Evaluation of Brentuximab Vedotin for Diffuse Cutaneous Systemic Sclerosis BRAVOS: A Phase 1/2 Multicenter Randomized, Double Blinded, Safety Study (ITN075AI)
Phase: PHASE1
Conditions: Diffuse Cutaneous Systemic Sclerosis, Scleroderma, dcSSc
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Immune Tolerance Network 
CONFIDENTIAL 
Page 1 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
Evaluation of Brentuximab Vedotin for Diffuse Cutaneous 
Systemic Sclerosis:  A Phase 1/2 Multicenter Randomized, 
Double Blinded, Safety Study 
 Protocol ITN075AI 
Version 5.0 (December 10, 2021) 
IND # 132661 
 
Protocol Co-Chair 
David Fox, MD 
Professor of Medicine 
University of Michigan 
1500 East Medical Center Dr., Rm 3918 
Ann Arbor, MI 48109 
Tel: 734-936-5566     
Email: dfox@umich.edu 
 
Protocol Co-Chair 
Dinesh Khanna, MD, MSc 
Professor of Medicine 
Division of Rheumatology 
University of Michigan  
300 North Ingalls Street, SPC 5422, Suite 7C27 
Ann Arbor, MI 48109 
Tel:  734-763-3110      
Email: khannad@med.umich.edu  
 
ITN Clinical Trial Physician 
Dawn Smilek, MD, PhD 
Chief Medical Officer 
Clinical Trials Group 
Immune Tolerance Network 
513 Parnassus Avenue, HSW 11, Box 0534 
San Francisco, CA 94143  
Tel: 415-610-5045    E-mail: 
dsmilek@immunetolerance.org 
NIAID Medical Monitor 
Ellen Goldmuntz, MD, PhD  
Chief, Rheumatologic Autoimmune Diseases Section 
Autoimmunity & Mucosal Immunology Branch 
Division of Allergy, Immunology & Transplantation  
National Institute of Allergy and Infectious Diseases 
5601 Fishers Lane Room 7D50 
Rockville, MD, 20852 
Tel : 240-627-3502 
Email : EGoldmuntz@niaid.nih.gov  
 
ITN Clinical Operations Manager 
Karen Chia, CCRP 
Clinical Trials Group 
Immune Tolerance Network 
513 Parnassus Avenue, HSW 11, Box 0534 
San Francisco, CA 94143 
Tel: 415-610-7179       
Email: kchia@immunetolerance.org 
NIAID Project Manager 
Angela Kibiy, RN, BSN, MPH 
Division of Allergy, Immunology, and 
Transplantation  
National Institute of Allergy and Infectious Diseases  
5601 Fishers Lane Room 7D34 
Rockville, MD, 20852 
Tel: 240-627-3474       
Email: angela.kibiy@nih.gov 
 

Immune Tolerance Network 
CONFIDENTIAL 
Page 2 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
ITN Lead Biologist 
Laura A Cooney, PhD 
Lead Biologist 
Autoimmune Disease Therapeutic Area 
Immune Tolerance Network 
109 Zina Pitcher Place, 4023 BSRB 
Ann Arbor, MI 48109-2200 
 
Tel: 734-274-1149Email: lcooney@umich.edu 
NIAID Regulatory Affairs 
Maria Concetta Veri, PhD 
Senior Regulatory Affairs Officer 
Division of Allergy, Immunology, and 
Transplantation  
National Institute of Allergy and Infectious Diseases  
5601 Fishers Lane Room 7B48 
Rockville, MD, 20852 
Tel: 240-627-3572        
Email: maria.veri@nih.gov  
  
Rho Senior Statistician 
William T Barry, PhD 
Senior Research Scientist 
Rho Federal Systems Division, Inc. 
2635 E. NC Hwy 54 
Durham, NC 27713 
Phone: 919-595-6867 
Fax: 919-287-3039 
Email: bill_barry@rhoworld.com 
 
 
This clinical study is supported and conducted by the Immune Tolerance Network, which is 
sponsored by the National Institute of Allergy and Infectious Diseases. 
This document is confidential. It is provided for review only to investigators, potential 
investigators, consultants, study staff, and applicable independent ethics committees or 
institutional review boards. It is understood that the contents of this document will not be 
disclosed to others without written authorization from ITN and NIAID unless it is necessary to 
obtain informed consent from potential study participants. 
 
 
 
 

Immune Tolerance Network 
CONFIDENTIAL 
Page 3 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
PROTOCOL APPROVAL 
Trial ID:  ITN075AI 
Protocol Version: 5.0 
Dated:  December 10, 2021 
IND # 132661 
Protocol Chairs:  David Fox, MD; Dinesh Khanna, MD, 
MSc  
 
Short Title:    Brentuximab Vedotin for Systemic Sclerosis 
I confirm that I have read the above protocol in the latest version. I understand it, and I will 
work according to the principles of good clinical practice (GCP) as described in the US Code of 
Federal Regulations (CFR)—45 CFR part 46 and 21 CFR parts 50, 56, and 312, 812 and in the 
International Conference on Harmonization (ICH) document entitled Integrated Addendum to 
ICHE6(R1): Guideline for Good Clinical Practice E6(R2). Further, I will conduct the study in 
keeping with local legal and regulatory requirements. 
 
As the principal investigator, I agree to carry out the study by the criteria written in the protocol 
and understand that no changes can be made to this protocol without written permission of the 
NIAID. 
 
 
__________________________________________                                        
Principal Investigator                        (Print)                     
 
 
__________________________________________         _________________ 
Principal Investigator                        (Sign)                      Date 
 
 
 
 
 

Immune Tolerance Network 
CONFIDENTIAL 
Page 4 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
TABLE OF CONTENTS 
PROTOCOL APPROVAL ........................................................................................................... 3 
TABLE OF CONTENTS .............................................................................................................. 4 
SYNOPSIS ................................................................................................................................... 9 
ABBREVIATIONS .................................................................................................................... 18 
1. 
BACKGROUND AND RATIONALE ................................................................................ 22 
1.1 
BACKGROUND ............................................................................................................. 22 
1.2 
SCIENTIFIC RATIONALE.............................................................................................. 22 
1.3 
PRECLINICAL AND CLINICAL EXPERIENCE ............................................................. 24 
1.3.1 
Preclinical Studies ......................................................................................................................24 
1.3.2 
Clinical Studies ...........................................................................................................................24 
1.4 
SUMMARY OF KNOWN AND POTENTIAL RISKS AND BENEFITS FOR HUMAN 
PARTICIPANTS ............................................................................................................ 26 
1.4.1 
Risks ...........................................................................................................................................26 
1.4.2 
Benefits .......................................................................................................................................31 
2. 
OBJECTIVES .................................................................................................................... 31 
2.1 
PRIMARY OBJECTIVE .................................................................................................. 31 
2.2 
SECONDARY OBJECTIVES .......................................................................................... 31 
2.3 
EXPLORATORY MECHANISTIC OBJECTIVES ............................................................ 32 
3. 
STUDY DESIGN................................................................................................................ 32 
3.1 
DESCRIPTION ............................................................................................................... 32 
3.2 
STUDY REGIMEN ......................................................................................................... 33 
3.3 
STUDY DURATION ....................................................................................................... 34 
3.4 
STUDY ENDPOINTS...................................................................................................... 34 
3.4.1 
Primary Endpoint........................................................................................................................34 
3.4.2 
Secondary Endpoints ..................................................................................................................34 
3.5 
RATIONALE FOR SELECTION OF DRUG, ROUTE, DOSE, AND REGIMEN ................ 35 
4. 
ELIGIBILITY ................................................................................................................... 35 
4.1 
INCLUSION CRITERIA.................................................................................................. 35 
4.2 
EXCLUSION CRITERIA................................................................................................. 36 
4.3 
PREMATURE DISCONTINUATION OF STUDY THERAPY .......................................... 40 
4.4 
PREMATURE TERMINATION OF A PARTICIPANT FROM THE STUDY ..................... 40 

Immune Tolerance Network 
CONFIDENTIAL 
Page 5 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
4.5 
REPLACEMENT OF STUDY PARTICIPANTS ............................................................... 40 
5. 
STUDY THERAPIES, MEDICATIONS AND PROCEDURES ......................................... 41 
5.1 
INVESTIGATIONAL MEDICATION: BRENTUXIMAB VEDOTIN ................................ 41 
5.1.1 
Formulation and Packaging ........................................................................................................41 
5.1.2 
Placebo Preparation ....................................................................................................................41 
5.1.3 
Dosage, Handling, Preparation, and Administration ..................................................................41 
5.2 
TOXICITY MANAGEMENT OF BRENTUXIMAB VEDOTIN ........................................ 43 
5.2.1 
SARS-CoV-2 Infection or Exposure ..........................................................................................43 
5.2.2 
Other Infection or AE .................................................................................................................44 
5.2.3 
Peripheral Neuropathy ................................................................................................................44 
5.2.4 
Permanent Discontinuation of Study Medication for Toxicity ..................................................44 
5.3 
CONCOMITANT MEDICATIONS .................................................................................. 45 
5.3.1 
Required Medications .................................................................................................................45 
5.3.2 
Recommended Prophylactic Medication ....................................................................................46 
5.3.3 
Permitted Medications ................................................................................................................46 
5.3.4 
Prohibited Medications and Vaccines ........................................................................................46 
5.4 
DRUG ACCOUNTABILITY ........................................................................................... 47 
5.5 
ASSESSMENT OF COMPLIANCE WITH STUDY MEDICATION .................................. 47 
6. 
STUDY ASSESSMENTS AND WINDOWS ....................................................................... 47 
6.1 
VISIT WINDOWS ........................................................................................................... 47 
6.1.1 
Scheduled Visits .........................................................................................................................47 
6.1.2 
Window for Administration of Study Medication ......................................................................48 
6.1.3 
Unscheduled Visits .....................................................................................................................48 
6.2 
RANDOMIZATION, BLINDING, AND UNBLINDING ................................................... 48 
6.2.1 
Randomization ............................................................................................................................48 
6.2.2 
Blinding ......................................................................................................................................48 
6.2.3 
Unblinding ..................................................................................................................................48 
6.3 
GENERAL ASSESSMENTS ............................................................................................ 49 
6.4 
CLINICAL LABORATORY ASSESSMENTS .................................................................. 50 
6.5 
GENERAL CLINICAL ASSESSMENTS .......................................................................... 50 
6.6 
DISEASE-SPECIFIC ASSESSMENTS ............................................................................. 50 
6.7 
MECHANISTIC ASSESSMENTS .................................................................................... 51 
7. 
MECHANISTIC ASSAYS ................................................................................................. 51 
7.1 
MECHANISTIC HYPOTHESES AND RATIONALE ....................................................... 51 

Immune Tolerance Network 
CONFIDENTIAL 
Page 6 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
7.2 
PLANNED MECHANISTIC ASSAYS ............................................................................. 52 
7.2.1 
Local Immune Responses in the Skin ........................................................................................52 
7.2.2 
Cellular Assays ...........................................................................................................................52 
7.2.3 
Serum and Plasma Assays ..........................................................................................................53 
7.2.4 
Whole Blood Assays ..................................................................................................................54 
7.3 
RETENTION OF SAMPLES............................................................................................ 54 
8. 
SAFETY MONITORING AND REPORTING ................................................................... 55 
8.1 
OVERVIEW ................................................................................................................... 55 
8.2 
DEFINITIONS ................................................................................................................ 55 
8.2.1 
Adverse Event (AE) ...................................................................................................................55 
8.2.2 
Adverse Reaction and Suspected Adverse Reaction (SAR) .......................................................55 
8.2.3 
Unexpected Adverse Event/Reaction .........................................................................................56 
8.2.4 
Serious Adverse Event (SAE) ....................................................................................................56 
8.3 
GRADING AND ATTRIBUTION OF ADVERSE EVENTS .............................................. 57 
8.3.1 
Grading Criteria ..........................................................................................................................57 
8.3.2 
Grading of Liver Chemistry Abnormalities ...............................................................................57 
8.3.3 
Attribution Definitions ...............................................................................................................58 
8.4 
COLLECTING AND RECORDING ADVERSE EVENTS................................................. 59 
8.4.1 
Collection Period ........................................................................................................................59 
8.4.2 
Collecting Adverse Events .........................................................................................................59 
8.4.3 
Recording Adverse Events .........................................................................................................59 
8.5 
REPORTING ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND EVENTS OF 
SPECIAL INTEREST TO SPONSOR: DAIT/NIAID ........................................................ 60 
8.5.1 
Reporting Adverse Events ..........................................................................................................60 
8.5.2 
Reporting of Serious Adverse Events and Events of Special Interest ........................................60 
8.6 
REPORTING TO HEALTH AUTHORITIES .................................................................... 62 
8.6.1 
Annual Reporting .......................................................................................................................62 
8.6.2 
Expedited Safety Reporting ........................................................................................................62 
8.7 
REPORTING OF ADVERSE EVENTS TO IRBS.............................................................. 63 
8.8 
REPORTING PREGNANCY ........................................................................................... 63 
8.9 
REPORTING UNANTICIPATED PROBLEMS ................................................................ 64 
8.10 
REVIEW OF SAFETY INFORMATION .......................................................................... 64 
8.10.1 
Medical Monitor Review ............................................................................................................64 
8.11 
DATA SAFETY AND MONITORING BOARD REVIEW ................................................ 64 
8.11.1 
Routine DSMB Reviews ............................................................................................................64 

Immune Tolerance Network 
CONFIDENTIAL 
Page 7 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
8.11.2 
Protocol-Defined Interim Safety Reviews ..................................................................................64 
8.11.3 
Ad hoc DSMB Reviews (Stopping Rule Guidance) ..................................................................65 
9. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN ................................... 66 
9.1 
ANALYSIS SAMPLES.................................................................................................... 66 
9.1.1 
Analysis Populations ..................................................................................................................66 
9.2 
ANALYSIS OF ENDPOINTS .......................................................................................... 66 
9.2.1 
Primary Endpoint........................................................................................................................66 
9.2.2 
Secondary and Exploratory Endpoints .......................................................................................66 
9.2.3 
Analysis of Dose-Response Relationship ...................................................................................68 
9.2.4 
Missing Data ...............................................................................................................................68 
9.2.5 
Baseline Characteristics and Demographics...............................................................................68 
9.2.6 
Safety Analysis ...........................................................................................................................68 
9.2.7 
Interim Analysis of Safety Data .................................................................................................69 
9.2.8 
Medical History ..........................................................................................................................69 
9.2.9 
Use of Medications .....................................................................................................................69 
9.3 
SAMPLE SIZE ................................................................................................................ 69 
9.4 
REPORTING DEVIATIONS FROM THE ORIGINAL STATISTICAL PLAN.................... 70 
10. ACCESS TO SOURCE DATA/DOCUMENTS .................................................................. 70 
11. QUALITY CONTROL AND QUALITY ASSURANCE ..................................................... 70 
12. ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD CLINICAL PRACTICE
 ...................................................................................................................................... 71 
12.1 
STATEMENT OF COMPLIANCE ................................................................................... 71 
12.2 
INFORMED CONSENT .................................................................................................. 71 
12.3 
PRIVACY AND CONFIDENTIALITY ............................................................................ 72 
13. PUBLICATION POLICY .................................................................................................. 72 
14. REFERENCES .................................................................................................................. 73 
 
LIST OF APPENDICES 
APPENDIX 1. Schedule of Events ...........................................................................................................78 
APPENDIX 2. Clinical Criteria For Diagnosing Anaphylaxis .................................................................79 
APPENDIX 3. Examples of Strong CYP3A4 Inhibitors, inducers, and P-gp inhibitors..........................80 
LIST OF TABLES 
Table 1 Attribution of Adverse Events .....................................................................................................58 
Table 2 Probability of Events……………. ..............................................................................................69 
Table 3 Confidence Limits ………………………………………………………………………………70 

Immune Tolerance Network 
CONFIDENTIAL 
Page 8 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
LIST OF FIGURES 
Figure 1. Study Schema…………………. ...............................................................................................33 
 
 

Immune Tolerance Network 
CONFIDENTIAL 
Page 9 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
SYNOPSIS 
 
Title 
Evaluation of Brentuximab Vedotin for Diffuse Cutaneous Systemic 
Sclerosis:  A Phase 1/2 Multicenter Randomized, Double Blinded, 
Safety Study 
IND Sponsor 
DAIT NIAID 
 
Conducted by 
Immune Tolerance Network 
 
Protocol Chair(s)  
David Fox and Dinesh Khanna 
 
Accrual Objective 
24 participants who receive sufficient doses of the investigational 
medication to assess safety 
 
Study Treatment 
Three ascending dose cohorts will receive brentuximab vedotin or placebo 
equivalent 
 
Study Design 
This trial will be conducted as a multicenter prospective double blind 
placebo-controlled dose escalation safety study with brentuximab vedotin 
and stable background immunosuppressive therapy in adult individuals with 
dcSSc. Adult male and female participants with dcSSc will be recruited by a 
collaborative group of clinical sites in the United States.   
 
Participants who meet the eligibility criteria will be enrolled without regard 
to gender, race, or ethnicity. Eligible participants will be randomly assigned 
to study treatment, either brentuximab vedotin or placebo equivalent in a 6:2 
ratio favoring brentuximab vedotin. Three dose cohorts are planned with 8 
participants in each cohort, for a total of 24 participants who receive 
sufficient doses of the investigational medication to assess safety. 
 
The doses planned for each ascending dose cohort include 0.6mg/kg, 1.2 
mg/kg, and 1.8 mg/kg brentuximab vedotin or placebo equivalent. All 
cohorts will receive intravenous administration of study medication every 3 
weeks for 21 weeks, for a total of eight doses. Following completion of 
treatment, participants will undergo follow-up visits at weeks 24, 28, 36 and 
48.  
 
After completion of the first 12 weeks of treatment for each of the first two 
cohorts of 8 participants, an interim safety analysis will be conducted and 
reviewed by an independent Safety Review Committee, as described in 
Section 8.11.2.  Approval by the Safety Review Committee following the 
12-week interim safety analysis will be required before proceeding to the 
next higher dose of brentuximab vedotin.  
 
Interim safety analysis will also be conducted at 24 weeks following 
completion of study treatment for each of the first two cohorts of 8 
participants. Following either the week 12 or the week 24 interim safety 

Immune Tolerance Network 
CONFIDENTIAL 
Page 10 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
reviews, the Safety Review Committee can recommend actions regarding 
study conduct, as described in Section 8.11.2. 
 
 
Cohort 1
Brentuximab vedotin
0.6 mg/kg
q3 weeks to week 21 
8 participants
6:2 randomization
SRC* after last 
participant reaches 
week 12
Cohort 2
Brentuximab vedotin
1.2 mg/kg
q3 weeks to week 21
8 participants
6:2 randomization
SRC* after last 
participant reaches 
week 12
Cohort 3
Brentuximab vedotin
1.8 mg/kg
q3 weeks to week 21
8 participants
6:2 randomization
SRC* after last 
participant reaches 
week 24
Safety assessments at 
weeks 24, 28, 36 and 48
SRC* after last 
participant reaches 
week 24
Safety assessments at 
weeks 24, 28, 36 and 48
Safety assessments at 
weeks 24, 28, 36 and 48
* Safety Review Committee: see section 8.11.2
Study Duration 
Total study duration target is 308 weeks: 
• 
Enrollment phase duration target is 260 weeks.  
• 
Study participation phase for each participant is 48 weeks, 
which includes a treatment phase of 21 weeks and a follow-up 
phase of 27 weeks.  
Primary Objective 
To assess the safety and tolerability of brentuximab vedotin in diffuse 
cutaneous systemic sclerosis (dcSSc). 
Primary Endpoint 
The primary endpoint will be the proportion of participants who experience 
at least one Grade 3 or higher adverse event at or before week 48. 
 
Secondary Endpoints 
Safety Endpoints: 
1. 
The proportion of participants who experience at least one 
Grade 3 or higher adverse event at or before weeks 12, 24, 
and 36. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 11 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
2. 
The proportion of participants who experience at least one 
Grade 2 or higher adverse event at or before weeks 12, 24, 
36, and 48. 
3. 
The proportion of participants with Grade 2 or higher 
peripheral neuropathy at or before weeks 12, 24, 36, and 48. 
4. 
The proportion of participants with Grade 3 or higher 
neutropenia at or before weeks 12, 24, 36, and 48. 
5. 
The proportion of participants with any of the following 
Grade 3 or higher adverse events at or before week 48: 
a. 
Peripheral neuropathy. 
b. Neutropenia. 
c. 
Infectious adverse events. 
d. Infusion reactions, including anaphylaxis and new onset 
rash consistent with Stevens-Johnson syndrome, toxic 
epidermal necrolysis, or other drug reaction. 
e. 
PML. 
Exploratory Efficacy Endpoints: 
1. 
Modified Rodnan Skin Score (mRSS) at weeks 12, 24, and 
48. 
2. 
Provisional American College of Rheumatology Combined 
Response Index in Systemic Sclerosis (CRISS) at weeks 24 
and 48. 
3. 
Percent predicted Forced Vital Capacity (FVC) at weeks 24 
and 48 weeks. 
4. 
Physician’s global assessment on a Likert scale at weeks 24 
and 48. 
5. 
Patient’s global assessment on a Likert scale at weeks 24 
and 48. 
6. 
Health-related quality of life (HRQOL) assessed by 
PROMIS-29 version 2.0 at weeks 24 and 48. 
7. 
Physical function assessed by the Scleroderma Health 
Assessment Questionnaire-Disability Index (SHAQ-DI) at 
weeks 24 and 48. 
 
Inclusion Criteria 
1. 
Classification of systemic sclerosis (SSc), as defined using 
the 2013 American College of Rheumatology/European 
Union League Against Rheumatism classification of SSc. 
2. 
Diagnosis of dcSSc, as defined by LeRoy and Medsger. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 12 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
3. 
Disease duration ≤ 60 months (defined as time from the first 
non-Raynaud phenomenon manifestation). 
4. 
mRSS units ≥ 15 and ≤ 45, and both of the following: 
a. 
At least mild skin thickening ( ≥ 1+ mRSS) of the 
forearm, and 
b. At least moderate skin thickening (≥ 2+ mRSS) at the 
planned forearm skin biopsy site. 
5. 
Documentation of at least 12 weeks of ongoing 
immunosuppressive therapy for SSc at the time of 
enrollment, and at least 4 weeks at a stable dose, of one of 
the following: 
a. Methotrexate ≤ 25 mg/week, or 
b. Mycophenolate mofetil ≤ 3 grams/day or 
mycophenolate sodium ≤ 2.16 grams/day, or 
c. Azathioprine ≤ 3mg/kg/day. 
6. 
Age 18-70 years inclusive. 
7. 
Completion of primary SARS-CoV-2 vaccination series is 
required at least 14 days prior to the first infusion of study 
medication at Visit 0. The dose and schedule of the vaccine 
is defined according to current FDA approval or Emergency 
Use Authorization at the time of screening. 
8. 
Ability to provide informed consent. 
 
Exclusion Criteria 
1. 
Rheumatic disease other than dcSSc; it is acceptable to 
include patients with osteoarthritis, fibromyalgia, sicca 
symptoms, and scleroderma-associated myopathy. 
2. 
Limited cutaneous SSc or sine scleroderma. 
3. 
Pulmonary disease with FVC ≤ 60% of predicted, or DLCO 
(corrected for hemoglobin) ≤ 60% of predicted. 
4. 
Pulmonary hypertension (PH) or moderate to severe left 
ventricular dysfunction defined as one of the following: 
a. Transthoracic echocardiography demonstrating at least 
one of the following (unless subsequent right heart 
catheterization does not demonstrate PH; or unless prior 
right heart catheterization within one year did not 
demonstrate PH and echocardiography results are not 
significantly changed):  

Immune Tolerance Network 
CONFIDENTIAL 
Page 13 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
i. Tricuspid regurgitation jet >2.8 m/sec or 
estimated right ventricular systolic pressure > 
42 mm Hg, or 
ii. At least one of the following: 
1. Abnormality of right atrial size, 
shape, or wall thickness consistent 
with PH, or 
2. Abnormality of right ventricular 
size, shape, or wall thickness 
consistent with PH, or 
3. Abnormal septal wall shape 
consistent with PH. 
iii. Left Ventricular Ejection Fraction (LVEF) < 
50%. 
b. Right heart catheterization showing mean pulmonary 
artery pressure ≥25 mm Hg at rest. 
c. Current use of approved medications for PH. It is 
acceptable to use phosphodiesterase type 5 (PDE-5) 
inhibitors for Raynaud’s, digital ulcers, and 
intermittently for erectile dysfunction. 
5. 
Active scleroderma renal crisis within the 4 months prior to 
enrollment.  
6. 
History of moderate-to-severe lower gastrointestinal 
dysmotility such as current use of parenteral nutrition and/or 
recent history of intestinal pseudo-obstruction within 3 
months prior to enrollment. 
7. 
The following medications: 
a. Oral corticosteroids >10 mg/day of prednisone or 
equivalent within 2 weeks prior to enrollment. 
b. Treatment with intravenous immunoglobulin (IVIG) 
within 12 weeks prior to enrollment. 
c. Treatment with cyclophosphamide within 6 months 
prior to enrollment. 
d. Use of investigational biologic or non-biologic 
medication within the past 90 days, or 5 half-lives prior 
to enrollment, whichever is greater, except for SARS-
CoV-2 vaccines, and medications used for prevention 
and treatment of COVID-19, per FDA Emergency Use 
Authorization. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 14 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
e. Use of anti-TNF medication or other biologic 
medications within the past 90 days, or 5 half-lives prior 
to enrollment, whichever is greater. 
f. Prior treatment with anti-CD20 if either of the following 
are true: 
i. B cells ≤ lower limit of normal (LLN), or 
ii. Treatment with anti-CD20 has been within 12 
months prior to enrollment. 
g. Any prior treatment with cell-depleting therapies other 
than anti-CD20, including investigational agents, 
including but not limited to, CAMPATH®, anti-CD4, 
anti-CD5, anti-CD3, anti-CD19. 
h. Any prior treatment with chlorambucil, bone marrow 
transplantation, or total lymphoid irradiation. 
8. 
Receipt of a live-attenuated vaccine within 3 months of 
study enrollment. 
9. 
Concomitant malignancies or a history of malignancy, with 
the exception of adequately treated basal and squamous cell 
carcinoma of the skin, or carcinoma in situ of the cervix. 
10. 
Major surgery (including joint surgery) within 8 weeks prior 
to enrollment. 
11. 
History of solid organ or hematopoietic stem cell 
transplantation.  
12. 
History of primary immunodeficiency. 
13. 
Comorbidities requiring systemic corticosteroid therapy, 
including those which have required three or more courses of 
systemic corticosteroids within the 12 months prior to 
enrollment. 
14. 
Current substance abuse or history of substance abuse within 
12 months prior to enrollment. 
15. 
History of severe depression or severe psychiatric condition. 
16. 
Lack of peripheral venous access. 
17. 
Known hypersensitivity to brentuximab vedotin, a 
component thereof, or the excipient contained in the drug 
formulation. 
18. 
Severe, progressive, or uncontrolled renal, hepatic, 
hematological, gastrointestinal, pulmonary, cardiac, or 
neurological disease (or, in the investigator’s opinion, any 
other concomitant medical condition that places the 

Immune Tolerance Network 
CONFIDENTIAL 
Page 15 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
participant at risk by participating in this study), including 
but not limited to: 
a. Uncompensated congestive heart failure (New York 
Heart Association Class III or VI). 
b. Clinically significant active coronary artery disease 
(e.g., unstable angina or acute myocardial infarction 
within 6 months prior to enrollment). 
c. Recently active cerebrovascular disease (e.g., stroke or 
transient ischemic attack within 6 months prior to 
enrollment). 
d. Uncontrolled systemic hypertension. 
e. Confirmed diagnosis of diabetes mellitus. 
f. Pancreatitis within 30 days prior to enrollment. 
g. History or presence of peripheral neuropathy, such as 
mononeuritis multiplex, acute or chronic inflammatory 
demyelinating polyneuropathy, axonal sensorimotor 
neuropathies, or drug related neuropathy or neuritis. 
19. 
Evidence of infection: 
a. Any infected ulcer at enrollment. 
b. Active bacterial, viral, fungal, or opportunistic 
infections requiring systemic anti-infective therapy. 
c. Evidence of current or prior infection with tuberculosis 
i. Positive QuantiFERON® – TB Gold or TB 
Gold Plus test results. Purified protein 
derivative (PPD) tuberculin test may be 
substituted for QuantiFERON® – TB Gold or 
TB Gold Plus test. 
ii. Indeterminant QuantiFERON® – TB Gold or 
TB Gold Plus test results, unless followed by 
a subsequent negative PPD or negative 
QuantiFERON® and clearance by local 
Infectious Disease department. 
d. Evidence of current or prior infection with  
i. Human immunodeficiency virus (HIV), or 
ii. Hepatitis B (as assessed by hepatitis B surface 
antigen, HBsAg and antibody to hepatitis B 
core antigen, anti-HBc), or  
iii. Hepatitis C (HCV), except adequately treated 
HCV with documentation of sustained 

Immune Tolerance Network 
CONFIDENTIAL 
Page 16 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
virologic response defined as undetectable 
HCV RNA at least 12 weeks after the end of 
treatment. 
e. History of progressive multifocal leukoencephalopathy 
(PML). 
f. Hospitalization for treatment of infections, or parenteral 
(intravenous or intramuscular) antibacterial, antivirals, 
anti-fungal, or anti-parasitic agents within the past 60 
days prior to enrollment. 
g. Chronic infection that is currently being treated with 
systemic suppressive antibiotic or antiviral therapy, 
including but not limited to tuberculosis, pneumocystis, 
cytomegalovirus, herpes simplex virus, herpes zoster, 
and atypical mycobacteria. 
h. History of significant infection or recurrent infection 
that, in the investigator’s opinion, places the participant 
at risk by participating in this study. 
i. Positive PCR test for SARS-CoV-2 within the two 
weeks prior to enrollment. 
20. 
The following laboratory abnormalities: 
a. Neutropenia (absolute neutrophil count <1500/mm3). 
b. Thrombocytopenia (platelets <100,000/mm3). 
c. Moderately severe anemia (hemoglobin, Hgb < 10 
g/dL). 
d. Liver function test (aspartate aminotransferase [AST], 
alanine aminotransferase [ALT], or alkaline 
phosphatase) results that are ≥ 1.5 times the upper limit 
of normal. 
e. Serum total bilirubin > 1.5 times the upper limit of 
normal, or > 3 times the upper limit of normal in the 
presence of Gilbert’s syndrome. 
f. Serum amylase and serum lipase > 1.5 times the upper 
limit of normal. 
21. 
Renal dysfunction, defined as either one of the following: 
a. Serum creatinine > 1.5 times the upper limit of normal. 
b. Estimated glomerular filtration rate (eGFR) < 60 
mL/min/1.73m2. 
22. 
Pregnancy. 
23. 
Breastfeeding. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 17 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
24. 
Unwillingness to use two forms of medically acceptable  
contraception methods by participants and their partners (if 
of reproductive potential) during the study and for at least 6 
months after last dose of study drug. 
25. 
Inability to comply with study and follow-up procedures. 
 
 
 

Immune Tolerance Network 
CONFIDENTIAL 
Page 18 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
ABBREVIATIONS 
ABVD 
Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine 
AE 
Adverse Event 
ALCL 
Anaplastic Large Cell Lymphoma 
ALT 
Alanine Aminotransferase 
ANA 
Anti-Nuclear Antibodies 
ASCT 
Autologous Stem Cell Transplant 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CBC  
Complete Blood Count 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CRISS 
Combined Response Index in Systemic Sclerosis 
CRP 
C-Reactive Protein 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP3A4 
Cytochrome P450 3A4 
dcSSC 
Diffuse Cutaneous Systemic Sclerosis 
DAIT 
Division of Allergy, Immunology, and Transplantation 
DSC 
Discontinuation Visit 
DLCO 
Diffusing Capacity of the Lung for Carbon Monoxide   
DSMB 
 
Data and Safety Monitoring Board 
eCRF  
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
EKG 
Electrocardiogram 
ELISPOT 
Enzyme-linked Immunospot 
ESR  
Erythrocyte Sedimentation Rate 
FDA 
Food and Drug Administration  

Immune Tolerance Network 
CONFIDENTIAL 
Page 19 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
FEV1 
Forced Expiratory Volume 1 
FVC 
Forced Vital Capacity 
GCP 
Good Clinical Practice  
GVHD 
Graft Versus Host Disease 
HBsAg 
Hepatitis B Surface Antigen 
HBc 
Hepatitis B Core Antigen 
HCG 
Human Chorionic Gonadotropin 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
HRQOL 
Health-related quality of life 
HL  
Hodgkin’s lymphoma 
IB 
Investigator’s brochure 
ICH 
International Conference on Harmonisation 
ICOS 
Inducible Costimulator 
IHC 
Immunohistochemistry 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ISH 
In Situ Hybridization 
ITN 
Immune Tolerance Network 
IVIG  
Intravenous Immunoglobulin 
LLN 
Lower Limit of Normal 
LVEF 
Left Ventricular Ejection Fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMAE  
Monomethyl Auristatin E 
mRSS 
Modified Rodnan Skin Score 
NCI 
National Cancer Institute 
NIAID 
National Institute of Allergy and Infectious Diseases 

Immune Tolerance Network 
CONFIDENTIAL 
Page 20 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
NIH 
National Institutes of Health 
NK  
Natural Killer 
OHRP 
Office for Human Research Protections 
OSHA 
Occupational Safety and Health Administration 
PBMC 
Peripheral Blood Mononuclear Cell 
PCR 
Polymerase Chain Reaction 
PDE-5 
Phosphodiesterase type 5 
P-gp 
P-glycoprotein 
PH  
Pulmonary Hypertension 
PML 
Progressive Multifocal Leukoencephalopathy 
PP 
Per Protocol 
PPD 
Purified Protein Derivative  
RA 
Rheumatoid Arthritis 
REMS 
Risk Evaluation and Mitigation Strategy 
RNA 
Ribonucleic Acid 
SACCC 
Statistical and Clinical Coordinating Center 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SCID  
Severe Combined Immunodeficiency 
SHAQ-DI 
Scleroderma Health Assessment Questionnaire-Disability 
Index 
SLE 
Systemic Lupus Erythematosus 
SNP 
Single Nucleotide Polymorphisms 
SOP 
Standard Operating Procedure 
SSc 
Systemic Sclerosis 

Immune Tolerance Network 
CONFIDENTIAL 
Page 21 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
 
 
 
 
 
 
SRC 
Safety Review Committee 
ULN 
     Upper Limit of Normal 
WHO 
     World Health Organization 
 
 

Immune Tolerance Network 
CONFIDENTIAL 
Page 22 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
1. 
BACKGROUND AND RATIONALE 
1.1 
BACKGROUND 
Systemic sclerosis (SSc) is a rare autoimmune condition characterized by fibrosis, 
inflammation, and micro vasculopathy affecting multiple organ systems.  Prevalence of 
SSc is reported at approximately 3/10,000 in the United States [3].  The disease is more 
common in females but appears to be more severe in males [1, 2].  Morbidity and 
mortality are high, and there is no effective approved therapy. The diffuse cutaneous 
form of systemic sclerosis (dcSSc), defined by widespread skin involvement, has a poor 
prognosis, with estimated 55% mortality at 10 years [2, 4].  It typically presents as 
Raynaud’s phenomenon and is characterized by sclerodactyly, digital ulcers, and 
proximal cutaneous involvement, complicated by pain, infection, and diminished 
function.  Pulmonary involvement includes interstitial lung disease and pulmonary 
hypertension and is the leading cause of mortality. Esophageal, articular, and cardiac 
manifestations are also common. Renal involvement is less common but life-threatening 
due to severe hypertension and scleroderma renal crisis [4, 5].   
There is no Food and Drug Administration (FDA)-approved treatment for dcSSc. 
Treatment options are extremely limited, and include general immunosuppressive agents 
such as methotrexate, mycophenolate mofetil, cyclophosphamide, azathioprine, and 
glucocorticoids [6]. Autologous stem cell transplantation is more efficacious than pulse 
cyclophosphamide for severe systemic sclerosis but is associated with treatment-related 
mortality [7-10]. Biologic therapies are under investigation, and rituximab and 
tocilizumab show promise.  Case series with rituximab have reported skin score 
improvements [11], but no placebo-controlled trial data is available. A recent phase II 
randomized controlled trial of tocilizumab did not meet its primary endpoint, but 
exploratory analyses suggested benefit in terms of pulmonary function, and a phase III 
trial is in progress [12, 13].   
In summary, there is significant unmet need for effective treatment options for dcSSc, a 
highly morbid disease associated with life-threatening complications. The present study 
will be a dose-escalation safety trial of brentuximab vedotin, a drug-antibody conjugate 
approved for the treatment of lymphoma and targeted to the CD30 molecule expressed on 
activated T and B lymphocytes. There is evidence for CD30 involvement in SSc, which 
will be described in section 1.2. The study presented in this protocol represents the first 
step in determining safety and tolerability of brentuximab vedotin in SSc, prior to 
proceeding to a future placebo-controlled efficacy study. 
1.2 
SCIENTIFIC RATIONALE 
SSc is characterized by organ fibrosis, with evidence for an underlying autoimmune 
pathogenesis [14].  Anti-nuclear antibodies (ANA) are nearly universal in SSc, and often 
are present with other clinically–associated autoantibodies, including anti-centromere, 
anti-ribonucleic acid (RNA) polymerase 3 and anti-topoisomerase 1 [15]. Autoantibodies 
are typically present at a stage of disease prior to full expression of the clinical 

Immune Tolerance Network 
CONFIDENTIAL 
Page 23 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
phenotype. Only 6.4% of SSc patients are ANA-negative, and these patients may have 
milder disease [16].  
Substantial evidence supports the concept that T cells play a key role in the pathogenesis 
and fibrotic complications of SSc. Skin biopsies obtained from SSc patients early in their 
disease demonstrate a perivascular, mononuclear cell infiltrate comprised of T cells and 
macrophages [17, 18]. T cells are the dominant population of lymphocytes in the skin, 
and are activated [17]. T cell infiltration correlates with skin thickening, suggesting a 
relationship between inflammation and fibrosis. The expression of inducible costimulator 
(ICOS), expressed on activated T cells, is elevated in patients with early dcSSc [19]. 
Also, the T lymphocytes in SSc tissue overexpress TNF receptor II and these cells, when 
costimulated with TNF-α, trigger collagen production by releasing profibrotic cytokines 
[20]. Th2 cells, defined by their production of IL-4, have been implicated in SSc because 
some of their cytokine products, such as IL-13, are pro-fibrotic [21-23]. Recently, a novel 
mechanism has been identified by which the production of IL-4, the signature Th2 
cytokine, leads to fibrosis, through activation of secretion by myeloid cells of pro-fibrotic 
factors that alter the program of gene expression in adjacent fibroblasts in the skin, 
leading to collagen fibril cross-linking [24]. 
CD30 is a target of interest for treatment in SSc. CD30 and its ligand, CD153, are 
members of the TNF-R and TNF families respectively and are expressed on various 
subsets of hematopoietic cells. CD30 is expressed on activated T and B lymphocytes and 
on natural killer cells, while CD153 is more broadly expressed on myeloid, erythroid, 
megakaryocytic and some lymphoid cells. CD30 has been reported to be preferentially 
expressed on Th2 cells [25], a subpopulation implicated in fibrosis [21-23]. Signal 
transduction through CD30 has a variety of consequences in T and B cells, including co-
stimulation, effector cell differentiation, and survival of antigen specific memory cells 
[26, 27], and thus may influence immune cell activation and tolerance.  CD30 is required 
for development of autoimmune disease in a Foxp3-deficient autoimmune mouse model, 
possibly related to CD30’s role in T and B cell memory responses [28, 29]. Moreover, an 
antibody to the CD30 ligand prevented the development of spontaneous diabetes in the 
NOD mouse model [30]. 
Membrane CD30 exists in 105kDa and 120kDa forms, which can be proteolytically 
cleaved to release an 88kDa soluble form of CD30.  Soluble CD30 is elevated in SSc, and 
levels correlate with clinical features such as number of skin lesions and number of 
involved body areas [31-34].  CD30 has been detected on CD4+ T cells in SSc skin 
biopsies, along with high expression of the Th2 cytokine IL-4 in SSc skin [31]. Soluble 
CD30 is also elevated in a number of other autoimmune conditions including rheumatoid 
arthritis (RA), systemic lupus erythematosus (SLE), Hashimoto’s thyroiditis, primary 
biliary cirrhosis, Sjogren’s syndrome, and Wegener’s granulomatosis, and in some cases 
CD30 is expressed on cells in blood and tissues in these conditions [35-44]. Lesional 
skin-infiltrating T lymphocytes express CD30 in acute atopic dermatitis, but not in acute 
contact dermatitis [45]. The association of CD30 with the pro-fibrotic Th2 phenotype and 

Immune Tolerance Network 
CONFIDENTIAL 
Page 24 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
the elevated levels observed in autoimmune diseases, including SSc, support a rationale 
for targeting CD30 as a treatment strategy for SSc. 
1.3 
PRECLINICAL AND CLINICAL EXPERIENCE 
Brentuximab vedotin, also known as SGN-35, is an antibody-drug conjugate, or 
immunotoxin, developed for the treatment of Hodgkin’s lymphoma (HL) and anaplastic 
large cell lymphoma (ALCL) based on expression of CD30 on these tumors [46, 47]. The 
ongoing manufacturer development portfolio includes 21 completed and 9 ongoing 
clinical trials.  Brentuximab vedotin consists of a chimeric IgG1 monoclonal antibody 
directed to CD30 coupled by way of a protease-cleavable linker to the antimitotic toxin 
monomethyl auristatin E (MMAE) [48].  The immunotoxin is internalized by clathrin-
mediated endocytosis upon antibody binding to target cells, followed by cathepsin-
mediated release of the toxin component.  Free intracellular MMAE then binds to  
tubulin, thereby disrupting the microtubule network which results in interruption of the 
cell cycle and cell apoptosis [48].  MMAE is also believed to cause bystander killing by 
way of diffusion into the tumor microenvironment [48, 49].  Other possible mechanisms 
of action of brentuximab vedotin include apoptosis via CD30 ligation [50], and antibody 
dependent cellular phagocytosis [51]. 
1.3.1 Preclinical Studies 
SGN-35 (brentuximab vedotin) was shown to prevent lymphoma tumor growth in Severe 
Combined Immunodeficiency (SCID) mice xenografted with human CD30+ Hodgkin’s 
lymphoma cells or anaplastic large cell lymphoma cells [52, 53].  Tumor growth was 
delayed even if SGN-35 was administered after the tumors were established.  Combining 
SGN-35 with the chemotherapeutic regimen ABVD (doxorubicin, bleomycin, 
vinblastine, and dacarbazine) or with gemcitabine was more effective in treating 
lymphoma tumors in mice than SGN-35 alone or chemotherapy alone [53]. No studies 
have been conducted with brentuximab vedotin in animal models of autoimmunity since 
the antibody component of the immunotoxin does not cross-react with CD30 on murine 
cells. 
Toxicology studies conducted with brentuximab vedotin in cynomologus monkeys 
demonstrated toxicities in hematopoietic compartments consistent with MMAE, 
including lymphoid depletion, bone marrow hypocellularity, and neutropenia [54].  
Studies in rats showed impaired fertility in males, lethal embryo and fetal effects, and 
teratogenicity, resulting in the assignment of Pregnancy Category D [54]. 
1.3.2 Clinical Studies  
1.3.2.1 Clinical studies with brentuximab vedotin for CD30-positive 
lymphomas. 
Brentuximab vedotin is approved for previously untreated Stage III or IV classical HL in 
combination with chemotherapy, for HL at high risk of relapse or progression following 
autologous stem cell transplant (ASCT), and for HL after failing ASCT or after failing at 
least two multi-agent chemotherapeutic regimens when transplant is not an option [55]. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 25 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
Brentuximab vedotin is also approved for previously untreated systemic ALCL or other 
CD-30 expressing peripheral T cell lymphoma in combination with chemotherapy, for 
systemic ALCL after failing at least one multi-agent chemotherapeutic regimen, and for 
primary cutaneous ALCL and CD30-expressing mycosis fungoides after receiving prior 
systemic treatment [55]. Accelerated approval was obtained in 2011 based on the results 
of two single arm phase II clinical trials in HL and ALCL [54].  
In a pivotal phase II trial in relapsed or refractory HL following ASCT, 102 participants 
received intravenous brentuximab vedotin 1.8 mg/kg every three weeks for up to 16 
doses [56]. The overall disease control rate (complete remission + partial remission + 
stable disease) was 96%, with a median progression-free survival of 5.6 months. 
Complete remission was observed in 34% of participants, and the median progression-
free survival in these complete remission participants was 20.5 months. Durable 
remission was reported in approximately half of the participants who achieved complete 
remission after a median of 53 months of follow-up [57].  
In a second pivotal phase II trial in relapsed or refractory ALCL, 58 participants received 
intravenous brentuximab vedotin 1.8 mg/kg every three weeks for up to 16 doses [58]. 
Complete remission was achieved in 57% of participants, and partial remission was 
achieved in 29% of participants. The estimated median duration of progression-free 
survival was 13.4 months.  
Of note, in a phase II trial of brentuximab vedotin monotherapy in treatment-naïve 
participants with HL who were age 60 and older, 73% of participants achieved complete 
remission and 100% of participants achieved stable disease or better [59]. Brentuximab 
vedotin was generally well-tolerated in this older group of participants (median age 78) 
who were not eligible for or who had declined conventional combination 
chemotherapeutic regimens. 
A phase III trial of brentuximab vedotin as consolidation therapy in 329 HL patients 
considered to be at risk for relapse or progression following ASCT demonstrated 
significant improvement in progression-free survival compared to placebo [60].  
Ongoing studies with brentuximab vedotin include monotherapy or combination with 
standard of care for treatment of HL, ALCL, CD30-positive cutaneous T cell lymphoma, 
CD30-positive mature T-cell lymphoma, and diffuse large B cell lymphoma. 
1.3.2.2 Clinical studies with brentuximab vedotin in graft versus host disease.  
A phase 1 trial of brentuximab vedotin for treatment of established steroid-refractory 
graft versus host disease (GVHD) was undertaken based on the observation that an 
increased percentage of central memory CD8 T cells express CD30 and soluble CD30 is 
elevated at the onset of acute GVHD [61]. This trial is completed (NCT01596218), and 
early results demonstrated a 37% response rate including some complete responses [62]. 
In contrast, a phase 1 trial of brentuximab vedotin for prevention of GVHD was stopped 
early due to the occurrence of GVHD in the participants [63].   

Immune Tolerance Network 
CONFIDENTIAL 
Page 26 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
1.3.2.3 Clinical studies with brentuximab vedotin in autoimmune disease.  
Seattle Genetics has received case reports of improvement in comorbid autoimmune 
disease manifestations in a number of individuals treated for lymphoma with 
brentuximab vedotin. The majority of reports indicate improvements in relatively 
common diseases such as RA and SLE, including one published case report in RA [64]. 
This report describes a 76-year-old woman with long-standing RA inadequately 
controlled on TNF inhibitor and methotrexate therapy, who experienced a complete 
remission of RA while treated with brentuximab vedotin for Stage IV Hodgkin’s 
lymphoma, despite discontinuation of TNF inhibitor therapy, methotrexate, and steroids. 
Improvements have also been observed in a number of less common autoimmune 
conditions, including SSc and interstitial lung disease. Based on the reports of 
improvement in SLE and other autoimmune conditions in patients treated with 
brentuximab vedotin for lymphoma, Seattle Genetics initiated a dose escalation phase 2a 
trial of brentuximab vedotin in SLE [65]. Seattle Genetics terminated the study before 
completion due to revised business portfolio prioritization (NCT02533570).  
1.4 
SUMMARY OF KNOWN AND POTENTIAL RISKS AND BENEFITS FOR 
HUMAN PARTICIPANTS  
1.4.1 Risks  
Brentuximab vedotin is associated with a number of known toxicities as summarized in 
the prescribing information [55].  A safety review of brentuximab vedotin for HL has 
been published [66]. Brentuximab vedotin has been tested and approved for relapsed or 
refractory HL and ALCL following at least one prior high dose multi-agent regimen of 
chemotherapy, and prior autologous stem cell transplant in the case of HL. As such, the 
adverse events described below have generally occurred in the setting of prior or 
concurrent high dose chemotherapy. 
Adverse events occurring in greater than or equal to 10% of participants in the pivotal 
phase II trial in HL included peripheral sensory neuropathy, nausea, fatigue, neutropenia, 
diarrhea, pyrexia, vomiting, arthralgia, pruritus, myalgia, peripheral motor neuropathy, 
and alopecia [56]. Treatment emergent hyperglycemia has been reported at 5.4% to 
12.1% across studies, with associated risk factors being pre-existing hyperglycemia and 
high body mass index greater than 30 kg/m2 [65]. Serious events of hyperglycemia 
reported in people treated with brentuximab vedotin include new onset hyperglycemia, 
exacerbations of pre-existing diabetes mellitus, and ketoacidosis (including fatal 
outcomes) [65]. The prescribing information highlights specific warnings for peripheral 
neuropathy, anaphylaxis and infusion reactions, neutropenia, thrombocytopenia, anemia, 
serious and opportunistic infections, hepatotoxicity, pulmonary toxicity, gastrointestinal 
complications, Stevens-Johnson syndrome, toxic epidermal necrolysis, and fetal harm, 
with a black box warning for progressive multifocal leukoencephalopathy (PML).  

Immune Tolerance Network 
CONFIDENTIAL 
Page 27 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
1.4.1.1 Risk of Peripheral Neuropathy 
Peripheral sensory neuropathy is the most commonly known risk of brentuximab vedotin, 
with peripheral motor neuropathy reported at a lower incidence. In the phase II pivotal 
clinical trial in HL, peripheral sensory neuropathy occurred in 42% of participants and 
peripheral motor neuropathy occurred in 11% of participants [56].  In this trial, 
brentuximab vedotin was administered every three weeks for a maximum of 16 doses. 
Peripheral neuropathy was the most common adverse event leading to treatment 
discontinuation or dose reduction. The majority of events were Grade 1 or Grade 2 
peripheral sensory neuropathy events, consisting of numbness and tingling of fingers and 
toes. The median time to onset of any peripheral neuropathy event was 12.4 weeks, to 
Grade 2 events was 27.3 weeks, and to Grade 3 events was 38.0 weeks.  The peripheral 
neuropathy events improved by at least one grade in 80% of those affected and resolved 
completely in 50% [56].  
Similar results were reported in the phase II pivotal trial in ALCL and a phase III 
placebo-controlled trial of brentuximab vedotin for consolidation therapy after ASCT for 
HL [58, 60]. There were no Grade 4 peripheral neuropathy events in any of these three 
studies, however peripheral motor neuropathy events were categorized as serious in 4% 
of participants in the pivotal phase II HL trial [54]. Of note, in the pivotal phase II trials, 
24% of participants had pre-existing peripheral neuropathy at baseline.  
As described in the Investigator’s Brochure (IB), the median duration of treatment was 
approximately 48 weeks in the phase III trial of consolidation therapy following ASCT in 
HL patients [60]. Worsening of neuropathy was mitigated by reduction and delay in 
dosing. Peripheral neuropathy events tended to worsen with longer treatment exposure, 
with the first onset at approximately 12 weeks after the first dose of brentuximab vedotin. 
Grade 3 peripheral neuropathy events occurred at a median of approximately 34 weeks. 
The majority of events improved or resolved by a median of approximately 23 weeks.  
Patients enrolled in a retreatment or extension treatment trial had more peripheral 
neuropathy at baseline compared to the pivotal phase II studies, and also developed more 
peripheral neuropathy events [65]. 
As of August 2020, a search of the clinical trial database found treatment emergent 
peripheral neuropathy (sensory and motor) occurred in 1394 participants (55%). Most of 
the events (1177, or 47%) were ≤ Grade 2 [65]. 
The prescribing information for brentuximab vedotin as monotherapy reports 62% of 
patients experienced any grade of neuropathy. The median time to onset was three 
months (range 0-12). Of patients experiencing neuropathy, 62% had complete resolution 
of symptoms, 24% had partial improvement, and 14% had no improvement at the time of 
the last evaluation. The prescribing information recommends temporary discontinuation 
and subsequent dose modification for Grade 2 or Grade 3 peripheral neuropathy, and 
permanent discontinuation for Grade 4 peripheral neuropathy [55]. In the trial described 
in this protocol, the dose of brentuximab vedotin will be suspended if a participant 

Immune Tolerance Network 
CONFIDENTIAL 
Page 28 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
develops Grade 2 peripheral neuropathy and restarted at a lower dose if the peripheral 
neuropathy resolves. Brentuximab vedotin will be permanently discontinued for Grade 3 
or greater peripheral neuropathy (see section 5.2). Participants will be excluded if they 
are older than 70 years of age, if they have diabetes, or if they have pre-existing 
peripheral neuropathy (see section 4.2).  In addition, participants will be monitored for 
peripheral neuropathy throughout the trial. 
1.4.1.1.1 
Risk of peripheral neuropathy in participants age 60 and older 
In a small trial of 27 participants age 60 and older with HL (median age 78), peripheral 
neuropathy events occurred in a higher proportion of participants than observed in the 
pivotal phase II trials [59]. Treatment emergent peripheral neuropathy adverse events 
occurred in 89% of participants, with Grade 3 peripheral neuropathy occurring in 30%. 
Peripheral neuropathy events improved or resolved in 58% of affected participants.  
Comorbid risk factors for peripheral neuropathy adverse events included diabetes, 
hypothyroidism and pre-existing peripheral neuropathy. Of 13 participants with diabetes 
and/or hypothyroidism, 6 participants developed Grade 3 peripheral neuropathy, 
compared to 2 of the 14 participants without diabetes and/or hypothyroidism. The first 
onset of grade 3 peripheral neuropathy occurred earlier in this older population compared 
to the onset observed in the pivotal phase II trials, at a median of 16.6 weeks for older 
participants with comorbid risk factors, and a median of 15.4 weeks for older participants 
without comorbid risk factors [59]. 
1.4.1.2 Risk of Cytopenia, Serious Infections, and PML. 
Neutropenia was the most common Grade 3 or Grade 4 adverse event in the pivotal phase 
II trials of brentuximab vedotin in HL and ALCL, occurring in 26% of participants.  
Grade 3 or greater thrombocytopenia and anemia were also reported [54, 56, 58]. The 
prescribing information for brentuximab vedotin recommends temporary discontinuation 
and consideration of G-CSF for grade 3 or grade 4 neutropenia, and permanent 
discontinuation or dose reduction for grade 4 neutropenia that recurs [55]. In this 
protocol, brentuximab vedotin will be discontinued for Grade 3 or greater neutropenia or 
thrombocytopenia (section 5.2). 
Although serious infections were not common in the pivotal phase II trials, one 
participant in an early dose finding study died after developing febrile neutropenia and 
sepsis. This participant received 3.6 mg/kg brentuximab vedotin (twice the dose that was 
subsequently approved) [46]. Other fatal infectious adverse events included influenzal 
pneumonia and cytomegalovirus infection [65]. Pneumocystic carinii pneumonia has also 
occurred [65]. Although rare, PML has been reported in 5 individuals receiving 
brentuximab vedotin [67, 68], resulting in the addition of a black box warning for PML to 
the prescribing information [55]. The incidence of PML in cancer patients treated with 
brentuximab vedotin was < 0.05% [65]. 
In the phase III trial of brentuximab vedotin as consolidation therapy following high dose 
immunotherapy and autologous stem cell transplantation for refractory HL, serious 

Immune Tolerance Network 
CONFIDENTIAL 
Page 29 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
infections were reported in 15 participants (9%) in the brentuximab vedotin arm and 7 
participants (4%) in the placebo arm, with pneumonia as the most common serious 
infection [65]. Herpes simplex and herpes zoster infections occurred more commonly in 
the brentuximab vedotin arm, while other opportunistic infections were rare. Overall, in 
the pivotal studies serious infections were reported in 10% of patients. Treatment-related 
serious adverse events included pneumonia, urinary tract infection, staphylococcus 
bacteremia, and pneumocystis carinii pneumonia. Grade 1 or Grade 2 upper respiratory 
infection was the infection with the highest incidence [65]. 
In a phase III trial of brentuximab vedotin compared to physician’s choice of 
methotrexate or bexarotene for CD-30 positive cutaneous T cell lymphoma, serious 
infectious adverse events related to study drug occurred in 4 participants. These included 
Grade 3 impetigo, Grade 3 diverticulitis, and Grade 3 cellulitis [65]. All three serious 
infectious adverse events resolved without sequelae. One participant in each arm of the 
trial had infectious adverse events associated with Grade 3 or Grade 4 neutropenia.  
 
1.4.1.2.1 
Risk of SARS-CoV-2 infection 
There is a risk of SARS-CoV-2 infection during study conduct. Participants will be 
educated and advised about the importance of strict adherence to the Centers for Disease 
Control and Prevention (CDC) recommendations for reducing the risk of SARS-CoV-2 
infection, including mask wearing, social distancing, and hand washing. Completion of a 
primary SARS-CoV-2 vaccination series is required 14 days prior to the first infusion of 
study medication. The dose and schedule of the vaccine is defined according to current 
FDA approval or Emergency Use Authorization at the time of screening. Additional 
doses of SARS-CoV-2 vaccines are permitted if authorized by the FDA during study 
conduct. 
Participants are required to have a negative SARS-CoV-2 PCR test prior to enrollment.  
Study medication will be suspended if the participant develops symptomatic or 
asymptomatic SARS-CoV-2 infection, or any other infection that the investigator judges 
to be significant. Participants with confirmed mild or moderate SARS-CoV-2 infection 
will be evaluated for treatment with a monoclonal antibody product authorized by the 
FDA for the treatment of COVID-19, as soon as possible following confirmation of the 
infection and within 10 days of symptom onset [69-71]. Additionally, any participant 
who has close contact with a SARS-CoV-2 infected individual should be evaluated for 
post-exposure prophylaxis as soon as possible after exposure [69, 70]. Use of other 
therapeutic agents for the treatment of SARS-CoV-2 that have been authorized or 
approved by the FDA may also be considered, depending on the clinical circumstance. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 30 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
1.4.1.3 Risk of Pancreatitis, Hepatotoxicity, and Other Gastrointestinal 
Complications 
Eight cases of pancreatitis have been reported to be associated with brentuximab vedotin, 
including two fatal cases.  All cases presented with abdominal pain, nausea, and elevated 
lipase [72].  One case of acute pancreatitis was also reported in the phase III placebo-
controlled trial of brentuximab vedotin consolidation therapy after HSCT for HL [60].  In 
clinical trials the incidence of acute pancreatitis is ≤0.3% and ≤0.2% in the post-
marketing setting [65]. 
Hepatotoxicity has been reported in association with brentuximab vedotin, in some cases 
fatal. The majority of events were mild to moderate asymptomatic transaminase 
elevations. The reported incidence of hepatobiliary disorder is < 2% in clinical studies 
and post-marketing experience [65]. 
Other gastrointestinal complications were reported to be common in trials with 
brentuximab vedotin, including nausea, vomiting, abdominal pain, and diarrhea, although 
the majority of these adverse events were Grade 2 or less [54, 56, 58].  Additional serious 
gastrointestinal complications have been reported, including perforation, hemorrhage, 
erosion, ulcer, intestinal obstruction, enterocolitis, neutropenic colitis, and ileus. 
1.4.1.4 Risk of Infusion Reactions, Pulmonary Toxicity, and Skin and 
Subcutaneous Tissue Disorders 
Two cases of anaphylaxis occurred in phase 1 trials with brentuximab vedotin. Grade 1 or 
Grade 2 infusion reactions were reported in 12% of participants in the pivotal phase II 
trials, including chills, nausea, dyspnea, pruritis, fever, and cough [54]. 
Pulmonary toxicity associated with brentuximab vedotin has been reported, primarily 
when combined with bleomycin [73]. Pulmonary adverse events were also reported in 
both the brentuximab vedotin group and the placebo group in a phase III trial of 
consolidation therapy following ASCT for HL, including two deaths in the brentuximab 
vedotin group resulting from acute respiratory distress syndrome [60]. Fatal and serious 
events of non-infectious pulmonary toxicity including pneumonitis, interstitial lung 
disease, and acute respiratory distress syndrome have been reported with brentuximab 
vedotin monotherapy. Although a causal relationship has not been established, pulmonary 
toxicity related to brentuximab vedotin monotherapy has not been ruled out [65]. 
Although rare, fatal and serious Stevens-Johnson syndrome and toxic epidermal 
necrolysis have been reported in association with brentuximab vedotin [54, 65, 74]. Rash 
and alopecia were common adverse events reported in the pivotal phase II clinical trials 
[54, 56, 58]. 
1.4.1.5 Risk of Embryo and Fetal Harm and Impaired Fertility 
Decreased embryo viability and teratogenicity, including fetal malformations, have been 
described in animal studies. Brentuximab vedotin may damage spermatozoa and 
testicular tissue, resulting in possible genetic abnormalities. Hence women receiving 

Immune Tolerance Network 
CONFIDENTIAL 
Page 31 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
brentuximab vedotin and female partners of men receiving brentuximab vedotin should 
take measures to prevent pregnancy during treatment with brentuximab vedotin and for at 
least six months after the final dose of brentuximab vedotin. Requirements for 
contraception are outlined in protocol section 5.3.1.2. Decreased male fertility has also 
been associated with brentuximab vedotin in animal studies [54, 55, 65].  
1.4.1.6 Risk of Drug Interaction with Cytochrome P450 3A4 Inhibitors or 
Inducers, or P-glycoprotein Inhibitors 
Concomitant use of strong Cytochrome P450 3A4 (CYP3A4) inhibitors or inducers, or P-
glycoprotein (P-gp) inhibitors, has the potential to affect the exposure to MMAE. 
Participants who are receiving strong CYP3A4 inhibitors or inducers, or P-gp inhibitors, 
should be closely monitored for adverse reactions [55]. A specific precaution for 
potential drug interactions is provided in Section 5.3.4.1, and examples are provided in 
Appendix 3. These agents will be avoided whenever possible. 
1.4.2 Benefits 
As noted in section 1.1, there are no FDA-approved therapies for dcSSc, and 
immunosuppressive drugs do not adequately control disease [6].  Although individual 
participants in this trial should not anticipate direct benefit, a dose escalation safety study 
is the first step in evaluating brentuximab vedotin as a treatment for dcSSc.  A future 
placebo-controlled clinical trial testing the efficacy of brentuximab vedotin for dcSSc 
could then lead to benefit for individuals suffering from this morbid and life-threatening 
condition. 
2. 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
To assess the safety and tolerability of brentuximab vedotin in diffuse cutaneous systemic 
sclerosis (dcSSc). 
2.2 
SECONDARY OBJECTIVES 
Safety Objectives 
1. 
To assess safety events that occur during and following brentuximab vedotin 
administration in dcSSc. 
2. 
To assess peripheral neuropathy and neutropenia during and following brentuximab 
vedotin administration in dcSSc. 
Exploratory Efficacy Objectives 
1. 
To assess cutaneous, pulmonary, and other clinical manifestations of dcSSc during 
and following brentuximab vedotin administration. 
2. 
To assess patient-reported quality of life measures in dcSSc during and following 
brentuximab vedotin administration. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 32 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
2.3 
EXPLORATORY MECHANISTIC OBJECTIVES 
1. 
To analyze immune cell populations and cytokines in the skin and blood during 
and following brentuximab vedotin administration. 
2. 
To analyze autoantibodies and soluble CD30 during and following brentuximab 
vedotin administration. 
3. 
To analyze genetic signatures of disease, inflammation, and fibrosis during and 
following brentuximab vedotin administration. 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION 
This trial will be conducted as a multicenter prospective double blind placebo-controlled 
dose escalation safety study with brentuximab vedotin and stable background 
immunosuppressive therapy in adult individuals with dcSSc. Adult male and female 
participants with dcSSc will be recruited by a collaborative group of clinical sites in the 
United States.  Participants who meet the eligibility criteria will be enrolled without 
regard to gender, race, or ethnicity. Eligible participants will be randomly assigned to 
study treatment, either brentuximab vedotin or placebo equivalent in a 6:2 ratio favoring 
brentuximab vedotin. Three dose cohorts are planned with 8 participants in each cohort, 
for a total of 24 participants who receive sufficient doses of the investigational 
medication to assess safety (Section 4.5). 
The doses planned for each ascending dose cohort include 0.6mg/kg, 1.2 mg/kg, and 1.8 
mg/kg brentuximab vedotin or placebo equivalent. All cohorts will receive intravenous 
administration of study medication every 3 weeks for 21 weeks, for a total of eight doses.  
Following completion of treatment, participants will undergo follow-up visits at weeks 
24, 28, 36 and 48.  
After completion of the first 12 weeks of treatment for each of the first two cohorts of 8 
participants, an interim safety analysis will be conducted and reviewed by an independent 
Safety Review Committee, as described in Section 8.11.2.  Approval by the Safety 
Review Committee following the 12-week interim safety analysis will be required before 
proceeding to the next higher dose of brentuximab vedotin.  
Interim safety analysis will also be conducted at 24 weeks following completion of study 
treatment for each of the first two cohorts of 8 participants. Following either the week 12 
or the week 24 interim safety reviews, the Safety Review Committee can recommend 
actions regarding study conduct, as described in Section 8.11.2. 
 
 

Immune Tolerance Network 
CONFIDENTIAL 
Page 33 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
Cohort 1
Brentuximab vedotin
0.6 mg/kg
q3 weeks to week 21 
8 participants
6:2 randomization
SRC* after last 
participant reaches 
week 12
Cohort 2
Brentuximab vedotin
1.2 mg/kg
q3 weeks to week 21
8 participants
6:2 randomization
SRC* after last 
participant reaches 
week 12
Cohort 3
Brentuximab vedotin
1.8 mg/kg
q3 weeks to week 21
8 participants
6:2 randomization
SRC* after last 
participant reaches 
week 24
Safety assessments at 
weeks 24, 28, 36 and 48
SRC* after last 
participant reaches 
week 24
Safety assessments at 
weeks 24, 28, 36 and 48
Safety assessments at 
weeks 24, 28, 36 and 48
* Safety Review Committee: see section 8.11.2
 
Figure 1. Study Schema 
 
3.2 
STUDY REGIMEN 
Brentuximab vedotin or placebo. 
• 
Cohort 1:  Intravenous brentuximab vedotin 0.6 mg/kg or placebo every three weeks 
for eight doses. 
• 
Cohort 2:  Intravenous brentuximab vedotin 1.2 mg/kg or placebo every three weeks 
for eight doses. 
• 
Cohort 3:  Intravenous brentuximab vedotin 1.8 mg/kg or placebo every three weeks 
for eight doses. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 34 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
3.3 
STUDY DURATION 
Total study duration target is 308 weeks: 
• 
Enrollment phase duration target is 260 weeks.  
• 
Study participation phase for each participant is 48 weeks, which includes a treatment 
phase of 21 weeks and a follow-up phase of 27 weeks.  
3.4 
STUDY ENDPOINTS 
3.4.1 Primary Endpoint 
The primary endpoint will be the proportion of participants who experience at least one 
Grade 3 or higher adverse event at or before week 48. 
3.4.2 Secondary Endpoints 
Safety Endpoints: 
1. 
The proportion of participants who experience at least one Grade 3 or higher 
adverse event at or before weeks 12, 24 and 36. 
2. 
The proportion of participants who experience at least one Grade 2 or higher 
adverse event at or before weeks 12, 24, 36, and 48. 
3. 
The proportion of participants with Grade 2 or higher peripheral neuropathy at or 
before weeks 12, 24, 36, and 48. 
4. 
The proportion of participants with Grade 3 or higher neutropenia at or before 
weeks 12, 24, 36, and 48. 
5. 
The proportion of participants with any of the following Grade 3 or higher adverse 
events at or before week 48: 
a. Peripheral neuropathy. 
b. Neutropenia. 
c. Infectious adverse events. 
d. Infusion reactions, including anaphylaxis and new onset rash consistent with 
Stevens-Johnson syndrome, toxic epidermal necrolysis, or other drug reaction. 
e. PML. 
Exploratory Efficacy Endpoints: 
1. 
Modified Rodnan Skin Score (mRSS) at weeks 12, 24, and 48. 
2. 
Provisional American College of Rheumatology Combined Response Index in 
Systemic Sclerosis (CRISS) [75] at weeks 24 and 48. 
3. 
Percent predicted Forced Vital Capacity (FVC) at weeks 24 and 48 weeks. 
4. 
Physician’s global assessment on a Likert scale at weeks 24 and 48. 
5. 
Patient’s global assessment on a Likert scale at weeks 24 and 48. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 35 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
6. 
Health-related quality of life (HRQOL) assessed by PROMIS-29 version 2.0 at 
weeks 24 and 48. 
7. 
Physical function assessed by the Scleroderma Health Assessment Questionnaire-
Disability Index (SHAQ-DI) at weeks 24 and 48. 
3.5 
RATIONALE FOR SELECTION OF DRUG, ROUTE, DOSE, AND 
REGIMEN 
The brentuximab vedotin route, dose, and regimen was selected based on the suggested 
dosing and administration of brentuximab vedotin for relapsed or refractory classical 
Hodgkin’s lymphoma and systemic anaplastic large cell lymphoma [55].  The dose 
recommended in the prescribing information is 1.8 mg/kg administered intravenously 
every three weeks for a maximum of 16 doses.   
Since the current study is a dose escalation safety evaluation in a non-oncology 
indication, the first cohort will receive one third of the recommended dose of 
brentuximab vedotin (0.6 mg/kg) for eight doses, the second cohort will receive two 
thirds of the recommended dose of brentuximab vedotin (1.2 mg/kg) for eight doses, and 
the final cohort will receive the recommended oncology dose of brentuximab vedotin (1.8 
mg/kg) for eight doses.   
Of note, Seattle Genetics undertook a dose escalation study of brentuximab vedotin in 
SLE [65]. The trial was planned as a blinded randomized safety study in a total of 40 
adult participants with active SLE, with each cohort of 10 participants receiving one of 
four escalating doses of brentuximab vedotin or placebo. The primary outcome measures 
were the number and percentage of participants experiencing adverse events over a 127-
day time frame. Although no safety concerns were noted in the first two dosing cohorts, 
Seattle Genetics terminated the study before completion due to revised business portfolio 
prioritization (NCT02533570).   
4. 
ELIGIBILITY 
4.1 
INCLUSION CRITERIA 
Patients must meet all of the following criteria to be eligible for this study: 
1. 
Classification of systemic sclerosis (SSc), as defined using the 2013 American 
College of Rheumatology/European Union League Against Rheumatism 
classification of SSc [76]. 
2. 
Diagnosis of dcSSc, as defined by LeRoy and Medsger [77]. 
3. 
Disease duration ≤ 60 months (defined as time from the first non-Raynaud 
phenomenon manifestation). 
4. 
mRSS units ≥ 15 and ≤ 45, and both of the following: 
a. At least mild skin thickening ( ≥ 1+ mRSS) of the forearm, and 

Immune Tolerance Network 
CONFIDENTIAL 
Page 36 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
b. At least moderate skin thickening (≥ 2+ mRSS) at the planned forearm skin 
biopsy site. 
5. 
Documentation of at least 12 weeks of ongoing immunosuppressive therapy for SSc 
at the time of enrollment, and at least 4 weeks at a stable dose, of one of the 
following: 
a. Methotrexate ≤ 25 mg/week, or 
b. Mycophenolate mofetil ≤ 3 grams/day or mycophenolate sodium ≤ 2.16 
grams/day, or 
c. Azathioprine ≤ 3mg/kg/day. 
6. 
Age 18-70 years inclusive. 
7. 
Completion of primary SARS-CoV-2 vaccination series is required at least 14 days 
prior to the first infusion of study medication at Visit 0. The dose and schedule of 
the vaccine is defined according to current FDA approval or Emergency Use 
Authorization at the time of screening. 
8. 
Ability to provide informed consent. 
4.2 
EXCLUSION CRITERIA 
Patients who meet any of the following criteria will not be eligible for this study: 
1. 
Rheumatic disease other than dcSSc; it is acceptable to include patients with 
osteoarthritis, fibromyalgia, sicca symptoms, and scleroderma-associated 
myopathy. 
2. 
Limited cutaneous SSc or sine scleroderma. 
3. 
Pulmonary disease with FVC ≤ 60% of predicted, or DLCO (corrected for 
hemoglobin) ≤ 60% of predicted. 
4. 
Pulmonary hypertension (PH) or moderate to severe left ventricular dysfunction, 
defined as one of the following: 
a. Transthoracic echocardiography demonstrating at least one of the following 
(unless subsequent right heart catheterization does not demonstrate PH; or 
unless prior right heart catheterization within one year did not demonstrate PH 
and echocardiography results are not significantly changed):  
i. Tricuspid regurgitation jet >2.8 m/sec or estimated right ventricular 
systolic pressure > 42 mm Hg, or 
ii. At least one of the following: 
1. Abnormality of right atrial size, shape, or wall thickness 
consistent with PH, or 
2. Abnormality of right ventricular size, shape, or wall thickness 
consistent with PH, or 
3. Abnormal septal wall shape consistent with PH. 
iii. Left Ventricular Ejection Fraction (LVEF) < 50%. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 37 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
b. Right heart catheterization showing mean pulmonary artery pressure ≥25 mm 
Hg at rest. 
c. Current use of approved medications for PH. It is acceptable to use 
phosphodiesterase type 5 (PDE-5) inhibitors for Raynaud’s, digital ulcers, and 
intermittently for erectile dysfunction. 
5. 
Active scleroderma renal crisis within the 4 months prior to enrollment. 
6. 
History of moderate-to-severe lower gastrointestinal dysmotility such as current use 
of parenteral nutrition and/or recent history of intestinal pseudo-obstruction within 
3 months prior to enrollment. 
7. 
The following medications: 
a. Oral corticosteroids >10 mg/day of prednisone or equivalent within 2 weeks prior 
to enrollment. 
b. Treatment with intravenous immunoglobulin (IVIG) within 12 weeks prior to 
enrollment. 
c. Treatment with cyclophosphamide within 6 months prior to enrollment. 
d. Use of investigational biologic or non-biologic medication within the past 90 days, 
or 5 half-lives prior to enrollment, whichever is greater, except for SARS-CoV-2 
vaccines, and medications used for prevention and treatment of COVID-19, per 
FDA Emergency Use Authorization. 
e. Use of anti-TNF medication or other biologic medications within the past 90 days, 
or 5 half-lives prior to enrollment, whichever is greater. 
f. Prior treatment with anti-CD20 if either of the following are true: 
i. B cells ≤ lower limit of normal (LLN), or  
ii. Treatment with anti-CD20 has been within 12 months prior to 
enrollment. 
g. Any prior treatment with cell-depleting therapies other than anti-CD20, including 
investigational agents, including but not limited to, CAMPATH®, anti-CD4, anti-
CD5, anti-CD3, anti-CD19. 
h. Any prior treatment with chlorambucil, bone marrow transplantation, or total 
lymphoid irradiation. 
8. 
Receipt of a live-attenuated vaccine within 3 months of study enrollment. 
9. 
Concomitant malignancies or a history of malignancy, with the exception of 
adequately treated basal and squamous cell carcinoma of the skin, or carcinoma in 
situ of the cervix. 
10. 
Major surgery (including joint surgery) within 8 weeks prior to enrollment. 
11. 
History of solid organ or hematopoietic stem cell transplantation.  
12. 
History of primary immunodeficiency. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 38 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
13. 
Comorbidities requiring systemic corticosteroid therapy, including those which 
have required three or more courses of systemic corticosteroids within the 12 
months prior to enrollment. 
14. 
Current substance abuse or history of substance abuse within 12 months prior to 
enrollment. 
15. 
History of severe depression or severe psychiatric condition. 
16. 
Lack of peripheral venous access. 
17. 
Known hypersensitivity to brentuximab vedotin, a component thereof, or the 
excipient contained in the drug formulation. 
18. 
Severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, 
pulmonary, cardiac, or neurological disease (or, in the investigator’s opinion, any 
other concomitant medical condition that places the participant at risk by 
participating in this study), including but not limited to: 
a. Uncompensated congestive heart failure (New York Heart Association Class III 
or VI). 
b. Clinically significant active coronary artery disease (e.g., unstable angina or 
acute myocardial infarction within 6 months prior to enrollment). 
c. Recently active cerebrovascular disease (e.g., stroke or transient ischemic 
attack within 6 months prior to enrollment). 
d. Uncontrolled systemic hypertension. 
e. Confirmed diagnosis of diabetes mellitus. 
f. Pancreatitis within 30 days prior to enrollment. 
g. History or presence of peripheral neuropathy, such as mononeuritis multiplex, 
acute or chronic inflammatory demyelinating polyneuropathy, axonal 
sensorimotor neuropathies, or drug related neuropathy or neuritis. 
19. 
Evidence of infection: 
a. Any infected ulcer at enrollment. 
b. Active bacterial, viral, fungal, or opportunistic infections requiring systemic 
anti-infective therapy. 
c. Evidence of current or prior infection with tuberculosis 
i. Positive QuantiFERON® – TB Gold or TB Gold Plus test results. 
Purified protein derivative (PPD) tuberculin test may be substituted 
for QuantiFERON® – TB Gold or TB Gold Plus test. 
ii. Indeterminant QuantiFERON® – TB Gold or TB Gold Plus test results, 
unless followed by a subsequent negative PPD or negative 
QuantiFERON® and clearance by local Infectious Disease 
department. 
d. Evidence of current or prior infection with  
i. Human immunodeficiency virus (HIV), or 

Immune Tolerance Network 
CONFIDENTIAL 
Page 39 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
ii. Hepatitis B (as assessed by hepatitis B surface antigen, HBsAg and 
antibody to hepatitis B core antigen, anti-HBc) or  
iii. Hepatitis C (HCV), except adequately treated HCV with 
documentation of sustained virologic response defined as 
undetectable HCV RNA at least 12 weeks after the end of treatment. 
e. History of progressive multifocal leukoencephalopathy (PML). 
f. Hospitalization for treatment of infections, or parenteral (intravenous or 
intramuscular) antibacterial, antivirals, anti-fungal, or anti-parasitic agents 
within the past 60 days prior to enrollment. 
g. Chronic infection that is currently being treated with systemic suppressive 
antibiotic or antiviral therapy, including but not limited to tuberculosis, 
pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster, and 
atypical mycobacteria. 
h. History of significant infection or recurrent infection that, in the investigator’s 
opinion, places the participant at risk by participating in this study. 
i. Positive PCR test for SARS-CoV-2 within 14 days prior to enrollment. 
20. 
The following laboratory abnormalities: 
a. Neutropenia (absolute neutrophil count <1500/mm3). 
b. Thrombocytopenia (platelets <100,000/mm3). 
c. Moderately severe anemia (hemoglobin < 10 g/dL). 
d. Liver function test (aspartate aminotransferase [AST], alanine aminotransferase 
[ALT], or alkaline phosphatase) results that are ≥ 1.5 times the upper limit of 
normal. 
e. Serum total bilirubin > 1.5 times the upper limit of normal, or > 3 times the 
upper limit of normal in the presence of Gilbert’s syndrome. 
f. Serum amylase and serum lipase > 1.5 times the upper limit of normal. 
21. 
Renal dysfunction, defined as either one of the following: 
a. Serum creatinine > 1.5 times the upper limit of normal. 
b. Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2. 
22. 
Pregnancy. 
23. 
Breastfeeding. 
24. 
Unwillingness to use two forms of medically acceptable  contraception methods by 
participants and their partners (if of reproductive potential) during the study and for 
at least 6 months after last dose of study drug. 
25. 
Inability to comply with study and follow-up procedures. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 40 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
4.3 PREMATURE DISCONTINUATION OF STUDY THERAPY 
Study treatment, defined as the dosing and administration of study medication according 
to study specification, will be discontinued for an individual participant if any of the 
following occurs: 
• 
A toxicity management discontinuation criterion is met for brentuximab vedotin 
(Section 5.2). 
• 
The participant’s dose of methotrexate, mycophenolate mofetil, azathioprine, or 
prednisone exceeds the allowed dose (Section 5.3.1.1 and section 5.3.3). 
• 
The investigator or the National Institute of Allergy and Infectious Diseases 
(NIAID) medical monitor determines that it is in the participant’s best interest to 
discontinue treatment for any reason, including non-adherence to the protocol. 
• 
The participant requests that treatment be halted. 
• 
The participant becomes pregnant (see section 8.8 Reporting Pregnancy). 
Further care will be provided according to the judgment and practice of the principal 
investigator. 
At this time the participant will complete all assessments listed for the discontinuation 
visit (DSC). The participant will be asked to return for safety follow-up visits at weeks 
12, 24, 36, and 48, if these visits have not already occurred. 
If study treatment is discontinued, the NIAID Medical Monitor should be notified.  
4.4 
PREMATURE TERMINATION OF A PARTICIPANT FROM THE STUDY 
Withdrawal of consent. Participants who withdraw consent will be asked to complete an 
end-of-study visit to include the assessments listed in visit 11. 
Failure to return. Participants who do not return for visits and who do not respond to 
repeated attempts by the site staff to have them return will be considered lost to follow-
up. 
Investigator decision. The investigator or the National Institute of Allergy and Infectious 
Diseases (NIAID) medical monitor determines that participation in the study is no longer 
in the best interest of the participant. 
4.5 
REPLACEMENT OF STUDY PARTICIPANTS 
Participants will be replaced if they do not receive 1 full dose of study medication, or if 
they discontinue before receiving 6 of 8 doses for a reason unrelated to treatment or the 
disease. A maximum of 8 extra participants may be enrolled in a single dosing cohort 
under these criteria. The procedures in section 4.3 will be followed for participants who 
receive any part of an infusion of study medication. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 41 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
5. 
STUDY THERAPIES, MEDICATIONS AND PROCEDURES 
5.1 
INVESTIGATIONAL MEDICATION: BRENTUXIMAB VEDOTIN 
5.1.1 Formulation and Packaging  
Brentuximab vedotin 50 mg is supplied as a sterile, white to off-white lyophilized, 
preservative-free cake or powder in a single-use vial for reconstitution. The pH of 
reconstituted product is approximately 6.6. Brentuximab vedotin will be provided by the 
manufacturer. Brentuximab vedotin will be distributed to sites by a designated drug 
distributor under contract to NIAID. 
5.1.2 Placebo Preparation 
Brentuximab vedotin placebo consisting of 0.9% Normal Saline will be prepared by the 
site pharmacist. 
5.1.3 Dosage, Handling, Preparation, and Administration 
5.1.3.1 Dosage 
Brentuximab vedotin dose will be determined based on the participant’s weight. 
Rounding is permissible within 5% of the nominal dose. Weight from the previous visit 
may be used to calculate the brentuximab vedotin dose unless the weight was obtained 
more than 30 days previously. Actual weight will be used except for participants 
weighing greater than 100kg; the dose for participants with weight greater than 100 kg 
will be calculated based on 100 kg. 
Brentuximab vedotin or placebo will be administered every 3 weeks from study week 0 
through study week 21, according to the schedule described in Section 3.1: 
• 
Cohort 1 will receive 0.6 mg/kg brentuximab vedotin or placebo (to a maximum 
dose 60 mg). 
• 
Cohort 2 will receive 1.2 mg/kg brentuximab vedotin or placebo (to a maximum 
dose 120 mg). 
• 
Cohort 3 will receive 1.8 mg/kg brentuximab vedotin or placebo (to a maximum 
dose 180 mg). 
5.1.3.2 Storage Conditions and Handling Precautions 
Brentuximab vedotin is an anti-neoplastic product, and must be handled and disposed 
according to guidelines provided by Occupational Safety and Health Administration 
(OSHA) for hazardous drugs [78]. Handling precautions include masks, protective 
clothing, gloves, and vertical laminar airflow safety cabinets. 
Brentuximab vedotin vials must be stored at 2-8o C and protected from light in the 
original container prior to reconstitution.  

Immune Tolerance Network 
CONFIDENTIAL 
Page 42 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
Following reconstitution and dilution, brentuximab vedotin solution can be stored at 2-8o 
C and administered within 24 hours of reconstitution and dilution. 
Do not freeze. 
5.1.3.3 Preparation 
5.1.3.3.1 
Reconstitution 
Brentuximab vedotin will be reconstituted according to the prescribing information [55]. 
The number of 50 mg vials of brentuximab vedotin needed will be calculated based on 
the participant’s weight, as described in section 5.1.3.1.  Each vial will be reconstituted 
with 10.5mL of Sterile Water for Injection USP, to yield a single-use solution containing 
5mg/ml brentuximab vedotin.  
 
The stream of Sterile Water will be directed toward the wall of the vial and not directly at 
the cake or powder. Gently swirl the vial to aid dissolution.  Do not shake. Upon 
inspection, the reconstituted solution should be clear to slightly opalescent, colorless, and 
free of particulate matter. 
 
Reconstituted brentuximab vedotin will be immediately diluted into an infusion bag. If 
not diluted immediately, reconstituted brentuximab vedotin will be stored according to 
section 5.1.3.2. 
 
The unused portion of brentuximab vedotin vials will be discarded according to 
guidelines provided by OSHA for hazardous drugs [78]. 
5.1.3.3.2 
Dilution 
Reconstituted brentuximab vedotin will be diluted according to the prescribing 
information [55]. The required volume of 5 mg/mL brentuximab vedotin will be 
calculated based on the participant’s weight. This volume will be withdrawn from the 
vials and immediately added to an infusion bag containing a minimum volume of 0.9% 
Normal Saline Injection, 5% Dextrose Injection, or Lactated Ringer’s Injection. The 
infusion bag will be gently inverted to mix. 
 
Following dilution, brentuximab vedotin will be infused immediately according to the 
instruction in section 5.1.3.4. If not infused immediately, brentuximab vedotin will be 
stored according to section 5.1.3.2. 
5.1.3.4 Administration and Monitoring 
5.1.3.4.1 
Pre-medication 
Routine premedication for brentuximab vedotin is not indicated [55]. However, 
premedication should be administered to any participant who experienced a Grade ≤ 2 
infusion reaction during or following a previous brentuximab vedotin administration.  
These participants should receive premedication one hour (plus or minus approximately 
15 minutes) prior to the brentuximab vedotin infusion with oral acetaminophen 650 mg, 
oral diphenhydramine 50 mg or equivalent antihistamine, and intravenous 
methylprednisolone 20 mg or equivalent corticosteroid. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 43 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
5.1.3.4.2 
Monitoring 
Brentuximab vedotin infusions will occur in a setting with access to ACLS certified 
personnel, resuscitative drugs, monitoring devices, and CPR equipment. Vital signs must 
be assessed prior to the infusion, approximately every 15 minutes during the infusion, at 
the end of the infusion, and 1 hour after the completion of the infusion. After the infusion 
is complete, the intravenous line must remain in the participant for at least 1 hour to 
facilitate administration of medical management if needed. 
5.1.3.4.3 
Administration 
Brentuximab vedotin or placebo will be administered as an intravenous infusion over 
approximately, but no less than, 30 minutes, as described in the prescribing information at 
study weeks 0 through 21. Hematology and serum chemistry results must be obtained 
within 72 hours prior to infusions at study weeks 3 through 21. 
Brentuximab vedotin must not be administered as an intravenous (IV) push or bolus. Do 
not mix brentuximab vedotin, or administer as an infusion, with any other medicinal 
products. If an infusion related reaction occurs, the infusion should be interrupted and 
medical management instituted as needed (e.g., corticosteroids, epinephrine, 
bronchodilators, or oxygen). In cases of mild reactions (≤ Grade 2), the infusion can be 
resumed at a 50% rate reduction when symptoms have resolved and are no longer 
deemed a threat to the participant’s well-being. If anaphylaxis occurs, immediately and 
permanently discontinue brentuximab vedotin and administer emergency medical 
therapy. 
5.2 
TOXICITY MANAGEMENT OF BRENTUXIMAB VEDOTIN 
5.2.1 SARS-CoV-2 Infection or Exposure 
Suspend brentuximab vedotin or placebo administration if the participant develops 
symptomatic or asymptomatic SARS-CoV-2 infection:  
• 
Participants with mild or moderate SARS-CoV-2 infection should be evaluated for 
treatment with a monoclonal antibody product authorized by the FDA for the 
treatment of COVID-19, as soon as possible following confirmation of the infection 
and within 10 days of symptom onset [69-71]. Use of other FDA authorized or 
approved therapeutic agents should also be considered as they become available, 
depending on the clinical circumstance.   
  
• 
Brentuximab vedotin may be restarted at the next scheduled dose, if symptoms have 
been absent for at least 10 days, or in the case of asymptomatic infection at least 10 
days have passed since the positive SARS-CoV-2 test. In addition, a negative PCR 
test for SARS-CoV-2 must be obtained prior to restarting brentuximab vedotin or 
placebo administration. 
 
• 
Any participant who has close contact with a SARS-CoV-2 infected individual 
should be evaluated for post-exposure prophylaxis as soon as possible after exposure 
[69, 70]. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 44 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
5.2.2 Other Infection or AE 
Suspend brentuximab vedotin or placebo administration if the participant develops any 
other infection or AE that the investigator judges to be significant. If the infection or AE 
resolves, brentuximab vedotin may be restarted at the next scheduled dose. 
5.2.3 Peripheral Neuropathy 
Suspend brentuximab vedotin administration if the participant develops a Grade 2 
peripheral neuropathy.  If the peripheral neuropathy resolves, brentuximab vedotin may 
be restarted at a lower dose as follows:  the affected participant in Cohort 1 will restart 
brentuximab vedotin at 0.3 mg/kg/dose, in Cohort 2 will restart brentuximab vedotin at 
0.6 mg/kg/dose, and in Cohort 3 will restart brentuximab vedotin at 1.2 mg/kg/dose. 
5.2.4 Permanent Discontinuation of Study Medication for Toxicity 
Permanently discontinue brentuximab vedotin if any of the following occurs: 
• 
The participant misses > 3 doses of brentuximab vedotin. 
• 
Grade 2 peripheral neuropathy recurs after brentuximab vedotin suspension and 
dose modification, as described above. 
• 
Grade 3 or greater peripheral neuropathy. 
• 
Grade 3 or greater neutropenia or thrombocytopenia. 
• 
Grade 3 or greater infusion reaction. 
• 
Anaphylaxis, defined as a serious allergic reaction that is rapid in onset and may 
cause death (see Appendix 2) [79]. 
• 
New onset rash consistent with Stevens-Johnson syndrome, toxic epidermal 
necrolysis, or other drug reaction. 
• 
eGFR < 30 ml/min/1.73m2. 
• 
Potential drug-induced liver injury, defined as all three of the following: 
o ALT or AST elevation > 3 times upper limit of normal (ULN), and 
o Total bilirubin > 2 times ULN, without initial findings of cholestasis 
(elevated serum alkaline phosphatase), and 
o No other immediately apparent possible causes of ALT or AST elevation 
and hyperbilirubinemia, including but not limited to viral hepatitis, pre-
existing chronic or acute liver disease, or the administration of other 
drugs known to be hepatotoxic. 
• 
Two or more Grade 3 or greater infections, or one Grade 4 infection. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 45 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
• 
A suspected case of PML. 
A diagnosis of PML should be considered in any participant presenting with new-onset or 
deteriorating neurological signs and symptoms.  The participant should be referred to a 
neurologist or other appropriate specialist for evaluation. If PML is suspected, this should 
be immediately reported to the NIAID Medical Monitor.  The appropriateness of 
continuing study medication, while the case is being assessed, should be discussed. 
If brentuximab vedotin is discontinued, the procedures in Section 4.3 should be followed. 
5.3 
CONCOMITANT MEDICATIONS 
5.3.1 Required Medications 
5.3.1.1 Required Immunosuppression 
Participants are required to be on one of the following medications at study entry: 
• 
Methotrexate ≤ 25 mg/week. 
• 
Mycophenolate mofetil ≤ 3 grams/day or mycophenolate sodium ≤ 2.16 
grams/day. 
• 
Azathioprine ≤ 3mg/kg/day. 
It is recommended that these medications are maintained at a stable dose, however dose 
reductions are allowed for toxicity associated with these medications or in case of 
infection, per investigator judgment. 
5.3.1.2 Contraception 
Use of two methods of medically acceptable contraception are required for participants 
and their partners (if of reproductive potential) during the study and for at least 6 months 
after last dose of study drug. Women of childbearing potential includes any female who 
has experienced menarche and who has not undergone successful surgical sterilization 
(hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not 
postmenopausal. Postmenopausal is defined as amenorrhea for 12 consecutive months 
without another cause, or documented follicle-stimulating hormone level > 35 mIU/mL 
for women with irregular menstrual periods and on hormone replacement therapy.  
Acceptable forms of effective contraception include established use of oral, injected, or 
implanted hormonal methods of contraception; placement of an intrauterine device or 
intrauterine system; barrier methods of contraception (condom or occlusive cap) with 
spermicidal foam/gel/film/cream/suppository; male sterilization; and true abstinence. 
Female participants of childbearing potential taking concomitant mycophenolate and oral 
contraceptives must use a barrier method of contraception along with their oral 
contraceptives. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 46 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
Mycophenolate Risk Evaluation and Mitigation Strategy (REMS). It is strongly 
recommended that investigators with female participants of childbearing potential taking 
mycophenolate mofetil enroll them in the Mycophenolate REMS program, as described 
in section 8.8. 
5.3.2 Recommended Prophylactic Medication 
Folic acid supplementation is strongly recommended for participants on methotrexate. 
5.3.3 Permitted Medications 
Use of hydroxychloroquine ≤ 400 mg/day is permitted at study enrollment and continuing 
during the study.  Initiation of hydroxychloroquine during the study is not permitted. 
Oral corticosteroids ≤ 10 mg/day prednisone or the equivalent are permitted.  
Corticosteroids may be increased for SSc or non-SSc indications on two separate 
occasions for a period of ≤14 days. Increases for SSc indications are not to exceed 
prednisone 20 mg per day or the equivalent and increases for non-SSc indications are not 
to exceed prednisone 0.5 mg/kg/day or the equivalent.  Corticosteroid dose may be 
increased one time between study weeks 0 and 24 and one time between study weeks 24 
and 48. 
Corticosteroids are also allowed as premedication for infusion reactions, as described in 
section 5.1.3.4.1. 
5.3.4 Prohibited Medications and Vaccines 
Participants may not use immunosuppressive or immunomodulatory medications, 
including biologics, except those specified in the protocol.  Increases above the dose at 
study enrollment are prohibited for the following medications:  
• 
Methotrexate. 
• 
Mycophenolate mofetil. 
• 
Azathioprine. 
The use of any investigational drug or investigational treatment other than those specified 
in the protocol is prohibited during study participation. SARS-CoV-2 vaccines and 
medications used for prevention and treatment of COVID-19, as authorized by the FDA 
for emergency use, are not prohibited. 
The use of live attenuated vaccines is prohibited during treatment with study medication 
and for 12 weeks following treatment. 
Concomitant administration of brentuximab vedotin and bleomycin is contraindicated 
due to pulmonary toxicity; therefore, bleomycin administration during the study is 
prohibited. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 47 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
5.3.4.1 Special Precautions for Cytochrome P450 3A4 Inhibitors or Inducers, 
or P-glycoprotein Inhibitors 
Concomitant use of strong Cytochrome P450 3A4 (CYP3A4) inhibitors or inducers, or P-
glycoprotein (P-gp) inhibitors, has the potential to affect the exposure to MMAE. 
Participants who are receiving strong CYP3A4 inhibitors or inducers, or P-gp inhibitors, 
should be closely monitored for adverse reactions [55]. See Appendix 3 for examples 
[80]. These medications should be avoided, and alternatives used whenever possible. 
5.4 
DRUG ACCOUNTABILITY 
Under federal regulations (21CFR 312.62) an investigator is responsible for delegating 
this responsibility to a qualified pharmacist of record (PoR) at every study site. The PoR 
is required to maintain adequate records of the disposition of the investigational product, 
including the date and quantity of drug that was received, the participants to whom drug 
was dispensed (participant by participant accounting), and an account of any drug 
accidentally or deliberately destroyed. The investigator will ensure that the 
investigational product supplies are stored as specified in the protocol and pharmacy 
manual in a secured area, with access limited to authorized study personnel as described 
in the clinical study agreement. 
Records for receipt, storage, use, and disposition of the study drug will be maintained by 
the study sites. A drug-dispensing log will be kept current for each participant and will 
contain the identification of each participant and the date and quantity of drug dispensed. 
All remaining unused investigational product will be returned to the sponsor or sponsor’s 
representative after study termination or destroyed with the permission of the sponsor in 
accordance with applicable law and study site procedures. If investigational product is to 
be destroyed locally, the investigator will provide documentation in accordance with 
sponsor’s specifications. 
All records regarding disposition of the investigational product will be available for 
inspection by the clinical trial monitor. 
5.5 
ASSESSMENT OF COMPLIANCE WITH STUDY MEDICATION 
All study medications will be administered at sites by trained medical staff. Therefore, 
compliance will be monitored by the site and documented on the eCRF. 
6. 
STUDY ASSESSMENTS AND WINDOWS 
6.1 
VISIT WINDOWS 
6.1.1 Scheduled Visits 
Appendix 1 presents the schedule of events for this trial. Visit 0 must occur within 28 
days of Visit –1. All other scheduled study visits must occur within the time limits 
specified below: 
Visits 1 through 8: +/-3 days 

Immune Tolerance Network 
CONFIDENTIAL 
Page 48 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
Visit 9: +/- 7 days 
Visits 10 and 11: +/- 14 days  
 
6.1.2 Window for Administration of Study Medication 
The schedule for administration of study medication is described in Appendix 1. Study 
medication infusions must occur at least 18 days after the prior infusion. 
6.1.3 Unscheduled Visits 
Unscheduled visits may be performed to document any symptoms or to document a 
scleroderma flare during the study. Unscheduled visits may also be performed for 
Neurologist assessment in the event of suspected peripheral neuropathy. Assessments for 
an unscheduled visit are listed in Appendix 1. Some of the assessments may be omitted at 
the discretion of the investigator if they are not indicated.  
6.2 
RANDOMIZATION, BLINDING, AND UNBLINDING  
6.2.1 Randomization 
Participants who meet the eligibility criteria will be randomly assigned to a study 
treatment group, either brentuximab vedotin or placebo control.  Enrollment is defined as 
the time of random assignment.  Participants will be randomly assigned to their treatment 
group utilizing a centralized, automated randomization system.  Randomization will not 
be stratified.  
6.2.2 Blinding 
Blinding will be maintained for all study participants and trial personnel, with the 
exception of the site pharmacist from the time of randomization throughout the study. 
6.2.3 Unblinding 
Unblinding before the study is completed will occur only if a participant’s well-being is 
threatened and the site investigator believes unblinding is necessary to protect the 
participant. Unblinding may also occur in the event of pregnancy in a female participant 
or a male participant’s partner. 
Whenever possible, before treatment assignment for an individual participant is 
unblinded, the site investigator must confer with the NIAID medical monitor and the 
protocol chair. The NIAID medical monitor will notify the study management team.  
If emergency unblinding is required for a subject’s well-being during non-business hours, 
the site principal investigator or designee (i.e., sub-investigator specified on Form FDA 
1572) must notify the investigative pharmacy of the need for the treatment assignment. 
The emergency unblinding will be recorded and reported to the DSMB. A full account of 
the event will be recorded, including the date and time of the emergency, the reason for 
the decision to unblind, and the names of the medical monitor and others who were 
notified of the emergency. During site visits, the site monitor must verify that the medical 
monitor was notified and that a written account was completed. The reasons for 
unblinding of a participant’s treatment will be included in the final study report. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 49 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
Immune Tolerance Network (ITN) and NIAID approval is required for unblinding the 
treatment of an individual participant or subgroups of participants for unplanned interim 
analyses to support DSMB reviews and final analysis.  
An exception to the above rule is that Investigational New Drug (IND) Safety Reports 
will be reported to the health authorities, DSMB, and Institutional Review Boards (IRB) 
or ethics review committee in an unblinded fashion as requested by current ICH and local 
guidance. 
6.3 
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.  
• 
Randomization.  
• 
Demographics: age 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. 
• 
Scleroderma history.  A history will be taken to determine the date of diagnosis of 
disease.  
• 
Comprehensive physical examination.  
• 
Limited physical examination.  A physical examination focused on participant’s 
current complaints and clinical status at the study visit will be conducted.    
• 
Peripheral neuropathy assessment, including 
o Pin sensibility. 
o Vibration sensibility. 
o Muscle strength. 
o Motor symptoms (dexterity, walking, climbing, activities of daily life).  
o Sensory symptoms (paresthesia, numbness, neuropathic pain). 
o Autonomic symptoms 
• 
Vital signs.  Weight, temperature, blood pressure, respiration, and pulse will be 
obtained at all visits. Height will be obtained at visit -1. Temperature, blood pressure, 
respiration, and pulse will be obtained immediately before study drug infusion, 
approximately every 15 minutes during the infusion, at the end of the infusion and 60 
minutes after the infusion is completed. 
• 
Adverse events.  Participants will be assessed for AEs. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 50 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
• 
Concomitant medications.  All concomitant medications and their indications will be 
recorded. 
6.4 
CLINICAL LABORATORY ASSESSMENTS 
• 
Hematology (complete blood count, differential and platelet count). 
• 
Serum chemistry: Blood urea nitrogen (BUN), creatinine, eGFR and liver panel 
(AST, ALT, alkaline phosphate, direct and total bilirubin). eGFR will be calculated 
according to the CKD-EPI formula [81]. 
• 
Serum amylase and lipase. 
• 
HIV, unless test has been performed within 30 days of visit -1 and documented test 
results are available. 
• 
Hepatitis B (surface antibody, core antibody, and surface antigen), unless test has 
been performed within 30 days of visit -1 and documented test results are available. 
• 
Hepatitis C (RNA and antibody), unless test has been performed within 30 days of 
visit -1 and documented test results are available. 
• 
Erythrocyte sedimentation rate (ESR).  
• 
Serum Human Chorionic Gonadotropin (HCG) for women of childbearing potential 
(see section 5.3.1.2). 
• 
STAT Urine Human Chorionic Gonadotropin (HCG) for women of childbearing 
potential (see section 5.3.1.2). 
• 
QuantiFERON®-TB Gold or TB Gold Plus, unless test has been performed within 30 
days of visit -1 and documented test results are available. (PPD tuberculin skin test 
may be substituted for the QuantiFERON®-TB Gold or TB Gold Plus). 
• 
PCR test for SARS-CoV-2 within 14 days prior to enrollment. 
6.5 
GENERAL CLINICAL ASSESSMENTS 
• 
Electrocardiogram (EKG).  
• 
Echocardiogram.  
6.6 
DISEASE-SPECIFIC ASSESSMENTS 
• 
Pulmonary function testing. Spirometry (FVC and FEV1) with DLCO. DLCO will be 
calculated according to the Global Lung Function Initiative (GLI) all-age reference 
values and corrected for hemoglobin [82, 83]. 
• 
Modified Rodnan Skin Score (mRSS). 
• 
Physician global assessment. 
• 
Patient reported outcomes (patient global assessments, PROMIS-29, SHAQ-DI) [84]. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 51 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
6.7 
MECHANISTIC ASSESSMENTS 
• 
Punch skin biopsies will be collected from fibrotic-skin areas.  
• 
Plasma/Serum assays. 
• 
PBMC assays.  
• 
Whole blood DNA genotyping. 
• 
Whole blood gene expression analysis. 
7. 
MECHANISTIC ASSAYS 
7.1 
MECHANISTIC HYPOTHESES AND RATIONALE 
SSc is characterized by fibrosis, inflammation, and micro vasculopathy in multiple organ 
systems, and there is substantial evidence linking these symptoms to an underlying 
autoimmune pathogenesis [14]. Nearly all patients diagnosed with SSc have anti-nuclear 
antibodies as well as other clinically–associated autoantibodies present in circulation 
[15]. Furthermore, biopsies taken from skin of SSc patients show infiltration of activated 
T cells [17], and this infiltration correlates with skin thickening, suggesting a relationship 
between fibrosis in the skin and inflammation. Recent data also suggests a key role for 
Th2 cells in skin fibrosis in which production of pro-fibrotic cytokines by Th2 cells 
ultimately leads to altered gene expression in skin fibroblasts [24].  
CD30 is expressed on several immune cell subsets, but reports suggest that the 
subpopulation of Th2 cells implicated in SSc skin fibrosis may preferentially express 
CD30 [25, 31]. Therefore, the primary mechanistic hypothesis is that brentuximab 
vedotin will alter the balance of pro- versus anti-fibrotic effects of autoreactive T cells by 
impacting pathogenic Th2 cell populations expressing CD30 in the skin and/or peripheral 
blood.  Brentuximab vedotin may also alter functional properties of new and/or pre-
existing T cell subtypes not eliminated by treatment in skin or blood. Given that CD30 is 
also expressed by activated B cells and natural killer (NK) cells [27, 85] it is possible 
brentuximab vedotin will alter the frequency and/or functional properties of these 
immune cell types in skin and/or blood as well. Mechanistic studies will address multiple 
questions but will be prioritized based on the amount of tissue and blood available. 
In this study, skin and blood samples will be collected with the objective of analyzing 
cellular infiltration and circulating immune cell populations, cytokine levels both in skin 
and circulation, autoantibodies, soluble CD30, and genetic signatures of disease, 
inflammation, and fibrosis. It is hypothesized that treatment with brentuximab vedotin 
may result in: 1) impact on CD30 expressing cells resulting in alterations in the number, 
proportion, and/or functional status of effector and regulatory T cells in peripheral blood 
and affected skin [25, 86-92], 2) favorable changes in gene expression in affected skin, 
specifically, downregulation of inflammatory and pro-fibrotic gene signatures and the 
expression of specific genes that have clinically-predictive value [93-96]. The following 
hypotheses will also be explored: 1) changes in the presence and titer of antinuclear 

Immune Tolerance Network 
CONFIDENTIAL 
Page 52 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
antibodies and other SSc-associated autoantibodies, 2) changes in the levels of circulating 
soluble CD30. 
7.2 
PLANNED MECHANISTIC ASSAYS 
Two skin biopsies will be collected from fibrotic-skin areas at weeks 0, 12, and 24. One 
biopsy will be used for RNA isolation and one biopsy for immunohistochemical analysis. 
Blood will be collected at week 0, 12, 24 and 48 in ABI Tempus™ blood collection tubes 
for gene expression analysis, in serum clot tubes for serum assessments, and in 
heparinized tubes for PBMC isolation and plasma characterization.  
7.2.1 Local Immune Responses in the Skin 
7.2.1.1 Immunohistochemistry/In Situ Hybridization (IHC/ISH)  
One of the two skin biopsies will be preserved for IHC/ISH upon collection. Skin 
sections may be stained with antibodies directed against T-cells and cytokines. Cellular 
infiltration can be compared between treatment groups to evaluate the efficacy of 
treatment on reducing the Th2 subsets and associated inflammatory and pro-fibrotic 
cytokines. 
7.2.1.2 Gene expression of RNAlater® biopsies 
CD30+ Th2 cells are critical to the pathogenesis of SSc and can be detected in lesional 
skin and blood [27, 34]. Treatment with brentuximab vedotin may impact CD30+ Th2 
cells in affected skin resulting in reduced lesional levels of pro-fibrotic Th2 cytokines 
such as IL-4, and stabilization or reduction in molecular signatures of active fibrosis in 
SSc lesions. 
Skin biopsies will be collected from enrolled participants to evaluate transcriptional 
changes following treatment with brentuximab vedotin. One of the two skin biopsies will 
be submerged in RNAlater® upon collection for evaluation of gene expression profiles. 
RNA will be isolated, and gene expression of selected cytokines and other immune 
regulatory molecules will be further evaluated using methods such as microarray, Nano 
string or RNA-seq. 
Biopsy tissue will be compared pre- and post-treatment to determine the effect of 
treatment on the global gene expression in participants with SSc. Care will be taken in the 
interpretation of data comparing participants since the drug effects of immunosuppressive 
therapy for SSc at the time of enrollment may confound mechanistic observations.  
Therefore, comparisons at baseline will be performed to evaluate inflammatory 
signatures in the participants prior to treatment with brentuximab vedotin. 
7.2.2 Cellular Assays 
7.2.2.1 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, 

Immune Tolerance Network 
CONFIDENTIAL 
Page 53 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
and that high quality material is obtained for testing. PBMCs will be stored in the vapor 
phase of liquid nitrogen until use. 
7.2.2.2 Multi-parameter immunoprofiling of PBMC 
Flow cytometry or mass cytometry may be done at ITN laboratories to analyze the impact 
of treatment on the frequency and functional status of specific immune cell populations in 
viably cryopreserved PBMC. We will investigate the hypothesis that treatment with 
brentuximab vedotin will impact CD30-expressing cells in peripheral blood. This may 
alter the proportion of activated effector T cell subtypes in the CD4 and CD8 T cell 
compartments, the ratio of effector T cell subsets to regulatory T cells, and/or the 
proportion of activated B cells and NK cells in the peripheral blood. 
7.2.2.3 Quantification of autoreactive B cells 
Activated B cells may express CD30 on their surface, thus treatment with brentuximab 
vedotin may have an impact on circulating B cells, specifically autoreactive B cells. 
Enzyme-linked immunospot (ELISPOT) assays may be used to quantify B cells with 
reactivity towards nuclear antigens. The kinetics of this response may be measured, and 
comparisons could be made between baseline and the time points following treatment. 
7.2.2.4 Epigenetic analysis of PBMC 
Recent data has emphasized the importance of epigenetic modifications in the 
pathogenesis of many disorders, including SSc [97, 98]. Current evidence demonstrates 
alterations in DNA methylation and histone code modifications in cells from patients 
with SSc [99]. While studies have revealed the significant role of epigenetic 
modifications in the pathogenesis of SSc, the causal nature of epigenetic alterations in 
SSc pathogenesis, as well as the effects of specific treatments, remains elusive. 
Epigenetic studies may therefore be designed to investigate correlations with disease 
progression and therapeutic response. 
7.2.3 Serum and Plasma Assays 
7.2.3.1 Serum cytokine assays 
Alterations in presence or function of effector T cell populations due to treatment with 
brentuximab vedotin may result in changes in the gene expression profile in SSc patients 
[93-96]. Participant serum/plasma may be analyzed to investigate the impact of treatment 
on circulating levels of cytokines and inflammatory mediators. Longitudinal assessment 
of serum cytokines and inflammatory mediators may be performed using immunoassay 
platforms. Additionally, the impact of treatment on levels of cytokines and inflammatory 
mediators could be evaluated for correlations with changes in immune cell populations 
and/or gene expression in peripheral blood and skin.   
7.2.3.2 Autoantibody titers 
SSc is associated with several autoantibodies that may be clinically relevant in 
determining the diagnosis and prognosis of affected individuals [100]. Given that 
activated B cells may express CD30, treatment with brentuximab vedotin may impact 

Immune Tolerance Network 
CONFIDENTIAL 
Page 54 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
autoantibody production [27, 85]. To explore the impact of treatment on autoantibody 
titers, participant serum may be analyzed for circulating levels of antinuclear or other 
autoantibodies by ELISA or similar method. Longitudinal assessment of autoantibody 
levels could be compared between baseline and the time points following treatment. 
7.2.3.3 Soluble CD30 levels 
Circulating levels of soluble CD30 in patients with SSc have been shown to correlate 
with disease activity of SSc [32, 33]. Elimination of CD30+ cells may lower sCD30, 
which could be a biomarker of response to brentuximab vedotin. In order to explore the 
impact of treatment on soluble CD30, participant serum may be analyzed for circulating 
levels of soluble CD30. Circulating levels of soluble CD30 could be compared between 
baseline and the time points following treatment. 
7.2.4 Whole Blood Assays 
7.2.4.1 Whole blood DNA genotyping 
It is reasonable to assume that treatment may not be equally effective in all individuals 
and that genetic differences may, in part, determine response. 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. 
7.2.4.2 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. 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 selected cytokines and other immune regulatory 
molecules may be further investigated using quantitative methods.  
7.3 
RETENTION OF SAMPLES 
A major priority of the Immune Tolerance Network, in partnership with the National 
Institute of Allergy and Infectious Diseases of the NIH, USA, is the development of 
novel immunoassays in order to better understand mechanisms of tolerance and to 
develop biomarkers to predict the development and maintenance of clinical tolerance. As 
in all Immune Tolerance Network-funded clinical trials, informed consent will be 
obtained from all participants for their samples to be stored for use in future studies. 
Biological specimens collected in this trial will be stored long-term in order to re-
evaluate biologic responses as new research tools to study tolerance become available. 
The specimens will therefore be stored at the ITN sample repository for a minimum of 10 
years. Residual specimens may be used by the investigators for development of new 
immunologic assays or for cross-trial comparisons. Although specimens in this protocol 

Immune Tolerance Network 
CONFIDENTIAL 
Page 55 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
are described in the context of assays to be performed, it should be noted that not 
necessarily all assays will be performed for all participants at each time point. Decisions 
to perform assays will be made based on statistical and scientific planning, hypotheses to 
be tested, and technologies available. Finally, clinical outcomes will be taken into 
account to determine the potential value of the assays. For example, if a clinical effect 
fails to occur, it may be decided that there is minimal value in performing certain 
mechanistic assays. The ITN sample sharing policy will apply for the provision of 
samples to study or outside investigators (www.immunetolerance.org). 
8. 
SAFETY MONITORING AND REPORTING  
8.1 
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 (per Section 8.5, Reporting of Adverse 
Events and Serious Adverse Events/Events of Special Interest) to the sponsor 
(DAIT/NIAID). Appropriate notifications will also be made to the Immune Tolerance 
Network (ITN), site principal investigators, Institutional Review Boards (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 (November 27, 2017): 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Q
uick_Reference_8.5x11.pdf 
8.2 
DEFINITIONS 
8.2.1 Adverse Event (AE) 
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)  
8.2.2 Adverse Reaction and Suspected Adverse Reaction (SAR)  
Suspected adverse reaction (SAR) is any adverse event for which there is a reasonable 
possibility that the investigational drug caused the adverse event. For the purposes of 
safety reporting, ‘reasonable possibility’ means there is evidence to suggest a causal 

Immune Tolerance Network 
CONFIDENTIAL 
Page 56 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
relationship between the drug and the adverse event. A suspected adverse reaction 
implies a lesser degree of certainty about causality than adverse reaction, which means 
any adverse event caused by a drug (21 CFR 312.32(a) and ICH E2A). 
An adverse reaction (AR) is any adverse event caused by the study drug. Adverse 
reactions are a subset of all suspected adverse reactions for which there is reason to 
conclude that the drug caused the event. 
8.2.3 Unexpected Adverse Event/Reaction 
A SAR is considered “expected” when it is listed in the investigator brochure, the 
package insert, or the protocol. A SAR is considered “unexpected” when its nature 
(specificity), severity, or rate of occurrence is not consistent with applicable product 
information as described in the safety information provided in the investigator brochure, 
the package insert, or the protocol (21 CFR 312.32(a) and ICH E2A). A serious 
unexpected suspected adverse reaction is referred to as a SUSAR. For this study, 
expectedness will be determined by product information provided in the investigator 
brochure, package insert, and protocol for brentuximab vedotin.   
8.2.4 Serious Adverse Event (SAE) 
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), and ICH E2A]. 
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 subject at immediate risk of death. It does not include an AE or SAR that, had 
it occurred in a more severe form, might have caused death.  
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 subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above. 
Elective hospitalizations are not to be reported as an SAE unless hospitalization is 
prolonged due to complications. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 57 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
8.3 
GRADING AND ATTRIBUTION OF ADVERSE EVENTS 
8.3.1 Grading Criteria 
The study site will grade the severity of adverse events experienced by the study subjects 
according to the criteria set forth in the National Cancer Institute’s Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0 (November 27, 2017), 
except for the grading of liver chemistry abnormalities, which is described in Section 
8.3.2. This document (referred to herein 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.  
Adverse events will be graded on a scale from 1 to 5 according to the following standards 
in the NCI-CTCAE manual: 
Grade 1 = mild adverse event. 
Grade 2 = moderate adverse event. 
Grade 3 = severe and undesirable adverse event. 
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 if related to a study-mandated procedure, 
treatment, or change in treatment (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. 
For additional information and a printable version of the NCI-CTCAE manual, consult 
the NCI-CTCAE web site: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Q
uick_Reference_8.5x11.pdf 
8.3.2 
Grading of Liver Chemistry Abnormalities 
For this study, AEs related to liver function testing will be graded 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 

Immune Tolerance Network 
CONFIDENTIAL 
Page 58 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
o Grade 3: > 5.0x ULN - 20.0x ULN  
o Grade 4: > 20.0x ULN 
• 
Alanine aminotransferase [ALT] 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 
• 
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 
8.3.3 Attribution Definitions 
The relationship, or attribution, of an adverse event to the study therapy regimen or study 
procedure(s) will initially be determined by the site investigator and recorded on the 
appropriate AE eCRF. Final determination of attribution for safety events that may be 
eligible for expedited reporting to the health authorities will be determined by the 
sponsor, DAIT/NIAID. The relationship of an adverse event to study therapy regimen or 
procedures will be determined using the descriptors and definitions provided in Table 1.  
Table 1 Attribution of Adverse Events 
Code 
Descriptor 
Relationship (to primary investigational product 
and/or other concurrent mandated study therapy or 
study procedure) 
UNRELATED CATEGORY 
1 
Not related 
The adverse event is clearly not related:  there is 
insufficient evidence to suggest a causal relationship. 
RELATED CATEGORIES 
2 
Possible 
The adverse event has a reasonable possibility to be 
related; there is evidence to suggest a causal 
relationship. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 59 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
3 
Related 
The adverse event is clearly related. 
 
8.4 
COLLECTING AND RECORDING ADVERSE EVENTS 
8.4.1 Collection Period  
All adverse events, regardless of NCI-CTCAE severity grade should be recorded in the 
study source documentation per the criteria below: 
• 
Adverse events will be collected from the time the subjects signs the informed 
consent until he/she initiates study intervention or until he/she is determined to be 
ineligible to receive study intervention, if the investigator determines that the 
adverse event is related to a study-mandated procedure, treatment, or change in 
treatment.   
• 
For all participants, adverse events will be collected from the time of initiation of 
study intervention until he/she completes study participation or until 30 days 
after he/she prematurely withdraws (without withdrawing consent) or is 
withdrawn from the study.  
8.4.2 Collecting Adverse Events 
Adverse events (including SAEs) may be discovered through any of these methods: 
• 
Observing the subject. 
• 
Interviewing the subject (e.g., using a checklist, structured questioning, diary, 
etc.). 
• 
Receiving an unsolicited complaint from the subject. 
• 
In addition, an abnormal value or result from a clinical or laboratory evaluation 
can also indicate an adverse event, as defined in Section 8.3.1. 
8.4.3 Recording Adverse Events  
Throughout the study, the investigator will record adverse events and serious adverse 
events as described previously (Section 8.2, Definitions) on the appropriate electronic 
CRF regardless of the relationship to study therapy regimen or study procedure. Events 
grade 2 or higher will be recorded on the appropriate AE case report form (eCRF) for this 
study. The only exception to the above is that Grade 1 or higher SARS-CoV-2 infection 
will be recorded. 
Once recorded, an AE will be followed until it resolves with or without sequelae, or until 
the end of study participation, or until 30 days after the subject prematurely withdraws 
(without withdrawing consent)/or is withdrawn from the study, whichever occurs first. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 60 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
An SAE will be followed until it resolves with or without sequelae OR until 30 days after 
the end of study participation.  
If the AE is related to a laboratory or diagnostic evaluation, the evaluation that produced 
the value or result should be repeated until that value or result returns to normal or can be 
explained and the participant’s safety is not at risk. 
8.5 
REPORTING ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND 
EVENTS OF SPECIAL INTEREST TO SPONSOR: DAIT/NIAID 
8.5.1 Reporting Adverse Events  
This section describes the responsibilities of site investigators to report adverse events to 
the study sponsor (DAIT/NIAID) via the DAIT- Statistical and Clinical Coordinating 
Center (DAIT-SACCC).  Timely reporting of adverse events of NCI-CTCAE Grade 2 
and higher is required.  
Unless otherwise noted below in Section 8.5.2 for serious adverse events and events of 
special interest, AEs must be recorded on the AE eCRF within five (5) days of discovery 
of the event. Whenever possible, a diagnosis should be provided, rather than compilation 
of signs/symptoms, with grade of the event dictated by highest grade of the sign/symptom 
component. 
8.5.2 Reporting of Serious Adverse Events and Events of Special Interest 
This section describes the responsibilities of the site investigator to report serious adverse 
events and events of special interest to the sponsor via the electronic CRF (eCRF). 
Timely reporting of adverse events is required by 21 CFR Part 312.32, and ICH E6 
guidelines.  
The adverse events outlined below must be reported by the site investigators to 
DAIT/NIAID via the DAIT-SACCC regardless of relationship or expectedness to study 
intervention within 1 business day of discovery of the event: 
• 
All SAEs per 21 CFR 312.32 definitions (see Section 8.2.4, Serious Adverse 
Events). 
• 
The following events of special interest regardless of drug relationship: 
o Grade 3 or higher peripheral neuropathy. 
o Grade 3 or higher neutropenia or thrombocytopenia. 
o Grade 3 or higher infusion reaction. 
o Anaphylaxis, defined as a serious allergic reaction that is rapid in onset 
and may cause death (see Appendix 2) [79]. 
o New onset rash consistent with Stevens-Johnson syndrome, toxic 
epidermal necrolysis, or other drug reaction. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 61 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
o eGFR < 30 ml/min/1.73m2. 
o Potential drug-induced liver injury, defined as all three of the following: 
 
ALT or AST elevation > 3 times ULN, and 
 
Total bilirubin > 2 times ULN, without initial findings of 
cholestasis (elevated serum alkaline phosphatase), and 
 
No other immediately apparent possible causes of ALT or AST 
elevation and hyperbilirubinemia, including but not limited to 
viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drugs known to be hepatotoxic. 
o Grade 3 or greater infection. 
o A suspected case of PML. 
• 
All other Clinical events with an NCI-CTCAE Grade 3 or greater severity 
deemed possibly or definitely related to brentuximab vedotin.  
Note: clinical events include signs/symptoms, diagnoses, and laboratory abnormalities 
with clinical consequence (defined as the requirement for intervention, correction, 
increased monitoring, or further evaluation). 
When a site investigator identifies a serious adverse event or event of special interest 
specified above, he or she must notify DAIT/NIAID via the DAIT-SACCC within 1 
business day. Site investigators are to report these events on the SAE eCRF in EDC. 
Should EDC become unavailable/ inaccessible, the site investigator should notify 
DAIT/NIAID via the DAIT-SACCC email at Rho_productsafety@rhoworld.com.  This 
email can serve as the initial notification; however, within the next business day the SAE 
eCRF must be completed. 
All requested information on the SAE eCRF should be provided. Unavailable details of 
the event at time of initial report should not delay submission of known information. The 
initial report should include at a minimum: AE term, relationship to brentuximab vedotin, 
and reason why event is serious (per definitions). Supplementary CRF pages including 
medical history, concomitant medications, demographics, study drug administration, and 
death must be provided. As additional details become available, the SAE eCRF should be 
updated and submitted. With each iteration of the form, the investigator (or designated 
sub-investigator) must sign the form electronically.  
For additional information regarding SAE reporting, contact Rho Product Safety (DAIT-
SACCC): 
Rho Product Safety 
2635 E NC Hwy 54 
Durham, NC 27713 

Immune Tolerance Network 
CONFIDENTIAL 
Page 62 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
Toll-free-(888)-746-7231 
SAE Fax Line: 1-888-746-3293 
Email: Rho_productsafety@rhoworld.com  
8.6 
REPORTING TO HEALTH AUTHORITIES 
After an adverse event requiring 1 business day reporting (per Section 8.5.2, Reporting of 
Serious Adverse Events of Special interest) 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 (Annual Reporting and Expedited Reporting). 
8.6.1 Annual Reporting  
DAIT/NIAID will include in the annual study report to health authorities all adverse 
events classified as: 
• 
Serious, expected, suspected adverse reactions  
• 
Serious and not a suspected adverse reaction  
• 
Pregnancy 
Note that all adverse events (not just those requiring 24-hour reporting) will be reported 
in the Annual IND Report.  
8.6.2 Expedited Safety Reporting  
This option applies if the adverse event is classified as one of the following: 
• 
Serious and unexpected suspected adverse reaction [SUSAR]: 
o A single occurrence of an event that is uncommon and known to be 
strongly associated with drug exposure  
o 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 
o An aggregate analysis of specific events observed in a clinical trial that 
indicates those events occur more frequently in the drug treatment group 
than in a concurrent or historical control group 
The sponsor (DAIT/NIAID) will notify the appropriate health authorities (FDA) and all 
participating investigators of Expedited Safety Reports within 15 calendar days; 
unexpected fatal or immediately life-threatening suspected adverse reaction(s) will be 
reported as soon as possible or within 7 calendar days.  
Final Study Report: A complete summary of safety information (including both 
Standard and Expedited reports as defined above) is included in the final study report 
to be submitted to both US FDA at the closure of the protocol. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 63 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
8.7 
REPORTING OF ADVERSE EVENTS TO IRBS 
All investigators shall report AEs and SAEs, including IND safety reports, in a timely 
fashion to their respective IRBs in accordance with applicable regulations and guidelines. 
8.8 
REPORTING PREGNANCY 
The investigator shall be informed immediately of any pregnancy in a study subject or a 
partner of a study subject. A pregnant subject shall be instructed to stop taking study 
medication. The investigator shall counsel the subject and discuss the risks of continuing 
with the pregnancy and the possible effects on the fetus. Monitoring of the pregnant 
subject shall continue until the conclusion of the pregnancy.    
The investigator shall report to the sponsor (DAIT/NIAID) via the DAIT-SACCC any  
pregnancy in a study subject or a partner of a study subject within one business day of 
becoming aware of the event according to the procedures specified in section 8.5.2. The 
pregnancy eCRF will be used to submit the information for tracking purposes only, as the 
pregnancy itself is not considered an SAE.  All pregnancies identified during the study 
shall be followed to conclusion and the outcome of each must be reported.  The 
Pregnancy information must be updated and submitted to the DAIT-SACCC via the 
eCRF form as new information becomes available. When possible, similar information 
should be obtained for a pregnancy occurring in a partner of a study subject. 
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 
All pregnancy complications that result in a congenital abnormality, birth defect, 
miscarriage, and medically indicated abortion should be submitted on the SAE eCRF 
form. 
Mycophenolate REMS Program. It is strongly recommended that investigators 
with female participants of childbearing potential taking mycophenolate mofetil 
(MMF) enroll them in the Mycophenolate Risk Evaluation and Mitigation Strategy 
(REMS) program (www.mycophenolaterems.com). Under this program, an 
investigator will be required to report any pregnancy occurring in a female 
participant while she is taking MMF or within the first 6 weeks following 
discontinuation of MMF treatment to the Mycophenolate Pregnancy Registry, which 

Immune Tolerance Network 
CONFIDENTIAL 
Page 64 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
is part of the MMF REMS program. Study participants will be encouraged to 
participate in the MMF REMS program as well. 
8.9 
REPORTING UNANTICIPATED PROBLEMS 
An investigator must promptly notify the sponsor (DAIT/NIAID) via the DAIT-SACCC 
if an “unanticipated problem involving risks to subjects or others” is identified, which is 
not otherwise reportable as an adverse event. 
8.10 
REVIEW OF SAFETY INFORMATION 
8.10.1  Medical Monitor Review 
The DAIT/NIAID Medical Monitor shall receive monthly reports from the DAIT-
SACCC 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 and pregnancy reports received from the DAIT-SACCC.   
8.11 
 DATA SAFETY AND MONITORING BOARD REVIEW  
8.11.1  Routine DSMB Reviews  
The progress of the study will be monitored by the NIAID Data and Safety Monitoring 
Board (NIAID DSMB). The NIAID Autoimmune DSMB will be chartered to review 
safety data and to make recommendations to NIAID regarding continuation, termination, 
or modification of the study.  The DSMB will review the safety data 6 months after the 
first participant is treated.  Following the initial review, the DSMB will review the safety 
data at least yearly during planned DSMB Data Review Meetings. Data for the planned 
safety reviews will include, at a minimum, a listing of all reported AEs and SAEs.   
The DSMB chair will be informed of any Expedited Safety Reports in a timely manner in 
order to make a recommendation for an ad hoc full board review and /or protocol 
suspension. Discontinuation of study treatment will also be periodically reported to the 
DSMB. In addition, safety data will be reviewed by the DSMB when an event occurs that 
is of sufficient concern to the NIAID medical monitor or protocol co-chairs to warrant 
review, or when an event occurs that could contribute to a stopping rule. 
8.11.2 Protocol-Defined Interim Safety Reviews 
Interim safety reviews will be undertaken by a Safety Review Committee (SRC) 
comprised of a subgroup of the DSMB. The study design (section 3.1) specifies interim 
safety analysis and review by the SRC after each of the first two dosing cohorts have 
completed 12 weeks of therapy.  Approval by the SRC is required following review of 
the 12-week interim safety data prior to proceeding to the next higher dosing cohort.   
Interim safety analysis will also be conducted after each of the first two dosing cohorts 
have completed 24 weeks of therapy.  

Immune Tolerance Network 
CONFIDENTIAL 
Page 65 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
Following each protocol-specified interim safety review, the SRC can recommend 
actions regarding study conduct, including, but not limited to, the following: 
1. Continue the study as planned. 
2. Add participants to an existing dosing cohort. 
3. Reduce the number of weeks of study drug administration for the next higher 
dosing cohort. 
4. Stop the study. 
8.11.3 Ad hoc DSMB Reviews (Stopping Rule Guidance)  
If any of the following events occur, the chair of the DSMB will be notified and a review 
of the safety data will be performed.  The DSMB will have the discretion to recommend 
actions regarding study conduct, and will determine if enrollment in the study should be 
stopped and/or administration of investigational study medication should be halted: 
1. Any death that is at least possibly related to use of the investigational study 
medication. 
2. Any life-threatening infusion reactions during infusion of study medication or within 
the observation period after study medication that lead to permanent discontinuation 
of the infusion, including anaphylaxis. 
3. One case of PML. 
4. Any grade 4 adverse event that is at least possibly related to use of the investigational 
study medication. 
5. Two or more Grade 3 or higher peripheral neuropathy events involving different 
participants. 
If stopping rule 1, 2, or 3 is met, then no new participants will be consented, and no new 
participants will be enrolled, until after the DSMB completes review of the safety data. 
Participants in the screening phase of the study may continue to undergo minimal risk 
procedures. 
If stopping rule 4 or 5 is met, the study will proceed as planned pending DSMB review of 
the data. However, if two weeks has elapsed and the DSMB has not met, then no new 
participants will be consented, and no new participants will be enrolled, until after the 
DSMB completes review of the safety data.  
In the event that a temporary halt is placed on consent and enrollment, participants 
already enrolled in the study will continue to receive study medication if they are not the 
subject of the DSMB review. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 66 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
9. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN 
9.1 
ANALYSIS SAMPLES 
9.1.1 Analysis Populations  
The safety sample is defined as all subjects who receive any amount of the placebo or the 
brentuximab vedotin study drug. They will be summarized and compared according to 
the treatment actually received. Because participants receive their assigned medication on 
the day of randomization, this is conceptually equivalent to the standard intention to treat 
analysis population. 
Supplementary per protocol (PP) analysis samples are defined as follows:   
• 
PP12: Treated participants who receive at least 4 of the 5 infusions over the first 
12 weeks, and who have no major protocol deviations that would affect the safety 
outcomes through the first 12 weeks. 
• 
PP24: Treated participants who receive at least 7 of the 8 infusions over the first 
21 weeks, and who have no major protocol deviations that would affect the safety 
outcomes through the first 24 weeks. 
• 
PP36: Treated participants who receive at least 7 of the 8 infusions over the first 
21 weeks, and who have no major protocol deviations that would affect the safety 
outcomes through the first 36 weeks. 
• 
PP48: Treated participants who receive at least 7 of the 8 infusions over the first 
21 weeks, and who have no major protocol deviations that would affect the safety 
outcomes through the first 48 weeks. 
9.2 
ANALYSIS OF ENDPOINTS 
9.2.1 Primary Endpoint 
For each dosing cohort, the primary endpoint is the proportion of participants who 
experienced at least one Grade 3 or higher adverse event at or before week 48. It will be 
analyzed using the safety sample and the PP48 analysis sample. Proportions will be 
estimated by treatment group together with their 95% confidence intervals derived using 
the Clopper-Pearson exact method. Although this study is not powered to detect it, a 
between-group comparison within each dosing cohort will be performed using Fisher’s 
exact test. 
9.2.2 Secondary and Exploratory Endpoints 
Secondary and exploratory endpoints consist of the following: 
1. The proportion of participants who experience at least one Grade 3 or higher adverse 
event at or before weeks 12, 24 and 36.  

Immune Tolerance Network 
CONFIDENTIAL 
Page 67 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
2. The proportion of participants who experience at least one Grade 2 or higher adverse 
event at or before weeks 12, 24, 36, and 48. 
3. The proportion of participants with Grade 2 or higher peripheral neuropathy at or 
before weeks 12, 24, 36, and 48. 
4. The proportion of participants with Grade 3 or higher neutropenia at or before weeks 
12, 24, 36, and 48. 
5. 
The proportion of participants with any of the following Grade 3 or higher adverse 
events at or before week 48: 
a. Peripheral neuropathy. 
b. Neutropenia. 
c. Infectious adverse events. 
d. Infusion reactions, including anaphylaxis and new onset rash consistent with 
Stevens-Johnson syndrome, toxic epidermal necrolysis, or other drug reaction. 
e. PML. 
6. Modified Rodnan Skin Score (mRSS) at weeks 12, 24, and 48. 
7. Provisional American College of Rheumatology Combined Response Index in 
Systemic Sclerosis (CRISS) at weeks 24 and 48. 
8. Percent predicted Forced Vital Capacity (FVC) at weeks 24 and 48 weeks. 
9. Physician’s global assessment on a Likert scale at weeks 24 and 48. 
10. Patient’s global assessment on a Likert scale at weeks 24 and 48. 
11. Health-related quality of life (HRQOL) assessed by PROMIS-29 version 2.0 at 
weeks 24 and 48. 
12. Physical function assessed by the Scleroderma Health Assessment Questionnaire-
Disability Index (SHAQ-DI) at weeks 24 and 48. 
All secondary and exploratory endpoints at all study weeks will be analyzed using the 
safety sample. Additionally, endpoints at weeks 12, 24, 36 and 48 will be analyzed using 
the corresponding PP12, PP24, PP36 and PP48 analysis samples.  
The proportions of participants with peripheral neuropathy and the different types of 
adverse events will be analyzed and compared in the same manner as described above for 
the primary endpoint. The numbers of AEs and SAEs will be summarized using simple 
descriptive statistics. Simple descriptive statistics will be provided overall and by 
treatment group for FVC and the different disease severity scales. In each dosing cohort, 
the Wilcoxon Signed Rank test will be used to determine if there was a significant change 
from baseline to the follow-up evaluations within each treatment group. Between-group 
comparisons within each dosing cohort will be performed using the Wilcoxon Rank Sum 
test. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 68 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
9.2.3 Analysis of Dose-Response Relationship 
The 3 dosing cohorts will be merged together to determine if there is a significant dose-
response relationship in the endpoints with the amount of brentuximab vedotin received. 
The 4 dose levels include placebo (0.0 mg/kg), and brentuximab vedotin at low (0.6 
mg/kg), medium (1.2 mg/kg), and high dose (1.8 mg/kg). The primary endpoint as well 
as the proportions of participants with peripheral neuropathy and the different types of 
adverse events will be analyzed using the exact version of the Cochran-Armitage test for 
trend. Additionally, these endpoints will be analyzed using a logistic regression model. 
For FVC and the disease severity scales, the Spearman correlation will be used to 
determine if there is an association in the change from baseline with the dose level. These 
analyses will be performed on the safety sample and the PP48 sample. 
9.2.4 Missing Data 
Standard procedures will be used to ensure that data are as complete and accurate as 
possible. Due to the fact that this is primarily a safety study and due to the small sample 
size in each dosing cohort, no imputation for missing data will be done. 
9.2.5 Baseline Characteristics and Demographics 
Summary statistics for baseline and demographic characteristics will be provided for the 
safety sample. Demographic data will include age, race, sex, weight, and height. These 
data will be presented in the following manner: 
• 
Continuous data (i.e., age, weight, and height) will be summarized by mean, 
standard deviation, median, and range. 
• 
Categorical data (i.e., sex and race) will be presented as counts and percentages. 
9.2.6 Safety Analysis 
Safety analyses will be performed on the safety sample. Missing safety information will 
not be imputed. Reports summarizing safety data will be prepared at the end of the study 
and periodically throughout the study for IND regulatory filings, the DSMB, and for the 
medical monitor and study management team. Safety reports will be prepared to meet the 
needs of those groups and individuals responsible for monitoring safety and may include 
(but are not limited to) summaries and listings of SAEs, AEs, vital signs, laboratory 
values, physical examination results, events requiring drug discontinuations for 
individual participants (see Section 4.3), and events listed as study stopping rules 
(Section 8.11.3). AEs and SAEs in the summary displays and listings will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA) system organ classes and/or 
preferred terms. Severity will be reported using NCI-CTCAE grading criteria. 
Relationship to study drug will be reported as per Section 8.3.2. Abnormal vital signs and 
laboratory values will be graded using the NCI-CTCAE criteria and grade will be 
included in listings. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 69 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
9.2.7 Interim Analysis of Safety Data 
Analysis of safety data is planned after the last participant in each of the first two dosing 
cohorts of 8 participants has completed the first 12 weeks and the first 24 weeks of 
treatment and evaluation. A Safety Review Committee (SRC) will review the safety data 
and make recommendations regarding study conduct, as described in Section 8.11.2.  
Tables, listings, and/or figures of all the measures listed in Section 9.2.6 will be presented 
for each of these interim safety analyses. 
9.2.8 Medical History 
Medical history within the 12 months prior to screening, including the existence of 
current signs and symptoms, will be collected for each body system. 
9.2.9  Use of Medications 
All medications taken by or administered to study participants beginning 30 days before 
enrollment and continuing throughout the study will be collected. All medications used 
will be coded according to the World Health Organization (WHO) drug dictionary. A 
listing of all prior and concomitant medications/therapies will be created. The number 
and percentage of participants receiving prior and concomitant medications/therapies will 
be presented overall and by medication class. 
9.3 
SAMPLE SIZE  
No formal power analyses were conducted since all safety and efficacy evaluations are 
exploratory. The total sample size for this study is 24 participants with 8 participants in 
each of 3 dosing cohorts including 6 participants receiving brentuximab vedotin and 2 
receiving placebo. The ability to detect significant events of certain frequencies was 
considered. Table 2 illustrates the probability of observing at least 1 significant event in a 
dosing cohort of 6 participants receiving brentuximab vedotin. A cohort of 3 participants 
has also been included in case there are partially enrolled cohorts.  
Table 2 Probability of Events  
 
True Probability of Event 
 
0.1 
0.2 
0.3 
Probability of observing at least 1 event in 3 participants 
0.27 
0.49 
0.66 
Probability of observing at least 1 event in 6 participants 
0.47 
0.74 
0.88 
 
Additionally, Table 3 displays the upper and lower limits of the exact 95% Clopper-
Pearson confidence interval for the primary outcome among the 6 participants treated 
with brentuximab vedotin in any dosing cohort. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 70 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
Table 3 Confidence Limits  
Number with 
Grade 3+ AE 
Proportion with 
Grade 3+ AE 
Lower Limit for 
Exact 95% CI 
Upper Limit for 
Exact 95% CI 
0 
0.000 
0.000 
0.459 
1 
0.167 
0.004 
0.641 
2 
0.333 
0.043 
0.777 
3 
0.500 
0.118 
0.882 
4 
0.667 
0.223 
0.957 
5 
0.833 
0.359 
0.996 
6 
1.000 
0.541 
1.000 
   
9.4 
REPORTING DEVIATIONS FROM THE ORIGINAL STATISTICAL PLAN 
The principal features of both the study design and the plan for statistical data analysis 
are outlined in this protocol and in the statistical analysis plan (SAP). Any change in 
these features requires either a protocol or an SAP amendment and subject to review by 
the DSMB, the study sponsor(s), and the health authorities. These changes will be 
described in the final study report as appropriate. 
10. 
ACCESS TO SOURCE DATA/DOCUMENTS 
The investigational sites participating in this study will maintain the highest degree of 
confidentiality permitted for the clinical and research information obtained from 
participants in this clinical trial. Medical and research records should be maintained at 
each site in the strictest confidence. However, as a part of the quality assurance and legal 
responsibilities of an investigation, the investigational sites must permit authorized 
representatives of the ITN, sponsor, and health authorities to examine (and to copy when 
required by applicable law) clinical records for the purposes of quality assurance reviews, 
audits, and evaluation of the study safety and progress. Unless required by the laws 
permitting copying of records, only the coded identity associated with documents or other 
participant data may be copied (and any personally identifying information must be 
obscured). Authorized representatives as noted above are bound to maintain the strict 
confidentiality of medical and research information that may be linked to identified 
individuals. The investigational sites will normally be notified in advance of auditing 
visits. 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The principal investigator is required to keep accurate records to ensure that the conduct 
of the study is fully documented. The principal investigator is required to ensure that all 
eCRFs are completed for every participant entered in the trial. 
The sponsor is responsible for regular inspection of the conduct of the trial, for verifying 
adherence to the protocol, and for confirming the completeness, consistency, and 
accuracy of all documented data. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 71 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
The eCRFs will be completed online via a web-based EDC system that has been 
validated and is compliant with Part 11 Title 21 of the Code of Federal Regulations. Data 
queries will be issued and resolved within the EDC system. Some data cleaning will be 
performed outside EDC using statistical analysis system (SAS®) software.  
Study staff at the site will enter information into the electronic CRFs, and the data will be 
stored remotely at a central database. Data quality will be ensured through the EDC 
system’s continuous monitoring of data and real-time detection and correction of errors. 
All elements of data entry (i.e., time, date, verbatim text, and the name of the person 
performing the data entry) will be recorded in an electronic audit trail to allow all 
changes in the database to be monitored and maintained in accordance with US and 
Canadian regulations.  
Study staff will enter data from a study visit on the relevant eCRFs within 5 business 
days following the visit or at the time when data become available. 
12. 
ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD CLINICAL 
PRACTICE 
12.1 
STATEMENT OF COMPLIANCE 
This trial will be conducted in compliance with the protocol, current GCP guidelines — 
as delineated in Guidance for Industry: E6 Good Clinical Practice Consolidated 
Guidance — and all applicable regulatory requirements. 
Prior to study initiation, the protocol and the informed consent documents will be 
reviewed and approved by the sponsor and the appropriate health authorities and ethics 
review committee (IRB). Any amendments to the protocol or consent materials must also 
be approved by the Sponsor, the ethics review committee (IRB), and submitted to FDA 
before they are implemented in the US. 
12.2 
INFORMED CONSENT 
The informed consent form is a means of providing information about the trial to a 
prospective participant and allows for an informed decision about participation in the 
study. All participants (or their legally acceptable representative) must read, sign, and 
date a consent form before participating in the study, taking the study drug, and/or 
undergoing any study-specific procedures. If a participant does not speak and read 
English, the consent materials must be translated into the appropriate language. 
The informed consent form must be updated or revised whenever important new safety 
information is available, whenever the protocol is amended, and/or whenever any new 
information becomes available that may affect participation in the trial. 
A copy of the informed consent will be given to a prospective participant for review. The 
study investigator, in the presence of a witness, will review the consent and answer 

Immune Tolerance Network 
CONFIDENTIAL 
Page 72 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
questions. The participant will be informed that participation is voluntary and that he/she 
may withdraw from the study at any time, for any reason. 
12.3 
PRIVACY AND CONFIDENTIALITY 
A participant’s privacy and confidentiality will be respected throughout the study. Each 
participant will be assigned a sequential identification number. This number, rather than 
the participant’s name, will be used to collect, store, and report participant information. 
13. 
PUBLICATION POLICY 
The ITN policy on publication of study results will apply to this study. Authorized 
participants may find details regarding the policy statement on the ITN internet website at 
http://www.immunetolerance.org.  
 
 
 
 

Immune Tolerance Network 
CONFIDENTIAL 
Page 73 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
14. 
REFERENCES 
1. 
Elhai, M., et al., A gender gap in primary and secondary heart dysfunctions in systemic sclerosis: 
a EUSTAR prospective study. Ann Rheum Dis, 2016. 75(1): p. 163-9. 
2. 
Mayes, M.D., et al., Prevalence, incidence, survival, and disease characteristics of systemic 
sclerosis in a large US population. Arthritis Rheum, 2003. 48(8): p. 2246-55. 
3. 
Barnes, J. and M.D. Mayes, Epidemiology of systemic sclerosis: incidence, prevalence, survival, 
risk factors, malignancy, and environmental triggers. Curr Opin Rheumatol, 2012. 24(2): p. 165-
70. 
4. 
Rubio-Rivas, M., et al., Mortality and survival in systemic sclerosis: systematic review and meta-
analysis. Semin Arthritis Rheum, 2014. 44(2): p. 208-19. 
5. 
Steen, V.D. and T.A. Medsger, Changes in causes of death in systemic sclerosis, 1972-2002. Ann 
Rheum Dis, 2007. 66(7): p. 940-4. 
6. 
Nagaraja, V., C.P. Denton, and D. Khanna, Old medications and new targeted therapies in 
systemic sclerosis. Rheumatology (Oxford), 2015. 54(11): p. 1944-53. 
7. 
Burt, R.K., et al., Autologous non-myeloablative haemopoietic stem-cell transplantation compared 
with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, 
randomised phase 2 trial. Lancet, 2011. 378(9790): p. 498-506. 
8. 
van Laar, J.M., et al., Autologous hematopoietic stem cell transplantation vs intravenous pulse 
cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA, 
2014. 311(24): p. 2490-8. 
9. 
Sullivan, K.M., et al., Myeloablative Autologous Stem-Cell Transplantation for Severe 
Scleroderma. N Engl J Med, 2018. 378(1): p. 35-47. 
10. 
Sullivan, K.M., et al., Review: Hematopoietic Stem Cell Transplantation for Scleroderma: 
Effective Immunomodulatory Therapy for Patients With Pulmonary Involvement. Arthritis 
Rheumatol, 2016. 68(10): p. 2361-71. 
11. 
Giuggioli, D., et al., Rituximab in the treatment of patients with systemic sclerosis. Our experience 
and review of the literature. Autoimmun Rev, 2015. 14(11): p. 1072-8. 
12. 
Khanna, D., et al., Safety and efficacy of subcutaneous tocilizumab in adults with systemic 
sclerosis (faSScinate): a phase 2, randomised, controlled trial. Lancet, 2016. 
13. 
Distler, O. and J.H. Distler, Tocilizumab for systemic sclerosis: implications for future trials. 
Lancet, 2016. 
14. 
Varga, J. and D. Abraham, Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin 
Invest, 2007. 117(3): p. 557-67. 
15. 
Hamaguchi, Y., Autoantibody profiles in systemic sclerosis: predictive value for clinical 
evaluation and prognosis. J Dermatol, 2010. 37(1): p. 42-53. 
16. 
Salazar, G.A., et al., Antinuclear antibody-negative systemic sclerosis. Semin Arthritis Rheum, 
2015. 44(6): p. 680-6. 
17. 
Kalogerou, A., et al., Early T cell activation in the skin from patients with systemic sclerosis. Ann 
Rheum Dis, 2005. 64(8): p. 1233-5. 
18. 
Roumm, A.D., et al., Lymphocytes in the skin of patients with progressive systemic sclerosis. 
Quantification, subtyping, and clinical correlations. Arthritis Rheum, 1984. 27(6): p. 645-53. 
19. 
Hasegawa, M., et al., Augmented ICOS expression in patients with early diffuse cutaneous 
systemic sclerosis. Rheumatology (Oxford), 2013. 52(2): p. 242-51. 
20. 
Hugle, T., et al., Tumor necrosis factor-costimulated T lymphocytes from patients with systemic 
sclerosis trigger collagen production in fibroblasts. Arthritis Rheum, 2013. 65(2): p. 481-91. 
21. 
Greenblatt, M.B., et al., Interspecies comparison of human and murine scleroderma reveals IL-13 
and CCL2 as disease subset-specific targets. Am J Pathol, 2012. 180(3): p. 1080-94. 
22. 
Kaviratne, M., et al., IL-13 activates a mechanism of tissue fibrosis that is completely TGF-beta 
independent. J Immunol, 2004. 173(6): p. 4020-9. 
23. 
Wynn, T.A., Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat Rev Immunol, 2004. 4(8): p. 
583-94. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 74 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
24. 
Knipper, J.A., et al., Interleukin-4 Receptor alpha Signaling in Myeloid Cells Controls Collagen 
Fibril Assembly in Skin Repair. Immunity, 2015. 43(4): p. 803-16. 
25. 
Romagnani, S., et al., CD30 and type 2 T helper (Th2) responses. J Leukoc Biol, 1995. 57(5): p. 
726-30. 
26. 
Kim, M.Y., et al., CD4(+)CD3(-) accessory cells costimulate primed CD4 T cells through OX40 
and CD30 at sites where T cells collaborate with B cells. Immunity, 2003. 18(5): p. 643-54. 
27. 
Opat, S. and J.S. Gaston, CD30:CD30 ligand interactions in the immune response. Autoimmunity, 
2000. 33(1): p. 45-60. 
28. 
Gaspal, F.M., et al., Mice deficient in OX40 and CD30 signals lack memory antibody responses 
because of deficient CD4 T cell memory. J Immunol, 2005. 174(7): p. 3891-6. 
29. 
Gaspal, F., et al., Abrogation of CD30 and OX40 signals prevents autoimmune disease in FoxP3-
deficient mice. J Exp Med, 2011. 208(8): p. 1579-84. 
30. 
Chakrabarty, S., et al., Critical roles of CD30/CD30L interactions in murine autoimmune 
diabetes. Clin Exp Immunol, 2003. 133(3): p. 318-25. 
31. 
Mavalia, C., et al., Type 2 helper T-cell predominance and high CD30 expression in systemic 
sclerosis. Am J Pathol, 1997. 151(6): p. 1751-8. 
32. 
Ihn, H., et al., Circulating levels of soluble CD30 are increased in patients with localized 
scleroderma and correlated with serological and clinical features of the disease. J Rheumatol, 
2000. 27(3): p. 698-702. 
33. 
Giacomelli, R., et al., Circulating levels of soluble CD30 are increased in patients with systemic 
sclerosis (SSc) and correlate with serological and clinical features of the disease. Clin Exp 
Immunol, 1997. 108(1): p. 42-6. 
34. 
D'Elios, M.M., et al., In vivo CD30 expression in human diseases with predominant activation of 
Th2-like T cells. J Leukoc Biol, 1997. 61(5): p. 539-44. 
35. 
Ciferska, H., et al., The levels of sCD30 and of sCD40L in a group of patients with systemic lupus 
erythematodes and their diagnostic value. Clin Rheumatol, 2007. 26(5): p. 723-8. 
36. 
Ulusoy, H., et al., Serum levels of soluble CD26 and CD30 and their clinical significance in 
patients with rheumatoid arthritis. Rheumatol Int, 2012. 32(12): p. 3857-62. 
37. 
Gerli, R., et al., High levels of the soluble form of CD30 molecule in rheumatoid arthritis (RA) are 
expression of CD30+ T cell involvement in the inflamed joints. Clin Exp Immunol, 1995. 102(3): 
p. 547-50. 
38. 
Caligaris-Cappio, F., et al., Circulating levels of soluble CD30, a marker of cells producing Th2-
type cytokines, are increased in patients with systemic lupus erythematosus and correlate with 
disease activity. Clin Exp Rheumatol, 1995. 13(3): p. 339-43. 
39. 
Okumura, M., et al., Increased serum concentration of soluble CD30 in patients with Graves' 
disease and Hashimoto's thyroiditis. J Clin Endocrinol Metab, 1997. 82(6): p. 1757-60. 
40. 
Harada, K., et al., Significance of CD30-positive lymphocytes in livers in primary biliary cirrhosis. 
J Gastroenterol Hepatol, 1999. 14(12): p. 1197-202. 
41. 
Wang, G., et al., High plasma levels of the soluble form of CD30 activation molecule reflect 
disease activity in patients with Wegener's granulomatosis. Am J Med, 1997. 102(6): p. 517-23. 
42. 
Cabrera, C.M., et al., Differential expression of CD30 on CD3 T lymphocytes in patients with 
systemic lupus erythematosus. Scand J Immunol, 2013. 78(3): p. 306-12. 
43. 
Barbieri, A., et al., Characterization of CD30/CD30L(+) Cells in Peripheral Blood and Synovial 
Fluid of Patients with Rheumatoid Arthritis. J Immunol Res, 2015. 2015: p. 729654. 
44. 
Ichikawa, Y., et al., Circulating soluble CD30 levels in primary Sjogren's syndrome, SLE and 
rheumatoid arthritis. Clin Exp Rheumatol, 1998. 16(6): p. 759-60. 
45. 
Caproni, M., et al., In vivo relevance of CD30 in atopic dermatitis. Allergy, 1997. 52(11): p. 1063-
70. 
46. 
Younes, A., et al., Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl 
J Med, 2010. 363(19): p. 1812-21. 
47. 
Ansell, S.M., Brentuximab vedotin. Blood, 2014. 124(22): p. 3197-200. 
48. 
Katz, J., J.E. Janik, and A. Younes, Brentuximab Vedotin (SGN-35). Clin Cancer Res, 2011. 
17(20): p. 6428-36. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 75 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
49. 
Okeley, N.M., et al., Intracellular activation of SGN-35, a potent anti-CD30 antibody-drug 
conjugate. Clin Cancer Res, 2010. 16(3): p. 888-97. 
50. 
Tian, Z.G., et al., In vivo antitumor effects of unconjugated CD30 monoclonal antibodies on 
human anaplastic large-cell lymphoma xenografts. Cancer Res, 1995. 55(22): p. 5335-41. 
51. 
Gul, N. and M. van Egmond, Antibody-Dependent Phagocytosis of Tumor Cells by Macrophages: 
A Potent Effector Mechanism of Monoclonal Antibody Therapy of Cancer. Cancer Res, 2015. 
75(23): p. 5008-13. 
52. 
Francisco, J.A., et al., cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with 
potent and selective antitumor activity. Blood, 2003. 102(4): p. 1458-65. 
53. 
Oflazoglu, E., et al., Combination of the anti-CD30-auristatin-E antibody-drug conjugate (SGN-
35) with chemotherapy improves antitumour activity in Hodgkin lymphoma. Br J Haematol, 2008. 
142(1): p. 69-73. 
54. 
de Claro, R.A., et al., U.S. Food and Drug Administration approval summary: brentuximab 
vedotin for the treatment of relapsed Hodgkin lymphoma or relapsed systemic anaplastic large-
cell lymphoma. Clin Cancer Res, 2012. 18(21): p. 5845-9. 
55. 
ADCETRIS Highlights of Prescribing Information. 2019 10/2019 [cited 2020 November 19, 
2020]; Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125388s100lbl.pdf. 
56. 
Younes, A., et al., Results of a pivotal phase II study of brentuximab vedotin for patients with 
relapsed or refractory Hodgkin's lymphoma. J Clin Oncol, 2012. 30(18): p. 2183-9. 
57. 
Gopal, A.K., et al., Durable remissions in a pivotal phase 2 study of brentuximab vedotin in 
relapsed or refractory Hodgkin lymphoma. Blood, 2015. 125(8): p. 1236-43. 
58. 
Pro, B., et al., Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic 
anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol, 2012. 30(18): p. 2190-6. 
59. 
Forero-Torres, A., et al., Phase 2 study of frontline brentuximab vedotin monotherapy in Hodgkin 
lymphoma patients aged 60 years and older. Blood, 2015. 126(26): p. 2798-804. 
60. 
Moskowitz, C.H., et al., Brentuximab vedotin as consolidation therapy after autologous stem-cell 
transplantation in patients with Hodgkin's lymphoma at risk of relapse or progression 
(AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet, 2015. 
385(9980): p. 1853-62. 
61. 
Chen, Y.B., et al., Expression of CD30 in patients with acute graft-versus-host disease. Blood, 
2012. 120(3): p. 691-6. 
62. 
https://ash.confex.com/ash/2015/webprogram/Paper81513.html. accessed July 2016. 
63. 
http://www.bbmt.org/article/S1083-8791(15)01704-8/abstract. accessed July 2016. 
64. 
Vachhani, P., et al., Remission of rheumatoid arthritis on brentuximab vedotin. Rheumatology 
(Oxford), 2014. 53(12): p. 2314-5. 
65. 
Seattle Genetics Brentuximab Vedotin Investigator's Brochure Version 18. September 28, 2020. 
66. 
Oak, E. and N.L. Bartlett, A safety evaluation of brentuximab vedotin for the treatment of Hodgkin 
lymphoma. Expert Opin Drug Saf, 2016. 15(6): p. 875-82. 
67. 
Wagner-Johnston, N.D., et al., Progressive multifocal leukoencephalopathy in a patient with 
Hodgkin lymphoma treated with brentuximab vedotin. Leuk Lymphoma, 2012. 53(11): p. 2283-6. 
68. 
Carson, K.R., et al., Progressive multifocal leukoencephalopathy associated with brentuximab 
vedotin therapy: a report of 5 cases from the Southern Network on Adverse Reactions (SONAR) 
project. Cancer, 2014. 120(16): p. 2464-71. 
69. 
FACT SHEET FOR HEALTH CARE PROVIDERS EMERGENCY USE AUTHORIZATION (EUA) 
OF REGEN-COVTM (casirivimab and imdevimab). 2021  [cited 2021; Available from: 
https://www.fda.gov/media/145611/download. 
70. 
FACT SHEET FOR HEALTH CARE PROVIDERS EMERGENCY USE AUTHORIZATION (EUA) 
OF BAMLANIVIMAB AND ETESEVIMAB. 2021  [cited 2021; Available from: 
https://www.fda.gov/media/145802/download. 
71. 
FACT SHEET FOR HEALTHCARE PROVIDERS EMERGENCY USE AUTHORIZATION (EUA) 
OF SOTROVIMAB. 2021  [cited 2021; Available from: 
https://www.fda.gov/media/149534/download. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 76 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
72. 
Gandhi, M.D., et al., Pancreatitis in patients treated with brentuximab vedotin: a previously 
unrecognized serious adverse event. Blood, 2014. 123(18): p. 2895-7. 
73. 
Younes, A., et al., Brentuximab vedotin combined with ABVD or AVD for patients with newly 
diagnosed Hodgkin's lymphoma: a phase 1, open-label, dose-escalation study. Lancet Oncol, 
2013. 14(13): p. 1348-56. 
74. 
http://www.targetedonc.com/publications/targeted-therapies-cancer/2015/april-2015/treatment-
strategies-to-optimize-outcomes-with-brentuximab-vedotin-management-of-common-and-rare-
toxicities. accessed July 2016. 
75. 
Khanna, D., et al., The American College of Rheumatology Provisional Composite Response Index 
for Clinical Trials in Early Diffuse Cutaneous Systemic Sclerosis. Arthritis Rheumatol, 2016. 
68(2): p. 299-311. 
76. 
van den Hoogen, F., et al., 2013 classification criteria for systemic sclerosis: an American College 
of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum, 
2013. 65(11): p. 2737-47. 
77. 
LeRoy, E.C. and T.A. Medsger, Jr., Criteria for the classification of early systemic sclerosis. J 
Rheumatol, 2001. 28(7): p. 1573-6. 
78. 
https://www.osha.gov/SLTC/hazardousdrugs/. accessed August 2016. 
79. 
Sampson, H.A., et al., Second symposium on the definition and management of anaphylaxis: 
summary report--Second National Institute of Allergy and Infectious Disease/Food Allergy and 
Anaphylaxis Network symposium. J Allergy Clin Immunol, 2006. 117(2): p. 391-7. 
80. 
Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. 2017 
11/14/2017 [cited 2018 May 29, 2018]; Available from: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm093664.htm#classSub. 
81. 
Levey, A.S., et al., A new equation to estimate glomerular filtration rate. Ann Intern Med, 2009. 
150(9): p. 604-12. 
82. 
Stanojevic, S., et al., Official ERS technical standards: Global Lung Function Initiative reference 
values for the carbon monoxide transfer factor for Caucasians. Eur Respir J, 2017. 50(3). 
83. 
Graham, B.L., et al., 2017 ERS/ATS standards for single-breath carbon monoxide uptake in the 
lung. Eur Respir J, 2017. 49(1). 
84. 
Steen, V.D. and T.A. Medsger, Jr., The value of the Health Assessment Questionnaire and special 
patient-generated scales to demonstrate change in systemic sclerosis patients over time. Arthritis 
Rheum, 1997. 40(11): p. 1984-91. 
85. 
Horie, R. and T. Watanabe, CD30: expression and function in health and disease. Semin 
Immunol, 1998. 10(6): p. 457-70. 
86. 
Duckett, C.S. and C.B. Thompson, CD30-dependent degradation of TRAF2: implications for 
negative regulation of TRAF signaling and the control of cell survival. Genes Dev, 1997. 11(21): 
p. 2810-21. 
87. 
Kurts, C., et al., Signalling through CD30 protects against autoimmune diabetes mediated by CD8 
T cells. Nature, 1999. 398(6725): p. 341-4. 
88. 
Telford, W.G., et al., CD30-regulated apoptosis in murine CD8 T cells after cessation of TCR 
signals. Cell Immunol, 1997. 182(2): p. 125-36. 
89. 
Amakawa, R., et al., Impaired negative selection of T cells in Hodgkin's disease antigen CD30-
deficient mice. Cell, 1996. 84(4): p. 551-62. 
90. 
Chiarle, R., et al., CD30 overexpression enhances negative selection in the thymus and mediates 
programmed cell death via a Bcl-2-sensitive pathway. J Immunol, 1999. 163(1): p. 194-205. 
91. 
Muta, H., et al., CD30 signals integrate expression of cytotoxic effector molecules, lymphocyte 
trafficking signals, and signals for proliferation and apoptosis. J Immunol, 2000. 165(9): p. 5105-
11. 
92. 
Grell, M., et al., Induction of cell death by tumour necrosis factor (TNF) receptor 2, CD40 and 
CD30: a role for TNF-R1 activation by endogenous membrane-anchored TNF. EMBO J, 1999. 
18(11): p. 3034-43. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 77 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
93. 
Hinchcliff, M., et al., Molecular signatures in skin associated with clinical improvement during 
mycophenolate treatment in systemic sclerosis. J Invest Dermatol, 2013. 133(8): p. 1979-89. 
94. 
van Bon, L., et al., Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis. N 
Engl J Med, 2014. 370(5): p. 433-43. 
95. 
Rice, L.M., et al., A longitudinal biomarker for the extent of skin disease in patients with diffuse 
cutaneous systemic sclerosis. Arthritis Rheumatol, 2015. 67(11): p. 3004-15. 
96. 
Lafyatis, R., Transforming growth factor beta--at the centre of systemic sclerosis. Nat Rev 
Rheumatol, 2014. 10(12): p. 706-19. 
97. 
Altorok, N. and A.H. Sawalha, Epigenetics in the pathogenesis of systemic lupus erythematosus. 
Curr Opin Rheumatol, 2013. 25(5): p. 569-76. 
98. 
Javierre, B.M., H. Hernando, and E. Ballestar, Environmental triggers and epigenetic deregulation 
in autoimmune disease. Discov Med, 2011. 12(67): p. 535-45. 
99. 
Gu, Y.S., et al., The immunobiology of systemic sclerosis. Semin Arthritis Rheum, 2008. 38(2): p. 
132-60. 
100. 
Ho, K.T. and J.D. Reveille, The clinical relevance of autoantibodies in scleroderma. Arthritis Res 
Ther, 2003. 5(2): p. 80-93. 
 
 
 

Immune Tolerance Network 
CONFIDENTIAL 
Page 78 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
APPENDIX 1. SCHEDULE OF EVENTS 
Study Week 
-1 
0 
3 
6 
9 
12 
15 
18 
21 
24 
28 
36 
48 
DSC 
UN 
Visit Number  
-1 
0 
1 
2 
3 
4 
5 
6 
7 
8 
94 
10 
11 
 
General Assessments 
Informed consent 
x 
 
Eligibility criteria 
x 
 
Randomization 
x 
 
Demographics  
x 
 
Medical History 
x 
 
Scleroderma History 
x 
 
Comprehensive physical examination  
x 
x 
x 
x 
Limited physical examination  
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
Peripheral neuropathy assessment 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x5 
x 
x 
x 
x 
Neurologist assessment1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x1 
Vital signs 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse Events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Clinical Laboratory Assessments 
Hematology 2 
x 
x 
x2 
x2 
x2 
x2 
x2 
x2 
x2 
x 
x 
x 
x 
x 
Serum chemistry 2 
x 
x 
x2 
x2 
x2 
x2 
x2 
x2 
x2 
x 
x 
x 
x 
x 
Serum amylase and lipase 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV 
x 
 
HBV 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HCV 
x 
 
ESR 
x 
x 
x 
x 
x 
Serum HCG3 
x3 
 
STAT Urine HCG3 
x3 
x3 
x3 
x3 
x3 
x3 
x3 
x3 
x3 
x3 
x3 
x3 
x3 
QuantiFERON Gold, Gold Plus or PPD 
x 
 
PCR test for SARS-CoV-2 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General Clinical Assessments 
EKG 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Echocardiogram   
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
Disease-Specific Assessments  
Spirometry (FVC and FEV1) with 
DLCO6 
x 
 
 
 
 
x 
 
 
 
x 
 
 
x 
x 
 
mRSS  
x 
x 
 
 
 
x 
 
 
 
x 
 
 
x 
x 
 
Physician global assessment 
 
x 
 
 
 
 
 
 
 
x 
 
 
x 
x 
 
Patient global assessment, PROMIS-
29, SHAQ-DI  
 
x 
 
 
 
 
 
 
 
x 
 
 
x 
x 
 
Study Medications 
Study medication administration  
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
Mechanistic Assessments 
Skin biopsy 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
 
 
Plasma/Serum assays 
 
x 
 
 
 
x 
 
 
 
x 
 
 
x 
x 
 
PBMC assays 
 
x 
 
 
 
x 
 
 
 
x 
 
 
x 
x 
 
Whole blood DNA genotyping 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole blood gene expression analysis 
 
x 
 
 
 
x 
 
 
 
x 
 
 
x 
x 
 
 
1 As indicated for suspected peripheral neuropathy 
2 Hematology and serum chemistry results must be obtained within 72 hours prior to infusions at weeks 3 through 21 
3 For women of childbearing potential (see section 5.3.1.2) 
4 Visit 9 will be conducted remotely except if the participant is being followed for a peripheral neuropathy adverse event. 
5 Performed only if the participant is being followed for a peripheral neuropathy adverse event. 
6 Negative SARS-CoV-2 test maybe required prior to PFTs per institutional guidelines. 

Immune Tolerance Network 
CONFIDENTIAL 
Page 79 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
APPENDIX 2. CLINICAL CRITERIA FOR DIAGNOSING ANAPHYLAXIS 
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled: 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or        
both (e.g., generalized hives, pruritus or flushing, swollen lips-tongue-uvula) 
AND AT LEAST ONE OF THE FOLLOWING 
a. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia) 
b. Reduced BP or associated symptoms of end-organ dysfunction (e.g., hypotonia [collapse], syncope, 
incontinence) 
2. Two or more of the following that occur rapidly after exposure to a likely allergen for that patient 
(minutes to several hours): 
a. Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, swollen lips-tongue-
uvula) 
b. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia) 
c. Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, incontinence) 
d. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting) 
3. Reduced BP after exposure to known allergen for that patient (minutes to several hours): 
a. Infants and children: low systolic BP (age specific) or greater than 30% decrease in systolic BP* 
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that person’s baseline 
 
PEF, Peak expiratory flow; BP, blood pressure. 
* Low systolic blood pressure for children is defined as less than 70 mm Hg from 1 month to 1 year, less than (70 mm Hg 
+ [2 x age]) from 1 to 10 years, and less than 90 mm Hg from 11 to 17 years. 
Adapted from the Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network [79] 
 
 

Immune Tolerance Network 
CONFIDENTIAL 
Page 80 
 
Protocol ITN075AI: BRAVOS 
Version 5.0 
December 10, 2021 
Brentuximab Vedotin for Systemic Sclerosis 
APPENDIX 3. EXAMPLES OF STRONG CYP3A4 INHIBITORS, INDUCERS, AND 
P-GP INHIBITORS 
 
Strong CYP3A4 Inhibitors 
Strong CYP3A4 Inducers 
P-gp inhibitors 
 
Antibiotics 
Clarithromycin 
Rifampin 
Clarithromycin 
Telithromycin 
 
 
Azamulin 
 
 
Troleandomycin 
 
 
Antidepressants 
Nefazodone 
 
 
Anti-epileptic 
 
Phenytoin 
 
 
Carbamazepine 
 
Antifungals 
Itraconazole 
 
Itraconazole 
Ketoconazole 
 
 
Posaconazole 
 
 
Voriconazole 
 
 
Cardiovascular 
Verapamil 
 
Verapamil 
Diltiazem 
 
Diltiazem 
 
 
Amiodarone 
 
 
Carvedilol 
 
 
Dronedarone 
 
 
Propafenone 
 
 
Quinidine 
 
 
Ranolazine 
Protease Inhibitors 
Ritonavir1 
 
Cobicistat 
Atazanavir 
 
Lopinavir 
Boceprevir 
 
Nelfinavir 
Danoprevir 
 
Ritonavir 
Elvitegravir 
 
Saquinavir 
Indinavir 
 
Telaprevir 
Lopinavir 
 
Tipranavir 
Nelfinavir 
 
 
Saquinavir 
 
 
Tipranavir 
 
 
Paritaprevir 
 
 
ombitasvir 
 
 
dasabuvir 
 
 
Vasopressin 
receptor inhibitor 
 
 
Conivaptan 
Oncology 
Idelalisib 
Enzalutamide 
Lapatinib 
 
Mitotane 
 
Other 
Grapefruit Juice2 
St. John’s wort3 
 
1Ritonavir is usually given in combination with other anti-HIV or anti-HCV drugs in clinical practice. Caution 
should be used when extrapolating the observed effect of ritonavir alone to the effect of combination 
regimens on CYP3A activities. 
2The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-
dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain 
preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another 
preparation was used (e.g., low dose, single strength). 
3The effect of St. John’s wort varies widely and is preparation dependent. 
 
Adapted from FDA drug development and drug interactions: Table of substrates, inhibitors and inducers 
[80].