Evaluation of AMG 714 for Vitiligo: A Phase 2a Randomized Double Blind Placebo Controlled Trial (ITN086AI)
Phase: PHASE2
Conditions: Vitiligo
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

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Protocol ITN086AI: REVEAL 
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Evaluation of AMG 714 for Vitiligo 
Protocol ITN086AI 
Evaluation of AMG 714 for Vitiligo: A Phase 2a Randomized Double Blind Placebo 
Controlled Trial  
 
Version 4.0 ( November 3, 2023) 
 
IND # 146561 
IND Sponsor(s): DAIT, NIAID 
NIAID Funding Mechanism: UM1AI109565 
 
 
Study Drug Manufacturer/Provider: Amgen  
Protocol Chair 
Brett King, MD, PhD 
Associate Professor of Dermatology 
Yale Dermatology Department 
 
 
 
 
 
ITN Clinical Trial Physician 
 
Chief Medical Officer 
Senior Director, Clinical and Translational Medicine 
Clinical Trials Group 
Immune Tolerance Network 
 
 
  
 
NIAID Medical Monitor 
 
Medical Officer 
Division of Allergy, Immunology, and 
Transplantation / NIAID  
 
 
  
 
NIAID Medical Monitor 
 
Medical Officer | Autoimmunity and Mucosal 
Immunology Branch 
Division of Allergy, Immunology, and Transplantation 
NIAID, NIH, DHHS 
 
 
 
 
 
NIAID Project Manager 
 
Senior Project Manager 
Division of Allergy, Immunology, and 
Transplantation / NIAID  
 
 
 
 

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ITN Clinical Operations Manager 
 
Clinical Operations Manager 
Clinical Trials Group 
Immune Tolerance Network 
 
 
 
  
  
 
 
ITN Lead Biologist 
 
Immune Tolerance Network 
University of Michigan 
 
 
 
  
  
NIAID Senior Regulatory Officer 
 
Regulatory Affairs Officer 
Division of Allergy, Immunology, and 
Transplantation / NIAID 
 
 
 
 
 
 
 
Rho Scientist  
 
Associate Director, Biostatistics  
Federal Systems Division, Rho Inc. 
 
 
 
  
 
 
Rho Biostatistician 
 
Biostatistician II 
Federal Systems Division, Rho Inc. 
 
 
  
 
 
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 ITN086AI: REVEAL 
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INVESTIGATOR SIGNATURE PAGE 
 
 
Protocol: ITN086AI REVEAL 
Version/Date: V4.0 / November 3, 2023 
Protocol Chair: Brett King, MD, PhD 
Title: Evaluation of AMG 714 for Vitiligo: A Phase 2a Randomized Double Blind Placebo Controlled 
Trial  
Study Sponsor: The National Institute of Allergy and Infectious Diseases (NIAID) 
INSTRUCTIONS: The site Principal Investigator should print, sign, and date at the indicated location 
below. The original of this form should be kept for your records. After signature, please return a copy of 
the signed form by email to:  
 
 
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 United States 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(R2) Good Clinical Practice: 
Integrated Addendum to ICH E6(R1) dated March 2018. Further, I will conduct the study in keeping 
with local legal and regulatory requirements. 
As the site 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 the written permission of the IRB 
and NIAID. 
 
 
 
___________________________________  
Site Principal Investigator (Print) 
 
 
____________________________________        _________________  
Site Principal Investigator (Signature)                           Date 

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TABLE OF CONTENTS 
INVESTIGATOR SIGNATURE PAGE ........................................................................... 3 
TABLE OF CONTENTS .............................................................................................. 4 
PROTOCOL SYNOPSIS .............................................................................................. 9 
GLOSSARY OF ABBREVIATIONS ............................................................................. 13 
1. 
BACKGROUND AND RATIONALE ..................................................................... 17 
1.1 
BACKGROUND AND SCIENTIFIC RATIONALE .................................................. 17 
1.2 
RATIONALE FOR SELECTION OF INVESTIGATIONAL DRUG .............................. 18 
1.3 
PRECLINICAL EXPERIENCE............................................................................ 19 
1.4 
CLINICAL STUDIES........................................................................................ 19 
1.4.1 
Safety Data for AMG 714 .............................................................................................................. 19 
1.4.2 
Clinical Efficacy Data .................................................................................................................... 20 
2. 
STUDY HYPOTHESES / OBJECTIVES ................................................................ 21 
2.1 
HYPOTHESIS ................................................................................................. 21 
2.2 
PRIMARY OBJECTIVE .................................................................................... 21 
2.3 
SECONDARY OBJECTIVES.............................................................................. 21 
2.4 
EXPLORATORY OBJECTIVES .......................................................................... 21 
3. 
STUDY DESIGN ................................................................................................ 22 
3.1 
DESCRIPTION OF THE STUDY DESIGN ............................................................ 22 
3.2 
PRIMARY ENDPOINT ..................................................................................... 23 
3.3 
SECONDARY ENDPOINTS............................................................................... 23 
3.3.1 
Secondary Efficacy Endpoints ....................................................................................................... 23 
3.3.2 
Secondary Safety Endpoints .......................................................................................................... 23 
3.4 
DEFINITIONS ................................................................................................ 23 
3.4.1 
F-VASI35 ........................................................................................................................................ 23 
3.4.2 
Vitiligo Activity .............................................................................................................................. 24 
3.5 
STRATIFICATION, RANDOMIZATION, AND BLINDING/MASKING....................... 24 
3.5.1 
Blinding ........................................................................................................................................... 24 
3.5.2 
Procedure for Unblinding / Unmasking ........................................................................................ 24 
4. 
SELECTION OF PARTICIPANTS........................................................................ 25 
4.1 
RATIONALE FOR STUDY POPULATION............................................................ 25 
4.2 
INCLUSION CRITERIA .................................................................................... 25 
4.3 
EXCLUSION CRITERIA ................................................................................... 25 

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5. 
KNOWN AND POTENTIAL RISKS AND BENEFITS TO PARTICIPANTS ................ 27 
5.1 
RISKS OF INVESTIGATIONAL DRUG AS CITED IN INVESTIGATOR’S BROCHURE 27 
5.2 
RISKS OF INVESTIGATIONAL DRUG CITED IN MEDICAL LITERATURE .............. 27 
5.3 
RISKS OF OTHER PROTOCOL SPECIFIED MEDICATIONS ................................... 28 
5.4 
RISKS OF STUDY PROCEDURES ...................................................................... 28 
5.5 
RISK OF SARS-COV-2 ..................................................................................... 28 
5.6 
POTENTIAL BENEFITS ................................................................................... 28 
6. 
INVESTIGATIONAL DRUG ............................................................................... 28 
6.1 
INVESTIGATIONAL DRUG .............................................................................. 28 
6.1.1 
AMG 714......................................................................................................................................... 28 
6.1.2 
AMG 714 Placebo .......................................................................................................................... 29 
6.1.3 
Dosage, Preparation, Administration, and Treatment of Hypersensitivity or Anaphylaxis....... 29 
6.2 
DRUG ACCOUNTABILITY............................................................................... 30 
6.3 
ASSESSMENT OF PARTICIPANT COMPLIANCE WITH INVESTIGATIONAL DRUG . 31 
6.4 
TOXICITY PREVENTION AND MANAGEMENT .................................................. 31 
6.4.1 
Hypersensitivity or Anaphylaxis.................................................................................................... 31 
6.4.2 
Liver Chemistry Abnormalities ..................................................................................................... 31 
6.5 
PREMATURE DISCONTINUATION OF INVESTIGATIONAL DRUG ........................ 32 
7. 
OTHER MEDICATIONS .................................................................................... 32 
7.1 
CONCOMITANT MEDICATIONS ...................................................................... 32 
7.1.1 
Protocol Mandated .......................................................................................................................... 32 
7.1.2 
Permitted Concomitant Medications ............................................................................................. 33 
7.1.3 
Prophylactic Medications ............................................................................................................... 33 
7.2 
PROHIBITED MEDICATIONS AND THERAPIES .................................................. 33 
7.3 
NARROW BAND UVB PHOTOTHERAPY ........................................................... 33 
7.4 
CONTRACEPTION USE ................................................................................... 34 
7.5 
RESCUE MEDICATIONS.................................................................................. 34 
8. 
STUDY PROCEDURES / ASSESSMENTS ............................................................. 34 
8.1 
ENROLLMENT............................................................................................... 34 
8.2 
SCREENING/BASELINE VISIT.......................................................................... 34 
8.2.1 
Screening Visit ................................................................................................................................ 34 
8.2.2 
Baseline Visit .................................................................................................................................. 34 
8.3 
STUDY ASSESSMENTS AND PROCEDURES ...................................................... 35 
8.3.1 
General Assessments ...................................................................................................................... 35 
8.3.2 
Study Drug Administration ............................................................................................................ 35 

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8.3.3 
Narrow Band UVB Phototherapy .................................................................................................. 35 
8.3.4 
Clinical Laboratory Assessments................................................................................................... 35 
8.3.5 
Disease Specific Assessments........................................................................................................ 36 
8.3.6 
Mechanistic Assessments ............................................................................................................... 36 
8.4 
TELEPHONE VISITS ....................................................................................... 36 
8.5 
WITHDRAWAL VISIT ..................................................................................... 36 
8.6 
UNSCHEDULED VISITS .................................................................................. 36 
8.7 
VISIT WINDOWS............................................................................................ 37 
9. 
MECHANISTIC ASSAYS.................................................................................... 37 
9.1 
MECHANISTIC HYPOTHESES AND RATIONALE................................................ 37 
9.2 
PROPOSED MECHANISTIC ASSAYS ................................................................. 38 
9.2.1 
Skin Biopsies................................................................................................................................... 38 
9.2.2 
PBMC-Based Assays...................................................................................................................... 38 
9.2.3 
Serum Assays .................................................................................................................................. 39 
9.2.4 
Whole Blood Assays ...................................................................................................................... 39 
10. BIOSPECIMEN STORAGE ................................................................................. 39 
11. CRITERIA FOR PARTICIPANT STUDY COMPLETION AND PREMATURE STUDY 
TERMINATION ............................................................................................ 40 
11.1 
PARTICIPANT COMPLETION........................................................................... 40 
11.2 
PARTICIPANT STOPPING RULES AND WITHDRAWAL CRITERIA ........................ 40 
11.3 
PARTICIPANT REPLACEMENT ........................................................................ 40 
11.4 
FOLLOW-UP AFTER STUDY WITHDRAWAL ..................................................... 40 
11.5 
STUDY STOPPING RULES ............................................................................... 41 
12. SAFETY MONITORING AND REPORTING ......................................................... 41 
12.1 
OVERVIEW ................................................................................................... 41 
12.2 
DEFINITIONS ................................................................................................ 41 
12.2.1 Adverse Event ................................................................................................................................. 41 
12.2.2 Unexpected Adverse Event ............................................................................................................ 42 
12.2.3 Serious Adverse Event ................................................................................................................... 42 
12.2.4 Adverse Events of Special Interest (AESI) ................................................................................... 42 
12.3 
GRADING AND ATTRIBUTION OF ADVERSE EVENTS ....................................... 42 
12.3.1 Grading of Hypersensitivity and Anaphylaxis.............................................................................. 42 
12.3.2 Grading of Liver Chemistry Abnormalities .................................................................................. 43 
12.3.3 Grading Criteria .............................................................................................................................. 44 
12.3.4 Attribution Definitions ................................................................................................................... 45 

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12.4 
COLLECTION AND RECORDING OF ADVERSE EVENTS ..................................... 45 
12.4.1 Collection Period ............................................................................................................................ 45 
12.4.2 Collecting Adverse Events ............................................................................................................. 45 
12.4.3 Recording Adverse Events ............................................................................................................. 45 
12.5 
REPORTING OF SERIOUS ADVERSE EVENTS AND ADVERSE EVENTS ................ 46 
12.5.1 Reporting of Serious Adverse Events to Sponsor......................................................................... 46 
12.5.2 Reporting to Health Authority ....................................................................................................... 46 
12.5.3 Reporting of Adverse Events to IRB/IECs ................................................................................... 47 
12.6 
PREGNANCY REPORTING .............................................................................. 48 
12.7 
REPORTING OF OTHER SAFETY INFORMATION ............................................... 48 
12.8 
REVIEW OF SAFETY INFORMATION................................................................ 48 
12.8.1 Medical Monitor Review................................................................................................................ 48 
12.8.2 DSMB Review ................................................................................................................................ 49 
13. STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN .............................. 49 
13.1 
OVERVIEW ................................................................................................... 49 
13.2 
ENDPOINTS................................................................................................... 49 
13.3 
MEASURES TO MINIMIZE BIAS ....................................................................... 50 
13.4 
ANALYSIS PLAN ........................................................................................... 50 
13.4.1 Analysis Populations ...................................................................................................................... 50 
13.4.2 Primary Analysis of Primary Endpoint ......................................................................................... 50 
13.4.3 Supportive Analyses of the Primary Endpoint(s)/Outcome(s) .................................................... 50 
13.4.4 Analyses of Secondary Endpoints ................................................................................................. 51 
13.4.5 Descriptive Analyses ...................................................................................................................... 53 
13.5 
INTERIM ANALYSES ...................................................................................... 53 
13.6 
STATISTICAL HYPOTHESES ........................................................................... 53 
13.7 
SAMPLE SIZE CONSIDERATIONS .................................................................... 53 
14. IDENTIFICATION AND ACCESS TO SOURCE DATA ........................................... 53 
14.1 
SOURCE DATA .............................................................................................. 53 
14.2 
ACCESS TO SOURCE DATA............................................................................. 53 
15. QUALITY ASSURANCE AND QUALITY CONTROL ............................................. 53 
16. PROTOCOL DEVIATIONS................................................................................. 54 
16.1 
PROTOCOL DEVIATION DEFINITIONS ............................................................. 54 
16.2 
REPORTING AND MANAGING PROTOCOL DEVIATIONS.................................... 54 
17. ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD CLINICAL PRACTICE54 

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17.1 
STATEMENT OF COMPLIANCE ....................................................................... 54 
17.2 
INFORMED CONSENT PROCESS ...................................................................... 55 
17.3 
PRIVACY AND CONFIDENTIALITY.................................................................. 55 
18. PUBLICATION POLICY .................................................................................... 55 
19. REFERENCES .................................................................................................. 56 
APPENDIX 1. SCHEDULE OF EVENTS ...................................................................... 59 
APPENDIX 2. VASI................................................................................................... 62 
APPENDIX 3. VES .................................................................................................... 65 
APPENDIX 4. VITIQOL ............................................................................................ 67 
APPENDIX 5. VNS .................................................................................................... 68 
APPENDIX 6. STUDY TREATMENT ASSIGNMENT SURVEY ....................................... 69 
APPENDIX 7. STATIC INVESTIGATOR GLOBAL ASSESSMENT (SIGA) ....................... 70 
 
 
LIST OF TABLES 
TABLE 1. DOSE MODIFICATION FOR LIVER CHEMISTRY ABNORMALITIES..................................... 31 
TABLE 2. VISIT WINDOWS .................................................................................................... 37 
TABLE 3. GRADING OF HYPERSENSITIVITY AND ANAPHYLAXIS REACTIONS ................................. 43 
TABLE 4. ATTRIBUTION OF ADVERSE EVENTS ......................................................................... 45 
 
 
LIST OF FIGURES 
FIGURE 1. STUDY DESIGN..................................................................................................... 22 
FIGURE 2. INDIVIDUAL STUDY PARTICIPATION ......................................................................... 23 
 
 
 

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PROTOCOL SYNOPSIS 
Title 
Evaluation of AMG 714 for Vitiligo: A Phase 2a Randomized Double Blind Placebo 
Controlled Trial 
Short Title 
Evaluation of AMG 714 for Vitiligo 
Clinical Phase 
Phase 2a 
Number of 
Sites 
5-10 sites 
IND Sponsor / 
Number  
DAIT, NIAID / IND 146561  
Study 
Objectives 
The primary objective is to determine the efficacy of IL-15 inhibition with AMG 714 at 
inducing facial repigmentation in vitiligo. 
The secondary objectives are to:  
1. Evaluate the safety and tolerability of AMG 714 in vitiligo. 
2. Determine the efficacy of IL-15 inhibition with AMG 714 at inducing total body skin 
repigmentation in vitiligo. 
3. Assess the durability of the skin repigmentation achieved by AMG 714 in vitiligo.  
4. Evaluate the efficacy of AMG 714 followed by narrow band UVB (nbUVB) 
phototherapy. 
Study Design 
This clinical trial is a phase 2a, double blind, placebo-controlled, multi-center, proof of concept 
trial of AMG 714 for the treatment of vitiligo. Fifty-seven participants ages 18-75 years old 
with vitiligo will be randomized 2:1 to receive AMG 714 300 mg or placebo subcutaneously 
(SQ) every 2 weeks for 6 doses beginning at Week 0 with the last dose at Week 10. 
Participants will be stratified based on vitiligo activity, as defined in Section 3.6. The primary 
endpoint will be assessed at Week 24. Participants with < 25% improvement in the T-VASI 
score at Week 24 compared to Week 0 will receive nbUVB phototherapy. Participants will be 
followed for an additional 24 weeks after assessment of the primary endpoint to evaluate 
change in the F-VASI and T-VASI scores through Week 48 with or without the addition of 
nbUVB, and to continue to collect safety information.  
Primary 
Endpoint 
Proportion of participants achieving ≥ 35% improvement in F-VASI (F-VASI35) at Week 24 
compared to Week 0. 
Secondary 
Endpoints  
Efficacy: 
1. Proportion of participants with F-VASI35 at Weeks 12, 36, and 48. 
2. Proportion of participants with F-VASI25, F-VASI50, F-VASI75, and F-VASI90 at 
Weeks 12, 24, 36, and 48.  
3. Proportion of participants with T-VASI25, T-VASI35, T-VASI50, T-VASI75, and T-
VASI90 at Weeks 12, 24, 36 and 48. 

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4. Change in each of the following at Weeks 12, 24, 36, and 48 compared to Week 0: 
a. F-VASI 
b. T-VASI 
c. Vitiligo Extent Score (VES) 
d. Vitiligo Quality of Life instrument (VitiQoL) 
e. Vitiligo Noticeability Scale (VNS) 
f. 
Static Investigator Global Assessment (sIGA) 
5. Percent change in each of the following at Weeks 12, 24, 36, and 48 compared to 
Week 0: 
a. F-VASI 
b. T-VASI 
 
Safety endpoints: 
1. Grade 2 or higher adverse events (AEs). 
2. Grade 3 or higher infectious AEs. 
  
Accrual 
Objective 
57 
Study Duration 
The target enrollment duration is 14 months. Participants will be followed for 48 weeks.  
Treatment 
Description  
AMG 714 300 mg or placebo injected subcutaneously every 2 weeks for 6 doses. 
Inclusion 
Criteria 
1. 
Adults 18-75 years of age.  
2. 
Clinical diagnosis of active or stable vitiligo made by a dermatologist, as defined in 
Section 3.4.2.  
3. 
F-VASI ≥ 0.25 (Appendix 2). 
4. 
T-VASI ≥ 3 (Appendix 2). 
5. 
Willingness to:  
a) Undergo nbUVB phototherapy, as outlined in Section 7.3. 
b) 
Stop all other treatments for vitiligo from screening through the final follow up 
visit as outlined in Section 7.2. 
Exclusion 
Criteria 
1. 
Inability or unwillingness of a participant to give written informed consent or comply 
with the study protocol. 
2. 
Segmental vitiligo. 
3. 
Contraindication to nbUVB phototherapy. 
4. 
More than 33% leukotrichia on the face or on the total body. 
5. 
Use of biologic immunosuppressive or immunomodulatory agents,  or investigational 
therapy or procedure within 12 weeks or 5 half-lives prior to Visit 0 (whichever is 
longer), except agents authorized for prevention and treatment of SARS-CoV-2 
infection according to FDA Emergency Use Authorization (EUA).  

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6. 
Use of laser or light-based treatment (phototherapy) including tanning beds within 8 
weeks prior to Visit 0. 
7. 
Use of non-biologic systemic or topical immunosuppressive or immunomodulatory 
agents within 4 weeks prior to Visit 0.  
8. 
History of melanocyte-keratinocyte transplantation procedure (MKTP) or other surgical 
treatment for vitiligo.  
9. 
Current or past use of the depigmenting agents monobenzyl ether of hydroquinone, 
including Benoquin® (Monobenzone). 
10. 
Presence of skin conditions or lesions that would confound the vitiligo assessments. 
11. 
Spontaneous repigmentation within 6 months prior to Visit 0 (repigmentation without 
any treatment and significant in amount as determined by the investigator).  
12. 
Uncontrolled thyroid function at screening as determined by the investigator. If the 
participant has a history of thyroid disease and is on treatment, the participant must be 
on a stable thyroid regimen for at least three months prior to Visit 0.  
13. 
Greater than 3 adequately treated nonmetastatic basal cell carcinomas (BCC) or 
squamous cell carcinomas (SCC) within 12 months prior to Visit 0; or previous history 
of multiple BCC or SCC which may pose additional risks from participation in the 
study in the opinion of the investigator. 
14. 
Previous or current diagnosis of other cancer, except adequately treated cervical 
carcinoma in situ.  
15. 
Acute or chronic infection, including current use of suppressive therapy for chronic 
infection, hospitalization for treatment of infection within 90 days prior to Visit 0, or 
parenteral anti-microbial (including anti-bacterial, anti-viral, or anti-fungal agents) use 
within 90 days prior to Visit 0.  
16. 
Evidence of infection, including: 
a) Human immunodeficiency virus (HIV) 
b) Current or prior infection with hepatitis B (HBV), as indicated by positive HBsAg 
or positive HBcAb 
c) Current or prior hepatitis C (HCV), unless treated with anti-viral therapy with 
achievement of a sustained virologic response (undetectable viral load 12 weeks 
after cessation of therapy) 
d) Positive Quantiferon-TB Gold or Quantiferon-TB Gold Plus test. PPD or T-
SPOT.TB test may be substituted for Quantiferon-TB Gold or Quantiferon-TB 
Gold Plus test 
17. 
Any of the following laboratory abnormalities: 
a) White blood count (WBC) < 3.5 x 103/μL 
b) Hemoglobin < 10 g/dL 
c) Platelets (Plt) < 125,000/mm 3  
d) Alanine aminotransferase (ALT) ≥ 2x ULN 

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e) Aspartate aminotransferase (AST) ≥ 2x ULN 
18. 
Women of child-bearing potential who are unwilling to use a medically acceptable form 
of contraception or be sexually inactive by abstinence until study Week 48 (Section 
7.4). Contraception or abstinence is required for 2 weeks prior to Visit 0. 
19. 
Women who are pregnant or lactating. 
20. 
Vaccination with a live attenuated vaccine within 30 days prior to Visit 0. 
21. 
Known drug allergy or reaction to any component of AMG 714 (Section 6.1.1) or 
proteins derived from mammalian cell lines. 
22. 
Past or current medical problems or findings from physical examination or laboratory 
testing, which, in the opinion of the investigator, may pose additional risks from 
participation in the study, may interfere with the participant’s ability to comply with 
study requirements or that may impact the quality or interpretation of the data obtained 
from the study. 
23. 
Current, diagnosed mental illness (e.g. severe depression) or current, diagnosed or self-
reported drug or alcohol abuse that, in the opinion of the investigator, would interfere 
with the participant’s ability to comply with study requirements. 
Study Stopping 
Rules 
• 
Any death that occurs in the study, which is possibly related or related to study 
medication (Table 4). 
• 
The occurrence of a Grade 3 or higher SAE related to study treatment that is also a 
SUSAR in one or more of the study participants who have received study treatment. 
• 
Any occurrence of a Grade 3 or higher anaphylaxis reaction (Table 3). 
• 
Two or more events of skin malignancy in individuals who receive nbUVB during the 
study. 
 
 
 

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GLOSSARY OF ABBREVIATIONS 
ACR 
American College of Rheumatology 
ADA 
anti-drug antibody 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ALP 
alkaline phosphatase 
BSA 
body surface area 
CBC 
complete blood count 
CDSMC 
CFR 
Clinical Data and Safety Management Center 
Code of Federal Regulations 
CRF 
case report form 
DAIT 
Division of Allergy, Immunology, and Transplantation 
DSMB 
Data and Safety Monitoring Board 
eCRF 
electronic case report form 
ELISA 
enzyme-linked immunosorbent assay 
EUA 
Emergency Use Authorization 
FDA 
US Food and Drug Administration  
F-VASI 
Facial Vitiligo Area Scoring Index  
GCP 
good clinical practice 
GLP 
good laboratory practice 

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GMP 
good manufacturing practice 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
IB 
investigator’s brochure 
ICH 
International Conference on Harmonization 
IEC 
independent ethics committee 
IEL(s) 
intraepithelial lymphocyte 
IFN-Ɣ 
interferon-gamma 
IL 
interleukin 
IND 
Investigational New Drug application 
IRB 
institutional review board 
ITN 
Immune Tolerance Network 
IV 
intravenous 
mITT 
modified intention to treat 
MKTP 
melanocyte-keratinocyte transplantation procedure 
nbUVB 
narrow band ultraviolet B 
NCI-
CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events  
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
NK 
natural killer  

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OHRP 
Office for Human Research Protections 
PBMC 
peripheral blood mononuclear cell 
PD 
pharmacodynamics 
PHI 
personal Health Identifiers 
PK 
pharmacokinetics 
Plt 
platelets 
PMEL 
premelanosome protein  
PoR 
Pharmacist of Record 
PP 
per protocol 
QA 
quality assurance 
QC 
quality control 
QOL 
quality of life 
RA 
rheumatoid arthritis 
TB 
tuberculosis 
SAE 
serious adverse event 
SAR 
suspected adverse reaction 
SCCC 
sIGA 
SOE 
Statistical and Clinical Coordinating Center 
Static Investigator Global Assessment 
schedule of events 
SOP 
standard operating procedures 
SPF 
sun protection factor 
SQ 
subcutaneous 

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SUSAR 
serious and unexpected suspected adverse reaction 
Tcm(s) 
central memory T cell(s) 
TCR 
T cell receptor 
TEAE 
treatment-emergent adverse events 
TGF-ß 
transforming growth factor beta 
Trm(s) 
resident memory T cell(s) 
T-VASI 
Total body Vitiligo Area Scoring Index  
ULN 
upper limit of normal 
UVB 
ultraviolet B 
VASI 
Vitiligo Area Scoring Index 
VES 
Vitiligo Extent Score 
VNS 
Vitiligo Noticeability Scale 
VitiQoL 
Vitiligo Quality of Life 
WBC 
white blood count 
 
 
 

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1. 
BACKGROUND AND RATIONALE 
1.1 
BACKGROUND AND SCIENTIFIC RATIONALE 
Vitiligo is an acquired autoimmune skin disorder characterized by T cell-mediated 
progressive destruction of melanocytes, which causes depigmented patches in the skin. 
Vitiligo is common and affects 0.5 to 2% of the world population, or approximately 3.5 
million in the U.S. alone.1 It equally affects both males and females without racial preference.  
The natural course of the disease is usually progressive, causing the generalized distribution 
of multiple and often symmetrical well-circumscribed areas of depigmented skin. Patients 
with vitiligo may develop extra-cutaneous manifestations, since melanocytes are also present 
in the uveal tract, retinal pigment epithelium, leptomeninges, heart, and membranous 
labyrinth of the inner ear. The destruction of melanocytes in these organs can lead to 
significant symptoms including cochlear dysfunction and sensorineural hearing loss. Vitiligo 
is also associated with other autoimmune diseases such as autoimmune thyroid disease, type 
1 diabetes mellitus, rheumatoid arthritis (RA), and pernicious anemia. Patients with vitiligo 
have significant psychological distress and suffer from anxiety and depression. Adverse 
effects of vitiligo on a person’s quality of life are similar to those with psoriasis and atopic 
dermatitis.2  
Currently, there are no FDA-approved medical treatments for vitiligo. Topical 
immunomodulatory agents and phototherapy are the most commonly used treatments. These 
treatments have varying efficacy, and produce results which are usually not sustained. In 
addition, these treatments are expensive, time consuming, and can have significant side 
effects.1 Janus kinase (JAK) inhibitor creams are under investigation for the treatment of 
vitiligo, however trials with these agents indicate efficacy primarily in sun-exposed areas.3-11 
There is unmet medical need in vitiligo for treatment that is effective, safe, and can produce 
predictable, sustained, and cosmetically acceptable results. 
Vitiligo represents a model of human organ-specific autoimmunity, and its pathogenesis 
includes the silent destruction of target cells, a role for cellular stress in initiating disease, 
importance of innate immunity, dependence on CD8+ T cells and IFNɣ, and a role for 
regulatory T cells (Tregs) in controlling disease.12 A murine model of vitiligo is available that 
closely resembles human disease. Affected mice develop patchy epidermal depigmentation 
with histological changes and gene expression profiles similar to human vitiligo. 13 The 
targeted antigen in the model, premelanosome protein (PMEL), is an important autoantigen in 
human vitiligo expressed physiologically in melanocytes.14,15 Maintenance of vitiligo in the 
murine model depends on the presence of both autoreactive tissue resident memory CD8+ T 
cells (Trms), as well as recirculating memory T cells. Autoreactive Trms are observed in 
vitiligo lesions in the skin of affected mice, and also in the interstitial skin fluid from human 
patients with vitiligo. These skin-infiltrating T cells are largely CD69+CD103+, and thus 
express phenotypic markers of Trm in skin.16-19  
Resident memory CD8+ T cells are generated in response to epidermal viral infections and 
remain in the tissue long-term to “raise an alarm” if infection returns.20-24 These cells 
cooperate with recirculating memory T cells and depend on CXCR3 chemokines to 

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efficiently clear reinfection.22,24 They depend on both TGF-β and IL-15 for their generation, 
and possibly for survival.22,24-28 Thus, targeting Trm survival could be an effective durable 
treatment strategy for vitiligo, as it would eliminate autoreactive memory within the tissue, 
requiring any return of disease to that location to begin de novo.  
The impact of anti-IL15 blockade was examined by using an antibody blocking IL-15Rβ in 
the murine model of vitiligo. Mice were exposed to this antibody for 8 weeks, which resulted 
in the depletion of autoreactive Trms in the skin and significant, durable treatment responses 
in the mice. A shorter 2-week treatment was also associated with long-lasting responses, but 
resulted primarily in altered Trm function (IFNɣ and granzyme B production) without 
significant depletion.16 While IL-15Rβ is a shared receptor subunit between IL-15 and IL-2, 
the effect is most likely due to the block in IL-15 signaling, since IL-15 more potently 
generates CD8+ Trm pools than residual IL-2 signaling in skin tissue,27 and IL-15 is required 
for the generation of CD8+ Trm in viral models in mice.23 Further, CD8+ T cells often express 
IL-15Rβ without CD25 (IL2Rα).29 Mice lacking IL-2 or CD25 develop autoimmunity, 
whereas mice lacking IL-15 are protected from autoimmunity.30 This preliminary study found 
that targeting IL-15 signaling through antibody treatment even after the generation of Trm in 
the tissue was effective at clearing these cells from the epidermis, and was associated with 
repigmentation of affected skin.16  
Overall, these findings suggest that blocking the IL-15 pathway may be a novel therapeutic 
strategy for vitiligo treatment that may induce immune tolerance by depleting autoreactive 
Trms in the skin. Therefore, the goal of this trial is to conduct a proof of concept study 
examining the ability of IL-15 blockade with AMG 714 to induce immune tolerance and treat 
vitiligo. After assessment of AMG 714 efficacy, standard-of-care nbUVB treatment will be 
provided for participants who do not sufficiently improve, since phototherapy might enhance 
melanocyte recovery and repigmentation in non-sun exposed areas of skin.    
1.2 
RATIONALE FOR SELECTION OF INVESTIGATIONAL DRUG 
IL-15 is a pro-inflammatory cytokine that promotes the development, homeostasis, and 
activation of memory CD8+ T cells and NK cells. It also stimulates the production of IL-1, 
IL-6, and TNFα. IL-15 is produced by monocytes, macrophages, epithelial and fibroblastic 
cells, as well as bone marrow stromal cells.31 Increased IL-15 expression has been observed 
in many immune-mediated conditions, including rheumatoid arthritis, psoriasis, inflammatory 
bowel disease, celiac disease, and solid organ transplant rejection.32 
AMG 714 is a fully human IgG1K monoclonal antibody that binds IL-15.32,33 It is under 
clinical development by Amgen, Inc., and has been evaluated in Phase I and Phase II studies 
as a potential treatment for rheumatoid arthritis, psoriasis, and celiac disease (Section 1.4). 
AMG 714 was chosen as the investigational drug for this study given its ability to neutralize 
the effects of IL-15 (Section 1.3), a key pro-inflammatory pathogenic mediator in vitiligo. 
AMG 714 also has an acceptable safety profile (Section 5).  

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1.3 
PRECLINICAL EXPERIENCE 
Preclinical studies show that AMG 714 recognizes an epitope of human IL-15 that is essential 
for its interaction with its receptor complex.33 AMG 714 neutralizes IL-15, and inhibits the 
IL-15 induced proliferation of peripheral blood T cells, as well as IL-15 induced TNFα 
production, in a dose-dependent fashion.  
Hu714MuXHu, a monoclonal anti-macaque-IL-15 antibody, neutralizes macaque IL-15 with 
a similar potency as AMG 714 neutralizing human IL-15, and was judged to be an 
appropriate surrogate of AMG 714 in studies of macaques.34 In a toxicity study of 
Hu714MuXHu in cynomolgus monkeys, there was no mortality and no effect on body 
weight, ophthalmoscopy, or electrocardiographic assessments. Administration of 
Hu714MuXHu was associated with histological signs of minimal to slight inflammation at 
injection sites without a clinical correlate.  
In addition, Hu714MuXHu administration was associated with marked reduction in 
individual absolute and relative NK cell counts with a progressive decrease in NK cell 
activity in all animals during the dosing phase. This was an expected pharmacodynamic 
response, given the known role of IL-15 in NK cell biology. The NK cell depletion was not 
accompanied by microscopic findings indicative of other systemic immunomodulatory 
effects. Of note, human NK cells are not dependent on IL-15 for their survival,33 possibly due 
to the redundant role of IL-2 on human NK cells. This difference in effect on NK cells may 
be related to a differential sensitivity of human versus cynomolgus monkey NK cells to IL-
15.  
The most common clinical signs included non-formed, discolored, mucoid, or liquid feces, 
which was not dose dependent. These cases were attributed to Campylobacter or Shigella 
infection, and responded well to antibiotic therapy. Of the six animals treated for diarrhea, 
five were infected with Shigella and successfully treated with enrofloxacin. 
In studies to assess off-target binding, AMG 714 was found to bind to several cell types in 
human tissues including epithelial, fibroblast, glial, muscle, peripheral nerve, endothelial, and 
mononuclear cells. This binding pattern is consistent with IL-15Rα expression patterns and 
the high affinity of IL-15 for its receptor. No studies evaluating the genotoxicity, 
carcinogenicity, or reproductive or development toxicity have been conducted. 
1.4 
CLINICAL STUDIES  
1.4.1 Safety Data for AMG 714 
According to the current version of the AMG 714 Investigator’s Brochure (IB),32 256 
individuals have received AMG 714, including 200 individuals who were dosed biweekly for 
12 weeks. These individuals participated in six completed clinical trials in healthy 
participants and participants with psoriasis, rheumatoid arthritis, celiac disease, and refractory 
celiac disease. In these six trials,32 treatment-emergent adverse events (TEAEs) were reported 
in 190 (74.2%) individuals receiving AMG 714 and in 70 (64.8%) individuals receiving 
placebo. Most TEAEs were non-serious and were mild to moderate in severity. Nineteen 
serious adverse events (SAEs) were reported, of which 15 occurred in individuals receiving 

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AMG 714. These SAEs included sepsis and deep vein thrombosis (80 mg AMG 714); hip 
fracture, nerve compression, C5-C6 nerve compression, and asthma (280 mg AMG 714); 
flare of rheumatoid arthritis (0.15 mg/kg single dose AMG 714 SQ); and peroneal nerve 
palsy, hepatitis, tuberculosis, pneumococcal infection, balance disorder and cerebellar 
syndrome (8 mg/kg AMG 714). None of these SAEs was assessed as related to AMG 714. 
Injection site reactions were the most commonly reported adverse event. No injection 
reactions were classified as an SAE. No deaths and no anaphylaxis events were reported in 
individuals treated with AMG 714.  
Anti-AMG 714 antibodies were detected in 8 of the 256 individuals treated with AMG 714 
and in 1 individual receiving placebo. Anti-drug antibodies (ADAs) were detected in 4 of the 
8 subjects before receiving any dose of AMG 714. Neutralizing antibodies were observed in 1 
subject who received a single dose of AMG 714. There were no effects on pharmacokinetics 
in any subject with detectable ADAs. The presence of ADAs does not appear to be associated 
with increased risk of adverse events or laboratory abnormalities. 
In summary, AMG 714 was well tolerated in the completed clinical trials and has 
demonstrated an acceptable safety profile. 
1.4.2 Clinical Efficacy Data  
Two studies of AMG 714 were conducted in patients with rheumatoid arthritis (RA). In a 
Phase 1 study (Hx-IL15-001), 24 participants with RA received a single dose (0.15, 0.5, 1.0, 
2.0, 4.0, or 8.0 mg/kg SQ injection) of AMG 714, while 6 participants received placebo. 
Twenty-four participants completed the second stage, an open-label extension study of 
repeated doses (0.5, 1.0, 2.0, or 4.0 mg/kg SQ injection; a total of 5 doses over 8 weeks).35 
Efficacy was assessed using the American College of Rheumatology (ACR) response criteria. 
In a pooled analysis of all dose cohorts, ACR20 response was achieved by week 8 in 15 of 24 
patients (63%), ACR50 in 9 patients (38%), and ACR70 in 6 patients (25%).32,35 
In a Phase 2 study, 180 participants with RA were randomized to receive placebo or AMG 
714 (40, 80, 160, 280 mg SQ injection dose every 2 weeks for 12 weeks with an initial 200% 
loading dose).32 Primary endpoint was the 14-week ACR20 response rate. At 14 weeks, the 
ACR20 response rate was higher in the AMG 714 280 mg group compared to placebo (54% 
vs. 38%), but the difference was not statistically significant (p=0.10). However, the difference 
in ACR20 responses was statistically significant between the AMG 714 280 mg and placebo 
groups at 12 weeks (64% vs. 34%, p=0.003) and at 16 weeks (66% vs. 38%, p=0.003). The 
DAS28, a measure of rheumatoid arthritis disease activity, was also reduced in the AMG 714 
280 mg group compared to placebo at weeks 8, 12, and 16 (p = 0.02, p = 0.005, and p = 0.01, 
respectively). Also, inflammatory biomarkers such as C-reactive protein and erythrocyte 
sedimentation rate also decreased. 
In a Phase 1b/2a dose escalation study in psoriasis,  the primary endpoint of improvement in 
PASI scores was not met.32   
Two studies of AMG 714 were completed for celiac disease. A Phase 2a double-blind, 
placebo-controlled, parallel group study was conducted in adult celiac disease participants on 

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a gluten-free diet. The study randomized 64 participants to placebo, AMG 714 150 mg, or 
AMG 714 300 mg SQ once every two weeks for six doses over 10 weeks. Primary efficacy 
endpoint was difference in the relative reduction in villous height to crypt depth ratio 
(VH:CD) between the AMG 714 and placebo groups after gluten challenge. The attenuation 
in reduction in VH:CD after gluten challenge was 11% compared to placebo but was not 
statistically significant. However, AMG 714 may ameliorate the effects of gluten challenge in 
this population compared to placebo, since the AMG 714 group had a statistically significant 
38% attenuation in the increase in intraepithelial lymphocytes (IELs) and improvement in 
clinical symptoms. No patient in the AMG 714 300 mg group had clinical disease activity 
despite high dose gluten challenge.32  
A Phase 2 study of Type II refractory celiac disease randomized 28 patients to receive 7 
doses of AMG 714 8 mg/kg IV or placebo over 10 weeks. The primary endpoint of reduction 
in aberrant IELs vs. total IELs between baseline and week 12 was not met. However after 12 
weeks of study treatment, the AMG 714 group saw improvement in diarrhea and T cell 
receptor clonality compared to the placebo group, which worsened.32 
Clinical studies of AMG 714 for the treatment of vitiligo have not been conducted.  
2. 
STUDY HYPOTHESES / OBJECTIVES 
2.1 
HYPOTHESIS 
The primary clinical hypothesis is that inhibition of the IL-15 pathway with AMG 714 will 
deplete autoreactive resident memory T cells in the skin and modulate pro-inflammatory 
mediators, resulting in durable repigmentation of skin affected by vitiligo. 
2.2 
PRIMARY OBJECTIVE 
The primary objective is to determine the efficacy of IL-15 inhibition with AMG 714 at 
inducing facial skin repigmentation in vitiligo. 
2.3 
SECONDARY OBJECTIVES 
The secondary objectives are to:  
1. Evaluate the safety and tolerability of AMG 714 in vitiligo. 
2. Determine the efficacy of IL-15 inhibition with AMG 714 at inducing total body skin 
repigmentation in vitiligo. 
3. Assess the durability of the skin repigmentation achieved by AMG 714 in vitiligo. 
4. Evaluate the efficacy of AMG 714 followed by narrow band UVB (nbUVB) 
phototherapy. 
2.4 
EXPLORATORY OBJECTIVES 
Exploratory mechanistic objectives are described in Section 9.    

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3.4.2 Vitiligo Activity 
1. Active vitiligo: New or expanding vitiligo lesions with or without the presence of 
confetti, trichrome, or inflammatory vitiligo lesion patterns, Koebner phenomenon, or 
other clinical signs of active vitiligo in the past 3 months. 
2. Stable vitiligo: No new depigmented lesions, and no confetti, trichrome, or 
inflammatory vitiligo lesion patterns, Koebner phenomenon, or other clinical signs of 
active vitiligo in the past 3 months. 
3.5 
STRATIFICATION, RANDOMIZATION, AND BLINDING/MASKING  
Participants who sign the informed consent form and meet the eligibility criteria will be 
randomly assigned 2:1 in favor of treatment with AMG 714 versus treatment with placebo. 
Random assignment will be stratified by active versus stable vitiligo, as defined in Section 
3.4.2.  
Randomization will be accomplished through a password-protected, web-based, 
randomization system. 
Randomization will occur at least one day prior to Visit 0. 
3.5.1 Blinding 
Blinding will be maintained for all study participants and trial personnel throughout the 
study, except for the study site Pharmacist of Record (PoR). As an extra blinding precaution, 
AMG 714 or placebo will be administered by qualified personnel not involved in the vitiligo 
assessment of the study participant. 
3.5.2 Procedure for Unblinding / Unmasking  
Before the study is complete, the blind for an individual participant should only be broken 
when appropriate medical management of the participant necessitates knowledge of treatment 
assignment. 
In the event of a medical emergency, when the immediate knowledge of the actual treatment 
is essential for the management of the participant, the site PI, or designee, can automatically 
obtain the participant’s treatment assignment from the randomization system. The site PI is 
encouraged to discuss the emergency unblinding with the NIAID Medical Monitor prior to 
unblinding the participant, if possible.  
If the randomization system is not available, the site PI can contact the Clinical Data and 
Safety Management Center (CDSMC) Client Support Services to obtain treatment 
assignment information. For more information and other unblinding pathways, please refer to 
the study Manual of Procedures (MOP). 
As soon as possible, the site investigator will provide a full account of unblinding to the 
NIAID Medical Monitor, Protocol Chair, and the Statistical and Clinical Coordinating Center 
(SCCC) of the unblinding event. The NIAID Medical Monitor will then notify the Data and 
Safety Monitoring Board (DSMB). A full account of the event will be recorded, including the 
date and time of the unblinding, the names of the individual(s) who made the decision, the 

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reason(s), the participant(s) affected, and individual(s) who were unblinded, and individual(s) 
who were notified.  
Unblinding the treatment of an individual participant or subgroups of participants for 
unplanned interim analyses to support DSMB reviews and final analysis will require written 
approval from NIAID.  
IND safety reports will be reported to the FDA, DSMB, and IRBs in an unblinded fashion. 
The final study report will contain any instances of unblinding prior to completion of the 
study along with the reason(s) for unblinding.  
4. 
SELECTION OF PARTICIPANTS  
4.1 
RATIONALE FOR STUDY POPULATION 
This study will recruit adults with vitiligo from age 18 to 75 years. Clinical diagnosis of 
vitiligo by a dermatologist is required to ensure vitiligo is correctly diagnosed. Vitiligo 
involvement of the face is required since facial repigmentation is the primary endpoint. 
Individuals with vitiligo that is segmental, or who have more than 33% leukotrichia on the 
face or total body will be excluded since these lesions are not expected to repigment. Some 
prior treatments for vitiligo within specific time periods will be excluded to avoid 
confounding of the results by prior therapy.  
4.2 
INCLUSION CRITERIA 
Individuals must meet all of the following criteria to be eligible for enrollment as study 
participants:  
1. 
Adults 18-75 years of age.  
2. 
Clinical diagnosis of active or stable vitiligo made by a dermatologist, as defined in 
Section 3.4.2.  
3. 
F-VASI ≥ 0.25 (Appendix 2). 
4. 
T-VASI ≥ 3 (Appendix 2). 
5. 
Willingness to:  
a) Undergo nbUVB phototherapy, as outlined in Section 7.3. 
b) Stop all other treatments for vitiligo from screening through the final follow up visit 
as outlined in Section 7.2. 
4.3 
EXCLUSION CRITERIA 
Individuals who meet any of the following criteria are not eligible for enrollment as study 
participants:  
1. 
Inability or unwillingness of a participant to give written informed consent or comply 
with the study protocol. 
2. 
Segmental vitiligo. 
3. 
Contraindication to nbUVB phototherapy. 

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4. 
More than 33% leukotrichia on the face or on the total body. 
5. 
Use of biologic immunosuppressive or immunomodulatory agents, or investigational 
therapy or procedure within 12 weeks or 5 half-lives prior to Visit 0 (whichever is 
longer), except agents authorized for prevention and treatment of SARS-CoV-2 
infection according to FDA Emergency Use Authorization (EUA).  
6. 
Use of laser or light-based treatment (phototherapy) including tanning beds within 8 
weeks prior to Visit 0. 
7. 
Use of non-biologic systemic or topical immunosuppressive or immunomodulatory 
agents within 4 weeks prior to Visit 0.  
8. 
History of melanocyte-keratinocyte transplantation procedure (MKTP) or other surgical 
treatment for vitiligo.  
9. 
Current or past use of the depigmenting agent monobenzyl ether of hydroquinone, 
including Benoquin® (Monobenzone). 
10. 
Presence of skin conditions or lesions that would confound the vitiligo assessments. 
11. 
Spontaneous repigmentation within 6 months prior to Visit 0 (repigmentation without 
any treatment and significant in amount as determined by the investigator).  
12. 
Uncontrolled thyroid function at screening as determined by the investigator. If the 
participant has a history of thyroid disease and is on treatment, the participant must be 
on a stable thyroid regimen for at least three months prior to Visit 0.  
13. 
Greater than 3 adequately treated nonmetastatic basal cell carcinomas (BCC) or 
squamous cell carcinomas (SCC) within 12 months prior to Visit 0; or previous history 
of multiple BCC or SCC which may pose additional risks from participation in the 
study in the opinion of the investigator. 
14. 
Previous or current diagnosis of other cancer, except adequately treated cervical 
carcinoma in situ. 
15. 
Acute or chronic infection, including current use of suppressive therapy for chronic 
infection, hospitalization for treatment of infection within 90 days prior to Visit 0, or 
parenteral anti-microbial (including anti-bacterial, anti-viral, or anti-fungal agents) use 
within 90 days prior to Visit 0.  
16. 
Evidence of infection, including: 
a) Human immunodeficiency virus (HIV) 
b) Current or prior infection with hepatitis B (HBV), as indicated by positive HBsAg 
or positive HBcAb 
c) Current or prior hepatitis C (HCV), unless treated with anti-viral therapy with 
achievement of a sustained virologic response (undetectable viral load 12 weeks 
after cessation of therapy) 
d) Positive Quantiferon-TB Gold or Quantiferon-TB Gold Plus test. PPD or T-
SPOT.TB test may be substituted for Quantiferon-TB Gold or Quantiferon-TB 
Gold Plus test 
17. 
Any of the following laboratory abnormalities: 
a) White blood count (WBC) < 3.5 x 103/μL 

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b) Hemoglobin < 10 g/dL 
c) Platelets (Plt) < 125,000/mm3  
d) Alanine aminotransferase (ALT) ≥ 2x ULN 
e) Aspartate aminotransferase (AST) ≥ 2x ULN 
18. 
Women of child-bearing potential who are unwilling to use a medically acceptable form 
of contraception or be sexually inactive by abstinence until study Week 48 (Section 
7.4). Contraception or abstinence is required for 2 weeks prior to Visit 0. 
19. 
Women who are pregnant or lactating. 
20. 
Vaccination with a live attenuated vaccine within 30 days prior to Visit 0. 
21. 
Known drug allergy or reaction to any component of AMG 714 (Section 6.1.1) or 
proteins derived from mammalian cell lines. 
22. 
Past or current medical problems or findings from physical examination or laboratory 
testing, which, in the opinion of the investigator, may pose additional risks from 
participation in the study, may interfere with the participant’s ability to comply with 
study requirements or that may impact the quality or interpretation of the data obtained 
from the study. 
23. 
Current, diagnosed mental illness (e.g. severe depression) or current, diagnosed or self-
reported drug or alcohol abuse that, in the opinion of the investigator, would interfere 
with the participant’s ability to comply with study requirements. 
5. 
KNOWN AND POTENTIAL RISKS AND BENEFITS TO PARTICIPANTS 
5.1 
RISKS OF INVESTIGATIONAL DRUG AS CITED IN INVESTIGATOR’S 
BROCHURE 
Precautions for hypersensitivity events are required. Hypersensitivity events such as injection 
site reaction (13.3%), injection site pain (2%), rash (4.7%), and eczema (3.1%) were reported 
in individuals receiving AMG 714.32 All hypersensitivity reactions were mild and transient. 
There are no reports of anaphylaxis to AMG 714. All individuals who receive AMG 714 or 
AMG 714 placebo will be monitored for 1 hour after injection to detect any possible injection 
site reaction, hypersensitivity, and/or anaphylactic reaction (Section 6.1.3.4). AMG 714 is 
contraindicated in individuals with a known sensitivity to proteins derived from mammalian 
cell lines or other components of this drug.  
The effect of AMG 714 on pregnancy, breast-feeding, pediatric participants, or geriatric 
participants is not known. No clinical studies have been conducted in individuals with renal 
or hepatic impairment. The effects of an overdose of AMG 714 are not known, and an 
antidote is not available. There is no evidence that AMG 714 use is habit forming.  
5.2 
RISKS OF INVESTIGATIONAL DRUG CITED IN MEDICAL LITERATURE 
The results of study Hx-IL15-001 with AMG 714 in rheumatoid arthritis have been 
published.35 Related adverse events reported in this study (n=30) include influenza-like 
symptoms, transient pyrexia, myalgia, injection site reactions, upper respiratory site infection 
(managed with antibiotics), herpes simplex virus, and aphthous stomatitis. None were 

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moderate or severe. In addition, fluorescence-activated cell sorting for T cell and NK cell 
subsets did not show significant changes from baseline up to 28 days after treatment.  
5.3 
RISKS OF OTHER PROTOCOL SPECIFIED MEDICATIONS  
There are no other protocol specified medications. 
5.4 
RISKS OF STUDY PROCEDURES 
The risks of the study procedures are as follows: 
1. Study drug administration: Injection site reactions such as pain, redness, or swelling at 
the injection site are common.  
2. Blood draw: Low risk of hemorrhage, hematoma, or infection at the venipuncture site.  
3. Skin biopsies: Low risk of hemorrhage, hematoma or infection at the biopsy site. 
Scarring at the biopsy site is expected, however the biopsy diameter will be small and 
every effort will be made to collect biopsies from non-exposed areas of the body.  
4. Narrow band UVB phototherapy: Low risk of erythema, xerosis, pruritus, folliculitis, 
sunlight-induced rash, or worsening of vitiligo. 
5. Questionnaires: Low risk of discomfort due to questions that may be sensitive in nature. 
5.5 
RISK OF SARS-COV-2 
Participants will be educated and advised about the importance of adherence to 
recommendations of the Center for Disease Control and Prevention (CDC) and other public 
health authorities for reducing the risk of SARS-CoV-2 infection, including vaccination. 
5.6 
POTENTIAL BENEFITS 
The overall goal of this study is to examine whether inhibition of the IL-15 pathway can 
induce immune tolerance in vitiligo by depleting autoreactive T-cells, leading to the 
repigmentation of vitiligo lesions. Participants themselves may not directly benefit from the 
trial since the active study medication may not be an effective treatment for vitiligo. In 
addition, some participants will receive placebo instead of active study medication. However, 
the insight gained from studying the clinical efficacy of IL-15 blockade in the treatment of 
vitiligo may improve the understanding of the pathogenesis of vitiligo and help identify novel 
therapeutic targets for future study. All participants whose T-VASI score does not improve 
by at least 25% by Week 24 will undergo 24 weeks of nbUVB phototherapy, a standard 
treatment for vitiligo. 
6. 
INVESTIGATIONAL DRUG  
6.1 
INVESTIGATIONAL DRUG  
6.1.1 AMG 714 
AMG 714 is the investigational drug used in the study and will be given at a dose of 300 mg 
SQ every 2 weeks for a total of 6 doses. AMG 714 is not FDA-approved and is in clinical 
development by Amgen.  

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Each sterile 10 cc vial of AMG 714 is filled with a 2 mL deliverable volume of 100 mg/mL 
AMG 714 formulated in 10 mM sodium acetate, 9.0% w/v sucrose, and 0.004% w/v 
polysorbate 20, pH 5.2. AMG 714 is stored as a frozen liquid at ≤ -30°C ± 10°C and 
protected from light. 
6.1.2 AMG 714 Placebo 
The AMG 714 placebo used in clinical trials contains the same liquid formulation as AMG 
714. Each sterile vial of AMG 714 placebo contains 1 ml volume of 10 mM sodium acetate, 
9% w/v sucrose, and 0.004% w/v polysorbate 20, pH 5.2 without the active ingredient. The 
placebo solution is not visually distinguishable from AMG 714.  
AMG 714 placebo is stored in the same fashion as AMG 714.  
6.1.3 Dosage, Preparation, Administration, and Treatment of Hypersensitivity or 
Anaphylaxis 
6.1.3.1 
Dosage 
The dose of AMG 714 to be used in this study is 300 mg every 2 weeks for a total of 6 doses. 
Each dose will be administered as 2 subcutaneous (SQ) injections (1.5 mL each). Placebo 
will also be administered as 2 SQ injections (1.5 mL each). 
6.1.3.2 
Preparation 
Doses of AMG 714 or placebo will be prepared by the unblinded study site PoR according to 
the investigational pharmacy manual. After preparation, AMG 714 or placebo may be stored 
for up to 72 hours at 2-8°C, and no longer than 12 hours at room temperature. Prolonged 
exposure to light during storage should be avoided. 
AMG 714 should be warmed to room temperature for a minimum of 1 hour before 
administration. Light exposure should continue to be avoided. The syringe should be 
inspected by the study staff member responsible for administering study drug for any visible 
foreign particles. If the study drug is not suitable for injection, it should be returned to the 
unblinded study PoR and replaced. 
6.1.3.3 
Administration 
Temperature, blood pressure, pulse and respirations will be obtained immediately before 
study drug administration and 60 minutes after study drug administration. Study participants 
will be monitored for 1 hour after study drug administration to detect any possible injection 
site reaction, hypersensitivity, and/or anaphylaxis (Section 6.1.3.4).  
AMG 714 or placebo will be administered subcutaneously by trained health care staff not 
otherwise involved in the vitiligo assessment of the participant (Section 3.5.1). Each dose will 
be comprised of two separate syringes, each containing 1.5 ml of AMG 714 or placebo. The 
SQ injections should be administered on the participant’s anterior abdominal wall in a 
consecutive fashion approximately 2 cm apart. The side of the abdominal wall should be 
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If more than one participant is scheduled to receive study drug on the same day at the same 
investigational site, at least 15 minutes must elapse between study drug administration to 
each participant. 
6.1.3.4 
Treatment of Hypersensitivity and/or Anaphylaxis 
Participants will be monitored as specified in Section 6.1.3.3 for 1 hour after administration 
of the study treatment for hypersensitivity and anaphylaxis reactions. Administration of AMG 
714 or placebo will be stopped immediately if any of the following 
hypersensitivity/anaphylaxis reactions occurs (Table 3 Section 12.3.1): 
• 
Any grade 2 or higher hypersensitivity/anaphylaxis reaction, or 
• 
A generalized pruritus or urticaria grade 1 hypersensitivity/anaphylaxis reaction. 
Appropriate treatment for the reaction per institution’s guidance will be instituted. 
Appropriate treatment may include corticosteroids, antihistamines, epinephrine, 
bronchodilators, or oxygen.   
All participants should be instructed to seek immediate medical attention if they experience 
any delayed onset hypersensitivity or anaphylaxis symptoms as listed in Table 3 (Section 
12.3.1). 
6.2 
DRUG ACCOUNTABILITY 
Under Title 21 of the Code of Federal Regulations (21CFR §312.62) the investigator is 
required to maintain adequate records of all investigational drug storage and disposition. For 
all DAIT-sponsored clinical trials, these responsibilities are delegated to the site’s PoR. The 
PoR must maintain all records related to storage and disposition of AMG 714 active and 
placebo vials including: 
1. Ensure drugs are stored in a secured area, with access limited to authorized pharmacy 
personnel and stored under appropriate temperature range as specified in the protocol 
and pharmacy manual. 
2. Date and quantity of the drug received. 
3. Date and quantity of the drug dispensed. 
a. A drug dispensing log will be kept current for each drug and participant. 
These logs will contain the drug information, identification of each 
participant, the date, and quantity of drug dispensed. Please see pharmacy 
manual for more detailed information. 
4. Detailed accountability of any unused (un-dispensed) AMG 714 active and placebo 
vials for return to DAIT/NIAID investigational drug distributor.  
a. All remaining unused and/or expired AMG 714 active and placebo vials will 
be returned to DAIT/NIAID investigational drug distributor during study and 
after study termination. 

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All records regarding drug disposition will be maintained by the study site’s investigational 
pharmacy and available for inspection.  
6.3 
ASSESSMENT OF PARTICIPANT COMPLIANCE WITH 
INVESTIGATIONAL DRUG  
Study treatment will be administered by trained health care staff. Compliance, therefore, will 
be monitored by the site and documented on the eCRF.  
6.4 
TOXICITY PREVENTION AND MANAGEMENT 
Study treatment must be suspended if the participant develops an infection or other AE that 
the investigator judges to be significant. Study treatment must be suspended if the participant 
develops a confirmed SARS-CoV-2 infection. 
If the infection or AE resolves, AMG 714 or placebo may be restarted at the next scheduled 
dose. 
Clinically significant laboratory abnormalities should be repeated within 48 hours of 
awareness. 
6.4.1 Hypersensitivity or Anaphylaxis  
Administration of AMG 714 or placebo will be permanently discontinued if the participant 
develops a hypersensitivity/anaphylactic reaction, as described in section 6.1.3.4.  
6.4.2 Liver Chemistry Abnormalities 
Participants will be monitored for drug induced liver injury. The recommended dose 
modifications for elevations in ALT and AST are summarized in Table 1. 
Table 1. Dose Modification for Liver Chemistry Abnormalities 
 
 
ALT/AST 
Action 
≤ 3xULN 
Maintain dose 
>3xULN to ≤5xULN with 
serum total bilirubin ≤ 2x 
ULN 
 
Suspend AMG 714 or placebo.  
 
Resume AMG 714 or AMG 714 placebo at the next 
expected dose if ALT and AST decrease to ≤3xULN.  
 
If AMG 714 or AMG 714 placebo is resumed, 
permanently discontinue AMG 714 or placebo if ALT or 
AST increases to >3xULN a second time. 
>3xULN with serum total 
bilirubin > 2xULN  
(Hy’s Law) 
Discontinue AMG 714 or placebo 
> 5xULN 
Discontinue AMG 714 or placebo 

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6.5 
PREMATURE DISCONTINUATION OF INVESTIGATIONAL DRUG 
AMG 714 or placebo will be permanently discontinued for any participant for any of the 
following reasons: 
1. A grade 3 or greater AE occurs that the investigator judges to be possibly or 
definitely related to study treatment. 
2. A grade 2 or greater cardiovascular AE occurs that the investigator judges to be 
possibly or definitely related to study treatment. 
3. A grade 2 or greater hematologic AE occurs that meets all of the following: 
a. ≥ 5% change from Visit 0, and  
b. Confirmed by repeat testing prior to the next scheduled dose of study 
medication, and  
c. Site investigator judges the AE to be possibly or definitely related to study 
treatment. 
4. The study participant becomes pregnant. 
5. The study participant develops a hypersensitivity or anaphylaxis reaction (Section 
6.4.1, Section 12.3.1). 
6. The study participant receives a prohibited biological agent, systemic 
immunosuppressive agent or live-attenuated vaccine (Section 7.2), except as 
described in Section 7.1.2. 
7. The study participant develops liver chemistry abnormalities according to Table 1 
(Section 6.4.2). 
8. The investigator believes that the study treatment is no longer in the best interest of 
the participant. 
Participants who discontinue study treatment will return for the Week 6 visit if it has not 
already occurred, and then will be followed per the Post-treatment follow-up schedule 
beginning at Week 12 as outlined in the Schedule of Events (Appendix 1). 
If study treatment is discontinued, the NIAID Medical Monitor should be notified. 
7. 
OTHER MEDICATIONS 
7.1 
CONCOMITANT MEDICATIONS 
7.1.1 Protocol Mandated 
There are no protocol mandated concomitant medications for this study.  

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7.1.2 Permitted Concomitant Medications 
All skin products and medication should remain stable during the study. The following 
medications and therapies are permitted during the study: 
1. Oral vitamins, minerals and dietary supplements. 
2. Camouflage make-up, except during nbUVB treatments. 
3. Sunscreen with SPF of at least 30 is recommended if participants will be exposed 
to sun for greater than 30 minutes. 
4. Corticosteroids: 
o Prednisone (or equivalent dose of other corticosteroid) for one course 
only at a maximum daily dose of ≤ 30 mg/day for up to 2 weeks. 
o One course of topical corticosteroids for up to 2 weeks. 
o One course of intra-articular corticosteroids. 
o Inhaled and nasal corticosteroids. 
7.1.3 Prophylactic Medications 
There are no prophylactic medications required for this study. 
7.2 
PROHIBITED MEDICATIONS AND THERAPIES 
The following medications and therapies are prohibited during the study: 
1. Investigational agents other than the study drug, except agents authorized for 
prevention and treatment of SARS-CoV-2 infection according to FDA EUA. 
2. Immunosuppressive or immunomodulatory biologic, systemic, and topical agents. 
Except as described in Section 7.1.2, these include, but are not limited to: 
a) Corticosteroids 
b) Calcineurin inhibitors 
3. Tanning beds.  
4. Medications that are contraindicated in the setting of phototherapy are prohibited 
while participants are receiving phototherapy. 
5. The depigmenting agent monobenzyl ether of hydroquinone, including Benoquin® 
(Monobenzone). 
6. Live-attenuated vaccines during treatment with study medication and for 12 weeks 
after treatment. 
7.3 
NARROW BAND UVB PHOTOTHERAPY 
Light or laser-based treatments (phototherapy) are prohibited for all study participants except 
as described below:  
Participants will undergo narrow band ultraviolet B (nbUVB) phototherapy if T-VASI does 
not improve by ≥ 25% at Week 24 compared to Week 0. Phototherapy will be administered in 

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accordance with the Vitiligo Working Group expert recommendations.39 Narrow band UVB 
phototherapy must be started within 28 days of the Week 24 study visit. 
7.4 
CONTRACEPTION USE 
All female participants of childbearing potential must not become pregnant during the course 
of the study and must either be sexually inactive by abstinence or use a medically acceptable 
form of contraception for the duration of the study. Women who are abstinent must have 
complete abstinence from intercourse from 2 weeks prior to the administration of the first 
dose of the study drug until Week 48. Periodic abstinence and withdrawal are not acceptable 
methods of contraception. 
Medically acceptable forms of birth control include oral contraceptive pills (combined 
hormone or progestin alone), injectable or implantable progestogens, intrauterine devices, 
estrogen vaginal rings, male partner sterilization, or double barrier methods (e.g., condom and 
occlusive cap with spermicidal agent). If using male partner sterilization (vasectomy with 
documentation of azoospermia), sterilization must occur prior to the female participant's entry 
into the study, and the male must be the sole partner for the participant. Documentation of 
male partner sterilization is required. 
Contraception use must start at least 2 weeks prior to the administration of the first dose of 
study drug and must continue until Week 48. If terminating study participation prior to Week 
48, participants will be instructed to continue contraception for at least 16 weeks after their 
last dose of study drug. 
7.5 
RESCUE MEDICATIONS 
Not applicable. 
8. 
STUDY PROCEDURES / ASSESSMENTS 
8.1 
ENROLLMENT 
The research study will be explained in lay terms to each potential research participant. The 
potential participant will sign an informed consent form before undergoing any study 
procedures. Participants who meet the eligibility criteria will be randomly assigned to a study 
treatment group, either AMG 714 or placebo, in a 2:1 fashion. Enrollment is defined as the 
time of randomization.  
8.2 
SCREENING/BASELINE VISIT 
8.2.1 Screening Visit 
The purpose of the screening period is to confirm eligibility to continue in the study. 
Screening of study participants will take place at Visit -1. Participants will be assessed for the 
eligibility criteria listed in Sections 4.2 and 4.3. 
8.2.2 Baseline Visit 
Baseline is defined as Week 0 (Visit 0).  

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8.3 
STUDY ASSESSMENTS AND PROCEDURES 
The study assessments to be performed at each study visit are listed in Appendix 1. 
8.3.1 General Assessments 
• 
Informed consent: Written informed consent will be obtained before any study 
assessments or procedures are performed 
• 
Eligibility criteria: Eligibility for study participation will be assessed during the screening 
period 
• 
Demographics: Age, sex, and ethnicity 
• 
Medical history: A history will be taken to determine if the participant has had any 
clinically significant diseases or medical procedures other than the disease under study  
• 
Vital signs: Height will be obtained at screening (V-1); weight, temperature, pulse, blood 
pressure, and respiration will be obtained at all visits  
• 
Comprehensive physical examination includes the following body systems: Skin, 
respiratory, cardiovascular, gastrointestinal, neurologic, and renal/urinary 
• 
Limited physical examination includes the skin and focuses on the body systems relevant 
to the participant’s clinical complaints and clinical status at the study visit 
• 
Vitiligo history, including date of diagnosis, type (active or stable), and previous 
treatments  
• 
Adverse events: Participants will be assessed for AEs. All adverse events will be graded, 
recorded on the case report forms (CRFs), and reported per Section 12 
• 
Concomitant medications: All concomitant medications and their indications for use will 
be recorded 
• 
Treatment Assignment Survey (Appendix 6) 
8.3.2 Study Drug Administration 
• 
Subcutaneous injection of study treatment (AMG 714 300 mg or placebo) 
8.3.3 Narrow Band UVB Phototherapy  
• 
NbUVB phototherapy for participants meeting the criterion described in Section 7.3 
8.3.4 Clinical Laboratory Assessments 
• 
Hematology: CBC with differential 
• 
Chemistry: Creatinine, total bilirubin, AST, ALT, alkaline phosphatase, and albumin 
• 
TSH, unless test has been performed within 30 days of Visit -1 and documented test 
results are available. 
• 
HIV (antibody), unless test has been performed within 30 days of Visit -1 and 
documented test results are available.  
• 
Hepatitis B (surface antigen and core antibody), unless test has been performed within 30 
days of Visit -1 and documented test results are available. 

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• 
Hepatitis C (antibody with RNA confirmation if indicated), unless test has been 
performed within 30 days of Visit -1 and documented test results are available. 
• 
Quantiferon-TB Gold or Quantiferon-TB Gold Plus (PPD skin test or T-SPOT.TB test 
may be substituted), unless test has been performed within 30 days of Visit -1 and 
documented test results are available.  
• 
Serum pregnancy (for women of child bearing potential)  
• 
STAT urine pregnancy (for women of child bearing potential)  
8.3.5 Disease Specific Assessments 
• 
Vitiligo assessments (T-VASI, F-VASI, VES) (Appendices 2 and 3) 
• 
Static Investigator Global Assessment (sIGA) (Appendix 7) 
• 
Patient reported outcome measures (VitiQoL, VNS) (Appendices 4 and 5)  
• 
Digital skin photography 
8.3.6 Mechanistic Assessments 
• 
Skin biopsies 
o Lesional punch. If the lesion has resolved, the punch biopsy will be taken from 
the previously lesional area. 
o Non-lesional punch 
• 
Peripheral blood mononuclear cells (PBMCs) 
• 
Serum 
• 
Whole blood DNA and whole blood RNA 
See Section 9 for detailed discussion of mechanistic assays. 
8.4 
TELEPHONE VISITS 
Visit 7 (Week 18) will be conducted as a telephone visit.  
After Week 12, remote follow-up contact will occur at least once between each visit to 
facilitate participant retention, and to discuss phototherapy in participants receiving this 
treatment after Week 24. 
8.5 
WITHDRAWAL VISIT 
Participants who withdraw from the study as described in Section 11.2 will be asked to 
complete the assessments outlined in the withdrawal (WD) visit in Appendix 1. 
8.6 
UNSCHEDULED VISITS 
If disease activity increases or other concerns arise between regularly scheduled visits, 
participants should contact study personnel and may be asked to return to the study site for an 
“unscheduled” visit to assess vitiligo disease activity or adverse events. Assessments obtained 
during an unscheduled visit are outlined in Appendix 1. Some assessments for an 
unscheduled visit may be omitted at the discretion of the investigator if not indicated.  

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8.7 
VISIT WINDOWS 
Study visits should take place within the time limits specified in Table 2. Visit 0 must occur 
within 28 days of Visit -1. All other scheduled study visits must occur within the time limits 
specified in Table 2. 
Table 2. Visit Windows 
Visit 
Timepoint 
Visit Window 
Screening: Visit -1 
Within 28 days of Day 0 
Baseline: Visit 0 
Day 0 
n/a 
Visits 1 to 6 
Every 2 weeks through week 12 
+/- 3 days 
Visits 7 to 10 
Weeks 18, 24, 36, and 48 
+/- 7 days 
9. 
MECHANISTIC ASSAYS 
Similar to other ITN studies, peripheral blood mononuclear cells and serum will be obtained 
at pre-specified time points (Appendix 1) for immunophenotyping and characterization of 
proinflammatory mediators to complement assessments of immune cells, melanocytes, and 
functional profiles from lesional and nonlesional skin biopsies. Whole blood will be collected 
to support future genomic, epigenomic, and transcriptomic studies. 
9.1 
MECHANISTIC HYPOTHESES AND RATIONALE 
Vitiligo is a chronic, progressive, autoimmune skin disease driven by the continued 
recruitment of autoreactive CXCR3+ T cells by the IFNγ-dependent chemokines, CXCL9, 
and CXCL10. Recent preclinical studies show that maintenance of vitiligo depends on the 
presence of both autoreactive resident memory CD8+ T cells (Trm), as well as recirculating 
memory T cell populations.16 CD8+ Trm cells are generated in response to epidermal viral 
infections and remain in the tissue long-term to “raise an alarm” if infection returns.20-24,40,41 
These cells cooperate with recirculating memory T cells and depend on CXCR3 chemokines 
to efficiently clear reinfection.22,24  
Trm cells depend on both TGF-β and IL-15 for their generation, and possibly for survival.25-28 
Thus, targeting Trm survival by blocking IL-15 signaling with AMG 714 could be an 
effective and durable treatment strategy for vitiligo, as it would eliminate autoreactive 
memory within the tissue, requiring any return of disease to that location to begin de novo. 
Indeed, targeting IL-15Rβ systemically with an antibody effectively depleted autoreactive 
Trms in the skin, and resulted in significant, durable treatment responses in a murine model 
of vitiligo.16 Another recent study found that IL-15Rβ antibody administration in rhesus 
macaques greatly reduced tissue effector memory T cell populations, while recirculating 
populations bounced back.42  
Thus, the primary mechanistic hypothesis is that short-term treatment with AMG 714 will 
reduce autoreactive CD8+ Trm cells within vitiligo lesions. Given the pleiotropic effects of 
IL-15, AMG 714 treatment may also alter frequencies and/or functional properties of effector 

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and regulatory T, NK, NKT, B, monocyte, and/or dendritic cell populations not eliminated by 
treatment in skin or blood.43,44 In addition, keratinocytes may also be directly or indirectly 
modulated by AMG 714.45-47 Mechanistic studies will address multiple questions, but will be 
prioritized based on the amount of tissue and blood available. 
In this study, serial skin and blood samples will be collected at the same time points. The 
objective is to analyze the frequencies, phenotypes, and functional profiles of immune cell 
populations in skin and blood, enumerate melanocytes in skin, and quantify soluble mediators 
in serum associated with vitiligo and blockade of IL-15R signaling. These studies will 
explore immune signatures that correlate with clinical response outcomes, and will help 
determine what, if any, immunological changes in skin are paralleled in blood by systemic 
IL-15 antibody treatment with AMG 714 compared to placebo.  
9.2 
PROPOSED MECHANISTIC ASSAYS 
9.2.1 Skin Biopsies 
This study will collect skin biopsies of lesional and nonlesional skin.  
Previous analyses indicate that vitiligo lesional skin contains increased numbers of 
CD103+CD69+CD8+ T cells that express GrzmB, CD49a, CXCR3 that produce IFN 
compared to nonlesional skin from patients with and without vitiligo.18,19 Elevated expression 
of pro-inflammatory chemokines CXCL9 is also increased in vitiligo lesions compared to 
nonlesional skin from patients with and without vitiligo.48 Therefore, punch skin biopsies will 
be used to determine the impact of AMG 714 on autoreactive Trm (e.g. CD103+CD69+ 
GrzmB+CD49a+CXCR3+), and recirculating memory T cells (e.g. CD103-CD69+CD44+). We 
will also determine if immune phenotypes and/or functional profiles in lesional skin correlate 
with clinical response outcomes. 
9.2.2    PBMC-Based Assays 
9.2.2.1 
Peripheral Blood Mononuclear Cell (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 (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. 
9.2.2.2 
Multi-parameter Immunoprofiling of PMBCs 
Flow cytometry or mass cytometry may be done at ITN laboratories to analyze the impact of 
AMG 714 treatment on the frequency and functional status of specific immune cell 
populations in viably cryopreserved PBMC. Proposed immunophenotyping panels will be 
finalized and validated by the ITN prior to starting batched analysis. Levels of circulating 
cells will be compared between the baseline and various time points following treatment. 
Additional comparisons will be made between treatment groups to evaluate the effect of 
treatment on specific cell phenotypes, and to identify phenotypes that correlate with clinical 
response outcomes.  

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Since vitiligo is an autoimmune skin disease characterized by IFN+, granzyme B+, and 
CXCR3+ T cell infiltration in lesional skin, it may be important to determine the effects of 
AMG 714 compared to placebo treatment on global and skin-homing effector (e.g. 
IFN+GZMB+CXCR3+) and regulatory (e.g. Foxp3+CD127lowCD45RO+) T cell subsets in the 
peripheral pool of CD8 and CD4 T cells. Tetramer staining may also be applied to HLA 
compatible participants to evaluate the impact of treatment on autoreactive T cells in blood 
capable of trafficking to lesional skin (CLA+ and CXCR3+) as previously reported.16,49  
9.2.3 Serum Assays 
Participant serum may be analyzed using validated immunoassay platforms to investigate the 
impact of AMG 714 treatment on circulating levels of cytokines and inflammatory mediators 
associated with vitiligo, such as CXCL9, CXCL10, and IL-15. Treatment-induced changes in 
mediators in serum may be evaluated for correlations with treatment-induced changes in Trm 
in lesional skin and recirculating memory T cell subsets in lesional skin and blood. In 
addition, AMG 714 serum levels may be assessed. 
9.2.4 Whole Blood Assays 
9.2.4.1 
Whole Blood DNA Genotyping  
It is reasonable to assume that AMG 714 treatment may not be equally effective in all 
individuals, and that genetic differences in IL-15 signaling pathway genes may influence 
response outcomes. DNA may be isolated from whole blood collected from all consenting 
participants, and the ITN may perform genotyping for HLA Class I/II alleles or single 
nucleotide polymorphisms (SNPs) in selected immune response genes to investigate 
correlations with disease progression and therapeutic response. HLA typing may be 
performed to identify HLA-compatible participants for tetramer-based evaluation of T cell 
autoreactivity in cryopreserved PBMC. 
9.2.4.2 
Gene Expression in Peripheral Blood  
Systemic treatment with biologic medications has been shown to modulate gene expression in 
autoimmune disease; therefore, whole blood can be used to evaluate changes in the peripheral 
circulation due to immunomodulation of the disease or the systemic nature of the treatment 
with AMG 714. Whole blood will be collected from enrolled participants and may be used to 
evaluate global changes in gene expression during and after treatment. Gene expression of 
molecules found to be modulated by treatment in skin biopsies and/or PBMC may be 
investigated in whole blood using quantitative methods. 
10. 
 BIOSPECIMEN STORAGE 
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 

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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 considered 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. The ITN sample sharing policy will apply for the provision of 
samples to study or outside investigators (www.immunetolerance.org). 
11. 
CRITERIA FOR PARTICIPANT STUDY COMPLETION AND PREMATURE 
STUDY TERMINATION 
11.1 
PARTICIPANT COMPLETION 
A participant is considered to have completed the study if s/he is enrolled and completes the 
last visit at Week 48 (Visit 10).  
11.2 
PARTICIPANT STOPPING RULES AND WITHDRAWAL CRITERIA 
Participants may be prematurely terminated from the study for the following reasons: 
1. The participant elects to withdraw consent from all future study activities, including 
follow-up. 
2. The participant is “lost to follow-up” (i.e., no further follow-up is possible because 
attempts to reestablish contact with the participant have failed). 
3. The participant dies.  
4. The Site Investigator believes that participation is no longer in the best interest of the 
participant. 
11.3 
PARTICIPANT REPLACEMENT 
Randomized participants will be replaced if they do not receive any part of any dose of study 
medication.  
11.4 
FOLLOW-UP AFTER STUDY WITHDRAWAL 
If a participant withdraws or is withdrawn from the study as described in Section 11.2, the 
participant will be asked to return for a final visit where the assessments outlined in the 
withdrawal (WD) visit in Appendix 1 will be performed. No additional follow-up will be 
requested from participants after early study withdrawal.  

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11.5 
STUDY STOPPING RULES 
If any of the events described in Section 12.8.2.2 occur, an ad hoc DSMB review will occur. 
After review of the data, the DSMB will make recommendations regarding the study conduct 
and/or continuation.  
12. 
SAFETY MONITORING AND REPORTING 
12.1 
OVERVIEW 
This section defines the types of safety data that will be collected under this protocol and 
outlines the procedures for appropriately collecting, grading, recording, and reporting those 
data. Adverse events that are classified as serious according to the definition of health 
authorities must be reported promptly (Section 12.5) to the Sponsor (DAIT/NIAID). 
Appropriate notifications will also be made to the IRBs and health authorities.  
Information in this section complies with ICH Guideline E2A: Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting, ICH Guideline E-6: 
Guideline for Good Clinical Practice, 21CFR Parts 312 and 320, and applies the standards set 
forth in the National Cancer Institute (NCI), Common Terminology Criteria for Adverse 
Events (CTCAE), Version 5.0: 
https://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/CTCAE v5 Quic
k Reference 5x7.pdf.  
12.2 
DEFINITIONS 
12.2.1 Adverse Event  
An adverse event (AE) is any untoward or unfavorable medical occurrence associated with 
the subject’s participation in the research, whether or not considered related to the subject’s 
participation in the research (modified from the definition of adverse events in the 1996 
International Conference on Harmonization E-6 Guidelines for Good Clinical Practice) (from 
OHRP "Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to 
Subjects or Others and Adverse Events [1/15/07]", 
http://www.hhs.gov/ohrp/policy/advevntguid.html#Q2).  
For this study, an adverse event will include any untoward or unfavorable medical occurrence 
associated with AMG 714 administration or any study mandated procedure (Section 5.4). 
12.2.1.1 
Suspected Adverse Reaction 
Any adverse event for which there is a reasonable possibility that the investigational study 
drug caused the adverse event. For the purposes of safety reporting, ‘reasonable possibility’ 
means there is evidence to suggest a causal relationship between the drug and the adverse 
event. A suspected adverse reaction (SAR) 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)). 

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12.2.2 Unexpected Adverse Event 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed 
in the current AMG 714 IB or is not listed at the specificity, severity or rate of occurrence 
that has been observed. 
“Unexpected” also refers to adverse events or suspected adverse reactions that are mentioned 
in the current IB as occurring with a class of drugs or as anticipated from the pharmacological 
properties of the drug, but are not specifically mentioned as occurring with the particular drug 
under investigation (21 CFR 312.32(a)). 
12.2.3 Serious Adverse Event 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator or Sponsor (DAIT/NIAID), it results in any of the following outcomes 
(21 CFR 312.32(a)): 
1. Death. 
2. A life-threatening event: An AE or SAR is considered “life-threatening” if, in the view of 
either the investigator or Sponsor (DAIT/NIAID), its occurrence places the participant 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.  
3. Inpatient hospitalization or prolongation of existing hospitalization. 
4. Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
5. Congenital anomaly or birth defect.  
6. Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the participant and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
Elective hospitalizations or hospital admissions for the purpose of conduct of protocol-
mandated procedures are not to be reported as an SAE unless hospitalization is prolonged due 
to complications. 
12.2.4 Adverse Events of Special Interest (AESI) 
Any occurrence of malignancy will be considered an Adverse Event of Special Interest 
(AESI) and must be reported to the IND Sponsor within 24 hours, according to the procedure 
for SAEs described in Section 12.5.1.  
12.3 
GRADING AND ATTRIBUTION OF ADVERSE EVENTS  
12.3.1 Grading of Hypersensitivity and Anaphylaxis 
For this study, hypersensitivity and anaphylaxis reactions will be graded according to Table 3 
below. The final grade of the reaction will not be determined until the event is over. Any 
reaction that results in the permanent discontinuation of the AMG 714 (Section 6.4.1) should 
be reported according to the procedure for SAEs described in Section 12.5.1. 

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Table 3. Grading of Hypersensitivity and Anaphylaxis Reactions  
(Modified from World Allergy Organization Subcutaneous Immunotherapy Systemic 
Reaction Grading System50). 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Symptom(s)/ sign(s) of one organ system 
present 
Cutaneous 
Generalized pruritus, urticaria, flushing or 
sensation of heat or warmth or 
Angioedema (not laryngeal, tongue or 
uvular)  
or 
Upper respiratory 
Rhinitis (e.g., sneezing, rhinorrhea, nasal 
pruritus and/or nasal congestion) 
or 
Throat-clearing (itchy throat) 
or 
Cough perceived to come from the upper 
airway, not the lung, larynx, or trachea  
or 
Conjunctival 
Conjunctival erythema, pruritus or tearing 
or 
Other 
Nausea, metallic taste, or headache 
Symptom(s)/ sign(s) of 
more than one Grade 1 
organ system present 
 
or 
 
Lower respiratory 
Asthma: cough, wheezing, 
shortness of breath (e.g., 
less than 40% PEF or 
FEV1 drop, responding to 
an inhaled bronchodilator) 
 
or 
Gastrointestinal 
Abdominal cramps, 
vomiting, or diarrhea 
 
or 
 
Other 
Uterine cramps 
Lower respiratory 
Asthma (e.g., 40% 
PEF or FEV1 drop, 
NOT responding to 
an inhaled 
bronchodilator) 
 
or 
 
Upper respiratory 
Laryngeal, uvula or 
tongue edema with 
or without stridor 
Lower or Upper 
respiratory 
Respiratory failure 
with or without loss 
of consciousness 
 
or 
 
Cardiovascular 
Hypotension with 
or without loss of 
consciousness 
 
Death 
12.3.2 Grading of Liver Chemistry Abnormalities 
For this study, liver function abnormalities will be graded using protocol specific criteria, and 
are defined relative to the upper limit of normal (ULN) as follows: 
• 
Aspartate aminotransferase [AST] increased 
o Grade 1: > ULN - 3.0x ULN 
o Grade 2: > 3.0x ULN - 5.0x ULN 
o Grade 3: > 5.0x ULN - 20.0x ULN  
o Grade 4: > 20.0x ULN 
• 
Alanine aminotransferase [ALT] increased 

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o Grade 1: > ULN - 3.0x ULN 
o Grade 2: > 3.0x ULN - 5.0x ULN 
o Grade 3: > 5.0x ULN - 20.0x ULN  
o Grade 4: > 20.0x ULN 
• 
Alkaline phosphatase [ALP] increased 
o Grade 1: > ULN - 2.5x ULN 
o Grade 2: > 2.5x ULN - 5.0x ULN 
o Grade 3: > 5.0x ULN - 20.0x ULN  
o Grade 4: > 20.0x ULN 
• 
Blood bilirubin increased  
o Grade 1: > ULN - 1.5x ULN 
o Grade 2: > 1.5x ULN - 3.0x ULN 
o Grade 3: > 3.0x ULN - 10.0x ULN  
o Grade 4: > 10.0x ULN  
12.3.3 Grading Criteria 
For all other adverse events not related to hypersensitivity, anaphylaxis or liver chemistry 
abnormalities, the study site will grade the severity of adverse events experienced by the 
study participants according to the criteria set forth in the NCI-CTCAE (version 5.0, 
November 27, 2017). This document (here in referred to as the NCI-CTCAE manual) 
provides a common language to describe levels of severity, to analyze and interpret data, and 
to articulate the clinical significance of all adverse events. The NCI-CTCAE manual has been 
reviewed by the Protocol Chair, ITN Clinical Trial Physician and NIAID Medical Monitor 
and has been deemed appropriate for the participant population to be studied in this protocol.  
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 adverse event. 
Grade 4 = life-threatening or disabling adverse event. 
Grade 5 = death. 
For grading an abnormal value or result of a clinical or laboratory evaluation (including, but 
not limited to, a radiograph, an ultrasound, an electrocardiogram etc.), a treatment-emergent 
adverse event is defined as an increase in grade from baseline or from the last post-baseline 
value that doesn’t meet grading criteria. Changes in grade from screening to baseline will also 
be recorded as adverse events, but are not treatment-emergent. If a specific event or result 
from a given clinical or laboratory evaluation is not included in the NCI-CTCAE manual, 
then an abnormal result would be considered an adverse event if changes in therapy or 
monitoring are implemented as a result of the event/result. 

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or confirmed Grade 1 SARS-CoV-2 infection will also be recorded (Section 6.1.3.4). The 
investigator will record these adverse events and serious adverse events (Section 12.2) on the 
appropriate AE/SAE eCRF regardless of the relationship to study treatment or study 
procedure. 
Once recorded, an AE/SAE will be followed until it resolves with or without sequelae, or 
until the end of study participation, or until 30 days after the participant prematurely 
withdraws (without withdrawing consent) or is withdrawn from the study, whichever occurs 
first. 
12.5 
REPORTING OF SERIOUS ADVERSE EVENTS AND ADVERSE EVENTS  
12.5.1 Reporting of Serious Adverse Events to Sponsor  
This section describes the responsibilities of the site investigator to report serious adverse 
events to the Sponsor (DAIT/NIAID) via the eCRF. Timely reporting of adverse events is 
required by 21 CFR and ICH E6(R2) guidelines.  
Site investigators will report all serious adverse events (Section 12.2.3), regardless of 
relationship or expectedness within 24 hours of discovering the event. Any AESI (Section 
12.2.4) or a hypersensitivity/anaphylactic reaction that results in permanent discontinuation 
of study medication (Section 6.4.1 and Section 12.3.1) will also be reported within 24 hours. 
For serious adverse events, all requested information on the AE/SAE eCRF will be provided. 
However, unavailable details of the event will not delay submission of the known 
information. As additional details become available, the SAE eCRF should be updated and 
submitted.  
For additional information regarding SAE reporting, contact Rho Product Safety: 
Rho Product Safety  
 
 
 
 
 
12.5.2 Reporting to Health Authority  
After an adverse event requiring 24-hour reporting (Section 12.5.1) is submitted by the site 
investigator and assessed by DAIT/NIAID, there are two options for DAIT/NIAID to report 
the adverse event to the appropriate health authorities: 
 
12.5.2.1 
Annual Reporting 
DAIT/NIAID will include in the annual study report to health authorities all adverse events 
classified as: 
• 
Serious, expected, suspected adverse reactions (Section 12.2.1.1)  

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• 
Serious and not a suspected adverse reaction (Section 12.2.2) 
• 
Pregnancies. 
Note that all adverse events (not just those requiring 24-hour reporting) will be reported in the 
Annual IND Report. 
12.5.2.2 
 Expedited Safety Reporting 
This option, with 2 possible categories, applies if the adverse event is classified as one of the 
following: 
Category 1: Serious and unexpected suspected adverse reaction (SUSAR) (see Section 
12.2.1.1, Section 12.2.2, and 21 CFR 312.32(c)(1)(i)).  
The Sponsor shall report any suspected adverse reaction that is both serious and unexpected. 
The Sponsor shall 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: 
1. 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); 
2. 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); 
3. 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. 
Category 2: Any findings from studies that suggests a significant human risk  
The Sponsor shall report any findings from other epidemiological studies, analyses of adverse 
events within the current study or pooled analysis across clinical studies or animal or in vitro 
testing (e.g. mutagenicity, teratogenicity, carcinogenicity) that suggest a significant risk in 
humans exposed to the drug that would result in a safety-related change in the protocol, 
informed consent, current IB or other aspects of the overall conduct of the study.  
DAIT/NIAID shall notify the FDA and all participating investigators of expedited Safety 
Report within 15 calendar days; unexpected fatal or immediately life-threatening suspected 
adverse reaction(s) shall be reported as soon as possible or within 7 calendar days. 
12.5.3 Reporting of Adverse Events to IRB/IECs 
All investigators shall report adverse events, including expedited reports, in a timely fashion 
to their respective IRBs/IECs in accordance with applicable regulations and guidelines. All 
Safety Reports to the FDA shall be distributed by DAIT/NIAID or designee to all 
participating institutions for site IRB/IEC submission. 

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12.6 
PREGNANCY REPORTING 
The investigator shall be informed immediately if a female study participant becomes 
pregnant, or if a male participant becomes aware of a pregnancy in a female partner. A 
pregnant participant shall be instructed to stop taking study medication. The investigator shall 
counsel the participant, and discuss the risks of continuing with the pregnancy and the 
possible effects on the fetus. Monitoring of a pregnant participant shall continue until the 
conclusion of the pregnancy.  
The investigator shall report to DAIT/NIAID all pregnancies that occur in female study 
participants within 1 business day of becoming aware of the event using the Pregnancy eCRF. 
All female participant pregnancies identified during the study shall be followed to conclusion 
and the outcome of each must be reported. The Pregnancy eCRF shall be updated and 
submitted to the CDSMC when details about the outcome are available. 
Information requested about the delivery shall include: 
• 
Gestational age at delivery 
• 
Birth weight, length, and head circumference 
• 
Gender 
• 
Appearance, pulse, grimace, activity, and respiration (APGAR) score at 1 minute, 5 
minutes, and 24 hours after birth, if available 
• 
Any abnormalities. 
For all pregnancy complications that result in a congenital abnormality, birth defect, 
miscarriage, and medically indicated abortion, an SAE shall be submitted to DAIT/NIAID 
using the SAE reporting procedures described above. 
The investigator shall also report to DAIT/NIAID all male participant partner pregnancy 
outcomes by eCRF when this information can be obtained. Specific information collected 
will include number of infants; gender, weight, length, and head circumference of each infant; 
any infant complications, medical problems, or congenital anomalies. 
12.7 
REPORTING OF OTHER SAFETY INFORMATION 
An investigator shall promptly notify the site IRB as well as DAIT/NIAID when an 
“unanticipated problem involving risks to participants or others” is identified, which is not 
otherwise reportable as an adverse event. 
12.8 
REVIEW OF SAFETY INFORMATION 
12.8.1 Medical Monitor Review 
The DAIT/NIAID Medical Monitor shall receive monthly reports from the SCCC compiling 
new and accumulating information on AEs, SAEs, and pregnancies recorded by the study 
site(s) on appropriate eCRFs. 
In addition, the Medical Monitor shall review and make decisions on the disposition of the 
SAE (Section 12.5.1) and pregnancy reports (Section 12.6) received by the CDSMC.  

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12.8.2 DSMB Review 
12.8.2.1 
Planned DSMB Reviews 
The NIAID Autoimmune DSMB will review safety data and make recommendations 
regarding the continuation, termination, or modification of the study. The DSMB shall review 
safety data at least yearly during planned DSMB Meetings. Data for the planned safety 
reviews will include, at a minimum, a listing of all reported AEs and SAEs. The DSMB will 
also review F-VASI and T-VASI results through Week 12 by treatment group in a closed 
session to monitor for an unexpected drug-induced worsening of vitiligo. 
The DSMB will be informed of an Expedited Safety Report in a timely manner.  
12.8.2.2 
 Ad hoc DSMB Reviews 
In addition to the pre-scheduled data reviews and planned safety monitoring, the DSMB may 
be called upon for ad hoc reviews. The DSMB will review any event that potentially impacts 
safety at the request of the protocol chair or DAIT/NIAID. In addition, the following events 
will trigger an ad hoc comprehensive DSMB Safety Review:  
• 
Any death that occurs in the study, which is possibly related or related to study 
medication (Table 4).  
• 
The occurrence of a Grade 3 or higher SAE related to study treatment that is also a 
SUSAR in one or more of the study participants who have received study treatment. 
• 
Any occurrence of a Grade 3 or higher anaphylaxis reaction (Table 3). 
• 
Two or more events of skin malignancy in individuals who receive nbUVB during 
the study. 
The DSMB will review the data within 2 weeks of the event being identified. If the DSMB 
has not reviewed the data within 2 weeks, study enrollment, as defined in Section 8.1, will be 
suspended and no additional participants will sign consent. Participants already in screening 
may continue with screening assessments, and participants already enrolled in the trial will 
continue as planned, pending completion of the DSMB ad hoc review. After review of the 
data, the DSMB will make recommendations regarding study conduct and/or continuation. 
13. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN 
13.1 
OVERVIEW 
ITN086AI is a Phase 2a, randomized, double-blind, placebo controlled trial in which 
participants with vitiligo will receive AMG 714 or placebo. The primary objective is to 
determine the efficacy of IL-15 inhibition with AMG 714 at inducing facial skin 
repigmentation compared to placebo. The study also aims to evaluate safety and assess the 
durability of repigmentation with AMG 714. 
13.2 
ENDPOINTS  
Primary and secondary endpoints are listed in Sections 3.2 and 3.3. 

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13.3 
MEASURES TO MINIMIZE BIAS 
This study has a randomized, double-blind, placebo-controlled, prospective design with well-
defined entry criteria. Participants and site personnel who manage participants will be blinded 
to treatment assignment throughout the trial. In addition, site personnel, including 
investigators, will not have access to any mechanistic data until completion of the study.  
13.4 
ANALYSIS PLAN 
13.4.1 Analysis Populations 
Safety sample (SS): All participants who receive any amount of AMG 714 or placebo. The 
safety analyses will be based on the actual treatment the participants receive. 
Modified Intent to treat (mITT) sample: All randomized participants who receive any dose 
of study treatment. The efficacy analyses will be based on the mITT sample according to the 
group to which the participants are assigned. 
Per protocol (PP) sample: All participants in the mITT sample with no major protocol 
deviations that impact efficacy assessments, who received at least 5 of the 6 doses of the 
expected study treatment, and who have the Week 24 F-VASI assessment. The reported major 
deviations will be reviewed during a masked data review after the last participant’s primary 
endpoint visit to determine which participants should be excluded from the per-protocol 
population. 
13.4.2 Primary Analysis of Primary Endpoint 
The primary endpoint is the proportion of participants achieving an F-VASI35 response at 
Week 24. 
The primary analysis of the primary endpoint will be performed on the mITT sample and is 
designed to test the following hypotheses:  
• 
Null hypothesis: The proportion achieving an F-VASI35 at Week 24 does not differ 
between the AMG 714 and placebo groups 
• 
Alternate hypothesis: The proportion achieving an F-VASI35 at Week 24 differs 
between the AMG 714 and placebo groups. 
The proportion of F-VASI35 responders will be estimated for each treatment group. Groups 
will be compared using two-sided Fisher’s Exact test evaluated using a Type 1 error rate of 
α=0.05. 
Missing Data. For a participant who is missing the baseline F-VASI, the screening F-VASI 
will be used. Participants for whom the Week 24 F-VASI cannot be evaluated will be deemed 
non-responders.  
13.4.3 Supportive Analyses of the Primary Endpoint(s)/Outcome(s)  
At a minimum, the following sensitivity analyses for the primary analyses will be performed: 

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• 
An analysis analogous to the primary endpoint analysis using only mITT participants 
with observed F-VASI data at Week 24 (i.e., dropping participants with missing 
Week 24 F-VASI rather than assuming non-response) 
• 
An analysis analogous to the primary endpoint analysis using the PP participants 
• 
A stratified analysis of F-VASI35 response using the Cochran-Mantel-
Haenszel statistic to compare treatment groups after controlling for active versus 
stable vitiligo at baseline. 
13.4.4 Analyses of Secondary Endpoints 
All secondary inferential analyses are considered supportive; p-values for test of differences 
among groups will be presented without adjustment for multiple comparisons. The mITT 
population will be used for all secondary analyses. For secondary response indices (e.g. F-
VASI25 at Week 12, F-VASI25 at Week 36, F-VASI25 at Week 48, T-VASI25 at Week 12, 
etc.), participants for whom endpoint data is unavailable will be deemed response failures.  
Otherwise, data will not be imputed for analyses of secondary endpoints. 
The null hypothesis proposes that there are no differences in the secondary endpoints 
(measured either as means or proportions) between study groups. The alternative hypothesis 
proposes that there are differences between groups.  
The following analyses are planned to evaluate the impact of treatment over the course of the 
study: 
1. For secondary dichotomous response variables including F-VASI25, F-VASI35, F-
VASI50, F-VASI75, F-VASI90, T-VASI25, T-VASI35, T-VASI50, T-VASI75, and 
T-VASI90 at each indicated secondary analysis time point, analyses will be 
analogous to those described for the primary endpoint. 
2. Estimated response rates for each dichotomous F-VASI and T-VASI responder 
variable (i.e. 25%, 35%, 50%, 75%, 90%) at each indicated analysis time point will 
be presented for subgroups defined by treatment and active/stable vitiligo status. 
3. For the change (and % change) in F-VASI, change (and % change) in T-VASI, 
change in VES, and change in VitiQoL at each indicated secondary analysis time 
point, the treatment group distributions will be compared using Mann-Whitney tests 
(2-sided). 
4. For the ordinal VNS endpoint at each secondary analysis time point,  
a. Treatment groups will be compared at each indicated secondary analysis time 
point using an extension of the Fisher’s Exact test.  
b. Shifts in distributions from baseline to each time point will be evaluated for 
each treatment arm using Bowker’s exact test of symmetry. 

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5. To evaluate treatment group differences longitudinally, separate general mixed linear 
models will be fit to the F-VASI, T-VASI, VES, and VitiQoL, over all time points 
from day 0 through Week 24 with fixed effects for time point (fit as categorical), 
treatment group and the time*treatment interaction. A 1-banded unstructured within-
subject covariance matrix will be assumed and fit separately for each treatment arm. 
Appropriate contrasts will evaluate trends over time and changes from baseline.  
After Week 24, participants who do not achieve a T-VASI25 response will receive nbUVB 
phototherapy. For T-VASI25 responders (who will not receive nbUVB phototherapy), the 
post-Week 24 analyses will evaluate durability of response. In contrast, for T-VASI25 non-
responders, the aim will be to evaluate improvement following the addition of nbUVB 
phototherapy. The following analyses are planned: 
1. Durability of response: For the subset of participants who achieve a T-VASI25 
response at Week 24 (and receive no nbUVB phototherapy), the null hypothesis of no 
change from Week 24 to Week 48 will be evaluated by treatment arm against the 1-
sided alternative of worsening from Week 24 to Week 48.  
a. For each treatment arm, descriptive statistics and p-values derived from 
Wilcoxon tests will be presented for change (and % change) in F-VASI, 
change (and % change) in T-VASI, change in VES, and change in VitiQoL 
from Week 24 to Week 48.  
b. For the VNS ordinal endpoint, shifts in distributions from Week 24 to Week 
48 will be evaluated for each treatment arm using Bowker’s exact test of 
symmetry. 
2. Improvement after nbUVB phototherapy: For the subset of participants who do not 
achieve a T-VASI25 response at Week 24 and receive nbUVB phototherapy, 
analyses will assess improvement in repigmentation and other key scales in the AMG 
714 and placebo arms following nbUVB phototherapy.  
a. For each treatment arm, descriptive statistics and p-values derived from 
Wilcoxon tests will be presented for change (and % change) in F-VASI, 
change (and % change) in T-VASI, change in VES, and change in VitiQoL 
from baseline to Week 48.   
b. For dichotomous response indices defined by % improvement from baseline 
to Week 48 (i.e. F-VASI25, F-VASI35, F-VASI50, F-VASI75, F-VASI90, 
T-VASI25, T-VASI35, T-VASI50, T-VASI75, and T-VASI90), estimated 
response rates will be presented for subgroups defined by treatment. 
c. For the VNS ordinal endpoint at Week 48,  
i. Shifts in distributions from baseline to Week 48 will be evaluated for 
each treatment arm using Bowker’s exact test of symmetry. 

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Treatment group differences for the incidence of AEs and the incidence of grade 3 or higher 
infectious AEs occurring over the first 24 weeks will be compared using a Fisher’s exact test. 
13.4.5 Descriptive Analyses 
Descriptive statistics will be provided by treatment group for participant disposition, baseline 
and demographic characteristics, and use of concomitant medications. Continuous measures 
will be summarized using n, mean, standard deviation (SD), median, minimum, and 
maximum. Categorical variables will be summarized using counts and percentages. 
13.5 
INTERIM ANALYSES 
No formal interim analyses for stopping the trial early for futility or efficacy are planned. 
13.6 
STATISTICAL HYPOTHESES 
Statistical hypotheses are provided in Sections 13.4.2 and 13.4.4. 
13.7 
SAMPLE SIZE CONSIDERATIONS 
The underlying F-VASI35 response rate at Week 24 was assumed to be 5% for the placebo 
arm based on clinical trial results with ruxolitinib cream for vitiligo.6,7 For the AMG 714 arm, 
the minimal clinically meaningful response rate was assumed to be 45%.  Under this 
scenario, a study of 57 individuals randomized 2:1 to AMG 714 and placebo, respectively, 
will provide 88% power using a 2-sided Fisher’s Exact test at α=0.05. If the placebo response 
rate is actually 7.5% (i.e. 50% higher than expected), power will still 81%. For the secondary 
PP analysis, if sample size drops to 48 (16% loss), then power is still 80%. 
14. 
IDENTIFICATION AND ACCESS TO SOURCE DATA 
14.1 
SOURCE DATA 
Source documents and source data are considered to be the original documentation where 
participant information, visits consultations, examinations and other information are 
recorded. Documentation of source data is necessary for the reconstruction, evaluation and 
validation of clinical findings, observations and other activities during a clinical trial.  
14.2 
ACCESS TO SOURCE DATA 
The site investigators and site staff will make all source data available to the Sponsor 
(DAIT/NIAID), ITN, and relevant health authorities. Authorized representatives as noted 
above are bound to maintain the strict confidentiality of medical and research information 
that may be linked to identified individuals. 
15. 
QUALITY ASSURANCE AND QUALITY CONTROL 
Each clinical site will perform internal quality management of study conduct, data collection, 
documentation and completion. An individualized quality management plan will be 
developed to describe a site’s quality management. Quality control (QC) procedures will be 
implemented beginning with the data entry system and data QC checks that will be run on the 

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database will be generated. Any missing data or data anomalies will be communicated to the 
site(s) for clarification/resolution. 
Following written SOPs, the monitors will verify that the clinical trial is conducted and data 
are generated, documented (recorded), and reported in compliance with the protocol, GCP, 
and the applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good 
Manufacturing Practices (GMP)).  
The investigational site will provide direct access to all trial related sites, source 
data/documents, and reports for the purpose of monitoring and auditing by the Sponsor, and 
inspection by local and regulatory authorities. 
16. 
PROTOCOL DEVIATIONS 
16.1 
PROTOCOL DEVIATION DEFINITIONS 
Protocol Deviation – The investigators and site staff will conduct the study in accordance to 
the protocol; no deviations from the protocol are permitted. Any change, divergence, or 
departure from the study design or procedures constitutes a protocol deviation. As a result of 
any deviation, corrective actions will be developed by the site and implemented promptly. 
Major Protocol Deviation (Protocol Violation) – A Protocol Violation is a deviation from 
the IRB approved protocol that may affect the participant's rights, safety, or well-being and/or 
the completeness, accuracy and reliability of the study data. In addition, protocol violations 
include willful or knowing breaches of human participant protection regulations, or policies, 
any action that is inconsistent with the NIH Human Research Protection Program’s research, 
medical, and ethical principles, and a serious or continuing noncompliance with federal, state, 
local or institutional human subject protection regulations, policies, or procedures.  
Non-Major Protocol Deviation – A non-major protocol deviation is any change, divergence, 
or departure from the study design or procedures of a research protocol that does not have a 
major impact on the participant's rights, safety or well-being, or the completeness, accuracy 
and reliability of the study data. 
16.2 
REPORTING AND MANAGING PROTOCOL DEVIATIONS 
The study site principal investigator has the responsibility to identify, document and report 
protocol deviations as directed by the study Sponsor. However, protocol deviations may also 
be identified during site monitoring visits or during other forms of study conduct review.  
17. 
ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD CLINICAL 
PRACTICE 
17.1 
STATEMENT OF COMPLIANCE 
This clinical study will be conducted using good clinical practice (GCP), as delineated in 
Guidance for Industry: E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1), 
and according to the criteria specified in this study protocol. Before study initiation, the 
protocol and the informed consent documents will be reviewed and approved by the IRB. 

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Any amendments to the protocol or to the consent materials will also be approved by the IRB 
before they are implemented. 
17.2 
INFORMED CONSENT PROCESS  
The consent process will provide information about the study to a prospective participant and 
will allow adequate time for review and discussion prior to his/her decision. The principal 
investigator or licensed physician designee listed on the FDA 1572 will review the consent 
and answer questions. The prospective participant will be told that being in the trial is 
voluntary and that he or she may withdraw from the study at any time, for any reason. All 
participants will read, sign, and date a consent form before undergoing any study procedures. 
Consent materials will be presented in participants’ primary language. A copy of the signed 
consent form will be given to the participant. 
The consent process will be ongoing. The consent form will be revised when important new 
safety information is available, the protocol is amended, and/or new information becomes 
available that may affect participation in the study. 
17.3 
PRIVACY AND CONFIDENTIALITY 
A participant’s privacy and confidentiality will be respected throughout the study. Each 
participant will be assigned a unique identification number and these numbers rather than 
names will be used to collect, store, and report participant information. Site personnel will not 
transmit documents containing personal health identifiers (PHI) to the study Sponsor or their 
representatives. 
18. 
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.  
 
 

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19. 
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Liu LY, Strassner JP, Refat MA, Harris JE, King BA. Repigmentation in vitiligo using the Janus kinase 
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McKesey J, Pandya AG. A pilot study of 2% tofacitinib cream with narrowband ultraviolet B for the 
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Romarin D. Efficacy and Safety of Ruxolitinib Cream for the Treatment of Vitiligo: Results of a 24-
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Congress of Dermatology2019; Milan, Italy. 
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Relke N, Gooderham M. The Use of Janus Kinase Inhibitors in Vitiligo: A Review of the Literature. J 
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Craiglow BG, King BA. Tofacitinib Citrate for the Treatment of Vitiligo: A Pathogenesis-Directed 
Therapy. JAMA Dermatol. 2015;151(10):1110-1112. 
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Rosmarin D, Pandya AG, Lebwohl M, et al. Ruxolitinib cream for treatment of vitiligo: a randomised, 
controlled, phase 2 trial. Lancet. 2020;396(10244):110-120. 
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Harris JE. Cellular stress and innate inflammation in organ-specific autoimmunity: lessons learned 
from vitiligo. Immunol Rev. 2016;269(1):11-25. 
13. 
Harris JE, Harris TH, Weninger W, Wherry EJ, Hunter CA, Turka LA. A mouse model of vitiligo with 
focused epidermal depigmentation requires IFN-gamma for autoreactive CD8(+) T-cell accumulation 
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14. 
Palermo B, Campanelli R, Garbelli S, et al. Specific cytotoxic T lymphocyte responses against Melan-
A/MART1, tyrosinase and gp100 in vitiligo by the use of major histocompatibility complex/peptide 
tetramers: the role of cellular immunity in the etiopathogenesis of vitiligo. J Invest Dermatol. 
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15. 
Lang KS, Caroli CC, Muhm A, et al. HLA-A2 restricted, melanocyte-specific CD8(+) T lymphocytes 
detected in vitiligo patients are related to disease activity and are predominantly directed against 
MelanA/MART1. J Invest Dermatol. 2001;116(6):891-897. 

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Richmond JM, Strassner JP, Zapata L, Jr., et al. Antibody blockade of IL-15 signaling has the potential 
to durably reverse vitiligo. Sci Transl Med. 2018;10(450). 
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Malik BT, Byrne KT, Vella JL, et al. Resident memory T cells in the skin mediate durable immunity to 
melanoma. Sci Immunol. 2017;2(10). 
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Cheuk S, Schlums H, Gallais Serezal I, et al. CD49a Expression Defines Tissue-Resident CD8(+) T 
Cells Poised for Cytotoxic Function in Human Skin. Immunity. 2017;46(2):287-300. 
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Boniface K, Jacquemin C, Darrigade AS, et al. Vitiligo Skin Is Imprinted with Resident Memory CD8 
T Cells Expressing CXCR3. J Invest Dermatol. 2018;138(2):355-364. 
20. 
Jiang X, Clark RA, Liu L, Wagers AJ, Fuhlbrigge RC, Kupper TS. Skin infection generates non-
migratory memory CD8+ T(RM) cells providing global skin immunity. Nature. 2012;483(7388):227-
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21. 
Mackay LK, Stock AT, Ma JZ, et al. Long-lived epithelial immunity by tissue-resident memory T 
(TRM) cells in the absence of persisting local antigen presentation. Proc Natl Acad Sci U S A. 
2012;109(18):7037-7042. 
22. 
Shin H, Iwasaki A. A vaccine strategy that protects against genital herpes by establishing local memory 
T cells. Nature. 2012;491(7424):463-467. 
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Mackay LK, Rahimpour A, Ma JZ, et al. The developmental pathway for CD103(+)CD8+ tissue-
resident memory T cells of skin. Nat Immunol. 2013;14(12):1294-1301. 
24. 
Schenkel JM, Fraser KA, Vezys V, Masopust D. Sensing and alarm function of resident memory 
CD8(+) T cells. Nat Immunol. 2013;14(5):509-513. 
25. 
Mackay LK, Wynne-Jones E, Freestone D, et al. T-box Transcription Factors Combine with the 
Cytokines TGF-beta and IL-15 to Control Tissue-Resident Memory T Cell Fate. Immunity. 
2015;43(6):1101-1111. 
26. 
Zhang N, Bevan MJ. Transforming growth factor-beta signaling controls the formation and 
maintenance of gut-resident memory T cells by regulating migration and retention. Immunity. 
2013;39(4):687-696. 
27. 
Adachi T, Kobayashi T, Sugihara E, et al. Hair follicle-derived IL-7 and IL-15 mediate skin-resident 
memory T cell homeostasis and lymphoma. Nat Med. Vol 212015:1272-1279. 
28. 
Mohammed J, Beura LK, Bobr A, et al. Stromal cells control the epithelial residence of DCs and 
memory T cells by regulated activation of TGF-beta. Nat Immunol. 2016;17(4):414-421. 
29. 
Zhang X, Sun S, Hwang I, Tough DF, Sprent J. Potent and selective stimulation of memory-phenotype 
CD8+ T cells in vivo by IL-15. Immunity. 1998;8(5):591-599. 
30. 
Nelson BH. IL-2, regulatory T cells, and tolerance. J Immunol. 2004;172(7):3983-3988. 
31. 
Fehniger TA, Caligiuri MA. Interleukin 15: biology and relevance to human disease. Blood. 
2001;97(1):14-32. 
32. 
AMG 714 Investigator's Brochure. Amgen Edition 9.0. November 6, 2018. 
33. 
Lebrec H, Horner MJ, Gorski KS, et al. Homeostasis of human NK cells is not IL-15 dependent. J 
Immunol. 2013;191(11):5551-5558. 

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34. 
Pan WJ, Li H, Xiao JJ, et al. Modeling the pharmacokinetic-pharmacodynamic relationship of the 
monoclonal anti-macaque-IL-15 antibody Hu714MuXHu in cynomolgus monkeys. Pharmacol Res 
Perspect. 2015;3(6):e00199. 
35. 
Baslund B, Tvede N, Danneskiold-Samsoe B, et al. Targeting interleukin-15 in patients with 
rheumatoid arthritis: a proof-of-concept study. Arthritis Rheum. 2005;52(9):2686-2692. 
36. 
van Geel N, Lommerts J, Bekkenk M, et al. Development and Validation of the Vitiligo Extent Score 
(VES): an International Collaborative Initiative. J Invest Dermatol. 2016;136(5):978-984. 
37. 
Lilly E, Lu PD, Borovicka JH, et al. Development and validation of a vitiligo-specific quality-of-life 
instrument (VitiQoL). J Am Acad Dermatol. 2013;69(1):e11-18. 
38. 
Batchelor JM, Tan W, Tour S, Yong A, Montgomery AA, Thomas KS. Validation of the Vitiligo 
Noticeability Scale: a patient-reported outcome measure of vitiligo treatment success. Br J Dermatol. 
2016;174(2):386-394. 
39. 
Mohammad TF, Al-Jamal M, Hamzavi IH, et al. The Vitiligo Working Group recommendations for 
narrowband ultraviolet B light phototherapy treatment of vitiligo. J Am Acad Dermatol. 
2017;76(5):879-888. 
40. 
Zaid A, Mackay LK, Rahimpour A, et al. Persistence of skin-resident memory T cells within an 
epidermal niche. Proc Natl Acad Sci U S A. 2014;111(14):5307-5312. 
41. 
Carbone FR, Mackay LK, Heath WR, Gebhardt T. Distinct resident and recirculating memory T cell 
subsets in non-lymphoid tissues. Curr Opin Immunol. 2013;25(3):329-333. 
42. 
DeGottardi MQ, Okoye AA, Vaidya M, et al. Effect of Anti-IL-15 Administration on T Cell and NK 
Cell Homeostasis in Rhesus Macaques. J Immunol. 2016;197(4):1183-1198. 
43. 
Mishra A, Sullivan L, Caligiuri MA. Molecular pathways: interleukin-15 signaling in health and in 
cancer. Clin Cancer Res. 2014;20(8):2044-2050. 
44. 
Waldmann TA. The biology of IL-15: implications for cancer therapy and the treatment of autoimmune 
disorders. J Investig Dermatol Symp Proc. 2013;16(1):S28-30. 
45. 
Jones AM, Griffiths JL, Sanders AJ, et al. The clinical significance and impact of interleukin 15 on 
keratinocyte cell growth and migration. Int J Mol Med. 2016;38(3):679-686. 
46. 
Luo X, Jin R, Wang F, et al. Interleukin-15 inhibits the expression of differentiation markers induced 
by Ca(2+) in keratinocytes. Exp Dermatol. 2016;25(7):544-547. 
47. 
Ruckert R, Asadullah K, Seifert M, et al. Inhibition of keratinocyte apoptosis by IL-15: a new 
parameter in the pathogenesis of psoriasis? J Immunol. 2000;165(4):2240-2250. 
48. 
Strassner JP, Rashighi M, Ahmed Refat M, Richmond JM, Harris JE. Suction blistering the lesional 
skin of vitiligo patients reveals useful biomarkers of disease activity. J Am Acad Dermatol. 
2017;76(5):847-855.e845. 
49. 
Rashighi M, Agarwal P, Richmond JM, et al. CXCL10 is critical for the progression and maintenance 
of depigmentation in a mouse model of vitiligo. Sci Transl Med. 2014;6(223):223ra223. 
50. 
Cox L, Larenas-Linnemann D, Lockey RF, Passalacqua G. Speaking the same language: The World 
Allergy Organization Subcutaneous Immunotherapy Systemic Reaction Grading System. The Journal 
of allergy and clinical immunology. 2010;125(3):569-574, 574.e561-574.e567. 

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APPENDIX 2. VASI 
Vitiligo Area Scoring Index (VASI)  
The vitiligo area scoring index (VASI) is a quantitative clinical tool to assess the area affected by 
vitiligo. The body is divided into 6 separate regions:  
• 
Head and neck (includes face) 
• 
Upper extremities (excluding hands). The axillae are considered part of the upper extremities. 
• 
Hands 
• 
Torso (excluding axillae). The genitalia are not included in the VASI assessment. 
• 
Lower extremities (excluding feet). The buttocks and inguinal area are considered part of the 
lower extremities.  
• 
Feet 
For each body region, the VASI is determined by the product of the area of vitiligo in hand units and 
the extent of depigmented skin within each hand unit-measured patch (estimated to the nearest of the 
following percentages: 0%, 10%, 25%, 50%, 75%, 90% or 100%). 
Body Surface Area (BSA) 
The percentage of the body surface area (BSA) affected with vitiligo can be estimated by the hand 
unit or thumb unit to the tenth decimal (0.1%). A hand unit encompasses the palm plus five digits, 
with fingers and thumb apposed. The hand unit is approximately 1% of the total BSA and the thumb 
is approximately 0.1% of the total BSA. The hand unit is based on each individual participant’s own 
hand size. 
Calculation of the T-VASI 
The total body VASI is then calculated using a formula that includes a contribution from all body 
sites, with a possible range of 0-100%. 
VASI =  [Hand Units] x [Residual Depigmentation] 
 All body sites  
The evaluable area for the T-VASI assessment is all of the following: 
1. The total body including the face and neck, and excluding the genitalia. 
2. Vitiligo lesions on fingers including and distal to the proximal interphalangeal joints, toes, 
palms, and soles will not be included in the T-VASI assessment. 
 
 

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Calculation of the F-VASI 
The F-VASI will be calculated separately. The F-VASI will be calculated in the same fashion as the 
T-VASI, except that the evaluable area is limited to the face only (see above). The %BSA will be 
measured to the tenth decimal (0.1%). The evaluable area is all of the following: 
1. From the top of the forehead at the hairline down to the jawline, and from the right to the left 
tragus anteriorly, excluding mucosal lips. For participants who have a receding hairline, the 
original hairline should be used as the border for the face. 
 
 
 Illustrations of Percent Depigmentation for the Vitiligo Area Scoring Index for the F-VASI and 
the T-VASI 
 
 
1.0 
(100%) 
Completely depigmented skin 
0.90 
(90%) 
Specks of pigmented skin present  
0.75 
(75%) 
Depigmented area exceeds the 
pigmented area  
0.50 
(50%) 
Pigmented and depigmented areas 
are equal 
0.25 
(25%) 
Pigmented area exceeds 
depigmented area  
0.10 
(10%) 
Only specks of depigmented skin 
present 
0.00 
(0%) 
No depigmented skin present  
 
 

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APPENDIX 3. VES 
The Vitiligo Extent Score (VES) is determined during the patient encounter using the calculator at 
www.vitiligo-calculator.com as follows: For each area, select 1 picture which best represents the 
extent of the vitiligo lesions. There are additional options for quantifying the extent, e.g. if the 
extent is half (½) or a quarter (¼) of the involved area in the picture or slightly less (-) or slightly 
more (+) than the involved area in the picture. The “>75%” option can be selected if the involved 
area is more than shown in the last picture, but less than 100% (i.e. complete depigmentation). The 
calculator will use the selected images to calculate the percentage of the body surface area (BSA) 
involved or grade of extent per region (Grade 0 to 6). 
 
© 2015. Nanja van Geel, Reinhart Speeckaert. All rights reserved. 

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© 2015. Nanja van Geel, Reinhart Speeckaert. All rights reserved. 
 
 
 

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APPENDIX 4. VITIQOL 
Vitiligo-specific Health-related Quality-of-life Instrument (VitiQoL) is a validated instrument that 
asks participants to rate various aspects of their vitiligo during the past month. Assessment will be 
conducted at the baseline visit, as well as visits during and after treatment per Appendix 1. The 
response to each question will be scored on a 0 (not at all) to 6 (all of the time) scale.  
 
 
 

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APPENDIX 5. VNS 
Vitiligo Noticeability Scale (VNS) is a validated patient-reported outcome measure of vitiligo 
treatment.38 Participants will be presented with one pre-treatment photograph of their face at different 
visits (see Schedule of Events, Appendix 1) and asked to answer the question below. The same pre-
treatment photograph must be used at each visit. 
 
Question 
Response option (Score) 
Success criteria  
Compared with before 
treatment, how noticeable is 
the vitiligo now? 
More noticeable (1) 
Score of 4 or 5  
As noticeable (2) 
 
Slightly less noticeable (3) 
 
A lot less noticeable (4) 
No longer noticeable (5)