physical Examinations ................................................................................................. 39 
10.8 
Pharmacokinetics ............................................................................................................... 39 
10.9 
Pharmacodynamics ............................................................................................................ 40 
10.10 Immunogenicity ................................................................................................................. 40 
11 REFERENCES ....................................................................................................................... 41 
12 APPENDICES ........................................................................................................................ 42 
LIST OF TABLES 
Table 1. 
Study Objectives and Associated Endpoints ......................................................... 11 
Table 2. 
Schedule of Assessments (as per V4 study protocol) ............................................ 43 
Table 3. 
Imputation Rules for Partial Dates – Adverse Events ........................................... 46 
Table 4. 
Imputation Rules for Partial Dates – Prior and Concomitant Medications and 
Procedures ............................................................................................................. 46 
Table 5. 
Planned Laboratory Assays ................................................................................... 47 
Table 6. 
Liver Function PCI Criteria ................................................................................... 49 
Table 7. 
Safety Laboratory PCI Criteria .............................................................................. 49 
Table 8. 
Vital Signs PCI Criteria ......................................................................................... 49 


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Table 9. 
Laboratory CTCAE Grade Version 5.0 Criteria .................................................... 50 
Table 10. 
Directionality of Worst Laboratory Parameters .................................................... 52 
LIST OF FIGURES 
Figure 1. 
Study Schema ........................................................................................................ 14 
 
LIST OF APPENDICES 
APPENDIX 1. 
SCHEDULE OF ASSESSMENTS AND PROCEDURES ............................. 43 
APPENDIX 2. 
IMPUTATION OF PARTIAL DATES .......................................................... 46 
APPENDIX 3. 
PLANNED LABORATORY ASSAYS .......................................................... 47 
APPENDIX 4. 
POTENTIALLY CLINICALLY IMPORTANT CRITERIA ......................... 49 
APPENDIX 5. 
LABORATORY CTCAE CRITERIA ............................................................ 50 
APPENDIX 6. 
DIRECTIONALITY OF WORST LABORATORY PARAMETERS ........... 52 
 


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2 SIGNATURE PAGE 
 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 
Parallel Group Study to Evaluate the Safety and Efficacy of 
AVTX-002 for the Treatment of Poorly Controlled 
Non-Eosinophilic Asthma 
Study Number: 
AVTX-002-NEA-201 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ACQ 
Asthma Control Questionnaire 
ADA 
anti-drug antibody 
AE 
adverse event 
AQLQ(S)+12 
Standardized Asthma Quality of Life Questionnaire for 12 to 70 years 
ASD 
Asthma Symptom Diary 
ATC 
Anatomical Therapeutic Chemical 
BMI 
body mass index 
CFB 
change from baseline 
CFB% 
percentage change from baseline 
CGI-I 
Clinician Global Impression of Improvement 
CGI-I/S 
Clinician Global Impression of Improvement/Severity 
CGI-S 
Clinician Global Impression of Severity 
CSR 
Clinical Study Report 
CTCAE 
common terminology criteria for adverse events 
DBP 
diastolic blood pressure 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EQ-5D-5L 
European Quality of Life – 5 dimension 5 level questionnaire 
EQ VAS 
European Quality of Life visual analogue scale 
ET 
Early Termination 
FAS 
Full Analysis Set 
FEV1 
forced expiratory volume in 1 second 
FeNO 
fractional exhaled nitric oxide 
ICS 
inhaled corticosteroid 


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IFN-γ 
interferon gamma 
IL-6 
interleukin 6 
LABA 
long-acting beta agonist 
LIGHT 
Lymphotoxin-like, exhibits Inducible expression, and competes with 
Herpes Virus Glycoprotein D for Herpesvirus Entry Mediator, a receptor 
expressed by T lymphocytes 
LFT 
liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
NEA 
non-eosinophilic asthma 
PCI 
potentially clinically important 
PD 
pharmacodynamic(s) 
PGI-C 
Patient Global Impression of Change 
PGI-C/S 
Patient Global Impression of Change/Severity 
PGI-S 
Patient Global Impression of Severity 
PK 
pharmacokinetic(s) 
PT 
preferred term 
ppb 
parts per billion 
RAS 
Randomized Analysis Set 
SABA 
short-acting beta agonist 
SAP 
statistical analysis plan 
SAS 
Safety Analysis Set 
SBP 
systolic blood pressure 
SC 
subcutaneous 
SD 
standard deviation 
SG 
Specific Gravity 
SOC 
system organ class 


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TEAE 
treatmentemergent adverse event 
TNF-α 
tumor necrosis factor alpha 
US 
United States 
VAS 
visual analogue scale 
WHO 
World Health Organization 
WHO-DD 
World Health Organization Drug Dictionary 
 


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4 INTRODUCTION 
The purpose of this SAP is to describe the framework for the reporting, summarization, and 
statistical analysis methodology of the safety and efficacy parameters measured throughout the 
study, applying principles and methodology per International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines [1, 2]. It is based 
on Protocol AVTX-002-NEA-201, Version 5.0, dated 17 Oct 2022. 


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5 STUDY OBJECTIVES AND ENDPOINTS 
Table 1. 
Study Objectives and Associated Endpoints 
Objectives 
Endpoints 
Primary 
To assess the ability of AVTX-002 to 
improve asthma control in subjects 
with poorly controlled NEA 
Primary Endpoint: 
Proportion of subjects who experience any of the following asthma 
related events: 
• 
≥ 6 additional reliever puffs of SABA (compared to baseline) in a 
24-hour period on 2 consecutive days (where baseline SABA use 
is the average daily number of individual SABA puffs/inhalations 
taken by the subject during the 7 days preceding Visit 2) or, 
• 
increase in ICS dose ≥ 4 times than the dose at baseline (where 
baseline ICS dose is the dosage the subject received during the 
30-day run-in period) or, 
• 
a decrease in peak flow of ≥ 30% (compared to baseline) on 
2 consecutive days of treatment (where baseline peak flow is the 
average of measurements in the 7 days preceding Visit 2) or, 
• 
an asthma exacerbation requiring the use of systemic 
corticosteroids (tablets, suspension, or injection) for at least 3 days 
or, 
• 
a hospitalization or emergency room visit because of an asthma 
exacerbation. 
 
Secondary Endpoints: 
 
Change from baseline in FEV1 at Weeks 2, 4, 6, 8, 12, and 14 
 
Time to asthma related event 
 
Change from baseline in FeNO at Weeks 2, 4, 6, 8, 12, and 14 
 
Change from baseline in ACQ at Weeks 2, 4, 6, 8, 12, and 14 
 
Change from baseline in AQLQ(S)+12 at Weeks 2, 4, 6, 8, 12, and 14 
 
Change from baseline in ASD score at Weeks 2, 4, 6, 8, 12, and 14 
 
Change from baseline in EQ-5D-5L at Weeks 2, 4, 6, 8, 12, and 14 
 
Change from baseline in PGI-C/S at Weeks 2, 4, 6, 8, 12, and 14 
 
Change from baseline in CGI-I/S at Weeks 2, 4, 6, 8, 12, and 14 
 
Incidence of SABA puffs/inhalations at Weeks 2, 4, 6, 8, 12, and 14 
Secondary 
To assess the safety and tolerability of 
AVTX-002 
Incidence of AEs, and changes from baseline in clinical laboratory 
tests, vital signs measurements, and physical examinations at Weeks 2, 
4, 6, 8, 12, and 14 
To evaluate biomarkers of PD activity 
and mechanism of action of 
AVTX-002 
Change from baseline in serum soluble LIGHT levels at Weeks 2, 4, 6, 
8, 12, and 14 
To evaluate the immunogenicity of 
AVTX-002 
Incidence of ADAs at Weeks 2, 4, 6, 8, 12, and 14 
Exploratory 
To assess the ability of AVTX002 to 
improve asthma control in subjects 
with poorly controlled NEA who also 
have < 150 eosinophils/μL 
Occurrence of an asthma related event in subjects with 
< 150 eosinophils/μL 
 
 


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Objectives 
Endpoints 
Exploratory (continued) 
 
To assess sputum soluble LIGHT 
levels and gene expression in a select 
subset of subjects 
Change from baseline in sputum soluble LIGHT and gene expression 
(select subset of site/subjects only) 
To evaluate inflammatory proteins 
including but not limited to: IL-6, 
IFN-γ, and TNF-α 
Change from baseline in inflammatory proteins including but not 
limited to: IL-6, IFN- γ, and TNF-α 
To evaluate the PK/PD relationship 
PK/PD assessments 
ACQ = Asthma Control Questionnaire; ADA = anti-drug antibody; AE = adverse event; 
AQLQ(S)+12 = Standardized Asthma Quality of Life Questionnaire for 12 to 70 years; ASD = Asthma Symptom 
Diary; CGI-I/S = Clinician Global Impression of Improvement/Severity; EQ-5D-5L = European Quality of Life – 
5 dimension 5 level questionnaire; FeNO = fractional exhaled nitric oxide; FEV1 = forced expiratory volume in 
1 second; ICS = inhaled corticosteroid; IFN-γ = interferon gamma; IL-6 = interleukin 6; 
LIGHT = Lymphotoxin-like, exhibits Inducible expression, and competes with Herpes Virus Glycoprotein D for 
Herpesvirus Entry Mediator, a receptor expressed by T lymphocytes; NEA = non-eosinophilic asthma; 
PD = pharmacodynamic(s); PGI-C/S = Patient Global Impression of Change/Severity; PK = pharmacokinetic(s); 
TNF-α = tumor necrosis factor alpha; SABA = short-acting beta agonist 
 


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6 STUDY DESIGN CONSIDERATIONS 
6.1 
Study Design 
This is a randomized, double-blind, placebo-controlled, Phase 2 study to evaluate the safety and 
efficacy of AVTX002 for the treatment of poorly controlled NEA. Upon confirmation of 
eligibility, subjects will complete a 30-day, stable therapy, run-in period with a LABA 
(salmeterol 50 μg twice daily) and an ICS (fluticasone, with starting dose at Investigator 
discretion). After the 30-day run-in is complete, subjects will be randomly assigned at the 
Baseline visit to receive either AVTX002 or placebo (1:1 ratio). 
Fourteen days after randomization, subjects will discontinue salmeterol therapy (ie, at Visit 4). 
After an additional 14 days (ie, at Visit 5), subjects will taper fluticasone dose to 50%. After 
another 14 days (ie, at Visit 6), fluticasone use will be completely discontinued. The final visit 
will be Visit 9 (98 days after randomization). 
Subjects will receive 3 doses of either AVTX002 or placebo (ie, at Visit 2, Visit 5, and Visit 7). 
AVTX002 or placebo will be administered by SC injection in the abdomen in a zone of 4 to 
10 cm from the umbilicus, with the injection site rotated based on the number of syringes used. 
AVTX002 will be administered at a dose of 600 mg. 
An adequate number of subjects will be enrolled to ensure approximately 80 subjects complete 
the study. Subjects who withdraw or are discontinued from the study or have poor study 
compliance may be replaced. The study will take place at approximately 25 study sites in the US. 
All subjects will undergo efficacy, safety, PK/PD, and immunogenicity assessments as described 
in Section 6.2, Section 6.3, Section 6.4, and Section 6.5, respectively. Time points for all 
assessments are summarized in Table 2. 
The study schema is presented in Figure 1 below. 


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Figure 1. Study Schema 
Note: refer to Section 8 for changes to numbering of assessment day, for purposes of reporting of 
study results. The assessment day as presented in Figure 1 below, reflects the numbering as 
presented in the study protocol. 
 
There is no interim analysis of data planned for this study. 
6.1.1 
Justification of Sample Size 
The sample size in this study will be approximately 80 subjects, ie, 40 subjects per treatment 
arm, randomized in a 1:1 ratio. 
The sample size estimate was based on the estimated proportions of subjects in the 2 treatment 
groups expected to have an asthma related event as defined by the primary endpoint. In a study 
of similar design with another asthma controller therapy, rates of 6% in the active group and 
44% in the placebo group were observed [3]. If these estimates were used as is, then a study with 
40 subjects per group would have over 95% power. Considering likely variations from the cited 
study, estimates of sample were assessed assuming a Type I error of 5% and the proportion of 
subjects with an asthma related event ranging from 30% to 50% in the placebo group and 5% to 
8% in the active group. In the 20 such scenarios examined, only in the cases in which the 
difference between treatments gets below 23% does the power fall slightly below 80%. In the 
vast majority of cases examined the power is greater than 90%. 
The overall event rate may be assessed in a blinded fashion when an adequate amount of subject 
followup has occurred. If this event rate is found to be much lower than assumed, a sample size 
reestimation may be performed. 
6.2 
Efficacy Measures 
Time points for all assessments are summarized in Table 2. 


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6.2.1 
Asthma Related Events 
The following are considered asthma related events: 
• ≥ 6 additional reliever puffs of SABA (compared to baseline) in a 24-hour period on 
2 consecutive days (where baseline SABA use is the average daily number of individual 
SABA puffs/inhalations taken by the subject during the 7 days preceding Visit 2) 
• increase in ICS dose ≥ 4 times than the dose at baseline at any time post-baseline (where 
baseline ICS dose is the dosage the subject received during the 30-day run-in period) 
• a decrease in peak flow of ≥ 30% (compared to baseline) on 2 consecutive days of treatment 
(where baseline peak flow is the average of measurements in the 7 days preceding Visit 2) 
• an asthma exacerbation requiring the use of systemic corticosteroids (tablets, suspension, or 
injection) for at least 3 days 
• a hospitalization or emergency room visit because of an asthma exacerbation 
 
 


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The occurrence of each of the above asthma related events will be derived programmatically using different baseline definitions 
(where applicable), and from the source data as specified below: 
Criterion to Meet for Asthma Related 
Event 
Applicable Source Data 
Baseline Definition 
≥ 6 additional reliever puffs of SABA 
(compared to baseline) in a 24-hour 
period on 2 consecutive days * 
ePRO Asthma Symptom Diary, ASD Morning and 
ASD Evening pages 
The derivation whether a subject meets this criterion for 
an asthma related event will be performed using each of 
the 4 baseline values for mean daily number of SABA 
puffs/inhalations calculated according to Definitions 1 
to 4 in Section 9.2 
Increase in ICS dose ≥ 4 times than the 
dose at baseline at any time post-baseline 
Prior and Concomitant Medications page of eCRF, 
coded appropriately so that ICS can be identified 
ICS dose which the subject received during the 30-day 
run-in period 
A decrease in peak flow of ≥ 30% 
(compared to baseline) on 2 consecutive 
days of treatment 
ePRO Asthma Symptom Diary, Peak Flow Diary page 
(before Peak Flow Diary page was available, this was 
collected as part of ASD Morning page) 
The derivation whether a subject meets this criterion for 
an asthma related event will be performed using each of 
the 4 baseline values for mean peak flow rate calculated 
according to Definitions 1 to 4 in Section 9.2 
An asthma exacerbation requiring the use 
of systemic corticosteroids (tablets, 
suspension, or injection) for ≥ 3 days ** 
Prior and Concomitant Medications page of eCRF, 
coded appropriately so that systemic corticosteroids 
can be identified 
Not applicable 
A hospitalization or emergency room 
visit because of an asthma exacerbation 
Asthma exacerbation reported as SAE; in case SAE 
was not reported (ie, in case asthma exacerbation 
required only emergency room visit which 
consequently is not reported as SAE), the Investigator 
assessment in the eCRF of occurrence of an asthma 
related event is to be utilized as the source data  
Not applicable 
ICS = inhaled corticosteroid; SABA = short-acting beta agonist 
* 
This criterion may be met via 2 consecutive calendar days of assessments (ie, morning and evening diary entries for calendar date 1 plus morning and 
evening diary entries for the calendar date 2) or over a span of 3 consecutive calendar days (ie, evening diary entry for calendar date 1 and morning diary 
entry for calendar date 2 plus evening diary entry for calendar date 2 and morning diary entry for calendar date 3). 
** In the case which use of systemic corticosteroids being administered for an asthma exacerbation is ongoing at the end of the study, the duration will be 
considered to be ≥ 3 days – as in clinical practice corticosteroid prescription including tapering usually last more than 3 days – and therefore the subject 
will be considered to have met this criterion for an asthma related event. 
** Subjects being administered systemic corticosteroids for ≥ 3 days for a nonasthma event, will be considered to have met this criterion for an asthma 
related event, provided they have corresponding signs and symptoms of an asthma exacerbation. Also, subjects being administered a single dose of a 
longterm acting systemic corticosteroid (eg, dexamethasone) with a dose equivalent to a treatment of ≥ 3 days with other short to midterm systemic 
corticosteroids will be considered to have met this criterion for an asthma related event. Such cases will be confirmed by the sponsor as having met the 
criterion for an asthma related event or not. 


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In addition, an Investigator assessment of the occurrence of an asthma related event is recorded 
in the eCRF at each visit during the course of the study. 
Time to first asthma related event will be measured in days as follows: 
• Subjects with an asthma related event (censor = 0): the first day of the event above denotes 
the first day the protocol defined criteria associated with the asthma related event occurred 
(eg, for peak flow, the first of 2 days a decrease of ≥ 30% occurred, or for systemic 
corticosteroid use, the start of the qualifying medication), ie, time to event is calculated as 
follows:  
("#$%# '$#( )* *+%"# $"#ℎ-$ %(.$#(' (/(0# −'$#( )* *+%"# $'-+0+"#%$#+)0 )* "#2'3 '%24) + 1 
For subjects that do NOT have an asthma related event (censor = 1), the day of the last subject 
visit denotes the day of censoring, ie, time to censoring is calculated as follows:  
("#$% '( )#*$ *+,-%.$ /0*0$ −"#$% '( (02*$ #"3040*$2#$0'4 '( *$+"5 "2+6) + 1 
Furthermore, an annual asthma related event rate will be calculated for each treatment group as 
follows (for exploratory reasons): 
365.25 ∗@ $'$#) 4+3,%2 '( #*$ℎ3# 2%)#$%" %/%4$* B0$ℎ04 $ℎ% $2%#$3%4$ 62'+C
$'$#) "+2#$0'4 '( *$+"5 C#2$0.0C#$0'4 B0$ℎ $ℎ% $2%#$3%4$ 62'+C ["#5*]F 
where total duration of study participation within treatment group (days) is the sum of 
("#$% '( )#*$ *+,-%.$ /0*0$ −"#$% '( (02*$ #"3040*$2#$0'4 '( *$+"5 "2+6) + 1 for all 
subjects. 
6.2.2 
Forced Expiratory Volume in 1 second 
FEV1 is the volume of air that can be forcibly exhaled from the lungs in the first second, 
measured in liters by a spirometer. FEV1 (L) will be reported in the study results. 
6.2.3 
Fractional Exhaled Nitric Oxide 
A FeNO test measures the levels of nitric oxide during exhalation, measured in ppb. A FeNO test 
will be done by breathing into a tube attached to a handheld monitor. 
6.2.4 
Asthma Control Questionnaire 
The ACQ is a questionnaire to measure the adequacy of asthma control and change in asthma 
control. The questionnaire has a multidimensional construct assessing symptoms (5 items, 
selfadministered, looking back at the past week), rescue bronchodilator use (1 item, 
selfadministered, looking back at the past week), and FEV1 (1 item, completed by study staff). 
For each of the self-administered questions (items), scoring is done on a 7point scale, ranging 
between 0 (totally controlled) and 6 (extremely poorly controlled). 


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All the items in the questionnaire are equally weighted and so the overall score for each 
assessment is the mean of the responses to the 7 items. The overall score also ranges between 0 
(totally controlled) and 6 (extremely poorly controlled) [4]. 
The aim is not to have any missing data on the questionnaire. If there is more than one missing 
value per completed questionnaire, the data for that questionnaire will not be used (ie, will be set 
to missing). The following interpolation method will be used to impute a missing value, in case 
of a single missing value other than Item 1 or Item 7 on the ACQ questionnaire (values from 
either previous or subsequent completions of the questionnaire for the same subject can be used 
to impute a missing value) – the method is explained by means of an example [4]: 
For the following example data (note that in the example the previous visit is used to impute the 
missing value at Visit 2; as a rule the closest complete previous visit will be used to impute a 
missing value, and if no complete previous visit is available, the closest complete subsequent 
visit’s data will be used to impute a missing value from an incomplete visit):  
 
Visit 1 
Visit 2 
Item 1 
4 
6 
Item 2 
3 
5 
Item 3 
4 
4 
Item 4 
5 
6 
Item 5 
2 
Missing 
Item 6 
4 
3 
Item 7 
3 
5 
 
Total Visit 1 score for items answered on both visits: 4 + 3 + 4 + 5 + 4 + 3 = 23 (I) 
Total Visit 2 score for items answered on both visits: 6 + 5 + 4 + 6 + 3 + 5 = 29 (K) 
Item 5 (item for which there is missing value at Visit 2) score at Visit 1 = 2 (L)  
Imputed Item 5 score at Visit 2: 
!
" × L =
#$
#% × 2 = 2.52 
After imputation of the missing value, the overall score for each of Visit 1 and Visit 2 therefore 
will be: 
Visit 1: 
('(%('()(#('(%)
+
= 3.57 
Visit 2: 
(,()('(,(#.)#(%())
+
= 4.50 
Imputed values will be flagged in subject listings. 
The overall score will be derived as the mean of the responses to the 7 items on the completed 
questionnaire when there is no missing data for a questionnaire or when a single missing value 
(ie, other than Item 1 or Item 7) was imputed according to the method above (in this case, the 
imputed value is used when calculating the mean). In the case where the only missing result for 
the completed questionnaire is either Item 1 or Item 7, the overall score will be derived using the 


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responses of the 6 completed items on the questionnaire (ie, the denominator when calculating 
the mean is 6 in this case). If there is more than one missing value per completed questionnaire, 
an overall score is not calculated (ie, will be set to missing). 
6.2.5 
Standardized Asthma Quality of Life Questionnaire for Ages 12 to 70 years 
The AQLQ(S)+12 includes 32 questions (items) in 4 domains (symptoms, activity limitation, 
emotional function, and environmental stimuli) [5]. 
The questionnaire is selfadministered. Subjects will be asked to recall their experiences during 
the previous 2 weeks and score each of the questions on a 7point scale, where 7=not at all limited 
and 1=totally limited. 
The 32 questions (items) are assigned as follows to the 4 domains: 
Symptoms: Items 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 29, 30 
Activity limitation: Items 1, 2, 3, 4, 5, 11, 19, 25, 28, 31, 32 
Emotional function: Items 7, 13, 15, 21, 27 
Environmental stimuli: Items 9, 17, 23, 26 
Individual items are equally weighted. The overall score of the AQLQ(S)+12 will be derived as 
the average of the 32 items; thus, the overall score ranges from 1 ("total impairment") to 7 ("no 
impairment"). The domains are summarized in exactly the same way – each domain score will be 
derived as the average score of the items for the specific domain. Each domain score thus also 
ranges from 1 ("total impairment") to 7 ("no impairment"). 
The aim is not to have any missing data on the questionnaire. The data for a completed 
questionnaire will not be used (ie, will be set to missing) in the following cases: 
• For calculation of overall score: if > 3 missing responses in total or > 1 missing response in 
any domain 
• For calculation of symptom or activity limitation domain scores: if > 1 missing response in 
the domain, or 
• For calculation of emotional function and environmental stimuli domain scores: if any 
missing response in the domain. 
In case the number of missing values does not exceed the specifications listed above, imputation 
of missing values will be performed using the same method as described for the ACQ 
questionnaire in Section 6.2.4 [5]. 
Imputed values will be flagged in subject listings. 


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6.2.6 
Asthma Symptom Diary 
For the data collected by subjects in their diaries, if any data are recorded after the subject end of 
study date, this will not be used for any of the presentations described in this SAP; ie, only diary 
data collected up to the earlier of the end of study date or the diary deactivation date will be used 
for study data analysis. 
6.2.6.1 
Symptom Scores 
The ASD is a 6item daily measure of asthma symptom severity that assesses 3 core categories of 
asthma symptoms: breathing symptoms (difficulty breathing; wheezing; shortness of breath), 
chest symptoms (chest tightness; chest pain), and cough. The ASD is intended for twice daily 
completion and comprises a morning diary (for completion upon waking and referring to asthma 
symptoms during the nighttime) and an evening diary (for completion before going to bed and 
referring to asthma symptoms during the day). 
Subjects are required to rate the 6 symptoms at their worst during the respective timeframes 
using an 11-point numeric rating scale ranging from 0 (‘None’) to 10 (‘As bad as you can 
imagine’) [6]. 
Individual morning and evening ASD symptom scores for the 6 symptoms of difficulty 
breathing, wheezing, shortness of breath, chest tightness, chest pain, cough will be reported for 
each symptom as recorded in the diary. If the assessment of a particular symptom is missing for 
either the morning or evening diary, then that symptom’s score for that diary timepoint will be 
missing. 
Mean symptom scores will be calculated for each symptom as the mean of the available scores 
for the applicable symptom for each week, as follows: 
*+3 '( #/#0)#,)% %4$20%* ('2 $ℎ% B%%P, ('2 %#.ℎ *53C$'3
4+3,%2 '( #/#0)#,)% %4$20%* ('2 $ℎ% B%%P, ('2 %#.ℎ *53C$'3 
A mean ASD score will be calculated as the mean of all available symptom scores for each 
week, as follows:  
*+3 '( #/#0)#,)% %4$20%* ('2 $ℎ% B%%P, ('2 #)) *53C$'3*
4+3,%2 '( #/#0)#,)% %4$20%* ('2 $ℎ% B%%P, ('2 #)) *53C$'3* 
The first week post-baseline will start with the morning diary on Day 1 and will end with the 
evening diary 1 week later on Day 7 (ie, if there are no missing entries, a week will comprise 
14 entries for each symptom). If Day 1 entries are utilized to calculate a baseline value (see 
Section 9.2), these Day 1 entries will not be part of the first week post-baseline (ie, in this case 
the first week post-baseline will start with the morning diary on Day 2 and will end with the 
evening diary on Day 7). For the mean symptom scores, if a subject has > 3 missing morning 
diary entries or > 3 missing evening diary entries for the applicable symptom in a week, then the 
mean symptom score for that week will be missing. For the mean ASD score, if a subject has 
> 3 missing morning diary entries or > 3 missing evening diary entries for any of the 6 symptoms 


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in a week, then the mean ASD score for that week will be missing. Mean scores for all 
subsequent weeks will be defined similarly, with the same rule for handling missing data. 
Baseline is defined in Section 9.2. 
6.2.6.2 
Additional Endpoints from Diary Data 
A peak flow meter measures how well the lungs are able to expel air. Subjects will measure peak 
flow daily on a device provided by the sponsor and record the results in their diary. The daily 
peak flow rate as well as the use of SABA, which will also be recorded in the diary, will be used 
to assess the occurrence of asthma related events (see Section 6.2.1). 
Peak flow rate is recorded daily by the subject. Mean peak flow rate will be calculated as the 
mean of all available recordings for each week, as follows: 
*+3 '( #/#0)#,)% %4$20%* ('2 $ℎ% B%%P
4+3,%2 '( #/#0)#,)% %4$20%* ('2 $ℎ% B%%P 
The first week post-baseline will start with the recording in the diary on Day 1 and will end with 
the recording in the diary on Day 7 (ie, if there are no missing entries, a week will comprise 
7 entries). If the Day 1 entry is utilized as baseline (see Section 9.2, Definition 1 for mean peak 
flow rate), the Day 1 entry will not be part of the first week post-baseline (ie, in this case the first 
week post-baseline will start with the Day 2 diary recording and will end with the Day 7 diary 
recording). If a subject has > 3 missing entries in a week, then the mean score for that week will 
be missing. Mean values for all subsequent weeks will be defined similarly, with the same rule 
for handling missing entries. Baseline is defined in Section 9.2 (Definition 1 for mean peak flow 
rate). 
The number of times (number of puffs/inhalations) a SABA is used will be assessed by 
reviewing the diary maintained by the subject. The number of puffs/inhalations of SABA is 
entered by the subject in their diary twice daily, ie, the morning diary is used to record number of 
SABA puffs/inhalations during the nighttime and the evening diary is used to record number of 
SABA puffs/inhalations during the day. For analysis of the SABA use data, beginning with the 
day on which the diary is activated through the earlier of the end of study date or the diary 
deactivation date, all missing entries will be considered 0 for analysis. Daily sums of SABA 
puffs/inhalations will be calculated as the sum of the morning diary and evening diary entries for 
the same calendar date. Mean daily number of puffs/inhalations over weekly periods will be 
calculated from the daily sums, as follows: 
*+3 '( "#0)5 *+3* ('2 $ℎ% B%%P
4+3,%2 '( "#5* $ℎ% "0#25 B#* #/#0)#,)% ('2 $ℎ% B%%P 
For the first mean daily number of puffs/inhalations post-baseline, the week will start with the 
morning diary on Day 1 and will end with the evening diary 1 week later on Day 7 (ie, a week 
will comprise 14 entries). If Day 1 entries are utilized as baseline (see Section 9.2, Definition 1 
for mean daily number of SABA puffs/inhalations), the Day 1 entries will not be part of the first 
week post-baseline (ie, in this case the first week post-baseline will start with the morning diary 
on Day 2 and will end with the evening diary on Day 7). Mean daily number of SABA 


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puffs/inhalations for all subsequent weeks will be defined similarly, with the same rule for 
handling missing entries. Baseline is defined in Section 9.2 (Definition 1 for mean daily number 
of SABA puffs/inhalations). 
6.2.7 
European Quality of Life – 5 Dimension 5 Level Questionnaire 
The EQ-5D-5L consists of the EQ-5D descriptive system and the EQ VAS. The descriptive 
system includes 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate 
problems, severe problems, and extreme problems. The EQ VAS records the subject’s self-rated 
health on a vertical VAS, where the endpoints are labelled ‘The best health you can imagine’ 
(100) and ‘The worst health you can imagine’ (0) [7]. 
6.2.8 
Patient Global Impression of Change/Severity 
The PGI-C/S scale is a global index that can be used to rate the severity of a specific condition (a 
single-state scale) from the patient’s perspective. 
The PGI-S for this study is a single question asking the subject to rate the current state of their 
overall asthma severity on a 7-point scale (normal, borderline, mild, moderate, marked, severe, 
extreme). The PGI-C for this study is a single question asking the subject to rate their overall 
asthma status since the start of the study, (ie, since baseline [Visit 2]) on a 7-point scale (very 
much improved, much improved, minimally improved, no change, minimally worse, much 
worse, very much worse). 
6.2.9 
Clinician Global Impression of Improvement/Severity 
The CGI-I/S is a global index that can be used to rate the severity of a specific condition (a 
single-state scale) from the clinician’s perspective. 
The CGIS for this study is a single question asking the clinician to rate the current state of the 
subject’s overall asthma severity on a 7point scale (normal, borderline, mild, moderate, marked, 
severe, extreme). The CGII for this study is a single question asking the clinician to rate the 
subject’s overall asthma status since the start of the study (ie, since baseline [Visit 2]) on a 7point 
scale (very much improved, much improved, minimally improved, no change, minimally worse, 
much worse, very much worse). 
6.3 
Safety Measures 
Safety and tolerability assessments will include the frequency and severity of AEs as well as the 
evaluation of changes in clinical laboratory values and vital signs. 
Time points for all assessments are summarized in Table 2. 
6.4 
Pharmacodynamic and Biomarker, and Pharmacokinetic Assessments 
Time points for all assessments are summarized in Table 2. 


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6.4.1 
Pharmacodynamics and Biomarkers 
Serum samples will be analyzed for soluble LIGHT levels. 
For a selected subset of sites or subjects, sputum samples will be analyzed for soluble LIGHT 
levels. Sputum samples may be evaluated for gene expression in the future. Biomarkers 
associated with inflammation will be collected and may be evaluated in the future, and samples 
for immunophenotyping of immune cell subsets in circulation will be collected and may be 
analyzed in the future. 
6.4.2 
Pharmacokinetics 
Blood samples will be collected for measurement of AVTX-002 in plasma. Time points for 
collection are indicated in Table 2. 
6.5 
Immunogenicity Measures 
Immunogenicity will be evaluated by means of the incidence of measured ADAs. Time points 
for all assessments are summarized in Table 2. 


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7 STUDY POPULATIONS 
7.1 
Analysis Populations 
7.1.1 
Randomized Analysis Set 
The RAS will include all subjects who are randomized in the study. Subjects will be categorized 
according to their randomized treatment group. The RAS will be used for all disposition, 
protocol deviations, and demographic and other baseline characteristics analyses. 
7.1.2 
Safety Analysis Set 
The SAS will include all subjects who are randomized in the study and receive at least one dose 
of investigational product. Subjects will be categorized according to their actual treatment group. 
The SAS will be used for all exposure, safety, and immunogenicity analyses. 
7.1.3 
Full Analysis Set 
The FAS will include all subjects who receive at least one dose of investigational product and 
have a baseline and at least one post-baseline value of any of the efficacy assessments. Subjects 
will be categorized according to their randomized treatment group. The FAS will be used for all 
efficacy and PD analyses. 
7.1.4 
Per Protocol Analysis Set 
The Per Protocol analysis set will include all subjects in the FAS who do not have significant 
protocol violations as determined by the sponsor as exclusionary from this analysis set prior to 
database lock (including, but not limited to, lack of compliance with study drug). 
7.1.5 
Pharmacokinetic Analysis Set 
The PK Analysis Set will include all subjects who receive at least one dose of investigational 
product and have at least one postdose measurable plasma AVTX002 concentration. Subjects 
will be categorized according to their actual treatment group. The PK Analysis Set will be used 
for all PK analyses. 
7.2 
Subgroups 
Occurrence of asthma related events will be evaluated in subjects with < 150 eosinophils/μL at 
baseline. 
Sputum soluble LIGHT levels will be assessed in a select subset of subjects. Inclusion of 
subjects in this subset will be presented (as recorded in the eCRF as a subject consented to 
sputum sample collection and with at least one sputum sample being collected), although any 
results from sputum samples do not form part of the statistical analysis described in this SAP 
(see Section 10.9). 


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8 CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE 
PROTOCOL 
The following changes from protocol conventions are applied: 
1.  
According to the Schedule of Assessments (Table 1 in study protocol), numbering of assessment 
day starts at Day 0 at Visit 2, Baseline; ie: 
Procedure 
Screening 
… 
Baseline 
Doubleblind Treatment Period 
Visit 
V 1 
… 
V 2 
V 3 
V 4 
V 5 
V 6 
V 7 
V 8 
V 9/ET 
Assessment 
Week 
-4 
… 
0 
1 
2 
4 
6 
8 
12 
14 
Assessment 
Day 
Appr -37 
… 
0 
7 
14 
28 
42 
No later 
than 56 
84 
98 
Appr = approximately; ET = early termination; V = Visit 
 
For the purpose of presentation of the study results however, the first day of dosing will be 
denoted Day 1 (ie, there will be no Day 0). This results in the following changes to numbering of 
assessment day, according to which the study results will be reported: 
Procedure 
Screening 
… 
Baseline 
Doubleblind Treatment Period 
Visit 
V 1 
… 
V 2 
V 3 
V 4 
V 5 
V 6 
V 7 
V 8 
V 9/ET 
Assessment 
Week 
-4 
… 
0 
1 
2 
4 
6 
8 
12 
14 
Assessment 
Day 
Appr -37 
… 
1 
8 
15 
29 
43 
No later 
than 57 
85 
99 
Appr = approximately; ET = early termination; V = Visit 
 
2.  
According to protocol Section 11.1.1, an AE will be considered treatmentemergent if it occurs 
after the first dose of investigational product and within 28 days after a subject’s last dose of 
investigational product. However, since the start time for AEs are collected in this study only if 
AE duration is < 24 hours, the definition for an AE to be considered treatmentemergent will be 
as follows: 
• If AE start time is recorded: an AE will be considered treatmentemergent if it occurs on or 
after the time of first dose of investigational product and within 28 days after a subject’s last 
dose of investigational product.  
• If AE start time is not recorded: an AE will be considered treatmentemergent if it occurs on 
or after the date of first dose of investigational product and within 28 days after a subject’s 
last dose of investigational product. 


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9 OVERALL STATISTICAL CONSIDERATIONS 
9.1 
General Conventions 
Efficacy, safety, PK, PD, and immunogenicity variables will be summarized using descriptive 
statistics. Descriptive statistics for continuous data will include number of subjects (n), mean, 
SD, median, minimum, and maximum. Summaries of change from baseline variables will 
include only subjects who have both a baseline value and corresponding value at the time point 
of interest. Descriptive statistics for categorical data will include frequency and percentage. Data 
will be summarized by treatment group (AVTX-002 and placebo) and overall (where 
applicable). 
Descriptive statistics for continuous data will be displayed with applicable decimal precision as 
follows in relation to the source data (N: number of decimals for source parameter value, with 
0≤N≤3): 
• Number (n) 
• Mean, Median: N + 1 
• SD: N + 2 
• Minimum, Maximum: N + 0 
Statistical hypothesis testing is planned to be performed on only the primary endpoint (see 
Section 10.6.1). 
Listings will be provided for all collected study data. 
Although the protocol defines the first day of administration of study drug as Day 0 (Visit 2, 
Baseline), for datasets and the study results reporting, the first day of administration of study 
drug is defined as Day 1. All other study days will be computed relative to Day 1. The study day 
for a particular event or visit will be calculated as R#$%./.01 −R#$%23451 785. + 1 (for event 
occurring on or after first dose), and R#$%./.01 −R#$%23451 785. (for events occurring prior to 
first dose). For concomitant medications, AEs, clinical laboratory and vital signs assessments, as 
well as efficacy, PK, and PD assessments which occurred or were performed on or after the date 
of last administration of study drug, the study day relative to last study drug dose will also be 
displayed, ie, R#5)#*$ = R#$%./.01 −R#$%9:51 785.. In case of missing or partial dates being 
recorded for an event, the study day will not be calculated and will appear as missing in the 
subject listings. 
9.2 
Baseline and Related Changes Definition 
In general and unless otherwise specified, baseline is defined as the last available assessment 
prior to the first dose of the study drug. 
CFB is calculated as: LSK = ',*%2/%" /#)+% −,#*%)04% /#)+% 


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CFB% is calculated as: LSK% = ULSK ,#*%)04% /#)+%
V
W × 100 (if the baseline value is 0, 
CFB% cannot be calculated) 
Where unscheduled/repeat assessments are relevant and exist for any subject at a particular visit 
they will also be considered in the baseline definitions, provided they remain prior to the first 
dose of study drug. 
Visit 1a (Day 7 [2 days]) with diary activation was added to the protocol Schedule of 
Assessments in Protocol Version 4.0 (Amendment 3), 05 May 2022. Therefore, subjects enrolled 
prior to this amendment did not have a diary activated until the day of randomization (ie, they 
will not have diary entries during the 7 days preceding Visit 2). A baseline value cannot be 
calculated for subjects with no diary entries before the day of randomization. To include such 
subjects in analyses, additional definitions of baseline have been included in which Day 1 entries 
or Day 1 through Day 7 entries may be used for calculation of baseline when a subject does not 
have sufficient diary entries prior to Day 1. This approach has been taken given that all subjects 
have received a 30day regimen of stable asthma medications leading up to Day 1 which will be 
maintained until Day 14 per protocol; therefore, a Day 1 (or Day 1 through Day 7) diary entry is 
a reasonable representation of their baseline. The baseline definitions are detailed below for each 
of the following subject diary assessments: 
Asthma Symptom 
Diary Assessment 
Baseline Definition 
Mean symptom score  
Subjects with at least 1 morning diary entry and at least 1 evening diary entry from 
Day -7 through Day -1 for the applicable symptom, will have their baseline value 
calculated as: 
!"# %& '(')*'+*, ,-./),! &/%# 0'1 -7 .ℎ/%"5ℎ 0'1 -1
-"#+,/ %& '(')*'+*, ,-./),! &/%# 0'1 -7 .ℎ/%"5ℎ 0'1 -1 
 
When the above criteria are not met, subjects with at least 1 morning diary entry and at 
least 1 evening diary entry from Day -7 through Day 1 for the applicable symptom, will 
have their baseline value calculated as: 
!"# %& '(')*'+*, ,-./),! &/%# 0'1 -7 .ℎ/%"5ℎ 0'1 1
-"#+,/ %& '(')*'+*, ,-./),! &/%# 0'1 -7 .ℎ/%"5ℎ 0'1 1 
 
Otherwise, subjects who do not have at least 1 morning diary entry and at least 1 evening 
diary entry from Day -7 through Day 1 for the applicable symptom will have a missing 
baseline value. 
Mean ASD score 
Subjects with at least 1 morning diary entry and at least 1 evening diary entry from 
Day -7 through Day -1 for each of the 6 symptoms, will have their baseline value 
calculated as: 
!"# %& '(')*'+*, ,-./),! &/%# 0'1 -7 .ℎ/%"5ℎ 0'1 -1
-"#+,/ %& '(')*'+*, ,-./),! &/%# 0'1 -7 .ℎ/%"5ℎ 0'1 -1 
 
When the above criteria are not met, subjects with at least 1 morning diary entry and at 
least 1 evening diary entry from Day -7 through Day 1 for each of the 6 symptoms, will 
have their baseline value calculated as: 
!"# %& '(')*'+*, ,-./),! &/%# 0'1 -7 .ℎ/%"5ℎ 0'1 1
-"#+,/ %& '(')*'+*, ,-./),! &/%# 0'1 -7 .ℎ/%"5ℎ 0'1 1 
 


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Otherwise, subjects who do not have at least 1 morning diary entry and at least 1 evening 
diary entry from Day -7 through Day 1 for each of the 6 symptoms will have a missing 
baseline value. 
Mean daily number 
of SABA 
puffs/inhalations 
Baseline values will be calculated by the following 4 separate definitions. The primary 
baseline definition (Definition 1) will be used for all output that requires a comparison of 
SABA use to baseline. Definition 2 through 4 will only be used for the primary endpoint 
summary in the FAS and associated listings (ie, occurrence of an asthma related event; 
see Section 6.2.1). 
 
Definition 1 (primary baseline definition): 
• 
Subjects whose diary was activated no later than Day -1, will have their baseline 
value calculated as: 
!"# %& 7')*1 !"#! &/%# 0'1 -7 .ℎ/%"5ℎ 0'1 -1
-"#+,/ %& 7'1! .ℎ, 7)'/1 8'! '(')*'+*, &/%# 0'1 -7 .ℎ/%"5ℎ 0'1 -1 
• 
Subjects for whom their diary was not activated by Day -1 but for whom the diary 
was activated on Day 1 and ≥ 1 Day 1 entry is available, will have their baseline 
value calculated as: 
!"# %& ,-./),! %- 0'1 1 
• 
Subjects for whom their diary was not activated by Day 1, will have a null 
baseline. 
 
Definition 2: 
• 
Subjects whose diary was activated no later than Day -1, will have their baseline 
value calculated as defined in Definition 1 above. 
• 
Subjects for whom their diary was not activated by Day -1 but for whom the diary 
was activated for ≥ 1 day between Day 1 and Day 7, will have their baseline 
value calculated as: 
!"# %& 7')*1 !"#! &/%# 0'1 1 .ℎ/%"5ℎ 0'1 7
-"#+,/ %& 7'1! .ℎ, 7)'/1 8'! '(')*'+*, &/%# 0'1 1 .ℎ/%"5ℎ 0'1 7 
• 
Subjects for whom their diary was not activated by Day 7, will have a null 
baseline. 
 
Definition 3: 
• 
Subjects whose diary was activated no later than Day -1, will have their baseline 
value calculated as defined in Definition 1 above. 
• 
Subjects for whom their diary was not activated by Day -1, will have a null 
baseline. 
 
Definition 4: 
• 
Subjects whose diary was activated no later than Day -4, will have their baseline 
value calculated as defined in Definition 1 above. 
• 
Subjects for whom their diary was not activated by Day -4, will have a null 
baseline. 
 
Note: for the days the diary was available (ie, any day from diary activation 
through deactivation), all missing entries will be considered 0 for calculation of the 
baseline value 
Mean peak flow rate 
Baseline values will be calculated by the following 4 separate definitions. The primary 
baseline definition (Definition 1) will be used for all output that requires a comparison of 
peak flow rate to baseline. Definition 2 through 4 will only be used for the primary 
endpoint summary in the FAS and associated listings (ie, occurrence of an asthma related 
event; see Section 6.2.1). 


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Definition 1 (primary baseline definition):  
• 
Subjects with ≥ 1 of the expected 7 entries from Day -7 through Day -1, will have 
their baseline value calculated as: 
!"# %& '(')*'+*, ,-./),! &/%# 0'1 -7 .ℎ/%"5ℎ 0'1 -1
-"#+,/ %& '(')*'+*, ,-./),! &/%# 0'1 -7 .ℎ/%"5ℎ 0'1 -1 
• 
Subjects with no entries from Day -7 through Day -1 but for whom the Day 1 
entry is available, will have their baseline value calculated as: 
0'1 1 ,-./1 
• 
For subjects with no entries from Day -7 through Day 1, the baseline value will 
be missing. 
 
Definition 2: 
• 
Subjects with ≥ 1 of the expected 7 entries from Day -7 through Day -1, will have 
their baseline value calculated as defined in Definition 1 above.  
• 
Subjects with no entries from Day -7 through Day -1 but for whom ≥ 1 entry 
between Day 1 and Day 7 is available, will have their baseline value calculated 
as: 
!"# %& '(')*'+*, ,-./),! &/%# 0'1 1 .ℎ/%"5ℎ 0'1 7
-"#+,/ %& '(')*'+*, ,-./),! &/%# 0'1 1 .ℎ/%"5ℎ 0'1 7 
• 
For subjects with no entries from Day -7 through Day 7, the baseline value will 
be missing. 
 
Definition 3: 
• 
Subjects with ≥ 1 of the expected 7 entries from Day -7 through Day -1, will have 
their baseline value calculated as defined in Definition 1 above.  
• 
For subjects with no entries from Day -7 through Day -1, the baseline value will 
be missing. 
 
Definition 4: 
• 
Subjects with ≥ 4 of the expected 7 entries from Day -7 through Day -1, will have 
their baseline value calculated as defined in Definition 1 above.  
• 
For subjects with < 4 entries from Day -7 through Day -1, the baseline value will 
be missing. 
ASD = Asthma Symptom Diary; FAS = Full Analysis Set; SABA = short-acting beta agonist 
 
9.3 
Handling of Partial Dates 
Rules for imputation of missing or partial dates to enable background calculation/classification 
of AEs and prior/concomitant medication/procedures are presented in Appendix 2. 
Listings will display the dates as collected on the eCRF. 
9.4 
Interim Analysis 
No interim analyses are applicable. 


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9.5 
Pooling Strategy for Study Sites 
Data from all subjects will be pooled across study sites. 
9.6 
Visit Windows / Unscheduled Visits 
A schedule of assessments is included in Table 2. Additional visit windowing, beyond the 
protocol-defined windows, will not be applied. 
Unscheduled measurements will be classified as unscheduled visits at the site. Unscheduled 
visits will not be included in by-visit summaries or analysis, but will be included in summaries of 
PCI values and will also be considered when the baseline assessment and worst overall 
post-baseline values are defined. 


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10 STATISTICAL ANALYSIS METHODS 
10.1 Subject Disposition 
The following subject listings will be provided, using the analysis set indicated: 
• Screen failures (all subjects) 
• Randomized subjects (RAS) 
• Subject completion/discontinuation information (RAS) 
• Inclusion/exclusion of subjects from analysis sets (RAS) 
Summary tables will be provided using the RAS/all subjects (as applicable), including the 
following information: number of subjects who completed the study, number of subjects who 
discontinued the study early (including reason for early discontinuation), number of subjects who 
completed study drug treatment, number of subjects who discontinued study drug treatment early 
(including reason for early discontinuation), and number of subjects in each analysis set. The 
number of subjects screened and number of screen failures (including reason for screen failures) 
will also be summarized for all subjects screened. These summaries will be presented by 
treatment group and overall. 
10.2 Protocol Deviations 
Reported protocol deviations will be categorized to a deviation category and will also be 
categorized as significant/not significant prior to unblinding of data. 
All deviations will be included in a subject listing, using the RAS. 
Significant deviations will be summarized by treatment group and overall, using counts and 
percentages by deviation category (as applicable) for the RAS. Subjects will only be counted 
once within each deviation category. 
10.3 Demographics and Baseline Characteristics 
The following demographic and baseline characteristics will be included in a subject listing, 
using the RAS: 
• Age 
• Sex 
• If female, whether of childbearing potential 
• Race 
• Ethnicity 
• Baseline height, body weight, and BMI 
• Screening and Baseline eosinophil level 
• Part of sputum subset of subjects 


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The demographic and baseline characteristics will be summarized by treatment group and overall 
using descriptive statistics, for the RAS (including screening eosinophil level 
[< 150 eosinophils/μL, ≥ 150 eosinophils/μL] and sputum subset [Yes, No] as categorical 
variables). 
BMI will be derived as: 
KXY = ,#*%)04% B%06ℎ$ (P6)
[,#*%)04% ℎ%06ℎ$ (3)]# 
10.3.1 
Medical History 
Medical history terms will be coded using MedDRA, version 24, 01 Sep 2021. 
Medical history items will be included in a subject listing, using the RAS. 
The number and percentage of subjects reporting any medical history will be summarized by 
SOC and PT, by treatment group and overall, for the RAS. A subject with multiple medical 
conditions will be counted once per SOC and PT. For computing percentages, the denominator 
will be the number of subjects in the RAS for each treatment group. The summary table will be 
sorted alphabetically for SOC, then by descending frequency of PT (for AVTX-002) within each 
SOC (then alphabetically for ties). 
10.4 Prior and Concomitant Medications and Procedures 
A prior medication or procedure is defined as having been received before the date of first study 
drug. A concomitant medication or procedure is defined as having been received on or after the 
date of the first dose of study drug (ie, either stops on/after the date of the first dose of study drug 
or is ongoing). Hence, a recorded medication may be both prior and concomitant. 
Prior medications are captured from the screening visit, with the exception of ICS and LABA, 
which should also be recorded for the 3 months immediately prior to screening. 
All prior and concomitant medications will be coded using the WHO-DD, version Sep 2021.  
All prior and concomitant medications and procedures will be included in a subject listing, using 
the SAS. Any record/s where criteria for an asthma related event were met (see Section 6.2.1), 
will be flagged in the listing. 
The number and percentage of subjects reporting prior and concomitant medications will be 
summarized by WHO-DD ATC Level 3 and preferred name, by treatment group, for the SAS. 
The same convention as detailed above for medical history (see Section 10.3.1) will be applied to 
the table summaries. 
Prior/concomitant status (according to the definition provided at the start of this section) will be 
derived using the medication/procedure start and stop dates. For partial dates, see imputation 
rules in Appendix 2 (Table 4). 
 


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10.4.1 
Salmeterol/Fluticasone Run-in 
A separate subject listing will be provided detailing the administration of salmeterol and 
fluticasone during the 30day runin period prior to randomization, for the SAS. The listing will 
display for each subject whether the 30day runin period was started, completed without 
interruption, and whether the dose was tapered and discontinued as per protocol, for salmeterol 
and fluticasone use during the runin period, as applicable. Reason/s for not receiving salmeterol 
and/or fluticasone per protocol specifications will also be presented, as applicable. 
10.5 Treatment Exposure 
Based upon the PK of the study drug (halflife of 18.0 to 27.0 days) and dosage administered, 
each dose will count as 28 days of exposure to study drug. Therefore, days of exposure to study 
drug will be calculated as:  
()#*$ *$+"5 "2+6 "'*% "#$% −(02*$ *$+"5 "2+6 "'*% "#$%) + 28 
A subject listing of treatment exposure will be presented, using the SAS, including the date and 
time of each study drug administration, reason for a dose not administered, location of each 
injection for each study drug administration, confirmation whether the injections were 
administered 4-10 cm from the umbilicus (with reason if not), and whether the complete dose 
was administered (with reason if not). The study drug exposure (days) will also be included in 
the listing. 
Exposure to study drug (days) will be summarized by treatment group and overall using 
descriptive statistics, for the SAS. The number and percentage of subjects receiving 3, 2, 1, and 
0 doses of study drug, respectively, will also be presented. 
10.6 Efficacy 
The following subject listings will be provided, using the FAS (observed as well as change from 
baseline values will be included as applicable): 
• Occurrence of asthma related events – based on programmatic derivations from raw data 
(including the specification that constitutes the asthma related event – see Section 6.2.1, date 
of first administration of study drug, first date of asthma related event/date of last subject 
visit, the applicable baseline definition – see Section 9.2, time to first asthma related 
event/time to censoring in days)  
• Individual daily recordings for peak flow measurements and number of SABA reliever puffs 
for subjects with an asthma related event; record/s where criteria for an asthma related event 
were met, will be flagged in this listing 
• Occurrence of asthma related events – based on Investigator assessment (including the 
specification that constitutes the asthma related event – see Section 6.2.1, date of first 
administration of study drug, first date of asthma related event/date of last subject visit) 
• Discordance between programmatic derivation from raw data and Investigator assessment in 
occurrence of asthma related events 


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• FEV1 (FEV1 [L]) and FeNO (nitric oxide level [ppb]) results 
• ACQ results (results for each individual item as well as the overall score – see Section 6.2.4) 
• AQLQ(S)+12 results (results for each individual item as well as the domain and overall 
scores – see Section 6.2.5) 
• ASD results (see Section 6.2.6) – this will include the following: 
o mean symptom scores for each symptom separately, as well as mean ASD scores, for 
each 1-week period 
o number of SABA reliever puffs (mean daily puffs/inhalations over each 1-week period) 
o peak flow measurements (mean measurement over each 1-week period) 
Note: Only the weekly mean data are presented by subject in these subject listings; all 
individual daily recordings are however available in the submission datasets. 
• EQ-5D-5L results (results for each of the 5 dimensions as well as for the EQ VAS – see 
Section 6.2.7) 
• PGI-C/S and CGI-I/S results (results for each question – see Section 6.2.8 and Section 6.2.9) 
 
10.6.1 
Primary Endpoint Analysis 
The primary endpoint analysis is performed using the assessments for the occurrence of asthma 
related events based on programmatic derivations from raw data. 
The proportion of subjects who experience any asthma related event will be summarized by 
treatment group, also including the proportion of subjects who experience each of the 5 separate 
criteria for an asthma related event (as identified in Section 6.2.1). A subject who experienced 
multiple asthma related events will be counted once in each of the applicable criteria categories 
and once for having an asthma related event.  
Summary statistics showing the number and percentage of subjects with and without asthma 
related events in each treatment group will be provided via a 2x2 table. Comparison of the 
proportions of subjects who had an asthma related event will be via a Wald Z-test (including and 
without continuity correction). The test statistic, its associated p-value and a 95% confidence 
interval for the treatment difference will also be provided. 
The summary table and associated statistical analysis of the occurrence of asthma related events 
will be repeated for results obtained using each of the 4 baseline values for mean daily number of 
SABA puffs/inhalations and mean peak flow rate calculated according to Definitions 1 to 4 in 
Section 9.2, for all subjects in the FAS. In addition, the results for occurrence of asthma related 
events using the baseline values for mean daily number of SABA puffs/inhalations and mean 
peak flow rate calculated according to Definition 1 in Section 9.2, for subjects in the Per Protocol 
Analysis Set, will also be presented. 
Figures (one per subject) will display the % change from baseline in peak flow rate and change 
from baseline in daily number of SABA puffs/inhalations over time. Baseline values calculated 
according to Definition 1 in Section 9.2 will apply. Occurrence of the following will also be 


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indicated on the figure for each subject: administration of each dose of study drug, reduction of 
fluticasone dose, discontinuation of salmeterol and fluticasone, end of study participation. As 
part of the figure, information on subject disposition (whether the subject completed the study or 
reason for early discontinuation from the study) and whether any criteria for occurrence of an 
asthma related event were met, will also be displayed. 
10.6.2 
Secondary Endpoints Summaries 
The following results will be summarized descriptively, using the FAS: 
• Time to first asthma related event/censoring (in days) will be summarized descriptively by 
treatment group as well as by a Kaplan-Meier plot of the time to asthma related event curves 
of the two treatment groups. A statistical comparison between treatment groups will be 
accomplished with the log rank test, for which the test statistic and associated p-value will be 
provided. For exploratory reasons, annual asthma related event rate will also be summarized 
descriptively by treatment group. As above for the primary endpoint analysis, this summary 
is performed using the assessments for the occurrence of asthma related events based on 
programmatic derivations from raw data and using the results from applying baseline 
Definition 1 where applicable (see Section 9.2). 
• FEV1 (FEV1 [L]) and FeNO (nitric oxide level [ppb]) results – summary statistics for 
observed as well as change from baseline values, by visit for each treatment group 
• ACQ results (overall score – see Section 6.2.4) – summary statistics for observed as well as 
change from baseline values, by visit for each treatment group 
• AQLQ(S)+12 results (4 domain scores and overall score - see Section 6.2.5) – summary 
statistics for observed as well as change from baseline values, by visit for each treatment 
group 
• Mean symptom score (each symptom separately) and mean ASD score (see Section 6.2.6.1) 
– summary statistics for observed as well as change from baseline values, by week for each 
treatment group 
• Mean daily number of SABA puffs/inhalations over 1-week period (see Section 6.2.6.2) – 
summary statistics for observed as well as change from baseline values, by week for each 
treatment group; the summary will present the results applying calculation of baseline values 
according to Definition 1 for mean daily number of SABA puffs/inhalations (see Section 9.2) 
• Mean peak flow rate (see Section 6.2.6.2) – summary statistics for observed as well as 
change from baseline values, by week for each treatment group; the summary will present the 
results applying calculation of baseline values according to Definition 1 for mean peak flow 
rate (see Section 9.2) 
• EQ-5D-5L results (VAS score – see Section 6.2.7) – summary statistics for observed as well 
as change from baseline values, by visit for each treatment group 
• EQ-5D-5L results (each of the 5 dimensions – see Section 6.2.7) – the shift from baseline to 
each post-baseline visit will be presented by treatment group 
• Patient and Clinician Global Impression Questionnaires (see Section 6.2.8 and Section 6.2.9)  


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o for numeric scores: summary statistics for observed as well as change from baseline 
values (change from baseline values only applicable for PGIS and CGIS), by visit for 
each treatment group;  
o for categorical result for each question: number and percentage of subjects for each rating 
for each visit by treatment group 
 
10.6.3 
Exploratory Endpoint Analyses 
The primary efficacy analysis (see Section 10.6.1) will be repeated for subjects in the FAS, for 
the subgroup of subjects with < 150 eosinophils/μL at the baseline visit. When evaluating SABA 
use and peak flow for this analysis, mean daily number of SABA puffs/inhalations and mean 
peak flow rate will be calculated according to baseline Definition 1 in Section 9.2. 
In addition, the primary efficacy analysis (see Section 10.6.1) will be repeated for subjects who 
experience an asthma related event in the period of time from date of first administration of study 
drug through 28 days after final dose of study drug. When evaluating SABA use and peak flow 
for this analysis, mean daily number of SABA puffs/inhalations and mean peak flow rate will be 
calculated according to baseline Definition 1 in Section 9.2. 
10.6.4 
Interim Analysis 
No formal interim analysis is planned for this study. 
10.7 Safety and Tolerability 
Safety analyses will be conducted using data from the SAS (as defined in Section 7.1.2). Safety 
variables will include TEAEs, clinical laboratory values, vital signs, and ECG results. No formal 
inferential analyses will be conducted for any safety variables, unless otherwise noted. 
10.7.1 
Adverse Events 
All AEs are collected from the time that the informed consent is signed until the end of study.  
The definition for an AE to be considered treatmentemergent is as follows:  
• If AE start time is recorded: an AE will be considered treatmentemergent if it occurs on or 
after the time of first dose of investigational product and within 28 days after a subject’s last 
dose of investigational product.  
• If AE start time is not recorded: an AE will be considered treatmentemergent if it occurs on 
or after the date of first dose of investigational product and within 28 days after a subject’s 
last dose of investigational product. 
Additionally, an AE that occurred prior to the date of first study drug dosing and increased in 
severity after start of first dosing and within 28 days of a subject’s last dose of investigational 
product will also be considered treatment-emergent. An AE that occurred prior to first study drug 
dose and then again after first study drug dose at the same severity is NOT considered 
treatment-emergent. 


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AE verbatim terms will be coded to a SOC and PT using MedDRA, version 24, 01 Sep 2021. 
For incidence of AEs by treatment group, SOC and PT, a subject will be counted only once per 
SOC and PT. 
For AE incidence presented as the number and percentage of subjects with a specific AE, if there 
is more than one occurrence of an event, the event with the worst severity or the highest rated 
causality category will be summarized. 
Summaries of AEs by SOC and PT will be sorted alphabetically for SOC, then by descending 
order of frequency of PT (for AVTX-002) within each SOC (then alphabetically for ties). 
Summaries of AEs by PT will be sorted by descending order of frequency of PT (for 
AVTX-002), then alphabetically for ties. 
Missing assessments of seriousness, intensity and relationship to study drug that have been 
queried and remain missing, will be treated ‘worst case’ for presentation filtering purposes as 
follows: 
• Missing seriousness assessment: AE will be regarded as serious. 
• Missing relationship to study drug: AE will be regarded probably related to study drug, 
except when start date is prior to first dose of study drug (in which case the AE will be 
regarded not related to study drug). 
• Missing intensity assessment: 
o If subject has died, AE will be regarded Grade 5 intensity. 
o If subject has not died but subject had intervention indicated for the AE, AE will be 
regarded Grade 4 intensity. 
o If none of the previous conditions are met, AE will be regarded Grade 3 intensity. 
 
The following subject listings will be provided, using the SAS: 
• All AEs (including TEAEs and nonTEAEs) 
• All serious AEs (including serious TEAEs and serious nonTEAEs) 
• All AEs leading to death 
• All AEs leading to discontinuation of study drug 
 
An overall summary of AEs will be provided, containing the number and percentage of subjects 
by treatment group with:  
• any AEs 
• any serious AEs 
• any TEAEs 
• any study drug related TEAEs 


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• any TEAEs leading to study drug discontinuation 
• any study drug related TEAEs leading to study drug discontinuation 
• any TEAEs by maximum CTCAE grade (Grade 1, Grade 2, Grade 3, Grade 4, Grade 5) 
• any serious TEAEs 
• any study drug related serious TEAEs 
• any TEAEs leading to death 
• any serious TEAEs by maximum CTCAE grade (Grade 1, Grade 2, Grade 3, Grade 4, 
Grade 5) 
 
The following summary tables will be provided by SOC and PT, by treatment group: 
• Incidence of TEAEs 
• Incidence of study drug related TEAEs 
• Incidence of TEAEs leading to study drug discontinuation. 
• Incidence of study drug related TEAEs leading to study drug discontinuation 
• Incidence of TEAEs by maximum CTCAE grade (Grade 1, Grade 2, Grade 3, Grade 4, 
Grade 5) 
• Incidence of serious AEs (only if incidence of serious AEs and serious TEAEs differs) 
• Incidence of serious TEAEs 
• Incidence of study drug related serious TEAEs 
• Incidence of serious TEAEs by maximum CTCAE grade (Grade 1, Grade 2, Grade 3, 
Grade 4, Grade 5) 
 
10.7.2 
Clinical Laboratory Values 
Subject listings, using the SAS, will be provided for all clinical laboratory tests, ie, hematology, 
clinical chemistry, urinalysis, and pregnancy tests. 
Observed values of hematology and clinical chemistry parameters, and continuous urinalysis 
parameters (SG, pH) at selected time points, and change from baseline in these parameters at 
each post-baseline time point, will be summarized descriptively by treatment group. The overall 
worst value post-baseline (which includes results from unscheduled visits) will also be included 
in the summaries. Table 10 provides the directionality of the worst values for each laboratory 
parameter. 
Shift tables for hematology and clinical chemistry laboratory parameters, using laboratory 
CTCAE version 5.0 grading (see Table 9) showing changes from baseline to post-baseline values 
will be summarized using counts and percentages. For a specific laboratory parameter, subjects 
with both baseline and a post-baseline value will be included for shift summaries. For computing 
percentages, the denominator will be the total number of subjects with non-missing baseline and 
post-baseline values for the respective post-baseline visit point and treatment group. 


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The number and percentage of subjects meeting criteria for abnormal LFTs (see Table 6) will be 
summarized by treatment group and time point (including results from unscheduled visits). For 
computing percentages, the denominator will be the number of subjects with a post-baseline 
value for the specific laboratory parameter and the respective time point. Only subjects with 
newly occurring values (at least one post-baseline measurement meeting the criterion but not 
meeting the criterion at baseline) will be counted. 
The number and percentage of subjects meeting PCI criteria for laboratory values (see Table 7) 
post-baseline will be presented by treatment group (including results from unscheduled visits). 
For computing percentages, the denominator will be the number of subjects with a post-baseline 
value for the specific laboratory parameter and time point; the exception is for hemoglobin where 
the denominator will be the number of subjects with both a baseline and a post-baseline value at 
the respective time point, given that the criteria for hemoglobin includes both an absolute value 
as well as change from baseline criteria. Only subjects with newly occurring values (at least one 
post-baseline measurement meeting the criterion but not meeting the criterion at baseline) will be 
counted. Subjects with laboratory values meeting PCI criteria will be included in a subject 
listing; all values for the laboratory parameter meeting PCI criteria will be included in the listing. 
For results reported as not fully numeric (eg, result is reported as < 3.5 mmol/L), the numeric 
portion of the result (ie, 3.5 in this case) will be used in case calculations/derivations need to be 
performed (eg, when summary statistics or change from baseline values are calculated, or 
toxicity grading is derived). 
10.7.3 
Electrocardiograms 
All ECG results will be listed by subject. 
10.7.4 
Vital Signs 
A subject listing, using the SAS, will be provided for all vital signs results. Results meeting PCI 
criteria (see Table 8) will be flagged in the listing. 
Observed values of SBP, DBP, pulse rate, respiratory rate, temperature, and body weight at 
baseline and at selected postbaseline time points, and change from baseline in these parameters 
at each postbaseline time point, will be summarized descriptively by treatment group. 
10.7.5 
Physical Examinations 
Any clinically significant findings during physical examinations are to be reported as medical 
history or AEs, depending on timing. No separate listing will be provided for physical 
examination results. 
10.8 Pharmacokinetics 
AVTX-002 plasma concentrations will be listed by subject (using the PK Analysis Set), and will 
be summarized by visit and treatment group, for the PK Analysis Set. 


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10.9 Pharmacodynamics 
Results from sputum soluble LIGHT levels and gene expression, inflammatory biomarkers, and 
immunophenotyping of immune cell subsets are reported separately (as applicable) and will not 
form part of the statistical analysis described in this SAP. 
Results from serum soluble LIGHT levels will be listed by subject in a subject listing, and 
descriptive statistics for actual as well as change from baseline values will be presented by 
treatment group and time point, using the FAS. 
10.10 Immunogenicity 
For the immunogenicity variables (ie, ADA), results will be listed by subject in a subject listing, 
and descriptive statistics for actual as well as change from baseline values will be presented by 
treatment group and time point, using the SAS. 


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11 REFERENCES 
1. 
EMA. Structure and Content of Clinical Study Reports. ICH E3. Jul 1996. 
2. 
EMA. Statistical Principles for Clinical Trials. ICH E9. Sep 1998. 
3. 
Wenzel, S., et al. Dupilumab in Persistent Asthma with Elevated Eosinophil Levels, 
N Engl J Med, Jun 2013; 368(26):2455-66. 
4. 
Asthma Control Questionnaire: Background, Administration and Analysis; 2004, QOL 
Technologies Ltd. 
5. 
Asthma Quality of Life Questionnaires (AQLQ, AQLQ(S), MiniAQLQ and Acute 
AQLQ): Background, Administration and Analysis; 1991, QOL Technologies Ltd. 
6. 
United States Food and Drug Administration. Clinical Outcome Assessments (COA) 
Qualification Program DDT COA #000006: Asthma Daytime Symptom Diary (ADSD) 
and Asthma Nighttime Symptom Diary (ANSD). Available from: https://www.fda.gov/ 
media/128296/download. 
7. 
EuroQol Group. EQ-5D-5L: About. 2017. Available from: https://euroqol.org/eq-
5dinstruments/eq-5d-5l-about/. 
 


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12 APPENDICES 


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Appendix 1. 
Schedule of Assessments and Procedures 
Note: refer to Section 8 for changes to numbering of assessment day, for purposes of reporting of study results. The assessment day as 
presented in Table 2 below, reflects the numbering as presented in the study protocol. 
Table 2. 
Schedule of Assessments (as per V4 study protocol) 
Procedure 
Screening 
30day Runin 
Period 
Baseline 
Doubleblind Treatment Period 
Visit 
Visit 1 
 
Visit 
1a 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9/
ET2 
Assessment Week 
-4 
 
 
0 
1 
2 
4 
6 
8 
12 
14 
Assessment Day 
Appr -371 
-30 
through 
-1 
-7 
0 
7 
14 
28 
42 
No later 
than 563 
84 
98 
Visit Window4 
NA 
 
-2 days 
+3 days5 
±1 day 
±1 day 
±3 days 
±3 days 
-3 days 
±3 days 
±3 days 
Phone visit 
 
 
X6 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion review 
X 
 
 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Prior medications 
X 
X 
X 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
 
 
 
 
Concomitant medications 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X8 
 
 
X7 
 
X 
X7 
X 
X7 
X 
X 
Physical examination 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
FEV1 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
FeNO 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Peak Flow Test (daily)9, 17 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ACQ 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
AQLQ(S)+12 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
ASD (2x daily)17 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record SABA use (2x daily)18 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EQ-5D-5L 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 


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Procedure 
Screening 
30day Runin 
Period 
Baseline 
Doubleblind Treatment Period 
Visit 
Visit 1 
 
Visit 
1a 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9/
ET2 
Assessment Week 
-4 
 
 
0 
1 
2 
4 
6 
8 
12 
14 
Assessment Day 
Appr -371 
-30 
through 
-1 
-7 
0 
7 
14 
28 
42 
No later 
than 563 
84 
98 
Visit Window4 
NA 
 
-2 days 
+3 days5 
±1 day 
±1 day 
±3 days 
±3 days 
-3 days 
±3 days 
±3 days 
PGI-C/S 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
CGI-I/S 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
ADA10 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Serum: soluble LIGHT 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Inflammatory proteins 
X 
 
 
 
 
 
X 
 
X 
X 
X 
Immunophenotyping of 
circulating immune cells 
 
 
 
X 
 
 
 
 
 
X 
X16 
Sputum: soluble LIGHT and 
gene expression11 
 
 
 
X 
 
 
 
 
 
X 
 
Plasma AVTX-002 level 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X16 
Clinical laboratory tests 
(hematology, clinical 
chemistries) 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
 
X 
 
X 
 
 
X 
X 
X 
Serum pregnancy test12 
X 
 
 
 
 
 
 
 
 
X 
X 
Urine pregnancy test12 
 
 
 
X 
 
 
X 
 
X 
 
 
Study drug administration 
(onsite)13, 14, 15 
 
 
 
X 
 
 
X 
 
X 
 
 
Salmeterol/Fluticasone runin 
 
X 
X 
 
 
 
 
 
 
 
 
Discontinue salmeterol 
 
 
 
 
 
X 
 
 
 
 
 
Taper/discontinue fluticasone 
 
 
 
 
 
 
X 
X 
 
 
 
ACQ = Asthma Control Questionnaire; ADA = anti-drug antibody; AE = adverse event; AQLQ(S)+12 = Standardized Asthma Quality of Life Questionnaire for 12 to 70 years; ASD = Asthma 
Symptom Diary; CGI-I/S = Clinician Global Impression of Improvement/Severity; ECG = electrocardiogram; EQ-5D-5L = European Quality of Life – 5 dimension 5 level questionnaire; ET = early 
termination; FeNO = fractional exhaled nitric oxide; FEV1 = forced expiratory volume in 1 second; LIGHT = Lymphotoxin-like, exhibits Inducible expression, and competes with Herpes Virus 
Glycoprotein D for Herpesvirus Entry Mediator, a receptor expressed by T lymphocytes; PGI-C/S = Patient Global Impression of Change/Severity; SABA = short-acting beta agonist 
1. 
Documentation of eligibility on all inclusion and exclusion criteria is required before a subject can enter the study 30-day run-in period prior to Visit 2 (randomization) when the subject is 
switched to stand alone salmeterol and fluticasone. Confirmation of eligibility should take place within a reasonable amount of time after the Screening Visit. If confirmation of eligibility is not 
available within 14 days from the date of screening, the study sponsor should provide approval for the subject to continue. 
2. 
If a subject discontinues from the study/study drug, the Visit 9/ET procedures will be performed 4 weeks post last dose (±3 days). 
3. 
A subject must be dosed with the Visit 7 (Week 8) dose no later than Day 56. 


Statistical Analysis Plan: AVTX-002-NEA-201 
Avalo Therapeutics, Inc. 
AVTX-002 
Final 4.0, 02 Jun 2023 
 
Confidential 
Page 45 of 52 
 
 
 
 
Procedure 
Screening 
30day Runin 
Period 
Baseline 
Doubleblind Treatment Period 
Visit 
Visit 1 
 
Visit 
1a 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9/
ET2 
Assessment Week 
-4 
 
 
0 
1 
2 
4 
6 
8 
12 
14 
Assessment Day 
Appr -371 
-30 
through 
-1 
-7 
0 
7 
14 
28 
42 
No later 
than 563 
84 
98 
Visit Window4 
NA 
 
-2 days 
+3 days5 
±1 day 
±1 day 
±3 days 
±3 days 
-3 days 
±3 days 
±3 days 
4. 
After Visit 2 (Day 0), visits should be scheduled relative to Visit 2 (Day 0). Visit 7 (Week 8) must not be performed later than Day 56. 
5. 
Baseline visit to occur the day following completion of the 30-day run-in period with a window of an additional 3 days. 
6. 
Visit 1a (Day -7) may be completed either by telephone or may be completed as an in-clinic visit, depending on the needs of the site and/or each individual subject. Visit 1a should occur with 7 
days remaining in the 30-day run-in (-2 day window for Visit 1a). During this phone call/onsite visit, the subject should be reminded to begin daily peak flow testing, and daily completion of 
their diary to capture asthma symptoms, SABA use, and daily peak flow values. 
7. 
At Visit 2 (Day 0), Visit 5 (Day 28), and Visit 7 (Day 56), pre and postdose vital signs will be measured: predose vital signs should be taken within 60 minutes before dosing; postdose vital 
signs should be taken at least 60 minutes after dosing, prior to discharge. 
8. 
Height will only be recorded at the Screening Visit. 
9. 
Subject should record the best result of 3 attempts daily at home. Subject should perform daily peak flow at approximately the same time each day between 10:00 AM and 2:00 PM. Subject 
should also bring peak flow meter to clinic visits. If peak flow has not been completed at home by the subject on the day of a clinic visit it should be completed at the clinic during the visit. 
10. In addition to ADA collection time points per the schedule of events, an ADA sample will be collected when an immunologically related AE is reported (eg, a skin reaction, lupuslike syndrome, 
unexplained thrombocytopenia). 
11. Select subset of sites/subjects only. 
12. For females of childbearing potential. A subject is not considered to be of childbearing potential if at least 6 weeks have passed since sterilization, defined as females having undergone one of 
the following surgeries: hysterectomy, bilateral tubal ligation or occlusion, bilateral oophorectomy, or bilateral salpingectomy; and males who are vasectomized. Contraception is not required 
where females are postmenopausal (defined as 12 consecutive months of spontaneous amenorrhea and age ≥51 years). 
13. On the day of randomization when the first dose of study drug is administered (Visit 2/Day 0), all visit procedures should be completed prior to study drug administration. At the other study 
drug administration days (Visit 5/Day 28 and Visit 7/Day 56), only the PK, ADA, serum soluble LIGHT, inflammatory proteins and immunophenotyping samples must be collected prior to 
study drug dosing. Other procedures can be performed as needed in the clinic on the visit day. 
14. Subjects will be required to remain in the clinic for at least 60 minutes after study drug administration for AE monitoring. 
15. Investigational product will be prepared by an unblinded pharmacist or appropriately qualified individual. 
16. Immunophenotyping and PK only required if an ET visit is completed. Immunophenotyping and PK not required at Visit 9/Day 98. 
17. Site regular assessment of diary completion for compliance. 
18. SABA use is defined as the number of individual puffs or inhalations taken by the subject. 


Statistical Analysis Plan: AVTX-002-NEA-201 
Avalo Therapeutics, Inc. 
AVTX-002 
Final 4.0, 02 Jun 2023 
 
Confidential 
Page 46 of 52 
 
 
 
 
Appendix 2. 
Imputation of Partial Dates 
Table 3. 
Imputation Rules for Partial Dates – Adverse Events
Parameter 
Missing 
Additional Condition 
Imputation 
Start Date 
D only 
M and Y are prior to first study drug dose 
First day of indicated month 
M and Y is same as first study drug dose 
Date of first study drug dose 
M and Y are after first study drug dose 
First day of indicated month 
M and D 
Y is prior to first study drug dose 
01 Jan of indicated year 
Y is same as first study drug dose 
Date of first study drug dose 
Y is after first study drug dose 
01 Jan of indicated year 
M, D, and Y 
--- 
assumed to be TEAE 
End Date 
D only 
M and Y are prior to last study drug dose 
Last day of indicated month 
M and Y is same as last study drug dose 
Date of last observation if within 
indicated M and Y; if date of last 
observation extends after indicated M 
and Y, then use last day of indicated 
month 
M and Y are after last study drug dose 
First day of indicated month 
M and D 
Y is prior to last study drug dose 
31 Dec of indicated year 
Y is same as last study drug dose 
Date of last observation if within 
indicated Y; if date of last 
observation extends after indicated Y, 
then use 31 Dec of indicated year 
Y is after last study drug dose 
01 Jan of indicated year 
M, D, and Y 
--- 
TEAE is ongoing 
--- 
Estimated end date is before a complete or 
imputed AE start date 
Last day of the month of AE start 
date 
AE = adverse event; D = day; M = month; TEAE = treatmentemergent adverse event; Y= year 
Note: The imputation of end date must be later than start date 
 
Table 4. 
Imputation Rules for Partial Dates – Prior and Concomitant Medications and 
Procedures 
Parameter 
Missing 
Additional Condition 
Imputation 
Start Date 
D only 
M and Y same as M and Y of first study drug 
dosing 
Date of first study drug dose 
M and/or Y not the same as M and Y of first study 
drug dosing 
First day of indicated month 
M and D 
Y same as Y of first study drug dosing 
Date of first study drug dose 
Y not the same as Y of first study drug dosing 
01 Jan of indicated year 
M, D, and Y 
--- 
Date of first study drug dose 
End date < date of first study drug dose 
End date 
End Date 
D only 
M and Y same as M and Y of last study drug dosing 
Date of last study drug dose 
M and/or Y not the same as M and Y of last study 
drug dosing 
Last day of indicated month 
M and D 
Y same as Y of last study drug dosing 
Date of last study drug dose 
Y not the same as Y of last study drug dosing 
31 Dec of indicated year 
M, D, and Y 
--- 
Date of last study drug dose 
D = day; M = month; Y= year 


Statistical Analysis Plan: AVTX-002-NEA-201 
Avalo Therapeutics, Inc. 
AVTX-002 
Final 4.0, 02 Jun 2023 
 
Confidential 
Page 47 of 52 
 
 
 
 
Appendix 3. 
Planned Laboratory Assays 
Table 5. 
Planned Laboratory Assays 
Laboratory Category 
Assay Grouping 
Assay 
Chemistry 
 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Glucose 
BUN 
Creatine 
Creatinine phosphokinase 
ALT 
AST 
GGT 
ALP 
TBL 
Calcium 
Magnesium 
Phosphorous 
LDH 
Uric acid 
Total protein 
Albumin 
CRP 
Total cholesterol 
HDL cholesterol 
LDL cholesterol 
Triglycerides 
Hematology 
 
Hemoglobin 
 
Hematocrit 
 
RBC count 
 
Platelet count 
RBC indices 
MCV 
MCH 
MCHC 
WBC count with differentials 
Neutrophils – absolute and percent 
Lymphocytes – absolute and percent 
Monocytes – absolute and percent 
Eosinophils – absolute and percent 
Basophils – absolute and percent 
Urinalysis 
Dipstick 
pH 
SG 
Protein 
Blood 


Statistical Analysis Plan: AVTX-002-NEA-201 
Avalo Therapeutics, Inc. 
AVTX-002 
Final 4.0, 02 Jun 2023 
 
Confidential 
Page 48 of 52 
 
 
 
 
Glucose 
Ketones 
 
Microscopic examination if blood or 
protein is present 
Serum/urine pregnancy tests 
 
Highly sensitive hCG pregnancy test* 
Other tests 
Immunogenicity 
ADA 
PD and biomarker assessments 
Serum: soluble LIGHT 
Serum: Inflammatory proteins** 
PBMC: Immunophenotyping** 
Sputum: soluble LIGHT** 
PK assessments 
Plasma: AVTX-002 
ADA = anti-drug antibody; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; BUN = blood urea nitrogen; CRP = Creactive protein; GGT = gamma glutamyl transferase; 
hCG = human chorionic gonadotropin; HDL = high-density lipoprotein; LDH = lactate dehydrogenase; 
LDL = low-density lipoprotein; LIGHT = Lymphotoxin-like, exhibits Inducible expression, and competes with 
Herpes Virus Glycoprotein D for Herpesvirus Entry Mediator, a receptor expressed by T lymphocytes; 
MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean 
corpuscular volume; PBMC = peripheral blood mononuclear cells; PD = pharmacodynamic/s; 
PK = pharmacokinetic/s; RBC = red blood cell; SAP = statistical analysis plan; SG = Specific Gravity; 
TBL = total bilirubin; WBC = white blood cell 
* For women of childbearing potential 
** Samples for these analyses are collected as per the Schedule of Assessments (Table 2); however, these results 
are reported separately (as applicable), and will not form part of the statistical analysis described in this SAP 
 


Statistical Analysis Plan: AVTX-002-NEA-201 
Avalo Therapeutics, Inc. 
AVTX-002 
Final 4.0, 02 Jun 2023 
 
Confidential 
Page 49 of 52 
 
 
 
 
Appendix 4. 
Potentially Clinically Important Criteria 
Table 6. 
Liver Function PCI Criteria 
Laboratory Parameter 
PCI Criteria 
ALT 
> 3 × ULN; > 5 × ULN; > 10 × ULN 
AST 
> 3 × ULN; > 5 × ULN; > 10 × ULN 
TBL 
> 1.5 × ULN 
ALT and TBL 
ALT > 3 × ULN and TBL > 2 × ULN 
AST and TBL 
AST > 3 × ULN and TBL > 2 × ULN 
ALT/AST and TBL and ALP 
ALT/AST > 3 × ULN and TBL > 2 × ULN and ALP < 2 × ULN 
(Hy’s Law Criteria) 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
PCI = potentially clinically important; TBL = total bilirubin; ULN = upper limit of normal 
 
Table 7. 
Safety Laboratory PCI Criteria 
Laboratory Parameter 
SI Unit 
Lower Limit 
Upper Limit 
Creatinine 
μmol/L 
 
> 150 
Sodium 
mmol/L 
≤ 130 
> 150 
Potassium 
mmol/L 
< 3.0 
> 5.5 
TBL 
μmol/L 
 
> 1.5 × ULN 
ALT 
U/L 
 
> 3 × ULN 
AST 
U/L 
 
> 3 × ULN 
Hemoglobin 
g/L 
< 0.8 × LLN and > 20% 
decrease from baseline 
> 1.3 × ULN and > 30% 
increase from baseline 
Leukocytes 
× 109/L 
≤ 2.8 
≥ 16.0 
Lymphocytes 
× 109/L 
< 0.5 
> 20 
Neutrophils 
× 109/L 
< 1.0 
 
Platelets 
× 109/L 
≤ 75 
≥ 500 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; LLN = lower limit of normal; 
PCI = potentially clinically important; TBL = total bilirubin; ULN = upper limit of normal 
 
Table 8. 
Vital Signs PCI Criteria 
Vital Signs Parameter 
PCI Criteria 
SBP 
≤ 90 mmHg and decrease of ≥ 20 mmHg from baseline 
 
≥ 180 mmHg and increase of ≥ 25 mmHg from baseline 
DBP 
≤ 50 mmHg and decrease of ≥ 15 mmHg from baseline 
 
≥ 105 mmHg and increase of ≥ 15 mmHg from baseline 
Pulse rate 
≤ 40 bpm 
 
≥ 100 bpm 
DBP = diastolic blood pressure; PCI = potentially clinically important; SBP = systolic blood pressure 
 


Statistical Analysis Plan: AVTX-002-NEA-201 
Avalo Therapeutics, Inc. 
AVTX-002 
Final 4.0, 02 Jun 2023 
 
Confidential 
Page 50 of 52 
 
 
 
 
Appendix 5. 
Laboratory CTCAE Criteria 
Table 9. 
Laboratory CTCAE Grade Version 5.0 Criteria 
Lab Parameter 
SI Unit 
CTCAE Grade v5.0 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
decreased (Anemia) 
g/L 
≥ LLN 
100 – < LLN 
80 – < 100 
< 80 
 
Hemoglobin 
increased  
g/L 
≤ ULN 
> ULN – 2 × 
ULN 
> 2 × ULN – 4 
× ULN 
> 4 × ULN 
 
Hypoglycemia 
(Glucose decreased) 
mmol/L 
≥ LLN 
3.0525 – 
< LLN 
2.22 – 
< 3.0525  
1.665 – 
< 2.22 
< 1.665 
Glucose 
(hyperglycemia) 
mmol/L 
LLN – 
ULN 
> ULN – 
8.88 
> 8.88 – 
13.875 
> 13.875 –
27.75 
> 27.75 
Albumin 
g/L 
≥ LLN 
< LLN – 30 
< 30 – 20 
< 20 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated* 
ALP 
 
≤ ULN 
> ULN – 2.5 
× ULN 
> 2.5 – 5.0 × 
ULN 
> 5.0 – 
20.0 × 
ULN 
> 20.0 × ULN 
ALT increased 
U/L 
≤ULN 
> ULN – 3 × 
ULN 
> 3 × ULN –  
5 × ULN 
> 5 × ULN 
– 20 × 
ULN 
> 20 × ULN 
AST increased 
U/L 
≤ULN 
> ULN – 3 × 
ULN 
> 3 × ULN –  
5 × ULN 
> 5 × ULN 
– 20 × 
ULN 
> 20 × ULN 
Blood bilirubin 
increased 
umol/L 
≤ULN 
> ULN – 1.5 
× ULN 
> 1.5 × ULN – 
3 × ULN 
> 3 × ULN 
– 10 × 
ULN 
> 10 × ULN 
Creatinine increased 
umol/L 
≤ULN 
> ULN – 1.5 
× ULN 
> 1.5 × ULN – 
3 × ULN 
> 3 × ULN 
– 6 × ULN 
> 6 × ULN 
Calcium 
(hypocalcemia) 
mmol/L 
LLN – 
ULN 
< LLN – 2.0 
< 2.0 – 1.8 
< 1.8 – 1.5 
< 1.5 
Calcium 
(hypercalcemia) 
mg/dL 
LLN – 
ULN 
> ULN – 2.9 
> 2.9 – 3.1 
> 3.1 – 3.4 
> 3.4 
Eosinophils increased 
× 109/L 
≤ ULN 
> ULN and 
> Baseline 
 
 
 
Lymphocyte count 
decreased 
× 109/L 
≥ LLN 
0.8 – < LLN 
0.5 – < 0.8 
0.2 – < 0.5 
< 0.2 
Lymphocyte count 
increased 
× 109/L 
≤ 4 
 
> 4 – 20 
> 20 
 
Neutrophil count 
decreased 
× 109/L 
≥ LLN 
1.5 – < LLN 
1 – < 1.5 
0.5 – < 1.0 
< 0.5 
Platelet count 
decreased 
× 109/L 
≥ LLN 
75 – < LLN 
50 – < 75 
25 – < 50 
< 25 


Statistical Analysis Plan: AVTX-002-NEA-201 
Avalo Therapeutics, Inc. 
AVTX-002 
Final 4.0, 02 Jun 2023 
 
Confidential 
Page 51 of 52 
 
 
 
 
Lab Parameter 
SI Unit 
CTCAE Grade v5.0 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
WBC count 
decreased 
× 109/L 
≥ LLN 
3 – < LLN 
2 – < 3 
1 – < 2 
< 1 
WBC count increased 
(leukocytosis) 
× 109/L 
≤ 10 
 
 
> 10 
 
Hyperkalemia 
(Potassium increased) 
mmol/L 
≤ ULN 
> ULN – 5.5  > 5.5 – 6.0  
> 6.0 – 7.0  
> 7.0 
Hypokalemia 
(Potassium 
decreased) 
mmol/L 
≥ LLN 
3.0 – < LLN 
Symptomatic 
with 3.0 – 
< LLN** 
2.5 – < 3.0  
< 2.5 
Hypernatremia 
(Sodium increased) 
mmol/L 
≤ ULN 
> ULN – 
150 
> 150 – 155  
> 155 – 
160  
> 160 
Hyponatremia 
(Sodium decreased) 
mmol/L 
≥ LLN 
130 – < LLN 
125 – < 130  
120 – 
< 125  
< 120 
Bicarbonate 
decreased 
 
≥ LLN 
< LLN 
 
 
 
CPK increased 
 
≤ ULN 
> ULN – 2.5 
× ULN 
> 2.5 × ULN – 
5 × ULN 
> 5 × ULN 
– 10 × 
ULN 
> 10 × ULN 
GGT increased 
 
≤ ULN if 
baseline 
was 
normal; 
≤ 2.0 × 
baseline if 
baseline 
was 
abnormal 
> ULN – 2.5 
× ULN if 
baseline was 
normal; 2.0 
– 2.5 × 
baseline if 
baseline was 
abnormal 
> 2.5 – 5.0 × 
ULN if 
baseline was 
normal; > 2.5 
– 5.0 × 
baseline if 
baseline was 
abnormal 
> 5 – 20.0 
× ULN if 
baseline 
was 
normal; 
> 5 – 20.0 
× baseline 
if baseline 
was 
abnormal 
> 20.0 × ULN 
if baseline was 
normal; > 20.0 
× baseline if 
baseline was 
abnormal 
Hypermagnesemia 
(magnesium 
increased) 
mmol/L 
≤ ULN 
> ULN – 
1.23 
 
> 1.23 – 
3.30 
> 3.30 
Hypomagnesemia 
(magnesium 
decreased) 
mmol/L 
≥ LLN 
< LLN – 0.5 
< 0.5 – 0.4 
< 0.4 – 0.3 
< 0.3 
LDH increased 
 
≤ ULN 
> ULN 
 
 
 
Total cholesterol high 
mmol/L 
≤ ULN 
> ULN – 
7.75 
> 7.75 – 10.34 
> 10.34 – 
12.92 
> 12.92 
Hypertriglyceridemia 
(triglycerides 
increased) 
mmol/L 
≤ 1.71 
1.71 – 3.42 
> 3.42 – 5.7 
> 5.7 – 
11.4 
> 11.4 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
CTCAE = common terminology criteria for adverse events; CPK = creatinine phosphokinase; GGT = gamma 
glutamyl transferase; LDH = lactate dehydrogenase; LLN = lower limit of normal; ULN = upper limit of normal; 
WBC = white blood cell 
* Any albumin < 20 g/L will be categorized as Grade 3 
** Any potassium 3.0 – < LLN will be categorized as Grade 1 
 


Statistical Analysis Plan: AVTX-002-NEA-201 
Avalo Therapeutics, Inc. 
AVTX-002 
Final 4.0, 02 Jun 2023 
 
Confidential 
Page 52 of 52 
 
 
 
 
Appendix 6. 
Directionality of Worst Laboratory Parameters 
Table 10. Directionality of Worst Laboratory Parameters 
Laboratory Parameter 
Worst Value 
Hematology: 
 
Hemoglobin 
Both highest and lowest value 
Hematocrit 
Both highest and lowest value 
RBC count 
Both highest and lowest value 
Platelet count 
Lowest value 
MCV 
Both highest and lowest value 
MCH 
Both highest and lowest value 
MCHC 
Both highest and lowest value 
WBC count 
Both highest and lowest value 
Neutrophils 
Lowest value 
Lymphocytes 
Both highest and lowest value 
Monocytes 
Both highest and lowest value 
Eosinophils 
Both highest and lowest value 
Basophils 
Both highest and lowest value 
Chemistry: 
 
Sodium 
Both highest and lowest value 
Potassium 
Both highest and lowest value 
Chloride 
Both highest and lowest value 
Bicarbonate 
Both highest and lowest value 
Glucose 
Both highest and lowest value 
BUN 
Highest value 
Creatine 
Highest value 
Creatinine phosphokinase 
Highest value 
ALT 
Highest value 
AST 
Highest value 
GGT 
Highest value 
ALP 
Highest value 
TBL 
Highest value 
Calcium 
Both highest and lowest value 
Magnesium 
Both highest and lowest value 
Phosphorous 
Both highest and lowest value 
LDH 
Highest value 
Uric acid 
Highest value 
Total protein 
Both highest and lowest value 
Albumin 
Lowest value 
CRP 
Highest value 
Total cholesterol 
Highest value 
HDL cholesterol 
Highest value 
LDL cholesterol 
Highest value 
Triglycerides 
Highest value 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood 
urea nitrogen; CRP = Creactive protein; GGT = gamma glutamyl transferase; HDL = high-density lipoprotein; 
LDH = lactate dehydrogenase; LDL = low-density lipoprotein; MCH = mean corpuscular hemoglobin; 
MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; RBC = red blood cell; 
TBL = total bilirubin; WBC = white blood cell