Clinical trial NCT03334851
Conditions: Systemic Lupus Erythematosus Rheumatoid Arthritis
Sponsor: Pfizer
Start date: 2017-11-17; Completion date: 2022-02-15
Enrollment: 74 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a Phase 1 single and multiple dose escalation study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of PF-06835375 in subjects with seropositive SLE or RA. The design is double-blind, sponsor open and placebo controlled. This study will include two parts: Part A and Part B. Part A will consist of single ascending dose cohorts, Part B of multiple ascending dose cohorts. This study will enroll up to a total of approximately 112 subjects at approximately 10 sites.

Detailed description:

Arms: arm 1: Subjects will receive a single dose of PF-06835375 or placebo on Day 1 via intravenous administration arm 2: Subjects will receive a single dose of PF-06835375 or placebo on Day 1 via intravenous administration. arm 3: Subjects will receive a single dose of PF-06835375 or placebo on Day 1 via intravenous administration. arm 4: Subjects will receive a single dose of PF-06835375 or placebo on Day 1 via intravenous administration. arm 5: Subjects will receive a single dose of PF-06835375 or placebo on Day 1 via intravenous administration. arm 6: Subjects will receive a single dose of PF-06835375 or placebo on Day 1 via intravenous administration. arm 7: Subjects will receive a single dose of PF-06835375 or placebo on Day 1 via intravenous administration. arm 8: Subjects will receive a single dose of PF-06835375 or placebo on Day 1 via intravenous administration. arm 9: Subjects will receive two doses of PF-06835375 or placebo on Day 1 and Day 29 via subcutaneous administration. arm 10: Subjects will receive two doses of PF-06835375 or placebo on Day 1 and Day 29 via subcutaneous or intravenous administration. arm 11: Subjects will receive two doses of PF-06835375 or placebo on Day 1 and Day 29 via subcutaneous or intravenous administration. arm 12: Subjects will receive two doses of PF-06835375 or placebo on Day 1 and Day 29 via subcutaneous or intravenous administration. arm 13: Subjects will receive two doses of PF-06835375 or placebo on Day 1 and Day 29 via subcutaneous or intravenous administration. arm 14: Subjects will receive two doses of PF-06835375 or placebo on Day 1 and Day 29 via subcutaneous or intravenous administration.
Interventions: intervention 1: PF-06835375 intervention 2: Placebo
Intervention descriptions: intervention 1: Intravenous (IV) or subcutaneous (SC) administration. Subjects will receive one or two doses. Doses will be ascending and determined by emerging data. intervention 2: Matching placebo for PF-06835375 IV or SC. Subjects will receive one or two doses.

Protocol documents:
Prot_000.pdf: 
PF-06835375 
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A PHASE 1, RANDOMIZED, MULTI-CENTER, DOUBLE-BLIND, SPONSOR 
OPEN, PLACEBO-CONTROLLED, SINGLE AND MULTIPLE
DOSE-ESCALATION STUDY TO EVALUATE THE SAFETY, TOLERABILITY, 
PHARMACOKINETICS AND PHARMACODYNAMICS OF PF-06835375 IN 
SUBJECTS WITH SEROPOSITIVE SYSTEMIC LUPUS ERYTHEMATOSUS OR
RHEUMATOID ARTHRITIS
Investigational Product Number:
PF-06835375
Investigational Product Name:
Not applicable (N/A)
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
2017-003077-34
Protocol Number:
C1131001
Phase:
1
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this information in 
confidence and not copy or disclose it to others (except where required by applicable law) or use it for 
unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer must be 
promptly notified.
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Document History
Document
Version Date
Summary of Changes and Rationale
Amendment 2
09 November 2018
1. Removed multiple clinical and laboratory 
assessments beyond Week 16 (Schedule of 
Activities).
Rationale: To remove unnecessary 
assessments beyond Week 16, based on 
emerging safety, PD and PK data, and which 
will not provide information crucial for 
defining the overall safety signal for 
PF-06835375.
2. Decreased frequency of visits and visit 
assessments for subjects who remain in the 
study beyond 52 weeks (Schedule of 
Activities).
Rationale: To remove unnecessary study 
assessments (including samples) which will 
not be informative due to a lack of disease 
activity requirements for entry and emerging 
data Reduction of study visits beyond 
Week 52 will maintain an appropriate level 
of follow up for safety at given the emerging 
safety profile of PF-06835375 and the
established safety signal from B-cell 
depleting agents.
3. Added complement lab for SLE subjects at 
Screening (Schedule of Activities).
Rationale: To align with SLICC and 
 lab requirements.
4. Removed follow up due to immunogenicity
related AE (Schedule of Activities, 
Sections 3.1, 3.5, 6.2).
Rationale: To align with frequency of 
immunogenicity testing while retaining the 
option for additional visits if needed for 
safety.
5. Added a requirement of sentinel dosing in 
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Part B in specific circumstances.
Rationale: To align Part A and B for safety 
monitoring at a given dose. 
6. Allowed independent dose escalation in 
Part A and Part B, provided SC is used in 
Part B (Section 3.3).
Rationale: To dose escalate SC cohorts 
based on safety, tolerability, PK and PD 
(B cell counts) from previous SC cohorts due 
to potential differences in bioavailability 
between IV and SC administration. 
7. Changed dose escalation criterion to require 
detectable B cells for a minimum of 
2 consecutive visits at least 2 weeks apart, 
starting at Week 12 (Section 3.4).
Rationale: To align dose escalation criterion 
with the end-of-study discharge criteria. 
This rationale is based on emerging safety, 
PK and PD profile of PF-06835375 and 
clinical experience with approved B cell 
depleting agents, including that for rituximab 
(redosing occurs with undetectable B-cell 
counts).
8. Clarified lymphopenia criterion in individual 
stopping rules with respect to pre-dose 
abnormalities (Section 3.4.3).
Rationale: To appropriately consider 
pre-dose lymphopenia (common in SLE), 
subjects with Grade 1 or 2 pre-dose 
lymphophenia (CTCAE v4.0) and 2 grade 
shift or less will not be considered to have 
this met individual stopping criterion.
9. Removed requirement for “stable or 
increasing” B-cell counts for end of 
study/subject discharge for subjects who 
have B cell counts above lower limit of 
normal (LLN; 80 cells/l) at Week 16 visit 
(Section 3.5).


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Rationale: Remove unnecessary and 
additional study visits after B-cell LLN has 
been reached.  The natural fluctuations of 
B-cell counts obviate the need for additional 
visits once the LLN threshold has been met.
10. Revised timing for end of study/subject 
discharge after Week 16 by requiring B cells 
to reach new stable or increasing detectable 
level for minimum of two consecutive visits 
starting at Week 20 (Section 3.5).
Rationale: To harmonize end-of-study 
discharge criteria with follow up 
commitment based on revised 
dose-escalation criteria.
11. Removed text applicable only for studies 
using a Medical Device (Sections 8.2.3).
Rationale: To remove text not applicable for 
this study since medical device is not used.
12. Administrative clarifications (Sections 3.1, 
3.4.1, 4.4.1, 7.1.1).
Rationale: To provide minor clarifications.
Amendment 1
16 February 2018
1. Changed screening window from 30 days to 
45 days (Schedule of Activities).
Rationale: To increase screening window 
given sizable number and complex nature of 
screening labs and required turnaround time.
 
 
3. Changed scheduled limited physical exam to 
6 hours post-dose, provided no new ongoing 
AEs or safety concerns (Schedule of 
Activities).
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Rationale: To improve study feasibility at 
sites.
4. Clarified window for assessments post-dose 
(Schedule of Activities).
Rationale: To incorporate protocol 
administrative letter.
5. Clarified criteria used to determine SLE and 
RA diagnosis and sample collection in case 
of combined diagnoses (Schedule of 
Activities, Sections 7.6.2 and 7.6.3).
Rationale: To clarify criteria used for RA 
and SLE diagnosis used for assessments in 
Schedule of Activities and blood sample 
collection regimen.
6. Changed JC virus sample collection to one 
sample (Schedule of Activities, 
Sections 7.1.1 and 7.1.14).
Rationale: To update based on availability of 
JC virus test.
7. Removed bioavailability from PD endpoints 
(Sections 2 and 9.3.2).
Rationale: To remove an endpoint which may 
not be calculated accurately given the 
uncertainty in doses and high number of 
cohorts.
8. Modified PK endpoints (Section 2) to align 
with Tables 5 and 6 (Section 9.3.2);
 
 
Rationale: To harmonize protocol sections 
and to include only key PK endpoints as 
secondary.
9. Clarified time point for secondary endpoint 
of depletion of B and cTfh cells (Section 2).
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Rationale: To clarify specific time for 
evaluating B and cTfh cell depletion.
10. Removed a requirement for two RA or SLE 
subjects per each cohort in Part B 
(Sections 3.1 and 4.3).
Rationale: To allow for faster enrollment, 
given that this is primarily safety and 
tolerability study.
11. Clarified that sponsor may elect to add more 
subjects into cohorts for any reason, 
including but not limited to a greater than 
expected PD effect (Section 3.1).
Rationale: To clarify sponsor may elect a 
higher number of subjects per cohort for any 
reason but the total number of subjects 
enrolled in study will be up to a total of 
approximately 112 subjects. 
12. Clarified that in cohorts A1-A4, sentinel 
dosing will apply only to the first four 
subjects (Section 3.2).
Rationale: To clarify sentinel dosing.
13. Clarified that sentinel dosing is required only 
when a given dose level is administered for 
the first time in Part A and not required in 
Part B (Sections 3.1 and 3.2).
Rationale: To clarify sentinel dosing 
requirements.
14. Clarified a minimum number of subjects per 
cohort, required to proceed with dose 
escalation (Section 3.4.1).
Rationale: To have sufficient data to 
determine whether dose escalation is 
appropriate.
15. Clarified dose escalation stopping rules for 
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Rationale: To clarify that if any dose cohort 
is repeated, this additional cohort will be 
considered a separate cohort for the purpose 
of dose escalation stopping rules. 
16. Clarified criteria for end of study 
(Section 3.5).
Rationale: To clarify that only one criterion 
is needed to be met for end of study.
17. Clarified restrictions on investigational 
biologics, which are biosimilars 
(Exclusion criterion #2, Section 4.2).
Rationale: To allow an appropriate time 
frame since dosing with biosimilars.
 
 
Rationale: To harmonize entry criteria 
during the entire study. 
19. Clarified exclusion criterion 7 (Section 4.2).
Rationale: To incorporate protocol 
administrative letter.
20. Clarified TB exclusion criteria 
(Criterion #12, Section 4.2).
Rationale: To clarify that subjects with 
current or past history of active TB or 
inadequately treated latent TB (or where 
documentation of treatment is not available) 
are not eligible. 
21. Clarified when re-screening and repeating 
screening assessments is permitted 
(Section 6.1 and Schedule of Activities).
Rationale: To clarify procedures for 
repeating screening assessments and 
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re-screening.
22. Added a requirement for sites to obtain 
approval from sponsor clinician for 
screening and dosing of each subject 
(Section 6.1 and Schedule of Activities).
Rationale: To ensure implementation of 
sentinel dosing and to ensure screening of an 
appropriate number of subjects in each 
cohort.
23. Allowed extension of screening window by 
5 days contingent on sponsor approval for 
scheduling or logistics reasons (Section 6.1). 
Rationale: To avoid unnecessary 
re-screening procedures. 
24. Increased blood volume in Part A and 
clarified blood volumes are approximate 
(Section 7.7).
Rationale: To update blood volume due to 
added Day 57 blood samples to clarify that 
blood volumes are approximate given 
additional blood samples may be taken 
eg, for safety assessments or to repeat 
screening procedures (if appropriate).
25. Changed assessments during early 
termination visit to harmonize with the rest 
of the protocol (Section 6.3).
Rationale: To harmonize data across the 
study. 
26. Removed band neutrophils from laboratory 
tests and clarified safety labs (Section 7.1.1).
Rationale: To remove laboratory test that is 
not required for safety and to clarify 
definition of safety labs.
27. Added neck & throat assessment as a part of 
the physical examination (Section 7.1.3).


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Rationale: To incorporate protocol 
administrative letter.
28. Clarified that temperature can be also 
measured at forehead (Section 7.1.4). 
Rationale: To incorporate protocol 
administrative letter.
29. Clarified recommended and mandatory 
timeframe for contraception (Inclusion 
criterion 4 in Section 4.1, Section 4.4.1). 
Rationale: To incorporate protocol 
administrative letter.
30. Clarified criterion for IGRA repeat without 
sponsor approval (Sections 6.1 and 7.1.10).
Rationale: To clarify criterion for repeating 
IGRA TB test without sponsor approval.
31. Clarified how adverse events associated with 
vaccinations may be managed and included a 
requirement for appropriate equipment and 
personnel to manage anaphylaxis or serious 
vaccine reactions (Section 7.6.1.3).
Rationale: To incorporate protocol 
administrative letter and to clarify 
requirements for sites.
 
 
33. Minor administrative changes and
typographical corrections: Schedule of 
Activities, Section 7.6.1.1, Appendix 5, 
exclusion criteria 22 (Section 4.2), 
Sections 1.2.5, 3.1, 3.4.1 and 6.2.
Rationale: To incorporate protocol 
administrative letters, to correct 
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typographical errors and to provide 
additional minor clarifications.
Original protocol
23 August 2017
Not applicable (N/A)
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and institutional review boards (IRBs)/ethics committees 
(ECs).


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................16
LIST OF FIGURES .................................................................................................................17
APPENDICES .........................................................................................................................17
SCHEDULE OF ACTIVITIES................................................................................................18
PROTOCOL SUMMARY.......................................................................................................30
1. INTRODUCTION ...............................................................................................................35
1.1. Mechanism of Action/Indication.............................................................................35
1.1.1. Indication....................................................................................................35
1.2. Background .............................................................................................................35
1.2.1. Drug Development Rationale .....................................................................35
1.2.2. Systemic Lupus Erythematosus..................................................................36
1.2.3. Rheumatoid Arthritis ..................................................................................37
1.2.4. Nonclinical Pharmacology..........................................................................37
1.2.5. Nonclinical Pharmacokinetics ....................................................................38
1.2.6. Nonclinical Safety ......................................................................................38
1.3. Dose Rationale ........................................................................................................38
1.4. Rationale for Assessment of Immune Function with Vaccine Challenges .............40
1.6. Summary of Benefits and Risks..............................................................................41
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................43
3. STUDY DESIGN.................................................................................................................44
3.1. Study Overview.......................................................................................................44
3.2. Sentinel Dosing .......................................................................................................47
3.3. Initiation of Part B...................................................................................................48
3.4. Dose Escalation and Stopping Rules.......................................................................48
3.4.1. Dose Escalation ..........................................................................................48
3.4.2. Dose Escalation Stopping Rules.................................................................49
3.4.3. Individual Stopping Rules ..........................................................................51
3.5. Criteria for End of Study.........................................................................................52
4. SUBJECT ELIGIBILITY CRITERIA.................................................................................53
4.1. Inclusion Criteria.....................................................................................................53
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4.2. Exclusion Criteria....................................................................................................55
4.3. Randomization Criteria ...........................................................................................58
4.4. Lifestyle Requirements ...........................................................................................58
4.4.1. Contraception..............................................................................................58
4.5. Sponsor’s Qualified Medical Personnel..................................................................60
5. STUDY TREATMENTS.....................................................................................................60
5.1. Allocation to Treatment ..........................................................................................60
5.2. Breaking the Blind ..................................................................................................61
5.3. Subject Compliance.................................................................................................61
5.4. Investigational and Non-Investigational Product Supplies.....................................61
5.4.1. Dosage Form(s) and Packaging..................................................................61
5.4.1.1. PF-06835375 or Placebo ...........................................................61
5.4.2. Preparation..................................................................................................62
5.4.2.1. PF-06835375 or Placebo Preparation........................................62
5.4.3. Administration............................................................................................62
5.4.3.1. PF-06835375 or Placebo Administration..................................62
 
5.4.4. Investigational Product Storage..................................................................64
5.5. Investigational Product Accountability...................................................................65
5.5.1. Destruction of Investigational Product Supplies ........................................65
5.6. Concomitant Treatment(s).......................................................................................65
5.6.1. Treatment Prior to IP Administration.........................................................65
5.6.2. Treatment Post-infusion/Injection ..............................................................66
5.6.3. Guidance for Investigators..........................................................................66
6. STUDY PROCEDURES .....................................................................................................66
6.1. Screening.................................................................................................................67
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6.2. Study Period ............................................................................................................67
6.3. Subject Withdrawal.................................................................................................68
7. ASSESSMENTS..................................................................................................................69
7.1. Safety.......................................................................................................................70
7.1.1. Laboratory Tests .........................................................................................70
7.1.2. Pregnancy Testing ......................................................................................71
7.1.3. Physical Examinations................................................................................72
7.1.4. Vital Signs ..................................................................................................72
7.1.5. Medical History ..........................................................................................73
7.1.6. Height and Weight......................................................................................73
7.1.7. Chest X-Ray................................................................................................73
7.1.8. Electrocardiogram.......................................................................................73
7.1.9. Hepatitis B and C Screening.......................................................................74
7.1.10. Tuberculosis Screening and Monitoring...................................................74
7.1.10.1. Interferon Gamma Release Assay Tuberculin Test.................74
7.1.10.2. Additional Measures for Tuberculosis (TB) Monitoring ........74
7.1.11. Monitoring for Infections .........................................................................75
7.1.12. Infusion Site Reactions.............................................................................76
7.1.13. Injection Site Reactions............................................................................77
7.1.14. JC Virus (JCV) Monitoring and Progressive Multifocal 
Leukoencephalopathy (PML) ..........................................................................77
7.1.15. Viral Surveillance.....................................................................................78
7.1.16. Suspected Herpetiform Rash ....................................................................78
7.1.17. Assessment of Suicidal Ideation and Behavior ........................................78
7.2. Pharmacokinetics ....................................................................................................79
7.2.1. Serum for Analysis of PF-06835375..........................................................79
7.2.2. Shipment of Pharmacokinetic Samples ......................................................80
7.3. Immunogenicity ......................................................................................................80
7.3.1. Serum for Analysis of Anti-PF-06835375 Antibodies and 
Neutralizing Anti-PF-06835375 Antibodies....................................................80
7.3.2. Immunogenicity Analyses ..........................................................................80
7.3.3. Shipment of Immunogenicity (ADA/NAb) Samples .................................81
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7.5. Rater Qualifications.................................................................................................82
7.6. Pharmacodynamics/Biomarkers..............................................................................83
7.6.1.5. Erythrocyte Sedimentation Rate (ESR).....................................84
7.6.1.6. B-cell Activating Factor (BAFF) ..............................................84
7.6.3. Samples Collected for Subjects with SLE..................................................85
7.6.3.1. Anti-nuclear Antibodies ............................................................85
7.7. Blood Volume .........................................................................................................85
7.8. Diagnostic and Efficacy Assessments.....................................................................86
7.8.1. American College of Rheumatology/European League Against 
Rheumatism Classification for RA..................................................................86
7.8.2. American College of Rheumatology/SLICC Criteria for the 
Classification of SLE.......................................................................................86
 
 
7.8.4.2. Patient’s Global Assessment (PtGA) of Arthritis .....................88
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8. ADVERSE EVENT REPORTING......................................................................................88
8.1. Requirements...........................................................................................................88
8.1.1. Additional Details On Recording Adverse Events on the CRF..................89
8.1.2. Eliciting Adverse Event Information..........................................................89
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the 
Subject Withdrawal section)............................................................................89
8.1.4. Time Period for Collecting AE/SAE Information......................................90
8.1.4.1. Reporting SAEs to Pfizer Safety...............................................90
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF .................90
8.1.5. Causality Assessment .................................................................................90
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................91
8.2. Definitions...............................................................................................................91
8.2.1. Adverse Events...........................................................................................91
8.2.2. Abnormal Test Findings .............................................................................92
8.2.3. Serious Adverse Events ..............................................................................92
8.2.4. Hospitalization............................................................................................93
8.3. Severity Assessment................................................................................................94
8.4. Special Situations ....................................................................................................94
8.4.1. Protocol-Specified Serious Adverse Events...............................................94
8.4.2. Potential Cases of Drug-Induced Liver Injury............................................94
8.4.3. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................96
8.4.3.1. Exposure During Pregnancy......................................................96
8.4.3.2. Exposure During Breastfeeding ................................................97
8.4.3.3. Occupational Exposure .............................................................98
8.4.4. Medication Errors .......................................................................................98
8.4.4.1. Medication Errors......................................................................98
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................99
9.1. Sample Size Determination.....................................................................................99
9.3. Pharmacokinetic Analysis.......................................................................................99
9.3.1. Analysis Population....................................................................................99
9.3.2. Derivation of Pharmacokinetic Parameters ................................................99
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9.4. Pharmacodynamic Analysis ..................................................................................101
9.6. Safety Analysis......................................................................................................102
9.6.1. Electrocardiogram (ECG) Analysis..........................................................102
9.7. Interim Analysis ....................................................................................................103
9.8. Data Monitoring Committee .................................................................................103
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................103
11. DATA HANDLING AND RECORD KEEPING ...........................................................104
11.1. Case Report Forms/Electronic Data Record .......................................................104
11.2. Record Retention.................................................................................................105
12. ETHICS............................................................................................................................105
12.1. Institutional Review Board/Ethics Committee....................................................105
12.2. Ethical Conduct of the Study ..............................................................................105
12.3. Subject Information and Consent........................................................................106
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................106
13. DEFINITION OF END OF TRIAL.................................................................................106
13.1. End of Trial in a Member State...........................................................................106
13.2. End of Trial in All Other Participating Countries...............................................107
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................107
15. PUBLICATION OF STUDY RESULTS........................................................................107
15.1. Communication of Results by Pfizer ..................................................................107
15.2. Publications by Investigators ..............................................................................108
16. REFERENCES ................................................................................................................110
LIST OF TABLES
Table 1.
Predicted Median Human Exposures and Safety Multiples for Expected 
Doses.....................................................................................................................40
Table 2.
Planned Cohorts....................................................................................................46
Table 3.
Laboratory Tests ...................................................................................................70
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Table 5.
PF-06835375 Serum Pharmacokinetic Parameters for Single Ascending 
Dose (SAD) Phase..............................................................................................100
Table 6.
PF-06835375 Serum Pharmacokinetic Parameters for Multiple Ascending 
Dose (MAD) Phase.............................................................................................101
Table 7.
Safety QTc..........................................................................................................103
LIST OF FIGURES
Figure 1.
Study Schematic ...................................................................................................46
APPENDICES
Appendix 1. Abbreviations....................................................................................................112
Appendix 2. List of SLE/RA-related Prohibited Medications (Immunosuppressants & 
Immunomodulators) ...........................................................................................117
Appendix 3. List of Allowed SLE/RA-related and Chronic Medications.............................118
Appendix 4. Oral Corticosteroids, Systemic Equivalencies25 ...............................................119
Appendix 5. SLICC Classification Criteria for SLE .............................................................120
Appendix 6. The 2010 American College of Rheumatology/European League Against 
Rheumatism Classification Criteria for Rheumatoid Arthritis21 ........................123
Appendix 7. Common Terminology Criteria For Adverse Events (Infusion Reactions) ......125
Appendix 8. Antigen Local Reactivity Due to IP or Vaccine Challenges.............................126
Appendix 10. Patient’s Global Assessment (PtGA) of Arthritis ...........................................128
 
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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the STUDY PROCEDURES and 
ASSESSMENTS sections of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities table, in order to 
conduct evaluations or assessments required to protect the well-being of the subject.
Part A (Single Ascending Dose)
Protocol activity
Outpatient
Inpatient
Outpatient
Visit Identifiera
Screeningff
Day 
1hh
Day
2
Day
4
Day 
8
Day
15
Day
29
Week 6/
Day 43
Week 8/ 
Day 57
Week 
12/Day 
85
Week 16 
/Day 
113 
Post-
week 16 
(every 
4 weeks
until 52 
weeks)b
Post-
week 52 
(every 12 
weeks)
End of 
study 
visitc
Visit window
-45 to -1
None
±1 day
±3 days
±7 days
±14 days
Visit window (days)
-45 to -1
1
2
3-5
7-9
12-18
26-32
40-46
54-60
78-92
106-120
N/A
N/A
N/A
Pre-
dose
Post-
dosed
Enrollment Procedures
Informed consent
X
Inclusion/exclusion criteria
X
X
Medical history 
X
Medication history
X
Demography
X
CRU confinemente
X
X
X
Medical Procedures
For all subjects
Physical examinationf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signsg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECGh
X
X
X
X
X
X
X
X
X
X
X
X
Weight and heighti
X
X
X
Xj
Chest X-rayk
X
C-SSRSl
X
X
X
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Protocol activity
Outpatient
Inpatient
Outpatient
Visit Identifiera
Screeningff
Day 
1hh
Day
2
Day
4
Day 
8
Day
15
Day
29
Week 6/
Day 43
Week 8/ 
Day 57
Week 
12/Day 
85
Week 16 
/Day 
113 
Post-
week 16 
(every 
4 weeks
until 52 
weeks)b
Post-
week 52 
(every 12 
weeks)
End of 
study 
visitc
Visit window
-45 to -1
None
±1 day
±3 days
±7 days
±14 days
Visit window (days)
-45 to -1
1
2
3-5
7-9
12-18
26-32
40-46
54-60
78-92
106-120
N/A
N/A
N/A
Pre-
dose
Post-
dosed
For subjects with RAgg
ACR/EULAR Criteria
X
Patient’s Global Assessment of 
Arthritis
X
X
X
X
X
For subjects with SLEgg
SLICC Criteria
X
 
Laboratory Assessments
Safety laboratoryn
X
X
X
X
X
X
X
X
X
X
X
X
X
X
FSHo
X
Serum pregnancyp
X
X
X
X
Urine pregnancyp
X
X
X
X
X
X
X
X
IGRA TB 
X
X
HIV and Hepatitis B & Cq
X
Viral Surveillancer
X
X
X
Xj
JCV 
X
X
Xj
Serum Igs
X
X
X
X
X
X
Xj
X
Pharmacokinetics
PK serumu
X
X
X
X
X
X
X
X
X
X
X
Immunogenicity serumv
X
X
X
X
X
X
X
X
Laboratory Biomarker 
Assessments
For all subjects
 
 
 
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Page 20
Protocol activity
Outpatient
Inpatient
Outpatient
Visit Identifiera
Screeningff
Day 
1hh
Day
2
Day
4
Day 
8
Day
15
Day
29
Week 6/
Day 43
Week 8/ 
Day 57
Week 
12/Day 
85
Week 16 
/Day 
113 
Post-
week 16 
(every 
4 weeks
until 52 
weeks)b
Post-
week 52 
(every 12 
weeks)
End of 
study 
visitc
Visit window
-45 to -1
None
±1 day
±3 days
±7 days
±14 days
Visit window (days)
-45 to -1
1
2
3-5
7-9
12-18
26-32
40-46
54-60
78-92
106-120
N/A
N/A
N/A
Pre-
dose
Post-
dosed
ESR
X
X
X
X
X
X
X
BAFF
X
X
X
X
X
X
Xj
 
 
For subjects with SLEgg
Anti-nuclear antibodies 
X
X
X
 
 
 
 
 
 
 
Investigational and 
Non-Investigational Product 
administration
Pre-treatmentz
X
Administration of PF-06835375 
or placeboaa
X
 
C
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Protocol activity
Outpatient
Inpatient
Outpatient
Visit Identifiera
Screeningff
Day 
1hh
Day
2
Day
4
Day 
8
Day
15
Day
29
Week 6/
Day 43
Week 8/ 
Day 57
Week 
12/Day 
85
Week 16 
/Day 
113 
Post-
week 16 
(every 
4 weeks
until 52 
weeks)b
Post-
week 52 
(every 12 
weeks)
End of 
study 
visitc
Visit window
-45 to -1
None
±1 day
±3 days
±7 days
±14 days
Visit window (days)
-45 to -1
1
2
3-5
7-9
12-18
26-32
40-46
54-60
78-92
106-120
N/A
N/A
N/A
Pre-
dose
Post-
dosed
Monitoring
Contraception check 
X
→
X
→
→
→
→
→
→
→
→
→
→
X
Serious and non-serious adverse 
event monitoring
X
→
→
→
→
→
→
→
→
→
→
→
→
→
X
Concomitant treatment(s)
X
→
→
→
→
→
→
→
→
→
→
→
→
X
TB monitoringcc
X
X
→
→
→
→
→
→
→
→
→
→
X
Infections monitoringdd
X
X
→
→
→
→
→
→
→
→
→
→
→
→
X
Infusion Site Reactionsee
X
→
→
→
X
Abbreviations: →= ongoing/continuous event; ACR/EULAR = American College of Rheumatology/European League Against Rheumatism; 
 
 BAFF = B-cell activating factor; 
 C-SSRS = Columbia-Suicide Severity Rating Scale; CRU = clinical 
research unit; ECG = electrocardiogram; ESR = erythrocyte sedimentation rate; FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; 
 
 Ig = Immunoglobulin; IGRA = Interferon gamma release assay; JCV = JC virus; PK = Pharmacokinetic; RA = rheumatoid arthritis; SLE = 
systemic lupus erythematosus;
 SLICC= Systemic Lupus International Collaborating Clinics; 
TB = tuberculosis.
a.
Day relative to start of study treatment (Day 1).
b.
Subjects, who do not meet the criteria to leave the study at Week 16, will continue with clinic visits every four weeks until Week 52 and then every 12 weeks until they meet 
these criteria. 
c.
B cell counts data will be available only after subject completes the clinic visit due to the required shipment of samples to central lab and their processing time.  Once subject 
meets the criterion, a phone visit will take place within approximately 1-2 weeks.  This phone visit will be considered the end of study visit/last visit.  Subjects may be 
requested to return for additional follow up visits, and additional safety assessments may be performed beyond the end of study visit for safety reasons as determined by the 
Investigator in consultation with the sponsor medical monitor. 
d.
Specific times for post-dose assessments are noted in the Post-dose Day 1 & Post-dose Day 29 Schedule of Activities below.
e.
Prior to admission, review changes in the subject’s medical history, concomitant medications and medical procedures since the Screening visit, perform contraception check 
and confirm that there are no changes to subject’s eligibility.  If a subject has any clinically significant, study related abnormalities at the conclusion of a scheduled inpatient 
portion of the study, it is at the investigator’s discretion to ask the subject to remain in the clinical unit until it is safe for outpatient follow up.  The investigator must promptly 
notify the sponsor clinician or medical monitor.  If the subject is unable or unwilling to remain in the clinical unit, the investigator should make every effort to arrange follow 
up evaluations at appropriate intervals.  All Day 2 assessments should be completed prior to discharge from the research unit.
f.
A full physical exam will be performed at Screening, Day 1 pre-dose and Week 16, and as needed at the discretion of the investigator.  A limited physical exam will be 
conducted at all other times.
g.
Includes pulse rate, sitting blood pressure and temperature.
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Page 22
h.
ECGs will be collected in triplicate on Day 1 and Day 2.  Single ECGs will be collected at all other times. 
i.
Height will be measured only at Screening.  Height and Weight will be measured without shoes.
j.
Assessment to be performed starting at Week 28 and every 12 weeks thereafter until Week 52. 
k.
Subjects who had chest X-ray performed within 3 months prior to the Screening visit do not require chest X-ray, provided documentation is available.
l.
C-SSRS Lifetime will be performed at Screening.  All subsequent assessments will be Since Last Visit.
n.
Includes hematology, chemistry and urinalysis.  Fasting is not required.
o.
Serum FSH will be performed to confirm postmenopausal status for females who have been amenorrheic for at least 12 consecutive months.  If post-menopausal for ≥5 years, 
it is at the investigator’s discretion whether to confirm post-menopausal status by FSH.
p.
Serum pregnancy test will be conducted at a central lab.  Urine pregnancy test will be conducted locally.  For female subjects of childbearing potential, 2 negative pregnancy 
tests are required prior to receiving IP on Day 1 (1 negative serum pregnancy test at Screening and 1 negative urine pregnancy test on Day 1).  Results of serum pregnancy test 
on Day 1 are not required prior to dosing. 
q.
Includes hepatitis B surface antigen (HepBsAg), hepatitis B core antibody (HepBcAb) and hepatitis C antibody (HCVAb).  Only subjects who are positive for HCV Ab will 
be reflex-tested for hepatitis C virus ribonucleic acid (HCV RNA).
r.
Includes testing for cytomegalovirus (CMV), Epstein Barr virus (EBV), herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2) and varicella zoster virus
(VZV).  Additional samples for viral surveillance sample may be taken at the time of an adverse event, as clinically appropriate.
s.
Includes total Ig, IgA, IgG, IgE and IgM.
 
u.
At dosing visits, PK samples will be collected preferably after vital signs and ECG, and within approximately 1 hour prior to dosing and at the end of infusion.  If end of 
infusion is within 10 minutes of a scheduled PK sample, then only the scheduled sample will be collected.
v.
Includes anti-drug antibodies (ADA) and neutralizing antibodies (NAb).  During dosing visits, samples to assess ADA and NAb will be collected prior to investigational drug 
administration.
 
 
 
z.
Approximately 1 hour prior to the administration of IP, each subject will be pre-treated with 1000 mg of oral acetaminophen, and an oral antihistamine (eg, 25 mg of oral 
diphenhydramine). 
aa.
The total infusion time will be 120 minutes ±10 minutes, unless a different time is needed to manage symptoms typical of infusion reactions.  In such a case, the entire 
duration of study drug infusion should not exceed approximately 4 hours unless a different time is communicated to the site by the sponsor.
cc.
Please see Section 7.1.10 for details.
dd. Please see Section 7.1.11 for details.
ee.
Subjects will be continuously monitored for infusion site reactions from the start of drug administration until the end of infusion and then at time points indicated in the 
Schedule of Activities.  Infusion site reactions may be monitored beyond the time points indicated in the Schedule of Activities based on investigator’s assessment.
ff.
Screening assessments may be repeated, provided this was approved by the sponsor clinician or medical monitor. Please see Section 6.1 for exceptions and details on 
potential re-screening. Sites must obtain an approval from sponsor study clinician to proceed with screening of each subject.
gg. SLE subjects must meet SLICC criteria described in Appendix 5, RA subjects must meet 2010 ACR/EULAR criteria described in Appendix 6. If subject meets criteria for 
both RA and SLE (note: this is relatively rare), then both SLE and RA assessments should be performed.
hh. In order to ensure sentinel dosing is implemented, sites need to obtain written approval from the sponsor clinician to proceed with dosing of each subject in this study. 
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Part B (Multiple Ascending Dose)
Protocol activity
Outpatient
Inpatient
Outpatient
Visit Identifiera
Screeninggg
Day 
1ii
Day 
2
Day 
4
Day 
8
Day
15
Day 
29b
Day 
30c
Day 
36
Week 
6/
Day 43
Week 
8/
Day 57
Week 
12/
Day 85
Week 
16/
Day 113
Post-
Week 16 
(every 4 
weeks)d
Post-
Week 52 
(every 12 
weeks)
End of 
study 
visite
Visit window
-45 to -1
None
±1 day
±3 days
±7 days
±14 days
Visit window (days)
-45 to -1
1
2
3-5
7-9 12-18
26-32
27-33 33-39 40-46
54-60
78-92
106-120
N/A
N/A
N/A
Pre-
dose
Post-
dosef
Pre-
dose
Post-
dosef
Enrollment Procedures
Informed consent
X
Inclusion/exclusion criteria
X
X
Medical history 
X
Medication history
X
Demography
X
CRU confinementb
X
X
X
Medical Procedures
For all subjects
Physical examinationg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signsh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECGi
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight and heightj
X
X
X
Xk
Chest X-rayl
X
C-SSRSm
X
X
X
X
For subjects with RAhh
ACR/EULAR Criteria
X
Patient’s Global Assessment of 
Arthritis
X
X
X
X
X
For subjects with SLEhh
SLICC Criteria
X
 
Laboratory Assessments
Safety laboratoryo
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
FSHp
X
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Final Protocol Amendment 2, 09 November 2018
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Page 24
Protocol activity
Outpatient
Inpatient
Outpatient
Visit Identifiera
Screeninggg
Day 
1ii
Day 
2
Day 
4
Day 
8
Day
15
Day 
29b
Day 
30c
Day 
36
Week 
6/
Day 43
Week 
8/
Day 57
Week 
12/
Day 85
Week 
16/
Day 113
Post-
Week 16 
(every 4 
weeks)d
Post-
Week 52 
(every 12 
weeks)
End of 
study 
visite
Visit window
-45 to -1
None
±1 day
±3 days
±7 days
±14 days
Visit window (days)
-45 to -1
1
2
3-5
7-9 12-18
26-32
27-33 33-39 40-46
54-60
78-92
106-120
N/A
N/A
N/A
Pre-
dose
Post-
dosef
Pre-
dose
Post-
dosef
Serum pregnancyq
X
X
X
X
Urine pregnancyq
X
X
X
X
X
X
X
X
X
IGRA TB test
X
X
HIV and Hepatitis B & Cr
X
Viral Surveillances
X
X
X
Xk
JCV 
X
X
Xk
Serum Igt
X
X
X
X
X
X
Xk
X
 
Pharmacokinetics
PK serumv
X
X
X
X
X
X
X
X
X
X
X
X
X
Immunogenicity serumw
X
X
X
X
X
X
X
X
Laboratory Biomarker 
Assessments
For all subjects
 
 
 
 
 
ESR
X
X
X
X
X
X
X
BAFF
X
X
X
X
X
X
Xk
 
For subjects with SLEhh
Anti-nuclear antibodies
X
X
X
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Final Protocol Amendment 2, 09 November 2018
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Page 25
Protocol activity
Outpatient
Inpatient
Outpatient
Visit Identifiera
Screeninggg
Day 
1ii
Day 
2
Day 
4
Day 
8
Day
15
Day 
29b
Day 
30c
Day 
36
Week 
6/
Day 43
Week 
8/
Day 57
Week 
12/
Day 85
Week 
16/
Day 113
Post-
Week 16 
(every 4 
weeks)d
Post-
Week 52 
(every 12 
weeks)
End of 
study 
visite
Visit window
-45 to -1
None
±1 day
±3 days
±7 days
±14 days
Visit window (days)
-45 to -1
1
2
3-5
7-9 12-18
26-32
27-33 33-39 40-46
54-60
78-92
106-120
N/A
N/A
N/A
Pre-
dose
Post-
dosef
Pre-
dose
Post-
dosef
 
 
 
Anti-phospholipid antibodies
X
X
Banked Biospecimens
 
 
 
Investigational and 
Non-Investigational Product 
administration
Pre-treatmentaa
X
X
Administration of 
PF-06835375 or placebo bb
X
X
Monitoring
Contraception check
X
X
X
→
→
→
X
X
→
→
→
→
→
→
→
X
Serious and non-serious 
adverse event monitoring
X
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
X
Concomitant treatment(s)
X
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
X
TB monitoringdd
X
X
→
→
→
X
X
→
→
→
→
→
→
→
X
Infections monitoringee
X
X
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
X
Infusion/Injection Site 
Reactionsff
X
→
→
X
X
→
X
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Final Protocol Amendment 2, 09 November 2018
PFIZER CONFIDENTIAL
Page 26
Abbreviations: →= ongoing/continuous event; ACR/EULAR = American College of Rheumatology/European League Against Rheumatism; 
 
 BAFF = B-cell activating factor; 
 C-SSRS = Columbia-Suicide Severity Rating Scale; CRU = clinical 
research unit; ECG = electrocardiogram; ESR = erythrocyte sedimentation rate; FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; 
 Ig = Immunoglobulin; IGRA = Interferon gamma release assay; JCV = JC virus; PK = Pharmacokinetic; RA = rheumatoid arthritis; 
SLE = systemic lupus erythematosus;
 SLICC= Systemic Lupus International Collaborating Clinics; 
TB = tuberculosis.
a.
Day relative to start of study treatment (Day 1).
b.
Prior to admission to the research unit, review changes in the subject’s medical history, concomitant medications and medical procedures since the Screening visit, perform 
contraception check and confirm that there are no changes to subject’s eligibility.  If a subject has any clinically significant, study related abnormalities at the conclusion of a 
scheduled inpatient portion of the study on Day 2 or at the end of the outpatient visit on Day 29, it is at the investigator’s discretion to ask the subject to remain in the clinical 
unit until it is safe for outpatient follow up.  The investigator must promptly notify the sponsor clinician or medical monitor.  If the subject is unable or unwilling to remain in 
the clinical unit, the investigator should make every effort to arrange follow up evaluations at appropriate intervals. All Day 2 assessments should be completed prior to 
discharge from the research unit.
c.
Day 30 phone visit to occur one day after administration of IP on Day 29.  It is at investigator’s discretion to conduct an in clinic visit instead of a phone visit.
d.
Subjects, who do not meet the criteria to leave the study at Week 16, will continue with clinic visits every four weeks until Week 52 and then every 12 weeks until they meet 
these criteria.  Post-week 16, some assessments will be conducted only every 12 weeks indicated with a footnote below.
e.
B cell counts data will be available only after subject completes the clinic visit due to the required shipment of samples to central lab and their processing time.  Once subject 
meets the criterion above, a phone visit will take place within approximately 1-2 weeks.  This phone visit will be considered the end of study visit/last visit.  Subjects may be 
asked to return for additional follow up visits beyond the anticipated end of study visit for safety reasons as determined by the Investigator in consultation with the sponsor 
medical monitor.
f.
Specific times for post-dose assessments are noted in the Post-dose Day 1 & Post-dose Day 29 Schedule of Activities below.
g.
A full physical exam will be performed at Screening, Day 1 pre-dose and Week 16, and as needed at the discretion of the investigator.  A limited physical exam will be 
conducted at all other times.
h.
Includes pulse rate, sitting blood pressure and temperature. 
i.
ECGs will be collected in triplicate on Day 1, Day 2 and Day 29.  Single ECGs will be collected at all other times. 
j.
Height will only be measured at Screening.  Height and Weight will be measured without shoes.
k.
Assessment to be performed starting at Week 28 and every 12 weeks thereafter until Week 52.
l.
Subjects who had chest X-ray performed within 3 months prior to the Screening visit do not require chest X-ray, provided documentation is available.
m.
C-SSRS Lifetime will be performed at Screening.  All subsequent assessments will be Since Last Visit.
o.
Includes hematology, chemistry and urinalysis.  Fasting is not required.
p.
Serum FSH will be performed to confirm postmenopausal status for females who have been amenorrheic for at least 12 consecutive months.  If post-menopausal for ≥5 years, 
it is at the investigator’s discretion whether to confirm post-menopausal status by FSH.
q.
Serum pregnancy test will be conducted at a central lab.  Urine pregnancy test will be conducted locally.  For female subjects of childbearing potential, 2 negative pregnancy 
tests are required prior to receiving investigational product on Day 1 (1 negative serum pregnancy test at Screening and 1 negative urine pregnancy test on Day 1).  Results of 
serum pregnancy test on Day 1 are not required prior to dosing. 
r.
Includes hepatitis B surface antigen (HepBsAg), hepatitis B core antibody (HepBcAb) and hepatitis C antibody (HCVAb).  Only subjects who are positive for HCV Ab will 
be reflex-tested for hepatitis C virus ribonucleic acid (HCV RNA).
s.
Includes testing for cytomegalovirus (CMV), Epstein Barr virus (EBV), herpes simplex virus type 1(HSV-1), herpes simplex virus type 2 (HSV-2) and varicella zoster virus 
(VZV).  Additional samples for viral surveillance sample may be taken at the time of an adverse event, as clinically appropriate.
t.
Includes total Ig, IgA, IgG, IgE and IgM.
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Final Protocol Amendment 2, 09 November 2018
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Page 27
 
v.
At dosing visits, PK samples will be collected preferably after vital signs and ECG, and within approximately 1 hour prior to dosing and at the end of infusion.  The sample at 
the end of infusion pertains only to IV cohorts and does not pertain to subcutaneous (SC) cohorts.  If end of infusion is within 10 minutes of scheduled PK sample, then only 
the scheduled sample will be collected. 
w.
Includes anti-drug antibodies (ADA) and neutralizing antibodies (NAb).  During dosing visits, samples to assess ADA and NAb will be collected prior to investigational drug 
administration.
 
 
aa.
Approximately 1 hour prior to the administration of IV or SC doses of IP, each subject will be pre-treated with 1000 mg of oral acetaminophen, and an oral antihistamine 
(eg, 25 mg of oral diphenhydramine).
bb. The total infusion time will be 120 minutes ±10 minutes, unless a different time is needed to manage symptoms typical of infusion reactions.  In such a case, the entire 
duration of study drug infusion should not exceed approximately 4 hours unless a different time is communicated to the site by the sponsor.
dd. Please see Section 7.1.10 for details.
ee.
Please see Section 7.1.11 for details.
ff.
For SC administration, subjects will be monitored continuously for injection site reactions for 30 minutes following study drug administration and then at time points 
indicated in the Schedule of Activities.  For IV administration, subjects will be continuously monitored for infusion site reactions from start of drug administration until the 
end of infusion and then at time points indicated in Schedule of Activities.  Infusion/injection site reactions may be monitored beyond the time points indicated in the 
Schedule of Activities based on investigator’s assessment.
gg. Screening assessments may be repeated provided this was approved by the sponsor clinician or medical monitor. Please see Section 6.1 for exceptions and details on potential 
re-screening. Sites must obtain an approval from sponsor study clinician to proceed with screening of each subject.
hh. SLE subjects must meet SLICC criteria described in Appendix 5, RA subjects must meet 2010 ACR/EULAR criteria described in Appendix 6. If subject meets criteria for 
both RA and SLE (note: this is relatively rare), then both SLE and RA assessments should be performed.
ii.
In order to ensure sentinel dosing is implemented, sites need to obtain written approval from the sponsor clinician to proceed with dosing of each subject in this study.
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Post-dose Day 1 (Parts A & B) & Post-dose Day 29 (Part B)a
Visit Identifier
Day 1/Day 29k
Study Hour
-2
to 0
0
0.25
0.5
0.75
1
1.5
2
2.5
3
3.5
4
4.5
5
5.5
6
8
12b
Medical procedures
Physical examination
Xc
Xd
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECGe
X
X
X
X
X
X
Laboratory assessments
Safety laboratoryf
X
X
Pharmacokinetics
PK serumg
X
X
X
X
X
X
Investigational product 
administration
Beginning of infusion or injection of 
PF-06835375 or placebo
X
Monitoring
Serious and non-serious adverse 
event monitoring
X
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
X
Concomitant treatment(s)
X
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
X
Infusion and Injection Site Reactionsj
X
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
X
Abbreviations: →= ongoing/continuous event; ECG = electrocardiogram; PK = Pharmacokinetic.
a.
Only assessments with post-dose time points are included in this table.  For these assessments, pre-dose time points are also included, as applicable.  For a complete list of 
pre-dose assessments, please refer to the Schedule of Activities for Parts A and B above.
b.
Applies only to Day 1.  Scheduled assessments on Day 29 will finish 8 hours post-dose.
c.
Full physical exam will be conducted on Day 1 pre-dose.  A limited physical exam will be conducted on Day 29 pre-dose.
d.
A limited physical exam will be conducted 6 hours post-dose on both dosing days: Day 1 and Day 29. If any new adverse reactions are observed after injection/infusion on 
these dosing days and these AEs have not resolved by 6 hours post-dose or if any safety concerns, a limited physical exam will be conducted at 12-hours post-dose on Day 1 
and at 8 hours post-dose on Day 29 instead. 
e.
ECGs will be collected in triplicate in Part A on Days 1, in Part B on Days 1 and 29. 
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f.
Includes hematology, chemistry and urinalysis.  Fasting is not required.
g.
PK samples will be collected preferably after vital signs and ECG.  A pre-dose PK sample will collected within approximately 1 hour prior to dosing.  A PK sample will be 
collected at the end of infusion (this sample at the end of infusion pertains only to IV cohorts and does not pertain to SC cohorts).  If the end of infusion is within 10 minutes 
of scheduled PK sample, then only the scheduled sample will be collected.  If infusion duration is greater than 2 h and 10 min, then the scheduled 2 hour post-dose PK sample 
will not be collected.
 
 
 
 
j.
For SC administration, subjects will be monitored continuously for injection site reactions for 30 minutes following study drug administration and then at least at 0.5, 1, 2, 3, 
4, 6, 8 hours post-dose.  For IV administration, subjects will be continuously monitored for infusion site reactions from start of drug administration until the end of infusion 
and then at least every 30 min post-dose until end of Day 1/Day 29.  Infusion/injection site reactions may be monitored beyond the time points indicated in the Schedule of 
Activities based on investigator’s assessment.
k.
All efforts should be made to perform the assessments (including blood sample collection) at the exact nominal time relative to dosing.  However, assessments (including
obtained blood samples) performed within 10% of the nominal time (eg, within 6 minutes of a 60 minute sample) from dosing will not be captured as a protocol deviation.  
The exact time of the sample collection must be noted on the source document and data collection tool (CRF).
C
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PROTOCOL SUMMARY 
Background and Rationale
PF-06835375 is a humanized, afucosyl immunoglobulin (Ig) G1 antibody against C-X-C 
chemokine receptor type 5 (CXCR5), a surface receptor that is expressed on B cells, bona
fide follicular T helper (Tfh) cells, and circulating follicular T helper-like (cTfh) cells.a
PF-06835375 is currently in development for the treatment of systemic lupus erythematosus 
(SLE).  However, there is potential utility for targeting CXCR5 for the treatment of systemic 
autoimmune diseases more broadly.  Therefore, other diseases, such as rheumatoid arthritis 
(RA), remain under consideration given their shared underlying pathophysiology of aberrant 
humoral immune responses involving B cells and Tfh cells.
CXCR5 is expressed by B cells, bona fide Tfh cells, and cTfh cells and, mediates their 
trafficking to and participation in germinal center (GC) immune responses.1 GCs, a critical 
component of the humoral immune response, are sites where antigen-activated B cells 
undergo somatic hypermutation and immunoglobulin (Ig) class switching of the antibodies 
they produce.  Bona fide Tfh cells provide instructive signals to aid this process, which 
culminates in the production of affinity-matured antibodies. Humoral “memory” of the GC 
immune response is maintained by long-lived plasma cells, which sustain antibody levels, 
and by memory B cells, which, upon re-challenge with antigen, trigger secondary GC 
immune responses with cognate help from memory Tfh cells that lead to the production of 
more high-affinity plasma cells.2  cTfh cells are thought to differentiate into bona fide Tfh 
cells upon re-encountering antigen to support these memory responses, as well.3
PF-06835375 is a selective antibody directed against the CXCR5 receptor that has two 
distinct mechanisms of action: (1) depletion of CXCR5-positive cells through 
antibody-dependent cellular cytotoxicity (ADCC), and (2) antagonism of C-X-C Motif 
Chemokine Ligand 13 (CXCL13)-dependent signaling.  By utilizing an antibody that is also 
antagonistic, cells that escape killing may still be inhibited from trafficking to and 
participating in GC immune responses. As such, the working hypothesis is that by targeting 
CXCR5 through a combination of depletion and antagonism, PF-06835375 will effectively 
impair autoreactive GC reactions, including humoral memory responses, thereby suppressing
autoantibody maturation and production known to, in part, underlie autoimmune disease 
pathology.
The goal of this first in human (FIH) study is to evaluate the safety, tolerability, 
pharmacokinetics (PK), and pharmacodynamics (PD) of PF-06835375.  In particular, PD 
characterization will include assessment of magnitude and duration of CXCR5-positive cell 
                                                
a Bona fide Tfh cells are located within lymphoid organs (ie, spleen, lymph nodes, tonsils, Peyer’s 
patches, and mucosa-associated lymphoid tissue).  cTfh cells are located in the peripheral blood.


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depletion and recovery.  Inhibition of the humoral immune responses via 
PF-06835375-mediated depletion of CXCR5-positive cells offers the potential for clinical 
evaluation in a population of seropositive autoimmune subjects.  Consequently, a mixed 
population of seropositive SLE or RA subjects will be enrolled into this study.
Objectives and Endpoints
Primary Objective: 
Primary Endpoints: 
•
To evaluate the safety and tolerability of single and 
multiple ascending intravenous (IV) and subcutaneous 
(SC) doses of PF-06835375 in subjects with SLE and 
RA.
•
Incidence of dose limiting or treatment related 
adverse events (AEs).
•
Incidence, severity and causal relationship of 
treatment emergent AEs (TEAEs) and withdrawals 
due to TEAE.
•
Incidence of abnormal chemistry, hematology, and 
urinalysis laboratory findings through the end of 
study.
•
Abnormal and clinically relevant changes in vital 
signs and electrocardiogram (ECG) parameters.
•
Incidence of infections.
Secondary Objectives: 
Secondary Endpoints: 
•
To evaluate the effect of PF-06835375 on depletion of 
circulating CXCR5 positive B cells and cTfh cells 
over time in subjects with SLE and RA.
•
Change from baseline in the number of circulating 
CXCR5 positive B cells and cTfh cells on Day 29 
single dose of PF-06835375 and at Week 8 following 
multiple doses of PF-06835375.
•
To characterize pharmacokinetics (PK) profile of 
PF-06835375 in subjects with SLE and RA.
•
Serum PF-06835375 PK parameters after single and 
multiple doses:
•
Single Ascending Dose Phase: Cmax, Tmax, 
AUCinf, AUClast.
•
Multiple Ascending Dose Phase:
•
First Dose: Cmax, Tmax, AUCtau.
•
Multiple Dose: Cmax, Tmax, AUClast, 
AUCtau, Cmin and observed accumulation 
ratio (Rac), peak-to-trough ratio (PTR).
•
To evaluate immunogenicity of PF-06835375 in 
subjects with SLE and RA.
•
Incidence of development of anti-drug antibodies 
(ADAs)/neutralizing antibodies (NAbs).
 
 
 
 
 
 
 
 
 
 
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•
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Design
This is a Phase 1, randomized, multi-center, double-blind, sponsor open, placebo-controlled, 
single and multiple dose-escalation study to evaluate the safety, tolerability, 
pharmacokinetics, and pharmacodynamics of PF-06835375 in subjects with seropositive SLE
or RA.  Both intravenous (IV) and subcutaneous (SC) routes of administration will be tested. 
This study will include two parts: Part A, consisting of approximately eight single ascending 
dose (SAD) cohorts, and Part B, consisting of approximately 6 multiple ascending dose 
(MAD) cohorts.  Cohorts in Part A will be initiated sequentially.  Subjects in Part B will 
receive two doses of investigational product, first dose on Day 1 and second dose on Day 29, 
and will be enrolled concurrently with Part A following the completion of the initial cohorts 
in Part A (See Section 3.3).  Subjects who are randomized in Part A will not be eligible to 
participate in Part B of this study.
This study will enroll up to a total of approximately 112 subjects at approximately 10 sites.  
Individual subjects are expected to stay in the study approximately 6-12 months (including 
screening), contingent on meeting criteria described for the end of study (See Section 3.5).  
Subjects who withdraw from the study may be replaced at the discretion of the sponsor.  A 
replacement subject will receive the same treatment as the withdrawn subject.
Both SLE and RA subjects will be enrolled into this study.  Minimum disease activity 
(ie, Systemic Lupus Erythematosus Disease Activity Index 2000, 
, or Disease 
Activity Score 28, DAS28) cutoffs is not required for entry as inclusion criteria. All subjects 
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in both Part A and B will be followed for a minimum of 16 weeks prior to being able to 
qualify for study completion based on the cellular recovery (See Section 3.5).
It is at the sponsor’s discretion to dose escalate (See Section 3.4.1), to repeat the same dose, 
or to test a lower dose based on emerging data. 
Throughout the study, B cell counts obtained from CLIA (Clinical Laboratory Improvement 
Amendments) certified central lab will be used for clinical decision making 
(inclusion/exclusion criteria, dose escalation, initiation of Part B and for the end of study 
criteria). 
Study Treatments
For this study, the investigational product is PF-06835375 or placebo.
PF-06835375 50 mg/mL injection is presented as a sterile solution for subcutaneous (SC) and 
intravenous (IV) administration. 
Placebo for PF-06835375 injection is presented as a sterile solution for SC and IV 
administration. 
In addition, Pfizer Global Clinical Supply (GCS), Worldwide Research and Development 
(WRD) will provide 
vaccine.  
will be purchased from 
commercial sources and will be packaged and presented with appropriate labels. 
 
 
All study treatments will be administered at the investigational site as detailed in the 
investigational product (IP) Manual.
Statistical Methods
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined in the protocol and further detailed in a statistical analysis plan (SAP), which will 
be maintained by the sponsor.  The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment.
The final analysis will be conducted when all subjects have completed all study visits.  In 
addition, unblinded data will be analyzed when all subjects have completed Week 16 visit or 
discontinued.  This analysis may take place prior to the enrollment of the optional cohort.
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Adverse events, Electrocardiograms (ECGs), blood pressure, pulse rate, oral temperature, 
continuous cardiac monitoring, and safety laboratory data will be reviewed and summarized 
on an ongoing basis during the study to evaluate the safety of subjects.  Any clinical 
laboratory, ECG, vital sign abnormalities of potential clinical concern will be described.  
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate.
The PK concentration population is defined as enrolled subjects who received at least one 
dose of PF-06835375 and have at least 1 concentration.  The PK parameter analysis 
population is defined as all enrolled subjects who received at least one dose of PF-06835375 
and that have at least 1 of the PK parameters of interest.  Samples from subjects who 
received the placebo will not be analyzed routinely.
The pharmacodynamic (PD) analysis population is defined as all randomized subjects treated 
who have at least one PD assessment in at least one cohort.  PD assessments will include but 
not limited to 
 data, soluble protein analytes, whole-blood ribonucleic acid 
(RNA) (inflammation and disease-related) and responses to vaccines.  The data will be 
summarized and plotted by treatment group and sampling time. 
 
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1. INTRODUCTION
1.1. Mechanism of Action/Indication
PF-06835375 is a humanized, afucosyl immunoglobulin (Ig) G1 antibody against C-X-C 
chemokine receptor type 5 (CXCR5), a surface receptor that is expressed on B cells, 
bona fide follicular T helper (Tfh) cells, and circulating follicular T helper-like (cTfh) cells.a
1.1.1. Indication
PF-06835375 is currently in development for the treatment of systemic lupus erythematosus 
(SLE).  However, there is potential utility for targeting CXCR5 for the treatment of systemic 
autoimmune diseases more broadly.  Therefore, other diseases, such as rheumatoid arthritis 
(RA), remain under consideration given their shared underlying pathophysiology of aberrant 
humoral immune responses involving B cells and Tfh cells. 
1.2. Background 
1.2.1. Drug Development Rationale
CXCR5 is expressed by B cells, bona fide Tfh cells, and cTfh cells and, mediates their 
trafficking to and participation in germinal center (GC) immune responses.1  GCs, a critical 
component of the humoral immune response, are sites where antigen-activated B cells 
undergo somatic hypermutation and immunoglobulin (Ig) class switching of the antibodies 
they produce.  Bona fide Tfh cells provide instructive signals to aid this process, which 
culminates in the production of affinity-matured antibodies. Humoral “memory” of the GC 
immune response is maintained by long-lived plasma cells, which sustain antibody levels, 
and by memory B cells, which, upon re-challenge with antigen, trigger secondary GC 
immune responses with cognate help from memory Tfh cells that lead to the production of 
more high-affinity plasma cells.2  cTfh cells are thought to differentiate into bona fide Tfh 
cells upon re-encountering antigen to support these memory responses, as well.3
Importantly, the generation of autoreactive B cells responding to self-antigen can arise from 
GC reactions, with undesired consequences.  Indeed, numerous chronic, systemic 
autoimmune diseases, such as SLE, RA, myositis, Sjögren’s syndrome, anti-neutrophil 
cytoplasmic antibody (ANCA)-associated vasculitis and scleroderma, show evidence of 
autoreactive humoral responses.  In addition, increased frequencies of cTfh cells have been 
detected in the peripheral blood of patients with many of these autoimmune diseases
compared to healthy controls, including both SLE and RA, the levels of which often correlate 
with autoantibody titers and/or disease severity.4,5 Taken together, these data highlight 
CXCR5-positive cells (ie, B cells, Tfh cells, and cTfh cells) as potential therapeutic targets 
for multiple systemic autoimmune diseases.
                                                
a Bona fide Tfh cells are located within lymphoid organs (ie, spleen, lymph nodes, tonsils, Peyer’s 
patches, and mucosa-associated lymphoid tissue).  cTfh cells are located in the peripheral blood.


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PF-06835375 is a selective antibody directed against the CXCR5 receptor that has two 
distinct mechanisms of action: (1) depletion of CXCR5-positive cells through 
antibody-dependent cellular cytotoxicity (ADCC), and (2) antagonism of 
CXCL13-dependent signaling.  By utilizing an antibody that is also antagonistic, cells that 
escape killing may still be inhibited from trafficking to and participating in GC immune 
responses.  As such, the working hypothesis is that by targeting CXCR5 through a 
combination of depletion and antagonism, PF-06835375 will effectively impair autoreactive 
GC reactions, including humoral memory responses, thereby suppressing autoantibody 
maturation and production known to, in part, underlie autoimmune disease pathology.
The goal of this first in human (FIH) study is to evaluate the safety, tolerability, 
pharmacokinetics (PK), and pharmacodynamics (PD) of PF-06835375.  In particular, PD
characterization will include assessment of magnitude and duration of CXCR5-positive cell 
depletion and recovery.  Inhibition of the humoral immune responses via
PF-06835375-mediated depletion of CXCR5-positive cells offers the potential for clinical 
evaluation in a population of seropositive autoimmune subjects.  Consequently, a mixed 
population of seropositive SLE or RA subjects will be enrolled into this study.
1.2.2. Systemic Lupus Erythematosus
Systemic Lupus Erythematosus (SLE) is a chronic systemic autoimmune disease that can 
affect virtually any organ, including the skin, joints, kidneys, lungs and central or peripheral 
nervous system.  Immunologic abnormalities, especially the loss of tolerance and production 
of anti-nuclear antibodies (ANA), are a prominent feature of SLE.6 The clinical course of 
SLE is variable and characterized by periods of remissions and relapses.  Women, especially 
in their childbearing years, are affected more frequently than men.  SLE is more prevalent in 
certain racial and ethnic groups, such as African-Americans, Asians, and Hispanics.  The 
prevalence of SLE ranges from approximately 40 cases per 100,000 persons among Northern 
Europeans to more than 200 per 100,000 persons among African-Americans.7
Available therapies for SLE offer limited clinical benefit, rarely induce lasting remissions,
and are associated with significant side effects (eg, cytopenias, increased infection and 
malignancy risk, hemorrhagic cystitis, and bone marrow suppression). Furthermore, 
although a central role for B and/or T cells in SLE pathogenesis has long been recognized, 
existing biologics targeting either B cells (eg, rituximab [Rituxan], belimumab [Benlysta]) 
or T cells alone (eg, abatacept [Orencia]) have demonstrated modest or minimal clinical 
benefit. Belimumab is approved for the treatment of autoantibody-positive active SLE.8
These targeted modalities have not been shown to be effective at reducing autoreactive 
memory, possibly due to limited effects on GC reactions, and, consequently have limited 
effect on SLE disease flares.  There remains a major unmet need for safer and/or more 
effective therapies that can induce a long-lasting remission in SLE. 


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1.2.3. Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a progressive, systemic autoimmune disease characterized by 
synovitis that damages diarthroidal joints and is accompanied by fatigue, anemia, and bone 
loss. Rheumatoid arthritis has a prevalence of 0.5% to 1.0% and a peak incidence between 
40 and 60 years of age and affects primarily women.9,10 Most RA patients show
seropositivity for RA-associated autoantibodies, such as anti-citrullinated peptide antibodies
(ACPA) or rheumatoid factor (RF), which may contribute to the chronic inflammation of the
synovium and subsequent joint damage that are hallmarks of RA disease pathology.11  In 
addition, approximately 30% of RA patients show formation of ectopic lymphoid organs in
inflamed synovia, which appears to correlate with enhanced autoantibody production and
disease severity.12
There are multiple approved therapeutic options for managing the pain and slowing the 
progression of RA, but none are curative.  Disease-modifying antirheumatic drugs 
(DMARDs) are the standard treatments for RA; conventional synthetic DMARDs 
(csDMARDs), such as methotrexate, are used either alone or in combination with newer 
biologic DMARDs.  Use of biologic DMARDs, most commonly tumor necrosis factor-α
(TNFα) inhibitors, is indicated when symptoms are not adequately controlled with 
csDMARDs.  Despite the numerous treatments for RA, there remain significant numbers of 
patients who do not achieve remission or indeed adequate reduction in disease activity.
1.2.4. Nonclinical Pharmacology
In vitro, PF-06835375 selectively binds human and cynomolgus monkey CXCR5-positive
cells with high affinity.  PF-06835375 does not bind mouse, rat, or rabbit CXCR5 orthologs
and therefore, the cynomolgus monkey is the only pharmacologically relevant species for 
toxicity testing.
In vitro functional assays have shown that PF-06835375 possess both potent depleting and
antagonistic activity.  Indeed, PF-06835375 triggers ADCC of CXCR5-positive cells in 
human donor and cynomolgus monkey leukocytes.  PF-06835375 does not have agonist or 
antagonist activity on any of the nineteen chemokine receptor family members related to 
CXCR5. Additional details are available in the Investigator Brochure.
In vivo studies in cynomolgus monkeys have confirmed that PF-06835375 elicits a 
dose-dependent depletion of CXCR5-positive cells that subsequently recover over time.  To 
evaluate the functional impact of PF-06835375 on humoral memory responses, a vaccine 
recall response study was conducted in cynomolgus monkeys previously immunized against 
tetanus.  PF-06835375 partially inhibited anti-tetanus toxoid Immunoglobulin G (IgG) titers 
elicited by a 
 challenge, thereby demonstrating that PF-06835375 can affect in 
vivo humoral memory responses.  Additional details are available in the Investigator 
Brochure.
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1.2.5. Nonclinical Pharmacokinetics
Single-dose pharmacokinetics (PK) and repeat-dose toxicokinetics (TK) were evaluated in 
cynomolgus monkeys following intravenous (IV) or subcutaneous (SC) dosing of 
PF-06835375.  The bioavailability of PF-06835375 after subcutaneous administration was 
estimated to be greater than 50%.  After single IV dosing in cynomolgus monkeys, the PK of 
PF-06835375 were characterized by a low clearance (CL), and a low volume of distribution 
(Vss), consistent with the PK profile for a typical human IgG1 monoclonal antibody (mAb).  
There were no apparent sex-related differences in systemic exposure (as assessed by the 
maximum observed concentration [Cmax] and area under the concentration-time curve from 
zero to 168 hours [AUC168]) following dosing once every 2 weeks at 5 (IV), 20 (SC) or 
200 (IV) mg/kg.  Systemic exposure was higher after repeat dosing and increased in a 
dose-proportional manner.  The overall incidence of anti-drug antibody (ADA) induction was 
14% (4 of 28 animals) across dose groups, and serum concentrations on Study Day 43 were 
generally lower in ADA-positive animals compared to ADA-negative animals.
1.2.6. Nonclinical Safety
Administration of PF-06835375 once every two weeks by IV bolus or SC injection for up to 
2 months in cynomolgus monkeys resulted in dose-independent depletion (maximum 
pharmacology reached at the lowest dose) of total B cells and cTfh/Tfh cells in the peripheral 
blood and spleen, and was associated with decreases in total lymphocyte and white blood cell 
counts and decreased lymphoid follicular cellularity in the spleen, lymph nodes and 
gut-associated lymphoid tissue for the dose range tested (5-200 mg/kg/dose).  These changes 
were nonadverse, partially to fully reversible, and consistent with the expected pharmacology 
of PF-06835375.  PF-06835375 did elicit cytokine release in the in vitro soluble and solid 
phase cytokine release assay using human whole blood or peripheral blood mononuclear cells
(PBMCs), however, cytokine release was not detected in the repeat-dose toxicity studies in 
cynomolgus monkeys.  At a SC dose of 20 mg/kg/dose, there were no local injection site 
reactions.  Reproductive and developmental toxicity studies have not been conducted, but 
there were no findings in male and female reproductive tissues evaluated in the repeat-dose 
toxicity studies.  The no observed adverse effect level (NOAEL) was 200 mg/kg/dose IV, the 
highest dose tested, which was associated with systemic exposure of 5220 g/mL (Cmax) and 
438,000 g•h/mL (AUC168). 
Additional information for PF-06835375 may be found in the single reference safety 
document (SRSD), which for this study is the current Investigator’s Brochure.
1.3. Dose Rationale
The doses being proposed for this study are based on data from in vivo nonclinical 
pharmacology and toxicology studies.  A model-based approach was adopted to characterize 
the relationship between dose, PF-06835375 concentrations, and modulation of B cell and 
cTfh cells in the serum of cynomolgus monkeys.  Based on the PK profiles of PF-06835375 
in cynomolgus monkeys, the exposure in humans is expected to be similar to that of a typical 
IgG1 antibody.13 Therefore, a two-compartment PK model was used to simulate 
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Published monkey and human PK/PD data for SBI-087,a a B cell depleting therapeutic, was 
used to translate B cell depletion parameters for PF-06835375 from monkey to human.14,15
Specifically, SBI-087 B cell depletion parameters in monkey and human were obtained by 
characterizing the available SBI-087 PK/PD data using the same model that was developed 
for PF-06835375.14,15 A comparison of the B cell depletion parameters for SBI-087 between 
monkey and human provided a cross-species scaling factor that was applied to the monkey 
B cell depletion parameters with PF-06835375 to predict corresponding B cell depletion 
parameters in human.  Unlike B cells, no human data were available for cTfh cell depletion;
therefore translation of cTfh cell depletion was assumed to be similar to that for B cells.  
Using baseline B and cTfh cell counts in SLE patients and predicted human cell depletion 
parameters, B cell and cTfh cell depletion kinetics following PF-06835375 administration in 
humans were simulated.15
Using a human equivalent dose (HED) approach, the maximum recommended starting dose 
is 6.5 mg/kg (assuming a safety factor of 10).  The proposed starting dose for this study is 
0.03 mg IV (~0.4 g/kg), which is predicted to result in ~50% depletion of B cells relative to 
baseline.  Relative to 1/10th of exposures at monkey NOAEL, the proposed starting dose 
provides a safety margin of 42,800 fold for Cmax and 60,100 fold for average observed 
concentration (Cav).  Based on HED approach the safety margin for proposed starting dose 
for a 70 kg individual is 150,500 fold (HED = 64.5 mg/kg).  For the highest planned dose of 
100 mg IV, the safety margins are 13 fold for Cmax and 18.1 fold for Cav relative to 1/10th of 
exposures at monkey NOAEL. 
The predicted efficacious dose of PF-06835375 is 10-30 mg IV multiple-dose regimen (dose 
on Day 1 and Day 29), and is based on the assumption that B cells in blood need to be 
depleted to 1 cells/L for ~8 weeks for clinical efficacy.  The PK/PD model may under 
predict the efficacious dose as it relies on data from another B cell depleting agent 
(ie, SBI-087) and the efficacious dose criterion only focuses on B cell depletion; the effects 
of PF-06835375 on cTfh and bona fide Tfh cells may lead to a lower efficacious dose range.  
PF-06835375 serum concentrations following the final (second) dose of 10-30 mg IV 
multi-dose regimen (dose on Day 1 and Day 29) were estimated as noted above and the 
predicted Cmax was 4.78-15.08 g/mL and the predicted Cav (calculated as AUCtau/28) was 
1.36-4.06 g/mL.  Relative to 1/10th of exposures at monkey NOAEL, the predicted 
efficacious dose provides a safety margin of 34.6-109 fold for Cmax and 64.3-192 fold for Cav.
In the multiple ascending dose (MAD) phase, the second dose will be given 4 weeks after the 
first dose.  This dosing interval was selected based on PK/PD modeling and with 
consideration for repeat dosing in future multiple dose studies.  Considering the dosing 
interval for the multiple dose phase of this study (4 weeks) will be different from the Good 
                                                
a SBI-087 is a humanized small modular immunopharmaceutical (SMIP™) biological agent directed 
against the CD20 antigen located on B lymphocytes.


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Laboratory Practice (GLP) monkey toxicity study (every 2 weeks), Cav is chosen to set the 
PK exposure limit.  Moreover, since the NOAEL in the GLP monkey toxicity study was the 
maximum dose (200 mg/kg IV) evaluated, the exposure stopping limit will be set to a Cav of 
261 μg/mL, determined as 1/10th of the NOAEL mean Cav exposure of 2610 μg/mL
(calculated as AUC168/168 reported in Section 1.2.6). Projected human exposures and safety 
margins relative to exposure stopping limit are listed in Table 1 for the planned dose levels, 
including single (Cohorts A1-A8) and multiple (Cohorts B1-B5) dose administration. Doses 
may be modified or repeated and MAD cohorts may be dosed SC or IV based on emerging 
data, but dose escalation will be restricted such that predicted exposures will not increase 
more than in semi-logarithmic increments.  For any dose administered, the predicted 
exposure will not exceed the exposure stopping limit. 
Table 1.
Predicted Median Human Exposures and Safety Multiples for Expected 
Doses
Cohort
Proposed 
Human Dose
Predicted human exposure
Safety 
Multiples
c
Cmax (μg/mL)
AUC
a
(μg*day/mL)
Cav (μg/mL)
b
Cav
Single-Dose Cohorts:
A1
0.03 mg IV
0.0122
0.1210
0.00434
60100
A2
0.1 mg IV
0.0433
0.4220
0.0151
17300
A3
0.3 mg IV
0.1240
1.23
0.044
5930
A4
1 mg IV
0.42
4.18
0.149
1750
A5
3 mg IV
1.24
11.9
0.424
616
A6
10 mg IV
4.2
40.8
1.46
179
A7
30 mg IV
12.7
123
4.38
59.6
A8
100 mg IV
40.3
402
14.4
18.1
Repeat-Dose Cohorts:
B1
0.3 mg SCd
0.0314
0.591
0.0211
12400
B2
1 mg SCd
0.107
1.96
0.0699
3730
B3
3 mg SCd
0.32
5.85
0.209
1250
B4
10 mg SCd
1.08
19.5
0.698
374
B5
30 mg SCd
3.3
59.3
2.12
123
a.
Single dose: AUCinf; Multiple dose: AUCtau after 2
nd dose where tau = 28 days.
b.
Cav is calculated as AUC divided by 28 days.
c.
Based on exposure stopping limit of Cav = 261 ug/mL, determined as 1/10
th of the NOAEL mean 
Cav exposure of 2610 ug/mL.
d.
SC bioavailability assumed to be 60%.
AUC = Area under the curve; Cav = Average observed concentration; Cmax = Maximum observed 
concentration; IV = Intravenous; NOAEL = No observed adverse effect level; SC = Subcutaneous.
1.4. Rationale for Assessment of Immune Function with Vaccine Challenges 
The functional effects of PF-06835375 on humoral immunity will be evaluated 
 
vaccine challenge.  As 
described in Section 1.6, both of these vaccines have been approved for use in humans, and 
contain inactivated immunogenic components of the specific pathogen.  The purpose of the 
vaccine challenges is to develop an understanding of the PD properties, particularly related to 
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the degree of B cell and cTfh cell depletion.  Assessment of the effect of PF-06835375 on 
neoantigen responses is precedented given prior observation of B cell depletion on 
neoantigen response.16 The reduced response to 
 in toxicity studies with non-human 
primates exposed to PF-06835375 supports further assessment of the recall response in 
humans to best assess the exposure/response properties.
 
.
 
 
 
 
 
 
 
 
 
 
 
1.6. Summary of Benefits and Risks
Based on the available nonclinical data, the risks and potential benefits for PF-06835375 are 
considered to be favorable and support clinical development in subjects with SLE and RA.
SLE and RA both have higher prevalence in females and hence the trial objectives cannot be 
met without inclusion of women of childbearing potential (WoCBP).  Nonclinical data to 
date (Section 1.2.6) have not identified any risk to reproductive organs in sexually mature 
cynomolgus monkeys, the pharmacologically relevant species.  Given that an enhanced 
pre- and postnatal development study (ePPND) will be conducted later in development, this 
protocol that allows enrollment of WoCBP has stringent requirements to mitigate unintended 
exposures (pregnancy testing and use of contraceptives; see Section 4.4.1).  Subjects will be 
followed for a minimum of 16 weeks after Day 1 during the study, which extends beyond 
predicted drug exposure of five half-lives based on expected PK. 
Based on studies with other B cell and T cell depleting agents, there is a dose-dependent risk 
for infusion and injection reactions with PF-06835375, potentially severe.  Subjects will be 
closely monitored for 8-12 hours post-infusion as per Schedule of Activities.  As described in 
Section 5, subjects will be pre-medicated to mitigate this risk, and peri- and post-infusion 
medications to manage infusion and/or injection reactions will be available for subjects 
receiving IP.
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Studies with other B cell depleting agents indicate the potential for viral and non-viral 
infections with PF-06835375, including severe cases resulting in death.  Multiple agents that 
deplete B cells have been approved in both oncology and non-oncology indications 
(including rituximab, ocrelizumab, obinatuzumab and ofatumumab) and all carry label 
warnings for infections. Progressive multifocal leukoencephalopathy (PML) resulting in 
death has occurred with B cell depleting agents (most notably rituximab given the extensive 
use in multiple diseases), and has also been observed in SLE and RA subjects receiving 
immunosuppressive agents. Investigators should consider PML in any patient with new 
onset of or changes in pre-existing neurological signs or symptoms (See Section 7.1.14).  The
role of the Tfh subset of T cells in human immunity has yet to be established, and may 
contribute to the effective control of acute and chronic pathogens.  Although no serious or 
opportunistic infections were observed in pre-clinical toxicity studies in non-human primates, 
subjects will be closely monitored throughout the study for signs/symptoms of infections.  
While appropriate risk mitigation has been incorporated into the study, possible risks will be 
communicated to study participants in the informed consent document.
Cytopenias have been observed with other depleting antibodies, including neutropenia, 
thrombocytopenia and anemia.  Subject blood counts will be closely monitored throughout 
the study, including both CXCR5-positive cells and other cell lineages.
The PD of PF-06835375 will be evaluated 
 
 
 
 
  When adverse reactions to the 
 occur, they are 
generally mild in nature and last for one or two days only.  Symptoms include erythema and 
swelling around the injection site, feelings of general malaise, headache, myalgia and fever, 
and can be managed with paracetamol.  Severe reactions are extremely rare; subjects with 
concomitant illnesses and a personal history of an allergic reaction to the 
 vaccine 
will be excluded.
 
 
 
  
Trumenba is approved for active immunization to prevent invasive disease caused by 
Neisseria meningitidis serogroup B, and is approved for use in individuals 10 through 
25 years of age.  The Centers for Disease Control and Prevention (CDC) has recommended
use of Trumenba routinely for people 10 years or older who are at an increased risk for 
serogroup B meningococcal infections.  The immunogenicity of Trumenba has been assessed 
in two-dose and three-dose regimens in multiple clinical trials to establish the safety profile.17
As of 23 March 2017, Trumenba has been approved in the European Union (EU) for active 
immunization of individuals 10 years and older to prevent invasive meningococcal disease 
caused by Neisseria meningitidis serogroup B. 
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In total, in controlled clinical studies in which over 15,000 active subjects (mostly 10 through 
25 years of age) received at least one dose of Trumenba, serious adverse events (SAEs) were 
reported at similar rates by active and control (both under 2.0%).  Overall non-serious
adverse events (AEs) in controlled studies were similar between active and control; AEs that 
occurred at a frequency of at least 2% and were more frequently observed in subjects who 
received Trumenba than subjects in the control group were local injection site pain, fever, 
and headache.  Severe allergic reactions have been observed (rarely) with Trumenba, and 
Epinephrine and other appropriate agents used to manage immediate allergic reactions must 
be immediately available should an acute anaphylactic reaction occur following 
administration of Trumenba.18  
2. STUDY OBJECTIVES AND ENDPOINTS
Primary Objective: 
Primary Endpoints: 
•
To evaluate the safety and tolerability of single and 
multiple ascending intravenous (IV) and subcutaneous 
(SC) doses of PF-06835375 in subjects with SLE and 
RA.
•
Incidence of dose limiting or treatment related 
adverse events (AEs).
•
Incidence, severity and causal relationship of 
treatment emergent AEs (TEAEs) and withdrawals 
due to treatment emergent adverse events.
•
Incidence of abnormal chemistry, hematology, and 
urinalysis laboratory findings through the end of 
study.
•
Abnormal and clinically relevant changes in vital 
signs and electrocardiogram (ECG) parameters.
•
Incidence of infections.
Secondary Objectives: 
Secondary Endpoints: 
•
To evaluate the effect of PF-06835375 on depletion of 
circulating CXCR5 positive B cells and cTfh cells in 
subjects with SLE and RA.
•
Change from baseline in the number of circulating 
CXCR5 positive B cells and cTfh cells on Day 29 
single dose of PF-06835375 and at Week 8 following 
multiple doses of PF-06835375.
•
To characterize pharmacokinetics (PK) profile of 
PF-06835375 in subjects with SLE and RA.
•
Serum PF-06835375 PK parameters after single and 
multiple doses:
•
Single Ascending Dose Phase: Cmax, Tmax, 
AUCinf, AUClast.
•
Multiple Ascending Dose Phase:
•
First Dose: Cmax, Tmax, AUCtau.
•
Multiple Dose: Cmax, , Tmax, AUClast, 
AUCtau, Cmin and observed accumulation 
ratio (Rac), peak-to-trough ratio (PTR).
•
To evaluate immunogenicity of PF-06835375 in 
subjects with SLE and RA.
•
Incidence of development of anti-drug antibodies 
(ADAs)/neutralizing antibodies (NAbs).
 
 
 
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3. STUDY DESIGN
3.1. Study Overview
This is a Phase 1, randomized, multi-center, double-blind, sponsor open, placebo-controlled, 
single and multiple dose-escalation study to evaluate the safety, tolerability, 
pharmacokinetics, and pharmacodynamics of PF-06835375 in subjects with seropositive SLE
or RA.  Both IV and SC routes of administration will be tested.
This study will include two parts: Part A, consisting of approximately eight single ascending 
dose (SAD) cohorts, and Part B, consisting of approximately 6 multiple ascending dose 
(MAD) cohorts. Fewer cohorts may be included in each part at Sponsor’s discretion. 
Cohorts in Part A will be initiated sequentially. Subjects in Part B will receive two doses of 
investigational product (first dose on Day 1 and second dose on Day 29), and will be enrolled 
concurrently with Part A following the completion of the initial cohorts in Part A (See 
Section 3.3).  Subjects who are randomized in Part A will not be eligible to participate in 
Part B of this study.
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This study will enroll up to a total of approximately 112 subjects at approximately 10 sites. 
The study includes a Screening visit to assess eligibility and subsequent visits for a minimum 
of 16 weeks.  Subjects who meet the end of study criteria (See Section 3.5) will have one 
follow-up phone call visit which will represent the end of study visit. Subjects, who do not 
meet the criteria to leave the study at Week 16, will continue with clinic visits every four 
weeks until Week 52 and then every 12 weeks until they meet these criteria.  Overall, 
subjects are expected to stay in the study approximately 6-12 months (including screening).  
Subjects who withdraw from the study may be replaced at the discretion of the sponsor.  A 
replacement subject will receive the same treatment as the withdrawn subject.
Both SLE and RA subjects will be enrolled into this study. Minimum disease activity 
(ie,
or DAS28 cutoffs) is not required for entry as inclusion criteria.  All 
subjects in both Part A and B will be followed for a minimum of 16 weeks prior to being able 
to qualify for study completion based on the cellular recovery (See Section 3.5).
It is at the sponsor’s discretion to dose escalate (See Section 3.4.1), to repeat the same dose,
or to test a lower dose based on emerging data. 
 
 
 
 
Throughout the study, B cell counts obtained from a CLIA (Clinical Laboratory 
Improvement Amendments) certified central lab will be used for clinical decision making 
(inclusion/exclusion criteria, dose escalation, initiation of Part B and for the end of study 
criteria). 
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Table 2.
Planned Cohorts
Cohort Name
Administration 
Route
Proposed Human 
Dosea (mg)
Expected Number of 
Subjects Per Cohortc
Part A (SAD)
A1
IV
0.03
3a, 1p
A2
IV
0.1
3a, 1p
A3
IV
0.3
3a, 1p
A4
IV
1
3a, 1p
A5
IV
3
6a, 2p
A6
IV
10
6a, 2p
A7
IV
30
6a, 2p
A8
IV
100
6a, 2p
Part B (MAD)
B1
SC
0.3
6a, 2p
B2
SCb
1
6a, 2p
B3
SCb
3
6a, 2p
B4
SCb
10
6a, 2p
B5
SCb
30
6a, 2p
X6d
SCb
up to 30
Up to 24 total (16a, 8p)
Abbreviations: a = active, p = placebo; IV = Intravenous; SC = subcutaneous
a.
Doses may be changed based on available emerging safety, tolerability, PK and 
PD.
b.
Route of administration may be changed based on available emerging safety, 
tolerability, PK and PD.
c.
Sponsor may elect to add more subjects into the planned cohorts for any reason, 
including but not limited to eg, subject withdrawal, higher than expected PD 
effect, etc. The study will enroll up to a total of approximately 112 subjects.
d.
Optional cohort called “X”.
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3.2. Sentinel Dosing 
In view of the mechanism of action (B cell and cTfh cell depletion), the interval between 
sentinel subjects and the remainder of the cohort is proposed to mitigate any unanticipated 
acute safety risks (ie, infusion/injection site reactions). Sentinel dosing will be employed as 
follows: 

In Part A, for Cohorts A1-A4 (with 4 subjects planned), subjects will be dosed IV at 
least 24 hours apart.  In order to avoid investigator unblinding, the one subject on 
placebo in these cohorts may be enrolled in any sequence.  The sponsor medical 
monitor will communicate with investigator(s) from each site after dosing of each 
subject (and prior to dosing of the next subject) in order to determine whether it is 
safe to proceed with continued dosing within a cohort. 
If the sponsor decides to increase the number of subjects in these A1-A4 cohorts, the 
sentinel dosing will apply only to the first four subjects as described in the paragraph 
above. After the sponsor medical monitor determines it is safe to proceed, the 
remaining subjects can be enrolled and dosed simultaneously.

In Part A, for cohorts A5-A8 (with more than 4 subjects planned), the first two 
subjects dosed IV will include one PF-06835375 and one placebo subject.  If safety 
and tolerability profile is acceptable in these two subjects, dosing of additional 
subjects can occur 24 hours after dosing of the first two subjects. These additional 
subjects within a cohort may be enrolled and dosed simultaneously.  The 
determination to proceed with dosing of additional subjects will be made by the 
sponsor following communication between sponsor medical monitor and 
investigator(s) from sites which enrolled sentinel subjects.

In Part B, for all SC cohorts, sentinel dosing for the first two subjects (as described 
for Cohort A5-A8 above) will only be employed if a given SC dose level (or higher) 
was not previously tested in Part A using the IV route of administration. For 
example, if Cohort A4 (single 1 mg IV dose) has not been tested, sentinel dosing will 
be used in Cohort B2 (two SC doses of 1 mg). If safety and tolerability profile is 
acceptable in two subjects after the first of two doses, dosing of additional subjects 
can occur 24 hours after dosing of the first two subjects. 
If in Part B the SC bioavailability is low and the decision is made to change the route 
of administration to IV, then sentinel dosing in Part B will not be repeated for dose 
levels already administered in Part A. 
Sentinel dosing in either Part A or Part B will not be used if the sponsor elects to test a dose 
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3.3. Initiation of Part B
Part B of the study is expected to be initiated after B cell counts in Part A have been depleted 
to approximately 10 cells/l.  B cell counts obtained from CLIA (Clinical Laboratory 
Improvement Amendments) certified central lab will be used for this determination. 
The decision to progress to Part B will be made at a dose escalation meeting following the 
review of the available data on safety/tolerability, PK and PD from Part A (See Section 3.4).  
The first dose in Part B will be administered via SC route. When progressing to Part B, this 
dose escalation meeting will also include a review of available safety data at the same 
IV dose level in Part A.  In addition, the next IV dose cohort in Part A will be dosed prior to 
dosing the first dose level in Part B.
3.4. Dose Escalation and Stopping Rules
3.4.1. Dose Escalation
The decision to progress to the next higher dose in Parts A and B will be made following the
review of available safety/tolerability, PK and PD data for the preceding dose levels (in a 
respective Part) and after the sponsor (Medical Monitor, Clinical Pharmacologist and Study 
Statistician at a minimum) and investigators (with active subjects or subjects enrolled in the 
dose level under review) determine that it is safe to proceed to the next dose level.
Once Part B has been initiated, dosing in subsequent cohorts in Part B may occur either via 
SC or IV routes. Specific criteria for dose escalation in Part B are provided below:

SC route of administration in Part B: dose escalation in SC cohorts in Part B may 
occur independent of IV cohorts in Part A.

IV route of administration in Part B: dose escalation in Part B will only occur after 
subjects have been dosed wih a three-fold higher IV dose in Part A.  For example, 
dosing in B2 (two 1 mg IV doses) may commence after dosing in Cohort A5 (single 
3 mg IV dose) occurred. 
If the decision has been made to dose escalate, it is at sponsor’s discretion whether to 
proceed with dose escalation. It is also at sponsor’s discretion whether to repeat the same 
dose or to test a lower dose based on emerging data.  The dose escalation meeting will review
infusion and injection site reactions, and the sponsor will provide guidance to Investigators 
on management of injection/infusion reactions in the subsequent cohort, including the need 
for pre-medication with corticosteroids. 
Review of ongoing safety data will continue after dose escalation has either been completed 
or stopped and subjects remain active in the study.  These meetings will include a similar 
group as the dose escalation meetings, and will be scheduled every three months at a 
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Dose escalation can proceed after the following criteria are met:

For cohorts with 4 planned subjects, all 4 subjects have been dosed.  For cohorts with 
8 planned subjects, at least 6 subjects have been dosed, including at least one placebo 
subject. 

Sponsor medical monitor and investigators who enrolled subjects in a given cohort
have reviewed all available safety data for dosed subjects, including:

minimum of 2 weeks of safety and tolerability data after the last study drug dose, 
AND

minimum 1 week of PK data after the last study drug dose.

In Part A, for cohorts A1-A4 (with 4 subjects planned), 4 subjects have completed 
two weeks post-dose in the study. In Part A, for Cohorts A5-A8 and B1-B5 (with 
8 subjects planned), 6 subjects must complete two weeks post-dose in the study. 

The majority of subjects dosed with PF-06835375 in a given cohort have a detectable 
B cell count (obtained from the CLIA certified central lab; LLOQ = 1 B cell per L 
of blood) for a minimum of 2 consecutive visits at least 2 weeks apart, starting at 
Week 12. Subjects, who reach detectable B cell counts and withdraw from the study 
earlier, will be considered as having met this criterion. Subjects who withdraw from 
the study prior to reaching a detectable B cell count will not be counted in the cohort 
size (this will be limited to 1 subject per cohort of 4 or 2 subjects per cohort of 8). 
Investigators will have access only to de-identified B-cell count data to remain 
blinded.

The sponsor and majority of investigators with active subjects and/or subjects
enrolled in the dose level under review (includes only subjects who received IP) agree
to proceed to the next dose level based on the overall safety profile.  For the purpose 
of defining the majority of investigators, only one investigator from each site will be 
counted. 
3.4.2. Dose Escalation Stopping Rules
Dose escalation stopping rules will be used to determine whether the maximal tolerated dose 
has been attained.  Dose escalation will be stopped if it is determined that the limits of safety 
and/or tolerability have been reached based on the criteria described in this section.  This
decision will be made after a discussion takes place between the sponsor study team and the 
investigator.  The sponsor study team may not overrule the investigator’s decision to stop 
dose escalation.  If dose escalation is stopped because of any of these criteria, additional 
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The dose escalation will be terminated based on the following criteria:

If 2 subjects within a dose cohort develop Common Terminology Criteria for 
Adverse Events (CTCAE) v4.0 Grade 3 adverse event considered to be serious 
(ie, SAE) in the same organ system, or if 1 subject develops a CTCAE v4.0 Grade 4 
or higher SAE, considered related to study drug, and not clearly related to the 
underlying disease (ie SLE or RA) process, concomitant medications or supplements. 

Laboratory abnormalities known to be associated with B-cell depleting therapies 
(neutropenia, thrombocytopenia and anemia) will not be considered for this 
criterion, instead these laboratory abnormalities will be considered for Individual 
Stopping Rules (Section 3.4.3).

If 50% or more subjects within a dose cohort experience a CTCAE v4.0 Grade 3 or 
higher infusion reaction as defined by the criteria in Appendix 7.

If a confirmed or probable case of Progressive Multifocal Leukoencephalopathy is 
observed, the sponsor will hold dosing for all subjects until the benefit risk 
assessment of PF-06835375 is re-evaluated by the sponsor (See Section 7.1.14).  If
the sponsor concludes the benefit risk assessment is favorable, investigators will be 
consulted on whether to proceed as described in this section.

If, at any dose level, the mean exposure for the treatment group reaches or exceeds 
the exposure stopping limit of Cav of 261 g/mL, OR, based on the observed data, the 
group mean Cav of the next planned dose is projected to exceed the exposure stopping 
limit (See Section 1.3).  Modified doses may be explored if they are not expected to 
exceed PK stopping criteria.
If any dose cohort is repeated, this additional cohort will be considered a separate cohort for 
the purpose of this dose escalation stopping rules.
To determine whether any of the above criteria for stopping dose escalation have been met,
the sponsor will convene a dose review team meeting between the sponsor (including at 
minimum Medical Monitor or Clinical Lead, Clinical Pharmacologist and Statistician) and 
Investigators who have active subjects or who enrolled in the dose cohort under review, to 
review adverse event(s) and all relevant safety data.  This meeting may take place as part of 
standard dose escalation meeting or ad-hoc based on emerging safety data.  Unblinding to 
determine relatedness to investigational product may be considered. 
If any of the above criteria is considered to have been met as determined by unanimous 
decision of the dose review team members OR if a unanimous decision cannot be reached: 

No further doses should be administered at this dose and no dose escalation will
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
Enrollment of the study may continue at a lower dose or a lower dose cohort may be 
added to the study.
Otherwise, upon unanimous decision of the dose review team members that it is safe to 
proceed, one of the following decisions may be made by the sponsor:

Enrollment of the cohort may resume as planned.

The cohort may be expanded at the same dose.

Enrollment of the study may continue at a lower dose or a lower dose cohort may be 
added to the study.
Unanimous decision is defined as all Investigators who have active subjects or enrolled in the 
dose cohort under review (one Investigator per site) and sponsor medical representative 
(medical monitor or clinical lead) agree.
3.4.3. Individual Stopping Rules
If an individual subject develops any of the following, the subject will not receive a second 
dose of IP in Part B.  Subjects in Part B (MAD cohort) who meet these criteria and who have 
received the first dose of IP will remain in the study and continue to be followed per the 
Schedule of Activities:

Laboratory values meeting criteria for potential drug induced liver injury (see 
Section 8.4.2).

Illness or clinical adverse event that prevents daily activity and requires medical
intervention (ie CTCAE v4.0 Grade 3).

Any serious adverse event (irrespective of relatedness to study drug).

Any infection requiring the use of oral or parenteral antibiotics between first and 
second dosing of IP requires approval by sponsor clinician or medical monitor prior 
to subject receiving a second dose of IP.

Increase in SLE or RA disease activity requiring use of prohibited medications (See 
Appendix 2), OR doses or formulations of medications inconsistent with those 
allowed (See Appendix 3). 

Prior CTCAE v4.0 Grade 4 infusion reaction during first infusion.


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The following criteria will not be considered as Individual Stopping Rules (due to the 
anticipated effects of PF-06835375 on blood counts):

Lymphopenia: CTCAE v4.0 Grade 2 lasting 14 days or less OR Grade 3 lymphopenia
lasting 7 days or less. For subjects with abnormalities present on Day 1 prior to dose 
(ie, CTCAE v4.0 Grade 1 or 2), a two-grade shift lasting 14 days or less.

Neutropenia: CTCAE v4.0 Grade 2 lasting 7 days or less OR Grade 3 lasting 3 days 
or less.

Thrombocytopenia: CTCAE v4.0 Grade 2 lasting 7 days or less OR Grade 3 lasting 
3 days or less.
3.5. Criteria for End of Study
All subjects will be followed through the Week 16 visit.  In order for the Week 16 visit to be 
the subject’s last clinic study visit, B cell counts meet at least one of these criteria:

B cell count is 50% of baseline value AND is stable or increasing between Week 12
and Week 16 measurements, OR

B cell count is lower limits of normal (defined as 80 cells/l19) at Week 16.
If at least one of the above criteria are not met at Week 16, subjects will continue in the 
study and will be followed until B cell count meets at least one of these criteria:

B cell count is 50% of baseline value AND is stable or increasing between the two 
measurements at least two weeks apart, OR

B cell count is lower limits of normal (defined as 80 cells/l19), OR

B cell count reaches a new stable (or increasing) detectable level AND subject is 
clinically stable for minimum of two consecutive visits, each at least two weeks apart, 
based on the assessment by both the sponsor AND the investigator.  The earliest 
B cell count that can be considered for this criterion is from the Week 20 visit. As a 
result, subjects will not be discharged prior to availability of Week 24 lab results for 
B cells under this criterion.
B-cell counts obtained from CLIA certified central lab will be used for this determination. 
Baseline value is defined as the average of Screening and Day 1 pre-dose values.  In cases 
where only one value (ie, screening or Day 1 pre-dose) is available, this one value will be 
used as the baseline.  Stable is defined as 5 cell/l.  Values obtained by the central lab will 
be used.


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B cell counts data will be available only after subject completes the clinic visit due to the 
required shipment of samples to central lab and their processing time.  Once subject meets 
the criteria for the end of study described above, a phone visit will take place within 
approximately 1-2 weeks, prior to the next scheduled in clinic visit.  This phone visit will be 
considered the end of study visit/last visit.
Subjects may be asked to return for additional follow up visits beyond the anticipated end of 
study visit for safety reasons as determined by the Investigator in consultation with the 
sponsor medical monitor.
4. SUBJECT ELIGIBILITY CRITERIA
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular subject is suitable for this protocol.
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study.
4.1. Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Evidence of a personally signed and dated informed consent document indicating that 
the subject has been informed of all pertinent aspects of the study.
2. Willing and able to comply with scheduled visits, treatment plan, laboratory tests and 
other study procedures.
3. Male or female subjects between the ages of 18 and 70 years (inclusive) at the time of 
Screening visit.
4. Subjects who are, in the opinion of the investigator, sexually active and at risk for 
pregnancy with their partner(s) must agree to use one highly effective form of 
contraception as outlined in this protocol for the duration of the study and for at least 
three months after the last dose of investigational product.  In addition, based on 
contraception use recommendations from other similar agents that deplete B-cells, the 
sponsor strongly recommends that all subjects use highly effective contraception for a 
minimum of 6 months following the last dose of IP.  This time frame of 6 months 
after the last dose of IP is strongly recommended but not required. Male subjects who 
are sexually active must agree to use a condom to prevent potential transmission of 
investigational product in seminal fluid starting for the same duration.


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Female subjects of non-childbearing potential must meet at least 1 of the following 
criteria:
a.
Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause and have a serum follicle-stimulating hormone (FSH) level 
confirming the postmenopausal state; If post-menopausal for 5 years, it is at the 
investigator’s discretion whether to confirm post-menopausal status by FSH.
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy.
c.
Have medically confirmed ovarian failure. 
All other female subjects (including female subjects with tubal ligations) are 
considered to be of childbearing potential. 
5. For females of childbearing potential, two negative pregnancy tests (one negative 
serum pregnancy test at Screening and one negative urine pregnancy test on Day 1)
are required before receiving the investigational product. 
6. Body Mass Index (BMI) of 17.5 to 40 kg/m2 AND total body weight >45 kg.
7. Subjects must meet diagnostic criteria either for Rheumatoid Arthritis or Systemic 
Lupus Erythematosus below:
a.
Rheumatoid Arthritis criteria:

Confirmed diagnosis of Rheumatoid Arthritis according to the 2010 American 
College of Rheumatology (ACR)/European League Against Rheumatism 
(EULAR) criteria (See Appendix 6) at Screening, with symptom duration at 
least 6 months prior to Screening visit.

Positive with Rheumatoid Factor and/or anti-citrullinated peptide antibody 
(ACPA) at Screening.
b. Systemic Lupus Erythematosus (SLE) criteria:

Confirmed diagnosis of SLE according to the Systemic Lupus International 
Collaborating Clinics (SLICC) Classification Criteria (See Appendix 5) at
Screening, with symptom duration at least 6 months prior to Screening visit. 

Positive antinuclear antibody (ANA) titer 1:80 AND/OR positive 
anti-double-stranded deoxyribonucleic acid (anti-dsDNA) AND/OR anti-Smith 
antibodies at Screening.


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4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
1. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or 
subjects who are Pfizer employees, including their family members, directly involved 
in the conduct of the study.
2. Participation in other studies involving investigational drug(s) within 30 days or 
5 half-lives (whichever is longer) prior to study entry and/or during study 
participation.  For investigational biologics, 5 half-lives or 180 days preceding the 
first dose of the investigational product (whichever is longer).  If subjects participated 
in studies involving investigational biologics, which are biosimilars, the timeframe 
from previous use described in Appendix 2 will apply instead.
3. Other acute or chronic medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation or behavior or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the subject inappropriate for entry into this 
study.
4. Subjects with DAS28 score >5.1 can be enrolled only after consultation with the 
sponsor medical monitor.
5. Subjects with Clinical SLEDAI-2K score >8 can be enrolled only after consultation 
with the sponsor medical monitor.
6. Active central nervous system (CNS) manifestations, systemic vasculitis or 
pleuro/pericarditis which, in the opinion of the investigator or sponsor, is 
uncontrolled within 2 months of the Screening visit or leading to the incapacity of the 
subject to comply with consent and protocol requirements.
7. Active lupus nephritis, as defined by any of the following:

Proteinuria >1.5 g/24 hr or urinary protein to urinary creatinine ratio [Upr/Ucr] 
>2.0 at Screening; only one of these two tests is required at Screening. 

Presence of red blood cell (RBC) casts or 10 RBC/hpf (in the absence of 
infection or menstrual hematuria at Screening);

Estimated Glomerular Filtration Rate (eGFR) <60ml/min/1.73 m2 at Screening.  
The following formula will be used: 175 x (Serum creatinine)-1.154 × (Age)-0.203 × 
(0.742 if female) × (1.212 if African-American);


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
Requiring high-dose prednisone (greater than or equal to 40 mg/day) within 
3 months prior to Screening;

Requiring hemodialysis or cyclophosphamide (Cytoxan) within the 6 months
prior to Screening.
8. Secondary antiphospholipid antibody syndrome (APS) associated with a 
thromboembolic event in 12 months prior to Screening and/or associated with any 
prior history of cerebro- or cardiovascular event due to APS.
9. Subject is taking or has taken prohibited medications (See Appendix 2), OR taking 
doses or formulations of medications not consistent with those allowed 
(See Appendix 3). 
10. Presence of any other systemic rheumatic disease other than and not related to 
SLE/RA (Secondary Sjogren's syndrome is permitted).
11. Baseline chronic co-morbidities (other than SLE/RA) requiring systemic 
corticosteroid therapy (such as asthma or inflammatory bowel disease) starting 
6 months prior to the Screening.  Systemic is defined as oral, rectal, or any injectable
route of administration (thus other routes are allowed, including inhaled, topical, 
ophthalmic, otic, and intranasal). 
12. Subjects with any of the following infections or infections history:
a.
Active clinically significant viral, bacterial, or fungal infection, or any major 
episode of infection requiring prescription anti-infective treatment 2 weeks prior 
to Screening.
b. History of recurrent infections defined as 3 or more of the same type of infection 
in a 12-month rolling period.  This does not include vaginal candidiasis or 
onychomycosis provided these are considered by the investigator to be well 
controlled.
c.
Herpes infection meeting at least one of the following criteria:

A herpes zoster episode 3 months prior to Screening;

History of recurrent (ie, more than one episode) herpes zoster;

History of a single episode of disseminated (multidermatomal) herpes zoster 
or herpes simplex.
d. Positive human immunodeficiency virus (HIV) serological test at screening.  
Note: a documented negative HIV test within 3 months of Screening visit is 
acceptable and does not need to be repeated at Screening.


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e.
Evidence of active or latent infection of hepatitis B or hepatitis C based on
screening tests (See Section 7.1.9).  Subjects who are positive for hepatitis C virus
antibody (HCV Ab) will be reflex-tested for hepatitis C virus ribonucleic acid
(HCV RNA) and only if HCV RNA is negative, they may be considered for
enrolled in this study.
f.
Current or past history of either 1) active tuberculosis (TB) infection or 2) latent
TB that was inadequately treated or where adequate treatment cannot be
documented.
g. Clinically significantly abnormal chest X-ray per investigator opinion or evidence
of active TB on chest X-ray.  Subjects who had chest X-ray performed within
3 months prior to the Screening visit do not have to have chest X-ray performed,
provided documentation is available.
13. Known hypersensitivity, intolerance or allergic reaction to the IP or placebo or any of
its excipients, or history of severe hypersensitivity to monoclonal antibodies.
14. Known hypersensitivity or allergic reaction to pre- or post-infusion medications
(corticosteroids, acetaminophen and antihistamines).
15. Known hypersensitivity or allergic reaction to Td or Trumenba vaccination.
16. Received any live virus or live-attenuated vaccines within 4 weeks prior to Screening,
or expected during the study period (from Screening to subject’s last visit).
17. Received plasmapheresis within 12 weeks prior to Screening or expected during the
study period (from Screening to subject’s last visit).
18. History of or planned organ transplant for the duration of the study (from Screening
to subject’s last visit).
19. Major surgery requiring use of general anesthesia within 6 weeks prior to Screening
or planned or expected major surgery during the study period (from Screening to
subject’s last visit).
20. History of any malignancy within past 5 years prior to Screening (except adequately
treated and removed basal and squamous cell carcinomas of the skin, and in situ
cervical cancer intraepithelial neoplasia of the uterine cervix).
21. Subject abused drugs or consumed an excessive amount of alcohol in the past
12 months, based on the opinion of the investigator.
22. Presence of any of the following laboratory abnormalities at Screening:

B-cell count at Screening below the lower limit of normal (LLN), defined as
80 cells/l (obtained from CLIA certified central lab).


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
Total serum IgG <5 mg/dl (or 5 g/l).

Hemoglobin <10 g/dL (100 g/L).

White blood cell count <2.5 x 109 /L (<2,500/mm3).

Platelet count <75 x 109/L per central laboratory results (75,000/mm3).

Neutrophil count <1.5 x 109/L (<1,500/mm3).

Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level
2.0 × upper limit of normal (ULN).

Total bilirubin level 2.0 × ULN; subjects with a history of Gilbert's syndrome 
may have direct bilirubin measured and would be eligible for this study provided 
the direct bilirubin level is ULN.
Any abnormal results may be confirmed by a single repeat test, if deemed necessary
by the investigator and approved by the sponsor medical monitor.
23. Pregnant female subjects; breastfeeding female subjects; fertile male subjects and 
female subjects of childbearing potential who are unwilling or unable to use one 
highly effective method of contraception as outlined in this protocol for the duration 
of the study and for at least three months after the last dose of investigational product. 
24. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing. 
25. Unwilling or unable to comply with the criteria in the Lifestyle Requirements section 
of this protocol.
4.3. Randomization Criteria 
Subjects will be randomized into the study provided they have satisfied all subject eligibility 
criteria.  Subjects will be randomized within each cohort to receive either PF-06835375 or 
placebo.  Both SLE and RA subjects will be enrolled into this study.  There are no 
requirements for a minimum number of RA or SLE subjects in each cohort.
In order to mitigate any unanticipated acute safety risks, sentinel dosing will be employed for 
this study as described in Section 3.2.
4.4. Lifestyle Requirements
4.4.1. Contraception
PF-06835375 has not been studied in embryofetal studies and therefore may have potential 
teratogenicity/fetotoxicity.  All fertile male subjects and female subjects who are of 
childbearing potential and who are, in the opinion of the investigator, sexually active and at 


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risk for pregnancy with their partner(s) must agree to use a highly effective method of 
contraception consistently and correctly for the duration of this study.  In addition, based on 
contraception use recommendations from other similar agents that deplete B-cells, the 
sponsor strongly recommends that all subjects, who leave study, should use highly effective 
contraception for a minimum of 6 months following the last dose of IP. This time frame of 
6 months after the last dose of IP is strongly recommended but not required. Male subjects 
who are sexually active must agree to use a condom to prevent potential transmission of 
investigational product in seminal fluid starting for the same duration.
The investigator or his or her designee, in consultation with the subject, will confirm that the 
subject has selected an appropriate method of contraception for the individual subject and his 
or her partner from the permitted list of contraception methods (see below) and will confirm 
that the subject has been instructed in its consistent and correct use.  At time points indicated 
in the Schedule of Activities, the investigator or designee will inform the subject of the need 
to use highly effective contraception consistently and correctly and document the 
conversation and the subject’s affirmation in the subject’s chart (subjects needs to affirm 
their consistent and correct use of at least 1 of the selected methods of contraception).  In 
addition, the investigator or designee will instruct the subject to call immediately if the 
selected contraception method is discontinued or if pregnancy is known or suspected in the 
subject or the partner.
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted, transdermal) provided the subject or 
male subject’s female partner plans to remain on the same treatment throughout the 
entire study and has been using that hormonal contraceptive for an adequate period of 
time to ensure effectiveness. 
2. Correctly placed copper-containing intrauterine device (IUD). 
3. Male sterilization with absence of sperm in the postvasectomy ejaculate.
4. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
NOTE: Sexual abstinence, defined as completely and persistently refraining from all 
heterosexual intercourse (including during the entire period of risk associated with the study 
treatments) may obviate the need for contraception ONLY if this is the preferred and usual 
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4.5. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the Shared Investigator 
Portal - Sponsor Contacts. 
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card.  The contact card contains, 
at a minimum, protocol and investigational product identifiers, subject study numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
subject’s participation in the study. The contact number can also be used by investigator
staff if they are seeking advice on medical questions or problems; however, it should be used
only in the event that the established communication pathways between the investigator site 
and the study team are not available. It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study.  The contact 
number is not intended for use by the subject directly, and if a subject calls that number, he 
or she will be directed back to the investigator site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonisation (ICH)
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator in a clinical trial, 
including a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use (ICH E6 1.33).
For this study, the investigational product is PF-06835375 or placebo.
5.1. Allocation to Treatment
Allocation of subjects to treatment groups will proceed through the use of an interactive 
response technology (IRT) system (interactive Web based response [IWR]).  The unblinded 
dispensing personnel will be required to enter or select information including but not limited 
to the user’s identification (ID) and password, the protocol number, and the subject number.  
The unblinded dispenser will then be provided with a randomization number, treatment 
assignment, and dispensable unit (DU) or container number when investigational product is 
being supplied via the IRT system.  The IRT system will provide a confirmation report 
containing the subject number, randomization number, and DU or container number 
assigned.  The confirmation report must be retained by the unblinded dispenser in the 
unblinded site files. 
The study specific IRT reference manual will provide the contact information and further 
details on the use of the IRT system. 


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5.2. Breaking the Blind
The study will be subject and investigator blinded.  To safeguard blinding of investigators, 
investigators will not be able to access potentially unblinding data (eg, individual B-cell 
counts), unless needed for safety.
At the initiation of the study, the investigator site will be instructed on the method for 
breaking the blind.  The method will be an electronic process.  Blinding codes should be 
broken only in exceptional circumstances when knowledge of the actual treatment code is 
absolutely essential for further management of the subject. Investigators are encouraged to 
discuss with the sponsor’s medical monitor if they believe that unblinding is necessary. 
When the blinding code is broken, the reason must be fully documented and entered on the 
case report form (CRF).
5.3. Subject Compliance
All doses of investigational product will be administered by the appropriately designated 
study staff at the investigator site.
5.4. Investigational and Non-Investigational Product Supplies
Clinical Trial supplies will be shipped to the study sites by Pfizer Global Clinical Supply 
(GCS), Worldwide Research and Development (WRD), and will include a Drug Shipment 
and Proof of Receipt form.  This form will be completed, filed, and the shipment confirmed 
as directed on the bottom of the Drug Shipment and Proof of Receipt form.  The Investigator 
shall take responsibility for and take all steps to maintain appropriate records and ensure 
appropriate supply, storage, handling, distribution, and usage of investigational product in 
accordance with the protocol and any applicable laws and regulations.
5.4.1. Dosage Form(s) and Packaging
5.4.1.1. PF-06835375 or Placebo
Investigational product PF-06835375 is supplied as a sterile solution, packaged in a single 
use, 6 mL clear glass vial sealed with a coated serum stopper and an aluminum overseal.  
Each vial contains 1.35 mL PF-06835375 investigational product at a nominal concentration 
of 50 mg/mL at pH 5.8, sufficient to deliver a 1 mL dose of PF-06835375 investigational 
product.  The PF-06835375 investigational product solution is a colorless to slightly brown 
colored solution and is labeled according to local regulatory requirements.
Placebo for PF-06835375 injection is presented as a sterile solution for SC and IV 
administration.  Each vial nominally contains 1 mL of placebo as an aqueous buffered 
solution, is sealed with a coated serum stopper and an overseal, and is labeled according to 
local regulatory requirements.  Placebo Solution is supplied as a sterile solution, packaged in 
a single use, 6 mL clear glass vial sealed with a coated serum stopper and an aluminum over 
seal.  Each vial of placebo contains 1.35 mL of volume sufficient to deliver a 1 mL dose of 
placebo solution.  The placebo solution should be clear, colorless and free of visible 
particulates, and is labeled according to local regulatory requirements.


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5.4.2. Preparation 
Within this protocol, preparation refers to the investigator site activities performed to make 
the investigational product ready for administration to the subject by qualified staff. 
See the Investigational Product Manual (IP manual), for instructions on how to prepare the 
investigational product for administration.  Investigational product should be prepared and 
dispensed by an appropriately qualified and experienced member of the study staff 
(eg, physician, nurse, physician’s assistant, nurse practitioner, pharmacy assistant/technician, 
or pharmacist) as allowed by local, state, and institutional guidance.  Vials are for single use 
only.
5.4.2.1. PF-06835375 or Placebo Preparation
PF-06835375 and placebo will be prepared by two qualified unblinded site personnel 
according to the IP manual. The investigational product will be administered in blinded 
fashion to the subject. 
 
5.4.3. Administration
All study treatments will be administered at the investigational site as detailed in the IP 
Manual. 
5.4.3.1. PF-06835375 or Placebo Administration
5.4.3.1.1. Intravenous Administration
Blinded IV PF-06835375 or placebo will be administered at the investigative site or clinic an 
IV infusion, using a calibrated infusion pump.  Please refer to the IP manual for specific 
instructions.
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Subjects should have venous access maintained for at least 2 hours after the completion of 
the infusion.  This will allow immediate administration of any IV medication deemed 
necessary by the investigator in the event of an infusion-related reaction.
5.4.3.1.1.1. Infusion Durations
Blinded IV PF-06835375 or placebo will be administered as an IV infusion at the 
investigative site or clinic using a calibrated infusion pump according to IP manual.  The 
total infusion time will be 120 minutes ±10 minutes, unless a different time is needed to 
manage symptoms typical of infusion reactions.  In such a case, the entire duration of study 
drug infusion should not exceed ~4 hours unless a different time is communicated to the site 
by the sponsor (See Section 5.4.3.1.1.2).  Once the infusion has completed, all subjects will 
be monitored according to the Schedule of Activities.  Refer to the IP manual for specific 
instructions for administration.
5.4.3.1.1.2. Infusion Discontinuation
The following rules should be followed by infusion discontinuation:
•
If a subject experiences symptoms typical of an allergic reaction, the study drug 
administration should be discontinued immediately and permanently. 
•
If a subject experiences symptoms typical of infusion reactions (eg, lightheadedness, 
nausea, chills, fever), the study drug infusion should be slowed down or stopped. 
•
If symptoms are resolved within 1 hour after the stop of infusion, the infusion can be 
restarted at the discretion of the investigator.  If symptoms return, then the study drug 
administration should be discontinued immediately and permanently. 
The entire duration of study drug infusion, from the initial start of infusion to the completion 
of infusion, should not exceed 4 hours unless a different time is communicated to the site by 
the sponsor.
5.4.3.1.2. Subcutaneous Administration
Blinded subcutaneous (SC) PF-06835375 or placebo will be administered at the investigative 
site or clinic. In Part B (MAD), the planned route of administration will be SC, however 
safety, tolerability, PK and PD data from the Part A (SAD) will be assessed prior to initiating 
Part B to determine route of administration.  Please refer to the IP manual for specific 
instructions.
The preferred body location of the SC injections is in the abdomen.  If abdominal injections 
are not possible, arm or thigh locations may also be used.  If an arm is used for the SC 
injection, the opposite arm should be used for the blood sample collections for PK analyses.
 
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5.4.4. Investigational Product Storage 
The investigator or an approved representative, eg, pharmacist, will ensure that all 
investigational products are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements.
Investigational products should be stored in their original containers and in accordance with 
the labels. 
Any storage conditions stated in the SRSD will be superseded by the storage conditions 
stated on the product label.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products).  This should 
be captured from the time of investigational product receipt throughout the study.  Even for 
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order. 
Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery. The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer. 
Once an excursion is identified, the investigational product must be quarantined and not used 
until Pfizer provides permission to use the investigational product.  It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion.  Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation. Specific details regarding information the site should report 
for each excursion will be provided to the site.
Receipt of materials, door opening and closing, and other routine handling operations where 
the products are briefly out of the temperature range described in the labeling are not 
considered excursions.
See the IP manual for complete information on storage conditions, handling and stability of 
the product.
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5.5. Investigational Product Accountability 
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record.
5.5.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site). If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
5.6. Concomitant Treatment(s)
Subjects should abstain from initiating new treatments during the study, except for the 
treatment of adverse events and continued use of those medications as described in
Appendix 3.  Limited use of non-prescription medications that are not believed to affect 
subject safety or the overall results of the study is permitted based on Investigator’s 
discretion.
All concomitant treatments taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration.  All subjects will be questioned about 
concomitant treatment at each clinic visit.
Treatments taken within 28 days before the first dose of study investigational product will be 
documented as a prior treatment.  Treatments taken after the first dose of study 
investigational product will be documented as concomitant treatments.
Females taking hormone replacement therapy may be eligible to participate in this study if 
they are willing to discontinue therapy at least 28 days prior to the first dose of study 
treatment and remain off hormonal therapy for the duration of the study.
5.6.1. Treatment Prior to IP Administration
Treatment with agents that deplete B-cells have the potential to cause serious and life 
threatening infusion reactions.  Appropriate equipment and personnel to manage anaphylaxis 
or serious infusion reactions are required.  Approximately 1 hour prior to the administration 
of IP, each subject will be pre-treated with 1000 mg oral acetaminophen and an oral 
antihistamine (eg, 25 mg of oral diphenhydramine).
Based on emerging safety/tolerability data, additional pre-treatment may be necessary to 
manage infusion or injection reactions, including administration of oral or IV corticosteroids. 
Specific instructions for pre-medication will be communicated by the sponsor to sites and 
investigators based on available safety data (both at dose escalation review meetings and 
periodically during the study as needed).


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5.6.2. Treatment Post-infusion/Injection
Based on discretion of the investigator, subjects may receive additional acetaminophen at 
4 hours and 8 hours after administration of IP based on clinical symptoms. 
In addition, subjects may be given anti-histamines, anti-pyretics and/or corticosteroids based 
on investigator’s discretion to manage infusion and injection reactions, particularly in the 
higher dose cohorts.  If none of these steps are successful in appropriately managing infusion 
reactions as determined by the investigator, the investigator should consider hospitalization 
of the subject for further management.
Specific instructions for post-infusion/injection medication will be communicated by the 
sponsor to sites and investigators based on available safety data, both at dose escalation 
review meetings and periodically during the study as needed.
5.6.3. Guidance for Investigators 
Subjects who have been dosed and who experience an increase in disease activity (ie flare)
should receive medication as needed based on the discretion of the Investigator.  The subject 
should continue to be followed as per Schedule of Activities.  If the subject requires 
medications inconsistent with the guidance in Appendix 2 and Appendix 3, a protocol 
deviation should be recorded and the sponsor clinician or medical monitor should be notified.
If medications inconsistent with the guidance in Appendix 2 and Appendix 3 are required to 
manage subject’s increase in SLE or RA disease activity in Part B after the first dose of IP 
but prior to the second dose of IP, the second dose of IP should not be administered.  The 
subject should continue to be followed as per Schedule of Activities (See Section 3.4.3).
6. STUDY PROCEDURES
Visits should occur when scheduled, within the time window indicated in the Schedule of 
Activities.  Written informed consent must be obtained prior to performing any 
protocol-specific procedures. 
Where possible the following order of activities (if applicable to a given visit) should be 
followed during the clinic visits:
1. The Columbia-Suicide Severity Rating Scale (C-SSRS).
2. Vital signs.
3. Physical exam.
4. Clinical scales (eg, 
, ACR/EULAR, SLICC, 
).
5. ECGs.
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7. Blood and Urine Sample Collection.
6.1. Screening
For screening procedures, see Schedule of Activities section.  Screening assessments may be 
repeated within the allowed screening visit window, provided this was approved by the 
sponsor clinician or sponsor medical monitor. An approval is not needed when repeating 
1) ECGs to rule out improper lead (see Section 7.1.8) or 2) Interferon gamma release assay
once only after an indeterminate result (see Section 7.1.10.1).
If a subject has been screen-failed, this subject may be re-screened one time, provided this 
was approved by the sponsor clinician or sponsor medical monitor. All screening 
assessments must be repeated during re-screening, with the exception of chest X-ray, HIV, 
Hepatitis and TB testing, which do not have to be repeated, provided re-screening is done 
within 3 months of the initial screening visit and these assessments were performed during 
the initial screening visit.
If for scheduling or logistics reasons, subject cannot be randomized within the screening 
window as described in Schedule of Activities, screening window subject may be extended 
by up to 5 days, provided this was approved by the sponsor clinician or sponsor medical 
monitor. 
In order to ensure sentinel dosing is implemented and that appropriate number of subjects is 
screened, sites need to obtain written approval from the sponsor clinician to proceed with 
screening and dosing of each subject in this study. 
6.2. Study Period
For procedures during study period, see Schedule of Activities section.  All subjects will be 
followed for a minimum of 16 weeks.
 
 
If a subject has any clinically significant, study related abnormalities at the conclusion of a 
scheduled inpatient portion of the study (or at the end of outpatient Day 29 for Part B), it is at 
the investigator’s discretion to ask the subject to remain in the clinical unit until it is safe for 
outpatient follow up.  The investigator must promptly notify the sponsor clinician or medical 
monitor.  If the subject is unable or unwilling to remain in the clinical unit, the investigator 
should make every effort to arrange follow up evaluations at appropriate intervals.
The study includes a Screening visit to assess eligibility and subsequent visits for a minimum 
of 16 weeks.  Subjects who meet the end of study criteria (See Section 3.5) will have one 
follow-up phone call visit which will represent the end of study visit (unless additional 
follow up is needed for safety reasons or) Subjects, who do not meet the criteria to leave the 
study at Week 16, will continue with clinic visits every four weeks until Week 52 and then 
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every 12 weeks until they meet these criteria Week 52 and then every 12 weeks until they 
meet these criteria.  
Subjects may be asked to return for additional follow up visits beyond the anticipated end of 
study visit for safety reasons as determined by the Investigator in consultation with the 
sponsor medical monitor.
6.3. Subject Withdrawal
Withdrawal of consent:
Subjects who request to discontinue receipt of study treatment will remain in the study and 
must continue to be followed for protocol specified follow-up procedures. The only 
exception to this is when a subject specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the subject to provide this information.
Subjects should notify the investigator in writing of the decision to withdraw consent from 
future follow-up, whenever possible. The withdrawal of consent should be explained in 
detail in the medical records by the investigator, as to whether the withdrawal is only from 
further receipt of investigational product or also from study procedures and/or posttreatment 
study follow-up, and entered on the appropriate CRF page. In the event that vital status 
(whether the subject is alive or dead) is being measured, publicly available information 
should be used to determine vital status only as appropriately directed in accordance with 
local law.
Lost to follow-up: 
All reasonable efforts must be made to locate subjects to determine and report their ongoing
status. This includes follow-up with persons authorized by the subject as noted above. Lost 
to follow-up is defined by the inability to reach the subject after a minimum of 2 documented 
phone calls, faxes, or e-mails as well as lack of response by the subject to 1 registered mail 
letter. All attempts should be documented in the subject’s medical records. If it is 
determined that the subject has died, the site will use locally permissible methods to obtain 
the date and cause of death. If the investigator’s use of a third-party representative to assist 
in the follow-up portion of the study has been included in the subject’s informed consent, 
then the investigator may use a sponsor-retained third-party representative to assist site staff 
with obtaining the subject’s contact information or other public vital status data necessary to 
complete the follow-up portion of the study. The site staff and representative will consult 
publicly available sources, such as public health registries and databases, in order to obtain 
updated contact information. If, after all attempts, the subject remains lost to follow-up, then 
the last-known-alive date as determined by the investigator should be reported and 
documented in the subject’s medical records.
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety (see also the 
Withdrawal From the Study Due to Adverse Events section) or behavioral reasons, or the 
inability of the subject to comply with the protocol-required schedule of study visits or 
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If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  The investigator or site staff should attempt to contact the subject twice.  After 
2 attempts, site staff may send a registered letter.  If no response is received from the subject, 
the subject will be considered lost to follow-up.  All attempts to contact the subject and 
information received during contact attempts must be documented in the subject’s medical 
record.  In any circumstance, every effort should be made to document subject outcome, if 
possible.  The investigator should inquire about the reason for withdrawal, request that the 
subject return for a final visit, if applicable, and follow up with the subject regarding any 
unresolved adverse events (AEs).
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
Subjects who withdraw from the study may be replaced at the discretion of the sponsor.  A 
replacement subject will receive the same treatment as the withdrawn subject.
The early termination visit only applies to subjects who are randomized, receive at least one 
dose of study drug and then are prematurely withdrawn from the study.  Subject should 
return to the clinic for final safety assessments to be scheduled as early as practically feasible 
following the decision to withdraw from the study.  At the early termination visit, every 
effort must be made to complete as many the following assessments:
•
Limited physical examination.
•
Sitting single blood pressure, temperature and pulse rate measurements.
•
Supine triplicate 12-lead ECG measurement.
•
Blood and urine specimens for safety laboratory (hematology, chemistry and 
urinalysis).
•
Urine pregnancy test for female of childbearing potential.
•
Collect blood samples for viral surveillance, 
 
, immunogenicity (ADA, neutralizing 
antibodies (NAb) and pharmacokinetic analysis.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside of the control of the investigator that may make it unfeasible to 
perform the test. In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the subject. When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
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he or she has taken to ensure that normal processes are adhered to as soon as possible. The 
study team will be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
7.1. Safety
7.1.1. Laboratory Tests
The following laboratory tests will be performed at times defined in the Schedule of 
Activities section of this protocol.  Safety labs include hematology, chemistry and urinalysis.
Additional laboratory results may be reported on these samples as a result of the method of 
analysis or the type of analyzer used by the clinical laboratory; or as derived from calculated 
values.  These additional tests would not require additional collection of blood.  Unscheduled 
clinical laboratory measurements may be obtained at any time during the study to assess any 
perceived safety concerns.
Table 3.
Laboratory Tests
Hematologya
Chemistrya
Urinalysisa
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
Blood urea nitrogen 
(BUN)
Creatinine
Glucose (non-fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST
ALT
Total bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
Creatine kinase
pH
Glucose (qual)
Protein (qual)l
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopyb
Creatininel
FSHc
β-hCGd
(TNF-α, IL6, IFN-γ)
IGRA TB test
HIV and hepatitis testingf
Viral surveillanceg  
Serum Igh
PK and Immunogenicityi
JCV
Additional Tests 
(Needed for Hy’s Law)
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AST, ALT (repeat)
Total bilirubin (repeat)
Albumin (repeat)
Alkaline phosphatase 
(repeat)
Direct bilirubin
Indirect bilirubin
Creatine kinase (repeat)
GGT
PT/INR
Total bile acids
Acetaminophen drug 
and/or protein adduct 
levels
a.
Safety labs include hematology, chemistry and urinalysis.  Fasting is not required.
b.
Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase.
c.
At Screening only, in females who are amenorrheic for at least 12 consecutive months.  If post-menopausal for 
≥5 years, it is at the investigator’s discretion whether to confirm post-menopausal status by FSH.
d.
Serum or urine β-hCG for female subjects of childbearing potential.
f.
At Screening only.  Includes HepBsAg, HepBcAb and HCVAb.  Only subjects who are positive for HCV Ab will 
be reflex-tested for hepatitis C virus ribonucleic acid (HCV RNA).
g.
Includes testing for CMV, EBV, HSV-1, HSV-2and VZV. 
h.
Includes testing for total Ig and Ig subtypes (IgA, IgG, IgE and IgM).
i.
See Section 7.2 and Section 7.3 for details.
j.
See Section 7.6 for details.
k.
See Section 7.1.14 for details.
l.
Urinary protein to urinary creatinine ratio will be calculated for all subjects at screening.
 
Any remaining serum/plasma from samples collected for clinical safety laboratory 
measurements at baseline and at all times after dose administration may be retained and 
stored for the duration of the study.  
 
 
 
 
 
7.1.2. Pregnancy Testing
For female subjects of childbearing potential, a serum or urine pregnancy test, with 
sensitivity of at least 25 mIU/mL, will be performed according to Schedule of Activities. 
A negative pregnancy test result is required before the subject may receive the study 
treatments.  Pregnancy tests will also be done whenever 1 menstrual cycle is missed during 
the active treatment period (or when potential pregnancy is otherwise suspected).  Pregnancy 
tests may also be repeated if requested by institutional review boards (IRBs)/ethics 
committees (ECs) or if required by local regulations. 
Urine pregnancy tests must be sensitive to at least 25 mIU/mL and will be conducted with the 
test kit provided by the central laboratory in accordance with instructions provided in its 
package insert.  Subjects who have missed a menstrual period or who show an indeterminate 
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or positive result on the urine test may not further progress in the study until pregnancy is 
ruled out using further diagnostic testing (eg, a negative quantitative serum pregnancy test 
conducted at a certified laboratory).
In the case of a positive confirmed pregnancy, the subject will be withdrawn from 
administration of investigational product but may remain in the study. 
7.1.3. Physical Examinations
Physical examinations may be conducted by a physician, trained physician's assistant, or 
nurse practitioner as acceptable according to local regulation.  A full physical examination 
will include head, ears, eyes, nose, mouth, neck, throat, skin, heart and lung examinations, 
lymph nodes, and gastrointestinal, musculoskeletal, and neurological systems.  The limited or 
abbreviated physical examination will be focused on general appearance, the respiratory and 
cardiovascular systems, and subject-reported symptoms.
For measuring weight, a scale with appropriate range and resolution is used and must be 
placed on a stable, flat surface. Subjects must remove shoes, bulky layers of clothing, and 
jackets so that only light clothing remains.  They must also remove the contents of their 
pockets and remain still during measurement of weight. 
Complete and brief physical examinations will be performed time points as described in 
Schedules of Activities.
7.1.4. Vital Signs
Sitting blood pressure (BP), pulse rate, and temperature will be measured after approximately 
5 minutes of rest at times specified in the Schedule of Activities.  It is preferred that the same 
measurement method be used consistently throughout the study.  Additional collection times 
or changes to collection times will be permitted, as necessary to ensure appropriate collection 
of safety data.  When the timing of these measurements coincides with a blood collection, it 
is preferred that vital signs be obtained prior to the nominal time of blood collection. 
Sitting blood pressure will be measured with the subject’s arm supported at the level of the 
heart, and recorded to the nearest mmHg.  It is preferred that the same arm (preferably the 
dominant arm) be used throughout the study. 
The same properly sized and calibrated Blood Pressure (BP) cuff, will be used to measure BP 
each time.  The use of automated devices for measuring BP and pulse rate is acceptable, 
although, when done manually, pulse rate will be measured in the brachial/radial artery for at 
least 30 seconds.  When the timing of these measurements coincides with a blood collection, 
BP and PR should be obtained prior to the nominal time of the blood collection.
It is preferred that body temperature be measured orally. A second acceptable method is 
temporal (forehead). Same method must be used consistently throughout the study for the 
same subject.  No eating, drinking, or smoking is allowed for 15 minutes prior to the 
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7.1.5. Medical History
Investigators should make all reasonable efforts to obtain an accurate and complete medical
history and history of prior medication use when evaluating whether a subject is eligible for
the study.  The following will be collected at Screening: complete medical history, SLE/RA
disease history (including disease duration, extent of disease, and prior treatments), 
cardiovascular disease history, venous thromboembolic event history, alcohol and tobacco 
use history.
If the status of a subject’s medical history is in doubt or information pertaining to a critical 
variable is conflicting, every reasonable step to secure proper documentation of correct 
medical status should be attempted.  Documentation of the medical and medication histories 
over the protocol defined time periods should be available for sponsor review during the 
source data verification process.  Questions about prior medications or eligibility should be 
directed to the sponsor Clinician or Medical Monitor.
7.1.6. Height and Weight
Height and weight will be measured without the subject wearing shoes.  Height and weight 
will be measured up to one decimal place and recorded in the source document at the 
baseline visit. 
Height will be measured only at Screening.  Weight will be assessed at times indicated in the 
Schedules of Activities.
7.1.7. Chest X-Ray
Subject must have a chest X-ray (posterior-anterior and lateral views) taken at Screening or 
within 3 months prior to the Screening visit and read by a qualified radiologist.  
Documentation of the official reading must be located and available in the source 
documentation. 
7.1.8. Electrocardiogram
12-lead ECGs should be collected at times specified in the Schedule of Activities.
All scheduled ECGs should be performed after the subject has rested quietly for at least 
10 minutes in a supine position and prior to any blood collection procedures. 
ECGs will be collected in triplicate in Part A on Days 1 and 2, in Part B on Days 1, 2 and 29.  
Single ECGs will be collected at all other times.  Triplicate 12-lead ECGs will be obtained 
approximately 2 to 4 minutes apart; the average of the triplicate ECG measurements 
collected pre-dose on Day 1 will serve as each subject’s baseline QTc value.
The Day 1 ECG values will serve as each subject’s baseline values.  To ensure safety of the 
subjects, a qualified individual (investigator or sub-investigator) at the investigator site will 
make comparisons to baseline measurements.  If the QTc interval is increased by 45 msec 
from the baseline, or an absolute QTc value is 500 msec for any scheduled ECG, then 
2 additional ECGs will be collected, approximately 2 to 4 minutes apart, to confirm the 


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original measurement.  If either of the QTc values from these repeated ECGs remains above 
the threshold value (ie, is 45 msec from the baseline, or is 500 msec), then a single ECG 
must be repeated at least hourly until QTc values from 2 successive ECGs fall below the 
threshold value that triggered the repeat measurement.
If QTc values remain 500 msec (or 45 msec from the baseline) for greater than 4 hours (or 
sooner, at the discretion of the investigator), or QTc intervals get progressively longer, the 
subject should be referred to a cardiologist for consultation. 
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality.  It is important that leads are placed in the 
same positions each time in order to achieve precise ECG recordings.  If a machine-read QTc 
value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTc values are in the 
acceptable range.
7.1.9. Hepatitis B and C Screening
At Screening, all subjects will be tested for hepatitis B surface antigen (HepBsAg), 
hepatitis B core antibody (HepBcAb) and hepatitis C virus antibody (HCV Ab).  Subjects 
who are HepBsAg or HepBcAb positive will not be enrolled in the study.  Subjects who are 
positive for HCV Ab will be reflex-tested for hepatitis C virus ribonucleic acid (HCV RNA) 
and if negative may be considered for enrollment into this study; subjects positive for HCV 
RNA will not be enrolled into this study.
7.1.10. Tuberculosis Screening and Monitoring
7.1.10.1. Interferon Gamma Release Assay Tuberculin Test
Subjects should be screened for tuberculosis (TB) using an Interferon gamma release assay 
(IGRA) per local guidelines.  IGRA will be tested during Screening.  QuantiFERON-TB 
Gold In-tube test (QFT-G) will be used.  Site personnel should follow the processing and 
analyses steps based on the assay chosen.  Ensure incubation steps are followed as 
appropriate.  Documentation of IGRA product used and the test result must be in the 
subject’s source documentation.
If the results of the IGRA are indeterminate, the test may be repeated once without sponsor 
approval.
Refer to lab manual for any additional processing information and shipping instructions.
7.1.10.2. Additional Measures for Tuberculosis (TB) Monitoring
Additional testing for TB will take place as specified in Schedule of Activities.  The 
following measures will be followed to ensure the continued safety of subjects and to further 
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
Subjects should be carefully monitored throughout the study for signs and symptoms 
of TB (during all clinic visits), such as chest pain, difficulty breathing, wheezing, 
fever, cough, excessive sweating (especially at night), lymphadenopathy, 
hepatosplenomegaly, new fatigue, anorexia or new unplanned weight loss.  Subjects 
with these symptoms should be carefully evaluated to determine if these symptoms 
are due to SLE/RA, TB, or other unrelated cause.  Referrals to infectious disease 
and/or pulmonology specialists should be considered on an individual basis.  The 
sponsor medical monitor should be immediately notified and may evaluate these 
cases in consultation with infectious disease and/or pulmonology specialists.

If a subject converts from a negative to positive TB test during the study, they are to 
be thoroughly evaluated.  The sponsor medical monitor should be notified as soon as 
possible.  Evaluations should include, and may not be limited, to a history, 
completion physical examination, repeat TB testing, and imaging, as appropriate.  
Referrals to an infectious disease and/or pulmonology specialists are to be considered 
on an individual basis.  Such subjects are not to receive additional investigational 
product until the details have been discussed with the sponsor.  Sponsor will evaluate 
these cases in consultation with infectious disease and/or pulmonology specialists. 

If it is confirmed that a subject has developed latent or active TB during the study 
based upon the above evaluations, the subject should not receive further doses of 
investigational product, and should be treated with standard antimycobacterial 
therapy.  Investigators should consider such an event as medically important and 
report the event as an SAE in accordance with the process described in Section 8. 

If the results of the IGRA test are indeterminate at any time in the study, the test 
should be repeated, and if a negative test result is obtained, the subject may remain in 
the study and continue treatment.  Subjects with a repeat indeterminate IGRA test 
result should be seen by an infectious disease and/or pulmonary specialist.  The 
sponsor medical monitor should be immediately notified and may evaluate these 
cases in consultation with infectious disease and/or pulmonology specialists.
7.1.11. Monitoring for Infections
Subjects will be monitored for development of any infection (viral, bacterial, and fungal) at 
each visit.  Infections will be classified as either treated or non-treated infections.  All treated 
infections occurring during the study require identification of the causative organism, if 
feasible, whether by culture, antigen assay, serology, etc. (as appropriate) and the results 
(eg, any identified organisms or absence of growth) recorded in the CRF.
Treated infections are infections that:

Require antimicrobial therapy by any route of administration or; 

Require any surgical intervention (eg, incision and drainage).


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A subject, who experiences an infection associated with SAE should not receive further 
dose(s) of investigational product.  Furthermore, a subject, who requires oral or parenteral 
antimicrobial therapy (with the exception of mild vulvovaginal/urogenital infections), should 
only be administered further dose(s) of investigational product after consultation with 
sponsor clinician or medical monitor. 
A serious infection should be reported as a SAE and should be listed as the reason for 
discontinuation in the CRF.  All serious infections occurring during the study should undergo 
appropriate laboratory investigations, including culture, and the results (eg, any identified 
organisms or absence of growth) should be recorded in the CRF.
7.1.12. Infusion Site Reactions 
Subjects will be continuously monitored for infusion site reactions from the start of drug 
administration until the end of infusion and then at time points indicated in the Schedule of 
Activities.  Infusion site reactions may be monitored beyond the time points indicated in the 
Schedule of Activities based on investigator’s assessment. 
Infusion reactions may include but are not limited to: rash, flushing, hypotension,
tachycardia, throat irritation or discomfort, difficulty swallowing, fever, chills.  Any signs or 
symptoms related to either an infusion or injection site reaction(s) should be treated 
according to the investigator’s standard of care and reported as adverse events.  See 
Appendix 7 for details regarding the grading of adverse events arising from infusion
reactions.  Infusion reactions will be categorized according to the following definitions:
1. Acute: From start of infusion to 2 hours after the infusion.  Infusion reaction AEs that 
occur during this time period be further classified as follows:
a.
Serious: Infusion reactions that meet the criteria of an SAE. 
b. Dose interrupted: Associated with temporary or permanent interruption and/or 
modification in dose.
c.
Infusion reaction AEs based on investigator’s judgment.
2. Immediate: 2 hours after the infusion to 24 hours after initiation of treatment.  
Infusion reaction AEs that occur during this time period can be further classified as 
follows:
a.
Serious: Infusion reactions that meet the criteria of an SAE. 
b. Infusion reaction AEs based on investigator’s judgment.
3. Late (delayed): 2 days to 14 days after initiation of treatment:
a.
Serious: Infusion reactions that meet the criteria of an SAE. 
b. Infusion reaction AEs based on investigator’s judgment.


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Information regarding infusion reactions will be collected on the Adverse Event Record.  If 
the infusion reaction requires a modification to the administration of test article, the
information must be recorded on the Test Article Record.  All infusion reactions that are 
considered SAEs should be reported as specified in Section 8.2.3.
7.1.13. Injection Site Reactions
Subjects will be monitored continuously for injection site reactions (ISR) for 30 minutes 
following study drug administration and then at time points indicated in the Schedule of 
Activities.  Injection site reactions may be monitored beyond the time points indicated in the 
Schedule of Activities based on investigator’s assessment. 
An ISR is a relatively common adverse event (AE) that develops following administration of 
subcutaneous/intramuscular injectable therapies. ISR may include but are not limited to: 
erythema, induration, ecchymosis, pain, and pruritus.  Any signs or symptoms related to 
injection site reaction(s) should be treated according to the investigator’s standard of care and 
reported as adverse events.  ISRs may be immediate or delayed.  The reaction to 
subcutaneous injections is varied and usually occurs immediately following an injection 
and/or up to 2 days later. Injection site reactions (which are generally delayed or prolonged) 
need to be clearly differentiated from symptoms associated with the technique of 
administering subcutaneous injections (eg, local trauma due to the injection).  An ISR may 
not be visible in 1 hour, therefore, the subject should be instructed to look for ISR symptoms 
(itching, redness, swelling, pain or skin ulceration) and report when the reaction occurred and 
describe it in detail.  ISR will be graded for intensity as described in Appendix 8.
For the purposes of data collection, only reactions that begin within the first 4 hours and are 
persistent following an injection and/or occur more than or equal to 4 hours following an 
injection will be collected and the appropriate CRF form will be completed.  The time period 
was selected as local reactions that are caused by mechanical injury generally abate within 
this time frame. 
The examiner will indicate for each injection site reaction(s) the presence or absence of 
pre-defined symptoms such as itching, redness, swelling, pain or ulceration. Bruising and/or 
bleeding at the injection site will be recorded as adverse events associated with the injection 
procedure, not as an ISR. Resolution of an ISR will mean that, in the judgment of the 
examiner, the defined features (itching, pain, redness, swelling, ulceration) have resolved.  
Secondary changes, eg, hyperpigmentation, may be recorded as an adverse event but will not 
influence the assessment of resolution of ISR.
7.1.14. JC Virus (JCV) Monitoring and Progressive Multifocal Leukoencephalopathy
(PML)
PML is an opportunistic infection of the brain caused by the JC virus (JCV) in 
immunosuppressed subjects, and has been observed in subjects receiving B-cell depleting 
agents, including rituximab, as well as with other immunosuppressive agents.  Investigators 
should consider a diagnosis of PML in subjects who present with new-onset neurological 
manifestations, such as gait disturbances, memory loss, cognitive disorders, or visual 


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symptoms, and a neurology consult, brain MRI and lumbar puncture should be considered.  
There is no currently accepted screening test for PML.  The disease course of PML is usually 
progressive and fatal.  To monitor for the potential of PML, samples for JCV testing will be 
collected according to Schedule of Activities.
Reductions or discontinuation of concomitant immunosuppressive therapy and appropriate 
treatment including antiviral therapy should be considered.  There are no known 
interventions that can reliably prevent PML or adequately treat PML if it occurs.  The 
majority of patients who develop PML have a fatal outcome.
Any suspected case of PML should be reported as an SAE.  If a confirmed or probable case 
of PML is observed in this or other ongoing PF-06835375 studies, the sponsor will hold 
dosing for all subjects until the benefit risk assessment of PF-06835375 is re-evaluated by the 
sponsor.
7.1.15. Viral Surveillance
Blood samples for possible analysis of cytomegalovirus (CMV), Epstein-Barr virus (EBV), 
herpes simplex virus type 1 & 2 (HSV-1, HSV-2) and varicella-zoster virus (VZV) will be 
collected according to the times outlined in the Schedule of Activities.  Details regarding the 
collection, processing, storage and shipping of the blood samples will be provided in the lab 
manual.
Note: Due to delayed reporting times for these assays, the results might not be available 
along with the other study tests. 
In addition to time points specified, a blood sample for viral surveillance sample may also be 
taken at the time of an AE, as clinically appropriate. 
7.1.16. Suspected Herpetiform Rash 
For any occurrence of a suspected herpetiform rash (eg, herpes simplex and herpes zoster), 
specimens for viral DNA analysis will be obtained: A swab of the affected area will be 
collected for confirmation; a blood sample for viral surveillance will be collected for the 
analysis of viral load.  Details for these collections will be provided in the laboratory manual.
7.1.17. Assessment of Suicidal Ideation and Behavior
The Columbia Suicide Severity Rating Scale (C-SSRS) is an interview based rating scale to 
systematically assess suicidal ideation and suicidal behavior.19  Versions are available for 
“Lifetime” and “Since Last Visit”.  The “Lifetime” evaluation is done at screening, and 
“Since Last Visit” is done at all other time points.
The C-SSRS should be collected at times specified in the Schedule of Activities section of 
this protocol by an appropriately trained clinical site staff member.  The C-SSRS can also be 
administered at any time in the study at the discretion of the investigator based on any 
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At each suicidality assessment as per Schedule of Activities, subjects felt to have significant 
suicidal ideation with actual plan and intent or suicidal behavior, must be evaluated by a 
clinician/mental health professional (MHP) skilled in the evaluation of suicidality in the 
subjects by virtue of training or experience (eg, psychiatrist, licensed clinical psychologist) 
who will determine if it is safe for the subject to participate/continue in the trial.  Specific 
criteria that indicate a need for such an assessment are:

Suicidal ideation associated with actual intent and/or plan in the past year; (a “YES” 
answer to C-SSRS questions 4 “some intent to act without specific plan” or 
5 “specific plan and intent”).

Previous history of suicide behaviors in the past 10 years (a “YES” answer to any of 
the suicidal behavior items of the C-SSRS with the behavior occurring in the past 
10 years).

The presence of any current major psychiatric disorder that is not explicitly permitted 
in the inclusion/exclusion criteria and in the investigator’s judgment would interfere 
with study participation.

Any lifetime history of serious or recurrent suicidal behavior.  [Non-suicidal 
self-injurious behavior is not a trigger for a risk assessment unless in the 
investigator’s judgment it is indicated].

In the investigators judgment a risk assessment or exclusion is warranted.
A written copy of the risk assessment should be included in the subject's source 
documentation.
Other possible suicidality adverse events or other clinical observations may, based on the 
judgment of the investigator, also trigger a risk assessment and require a narrative.
Suicidality adverse events or other clinical observations may, based on the judgment of the 
investigator and clinician/MHP, also trigger a risk assessment and a narrative using 
information from the C-SSRS, and available information, prior to screening and baseline 
information, and the clinician/MHP assessment.  When there is a positive response to any 
question on the C-SSRS, the investigator should determine whether an adverse event has 
occurred.
7.2. Pharmacokinetics
7.2.1. Serum for Analysis of PF-06835375
During all study periods, blood samples for PK analysis will be collected at times specified in 
the Schedule of Activities.  A serum separator tube should not be used. 
The actual times may change but the number of samples will remain the same.  All efforts 
will be made to obtain the PK samples at the exact nominal time relative to dosing.  
However, samples obtained within 10% of the nominal time (eg, within 6 minutes of a 


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60 minute sample) from dosing will not be captured as a protocol deviation, as long as the 
exact time of the sample collection is noted on the source document and data collection tool 
(CRF).
•
Samples will be analyzed using a validated analytical method in compliance with 
Pfizer standard operating procedures.  Placebo PK samples will not be analyzed.
•
Details regarding the collection, processing, storage and shipping of the blood 
samples will be provided in the lab manual.
•
The PK samples must be processed and shipped as indicated to maintain sample 
integrity. Any deviations from the PK processing steps, including any actions taken, 
must be documented and reported to the sponsor. On a case-by-case basis, the 
sponsor may make a determination as to whether sample integrity has been 
compromised.  Any sample deemed outside of established stability, or of questionable 
integrity, will be considered a protocol deviation.
 
 
 
 
7.2.2. Shipment of Pharmacokinetic Samples
The shipment address and assay lab contact information will be provided to the investigator 
site prior to initiation of the study.
7.3. Immunogenicity
7.3.1. Serum for Analysis of Anti-PF-06835375 Antibodies and Neutralizing 
Anti-PF-06835375 Antibodies
Blood samples for the detection of Anti-PF-06835375 Antibodies (ADA) and Neutralizing 
Anti-PF-06835375 Antibodies (NAb) will be collected at the times specified in the Schedule 
of Activities.
Details regarding the collection, processing, storage and shipping of the blood samples will 
be provided in the lab manual.
7.3.2. Immunogenicity Analyses
The immunogenicity samples must be processed and shipped as indicated to maintain sample 
integrity. Any deviations from the immunogenicity processing steps, including any actions 
taken, must be documented and reported to the sponsor. On a case-by-case basis, the sponsor 
may make a determination as to whether sample integrity has been compromised. Any 
sample deemed outside of established stability, or of questionable integrity, will be 
considered a protocol deviation.
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Samples will be analyzed using validated analytical methods in compliance with sponsor 
standard operating procedures. Samples tested as ADA positive, (not just confirmed 
positive, but also with a titer positive result) will be further tested for NAb using validated
NAb assays. 
Samples collected for detecting ADA and NAb will be retained in accordance to local 
regulations and if not used within this timeframe, will be destroyed.  
 
 
7.3.3. Shipment of Immunogenicity (ADA/NAb) Samples
The shipment address and assay lab contact information will be provided to the investigator 
site prior to initiation of the study.
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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DNA; however, the biospecimen may also be used to study other molecules (eg, RNA, 
proteins, and metabolites).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
7.5. Rater Qualifications 
For specific rating assessments, only qualified raters will be allowed to evaluate and/or rate 
subjects in this study.  The minimum qualifications a rater must meet for each study rating 
assessment will be outlined in the Rater Assessment Manual provided to each participating 
site.  The level of experience with the target population (or equivalent), specific scale 
experience (or equivalent), and certification required (if applicable) will be listed and used to 
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determine whether a rater is approved for a given assessment.  Proposed raters who do not 
meet specific criteria but who may be qualified based on unique circumstances may be 
individually reviewed by the study clinical team to determine whether or not a waiver may be 
issued. The rater must become certified to perform selected study assessments before he or 
she can participate in the conduct of the study.  For specifically defined assessments, rater 
training and standardization exercises may be conducted, and written and signed 
documentation will be provided by the site for each rater’s certification.  In return, each site 
will be provided written and signed documentation outlining each rater’s certification for 
specific study assessments.  Recertification may be required at periodic intervals during the 
study.  The raters who administer specific study assessments will be documented in a 
centralized location and all site staff who administer ratings will be verified in the site study 
documentation during the conduct of the study.
7.6. Pharmacodynamics
Blood samples for pharmacodynamics (PD) will be collected according to the Schedule of
Activities.  Details regarding the collection, processing, storage and shipping of the blood
samples will be provided in the lab manual.
The PD samples must be processed and shipped as indicated to maintain sample integrity.  
Any deviations from the PD processing steps, including any actions taken, must be 
documented and reported to the sponsor.  On a case-by-case basis, the sponsor may make a 
determination as to whether sample integrity has been compromised.  Any sample deemed 
outside of established stability or of questionable integrity will be considered a protocol 
deviation. 
 
 
7.6.1. Samples Collected for All Subjects (both RA and SLE)
The following samples will be collected for all subjects
 
 
 
 
 
 
 
 
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7.6.1.5. Erythrocyte Sedimentation Rate (ESR)
Blood samples for analysis of ESR will be collected at the visits specified in the Schedule of 
Activities. The ESR will be done locally.
7.6.1.6. B-cell Activating Factor (BAFF)
Blood samples for the analysis of B-cell activating factor (BAFF) will be collected according 
to times outlined in the Schedule of Activities.  BAFF is also known as B Lymphocyte
Stimulator (BLyS).
 
 
 
 
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7.6.3. Samples Collected for Subjects with SLE 
The following samples will be collected for subjects with SLE. In case a subject has 
diagnoses of both RA and SLE, both RA and SLE samples will be collected.
7.6.3.1. Anti-nuclear Antibodies
Blood samples will be collected for Anti-nuclear Antibodies (ANA), according to the times 
outlined in the Schedule of Activities.
 
 
 
 
 
 
 
7.7. Blood Volume
The total blood sampling volume for individual subjects in this study is as follows.
In Part A, during the first 16 weeks, the total blood volume will be approximately 820 mL.  If 
subjects remain in the study in Part A beyond Week 16, the total blood volume every 
12 weeks will be approximately 250 ml.
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In Part B, during the first 16 weeks, the total blood volume will be approximately 900 mL. If 
subjects remain in the study in Part B beyond Week 16, the total blood volume every 
12 weeks will be approximately 250 ml.
Additional blood samples may be taken for safety assessments or to repeat screening 
assessments (if appropriate) as described in the Schedule of Activities, provided the total 
volume taken during the study does not exceed 550 mL during any period of 30 consecutive 
days.
7.8. Diagnostic and Efficacy Assessments
7.8.1. American College of Rheumatology/European League Against Rheumatism 
Classification for RA
Eligibility for the study for subjects with RA will be evaluated according to the 2010 
American College of Rheumatology (ACR)/European League Against Rheumatism 
(EULAR) Classification Criteria for Rheumatoid Arthritis (See Appendix 6).21 Subjects are 
required to have a score of 6 or greater at Screening, with symptom duration at least 
6 months prior to Screening visit.
7.8.2. American College of Rheumatology/SLICC Criteria for the Classification of SLE
Eligibility for the study for subjects with SLE will be evaluated according to the American 
College of Rheumatology (ACR) / SLICC Criteria for the Classification of SLE (See
Appendix 5).22  These criteria require that subjects satisfy 4 of the clinical and immunologic
criteria used in the SLICC classification criteria, including at least 1 clinical criterion and
1 immunologic criterion, OR that subject has biopsy-proven nephritis compatible with SLE 
in the presence of ANAs or anti-dsDNA antibodies.
In addition, subjects are also required to have symptoms at least 6 months prior to Screening 
visit.
 
 
  
 
 
 
 
 
 
 
 
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7.8.4.2. Patient’s Global Assessment (PtGA) of Arthritis
This will be collected only for RA subjects.  Subject will answer the following question, 
“Considering all the ways your arthritis affects you, how are you feeling today?”  The 
subject’s response will be recorded using a 100 mm visual analog scale (VAS) (See
Appendix 10).  This assessment must be performed early in the clinic visit and before the
subject has extensive contact with site personnel and/or investigator and prior to dosing.
8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; 
(2) non-serious adverse events (AEs); and (3) exposure to the investigational product under 
study during pregnancy or breastfeeding, and occupational exposure. 
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the 
investigational product 
under study during 
pregnancy or 
breastfeeding, and 
occupational exposure
All (regardless of whether 
associated with an AE), 
except occupational 
exposure
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure 
(regardless of whether 
associated with an AE)
All observed or volunteered events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
paragraphs.
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the investigator are to be reported 
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information.  This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the investigator does not become 
immediately aware of the occurrence of an event, the investigator must report the event 
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within 24 hours after learning of it and document the time of his/her first awareness of the 
event.
For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below).  In addition, the investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
This information is more detailed than that recorded on the CRF.  In general, this will include 
a description of the event in sufficient detail to allow for a complete medical assessment of 
the case and independent determination of possible causality.  Any information relevant to 
the event, such as concomitant medications and illnesses, must be provided.  In the case of a 
subject death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety.  Any pertinent additional information must be reported on the CT SAE 
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request.
As part of ongoing safety reviews conducted by the sponsor, any non-serious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.1.1. Additional Details On Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information.
8.1.2. Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study subject.  In addition, each study subject will be questioned about the 
occurrence of AEs in a non-leading manner.
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the Subject 
Withdrawal section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes,
according to the definition of AE noted below, and recorded on the CRF. 
When a subject withdraws from the study because of an SAE, the SAE must be recorded on
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
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8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each subject begins from the time the subject provides informed consent, which 
is obtained before the subject’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product), through and including and 
including a minimum of 90 calendar days after the last administration of the investigational 
product.  For subjects who are in the study beyond 90 calendar days after the last 
administration of the investigational product (expected for most subjects), the end of study 
visit will be used as a minimum cut-off.
For subjects who are screen failures, the active collection period ends when screen failure 
status is determined.
8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a subject during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a subject after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.
Follow up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
8.1.5. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship on the CRF, and report such 
an assessment in accordance with the SAE reporting requirements, if applicable.  An 
investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE; generally the facts 
(evidence) or arguments to suggest a causal relationship should be provided.  If the 
investigator does not know whether or not the investigational product caused the event, then 
the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the sponsor.  If the investigator's causality assessment is “unknown but not 
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In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study subject administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage.  Examples of AEs include, but are not limited to: 

Abnormal test findings;

Clinically significant signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease;

Drug abuse;

Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

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
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
Occupational exposure.
8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
recording as an AE.
8.2.3. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Or that is considered to be:

An important medical event.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the 
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Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.2.4. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility, or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is assessed for medical importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical 
AE is not in itself an SAE.  Examples include:

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of a persistent pretreatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
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
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
Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as SAEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE.  For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE.
8.3. Severity Assessment
If required on the AE page of the CRF, the investigator will use the adjectives MILD, 
MODERATE, or SEVERE to describe the maximum intensity of the AE.  For purposes of 
consistency, these intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.4. Special Situations
8.4.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported to Pfizer 
Safety by the investigator as described in previous sections, and will be handled as SAEs in 
the safety database. 
8.4.2. Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some subjects, transaminase elevations are a harbinger of a more 
serious potential outcome.  These subjects fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Subjects who experience a transaminase elevation above 3 times the upper limit of 
normal (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
or are “susceptible.”
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 × ULN) by several 
days or weeks.  The increase in TBili typically occurs while AST/ALT is/are still elevated 
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In rare instances, by the time TBili elevations are detected, AST/ALT values might have 
decreased.  This occurrence is still regarded as a potential DILI.  Therefore, abnormal 
elevations in either AST OR ALT in addition to TBili that meet the criteria outlined below 
are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 
considered important medical events, even before all other possible causes of liver injury 
have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the subject’s 
individual baseline values and underlying conditions.  Subjects who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:

Subjects with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available;

For subjects with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches >3 × ULN 
(whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
The subject should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT and TBili, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels.  
Consideration should also be given to drawing a separate tube of clotted blood and an 
anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a coformulated product in prescription or over-the-counter medications), 


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recreational drug, supplement (herbal) use and consumption, family history, sexual history, 
travel history, history of contact with a jaundiced person, surgery, blood transfusion, history 
of liver or allergic disease, and potential occupational exposure to chemicals, should be 
collected.  Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging 
(eg, biliary tract) may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found.  Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
8.4.3. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.4.3.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;
An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a subject or subject’s partner becomes or is found to be pregnant during the subject’s 
treatment with the investigational product, the investigator must report this information to 
Pfizer Safety on the CT SAE Report Form and an EDP supplemental form, regardless of 
whether an SAE has occurred.  In addition, the investigator must submit information 
regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a subject 
reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or 
spillage) to Pfizer Safety using the EDP supplemental form.  This must be done irrespective 
of whether an AE has occurred and within 24 hours of awareness of the exposure.  The 


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information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
pre-procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.
Additional information regarding the EDP may be requested by the sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the subject with the Pregnant Partner Release of Information Form 
to deliver to his partner.  The investigator must document in the source documents that the 
subject was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.4.3.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.


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8.4.3.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated
SAE.  Since the information does not pertain to a subject enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.4.4. Medication Errors
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with an 
SAE
8.4.4.1. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong subject, or at the wrong time, or at the wrong dosage strength. 
Medication errors include:

Medication errors involving subject exposure to the investigational product.

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.

The administration of an incorrect dosage.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
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Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the sponsor.  The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment.
The final analysis will be conducted when all subjects have completed all study visits.  In 
addition, unblinded data will be analyzed when all subjects have completed the Week 16 
Visit or discontinued.  This analysis may take place prior to the enrollment of the optional 
cohort. 
9.1. Sample Size Determination
The sample size was primarily based on the clinical consideration to provide sufficient safety 
and tolerability data.  In addition, the need to obtain PK/PD data and minimize number of 
RA/SLE subjects exposed to PF-06835375 was taken into consideration.  The sample size is 
not based on any statistical considerations.  No formal inferential statistics will be applied to 
the safety or PK data.
 
9.3. Pharmacokinetic Analysis
9.3.1. Analysis Population
The PK concentration population is defined as enrolled subjects who received at least one 
dose of PF-06835375 and have at least 1 concentration.  The PK parameter analysis 
population is defined as all enrolled subjects who received at least one dose of PF-06835375 
and that have at least 1 of the PK parameters of interest.  Samples from subjects who 
received the placebo will not be analyzed routinely.  Subjects who withdraw from the study 
may be replaced at the discretion of the sponsor.  A replacement subject will receive the 
same treatment as the withdrawn subject.
9.3.2. Derivation of Pharmacokinetic Parameters
PK parameters for PF-06835375 following single and multiple dose administration will be 
derived from the concentration-time profiles by non-compartmental analysis as described in
Table 5 and Table 6.  Additional PK analyses may be performed if deemed appropriate.  The 
PK parameters will be calculated using actual time and summarized descriptively by dose 
and regimen in accordance with Pfizer data standards.  Details of the analysis will be 
provided in the SAP.
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Table 5.
PF-06835375 Serum Pharmacokinetic Parameters for Single Ascending 
Dose (SAD) Phase
Parameter
Definition
Method of Determination
Cmax
Maximum serum concentration
Observed directly from data
Tmax
Time at which Cmax occurred
Observed directly from data as time of first 
occurrence
 
 
AUClast
Area under the concentration-time 
profile from time 0 to the time of the last 
quantifiable concentration (Clast)
Linear/log trapezoidal method
AUCinf
a
Area under the concentration-time 
profile from time 0 extrapolated to 
infinite time
AUClast + (Clast*/kel), where Clast* was the 
predicted serum concentration at the last 
quantifiable time point estimated from the 
log-linear regression analysis
 
 
 
 
AUClast (dn)
Dose normalized AUClast
AUClast/dose
AUCinf (dn)a
Dose normalized AUCinf
AUCinf/dose
a.
If data permitted. 
Abbreviations: 
; dn = Dose normalized to 1 mg; DOF = Duration of the IV infusion dose;
IV = Intravenous. 
PK parameters following multiple dose administration will be derived from the concentration 
time profiles of the repeat dose cohorts as follows:
CCI
C
C
I
CC
I
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Table 6.
PF-06835375 Serum Pharmacokinetic Parameters for Multiple Ascending 
Dose (MAD) Phase
Parameter
Definition
Method of Determination
AUCtau
Area under the concentration-time profile 
from time 0 to time tau, the dosing 
interval, where tau= 28 days 
Linear/log trapezoidal method
AUClast
Area under the concentration-time profile 
from time 0 to Tlast
Linear/log trapezoidal method
 
 
 
Cmax
Maximum serum concentration during the 
dosing interval
Observed directly from data
Tmax
Time at which Cmax occurred
Observed directly from data as time of first 
occurrence
t½
a
Terminal half-life
Loge(2)/kel, where kel was the terminal phase 
rate constant calculated by a linear regression 
of the log-linear concentration-time curve
AUClast (dn)
Dose normalized AUClast
AUClast/dose
 
 
 
Cmin
Lowest concentration observed during the 
dosing interval
Observed directly from data
Rac
Observed accumulation ratio
MD AUCτ/Day 1 AUCτ
Rac, Cmax
Observed accumulation ratio for Cmax
MD Cmax/Day 1 Cmax
PTF
Peak-to-trough fluctuation at steady state
(Cmax - Cmin)/Cav
a.
If data permitted. 
Abbreviations: dn = dose normalized to 1 mg, DOF = duration of the IV infusion dose, IV = intravenous, 
MAD = multiple ascending dose, SC = subcutaneous.
9.4. Pharmacodynamic Analysis 
The pharmacodynamic (PD) analysis population is defined as all randomized subjects treated 
who have at least one PD assessment in at least one cohort.  PD assessments will include, but 
not limited to,
 soluble protein analytes, whole-blood RNA 
(inflammation and disease-related) and responses to vaccines.  The data will be summarized 
and plotted by treatment group and sampling time. Further details will be documented in the 
SAP.
C
C
I
CCI
C
C
I
C
CI
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9.6. Safety Analysis
Adverse events, ECGs, blood pressure, pulse rate, oral temperature, continuous cardiac 
monitoring, and safety laboratory data will be reviewed and summarized on an ongoing basis 
during the study to evaluate the safety of subjects.  Any clinical laboratory, ECG, vital sign 
abnormalities of potential clinical concern will be described.  Safety data will be presented in 
tabular and/or graphical format and summarized descriptively, where appropriate.
Immunogenicity (ADA, NAb) results will be listed and summarized by cohorts and time 
points.  Subject level immune response will also be summarized by cohorts.  Effect of 
positive ADA and neutralizing immune response on safety, PD and PK may be assessed, if 
appropriate.
Incidence of viral infections or change in baseline of viral loads (CMV, VZV, EBV,and 
HSV-1/2) if they occur, will be summarized by treatment group.
Medical history and physical examination and neurologic examination information, as 
applicable, collected during the course of the study will be considered source data and will 
not be required to be reported, unless otherwise noted.  However, any untoward findings 
identified on physical and/or neurologic examinations conducted during the active collection 
period will be captured as an adverse event, if those findings meet the definition of an 
adverse event. Data collected at Screening that are used for inclusion/exclusion criteria, such 
as laboratory data, ECGs and vital signs will be considered source data, and will not be 
required to be reported, unless otherwise noted.  Demographic data collected at Screening 
will be reported.
9.6.1. Electrocardiogram (ECG) Analysis
Changes from baseline for the ECG parameters QT interval, heart rate, QTc interval, PR 
interval and QRS interval will be summarized by treatment and time.
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The number (%) of subjects with maximum post dose QTc values and maximum increases 
from baseline in the following categories will be tabulated by treatment: 
Table 7.
Safety QTc
Borderline (msec)
Prolonged (msec)
Absolute Value
450 - <480
480
Absolute Change
30-<60
60
In addition, the number of subjects with corrected and uncorrected QT values 500 msec will 
be summarized.
If more than one ECG is collected at a nominal time after dose administration (for example, 
triplicate ECGs), the mean of the replicate measurements will be used to represent a single 
observation at that time point.  If any of the three individual ECG tracings has a QTc value 
500 msec, but the mean of the triplicates is not 500 msec, the data from the subject’s 
individual tracing will be described in a safety section of the CSR in order to place the 
500 msec value in appropriate clinical context.  However, values from individual tracings 
within triplicate measurements that are 500 msec will not be included in the categorical 
analysis unless the average from the triplicate measurements is also 500 msec.  Changes 
from baseline will be defined as the change between postdose QTc value and the average of 
the pre-dose triplicate values on Day 1.  The average of the pre-dose triplicate QTc values on 
Day 1 will serve as each subject’s baseline QTc value. Standard algorithms and reporting 
formats will be applied.
In addition, an attempt may be made to explore and characterize the relationship between 
serum concentration and appropriately corrected QT interval length.  The results from this 
analysis will be reported separately from CSR.
9.7. Interim Analysis
No formal interim analysis will be conducted for this study.  However, as this is a 
sponsor-open study, the sponsor may conduct unblinded reviews of the data during the 
course of the study for the purpose of safety assessment, facilitating dose-escalation 
decisions, facilitating PK/PD modeling, and/or to support clinical development. 
9.8. Data Monitoring Committee 
This study will not use a data monitoring committee.  Ongoing safety reviews in support of 
dose escalation and during the study will be conducted by blinded and unblinded personnel
as described in Section 3.4.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 


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regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the investigator site may be subject to 
review by the IRB/EC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study. Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection.  The investigator site and 
investigator will promptly resolve any discrepancies that are identified between the study 
data and the subject's medical records.  The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent.  Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true. Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the hospital or the physician subject chart.  In these 
cases, data collected on the CRFs must match the data in those charts. 


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In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document.
11.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating subjects 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent documents, copies of all CRFs, safety reporting forms, source documents, 
and detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to the ICH guidelines, according to local 
regulations, or as specified in the clinical study agreement (CSA), whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, legal and regulatory 
requirements, and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
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12.3. Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data in any reports, publications, or other disclosures, except where
required by law.
When study data are compiled for transfer to Pfizer and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by numerical codes based on a 
numbering system provided by Pfizer in order to de-identify study subjects. The investigator
site will maintain a confidential list of subjects who participated in the study, linking each 
subject’s numerical code to his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of subjects’ personal data consistent 
with applicable privacy laws.
The informed consent documents and any subject recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.
The informed consent documents used during the informed consent process and any subject 
recruitment materials must be reviewed and approved by Pfizer, approved by the IRB/EC
before use, and available for inspection.
The investigator must ensure that each study subject, is fully informed about the nature and 
objectives of the study and possible risks associated with participation. 
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject before any study-specific activity is performed. The investigator 
will retain the original of each subject's signed consent document.
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State 
End of trial in a Member State of the European Union is defined as the time at which it is 
deemed that a sufficient number of subjects have been recruited and completed the study as 
stated in the regulatory application (ie, clinical trial application [CTA]) and ethics application 
in the Member State.  Poor recruitment (recruiting less than the anticipated number in the 


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CTA) by a Member State is not a reason for premature termination but is considered a 
normal conclusion to the study in that Member State.
13.2. End of Trial in All Other Participating Countries 
End of trial in all other participating countries is defined as last subject last visit (LSLV), 
which may be determined by the point at which the dose-escalation and study stopping rules
(Section 3.4) have been met.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer. In addition, Pfizer retains the right to discontinue development of 
PF-06835375 at any time.
If a study is prematurely terminated, Pfizer will promptly notify the investigator.  After 
notification, the investigator must contact all participating subjects and the hospital pharmacy 
(if applicable) within a time period set by Pfizer.  As directed by Pfizer, all study materials 
must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date (PCD) 
for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final subject was examined or received an intervention for 
the purposes of final collection of data for the primary outcome, whether the clinical study 
concluded according to the prespecified protocol or was terminated.


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EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by the 
principal investigator (PI) of the results of the study based on information collected or 
generated by the PI, whether or not the results are favorable to the Pfizer product.  However, 
to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before it is submitted 
for publication or otherwise disclosed. If any patent action is required to protect intellectual 
property rights, the investigator agrees to delay the disclosure for a period not to exceed an 
additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all investigator sites, and that any subsequent publications 
by the PI will reference that primary publication. However, if a joint manuscript has not 
been submitted for publication within 12 months of completion or termination of the study at 
all participating sites, the investigator is free to publish separately, subject to the other 
requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.


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Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.


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Manzo A, Bombardieri M, Humby F, et al. Secondary and ectopic lymphoid tissue 
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Dirks, N.L. & Meibohm, B. Population pharmacokinetics of therapeutic monoclonal 
antibodies. Clinical Pharmacokinetics 2010; 49(10): 633-59.
14.
Danussi-Joannopoulos K, Tchistiakova L, Olland S. Kinetics of B cell depletion and 
reconstitution in peripheral blood and lymphoid tissues after single dose of SBI-087, a 
humanized anti-CD20 SMIP, in cynomolgus monkeys. Ann Rheum Dis. 2008; 61:190.


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15.
Cohen S, Clowse M, Pardo M, et al. Safety, tolerability, pharmacokinetic and 
pharmacodynamics properties of SBI-087, a CD20-directed B-cell depleting agent: 
Phase 1 dose escalating studies in patients with either mild rheumatoid arthritis or 
systemic lupus. Clinical Therapeutics 2016; 38(6):1417-34. 
16.
Bingham CO, Looney RJ et al. Immunization responses in rheumatoid arthritis patients 
treated with rituximab: results from a controlled clinical trial. Arthritis Rheum. 2010 
Jan; 62(1):64-74.
17.
Wang X, et al. Prevalence and genetic diversity of candidate vaccine antigens among 
invasive Neisseria meningitidis isolates in the U.S. Vaccine 2011; 29:4739-4744.
18.
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=bcaf5f75-caaf-41fd-875b-
5800310070d1.
19.
Rubbert-Roth A, Tak Paul P, Zerbini C, Tremblay JC, Carreño L., Armstrong G, 
Collinson N, Shaw TM on behalf of the MIRROR Trial Investigators. Efficacy and 
safety of various repeat treatment dosing regimens of rituximab in patients with active 
rheumatoid arthritis: results of a Phase III randomized study (MIRROR). Rheumatology 
2010, Sept; 49(9): 1683–1693.
20.
Posner K, Oquendo MA, Gould M, et al.  Columbia-classification algorithm of suicide 
assessment (C-CASA): classification of suicidal events in the FDA’s pediatric suicidal 
risk analysis of antidepressants. Am J Psychiatry 2007; 164(7):1035-43.
21.
Aletaha et al. The 2010 American College of Rheumatology/European League against 
Rheumatism classification criteria for rheumatoid arthritis: Phase 2 methodological 
report. Arthirits & Rheumatism 2010; 62(9):2569-2581.
22.
Petri et al. Derivation and validation of the Systemic Lupus International Collaborating 
Clinics classification criteria for systemic lupus erythematosus. Arthritis & Rheumatism 
2012; 64 (8): 2677-2686.
 
 
25.
Lacy CF, Armstrong LL, Goldman MP, et al.  Drug Information Handbook, Ninth 
Edition.  Cleveland, OH: LexiComp Inc; 2001 2002:1354.
CCI
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Appendix 1. Abbreviations 
The following is a list of abbreviations used in the protocol.
Abbreviation
Term
Abs
Absolute
AE
Adverse event
ACPA
Anti- Citrullinated Peptide Antibody
ACR
American College of Rheumatology
ADA
Anti-drug antibody
ADCC
Antibody-dependent cellular cytotoxicity
ALT
Alanine aminotransferase
ANA
Anti-nuclear antibodies
ANC
Absolute neutrophil count
ANCA
Anti-neutrophil cytoplasmic antibody
Anti-dsDNA
Anti-double-stranded deoxyribonucleic acid
APS
Antiphospholipid antibody syndrome
AST
Aspartate aminotransferase
AUC
Area under the curve
BA
Bioavailability
BE
Bioequivalence
β-hCG
Beta-human chorionic gonadotropin
BLyS
B Lymphocyte Stimulator
BMI
Body mass index
BP
Blood pressure
Bpm
Beats per minute
BUN
Blood urea nitrogen
Cav
Average observed concentration
CDC
Centers for Disease Control and Prevention
CK
Creatine kinase
CL
Clearance
CLIA
Clinical Laboratory Improvement Amendments
Cmax
Maximum observed concentration
CMV
Cytomegalovirus
CNS
Central nervous system
CO2
Carbon dioxide (bicarbonate)
CRF
Case report form
CRP
C-reactive protein
CRU
Clinical research unit
CSA
Clinical study agreement
csDMARDs
Conventional synthetic Disease-modifying antirheumatic drugs
CSF
Cerebrospinal fluid
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Abbreviation
Term
CSR
Clinical study report
C-SSRS
The Columbia Suicide Severity Rating Scale
CT
Clinical Trial
CTA
Clinical trial application
CTCAE
Common Terminology Criteria for Adverse Events
cTfh
Circulating follicular T helper-like 
CXCL13
C-X-C Motif Chemokine Ligand 13
CXCR5
C-X-C chemokine receptor type 5
DILI
Drug-induced liver injury
DMARDs
Disease-modifying antirheumatic drugs
DMC
Data monitoring committee
DNA
Deoxyribonucleic acid
DU
Dispensable unit
EBV
Epstein Barr virus
EC
Ethics committee
ECG
Electrocardiogram
E-DMC
External data monitoring committee 
EDP
Exposure during pregnancy
EDR
Extemporaneous dispensing record
EDTA
Edetic acid (ethylenediaminetetraacetic acid)
eGFR
Estimated Glomerular Filtration Rate
ePPND
Enhanced pre- and postnatal development study
ESR
Erythrocyte sedimentation rate
EU
European Union
EULAR
European League Against Rheumatism
EudraCT
European Clinical Trials Database
fHBP
Factor H binding protein
FIH
First in human
FSH
Follicle-stimulating hormone
GC
Germinal center
GCP
Good Clinical Practice
GCS
Global Clinical Supply
GGT
Gamma-glutamyl transferase
GLP
Good Laboratory Practice
hCG
Human chorionic gonadotropin
HepBcAb
Hepatitis B core antibody
HepBsAg 
Hepatitis B surface antigen
HCV
Hepatitis C virus
HCVAb
Hepatitis C antibody
HED
Human equivalent dose
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Abbreviation
Term
HIV
Human immunodeficiency virus
HSV
herpes simplex virus
ICH
International Conference on Harmonisation
ID
Identification
Ig
Immunoglobulin
IgG
Immunoglobulin G
IGRA
Interferon gamma release assay
IND
Investigational new drug application
INR
International normalized ratio
IP
Investigational product
IRB
Institutional review board
IRC
Internal review committee
IRT
Interactive response technology
ISR
Injection site reactions
IUD
Intrauterine device
IV
Intravenous
IWR
Interactive Web-based response
JCV
JC virus
LFT
Liver function test
LLN
Lower limit of normal
LSLV
Last subject last visit 
mAb
Monoclonal antibody
MAD
Multiple Ascending Dose
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCP
Metacarpophalangeal
MCV
Mean corpuscular volume
MHP
Mental health professional
N/A
Not applicable
Nab
neutralizing antibodies
NK
Natural killer
NOAEL
No observed adverse effect level
NSAIDS
Nonsteroidal anti-inflammatory drugs
PBMCs
Peripheral blood mononuclear cells
PCD
Primary completion date
PD
Pharmacodynamic(s)
PGx 
Pharmacogenomic(s)
pH
Potential of hydrogen
PI
Principal investigator
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Abbreviation
Term
PIB
Powder in bottle
PIP
Proximal interphalangeal
PK
Pharmacokinetic(s)
PML
Progressive Multifocal Leukoencephalopathy
PR
Pulse rate
PT
Prothrombin time
PtGA
Patient’s Global Assessment of Arthritis
QFT-G
QuantiFERON®-TB Gold In-tube test 
QTc
Corrected QT
qual
Qualitative
RA
Rheumatoid arthritis
RBC
Red blood cell
RF
Rheumatoid factor
RNA
Ribonucleic acid
SAD
Single ascending dose
SAE
Serious adverse event
SAP
Statistical analysis plan
SC
Subcutaneous
SCr
Serum creatinine
SIE
Serious infectious event
SLE
Systemic lupus erythematosus
SOP
Standard operating procedure
SRSD
Single reference safety document
TB
Tuberculosis
TBili
Total bilirubin
Td
Tetanus and Diphtheria
Tfh
Follicular T helper 
THC
Tetrahydrocannabinol
TK
toxicokinetics
TMCs
Tonsillar mononuclear cells 
TNF
Tumor necrosis factor
ULN
Upper limit of normal
Upr/Ucr
Urinary protein to urinary creatinine ratio
US
United States
WBC
White blood cell
WNL
Within normal limits
WoCBP
Women of childbearing potential
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Abbreviation
Term
WRD
Worldwide Research and Development
VAS
Visual analog scale
Vss
Volume of distribution at steady state
VZV
Varicella zoster virus


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Appendix 2. List of SLE/RA-related Prohibited Medications (Immunosuppressants & 
Immunomodulators)
These medications are prohibited starting from specified period prior to Screening until the 
subject’s end of study visit.  If subject requires any prohibited medication during the study, 
the Investigator should contact sponsor medical monitor or Clinician.  Subject should remain 
in the study and be followed per Schedule of Activities in the event of receiving a prohibited 
medication for disease-flare. 
Drug/class
Timeframe of restriction prior to Screening
B cell depleting agents (eg, Rituximab)
52 weeks
Intravenous immunoglobulin [IVIG]
16 weeks
TNF-α inhibitors (ie, etanercept, adalimumab, 
infliximab) including investigational TNF-a 
biosimilars
8 weeks
Belimumab
12 weeks
Cyclophosphamide
24 weeks
Abatacept
8 weeks
Tofacitinib, Baricitinib or other JAK 
inhibitors
4 weeks
Calcineurin inhibitors (eg, cyclosporine,
tacrolimus)
8 weeks
IL-6 or IL-6 receptor targeting agents
(eg, sarilimab, tocilizumab)
8 weeks
Intravenous corticosteroids 
(ie, methylprednisolone)
8 weeks
Oral corticosteroidsa
4 weeks
Intramuscular corticosteroidsb
4 weeks
Any other immunosuppressant or 
immunomodulating drugs, including biologic 
and/or non-biologic therapies.
8 weeks
a.
Use of oral corticosteroids greater than prednisone 20 mg (or equivalent) is not permitted within 4 weeks of Screening.  
As noted in Appendix 3, oral prednisone (10 mg or less) is allowed during the study, but must be at a stable dose for 
4 weeks prior to Day 1.
b.
Use of intramuscular corticosteroids is not permitted within 4 weeks of screening and during the study.


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Appendix 3. List of Allowed SLE/RA-related and Chronic Medications 
All allowed medications must be taken as described in the table below at stable doses, 
defined as no more than 20% change in dose.  This applies from the timeframe specified in 
the table until the subject’s end of study visit.  If subject requires any of the below 
medications at higher doses during the study, investigator should contact sponsor to 
determine if the subject should be discontinued from the study.
Only one drug from each of the classes below (immunosuppressants, anti-malarials and 
corticosteroids) is allowed. 
Drug/class
Timeframe of 
restriction prior to 
Day 1 visit
Maximum allowed dose 
(stable)
Other restrictions
Immunosuppressants & 
Immunomodulators
Methotrexate
8 weeks
25 mg/week
N/A
Leflunomide 
8 weeks
20 mg/day
N/A
Sulfasalazine
8 weeks
3 g/day
N/A
Azathioprine
8 weeks
1 mg/kg/day
N/A
Mycophenolate
8 weeks
1.5 g/day
N/A
Anti-malarial
Hydroxychloroquine
8 weeks
400 mg/day
Only oral formulations 
permitted
Chloroquine
8 weeks
250 mg/day
Only oral formulations 
permitted
Corticosteroids
Oral 
4 weeks
10 mg/day prednisone 
equivalent
N/A
Intra-articular injections
2 weeks
20 mg triamcinolone 
equivalent per joint
N/A
Drugs to treat chronic
medical conditions
4 weeks
N/A
N/A


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Appendix 4. Oral Corticosteroids, Systemic Equivalencies25
Glucocorticoid
Equivalent Dose (mg)
Short Acting
Cortisone
25
Hydrocortisone
20
Intermediate Acting
Methylprednisolone
4
Prednisolone
5
Prednisone
5
Triamcinolone
4
Long Acting
Betamethasone
0.6
Dexamethasone
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Appendix 5. SLICC Classification Criteria for SLE 
A subject is classified as having SLE if he or she satisfies 4 of the clinical and immunologic 
criteria used in the SLICC classification criteria, including at least 1 clinical criterion and
1 immunologic criterion, OR if he or she has biopsy-proven nephritis compatible with SLE in 
the presence of ANAs or anti-dsDNA antibodies.
The criteria do not need to be present concurrently.  A criterion should only be judged as 
fulfilled if better explained by other causal relationships (eg, other disease, drug-site 
effects).22
2012 SLICC SLE Criteria
Clinical Criteria
Has the subject ever experienced any of the following clinical criteria?
1. Acute Cutaneous Lupus
Lupus malar rash (do not count if malar discoid)
Yes
No
Bullous lupus
Yes
No
Toxic epidermal necrolysis variant of SLE
Yes
No
Maculopapular lupus rash
Yes
No
Photosensitive lupus rash in the absence of dermatomyositis
Yes
No
Subacute cutaneous lupus (nonindurated psoriasiform and/or annular polycyclic lesions that 
resolve without scarring, although occasionally with postinflammatory dyspigmentation or 
telangiectasias)
Yes
No
2. Chronic Cutaneous Lupus
Localized classical discoid rash (above the neck)
Yes
No
Generalized classical discoid rash (above and below the neck)
Yes
No
Hypertrophic (verrucous) lupus
Yes
No
Lupus panniculitis (profundus)
Yes
No
Mucosal lupus
Yes
No
Lupus erythematosus tumidus
Yes
No
Chillblains lupus
Yes
No
Discoid lupus/lichen planus overlap
Yes
No
3. Oral or nasal ulcers in the absence of other causes, such as vasculitis, Behcet’s 
disease/syndrome,  infection (herpes), inflammatory bowel disease, reactive arthritis, and acidic 
foods
Palate
Yes
No
Buccal
Yes
No
Tongue
Yes
No
Nasal
Yes
No


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4. Non-scarring alopecia (diffuse thinning or hair fragility with visible broken hairs) in the 
absence of other causes such as alopecia areata, drugs, iron deficiency and androgenic alopecia
Yes
No
5. Synovitis involving 2 or more joints, characterized by swelling or effusion OR tenderness in 
2 or more joints and thirty minutes or more of morning stiffness
Yes
No
6. Serositis
Typical pleurisy for more than 1 day
Yes
No
Pleural effusions
Yes
No
Pleural rub
Yes
No
Typical pericardial pain (pain with recumbency improved by sitting forward) for more than 1 
d
Yes
No
Pericardial effusion
Yes
No
Pericardial rub
Yes
No
Pericarditis by ECG in the absence of other causes, such as infection, uremia, and Dressler's 
pericarditis
Yes
No
7. Renal
Urine protein/creatinine ratio (or 24 hour urine protein) representing 500 mg of protein/24hr
Yes
No
Red blood cell casts
Yes
No
8. Neurologic
Seizures
Yes
No
Psychosis
Yes
No
Mononeuritis multiplex in the absence of other known causes such as primary vasculitis
Yes
No
Myelitis
Yes
No
Peripheral or cranial neuropathy in the absence of other known causes such as primary 
vasculitis, infection, and diabetes mellitus
Yes
No
Acute confusional state in the absence of other causes, including toxic-metabolic, uremia, drugs
Yes
No
9. Hemolytic anemia
Yes
No
10. Leukopenia
Leukocytes <4000/mm3 at least once in the absence of other known causes such as Felty's 
syndrome, drugs, and portal hypertension
Yes
No
Lymphocytes <1000/mm3 at least once in the absence of other known causes such as 
corticosteroids, drugs and infection
Yes
No
11. Thrombocytopenia (<100,000/mm3) at least once in the absence of other known causes 
such as drugs, portal hypertension, and thrombotic thrombocytopenic purpura (TTP)
Yes
No
Immunological criteria
1. ANA above laboratory reference range increase
Yes
No
2. Anti-dsDNA antibody above laboratory reference range, except enzyme-linked 
immunosorbent assay (ELISA): twice above laboratory reference range
Yes
No
3. Anti-Sm
Yes
No


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4. Antiphospholipid antibody
Lupus anticoagulant
Yes
No
False-positive rapid plasma regain (RPR)
Yes
No
Medium or high titer anticardiolipin antibody level (IgA, IgG, or IgM) 
Yes
No
Anti-β2 glycoprotein I (IgA, IgG, or IgM)
Yes
No
5. Low complement
Low C3
Yes
No
Low C4
Yes
No
Low CH50
Yes
No
6. Direct Coombs test in the absence of hemolytic anemia
Yes
No


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Appendix 6. The 2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria for 
Rheumatoid Arthritis21
Score
Target population (Who should be tested?): Patients who
Have at least 1 joint with definite clinical synovitis (swelling)*
With the synovitis not better explained by another disease†
Classification criteria for RA (score-based algorithm: add score of categories A-D; a score of 6/10 is needed for 
classification of a patient as having definite RA)‡
Joint involvement§
1 large joint¶
2-10 large joints
1-3 small joints (with or without involvement of large joints)#
4-10 small joints (with or without involvement of large joints)
>10 joints (at least 1 small joint)**
0
1
2
3
5
Serology (at least 1 test result is needed for classification)††
Negative RF and negative ACPA
Low-positive RF or low-positive ACPA
High-positive RF or high-positive ACPA
0
2
3
Acute-phase reactants (at least 1 test result is needed for classification)‡‡
Normal CRP and normal ESR
Abnormal CRP or abnormal ESR
0
1
Duration of symptoms§§
<6 weeks
6 weeks
0
1
*The criteria are aimed at classification of newly presenting patients.  In addition, patients with erosive disease typical of rheumatoid arthritis 
(RA) with a history compatible with prior fulfillment of the 2010 criteria should be classified as having RA.  Patients with longstanding disease, 
including those whose disease is inactive (with or without treatment) who, based on retrospectively available data, have previously fulfilled the 
2010 criteria should be classified as having RA.
†Differential diagnoses vary among patients with different presentations, but may include conditions such as systemic lupus erythematosus, 
psoriatic arthritis, and gout.  If it is unclear about the relevant differential diagnoses to consider an expert rheumatologist should be consulted.
‡Although patients with a score of <6/10 are not classifiable as having RA, their status can be reassessed and the criteria might be fulfilled 
cumulatively over time.


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§Joint involvement refers to any swollen or tender joint on examination, which may be confirmed by imaging evidence of synovitis.  Distal 
interphalangeal joints, first carpometacarpal joints, and first metatarsophalangeal joints are excluded from assessment.  Categories of joint 
distribution are classified according to the location and number of involved joints, with placement into the highest category possible based on 
the pattern of joint involvement.
¶“Large joints” refers to shoulders, elbows, hips, knees, and ankles.
#“Small joints” refers to the metacarpophalangeal joints, proximal interphalangeal joints, second through fifth metatarsophalangeal joints, 
thumb interphalangeal joints, and wrists.
**In this category, at least 1 of the involved joints must be a small joint; the other joints can include any combination of large and additional 
small joints, as well as other joints not specifically listed elsewhere (eg, temporomandibular, acromioclavicular, sternoclavicular, etc.).
†† Negative refers to IU values that are less than or equal to the upper limit of normal (ULN) for the laboratory and assay; low-positive refers to
IU values that are higher than the ULN but 3 times the ULN for the laboratory and assay; high-positive refers to IU values that are >3 times 
the ULN for the laboratory and assay.  Where rheumatoid factor (RF) information is only available as positive or negative, a positive result 
should be scored as low-positive for RF.  ACPA = anti-citrullinated protein antibody.
‡‡Normal/abnormal is determined by local laboratory standards.  CRP = C-reactive protein; ESR = erythrocyte sedimentation rate.
§§ Duration of symptoms refers to patient self-report of the duration of signs or symptoms of synovitis (eg, pain, swelling, tenderness) of joints 
that are clinically involved at the time of assessment, regardless of treatment status.


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Appendix 7. Common Terminology Criteria For Adverse Events (Infusion Reactions)
Grade
Adverse Event
Short Name
1
2
3
4
5
Allergic reaction/ 
Hypersensitivity 
(including drug 
fever)
Allergic 
Reaction
Transient flushing or 
rash; drug fever
<38C (<100.4F)
Rash; flushing; urticaria; 
dyspnea; drug fever
38C (100.4F)
Symptomatic 
bronchospasm, with or 
without urticaria; 
parenteral medication(s) 
indicated; allergy-related 
edema/angioedema; 
hypotension
Anaphylaxis
Death
Remark: Urticaria with manifestations of allergic or hypersensitivity reaction is graded as Allergic reaction/hypersensitivity 
(including drug fever).
Hypertension
Hypertension
Asymptomatic, 
transient (<24 hrs) 
increase by 
>20 mmHg 
(diastolic) or to 
>150/100 if 
previously WNL; 
intervention not 
Recurrent or persistent 
(24 hrs) or symptomatic 
increase by >20 mmHg 
(diastolic) or to >150/100 
if previously WNL; 
monotherapy may be 
indicated
Requiring more than one 
drug or more intensive 
therapy than previously
Life-threatenin
g 
consequences 
(eg, 
hypertensive 
crisis)
Death
Hypotension
Hypotension
Changes, intervention
not indicated
Brief (<24 hrs) fluid 
replacement or other 
therapy; no physiologic 
consequences
Sustained (4 hrs) therapy, 
resolves without persisting 
physiologic consequences
Shock 
(eg, acidemia; 
impairment of 
vital organ 
Death
Fever (in the absence 
of neutropenia, where 
neutropenia is defined 
as ANC
<1.0 x 109/L)
Fever
38.0 to 39.0C (100.4 
to 102.2F)
>39.0 to 40.0 degrees C
(102.3 to 104.0F)
>40.0C (>104.0F) for
≤24 hrs
>40.0C 
(>104.0F
) for
>24 hrs
Death
Remark: The temperature measurements listed are oral or tympanic.
Rigors/chills
Mild
Moderate, narcotics 
indicated
Severe or prolonged, not 
responsive to narcotics
--
--
Cytokine release 
syndrome/acute 
infusion reaction
Cytokine 
release
Mild reaction; 
infusion interruption 
not indicated; 
intervention not 
indicated
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
NSAIDS, narcotics, IV 
fluids); prophylactic 
medications indicated for
24 hrs
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; 
hospitalization indicated 
for other clinical sequelae 
(eg, renal impairment, 
pulmonary infiltrates)
Life-threateni
ng; pressor or 
ventilatory 
support 
indicated
Death
Remark: Cytokine release syndromes/acute infusion reactions are different from Allergic/hypersensitive reactions, although some of the 
manifestations are common to both AEs.  An acute infusion reaction may occur with an agent that causes cytokine release (eg, monoclonal 
antibodies or other biological agents).  Signs and symptoms usually develop during or shortly after drug infusion and generally resolve 
completely within 24 hrs of completion of infusion.  Signs/symptoms may include: Allergic reaction/hypersensitivity (including drug fever); 
Arthralgia (joint pain); Bronchospasm; Cough; Dizziness; Dyspnea (shortness of breath); Fatigue (asthenia, lethargy, malaise); Headache; 
Hypertension; Hypotension; Myalgia (muscle pain); Nausea; Pruritis/itching; Rash/desquamation; Rigors/chills; Sweating (diaphoresis); 
Tachycardia; Tumor pain (onset or exacerbation of tumor pain due to treatment); Urticaria (hives, welts, wheals); Vomiting.


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Appendix 8. Antigen Local Reactivity Due to IP or Vaccine Challenges
All local reactions at the site of IP injection or antigen injections 
 will be 
recorded as AEs.  Antigen injection sites will be monitored for pain, tenderness, erythema 
and swelling using the intensity grading scheme presented below
Injection Site Reaction Grading Scheme
Intensity Grading
Reaction
Mild
Moderate
Severe
Potentially 
Life-threatening
Pain
Does not interfere 
with activity
Repeated use of 
non-narcotic pain 
reliever >24 hours 
or interferes with 
activity
Any use of 
narcotic pain 
reliever or prevents 
daily activity
Emergency room 
visit or 
hospitalization
Tenderness
Mild discomfort to 
touch
Discomfort with 
movement
Significant 
discomfort at rest
Emergency room 
visit or 
hospitalization
Erythema/redness
2.5 to 5 cm
5.1 to 10 cm
>10 cm
Necrosis or 
exfoliative 
dermatitis
Induration/swelling
2.5 to 5 cm and 
does not interfere 
with activity
5.1 to 10 cm or 
interferes with 
activity
>10 cm or prevents 
daily activity
Necrosis
CCI


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Appendix 10. Patient’s Global Assessment (PtGA) of Arthritis
CONSIDERING ALL THE WAYS YOUR ARTHRITIS AFFECTS YOU, HOW ARE 
YOU FEELING TODAY?
(PLEASE MAKE AN X MARK ON THE LINE BELOW.)
Very   ______________________________________________________ Very 
Well
Poorly
[Note: Scale will be 100 mm in length]


PF-06835375 
C1131001
Final Protocol Amendment 2, 09 November 2018
PFIZER CONFIDENTIAL
Page 129
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
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Protocol C1131001 (PF-06835375) Statistical Analysis Plan
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PFIZER CONFIDENTIAL
Protocol C1131001
PHASE 1, RANDOMIZED, MULTI-CENTER, DOUBLE-BLIND, SPONSOR OPEN, 
PLACEBO-CONTROLLED, SINGLE AND MULTIPLE DOSE-ESCALATION 
STUDY TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS 
AND PHARMACODYNAMICS OF PF-06835375 IN SUBJECTS WITH
SEROPOSITIVE SYSTEMIC LUPUS ERYTHEMATOSUS OR RHEUMATOID 
ARTHRITIS
Statistical Analysis Plan 
(SAP)
Version:
3.0
Authors: 
(SAP Authors
)
Date: 14 January 2022
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Revision History
Version
Date
Author(s)
Summary of Changes/Comments
Version 1.0
25-May-2018
Not applicable
Version 2.0
08-Oct-2021
Section 2.3: Added mapping of the analyses 
required for evaluation of exploratory 
objectives to SAP and bSAP.
Section 6.3: Separated table for PK parameters 
into the separate tables for single dose and 
multiple doses phases of the trial.
Sections 6.4, 6.5: Updated mapping of 
endpoints to SAP and bSAP analyses.
Section 8.2.2: Separated table for PK 
parameters into the separate tables for single 
dose and multiple doses phases of the trial.
Section 8.2.3: Added description of 
pharmacodynamic analyses.
Section 8.3.4: Described additional analyses: 
mapping of toxicity to severity and search for 
adverse events that may be caused by the 
cytokine release syndrome.
Version 3.0
14-Jan-2022
Section 6.6: Added plots for time to ADA/NAb 
detection, spaghetti plots of PK,
 
and PK concentration and parameter
summary by ADA/NAb status.
Section 8.2.3: Removed semi-log scale plots for 
CFB outcomes; removed subject level plots for 
NOTE: Italicized text within this document has been taken verbatim from the Protocol.
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................5
LIST OF FIGURES ...................................................................................................................5
APPENDICES ...........................................................................................................................5
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................6
2. INTRODUCTION .................................................................................................................6
2.1. Study Design .............................................................................................................7
2.2. Study Objectives .......................................................................................................9
2.2.1. Primary .........................................................................................................9
2.2.2. Secondary .....................................................................................................9
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING................................10
4. HYPOTHESES AND DECISION RULES.........................................................................10
4.1. Statistical Hypotheses .............................................................................................10
4.2. Statistical Decision Rules........................................................................................10
5. ANALYSIS SETS ...............................................................................................................10
5.1. Full Analysis Set .....................................................................................................10
5.2. Pharmacokinetic Analysis Sets ...............................................................................11
5.2.1. Concentration Analysis Set.........................................................................11
5.2.2. Parameter Analysis Set...............................................................................11
5.3. Pharmacodynamic Analysis Set..............................................................................11
5.4. Safety Analysis Set..................................................................................................11
5.5. Other Analysis Sets .................................................................................................11
5.6. Treatment Misallocations........................................................................................11
5.7. Protocol Deviations.................................................................................................11
5.7.1. Deviations Assessed Prior to Randomization.............................................11
5.7.2. Deviations Assessed Post-Randomization..................................................12
6. ENDPOINTS AND COVARIATES ...................................................................................12
6.2. Safety Endpoints .....................................................................................................12
6.2.1. Adverse Events...........................................................................................12
6.2.2. Laboratory Safety Tests..............................................................................12
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6.2.3. Vital Signs ..................................................................................................13
6.2.4. ECG ............................................................................................................13
6.2.5. Other Safety Data .......................................................................................14
6.3. Pharmacokinetic Endpoints.....................................................................................14
6.4. Pharmacodynamic (PD) Endpoints that Will be Addressed in SAP.......................15
6.7. Covariates................................................................................................................16
7. HANDLING OF MISSING VALUES ................................................................................16
7.1. Concentrations Below the Limit of Quantification.................................................16
7.2. Deviations, Missing Concentrations and Anomalous Values .................................17
7.3. Pharmacokinetic Parameters ...................................................................................17
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........................17
8.1. Statistical Methods ..................................................................................................17
8.2. Statistical Analyses .................................................................................................17
8.2.1. Analysis of Efficacy Data...........................................................................17
8.2.2. Pharmacokinetic Analysis ..........................................................................17
8.2.3. Pharmacodynamic Analysis........................................................................19
8.3. Safety Analysis........................................................................................................21
8.3.1. Treatment and Disposition of Participants .................................................21
8.3.2. Demographic and Clinical Examination Data............................................21
8.3.3. Discontinuation(s).......................................................................................21
8.3.4. Adverse Events ...........................................................................................22
8.3.5. Laboratory Data..........................................................................................22
8.3.6. Vital Signs Data..........................................................................................22
8.3.7. ECG Data....................................................................................................23
8.3.8. Other Safety Data .......................................................................................24
8.3.9. Concomitant Treatments.............................................................................24
9. REFERENCES ....................................................................................................................25
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LIST OF TABLES
Table 1.
Planned Cohorts..........................................................................................9
Table 2.
Noncompartmental PK Parameters for Part A (Single Ascending 
Dose).........................................................................................................14
Table 3.
Noncompartmental PK Parameters for Part B (Multiple Ascending 
Dose).........................................................................................................15
Table 4.
PK Parameters to be Summarized Descriptively for Part A (Single 
Ascending Dose).......................................................................................18
Table 5.
PK Parameters to be Summarized Descriptively for Part B 
(Multiple Ascending Dose).......................................................................18
LIST OF FIGURES
Figure 1.
Study Schematic .........................................................................................8
APPENDICES
Appendix 1. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern .....26


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1. AMENDMENTS FROM PREVIOUS VERSION(S) 
•
Section 2.1
•
Added a description of the cohorts actually used, and the actual doses to the 
description of planned cohorts and doses.
•
Section 2.3
•
Added mapping of the analyses required for evaluation of exploratory objectives 
to SAP and bSAP.
•
Section 6.3
•
Separated table for PK parameters into the separate tables for single dose and 
multiple doses phases of the trial.
•
Sections 6.4, 6.5
•
Updated mapping of endpoints to SAP and bSAP analyses.
•
Section 6.6
•
Added plots for time to ADA/NAb detection, spaghetti plots of PK,
 
, and PK concentration and parameter summary by ADA/NAb status.
•
Section 8.2.2 
•
Separated table for PK parameters into the separate tables for single dose and 
multiple doses phases of the trial.
•
Section 8.2.3
•
Added description of pharmacodynamic analyses.
•
Removed semi-log scale plots for CFB outcomes; removed subject level plots for 
.
•
Section 8.3.4
•
Described additional analyses: mapping of toxicity to severity and search for
adverse events that may be caused by the cytokine release syndrome.
2. INTRODUCTION
PF-06835375 is a humanized, afucosyl immunoglobulin (Ig) G1 antibody against C-X-C 
chemokine receptor type 5 (CXCR5), a surface receptor that is expressed on B cells, 
bona fide follicular T helper (Tfh) cells, and circulating follicular T helper-like (cTfh) cells.
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The goal of this first in human (FIH) study is to evaluate the safety, tolerability, 
pharmacokinetics (PK), and pharmacodynamics (PD) of PF-06835375.  In particular, PD 
characterization will include assessment of magnitude and duration of CXCR5-positive cell 
depletion and recovery.  Inhibition of the humoral immune responses via 
PF-06835375-mediated depletion of CXCR5-positive cells offers the potential for clinical 
evaluation in a population of seropositive autoimmune participants. Consequently, a mixed 
population of seropositive SLE or RA participants will be enrolled into this study. 
2.1. Study Design
This is a Phase 1, randomized, multi-center, double-blind, sponsor open, placebo-controlled, 
single and multiple dose-escalation study to evaluate the safety, tolerability, 
pharmacokinetics, and pharmacodynamics of PF-06835375 in participants with seropositive 
SLE or RA.  Both IV and SC routes of administration will be tested. 
This study will include two parts: Part A, consisting of approximately eight single ascending 
dose (SAD) cohorts, and Part B, consisting of approximately 6 multiple ascending dose 
(MAD) cohorts.  Cohorts in Part A will be initiated sequentially.  Participants in Part B will 
receive two doses of investigational product (first dose on Day 1 and second dose on 
Day 29), and will be enrolled concurrently with Part A following the completion of the initial 
cohorts in Part A.  Participants who are randomized in Part A will not be eligible to 
participate in Part B of this study.
The study includes a Screening visit to assess eligibility and subsequent visits for a minimum 
of 16 weeks.  Participants who meet the end of study criteria will have one follow-up phone 
call visit which will represent the end of study visit (unless additional follow up is needed for 
safety reasons or unresolved AEs attributable to immunogenicity).  Participants, who do not 
meet the criteria to leave the study at Week 16, will continue with clinic visits every four
weeks until they meet these criteria.  Overall, participants are expected to stay in the study 
approximately 6-12 months (including screening).  Participants who withdraw from the study 
may be replaced at the discretion of the sponsor.  A replacement subject will receive the 
same treatment as the withdrawn subject.
Both SLE and RA participants will be enrolled into this study.  Minimum disease activity
(ie, SLEDAI-2K or DAS28 cutoffs) is not required for entry as inclusion criteria.  All subjects 
in both Part A and B will be followed for a minimum of 16 weeks prior to being able to 
qualify for study completion based on the cellular recovery.  
It is at the sponsor’s discretion to dose escalate, to repeat the same dose, or to test a lower 
dose based on emerging data. 
The PD effects of PF-06835375 on the immune system will be evaluated using multiple 
biomarkers, including extensive longitudinal flow cytometry assessment pre- and 
post-administration of IP (investigational product).  In addition, the functional effects of 
PF-06835375 will be assessed with two vaccine challenges 
 
  
 
.
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Throughout the study, B cell counts obtained from a CLIA (Clinical Laboratory Improvement 
Amendments) certified central lab will be used for clinical decision making 
(inclusion/exclusion criteria, dose escalation, initiation of Part B and for the end of study 
criteria). 
Figure 1 (below) shows the study schematic and Table 1 shows the planned cohorts and 
actual dosing regimens Cohorts A7, A8, X6 were not used, the doses in both cohorts A6 and 
B4 were both reduced from 10 mg to 6 mg and the dose in cohort B5 was reduced from 
30 mg to 10 mg.
Figure 1.
Study Schematic


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Table 1.
Planned Cohorts
Cohort Name
Administration 
Route
Proposed Human 
Dosea (mg)
Actual dose (mg)
Expected Number of 
Participants Per Cohortc
Part A (SAD)
A1
IV
0.03
0.03
3a, 1p
A2
IV
0.1
0.1
3a, 1p
A3
IV
0.3
0.3
3a, 1p
A4
IV
1
1
3a, 1p
A5
IV
3
3
6a, 2p
A6
IV
10
6
6a, 2p
A7
IV
30
Not used
6a, 2p
A8
IV
100
Not used
6a, 2p
Part B (MAD)
B1
SCb
0.3
0.3
6a, 2p
B2
SCb
1
1
6a, 2p
B3
SCb
3
3
6a, 2p
B4
SCb
10
6
6a, 2p
B5
SCb
30
10 mg
6a, 2p
X6d
SCb
up to 30
Not used
Up to 24 total (16a, 8p)
Abbreviations: a = active, p = placebo; IV = Intravenous; SC = subcutaneous
a.
Doses may be changed based on available emerging safety, tolerability, PK and PD.
b.
Route of administration may be changed based on available emerging safety, tolerability, PK and PD.
c.
Sponsor may elect to add more subjects into the planned cohorts for any reason, including but not 
limited to eg, subject withdrawal, higher than expected PD effect, etc. The study will enroll up to a total 
of approximately 112 participants.
d.
Optional cohort called “X”.
2.2. Study Objectives
2.2.1. Primary
•
To evaluate the safety and tolerability of single and multiple ascending intravenous 
(IV) and subcutaneous (SC) doses of PF-06835375 in participants with SLE and RA.
2.2.2. Secondary 
1. To evaluate the effect of PF-06835375 on depletion of circulating CXCR5 positive 
B cells and cTfh cells in participants with SLE and RA.
2. To characterize pharmacokinetics (PK) profile of PF-06835375 in participants with 
SLE and RA.
3. To evaluate immunogenicity of PF-06835375 in participants with SLE and RA.
 
 
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3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING
This is a sponsor open study, with the investigator and subject blinded to study treatment. To 
minimize the potential for bias, treatment randomization information will be kept 
confidential by Pfizer personnel and will not be released to the investigator/study staff until 
the conclusion of the study. Final analysis will follow the official database release.
Specific Pfizer personnel (clinician, statisticians, and clinical pharmacologists) will be 
un-blinded to subject treatment assignments in order to permit real-time interpretation of the 
pharmacokinetic, flow cytometry and safety data, and to provide information necessary to 
potentially alter the dose escalation sequence.  
4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
No statistical hypotheses will be tested in this study.
4.2. Statistical Decision Rules
No statistical decision rules will be used for this study.
5. ANALYSIS SETS
5.1. Full Analysis Set
The full analysis set is comprised of all randomized participants.  
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5.2. Pharmacokinetic Analysis Sets
5.2.1. Concentration Analysis Set
The PK concentration population is defined as all enrolled participants treated who have at 
least 1 concentration.
5.2.2. Parameter Analysis Set
The PK parameter analysis population is defined as all enrolled participants treated who 
have at least 1 of the PK parameters of interest.
5.3. Pharmacodynamic Analysis Set
The pharmacodynamic analysis population is defined as all enrolled participants who receive 
at least 1 dose of study medication and have at least 1 pharmacodynamic measurement.
5.4. Safety Analysis Set
All participants who receive at least 1 dose of study medication will be included in the safety 
analyses and listings.
5.5. Other Analysis Sets
None.
5.6. Treatment Misallocations
All analyses will be performed on an “as-treated” basis and will not include data from 
participants who are randomized but not treated.
If a subject takes a treatment that is not consistent with the treatment they are randomized to, 
for example takes a treatment out of sequence or takes the same treatment twice, then they 
will be reported under the treatment that they actually receive for all safety, PK and 
pharmacodynamic analyses, where applicable.
5.7. Protocol Deviations
Participants who experience events that may affect their PK profile may be excluded from 
the PK analysis.  At the discretion of the pharmacokineticist a concentration value may also 
be excluded if the deviation in sampling time is of sufficient concern or if the concentration 
is anomalous for any other reason.  
A full list of protocol deviations will be compiled and reviewed to identify major and minor 
deviations prior to database closure.
5.7.1. Deviations Assessed Prior to Randomization
At screening, the investigator will assess participants against the inclusion and exclusion 
criteria as set out in Sections 4.1 and 4.2 of the protocol.


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5.7.2. Deviations Assessed Post-Randomization
Any significant deviation from the protocol will be reviewed prior to database closure and a 
decision taken regarding evaluation for each analysis population.
6. ENDPOINTS AND COVARIATES
 
 
6.2. Safety Endpoints
In this section, the safety endpoints that will be measured during the study are detailed.  
Where applicable, details of the endpoints to be derived and definition of baseline are also 
provided.
The following data are considered in standard safety summaries (see protocol for collection 
days and list of parameters):
•
adverse events,
•
laboratory data,
•
vital signs data,
•
ECG results.
6.2.1. Adverse Events
Any events occurring following start of treatment will be counted as treatment emergent. 
Events that occur in a non-treatment period (for example, washout or follow-up) will be 
counted as treatment emergent and attributed to the previous treatment taken.
6.2.2. Laboratory Safety Tests
Safety laboratory tests will be performed as described in the protocol.
To determine if there are any clinically significant laboratory abnormalities, the 
haematological, clinical chemistry (serum) and urinalysis safety tests will be assessed against 
the criteria specified in the sponsor reporting standards.  The assessment will take into 
account whether each subject’s baseline test result is within or outside the laboratory 
reference range for the particular laboratory parameter.
Baseline will be the last pre-dose measurement (first treatment for MAD cohorts).
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6.2.3. Vital Signs
Single sitting blood pressure, pulse measurements and temperature will be taken at times 
detailed in the Schedule of Activities given in the protocol. 
The last pre-dose measurement at Day 1 will be used as the baseline. The maximum increase 
from baseline will be calculated by first subtracting the baseline value from each post-dose 
measurement to give the change from baseline.  The maximum of these values over the 
respective period will then be selected, except in the case where a subject does not show an 
increase.  In such an instance, the minimum decrease should be taken.
Similarly, the maximum decrease from baseline will be determined by selecting the 
minimum value of the changes from baseline.  In cases where a subject does not show a 
decrease, the minimum increase should be taken.
6.2.4. ECG
A single 12-lead ECG will be obtained on all participants at screening and follow-up. ECGs 
will be collected in triplicate in Part A on Days 1 and 2, in Part B on Days 1, 2 and 29. The 
Day 1 ECG values will serve as each subject’s baseline values
The QT, QTc, PR, RR, QRS and heart rate will be recorded at each assessment time.
If not supplied, QTcF will be derived using Fridericia’s heart rate correction formula:
QTcF = QT / (RR)1/3
where RR = 60/HR (if not provided)
If not supplied, QTcB will be derived using Bazett’s heart rate correction formula:
QTcB = QT / (RR)1/2
where RR = 60/HR (if not provided)
The average of the triplicate readings collected at each assessment time will be calculated for 
each ECG parameter.  Baseline will be defined as the average of the triplicate pre-dose 
recordings at Day 1.
The maximum absolute value (post-dose) and the maximum increase from baseline for 
QTcF, QT, heart rate, PR and QRS, will be determined over the first 12 hours postdose for 
Day 1 and Day 29 (part B only) separately, and also over all measurements taken postdose 
for QTcF, PR and QRS.
The maximum increase from baseline will be calculated by first subtracting the baseline 
value from each post-dose measurement to give the change from baseline.  The maximum of
these values over the respective period will then be selected, except in the case where a 
subject does not show an increase.  In such an instance, the minimum decrease should be 
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6.2.5. Other Safety Data
Additional safety data will be collected as described in the protocol and will be listed as 
necessary.
6.3. Pharmacokinetic Endpoints
Blood samples for PK analysis of PF-06835375 will be taken according to the Schedule of 
Activities given in the protocol. 
The following PK parameters that will be calculated for PF-06835375 (if possible) for 
PF-06835375 for Part A (see Table 2) and Part B (see Table 3) from the concentration-time 
values using standard non-compartmental methods.
Table 2.
Noncompartmental PK Parameters for Part A (Single Ascending Dose)
Parameter
Analysis Scale
PF-06835375
AUC672
ln
D
AUClast
ln
D
 
AUCinf*
ln
D
AUCinf(dn)*
ln
D
Cmax
ln
D
 
Tmax
R
D
 
Key:
A=analyzed using statistical model, D=displayed with descriptive statistics, ln=natural-log 
transformed, R=raw (untransformed), *=if data permits
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Table 3.
Noncompartmental PK Parameters for Part B (Multiple Ascending Dose)
Parameter
Dosing Day
Analysis scale
PF-06835375
AUCτ
1, 29
ln
D
 
Cav(dn)
1, 29
ln
D
AUClast
1, 29
ln
D
AUClast (dn)
1, 29
ln
D
Cmax
1, 29
ln
D
 
Tmax
1, 29
R
D
  
Cmin
29
ln
D
PTF
29
ln
D
Rac
29
ln
D
Rac Cmax
29
ln
D
Key:
A=analyzed using statistical model, D=displayed with descriptive statistics, ln=natural-log 
transformed, R=raw (untransformed), *=if data permits
6.4. Pharmacodynamic (PD) Endpoints that Will be Addressed in SAP
Change from baseline will be explored for the concentrations of following biomarkers. 
1. Circulating CXCR5 positive B cells, cTfh cells.
 
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6.7. Covariates
None.
7. HANDLING OF MISSING VALUES
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied.
7.1. Concentrations Below the Limit of Quantification
In all data presentations (except listings and PK analyses), concentrations below the limit of
quantification (BLQ) will be set to LLOQ/2, where LLOQ denotes the lower limit of 
quantification. For the PK analyses the concentrations below the limit of quantification 
(BLQ) will be set to zero.
(In listings BLQ values will be reported as “<LLOQ”, where LLOQ will be replaced with the
value for the lower limit of quantification). 
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7.2. Deviations, Missing Concentrations and Anomalous Values
In summary tables and plots of median profiles, statistics will be calculated having set 
concentrations to missing if 1 of the following cases is true:
1. A concentration has been collected as ND (ie, not done) or NS (ie, no sample).
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than 
50% of the data are missing.
7.3. Pharmacokinetic Parameters
Actual PK sampling times will be used in the derivation of PK parameters.
If a PK parameter cannot be derived from a subject’s concentration data, the parameter will 
be coded as NC (ie, not calculated). (Note that NC values will not be generated beyond the 
day that a subject discontinues).
In summary tables, statistics will be calculated by setting NC values to missing; and statistics 
will be presented for a particular dose with ≥3 evaluable measurements.
If an individual subject has a known biased estimate of a PK parameter (due for example to
deviation in dosing), this will be footnoted in summary tables and will not be included in the 
calculation of summary statistics or statistical analyses.
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
8.1. Statistical Methods
As this is an exploratory study, no formal hypothesis testing will be performed.
8.2. Statistical Analyses
8.2.1. Analysis of Efficacy Data
Standard descriptive summaries will be presented for SLEDAI-2K (SLE patients) and 
DAS28 (RA patients).
8.2.2. Pharmacokinetic Analysis
To assess the pharmacokinetics of PF-06835375, the PK parameters detailed in Section 6.3
will be listed and summarized for participants in the PK analysis set (as defined in 
Section 5.2).  Missing values will be handled as detailed in Section 7.  Each PK parameter 
will be summarized by dose which will be performed separately for the SAD and MAD parts 
of the study. Each summary will include the set of of summary statistics as specified in the 
Table 4 for SAD and Table 5 for the MAD respectively.


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Table 4.
PK Parameters to be Summarized Descriptively for Part A (Single 
Ascending Dose)
Parameter
Summary Statistics
Cmax, 
 AUCinf, AUCinf (dn), 
AUClast, AUClast (dn), AUC672, 
 
N, arithmetic mean, median, cv%, standard 
deviation, minimum, maximum, geometric mean 
and geometric cv%.
Tmax
N, median, minimum, maximum.
 
Table 5.
PK Parameters to be Summarized Descriptively for Part B (Multiple 
Ascending Dose)
Parameter
Summary Statistics
AUCτ, 
, AUClast,
AUClast(dn), 
, Cmax, 
 
Cav (dn), Cmin, 
 PTF, Rac, 
Rac Cmax
N, arithmetic mean, median, cv%, standard 
deviation, minimum, maximum, geometric 
mean and geometric cv%.
Tmax
N, median, minimum, maximum.
 
There will be summary tables presenting all PK parameters.  Visit will be included in the 
subheading of PK parameter summary table. PK parameters will be summarized 
descriptively by dose/treatment group in concordance with sponsor’s reporting standard.
To assess the relationship between the PK parameters and dose, 
 
 AUClast (Part A only) and Cmax will be plotted against dose (using a 
logarithmic scale), and will include individual subject values and the geometric means for 
each dose.  Geometric means will have a different symbol than the individual values.  The 
values will be dose normalized (to a 1 mg dose) by dividing the individual values and raw 
geometric means by dose.  A footnote will be added to the plots to indicate that geometric 
means are presented and that data from both cohorts are presented on the plot.
Supporting data from the estimation of t½ and AUCinf will be listed by analyte where 
applicable: terminal phase rate constant (kel); goodness of fit statistic from the log-linear 
regression (r2); the percent of AUCinf based on extrapolation (AUCextrap%); and the first, last, 
and number of time points used in the estimation of kel. This data may be included in the 
clinical study report.
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Some presentations for PF-06835375 concentrations will include:

A listing of all concentrations sorted by subject ID, treatment group, dose, day and
nominal time post dose.  The concentration listing will also include the actual times.  
Deviations from the nominal time will be given in a separate listing.

A summary of concentrations by treatment, dose, day and nominal time post dose, 
where the set of statistics will include n, mean, median, standard deviation, 
coefficient of variation (cv), minimum, maximum and the number of concentrations 
above the lower limit of quantification.

Median concentrations time plots (on both linear and semi-log scales) against 
nominal time post first dose by treatment group and dose (all treatments on the same 
plot per scale, based on the summary of concentrations by treatment group, dose and 
time post dose).

Mean concentrations time plots (on both linear and semi-log scales) against nominal 
time post first dose by treatment group and dose (all treatments on the same plot per 
scale, based on the summary of concentrations by treatment group, dose and time 
postdose).

Individual concentration time plots by treatment group and dose (on both linear and
semi-log scales) against actual time post dose (there will be separate spaghetti plots 
for each dose per scale).

Individual concentration time plots by subject (on both linear and semi-log scales) 
against actual time post first dose [there will be separate plots for each subject].
The length of time used for the x-axes of these plots will be decided on review of the data, 
and will depend on how long the PF-06835375 concentration is quantifiable in the matrix.
For summary statistics, median and mean plots by sampling time, the nominal PK sampling 
time will be used, for individual subject plots by time, the actual PK sampling time will be 
used.
8.2.3. Pharmacodynamic Analysis
All of the PD endpoints described in the Section 6.4 will be summarized by dose at each time
point presented in tabular form or graphically. The descriptive statistics will include standard
summaries of absolute concentrations, changes from baseline and percentage change from 
baseline. The presentations of PD endpoints will include:

Listing of B and TfH cells sorted by subject ID, treatment group, dose and visit.

Summary of B and cTfh Cell Depletion Parameters (Mean maximum % decrease 
from baseline, Mean duration of depletion below 10 cells/µL after first dose) 
following Single Dose Intravenous Administration.


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•
Summary of B and cTfh Cell Depletion Parameters (Mean maximum % decrease 
from baseline, Mean duration of depletion below 10 cells/μL after first and second 
dose) following Multiple Dose Subcutaneous Administration.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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The length of time used for the x-axes of these plots will be decided on review of the data,
and will depend on follow-up duration of participants.
8.3. Safety Analysis
A set of summary tables split by treatment will be produced to evaluate any potential risk 
associated with the safety and toleration of administering PF-06835375. 
No formal analyses are planned for safety data.  The safety and other endpoints detailed in 
Section 6.2 will be listed and summarized in accordance with sponsor reporting standards, 
where the resulting data presentations will consist of participants from the safety analysis set.
8.3.1. Treatment and Disposition of Participants
Subject evaluation groups will show end of study subject disposition and will show which
subjects were analyzed for pharmacokinetics, as well as for safety (adverse events and 
laboratory data).  Frequency counts will be supplied for subject discontinuation(s) by 
treatment.
Data will be reported in accordance with the sponsor reporting standards.
8.3.2. Demographic and Clinical Examination Data
A breakdown of demographic data will be provided for age, race, gender (at birth), weight, 
body mass index, height, and primary diagnosis (SLE or RA).  Each will be summarized by 
treatment group in accordance with the sponsor reporting standards. Background medication 
data will be summarized for each of the treatment groups.
8.3.3. Discontinuation(s)
Subject discontinuations, temporary discontinuations or dose reductions due to adverse
events will be detailed and summarized by treatment.
Data will be reported in accordance with the sponsor reporting standards.
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8.3.4. Adverse Events
Adverse events will be reported in accordance with the sponsor reporting standards. Several 
minor ad-hoc adjustments and additions will be conducted.
In the case report forms (CRF) the infusion-related adverse effect was characterized by 
toxicity grade, instead of the conventional characterization of the AE by severity. The
possible toxicity grades are 0,1,2,3,4. The values of toxicity grades = 0, 1, 2 will be mapped 
to the “mild” category of the AE severity score and values of the toxicity score equal to 3 and
4 will be mapped to the “moderate” and “severe” scores accordingly. The explanation of this 
mapping from toxicity to severity scale needs to be included into the footnote of the 
otherwise standard summaries of the adverse events. 
Listings with the descriptions of infusion-related reactions (IRR) and injection site reactions
(ISR) will be created (separately for all causalities and treatment related adverse events) with 
the description of individual adverse effects. 
Similar listings describing subsets of all events of participants who had preferred term of a
special interest that may suggest the occurrence of cytokine release syndrome, with start on 
Day 1-3 after dose 1 (IV or SC) or Day 1- 4 after dose 2 (SC) will be created (separately for
all causalities and treatment related adverse events). The set of preferred term of interest will
include tachycardia, hypotension, hypertension, chills, vomiting, nausea, headache, pyrexia,
dizziness, and palpitations. The observation of a group of two or more events from this set
within a short time window after the dosing will be viewed as a potential cytokine release
syndrome event (PCRE). The tabulation showing total number of participants and number 
and percent of PCREs within each of the doses will be created. Note that this analysis is 
exploratory and the list of preferred terms may be modified if needed.
8.3.5. Laboratory Data
Laboratory data will be listed and summarized by treatment in accordance with the sponsor 
reporting standards.  Baseline is as defined in Section 6.2.2.
8.3.6. Vital Signs Data
Absolute values and changes from baseline for systolic and diastolic blood pressure and 
pulse rate will be summarized by treatment group and time post-dose, according to sponsor 
reporting standards.  Tables will be paged by parameter.  Baseline is as defined in 
Section 6.2.3.
Mean changes from baseline for systolic and diastolic blood pressure and pulse rate will be 
plotted against time post-dose.  On each plot there will be 1 line for each treatment.  Data 
from all cohorts will be plotted on the same figure using separate lines for the 2 placebos.  
Corresponding individual plots of changes from baseline will also be produced for each 
treatment group.


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For systolic and diastolic blood pressure and pulse rate, the differences between each dose
and placebo (dose – placebo) will be summarized (N, mean, 90% confidence interval) and 
plotted (mean) for each treatment group, dose and time point (including baseline).
Maximum absolute values and changes from baseline for vital signs will also be summarized 
descriptively by treatment using categories as defined in Appendix 1.  Numbers and 
percentages of participants meeting the categorical criteria will be provided.  All planned and 
unplanned post dose time points will be counted in these categorical summaries.  All values 
meeting the criteria of potential clinical concern will be listed.
If necessary, maximum increases or decreases in vital signs may be summarized in addition 
to the above.
8.3.7. ECG Data
Absolute values and changes from baseline in QT, heart rate, QTcF, PR and QRS will be 
summarized by treatment group, and time postdose using sponsor reporting standards.  
Tables will be paged by parameter. Baseline is as defined in Section 6.2.4.
Mean changes from baseline in QT, heart rate and QTcF will be plotted against time 
postdose.  On each plot there will be 1 line for each treatment.  Data from all cohorts will be 
plotted on the same figure using separate lines for the 2 placebos.  Corresponding individual 
plots of changes from baseline will also be produced for each treatment group.
Changes from baseline in QTcF will also be plotted separately against drug concentrations.  
This will be a scatter plot for all observations where QTcF and drug concentration are 
recorded.  Placebo data will also be included (with drug concentration set to zero).  Different 
symbols will be used for each treatment.  There will be 1 plot for each cohort.
Maximum increase from baseline (0 to 12 hours) for QTcF, heart rate, QT, PR and QRS will 
be summarized by treatment group, according to sponsor reporting standards. 
In addition for QTcF, heart rate and QT, the differences between each dose and placebo 
(dose – placebo) for each subject will be summarized and plotted (N, mean, 90% confidence 
interval) for each cohort, dose and timepoint (including baseline). 
ECG endpoints and changes from baseline (QTcF, PR and QRS) will also be summarized 
descriptively by treatment group using categories as defined in Appendix 1 (for QTc these 
correspond to ICH E141).  Numbers and percentages of participants meeting the categorical 
criteria will be provided.  All planned and unplanned post-dose timepoints will be counted in 
these categorical summaries.  All values meeting the criteria of potential clinical concern will 
be listed.
Listings of participants with any single post-dose value ≥500 msec will also be produced for 
QTcF.
QTcB will be listed only and not summarized.


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8.3.8. Other Safety Data
None.
8.3.9. Concomitant Treatments
All concomitant medication(s) as well as non-drug treatment(s) will be provided in the 
listings.


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9. REFERENCES
1.
ICH E14 - The clinical evaluation of QT/QTc interval prolongation and proarrhythmic 
potential for non-antiarrhythmic drugs.  CHMP/ICH/2/04.


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Appendix 1. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern
Categories for QTcF
QTcF (ms)
450max. <480
480max.<500
max. 500
QTcF (ms) 
increase from 
baseline
30max. <60
max. 60
Categories for PR and QRS
PR (ms)
max. 300
PR (ms) increase 
from baseline
Baseline >200 
and max. 
25% increase
Baseline 200 and 
max. 50% increase
QRS (ms)
max. 140
QRS (ms)
increase from 
baseline
50% increase
Categories for Vital Signs
Systolic BP (mm Hg)
min. <90
Systolic BP (mm Hg) 
change from baseline
max. decrease 30
max. increase 30
Diastolic BP (mm Hg)
min. <50
Diastolic BP (mm Hg) 
change from baseline
max. decrease 20
max. increase 20
Supine pulse rate (bpm)
min. <40
max. >120
Standing pulse rate (bpm)
min. <40
max. >140
Measurements that fulfill these criteria are to be listed in report.