Anti-TSLP (AMG 157) Plus Antigen-Specific Immunotherapy for Induction of Tolerance in Individuals With Cat Allergy (ITN057AD)
Phase: PHASE1
Conditions: Cat Allergy, Cat Hypersensitivity
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

 
 
 
 
Immune  
Tolerance 
Network 
 
Anti-TSLP (AMG 157) plus antigen-specific immunotherapy for 
induction of tolerance in individuals with cat allergy 
 Protocol ITN057AD 
Version 6.0 (August 14, 2017) 
IND # 117,529 
 
 
 
 
 
Protocol Chair 
Jonathan Corren, MD 
University of California, Los Angeles 
Allergy Medical Clinic, Research Division 
10780 Santa Monica Blvd., Suite 280 
Los Angeles, CA 90025 
Tel: 310-312-5050    Fax: 310-575-9292     
Email: jcorren@ucla.edu  
 
ITN Clinical Trial Physician 
Srinath Sanda, MD 
Clinical Trial Physician 
Clinical Trials Group 
Immune Tolerance Network 
185 Berry Street, Suite 3515 
San Francisco, CA 94107 
Tel: 415-353-4414 Fax: 415-353-4404 
Email: ssanda@immunetolerance.org 
NIAID Medical Monitor 
Lisa M. Wheatley, MD, MPH 
Medical Officer, Section Chief, 
Allergy, Asthma and Airways Biology Branch 
Division of Allergy, Immunology,  and 
Transplantation  
National Institute of Allergy and Infectious 
Diseases 
5601 Fishers Lane Rm 6B56 
Rockville, MD, 20852  
Tel: 240-627-3573     Fax:  301-402-0175 
Email: lisa.wheatley@nih.gov 
 
ITN Clinical Operations Manager 
Rachel Yan 
Clinical Operations Manager 
Clinical Trials Group 
Immune Tolerance Network 
185 Berry Street, Suite 3515 
San Francisco, CA 94107 
Tel: 415-353- 4425     Fax: 415-353-4404 
Email: ryan@immunetolerance.org  
 
NIAID Project Manager 
Joy Laurienzo Panza, RN, BSN 
NIAID Project Manager 
Division of Allergy, Immunology, and 
Transplantation 
National Institute of Allergy and Infectious 
Diseases 
5601 Fishers Lane Rm 6B51 
Rockville, MD 20852 
Tel: 240-627-3515  Fax: 301-480-2381 
Email: jlaurienzo@niaid.nih.gov 
 
 
 

 
Protocol ITN057AD 
Version 6.0 
 August 14, 2017 
Anti-TSLP and cat immunotherapy 
 
 
ITN Associate Director, Biomarker & 
Discovery Research  
David Larson, PhD 
Biomarker & Discovery Research 
Immune Tolerance Network 
7500 Old Georgetown Road, Suite 800 
Bethesda, MD 20814  
Tel: 240-235-6159     Fax: 240-235-6198 
Email: dlarson@immunetolerance.org   
NIAID Regulatory Officer 
Maria Veri, PhD 
Regulatory Officer 
Division of Allergy, Immunology, and Transplantation
National Institute of Allergy and Infectious Diseases 
5601 Fishers Lane 7B48, MSC9828 
Rockville, MD 20852 
Tel: 240-627-3572     Fax: 301-480-1537 
Email: maria.veri@nih.gov 
 
Rho Scientist 
Michelle Sever, PhD 
Senior Research Scientist 
Rho Inc. 
6330 Quadrangle Drive 
Chapel Hill, NC 27517  
Tel: 919-595-6382 
Fax 919-287-3009 
Email: michelle_sever@rhoworld.com 
 
 
Rho Biostatistician 
Miguel Villarreal, M.S. 
Senior Biostatistician 
Rho Inc. 
6330 Quadrangle Drive 
Chapel Hill, NC 27517  
Tel: 919-595-6588 
Fax 919-287-3009 
Email: miguel_villarreal@rhoworld.com 
 
This clinical study is supported and conducted by the Immune Tolerance Network, which is 
sponsored by the National Institute of Allergy and Infectious Diseases. 
This document is confidential. It is provided for review only to investigators, potential 
investigators, consultants, study staff, and applicable independent ethics committees or institutional 
review boards. It is understood that the contents of this document will not be disclosed to others 
without written authorization from ITN and NIAID unless it is necessary to obtain informed consent 
from potential study participants.
 
 
 
 
 
 
 
 

 
 
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Protocol ITN057AD 
Version 6.0 
August 14, 2017 
Anti-TSLP and cat immunotherapy 
 
 
 
Protocol Approval 
 
 
Trial ID:  ITN057AD 
Protocol Version: 6.0 
Date:  August 14, 2017 
IND # 117,529 
Protocol Chair:  Jonathan Corren, MD 
 
Title:    Anti-TSLP (AMG 157) plus antigen-specific immunotherapy for induction of tolerance in 
individuals with cat allergy
I confirm that I have read the above protocol in the latest version. I understand it, and I will 
work according to the principles of good clinical practice (GCP) as described in the US Code of 
Federal Regulations (CFR)—45 CFR part 46 and 21 CFR parts 50, 56, and 312, and in the 
International Conference on Harmonization (ICH) document Guidance for Industry: E6 Good 
Clinical Practice: Consolidated Guidance dated April 1996. Further, I will conduct the study in 
keeping with local legal and regulatory requirements. 
 
As the principal investigator, I agree to carry out the study by the criteria written in the protocol 
and understand that no changes can be made to this protocol without written permission of the 
NIAID. 
 
      By participating in this protocol, investigators and their designees also agree to: 
i) 
Use AMG 157 and placebo for AMG 157 only in accordance with the Protocol and for 
no other Purpose 
ii) Not transfer AMG 157 or Placebo for AMG 157 to any parties other than the 
Distributor identified by the NIAID 
iii) Not chemically modify, replicate, make derivatives of, or reverse engineer AMG 157 or 
Placebo for AMG 157 
 
 
__________________________________________                                        
Principal Investigator                        (Print)                     
 
__________________________________________         _________________ 
Principal Investigator                        (Sign)                   Date 

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Protocol ITN057AD 
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Anti-TSLP and cat immunotherapy 
 
Table of Contents 
1 
BACKGROUND AND RATIONALE ................................................................................ 17 
1.1 
CAT ALLERGY AS A CLINICAL PROBLEM ................................................................ 17 
 
Overview ................................................................................................................................... 17 
 
Current Approaches to Cat Allergy ........................................................................................... 17 
 
Clinical Outcomes with Subcutaneous Cat Dander Immunotherapy ........................................ 17 
 
Mechanisms of Allergen-specific Immunotherapy ................................................................... 18 
 
Why New Approaches are Needed ........................................................................................... 19 
1.2 
THYMIC STROMAL LYMPHOPOIETIN (TSLP) ............................................................ 19 
 
Role in Immune Responses ....................................................................................................... 19 
 
Role in Asthma ......................................................................................................................... 20 
 
Role in Allergic Rhinitis ........................................................................................................... 20 
1.3 
TSLP INHIBITION ......................................................................................................... 20 
 
Principle .................................................................................................................................... 20 
 
AMG 157 .................................................................................................................................. 20 
1.4 
COMBINATION OF IMMUNOTHERAPY WITH TSLP INHIBITION ............................. 21 
 
Combining Antigen with an Immunomodulatory Agent ........................................................... 21 
 
Why the Combination Might Lead to Long-lasting Effects or Tolerance ................................. 22 
1.5 
TRIAL DESIGN.............................................................................................................. 22 
 
Overview ................................................................................................................................... 22 
 
Why Total Nasal Symptom Score (TNSS) was Chosen as an Endpoint ................................... 23 
 
Why a Tolerance Trial .............................................................................................................. 23 
 
Why Cat Dander as an Allergen for Study ................................................................................ 24 
 
Mechanistic Questions: Overview ............................................................................................ 24 
1.6 
SUMMARY OF KNOWN AND POTENTIAL RISKS AND BENEFITS FOR HUMAN 
PARTICIPANTS ............................................................................................................ 24 
 
Study Medication Risks ............................................................................................................ 24 
 
Study Procedure Risks .............................................................................................................. 25 
 
Potential Benefits ...................................................................................................................... 26 
2 
OBJECTIVES ................................................................................................................... 26 
2.1 
PRIMARY OBJECTIVE .................................................................................................. 26 
2.2 
SECONDARY OBJECTIVES .......................................................................................... 26 
2.3 
EXPLORATORY OBJECTIVES ...................................................................................... 26 
3 
STUDY DESIGN ............................................................................................................... 27 
3.1 
DESCRIPTION ............................................................................................................... 27 
 
Overview ................................................................................................................................... 27 

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Dose and Schedule .................................................................................................................... 27 
 
Interim Analysis ........................................................................................................................ 29 
3.2 
STUDY DURATION ...................................................................................................... 29 
3.3 
STUDY ENDPOINTS ..................................................................................................... 29 
 
Primary Endpoint ...................................................................................................................... 29 
 
Secondary Endpoints................................................................................................................. 29 
 
Exploratory Endpoints .............................................................................................................. 30 
3.4 
STOPPING RULES ......................................................................................................... 30 
 
Ongoing Review ....................................................................................................................... 30 
 
Stopping Rules Guidance .......................................................................................................... 30 
3.5 
DEFINITION OF HIGH AND LOW EXPOSURE TO CAT ALLERGEN ........................... 31 
4 
ELIGIBILITY ................................................................................................................... 31 
4.1 
INCLUSION CRITERIA ................................................................................................. 31 
4.2 
EXCLUSION CRITERIA ................................................................................................ 32 
4.3 
PREMATURE TERMINATION OF A PARTICIPANT FROM THE STUDY ..................... 34 
5 
STUDY MEDICATIONS ................................................................................................... 34 
5.1 
INVESTIGATIONAL MEDICATION - AMG 157 AND PLACEBO .................................. 34 
 
Formulation and Packaging....................................................................................................... 34 
 
Dosage, Preparation, and Administration ................................................................................. 35 
 
Recommended Storage Conditions ........................................................................................... 35 
5.2 
INVESTIGATIONAL MEDICATION – CAT IMMUNOTHERAPY AND PLACEBO ........ 35 
 
Formulation and Packaging....................................................................................................... 35 
 
Dosage, Preparation, and Administration ................................................................................. 36 
 
Recommended Storage Conditions ........................................................................................... 38 
5.3 
DISCONTINUATION OF STUDY TREATMENT ............................................................ 38 
5.4 
CONCOMITANT MEDICATIONS .................................................................................. 38 
 
Prophylactic and Emergency Rescue Medications ................................................................... 38 
 
Contraception ............................................................................................................................ 39 
 
Prohibited Medications ............................................................................................................. 39 
5.5 
DRUG ACCOUNTABILITY ........................................................................................... 39 
5.6 
ASSESSMENT OF COMPLIANCE WITH STUDY MEDICATION .................................. 39 
6 
STUDY PROCEDURES .................................................................................................... 39 
6.1 
VISIT WINDOWS .......................................................................................................... 39 
 
Scheduled Visits ........................................................................................................................ 39 
 
Unscheduled Visits ................................................................................................................... 40 

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6.2 
RANDOMIZATION, BLINDING, AND UNBLINDING ................................................... 40 
 
Randomization and Stratification .............................................................................................. 40 
 
Blinding .................................................................................................................................... 40 
 
Unblinding ................................................................................................................................ 40 
6.3 
GENERAL ASSESSMENTS ........................................................................................... 41 
6.4 
CLINICAL ALLERGY ASSESSMENTS .......................................................................... 41 
 
Overview and Washout Periods ................................................................................................ 41 
 
Nasal Allergen Challenges ........................................................................................................ 42 
 
Skin Testing .............................................................................................................................. 43 
6.5 
CLINICAL LABORATORY ASSESSMENTS .................................................................. 43 
6.6 
PHARMACOKINETIC AND AMG 157 NEUTRALIZING ANTIBODY TESTING ........... 44 
7 
TOLERANCE ASSAYS ..................................................................................................... 44 
7.1 
RATIONALE FOR IMMUNE STUDIES .......................................................................... 44 
7.2 
HYPOTHESES TO BE TESTED ...................................................................................... 45 
7.3 
RETENTION OF SAMPLES ........................................................................................... 46 
7.4 
LOCAL IMMUNE RESPONSES IN NASAL MUCOSA ................................................... 46 
7.5 
WHOLE BLOOD ASSAYS ............................................................................................. 48 
 
DNA-HLA Genotypes and Single Nucleotide Polymorphisms ................................................ 48 
 
Gene Expression Profiling ........................................................................................................ 48 
7.6 
CELL ASSAYS............................................................................................................... 48 
7.6.1 PBMC Preparation ......................................................................................................................... 48 
7.6.2 Cellular Assays ............................................................................................................................... 49 
7.7 
SERUM ASSAYS ........................................................................................................... 50 
8 
ADVERSE EVENTS .......................................................................................................... 50 
8.1 
OVERVIEW ................................................................................................................... 50 
8.2 
DEFINITIONS ................................................................................................................ 51 
 
Adverse Event ........................................................................................................................... 51 
 
Study-Specific Adverse Events ................................................................................................. 51 
 
Suspected Adverse Reaction and Adverse Reaction ................................................................. 52 
 
Serious Adverse Event .............................................................................................................. 53 
 
‘Expected’ versus ‘Unexpected’ Suspected Adverse Reaction ................................................. 53 
8.3 
COLLECTING AND RECORDING ADVERSE EVENTS ................................................ 54 
 
Methods of Collection ............................................................................................................... 54 
8.3.2  
Collection Period for Adverse Events and Serious Adverse Events ......................................... 54 
8.3.3 
Methods of Recording ............................................................................................................... 54 
8.4 
GRADING AND ATTRIBUTION OF ADVERSE EVENTS .............................................. 55 

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8.4.1 
Grading Criteria ........................................................................................................................ 55 
8.4.2 
Attribution Definitions .............................................................................................................. 56 
8.5 
REPORTING SERIOUS ADVERSE EVENTS .................................................................. 57 
8.5.1 
Reporting SAEs to the IND Sponsor......................................................................................... 57 
8.5.2 
Reporting SAEs to Health Authorities ...................................................................................... 57 
8.5.3 
Reporting SAEs to the DSMB .................................................................................................. 58 
8.5.4 
Reporting Pregnancy ................................................................................................................. 58 
9 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN ................................... 59 
9.1 
ANALYSIS SAMPLES ................................................................................................... 59 
9.2 
ANALYSIS OF ENDPOINTS .......................................................................................... 59 
9.2.1 
Overview ................................................................................................................................... 59 
9.2.2 
Primary Endpoint ...................................................................................................................... 59 
9.2.3 
Secondary Endpoints................................................................................................................. 60 
9.2.4 
Exploratory Endpoints .............................................................................................................. 60 
9.2.5 
Interim Analysis ........................................................................................................................ 60 
9.2.6 
Safety Analysis ......................................................................................................................... 61 
9.2.7 
Medical History ........................................................................................................................ 62 
9.2.8 
Use of Medications ................................................................................................................... 62 
9.3 
SAMPLE SIZE................................................................................................................ 62 
9.4 
MISSING DATA............................................................................................................. 63 
9.5 
REPORTING DEVIATIONS FROM THE ORIGINAL STATISTICAL PLAN ................... 64 
10 
ACCESS TO SOURCE DATA/DOCUMENTS .................................................................. 64 
11 
QUALITY CONTROL AND QUALITY ASSURANCE ..................................................... 64 
12 
ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD CLINICAL 
PRACTICE .................................................................................................................. 65 
12.1 
STATEMENT OF COMPLIANCE ................................................................................... 65 
12.2 
INFORMED CONSENT .................................................................................................. 65 
12.3 
PRIVACY AND CONFIDENTIALITY ............................................................................ 66 
13 
PUBLICATION POLICY .................................................................................................. 66 
14 
REFERENCES .................................................................................................................. 67 
APPENDIX 1 SCHEDULE OF EVENTS:  SCREENING AND UPDOSING .................................. 69 
APPENDIX 2 SCHEDULE OF EVENTS:  MAINTENANCE ........................................................ 71 
APPENDIX 3 SCHEDULE OF EVENTS:  OBSERVATION ......................................................... 73 
APPENDIX 4: WORLD ALLERGY ORGANIZATION SUBCUTANEOUS IMMUNOTHERAPY 
SYSTEMIC REACTION GRADING SYSTEM ............................................................... 75 

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Table of Tables 
Table 1:  Schedule of cluster immunotherapy injections ......................................................................... 37 
Table 2: Medication washout periods ...................................................................................................... 42 
Table 3: Grading of local reactions to cat immunotherapy and to study procedures ............................... 52 
Table 4: Attribution of adverse events .................................................................................................... 56 
Table 5: Sample size estimates based on pilot studies of TNSS ............................................................. 63 
 
 
Table of Figures 
Figure 1: Screening, allergen challenge, random assignment, treatment, and observation ..................... 28 
Figure 2: Th 2 cytokine levels 46 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Anti-TSLP and cat immunotherapy 
 
 
Synopsis 
 
Title 
 
Anti-TSLP plus antigen-specific immunotherapy for induction of 
tolerance in individuals with cat allergy 
IND Sponsor 
NIAID 
Conducted by 
Immune Tolerance Network 
Protocol Chair(s)  
Jonathan Corren, MD 
Accrual Objective 
121 participants total enrollment 
Study Design and 
Treatment 
This is a randomized, placebo-controlled trial in which four groups of 
cat-allergic subjects are treated until week 48 and then are followed 
without additional treatment until week 104. Allergy-related 
endpoints and exploratory endpoints related to mechanisms of 
immune modulation and tolerance will be assessed at baseline and at 
26, 52, 78 and 104 weeks. 
Starting 1-3 days prior to immunotherapy or placebo for 
immunotherapy, AMG 157 or placebo will be administered 
intravenously using investigational product supplied by the 
manufacturer. AMG 157 will then be administered once every 4 
weeks at a dose of 700 mg IV. Each AMG 157 dose will be 
administered at least 1 day before immunotherapy through week 24, 
then on the same day as immunotherapy thereafter. The treatment 
period for AMG 157 or placebo will be 48 weeks.  
Concurrently, immunotherapy using a standard cat allergen extract or 
placebo will be administered subcutaneously with a cluster dose and 
schedule currently in widespread use in the clinical practice of allergy 
in the United States. There will be an up-dosing period 
(approximately 12 weeks) during which small doses are gradually 
increased to a maintenance dose. Dosing levels may be individually 
tailored based on subject response. The combined up-dosing and 
maintenance periods will total 48 weeks.  
Study Duration 
Total study duration will be 154 weeks: 
 
Study enrollment to occur over 46 weeks. 
 
Individual subject study participation will be 108 weeks. 
Primary Objective 
To determine if anti-TSLP in conjunction with antigen-specific 
immunotherapy can induce tolerance to cat allergen. 
 

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Protocol ITN057AD 
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Primary Endpoint 
Total nasal symptom score (TNSS) AUC from 0 to 1 hour after cat 
allergen challenge at 104 weeks. TNSS is calculated with a scale of 0 
to 3 on the 4 parameters of sneezing, rhinorrhea, nasal congestion and 
blockade, and pruritus. Maximum score is 12 
Secondary 
Endpoints 
Other measures of allergic response including: 
 
Skin prick test endpoint titration at baseline, 1, 4, 12, 26, 52, 
78, 104 weeks. 
 
Skin early phase response (EPR) to intradermal testing at 
baseline, 26, 52, 104 weeks. EPR is the skin response at 15 
minutes. 
 
Skin late phase response (LPR) to intradermal testing at 
baseline, 26, 52, 104 weeks. LPR is the skin response at 6 
hours. 
 
Peak TNSS EPR at baseline, 26, 52, 78, 104 weeks. Peak is 
the highest value recorded between 0 and 1 hour inclusive 
 
TNSS EPR at baseline, 26, 52, 78, 104 weeks. EPR is the 
TNSS AUC from 0 to 1 hour. 
 
TNSS LPR at baseline, 26, 52, and 104 weeks. LPR is the 
TNSS AUC from 5 to 6 hours. 
 
Peak nasal inspiratory flow (PNIF) LPR AUC at baseline, 
26, 52, 104 weeks.  LPR is the PNIF AUC from5 to 6 hours. 
 
PNIF EPR AUC at baseline, 26, 52, 78, 104 weeks. EPR is 
the PNIF AUC from 0 to 1 hour. 
Inclusion Criteria 
Patients must meet all of the following criteria to be eligible for this 
study: 
1. Age 18-65 years. 
2. Removed in protocol version 4.0. 
3. History of moderate-severe allergic rhinitis (AR) caused by 
cat exposure for at least 2 years.  
4. Skin prick test wheal greater than or equal to 5 mm to 
standardized cat extract.  
5. Removed in protocol version 3.0. 
6. Screening nasal allergen challenge in which: 
 
TNSS is less than or equal to 3 after the 0 
concentration (vehicle control only) dose, 

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Protocol ITN057AD 
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Anti-TSLP and cat immunotherapy 
 
 TNSS increase is less than or equal to 1 
from the TNSS prior to allergen 
administration to the TNSS after the 0 
concentration (vehicle control only) dose, 
 
TNSS is greater than or equal to 8 after the highest 
dose, 
 
Between the first non-zero dose and 10 minutes 
after the highest dose, either: 
 3 or more sneezes are counted or 
 Greater than 20% drop in PNIF is 
recorded. 
7. Body mass index (BMI) is greater or equal to 18.0 and less 
than or equal to 35.0 kg/m2, at screening. 
8. Clinically acceptable physical examination and 
electrocardiogram (ECG) results (12-lead reporting RR, 
PR, QRS, QT and QTcF) prior to Day 0 based on the 
opinion of the investigator. 
9. Adequate renal function defined as CrCl greater than 80 
mL/min using the Cockcroft Gault equation. 
10. For women of childbearing age, a willingness to use a 
highly effective form of contraception for four months after 
last dose of study medication. Highly effective methods of 
birth control include abstinence, vasectomy by the male 
partner, or a condom with spermicide in combination with 
either hormonal birth control, IUD or barrier methods used 
by the woman. 
11. For men with female partners of childbearing potential, 
agreement not to donate sperm and to inform their female 
partner of their participation in this clinical study and use 
highly effective methods of birth control for four months 
after last dose of study medication. Highly effective 
methods of birth control include abstinence, vasectomy, or 
a condom with spermicide in combination with either 
hormonal birth control, IUD or barrier methods used by the 
woman. 
12. The ability to give informed consent and comply with study 
procedures.   
13. Not currently taking and, for the duration of the study, 

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Protocol ITN057AD 
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Anti-TSLP and cat immunotherapy 
 
agreement not to take any form of immunotherapy, 
including sublingual, subcutaneous or investigational 
immunotherapy. 
Exclusion Criteria 
Patients who meet any of the following criteria will not be eligible 
for this study: 
1. Removed in protocol version 4.0. 
2. Prebronchodilator FEV1 less than 80% of predicted value at 
screening visit. 
3. Removed in protocol version 3.0.  
4. History of asthma meeting the NAEPP EPR3 classification 
of mild-persistent or worse in the past year, other than with 
cat exposure, requiring regular inhaled corticosteroids for 
greater than 4 weeks per year. 
5. History of serious chronic medical conditions which might 
interfere with treatment or assessments. 
6. History of emergency visit or hospital admission for asthma 
in the previous 12 months. 
7. History of chronic obstructive pulmonary disease (COPD). 
8. History of significant recurrent acute sinusitis, defined as 2 
episodes per year for the last 2 years, all of which required 
antibiotic treatment. 
9. History of chronic sinusitis, defined as a sinus symptoms 
lasting greater than 12 weeks that includes 2 or more major 
factors or 1 major factor and 2 minor factors. Major factors 
are defined as facial pain or pressure, nasal obstruction or 
blockage, purulent or discolored postnasal discharge, 
purulence in nasal cavity, or impaired or loss of smell. 
Minor factors are defined as headache, fever, halitosis, 
fatigue, dental pain, cough, and ear pain, pressure, or 
fullness. 
10. History of systemic disease affecting the immune system 
such as autoimmune diseases, immune complex disease, or 
immunodeficiency, where, in the opinion of the study 
physician, participation in the trial would pose a risk or 
significant effect on the immune system.  
11. Type I or type II diabetes. 
12. Evidence of any clinically significant active or suspected

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bacterial, viral, fungal or parasitic infections within 14 days 
prior to screening nasal allergen challenge. Participants may 
be re-evaluated for eligibility after an appropriate course of 
treatment has been completed and symptoms have resolved.  
13. High risk of parasitic disease as judged by the investigator. 
14. Positive QuantiFERON® tuberculin test unless the potential 
subject has been treated with appropriate chemoprophylaxis. 
15. Exposure to an individual with active tuberculosis within 
six months from randomization. 
16. Subjects tested positive for HIV antibody, Hep B surface 
antigen, or Hep C antibody. 
17. Removed in protocol version 3.0. 
18. History of malignancy of any type, including basal cell and 
squamous cell cancers of the skin, within 5 years of 
enrollment  
19. Any smoking within the last year or a history of greater than 
or equal to 10 pack years. 
20. Previous immunotherapy treatment with cat allergen within 
the previous 10 years. 
21. Any history of grade 4 anaphylaxis due to any cause as 
defined by the CTCAE grading criteria for immunotherapy. 
22. History of bleeding disorders or treatment with 
anticoagulation therapy. 
23. Treatment with omalizumab within 6 months prior to 
randomization. 
24. Currently taking any of the following medications:  beta 
blockers; tricyclic antidepressants; monoamine oxidase 
inhibitors; or anti-IgE monoclonal antibody treatment. 
25. Ongoing systemic immunosuppressive treatment. 
26. History of intolerance to the study therapy, rescue 
medications, or their excipients. 
27. For women of childbearing age a positive serum or urine 
pregnancy test with sensitivity of less than 50 mIU/mL 
within 72 hours before the start of study therapy. 
28. The use of any investigational drug or currently using an 

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investigational device within 30 days or five half-lives 
(whichever is longer) prior to randomization.   
29. The presence of any medical condition that the investigator 
deems incompatible with participation in the trial. 
 
 
 

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Abbreviations  
 
AE 
adverse event 
AR 
Adverse reaction 
ARIA 
Allergic Rhinitis and its Impact on Asthma 
AUC 
area under the curve 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CFSE 
fluoroscein succinimidyl ester 
CRF 
case report form 
COPD 
chronic obstructive pulmonary disease 
CRO 
contract research organization 
DSMB 
Data and Safety Monitoring Board 
EDC 
electronic data capture 
EPR 
early phase reaction 
FDA 
US Food and Drug Administration  
GCP 
good clinical practice 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonisation 
IRB 
institutional review board 
ITN 
Immune Tolerance Network 
LPR 
late phase reaction 
MedDRA 
Medical Dictionary for Regulatory Activities 
NAC 
nasal allergen challenge 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events (version 
4.03, June 14, 2010)
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
PD 
pharmacodynamics 
PK 
pharmacokinetics 

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PNIF 
peak nasal inspiratory flow 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAR 
serious adverse reaction 
SUSAR 
suspected unexpected serious adverse reaction 
SIT 
allergen-specific immunotherapy 
SOE 
schedule of events 
SPT 
skin prick test 
TNSS 
total nasal symptom score 
WAO 
World Allergy Organization 
WHO 
World Health Organization 
 
 

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1 
BACKGROUND AND RATIONALE 
1.1 
CAT ALLERGY AS A CLINICAL PROBLEM 
 
Overview 
Sensitization to cats is a common contributor to nasal allergy symptoms in the United 
States. The 2005-2006 NHANES survey demonstrated that approximately 28% of 
current hay fever sufferers had IgE to cat extract.1  Cat allergen exposure is also a 
widespread issue, with as many as 33% of homes in the United States having a pet 
cat (Humane Society of United States, 2011). Cat dander allergens have also been 
shown to exist in significant quantities in public buildings 2 and even in homes that 
do not have cats. 3 
 
Current Approaches to Cat Allergy 
Treatment of cat allergy usually includes a recommendation to remove the cat from 
the home environment. Often, however, even highly sensitive patients will not 
comply with this. Once a cat has been removed from inside the home, concentrations 
of cat allergen do not decrease for periods of a year or longer unless very aggressive 
allergen abatement also takes place, including removal of the carpet and thorough 
cleaning.4 An alternative strategy of allergen avoidance consists of leaving the cat in 
the home and removal of carpet, exclusive use of non-fabric furniture, and high-flow 
ventilation.4  Unfortunately, despite these efforts patients may continue to have 
significant cat exposure outside of the home. Medications for rhinoconjunctivitis and 
asthma including oral, intranasal, and ocular antihistamines, oral leukotriene receptor 
antagonists, and intranasal and inhaled corticosteroids are variably effective in 
patients who are allergic to cats and have ongoing exposure.5,6 Prevention of cat-
induced asthma may be particularly challenging, with most available therapies 
(including omalizumab) inhibiting cat-induced decreases in FEV1 by approximately 
50%.6 
 
Clinical Outcomes with Subcutaneous Cat Dander Immunotherapy 
Subcutaneous immunotherapy with high doses of cat dander extract has been shown 
to effectively reduce symptoms in 3 studies. Alvarez-Cuesta et al. performed a 
double-blind trial of cat dander immunotherapy (containing 13.2 mcg of Fel d 1) for 
1 year in 28 patients with cat-induced rhinitis and asthma.7  In patients who received 
active therapy, the medication-symptoms score, skin prick tests, conjunctival 
provocation test, and allergen bronchoprovocation test were all significantly 
improved compared with placebo. Varney et al. compared cat dander extract 
(containing 15 mcg of Fel d 1) in a controlled trial of 28 patients for 3 months. The 
actively treated group showed significant reductions in symptoms induced by cat 
room exposure (mean score 61.6 vs. 17.1) with no change in the placebo group (64.7 
vs. 62.1).8 The active group also showed reductions in conjunctival provocation 
sensitivity and skin sensitivity to cat extract. In the third study, patients with cat 
allergy received either cat dander immunotherapy (at a dose of 17.3 mcg of Fel d 1) 
or placebo for 3 years.9 Bronchial sensitivity to inhaled cat allergen decreased 

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significantly after 1 year and continued to improve during the next 2 years compared 
with placebo.  
Two more recent studies attempted to identify whether high doses of cat dander 
immunotherapy has greater immunologic and clinical effects than lower doses. 
Ewbank et al. examined the efficacy of cat immunotherapy in a placebo-controlled 
trial.10 Escalating doses were given in 8 visits over a 4-week period to a target 
maintenance dose of 0 (placebo), 0.6, 3.0 or 15 microgram. Titrated skin prick tests, 
nasal allergen challenges and immunologic measurements were performed one week 
after the first maintenance dose. The concentration of antigen needed to generate an 
immediate 5 mm wheal was increased in the dose groups with 3.0 or 15 micrograms. 
Nasal allergen challenge thresholds were not increased. These data indicate that 
detectable responses to subcutaneous immunotherapy can be detected as early as five 
weeks after starting therapy. 
The same group performed a similar small trial (N = 26 evaluable) with longer 
follow-up to examine the impact of extended treatment.11 This study yielded 
inconsistent results, with some effects seen at 5 weeks being less apparent at one 
year. Nasal challenges were reported as symptom scores rather than as a threshold 
dose. With this endpoint both placebo and high dose treatment groups showed a 
decline in nasal symptom scores. These data demonstrate that the surrogate measures 
of response in skin and nasal mucosa may be detectable early but should be 
interpreted with caution in small groups of patients.  
 
Mechanisms of Allergen-specific Immunotherapy 
Mechanisms of immunotherapy have been described for grass immunotherapy. These 
may include stimulation of Th 1-type helper lymphocytes, decrease in Th 2 cells and 
induction of T regulatory cells that produce IL-10 and TGF-beta.12,13 Immunotherapy 
has an effect on early allergic responses which occur in minutes and are due to IgE-
mediated effects on mast cells, and on late phase responses which occur in hours and 
are due to effects mediated by T cells, eosinophils, and basophils that infiltrate skin 
or other tissues. There is experimental evidence, however, that immunotherapy 
preferentially suppresses the late phase response.14 
Immunotherapy consistently results in long-term increase in antigen-specific IgG4. 
These antibodies may inhibit allergic responses through inhibitory effects on Fc-
gamma-RII receptors on basophils or via direct interactions with antigen. Serum 
activity associated with IgG4 has been shown to block IgE-facilitated antigen 
presentation after effective immunotherapy.15 
Immunotherapy can also result in long-lasting immune deviation from an allergic Th 
2-based response to a protective Th 1-type response. This likely occurs as a local 
event in nasal mucosa in patients with rhinitis. In addition, allergen immunotherapy 
may influence both native and induced T regulatory cells. Local production of IL-10 
may play a central role in suppression of mucosal responses in successfully treated 
allergic rhinitis. 

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The time course of effects of immunotherapy varies according to the immune 
measure:  late phase skin responses are suppressed after as little as two weeks of 
therapy whereas clinical symptoms require 2-3 months for a reduction in severity. 
Less is known about the corresponding mechanisms after cat immunotherapy. 
Ewbank et al. and Nanda et al. both reported approximately two to three-fold 
increases in cat-specific IgG4 after as little as 5 weeks of subcutaneous 
immunotherapy.10,11 In one report there was a decrease in CD4/IL-4-positive (Th 2-
like) cells10 but this has not been a consistent finding.3 
 
Why New Approaches are Needed 
Prior studies of cat dander immunotherapy have demonstrated a significant but 
variable effect upon cat-induced nasal and pulmonary symptoms. While cat 
immunotherapy has been administered for up to 3 years in past studies, it is unknown 
whether this therapy is capable of inducing tolerance. Immunotherapy studies 
employing other allergens have demonstrated that at least 2 years of maintenance 
treatment is necessary in order to achieve tolerance. Therefore, it would be highly 
beneficial to determine whether achievement of tolerance with cat immunotherapy 
could be achieved in a shorter time than with other allergens using adjunct agents 
such as specific cytokine inhibitors. 
1.2 
THYMIC STROMAL LYMPHOPOIETIN (TSLP) 
 
Role in Immune Responses 
Thymic stromal lymphopoetin is an IL-7-like cytokine discovered in thymic stromal 
cell supernatents originally found to support B cell development.16 It is largely 
produced by epithelial cells in nasal and bronchial mucosa and is increased in states 
of allergic and non-allergic inflammation. The TSLP receptor complex comprises the 
TSLP-binding chain (TSLP-R) and the IL-7R-alpha chain. The receptor is expressed 
on dendritic cells, T cells, B cells, mast cells, and NKT cells. Although originally 
recognized as a B cell factor, it acts on a variety of cell types to promote 
inflammation.16,17 
TSLP produced by epithelium can activate dendritic cells leading to OX40L 
expression and resulting in differentiation of naïve CD4 cells into Th 2 cells. These 
secrete high levels of inflammatory cytokines IL-4, IL-5 and IL-13. Thus TSLP is 
associated with a Th 2-skewed immune response consistent with a role in allergy. 
TSLP also acts directly on T cells to promote Th 2 differentiation at least in murine 
model systems. This effect is enhanced in the presence of IL-4. Kitajima et al. 
demonstrated that the TSLP receptor was expressed at high levels on mouse effector 
Th 2 cells compared to Th 1 and Th 17 cells and showed that TSLP preferentially 
induced proliferation of effector Th 2 cells. These results indicate that TSLP is 
involved in exacerbation of mouse Th 2-mediated allergic inflammation.18 
TSLP also has direct effects on mast cells and enhances mast cell IL-13 production. 
In a study of in vitro-generated mast cells derived from peripheral or cord blood, 

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TSLP in the presence of IL-1 was found to act directly on mast cells to stimulate 
production of inflammatory cytokines IL-5, IL-13 and IL-6.19 
 
Role in Asthma 
Several studies indicate that TSLP may have a role in allergic asthma. In a study in 
two cohorts of 36 and 16 subjects with mild to severe asthma, Shikotra et al. reported 
an increase in expression of TSLP protein primarily in epithelial cells from bronchial 
biopsies; increased TSLP levels were associated with expression of other Th 2-
related genes.20 IL-13 expression was increased in non-epithelial cells. These findings 
suggest a role for TSLP in generating or maintaining the inflammatory state 
associated with allergic asthma and are supported by mouse models.21 
 
Role in Allergic Rhinitis 
Miyata et al. described a role for TSLP in a mouse model of allergic rhinitis.22 In this 
study neutralizing antibody to TSLP also diminished response in an OVA-induced 
model of allergic rhinitis. TSLP protein and mRNA are overexpressed in nasal 
mucosa in turbinate biopsies of patients with allergic rhinitis.19 Epithelial cells 
expressing TSLP were found in higher numbers and TSLP protein was expressed at 
higher levels assessed by immunohistochemistry in patients with atopic as compared 
to non-allergic rhinitis.23 Genetic studies indicated that a polymorphism at the TSLP 
gene locus was associated with reduced risk of allergic rhinitis in children with 
asthma in three distinct populations, supporting a role for TSLP in the pathogenesis 
of allergic rhinitis.24 
1.3 
TSLP INHIBITION 
 
Principle 
Preclinical data indicate inhibition of TSLP may block immune-mediated responses 
in an animal model of allergic skin inflammation.25 Zhang et al. examined TSLP 
inhibition in a murine model of allergic asthma. They found an inhibitor comprising a 
soluble TSLP receptor-immunoglobulin molecule reduced inflammatory cell 
infiltrates, and levels of Th 2 cytokines, IL-4 and IL-5, were also reduced in 
bronchoalveloar lavage fluid.26 TSLP is involved in disease pathogenesis in a murine 
model of allergic rhinitis induced by OVA. In this model neutralizing TSLP antibody 
administered during the mucosal challenge phase after intraperitoneal sensitization 
inhibited allergic inflammation in the nasal mucosa.22 These studies support the 
examination of TSLP inhibition in human allergic disease. 
 
AMG 157 
1.3.2.1 Name of Investigational Product 
In this protocol the investigational anti-TSLP agent is referred to as AMG 157 with 
Amgen, Inc. as the manufacturer. In 2012, MedImmune partnered with Amgen on 
AMG 157 and as a result the agent can also be identified as MEDI9929/AMG 157. 
 
http://www.amgen.com/media/media_pr_detail.jsp?year=2012&releaseID=1679295  
http://www.medimmune.com/research/pipeline  
 

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1.3.2.2 Description and Previous Experience 
The following information has been obtained from the Amgen Investigator’s 
Brochure for MEDI19929/AMG 157. 
AMG 157 is a fully human monoclonal IgG2λ directed against TSLP expressed in a 
Chinese hamster ovary cell line (Investigator’s Brochure for MEDI9929/AMG 157). 
The molecule is a heterotetramer consisting of two heavy chains of the IgG2 subclass 
and two light chains of the lambda subclass, which are covalently linked through 
disulfide bonds. The antibody binds with high affinity to human and cynomolgus 
TSLP. It inhibits TSLP-induced STAT5 phosphorylation in human dendritic cells. It 
does not bind to mouse TSLP. 
AMG 157 has been assessed in four completed phase I pharmacokinetic trials in 
healthy subjects and in individuals with atopic dermatitis, and mild atopic asthma. It 
is currently (September 2015) being assessed by the Manufacturer in three phase I/IIa 
trials evaluating pharmacokinetics, pharmacodynamics, safety/efficacy in adults with 
moderate to severe atpic dermatitis, adults with inadequately controlled severe 
asthma and adolescents with mild to moderate asthma.  
In summary, information is available for four of the completed and two of the 
ongoing trials. Based on data collected in these trials,  AMG 157 has demonstrated an 
acceptable safety profile, predictable and consistent pharmacokinetics, and high 
bioavailability after subcutaneous and intravenous dosing. It has a prolonged half-life 
which makes intermittent dosing feasible.To date, limited pharmacodynamics and 
clinical efficacy information is available. Based on the most recent version of 
MedImmune’s Investigator’s Brochure for AMG 157 (Version 3.0), a multiple dose 
study in subjects with mild atopic asthma (Study 20101183) demonstrated a decrease 
in blood and sputum eosinophils and a decrease in the Th2/Th1 balance based upon a 
new exploratory biomarker assay. Study 20101183 also showed that AMG 157 
attenuates both the early and late asthmatic responses after allergen challenge 
comparing to pre-allergen challenge days. AMG 157 has not shown any effect on 
several lymphocyte subsets (CD3+, CD4+, CD8+ or CD19+), IgE scores, or plasma 
levels of CCL17, CCL22, or CCL27. 
1.4 
COMBINATION OF IMMUNOTHERAPY WITH TSLP INHIBITION 
 
Combining Antigen with an Immunomodulatory Agent 
The pathways affected by allergen-specific immunotherapy may also be effectively 
modified by adjuvant anti-inflammatory strategies. Based on the emerging role of 
TSLP in allergic responses, TSLP inhibition has the potential to combine with 
allergen-specific immunotherapy with beneficial effects on both the antigen-specific 
T-cell mediated elements and the inflammatory elements mediated by basophils and 
mast cells. 
If TSLP stimulates Th 2 responses and allergic rhinitis related to cat allergy is a Th 2-
mediated condition, then TSLP inhibition may be combined with immunotherapy to 
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The current trial plans for administration of anti-TSLP during immunotherapy. 
Several experiments in animal models suggest that TSLP may be most important 
during the sensitization or priming phase of allergy. Immunotherapy presents a strong 
antigenic challenge to individuals who are already allergic with effects that may to 
some extent mimic those of sensitization. The concurrent administration of anti-
TSLP and antigen may thus provide clear advantages over single interventions. 
 
Why the Combination Might Lead to Long-lasting Effects or 
Tolerance 
As discussed in Section 1.2, there are at least two key effects of TSLP which 
contribute significantly to the persistence of allergic responses.  
First, TSLP-activated dendritic cells support the maintenance and further polarization 
of CRTH2+ Th 2 effector memory cells.27 Only dendritic cells (DCs) activated by 
TSLP can induce a robust expansion of CRTH2+CD4+ Th 2 memory cells, while 
maintaining their central memory phenotype and Th 2 commitments.  
Second, some studies have indicated that TSLP might hinder the production and/or 
maintenance of Foxp3 + T-regulatory (Treg) cells in allergy. Specifically, in both 
mice and humans, low doses of TSLP have been shown to be capable of inhibiting 
Treg cell induction without significantly promoting Th 2 development, indicating that 
there is some degree of separation of these functions.28 These effects may be 
complex, however, as data from patients with Crohn’s disease have suggested that 
intestinal epithelial cells are also capable of promoting the differentiation of 
tolerogenic DCs which drive the development of Treg cells.29 Clinical trials of TSLP 
inhibition will help resolve which effect is predominant in humans. 
Given the generally pro-inflammatory and T regulatory-inhibitory effects of TSLP, 
inhibition of this cytokine as proposed in the current trial may lead to a reduction in 
Th 2 memory cells and increase in Treg cells and, when co-administered with 
allergen to allergic patients, may enhance or expedite the achievement of tolerance. 
1.5 
TRIAL DESIGN 
 
Overview 
The primary goal of this study is to determine whether the combination of anti-TSLP 
(AMG 157) plus antigen-specific immunotherapy will result in tolerance to the 
therapeutic antigen, as demonstrated by the persistence of a therapeutic effect for a 
substantial period after stopping immunotherapy. To address this we propose a 
randomized, placebo-controlled trial in which four groups of cat-allergic subjects are 
treated until week 48 and then are followed without additional treatment until week 
104. Allergy-related endpoints and exploratory endpoints related to mechanisms of 
immune modulation and tolerance will be assessed at baseline and at 26, 52, 78, and 
104 weeks during participation. 

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Why Total Nasal Symptom Score (TNSS) was Chosen as an Endpoint 
The use of total nasal symptom score (TNSS) relies on its relation to clinical 
symptoms and to experience gained in mechanistic analysis of nasal and other 
samples after in vivo challenge in the target organ for allergic rhinitis. TNSS is 
calculated with a scale of 0 to 3 on the 4 parameters of sneezing, rhinorrhea, nasal 
congestion and blockade, and pruritus. The maximum score is 12. 
TNSS is a reflection of disease activity in response to allergen exposure.30 Prior 
studies have demonstrated that both early and late allergen-induced symptoms are 
reproducible and amenable to change with a variety of clinically effective therapies. 
Nasal allergen challenge has been studied in detail after grass allergen challenge. 
Scadding and colleagues have reported on a standardized approach to nasal challenge 
in which grass pollen-allergic individuals received increasing doses of grass pollen to 
determine the threshold dose that elicited a response. In subsequent challenges they 
received the same threshold dose that elicited a response and symptoms; tryptase and 
nasal cytokine levels were assessed over 6 hours.31 Consistent findings among 18 
subjects included an early peak of tryptase levels in nasal fluid coincident with a peak 
in symptom scores and increasing levels of Th 2 cytokines IL-4, IL-5 and IL-13. This 
response was first detected at 2 hours, and was still increasing at 6 hours. This 
procedure provides a robust platform to assess the effects of distinct treatment arms 
on in vivo allergen challenge which can be considered a surrogate for clinical 
efficacy while at the same time probing mechanism such as Th 2 deviation. 
Nasal allergen challenges were used in a study of IL-13 blockade. In this study 
systemic treatment with anti-IL-13 resulted in a significant decrease in IL-13 isolated 
from nasal secretions 5 days after antibody administration.32 This demonstrates the 
potential for nasal cytokine measurement to serve as a pharmacodynamic marker for 
anti-allergic treatment strategies. 
 
Why a Tolerance Trial 
The current trial proposes a treatment period followed by a period of observation off 
the therapy. The demonstration of a persistent treatment effect in the absence of 
ongoing therapy, is a characteristic of immune tolerance. We hypothesize that a 
major effect of anti-TSLP will be to shorten substantially the duration of allergen 
immunotherapy that is needed to induce tolerance.  
There are substantial unknowns in this trial of previously tested and untested 
interventions. The consistency and magnitude of the effect of cat allergen 
immunotherapy on nasal challenge and other endpoints is incompletely defined in the 
published literature. Analysis at the conclusion of the treatment phase will allow 
confirmation of treatment effect for immunotherapy in the selected patient group and 
investigation of whether there is a detectable effect of TSLP blockade alone. The role 
of anti-TSLP alone or in combination in providing immunotherapeutic benefit for 
patients with allergic rhinitis during and after treatment has not been tested. We do 
know that a tolerance effect cannot be demonstrated without a foundation of a 
treatment effect. The interim analysis aims to control the risk that a treatment effect is 

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not observed. It does not address the likelihood of a tolerance outcome but provides 
some protection against proceeding in a trial highly unlikely to reach its aims. 
 
Why Cat Dander as an Allergen for Study 
There are several important clinical reasons justifying the choice to study cat allergic 
patients in this study:  1)  Cat-induced rhinitis and asthma occur commonly in the 
general population and represent a significant source of morbidity4;  2)  Clinical 
responses to cat allergen can be studied using reproducible methods, including nasal 
allergen challenge (NAC) and cat room challenge11; 3) Commercial cat dander 
extracts are well-standardized with respect to the allergenic potency.33  
In addition to its relevance as a clinical problem, there are good technical and 
scientific reasons to study cat allergy and the response to the immunodominant 
protein Fel d1.34 There are excellent reagents to study the immune response in cat 
allergy. Many of the epitopes of the major immunogenic protein Fel d1 are well-
characterized. A variety of assays exist to measure T cell responses. Tetramers may 
be produced with principal epitopes for a variety of HLA alleles, which can be used 
to study the evolution of antigen-specific reactions in individuals. 
 
Mechanistic Questions: Overview 
The current trial allows for the exploration of mechanistic questions in several areas. 
The mechanisms of immunotherapy previously identified for other allergens 
including Th 1 deviation, production of blocking antibodies, and the generation of 
regulatory cells can be examined for cat immunotherapy. The study arm in which 
subjects receive both immunotherapy and anti-TSLP inhibition allows for the 
exploration of whether these same effects are magnified in extent or duration when 
TSLP signaling is impaired. It will be important to assess whether anti-TSLP alone 
has measurable mechanistic effects. These issues will be addressed in peripheral 
blood, skin, and nasal compartments. The mechanistic hypotheses and proposed 
techniques are laid out in more detail in Section 7. 
1.6 
SUMMARY OF KNOWN AND POTENTIAL RISKS AND BENEFITS 
FOR HUMAN PARTICIPANTS  
 
Study Medication Risks 
1.6.1.1 
Allergenic Extract SQ (Standardized Cat Hair) 
Injection immunotherapy is commonly associated with local swelling at the allergen 
injection site, sometimes occurring within minutes but more typically several hours 
after injection. Large local cutaneous reactions may have associated pain and pruritus 
and occur in up to 10% of recipients. Occasionally systemic allergic symptoms can 
occur, such as rhinitis, ocular symptoms, or urticaria. These symptoms can generally 
be managed with oral antihistamines. Rarely, anaphylaxis with wheezing and 
hypotension may occur. In this trial immunotherapy will be carried out in well-
equipped facilities by personnel trained and experienced in immunotherapy and its 
potential complications. Both local and systemic reactions are most common during 
the build-up phase of immunotherapy. 

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1.6.1.2 
AMG 157 
As discussed in Section 1.3.2, the investigational drug AMG 157 or placebo has been 
administered to a  total of 652 subjects in phase I and Phase II clinical trials either as 
single or multiple SC or IV doses as of September 2015.  No specific risks have been 
identified with AMG 157 administration. 
Important potential risks include Immune Complext Disease (Type III 
Hypersensitivity Reactions), Serious Infections, Parasitic Infestation/Infections , 
Hypersensitivity/Allergic Reactions and Infusion Reactions.  
Immune Complex Disease results from the formation of ADA, which can be a result 
of the administration of a mAb. No subjects received AMG 157 in the previous 
studies developed ADA.  
Due to the blockade of TSLP, AMG 157 has the potential to modulate systemic 
immune responses by reducing number or activity of Th 2-type T-cells. 
Therefore,there is a theoretical increased risk of serious infection,includingparasitic 
infections.In this trial participants will be screened and excluded for history of known 
immunosuppressive disorder, clinically significant infection and untreated systemic 
helminthic parasitic infection.  
As with any large molecule therapeutics, administration of AMG 157 may result in 
systemic and/or local reactions, as well as infusion-hypersensitivity reactions. To 
mitigate the risk of  severe hypersnsitivy and infusion reactions, subjects will be 
monitored for AEs and vital sign before, during and for 1 hour after the AMG 157 
administration. In addition, medical equipment  and study personnel trained to treat 
acute anaphylactic reactions will be immediately available.  
 
Study Procedure Risks 
1.6.2.1 Intradermal and Skin Prick Tests 
Participants may experience mild to moderate itchiness or local discomfort at the 
sites of intradermal injections and skin pricks with allergen and the positive control 
(histamine dihydrochloride 10 mg/mL). The symptoms are not bothersome and 
treatment with oral antihistamines is always available and is effective although 
almost never required. Systemic reactions including anaphylaxis after skin tests with 
standardized aeroallergen extracts are a theoretical risk but exceedingly rare. 
However, a physician is always present and drugs and equipment for treatment of 
anaphylactic reactions available. 
1.6.2.2 Nasal Allergen Challenge (NAC) 
This trial will use nasal allergen challenge as one of several outcome measures. 
Challenge is expected to cause early (0-1 hr) and late (1-6 hr) allergic symptoms such 
as nasal congestion, sneezing, nasal discharge, and itchy, watery eyes. If nasal and/or 
ocular symptoms persist after the period of 6 hours observation in the clinical unit 
participants will be offered treatment with oral antihistamines. There is a small risk 
of provoking asthmatic symptoms. Participants will perform peak flow recordings 

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before and after nasal challenge and treatment with inhaled bronchodilators and 
corticosteroids will be immediately available. To minimize this risk, individuals with 
a pre-bronchodilator FEV1 of less than 80% of predicted are excluded from this trial. 
As for any intervention with allergen to which the patient is sensitive there is the 
theoretical risk of developing an anaphylactic reaction. Trained personnel, including 
a physician, as well as medications and equipment, will be immediately available to 
treat any reaction. 
1.6.2.3 Nasal Lavage 
Prior to nasal challenge a saline nasal lavage with be performed with a commercially 
available preparation (SinuRinse®, NeilMed Pharmaceuticals) diluted in 240 mL (8 
oz) of warm distilled water. This is a non-irritant, preservative free, pH neutral 
solution that contains sodium chloride, sodium bicarbonate and iodine. SinuRinse® 
is widely available and no adverse effects are expected. 
1.6.2.4 Nasal Brushings 
Cells from the nasal epithelium may be collected by nasal brushing after the nasal 
allergen challenges. Risks include local burning with eye tearing, and rarely local 
bleeding. The symptoms are generally mild and resolve within minutes. 
1.6.2.5 Venipuncture and Intravenous Access 
Participation in the trial requires blood drawing for laboratory assessment and 
intravenous access for drug administration. Potential risks are those associated with 
phlebotomy and include ecchymosis and infections at the site of needle puncture.  
 
Potential Benefits 
Based on previous studies8 it is possible that participants who receive cat 
immunotherapy may have an improvement in symptoms. The impact of anti-TSLP, 
however, is unknown.  Some participants will not receive either cat immunotherapy 
or anti-TSLP. There is thus no assurance of therapeutic benefit from participation. 
2 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
To determine if anti-TSLP in conjunction with antigen-specific immunotherapy can 
induce tolerance to cat allergen. 
2.2 
SECONDARY OBJECTIVES 
To determine if anti-TSLP alone modifies the nasal allergic response to cat allergen. 
2.3 
EXPLORATORY OBJECTIVES 
To explore immunologic mechanisms of tolerance induction by the combination of 
anti-TSLP and antigen-specific immunotherapy.  

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3 
STUDY DESIGN 
3.1 
DESCRIPTION 
 
Overview 
This is a randomized, double-blind, multi-center, placebo-controlled, four-arm study 
in 121 cat-allergic subjects. 
Potentially eligible subjects will be screened for eligibility with assessments starting 
with a skin prick test. 
It is estimated that: 
 
of those, 80% will meet the skin test eligibility criterion and undergo the 
nasal allergen challenge, 
 
of those, 90% will meet the screening nasal allergen challenge eligibility 
criteria and undergo the remaining screening assessments; 
 
of those, 90% will meet the remaining eligibility criteria and be enrolled; and  
 
of those enrolled, 90% will successfully complete the baseline nasal allergen 
challenge and be randomly assigned. 
Thus it is estimated that about 205 individuals will need to be screened to meet the 
target randomization. 
Random assignment will be 1:1:1:1 to four groups: 
A) AMG 157 plus immunotherapy,  
B) placebo for AMG 157 plus immunotherapy, 
C) AMG 157 plus placebo for immunotherapy, or 
D) placebo for AMG 157 plus placebo for immunotherapy. 
Participants are treated in their assigned group for 48 weeks. At that point study 
therapy is stopped. Participants undergo observation until week 104. 
 
Dose and Schedule 
Starting 1-3 days prior to immunotherapy or placebo for immunotherapy, AMG 157 
or placebo will be administered intravenously using investigational product supplied 
by the manufacturer. AMG 157 will then be administered once every 4 weeks at dose 
of 700 mg IV. Each AMG 157 dose will be administered at least 1 day before 
immunotherapy through week 24. After week 24, AMG 157 may be given before or 
on the same day as immunotherapy. The treatment period for AMG 157 or placebo 
will be 48 weeks.  
Concurrently, immunotherapy using a standard cat allergen extract or placebo will be 
administered subcutaneously with a cluster dose and schedule currently in 

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widespread use in the clinical practice of allergy in the United States. There will be 
an up-dosing period (approximately 12 weeks) during which small doses are 
gradually increased to a maintenance dose. Dosing levels may be individually 
tailored based on subject response. The combined up-dosing and maintenance periods 
will total 48 weeks.  
Cat allergic subjects by history and 
otherwise suitable
Randomly 
assign
Nasal allergen 
challenge
TNSS greater than or equal to 8
Screen 
failure.
Stop
B
Cat immunotherapy.
Placebo.
C
Placebo.
AMG 157.
A
Cat immunotherapy.
AMG 157.
TNSS 7 or less
D
Placebo.
Placebo.
week 0 to 11: Weekly cat immunotherapy or placebo updosing
Q4W AMG 157 IV (anti-TSLP) or placebo 
week 20 to 48:  Q4W cat immunotherapy or placebo maintenance
Q4W AMG 157 IV (anti-TSLP) or placebo
week 48 to 104: observation with nasal allergen challenges at weeks 52, 78, and 104
main comparison
B
Cat 
immunotherapy.
Placebo.
C
Placebo.
AMG 157.
A
Cat immunotherapy.
AMG 157.
D
Placebo.
Placebo.
week 11 to 14: Weekly cat immunotherapy or placebo maintenance
Week 14 to 20: Q2W cat IT or placebo maintenance
Q4W AMG 157 IV (anti-TSLP) or placebo 
 
Figure 1: Screening, allergen challenge, random assignment, treatment, and 
observation 
 

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Interim Analysis 
The first 10 participants enrolled into each treatment group will form initial cohorts 
for a planned interim analysis based on week 52 assessment. When the last 
participant in this cohort completes the week 52 assessment, an interim analysis of 
TNSS response to challenge with cat allergen will compare the initial cohorts of the 
combined groups A and B to the initial cohort of group D. During the interim 
analysis, enrollment in the rest of the trial will continue. Treatment of this cohort and 
of other enrolled participants will also continue. 
If there is strong evidence that the fully enrolled groups A and B will not show a 
significant decrease from baseline in TNSS compared to fully enrolled group D, the 
trial will be stopped. Otherwise, the trial will continue. This evaluation will be made 
based on an analysis described in Section 9.2.5. 
3.2 
STUDY DURATION 
Total study duration will be 154 weeks: 
 
Study enrollment to occur over 46 weeks. 
 
Individual subject study participation will be 108 weeks..  
3.3 
STUDY ENDPOINTS 
 
Primary Endpoint 
Total nasal symptom score (TNSS) AUC from 0 to 1 hour after cat allergen challenge 
at 104 weeks. TNSS is calculated with a scale of 0 to 3 on the 4 parameters of 
sneezing, rhinorrhea, nasal congestion and blockade, and pruritus. Maximum score is 
12. 
 
Secondary Endpoints 
 
Other measures of allergic response including: 
 
1. Skin prick test endpoint titration at baseline, 1, 4, 12, 26, 52, 78, 104 weeks. 
2. Skin early phase response (EPR) to intradermal testing at baseline, 26, 52,104 
weeks. EPR is the skin response at 15 minutes. 
3. Skin late phase response (LPR) to intradermal testing at baseline, 26, 52, 104 
weeks. LPR is the skin response at 6 hours. 
4. Peak TNSS EPR at baseline, 26, 52, 78, 104 weeks. Peak is the highest value 
recorded between 0 and 1 hour inclusive. 
5. TNSS EPR at baseline, 26, 52, 78, 104 weeks. EPR is the TNSS AUC from 0 to 
1 hour. 
6. TNSS LPR at baseline, 26, 52, 104 weeks. LPR is the TNSS AUC from 5 to 6 
hours. 

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7. Peak nasal inspiratory flow (PNIF) LPR AUC at baseline, 26, 52, 104 weeks. 
LPR is the PNIF AUC from5 to 6 hours. 
8. PNIF EPR AUC at baseline, 26, 52, 78, 104 weeks. EPR is the PNIF AUC from 
0 to 1 hour. 
 
Exploratory Endpoints 
Exploratory endpoints related to mechanisms of immune modulation and tolerance 
assessed prior to, during, and after therapy, including those related to: 
1. Local immune response in nasal fluid and/or cells for inflammatory cytokines 
and inflammatory mediators.  
2. Cells in peripheral blood will be collected for basophil activation at various time 
points during and after immunotherapy to measure basophil activation, cat 
antigen tetramers and cytokine profiles in response to in vitro cat antigen 
stimulation; cat antigen tetramers for changes during and after immunotherapy; 
and cytokine profiles after in vitro cat antigen stimulation. 
3. Serum components of cat-specific IgE; IgG and subclasses; and IgA inhibition of 
facilitated antigen presentation. 
3.4 
STOPPING RULES 
 
Ongoing Review 
The progress of the study will be monitored by the NIAID Allergy-Asthma Data and 
Safety Monitoring Board (NIAID DSMB), which will review safety data and make 
recommendations regarding continuation, termination, or modification of the study. 
The DSMB will formally review the safety data six months after the first participant 
is randomized and then annually thereafter. The number of subjects who discontinue 
study treatment will be included in the reports prepared for the DSMB. 
In addition, safety data will be reviewed by the DSMB when an event occurs that is 
of sufficient concern to the NIAID medical monitor, ITN clinical trial physician, or 
protocol chair to warrant review, or when events occur that contribute to a stopping 
rule listed in Section 3.4.2. 
 
Stopping Rules Guidance 
Enrollment in the study will be stopped and administration of the investigational 
medication AMG 157 will be halted pending review by DSMB, DAIT and the ITN if 
any of the following criteria are met: 
1. Death of any participant at least possibly related to study participation.  
2. Grade 4 anaphylaxis at least possibly related to study participation. 
3. Two participants have a grade 3 or higher adverse event at least possibly related 
to AMG 157. 
4. Five participants meet the first individual stopping rule in Section 5.3.  

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5. Two participants have a systemic infection which in the judgment of the NIAID 
medical monitor is unusual or unusually severe. 
6. Grade 3 serum sickness at least possibly related to study participation. 
3.5 
DEFINITION OF HIGH AND LOW EXPOSURE TO CAT ALLERGEN 
Exposure to cats is assessed at screening. This assessment will determine whether a 
participant is stratified as described in section 6.2.1 to the high exposure or low 
exposure stratum. Exposure to cats is also assessed at intervals during participation. 
These assessments will allow tabulation of a participant’s exposure to cats during the 
trial. 
High exposure is defined as exposure to cats at least three times per week during each 
of the four weeks prior to the time of assessment. 
Low exposure is defined as not meeting the high exposure definition. In cases of 
uncertainty the clinical site investigator will determine high versus low exposure. 
4 
ELIGIBILITY 
4.1 
INCLUSION CRITERIA 
Patients must meet all of the following criteria to be eligible for this study: 
1. 
Age 18-65 years. 
2. 
Removed in protocol version 4.0. 
3. 
History of moderate-severe allergic rhinitis (AR) caused by cat exposure for at 
least 2 years. 
4. 
Skin prick test wheal greater than or equal to 5 mm to standardized cat extract.  
5. 
Removed in protocol version 3.0. 
6. 
Screening nasal allergen challenge in which: 
 
TNSS is less than or equal to 3 after the 0 concentration (vehicle control 
only) dose,  
 
TNSS increase is less than or equal to 1 from the TNSS prior to 
allergen administration to the TNSS after the 0 concentration (vehicle 
control only) dose, 
 
TNSS is greater than or equal to 8 after the highest dose, and 
 
Between the first non-zero dose and 10 minutes after the highest dose, 
either:  
 
3 or more sneezes are counted or  
 
Greater than 20% drop in PNIF is recorded. 
7. 
Body mass index (BMI) is greater or equal to 18.0 and less than or equal to 
35.0  kg/m2, at screening. 

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8. 
Clinically acceptable physical examination and electrocardiogram (ECG) 
results (12-lead reporting RR, PR, QRS, QT and QTcF) prior to Day 0 based 
on the opinion of the investigator. 
9. 
Adequate renal function defined as CrCl greater than 80 mL/min using the 
Cockcroft Gault equation. 
10. 
For women of childbearing age, a willingness to use a highly effective form of 
contraception for four months after last dose of study medication. Highly 
effective methods of birth control include abstinence, vasectomy by the male 
partner, or a condom with spermicide in combination with either hormonal 
birth control, IUD or barrier methods used by the woman. 
11. 
For men with female partners of childbearing potential, agreement not to 
donate sperm and to inform their female partner of their participation in this 
clinical study and use highly effective methods of birth control for four 
months after last dose of study medication. Highly effective methods of birth 
control include abstinence, vasectomy, or a condom with spermicide in 
combination with either hormonal birth control, IUD or barrier methods used 
by the woman. 
12. 
The ability to give informed consent and comply with study procedures.  
13. 
Not currently taking and, for the duration of the study, agreement not to take 
any form of immunotherapy, including sublingual, subcutaneous or 
investigational immunotherapy. 
4.2 
EXCLUSION CRITERIA 
Patients who meet any of the following criteria will not be eligible for this study: 
1. 
Removed in protocol version 4.0. 
2. 
Prebronchodilator FEV1 less than 80% of predicted value at screening visit. 
3. 
Removed in protocol version 3.0.   
4. 
History of asthma meeting the NAEPP EPR3 classification of mild-persistent 
or worse in the past year, other than with cat exposure, requiring regular 
inhaled corticosteroids for greater than 4 weeks per year. 
5. 
History of serious chronic medical conditions which might interfere with 
treatment or assessments. 
6. 
History of emergency visit or hospital admission for asthma in the previous 
12 months. 
7. 
History of chronic obstructive pulmonary disease (COPD). 
8. 
History of significant recurrent acute sinusitis, defined as 2 episodes per year 
for the last 2 years, all of which required antibiotic treatment. 

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9. 
History of chronic sinusitis, defined as a sinus symptoms lasting greater than 
12 weeks that includes 2 or more major factors or 1 major factor and 2 minor 
factors. Major factors are defined as facial pain or pressure, nasal obstruction 
or blockage, purulent or discolored postnasal discharge, purulence in nasal 
cavity, or impaired or loss of smell. Minor factors are defined as headache, 
fever, halitosis, fatigue, dental pain, cough, and ear pain, pressure, or fullness. 
10. 
History of systemic disease affecting the immune system such as autoimmune 
diseases, immune complex disease, or immunodeficiency, where, in the 
opinion of the study physician, participation in the trial would pose a risk or 
significant effect on the immune system.  
11. 
Type I or type II diabetes. 
12. 
Evidence of any clinically significant active or suspected bacterial, viral, 
fungal or parasitic infections within 14 days prior to screening nasal allergen 
challenge. Participants may be re-evaluated for eligibility after an appropriate 
course of treatment has been completed and symptoms have resolved. 
13. 
High risk of parasitic disease as judged by the investigator. 
14. 
Positive QuantiFERON® tuberculin test unless the potential subject has been 
treated with appropriate chemoprophylaxis.  
15. 
Exposure to an individual with active tuberculosis within six months from 
randomization. 
16. 
Subjects tested positive for HIV antibody, Hep B surface antigen, or Hep C 
antibody. 
17. 
Removed in protocol version 3.0. 
18. 
History of malignancy of any type, including basal cell and squamous cell 
cancers of the skin, within 5 years of enrollment. 
19. 
Any smoking within the last year or a history of greater than or equal to 10 
pack years. 
20. 
Previous immunotherapy treatment with cat allergen within the previous 
10 years. 
21. 
Any history of grade 4 anaphylaxis due to any cause as defined by the CTCAE 
grading criteria for immunotherapy. 
22. 
History of bleeding disorders or treatment with anticoagulation therapy. 
23. 
Treatment with omalizumab within 6 months prior to randomization. 
24. 
Currently taking any of the following medications:  beta blockers; tricyclic 
antidepressants; monoamine oxidase inhibitors; or anti-IgE monoclonal 
antibody treatment. 
25. 
Ongoing systemic immunosuppressive treatment. 

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26. 
History of intolerance to the study therapy, rescue medications, or their 
excipients. 
27. 
For women of childbearing age a positive serum or urine pregnancy test with 
sensitivity of less than 50 mIU/mL within 72 hours before the start of study 
therapy. 
28. 
The use of any investigational drug or currently using an investigational device 
within 30 days or five half-lives (whichever is longer) prior to randomization. 
29. 
The presence of any medical condition that the investigator deems 
incompatible with participation in the trial. 
4.3 
PREMATURE TERMINATION OF A PARTICIPANT FROM THE 
STUDY 
Withdrawal of consent. Participants who withdraw consent for further treatment or 
study procedures will be asked if they would be willing to complete an early 
termination visit (Appendix 3). 
Investigator decision. The principal investigator may choose to withdraw a 
participant from the study for any reason.  
Failure to return. Participants who do not return for visits and who do not respond 
to repeated attempts by the site staff to have them return will be considered lost to 
follow-up.  
Participants who terminate after randomization from the study will not be replaced.  
Participants who prematurely terminate due to withdrawal of consent for further 
treatment or investigator decision will be invited to complete study assessments at 
week 104 and any other preceding clinical allergy assessment visits including visits 
at weeks 26, 52, and 78 if applicable. However if they decline they will be asked to 
complete an early termination visit (Appendix 3) and will be discharged from the 
study. 
5 
STUDY MEDICATIONS 
5.1 
INVESTIGATIONAL MEDICATION - AMG 157 AND PLACEBO 
 
Formulation and Packaging  
AMG 157 is not approved for any use in the US or elsewhere. 
AMG 157 is a fully human monoclonal IgG2λ directed against TSLP, expressed in a 
Chinese hamster ovary cell line. The molecule is a heterotetramer consisting of 2 
heavy chains of the IgG2 subclass and 2 light chains of the lambda subclass, which 
are covalently linked through disulfide bonds. 
AMG 157 (manufactured by Amgen, Thousand Oaks, CA) is presented as a sterile, 
clear, and colorless to slightly yellow liquid for subcutaneous or intravenous 
administration. Each sterile vial is filled with 1 mL deliverable volume of 70 mg/mL 

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AMG 157 formulated with 10 mM sodium acetate, 9% (w/v) sucrose, 0.004% (w/v) 
polysorbate 20, pH 5.2. 
Placebo for AMG 157, maufactured by Amgen, has the same formulation as ther 
drug product except there is no active AMG157. 
AMG 157 and placebo will be packaged and distributed by a Drug Distributor under 
contract to DAIT, NIAID. 
 
Dosage, Preparation, and Administration 
AMG 157 at 700 mg or placebo of similar appearance will be administered by 
intravenous injection every four weeks as specified in the schedule of events. Every 
four-week dosing has been previously tested and is based on information obtained in 
pharmacokinetic studies which demonstrate a prolonged (approximately 21 day) half-
life which supports dosing at this interval. The duration of AMG 157 specified in the 
current protocol has not been previously assessed.  
Both the drug and the placebo will be delivered by an infusion in 100 ml of sterile 
diluent (5% dextrose) over a 1-hour period using a peristaltic pump. Participants will 
be observed in the clinic for 2 hours prior to discharge or receiving cat 
immunotherapy or placebo. 
Infusion of AMG 157 or placebo should not be given if the participant has significant 
illness.  The infusion may be rescheduled when the symptoms have resolved and 
treatment has been completed.  Persistent of serous otitis is not a reason to continue 
to hold the infusion. If the illness will require a hold of greater than 14 days, then the 
infusion should be skipped and the next dose given per the original schedule. 
 
Recommended Storage Conditions  
AMG 157 should be stored frozen, protected from light and according to the storage 
and expiration information provided on the label that is affixed to the package 
containing the investigational product. 
AMG 157 should be thawed per the instructions provided in the Pharmacy Guide or 
Investigational Product Information Manual. Vials should be checked for cracks or 
damage that may occur during the thawing process if not performed properly. 
Damaged product should not be administered and if damage is observed, the study 
sponsor (DAIT NIAID) should be notified to obtain further instructions. 
The placebo for AMG 157 should be handled in the same way as AMG 157. 
5.2 
INVESTIGATIONAL MEDICATION – CAT IMMUNOTHERAPY AND 
PLACEBO 
 
Formulation and Packaging  
Cat immunotherapy will comprise standardized cat allergen extract and is licensed in 
the US for allergen immunotherapy, and it is formulated as a long-acting suspension 
for subcutaneous injection. 

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The standardized allergen extract will be obtained from ALK-Abelló, Inc. Port 
Washington, NY. 
The cat immunotherapy is 10,000 BAU/ml with inactive ingredients sodium chloride 
(0.5%) sodium bicarbonate (0.25%) and glycerin 50% (v/v). 
The placebo for immunotherapy will consist of the same inactive ingredients as the 
standardized cat allergen extract.  The placebo will be obtained from Allergy 
Laboratories, Inc., Oklahoma City, OK. 
Allergen and placebo are diluted in normal saline with phenol (0.4%) and 0.03% 
human serum albumin also obtained from Allergy Laboratories, Inc., Oklahoma City, 
OK. 
Cat immunotherapy/placebo will be packaged and distributed by a vendor under 
contract to DAIT, NIAID 
 
Dosage, Preparation, and Administration 
Cat immunotherapy or placebo will be administered weekly during the updosing 
phase. The dosing schedule is shown in the table 1 in this section and in the schedule 
of events. Allergen extract for immunotherapy is supplied as a custom kit for each 
individual participant.  These kits were designed to contain sufficient cat allergen 
extract or placebo and diluent to see the participant through the entire course of 
immunotherapy.  In the event that this is not possible, the site will contact the 
NIAID Project Manager who will work with the pharmacy distribution center to 
identify a new kit that was made from the same lot of cat allergen extract or placebo 
that was used in the kit to be replaced.  In the case where a kit with a different lot of 
cat hair allergen or placebo must be used as a replacement, the first dose from the 
new kit will be reduced to half of the most recent dose from the kit that is being 
replaced, unless the investigator feels further dose reduction is needed based on their 
assessment of the situation. The participant will re-escalate per schedule to the 
maintenance dose.  
Participants will be pre-medicated with a fast acting antihistamine (loratadine, or 
similar) at least 60 minutes but not more than 6 hours prior to each dose. Each dose 
should be administered as a subcutaneous injection with monitoring of peak 
expiratory flow and monitoring for clinical signs of anaphylaxis. Participants will be 
observed in the clinic for 30 minutes prior to discharge. When two doses are 
administered in one visit, there should be a 30 minute interval between each 
injection. 
Additional details on formulation, dosage, preparation and administration can be 
found in the package insert available at: 
http://www.alk-
abello.com/US/products/productinformation/Lists/Package%20Inserts/Standardized%20Cat%
20Hair.pdf  

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Table 1:  Schedule of cluster immunotherapy injections 
Day 
Visit 
Volume (ml) 
 Vial # 
Fel d 1 
(BAU/ml) 
Feld1 
(BAU) 
Fel d 1 
(approx 
mcg) 
1
1
0.10
4
10
1
0.003
0.40
4
10
4
0.012
8
2
0.10
3
100
10
0.03
0.20
3
100
20
0.06
15
3
0.40
3
100
40
0.12
0.07
2
1000
70
0.21
22
4
0.10
2
1000
100
0.3
0.15
2
1000
150
0.45
29
6
0.25
2
1000
250
0.75
0.35
2
1000
350
1.05
36
7
0.50
2
1000
500
1.5
0.07
1
10,000
700
2.1
43
8
0.10
1
10,000
1000
3
50
9
0.15
1
10,000
1500
5
57
11
0.20
1
10,000
2000
6
64
12
0.30
1
10,000
3000
9
71
13
0.40
1
10,000
4000
12
78 
14 
0.50 (end of 
updosing)
1 
10,000 
5000 
15 
 
Additional visits at the discretion of the investigator may be required for adjustment 
of allergen doses for individual participants during the updosing or maintenance 
phases of immunotherapy. These extra visits for dose adjustments could result in the 
requirement for more than the 4.5- 5.0 mls in vials 2, 3 or 4 that are created in the 
original dilution series.  The clinical coordinator should inform the NIAID Project 
Manager of this need, and a new kit of diluent will be supplied. 
If participants develop side effects during the updosing phase of subcutaneous 
immunotherapy, such as repeated large immediate local reactions or grade 1-3 
systemic reactions requiring dosage adjustment, the site principle investigator, in 
consultation with the protocol chair and NIAID medical monitor, may decide to limit 
the planned maintenance dose of immunotherapy injections to less than 5,000 BAU., 
.Efforts should be made to reach a dose of at least 3000 BAU to maximize potential 
for effectiveness. 
In the case of a failure to reach a dose of 3000 BAU by week 26, and if the 
participant cannot, for whatever reason, continue weekly dosing attempts to increase 
to 3000 BAU, a panel comprised of the protocol chair, site investigator and NIAID 
medical monitor, will convene to determine the best course of action for the 
particular participant to determine an appropriate maintenance dose. 
 

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Similar visits may be required for dosage adjustments due to intercurrent illness, 
concomitant allergen exposure, or a prolonged interval between doses for personal or 
other reasons. 
 
Recommended Storage Conditions  
The extract concentrate and all dilutions should be kept refrigerated at 2-8°C. Do not 
freeze, and do not open extract concentrate or placebo vials after the expiration date 
indicated on the vial label.  The extract concentrate or placebo vial can be used for 13 
weeks after first puncture. Sites will write on the vial the 13 week expiration date 
upon initial puncture of the vial. 
5.3 
DISCONTINUATION OF STUDY TREATMENT 
Study treatment, defined as the dosing and administration of study medication 
according to study specification, will be discontinued for an individual participant if 
any of the following criteria are met: 
 
Two occurrences of grade 3 systemic reaction after administration of study 
therapy or nasal challenge. 
 
An adverse event that, in the judgment of the principal investigator or the 
medical monitor, presents an unacceptable consequence or risk to the participant. 
 
An illness or infection that is not associated with the condition under study and 
that requires treatment not consistent with protocol requirements; or, if a 
participant develops an intercurrent illness that in the judgment of the principal 
investigator in any way justifies discontinuation. 
 
Grade 3 serum sickness at least possibly related to study participation. 
 
An inability or unwillingness to comply with the study protocol, and the protocol 
deviations are sufficient to jeopardize the participant’s well-being or the integrity 
of the study. 
 
Pregnancy occurs during study participation. 
Participants who prematurely discontinue study treatment will be invited to complete 
study assessments at week 104 and any other proceeding clinical allergy assessment 
visits including visits at weeks 26, 52, and 78 if applicable. However if they decline 
they will be asked to complete the early termination visit (Appendix 3). 
If study treatment is discontinued, the NIAID medical monitor should be notified. 
5.4 
CONCOMITANT MEDICATIONS 
 
Prophylactic and Emergency Rescue Medications 
Antihistamine (loratadine) will be provided and should be taken prior to each 
immunotherapy injection. 
EpiPen® (epinephrine) will be provided and participants will be instructed to bring 
the medication to each immunotherapy visit. A research staff member will verify that 

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the participant has the EpiPen® with them prior to each study treatment 
administration. 
 
Contraception 
Low-dose estrogen containing oral contraception is permitted. 
 
Prohibited Medications 
Use of the medications listed in the exclusion criteria in Section 4.2 is prohibited 
during study participation. 
5.5 DRUG ACCOUNTABILITY 
Under federal regulations (21CFR 312.62) an investigator is required to maintain 
adequate records of the disposition of the investigational product, including the date 
and quantity of drug that was received, the participants to whom drug was dispensed 
(participant by participant accounting), and an account of any drug accidentally or 
deliberately destroyed. The investigator will ensure that the investigational product 
supplies are stored as specified in the protocol and pharmacy manual in a secured 
area, with access limited to authorized study personnel as described in the clinical 
study agreement. 
Records for receipt, storage, use, and disposition of the study drug will be maintained 
by the study sites. A drug-dispensing log will be kept current for each participant and 
will contain the identification of each participant and the date and quantity of drug 
dispensed. All remaining unused investigational product will be returned to the 
sponsor or sponsor’s representative after study termination, or destroyed with the 
permission of the sponsor in accordance with applicable law and study site 
procedures. If investigational product is to be destroyed locally, the investigator will 
provide documentation in accordance with sponsor’s specifications. 
All records regarding disposition of the investigational product will be available for 
inspection by the clinical trial monitor. 
5.6 ASSESSMENT OF COMPLIANCE WITH STUDY MEDICATION 
All study medications will be administered at sites by trained medical staff. 
Compliance, therefore, will be monitored by the site and documented on the eCRF. 
6 
STUDY PROCEDURES 
6.1 
VISIT WINDOWS 
 
Scheduled Visits 
Appendices 1, 2, and 3 present the schedule of events for this trial. Windows for 
visits -1 and visit 0 are defined with respect to visit -2. Windows for the remainder of 
the visits are defined with respect to visit 0. All scheduled study visits must occur 
within the time limits specified below: 
Visit -2:   
no window 

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Visit -1:   
+14 days 
Visit 0:  
 
+7 days 
Visits 1 through 25:  ±3days  
Visits 26 – 31:   
AMG 157/placebo and cat immunotherapy/placebo may be 
given on separate days, ±3 days 
Visit 32: 
±7 days 
Visits 33 through 39:  
±30 days 
 
Unscheduled Visits 
Unscheduled visits may be performed to investigate poorly controlled allergic 
symptoms or symptoms that may be related to study therapy. Assessments for an 
unscheduled visit are listed in Appendices 1, 2 and 3. 
6.2 
RANDOMIZATION, BLINDING, AND UNBLINDING  
 
Randomization and Stratification 
Participants who sign the informed consent, meet the eligibility criteria, and 
successfully complete the baseline nasal allergen challenge will be randomly 
assigned to one of the four study groups. Randomization will be accomplished 
through a password-protected, web-based, randomization system (RhoRAND™) 
maintained by the Statistical and Data Coordinating Center (SDCC). 
Random assignment will be stratified by high versus low exposure to cat allergen 
assessed at screening and as defined in Section 3.5, and by clinical investigative site. 
 
Blinding 
Blinding will be maintained for all study participants and trial personnel after 
randomization, with the exception of the site’s pharmacy staff and unblinded 
qualified individual to administer cat immunotherapy or placebo.  This  unblinded 
qualified individual may also infuse the AMG 157 or placebo but will not be 
involved in performing any study assessments . 
 
Unblinding 
Unblinding before the study is completed will occur only if a participant’s well-being 
is threatened and the investigator believes unblinding is necessary to protect the 
participant.  
Before treatment assignment for an individual participant is unblinded, the 
principal/site investigator must confer with the NIAID medical monitor. The site 
investigator will notify the protocol chair of the unblinding event, and the medical 
monitor will notify the study management team (SMT).  
The emergency unblinding will be recorded and reported to the DSMB. A full 
account of the event will be recorded, including the date and time of the emergency, 
the reason for the decision to unblind, and the names of the medical monitor and 
others who were notified of the emergency. During site visits, the site monitor must 
verify that the medical monitor was notified and that a written account was 

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completed. The reasons for unblinding of a participant’s treatment will be included in 
the final study report. ITN and NIAID approval is required for unblinding the 
treatment of an individual participant or subgroups of participants for unplanned 
interim analyses to support DSMB reviews and final analysis.  
An exception to the above rule is that IND Safety Reports that will be reported to the 
FDA, DSMB, and IRBs in an unblinded fashion as requested by current FDA 
guidance. 
6.3 
GENERAL ASSESSMENTS 
 
Medical history 
 
Allergy history 
 
Comprehensive physical examination (includes height and weight) 
 
Limited physical examination 
 
Vital signs: blood pressure, temperature, pulse, and respiratory rate 
 
Pulmonary function testing (spirometry) 
 
Pre and post peak flow testing 
 
Adverse events 
 
Concomitant medications 
6.4 
CLINICAL ALLERGY ASSESSMENTS 
 
Overview and Washout Periods 
Clinical allergy assessments comprise nasal allergen challenges and several forms of 
skin testing and provide eligibility information, clinical characterization and 
assessments of allergy status. It is important that participants avoid medications in the 
period prior to all such assessments that might unduly modify allergic responses 
independent of the study interventions. Washout periods for specific medications are 
shown in the accompanying table. 

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Table 2: Medication washout periods 
Medication
Time 
Inhaled β-agonists 
Short acting (e.g., Albuterol)
6 hours
Long acting (e.g., Salmeterol, Serevent, Formoterol, Foradil, Oxis)
2 days
Oral β-agonists 
Conventional release (e.g., Albuterol, Ventolin)
12 hours
Extended release (e.g., albuterol-ER)
2 days   
Romolyn drugs (e.g., Intal nebulizer solution)
7 days
Leukotriene modifiers, short-acting (e.g., zafirlukast, Accolate)
3 days
Leukotriene modifiers, long-acting (e.g., montelukast, Singulair)
7 days
Inhaled corticosteroids (e.g., beclomethasone,   Qvar, Budesonide, Pulmicort, Symbicort, 
mometasone, Asmanex, Dulera, fluticasone, Flovent, Advair) 
14 days
Oral steroid (e.g., prednisone, prenisolone)
14 days
Theophylline product 
14 days
Short-acting preparation (e.g., theophylline, Aminophylline)
3 days
Long-acting preparation (e.g., Slo-bid, Theodur)
7 days
Rhinitis Medications
Time 
Cromolyn sodium (e.g., Nasalcrom)
7 days
Oral Antihistamines (e.g., Cetirizine, Desloratadine, Claritin, Fexofenadine, Allegra, 
Levocetirizine, Xyzal. Loratadine, Chlorphenamine, Bendryl, Atarax)
5 days
Topical Antihistamines (e.g. azelastine, Astelin) 
5 days
Decongestants (e.g., pseudoephedrine, phenylephrine) 
3 days
Antihistamine-decongestant tablets/liquids (e.g., Zyrtec D, Claritin-D)  
5 days
Nasal corticosteroids (e.g., Flonase, Nasonex, Nasacort, Fluticasone Propionate, Qnasl, 
Beclomethasone, flunisolide,  Budesonide, Rhinocort Aqua, Dymista)
14 days
Topical anticholinergics (e.g. Atrovent, ipratropium) 
3 days
Anticoagulants and Anti-platelet agents  
Time 
Low-dose aspirin, NSAIDs, other anti-platelet agents
2 days
 
 
Nasal Allergen Challenges 
The screening nasal allergen challenge is carried out as a graded, up-dosing allergen 
exposure starting with the vehicle control only (16.7% glycerin and normal saline) 
dose and then with the same, commercially available, standardized cat allergen 
extract used for immunotherapy as described in an accompanying standard operating 
procedure. A procedure similar to that reported by Scadding et al. (2012) will be 
used. Subjects who meet protocol inclusion criteria with respect skin testing may 
undergo the nasal allergen challenge at screening visit, baseline visit and subsequent 
challenge visits(See Section 4.). Assessments performed during the challenges 
include peak expiratory flow, forced expiratory volume in 1 second, total nasal 
symptom score, and peak nasal inspiratory flow rate. 
When possible, all nasal allergen challenges in an individual participant will be 
completed using the same lot of cat allergen extract manufactured by ALK-Abello.  
Investigators should contact NIAID Project Manager if the lot of cat allergen extract 
used for a NAC must be changed for any reason. The NIAID Project Manager will be 
responsible for communicating replacement lot information to the sites.  
If the same lot of cat allergen is not  available or expires before the week 104 
assessment, the participants will be challenged with a new lot of cat allergen extract 
with a similar Fel d 1 microgram/mL levels.  The choice of a replacement lot will be 

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based on a side-by-side ELISA assay performed at ALK-Abello. The new lot must be 
within +/- 26% of the lot being substituted. 
When a lot change  is  anticipated due to the expiration of the original lot prior to the 
week 104 assessment, the lot change will take place at the week 52 nasal allergen 
challenge. 
The lots of cat allergen extract used for the nasal allergen challenges may be the same 
as, or different than, the lot used for immunotherapy in any one participant. 
 
Skin Testing 
6.4.3.1 Overview 
All skin test procedures are consistent with current clinical practice and product 
labeling. All cat allergen extracts will be purchased from ALK-Abelló and packaging 
and delivery of these materials will be done by a designated drug distributor under 
contract to NIAID. Skin testing should be done with the same lot of cat allergen 
extract that is used for nasal allergen assessments in an individual participant. 
Washout periods for specific medications prior to skin testing are listed in the table. 
6.4.3.2 Skin Prick Test for Cat Allergen 
Skin prick test (SPT) for cat allergen will be done as indicated in the SOE.  
Controls include:  negative control (50% glycerin), and positive control (10 mg/mL 
histamine dihydrochloride). Subjects will be assessed 15 (+2) minutes after 
application. 
6.4.3.3 Intradermal Skin Test for Early and Late Phase Responses: 
Cat Allergen Extract 
Intradermal skin testing with cat allergen extract will be done at times indicated in 
the SOE. 
For this test, concentrations of standardized cat hair extract specified in an SOP will 
be applied intradermally to the forearm. Subjects will be assessed 15 (+2) minutes 
and 6 hours (± 15 minutes) after application.  
6.4.3.4 Skin Prick Test (SPT) Serial Titration: Cat Allergen Extract 
Skin prick test titration with cat allergen extract will be done at times indicated in the 
SOE. 
A dilution series of standardized cat allergen extracts will be prepared. Each dilution 
will be applied and punctured in duplicate. Subjects will be assessed 15 (+2) minutes 
after application.  
6.5 
CLINICAL LABORATORY ASSESSMENTS 
 
Serum pregnancy test 
 
Urine pregnancy test 

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 
Hematology: Complete blood count with differential 
 
Comprehensive chemistry:  Albumin, bilirubin total, creatinine, glucose, 
potassium, protein total, sodium, alamine amino transferase (ALT) (SPGT), 
aspartate amine transferase (AST) (SGOT), and urea nitrogen (BUN) 
 
QuantiFERON® TB test 
 
HIV Antibody  
 
Hepatitis B surface antigen test 
 
Hepatitis C antibody test 
 
Creatinine Clearance 
6.6 
PHARMACOKINETIC AND AMG 157 NEUTRALIZING ANTIBODY 
TESTING 
Serum samples to assess pharmacokinetic and AMG 157 serum antibody levels will 
be collected at drug trough from all participants at the times indicated in the schedule 
of events.  
7 
TOLERANCE ASSAYS 
7.1 
RATIONALE FOR IMMUNE STUDIES 
Thymic stromal lymphopoietin (TSLP), a member of the IL-2 cytokine family and an 
IL-7 like cytokine, was initially identified as being involved in lymphocyte 
development.35 TSLP is now known to impact many different cell types including: 
dendritic cells (DCs), basophils, eosinophils, mast cells, T cells, B cells, and 
epithelial cells.16 Multiple murine studies in 2005, two by Steven Ziegler and 
colleagues at the Benaroya Institute, demonstrated that TSLP is a key initiator of 
allergic diseases, that is, asthma and atopic dermatitis.21,36_ENREF_37 More recent 
studies have implicated TSLP in the pathogenesis of allergic diseases in 
humans.16,20_ENREF_21 
Mechanisms of immunotherapy have been described for grass immunotherapy. These 
may include stimulation of Th 1-type helper lymphocytes, decrease in Th 2 cells and 
induction of T regulatory (Treg) cells that produce IL-10 and TGF-.12,13  They also 
include the production of blocking antibodies as well as effects on other 
inflammatory cells including mast cells, eosinophils and basophils. As noted in the 
introduction, less is known about the corresponding mechanisms after cat 
immunotherapy. Ewbank et al. and Nanda et al. both reported approximately two to 
three-fold increases in cat-specific IgG4 after as little as 5 weeks of subcutaneous 
immunotherapy.10,11 In one report there was a reported decrease in CD4/IL-4-positive 
(Th 2-like) cells10 but this was not a consistent finding.11  
Recent data elucidating the role of TSLP in allergic responses suggests that TSLP 
inhibition has the potential to combine with allergen-specific immunotherapy to give 
beneficial effects on both the antigen-specific T-cell mediated elements and 

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inflammatory elements mediated by basophils and mast cells. We hypothesize that 
TSLP blockade by anti-TSLP will inhibit Th 2 responses and thus combine with 
immunotherapy to lead to a long-lasting desensitization to cat allergens and 
potentially to tolerance of these allergens. 
Mechanistically tolerance could occur through multiple routes and the experiments 
summarized below are designed to address these questions. Note that the primary 
goal of this study is to determine whether the combination of anti-TSLP (AMG 157) 
plus antigen-specific immunotherapy will result in tolerance to the therapeutic 
antigen that persists for a substantial period after stopping immunotherapy. 
Previous studies of the mechanism of subcutaneous immunotherapy, including those 
performed by the ITN, have highlighted the value of studying immune and 
inflammatory responses in the target organ rather than just in the peripheral blood. 
Therefore, this study will compare changes in the nasal mucosa/secretions with 
systemic changes in T-cell and humoral responses and the clinical response to nasal 
allergen provocation before, during and at intervals after immunotherapy and TSLP 
blockade. 
7.2 
HYPOTHESES TO BE TESTED 
Subcutaneous immunotherapy with cat allergens induces desensitization to cat 
allergens of unknown durability. We hypothesize that adding anti-TSLP to cat 
immunotherapy will increase the duration of desensitization and potentially induce 
tolerance to cat antigens by all or some of the mechanisms proposed below:  
1. 
Long-lived suppression of allergen-induced early and late phase responses for at 
least 52 weeks after discontinuation of immunotherapy. 
2. 
Change in the T effector/T regulatory cell balance. We predict that either 
antigen-specific T effector cells will decrease and/or T regulatory cells will 
increase. 
3. 
Immune deviation in favor of Th 1 responses and relative suppression of local Th 
2-mediated allergic inflammation in the nasal mucosa. 
4. 
“Protective” inhibitory antibody responses that persist for at least 56 weeks after 
discontinuation and are surrogate and/or predictive of the clinical response to 
immunotherapy. 
In order to test these hypotheses, we shall perform intradermal skin provocation 
testing with measurement of immediate and late skin responses before and at 
intervals after immunotherapy. Early skin responses occur in minutes and represent 
IgE-driven mast cell activation and degranulation. Late responses occur several hours 
later and are mediated by T cells, eosinophils, and basophils. At corresponding time 
points we will perform nasal allergen challenge with measurement of early and late-
phase nasal symptoms, along with nasal fluid, nasal epithelial cell brushings, and 
peripheral blood sampling. The hypotheses described above will be tested using a 
variety of  assays, examples of which are described in the sections below. 

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7.3 
RETENTION OF SAMPLES 
A major priority of the Immune Tolerance Network, in partnership with the National 
Institute of Allergy and Infectious Diseases of the NIH, USA, is the development of 
novel immunoassays in order to better understand mechanisms of tolerance and to 
develop biomarkers to predict the development and maintenance of clinical tolerance. 
As in all Immune Tolerance Network-funded clinical trials, informed consent will be 
obtained from all participants for their samples to be stored for use in future studies. 
Biological specimens collected in this trial will be stored long-term in order to re-
evaluate biologic responses as new research tools to study tolerance become 
available. The specimens will therefore be stored at the ITN sample repository for a 
minimum of 10 years. Residual specimens may be used by the investigators for 
development of new immunologic assays or for cross-trial comparisons. Although 
specimens in this protocol are described in the context of assays to be performed, it 
should be noted that not necessarily all assays will be performed for all participants at 
each time point. Decisions to perform assays will be made based on statistical and 
scientific planning, hypotheses to be tested, and technologies available. Finally, 
clinical outcomes will be taken into account to determine the potential value of the 
assays. For example, if a clinical effect fails to occur, it may be decided that there is 
minimal value in performing certain mechanistic assays. 
7.4 
LOCAL IMMUNE RESPONSES IN NASAL MUCOSA 
Nasal allergen challenge will be performed at baseline and at 26, 52, and 104 weeks. 
Along with clinical signs and symptoms score, nasal secretions will be collected at 
multiple time points at baseline, and at 26, 52, and 104 weeks. These analyses are 
based on pilot work performed by Drs. Scadding, Durham et al. in collaboration with 
the ITN, to support the GRASS study (ClinicalTrials.gov Identifier: NCT0335139). 
Note, that as shown in Figure 2 Th 2 cytokine levels continue to rise to 6 hours post 
challenge.31 Therefore to ensure that we capture the entire late phase responses, 
samples in this trial will be collected several hours post-challenge. 
 
Figure 2: Th 2 cytokine levels 
 
 
 
 
 
 
Baseline
Post-lavage
+00:05
+00:15
+00:30
+01:00
+02:00
+03:00
+04:00
+05:00
+06:00
0
20
40
60
80
100
pg/ml
*
*
*
*
*
n=7
Baseline
Post-lavage
+00:05
+00:15
+00:30
+01:00
+02:00
+03:00
+04:00
+05:00
+06:00
0
500
1000
1500
2000
pg/ml
*
*
*
*
*
n=38
IL-4 
IL-5 

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Epithelial cells harvested by nasal brushing/scraping may also be collected at each 
nasal allergen challenge visit. However, brushings will only be taken 6 hours after the 
challenge to avoid inflammatory sampling effects on nasal secretions taken at earlier 
time-points.  
Nasal secretions will be assayed for inflammatory mediators, including TSLP, and 
local antibodies. RNA will be extracted from the epithelial cells harvested by nasal 
brushing and the expression of various cytokines and chemokines assessed by 
quantitative gene expression technology, such as RT-PCR or RNAseq, for 
comparison between the four treatment groups. 
 Nasal fluid will be obtained before and at intervals up to 6 hours after nasal 
allergen challenge for measurement of cytokines, such as IL-5, IL-13, IF -, IL-10, 
TGF-, antibodies (IgE, IgG4 and IgA2 using CAPRAST) and inflammatory 
mediators such as ECP (eosinophilic cationic protein), tryptase, basogranulin, and 
TSLP. 
 Nasal epithelial cells may be collected from the nasal epithelium by gently 
brushing the inferior turbinates using an interdental brush (2 or 3 mm). The brush 
will be introduced into a microcentrifuge tube, covered with 1.5 mL extraction 
buffer RLT (Qiagen), and stored in this buffer at －80 °C for up to 6 months until 
batched extraction of the RNA. 
Depending on the results of pilot studies and future publications, RNA extracted from 
the epithelial cells may be analyzed for genes of interest by RT-PCR. These may 
include genes for:  
 epithelial cell-derived chemokines such as TSLP, MDC, TARC, Eotaxin, 
RANTES 
 adhesion molecules such as ICAM-1 
 cytokines such as IL-8, GM-CSF and those that may possibly be detected in trans-
epithelial migratory effector cells, including IL-4, IL-5, IL-9, IL-13, Interferon-
gamma, IL-10 and TGF-beta 
Baseline
Post-lavage
+00:05
+00:15
+00:30
+01:00
+02:00
+03:00
+04:00
+05:00
+06:00
0
50
100
150
200
pg/ml
*
*
IL-13
*
*
*
*
*
n=38

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 newer cytokines of potential interest e.g., IL-25, IL-22, IL-33 and IL-35 
 transcription factors of interest e.g., GATA-3, STAT-6, T Bet and FOXP3  
7.5 
WHOLE BLOOD ASSAYS 
 
DNA-HLA Genotypes and Single Nucleotide Polymorphisms 
MHC tetramers bind to the T-cell receptor in an HLA-specific context. Therefore, 
DNA will be collected from participants to perform sequence-based HLA typing, 
such that appropriate candidates can be identified for tetramer analysis. 
In 2008, Dr. Ziegler conducted analyses of single nucleotide polymorphisms (SNPs) 
of the TSLP gene in human bronchial epithelial cells, to determine if there are 
functional genetic variants of TSLP that contribute to disease.37 He surveyed SNPs 
on the TSLP gene by sequencing genomic DNA from 36 subjects, and characterized 
the linkage disequilibrium of the gene. Dr. Ziegler identified a total of 23 
polymorphisms in the TSLP gene. Two splice variants of TSLP have been identified: 
the long form, which is associated with allergic inflammation, was highly induced by 
poly (I:C) (double-stranded RNA) stimulation in normal human bronchial epithelial 
cells (NHBE) (P = 0.0060). The SNP rs3806933 (−847C > T) in the promoter region 
of long-form TSLP was found to create a binding site for the transcription factor 
activating protein (AP)-1, and in vitro functional analyses demonstrated that the SNP 
enhanced AP-1 binding to the regulatory element. The functional variant increased 
promoter-reporter activity of long-form TSLP in response to poly (I:C) stimulation in 
NHBE. Functional genetic polymorphism of the TSLP gene thus appears to have the 
potential to contribute to Th 2-polarized immunity through higher TSLP production 
by bronchial epithelial cells in response to viral respiratory infections.37 
Although there are relatively few patients in this study and all are cat allergic, so 
much is known about TSLP SNPs that we may wish to look for variants and correlate 
them with response to therapy and to the expected frequency of TSLP alleles in the 
general non-allergic, appropriately race-matched population. 
 
Gene Expression Profiling 
To further elucidate possible changes in cytokines, signaling pathways and cellular 
profiles, gene expression profiling analysis may be performed on RNA isolated from 
peripheral blood using RNAseq, nanostring, or high-throughput real-time PCR 
methods.  The goal of these assays is to identify differences in transcriptional profiles 
between treatment arms and clinical outcome groups, and to monitor the durability of 
these potential changes after discontinuation of immunotherapy.  These types of 
analyses may also explain why some individuals respond to treatment or elucidate 
mechanisms resulting in adverse responses to treatment.       
7.6 
CELL ASSAYS 
7.6.1 PBMC Preparation 
All blood samples collected for PBMC isolation will be shipped from the clinical 
sites to the ITN core facility for processing using ITN standard operating procedures 

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(SOPs) for PBMC separation, and freezing. This will ensure that standardized 
procedures are used and that high quality material is obtained for testing. PBMCs 
will be stored in the vapor phase of liquid nitrogen until use. 
7.6.2 Cellular Assays 
To address the functional status of T cell responses, various cell-based assays using 
previously frozen PBMCs can be used to estimate the frequency, phenotype, cytokine 
and transcriptional profiles of allergen-specific T cells. 
Allergen specific CD4 T cells are present at very low frequencies in peripheral blood 
and differ in function/frequency in allergic vs. non-allergic individuals. MHC (major 
histocompatibility complex) class II “tetramers”, a fluorescently tagged multivalent 
synthetic mimic of the peptide binding proteins found on the surface of antigen 
presenting cells can be used to directly identify and enumerate cat allergen Fel d1 
epitope specific CD4 T cells using flow cytometry. Additional steps may be 
performed to determine the effector function of antigen-specific CD4 T cells.  For 
example, intracellular cytokine staining for IL-4, IL-5, IL-9, IL-13, IFNg, IL-17, 
IL10, Foxp3 and TGF could be performed to assess frequencies and ratios of Th1, 
Th2, Th9, Th17, Th17.1, and Treg cells.  Alternatively, antigen-specific CD4 T cells 
could be FACS sorted for transcriptional analysis by RNAseq or related platform. 
The ability to use these reagents will depend on the overlap between HLA alleles 
among study participants and available reagents.  
Since tetramers are not currently available for all haplotypes other T-cell assays may 
also be performed.  We plan to pilot a CD154 up-regulation assay for monitoring cat 
allergen-reactive CD4 T cells with Bill Kwok at BRI using PBMC isolated from ~70 
mL fresh blood collected from 15 study participants at the Asmthma Inc Site.  This 
assay requires overnight in vitro stimulation of ~40 million PBMCs with Fel d 1 and 
Feld 4 peptides/cat allergen extract in the presence of anti-human CD40 blocking 
mAb.  ½ of the cells will be collected and analyzed by flow cytometry, and the other 
half will be used for sorting CD154+ and CD154- CD4 T cells for RNAseq analysis.  
Since additional PBMCs from these same study participants/visits will be processed 
and cryopreserved by the ITN Core PBMC Processing Lab, we will be able to 
directly compare the performance and utility of the CD154 up-regulation assay for 
cryopreserved PBMCs tested in a single batch compared to fresh PBMC tested in 
real-time.  If the CD154 upregulation assay can be validated on cryopreserved 
PBMCs, this assay would be an attractive option for determining the impact and 
durability of treatment on frequencies and phenotypes of cat allergen specific CD4 T 
cells in all study participants. 
 For optimum use, these assays require 40 million viable cells per assay, so it is 
important that every effort is made to collect the full planned blood volumes at the 
time points specified the SOE. 
We may also use surface flow cytometry to determine the frequency of TH2A cells as 
this subset of Th2 cells may be a biomarker for allergy. Work by Wambre suggests 
that this subset includes the vast majority of allergen-specific CD4 T cells as 

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determined by tetramer analysis. This assay has the advantage that it can be reliably 
performed with only two million previously frozen, viable PBMCs.  
Treatment with anti-TSLP may lead to decreased STAT 5/6 signaling and potentially 
increased STAT 1 or STAT 3 signaling in multiple immune cell types. Activation 
status of these signaling pathways may be measured by flow cytometry using 
antibodies that discriminate between the phosphorylation states of these molecules in 
specific cell populations upon appropriate stimulation in vitro.  
This protocol has been designed to allow us to store multiple aliquots of PBMCs 
taken at major time points in the study. This will allow us to look at additional 
markers and to address new reports of relevant markers. For example, recent 
publications38 suggest that changes in the surface expression of FcRI may enhance 
local inflammation after cell recruitment to the site of allergen challenge. Up-
regulation of FcRI is known to amplify the capacity for uptake and presentation of 
allergen to Th 2 effector cells via IgE mediated allergen capture and secondarily 
programming of IL-4/IL-13 dependent activated macrophages. Therefore, we may 
measure surface expression of FcRI on plasmacytoid and myeloid dendritic cells as 
well as monocytes by flow cytometry using frozen PBMCs. 
7.7 
SERUM ASSAYS 
Serum antibody responses will be measured to determine levels of total and 
allergen-specific antibodies. These measurements will include testing for total IgE 
and IgG and allergen-specific IgE, IgG1, IgG4, and IgA2, and will be performed in 
the ITN core. A role for IgG1, IgG4, and IgA2 in blocking allergen-specific 
reactivity is postulated; however, previous studies showed various results in allergen-
specific antibody induction after immunotherapy. 
In addition to antibody testing, serum samples may be used in functional assays 
including measurement of IgG-associated serum inhibitory activity of IgE-facilitated 
binding of allergen-IgE complexes to B cells (IgE-FAB (facilitated antigen binding), 
a surrogate measure of IgE-FAP (facilitated antigen presentation) and serum 
inhibitory activity for basophil histamine release (BHR). These two assays address 
the degree of blocking of binding of allergen-IgE complexes to low- and high affinity 
IgE receptors (respectively). Serum from treatment and placebo groups will be 
assessed for its inhibitory activity for IgE-FAB. The time course and magnitude of 
changes in inhibitory activity for IgE-FAB will be compared with clinical symptoms, 
clinical scores, and allergen-specific IgE, IgG1, IgG4, and IgA2 levels. Similarly, 
serum will be screened for its inhibitory activity in BHR assays. 
8 
ADVERSE EVENTS 
8.1 
OVERVIEW 
The investigator is responsible for the detection and documentation of events meeting 
the criteria and definition of an AE (adverse event) or SAE (serious adverse event) as 
described in Section 8.2.2 and Section 8.2.4 in this protocol. All AEs and SAEs will 

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be recorded in the source documents and on the appropriate electronic CRF(s). All 
data will be reviewed periodically by the DSMB, which may provide 
recommendations to NIAID about withdrawing any participant and/or terminating the 
study because of safety concerns. 
Adverse events that are classified as serious according to the definition of health 
authorities must be reported promptly and appropriately to the NIAID, ITN, principal 
investigators in the trial, IRBs, and health authorities. This section defines the types 
of AEs and outlines the procedures for appropriately collecting, grading, recording, 
and reporting them. Information in this section complies with 21CFR 312; ICH 
Guideline E2A: Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting; and ICH Guideline E-6: Guidelines for Good Clinical Practice; 
and applies the following standards: 
 
Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials (published September 
2007) for local reactions to immunotherapy and study procedures. 
 
WAO Subcutaneous Immunotherapy Systemic Reaction Grading System for 
systemic reactions to immunotherapy and study procedures. 
 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events Version 4.03 (published June 14, 2010) for all other reactions to 
immunotherapy and study procedures. (This document is referred to herein as the 
“NCI-CTCAE manual.”)  
8.2 
DEFINITIONS 
 
Adverse Event 
An adverse event (AE) is any occurrence or worsening of an undesirable or 
unintended sign, symptom, laboratory finding, or disease that occurs during 
participation in the trial. An AE will be followed until it resolves or until 30 days 
after a participant terminates from the study, whichever comes first. All AEs will be 
reported as specified in Section 8 whether they are or are not related to disease 
progression or study participation. 
 
Study-Specific Adverse Events 
Allergic rhinitis 
During the study it is anticipated that participants will experience allergic rhinitis 
symptoms related to cat exposure including itching, sneezing, watery discharge, nasal 
congestion, and eye symptoms. These symptoms are consistent with moderate-severe 
allergic rhinitis caused by cat exposure which is an entry criterion for the study. 
These symptoms therefore will not be reported as adverse events. 
Local reactions to immunotherapy and study procedures 

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Common local symptoms due to immunotherapy, skin testing and nasal allergen 
challenge will be graded according to table 3 below. Only those reactions assessed as 
grade 2 or greater will be reported as adverse events. Please refer to Section 8.4.1 for 
specifications of local reactions related to nasal allergen challenge.  
Table 3: Grading of local reactions to cat immunotherapy and to study 
procedures 
(Adapted from Guidance for Industry: Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (published 
September 2007). 
Grade 
1 
2 
3 
4 
Cat immunotherapy and skin testing 
Pruritis 
Interfering with 
the usual daily 
activities or sleep, 
but requiring no 
medication other 
than topical 
corticosteroids, or 
antihistamines.
Interfering with 
the usual daily 
activities or sleep 
and requiring 
oral steroids. 
Requiring a visit 
to a health care 
provider  for 
treatment 
Not applicable 
Pain 
Does not interfere 
with activity 
Repeated use of 
non-narcotic 
pain reliever > 
24 hours or 
interferes with 
activity
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity 
Emergency room 
(ER) visit or 
hospitalization 
Tenderness 
Mild discomfort 
to touch 
Discomfort with 
movement 
Significant 
discomfort at rest 
ER visit or 
hospitalization 
Erythema/ 
Redness* 
2.5 – 5 cm 
> 5 cm and 
interferes with 
activity 
>10 cm or 
prevents daily 
activity 
Necrosis or 
exfoliative 
dermatitis 
Induration/ 
Swelling** 
2.5 – 5 cm and 
does not interfere 
with activity 
> 5 cm and 
interferes with 
activity 
>10 cm or 
prevents daily 
activity 
Necrosis
Nasal allergen challenge 
 
Requiring 
antihistamines, 
decongestants or 
nasal steroids as 
rescue medication 
Requiring oral 
steroids as rescue 
medication  
 Requiring a visit 
to a health care 
provider for 
treatment. 
Life threatening 
and/or requiring 
hospitalization 
(local upper 
airway 
obstruction)
*  
In addition to grading the measured local reaction at the greatest single diameter, the measurement 
should be recorded as a continuous variable. 
**  Induration/Swelling should be evaluated and graded using the functional scale as well as the actual 
measurement. 
 
Suspected Adverse Reaction and Adverse Reaction  
Suspected adverse reaction (SAR) means any adverse event for which there is a 
reasonable possibility that the study drug caused the adverse event. For the purposes 

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of safety reporting, ‘reasonable possibility’ means there is evidence to suggest a 
causal relationship between the drug and the adverse reaction. A suspected adverse 
reaction implies a lesser degree of certainty about causality than adverse reaction, 
which means any adverse event caused by a drug (21 CFR 312.32(a)).  
An adverse reaction (AR) means any adverse event caused by a study drug. Adverse 
reactions are a subset of all suspected adverse reaction for which there is reason to 
conclude that the drug caused the event. 
 
Serious Adverse Event  
An AE or SAR is considered “serious” if, in the view of either the investigator or 
DAIT/NIAID it results in any of the following outcomes (21 CFR 312.32(a)): 
 Death:  A death that occurs during the study or that comes to the attention of the 
investigator during the protocol-defined follow-up period must be reported 
whether it is considered treatment related or not. 
 A life-threatening event: An AE or SAR is considered “life-threatening” if, in the 
view of either the investigator or the medical monitor, its occurrence places the 
subject at immediate risk of death. It does not include an AE or SAR that, had it 
occurred in a more severe form, might have caused death.  
 Inpatient hospitalization or prolongation of existing hospitalization. 
 Persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
 An event that requires intervention to prevent permanent impairment or damage. 
An important medical event that may not result in death, be life threatening, or 
require hospitalization may be considered an SAE when, based on appropriate 
medical judgment, it may jeopardize the participant and may require medical or 
surgical intervention to prevent one of the outcomes listed above. 
 Congenital anomaly or birth defect. 
 
‘Expected’ versus ‘Unexpected’ Suspected Adverse Reaction 
A suspected adverse reaction is considered “expected” when it is listed in the 
investigator brochure, the package insert or the protocol. A suspected adverse 
reaction is considered “unexpected” when its nature (specificity), severity, or rate of 
occurrence is not consistent with applicable product information as described in the 
safety information provided in the investigator brochure, the package insert or the 
protocol (21 CFR 312.32(a)). A serious unexpected suspected adverse reaction is 
referred to as a SUSAR. 
For this study, expectedness will be determined by product information provided in 
the package insert for cat immunotherapy and in the investigator’s brochure for AMG 
157. Expectedness for study procedures (nasal allergen challenge, intradermal skin 
test and skin prick test) will be determined by information in the protocol. 

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8.3 
COLLECTING AND RECORDING ADVERSE EVENTS 
 
Methods of Collection 
Adverse events may be collected as follows: 
 
Observing the participant. 
 
Questioning the participant in an objective manner. 
 
Receiving an unsolicited complaint from the participant. 
An abnormal value or result from a clinical or laboratory evaluation (e.g., a 
radiograph, an ultrasound, or an electrocardiogram) can also indicate an AE if it is 
either determined by the investigator to be clinically significant or meets the criteria 
for a grade 2 or greater AE per CTCAE criteria. If this is the case, it must be recorded 
in the source document and as an AE on the appropriate AE form(s). The evaluation 
that produced the value or result should be repeated until that value or result returns 
to normal or can be explained and the participant’s safety is not at risk. 
8.3.2  Collection Period for Adverse Events and Serious Adverse 
Events 
8.3.2.1 Adverse Events 
All systemic reactions and all grade 2 or greater local reactions occurring within 72 
hours after cat immunotherapy and/or study procedures (see Section 8.2.2) will be 
collected from visit -2 (week -4) until the participant completes the study (visit 
40/week 104) or prematurely withdraws from the study. All other AEs will be 
collected from visit 0 (week 0) until the participant completes the study (visit 
40/week 104) or prematurely withdraws from the study. 
8.3.2.2 Serious Adverse Events 
Serious AEs will be collected from visit -2 (week -4) until 30 days after the 
participant completes the study (visit 40/week 104) or prematurely withdraws from 
the study. 
8.3.3 Methods of Recording 
8.3.3.1Recording AEs 
Throughout the study, the investigator will record all AEs on the appropriate eCRF. 
The investigator will treat participants experiencing AEs appropriately and observe 
them at suitable intervals until their symptoms resolve or their status stabilizes. 
8.3.3.2 Recording SAEs 
Serious AEs will be recorded on the SAE eCRF and health authorities will be 
notified as outlined in Section 8.5.2. 

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8.4 
GRADING AND ATTRIBUTION OF ADVERSE EVENTS 
8.4.1 Grading Criteria 
8.4.1.1 Adverse Events Related to Cat Immunotherapy or to AMG 157 
Immunotherapy 
Local reactions to cat immunotherapy not associated with systemic signs or 
symptoms will be graded according to the table in Section 8.2.2.  
Systemic reactions to cat immunotherapy will be graded according to the WAO 
Subcutaneous Immunotherapy Systemic Reaction Grading System (see appendix 4).  
All other adverse events related to cat immunotherapy will be graded according to the 
criteria set forth in the NCI-CTCAE (v4.03 published June 14, 2010). 
AMG 157 
All adverse reactions related to AMG 157 will be graded according to the NCI-
CTCAE v4.03, published June 14, 2010. 
8.4.1.2 Adverse Events Related to Nasal Allergen Challenge and Skin 
Testing 
Local reactions related to nasal allergen challenge and skin testing not associated 
with systemic signs or symptoms will be graded according to the table in Section 
8.2.2. Only grade 2 or greater local reactions will be recorded as AEs. Systemic 
reactions related to skin testing or to nasal allergen challenge procedure will be 
graded according to the WAO Subcutaneous Immunotherapy Systemic Reaction 
Grading System (see Appendix 4). All grades of system reactions should be recorded 
as AEs and as SAEs if serious criteria are met.  
The following specifications considered local, not systemic reactions will apply for 
nasal allergen challenges:  
 
rhinitis (e.g., sneezing, rhinorrhea, nasal pruritus and/or nasal congestion) and  
 
cough perceived to originate in the upper airway, not the lung, larynx, or trachea 
All other adverse events related to study procedures will be graded according to the 
criteria set forth in the National Cancer Institute’s Common Terminology Criteria for 
Adverse Events, Version 4.03 (published June 14, 2010). 
8.4.1.3 All Other Adverse Events 
All other adverse events will be graded on a scale from 1 to 5 according to the 
following standards in the NCI-CTCAE manual: 
 Grade 1 = mild adverse event 
 Grade 2 = moderate adverse event 
 Grade 3 = severe and undesirable adverse event 

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 Grade 4 = life-threatening or disabling adverse event 
 Grade 5 = death 
For additional information and a printable version of the NCI-CTCAE manual, go to 
http://ctep.cancer.gov/reporting/ctc.html   
8.4.2 Attribution Definitions 
Adverse events will be categorized for their relation to one or more of the following: 
 
Study medications:  
o AMG157/AMG 157 placebo  
o Cat immunotherapy/Cat immunotherapy placebo 
 
Study procedures: 
o Nasal allergen challenge 
o Intradermal skin test 
o Skin prick test 
The investigator will make the initial determination of the relation, or attribution, of 
an AE to participation and will record the initial determination on the appropriate 
eCRF and/or SAE reporting form. The relation of an AE to study drug will be 
determined using definitions in the Table 4. Final determination of attribution for 
safety reporting will be decided by DAIT/NIAID. 
Table 4: Attribution of adverse events 
Code 
Descriptor 
Definition 
Unrelated Category  
1 
Unrelated 
The adverse event is clearly not related. 
2 
Unlikely 
The adverse event is unlikely related. 
Related Categories 
3 
Possible 
The adverse event has a reasonable possibility of being related; 
there is evidence to suggest a causal relationship. 
4 
Probable 
The adverse event is likely related. 
5 
Definite 
The adverse event is clearly related. 

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8.5 
REPORTING SERIOUS ADVERSE EVENTS 
8.5.1 Reporting SAEs to the IND Sponsor  
The following process for reporting an SAE ensures compliance with 21CFR 312 and 
ICH guidelines. After learning that a participant has experienced an SAE, the 
principal investigator or designee will report the SAE via the electronic SAE report 
form (SAE eCRF) within 24 hours of becoming aware of the event. The initial SAE 
eCRF should include as much information as possible, but at a minimum must 
include: 
 AE term 
 Study drug treatment 
 Relationship to study medications 
 Reason why the event is serious 
 Supplementary CRF pages must be current at the time of SAE reporting: medical 
history, concomitant medications, demographics, study drug administration, 
death.  
As additional details become available, the SAE eCRF should be updated and 
submitted. Every time the SAE eCRF is submitted, it should be electronically signed 
by the investigator or subinvestigator.  
For additional information regarding SAE reporting, contact Rho Product Safety: 
Rho Product Safety  
6330 Quadrangle Drive, Suite 500 
Chapel Hill, NC  27517 
Toll-free - (888) 746-7231 
SAE Fax Line: 1-888-746-3293 
Email: rho_productsafety@rhoworld.com 
8.5.2 Reporting SAEs to Health Authorities 
After the SAE has been reported by the principal investigator and assessed by the 
IND sponsor, the IND sponsor must report the event to the appropriate health 
authorities using one of these two options: 
 Standard reporting (IND annual report). This option applies if the AE is 
classified as:  
o Serious, expected, suspected adverse reactions described in Section 8.2.2, 
Section 8.2.3 and Section 8.2.4. 
o Serious and not a suspected adverse reaction described in Section 8.2.2 and 
Section 8.2.3. 
 Expedited reporting (IND safety report). This option applies if the AE is 
classified as one of the following: 

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1. Serious and unexpected suspected adverse reaction (SUSAR) per Section 
8.2.2, Section 8.2.3 and Section 8.2.4. 
The sponsor must report any suspected adverse reaction that is both serious 
and unexpected. The sponsor must report an adverse event as a suspected 
adverse reaction only if there is evidence to suggest a causal relationship 
between the study drug and the adverse event, such as: 
  
 
A single occurrence of an event that is uncommon and known to be 
strongly associated with drug exposure (e.g., angioedema, hepatic injury, 
or Stevens-Johnson Syndrome); 
 
 
One or more occurrences of an event that is not commonly associated 
with drug exposure, but is otherwise uncommon in the population 
exposed to the drug (e.g., tendon rupture); 
 
 
An aggregate analysis of specific events observed in a clinical trial (such 
as known consequences of the underlying disease or condition under 
investigation or other events that commonly occur in the study 
population independent of drug therapy) that indicates those events occur 
more frequently in the drug  treatment group than in a concurrent or 
historical control group. 
 
2. Any findings from other studies: The sponsor must report any findings from 
other epidemiological studies, pooled analysis of multiple studies, or clinical 
studies that suggest a significant risk in humans exposed to the drug that 
would result in a safety-related change in the protocol, informed consent, 
investigator brochure, or other aspects of the overall conduct of the study. 
Safety reports must be reported by DAIT/NIAID to the appropriate health authorities 
within 15 calendar days; fatal or immediately life-threatening, serious, unexpected, 
suspected adverse reactions must be reported within 7 calendar days.  
All principal investigators must report SAEs to their respective IRBs as mandated by 
them. 
8.5.3 Reporting SAEs to the DSMB 
The NIAID and ITN will provide the DSMB with data of all SAEs on an ongoing 
basis, including quarterly reports of all SAEs and as indicated in the stopping rules. 
8.5.4 Reporting Pregnancy  
The principal investigator should be informed immediately of any pregnancy and all 
available pregnancy information should be entered into the electronic data capture 
(EDC) system within 24 hours of becoming aware of the event. The investigator 
should counsel the participant and discuss the risks of continuing with the pregnancy 
and the possible effects on the fetus. Monitoring of the participant should continue 
until the conclusion of the pregnancy. Follow-up information detailing the outcome 
of the pregnancy should be entered into the EDC system as it becomes available. Any 
premature termination of the pregnancy will be reported.  

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Any pregnancy complication or elective termination of a pregnancy for medical 
reasons will be recorded as an AE or SAE as described in Section 8.3.1 and Section 
8.3.2.  
9 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN 
9.1 
ANALYSIS SAMPLES  
Intent to treat (ITT) sample:  All subjects who are randomly assigned to treatment 
or placebo. 
Per protocol (PP) samples:  All ITT sample participants who remain in the study for 
at least 2 years and in whom the primary endpoint is assessed. Participants in the PP 
sample must be compliant with study medication and study assessments, defined as 
1) The primary TNSS AUC endpoint at 104 weeks is collected, and 2) Taking 75% 
of their study medication for the duration of the study. Compliance with study 
medication will be as assessed by meeting one or both of these conditions: 
-48 weeks of both SIT and AMG157 treatment  are taken regardless of dosage. 
-At least 12 of 16 (≥75%) prescribed SIT doses of 3000+ and 10 of 13 (75%) 
AMG 157 infusions are taken. 
Safety sample (SS):  All randomized participants who receive at least one dose of 
study medication. Participants in the safety sample will be analyzed with the group 
according to the medication they actually received, regardless of their randomized 
assignment. 
9.2 
ANALYSIS OF ENDPOINTS 
9.2.1 Overview 
Analysis of study data will be conducted to address all objectives of the trial and 
other interrelationships among all data elements of interest to the investigators and of 
relevance to the objectives of the study. 
9.2.2 Primary Endpoint 
The primary endpoint is the nasal allergen challenge TNSS AUC from 0 to 1 hour at 
104 weeks and will be analyzed as described below. 
The primary analysis will compare the mean TNSS AUC from 0 to 1 hour after cat 
allergen challenge at 104 weeks, using a longitudinal repeated measures model  in the 
ITT sample. The model will include fixed effects for treatment, time, and treatment 
by time interaction and will include covariates for site and baseline TNSS AUC. 
Since a nonlinear relationship between the TNSS AUC outcome and time is 
expected, time will be treated as a categorical variable. An unstructured covariance 
structure will be used to model the correlation among time points within a subject. If 
the model assuming an unstructured covariance matrix does not converge, a spatial 
power covariance structure will be used instead. The primary endpoint will be 
assessed at week 104 using a contrast in least squares means between the following 

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groups: cat immunotherapy plus AMG 157 (group A in Figure 1) and cat 
immunotherapy plus placebo (group B in Figure 1).  
The 0 to 1 hour TNSS AUC will be calculated using the trapezoidal rule. 
A supplementary analysis of the primary endpoint will also be performed using the 
PP sample. 
9.2.3 Secondary Endpoints 
This study is not designed or powered to perform hypothesis testing on secondary 
endpoints. All secondary analyses will be treated as supportive. P-values will be 
presented for the secondary endpoints but will not be adjusted for multiplicity and 
should be interpreted with caution. The secondary endpoints will be analyzed using 
the ITT sample and will include all pairwise comparisons among the four study 
groups. 
Secondary endpoints include measures of allergic response assessed at the timepoints 
listed in Section 3.3.2 including: 
 
Skin prick test endpoint titration 
 
Skin early phase response (EPR) to intradermal testing 
 
Skin late phase response (LPR) to intradermal testing 
 
Peak TNSS EPR 
 
TNSS EPR 
 
TNSS LPR 
 
PNIF LPR AUC  
 
PNIF EPR AUC  
9.2.4 Exploratory Endpoints 
Exploratory endpoints related to mechanisms of immune modulation and tolerance 
assessed prior to, during and after therapy, including those related to: 
 
Local immune response in nasal fluid for inflammatory cytokines. Nasal 
brushing for cells for RNA extraction. 
 
Cells in peripheral blood basophil activation at various timepoints during and 
after immunotherapy, cat antigen tetramers for changes during and after 
immunotherapy, cytokine profiles after in vitro cat antigen stimulation. 
 
Serum components of cat-specific IgE, IgG and subclasses, IgA inhibition of 
facilitated antigen presentation. 
9.2.5 Interim Analysis 
An interim analysis for futility based on conditional power for the comparison 
between immunotherapy and placebo groups as described below will be performed 

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when the first 10 participants in each treatment group (30% of the total planned 
sample size) have all reached their week 52 TNSS assessment  
The interim analysis will be performed by a statistician not associated with the study 
team. The data will only be reviewed by the DSMB and will not be made available to 
the study team. 
The rationale for the interim analysis is that if there is good evidence for absence of a 
difference between immunotherapy groups and placebo group, the study hypotheses 
as outlined in Section 9.3 is unlikely to be provable. 
Conditional power will be calculated assuming that there will be an observed 
difference in TNSS AUC 0-1 hr at week 52 of 32% comparing: 
 
cat immunotherapy plus AMG 157 (Figure 1, group A) to placebo-placebo 
(Figure 1, group D) 
 
cat immunotherapy plus placebo (Figure 1, group B) to placebo-placebo (Figure 
1, group D) 
 
the combination of cat immunotherapy plus AMG 157 and cat immunotherapy 
plus placebo (Figure 1, groups A and B) to placebo-placebo (Figure 1, group D) 
First, conditional power will be calculated using the originally planned sample size, 
the assumed treatment effect, and the currently observed distribution for the endpoint. 
Second, conditional power will be calculated using the originally planned sample 
size, the currently observed treatment effect, and the currently observed distribution 
for the endpoint. 
If the conditional power is ≥33% for any of the comparisons, that will be taken as 
evidence against futility and as an indication that the trial should proceed.  
If the conditional power is <33% for all the comparisons, that will be taken as 
evidence of futility and consideration will be given to terminating the study based 
upon the recommendation of the DSMB and at the discretion of the ITN and NIH.  
Since the main outcome of the study, tolerance, cannot be measured at week 52, and 
the main comparison for the primary endpoint, which is between groups A and B, is 
not used in the interim analysis, no alpha adjustment will be made for the final 
analysis. 
9.2.6 Safety Analysis 
Safety analyses will include AEs, SAEs, laboratory abnormalities, and physical 
examination abnormalities. All participants in the safety sample will be included in 
all safety analyses. 
Frequency of AEs will be tabulated by system organ class and preferred term, as well 
as by seriousness, severity, and treatment relatedness. Frequency of SAEs will be 
tabulated by system organ class and preferred term. For pertinent laboratory 

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measurements, mean and mean change from baseline values will be presented by 
treatment group and visit. Frequency of physical examination abnormalities will be 
tabulated by treatment group, visit, and organ class. Safety data will also be listed by 
treatment group and subject. 
9.2.7 Medical History 
Medical history within the past 12 months—including the existence of current signs 
and symptoms—will be collected for each body system. 
9.2.8 Use of Medications 
All medications taken by or administered to study participants beginning 30 days 
before enrollment and continuing throughout the study will be collected. All 
medications used will be coded according to the WHO drug dictionary. The number 
and percentage of participants receiving prior and concomitant medications/therapies 
will be presented overall and by medication class. 
9.3 
SAMPLE SIZE  
The sample size is based on detecting a difference in TNSS AUC 0-1hr between the 
immunotherapy plus AMG 157 combination group and the immunotherapy plus 
placebo group at 104 weeks. 
We assume that both active cat immunotherapy groups will demonstrate a reduction 
from baseline in mean TNSS AUC 0-1 hr by the conclusion of therapy at 52 weeks. 
In contrast, the placebo arm (group D) will not show any improvement in TNSS over 
time. At week 52, we assume that the difference in mean TNSS AUC 0-1 hr between 
the active cat immunotherapy groups and placebo (group D) will be approximately 
40%. These assumptions have been observed in previous cat immunotherapy trials. 
We further assume that TNSS AUC will return close to pre-therapy levels in the 
group that receives immunotherapy alone. This is based on the assumption that the 
immunomodulatory effect of approximately 52 weeks of cat allergen immunotherapy 
alone is too short to induce tolerance, with tolerance defined as the persistent 
reduction of TNSS even after immunotherapy is discontinued. 
In contrast, and consistent with the overall study hypothesis, we assume that the 
group receiving combination treatment will lead to tolerance and remain relatively 
stable in terms of TNSS from week 52 through week 104. This would demonstrate 
that AMG 157 contributes to the induction of tolerance. 
These assumptions imply a 40% difference in mean TNSS AUC 0-1 hr for the 
primary comparison, which is between cat immunotherapy plus AMG 157 (group A) 
and cat immunotherapy plus placebo (group B).  
Pilot studies were conducted to estimate the mean and standard deviation for the 
TNSS in response to cat nasal allergen challenge in untreated cat-allergic subjects 
(Stephen Durham Imperial College London, personal communication). Table 5  
below illustrates the means and standard deviations for several durations of AUC. 

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The highest ratio for the mean to standard deviation is for the 0-1 hr period. For this 
period, the mean is estimated at 4.56 with standard deviation of 1.5, and an effect size 
for a 40% difference between groups of 1.82. This higher effect size in large measure 
drove the decision to use this AUC period for the primary endpoint. 
Table 5: Sample size estimates based on pilot studies of TNSS  
Total Nasal Symptom Score 
Number of Subjects per Group 
 
No dropout 
15% dropout 
Parameter 
Mean 
SD 
Diff 
between 
groups
Approximate 
Effect Size 
(mean/SD)
80% 
power 
90% 
power 
80% 
power 
90% 
power 
AUC 0-
8h 
14.93 
7.1 
40% 
35% 
30% 
25%
1.26 
1.37 
1.47 
1.58
24 
30 
41 
58
31 
40 
54 
78
29 
36 
49 
69
37 
48 
64 
92
AUC 0-
6h 
13.27 
6.2 
40% 
35% 
30% 
25%
1.28 
1.39 
1.50 
1.61
23 
29 
39 
56
30 
39 
52 
74
28 
35 
46 
66
36 
46 
62 
88
AUC 0-
1h 
4.56 
1.5 
40% 
35% 
30% 
25%
1.82 
1.98 
2.13 
2.28
13 
16 
21 
30
16 
21 
28 
39
16 
19 
25 
36
19 
25 
33 
46
 
Allowing for approximately 15% dropouts, for 90% power to determine this 
treatment effect at a two-sided 0.05 level of significance, a sample size of 
approximately 19 per group would be required. However, in order to account for 
differences compared to previous trials in immunotherapy dosing and uncertainties 
regarding the size and duration of the treatment effect, a sample size of 
approximately 30 per group will be enrolled in the treatment phase. This will allow 
the study to detect a treatment effect as small as 32%. 
Repeated measures analysis commonly provides more statistical power than cross-
sectional studies, since the greater total number of observations over all participants 
and time points increases the degrees of freedom available for hypothesis tests. 
Hence, with the current sample size, the power to detect the expected treatment effect 
is anticipated to be greater than 90%. 
9.4 
MISSING DATA 
The dropout rate in this study is anticipated to be less than or equal to 15% and to be 
equally distributed among the randomized groups. The primary analysis does not 
require that missing data be imputed. However, any supportive cross-sectional 
analyses of the primary or secondary endpoints for the ITT population will require 
missing data to be imputed. 

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If missing data are not equally distributed between groups, biases can be created.  
Optimistic and pessimistic imputation methods and sensitivity analyses will be used 
to provide upper and lower bounds for potential bias. These will provide a measure of 
robustness of the treatment effect as it relates to the causes and consequences of 
missing data. More specific details of the imputation methods and sensitivity 
analyses will be specified in the SAP. Generally, a combination of multiple 
imputation methods for missing data will be used, including for example: regression, 
propensity scoring, and/or Markov chain Monte Carlo methods. 
9.5 
REPORTING DEVIATIONS FROM THE ORIGINAL STATISTICAL 
PLAN 
The principal features of both the study design and the plan for statistical data 
analysis are outlined in this protocol and in the statistical analysis plan (SAP). Any 
change in these features requires either a protocol or an SAP amendment, which is 
subject to review by the DSMB, the study sponsor(s), and the health authorities. 
These changes will be described in the final study report as appropriate. 
10 
ACCESS TO SOURCE DATA/DOCUMENTS 
The investigational sites participating in this study will maintain the highest degree of 
confidentiality permitted for the clinical and research information obtained from 
participants in this clinical trial. Medical and research records should be maintained 
at each site in the strictest confidence. However, as a part of the quality assurance and 
legal responsibilities of an investigation, the investigational sites must permit 
authorized representatives of the ITN, sponsor, and health authorities to examine (and 
to copy when required by applicable law) clinical records for the purposes of quality 
assurance reviews, audits, and evaluation of the study safety and progress. Unless 
required by the laws permitting copying of records, only the coded identity associated 
with documents or other participant data may be copied (and any personally 
identifying information must be obscured). Authorized representatives as noted 
above are bound to maintain the strict confidentiality of medical and research 
information that may be linked to identified individuals. The investigational sites will 
normally be notified in advance of auditing visits. 
11 
QUALITY CONTROL AND QUALITY ASSURANCE 
The principal investigator is required to keep accurate records to ensure that the 
conduct of the study is fully documented. The principal investigator is required to 
ensure that all eCRFs are completed for every participant entered in the trial. 
The sponsor is responsible for regular inspection of the conduct of the trial, for 
verifying adherence to the protocol, and for confirming the completeness, 
consistency, and accuracy of all documented data. 
The eCRFs will be completed online via a web-based electronic data capture (EDC) 
system that has been validated and is compliant with Part 11 Title 21 of the Code of 
Federal Regulations. Some data requirements will be addressed outside the EDC 

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using SAS® software. Data queries will be issued and resolved within the EDC 
system or SAS®. 
Study staff at the site will enter information into the electronic CRFs, and the data 
will be stored remotely at a central database. Data quality will be ensured through the 
EDC system’s continuous monitoring of data and real-time detection and correction 
of errors. All elements of data entry (i.e., time, date, verbatim text, and the name of 
the person performing the data entry) will be recorded in an electronic audit trail to 
allow all changes in the database to be monitored and maintained in accordance with 
federal regulations.  
Study staff will enter data from a study visit on the relevant eCRFs within 3 days 
following the visit or the time when data become available. 
12 
ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD CLINICAL 
PRACTICE 
12.1 STATEMENT OF COMPLIANCE 
This trial will be conducted in compliance with the protocol, current Good Clinical 
Practice (GCP) guidelines—adopting the principles of the Declaration of Helsinki—
and all applicable regulatory requirements. 
Prior to study initiation, the protocol and the informed consent documents will be 
reviewed and approved by the sponsor and an appropriate ethics review committee or 
institutional review board (IRB). Any amendments to the protocol or consent 
materials must also be approved by the Sponsor, the IRB and submitted to FDA 
before they are implemented. 
12.2 INFORMED CONSENT 
The informed consent form is a means of providing information about the trial to a 
prospective participant and allows for an informed decision about participation in the 
study. All participants (or their legally acceptable representative) must read, sign, and 
date a consent form before participating in the study, taking the study drug, and/or 
undergoing any study-specific procedures. If a participant does not speak and read 
English, the consent materials must be translated into the appropriate language. 
The informed consent form must be updated or revised whenever important new 
safety information is available, whenever the protocol is amended, and/or whenever 
any new information becomes available that may affect participation in the trial. 
A copy of the informed consent will be given to a prospective participant for review. 
The study investigator, in the presence of a witness, will review the consent and 
answer questions. The participant will be informed that participation is voluntary and 
that he/she may withdraw from the study at any time, for any reason. 

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 August 14, 2017 
Anti-TSLP and cat immunotherapy 
 
12.3 PRIVACY AND CONFIDENTIALITY 
A participant’s privacy and confidentiality will be respected throughout the study. 
Each participant will be assigned a sequential identification number. This number, 
rather than the participant’s name, will be used to collect, store, and report participant 
information. 
13 
PUBLICATION POLICY 
The ITN policy on publication of study results will apply to this study. Authorized 
participants may find details regarding the policy statement on the ITN internet 
website at http://www.immunetolerance.org.  

Immune Tolerance Network 
CONFIDENTIAL 
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Protocol ITN057AD 
Version 6.0 
 August 14, 2017 
Anti-TSLP and cat immunotherapy 
 
14 REFERENCES 
1. Salo PM, Calatroni A, Gergen PJ, et al. Allergy-related outcomes in relation to serum IgE: results from the 
National Health and Nutrition Examination Survey 2005-2006. The Journal of allergy and clinical 
immunology 2011;127:1226-35 e7. 
2. Custovic A, Taggart SC, Woodcock A. House dust mite and cat allergen in different indoor environments. 
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 
1994;24:1164-8. 
3. Ingram JM, Sporik R, Rose G, Honsinger R, Chapman MD, Platts-Mills TA. Quantitative assessment of 
exposure to dog (Can f 1) and cat (Fel d 1) allergens: relation to sensitization and asthma among children 
living in Los Alamos, New Mexico. The Journal of allergy and clinical immunology 1995;96:449-56. 
4. Chapman MD, Wood RA. The role and remediation of animal allergens in allergic diseases. The Journal of 
allergy and clinical immunology 2001;107:S414-21. 
5. Corren J, Diaz-Sanchez D, Saxon A, et al. Effects of omalizumab, a humanized monoclonal anti-IgE 
antibody, on nasal reactivity to allergen and local IgE synthesis. Annals of allergy, asthma & immunology : 
official publication of the American College of Allergy, Asthma, & Immunology 2004;93:243-8. 
6. Corren J, Wood RA, Patel D, et al. Effects of omalizumab on changes in pulmonary function induced by 
controlled cat room challenge. The Journal of allergy and clinical immunology 2011;127:398-405. 
7. Alvarez-Cuesta E, Cuesta-Herranz J, Puyana-Ruiz J, Cuesta-Herranz C, Blanco-Quiros A. Monoclonal 
antibody-standardized cat extract immunotherapy: risk-benefit effects from a double-blind placebo study. 
The Journal of allergy and clinical immunology 1994;93:556-66. 
8. Varney VA, Edwards J, Tabbah K, Brewster H, Mavroleon G, Frew AJ. Clinical efficacy of specific 
immunotherapy to cat dander: a double-blind placebo-controlled trial. Clinical and experimental allergy : 
journal of the British Society for Allergy and Clinical Immunology 1997;27:860-7. 
9. Hedlin G, Graff-Lonnevig V, Heilborn H, et al. Immunotherapy with cat- and dog-dander extracts. V. 
Effects of 3 years of treatment. The Journal of allergy and clinical immunology 1991;87:955-64. 
10. Ewbank PA, Murray J, Sanders K, Curran-Everett D, Dreskin S, Nelson HS. A double-blind, placebo-
controlled immunotherapy dose-response study with standardized cat extract. The Journal of allergy and 
clinical immunology 2003;111:155-61. 
11. Nanda A, O'Connor M, Anand M, et al. Dose dependence and time course of the immunologic response to 
administration of standardized cat allergen extract. The Journal of allergy and clinical immunology 
2004;114:1339-44. 
12. James LK, Durham SR. Update on mechanisms of allergen injection immunotherapy. Clinical and 
experimental allergy : journal of the British Society for Allergy and Clinical Immunology 2008;38:1074-
88. 
13. Calderon MA, Casale TB, Togias A, Bousquet J, Durham SR, Demoly P. Allergen-specific immunotherapy 
for respiratory allergies: from meta-analysis to registration and beyond. The Journal of allergy and clinical 
immunology 2011;127:30-8. 
14. Arvidsson MB, Lowhagen O, Rak S. Allergen specific immunotherapy attenuates early and late phase 
reactions in lower airways of birch pollen asthmatic patients: a double blind placebo-controlled study. 
Allergy 2004;59:74-80. 
15. Nouri-Aria KT, Wachholz PA, Francis JN, et al. Grass pollen immunotherapy induces mucosal and 
peripheral IL-10 responses and blocking IgG activity. J Immunol 2004;172:3252-9. 
16. Roan F, Bell BD, Stoklasek TA, Kitajima M, Han H, Ziegler SF. The multiple facets of thymic stromal 
lymphopoietin (TSLP) during allergic inflammation and beyond. Journal of leukocyte biology 
2012;91:877-86. 
17. Zhang Y, Zhou B. Functions of thymic stromal lymphopoietin in immunity and disease. Immunologic 
research 2012;52:211-23. 
18. Kitajima M, Lee HC, Nakayama T, Ziegler SF. TSLP enhances the function of helper type 2 cells. 
European journal of immunology 2011;41:1862-71. 
19. Mou Z, Xia J, Tan Y, et al. Overexpression of thymic stromal lymphopoietin in allergic rhinitis. Acta oto-
laryngologica 2009;129:297-301. 

Immune Tolerance Network 
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Protocol ITN057AD 
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 August 14, 2017 
Anti-TSLP and cat immunotherapy 
 
20. Shikotra A, Choy DF, Ohri CM, et al. Increased expression of immunoreactive thymic stromal 
lymphopoietin in patients with severe asthma. The Journal of allergy and clinical immunology 
2012;129:104-11 e1-9. 
21. Zhou B, Comeau MR, De Smedt T, et al. Thymic stromal lymphopoietin as a key initiator of allergic 
airway inflammation in mice. Nature immunology 2005;6:1047-53. 
22. Miyata M, Hatsushika K, Ando T, et al. Mast cell regulation of epithelial TSLP expression plays an 
important role in the development of allergic rhinitis. European journal of immunology 2008;38:1487-92. 
23. Kimura S, Pawankar R, Mori S, et al. Increased expression and role of thymic stromal lymphopoietin in 
nasal polyposis. Allergy, asthma & immunology research 2011;3:186-93. 
24. Bunyavanich S, Melen E, Wilk JB, et al. Thymic stromal lymphopoietin (TSLP) is associated with allergic 
rhinitis in children with asthma. Clinical and molecular allergy : CMA 2011;9:1. 
25. He R, Oyoshi MK, Garibyan L, Kumar L, Ziegler SF, Geha RS. TSLP acts on infiltrating effector T cells to 
drive allergic skin inflammation. Proceedings of the National Academy of Sciences of the United States of 
America 2008;105:11875-80. 
26. Zhang F, Huang G, Hu B, Song Y, Shi Y. A soluble thymic stromal lymphopoietin (TSLP) antagonist, 
TSLPR-immunoglobulin, reduces the severity of allergic disease by regulating pulmonary dendritic cells. 
Clinical and experimental immunology 2011;164:256-64. 
27. Wang YH, Ito T, Homey B, et al. Maintenance and polarization of human TH2 central memory T cells by 
thymic stromal lymphopoietin-activated dendritic cells. Immunity 2006;24:827-38. 
28. Lei L, Zhang Y, Yao W, Kaplan MH, Zhou B. Thymic stromal lymphopoietin interferes with airway 
tolerance by suppressing the generation of antigen-specific regulatory T cells. J Immunol 2011;186:2254-
61. 
29. Iliev ID, Spadoni I, Mileti E, et al. Human intestinal epithelial cells promote the differentiation of 
tolerogenic dendritic cells. Gut 2009;58:1481-9. 
30. Togias A ea. Nasal Provocation Testing.  Middleton's Allergy: Principles and Practice. 7th ed. London: 
Elsevier; 2009:1281-94. 
31. Scadding GW, Calderon MA, Bellido V, et al. Optimisation of grass pollen nasal allergen challenge for 
assessment of clinical and immunological outcomes. Journal of immunological methods 2012;384:25-32. 
32. Nicholson GC, Kariyawasam HH, Tan AJ, et al. The effects of an anti-IL-13 mAb on cytokine levels and 
nasal symptoms following nasal allergen challenge. The Journal of allergy and clinical immunology 
2011;128:800-7 e9. 
33. Allergenic Extract (Standard Cat Hair) [Package Insert]. ALK-Abello, Inc Port Washington, NY October 
2008. 
34. Worm M, Lee HH, Kleine-Tebbe J, et al. Development and preliminary clinical evaluation of a peptide 
immunotherapy vaccine for cat allergy. The Journal of allergy and clinical immunology 2011;127:89-97,  
e1-14. 
35. Vosshenrich CA, Cumano A, Muller W, Di Santo JP, Vieira P. Thymic stromal-derived lymphopoietin 
distinguishes fetal from adult B cell development. Nature immunology 2003;4:773-9. 
36. Yoo J, Omori M, Gyarmati D, et al. Spontaneous atopic dermatitis in mice expressing an inducible thymic 
stromal lymphopoietin transgene specifically in the skin. The Journal of experimental medicine 
2005;202:541-9. 
37. Harada M, Hirota T, Jodo AI, et al. Functional analysis of the thymic stromal lymphopoietin variants in 
human bronchial epithelial cells. American journal of respiratory cell and molecular biology 2009;40:368-
74. 
38 Hamida Hammad et al. Inflammatory dendritic cells—not basophils—are necessary and sufficient for 
induction of Th2 immunity to inhaled house dust mite allergen. 2010 J Exp Med 207 (10):2097 
 

Immune Tolerance Network 
CONFIDENTIAL 
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Protocol ITN057AD 
Version 6.0 
 August 14, 2017 
Anti-TSLP and cat immunotherapy 
 
APPENDIX 1 SCHEDULE OF EVENTS:  SCREENING AND UPDOSING  
 
Screening Baseline
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 
-28 
-14 
0 
1 
8 
15 
22 
28 
29 
36 
43 
50 
56 
57 
64 
71 
78 
 
Week 
-4 
-2 
0 
0 
1 
2 
3 
4 
4 
5 
6 
7 
8 
8 
9 
10 
11 
 
Visit 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
UN 
General Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Allergy history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Comprehensive physical exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Limited physical exam 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital signs 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
Pulmonary function testing 
(spirometry)
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre and post peak flow testing 
X 
X 
 
X 
X
X
X 
 
X
X 
X
X
 
X
X
X 
X
 
Adverse events 
X 
X 
X 
X 
X
X
X 
X 
X
X 
X
X
X 
X
X
X 
X
X 
Concomitant medications 
X 
X 
X 
X 
X
X
X 
X 
X
X 
X
X
X 
X
X
X 
X
X 
Cat exposure level 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
Clinical Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening nasal allergen 
challenge
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nasal allergen challenge 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total nasal symptom score 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Peak nasal inspiratory flow 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Intradermal skin test 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Skin prick test cat allergen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Skin prick test serial titration  
 
X 
 
 
X
 
 
X 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Medication  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AMG 157 or matched placebo 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
SIT or matched placebo 
 
 
 
X 
X
X
X 
 
X
X 
X
X
 
X
X
X 
X
 
Local Clinical Laboratory 
Assessments
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
Hematology 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Comprehensive chemistry 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QuantiFERON® TB testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV antibody  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B surface antigen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis C antibody 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Creatinine clearance 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Immune Tolerance Network 
CONFIDENTIAL 
Page 70 
 
Protocol ITN057AD 
Version 6.0 
 August 14, 2017 
Anti-TSLP and cat immunotherapy 
 
 
Screening Baseline
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 
-28 
-14 
0 
1 
8 
15 
22 
28 
29 
36 
43 
50 
56 
57 
64 
71 
78 
 
Week 
-4 
-2 
0 
0 
1 
2 
3 
4 
4 
5 
6 
7 
8 
8 
9 
10 
11 
 
Visit 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
UN 
Pharmacokinetics and 
Antibody Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-AMG 157 antibody 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
AMG 157 pharmacokinetics 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Mechanistic Laboratory 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nasal fluid cytokines 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nasal brushing 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PBMC 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ImmunoCAP for multiple 
allergens
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IgG 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IgA 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total IgE 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cat-specific IgE 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum (FAB and other assays) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole-blood DNA-HLA 
genotypes
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD154 Assays 
 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole blood RNA expression 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                          
1 Only to be collected for participants at ASTHMA Inc. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 71 
 
Protocol ITN057AD 
Version 6.0 
 August 14, 2017 
Anti-TSLP and cat immunotherapy 
 
 
APPENDIX 2 SCHEDULE OF EVENTS:  MAINTENANCE 
 
Day 
84 
85 
92 
99 
112
113
127
140
141
168 
169 182 196 
224
252
280
308
336
 
Week 
12 
12 
13 
14 
16 
16 
18 
20 
20 
24 
24 
26 
28 
32 
36 
40 
44 
48 
 
Visit 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
UN 
General Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Allergy history 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Comprehensive physical 
exam
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Limited physical exam 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital signs 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Pulmonary function 
testing (spirometry)
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Pre and post peak flow 
testing
 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cat exposure level 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Clinical Assessments
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening  nasal allergen 
challenge
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nasal allergen challenge
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Total nasal symptom 
score
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Peak nasal inspiratory 
flow
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Intradermal skin test 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Skin prick test cat 
allergen
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
Skin prick test serial 
titration 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Study Medication  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AMG 157 or matched 
placebo
X 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
SIT or matched placebo
 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Local Clinical 
Laboratory Assessments
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test
X 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Hematology
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
Comprehensive chemistry
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
Creatinine clearance
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 

Immune Tolerance Network 
CONFIDENTIAL 
Page 72 
 
Protocol ITN057AD 
Version 6.0 
 August 14, 2017 
Anti-TSLP and cat immunotherapy 
 
Day 
84 
85 
92 
99 
112
113
127
140
141
168 
169 182 196 
224
252
280
308
336
 
Week 
12 
12 
13 
14 
16 
16 
18 
20 
20 
24 
24 
26 
28 
32 
36 
40 
44 
48 
 
Visit 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
UN 
Pharmacokinetics and 
Antibody Assessments
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-AMG 157 antibody
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
AMG 157 
pharmacokinetics
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Mechanistic Laboratory 
Assessments
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nasal fluid cytokines
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Nasal brushing
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PBMC
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
IgG
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
IgA
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Total IgE
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Cat-specific IgE
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Serum (FAB and other 
assays)
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Whole-blood DNA-HLA 
genotypes
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD154 Assays 
X2 
 
 
 
 
 
 
 
 
 
 
X2 
 
 
 
 
 
 
 
Whole blood RNA 
expression
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
                                                          
2 Only to be collected for participants at ASTHMA Inc. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 73 
 
Protocol ITN057AD 
Version 6.0 
 August 14, 2017 
Anti-TSLP and cat immunotherapy 
 
APPENDIX 3 SCHEDULE OF EVENTS:  OBSERVATION 
Day 
365 
 421 
477 
 547 
 617 
673 
729 
 
 
Week 
52 
60 
 68 
78 
88 
96 
104 
 
 
Visit 
33 
34 
35 
36 
37 
38 
39 
UN 
Early 
Termination 
General Assessments 
 
 
 
 
 
 
 
 
 
Informed consent 
 
 
 
 
 
 
 
 
 
Medical history 
 
 
 
 
 
 
 
 
 
Allergy history 
 
 
 
 
 
 
 
 
 
Comprehensive physical exam 
 
 
 
 
 
 
 
 
 
Limited physical exam 
X 
 
 
X 
 
 
X 
X 
X 
Vital signs 
X 
 
 
X 
 
 
X 
X 
 
Pulmonary function testing (spirometry) 
X 
 
 
X 
 
 
X 
 
 
Pre and post peak flow testing 
X 
 
 
X 
 
 
X 
 
 
Adverse events 
X 
X3 
X3 
X 
X3 
X3 
X 
X 
X 
Concomitant medications 
X 
X3 
X3 
X 
X3 
X3 
X 
X 
X 
Cat exposure level 
X 
X3 
X3 
X 
X3 
X3 
X 
 
X 
Clinical Assessments
 
 
 
 
 
 
 
 
 
Screening  nasal allergen challenge
 
 
 
 
 
 
 
 
 
Limited Nasal Allergen Challenge
 
 
 
X 
 
 
 
 
 
Nasal allergen challenge
X 
 
 
 
 
 
X 
 
 
Total nasal symptom score
X 
 
 
X 
 
 
X 
 
 
Peak nasal inspiratory flow
X 
 
 
X 
 
 
X 
 
 
Intradermal skin test 
X 
 
 
 
 
 
X 
 
 
Skin prick test cat allergen 
 
 
 
 
 
 
 
 
 
Skin prick test serial titration 
X 
 
 
X 
 
 
X 
 
 
Study Medication  
 
 
 
 
 
 
 
 
 
Randomization
 
 
 
 
 
 
 
 
 
AMG 157 or matched placebo
 
 
 
 
 
 
 
 
 
SIT or matched placebo
 
 
 
 
 
 
 
 
 
Local Clinical Laboratory Assessments
 
 
 
 
 
 
 
 
 
Serum pregnancy test
 
 
 
 
 
 
 
 
 
Urine pregnancy test
X 
 
 
X 
 
 
X 
 
Hematology
X 
 
 
 
 
 
 
 
Comprehensive chemistry
X 
 
 
 
 
 
 
 
Creatinine clearance
X 
 
 
 
 
 
 
 
 
 
                                                          
3 For Visits 34, 35, 37, and 38, participants will be followed up via telephone. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 74 
 
Protocol ITN057AD 
Version 6.0 
 August 14, 2017 
Anti-TSLP and cat immunotherapy 
 
 
Day 
365 
 421 
477 
 547 
 617 
673 
729 
 
 
Week 
52 
60 
 68 
78 
88 
96 
104 
 
 
Visit 
33 
34 
 35 
36 
 37 
 38 
 39 
UN 
Early 
Termination 
Pharmacokinetics and Antibody 
Assessments
 
 
 
 
 
 
 
 
 
Anti-AMG 157 antibody
X 
 
 
 
 
 
X 
 
X 
AMG 157 pharmacokinetics
X 
 
 
 
 
 
X 
 
X 
Mechanistic Laboratory Assessments
 
 
 
 
 
 
 
 
 
Nasal fluid cytokines
X 
 
 
 
 
 
X 
 
 
Nasal brushing
X 
 
 
 
 
 
X 
 
 
PBMC
X 
 
 
X 
 
 
X 
 
 
IgG
X 
 
 
X 
 
 
X 
 
 
IgA
X 
 
 
X 
 
 
X 
 
 
Total IgE
X 
 
 
X 
 
 
X 
 
 
Cat-specific IgE
X 
 
 
X 
 
 
X 
 
 
Serum (FAB and other assays) 
X 
 
 
X 
 
 
X 
 
 
Whole-blood DNA-HLA genotypes 
 
 
 
 
 
 
 
 
 
CD154 Assays 
X4 
 
 
X4 
 
 
X4 
 
 
Whole blood RNA expression 
X 
 
 
X 
 
 
X 
 
 
 
 
                                                          
4 Only to be collected for participants at ASTHMA Inc. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 75 
 
Protocol ITN057AD 
Version 6.0 
 August 14, 2017 
Anti-TSLP and cat immunotherapy 
 
APPENDIX 4: WORLD ALLERGY ORGANIZATION SUBCUTANEOUS 
IMMUNOTHERAPY SYSTEMIC REACTION GRADING SYSTEM 
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Symptom(s)/ sign(s) 
of one organ system 
presenti 
Symptom(s)/ sign(s) 
of more than 
one organ system 
present 
Lower respiratory 
Asthma (e.g., 40% 
PEF or FEV1 drop, 
NOT responding to 
an inhaled 
bronchodilator)
Lower or Upper 
respiratory 
Respiratory failure 
with or without loss 
of consciousness 
Death 
or
or
or
Cutaneous 
Generalized pruritus, 
urticaria, flushing or 
sensation of heat or 
warmthii 
Lower respiratory 
Asthma: cough, 
wheezing, shortness 
of breath (e.g., less 
than 40% PEF or 
FEV1 drop, 
responding 
to an inhaled 
bronchodilator)
Upper respiratory 
Laryngeal, uvula or 
tongue edema with 
or without stridor 
Cardiovascular 
Hypotension with or 
without loss of 
consciousness 
 
or
or
Upper respiratory 
Rhinitis (e.g., 
sneezing, rhinorrhea, 
nasal pruritus and/or 
nasal congestion)
Gastrointestinal 
Abdominal cramps, 
vomiting, or 
diarrhea 
 
 
 
or
Throat-clearing 
(itchy throat)
Other 
Uterine cramps
 
 
 
or
Cough perceived to 
come from the upper 
airway, not the lung, 
larynx, or trachea
 
 
 
 
or
Conjunctival 
Conjunctival 
erythema, pruritus or 
tearing
 
 
 
 
Other 
Nausea, metallic 
taste, or headache
 
 
 
 
 
Patients may also have a feeling of impending doom, especially in grades 2, 3, or 4. 
Note: children with anaphylaxis seldom convey a sense of impending doom and their behavior changes may be a 
sign of anaphylaxis, e.g., becoming very quiet or irritable and cranky. 
Scoring includes a suffix that denotes if and when epinephrine is or is not administered in relationship to 
symptom(s)/sign(s) of the SR: a, ≤ 5 minutes; b, >5 minutes to ≤10 minutes; c, >10 to ≤ 20 minutes; d, >20 
minutes; z, epinephrine not administered. 
 
The final grade of the reaction will not be determined until the event is over, regardless of the medication 
administered. 
 
The final report should include the first symptom(s)/sign(s) and the time of onset after the subcutaneous allergen 
immunotherapy injectioniii and a suffix reflecting if and when epinephrine was or was not administered, e.g., Grade 
2a; rhinitis:10 minutes. Commentsiv may be added. 

Immune Tolerance Network 
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Protocol ITN057AD 
Version 6.0 
 August 14, 2017 
Anti-TSLP and cat immunotherapy 
 
 
i. Each Grade is based on organ system involved and severity. Organ systems are defined as: cutaneous, 
conjunctival, upper respiratory, lower respiratory, gastrointestinal, cardiovascular and other. A reaction from a 
single organ system such as cutaneous, conjunctival, or upper respiratory, but not asthma, gastrointestinal, or 
cardiovascular is classified as a Grade 1. Symptom(s)/sign(s) from more than one organ system or asthma, 
gastrointestinal, or cardiovascular are classified as Grades 2 or 3. Respiratory failure or hypotension, with or 
without loss of consciousness, defines Grade 4 and death Grade 5.The Grade is determined by the physician’s 
clinical judgment. 
ii. This constellation of symptoms may rapidly progress to a more severe reaction. 
iii. Symptoms occurring within the first minutes after the injection may be a sign of severe anaphylaxis. Mild 
symptoms may progress rapidly to severe anaphylaxis and death. 
iv. If signs or symptoms are not included in the Table or the differentiation between an SR and vasovagal 
(vasodepressor) reaction, which may occur with any medical intervention, is difficult, please include comment, as 
appropriate. 
 
From: Cox L, Larenas-Linnemann D, Lockey RF, Passalacqua G. Speaking the same language: The World Allergy 
Organization Subcutaneous Immunotherapy Systemic Reaction Grading System. J Allergy Clin Immunol 
2010;125:569-74, 74 e1-74 e7