Conditions: Systemic Lupus Erythematosus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 260
Healthy volunteers: no

Brief summary:
This is a study to evaluate the safety and efficacy of GDC-0853 in combination with standard of care therapy in participants with moderate to severe active systemic lupus erythematosus (SLE).

Detailed description:

Arms:
arm 1: Participants received matching placebo to GDC-0853 orally starting on Day 1 and ending at Week 48, in combination with background standard of care therapy. arm 2: Participants received GDC-0853 (150mg) orally once daily (QD) starting on Day 1 and ending at Week 48, in combination with background standard of care therapy. arm 3: Participants received GDC-0853 (200mg) orally twice daily (BID) starting on Day 1 and ending at Week 48, in combination with background standard of care therapy.

Interventions: intervention 1: GDC-0853 intervention 2: Placebo
Intervention descriptions: intervention 1: Participants received GDC-0853 at dosages of 150 or 200mg as per the dosing schedules described above. intervention 2: Participants received matching placebo to GDC-0853 at dosages of 150 and 200mg as per the dosing schedules described above.

Protocol document:
Prot_SAP_000.pdf: 
 
Official Title: A Phase II, Randomized, Double-blind, Placebo-controlled Study of 
the Safety and Efficacy of GDC-0853 in Patients With Moderate to 
Severe Active Systemic Lupus Erythematosus 
NCT Number: 
NCT02908100 
Document Date: 
Protocol Version 3: 09-February-2018 
 
 


FINAL PROTOCOL APPROVAL
CONFIDENTIAL
The information contained in this document, especially any unpublished data, is the property of 
Genentech, Inc. (or under its control) and therefore is provided to you in confidence as an 
investigator, potential investigator, or consultant, for review by you, your staff, and an applicable 
Ethics Committee or Institutional Review Board.  It is understood that this information will not be 
disclosed to others without written authorization from Genentech except to the extent necessary 
to obtain informed consent from persons to whom the drug may be administered.
GDC-0853—Genentech, Inc.
1/Protocol GA30044, Version 3
PROTOCOL
TITLE:
A PHASE II, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY OF THE SAFETY 
AND EFFICACY OF GDC-0853 IN PATIENTS WITH 
MODERATE TO SEVERE ACTIVE SYSTEMIC LUPUS
ERYTHEMATOSUS
PROTOCOL NUMBER: GA30044
VERSION NUMBER:
3
EUDRACT NUMBER:
2016-001039-11
IND NUMBER:
130,011
TEST PRODUCT:
GDC-0853 (RO7010939)
MEDICAL MONITOR:
, M.D., MPH
SPONSOR:
Genentech, Inc.
DATE FINAL:
Version 1:  27 June 2016
DATE AMENDED:
Version 2:  12 May 2017
Version 3:  See electronic date stamp below
 
09-Feb-2018 22:54:12
Title
Approver's Name
Company Signatory
Date and Time (UTC)


GDC-0853—Genentech, Inc.
2/Protocol GA30044, Version 3
PROTOCOL AMENDMENT, VERSION 3:
RATIONALE
Changes to the protocol, along with a rationale for each change, are summarized as 
follows and are reflected as applicable in the protocol:

The Medical Monitor has been updated.

The study design figure has been modified without changes to the overall design 
(Figure 1).

The British Isles Lupus Activity Group (BILAG) and Physician’s Global Assessment
(PGA) components of the SRI-4 have been removed from the secondary endpoints 
because those components are not standalone endpoints. The reduction of at least 
4 points from baseline in the Systemic Lupus Erythematosus Disease Activity Index 
(SLEDAI)-2K remains an exploratory endpoint because it is the only component 
within the SRI-4 that shows clinical improvement (Section 2).

The endpoint to evaluate SRI-4 response at Week 48 with and without oral 
corticosteroid (OCS) taper to evaluate patients with high plasmablast signature 
levels to have an enhanced clinical response to GDC-0853 relative to patients with 
low levels remains a secondary endpoint. The other corresponding endpoints to 
evaluate SRI-4 response at Week 24 with and without OCS taper have been 
re-categorized as exploratory endpoints (Section 2, Section 6.4.2, and 
Section 6.4.3).

To better characterize the progression of lupus in patients on trial and provide other 
endpoints that may be less sensitive to placebo response, the BILAG-based 
Composite Lupus Assessment (BICLA) and SRI-6 endpoints have been re-
categorized from exploratory to secondary endpoints (Section 2).

Pharmacokinetic (PK) objectives and endpoints have been updated to clarify that 
the stated analysis will be conducted solely on pharmacokinetic data generated from 
the current study. PK analyses that incorporate data from multiple clinical studies 
(potentially including GS39684), including population PK analyses using models that 
incorporate pooled data, may be conducted separately (Section 2).

The length of the study has been updated from 62 to 61 weeks to reflect the sum of 
the 5-week screening period, 48-week study conduct period, and 8-week safety 
follow-up period (Section 3.2.1). 

Language has been added to clarify the reference for nonclinical efficacy data for 
the BTK inhibitor GDC-0834 (Section 3.3.1).

The minimum SLEDAI-2K score requirement for subjects to enroll in the study has 
been increased from a 6 to an 8 to ensure severity of lupus is appropriate for the 
study (Section 4.1.1).

The requirements for at least one standard oral treatment for SLE within the dose 
ranges specified in the inclusion criteria have been clarified. Additional SLE 
treatments do not need to be above the lower limits of doses listed (Section 4.1.1).


GDC-0853—Genentech, Inc.
3/Protocol GA30044, Version 3

The maximum doses of mycophenolate mofetil and mycophenolic sodium have
been increased to allow for patients with stable renal function or patients with more 
active lupus disease to be included in the study (Section 4.1.1).

The lupus nephritis exclusion criteria have been updated to allow for patients with 
mild renal dysfunction, similar to other recent lupus trials, to enrich for patients with 
more serologic activity who might be expected to respond better to study treatment
(Section 4.1.2).

The exclusion criterion regarding history of anti-phospholipid antibody syndrome has 
been further clarified to explain that low doses of aspirin or clopidogrel for 
anti-coagulation are not excluded but should follow local regulations (Section 4.1.2).

Language has been added to clarify tuberculosis exclusion criteria (Section 4.1.2).

Time-specific medications that cannot be taken prior to screening have been 
clarified from days to weeks (Section 4.1.2).

Language has been added to clarify how sites should document study drug 
administration (Section 4.3.2.2).

Language has been added to clarify that anti-malarial doses should remain stable 
on study (Section 4.3.2.3.1).

Steroid burst treatment and tapering requirement language has been clarified 
(Section 4.3.2.3.3).

Clarification has been provided for steroid doses that are considered escape 
therapy (Section 4.3.2.3.4).

Language has been added to clarify that low doses of aspirin may not be taken at 
the same time as anti-platelet agents (Section 4.4.1.5). 

Anti-platelet agents have been removed from the list of prohibited therapies as there 
have been no bleeding events to date and there does not appear to be an increased
risk from anti-platelet agents (Section 4.4.2).

Leflunomide, penicillamine, and sulfasalazine were primarily considered 
exclusionary since they affect the progression of rheumatoid arthritis (another 
indication being assessed with GDC-0853). Since these medications are unlikely to 
be used in lupus, they have been removed from the prohibited medications list
(Section 4.4.2).

IV and IM steroids (except as escape therapy) have been added to the prohibited 
therapies section (Section 4.4.2).

The CYP3A drug-drug interaction section was updated based on new data from 
clinical pharmacology studies (Section 4.4.2.2).

Clarifying language has been added to patient preparation for electrocardiograms 
(Section 4.5.10.2).

The hepatotoxicity language has been updated to clarify the expected AST/ALT 
values required for eligibility on study do not depend on creatinine kinase (CK), 
aldolase, and lactate dehydrogenase (LDH) values obtained at screening
(Section 5.1.1.6).


GDC-0853—Genentech, Inc. 
4/Protocol GA30044, Version 3 
• 
Language has been revised to account for the fact that some sites may not allow 
follow-up on partner pregnancies (Section 5.4.3.2). 
• 
Language has been updated to clarify the analysis method for the primary endpoint 
(Section 6.4.1). 
• 
Language has been revised to clarify the PK analysis details (Section 6.6). 
• 
Language has been added to clarify that the Sponsor will review all protocol 
deviations as per the Sponsor’s Standard Operating Procedures, and prospective 
requests to deviate from the protocol are not allowed (Section 9.2). 
• 
The Web site URL for the "Roche Global Policy on Sharing of Clinical Trials Data" 
has been corrected (Section 9.5). 
• 
Height measurement has been added to the Week 48 visit to align with the 
open-label extension study and to allow for comparison to baseline (Appendix 1). 
• 
CK, aldolase, and LDH have been added to the Week 48 visit to align with the 
open-label extension study and to allow for comparison to baseline (Appendix 1). 
• 
T, B, and natural killer cells (TBNK) has been added at screening to allow the 
adjudication committee to review CD19 count during screening (Appendix 1). 
• 
The blood sample for pharmacodynamics (PD) RNA, PD biomarker serum and 
plasma, exploratory urinary biomarker collection, and peripheral blood mononuclear 
cells (PBMC) will no longer be collected at the early termination visit in order to 
reduce study procedure related burden for patients as these samples are not 
necessary for safety follow-up (Appendix 1). 
• 
The Systemic Lupus International Collaborating Clinics (SLICC) Damage Index has 
been updated to the 1997 version including pancreatic insufficiency and tendon 
rupture (Appendix 7). 
• 
Appendix 19 has been updated based on new clinical pharmacology data. 
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 
 


GDC-0853—Genentech, Inc.
5/Protocol GA30044, Version 3
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 14
PROTOCOL SYNOPSIS .................................................................................... 15
1.
BACKGROUND .......................................................................................... 32
1.1
Background ........................................................................... 32
1.2
Background on Bruton’s Tyrosine Kinase and 
GDC-0853 ............................................................................. 33
1.2.1
Bruton’s Tyrosine Kinase....................................................... 33
1.2.2
Nonclinical Experience with GDC-0853................................. 33
1.2.3
Clinical Experience with GDC-0853....................................... 35
1.3
Study Rationale and Benefit-Risk Assessment...................... 36
1.3.1
Primary Nonclinical Toxicity Findings .................................... 37
1.3.2
Potential Risks for Clinical Toxicities ..................................... 38
1.3.2.1
Infections.............................................................................. 38
1.3.2.2
Vaccinations......................................................................... 38
1.3.2.3
Bleeding ............................................................................... 39
1.3.2.4
Cytopenias ........................................................................... 39
1.3.2.5
Gastrointestinal Effects ........................................................ 39
1.3.2.6
Hepatotoxicity....................................................................... 39
1.3.2.7
Cardiovascular Effects ......................................................... 40
1.3.2.8
Vascular Inflammation.......................................................... 40
1.3.2.9
Malignancy ........................................................................... 40
2.
OBJECTIVES AND ENDPOINTS ............................................................... 40
3.
STUDY DESIGN......................................................................................... 43
3.1
Description of the Study......................................................... 43
3.1.1
Study Design ......................................................................... 43
3.1.2
Internal Monitoring Committee and Scientific 
Oversight Committee ............................................................................... 46
3.2
End of Study and Length of Study......................................... 47
3.2.1
Length of Study ..................................................................... 47
3.2.2
End of Study.......................................................................... 47
3.3
Rationale for Study Design.................................................... 47


GDC-0853—Genentech, Inc.
6/Protocol GA30044, Version 3
3.3.1
Rationale for GDC-0853 Dose and Schedule........................ 47
3.3.2
Rationale for Patient Population ............................................ 48
3.3.3
Rationale for Control Group................................................... 49
3.3.4
Rationale for Biomarker Assessments................................... 50
3.3.5
Rationale for PK Sample Collection Schedule....................... 50
3.3.6
Rationale for Other Study Design Elements .......................... 50
3.3.6.1
Pre-Enrollment Adjudication................................................. 50
3.3.6.2
Efficacy Measurements........................................................ 50
3.3.6.3
Corticosteroid Taper............................................................. 51
3.3.6.4
Clinical Outcomes Assessments .......................................... 51
3.3.6.5
Stratification ......................................................................... 51
3.3.6.6
Concomitant Medication Rationale....................................... 52
4.
MATERIALS AND METHODS .................................................................... 52
4.1
Patients.................................................................................. 52
4.1.1
Inclusion Criteria.................................................................... 52
4.1.2
Exclusion Criteria................................................................... 54
4.2
Method of Treatment Assignment and Blinding..................... 59
4.3
Study Treatment.................................................................... 60
4.3.1
Formulation, Packaging, and Handling.................................. 60
4.3.1.1
GDC-0853 50-mg Tablet and Placebo Tablet ...................... 60
4.3.1.2
Background Standard of Care Therapy................................ 60
4.3.2
Dosage, Administration, and Compliance.............................. 60
4.3.2.1
GDC-0853 and Placebo Dose and 
Administration..................................................................................... 60
4.3.2.2
GDC-0853 and Placebo Compliance ................................... 61
4.3.2.3
Background Standard of Care Therapy................................ 62
4.3.2.3.1
Immunosuppressant Therapy ...................................... 62
4.3.2.3.2
Corticosteroid............................................................... 63
4.3.2.3.3
Burst Treatment ........................................................... 64
4.3.2.3.4
Escape Therapy........................................................... 65
4.3.2.4
Background Standard of Care Therapy 
Compliance ........................................................................................ 65
4.3.3
Investigational Medicinal Product Accountability ................... 65


GDC-0853—Genentech, Inc.
7/Protocol GA30044, Version 3
4.3.4
Post-Trial Access to GDC-0853............................................. 66
4.4
Concomitant Therapy, Prohibited Food, and 
Additional Restrictions ........................................................... 66
4.4.1
Permitted Therapy................................................................. 66
4.4.1.1
Anti-malarials (E.g., Hydroxychloroquine, 
Chloroquine)....................................................................................... 67
4.4.1.2
Mycophenolate Mofetil/Mycophenolic Acid.......................... 67
4.4.1.3
Azathioprine ......................................................................... 67
4.4.1.4
Methotrexate ........................................................................ 67
4.4.1.5
Non-Steroidal Anti-inflammatory Drugs................................ 68
4.4.1.6
ACE Inhibitors and ARBs ..................................................... 68
4.4.1.7
Dietary Supplements............................................................ 68
4.4.1.8
Acid Reducing Agents.......................................................... 68
4.4.2
Prohibited Therapy ................................................................ 69
4.4.2.1
Live or Attenuated Vaccinations........................................... 69
4.4.2.2
CYP3A and BCRP-Mediated Drug Interactions .................. 70
4.4.3
Prohibited Food ..................................................................... 71
4.4.4
Additional Restrictions ........................................................... 71
4.5
Study Assessments ............................................................... 71
4.5.1
Informed Consent Forms and Screening Log........................ 72
4.5.2
Eligibility Assessment at Screening....................................... 72
4.5.2.1
Re-Testing:  Laboratory Inclusion/Exclusion ........................ 72
4.5.2.2
Re-Screening ....................................................................... 73
4.5.3
Medical History and Demographic Data ................................ 73
4.5.4
Physical Examinations........................................................... 73
4.5.5
Vital Signs.............................................................................. 74
4.5.6
Chest Radiograph.................................................................. 74
4.5.7
Tuberculin Purified Protein Derivative Skin Test.................... 74
4.5.8
SLE Disease Activity Assessments ....................................... 74
4.5.8.1
BILAG 2004 Index................................................................ 75
4.5.8.2
Systemic Lupus Erythematosus Disease Activity 
Index 2000 (SLEDAI-2K) and SELENA-SLEDAI Flare 
Index (SFI).......................................................................................... 75
4.5.8.3
Glucocorticoid Toxicity Change Index .................................. 76


GDC-0853—Genentech, Inc. 
8/Protocol GA30044, Version 3 
4.5.8.4 Systemic Lupus International Collaborating 
Clinics (SLICC)/ ACR Damage Index for Systemic Lupus 
Erythematosus ................................................................................... 76 
4.5.8.5 28-Joint Count ...................................................................... 76 
4.5.8.6 Cutaneous Lupus Erythematosus Disease Area 
and Severity Index (CLASI) ................................................................ 76 
4.5.8.7 Physician’s Global Assessment ........................................... 76 
4.5.8.8 Patient’s Global Assessment ................................................ 77 
4.5.8.9 Systemic Lupus Erythematosus Responder 
Index 
 ............................................................................................. 77 
4.5.8.10 BICLA ................................................................................. 77 
4.5.8.11 Optional Photography (for United States only, 
as applicable) ...................................................................................... 77 
4.5.9 
Laboratory, Biomarker, and Other Biological 
Samples 
 .............................................................................................. 78 
4.5.10 
Electrocardiograms ................................................................ 81 
4.5.10.1 Timing of Electrocardiograms ............................................. 81 
4.5.10.2 Patient Preparation for Electrocardiogram ......................... 81 
4.5.10.3 Monitoring and Reporting of 
Electrocardiograms ............................................................................. 81 
4.5.11 
Patient-Reported Outcomes .................................................. 82 
4.5.11.1 Functional Assessment of Chronic Illness 
Therapy-Fatigue Scale (FACIT Fatigue) ............................................. 82 
4.5.12 
Mandatory Samples for Whole Genome 
Sequencing .............................................................................................. 82 
4.5.13 
Optional Samples for Research Biosample 
Repository  .............................................................................................. 83 
4.5.13.1 Overview of the Research Biosample 
Repository .......................................................................................... 83 
4.5.13.2 Approval by the Institutional Review Board or 
Ethics Committee ............................................................................... 84 
4.5.13.3 Sample Collection .............................................................. 84 
4.5.13.4 Confidentiality ..................................................................... 84 
4.5.13.5 Consent to Participate in the Research 
Biosample Repository ......................................................................... 85 
4.5.13.6 Withdrawal from the Research Biosample 
Repository .......................................................................................... 85 


GDC-0853—Genentech, Inc. 
9/Protocol GA30044, Version 3 
4.5.13.7 Monitoring and Oversight ................................................... 85 
4.6 
Patient, Treatment, Study, and Site 
Discontinuation ...................................................................... 86 
4.6.1 
Patient Discontinuation .......................................................... 86 
4.6.2 
Study Treatment Discontinuation ........................................... 86 
4.6.3 
Study and Site Discontinuation .............................................. 87 
5. 
ASSESSMENT OF SAFETY ....................................................................... 88 
5.1 
Safety Plan ............................................................................ 88 
5.1.1 
Safety Plan for Potential Risks Associated with 
GDC-0853  .............................................................................................. 88 
5.1.1.1 Infections .............................................................................. 88 
5.1.1.2 Vaccinations ......................................................................... 90 
5.1.1.3 Bleeding ............................................................................... 90 
5.1.1.4 Cytopenias ........................................................................... 92 
5.1.1.5 Gastrointestinal Effects ........................................................ 92 
5.1.1.6 Hepatotoxicity ....................................................................... 92 
5.1.1.7 Cardiovascular Effects ......................................................... 93 
5.1.1.8 Vascular Inflammation .......................................................... 93 
5.1.1.9 Malignancy ........................................................................... 94 
5.1.2 
Management of Study Treatment in Patients Who 
Experience Specific Adverse Events ....................................................... 94 
5.2 
Safety Parameters and Definitions ........................................ 98 
5.2.1 
Adverse Events ..................................................................... 98 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor) ........................................................................................ 99 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .................................................................... 100 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters .............................................. 100 
5.3.1 
Adverse Event Reporting Period ......................................... 100 
5.3.2 
Eliciting Adverse Event Information ..................................... 101 
5.3.3 
Assessment of Severity of Adverse Events ......................... 101 
5.3.4 
Assessment of Causality of Adverse Events ....................... 102 
5.3.5 
Procedures for Recording Adverse Events .......................... 103 


GDC-0853—Genentech, Inc. 
10/Protocol GA30044, Version 3 
5.3.5.1 Diagnosis versus Signs and Symptoms ............................. 103 
5.3.5.2 Adverse Events That Are Secondary to Other 
Events  ........................................................................................... 103 
5.3.5.3 Persistent or Recurrent Adverse Events ............................ 104 
5.3.5.4 Abnormal Laboratory Values .............................................. 104 
5.3.5.5 Abnormal Vital Sign Values ................................................ 105 
5.3.5.6 Abnormal Liver Function Tests ........................................... 106 
5.3.5.7 Deaths ................................................................................ 106 
5.3.5.8 Preexisting Medical Conditions .......................................... 106 
5.3.5.9 Lack of Efficacy or Worsening of Lupus ............................. 107 
5.3.5.10 Hospitalization or Prolonged Hospitalization .................... 107 
5.3.5.11 Adverse Events Associated with an Overdose 
or Error in Drug Administration ......................................................... 107 
5.3.5.12 Patient-Reported Outcome Data ...................................... 108 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor ........................................................ 108 
5.4.1 
Emergency Medical Contacts .............................................. 108 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest ..................................... 109 
5.4.2.1 Events That Occur prior to Study Drug Initiation ................ 109 
5.4.2.2 Events That Occur after Study Drug Initiation .................... 109 
5.4.3 
Reporting Requirements for Pregnancies ............................ 109 
5.4.3.1 Pregnancies in Female Patients ......................................... 109 
5.4.3.2 Pregnancies in Female Partners of Male 
Patients  ........................................................................................... 110 
5.4.3.3 Congenital Anomalies/Birth Defects and 
Abortions .......................................................................................... 110 
5.5 
Follow-Up of Patients after Adverse Events ........................ 110 
5.5.1 
Investigator Follow-Up ......................................................... 110 
5.5.2 
Sponsor Follow-Up .............................................................. 111 
5.6 
Adverse Events That Occur after the Adverse 
Event Reporting Period........................................................ 111 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees ............................................................... 111 


GDC-0853—Genentech, Inc.
11/Protocol GA30044, Version 3
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 112
6.1
Determination of Sample Size ............................................. 112
6.2
Summaries of Conduct of Study.......................................... 112
6.3
Summaries of Treatment Group Comparability ................... 112
6.4
Efficacy Analyses ................................................................ 113
6.4.1
Primary Efficacy Endpoint.................................................... 113
6.4.2
Secondary Efficacy Endpoints............................................. 113
6.4.3
Exploratory Efficacy Endpoints............................................ 114
6.5
Safety Analyses................................................................... 115
6.6
Pharmacokinetic Analyses................................................... 115
6.7
Biomarker Analyses............................................................. 115
6.8
Interim Analysis ................................................................... 115
7.
DATA COLLECTION AND MANAGEMENT ............................................. 116
7.1
Data Quality Assurance....................................................... 116
7.2
Electronic Case Report Forms............................................. 117
7.3
Source Data Documentation................................................ 117
7.4
Use of Computerized Systems ............................................ 118
7.5
Retention of Records........................................................... 118
8.
ETHICAL CONSIDERATIONS.................................................................. 118
8.1
Compliance with Laws and Regulations .............................. 118
8.2
Informed Consent................................................................ 119
8.3
Institutional Review Board or Ethics Committee.................. 120
8.4
Confidentiality...................................................................... 120
8.5
Financial Disclosure ............................................................ 121
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 121
9.1
Study Documentation .......................................................... 121
9.2
Protocol Deviations.............................................................. 121
9.3
Site Inspections ................................................................... 121
9.4
Administrative Structure....................................................... 122
9.5
Publication of Data and Protection of Trade 
Secrets ................................................................................ 122
9.6
Protocol Amendments ......................................................... 123


GDC-0853—Genentech, Inc. 
12/Protocol GA30044, Version 3 
10. REFERENCES ......................................................................................... 125 
 
LIST OF TABLES 
Table 1 
Objectives and Corresponding Endpoints ................................... 41 
Table 2 
Study Drug Dosing Regimen by Treatment Arm ......................... 61 
Table 3 
Proposed Biomarkers for Exploratory Research ......................... 80 
Table 4 
Guidelines for Management of Study Treatment in Patients 
Who Experience Specific Adverse Events .................................. 95 
Table 5 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 103 
Table 6 
Causal Attribution Guidance ..................................................... 104 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................... 46 
 
 
LIST OF APPENDICES 
Appendix 1 
 Schedule of Activities ............................................................... 129 
Appendix 2 
 Schedule of Pharmacokinetic and Biomarker Samples ........... 137 
Appendix 3 
 Pre-Enrollment Adjudication ..................................................... 139 
Appendix 4 
 Suggested Prednisone Taper Schedule Achieving 
< 10 mg/day by 12 and 36 Weeks ............................................. 140 
Appendix 5 
 American College of Rheumatology Revised Criteria for 
Classification of Systemic Lupus Erythematosus ...................... 141 
Appendix 6 
 Clinical and Immunologic Criteria Used in the SLICC 
Classification System ................................................................ 143 
Appendix 7 
 Systemic Lupus International Collaborating Clinics / 
American College of Rheumatology Damage Index for 
Systemic Lupus Erythematosus ................................................ 146 
Appendix 8 
 Childbearing Potential, Pregnancy Testing, and 
Contraception ............................................................................ 150 
Appendix 9 
 BILAG-2004 Index Glossary .................................................... 152 
Appendix 10 
 Systemic Lupus Erythematosus Disease Activity Index  
(SLEDAI-2K) ............................................................................. 170 
Appendix 11 
 SELENA-SLEDAI FLARE INDEX (SFI) ................................... 182 
Appendix 12 
 Glucocorticoid Toxicity Change Index ...................................... 183 
Appendix 13 
 28-Joint Count .......................................................................... 190 
Appendix 14 
 Cutaneous Lupus Erythematosus Disease Area and 
Severity Index (CLASI) ............................................................. 191 
Appendix 15 
 Physician’s Global Assessment ............................................... 194 


GDC-0853—Genentech, Inc. 
13/Protocol GA30044, Version 3 
Appendix 16 
 Patient’s Global Assessment ................................................... 195 
Appendix 17 
 Functional Assessment of Chronic Illness Therapy 
(FACIT)-Fatigue Scale (Version 4) ............................................ 196 
Appendix 18 
 Types and Doses of Standard Oral Treatments for Systemic 
Lupus Erythematosus Permitted in Study ................................. 197 
Appendix 19 
 Concomitant Medications (Including Foods and 
Herbal Products) ....................................................................... 198 


GDC-0853—Genentech, Inc.
14/Protocol GA30044, Version 3 
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE II, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY OF THE SAFETY AND 
EFFICACY OF GDC-0853 IN PATIENTS WITH 
MODERATE TO SEVERE ACTIVE SYSTEMIC LUPUS
ERYTHEMATOSUS
PROTOCOL NUMBER:
GA30044
VERSION NUMBER:
3
EUDRACT NUMBER:
2016-001039-11
IND NUMBER:
130,011
TEST PRODUCT:
GDC-0853 (RO7010939)
MEDICAL MONITOR:
, M.D., MPH
SPONSOR:
Genentech, Inc.
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy to the 
contact provided to the investigator at study start.








GDC-0853—Genentech, Inc.
18/Protocol GA30044, Version 3
AUC0-t area under the concentration–time curve from time 0 to time t; BICLA BILAG-based 
Composite Lupus Assessment; BILAG British Isles Lupus Activity Group; CLASI Cutaneous 
Lupus Erythematosus Disease Area and Severity Index; CL/F apparent clearance; 
Cmaxmaximum concentration observed; CTCAE Common Terminology Criteria for Adverse 
Events; Ctroughsteady-state concentration at the end of a dosing interval;
ECGelectrocardiogram; FACIT Functional Assessment of Chronic Illness Therapy;
GTCIGlucocorticoid Toxicity Change Index; NCI National Cancer Institute; OCS oral 
corticosteroids; PK pharmacokinetic; QOLquality of life; SLEDAI -2K Systemic Lupus 
Erythematosus Disease Activity Index 2000; SFI SELENA-SLEDAI SLE Flare Index;
SLICCSystemic Lupus International Collaborating Clinics; SLE systemic lupus erythematosus; 
SOC standard of care; SRI Systemic Lupus Erythematosus Responder Index; t1/2 half-life;
tmaxtime to maximum concentration.
Study Design
Description of Study
This is a multicenter, Phase II, randomized, double-blind, placebo-controlled, parallel-group, 
dose-ranging study to evaluate the safety and efficacy of GDC-0853 in combination with SOC 
therapy in patients with moderate to severe active SLE.  Moderate to severe SLE will be defined 
at screening and baseline (i.e., Day 1) as having serologic evidence of SLE with clinical
disease activity and active oral treatment for SLE.
The study will consist of a screening period (up to 35 days) and a 48-week treatment period, 
followed by either an 8-week safety follow-up visit at Week 56 or possible enrollment into an 
open-label extension (OLE) study.  Approximately 240 patients, meeting all eligibility criteria, will 
be randomized in a 1:1:1 ratio to one of the following 3 arms: 
Arm A:  GDC-0853 200 mg twice daily (BID)
Arm B:  GDC-0853 150 mg once daily (QD)
Arm C:  placebo 
All 3 arms will receive blinded study drug in combination with background SOC therapy.  
Randomization will be stratified by disease activity at screening, entry dose of oral 
corticosteroids (OCS), and geographic region. All patients will receive blinded study drug twice 
daily (GDC-0853, placebo, or both to maintain the blind) from baseline to Week 48 and will be 
assessed at site visits every 4 weeks (including a site-initiated phone call at Week 1) during the 
treatment period.  
Pre-enrollment adjudication by the Medical Monitor and his/her designees will occur for all 
patients who complete screening prior to their randomization into the study.  The Medical 
Monitor or assigned designee will make the final decision whether or not a patient is eligible for 
randomization.  
Background SOC therapy may consist of an OCS (which must be stable for 2 weeks prior to 
screening, dose not to exceed 40 mg/day of prednisone or equivalent) and/or certain oral 
immunosuppression regimens (which must be stable for 2 months prior to screening). All 
immunosuppressive and anti-malarial medication will be kept stable throughout the trial unless 
dose reductions are necessary due to toxicity.  All patients receiving immunosuppressive 
treatments are also encouraged to be on supportive therapy (e.g., folic acid, calcium, vitamin D). 
For patients who are on angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor 
blockers (ARBs) at study entry, doses of ACE inhibitors or ARBs should be kept stable for at 
least 10 days prior to randomization and throughout the trial whenever possible.  It is strongly 
recommended that ACE inhibitors or ARBs not be initiated during the OCS stability windows.
For patients on an OCS at baseline, there will be two, 12-week, OCS taper windows available to 
achieve the pre-specified OCS taper of 10 mg/day prednisone or equivalent.  The dose at the 
end of each OCS-stability window (i.e., the 12-week period immediately following the 12-week 
OCS taper window) will then be kept stable for an additional 12 weeks.  
In the case of increased SLE disease activity, there can be two temporary increases in the 
corticosteroid dose, called “bursts,” that may be administered if needed.  A burst may only be 
administered during a burst window (defined as the first 10 weeks of each OCS taper window)


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and only once per window.  A burst is defined as a temporary increase in corticosteroid dose 
(up to 40 mg/d prednisone or equivalent for Burst Window 1, and up to 20 mg/d prednisone or 
equivalent for Burst Window 2) with a taper back down to the dose immediately preceding the 
burst, all within a 2-week period.
If additional treatment is needed beyond the permitted burst therapy because of active SLE, as 
identified by the investigator, the patient may receive escape therapy; however, such patients 
will be considered trial-defined non-responders for the purposes of the primary analysis.
During taper, burst, and permitted escape therapies, patients will continue to receive their 
designated dose of study treatment.
Starting at the screening period, all patients must record their actual OCS use weekly, as 
instructed by study staff.
An unblinded IMC and Scientific Oversight Committee will be used to monitor multiple safety
assessments.  In addition, an interim analysis will be conducted after 50-80 patients in each 
treatment arm have completed 24 weeks of treatment and have been evaluated for SLE 
Responder Index (SRI)-4 response, in order to conduct a preliminary assessment of the 
benefit-risk profile of GDC 0853 and potentially enable early stopping for futility and/or safety 
issues.
Number of Patients
Approximately 240 patients, who meet all eligibility criteria, will be enrolled into the study. 
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 1875 years, inclusive

Able to comply with the study protocol

Fulfillment of SLE classification criteria according to either the current American College of 
Rheumatology (ACR) or Systemic Lupus International Collaborating Clinics (SLICC) criteria 
at any time prior to or at screening 

At least one serologic marker of SLE at screening as follows:
–
Positive antinuclear antibody (ANA) test by immunofluorescent assay with titer 
1:80; OR
–
Positive anti-double-stranded DNA (anti-dsDNA) antibodies; OR 
–
Positive anti-Smith antibody 

At both screening and Day 1, moderate to severe active SLE, defined as meeting all of the 
following unless indicated otherwise:
–
SLEDAI-2K score 8 (at screening only) with clinical SLEDAI-2K score 4.0 (at both 
screening and Day 1)
–
Physician’s Global Assessment 1.0 (out of 3) 
–
Currently receiving at least one standard oral treatment (e.g., corticosteroids, 
anti-malarials, and/or immunosuppressants) for SLE within the dose ranges, as 
specified below

If on an OCS, the dose must be 40 mg/day prednisone (or equivalent) and must 
have been stable for at least 2 weeks prior to screening as well as during screening

If on anti-malarial or immunosuppressant therapies, may only be receiving 
medications from the following list within the specified dose range; dose and route 
of administration must be stable for 8 weeks prior to screening as well as during 
screening:
–
Azathioprine:  1 to 2.5 mg/kg/day 
–
Methotrexate:  7.5 to 25 mg/week 
–
Mycophenolate mofetil:  500 to 3000 mg/day


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–
Mycophenolic sodium:  360 to 2160 mg/day
–
Hydroxychloroquine:  200 to 400 mg/day
–
Chloroquine:  100 to 250 mg/day 
–
Quinacrine: 100 to 200 mg/day
–
Other:  Consult with Medical Monitor
Note:  Any combination of azathioprine, methotrexate, mycophenolate mofetil, or 
mycophenolic sodium is prohibited.

For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate of 1% 
per year during the study treatment period and for a minimum of 60 days after the last dose 
of study drug or longer as required by local requirements for other standard of care 
medications.  Women using estrogen-containing hormonal contraceptives as a method of 
contraception must also use a barrier.
–
A woman is considered to be of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).
–
Examples of contraceptive methods with a failure rate of 1% per year include bilateral 
tubal ligation, male sterilization, hormone-releasing intrauterine devices, and copper 
intrauterine devices.  Established proper use of hormonal contraceptives that inhibit 
ovulation also have a failure rate of 1% per year; however, women using estrogen-
containing hormonal contraceptives as a method of contraception must also use a 
barrier, such as a male condom, in conjunction with the hormonal contraceptives.
–
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal 
are not acceptable methods of contraception.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, and agreement to refrain from donating sperm as defined below:
–
Men with female partners of childbearing potential must remain abstinent or use a 
condom plus an additional contraceptive method that together result in a failure rate of 
1% per year during the treatment period and for at least 120 days (16 weeks) after 
the last dose of study treatment.  Men must refrain from donating sperm during this 
same period.
–
Men with pregnant female partners must remain abstinent or use a condom during the 
treatment period and for at least 28 days after the last dose of study treatment to avoid 
exposing the embryo.
–
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal 
are not acceptable methods of contraception.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Proteinuria > 3.5 g/24 h or equivalent using urine protein-to-creatinine ratio (uPCR) in 
a first morning void urine sample

Active proliferative lupus nephritis (as assessed by the investigator) or histological 
evidence of active Class III or Class IV lupus nephritis on renal biopsy performed in the 6 
months prior to screening (or during the screening period)


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
History of having required hemodialysis or high dose corticosteroids (>100 mg/d 
prednisone or equivalent) for the management of lupus renal disease within 90 days of 
Day 1

Neuropsychiatric or central nervous system lupus manifestations, including but not limited 
to: seizure, psychosis, or acute confusional state within 52 weeks of screening

Serum creatinine > 2.5 mg/dL, or estimated glomerular-filtration rate (based on the 
4-variable Modification of Diet in Renal Disease equation) 30 mL/min or on chronic renal 
replacement therapy

History of receiving a solid organ transplant

Newly diagnosed (within the last 24 weeks) transverse myelitis 

History of anti–phospholipid antibody syndrome (APLS) with or without associated 
consumptive coagulopathy [catastrophic anti-phospholipid syndrome] at any time; presence 
of anti-phospholipid antibodies or a history of fetal loss, but without a history of 
thromboembolism or current requirement for anti-coagulation, are not exclusionary.
–
Patients on either aspirin up to 325 mg/day or clopidogrel are not excluded.  The 
permitted dose of aspirin to reduce the risk of non-fatal stroke, non-fatal myocardial 
infarction, and vascular death in patients at high risk of arterial thrombosis should 
follow local regulations and guidelines.

Evidence of active, latent, or inadequately treated infection with Mycobacterium tuberculosis
(TB) as follows:
–
A positive QuantiFERON TB-Gold® (QFT) performed at screening visit
–
If QFT unavailable, a Mantoux purified protein derivative (PPD) skin test as 
defined by the Centers for Disease Control and Prevention (CDC) guidelines, 
performed at the screening visit or within the 12 weeks prior to screening and read 
locally
–
A chest radiograph taken at the screening visit or documented results within the 
12 weeks prior to screening (chest radiograph must be read by a radiologist), without 
changes suggestive of active TB infection
–
If a patient has previously received an adequate documented course of therapy for 
either latent (36 weeks of isoniazid in a locale where rates of primary multi-drug 
resistant TB infection are < 5% or an acceptable alternative regimen, according to local 
guidelines) or active (acceptable multi-drug regimen, according to local guidelines) 
TB infection, neither a PPD test nor a QFT test need to be obtained, but a chest 
radiograph must still be obtained if not performed within the prior 12 weeks; this chest 
radiograph must be without changes suggestive of active TB infection

NOTE: Patients with a history of Bacille Calmette-Guérin (BCG) vaccination should be 
screened using the QFT test only.
If the initial QFT test is indeterminate, a confirmatory test with either a QFT or T-SPOT® TB 
test (performed locally if available).  The PI may consult with the Medical Monitor to discuss 
selection of confirmatory test based on the patient’s disease status and baseline 
immunosuppression.
–
An indeterminate QFT test followed by a negative QFT or negative T-SPOTtest 
should be considered a negative diagnostic TB test.
–
An indeterminate QFT test followed by an indeterminate QFT test or indeterminate 
T-SPOTtest should be considered a positive diagnostic TB test

Women who are pregnant or nursing (breastfeeding; within the last 12 weeks), or women 
intending to become pregnant, donate eggs or breast milk, or participate in in vitro 
fertilization during the study
–
For women of childbearing potential:  Positive serum pregnancy test result at screening 
or on Day 1 (a serum pregnancy test is needed on Day 1 ONLY if the urine pregnancy 
test is positive)


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
Significant and uncontrolled medical disease within the 12 weeks prior to screening in any 
organ system (e.g., cardiac, neurologic, pulmonary, renal, hepatic, endocrine [including 
uncontrolled diabetes mellitus], metabolic, GI, or psychiatric [including suicidality]) not 
related to SLE, which, in the investigator’s or Sponsor’s opinion, would preclude patient 
participation

Concomitant chronic conditions, in addition to SLE, (e.g., asthma, Crohn’s disease) that 
required oral, IV, or intramuscular (IM) steroids or immunosuppressive use in the 24 weeks 
prior to screening or are likely to require these during the course of the study

History of nongallstone-related pancreatitis or chronic pancreatitis that is judged to be 
clinically significant, in the opinion of the investigator (e.g., accompanied by upper 
abdominal pain or malabsorptive diarrhea)  

Evidence of autoimmune myositis 

History of cancer, including hematological malignancy and solid tumors, within 10 years of 
screening; basal or squamous cell carcinoma of the skin that has been excised and is 
considered cured and in situ carcinoma of the cervix adequately treated by curative therapy 
more than 1 year prior to screening are not exclusionary 

History of alcohol, drug, or chemical abuse within the 1 year prior to screening as 
determined by the investigator

Major surgery requiring hospitalization within 4 weeks of screening 

History of cerebrovascular accident (CVA) within 10 years or any history of hemorrhagic 
CVA, any history of spontaneous intracranial hemorrhage or a history of traumatic 
intracranial hemorrhage within 10 years

History of clinically uncontrolled cardiac arrhythmias 

Screening 12-lead ECG that demonstrates clinically relevant abnormalities that may affect 
patient safety or interpretation of study results, including
–
QT interval corrected using Fridericia’s formula (QTcF) 450 msec for female patients 
and 430 msec for male patients demonstrated by at least two ECGs 30 minutes 
apart

History of clinically significant ventricular dysrhythmias or risk factors for ventricular 
dysrhythmias such as long QT syndrome or other genetic risk factors (e.g., Brugada 
syndrome), structural heart disease (e.g., severe left ventricular systolic dysfunction, severe 
left ventricular hypertrophy), coronary heart disease (symptomatic, or with ischemia 
demonstrated by diagnostic testing, prior coronary artery bypass grafting, or coronary 
lesions 70% diameter stenosis that have not been or cannot be re-vascularized), or family 
history of sudden unexplained death or cardiac ion channel mutations 

Current treatment with medications that are well known to prolong the QT interval (except for 
anti-malarials) at doses that have a clinically meaningful effect on QT, as determined by the 
investigator.  The investigator may contact the Sponsor for confirmation if needed.  The 
investigator may reference the website: 
https://www.crediblemeds.org/pdftemp/pdf/CompositeList.pdf

Any condition possibly affecting oral drug absorption (e.g., gastrectomy, clinically significant 
diabetic gastroenteropathy, or certain types of bariatric surgery such as gastric bypass); 
procedures, such as gastric banding, that simply divide the stomach into separate chambers 
are not exclusionary

Need for systemic anticoagulation with warfarin, or other oral or injectable anticoagulants
(other than NSAIDs, aspirin (325 mg/day), or other salicylates)

Known bleeding diathesis

Any history of hospitalization or transfusion for a GI bleed 

History of or currently active primary or secondary immunodeficiency, including known 
history of HIV infection or IgG 500 mg/dL


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
Any known active infection during screening up to and including at the time of enrollment 
(with the exception of fungal nail infections or oral herpes)

History of treated recurrent bacterial, viral, mycobacterial, or fungal infections, defined as 
2 similar episodes requiring anti-microbial treatment within the past 52 weeks, with the 
exception of the following:
–
Oral or genital herpes (herpes simplex virus 1 [HSV1]/ herpes simplex virus 2 [HSV2])
–
Uncomplicated cystitis or asymptomatic bacteriuria
–
Uncomplicated viral, bacterial or culture-negative bronchitis without pneumonia
–
Bacterial or viral sinusitis
–
Bacterial or fungal (yeast) vaginal infections

Any history of opportunistic infections that, in the Investigator's or Sponsor’s judgment, 
would raise safety concerns regarding the patient's participation in the study

Any major episode of infection requiring hospitalization or treatment with IV or IM 
antimicrobials within 4 weeks prior to or during screening or treatment with oral 
antimicrobials within 2 weeks prior to and during screening (with the exception of prophylaxis 
for Pneumocystis jiroveci pneumonia)

History of severe and/or disseminated viral infections, particularly herpes viruses, such as 
HSV1, HSV2, varicella zoster virus (VZV), cytomegalovirus (e.g., herpes encephalitis, 
ophthalmic herpes, disseminated zoster, cytomegalovirus colitis); uncomplicated influenza 
during a flu season, herpes labialis, and genital herpes are not exclusionary

Evidence of chronic and/or active hepatitis B or C
–
Positive hepatitis B surface antigen (HBsAg) or hepatitis C serology (regardless of 
treatment status)
–
Positive hepatitis B core antibody (HBcAb)

Received any of the following medications and/or treatments within the indicated period of 
time:
–
Plasmapheresis or IV Ig in the last 12 weeks prior to screening
–
B cell–depleting therapy (e.g., anti-CD20 or anti-CD19) within 24 weeks prior to 
screening 
–
Belimumab, blisibimod, tabalumab (or other anti-B-cell activating factor [BAFF] agents), 
atacicept (or other anti-transmembrane activator and calcium-modulator and cyclophilin 
ligand [CAML] interactor [TACI] agents), epratuzumab (or other anti-CD22 agents), or 
denosumab within 5 half-lives or 12 weeks (whichever is longer) prior to screening
–
Cyclophosphamide or other alkylating agents within 12 weeks prior to screening
–
Oral cyclosporine, tacrolimus, topical calcineurin inhibitors, anakinra (inhibitor IL-1), 
sirolimus (inhibitor IL-2), or other calcineurin inhibitors within 4 weeks prior to screening  
–
Thalidomide or thalidomide derivatives within 24 weeks prior to screening 
–
Tumor necrosis factor (TNF)-antagonists, tocilizumab, or other biologics not previously 
mentioned above within 12 weeks prior to screening
–
Any investigational drug within 4 weeks or 5 half-lives, whichever is longer, of 
screening
–
Any parenteral (IV), IM, or intra-articular steroid administration within 4 weeks prior to 
screening
–
Any other immunosuppressive medication for SLE not listed in the inclusion criteria, 
within 12 weeks or 5 half-lives prior to screening, whichever is longer, unless approved 
by the Medical Monitor 
–
Live vaccines within 6 weeks prior to randomization; seasonal influenza and H1N1 
vaccination are permitted if the inactivated vaccine formulation is administered


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
Use of any of the medications, herbal supplements, or foods in the categories below should 
be avoided within 1 week or 5 half-lives, whichever is longer, prior to randomization, on the 
basis of possible drug interactions with GDC-0853 unless otherwise advised by the Medical 
Monitor (or delegate) as part of the adjudication process (see Section 4.4 for additional 
information; the screening period may be extended to meet these criteria if approved by the 
Medical Monitor):  
–
Strong CYP3A inhibitors (refer to Appendix 19 for examples)
–
Moderate or strong CYP3A inducers (refer to Appendix 19 for examples)

Any uncontrolled, clinically significant, laboratory abnormality that would affect safety, 
interpretation of study data, or the patient’s participation in the study

Any of the following laboratory results, for which testing may be repeated once if the initial 
results are out of range during screening:
–
AST or ALT 1.5 ULN
–
Total bilirubin 1.2 ULN
–
Amylase or lipase 2 ULN
–
Hemoglobin 7 g/dL
–
Absolute neutrophil count (ANC) 1.5 109/L
–
Absolute lymphocyte count (ALC) 0.5 109/L
–
Platelet count 50,000/L
–
Note: Other abnormal labs may be repeated at the discretion of the investigator.  
Final determination of whether the lab result is exclusionary will be made by the 
adjudication committee and Medical Monitor.
End of Study
The end of study is defined as the last patient, last safety follow-up visit in this protocol, last 
patient to discontinue from the study, or the last patient enrolled into an OLE, if initiated, 
whichever occurs latest.
Length of Study
The maximum length of time on study for a patient is 61 weeks, including screening for up to 
35 days, treatment for 48 weeks, and a safety follow-up period for 8 weeks (unless enrolled into 
an OLE study). 
Investigational Medicinal Products
Test Product (Investigational Drug)
The investigational medicinal product (IMP) for this study is GDC-0853 50-mg tablets.
Comparator
The comparator will comprise corresponding matching placebo tablets, which will be 
indistinguishable in appearance.
Non-Investigational Medicinal Products
All patients who enter the study on oral immunosuppressant therapy (not including 
corticosteroids) or anti-malarial medications will be instructed to maintain their medications 
and doses from screening throughout the rest of the study treatment period.  After entering the 
study, patients may not begin taking a new oral immunosuppressant except in the case of 
increased clinical activity requiring escape therapy.
Corticosteroids
For all patients who enter the study on oral prednisone (or permitted equivalent OCS), there will 
be two, 12-week, OCS taper windows (Weeks 0 to 12, and Weeks 24 to 36) where their dose, if 
10 mg/day, will be tapered to 10 mg/day.  During a taper window, patients will continue to 
receive their designated dose of study treatment. 


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The OCS rules are as follows:  the OCS dose level achieved at the end of each OCS taper 
window will be maintained during the 12-week, OCS stability windows (Weeks 12 to 24 and 
Weeks 36 to 48), whether or not the target OCS dose was achieved.  Patients will be instructed 
not to deviate from this dose level achieved at the end of the OCS taper window, unless 
considered clinically appropriate by the investigator.  
Patients should follow the appropriate tapering schedule as determined by the investigator, 
taking into account the taper window timing and the target OCS dose (10 mg/day and Day 1 
dose).  The investigator may modify a tapering schedule based on the patient’s response to the 
reduction in corticosteroid dose.  A suggested prednisone tapering schedule is provided; in 
addition, the investigator may consult the Medical Monitor.  Once 10 mg/day is achieved, 
tapering completely off corticosteroids is allowed if this is deemed clinically appropriate by the 
investigator (i.e., if there is minimal risk of inducing flare). 
It is recommended that all patients receiving corticosteroids should receive appropriate 
supportive therapy to help prevent steroid-induced osteoporosis (e.g., calcium, vitamin D 
supplements, bisphosphonates) as per local guidelines and physician preference.  
Pneumocystis jiroveci pneumonia prophylaxis is also recommended to be used as per local 
SOC.
Intra-articular injections and intra-lesional cutaneous injections of corticosteroids must be 
avoided during the study if possible, as these interventions will confound the efficacy 
assessments.
If a patient entered the study on low potency topical steroids (e.g., Class VI and Class VII), the 
steroid can be continued during the course of the study at a stable dose
Burst Treatment
In the case of increased disease activity, the patient will have the opportunity to receive burst 
treatment, in addition to the study treatment, during the defined burst treatment window.  The 
patient should return to the clinic, either at a scheduled study visit or unscheduled flare visit, to 
be evaluated and to receive an increase or new dose of oral prednisone as follows:

Burst Window 1 (Weeks 0 to 10):  An increase or new dose of oral prednisone up to 
40 mg/day (or equivalent)

Burst Window 2 (Weeks 24 to 34):  An increase or new dose in oral prednisone up to 20 
mg/day (or equivalent)
When using corticosteroids as a burst treatment, the investigator will temporarily increase the 
dose of corticosteroids and then taper the patient back down to their previous corticosteroid 
dose used prior to the initiation of the burst, all over the course of 2 weeks.  Patients will 
continue to receive their designated dose of study treatment during the burst treatment.  The 
previous corticosteroid dose is defined as the dose of corticosteroids taken for the 2 weeks prior 
to the burst (if the dose changed during the 2 weeks, the investigator may choose which dose to 
use).  If the patient was not previously on corticosteroids, the investigator will taper the patient 
back off corticosteroids completely.  If the patient was on a corticosteroid-tapering schedule at 
the time of the burst treatment, the investigator will revise the tapering schedule as necessary to 
meet the target OCS dose (10 mg/day and Day 1 dose) by the end of the taper window, if 
clinically appropriate.
Patients may receive corticosteroids for emergent illness other than SLE (e.g., trauma, asthma) 
or if clinically warranted to prevent adrenal crisis (e.g., prior to surgery).  If possible, treatment in 
these cases should last no more than 7 days.
Escape Therapy
If an increase in immunosuppressive therapy (referred to as “escape therapy”) is deemed 
medically necessary due to increased SLE disease activity, the patient will be given escape 
therapy, which will be recorded on the Steroid and Immunosuppressant eCRF.  Patients 
receiving the following escape therapies, may be allowed to remain on study drug after 
discussion with the Medical Monitor but will be considered a protocol-defined “non-responder” 
in the primary analysis:  

IV or IM steroids (at doses greater than 40 mg prednisone PO or equivalent)


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
OCS doses exceeding the limits described elsewhere in the protocol (e.g., prednisone (or 
equivalent) doses of > 40 mg/day during the first 24 weeks of the study, or > 20 mg/day 
between Weeks 24 and 48)

New or increased doses of an immunosuppressant or anti-malarial medication up to the 
maximum allowed in the study 
NOTE:  Combinations of immunosuppressant medications that are not allowed in the inclusion 
and exclusion criteria are prohibited during the study.
Statistical Methods
Primary Analysis
The primary efficacy endpoint for this study is SRI-4 response at Week 48.
The primary endpoint will be compared between each of the two GDC-0853 arms and the 
placebo arm by using the Cochran-Mantel-Haenszel test statistic, stratified by the factors 
used at randomization. The absolute difference in remission rates and 95% CI for the point 
estimate will be provided.  
Determination of Sample Size  
The purpose of this study is estimation and hypothesis generation regarding the effect of 
GDC-0853 on Week 48 SRI-4 response rate relative to placebo in moderate to severe active 
SLE patients and a biomarker-defined subgroup of patients.  A total of 240 patients will be 
randomly allocated in a 1:1:1 ratio to receive one of two doses of GDC-0853 (200 mg BID 
GDC-0853 [Arm A] or 150 mg QD GDC-0853 [Arm B]) or placebo (Arm C).  This sample size 
will provide approximately 88% power at a 2-sided 0.05 significance level to detect a 25% 
absolute improvement in the response rate for a GDC-0853 containing arm relative to the 
placebo arm assuming a placebo response-rate of 50%.  Patients without post-baseline 
response assessments will be treated as non-responders.  For an evaluation of efficacy in a 
subgroup defined by a predictive biomarker with 50% prevalence, the total sample-size of 
80 patients per arm provides approximately 80% power to detect a 25% improvement with 2-
sided 0.20 significance level, using the Fisher’s Exact Test.  No adjustment for multiple 
comparisons will be made.
Interim Analyses
An interim analysis will be performed after 5080 patients in each of treatment arm have 
completed their 24-week SRI-4 response evaluation.  The purpose of the interim analysis is to 
conduct a preliminary benefit-risk assessment of GDC-0853 treated arms compared with the 
placebo-treated arm and enable potential stopping for futility and/or safety concerns or to 
potentially inform the clinical development plan for GDC-0853. The interim analysis will be 
performed and interpreted by the IMC in conjunction with a Scientific Oversight Committee who 
will be unblinded at the treatment group level.  Additional personnel, such as Clinical 
Pharmacology and biomarker scientists, may be unblinded in order to prepare additional data 
displays relevant for IMC and Scientific Oversight Committee review.  
The study will continue to enroll while the interim analysis is being performed.  If the interim 
analysis indicates that one of the two dose levels of GDC-0853 does not have an appropriate 
safety profile or meets futility criteria as defined in the interim analysis plan in the DAP which will 
be written prior to conducting the interim analysis, the Sponsor may discontinue enrollment into 
that dose arm and switch patients to the other dose arm for the remainder of the study.  The 
Sponsor may also elect to amend the protocol to change the dose level of GDC-0853.   
Given the hypothesis-generating nature of this study, the Sponsor may choose to conduct an 
additional efficacy interim efficacy analysis in order to further guide internal decision making 
around issues such as the adequacy of dose ranging, the adequacy of sample sizes for safety 
and/or efficacy analyses, or to inform the clinical development plan for GDC-0853.  The study 
will not be stopped for any other reason other than futility or safety concerns at the time of the 
interim analysis.  The interim analysis will be performed and interpreted by the IMC in 
conjunction with a Scientific Oversight Committee who will be unblinded at the treatment group 
level.  Additional personnel, such as Clinical Pharmacology and biomarker scientists, may be 
unblinded in order to prepare additional data displays relevant for IMC and Scientific Oversight 
Committee review.  The decision to conduct an additional interim analysis and the timing of the 


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analysis will be documented in the Sponsor’s trial master file and updated DAP prior to the 
conduct of the interim analysis.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ACE
angiotensin converting enzyme
ACR
American College of Rheumatology
AESI
adverse event of special interest
ALP
alkaline phosphatase,
ALT
alanine aminotransferase
ANA
antinuclear antibody
ALC
absolute lymphocyte count
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
ARB
angiotensin receptor blocker
AST
aspartate aminotransferase
AUC
area under the concentration timecurve
AUC0-24
area under the concentration timecurve from time 0 to Hour 24
BAFF
anti-B-cell activating factor
BCG
Bacillus Calmette-Guérin
BCR
B-cell receptor
BCRP
breast cancer resistance protein
BICLA
BILAG-based Composite Lupus Assessment
BID
twice daily
BILAG
British Isles Lupus Activity Group
BTK
Bruton’s tyrosine kinase
Cmax
maximum concentration observed
Css,ave
mean plasma concentration
Ctrough
steady-state concentration at the end of a dosing interval
CAML
calcium-modulator and cyclophilin ligand
CBC
complete blood count
CDC
Centers for Disease Control and Prevention
CIA
collagen-induced arthritis
CK
creatinine kinase
CLASI
Cutaneous Lupus Erythematosus Disease Area and Severity Index
CLL
chronic lymphocytic leukemia
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
CVA
cerebrovascular accident
CyTOF
mass cytometry
DAP
data analysis plan


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Abbreviation
Definition
DLAE
dose-limiting adverse event
DMARD
disease-modifying antirheumatic drug
dsDNA
double stranded DNA
E.U.
European Union
EC
Ethics Committee
ECG
electrocardiogram
eCRF
electronic Case Report Form
EDC
electronic data capture
EDTA
European Dialysis and Transplant Association
ERA
European Renal Association
EULAR
European League Against Rheumatism
FACIT
Functional Assessment of Chronic Illness Therapy
FDA
Food and Drug Administration
GERD
gastroesophageal reflux disease
GGT
gamma-glutamyl transpeptidase
GI
gastrointestinal 
GTCI
Glucocorticoid Toxicity Change Index
H2RA
H2 receptor antagonists
HbA1c
hemoglobin A1c
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HDL
high-density lipoprotein
HIPAA
Health Insurance Portability and Accountability Act
HN
home nurse
HPF
high-power field
HSV1
herpes simplex virus 1
HSV2
herpes simplex virus 2
ICH
International Conference on Harmonisation
IFN
interferon
IFN-
interferon-alpha
Ig
immunoglobulin 
IL
interleukin
IM
intramuscular


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Abbreviation
Definition
IMP
investigational medicinal product
IND
Investigational New Drug (application)
INR
international normalized ratio
IRB
Institutional Review Board
IV
intravenous
Ki
inhibitory constant
LDH
lactate dehydrogenase
LDL
low-density lipoprotein
LPLV
last patient, last visit
MAD
multiple-ascending dose
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MDD
minimal detectible difference
NCI
National Cancer Institute
NOAEL
no observed adverse effect level
NSAID
nonsteroidal anti-inflammatory drug
NZB
New Zealand Black
NZW
New Zealand White
OCS
oral corticosteroids
OLE
open-label extension
PBMC
peripheral blood mononuclear cells
PD
pharmacodynamics(s)
PK
pharmacokinetic(s)
PPD
purified protein derivative
PPI
proton pump inhibitors 
PRO
patient-reported outcome
PT
prothrombin time
QTcF
QT interval corrected using Fridericia’s formula
QFT
QuantiFERON TB-Gold®
QD
daily
RA
rheumatoid arthritis
RBC
red blood cell
RBR
Research Biosample Repository
RDW
red cell distribution width
SAD
single-ascending dose
SELENA
Safety of Estrogen in Lupus Erythematosus National Assessment


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Abbreviation
Definition
SFI
SELENA- SLEDAI Flare Index
SLE
systemic lupus erythematosus 
SLEDAI
Systemic Lupus Erythematosus Disease Activity Index
SLICC
Systemic Lupus International Collaborating Clinics
SOC
standard of care
SRI
Systemic Lupus Erythematosus Responder Index
SUSAR
serious, unexpected suspected adverse reaction
t1/2
half-life
tmax
time to maximum concentration
TACI
transmembrane activator and CAML interactor
TB
tuberculosis
TBNK
T, B, and natural killer cells
TDAR
T-dependent antigen response test
TNF
tumor necrosis factor
TNF-
tumor necrosis factor-alpha
TWEAK
TNF-like weak inducer of apoptosis
U.S.
United States
ULN
upper limit of normal
VAS
visual analogue scale
VZV
varicella zoster virus
WBC
white blood cell
WGS
whole-genome sequencing
XLA
X-linked agammaglobulinemia


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1.
BACKGROUND
1.1
BACKGROUND
Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease that occurs 
primarily in women of childbearing age.  It is characterized by multisystem involvement 
and immunological abnormalities, and much of the tissue damage is thought to occur 
through autoantibody formation and immune complex deposition.  The disease is 
heterogeneous in its clinical presentation, course, and prognosis.  However, most 
patients present with joint involvement, skin rashes, mouth ulcers, Raynaud’s 
phenomenon, and/or severe fatigue.  Inflammation of pericardial and pleural tissues may 
also be present.  The most serious manifestations include central nervous system and 
renal involvement, which correlate with poor outcomes that include temporary or 
permanent disability or death.  Typically, the disease follows a relapsing-remitting course 
with intermittent periods of disease activity (flare) interspersed with periods of relative 
quiescence.
The incidence and prevalence of SLE varies with sex, race, and ethnicity.  The 
estimated prevalence of SLE ranges between 65 and 155 per 100,000 
(Walsh et al. 2001; Ward 2004; Naleway et al. 2005; Chakravarty et al. 2007; 
Molina et al. 2007; Sacks et al. 2010; Feldman et al. 2013; Furst et al. 2013; 
Lim et al. 2014).  In adulthood, approximately nine times as many women as men are 
affected.  The disease has a higher incidence and worse outcome among 
African-Americans, Afro-Caribbeans, Hispanics, and Asians compared with Caucasians.
Medications for the successful treatment of SLE as measured by long-term remission 
are limited, and only one new medication for SLE treatment has been approved in more 
than 50 years (Burness and McCormack 2011).  Analgesics and nonsteroidal 
anti-inflammatory drugs (NSAIDs) provide partial symptomatic relief.  Anti-malarial drugs 
are generally well tolerated by patients with SLE and appear to have a beneficial effect 
on the prevention of lupus flares, increasing long-term survival, and possibly 
ameliorating certain types of organ damage (Ruiz-Irastorza et al. 2009).  However, these 
agents are generally regarded as having insufficient efficacy for moderate to severe 
manifestations of SLE.
The mainstays of therapy for more significant manifestations of SLE are corticosteroids 
and off-label use of immunosuppressive drugs (e.g., methotrexate, mycophenolic acid 
[as either mycophenolate mofetil or Myfortic(mycophenolic acid as sodium salt)], 
azathioprine, and cyclophosphamide), which have profound and diverse effects on the 
immune system in patients with lupus (Tunnicliffe et al. 2015).  However, the use of 
these immunosuppressant agents is limited by their safety profiles.  Corticosteroids, for 
example, are effective for many of the manifestations of SLE but have significant 
short- and long-term adverse effects, including infections, osteoporosis, hyperglycemia, 
hypertension, osteonecrosis, cataracts, and hyperlipidemia.


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As a measure of unmet need, the risk of mortality remains elevated for patients with 
lupus.  In the modern era, on the basis of a multisite international cohort of 9500 patients 
with lupus, the standardized mortality ratio was 2.4, with particularly high mortality seen 
with renal disease (Fors Nieves and Izmirly 2016).  The development of new treatments 
for SLE patients with increased efficacy and decreased toxicity remains an important 
and a necessary area of investigation. 
1.2
BACKGROUND ON BRUTON’S TYROSINE KINASE AND 
GDC-0853
1.2.1
Bruton’s Tyrosine Kinase
Discovery of the genetic basis for primary immunodeficiencies has been the source 
of new therapeutic targets in immunomodulatory therapies (Puri et al. 2013; 
Bugatti et al. 2014; Whang and Chang 2014). In humans, inactivating mutations in the
gene for Bruton’s Tyrosine Kinase (BTK), which is located on the X chromosome, can
result in the development of an immunodeficiency state characterized by a significant
absence of circulating B cells (Bruton 1952; Tsukada et al. 1993; Vetrie et al. 1993;
Conley et al. 2005) and very low immunoglobulin (Ig) levels due to a defect in B-cell 
differentiation at the pro- to pre-B cell stage that precludes assembly of the B-cell 
receptor (BCR) complex and Ig gene expression (Reth and Nielsen 2014).  Affected male 
patients have a primary immune deficiency called X-linked agammaglobulinemia (XLA) 
and are susceptible to recurrent infections starting shortly after birth.  XLA patients can 
live relatively normal lives on a standard therapy of intravenous (IV) Ig (Kaveri et al. 
2011), suggesting that BTK can be safely inhibited especially in people with established 
immune systems.
BTK is a tyrosine kinase essential for signaling events required for the differentiation and
activity of B cells during immune system ontology and normal adaptive immune
responses. In addition, BTK is required for signaling associated with FcR, expressed 
on a variety of myeloid cells.  BTK is activated by phosphatidylinositol 
3-kinasedependent plasma membrane recruitment and phosphorylation on tyrosine 
Y551 by the Src-family kinase Lyn. Autophosphorylation and activation also occurs on
tyrosine Y223 in a BTK-specific manner.  Once activated, BTK induces PLC2- and 
Ca2-dependent signaling, which leads to the activation of NF-κBand NFAT-dependent
pathways leading to cellular activation and differentiation (Niiro and Clark 2002). 
The therapeutic potential of BTK inhibitors as anti-cancer agents has been established in 
clinical trials with agents, including ibrutinib, a covalent inhibitor of BTK, which has been 
approved in the United States and Europe for use in patients with mantle-cell lymphoma, 
chronic lymphocytic leukemia (CLL), and Waldenstrom’s macroglobulinemia.
1.2.2
Nonclinical Experience with GDC-0853
GDC-0853 is a highly selective, orally administered, reversible inhibitor of BTK that is 
being developed by Genentech, Inc. as a potential therapeutic for autoimmune diseases, 


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including rheumatoid arthritis (RA) and SLE.  GDC-0853 has undergone extensive 
investigation in nonclinical in vitro and in vivo studies to characterize its pharmacological, 
metabolic, and toxicological properties (see the GDC-0853 Investigator’s Brochure).
In vitro cell-based experiments suggest that antagonism of BTK leads to inhibition of 
BCR-dependent cell proliferation and a reduction of inflammatory cytokine production 
from myeloid cells (including tumor necrosis factor alpha [TNF-, interleukin [IL]-1, and
IL-6) by preventing signaling through the FcRIII receptor (di Paolo et al. 2011; Liu et al.
2011).  GDC-0853 effectively blocks BCR- and CD40-mediated activation and 
proliferation of B cells. BTK in B cells also plays a role in TLR4-mediated B-cell 
proliferation and class switching.  In monocytes, GDC-0853 inhibits TLR4- and immune 
complex-mediated inflammatory cytokine production, including TNF-, which contributes
to disease pathogenesis in SLE (Mina-Osorio et al. 2013; Bender et al. 2016). In 
dendritic cells, BTK contributes to TLR8-mediated cytokine production (TNF-and IL-6) 
(Sochorová et al. 2007). In basophils, BTK-dependent activation of the FcR leads to 
activation and up-regulation of CD63.  In addition, GDC-0853 has been shown to inhibit 
the differentiation of human plasmablasts into plasma cells in vitro (see the GDC-0853 
Investigator’s Brochure).  Patients with lupus have multiple abnormalities in the blood,
including increased levels of plasmablasts (Anolik et al. 2004).  Together, these data 
suggest that lupus patients with elevated levels of plasmablasts might demonstrate a 
more robust clinical response to GDC-0853.  Therefore, an RNA signature biomarker 
encompassing genes preferentially expressed in plasmablasts was developed to detect 
the presence of elevated plasmablasts in the peripheral blood.  In addition, efficacy in 
patients with high or low levels of the plasmablast signature will be compared for 
potential increased or decreased efficacy, respectively (see Table 1). 
The efficacy of GDC-0853 has been investigated in inflammatory models of arthritis as 
well as immune-complex mediated renal-injury models similar to the manifestations of 
human SLE.  Arthritis was investigated in female Lewis rats with developing Type II 
collagen-induced arthritis (CIA).  GDC-0853 treatment was well tolerated and resulted in 
significant and dose-dependent reduction in ankle swelling.  GDC-0853 was effective at 
significantly reducing anti-rat collagen II IgG antibodies in the serum (obtained on 
Day 16) with daily (QD) doses 0.25 mg/kg/day.  However, there was no effect of 
GDC-0853 treatment on total anti-rat IgG antibodies in the serum.  Findings from the 
histopathology evaluation were consistent with the clinical findings.  Immune-complex 
mediated inflammation (induced by autoantibodies) and tissue injury is central to the 
pathogenesis and the majority of clinical manifestations of SLE.  GDC-0853 in 
nonclinical studies is a potent inhibitor of these processes.  Studies in interferon-alpha 
(IFN-)accelerated, New Zealand Black (NZB)/New Zealand White (NZW), lupus-prone 
mice have shown that BTK-inhibition resulted in dose-dependent improvement in 
survival (see the GDC-0853 Investigator’s Brochure).  In addition, BTK inhibition reduces 
the development and levels of splenic plasmablasts, a pool of activated 


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antibody-producing B-cells, and systemic inflammation as evidenced by a decrease in 
the Type-1 interferon (IFN) signature in peripheral blood mononuclear cells (PBMCs).  
The GDC-0853 safety profile has been assessed in repeat-dose, general toxicology 
studies (daily oral dosing) ranging from 1 week to 9 months in rats and dogs; in vitro and 
in vivo genetic toxicology studies; in vitro phototoxicity evaluation; in vitro and in vivo 
safety pharmacology studies of the central nervous, respiratory, and cardiovascular 
system; and embryo-fetal development (Seg II) studies in rats and rabbits.  Overall, 
GDC-0853 was well tolerated for 6 months in rats (up to 104 M hr) and 9 months in 
dogs (up to 36 M hr).  Notable findings identified in nonclinical toxicology studies 
include vascular inflammation in dogs (56 M hr), hepatotoxicity in dogs (180 M hr), 
and a minimal increase in corrected QT interval in dogs (QTc; 7 msec or 3%; 
extrapolated unbound maximum observed concentration [Cmax] of 3.17 M). Fetal 
malformations in rats (at 627 M hr) and rabbits (10.6 M hr) warrant the continued 
use of contraception in clinical trials. On the basis of the nonclinical and clinical safety 
data to date, GDC-0853 is expected to be well tolerated at the doses and duration 
administered in the current study, GA30044.
1.2.3
Clinical Experience with GDC-0853
As of January 2016, GDC-0853 has been administered to 179 subjects (i.e., 155 healthy 
subjects, and 24 patients with hematological malignancies, at doses ranging from 0.5 to 
600 mg, and has been well tolerated with no safety signals.  In the single-ascending 
dose (SAD; GP29318), multiple-ascending dose (MAD; GA29347), ongoing relative 
bioavailability (GP29832), and oncology (GO29089) studies, GDC-0853 was generally 
well tolerated with adverse events being mostly non-serious, mild, and self-limited and 
with no dose-limiting adverse events (DLAEs) or dose-limiting toxicities.  
In healthy volunteer studies, there were no DLAEs, serious adverse events, study drug 
discontinuations for adverse events, or concerning patterns of adverse events that would 
preclude further development of GDC-0853.  Adverse events in healthy volunteers were 
all mild and included skin reactions (rash, contact dermatitis, and skin irritation from 
electrocardiogram [ECG] leads; 1 subject each), nausea (2 subjects), headache, 
toothache, contusion, and asymptomatic bacteriuria (1 subject each). 
In patients with hematological malignancies, the majority of adverse events were 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE) Grade 1 or Grade 2 and included fatigue, nausea, diarrhea, headache, 
abdominal pain, dizziness, cough, and thrombocytopenia.  There were nine serious 
adverse events reported in 5 patients: abdominal pain, lung infiltration, lung infection 
and pneumonia, febrile neutropenia, gastrointestinal (GI) hemorrhage and upper GI 
hemorrhage, and H1N1 influenza and influenza pneumonia.  There were two deaths 
during the study due to complications of confirmed influenza (H1N1 influenza and 
influenza pneumonia). As of March 2016, 7 patients remain on GDC-0853 (400 mg QD) 


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in Study GO29089 with daily dosing lasting up to 23 months (range 1823, average 
21 months).
Refer to the GDC-0853 Investigator’s Brochure for additional details on clinical studies.
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
The results from the Phase I studies, nonclinical toxicology studies, and studies in a 
nonclinical model of SLE support further evaluation of GDC-0853 as a potential 
treatment for SLE.  The goal of this Phase II study (GA30044) is to evaluate the safety 
and efficacy of GDC-0853 in combination with standard of care (SOC; see Section 2) in 
patients with moderate to severe SLE.  The study will test two dose levels of GDC-0853 
in comparison to placebo when added to background SOC.  The study is powered to 
detect a meaningful clinical benefit, in a composite measure of disease activity across 
multiple organ systems (see Section 3.3.6.2), and includes multiple safety assessments 
and monitoring by an unblinded Internal Monitoring Committee (IMC) and a Scientific 
Oversight Committee. 
Inhibition of BTK offers a promising mechanism for the treatment of autoimmune 
diseases, such as RA and SLE (Section 1.2.1); however, data from clinical studies are 
lacking.  Humans with a mutation in the XLA gene and who, therefore, lack functional 
BTK from birth, can live relatively normal lives on a standard therapy of IV Ig (Kaveri et 
al. 2011), suggesting that BTK can be safely inhibited, especially in people with 
established immune systems.  GDC-0853 did not deplete IgG substantially during short 
term treatment of healthy subjects in Phase I studies (see GDC-0853 Investigator’s 
Brochure), but it is not known whether longer term treatment of patients will induce 
depletion, therefore IgG levels will be monitored in this study.  Clinical data to date 
suggest that IgG levels in patients with an established immune system may not be 
significantly depleted, perhaps because BTK inhibitors target only the kinase domain 
and other BTK activities remain intact (Byrd et al. 2013). 
Overall, GDC-0853 has been well tolerated in Phase I healthy subjects and oncology 
studies.  Based on the compelling mechanism for BTK inhibition in SLE and the 
promising results in NZB/NZW lupus-prone mice, the risk-benefit ratio for this study is 
considered appropriate (see the GDC-0853 Investigator’s Brochure).  The safety profile 
of GDC-0853 will be further characterized in this Phase II study, and a robust 
safety-monitoring plan that describes the potential risks for GDC-0853 and the 
risk-mitigation strategies to minimize risks for the patients in this trial is provided in 
Section 5.1.  
Clinical experience with GDC-0853 to date has not generated safety concerns that 
would preclude further evaluation in patients with autoimmune diseases (see the 
GDC-0853 Investigator’s Brochure).  




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monitorable by changes in plasma transaminases and bilirubin that occurred at 
doses lower than those producing histopathology findings. No adverse liver findings 
were observed in the chronic toxicity studies in rats (104 M hr) and dogs 
(36 M hr). See Section 4 of the GDC-0853 Investigator’s Brochure for further 
details.

Fetal malformations were observed in rats (i.e., cleft palate observed at 627 M hr) 
and rabbits (i.e., domed-shaped heads with enlarged lateral/third ventricles at 
10.6 M hr).  Thus, highly effective contraception will be mandatory for trial 
participation, and pregnancy monitoring will be performed at least monthly in 
Study GA30044.

Pancreatic findings observed in rats administered GDC-0853, and other BTK 
inhibitors, were considered to be an on-target, species-specific effect, supported by 
a number of investigative studies (see the GDC-0853 Investigator’s Brochure for 
details).  
1.3.2
Potential Risks for Clinical Toxicities
GDC-0853 is in early clinical development and there is limited safety experience, so the 
actual risks in patients with SLE are unknown.  However, there are several potential 
risks on the basis of the expected mechanism of action of GDC-0853, published 
literature for similar molecules, nonclinical and clinical studies. Several measures will be 
taken to ensure the safety of patients participating in this study based on these potential 
risks (see Section 5.1 for details).  In addition, guidelines for the management of study 
treatment in patients who experience specific adverse events have been established 
(see Section 5.1.2 and Table 4).  Eligibility criteria in this study have been designed to 
exclude patients at higher risk for potential toxicities (see Section 4.1).  
1.3.2.1
Infections
GDC-0853 is a targeted immunomodulator and the degree to which GDC-0853 
antagonism of BTK signaling may suppress immune activity is unknown.  Patients 
participating in this study may be at risk for infections, including opportunistic infections.  
Therefore, the eligibility criteria are intended to protect patient safety and exclude 
patients that may be at a particularly increased risk of infection including those with 
marked baseline lymphopenia.  Total Ig concentrations will also be measured regularly 
throughout the study.  During the study, any serious infection, any infection requiring IV 
antimicrobials, or any opportunistic infection is considered an adverse event of special 
interest (AESI) with expedited reporting requirements to the Sponsor.
1.3.2.2
Vaccinations
The effect of GDC-0853 upon the efficacy of vaccinations is unknown.  It is 
recommended that appropriate vaccinations per European League Against Rheumatism 
(EULAR) recommendations (van Assen et al. 2010) or local guidelines be up to date 
before study participation.  However, as a safety measure, patients will be excluded from 
study participation and will not be dosed with GDC-0853 if they have been vaccinated 
with live, attenuated vaccines (e.g., the intranasal live attenuated influenza vaccines, 


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Bacillus Calmette-Guérin virus [BCG], and varicella) within 6 weeks before planned 
dosing.  
1.3.2.3
Bleeding
BTK is expressed in platelets and is involved in platelet function via GPVI/Collagen 
receptor signaling and GP1b receptor signaling.  Platelets from patients with XLA 
demonstrate decreased activation in response to submaximal collagen stimulation but 
normal response to thrombin.  However, clinically, there is no reported bleeding 
propensity in XLA patients (Howard et al. 2006).  In the GDC-0853 clinical study 
involving patients with cancer, two patients experienced Grade 3 GI bleeding.  These 
events were not dose related and occurred in patients on NSAIDs/acetylsalicylic acid 
with a history of gastroesophageal or peptic ulcer disease.
It is unknown if GDC-0853 will increase the risk of bleeding in SLE patients receiving 
antiplatelet or anticoagulant therapies.  Therefore, the eligibility criteria will exclude 
patients at highest risk for GI bleeding.  Patients at high risk for NSAID-related GI injury 
are advised to follow local or recognized guidelines, including concomitant use of proton 
pump inhibitors (PPIs), if indicated.  Any bleeding event of Grade 2 or above is 
considered an AESI with expedited reporting requirements to the Sponsor (see 
Section 5.4.2).
1.3.2.4
Cytopenias
Neutropenia, anemia, and thrombocytopenia have been observed in patients with 
hematologic malignancies who received GDC-0853.  Events have been monitorable and 
clinically manageable without dose discontinuations.  As patients with SLE may have 
cytopenias as a result of their intrinsic SLE disease activity, study eligibility criteria are 
designed to exclude those patients with more marked baseline cytopenias that may 
affect patient safety, and complete blood counts (CBCs) will be monitored regularly 
throughout the study.
1.3.2.5
Gastrointestinal Effects
Healthy subjects in the multiple ascending-dose study, GA29347, reported events of 
mild self-limited nausea.  In addition, Grade 1 diarrhea, nausea, and abdominal pain 
have been reported in patients with hematological malignancies treated with GDC-0853; 
however, the events resolved and have not led to study drug discontinuation.  
Throughout the study, patients will be monitored for GI side effects.  
1.3.2.6
Hepatotoxicity
Evidence of hepatobiliary injury was observed in animals administered relatively high 
doses of GDC-0853 in repeat-dose toxicity studies.  In clinical studies to date, including 
single dose and multiple dosing for 14 days in healthy subjects and daily dosing for over 
1 year in patients with hematological malignancies, there have been no adverse events 
of liver enzyme elevations or trends towards elevations in laboratory evaluations.  For 
inclusion in this study, AST and ALT levels should be no more than 1.5 times the upper 


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limit of normal (ULN), and total bilirubin levels should be normal at screening.  Baseline 
and routine evaluations of AST/ALT and total bilirubin levels will be performed 
throughout the study.  Elevated AST or ALT levels of Grade 3 (5ULN) or cases of 
potential drug-induced liver injury that include an elevated ALT or AST level in 
combination with either an elevated bilirubin level or clinical jaundice, as defined by Hy’s 
law (see Section 5.3.5.6), are AESIs with expedited reporting requirements to the 
Sponsor (see Section 5.4.2).  
1.3.2.7
Cardiovascular Effects
GDC-0853 is considered to have a low potential to cause QT interval prolongation or to 
directly affect other cardiovascular parameters at therapeutic exposures.  A minimal 
increase in corrected QT (QTc; 7 msec or 3%) interval was noted at 45 mg/kg in the 
single-dose cardiovascular safety pharmacology study in telemetry-instrumented dogs 
that was not considered to be clinically significant/meaningful.  Analysis of ECG data 
from the SAD and MAD studies in healthy subjects did not demonstrate any significant 
increase in either QRS interval or QTcF intervals.  Cardiac safety will be evaluated in all 
patients at baseline and throughout the study with routine monitoring of vital signs, 
including heart rate and blood pressure, collection of ECGs, and reporting of cardiac 
adverse events.  Patients with high cardiovascular risk will be excluded from study 
participation.
1.3.2.8
Vascular Inflammation
The risk to human safety based on toxicological findings of vascular inflammation in 
animal studies is uncertain.  As a safety risk-mitigation measure, CBC results, creatinine 
levels, and urinalysis findings will be monitored in all patients during the study.  Any 
patient that develops treatment-emergent vasculitis should be discussed with the 
Medical Monitor.
1.3.2.9
Malignancy
The impact of BTK inhibition on the development of malignancies is not known; however, 
malignancies are considered a potential concern for all immunomodulatory agents.  
Patients with a history of cancer within 10 years of screening will be excluded from study 
participation, except for basal or squamous cell carcinoma of the skin that has been 
excised and is considered cured and in situ carcinoma of the cervix treated with 
apparent success by curative therapy more than 1 year prior to screening.  All 
malignancies are AESIs with expedited reporting requirements to the Sponsor.  
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy, safety, and pharmacokinetics of GDC-0853
compared with placebo in patients with moderately to severely active SLE.  Specific 
objectives and corresponding endpoints for the study are outlined in Table 1.








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The study will consist of a screening period (up to 35 days) and a 48-week treatment 
period, followed by either an 8-week safety follow-up visit at Week 56 or possible
enrollment into an open-label extension (OLE) study.  Approximately 240 patients, 
meeting all eligibility criteria, will be randomized in a 1:1:1 ratio to receive GDC-0853 at 
one of two doses (200 mg BID [Arm A] or 150 mg QD [Arm B]) or placebo (Arm C), in 
combination with background SOC therapy.  Randomization will be stratified by disease 
activity at screening, entry dose of oral corticosteroids (OCS), and geographic region.
All patients will receive blinded study drug twice daily (GDC-0853, placebo, or both to 
maintain the blind) from baseline to Week 48 and will be assessed at site visits every 
4 weeks (including a site-initiated phone call at Week 1) during the treatment period (see
Figure 1).  
Pre-enrollment adjudication by the Medical Monitor and his/her designees will occur for 
all patients who complete screening prior to their randomization into the study (see
Appendix 3).  The Medical Monitor or assigned designee will make the final decision 
whether or not a patient is eligible for randomization.  
Background SOC therapy may consist of an OCS (which must be stable for 2 weeks 
prior to screening, dose not to exceed 40 mg/day of prednisone or equivalent) and/or 
certain oral immunosuppression regimens (which must be stable for 2 months prior to 
screening; see Section 4.1.1). All immunosuppressive and anti-malarial medication will 
be kept stable throughout the trial unless dose reductions are necessary due to toxicity.
All patients receiving immunosuppressive treatments are also encouraged to be on 
supportive therapy (e.g., folic acid, calcium, vitamin D). For patients who are on 
angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs)
at study entry, doses of ACE inhibitors or ARBs should be kept stable for at least 
10 days prior to randomization and throughout the trial whenever possible.  It is strongly 
recommended that ACE inhibitors or ARBs not be initiated during the OCS stability 
windows.
For patients on an OCS at baseline, there will be two, 12-week, OCS taper windows
available to achieve the pre-specified OCS taper of 10 mg/day prednisone or 
equivalent (see Appendix 4 and Figure 1).  The dose at the end of each OCS-stability 
window (i.e., the 12-week period immediately following the 12-week OCS taper window) 
will then be kept stable for an additional 12 weeks.  See Section 4.3.2.3 for more details.  
In the case of increased SLE disease activity, there can be two temporary increases in 
the corticosteroid dose, called “bursts,” that may be administered if needed (Figure 1).  A 
burst may only be administered during a burst window (defined as the first 10 weeks of 
each OCS taper window) and only once per window (see Section 4.3.2.3.3). A burst is 
defined as a temporary increase in corticosteroid dose (up to 40 mg/d prednisone or 
equivalent for Burst Window 1, and up to 20 mg/d prednisone or equivalent for Burst 
Window 2) with a taper back down to the dose immediately preceding the burst, all 
within a 2-week period.  


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If additional treatment is needed beyond the permitted burst therapy because of active 
SLE, as identified by the investigator, the patient may receive escape therapy; however, 
such patients will be considered trial-defined non-responders for the purposes of the 
primary analysis (see Section 4.3.2.3.4).
During taper, burst, and permitted escape therapies, patients will continue to receive 
their designated dose of study treatment (see Section 4.3.2).
Starting at the screening period, all patients must record their actual OCS use weekly, as 
instructed by study staff (see Section 4.3.2.4).
An unblinded IMC and Scientific Oversight Committee will be used to monitor multiple 
safety assessments (see Section 3.1.2).  In addition, an interim analysis will be 
conducted after 5080 patients in each treatment arm have completed 24 weeks of 
treatment and have been evaluated for SLE Responder Index (SRI)-4 response, in order
to conduct a preliminary assessment of the benefit-risk profile of GDC-0853 and 
potentially enable early stopping for futility and/or safety issues (see Figure 1 and 
Section 6.8 for details).
The study schema is displayed in Figure 1, and a schedule of activities is provided in 
Appendix 1.


 
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Figure 1 
Study Schema 
 
BID = twice daily; OCS = oral corticosteroid; OLE = open label extension; QD = daily. 
  
3.1.2 
Internal Monitoring Committee and Scientific Oversight 
Committee 
Regular safety reviews and the interim analysis will be performed by the Sponsor’s IMC.  
This committee will be unblinded to treatment assignments and will include a clinical 
scientist, in conjunction with a safety scientist, biostatistician, and statistical programmer 
from the Sponsor who are not members of the study management team.  The IMC 
members will not have direct contact with investigational staff or site monitors.  The IMC 
may request that additional Sponsor scientists (e.g., clinical pharmacology, biomarker) 
participate in data analysis.  The IMC members will also be part of a companion 
Scientific Oversight Committee.  This committee will review safety, pharmacokinetic (PK), 
and pharmacodynamic (PD) data and make recommendations to the Sponsor regarding 
continuation of the study and/or study drug dose modifications.  For further information, 
please see the Internal Monitoring Committee Charter. 
The Scientific Oversight Committee will be unblinded to treatment assignments and will 
include the IMC members and at least two external SLE experts who are not 
investigators in this study.  The Scientific Oversight Committee will meet periodically to 
review the study data.   


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After each meeting, either the IMC or Scientific Oversight Committee will recommend 
that the Sponsor proceed with one of the four following actions:  1) continue the study 
unchanged, 2) discontinue the study for safety reasons, 3) discontinue the study for 
futility (at the interim analysis), or 4) amend the study protocol.  For further information, 
please see the IMC and Scientific Oversight Committee Charter.  
3.2
END OF STUDY AND LENGTH OF STUDY
3.2.1
Length of Study
The maximum length of time on study for a patient is 61 weeks, including screening for 
up to 35 days, treatment for 48 weeks, and a safety follow-up period for 8 weeks (unless 
enrolled into an OLE study).  
3.2.2
End of Study
The end of study is defined as the last patient, last safety follow-up visit in this protocol, 
last patient to discontinue from the study, or the last patient enrolled into an OLE, 
whichever occurs latest.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for GDC-0853 Dose and Schedule
The proposed GDC-0853 doses of 150 mg QD and 200 mg BID for 48 weeks are 
expected to be well tolerated and to demonstrate BTK inhibition on the basis of the 
available safety, PK, and PD results from Phase I studies, nonclinical toxicology studies, 
and studies in nonclinical inflammatory models. 
These doses are expected to achieve exposures (i.e., area under the concentrationtime 
curve [AUC] and Cmax) below those achieved at the highest doses evaluated in the 
Phase I SAD and MAD studies (GP29318 and GA29347, respectively) and 5-fold below 
the exposures at the NOAEL of the nonclinical chronic toxicity studies (see the 
GDC-0853 Investigator’s Brochure).  In healthy subjects, doses up to 600 mg in Study 
GP29318 and 250 mg BID and 500 mg QD in Study GA29347 were well tolerated; all 
adverse events were Grade 1 (mild) and transient, there were no DLAEs, and no 
maximum tolerated dose (MTD) was identified.  
Dose-dependent BTK inhibition was demonstrated in the Phase I SAD and MAD studies 
(GP29318 and GA29347, respectively) through use of PD biomarker assays (e.g., CD63 
expression in basophils, phosphorylated-BTK inhibition).  PK and PD data from these 
studies were used to model the relationship between GDC-0853 systemic exposures 
and BTK-dependent biomarker inhibition.  
 

 
 
  


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
 
 
  
The efficacy of GDC-0853, as well as GDC-0834 (Liu et al. 2011) and G-744 (related 
small-molecule BTK inhibitors used to demonstrate the effect of BTK inhibition in 
nonclinical studies), was evaluated in nonclinical inflammatory models of arthritis and 
immune complexmediated renal injury (see Liu et al. 2011 for GDC-0834, and the 
GDC-0853 Investigator’s Brochure for GDC-0853 and G-744), in which disease 
manifestations are similar to those of human SLE.  In female Lewis rats with developing 
Type II CIA, GDC‑0853 treatment was well tolerated and resulted in significant and 
beneficial dose-dependent effects on ankle swelling.  Doses 0.25 mg/kg/day of 
GDC-0853 significantly reduced serum levels of anti-rat collagen II IgG, whereas total 
anti-rat IgG antibody serum levels did not change.  The histopathology findings were 
consistent with the clinical findings.  Studies in NZB/NZW lupus-prone mice with G-744 
have shown that BTK inhibition resulted in dose-dependent improvement in survival (see 
GDC-0853 Investigator’s Brochure).
These nonclinical studies suggest that 70% BTK inhibition, as measured by 
phosphorylated-BTK inhibition, is required for half-maximal activity in disease models 
(see the GDC-0853 Investigator’s Brochure; Liu et al. 2011).  
 
 
 however, whether BTK inhibition in the rat CIA 
or the mouse SLE model accurately predicts efficacy in human SLE is currently unknown.
The Sponsor believes that the existing clinical and nonclinical data support the proposed 
GDC-0853 doses of 150 mg QD and 200 mg BID for 48 weeks.  In addition, the Sponsor 
believes that these doses will enable robust characterization of exposure-response 
relationships across a wide range of exposures because of inter-individual PK variability.
 
 
 
 
 
 
 
 
 
 
 
3.3.2
Rationale for Patient Population
A substantial number of SLE patients fail to achieve an adequate response on the 
current SOC therapy and often the patients experience flares despite their current 


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treatment and medical compliance.  Furthermore, the mainstay of therapy for SLE is 
systemic corticosteroids, which can lead to significant morbidities.  Given the limitations 
with the current therapeutic options for SLE, there remains a need for therapies that 
provide a higher degree of both safety and efficacy.  
BTK inhibition should target several pathways and cell types central to SLE 
pathogenesis.  B-cell activation and differentiation into plasma cells is central to the
development of pathogenic autoantibodies (see the GDC-0853 Investigator’s Brochure 
for details).  BTK activity is central to B-cell activation and autoantibody production.  In 
addition, autoantigen-containing immune complexes are bound to Fc receptors on 
myeloid cells and their activation can lead to both inflammatory cytokine production as 
well as the presentation of additional autoantigens.  These processes can lead to a cycle 
of tissue injury, inflammation, and new autoantibody production.  BTK inhibition of both 
B cells and myeloid cells may contribute to efficacy (Chang et al. 2011; di Paolo et al. 
2011).  In addition, the reversible inhibition of BTK by GDC-0853 may allow for more 
rapid removal of suppression if infection occurs.  
This Phase II study will evaluate patients with unmet need due to active SLE despite 
being treated with SOC, including corticosteroids and/or concomitant 
immunosuppression.  Eligibility criteria for this study are similar to other Phase II 
proof-of-concept SLE studies and have been customized in some cases for patient 
safety (see Section 4.1). 
3.3.3
Rationale for Control Group
All patients in this study will receive SOC therapy for SLE.  Arm C is treated with placebo 
in combination with SOC in order to maintain the blind.  It is not known whether 
GDC-0853 will be better or worse than placebo in combination with SOC. 
The placebo-treated control group in Arm C is required for this study to achieve the 
safety and efficacy objectives.  Historical control groups are not sufficiently comparable 
given changes in SLE populations and treatment patterns over time and around the 
world.  Furthermore, refinements in study conduct, inherent variability in the subjective 
assessments and regional differences in the management of SLE patients require a 
placebo-treated control group to accurately determine the safety and efficacy of 
GDC-0853 relative to current SOCs.  The study treatment period, including the 
placebo-treatment period, will be 48 weeks, which has been the time necessary to 
establish the peak-level efficacy of SLE therapeutics, based on prior SLE studies.  
Multiple recent Phase II and Phase III studies incorporate 48-week placebo-comparator 
groups (Furie et al. 2017; Khamashta et al. 2016; Navarra et al. 2011).  If placebo patients 
have increased SLE disease activity, burst therapy, escape therapy, or both will be 
available (see Section 4.3.2.3.3 and Section 4.3.2.3.4 for details).


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3.3.4
Rationale for Biomarker Assessments
Diagnostic biomarker assessments aim to identify a biomarker that predicts response to 
GDC0853, which would be valuable to patients and treating physicians as an aid in 
identifying patients with increased likelihood to achieve clinical benefit, thus guiding 
treatment decisions.  In addition, at various timepoints after treatment, 
pharmacodynamic biomarker samples will be collected and used to advance the 
understanding of the mechanism of action of GDC-0853 and define PK/PD relationships 
in SLE patients aiding in dose evaluation in this study as well as dose-regimen selection 
for future studies (see Appendix 2).  
3.3.5
Rationale for PK Sample Collection Schedule
PK results will be used to perform robust exposure-response and exposure-safety 
analyses, which will help to characterize how safety and efficacy are impacted by drug 
exposure and, thus, inform appropriate doses and regimens for future studies of 
GDC-0853.  The PK sampling schedule is designed to capture data at several points 
during the study in order to enable the estimation of systemic GDC-0853 exposures and
subsequent exposure-response evaluations and dose-regimen selection for future 
studies (see Appendix 2), which may be reported separately.  
3.3.6
Rationale for Other Study Design Elements
3.3.6.1
Pre-Enrollment Adjudication
Enrollment into this trial is subject to adjudication by the Sponsor’s Medical Monitor or 
medically qualified designee.  The objective of the adjudication process is to ensure that 
eligibility is based on objectively ascertained, well-documented, and clinically important 
disease activity.  The scope and detailed procedures for the adjudication process are 
described in Appendix 3.
3.3.6.2
Efficacy Measurements
The primary efficacy endpoint in this study is a composite of the Systemic Lupus 
Erythematosus Responder Index (SRI)-4 at Week 48 (see Table 1).  The SRI-4 
response criterion is commonly used in SLE studies, is accepted by health authorities to 
measure reduction in SLE disease activity, and it is a composite measure that includes 
the SLE Disease Activity Index (SLEDAI-2K), British Isles Lupus Activity Group (BILAG) 
2004, and Physician Global Assessment.  SRI responses have been detected at 
timepoints as early as 12 weeks in prior clinical trials; however, therapeutic benefit is 
often measured at 24 weeks with maximal benefit seen as late as 48-52 weeks post-
treatment intervention (Burgess and McCormack 2011; Furie et al. 2017; Khamashta et al. 
2016; Navarra et al. 2011).  SRI-4 alone is the primary efficacy endpoint. Achievement 
of a low, stable, corticosteroid dose has been added to the SRI-4 in the secondary 
endpoint in order to minimize the confounding effect of corticosteroids, including inflation 
of the response rates in the comparator arm that can obscure detection of an efficacy 
signal. The BILAG-based Composite Lupus Assessment (BICLA) and the SRI-6 are also 
secondary endpoints as they provide a meaningful metric of SLE disease activity.


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In addition to the primary and secondary SRI endpoints, SRI 5, 7, and 8 are exploratory 
efficacy endpoints.  Furthermore, several other clinically meaningful and exploratory 
aspects of SLE disease activity will be evaluated, using the Cutaneous Lupus 
Erythematosus Disease Area and Severity Index (CLASI), SLICC/ACR Damage Index,
Physician Global Assessment, SELENA-SLEDAI Flare Index (SFI), 28-joint count, and 
patient-reported outcome (PRO) measures (i.e., Functional Assessment of Chronic 
Illness Therapy [FACIT]-Fatigue and Patient Global Assessment).  Each of these 
measures has been well established and validated in previous studies.  
3.3.6.3
Corticosteroid Taper
There is a substantial unmet need for effective corticosteroid-sparing treatments for SLE 
and this study will assess the corticosteroid sparing potential of GDC-0853.  Chronic 
corticosteroid use has many adverse short- and long-term consequences, so reducing 
corticosteroid doses in patients with SLE will decrease the incidence of short- and 
long-term co-morbidities and potential adverse events, including in patients in this trial. 
The Glucocorticoid Toxicity Change Index (GTCI) will be used to determine the potential 
of GDC-0853 to reduce steroid-induced systemic side effects (see Appendix 12).  In 
addition, the unrestricted use of corticosteroids in SLE clinical trials can confound safety 
and efficacy measurements and decrease the ability to detect the biologic 
activity/efficacy of the experimental drug (Reddy et al. 2013).  Thus, to best determine 
the safety and efficacy of GDC-0853, corticosteroids should be tapered according to a 
suggested taper schedule, as tolerated (see Appendix 4).  Furthermore, if a patient 
requires a corticosteroid burst during the Burst Windows, corticosteroids should be 
tapered back down to baseline (either the Day 1 dose or lowest stable dose the patient 
achieves) using the suggested taper schedule.  Study patients with disease activity that 
precludes tapering corticosteroid to the target level will be considered trial defined 
non-responders for the analysis of secondary and exploratory endpoints that incorporate 
the requirement for OCS tapering.
3.3.6.4
Clinical Outcomes Assessments
PRO and clinician-reported outcome data will be collected to more fully characterize the 
clinical profile of GDC-0853.  To minimize the confounding of PRO assessments that 
evaluate pain, any potentially painful procedures (e.g., blood draws) should be 
performed after the pain assessment.  
3.3.6.5
Stratification
Randomization will be stratified by disease activity based on the SLEDAI-2K score, entry 
dose of OCS, and geographic region obtained at screening.
Levels of baseline disease activity (SLEDAI-2K score) and corticosteroid use as well as 
geographic region independently impact a patient’s ability to achieve response on the 
primary efficacy endpoint.  Specifically, a reduction of 4 points in the SLEDAI-2K must 
be achieved to be classified as a responder.  In addition, use of corticosteroids in SLE 
clinical trials can confound efficacy measurements and decrease the ability to detect the 


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biologic activity/efficacy of the experimental drug.  For this reason, it is important to 
prevent treatment imbalances in these factors at baseline and thus randomization will be 
stratified by both SLEDAI-2K score (10 or 10) and baseline corticosteroid use.  
Geographic region was chosen as the third strata, because regional variations in the 
management of SLE can manifest as variability in response rates, including differences 
in placebo rates (Kalunian et al. 2016; Khamashta et al. 2016).  The stratification is 
intended to balance the proportion of patients from different regions across the study 
arms in order to limit any confounding of the study results. 
3.3.6.6
Concomitant Medication Rationale
Patients in this study will continue on their background SOC therapy in order to ensure 
that all patients receive effective therapy for SLE. GDC-0853 or placebo will be added to 
determine if GDC-0853 improves clinical response and/or reduces the need for systemic 
steroids in combination with SOC.  The eligibility criteria exclude patients on certain SLE 
therapies in order to reduce the risk of participation in this study.  Concomitant SLE 
therapies other than OCS will not be changed during the study (except in the event of 
toxicity), in order to reduce confounding effects on the safety and efficacy results of the 
study.  OCS doses may be changed during certain time windows to minimize toxicity or 
for short-term treatment of increased SLE disease activity (see Section 4.3.2.3.3).  
For guidance on concomitant medications that are unrelated to background SOC
therapy, please refer to Section 4.4. 
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 240 patients with moderate to severe active SLE will be enrolled in this 
study.
4.1.1
Inclusion Criteria
Patients must meet all of the following criteria for study entry:

Signed Informed Consent Form

Age 1875 years, inclusive

Able to comply with the study protocol

Fulfillment of SLE classification criteria according to either the current American 
College of Rheumatology (ACR) or Systemic Lupus International Collaborating 
Clinics (SLICC) criteria at any time prior to or at screening (see Appendix 5 and 
Appendix 6, respectively)

At least one serologic marker of SLE at screening as follows:
–
Positive antinuclear antibody (ANA) test by immunofluorescent assay with titer 
1:80; OR
–
Positive anti-double-stranded DNA (anti-dsDNA) antibodies; OR 


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–
Positive anti-Smith antibody 

At both screening and Day 1, moderate to severe active SLE, defined as meeting all
of the following unless indicated otherwise:
–
SLEDAI-2K score 8 (at screening only) with clinical SLEDAI-2K score 4.0
(at both screening and Day 1) (see Appendix 10) 
–
Physician’s Global Assessment 1.0 (out of 3) (see Appendix 15)
–
Currently receiving at least one standard oral treatment (e.g., corticosteroids, 
anti-malarials, and/or immunosuppressants) for SLE within the dose ranges, 
as specified below (see Appendix 18):
–
If on an OCS, the dose must be 40 mg/day prednisone (or equivalent, see 
Appendix 18) and must have been stable for at least 2 weeks prior to 
screening as well as during screening
–
If on anti-malarial or immunosuppressant therapies, may only be receiving 
medications from the following list within the specified dose range; dose 
and route of administration must be stable for 8 weeks prior to screening as 
well as during screening:
–
Azathioprine:  1 to 2.5 mg/kg/day
–
Methotrexate: 7.5 to 25 mg/week 
–
Mycophenolate mofetil:  500 to 3000 mg/day
–
Mycophenolic sodium:  360 to 2160 mg/day
–
Hydroxychloroquine:  200 to 400 mg/day
–
Chloroquine: 100 to 250 mg/day 
–
Quinacrine: 100 to 200 mg/day
–
Other: Consult with Medical Monitor
Note:  Any combination of azathioprine, methotrexate, mycophenolate mofetil, or 
mycophenolic sodium is prohibited.

For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods listed in Appendix 8 that 
result in a failure rate of 1% per year during the study treatment period and for a 
minimum of 60 days after the last dose of study drug or longer as required by local 
requirements for other standard of care medications.  Women using 
estrogen-containing hormonal contraceptives as a method of contraception must
also use a barrier.
–
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).
–
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, hormone-releasing intrauterine 


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devices, and copper intrauterine devices.  Established proper use of hormonal 
contraceptives that inhibit ovulation also have a failure rate of 1% per year; 
however, women using estrogen-containing hormonal contraceptives as a 
method of contraception must also use a barrier, such as a male condom, in 
conjunction with the hormonal contraceptives.
–
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, and agreement to refrain from donating sperm as 
defined below.  Please also see Appendix 8 for details:
–
Men with female partners of childbearing potential must remain abstinent or 
use a condom plus an additional contraceptive method that together result in a 
failure rate of 1% per year during the treatment period and for at least 
120 days (16 weeks) after the last dose of study treatment.  Men must refrain 
from donating sperm during this same period.
–
Men with pregnant female partners must remain abstinent or use a condom 
during the treatment period and for at least 28 days after the last dose of study 
treatment to avoid exposing the embryo.
–
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Proteinuria > 3.5 g/24 h or equivalent using urine protein-to-creatinine ratio 
(uPCR) in a first morning void urine sample

Active proliferative lupus nephritis (as assessed by the investigator) or histological 
evidence of active Class III or Class IV lupus nephritis on renal biopsy performed 
in the 6 months prior to screening (or during the screening period)

History of having required hemodialysis or high dose corticosteroids (>100 mg/d 
prednisone or equivalent) for the management of lupus renal disease within 90 days 
of Day 1

Neuropsychiatric or central nervous system lupus manifestations, including but not 
limited to: seizure, psychosis, or acute confusional state within 52 weeks of 
screening

Serum creatinine > 2.5 mg/dL, or estimated glomerular-filtration rate (based on the 
4-variable Modification of Diet in Renal Disease equation) 30 mL/min, or on 
chronic renal replacement therapy

History of receiving a solid organ transplant


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
Newly diagnosed (within the last 24 weeks) transverse myelitis 

History of anti–phospholipid antibody syndrome (APLS) with or without associated 
consumptive coagulopathy [catastrophic anti-phospholipid syndrome] at any time;
presence of anti-phospholipid antibodies or a history of fetal loss, but without 
a history of thromboembolism or current requirement for anti-coagulation, are not 
exclusionary.
–
Patients on either aspirin up to 325 mg/day or clopidogrel are not excluded.
The permitted dose of aspirin to reduce the risk of non-fatal stroke, non-fatal 
myocardial infarction, and vascular death in patients at high risk of arterial 
thrombosis should follow local regulations and guidelines.

Evidence of active, latent, or inadequately treated infection with Mycobacterium 
tuberculosis (TB) as follows:

A positive QuantiFERON TB-Gold® (QFT) performed at screening visit 
–
If QFT unavailable, a Mantoux purified protein derivative (PPD) skin test as 
defined by the Centers for Disease Control and Prevention (CDC)
guidelines, performed at the screening visit or within the 12 weeks prior to 
screening and read locally

A chest radiograph taken at the screening visit or documented results within the 
12 weeks prior to screening (chest radiograph must be read by a radiologist), 
without changes suggestive of active TB infection

If a patient has previously received an adequate documented course of therapy 
for either latent (36 weeks of isoniazid in a locale where rates of primary multi-
drug resistant TB infection are < 5% or an acceptable alternative regimen,
according to local guidelines) or active (acceptable multi-drug regimen, 
according to local guidelines) TB infection, neither a PPD test nor a QFT test 
need to be obtained, but a chest radiograph must still be obtained if not 
performed within the prior 12 weeks; this chest radiograph must be without 
changes suggestive of active TB infection

NOTE: Patients with a history of Bacille Calmette-Guérin (BCG) vaccination should 
be screened using the QFT test only.
If the initial QFT test is indeterminate, a confirmatory test with either a QFT or T-
SPOT® TB test (performed locally if available). The PI may consult with the 
Medical Monitor to discuss selection of confirmatory test based on the patient’s 
disease status and baseline immunosuppression.
–
An indeterminate QFT test followed by a negative QFT or negative 
T-SPOT® test should be considered a negative diagnostic TB test.
–
An indeterminate QFT test followed by an indeterminate QFT test or 
indeterminate T-SPOT® test should be considered a positive diagnostic TB 
test

Women who are pregnant or nursing (breastfeeding; within the last 12 weeks), or 
women intending to become pregnant, donate eggs or breast milk, or participate in 
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–
For women of childbearing potential:  Positive serum pregnancy test result at 
screening or on Day 1 (a serum pregnancy test is needed on Day 1 ONLY if 
the urine pregnancy test is positive)

Significant and uncontrolled medical disease within the 12 weeks prior to screening 
in any organ system (e.g., cardiac, neurologic, pulmonary, renal, hepatic, endocrine 
[including uncontrolled diabetes mellitus], metabolic, GI, or psychiatric [including 
suicidality]) not related to SLE, which, in the investigator’s or Sponsor’s opinion, 
would preclude patient participation

Concomitant chronic conditions, in addition to SLE, (e.g., asthma, Crohn’s disease) 
that required oral, IV, or intramuscular (IM) steroids or immunosuppressive use in 
the 24 weeks prior to screening or are likely to require these during the course of the 
study

History of nongallstone-related pancreatitis or chronic pancreatitis that is judged to 
be clinically significant, in the opinion of the investigator (e.g., accompanied by 
upper abdominal pain or malabsorptive diarrhea) 

Evidence of autoimmune myositis

History of cancer, including hematological malignancy and solid tumors, within 
10 years of screening; basal or squamous cell carcinoma of the skin that has been 
excised and is considered cured and in situ carcinoma of the cervix adequately 
treated by curative therapy more than 1 year prior to screening are not exclusionary 

History of alcohol, drug, or chemical abuse within the 1 year prior to screening as 
determined by the investigator

Major surgery requiring hospitalization within 4 weeks of screening 

History of cerebrovascular accident (CVA) within 10 years or any history of 
hemorrhagic CVA, any history of spontaneous intracranial hemorrhage or a history 
of traumatic intracranial hemorrhage within 10 years

History of clinically uncontrolled cardiac arrhythmias 

Screening 12-lead ECG that demonstrates clinically relevant abnormalities that may 
affect patient safety or interpretation of study results, including
–
QT interval corrected using Fridericia’s formula (QTcF) 450 msec for female 
patients and 430 msec for male patients demonstrated by at least two ECGs
30 minutes apart

History of clinically significant ventricular dysrhythmias or risk factors for ventricular 
dysrhythmias such as long QT syndrome or other genetic risk factors (e.g., Brugada 
syndrome), structural heart disease (e.g., severe left ventricular systolic dysfunction, 
severe left ventricular hypertrophy), coronary heart disease (symptomatic, or with 
ischemia demonstrated by diagnostic testing, prior coronary artery bypass grafting, 
or coronary lesions 70% diameter stenosis that have not been or cannot be 
re-vascularized), or family history of sudden unexplained death or cardiac ion 
channel mutations 

Current treatment with medications that are well known to prolong the QT interval 
(except for anti-malarials) at doses that have a clinically meaningful effect on QT, as 


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determined by the investigator. The investigator may contact the Sponsor for 
confirmation if needed. The investigator may reference the website: 
https://www.crediblemeds.org/pdftemp/pdf/CompositeList.pdf

Any condition possibly affecting oral drug absorption (e.g., gastrectomy, clinically 
significant diabetic gastroenteropathy, or certain types of bariatric surgery such as 
gastric bypass); procedures, such as gastric banding, that simply divide the stomach 
into separate chambers are not exclusionary

Need for systemic anticoagulation with warfarin, or other oral or injectable 
anticoagulants (other than NSAIDs, aspirin (325 mg/day), or other salicylates)

Known bleeding diathesis

Any history of hospitalization or transfusion for a GI bleed 

History of or currently active primary or secondary immunodeficiency, including 
known history of HIV infection or IgG 500 mg/dL

Any known active infection during screening up to and including at the time of 
enrollment (with the exception of fungal nail infections or oral herpes)

History of treated recurrent bacterial, viral, mycobacterial, or fungal 
infections, defined as 2 similar episodes requiring anti-microbial treatment within 
the past 52 weeks, with the exception of the following:
–
Oral or genital herpes (herpes simplex virus 1 [HSV1]/ herpes simplex virus 2 
[HSV2])
–
Uncomplicated cystitis or asymptomatic bacteriuria
–
Uncomplicated viral, bacterial or culture-negative bronchitis without pneumonia
–
Bacterial or viral sinusitis
–
Bacterial or fungal (yeast) vaginal infections

Any history of opportunistic infections that, in the Investigator's or Sponsor’s 
judgment, would raise safety concerns regarding the patient's participation in the 
study

Any major episode of infection requiring hospitalization or treatment with IV or IM 
antimicrobials within 4 weeks prior to or during screening or treatment with oral 
antimicrobials within 2 weeks prior to and during screening (with the exception of 
prophylaxis for Pneumocystis jiroveci pneumonia)

History of severe and/or disseminated viral infections, particularly herpes 
viruses, such as HSV1, HSV2, varicella zoster virus (VZV), cytomegalovirus (e.g., 
herpes encephalitis, ophthalmic herpes, disseminated zoster, cytomegalovirus 
colitis); uncomplicated influenza during a flu season, herpes labialis, and genital 
herpes are not exclusionary

Evidence of chronic and/or active hepatitis B or C
–
Positive hepatitis B surface antigen (HBsAg) or hepatitis C serology (regardless 
of treatment status)


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–
Positive hepatitis B core antibody (HBcAb)

Received any of the following medications and/or treatments within the indicated 
period of time:
–
Plasmapheresis or IV Ig in the last 12 weeks prior to screening
–
B cell–depleting therapy (e.g., anti-CD20 or anti-CD19) within 24 weeks prior to 
screening 
–
Belimumab, blisibimod, tabalumab (or other anti-B-cell activating factor [BAFF] 
agents), atacicept (or other anti-transmembrane activator and 
calcium-modulator and cyclophilin ligand [CAML] interactor [TACI] agents), 
epratuzumab (or other anti-CD22 agents), or denosumab within 5 half-lives or 
12 weeks (whichever is longer) prior to screening
–
Cyclophosphamide or other alkylating agents within 12 weeks prior to screening
–
Oral cyclosporine, tacrolimus, topical calcineurin inhibitors, anakinra (inhibitor 
IL-1), sirolimus (inhibitor IL-2), or other calcineurin inhibitors within 4 weeks 
prior to screening  
–
Thalidomide or thalidomide derivatives within 24 weeks prior to screening 
–
Tumor necrosis factor (TNF)-antagonists, tocilizumab, or other biologics not 
previously mentioned above within 12 weeks prior to screening
–
Any investigational drug within 4 weeks or 5 half-lives, whichever is longer, of 
screening
–
Any parenteral (IV), IM, or intra-articular steroid administration within 4 weeks
prior to screening
–
Any other immunosuppressive medication for SLE not listed in the inclusion 
criteria, within 12 weeks or 5 half-lives prior to screening, whichever is longer, 
unless approved by the Medical Monitor 
–
Live vaccines within 6 weeks prior to randomization; seasonal influenza and 
H1N1 vaccination are permitted if the inactivated vaccine formulation is 
administered

Use of any of the medications, herbal supplements, or foods in the categories below
should be avoided within 1 week or 5 half-lives, whichever is longer, prior to 
randomization, on the basis of possible drug interactions with GDC-0853 unless 
otherwise advised by the Medical Monitor (or delegate) as part of the adjudication 
process (see Section 4.4 for additional information; the screening period may be 
extended to meet these criteria if approved by the Medical Monitor):  
–
Strong CYP3A inhibitors (refer to Appendix 19 for examples) 
–
Moderate or strong CYP3A inducers (refer to Appendix 19 for examples)

Any uncontrolled, clinically significant, laboratory abnormality that would affect 
safety, interpretation of study data, or the patient’s participation in the study

Any of the following laboratory results, for which testing may be repeated once if the 
initial results are out of range during screening:


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–
AST or ALT 1.5ULN
–
Total bilirubin 1.2 ULN
–
Amylase or lipase 2ULN
–
Hemoglobin 7 g/dL
–
Absolute neutrophil count (ANC) 1.5109/L
–
Absolute lymphocyte count (ALC) 0.5109/L
–
Platelet count 50,000/L
–
Note: Other abnormal labs may be repeated at the discretion of the 
investigator. Final determination of whether the lab result is exclusionary 
will be made by the adjudication committee and Medical Monitor.
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
The Sponsor will define the randomization algorithm for implementation by the IxRS 
vendor.  Randomization will be stratified by region, entry dose of OCS, and disease 
activity at screening.  
To minimize bias in safety and efficacy assessments, this study uses a blinded, 
matching placebo for GDC-0853.  
To maintain the blind, after screening, sites will not receive data related to selected 
laboratory parameters, including but not limited immunophenotyping.
PK samples will be collected from patients assigned to all arms in order to maintain the 
blinding of the treatment assignments.  Since PK assay results for patients in the 
placebo arm are generally not needed for the safe conduct or proper interpretation of 
this trial, samples from patients assigned to the placebo arm will not be analyzed except 
by request (e.g., to evaluate a possible error in dosing).  Sponsor personnel responsible 
for performing PK assays and PK/PD assessments, which may include contracted 
laboratory personnel, will be unblinded to patients’ treatment assignment to identify 
appropriate samples to be analyzed.
Additional Sponsor staff will be unblinded to patients’ treatment assignments in order to 
support the IMC and Scientific Oversight Committee, including a clinician, statistician, 
statistical programming analyst, biomarker scientist, clinical pharmacologist, and others 
at the request of the IMC.  Certain Sponsor representatives not involved with study 
conduct or the study team (e.g., governance committee members) may review unblinded 
safety data or interim efficacy data to enable decision-making.
If unblinding is necessary for patient management (e.g., in the case of a serious adverse 
event or unanticipated pregnancy for which patient management might be affected by 
knowledge of treatment assignment), the investigator will be able to break the treatment 
code by contacting the IxRS.  Treatment codes should not be broken except in 


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emergency situations.  If the investigator wishes to know the identity of the study drug for 
any other reasons, he or she should contact the medical monitor directly to discuss the 
rationale for unblinding and further management plan for the patient (e.g., discontinuing 
drug treatment), prior to contacting the IxRS for unblinding.  The Medical Monitor is not 
allowed to break the blinding on the investigator’s behalf.  The investigator should 
document and provide an explanation for any premature unblinding (e.g., accidental 
unblinding and unblinding due to a serious adverse event), without disclosing the 
treatment assignment in the documentation.
For regulatory reporting purposes, and if required by local health authorities, the 
Sponsor will break the treatment code for all serious, unexpected suspected adverse 
reactions (SUSARs, see Section 5.7) that are considered by the investigator or Sponsor 
to be related to study drug.
4.3
STUDY TREATMENT 
The investigational medicinal product (IMP) for this study is GDC-0853 50-mg tablets.
4.3.1
Formulation, Packaging, and Handling
4.3.1.1
GDC-0853 50-mg Tablet and Placebo Tablet
GDC-0853 will be provided by the Sponsor as 50-mg dose strength tablets with 
corresponding matching placebo tablets, which will be indistinguishable in appearance.  
Tablets will be supplied in blister wallets for the treatment arm to which the patient is 
randomized.  GDC-0853 and placebo tablets should be stored at 2C8C.
For information on the formulation and handling of GDC-0853, see the GDC-0853 
Investigator’s Brochure.
4.3.1.2
Background Standard of Care Therapy
For information on the formulation, packaging, and handling of background SOC therapy 
(i.e., immunosuppressive therapy and corticosteroids) see the local prescribing 
information.
4.3.2
Dosage, Administration, and Compliance
4.3.2.1
GDC-0853 and Placebo Dose and Administration
The GDC-0853 dose levels are 150 mg QD and 200 mg BID with matching placebo (see 
Table 2).  Patients will receive GDC-0853/placebo BID approximately every 12 hours 
starting on Day 1 and ending on the evening (p.m. dose) prior to the Week 48 visit.  
Patients should be directed to take one dose (a total of 4 tablets) BID (total of 8 tablets 
each day).  On clinic visit days when PK assessments are performed (Day 1, Week 4, 
and Week 24), patients should be instructed that study drug will be administered in the 
clinic.  
In general, a dosing window of 2 hours is acceptable. If a dose is taken more than 
2 hours late or is missed altogether, the patient should resume normal dosing with the 


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next scheduled dose.  Patients should record the dose that was missed on the blister 
wallet.  Doses that are vomited will be considered missed doses.
GDC-0853 or placebo will be orally administered and may be taken with or without food, 
except the dose of oral study drug taken at the clinic visit on Day 1 and Week 24 (see 
Section 4.4.4 and Appendix 1 and Appendix 2), which will be administered at the clinic 
visit while fasting.  The dates and times of the most recent prior meal, last dose of oral 
study drug (prior to clinic visit), and timing of oral study drug administration in clinic 
should be recorded at clinic visits with PK and/or fasting lipid assessments.  In addition, 
any use of PPIs, H2 receptor antagonists (H2RAs), and/or short-acting antacids (e.g., 
Maalox®, Pepto-Bismol®, Rolaids®) should be recorded as concomitant medications, 
including date and time of last administration prior to the PK clinic visits.  Administration 
of study drug should be staggered with short-acting antacid use (i.e., oral study drug 
should be taken 2 hours before or 2 hours after the short-acting antacid).  Staggering is 
not required for PPIs or H2RAs; however, PPI and H2RA medications are recommended 
to be maintained at a constant dose and regimen throughout the study if possible.
Table 2
Study Drug Dosing Regimen by Treatment Arm
Arm
GDC-0853
Dose (mg)
Number of 
GDC-0853 Tablets 
(a.m./p.m.)
Number of placebo 
(a.m./p.m.)
A
200 BID
4/4
0/0
B
150 QD
3/0
1/4
C
0
0/0
4/4
a.m.in the morning; BIDtwice daily; p.m.in the afternoon; QDdaily.
Note:  All patients will take 4 tablets BID (i.e., 8 tablets daily) regardless of assigned 
GDC-0853 dose regimen in order to maintain the blind.
At study visits, sufficient study medication will be dispensed to complete dosing until the 
next scheduled visit.  When study medication is administered at the site, it will be 
administered under supervision of study personnel, and the amount of study medication 
dispensed must be recorded.  
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.
4.3.2.2
GDC-0853 and Placebo Compliance
The following measures will be taken to assess patient compliance with study drug: 
Sites will be responsible for prepopulating the dates on the blister wallets for when 
patients are scheduled to take study drug. Under the corresponding dates listed, the 
patients will record the times (a.m. or p.m.) that they take each dose directly on the 
blister wallet.  Patients should only remove tablets from the wallet at the time they take 


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the tablets (e.g., patients should not transfer the tablets to another container with their 
other medications for future use).  Patients will be instructed by the site staff on how to 
properly take the study drug, including recording the IP intake time on the blister 
wallet and a reminder to bring all blister wallets (used and unused) to each study visit for 
assessment of compliance (based on the tablets remaining in the wallets as well as the 
recorded dates and times) and for medication disposal.
Compliance will be documented on the source record.  If compliance is 80% (correct 
dosage at the correct time), the investigator or designee is to counsel the patient and 
ensure steps are taken to improve compliance.  
In order to maintain the proper source documentation of subjects’ IP compliance, the 
investigator should follow one of the two processes listed below:
1.
The site will keep the blister wallets on-site, together with all other subject source 
documents (e.g. signed ICFs, medical notes, completed PROs, etc.). Blister wallets 
may not be destroyed until all trial related documents are approved to be discarded 
if this process is followed.
2.
Site staff will generate certified copies of the blister wallets, showing IP intake 
times recorded by the subjects on the wallets.  After PI accountability is performed, 
blister packs are checked by the site monitor, and sponsor approval is obtained, the 
blister packs may be destroyed at the site or returned for destruction. If the 
investigator chooses to follow this process, all copies of blister wallets must be 
signed and dated by the person making the copy and noted with a statement such as 
“I certify that this is the true and correct copy of the original.”  For this trial, only 
printed copies of blister wallets will be accepted.  Electronic copies are not allowed.
Any overdose or incorrect administration of study drug should be noted on the Study 
Drug Administration eCRF.  Adverse events associated with an overdose or incorrect 
administration of study drug should be recorded on the Adverse Event eCRF.
4.3.2.3
Background Standard of Care Therapy
4.3.2.3.1
Immunosuppressant Therapy
All patients who enter the study on oral immunosuppressant therapy (not including 
corticosteroids) or anti-malarial medications will be instructed to maintain their 
medications and doses from screening throughout the rest of the study treatment period.  
After entering the study, patients may not begin taking a new oral immunosuppressant 
except in the case of increased clinical activity requiring escape therapy, as described in 
Section 4.3.2.3.4.
If dose reduction of an immunosuppressant is required because of toxicity, this must be 
recorded as an adverse event on the Adverse Event eCRF, and the dose modification 
must be recorded in the Immunosuppressant Review eCRF. 


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Any overdose or incorrect administration of an immunosuppressant should be noted on 
the Immunosuppressant Review eCRF.  Adverse events associated with an overdose or 
incorrect administration of an immunosuppressant should be recorded on the 
Adverse Event eCRF.
4.3.2.3.2
Corticosteroid 
For all patients who enter the study on oral prednisone (or permitted equivalent OCS; 
see Appendix 18), there will be two, 12-week, OCS taper windows (Weeks 0 to 12 and 
Weeks 24 to 36) where their dose, if 10 mg/day, will be tapered to 10 mg/day.  During 
taper windows, patients will continue to receive their designated dose of study treatment 
(see Section 4.3.2).  
The OCS rules are as follows:  the OCS dose level achieved at the end of each OCS 
taper window will be maintained during the 12-week, OCS stability windows (Weeks 12 
to 24 and Weeks 36 to 48; see Figure 1), whether or not the target OCS dose was 
achieved.  Patients will be instructed not to deviate from this dose level achieved at the 
end of the OCS taper window, unless considered clinically appropriate by the 
investigator.  
Patients should follow the appropriate tapering schedule as determined by the 
investigator, taking into account the taper window timing and the target OCS dose 
(10 mg/day and Day 1 dose).  The investigator may modify a tapering schedule 
based on the patient’s response to the reduction in corticosteroid dose.  A suggested 
prednisone tapering schedule is provided in Appendix 4; in addition, the investigator may
consult the Medical Monitor.  Once 10 mg/day is achieved, tapering completely off 
corticosteroids is allowed if this is deemed clinically appropriate by the investigator (i.e., 
if there is minimal risk of inducing flare).
Inability to comply with any of the OCS rules and any change in steroid dose must be 
recorded on the Corticosteroid Medication eCRF.  In addition, the patient will be 
considered a non-responder for the analysis that requires the steroid taper criteria to be 
satisfied (see Section 3.3.6.3).   
It is recommended that all patients receiving corticosteroids should receive appropriate 
supportive therapy to help prevent steroid-induced osteoporosis (e.g., calcium, vitamin D 
supplements, bisphosphonates) as per local guidelines and physician preference.  
Pneumocystis jiroveci pneumonia prophylaxis is also recommended to be used as per 
local SOC.
Intra-articular injections and intra-lesional cutaneous injections of corticosteroids must be 
avoided during the study if possible, as these interventions will confound the efficacy 
assessments.  


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If a patient entered the study on low potency topical steroids (e.g., Class VI and 
Class VII), the steroid can be continued during the course of the study at a stable dose. 
4.3.2.3.3
Burst Treatment
In the case of increased disease activity, the patient will have the opportunity to receive 
burst treatment, in addition to the study treatment, during the defined burst treatment 
window (see Figure 1).  The patient should return to the clinic, either at a scheduled 
study visit or unscheduled flare visit, to be evaluated and to receive an increase or new 
dose of oral prednisone as follows:

Burst Window 1 (Weeks 0 to 10):  An increase or new dose of oral prednisone up to 
40 mg/day (or equivalent; see Appendix 18)

Burst Window 2 (Weeks 24 to 34):  An increase or new dose in oral prednisone up 
to 20 mg/day (or equivalent; see Appendix 18)
When using corticosteroids as a burst treatment, the investigator will temporarily 
increase the dose of corticosteroids and then taper the patient back down to their 
previous corticosteroid dose used prior to the initiation of the burst, all over the course 
of 2 weeks.  Patients will continue to receive their designated dose of study treatment 
(see Section 4.3.2) during the burst treatment.  The previous corticosteroid dose is 
defined as the dose of corticosteroids taken for the 2 weeks prior to the burst (if the dose 
changed during the 2 weeks, the investigator may choose which dose to use).  If the 
patient was not previously on corticosteroids, the investigator will taper the patient back 
off corticosteroids completely.  If the patient was on a corticosteroid-tapering schedule at 
the time of the burst treatment, the investigator will revise the tapering schedule as 
necessary to meet the target OCS dose (10 mg/day and Day 1 dose) by the end of 
the taper window, if clinically appropriate.  
Patients may receive corticosteroids for emergent illness other than SLE (e.g., trauma, 
asthma) or if clinically warranted to prevent adrenal crisis (e.g., prior to surgery).  If 
possible, treatment in these cases should last no more than 7 days. 
Any dose of steroid higher than the maximum burst levels above, any failure to taper the 
burst down to the previous level over the course of 2 weeks, or any necessity for 
additional burst treatments for increased SLE-related activity (either a second treatment 
within the burst window or a burst treatment outside the burst window), as determined by 
the investigator, will be recorded in the Steroid and immunosuppressant eCRF.  
Use of burst therapy to treat worsening of lupus will be captured on the Adverse Event 
eCRF (see Section 5.3.5.9).  If any patient needs additional corticosteroids for any 
reason that falls outside the permitted OCS rules stated above (Sections 4.3.2.3.2 and 
4.3.2.3.3), the Medical Monitor needs to be informed and the reason recorded on the 
Corticosteroid Medication eCRF.  


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4.3.2.3.4
Escape Therapy
If an increase in immunosuppressive therapy (referred to as “escape therapy”) is 
deemed medically necessary due to increased SLE disease activity, the patient will be 
given escape therapy, which will be recorded on the Steroid and Immunosuppressant 
eCRF.  Patients receiving the following escape therapies may be allowed to remain on 
study drug after discussion with the Medical Monitor but will be considered a 
protocol-defined “non-responder” in the primary analysis:  

IV or IM steroids (at doses greater than 40 mg prednisone PO or equivalent)

OCS doses exceeding the limits described elsewhere in the protocol (e.g., 
prednisone (or equivalent) doses of > 40 mg/day during the first 24 weeks of the 
study, or > 20 mg/day between Weeks 24 and 48) 

New or increased doses of an immunosuppressant or anti-malarial medication up 
to the maximum allowed in the study (see Section 4.3.2.3)
NOTE: Combinations of immunosuppressant medications that are not allowed in the 
inclusion and exclusion criteria (see Section 4.1) are prohibited during the study (see
Section 4.6.2).
Whenever possible, a patient being evaluated for escape therapy will undergo 
assessment at either an unscheduled or flare visit prior to the increase in 
immunosuppression in order to quantify and record the increased disease activity, 
unless this occurs at a scheduled study visit (see Appendix 1).  
If the patient requires any further treatment for SLE activity beyond the escape therapy 
described above (e.g., prohibited medications as defined in Section 4.4.2 or any 
accepted immunosuppressive that exceeds the maximum dose as defined by the 
protocol, or any increase in therapy not approved by the Medical Monitor), the patient 
should stay in the study but will be discontinued from study treatment (see Section 4.6.2).  
Use of escape therapy to treat worsening of lupus will be captured on the Adverse Event 
eCRF (see Section 5.3.5.9).  If any patient needs additional corticosteroids for this or 
any other reason, the Medical Monitor needs to be informed and the reason recorded on 
the Corticosteroid Medication eCRF.  
4.3.2.4
Background Standard of Care Therapy Compliance
Starting at the screening period, all patients must keep a weekly diary of their actual 
OCS use as instructed by study staff.  Patients will record their actual OCS dose on a 
weekly basis using a paper diary and as instructed by study staff.  OCS usage will be 
recorded in the Corticosteroid Medication eCRF.
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (GDC-0853 50-mg tablet and placebo 
tablet) will be provided by the Sponsor where required by local health authority 


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regulations.  The study site will acknowledge receipt of IMPs using the IxRS to confirm 
the shipment condition and content.  Any damaged shipments will be replaced. 
IMPs either will be disposed of at the study site according to the study site’s institutional 
standard operating procedure or will be returned to the Sponsor with the appropriate 
documentation.  The site’s method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log.
4.3.4
Post-Trial Access to GDC-0853
Patients may be screened for enrollment into an OLE study. If they meet all OLE 
eligibility criteria, they may be enrolled if considered appropriate for participation, 
according to the investigator.
Currently, the Sponsor (Genentech, a member of the Roche Group) does not have any 
plans to provide GDC-0853 or any other study treatments or interventions to patients 
who have completed the study and are not qualified or elect not to enter an OLE study, if 
available, in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, available at the following Web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY, PROHIBITED FOOD, AND
ADDITIONAL RESTRICTIONS
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient from 7 days prior to initiation of study drug through 8 weeks after the last dose of 
study drug or entrance into an OLE, if initiated, whichever occurs first. All concomitant 
medication taken during the study must be documented on the eCRF along with 
indication, daily dose, and start and stop dates of administration.  Adverse events related 
to the administration of a concomitant medication or the performance of a procedure 
must also be documented on the appropriate adverse event page of the eCRF.
It is recommended that patients avoid changing other concomitant prescription or non-
prescription drugs, vitamins, and dietary supplements within 7 days or 5 half-lives, 
whichever is longer, prior to the first dose of study medication and throughout the study.
4.4.1
Permitted Therapy 
Note for all concomitant immunosuppressive and anti-malarial medications:  reductions 
to the concomitant immunosuppressive medication dose will not be allowed except in the 
case of intolerance or toxicity or for the safety of the patient, as determined by the 
investigator; any changes in the doses of concomitant immunosuppressive and anti-


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malarial medications must be discussed in advance with the Medical Monitor unless 
medically emergent.  Patients who require a new or increased dose of concomitant 
immunosuppressive medications will be considered protocol-defined non-responders 
(see Section 4.3.2.3). 
Addition, discontinuation, and dose adjustment of concomitant medications for 
conditions other than SLE are discouraged but permitted when required for the safe and 
effective treatment of patients. 
Any case of medication intolerance or toxicity must be recorded as an adverse event
and any dose modification recorded in the eCRF.  
Certain combinations of the SLE therapies below are not permitted (see Section 4.1)
4.4.1.1
Anti-malarials (E.g., Hydroxychloroquine, Chloroquine)
Patients taking anti-malarial medications at study entry should be on a stable dose for at 
least 8 weeks prior to screening and should maintain a constant dosage throughout the 
study.  Patients not previously on anti-malarial medications may be enrolled in the study 
but should not initiate anti-malarial medications during the course of the blinded study.  
Replacement of one anti-malarial with another may be allowed in cases where there is 
limited supply of the original medication, or if there are issues with toxicity or intolerance; 
however, the change must be discussed with the Medical Monitor.  Refer to Appendix 18
for anti-malarial list.
4.4.1.2
Mycophenolate Mofetil/Mycophenolic Acid
All patients who are taking mycophenolate mofetil (or mycophenolic acid) should be on a 
stable dose for 8 weeks prior to screening.  When mycophenolic acid is used instead of 
mycophenolate mofetil, a 360-mg dose of mycophenolic acid is considered to be 
equivalent to a 500-mg dose of mycophenolate mofetil.  Mycophenolate mofetil may 
have an interaction with oral contraceptives that may decrease their effectiveness; 
however, patients enrolling in this study and using hormonal contraceptives as a method 
of contraception are required to also use a barrier, such as a male condom.
4.4.1.3
Azathioprine 
It is strongly recommended that prior to starting azathioprine, patients should have been 
evaluated for thiopurine methyltransferase variant alleles that have been associated with 
decreased activity in vitro and lead to the accumulation of the drug and/or its metabolites.  
A stable dose used for at least 8 weeks duration prior to screening of up to 2.5 
mg/kg/day is allowed. 
4.4.1.4
Methotrexate
Treatment must have been stable for at least the 8 weeks before screening.  Patients 
taking methotrexate (oral or parenteral) must stay on the same dose delivered by the 
same route for the duration of their participation in this study.  To prevent methotrexate-


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associated adverse events, all patients on methotrexate are required to take folic acid 
(e.g., 1 mg/day) or equivalent at a stable dose of at least 5 mg/week or equivalent as per 
local standard of care.
4.4.1.5
Non-Steroidal Anti-inflammatory Drugs
As needed use of NSAIDs should be avoided within 24 hours before a visit where clinical 
efficacy assessments are scheduled to be performed and recorded.   
Aspirin can be taken to reduce cardiovascular risk, but the dose is not to exceed 
325 mg/day.  
In order to prevent NSAID-related GI complications in high-risk patients, concomitant 
acid reducing agents (e.g., PPIs) should be used according to local guidelines (see 
Section 5.1.1.3).
Note that patients on anti-platelet agents may not be taking aspirin at the same time.
4.4.1.6
ACE Inhibitors and ARBs 
For patients who are on ACE inhibitors or ARBs at study entry, it is strongly 
recommended that doses of ACE inhibitors or ARBs be kept stable for at least 10 days 
prior to randomization and throughout the trial whenever possible. It is strongly 
recommended that ACE inhibitors or ARBs not be initiated during the OCS stability 
windows.
4.4.1.7
Dietary Supplements 
For the purposes of this protocol, dietary supplements are defined as vitamins, minerals, 
purified food substances, and herbals with pharmaceutical properties.  Vitamins, 
minerals, and purified food substances are allowed in amounts not known to be 
associated with adverse events (e.g., hypervitaminosis). Herbals with pharmaceutical 
properties are allowed only if there is acceptable evidence of no CYP3A inhibition or 
induction (refer to Appendix 19).
for a list of prohibited concomitant medications, including herbal products).  Otherwise, 
herbals with pharmaceutical properties must be discontinued for at least 4 weeks prior to 
the first dose of study medication, unless there is sufficient data available regarding the 
duration of an herbal medication’s PK and PD effects to allow a shorter washout to be 
specified (e.g., 5 half-lives).  Please direct any questions to the Medical Monitor.
4.4.1.8
Acid Reducing Agents 
Patients who use short-acting antacids (e.g., Maalox®, Pepto-Bismol®, Rolaids® for 
symptomatic relief of heartburn) should take GDC-0853 or matching placebo 2 hours 
before or 2 hours after short-acting antacid administration because gastric acid improves 
GDC-0853 absorption.  Patients may be treated with PPIs or H2RAs at up to the 
maximum recommended dose according to local labeling.  The dose should remain 
stable for at least the 2 weeks before randomization and throughout the study.  At visits 


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with scheduled PK assessments (see Appendix 1 and Appendix 2), the date and time of 
last administration of any PPIs, H2RA, and/or short-acting antacids taken should be 
recorded on the concomitant medication eCRF.
4.4.2
Prohibited Therapy
A listing of concomitant medications and foods that are prohibited or should be used with 
caution due to potential PK drug-drug interactions is provided in Appendix 19.  Biologic 
response modifiers and disease-modifying antirheumatic drugs (DMARDs) other than 
those mentioned above are not allowed during this study and any use will require 
discontinuation of study treatment.  
Specifically, the use of the following therapies is prohibited in conjunction with study drug 
treatment:

All biosimilar and biological agents (e.g., TNF inhibitors, IL-17, IL-12/23, abatacept, 
denosumab) as well as biosimilars (investigational or approved)

Anti-CD20 monoclonal antibody

Belimumab (Benlysta)

Chlorambucil

Cyclophosphamide

Heparin, low molecular weight heparin, and other injectable systemic anticoagulants

Immunosorbent column

Investigational therapy other than study drug

IV Ig

Oral anticoagulants, including but not limited to warfarin, dabigatran, rivaroxaban, 
and apixaban 

Sirolimus

Systemic calcineurin inhibitors (e.g., tacrolimus, cyclosporine)

Tocilizumab and other anti-IL6R or anti-IL6 agents 

Tofacitinib and other JAK inhibitors

IV or IM steroids at doses greater than 40 mg prednisone PO or equivalent with 
the exception of use as escape therapy
Please see Appendix 19 for additional prohibited therapies during this study.
4.4.2.1
Live or Attenuated Vaccinations
Immunization with a live or attenuated vaccine is prohibited within 6 weeks prior to
randomization and for the duration of study participation, including the 8-week follow-up 
period after the administration of the last dose.  See Section 5.1.1.2 for further details 
and precautions around vaccinations.


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4.4.2.2
CYP3A and BCRP-Mediated Drug Interactions
Preliminary data from a clinical drug-drug interaction study (Study GP39616) suggest 
that GDC-0853 may be classified as a mild inhibitor of CYP3A at clinically relevant 
doses.  It is possible that GDC-0853 inhibition of CYP3A may alter the metabolism of 
CYP3A substrates and result in increased plasma concentrations of CYP3A substrates.
Therefore, medications in the following categories (listed in detail in Appendix 19) 
should be used with caution in consultation with the Medical Monitor (or delegate) as 
necessary unless otherwise specified in Section 4.4.2:

Sensitive CYP3A substrates

CYP3A substrates with a narrow therapeutic index 
The use of hormone-replacement therapy or hormonal contraceptives containing the 
CYP3A substrate ethinylestradiol (with the concomitant use of a barrier method) is 
permitted; however, patients should be counseled regarding the potential risks and 
benefit of these medications per the local prescribing information.  Any increase in 
ethinylestradiol plasma concentrations is anticipated to be modest at most due to the 
relatively minor contribution of CYP-mediated oxidation in the clearance of orally 
administered ethinylestradiol (Zhang et al. 2007); however, increased ethinylestradiol 
plasma concentrations may lead to an increase in common side effects (e.g. nausea, 
breast tenderness, and headaches) and a theoretical increase in rare dose-related events 
(e.g. thromboembolism; Inman et al. 1970).
Preliminary data from Study GP39616 also suggest that GDC-0853 may be classified 
as a moderately sensitive substrate of CYP3A at clinically relevant doses. There is a 
moderate potential for a drug-drug interaction with any medication that strongly inhibits or 
induces this enzyme. Therefore, medications in the following categories (listed in detail 
in Appendix 19) should be avoided for 7 days or 5 half-lives, whichever is longer, prior to 
the first dose of study drug until the last dose of study drug, unless otherwise advised by 
the Medical Monitor (or delegate).  If use of one of these medications is necessary, the 
risks and benefits should be discussed with the Medical Monitor prior to concomitant 
administration with study drug.

Strong CYP3A inhibitors

Moderate or strong CYP3A inducers 
Lastly, preliminary data from Study GP39616 suggest that GDC-0853 is a moderate 
inhibitor of the breast cancer resistance protein (BCRP) (also known as ABCG2) 
transporter protein at clinically relevant doses. There is a potential for increased 
plasma concentrations of drugs known to be substrates of the BCRP transporter.  
Plasma concentrations of the medications in the following category (listed in detail in 
Appendix 19) may increase; therefore, they should be used with caution in consultation 


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with the Medical Monitor (or delegate) as necessary unless otherwise specified in 
Section 4.4.2:

BCRP substrates with a narrow therapeutic index
The medications listed in Appendix 19 are not necessarily comprehensive.  Thus, the 
investigator should consult the prescribing information for concomitant medications as 
well as the Internet references provided below when determining whether a certain 
medication is metabolized by or strongly inhibits or induces CYP3A or is a sensitive 
substrate of BCRP.  The investigator should contact the Medical Monitor if questions 
arise regarding medications that may interact with CYP3A or BCRP.  
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/
DrugInteractionsLabeling/ucm093664.htm (Tables 3-1, 3-2, 3-3, and 5-1)
http://medicine.iupui.edu/clinpharm/ddis/table.aspx
4.4.3
Prohibited Food 
Use of the following foods is prohibited during the study and for at least 7 days prior to 
initiation of study treatment due to their effects on the cytochrome P450 3A4 enzyme, 
which is involved in GDC-0853 metabolism:  furanocoumarin derivatives as found in 
grapefruit, Seville orange, pomegranate, or star fruit juice or products. Please refer to
Appendix 19 for additional information.
4.4.4
Additional Restrictions
Patients should be fasting for 4 hours prior to pre-dose PK draws at Day 1 and 
Week 24, and also when fasting lipids are drawn (Day 1, Week 12, Week 24, Week 36, 
and Week 48).  At Week 24, patients should also remain fasting for the 2-hour PK 
timepoint (see Appendix 1 and Appendix 2).  The morning dose of oral study drug will be 
administered at the strongly recommended morning clinic visit while fasting.
4.5
STUDY ASSESSMENTS
Please see Appendix 1 and Appendix 2 for the schedule of activities to be performed 
during the study.
The screening visit can occur up to 35 days prior to the first dose of study drug.  The 
screening period may be extended upon the approval of the Medical Monitor.  The Day 1 
(baseline and randomization) visit occurs on the first day of study drug administration.  
At applicable sites (United States only), if the patient is unable to return to the clinic at 
the Week 24 visit for the PK blood draw at the 8- to 10-hour timepoint, then this sample 
may be collected by a home nurse (HN) professional at the patient's home or another 
suitable location to improve access and convenience for patients participating in the 
study.  The Sponsor will select a healthcare company that will be responsible for 


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providing HN services for participating sites (the HN vendor).  The HN vendor is 
responsible for ensuring that all HN professionals are licensed, qualified, and in good 
standing, as per applicable regulations, and that appropriate background checks have 
been performed.  If the investigator at a participating site determines that HN services 
are appropriate for a patient and the patient gives written informed consent to participate 
in HN visits, the HN network will communicate with the patient and the patient’s site.  HN 
visits will be scheduled on specified visit days, to allow for relevant assessments to be 
performed by the HN professional.  The schedule of activities will specify the 
assessments that may be performed by an HN professional (see Appendix 1 and 
Appendix 2).
4.5.1
Informed Consent Forms and Screening Log
Patients will be screened within a period of up to 35 days prior to administration of study 
medication to confirm that they meet the entrance criteria for the study.  The study 
investigator or sub-investigator will discuss with each patient the nature of the study, its 
requirements, and its restrictions and potential risks.
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures.  Informed Consent Forms for enrolled patients 
and for patients who are not subsequently enrolled will be maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  Pre-enrollment adjudication by the Medical 
Monitor and his/her designees will occur for all patients who complete screening prior to 
their randomization into the study (see Appendix 3).  The investigator will maintain a 
screening log to record details of all patients screened and to confirm eligibility or record 
reasons for screening failure, as applicable.
4.5.2
Eligibility Assessment at Screening
At screening, patients who fail to meet any laboratory inclusion/exclusion criteria or other 
eligibility criteria may be retested or rescreened per the instructions in Section 4.5.2.1
and Section 4.5.2.2, respectively.
4.5.2.1
Re-Testing:  Laboratory Inclusion/Exclusion
If a patient fails certain laboratory inclusion/exclusion criteria at screening, the 
investigator may repeat the test once within the screening period; see Section 4.1.2 for a 
list of laboratory tests and levels that can be retested.  If the patient passes the 
laboratory eligibility criteria on the second assessment, he/she will be adjudicated and 
may enter the study.  It will not be considered a re-testing if blood samples have to be 
redrawn due to sample handling problems, breakage, sample integrity, or laboratory 
error.


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4.5.2.2
Re-Screening
Re-screening refers to repeating the whole screening process.  Re-screening is required 
if a patient has not met all of the eligibility criteria within the original screening period 
(Note:  patients who have failed two laboratory testing attempts as described in 
Section 4.5.2.1 cannot be re-screened).  Patients are only allowed to be re-screened 
once.  Each patient must be re-consented before re-screening occurs.  It will not be 
considered a re-screening if blood samples have to be redrawn due to sample handling 
problems, breakage, sample integrity, or laboratory error.
4.5.3
Medical History and Demographic Data
A complete medical history will be taken at the screening visit and should include details 
of past and current manifestations of SLE, past and current concomitant medical 
conditions, previous surgical procedures, and previous treatment regimens for SLE 
including any history of adverse drug reactions.  In addition, all medications 
(e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic 
remedies, nutritional supplements) used by the patients within 7 days prior to screening
will be recorded.
Particular emphasis should be placed on manifestations of active SLE as well as the 
clinical and laboratory findings that identified the patient as having SLE (ACR or SLICC 
criteria) and on identifying any medical conditions (e.g., active or latent infection) that 
might place the patient at increased risk or which might confound the interpretation of 
safety or efficacy signals.  At subsequent visits, the investigator will focus on changes in 
the patient’s symptoms since the previous visit, including but not limited to features 
indicating current SLE activity, changes in disease activity since the previous visit, and 
potential adverse events.
The medical history must also include clinically significant diseases, surgeries, cancer 
history (including prior cancer therapies and procedures), reproductive status, family 
history of autoimmunity, vaccine history, smoking history, use of alcohol, and drugs of 
abuse.
A detailed history of medication used for SLE is required.  All prior immunosuppressant 
drugs used to treat lupus 12 months prior to screening (including drug name, maximum 
dose used, and start and stop dates, as applicable) will be recorded.  The year of onset 
as well as the symptoms that lead to the diagnosis of SLE in the patient as defined by 
either the ACR or SLICC inclusion criteria should be captured. 
Demographic data will include age, sex, and self-reported race/ethnicity.
4.5.4
Physical Examinations
A complete physical examination should be performed at screening and should include 
an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, 
dermatological, musculoskeletal, respiratory, GI, genitourinary, and neurological systems.  


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Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF.  Particular attention should be given to 
evaluation of potential manifestations of active SLE and of infections or other medical 
conditions, which could place the patient at increased risk. 
At subsequent visits (or as clinically indicated), limited, efficacy assessmentdirected or 
symptom-directed physical examinations should be performed.  Changes from baseline 
abnormalities should be recorded in patient notes.  New or worsened clinically significant 
abnormalities should be recorded as adverse events on the Adverse Event eCRF.
4.5.5
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, temperature, and 
systolic and diastolic blood pressures while the patient is in a seated position for at least 
5 minutes.
4.5.6
Chest Radiograph 
Chest radiographs of appropriate quality (to adhere to local standards for the exclusion 
of active TB) and with formal readings by a radiologist will be obtained at screening.  If 
chest radiographs have been taken and read by a radiologist within 12 weeks prior to 
screening and documented results (as read by a radiologist) show no clinically 
significant abnormality as determined by the investigator, the chest radiograph does not 
need to be repeated.
4.5.7
Tuberculin Purified Protein Derivative Skin Test
The QuantiFERON TB-Gold(QFT) should be used as the initial screening test for 
tuberculosis and, if indeterminate, this QFT test should be followed by a repeat QFT or a 
T-SPOTtest.  If QFT is not available, a Mantoux PPD skin test will be performed at the 
screening visit or within the 12 weeks prior to screening and read locally.  The PPD skin 
test will be performed per the CDC guidelines using 5 tuberculin units per 0.1 mL [5TU].  
An intradermal injection into flexor or dorsal surface of forearm will be performed.
4.5.8
SLE Disease Activity Assessments
The following applicable SLE disease activity assessments will be used in this study: 
BILAG-2004, SLEDAI-2K, SELENA-SLEDAI Flare Index (SFI), Glucocorticoid Toxicity 
Change Index [GTCI], SLICC/ACR Damage Index (SDI), 28-Joint Count, CLASI, 
Physician’s Global Assessment, and Patient’s Global Assessment.  In addition, the SRI 
and BICLA composite endpoints will be evaluated.  Throughout the study, each
assessment ideally should be conducted by the same assessor, if possible (e.g., the 
same assessor should conduct the 28-joint count at each visit for a particular patient, if 
possible). Detailed instructions and training on the use of clinical instruments performed 
by the investigators in this study will be provided by the Sponsor or Sponsor designee.
Investigators must demonstrate the ability to perform disease activity assessments 


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and/or they must provide valid training certificates obtained within 2 years of the start of 
the study for versions used in this study.
4.5.8.1
BILAG 2004 Index
The BILAG 2004 index (BILAG) will be used as a method to assess disease activity in 
this study.
The BILAG assesses 97 clinical signs, symptoms, and laboratory parameters across 
nine organ or system domains:  constitutional, mucocutaneous, neuropsychiatric,
musculoskeletal, cardiorespiratory, GI, ophthalmic, renal, and hematological.  The 
97 symptoms are rated with respect to severity over the previous month (4 weeks) and 
with respect to any change from the previous examination (new, improving, stable, 
worsening, absent).  For each of the nine domains, a single, alphabetic score (i.e., 
A through E) is then derived from the examination results in each organ category.  
Detailed instructions and training on the use of the BILAG will be provided as described 
in Appendix 9.
4.5.8.2
Systemic Lupus Erythematosus Disease Activity Index 2000
(SLEDAI-2K) and SELENA-SLEDAI Flare Index (SFI)
The SLEDAI-2K will be used to approximate disease activity for entry into the study and 
at every subsequent study visit (see Appendix 10).  
SLEDAI-2K measures disease activity at the visit or within the preceding 28 days.  
Detailed instructions and training on the use of the SLEDAI-2K will be provided during 
training sessions at each investigator meeting, and through online resources. It is critical 
that investigators have a thorough understanding of both the BILAG and SLEDAI-2K
instruments and the differences between them.
The SFI categorizes SLE flare as “mild or moderate” or “severe” based on 6 variables 
(Buyon et al, 2005; Petri et al. 1999; Petri et al. 2005):

Change in SELENA-SLEDAI (or SLEDAI-2K) score from the most recent 
assessment to current

Change in signs or symptoms of disease activity

Change in prednisone dosage

Use of new medications for disease activity or hospitalization

Change in PGA score 

Hospitalization for activity (severe flare only)
The SFI will be modified such that severe flares defined only by the occurrence of an 
increase in SLEDAI-2K score to 12 will be excluded. One or more other items defining 
severe flare in the SFI needed to be present for a severe flare to be recorded. This 
modification was made because patients entering the trial with high disease activity 


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(e.g., 11) could too easily trigger a severe flare by minor increases in the SLEDAI-2K 
score.
4.5.8.3
Glucocorticoid Toxicity Change Index
The GTCI is an exploratory standardized measure of damage related to use of 
glucocorticoids (see Appendix 12).  The GTCI will be incorporated into this study to 
better quantify the accrual of damage linked to corticosteroid use in patients with lupus 
and may allow for an improved understanding of standard of care and patient phenotype.
4.5.8.4
Systemic Lupus International Collaborating Clinics (SLICC)/ 
ACR Damage Index for Systemic Lupus Erythematosus
The SLICC/ACR Damage Index (SDI) for SLE will be utilized to assess organ damage 
as opposed to the collection of disease activity (see Appendix 7).  Damage is defined as 
non-reversible change not related to active inflammation.
4.5.8.5
28-Joint Count
For all patients, 28-joint counts should be performed at the intervals specified in the 
Schedule of Activities (see Appendix 1).  The joint counts must be performed by an 
assessor with experience in performing these assessments; this may be the Principal 
Investigator, subinvestigator, or another trained individual approved by the Sponsor.  
The joint counts on a given patient are strongly recommended to be performed by the 
same assessor, whenever possible, at each study visit. 
The 28 joints included in this assessment are listed in Appendix 13. 
4.5.8.6
Cutaneous Lupus Erythematosus Disease Area and Severity 
Index (CLASI)
The CLASI is an instrument designed to capture SLE-specific mucocutaneous disease 
manifestations (see Appendix 14).  It comprises a score for the activity of the disease 
and a score for the damage caused by the disease.  The CLASI should be completed at 
intervals as indicated in the schedule of assessments for any patient who has 
mucocutaneous manifestations of SLE at a given study visit and at all subsequent visits.  
The CLASI will be used to capture mucocutaneous disease in any patient with 
mucocutaneous disease manifestations beginning on the visit that the mucocutaneous 
manifestation is first observed and periodically thereafter as outlined in the Schedule of 
Activities (see Appendix 1).  
It is important that only SLE-specific lesions are included in this assessment.  Training in 
the use of the CLASI will be available online and will be required for any new investigator 
from the beginning of Study GA30044.
4.5.8.7
Physician’s Global Assessment
The Physician’s Global Assessment (see Appendix 15) is a visual analog scale
(VAS). Physicians are to rate the patient’s disease activity over the past 28 days and place 
a vertical tick mark on a 100-mm analog scale from 0 to 3. The left-hand extreme of the 


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line is described as “None” and the right–hand extreme as “Severe.”  Patient history, 
results of the physical examination, as well as pertinent laboratory values should be taken 
into account when rating the patient’s disease activity. Physicians should also refer to the 
value recorded at the previous visit and move the tick mark as appropriate.
4.5.8.8
Patient’s Global Assessment
The Patient’s Global Assessment is a VAS (see Appendix 16).  The patient’s overall 
assessment of their current disease activity is measured using a vertical tick mark on a 
100-mm VAS.  The left-hand extreme of the line is described as “None” and the right–
hand extreme as “Maximum.”
4.5.8.9
Systemic Lupus Erythematosus Responder Index
The SRI is a categorical assessment that evaluates disease activity in SLE based on the 
different organ systems.  This index utilizes a combined evaluation of the SLEDAI-2K, 
BILAG, and Physician Global Assessment to measure response to treatment (see 
Sections 4.5.8.2, 4.5.8.1; 4.5.8.7).  The SRI-4 primary endpoint defines response as 
meeting all of the following criteria at Week 48 compared with baseline: 

4 point reduction in SLEDAI-2K score

No new BILAG A organ domain score or 2 new BILAG B organ domain scores

No worsening (worsening defined as a > 0.3 point increase) in the Physician’s 
Global Assessment.
4.5.8.10
BICLA
The BICLA is a composite index that was originally derived by expert consensus of 
disease activity indices (Wallace et al. 2011).  BICLA response is defined as follows:

At least one gradation of improvement in baseline BILAG scores in all body systems 
with moderate or severe disease activity at entry (e.g., all A (severe disease) scores 
falling to B (moderate), C (mild), or D (no activity) and all B scores falling to C or D

No new BILAG A or more than one new BILAG B scores

No worsening of total SLEDAI-2K score from baseline

No significant deterioration (10%) in physician’s global assessment, and

No treatment failure (initiation of non-protocol treatment)
4.5.8.11
Optional Photography (for United States only, as applicable)
For patients with cutaneous manifestations of SLE, optional photographs of the affected 
areas may be taken to document change over time while the patient is receiving study 
treatment. Photography is an optional assessment for patients (United States only, as 
applicable) who sign the optional photography consent and is contingent on EC/IRB 
approval.


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4.5.9
Laboratory, Biomarker, and Other Biological Samples
Laboratory assessments will be performed as indicated on the Schedule of Activities 
(see Appendix 1 and Appendix 2).  All laboratory tests will be sent to one or more central 
laboratories for analysis, with the exception of serum and urine pregnancy tests, and 
erythrocyte sedimentation rate (ESR), which will be conducted locally.
At clinic visits at which study drug will be administered, laboratory samples should 
generally be drawn before the administration of study drug and after the administration 
of PRO assessments.  An exception is on Week 24, where indicated PK samples should 
be collected prior to dosing and at timepoints also following study treatment 
administration (see Appendix 1 and Appendix 2).
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis:

ESR:  Can be performed at local laboratory or as point of care test in clinic. The kits 
to perform the test will be provided by the central laboratory.

Pregnancy test
–
All women of childbearing potential (including those who have had a tubal 
ligation) will have a serum pregnancy test at screening.  Urine pregnancy tests 
will be performed at specified subsequent visits.  If a urine pregnancy test is 
positive, it must be confirmed by a serum pregnancy test.  Should a positive 
result be recorded at any time, the procedures detailed in Section 5.4.3 should 
be followed.

Direct Coombs Test:  Will be performed at a local laboratory per the SOA and 
should also be tested if the patient develops anemia that may be autoimmune in 
etiology. 

T-SPOTTest for tuberculosis: may be performed at a local laboratory (optional)
Samples for the following laboratory tests will be sent to one or several central 
laboratories for analysis:

Anti-dsDNA

Anti-nuclear antibody test (immunofluorescence assay)

Autoantibody panel:  anti-Smith, anti-RNP, anti-Ro, anti-La, anti-cardiolipin, and 
anti-B2 glycoprotein

C3, C4, and CH50

Chemistry panel (serum or plasma):  electrolytes (Na, K, Cl, bicarbonate, 
phosphorus), urea, creatinine, glucose, ALT, AST, amylase, lipase, total and direct 
bilirubin, ALP, GGT, albumin, globulin, total protein, calcium, uric acid 

Creatinine kinase (CK), aldolase, and lactate dehydrogenase (LDH)

Coagulation panel:  international normalized ration (INR), activated partial 
thromboplastin time (aPTT), prothrombin time (PT)


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
High sensitivity C-reactive protein

Fasting Lipids:  Triglycerides, high-protein lipoprotein (HDL), low-density lipoprotein 
(LDL), hemoglobin A1c (HbA1C), and total cholesterol

Hematology:  hemoglobin, hematocrit, red blood cell (RBC) count, calculated indices 
(mean corpuscular volume [MCV], mean corpuscular hemoglobin [MCH], mean 
corpuscular hemoglobin concentration [MCHC], red cell distribution width [RDW]), 
platelets, WBC with differential 

Immunology:  total immunoglobulins, IgG, IgM, IgE, and IgA

TBNKs:  Once treatment with study medication begins, TBNK results will be blinded.

Urinalysis:  dipstick (blood, protein, glucose, nitrites, and leukocyte esterase), 
microscopic analysis (RBC, WBC, red cell casts, white cell casts, epithelial cells)

Viral serology
–
Hepatitis B:  HBsAg, total HBcAb, and Hepatitis B surface antibody (HBsAb)
–
Hepatitis C (HCV) antibody

QuantiFERON TB-Gold(QFT); if QFT not available, a PPD skin test will be 
administered (see Section 4.5.7)
The following samples will be sent to the Sponsor or a designee for analysis:

Plasma samples for PK analysis and metabolite identification, as needed.

Plasma, serum, whole blood, urine, and RNA from blood for exploratory 
non-heritable PD markers potentially related to disease, drug, or clinical response; 
see Table 3.

Whole blood for DNA extraction for exploratory research on inherited biomarkers 
(including, but not limited to, genes that express proteins which may influence 
GDC-0853 pharmacokinetics)


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Table 3
Proposed Biomarkers for Exploratory Research
Sample Type 
Timing 
Proposed Biomarkers
Plasma
Baseline and subsequent 
timepoints during and after 
treatment 
Markers including but not limited 
to:  CCL3, CCL4
Serum
Baseline and subsequent 
timepoints during and after 
treatment
Markers including but not limited 
to: CXCL13, CCL20, and 
autoantibodies
Whole blood for FACS
Baseline and subsequent 
timepoints during and after 
treatment 
Cells including but not limited to 
basophils and plasmablasts
RNA extracted from blood
Baseline and subsequent 
timepoints during and after 
treatment
Markers including but not limited to 
the plasmablast signature 
Blood for peripheral blood 
mononuclear cells for 
CyTOF analysis
Baseline and subsequent 
timepoints during and after 
treatment
Cells and surface or activation 
markers, including but not limited 
to B and T cell subsets
Blood for peripheral blood 
mononuclear cells lysate
Baseline and subsequent 
timepoints during and after 
treatment 
Markers including but not limited to 
phosphorylated and total BTK 
protein
Urine
Baseline and subsequent 
timepoints during and after 
treatment
Urinary biomarkers including but 
not limited to CXCL13, TWEAK, 
BAFF and lipids
BAFF anti-B-cell activating factor; BTK bruton’s tyrosine kinase; CyTOF cytometry by time
of flight; FACS fluorescence-activated cell sorting; TNF tumor necrosis factor; 
TWEAK TNF-like weak inducer of apoptosis.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.13), biological samples will be destroyed 
when the final Clinical Study Report has been completed, with the following exception:

Plasma samples collected for PK analysis will be destroyed no later than 5 years 
after the final Clinical Study Report has been completed.

Blood, plasma, serum, and urine samples collected for biomarker analyses will be 
destroyed no later than 15 years after the final clinical study report (CSR) has been 
completed.  
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.
Data arising from sample analysis, including data on germline mutations, will be subject 
to the confidentiality standards described in Section 8.4.


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4.5.10
Electrocardiograms
All ECG recordings must be performed using a standard, high-quality, high-fidelity, 
digital ECG machine equipped with computer-based interval measurements.  Lead 
placement should be as consistent as possible.  
4.5.10.1
Timing of Electrocardiograms
Triplicate or single ECG recordings will be obtained at specified timepoints, as outlined 
in the Schedule of Activities (see Appendix 1). Triplicate ECG recordings will be obtained 
within approximately 2-5 minutes of each other.
When triplicate ECGs are required, three interpretable ECG recordings (e.g., without 
artifacts) must be obtained.  Triplicate ECGs will be captured as follows: 

Day 1: Triplicate ECG (pre-dose)

Week 24: Triplicate ECG (2 hours 30 minutes, post-dose)
The ECG intervals (e.g., PR, QRS, QT, QTcF, and RR) and heart rate from these three 
ECGs will be entered into the eCRF: in addition, these triplicate readings will be stored 
for future analysis, if needed.  
Single ECG recordings may be obtained at unscheduled and other timepoints as 
indicated. 
4.5.10.2
Patient Preparation for Electrocardiogram
ECG recordings are recommended to not be obtained within 3 hours after any meal, 
whenever possible.  ECG recordings must be performed after the patient has been 
resting in a supine position for at least 10 minutes.  All ECGs are strongly recommended 
to be obtained prior to other procedures scheduled at that same time (e.g., vital sign 
measurements, blood draws), whenever possible, except for PROs which should 
generally be collected first at a visit.  Circumstances that may induce changes in heart 
rate, including environmental distractions (e.g., television, radio, conversation) should be 
avoided during the pre-ECG resting period and during ECG recording.
4.5.10.3
Monitoring and Reporting of Electrocardiograms
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  Digital recordings will be stored at a central laboratory.  The 
following should be recorded in the appropriate eCRF:  heart rate, RR interval, QRS 
interval, PR duration, uncorrected QT interval, and QTcF based on the machine 
readings of the individual ECG tracings.  Any morphologic waveform changes or other 
ECG abnormalities must be documented on the eCRF.  If considered appropriate by the 
Sponsor, ECGs may be analyzed retrospectively at a central laboratory.
If at a particular post-dose timepoint, the mean QTcF is 500 msec and/or 60 msec
longer than the baseline value, another triplicate ECG must be recorded, ideally within 


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the next 5 minutes, and triplicate ECG monitoring should continue at least hourly until 
the QTcF has stabilized on two successive ECGs.  The Medical Monitor should be 
notified.  SOC treatment may be instituted per the discretion of the investigator.  If a PK 
sample is not scheduled for that timepoint, an unscheduled PK sample should be 
obtained.  A decision on study drug discontinuation should be made, as described in 
Section 5.1.  The investigator should also evaluate the patient for potential concurrent 
risk factors (e.g., electrolyte abnormalities, co-medications known to prolong the QT 
interval, severe bradycardia).
4.5.11
Patient-Reported Outcomes
PRO data will be collected via questionnaires to more fully characterize the clinical 
profile of GDC-0853.  The questionnaires, translated into the local language as required, 
will be completed in their entirety at specified timepoints during the study.  To ensure 
instrument validity and that data standards meet health authority requirements, 
questionnaires will be self-administered before the patient or clinician receives any 
information on disease status, prior to the performance of non-PRO assessments, and 
prior to the administration of study treatment, unless otherwise specified.  
Patients and clinicians will use paper based questionnaires to capture PRO data.  The 
instructions for completing the questionnaires will be provided by the investigator staff.  
4.5.11.1
Functional Assessment of Chronic Illness Therapy-Fatigue 
Scale (FACIT Fatigue)
The FACIT-Fatigue scale will be used to assess patients’ fatigue (Cella et al. 2005).  The 
13-item questionnaire has been validated for use with SLE patients and has a 7-day 
recall period.  Items are assessed on a 5-point Likert scale with responses ranging from 
0 “not at all” to 4 “very much” and possible total scores range from 0 to 52.  A higher 
score indicates less fatigue, and the minimal important different has been identified at a 
change of 3 points (Lai et al. 2011).  See Appendix 17 for a list of questions in the 
FACIT-Fatigue. 
4.5.12
Mandatory Samples for Whole Genome Sequencing
At participating sites, a blood sample will be collected for DNA extraction to enable 
whole genome sequencing (WGS).  This sample may be sent to one or more 
laboratories for analysis.
Collection and submission of WGS samples is contingent upon the review and approval 
of the exploratory research and the WGS portion of the ICF by each site's Institutional 
Review Board or Ethics Committee (IRB/EC) and, if applicable, an appropriate 
regulatory body.  If a site has not been granted approval for WGS sampling, this section 
of the protocol (i.e., Section 4.5.12) will not be applicable at that site.
Genomics are increasingly informing researchers' understanding of disease 
pathobiology.  WGS provides a comprehensive characterization of the genome and, 


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along with clinical data collected in this study, may increase the opportunity for 
developing new therapeutic approaches.  Data will be analyzed in the context of this 
study but will also be explored in aggregate with data from other studies.  The availability 
of a larger dataset will assist in the identification of important pathways, thus guiding the 
development of new targeted agents.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
Blood samples collected for WGS are to be stored until they are no longer needed or 
until they are exhausted.  However, the storage period will be in accordance with the 
IRB/EC-approved ICF and applicable laws (e.g., health authority requirements).
Patient medical information associated with WGS specimens is confidential and may be 
disclosed to third parties only as permitted by the ICF (or separate authorization for use 
and disclosure of personal health information) signed by the patient, unless permitted or 
required by law.
Given the complexity and exploratory nature of the analyses, data derived from WGS 
specimens will, generally, not be provided to study investigators or patients unless 
required by law.  The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication.
4.5.13
Optional Samples for Research Biosample Repository
4.5.13.1
Overview of the Research Biosample Repository
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection, 
storage, and analysis of RBR specimens will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future.
Specimens for the RBR will be collected from patients who give specific consent to 
participate in this optional research. RBR specimens will be used to achieve the 
following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays


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4.5.13.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection and submission of biological samples to the RBR is contingent upon the 
review and approval of the exploratory research and the RBR portion of the Informed 
Consent Form by each site's Institutional Review Board or Ethics Committee (IRB/EC) 
and, if applicable, an appropriate regulatory body.  If a site has not been granted 
approval for RBR sampling, this section of the protocol (see Section 4.5.13) will not be 
applicable at that site.
4.5.13.3
Sample Collection
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to GDC-0853 and lupus:

Serum and blood for RNA samples collected at screening; Day 1 (pre-dose); 
Weeks 12, 24, and 48; and flare visit. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
RBR specimens are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
4.5.13.4
Confidentiality
Specimens and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RBR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Given the complexity and exploratory nature of the analyses, data derived from RBR 
specimens will generally not be provided to study investigators or patients unless 
required by law.  The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication.
Data generated from RBR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.


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4.5.13.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR specimens.  
Patients who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF.
In the event of an RBR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RBR research.
4.5.13.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR specimens have the right to withdraw their 
specimens from the RBR at any time for any reason.  If a patient wishes to withdraw 
consent to the testing of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the appropriate RBR Subject 
Withdrawal Form and, if the trial is ongoing, must enter the date of withdrawal on the 
RBR Research Sample Withdrawal of Informed Consent eCRF.  The patient will be 
provided with instructions on how to withdraw consent after the trial is closed.  A 
patient's withdrawal from Study GA30044 does not, by itself, constitute withdrawal of 
specimens from the RBR.  Likewise, a patient's withdrawal from the RBR does not 
constitute withdrawal from Study GA30044.
4.5.13.7
Monitoring and Oversight
RBR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Sponsor monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RBR for the purposes 
of verifying the data provided to the Sponsor.  The site will permit monitoring, audits, 
IRB/EC review, and health authority inspections by providing direct access to source 
data and documents related to the RBR samples.


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4.6
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Patient Discontinuation
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
Reasons for withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent at any time

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study

Investigator or Sponsor determines it is in the best interest of the patient

Patient non-compliance, as per Principal Investigator’s discretion
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study will not be replaced.
If possible, the investigator will clarify the following: 

If the patient withdrew consent for the remaining study procedures only OR 

If the patient withdrew consent for the remaining study procedures as well as the 
use of all banked samples OR

If the patient withdrew consent for the remaining study procedures as well as all use 
of study acquired clinical and laboratory data
If a patient discontinues the study prior to the Week 48 treatment completion visit, an 
early termination visit should be conducted.  These patients should return for the 8-week 
safety follow-up visit in this study (see Appendix 1).  If the patient is unable to return for a 
follow-up visit, the trial site may contact the patient by telephone to determine their 
clinical status.  
Patients who discontinue the study during the safety follow-up period but prior to 
completion of the 8-week safety follow up will be asked to return to the clinic within 
30 days (7 days) after the last dose of study drug or last scheduled visit for an early 
termination visit.
4.6.2
Study Treatment Discontinuation
Patients must discontinue study treatment (and will continue in the study) if they 
experience any of the following:

Requirement of any prohibited medication as defined in Section 4.4.2

Treated with accepted immunosuppressive that exceeds the maximum dose as 
defined by the protocol (see Section 4.4.1)

Combination immunosuppressive medications not allowed in the inclusion and 
exclusion criteria (see Section 4.1) 


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
Grade 2 AST or ALT elevation: (AST or ALT 3ULN) in combination with total 
bilirubin 2ULN or clinical jaundice as defined by Hy’s law

Grade 3 AST or ALT elevation:  (AST or ALT 5ULN)

Grade 4 Neutropenia:  ANC 500/mm³

Grade 4 Lymphopenia: absolute lymphocyte count (ALC) 200/mm³

Grade 4 Thrombocytopenia:  platelet count 25,000/mm³

Pregnancy

Malignancy (with the exception of non-serious local and resectable basal or 
squamous cell carcinoma of the skin)

An episode of torsade de pointes
Patients must discontinue study treatment if they receive any new or increased dose of 
SLE treatment that is not specifically permitted in this protocol (see Section 4.4.1) and 
approved by the Medical Monitor. 
Investigators may discontinue study treatment for:

Any medical condition that may jeopardize the patient’s safety if he or she continues 
on study treatment

The best interest of the patient

Patient non-compliance
If study treatment is discontinued prematurely, patients will be asked to stay in the study 
and continue with all scheduled visits for the remainder of the 48-week treatment period. 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced.
In some cases, study treatment may be resumed if approved by both the investigator 
and the Medical Monitor.  
4.6.3
Study and Site Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients.

Patient enrollment is unsatisfactory.
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  


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The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
To protect patient safety, an unblinded IMC in collaboration with a Scientific Oversight 
Committee will monitor safety throughout the study (see Section 3.1.2).
The safety risk management plan for patients in this study is based on nonclinical and 
clinical experience with GDC-0853 in completed and ongoing studies as well as 
published literature on other BTK inhibitors and takes into account the population under 
study.  The important potential safety risks for GDC-0853 are outlined below.  Please
refer to the GDC-0853 Investigator’s Brochure for a complete summary of safety 
information. 
Several measures will be taken to ensure the safety of patients participating in this study.  
Eligibility criteria have been designed to exclude patients at higher risk for potential 
toxicities.  Patients will undergo safety monitoring during the study, including monitoring 
of vital signs, physical examination, ECGs, and routine laboratory safety assessments 
(hematology, chemistry, and urinalysis) and assessment of the nature, frequency, and 
severity of adverse events.  In addition, guidelines for managing potential adverse 
events, including criteria for treatment interruption or discontinuation, and enhanced 
safety reporting are provided below and in Table 5.  
5.1.1
Safety Plan for Potential Risks Associated with GDC-0853 
5.1.1.1
Infections
On the basis of the well described phenotype of patients with XLA, a primary 
immunodeficiency of B cells and immunoglobulin production, it is anticipated that 
inhibitors of BTK may raise the risk for certain bacterial infections 
(Lederman and Winkelstein 1985; Broides et al. 2006), enteroviral infections (Misbah et 
al. 1992; Ziegner et al. 2002), intestinal infections with Giardia and Campylobacter 
species (Winkelstein et al. 2006; van den Bruele et al. 2010), or other opportunistic 
infections which are primarily cleared by B-cell adaptive immune responses.  This risk is 
likely independent of sex for patients exogenously administered GDC-0853.  


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Unlike XLA, GDC-0853 is a reversible inhibitor of BTK that will be initiated after the 
immune system has developed, and so the degree to which GDC-0853 antagonism of 
BTK signaling may suppress immune activity or resemble XLA is unknown.  However, 
data to date suggest that since BTK inhibitors target only the kinase domain, other BTK 
activities may remain intact and IgG levels in patients with an established immune 
system may not be significantly depleted (Byrd et al. 2013).  
Effects on lymphocytes and immunoglobulins in rats and dogs were reversible and 
considered to be related to pharmacological activity involving BTK inhibition.  See 
Section 1.3.1 for related primary nonclinical toxicity findings and Section 4 of the 
GDC-0853 Investigator’s Brochure for further details.  
To date, no immune-challenge experiments (e.g., T-dependent antigen response test 
[TDAR]) have been conducted in animals.  It is not known if these effects on B cells and 
IgG concentrations in animals will translate to humans, or if such changes would have 
functional/deleterious impact on immune function.
Infections, including pneumonia and fatal influenza, have occurred in patients with B-cell 
malignancies treated with GDC-0853.  In studies with healthy subjects with single doses 
and with dosing for 14 days, self-limited Grade 1 events of nasopharyngitis were 
reported but did not lead to any change in study drug dosing.  One subject had 
asymptomatic bacteriuria, which resolved while study drug dosing continued.
Patients will be excluded from the study if they have a history of any major episode of 
infection requiring hospitalization or treatment with IV or IM antimicrobials within 4 weeks 
prior to or during screening or treatment with oral antimicrobials within 2 weeks prior to 
and during screening, evidence of active or latent or inadequately treated infection with 
TB, known active infection (current) or history of recurrent infection, or any known 
immunodeficiency including IgG 500 mg/dL (see Section 4.1.2).
Total Ig concentrations will be measured regularly throughout the study. All patients in 
the study should be monitored for fever and potential infectious complications, including 
opportunistic infections and tuberculosis, and should be evaluated promptly. Physicians 
or a health care provider should give patients advice to prevent potential transmission of 
and exposure to endemic infections according to local or CDC guidelines. Patients 
should be advised to seek immediate medical attention if they develop signs and 
symptoms suggestive of an infection.  All infections occurring during the study that 
require treatment, including, but not limited to, respiratory infections, cutaneous 
infections, urinary tract infections and systemic viral infections and episodes of 
suspicious or febrile diarrhea, should be evaluated using serology or PCR (if available, 
and as appropriate) and cultured if feasible and any identified organisms noted in the 
Adverse Event eCRF.  Any serious infection, any infection requiring IV antimicrobials 
(i.e., any Grade 3 infection), or any opportunistic infection is considered an adverse 


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event of special interest (AESI) and should reported to the Sponsor in an expedited 
manner as outlined in Section 5.2.3.
Guidelines for management of study treatment in the event that a patient experiences an 
infection are provided in Table 4.
5.1.1.2
Vaccinations
The effect of GDC-0853 upon the efficacy of vaccinations is unknown. It is 
recommended that appropriate vaccinations per EULAR (van Assen et al. 2011) 
recommendations or local guidelines be up to date before study participation.  Patients 
will be excluded from study participation and will not be dosed with GDC-0853 if they 
have been vaccinated with live, attenuated vaccines (e.g., the intranasal live attenuated 
influenza vaccines, BCG, varicella) within 6 weeks before planned dosing.  Immunization 
with a live or attenuated vaccine is prohibited for the duration of study participation, 
including the safety follow-up period after the administration of the last dose however 
inactivated vaccine formulations are permitted (e.g., seasonal influenza).  
In addition, current routine household contact with children or others who have been 
vaccinated with live vaccine components may pose an unknown risk to the patient during 
study treatment with GDC-0853.  Some of these vaccines include varicella (“chickenpox”) 
vaccine, oral polio vaccine, and the inhaled flu vaccine.  Following vaccination with live 
component vaccines, the virus may be shed in bodily fluids, including stool, and there is 
a potential risk that the virus may be transmitted to the patient. 
General guidelines for immunosuppressed patients suggest that exposure to vaccinated 
individuals should be avoided following vaccination with these vaccines for the stated 
time periods:

Varicella or attenuated typhoid fever vaccination for 4 weeks following vaccination;

Oral polio vaccination for 6 weeks following vaccination;

Attenuated rotavirus vaccine for 10 days following vaccination;

FluMist(inhaled flu vaccine) for 1 week following vaccination.
5.1.1.3
Bleeding
No decrease in platelets, changes in coagulation parameters or bleeding events were 
observed in nonclinical studies with GDC-0853.  Bleeding events, including non-serious 
CTCAE Grade 1 bruising and serious Grade 3 GI bleeding have been reported in 
patients with hematological malignancies treated with GDC-0853 in Study GO29089.  
The GI bleeding events have not been dose related, and the events occurred in patients 
who were taking concomitant NSAIDs/acetylsalicylic acid and who had a history of 
gastroesophageal or peptic ulcer disease.  The impact of BTK inhibition as a potential 
risk factor for bleeding is unknown.  BTK is expressed in platelets and is involved in 
platelet function via GPVI/Collagen receptor signaling and GP1b receptor signaling.  
Platelets from patients with XLA, a genetic deficiency of BTK, demonstrate decreased 


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activation in response to submaximal collagen stimulation but normal response to 
thrombin; clinically, there is no reported bleeding propensity of XLA patients (Howard et 
al. 2006).
Bruising or bleeding events related to GDC-0853 have not been reported in healthy 
subjects.
It is unknown if GDC-0853 will increase the risk of bleeding in patients, especially in 
those receiving antiplatelet or anticoagulant therapies.  As a precautionary safety 
measure, patients will be excluded from study participation if they have a need for 
systemic anticoagulation with warfarin or other oral or injectable anti-coagulants or 
anti-platelet agents (other than NSAIDs, aspirin, and other salicylates), any history of 
hospitalizations or transfusion for a GI bleed, any history of a hemorrhagic CVA, any 
history of spontaneous intracranial hemorrhage, traumatic intracranial hemorrhage within 
10 years prior to the study or a known bleeding diathesis.  Patients should be advised to 
seek immediate medical attention if they develop signs and symptoms suggestive of 
clinically significant bleeding.  
Several risk factors including patient age, co-morbidities, concurrent medications, prior 
medical history, and Helicobacter pylori infection have been demonstrated in a variety of 
studies to increase the risk of NSAID-related GI injury (Lanza et al. 2009).  It is unknown 
if GDC-0853 will increase the risk of bleeding in patients receiving NSAIDs.  Therefore, 
in order to prevent NSAID-related GI complications in high-risk patients, concomitant use 
of PPI should be considered (Bhatt et al. 2008) and used according to local or 
recognized guidelines (e.g., ACCF/ACG/AHA 2008 Expert Consensus Document).
Patients at high risk for NSAID-related GI toxicity include the following:

Patients using both aspirin and an NSAID

Patients with a history of ulcer disease

Patients with one or more of the following:
–
Age 60 years
–
High-dose NSAID use
–
Concurrent corticosteroid use
–
Dyspepsia or gastroesophageal reflux disease (GERD) symptoms
Any bleeding event Grade 2 is considered an adverse event of special interest and 
should be reported to the Sponsor in an expedited manner as outlined in Section 5.2.3.  
Guidelines for management of study treatment in the event that bleeding is observed in 
patients are provided in Table 4.


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5.1.1.4
Cytopenias
Cytopenias have been observed in patients with hematological malignancies who 
received GDC-0853, including neutropenia, anemia, and thrombocytopenia; events have 
been monitorable and clinically manageable (see the GDC-0853 Investigator’s Brochure 
for further details).  
Patients should be monitored regularly with hematology laboratory evaluations as 
outlined in the schedule of assessments and should receive appropriate supportive care 
as clinically indicated.  Patients should be advised to seek immediate medical attention if 
they develop signs and symptoms suggestive of cytopenias (e.g., persistent fever, 
bruising, bleeding, pallor). 
Guidelines for the management of study treatment, including dose holding, in the event 
of cytopenias in patients are provided in Table 4.  
5.1.1.5
Gastrointestinal Effects
Body weight gain and food consumption changes have been observed in animals, 
including nonsignificant increases in male Wistar-Han rats administered 2 mg/kg/day 
(4.3 M hr) for 6 months, and significant reductions in rats administered 100 mg/kg/day 
(1438 M hr) and dogs administered 25 mg/kg (180 M hr) for 4 weeks.  These effects 
on body weight gain and food consumption were reversible following discontinuation of 
GDC-0853 dosing.
Grade 1 diarrhea, nausea, and abdominal pain have been reported in patients with 
hematological malignancies treated with GDC-0853; however, the events resolved and 
have not led to study drug discontinuation.  Healthy subjects in the multiple 
ascending-dose study, GA29347, reported events of mild self-limited nausea.  
Throughout the study, patients will be monitored for GI side effects.  Guidelines for 
management of study treatment in the event of GI side effects in patients are provided in
Table 4.
5.1.1.6
Hepatotoxicity
Evidence of hepatobiliary injury was observed in animals administered relatively high 
doses of GDC-0853 in repeat-dose toxicity studies (see Section 1.3.1 for related primary 
nonclinical toxicity findings).  
In clinical studies to date, including single dosing and multiple dosing for 14 days in 
healthy subjects and daily dosing for up to 2 years in patients with hematological 
malignancies, there have been no adverse events of liver enzyme elevations or trends 
towards elevations in laboratory evaluations.  
As a safety riskmitigation measure, to be eligible for the study, AST and/or ALT levels 
should be no more than 1.5 times the ULN and total bilirubin levels should be 1.2ULN 
at screening.  Safety monitoring for potential hepatotoxicity includes baseline and routine 


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evaluations of AST/ALT and total bilirubin levels throughout the study as outlined in the 
schedule of assessments.  
Laboratory results of Grade 3 (5ULN) AST or ALT elevation, or ALT or AST 
elevations 3 ULN in combination with clinical jaundice (total bilirubin 2 ULN) are 
considered AESIs and should be reported to the Sponsor in an expedited manner as 
outlined in Section 5.2.3. 
Guidelines for the management of study treatment in the event of hepatotoxicity in 
patients are provided in Table 4.  
5.1.1.7
Cardiovascular Effects
GDC-0853 is considered to have a low potential to cause QT interval prolongation or to 
directly affect other cardiovascular parameters, at therapeutic exposures.  A minimal 
increase in corrected QT (QTc; 7 msec or 3%) interval was noted at 45 mg/kg in the 
single dose cardiovascular safety pharmacology study in telemetry-instrumented dogs.  
Based on extrapolated/interpolated toxicokinetic data, the unbound Cmax at 45 mg/kg 
(considered a NOAEL) 
 
  There were no GDC-0853-related changes in ECG parameters in the 
repeat-dose 4-week or 9-month dog toxicity studies. 
Analysis of ECG data from the SAD and MAD studies in healthy subjects did not 
demonstrate any significant increase in either QRS interval or QTcF intervals.  However, 
cardiac safety will continue to be evaluated in all patients at baseline and throughout the 
study, with routine monitoring of vital signs (including heart rate and blood pressure), 
collection of routine safety ECGs, triplicate ECGs with appropriate PK-matched
timepoints, and collection of adverse events (see Appendix 1).
Management of patients with sustained QTcF prolongation (QTcF that is 500 msec 
and/or 60 msec longer than the baseline value on at least two ECG measurements 
30 minutes apart) should include close monitoring, with ECGs repeated at least hourly 
until two successive ECGs show stabilization of the findings, correction of any electrolyte 
abnormalities, and possible discontinuation of other concomitant medications that are 
known to prolong the QT interval.  Consultation with a cardiologist or electrophysiologist 
is recommended, to help in the management of such patients.  The Medical Monitor 
should be notified as soon as possible (see Section 4.5.8.11 and Section 4.5.10)
Guidelines for management of study treatment in the event of cardiovascular effects in 
patients are provided in Table 4.
5.1.1.8
Vascular Inflammation
 
  The translatability of the nonclinical findings to 


 
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humans is unknown; however, Beagle dogs are susceptible to spontaneous 
development of polyarteritis syndrome (Snyder et al. 1995) and may be more sensitive 
to any drug-induced effects.  Further, there are several examples of approved therapies 
for which there is no correlation between the finding of vasculitis in dogs or rats at 
clinically relevant exposures and adverse outcomes in patients (FDA 2003; FDA 2011).   
As a safety risk-mitigation measure, CBC, creatinine, and urinalysis will be monitored in 
all patients during the study.   
Guidelines for management of study treatment in the event of a new treatment emergent 
vasculitis in patients are provided in Table 4. 
5.1.1.9 
Malignancy 
The impact of BTK inhibition on the development of malignancies is not known; however, 
malignancies have been identified as a potential concern for immunomodulatory agents.  
Malignancies have been reported in patients with XLA, including lymphoreticular 
malignancies, gastric and colorectal adenocarcinoma, and squamous cell carcinoma of 
the lung. 
Patients with a history of cancer, including hematologic malignancy and solid tumors, 
within 10 years of screening will be excluded from the study.  Basal or squamous cell 
carcinoma of the skin that has been excised and is considered cured and in situ 
carcinoma of the cervix treated with apparent success by curative therapy more than 
1 year prior to screening are not exclusionary. 
All malignancies are considered adverse events of special interest for this study and 
should be reported to the Sponsor in an expedited manner as outlined in Section 5.2.3.   
Guidelines for management of study treatment in the event of malignancies in patients 
are provided in Table 4.  Please refer to the GDC-0853 Investigator’s Brochure for 
further details. 
5.1.2 
Management of Study Treatment in Patients Who Experience 
Specific Adverse Events 
Guidelines for management of study treatment in patients who experience specific 
adverse events are outlined in Table 4.   
 
 
 
 


 
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Table 4 
Guidelines for Management of Study Treatment in Patients Who 
Experience Specific Adverse Events 
Event 
Action to Be Taken a 
Infection b 
 
Serious infection or any infection 
requiring treatment with an IV 
antimicrobial agent 
Withhold study treatment.  Once the infection has resolved, 
consult with Medical Monitor to discuss potential resumption 
of study treatment.   
Self-limited infections that require 
treatment 
Withhold study treatment during antimicrobial therapy. 
Bleeding 
Any Grade ≥ 2 bleeding event is considered an adverse 
event of special interest and should be reported to the 
Sponsor in an expedited manner. 
 
For Grade 3 or higher bleeding events or any serious 
bleeding event withhold study treatment and consult with the 
Medical Monitor.  Once bleeding event has resolved, consult 
with Medical Monitor to discuss the potential resumption of 
study treatment. 
Neutropenia c 
 
Grade 2:  ANC > 1000 and 
< 1500/mm³ 
Maintain study treatment dosing. 
Grade 3:  ANC > 500 and 
< 1000/mm³ 
For the first event, hold study treatment and recheck CBC in 
7 days.  If neutrophil count has recovered to Grade 1 
(> 1500/mm3) or has returned to baseline, study treatment 
can be resumed unless there is a concurrent serious or 
Grade 3 infection.  If Grade 3 neutropenia persists, or for 
recurrent Grade 3 neutropenia, discuss with the Medical 
Monitor. 
Grade 4: ANC < 500 /mm³ 
Discontinue study treatment. 
Lymphopenia  
 
Treatment emergent Grade 2 
lymphopenia: lymphocyte count 
500−800/mm³ 
Maintain study treatment dosing unless concurrent active 
infection or other clinical concern. 
Treatment emergent Grade 3 
lymphopenia:  lymphocyte count 
200−500/mm³ 
For the first event, hold study treatment and recheck CBC in 
7 days.  If lymphocyte count has recovered, study treatment 
can be resumed unless there is a concurrent serious or 
Grade 3 infection.  If Grade 3 lymphopenia persists, or for 
recurrent Grade 3 lymphopenia, discuss with the Medical 
Monitor. 
Grade 4 Lymphopenia:  
lymphocyte count < 200/mm³ 
Discontinue study treatment. 
 


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Table 4
Guidelines for Management of Study Treatment in Patients Who 
Experience Specific Adverse Events (cont.)
Event
Action to Be Taken a
Thrombocytopenia d
Treatment-emergent Grade 1:  
PLT 75,000/mm³
In the absence of bleeding event(s), maintain study 
treatment dosing.
Treatment-emergent Grade 2:  
PLT 50,00075,000/mm³
For the first treatment emergent drop in platelet count to 
50,00075,000/mm³ that cannot be attributed to an SLE 
flare, hold study treatment and recheck CBC in 7 days. 
If platelet count has recovered to >75,000/mm3 or to baseline
and there have been no bleeding events, study treatment
can be resumed. 
For recurrent or persistent Grade 2 treatment-emergent 
thrombocytopenia that cannot be attributed to an SLE flare,
or for thrombocytopenia associated with bleeding events, 
discuss with the Medical Monitor (and consider discontinuing
study treatment).
Treatment-emergent Grade 3:  
PLT 50,000/mm³
For the first treatment emergent drop in platelet count to < 
50,000/mm³ that cannot be attributed to an SLE flare, hold 
study treatment and recheck CBC in 7 days. If the platelet 
count has recovered to baseline or >75,000/mm3, study 
treatment can be resumed.
1) If the platelet count fails to return to baseline or 
>75,000/mm3, 2) if there is recurrence of Grade 3 treatment-
emergent thrombocytopenia that cannot be attributed to an 
SLE flare, or 3) if the thrombocytopenia is associated with 
bleeding events, discuss with the Medical Monitor (and 
consider discontinuing study treatment).
Grade 4: PLT < 25,000/mm³
Discontinue study treatment
Gastrointestinal Effects
Nausea, vomiting, and/or 
diarrhea
Manage according to site institutional guidelines.
Consider administration of GDC-0853 with food as a 
possible mitigation strategy.  Consult with Medical Monitor.
Malignancy
Any malignancy 
Discontinue study treatment with the exception of 
non-serious local and resectable basal or squamous cell 
carcinoma of the skin.  Report event as an adverse event of 
special interest to the Sponsor in an expedited manner.


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Table 4
Guidelines for Management of Study Treatment in Patients Who 
Experience Specific Adverse Events (cont.)
Event
Action to Be Taken a
Hepatotoxicity
Grade 2 AST or ALT elevation: 
(AST or ALT 3.05.0ULN)
Withhold study treatment and consult with the Medical 
Monitor
Grade 2 AST or ALT elevation; 
(AST or ALT 3ULN) in 
combination with total bilirubin 
2ULN or clinical jaundice as 
defined by Hy’s law
Discontinue study treatment and consult with the Medical 
Monitor. Recheck liver laboratory tests, to include AST/ALT, 
ALP, and total bilirubin, and CBC with differential (to 
determine eosinophil count), within 1 week (preferably within 
72 hours).  Assess patient for signs/symptoms of hepatic 
failure and assess for other causes of liver dysfunction (e.g. 
viral hepatitis, concomitant medications, etc.) Continue to 
monitor liver function tests until abnormalities resolve.  
Report Hy’s Law cases as as adverse events of special 
interest to the Sponsor in an expedited manner.
Grade 3 AST or ALT elevation: 
(AST or ALT 5ULN)
Discontinue study treatment and consult with the Medical 
Monitor. Recheck liver laboratory tests, to include AST/ALT, 
ALP, and total bilirubin, and CBC with differential (to 
determine eosinophil count) within 1 week (preferably within 
72 hours).  Assess patient for signs/symptoms of hepatic 
failure and assess for other causes of liver dysfunction (e.g. 
viral hepatitis, concomitant medications, etc.) Continue to 
monitor liver function tests until abnormalities resolve.
Elevation of AST or ALT of Grade 3 (i.e., AST or ALT 
5ULN) should be reported as an adverse event of special 
interest to the Sponsor in an expedited manner. 
Cardiovascular Effects 
Sustained (at least two ECG 
measurements 30 minutes 
apart) QTcF that is 500 msec 
and/or 60 msec longer than the 
baseline value
Discontinue study treatment unless there is a clear alternative 
cause other than study drug.e
Sustained absolute QT that is 
515 msec or a new ECG finding 
of clinical concern
Discontinue study treatment and discuss with the Medical 
Monitor unless there is a clear cause other than study drug. e
An episode of torsades de 
pointes 
Discontinue study treatment. 


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Table 4
Guidelines for Management of Study Treatment in Patients Who 
Experience Specific Adverse Events (cont.)
Event
Action to Be Taken a
Vascular Inflammation
Treatment emergent vasculitis
Initiate appropriate evaluation and consult with the Medical 
Monitor.  
ALPalkaline phosphatase; ALT alanine aminotransferase; ANCabsolute neutrophil count; 
AST aspartate aminotransferase; CBCcomplete blood count; ECG electrocardiogram; 
IVintravenous; OLEopen label extension; PLT platelet count; SLEsystemic lupus 
erythematosus; ULNupper limit of normal.
Note:  “Study treatment” includes study drug (GDC-0853 or placebo) 
a Patients who discontinue study drug treatment due to an adverse event should remain in the 
blinded study if feasible however they will not be eligible for an OLE, if initiated. If they 
discontinue the study, the patient should enter safety follow up.
b Appropriate laboratory investigations, including but not limited to cultures, should be performed 
to establish the etiology of any serious infection.  
c Patients withdrawn from the study due to a reduced neutrophil count must be followed closely 
for signs of infection, with treatment and repeated laboratory analysis as deemed appropriate 
by the investigator including discontinuation of other treatments if indicated.
d Patients withdrawn from the study due to a reduced platelet count should have additional 
management and treatment as deemed appropriate by the investigator including 
discontinuation of other treatments if indicated.  
e In rare circumstances, it may be acceptable to resume study drug, provided that any ECG 
abnormalities have resolved and that the patient is appropriately monitored.  Prior to 
re-administering drug, consult with the Medical Monitor.  Clinical judgment should be applied.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product


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
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.9.  

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that had it occurred in a more severe 
form or was allowed to continue might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.10)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).


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5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
include the following:
Adverse Events of Special Interest for GDC-0853

Any serious infection, any infections requiring IV antimicrobials and any 
opportunistic infections

Any bleeding event Grade 2 or above

All malignancies

A laboratory result of Grade 3 (i.e., 5ULN) AST or ALT elevation
Adverse Events of Special Interest for General Drug Development

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s 
law (see Section 5.3.5.6)

Suspected transmission of an infectious agent by the study drug, as defined below
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Section 5.4Section 5.6.  
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 


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procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events will be reported until 8 weeks after the 
last dose of study drug the patients receives, either in this study or in an OLE, if initiated.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?" 
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity.  Table 5 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.


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Table 5
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v4.0), which can be found at:   
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see also
Table 6):

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
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Table 6
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Diagnosis versus Signs and Symptoms
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
5.3.5.2
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.


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
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe GI hemorrhage leads to renal failure, both events should be reported 
separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.3
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF. If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.4
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.


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If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5 ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events).
5.3.5.5
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.5 for 
details on recording persistent adverse events).


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5.3.5.6
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3 ULN in combination with total bilirubin 
2ULN

Treatment-emergent ALT or AST 3 ULN in combination with clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.4) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2).
5.3.5.7
Deaths
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed to progression of lupus.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
If the death is attributed to progression of lupus, "systemic lupus erythematosus
progression" should be recorded on the Adverse Event eCRF.  
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.8
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 


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recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.9
Lack of Efficacy or Worsening of Lupus
Medical occurrences or symptoms of deterioration that are anticipated as part of lupus 
should be recorded as an adverse event if judged by the investigator to have 
unexpectedly worsened in severity or frequency or changed in nature at any time during 
the study.  When recording an unanticipated worsening of lupus on the Adverse Event 
eCRF, it is important to convey the concept that the condition has changed by including 
applicable descriptors (e.g., "accelerated systemic lupus erythematosus").
5.3.5.10
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.11
Adverse Events Associated with an Overdose or Error in Drug 
Administration
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not itself 
an adverse event, but it may result in an adverse event.  All adverse events associated with 
an overdose or incorrect administration of study drug should be recorded on the Adverse 
Event eCRF.  If the associated adverse event fulfills seriousness criteria, the event should 
be reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).  No safety data related to overdosing of GDC-0853 are available.


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5.3.5.12
Patient-Reported Outcome Data
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data.  However, if any PRO responses 
suggestive of a possible adverse event are identified during site review of the PRO data, 
the investigator will determine whether the criteria for an adverse event have been met 
and, if so, will report the event on the Adverse Event eCRF.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (see Section 5.4.2 for further details)

Adverse events of special interest (see Section 5.4.2 for further details)

Pregnancies (see Section 5.4.3 for further details)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information 
Genentech Medical Monitor contact information for all sites:
Medical Monitor:
, M.D., MPH
Telephone Nos.:
(
, 
, U.S.)


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 Medical Monitor contact information:
Medical Monitors:
, M.D.
Telephone No.:
 (
 Argentina)
24-hour Telephone No.:
 or 
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to investigators should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or 
by scanning and emailing the form using the fax number or email address provided to 
investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 8 weeks after the last dose of study drug the patients 
receives, either in this study or an OLE, if initiated. Investigators should record all case 
details that can be gathered immediately (i.e., within 24 hours after learning of the event) 
on the Adverse Event eCRF and submit the report via the electronic data capture (EDC) 
system.  A report will be generated and sent to Safety Risk Management by the EDC 
system.
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the event), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.  
Instructions for reporting serious adverse events that occur after the last dose of study 
treatment are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within or within 8 weeks after 
the last dose of study drug, either in this study or an OLE, if initiated.  A Clinical Trial 
Pregnancy Reporting Form should be completed and submitted to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or email 


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address provided to investigators.  Pregnancy should not be recorded on the Adverse 
Event eCRF.  The investigator should discontinue study drug and counsel the patient, 
discussing the risks of the pregnancy and the possible effects on the fetus.  Monitoring 
of the patient should continue until conclusion of the pregnancy.  Any serious adverse 
events associated with the pregnancy (e.g., an event in the fetus, an event in the mother 
during or after the pregnancy, or a congenital anomaly/birth defect in the child) should be 
reported on the Adverse Event eCRF.  In addition, the investigator will submit a Clinical 
Trial Pregnancy Reporting Form when updated information on the course and outcome 
of the pregnancy becomes available.  
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
120 days (4 months) after the last dose of study drug.  A Clinical Trial Pregnancy 
Reporting Form should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the pregnancy), either by 
faxing or by scanning and emailing the form using the fax number or email address 
provided to investigators.  Attempts should be made to collect and report details of the 
course and outcome of any pregnancy in the partner of a male patient exposed to study 
drug.  When permitted by the site, the pregnant partner would need to sign an 
Authorization for Use and Disclosure of Pregnancy Health Information to allow for 
follow-up on her pregnancy.  If the authorization has been signed, the investigator 
should submit a Clinical Trial Pregnancy Reporting Form when updated information on 
the course and outcome of the pregnancy becomes available.  An investigator who is 
contacted by the male patient or his pregnant partner may provide information on the 
risks of the pregnancy and the possible effects on the fetus, to support an informed 
decision in cooperation with the treating physician and/or obstetrician.
5.4.3.3
Congenital Anomalies/Birth Defects and Abortions
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).  Any abortion should be reported in the same fashion (as the Sponsor 
considers abortions to be medically significant).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.


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During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
8 weeks after the last dose of study drug the patients receives, either in this study or an 
OLE, if initiated), if the event is believed to be related to prior study drug treatment.  
These events should be reported through use of the Adverse Event eCRF.  However, if 
the EDC system is not available, the investigator should report these events directly to 
the Sponsor or its designee, either by faxing or by scanning and emailing the Serious 
Adverse Event/Adverse Event of Special Interest Reporting Form using the fax number 
or email address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the GDC-0853 Investigator’s Brochure.
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.


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An unblinded IMC and Scientific Oversight Committee will monitor the incidence of 
adverse events during the study.  An aggregate report of any clinically relevant 
imbalances that do not favor the test product will be submitted to health authorities.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
Details of all statistical methods (including scoring of disease-activity or PRO 
instruments and missing data handling) will be provided in the Data Analysis Plan (DAP).
6.1
DETERMINATION OF SAMPLE SIZE
The purpose of this study is estimation and hypothesis generation regarding the effect of 
GDC-0853 on Week 48 SRI-4 response rate relative to placebo in moderate to severe 
active SLE patients and a biomarker-defined subgroup of patients. A total of 
240 patients will be randomly allocated in a 1:1:1 ratio to receive one of two doses of 
GDC-0853 (200 mg BID GDC-0853 [Arm A] or 150 mg QD GDC-0853 [Arm B]) or 
placebo (Arm C).  This sample size will provide approximately 88% power at a 2-sided 
0.05 significance level to detect a 25% absolute improvement in the response rate for a 
GDC-0853 containing arm relative to the placebo arm assuming a placebo 
response-rate of 50%. Patients without post-baseline response assessments will be 
treated as non-responders.  For an evaluation of efficacy in a subgroup defined by a 
predictive biomarker with 50% prevalence, the total sample-size of 80 patients per arm 
provides approximately 80% power to detect a 25% improvement with 2-sided 0.20
significance level, using the Fisher’s Exact Test. No adjustment for multiple 
comparisons will be made.
6.2
SUMMARIES OF CONDUCT OF STUDY
The final analysis will be based upon patient data collected through patient 
discontinuation or study discontinuation, whichever occurs first.  The number of patients 
who enroll, discontinue, or complete the study will be summarized.  Reasons for 
premature study withdrawal will be listed and summarized.  Enrollment and major 
protocol deviations will be listed and evaluated for their potential effects on the 
interpretation of study results.  All summaries will be presented according to randomized 
treatment assignment.
6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Treatment group comparability will be analyzed.  Demographic and baseline 
characteristics such as age, sex, weight, and disease activity will be summarized by 
treatment group.  For categorical variables, the descriptive statistics will include counts 
and proportions.  For continuous variables, the descriptive statistics will include the 
number of observations, mean, standard deviation, median, minimum, and maximum 
values.  


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6.4
EFFICACY ANALYSES
Efficacy analysis will be conducted for the intent-to-treat population, defined as all 
randomly allocated patients.  Sensitivity analyses of additional study population (e.g., 
completers, or per protocol [excluding major protocol violators]) may also be performed
for the primary endpoint or key secondary endpoints and will be detailed in the DAP.  
Biomarker-defined subgroup analyses will also be performed to identify subsets of 
patients who derive enhanced clinical benefit from GDC-0583.  The focus of the 
subgroup efficacy analyses is on, but not limited to, subgroups defined by plasmablast 
signature levels.
Statistical tests will be conducted at the 0.05 significance level for the intent-to-treat (ITT)
population and at the 0.20 significance level for plasmablast-signature defined 
subgroups.  No multiplicity adjustments will be made to control the overall Type I error, 
and positive tests will be viewed as hypothesis generating rather than confirmatory.
6.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint for this study is SRI-4 response at Week 48.
The primary endpoint will be compared between each of the two GDC-0853 arms and 
the placebo arm by using the Cochran-Mantel-Haenszel test statistic, stratified by the 
factors used at randomization. The absolute difference in remission rates and 95% CI 
for the point estimate will be provided.
6.4.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints for this study are as follows:

SRI-4 response at Week 48 with a sustained reduction of OCS dose to 10 mg/day 
and Day 1 dose during Week 36 through Week 48

SRI-4 response at Week 24 with a sustained reduction of OCS dose to 10 mg/day 
and Day 1 dose during Week 12 through Week 24

SRI-4 response at Week 24

SRI-6 response at Weeks 24 and 48

BICLA response at Weeks 24 and 48

SRI-4 response at Week 48 in patients with high plasmablast signature levels 
relative to patients with low levels

SRI-4 response at Week 48 with a sustained reduction of OCS dose to < 10 mg/day 
and ≤ Day 1 dose during Week 36 through Week 48 in patients with high 
plasmablast signiature levels relative to patients with low levels
The secondary endpoints will be analyzed in the same fashion as the primary endpoint.
Further details for the secondary efficacy analyses will be specified in the DAP.


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6.4.3
Exploratory Efficacy Endpoints
The exploratory efficacy endpoints are as follows:

SRI-5, 7, and 8 response at Weeks 24 and 48

SRI-5-8 response at Week 48 with a sustained reduction of OCS dose to 
10 mg/day and Day 1 dose during Week 36 through Week 48

SRI-5-8 response at Week 24 with a sustained reduction of OCS dose to 
10 mg/day and Day 1 dose during Week 12 through Week 24

Time to first SLE flare as defined by the SFI

Time to first SLE flare as defined by the BILAG 

Total number of SLE flares as defined by the SFI

Total number of SLE flares as defined by the BILAG 

Reduction of ≥ 4 points from baseline in the SLEDAI-2K at Weeks 24 and 48

SRI-4 response at Week 24 in patients with high plasmablast signature levels 
relative to patients with low levels

SRI-4 response at Week 24 with a sustained reduction of OCS dose to < 10 mg/day 
and ≤ Day 1 dose during Week 12 through Week 24 in patients with high 
plasmablast signiature levels relative to patients with low levels

Change in CLASI Total Activity Score at Week 24 and Week 48 relative to baseline

50% improvement in CLASI score in patients with at least moderate skin 
involvement (baseline CLASI 10)

Change in SLICC/ACR Damage Index at Week 24 and Week 48 relative to baseline

Change in joint involvement at Week 24 and Week 48 relative to baseline

50% improvement in swollen or tender joint count (28 joints) for patients with 8 
swollen or tender joints at baseline

Change in FACIT-Fatigue score at Week 24 and Week 48 relative to baseline

Change in Patient’s Global Assessment of disease activity at Week 24 and Week 48 
relative to baseline

Change in cumulative steroid dose use at Week 24 and Week 48 relative to 
baseline

Glucocorticoid toxicity at Weeks 12, 24, 36, and 48 relative to baseline using the 
GTCI

Achieving corticosteroid dose of 10 mg/day among patients with a dose 10 
mg/day at baseline
Exploratory endpoints will be evaluated for the ITT population.  Time-to-event endpoints 
will be analyzed using the Kaplan-Meier methodology.  Continuous endpoints will be 
analyzed using an appropriate analysis method, such as analysis of covariance, or 


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mixed-model repeated measures.  Categorical endpoints will be analyzed using an 
appropriate statistical method, such as Cochran-Mantel-Haenszel or Fisher’s exact test.
6.5
SAFETY ANALYSES
Safety analyses will include all patients who receive at least one dose of study drug 
(GDC-0853 or placebo) with patients grouped according to the treatment they received.  
Safety will be assessed through summaries of adverse events, laboratory test results, 
ECGs, and vital signs.  Verbatim descriptions of treatment-emergent adverse events will 
be coded, and their incidence will be summarized by treatment arm.  A 
treatment-emergent adverse event is defined as any new adverse event reported or 
worsening of an existing condition on or after the first dose of study drug during AE 
reporting period.  In addition, separate summaries will be generated for serious adverse 
events, AESI, deaths, pregnancies, malignancies, adverse events leading to 
discontinuation from the study, and adverse events leading to discontinuation of study 
drug.
6.6
PHARMACOKINETIC ANALYSES
The PK analyses will include tabulation of plasma concentration data and 
summarization of plasma concentrations by visits, with patients grouped according to 
treatment received.  Descriptive summary statistics will include the arithmetic mean, 
median, range, SD, and coefficient of variation, as appropriate.
The extent of inter-patient variability will be evaluated, and potential sources of variability 
may be assessed.  Relationships between PK and PD, efficacy, and safety endpoints 
may be explored.
Additional PK analyses will be conducted during and/or at the end of the study as 
appropriate and may be reported separately.
6.7
BIOMARKER ANALYSES
PD biomarkers (e.g., but not limited to CCL3, CCL4, and plasmablast signature) will be 
analyzed to assess the pharmacological activity and mechanism of action of GDC-0853 in 
patients with moderate to severe active SLE.  Data will be summarized by absolute 
levels of the biomarker, as well as absolute and relative changes from baseline levels for 
each treatment group. Additional PD analyses may be conducted as appropriate.  
6.8
INTERIM ANALYSIS
An interim analysis will be performed after 5080 patients in each of treatment arm have
completed their 24-week SRI-4 response evaluation.  The purpose of the interim 
analysis is to conduct a preliminary benefit-risk assessment of GDC-0853 treated arms 
compared with the placebo-treated arm and enable potential stopping for futility and/or 
safety concerns or to potentially inform the clinical development plan for GDC-0853. The 


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interim analysis will be performed and interpreted by the IMC in conjunction with a 
Scientific Oversight Committee who will be unblinded at the treatment group level.  
Additional personnel, such as Clinical Pharmacology and biomarker scientists, may be 
unblinded in order to prepare additional data displays relevant for IMC and Scientific 
Oversight Committee review.
The study will continue to enroll while the interim analysis is being performed.  If the 
interim analysis indicates that one of the two dose levels of GDC-0853 does not have an 
appropriate safety profile or meets futility criteria as defined in the interim analysis plan 
in the DAP which will be written prior to conducting the interim analysis, the Sponsor 
may discontinue enrollment into that dose arm and switch patients to the other dose arm 
for the remainder of the study.  The Sponsor may also elect to amend the protocol to 
change the dose level of GDC-0853.   
Given the hypothesis-generating nature of this study, the Sponsor may choose to 
conduct an additional efficacy interim efficacy analysis in order to further guide internal 
decision making around issues such as the adequacy of dose ranging, the adequacy of 
sample sizes for safety and/or efficacy analyses, or to inform the clinical development 
plan for GDC-0853. The study will not be stopped for any other reason other than futility 
or safety concerns at the time of the interim analysis.  The interim analysis will be 
performed and interpreted by the IMC in conjunction with a Scientific Oversight 
Committee who will be unblinded at the treatment group level.  Additional personnel, 
such as Clinical Pharmacology and biomarker scientists, may be unblinded in order to 
prepare additional data displays relevant for IMC and Scientific Oversight Committee
review.  The decision to conduct an additional interim analysis and the timing of the 
analysis will be documented in the Sponsor’s trial master file and updated DAP prior to 
the conduct of the interim analysis.
Further details about the interim analyses, including the IMC and Scientific Oversight 
Committee responsibilities and decision criteria, will be specified in the IMC and 
Scientific Oversight Committee Charter.  
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor or its designee will request data clarification from the sites, 
which the sites will resolve electronically in the EDC system.
The Sponsor or functional service provider will produce an EDC Study Specification 
document that describes the quality checking to be performed on the data.  Central 
laboratory data and any other electronic data will be sent directly to the Sponsor, using 


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the Sponsor’s standard procedures to handle and process the electronic transfer of 
these data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
PRO data will be collected on paper questionnaires.  The data from the questionnaires 
will be entered into the EDC system by site staff.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.


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Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic PRO data (if applicable), Informed Consent Forms, 
laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for at least 15 years after completion or discontinuation of the 
study or for the length of time required by relevant national or local health authorities, 
whichever is longer.  After that period of time, the documents may be destroyed, subject 
to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a United States 
(U.S.) Investigational New Drug (IND) application will comply with U.S. Food and Drug 
Administration (FDA) regulations and applicable local, state, and federal laws.  Studies 


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conducted in the European Union or European Economic Area will comply with the 
European Union (E.U.) Clinical Trial Directive (2001/20/EC).
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Mobile Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the "Consent Forms") 
before IRB/EC submission.  The final IRB/ECapproved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient before his or her 
participation in the study.  The case history or clinical records for each patient shall 
document the informed consent process and that written informed consent was obtained 
prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.


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For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Given the complexity and exploratory nature of the analyses, data derived from 
exploratory biomarker specimens will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 


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be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.5).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., last patient, last visit 
[LPLV]).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities. As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, subjects’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.


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9.4
ADMINISTRATIVE STRUCTURE
The study will be conducted globally and include approximately 240 patients.  The 
contract research organization 
 will be responsible for submission to IRB/ECs 
for approval of the study protocol, patient recruitment, study conduct, data collection, 
and reporting.
9.5
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals. The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site:
http://www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.p
df
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective CSR.  In addition, for all clinical trials in patients involving an IMP for 
which a marketing authorization application has been filed or approved in any country, 
the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.


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9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


 
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10. 
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Appendix 1
Schedule of Activities (cont.)
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their first open-label dose of GDC-0853 on Day 1 of Study GA30066 (after a trough PK level is drawn) or they will proceed to the SFU period and 
return for the SFU visit on Week 56 (8 weeks after last dose of study drug). For patients enrollng into the OLE Study GA30066, Day 1 is the same day 
as the Week 48 visit of Study GA30044.
d At an unscheduled visit (UV), adverse events and concomitant medications must be assessed. All other assessments are to be performed only if 
medically indicated based on the reason for the UV. If the patient returns for an unscheduled visit or regular study visit and has any evidence of 
increased SLE-activity requiring treatment, perform assessments required for a flare visit (FV).  
e A flare visit (FV) is any unscheduled visit where the patient may require escalation of treatment for increased SLE activity.  Assessments are to be 
performed only if medically indicated based on the reason for the FV.
f
Patients will receive a telephone call from study staff to follow up for assessment of adverse events.
g
Either the ACR or SLICC diagnostic criteria for SLE may be used at screening to determine study inclusion.
h Starting at the screening period, all patients must record their actual OCS use on a weekly basis and as instructed by study staff (see Section 4.3.2.4).
i
The OCS taper windows occur during Weeks 0-12 and Weeks 24-36 (tapering may be initiated after the Week 24 assessments are completed).  For 
complete instructions on OCS tapering, see Section 3.3.6 and Appendix 4.
j
After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated intervention 
should be reported.  After initiation of study drug, all adverse events will be reported until 8 weeks after the last dose of study drug.  After this period, 
the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is believed to be related to prior study drug 
treatment (see Section 5.6).  The investigator should follow each adverse event until the event has resolved to baseline grade or better, the event is 
assessed as stable by the investigator, the patient is lost to follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures until a final outcome can be reported.
k Includes respiratory rate, pulse rate, temperature, and systolic and diastolic blood pressures while the patient is in a seated position for at least 
5 minutes.
l
Include an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurological systems.  Any abnormality identified at baseline should be recorded on the General Medical History and Baseline 
Conditions eCRF.  Particular attention should be given to evaluation of potential manifestations of active SLE (see Appendix 9 BILAG 2004 Index; 
Appendix 10, SLEDAI-2K; Appendix 14, CLASI; and Appendix 13, 28-Joint Counts, Appendix 11, SFI) and of infections or other medical conditions, 
which could place the patient at increased risk.
m Limited, efficacy assessmentdirected or symptom-directed physical examinations should be performed that also allow for completion of SLEDAI-2K 
and BILAG-2004 assessments.  Changes from baseline abnormalities should be recorded in patient notes.  New or worsened clinically significant 
abnormalities should be recorded as adverse events on the Adverse Event eCRF.
n For visits at which study drug is administered, the ECG will be recorded pre-dose (Day 1, Week 4 and Week 48).  ECG recordings must be performed 
after the patient has been resting in a supine position for at least 10 minutes prior to beginning the first ECG recording.  All ECGs should be obtained 
prior to the other procedures scheduled at that same time (e.g., vital sign measurements, blood draws).  Body position should be consistently 


Appendix 1
Schedule of Activities (cont.)
GDC-0853—Genentech, Inc.
134/Protocol GA30044, Version 3
maintained for each ECG evaluation to prevent changes in hear rate.  Environmental distractions (e.g., television, radio, conversation) should be 
avoided during the pre-ECG resting period and during ECG recording.  ECGs for each patient should be obtained from the same machine whenever 
possible.
o Triplicate digital ECG recordings are required pre-dose (Day 1) and 2 hours 30 minutes post dose for Week 24 only. The ECG intervals (e.g., PR, 
QRS, QT, QTcF, and RR) and heart rate from these three ECGs will be entered into the eCRF, in addition, these triplicate readings will be stored for 
future analysis, if needed
p Not required if documented results are available of a chest radiograph (read by a radiologist) taken within the 12 weeks preceding the screening visit.
q PPD should be performed only if QFT (which is to be used as the initial TB screening test) is not available. For the Week 44 visit, follow the same 
method of testing and assessment that was completed during screening period.
r
Can be collected as needed to complete SLEDAI-2K or BILAG-2004 assessments, e.g. myositis. 
s Includes HBsAg, HBsAb, HBcAb, HCV Ab.
t
The Coombs test should be performed at a local laboratory.
u Includes hemoglobin, hematocrit, RBC count, calculated indices (MCV, MCH, MCHC, RDW), platelet count, and WBC count with differential.
v Includes electrolytes (Na, K, Cl, bicarbonate, phosphorus), urea, creatinine, glucose, ALT, AST, amylase, lipase, total and direct bilirubin, alkaline
phosphatase, GGT, albumin, globulin, total protein, calcium, uric acid
w Includes INR, aPTT, and PT.
x Includes total immunoglobulins, IgG, IgM, IgE, and IgA.
y All women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test at screening.  Urine pregnancy 
tests will be performed locally at specified subsequent visits.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test 
(performed locally).
z Once treatment with study medication begins, TBNK results will be blinded.
aa Includes dipstick (blood, protein, glucose, nitrites, and leukocyte esterase), microscopic analysis (RBC, WBC, red cell casts, white cell casts). 
bb C3, C4, and CH50 conducted monthly on the same day as the SLEDAI-2K.
cc Autoantibody panel includes anti-Smith, anti-RNP, anti-Ro, anti-La, anti-cardiolipin, and anti-beta 2 glycoprotein
dd A FMV urine sample must be collected at Weeks 0, 4, 24, and 48.  FMV urine samples should be collected at all other indicated visits unless the 
patient forgets to collect the FMV or forgets to bring the urine to the visit (refer to laboratory manual for details on urine collection instructions), in which 
case a random urine sample is acceptable.
ee Screening urine sample needs to be a FMV (in mg/mg) and must be collected during the screening period (refer to laboratory manual for details on 
urine collection instructions). Patients will receive the urine collection kit at the first screening visit and will bring the FMV urine collection to the second
screening visit.


Appendix 1
Schedule of Activities (cont.)
GDC-0853—Genentech, Inc.
135/Protocol GA30044, Version 3
ff Collect prior to drug administration.  
gg Collect PK samples at four timepoints:  prior to study drug, 2 hours (30 minutes) post-dose (fasting), 46 hours post-dose, and 810 hours post 
dose (U.S. sites only).  If the patient is unable to stay or return to clinic for the post-dose 8-10 hour timepoint, this sample may be collected by a home
nurse visit.
hh Sample to be collected at baseline.  However, if sample not drawn at baseline, it may be collected at any other timepoint.
ii Three PaxGene whole blood tubes to be collected prior to study drug administration for PD sample.  Please see laboratory manual for PaxGene blood 
sample handling.
jj Collect serum and plasma tubes prior to study drug administration for PD biomarker serum and PD biomarker plasma.
kk U.S. sites only: Blood for PBMCs will be shipped overnight to a central laboratory for processing.  To be performed at centers where samples can be 
shipped to central laboratory within 24 hours.
ll
U.S. and selected sites only:  Includes multi-color flow cytometry analysis of B cells and B cell subsets
mm
Includes multi-color flow cytometry analysis of basophil activation.  To be performed at centers in the United States where samples can be shipped 
to FACS laboratory within 24 hours.
nn U.S. sites only: Blood for PBMCs will be shipped overnight to a central laboratory for processing and cryopreserved.  To be performed at centers 
where samples can be shipped to central laboratory within 24 hours.
oo Fasting lipid panel includes triglycerides, HDL, LDL, HbA1C, and total cholesterol. The patient should be fasting (4 hours).
pp For patients with arthritis present at current visit prior to Week 24 or any past visit during the study.  
qq WGS and photography are contingent upon the review and approval by each site's IRB/EC and, if applicable, an appropriate regulatory body.
rr The same clinician is strongly recommended to complete the Physician’s Global Assessment throughout the study.
ss To ensure instrument validity and that data standards meet health authority requirements, the questionnaire will be self-administered before the patient 
or clinician receives any information on disease status, prior to the performance of non-PRO assessments, and prior to the administration of study 
treatment, unless otherwise specified.  See Appendix 17 for sample questionnaires for FACIT-Fatigue.
tt
Patients will receive GDC-0853/placebo BID starting on Day 1 and ending on the evening (p.m. dose) prior to the Week 48 visit.  GDC-0853/placebo 
should be taken with water by mouth.  The dates and times of the most recent prior meal and most recent prior dose of short-acting antacid, PPI, or 
H2RA, last dose of oral study drug (prior to clinic visit), and timing of study drug administration in clinic (if applicable) should be recorded at each clinic 
visit.
uu Not applicable for a site that has not been granted approval for RBR sampling.  


GDC-0853—Genentech, Inc.
136/Protocol GA30044, Version 3
Appendix 2
Schedule of Pharmacokinetic and Biomarker Samples
Visit
Timepoint
Sample Type
Screening 
(Day -35 to Day -1)
NA
Blood for PD RNA 
PD biomarker serum 
PD biomarker plasma 
Blood for PBMC (U.S. Sites only)
Flow cytometry (B-cell subsets) (U.S. and selected sites only)
Flow cytometry (basophils) (U.S. sites only)
Blood for serum for RBR (optional)
Blood for RNA for RBR (optional)
Day 1 a, 29, 337
(Weeks 4 and 48)
Prior to dose (to 
be administered in 
clinic if applicable)
Blood for PK  
Blood for PG (Day 1 only)
Blood for PD RNA
PD biomarker (serum)
PD biomarker (plasma) 
Exploratory urinary biomarker collection (first void)
Blood for PBMC (U.S. sites only)
Flow cytometry (B-cell subsets) (U.S. and selected sites only)
Flow cytometry (basophils) (U.S. sites only) 
(Days 1 and 29 only)
Blood for immunophenotyping (U.S. sites only) 
(Day 1 only)
Blood for serum for RBR (optional) (Days 1 & 337 only)
Blood for RNA for RBR (optional) (Days 1 & 337 only)
Blood for WGS for RBR (optional) (Day 1 only)
Day 85
(Week 12)
Prior to dose
Blood for serum for RBR (optional)
Blood for RNA for RBR (optional)
Day 169 a
(Week 24)
Prior to dose
(must be 
administered in 
clinic if applicable)
Blood for PK 
Blood for PD RNA
PD biomarker (serum)
PD biomarker (plasma)
Exploratory urinary biomarker collection (first void)
Blood for PBMC (U.S. sites only)
Flow cytometry (B-cell subsets) (U.S. and selected sites only)
Flow cytometry (basophils) (U.S. sites only)
Blood for immunophenotyping (U.S. sites only)
Blood for serum for RBR (optional)
Blood for RNA for RBR (optional)
2 hr (30 min)
post dose, fasting
Blood for PK 
46 hr post dose
Blood for PK 


Appendix 2
Schedule of Pharmacokinetic and Biomarker Samples (cont.)
GDC-0853—Genentech, Inc.
137/Protocol GA30044, Version 3
Visit
Timepoint
Sample Type
810 hr post dose 
(U.S. sites only) b
Blood for PK 
Day 393 (SFU)
(Week 56)
Prior to dose
Blood for PD RNA
PD Biomarker (serum)
PD biomarker (plasma)
Exploratory urinary biomarker collection (first void)
Blood for PBMC (U.S. sites only)
Flow cytometry (B-cell subsets) (U.S. and selected sites only)
UV, FV or ET visits NA
Blood for PK 
Blood for PD RNA (FV and ET only)
PD biomarker (serum) (FV and ET only)
PD biomarker (plasma) (FV and ET only)
Exploratory urinary biomarker collection (first void) 
(FV and ET only)
Blood for PBMC (U.S. sites only) (FV and ET only)
Flow cytometry (B-cell subsets) (U.S. and selected sites only)
(FV only)
Flow cytometry (basophils) (U.S. sites only) (ET only)
Blood for serum for RBR (optional) (FV only)
Blood for RNA for RBR (optional) (FV only)
ET early termination visit; FACSfluorescence-activated cell sorting; FVflare visit; H2RAH2 
receptor antagonist; hr hours; minminutes; NAnot applicable; PBMCperipheral blood 
mononuclear cell; PDpharmacodynamics; PG pharmacogenomics; PKpharmacokinetic; 
PPIproton-pump inhibitor; RBRResearch Biosample Repository; SFUSafety Follow Up Visit; 
U.S.United States; UVunscheduled visit.
Note:  Study assessments may be delayed or moved ahead of the window to accommodate holidays, 
vacations, and unforeseen 
Morning clinic visits are preferred for all visits but are especially encouraged on Day 1 and Week 24.  
Prior to visits on Day 1, Week 4, and Week 24, patients should be instructed not to take their morning 
dose and to bring their study medication with them to their clinic visit. For all visits with PK samples, 
the date and time of the last dose of study drug, last dose of acid-reducing medication (PPI, H2RA, or 
short-acting antacid), and last meal should be recorded, along with the actual time of the PK blood 
draw. The procedures for collection, handling, and shipping of PK samples can be found in the study's 
Laboratory Manual.
a Morning visit is strongly recommended. Patients must be fasting (4 hours) prior to the pre-dose PK 
draw. 
b U.S. sites only: If the patient is unable to stay or return to clinic for the post-dose 810 hour 
timepoint, this sample may be collected by a home nurse visit on the Week 24 visit.


GDC-0853—Genentech, Inc.
138/Protocol GA30044, Version 3
Appendix 3
Pre-Enrollment Adjudication 
Enrollment into this trial is subject to adjudication by the Sponsor’s Medical Monitor or 
designated staff.  
The purpose of the adjudication process is to ensure that clinical manifestations 
qualifying the patient for entry to the study (i) are adequately documented, (ii) are 
attributable to SLE, and (iii) are of sufficient severity to mandate significant 
immunomodulatory therapy.
The Medical Monitor will make the final decision regarding whether or not a patient is 
eligible for enrollment. Every effort will be made to complete the adjudication process as 
quickly as possible.  In exceptional circumstances the screening period may, at the 
Medical Monitor’s discretion, be extended to allow for completion of the adjudication 
process. 
Steps in Adjudication Process
3.
Investigative site identifies a potentially eligible patient.
4.
Following informed consent, the Investigator reviews the patient for eligibility based 
on SLE diagnostic criteria, trial inclusion criteria (see Section 4.1.1), and the 
absence of exclusion criteria.
5.
As soon as screening procedures are complete the Investigator completes the forms 
required for screening and adjudication.  
6.
The Investigator or Study Coordinator transmits the completed forms to the Sponsor 
or designated contract research organization.  
7.
The Sponsor’s Medical Monitor or designee will perform an initial triage of the 
disease manifestations contributing to eligibility for entry.  The triage decision will be 
based on the information supplied by the Investigator.  This period may be extended 
if there is a delay in the availability of key screening laboratory results from the 
central laboratory. 
8.
The Sponsor’s Medical Monitor or designee will review the patient’s clinical and 
laboratory data, including additional data requested from the site, and reach a 
decision on the patient’s eligibility for the study. This decision will be conveyed to 
the Investigator within approximately 3 working days of receipt of the requested 
additional data by the Sponsor.
Training in the Adjudication process will be provided to Investigators.


GDC-0853—Genentech, Inc.
139/Protocol GA30044, Version 3
Appendix 4
Suggested Prednisone Taper Schedule Achieving 10 mg/day 
by 12 and 36 Weeks
Starting Prednisone Dose (mg/day)
10
20
30
40
Weeks 02 
10
20
30
40
Weeks 34 
10
15
25
30
Weeks 56 
10
10
20
25
Weeks 78 
10
10
15
15
Weeks 910 
10
10
10
10
Weeks 1112 
10
10
10
10
Starting Prednisone Dose (mg/day)
10
20
Weeks 24-26 
10
20
Weeks 27-28 
10
15
Weeks 29-30 
10
10
Weeks 31-32
10
10
Weeks 33-34
10
10
Weeks 35-36 
10
10


GDC-0853—Genentech, Inc.
140/Protocol GA30044, Version 3
Appendix 5
American College of Rheumatology Revised Criteria for 
Classification of Systemic Lupus Erythematosus
Criterion
Definition
1. Malar Rash
Fixed erythema, flat or raised, over the malar eminences, tending to 
spare the nasolabial folds
2. Discoid rash
Erythematous raised patches with adherent keratotic scaling and 
follicular plugging; atrophic scarring may occur in older lesions
3. Photosensitivity
Skin rash as a result of unusual reaction to sunlight, by patient history 
or physician observation
4. Oral ulcers
Oral or nasopharyngeal ulceration, usually painless, observed by 
physician
5. Nonerosive Arthritis
Involving 2 or more peripheral joints, characterized by tenderness, 
swelling, or effusion 
6. Serositis
1. Pleuritis convincing history of pleuritic pain or rubbing heard by a 
physician or evidence of pleural effusion
OR
2. Pericarditis documented by electrocardiogram or rub or evidence 
of pericardial effusion
7. Renal Disorder
1. Persistent proteinuria 0.5 grams per day or than 3if 
quantitation not performed 
OR
2. Cellular casts may be red cell, hemoglobin, granular, tubular, or 
mixed
8. Neurologic Disorder
1. Seizures in the absence of offending drugs or known metabolic 
derangements; e.g., uremia, ketoacidosis, or electrolyte imbalance
OR
2. Psychosis in the absence of offending drugs or known metabolic 
derangements, e.g., uremia, ketoacidosis, or electrolyte imbalance
9. Hematologic Disorder
1. Hemolytic anemia—with reticulocytosis
OR
2. Leukopenia4,000/mm3 on 2 occasions
OR
3. Lymphopenia1,500/ mm3 on 2 occasions
OR
4. Thrombocytopenia100,000/mm3 in the absence of offending 
drugs


Appendix 5
American College of Rheumatology Revised Criteria for 
Classification of Systemic Lupus Erythematosus (cont.)
GDC-0853—Genentech, Inc.
141/Protocol GA30044, Version 3
Criterion
Definition
10. Immunologic 
Disorder
1. Anti-DNA: antibody to native DNA in abnormal titer
OR
2. Anti-Smith: presence of antibody to Sm nuclear antigen
OR
3. Positive finding of antiphospholipid antibodies on:  an abnormal 
serum level of IgG or IgM anticardiolipin antibodies, a positive test 
result for lupus anticoagulant using a standard method,
OR
4. A false-positive test result for at least 6 months confirmed by 
Treponema pallidum immobilization or fluorescent treponemal 
antibody absorption test
11. Positive Antinuclear 
Antibody
An abnormal titer of antinuclear antibody by immunofluorescence or 
an equivalent assay at any point in time and in the absence of drugs
Source: Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, et al. The 1982 
revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 
1982;25:1271-7.


GDC-0853—Genentech, Inc.
142/Protocol GA30044, Version 3
Appendix 6
Clinical and Immunologic Criteria Used in the SLICC 
Classification System
The criteria do not need to be present concurrently.  The proposed classification rule is 
as follows: classify a patient as having SLE if he or she satisfies 4 of the clinical and 
immunologic criteria used in the SLICC classification criteria, including at least one 
clinical criterion and one immunologic criterion, OR if he or she has biopsy-proven 
nephritis compatible with SLE in the presence of ANAs or anti-dsDNA antibodies.
Clinical Criteria
1.
Acute cutaneous lupus, including: 

Lupus malar rash (do not count if malar discoid)

Bullous lupus

Toxic epidermal necrolysis variant of SLE

Maculopapular lupus rash

Photosensitive lupus rash in the absence of dermatomyositis -OR-

Subacute cutaneous lupus (nonindurated psoriaform and/or annular polycyclic 
lesions that resolve without scarring, although occasionally with 
postinflammatory dyspigmentation or telangiectasias)
2.
Chronic cutaneous lupus, including: 

Classic discoid rash

Localized (above the neck)

Generalized (above and below the neck)

Hypertrophic (verrucous) lupus

Lupus panniculitis (profundus)

Mucosal lupus

Lupus erythematosus tumidus

Chillblains lupus

Discoid lupus/lichen planus overlap
3.
Oral ulcers 

Palate

Buccal

Tongue -OR-

Nasal ulcers in the absence of other causes, such as vasculitis, Behçet's 
disease, infection (herpesvirus), inflammatory bowel disease, reactive arthritis, 
and acidic foods


Appendix 6
Clinical and Immunologic Criteria Used in the SLICC 
Classification System (cont.)
GDC-0853—Genentech, Inc.
143/Protocol GA30044, Version 3
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
5.
Synovitis involving 2 or more joints, characterized by swelling or effusion -OR-

Tenderness in 2 or more joints and at least 30 minutes of morning stiffness
6.
Serositis 

Typical pleurisy for more than 1 day 

Pleural effusions 

Pleural rub 

Typical pericardial pain (pain with recumbency improved by sitting forward) for 
more than 1 day

Pericardial effusion

Pericardial rub -OR-

Pericarditis by electrocardiography in the absence of other causes, such as 
infection, uremia, and Dressler's pericarditis
7.
Renal 

Urine protein-to-creatinine ratio (or 24-hour urine protein) representing 500 mg 
protein/24 hours -OR-

Red blood cell casts
8.
Neurologic 

Seizures

Psychosis

Mononeuritis multiplex in the absence of other known causes, such as primary 
vasculitis

Myelitis

Peripheral or cranial neuropathy in the absence of other known causes, such as 
primary vasculitis, infection, and diabetes mellitus

Acute confusional state in the absence of other causes, including 
toxic/metabolic, uremia, drugs
9.
Hemolytic anemia
10. Leukopenia (4,000/mm3 at least once) in the absence of other known causes, 
such as:

Felty's syndrome, drugs, and portal hypertension -OR-


Appendix 6
Clinical and Immunologic Criteria Used in the SLICC 
Classification System (cont.)
GDC-0853—Genentech, Inc.
144/Protocol GA30044, Version 3

Lymphopenia (1,000/mm3 at least once) in the absence of other known 
causes, such as corticosteroids, drugs, and infection
11. Thrombocytopenia (100,000/mm3) at least once in the absence of other known 
causes, such as drugs, portal hypertension, and thrombotic thrombocytopenic 
purpura
Immunologic Criteria 
1.
ANA level above laboratory reference range
2.
Anti-dsDNA antibody level above laboratory reference range (or 2-fold the 
reference range if tested by ELISA)
3.
Anti-Sm: presence of antibody to Sm nuclear antigen
4.
Antiphospholipid antibody positivity as determined by any of the following: 

Positive test result for lupus anticoagulant

False-positive test result for rapid plasma reagin

Medium- or high-titer anticardiolipin antibody level (IgA, IgG, or IgM)

Positive test result for anti–2-glycoprotein I (IgA, IgG, or IgM)
5.
Low complement 

Low C3

Low C4

Low CH50
6.
Direct Coombs' test in the absence of hemolytic anemia
*
Criteria are cumulative and need not be present concurrently. 
ANAantinuclear antibody; anti-dsDNAanti–double-stranded DNA; ELISAenzyme-
linked immunosorbent assay; SLICCSystemic Lupus International Collaborating 
Clinics; SLEsystemic lupus erythematosus.


GDC-0853—Genentech, Inc.
145/Protocol GA30044, Version 3
Appendix 7
Systemic Lupus International Collaborating Clinics / American 
College of Rheumatology Damage Index for Systemic Lupus 
Erythematosus
Damage (non-reversible change, not related to active inflammation) occurring since onset of lupus, ascertained by clinical assessment 
and present for at least 6 months unless otherwise stated.  Repeat episodes must occur at least 6 months apart to score 2.  The same 
lesion cannot be scored twice.
OCULAR (either eye, by clinical assessment)
Any cataract ever (documented by ophthalmoscopy)
1
Retinal change OR Optic atrophy (documented by ophthalmoscopy)
1
NEUROPSYCHIATRIC
Cognitive impairment (eg memory deficit, difficulty with calculation, poor concentration, difficulty in spoken or
written language, impaired performance level) OR Major psychosis
1
Seizures requiring therapy for 6 months
1
Cerebrovascular accident or surgical resection (for non-malignant causes) 
(score 2 if >1)
1 (2)
Cranial or peripheral neuropathy (excluding optic)
1
Transverse myelitis
1
RENAL
Estimated/Measured GFR < 50%
1
Proteinuria ≥3.5g/24 hours
1
OR
End-stage renal failure (regardless of dialysis or transplantation)
3
PULMONARY
Pulmonary hypertension (right ventricular prominence or loud P2)
1
Pulmonary fibrosis (physical & radiograph)
1
Shrinking lung (radiograph)
1
Pleural fibrosis (radiograph)
1
Pulmonary infarction (radiograph) or resection for malignancy
1
CARDIOVASCULAR
Angina OR Coronary artery bypass
1
Myocardial infarction ever
(score 2 if > 1)
1 (2)
Cardiomyopathy (ventricular dysfunction)
1
Valvular disease (diastolic, murmur, or systolic murmur > 3/6)
1
Pericarditis for 6 months OR Pericardiectomy
1
PERIPHERAL VASCULAR
Claudication for 6 months
1
Minor tissue loss (pulp space)
1
Significant tissue loss ever (eg loss of digit or limb) 
(score 2 if > 1 site)
1 (2)
Venous thrombosis with swelling, ulceration, OR Venous stasis
1
GASTROINTESTINAL
Infarction or resection of bowel below duodenum, spleen, liver or gallbladder for any cause
(score 2 if > 1 site)
1 (2)
Mesenteric insufficiency
1
Chronic peritonitis
1
Stricture OR Upper gastrointestinal surgery ever
1
Pancreatic insufficiency requiring enzyme replacement or with pseudocyst
1
MUSCULOSKELETAL
Muscle atrophy or weakness
1
Deforming or erosive arthritis (including reversible deformities, excluding avascular necrosis)
1
Osteoporosis with fracture or vertebral collapse (excluding avascular necrosis)
1
Avascular necrosis (imaging) 
(score 2 if > 1)
1 (2)
Osteomyelitis
1
Tendon rupture
1
SKIN
Scarring chronic alopecia
1
Extensive scarring or panniculum other than scalp and pulp space
1
Skin ulceration for > 6 months (excluding thrombosis)
1
CONTINUED…


 
 
Appendix 7  
Systemic Lupus International Collaborating Clinics /American 
College of Rheumatology Damage Index for Systemic Lupus 
Erythematosus ) (cont.) 
 
GDC-0853—Genentech, Inc. 
146/Protocol GA30044, Version 3 
(Cont.) 
Damage (non-reversible change, not related to active inflammation) occurring since onset of lupus, ascertained by clinical assessment 
and present for at least 6 months unless otherwise stated.  Repeat episodes must occur at least 6 months apart to score 2.  The same 
lesion cannot be scored twice. 
 
PREMATURE GONADAL FAILURE (secondary amenorrhoea before age 40)  
 
 
 
 
 
1 
 
DIABETES MELLITUS (regardless of treatment)   
 
 
 
 
 
 
 
 
 
1 
 
MALIGNANCY (exclude dysplasia) 
 
 
 
 
  
 
 
 
(score 2 if > 1 site)   
1 (2) 
Source: Gladman 1997 
 
GLOSSARY OF TERMS:  SYSTEMIC LUPUS INTERNATIONAL COLLABORATING 
CLINICS/AMERICAN COLLEGE OF RHEUMATOLOGY DAMAGE INDEX FOR 
SYSTEMIC LUPUS ERYTHEMATOSUS:  
Source:  Gladman 1996 
 
Damage: 
Non-reversible change, not related to active inflammation, occurring since diagnosis of 
lupus, ascertained by clinical assessment and present for at least 6 months unless 
otherwise stated.  Repeat episodes must occur at least 6 months apart to score 2.  The 
same lesion cannot be scored twice. 
Cataract: 
A lens opacity (cataract) in either eye, ever, whether primary or secondary to steroid 
therapy, documented by ophthalmoscopy. 
Retinal change: 
Documented by ophthalmoscopic examination, may result in field defect, legal blindness. 
Optic Atrophy: 
Documented by ophthalmoscopic examination. 
Cognitive Impairment: 
Memory deficit, difficulty with calculation, poor concentration, difficulty in spoken or 
written language, impaired performance level, documented on clinical examination or by 
formal neurocognitive testing. 
Major Psychosis: 
Altered ability to function in normal activity due to psychiatric reasons.  Severe 
disturbance in the perception of reality characterized by the following features: delusions, 
hallucinations (auditory, visual), incoherence, marked loose associations, impoverished 
thought content, marked illogical thinking, bizarre, disorganized or catatonic behavior. 
 
 
 


 
 
Appendix 7  
Systemic Lupus International Collaborating Clinics /American 
College of Rheumatology Damage Index for Systemic Lupus 
Erythematosus ) (cont.) 
 
GDC-0853—Genentech, Inc. 
147/Protocol GA30044, Version 3 
Seizures: 
Paroxysmal electrical discharge occurring in the brain and producing characteristic 
physical changes including tonic and clonic movements and certain behavioral disorders. 
Only seizures requiring therapy for 6 months are counted as damage. 
CVA: 
Cerebrovascular accident resulting in focal findings such as paresis, weakness, etc., or 
surgical resection for causes other than malignancy. 
Neuropathy: 
Damage to either a cranial or peripheral nerve, excluding optic nerve, resulting in either 
motor or sensory dysfunction. 
Transverse Myelitis: 
Lower-extremity weakness or sensory loss with loss of rectal and urinary bladder 
sphincter control. 
Renal: 
Estimated or measured glomerular filtration rate < 50%, proteinuria < 3.5gm/24 hours, or 
end-stage renal disease (regardless of dialysis or transplantation). 
Pulmonary: 
Pulmonary hypertension (right ventricular prominence, or loud P2), pulmonary fibrosis 
(physical and radiograph), shrinking lung (radiograph), pleural fibrosis (radiograph), 
pulmonary infarction (radiograph), resection for cause other than malignancy. 
Cardiovascular: 
Angina or coronary artery bypass, myocardial infarction (documented by 
electrocardiograph and enzyme studies) ever, cardiomyopathy (ventricular dysfunction 
documented clinically), valvular disease (diastolic murmur, or systolic murmur > 3/6), 
pericarditis for 6 months, or pericardiectomy. 
Peripheral Vascular: 
Claudication, persistent for 6 months, by history, minor tissue loss, such as pulp space, 
ever, significant tissue loss, such as loss of digit or limb, or resection, ever, venous 
thrombosis with swelling, ulceration or clinical evidence of venous stasis. 
Gastrointestinal: 
Infarction or resection of bowel below duodenum, by history, resection of spleen, liver, or 
gall bladder ever, for whatever cause, mesenteric insufficiency, with diffuse abdominal 
pain on clinical examination, chronic peritonitis, with persistent abdominal pain and 
peritoneal irritations, on clinical examination, esophageal stricture, shown on endoscopy, 
upper gastrointestinal tract surgery, such as correction of stricture, ulcer surgery, etc., 
ever, by history. 


Appendix 7
Systemic Lupus International Collaborating Clinics /American 
College of Rheumatology Damage Index for Systemic Lupus 
Erythematosus ) (cont.)
GDC-0853—Genentech, Inc.
148/Protocol GA30044, Version 3
Musculoskeletal:
Muscle atrophy or weakness, demonstrated on clinical examination, deforming or 
erosive arthritis, including reducible deformities, (excluding avascular necrosis) on 
clinical examination, osteoporosis with fracture or vertebral collapse (excluding 
avascular necrosis) demonstrated radiographically, avascular necrosis, demonstrated by 
any imaging technique, osteomyelitis, documented clinically, and supported by culture 
evidence.
Skin:
Scarring, chronic alopecia, documented clinically, extensive scarring or panniculum 
other than scalp and pulp space, documented clinically, skin ulceration (excluding 
thrombosis) for more than 6 months.
Premature gonadal failure:
Secondary amenorrhea, prior to age 40.
Diabetes:
Diabetes requiring therapy, but regardless of treatment.
Malignancy:
Documented by pathologic examination, excluding dysplasias. 


GDC-0853—Genentech, Inc.
149/Protocol GA30044, Version 3
Appendix 8
Childbearing Potential, Pregnancy Testing, and Contraception
For Women
All women of childbearing potential (including those who have had a tubal ligation) will 
have a serum pregnancy test at screening and a urine pregnancy test on study day 1 
prior to administration of study drug and at subsequent clinic visits.  If a urine pregnancy 
test result is positive, study drug will not be administered until pregnancy is ruled out.  
The result must be confirmed by a serum pregnancy test (conducted by the local 
laboratory).
Refer to Section 5.4.3 of the protocol for management of a patient with a confirmed 
pregnancy.
All female patients are considered to be of childbearing potential unless they meet one 
of the following criteria:

The patient has been postmenopausal (non−therapy-induced amenorrhea) for at 
least 12 continuous months with no other identified cause

The patient had a surgical bilateral oophorectomy (with or without hysterectomy) 
more than 6 weeks prior to enrollment

The patient had a hysterectomy
Female patients of reproductive or childbearing potential who are unwilling to use a
method of contraception that results in a failure rate of 1 % per year or remain 
abstinent (refrain from heterosexual intercourse) during the treatment period and for at 
least 60 days after the last dose of study drug, or longer as required by local 
requirements for other standard of care medications, will be excluded from study 
participation.
Abstinence is acceptable only if it is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.
Examples of contraceptive methods with a failure rate of 1% per year include the
following:

Sterilization, bilateral surgical tubal ligation

Intrauterine device

Combined oral contraceptive pill*

Contraceptive transdermal patch (estrogen and progestin containing)*

Hormonal vaginal device

Progestogen-only hormonal contraception associated with inhibition of ovulation

Implants for contraception


Appendix 8
Childbearing Potential, Pregnancy Testing, and Contraception
(cont.)
GDC-0853—Genentech, Inc.
150/Protocol GA30044, Version 3

Injections for contraception (with prolonged release)

Sole sexual partner consisting of surgically sterilized male partner with appropriate 
postsurgical verification of the absence of spermatozoa in the ejaculate.  Patients 
may provide verbal confirmation that the partner completed appropriate follow-up 
after vasectomy.  Sites are not required to obtain partner medical records.

Same sex partner
*
Women using estrogen containing hormonal contraceptives as a method of 
contraception must also use a barrier such as a male condom in conjunction 
with the hormonal contraceptives.
For Men
All men must agree to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures and agreement to refrain from donating sperm, as defined 
below:

With female partners of childbearing potential (including those who have had a tubal 
ligation), men must remain abstinent or use a condom plus an additional 
contraceptive method that together result in a failure rate of 1% per year during the 
treatment period and for at least 120 days (4 months) after the last dose of study 
treatment.  Men must refrain from donating sperm during this same period.

With pregnant female partners, men must remain abstinent or use a condom during 
the treatment period and for at least 28 days after the last dose of study treatment to 
avoid exposing the embryo.
For Men and Women
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, and post-ovulation methods) and withdrawal are not 
acceptable methods of contraception.


GDC-0853—Genentech, Inc.
151/Protocol GA30044, Version 3
Appendix 9
BILAG-2004 Index Glossary
INSTRUCTIONS
     only record features that are attributable to SLE disease activity and not due to 
        damage, infection, thrombosis (in absence of inflammatory process) or other 
        conditions
     assessment refers to manifestations occurring in the last 4 weeks compared with the 
        previous 4 weeks
     activity refers to disease process which is reversible while damage refers to permanent 
        process/scarring (irreversible)
     damage due to SLE should be considered as a cause of features that are fixed/persistent 
        (SLICC/ACR damage index uses persistence 6 months to define damage)
     in some manifestations, it may be difficult to differentiate SLE from other 
conditions as there may not be any specific test and the decision would then lies with the 
physician’s judgement on the balance of probabilities
     ophthalmic manifestations usually need to be assessed by an ophthalmologist and these 
        items would need to be recorded after receiving the response from the ophthalmologist
     guidance for recording:
          (4) NEW 
                 manifestations are recorded as new when it is a new episode occurring in the last  
                    4 weeks (compared to the previous 4 weeks) that has not improved and this 
                    includes new episodes (recurrence) of old manifestations 
                 new episode occurring in the last 4 weeks but also satisfying the criteria for    
                    improvement (below) would be classified as improving instead of new
          (3) WORSE
                 this refers to manifestations that have deteriorated/worsened significantly in the 
                    last 4 weeks compared to the previous 4 weeks, sufficient for consideration of 
                    increase in therapy
          (2) SAME
                 this refers to manifestations that have been present for the last 4 weeks and the 
                    previous 4 weeks without significant improvement or deterioration (from the 
                    previous 4 weeks)
                 this also applies to manifestations that have improved over the last 4 weeks 
                    compared to the previous 4 weeks but do not meet the criteria for improvement


Appendix 9
BILAG-2004 Index Glossary (cont.)
GDC-0853—Genentech, Inc.
152/Protocol GA30044, Version 3
          (1) IMPROVING
                 definition of improvement: (a) the amount of improvement is sufficient for 
consideration of reduction in therapy and 
                                                                       would not justify escalation in therapy
AND  
              
                                                                 (b) improvement must be present currently and
                                                                       for at least 2 weeks out of the last 4 weeks
                                                                        OR
                                                                      manifestation that has completely resolved and 
                                                                      remained absent over the whole of last 1 week
          (0) NOT PRESENT
          (ND) NOT DONE
                 it is important to indicate if a test has not been performed (particularly laboratory 
                    investigations) so that this will be recorded as such in the database & not as 
                    normal or absent (which is the default)
          Y/N - INDICATE IF ITEM IS DUE TO SLE ACTIVITY
                 for descriptors that are based on measurements (in renal and haematology 
                    systems), it is important to indicate if these are not due to lupus disease activity 
                    (for consideration of scoring) as they are usually recorded routinely into a 
                    database
          TRICKLE DOWN RULE
     when item of highest level of severity is recorded, similar item of lower level of 
        severity must be recorded as well (item of lower level of severity must not be 
        recorded as not present)
          CHANGE IN SEVERITY CATEGORY
                 there are several items in the index which have been divided into categories of 
                    mild and severe (depending on definition). It is essential to record mild and 
                    severe items appropriately if the manifestations fulfil both criteria during the last 
                    4 weeks
                 if a mild item deteriorated to the extent that it fulfilled the definition of severe 
                    category (ie changed into severe category) within the last 4 weeks:
       severe item scored as new (4) 
                    AND  mild item scored as worsening (3)


Appendix 9
BILAG-2004 Index Glossary (cont.)
GDC-0853—Genentech, Inc.
153/Protocol GA30044, Version 3
                 if a severe item improved (fulfilling the improvement criteria) to the extent that it 
                    no longer fulfilled the definition of severe category (ie changed into mild 
                    category) within the last 4 weeks:
                               severe item scored as not present (0) if criteria for severe category has not 
                                                                                              been met over last 4 weeks
                                                         or as improving (1) if criteria for severe category has been                 
                                                                                             met at some point over last 4 weeks
                   AND
                               mild item scored as improving (1) if it is improving over last 4 weeks
                                                      or as the same (2) if it has remained stable over last 4 weeks




Appendix 9
BILAG-2004 Index Glossary (cont.)
GDC-0853—Genentech, Inc.
155/Protocol GA30044, Version 3
exclude infection
4. Anorexia
MUCOCUTANEOUS
5. Severe eruption
> 18% body surface area
                        
any lupus rash except panniculitis, bullous lesion & 
angio-oedema
body surface area (BSA) is estimated using the rules of 
nines (used to assess extent of burns) as follows:
palm(excluding fingers) = 1% BSA
each lower limb = 18% BSA
each upper limb = 9% BSA
torso (front) = 18% BSA
torso (back) = 18% BSA
head = 9% BSA
genital (male) = 1% BSA
6. Mild eruption
≤ 18% body surface area


Appendix 9
BILAG-2004 Index Glossary (cont.)
GDC-0853—Genentech, Inc.
156/Protocol GA30044, Version 3
any lupus rash except panniculitis, bullous 
lesion & angio-oedema
malar rash must have been observed by a 
physician and has to be present continuously 
(persistent) for at least 1 week to be considered 
significant (to be recorded)
7. Severe angio-oedema
potentially life-threatening eg: stridor
angio-oedema is a variant form of urticaria 
which affects the subcutaneous, submucosal and 
deep dermal tissues
8. Mild angio-oedema
not life threatening
9. Severe mucosal ulceration
disabling (significantly interfering with oral 
intake), extensive & deep ulceration
must have been observed by a physician
10. Mild mucosal ulceration
localised &/or non-disabling ulceration
11. Severe panniculitis or bullous lupus
any one:
> 9% body surface area
facial  panniculitis
     panniculitis that is beginning to ulcerate
     panniculitis that threatens integrity of 
       subcutaneous tissue (beginning to cause  
       surface depression) on > 9% body surface 
       area
panniculitis presents as a palpable and tender 
subcutaneous induration/nodule 
note that established surface depression and 
atrophy alone is likely to be due to damage
12. Mild panniculitis or bullous lupus
≤ 9% body surface area  
does not fulfil any criteria for severe panniculitis 
(for panniculitis)
13. Major cutaneous vasculitis/thrombosis
resulting in extensive gangrene or ulceration or 
skin infarction


Appendix 9
BILAG-2004 Index Glossary (cont.)
GDC-0853—Genentech, Inc.
157/Protocol GA30044, Version 3
14. Digital infarct or nodular vasculitis
localised single or multiple infarct(s) over 
digit(s) or tender erythematous nodule(s)
15. Severe alopecia
clinically detectable (diffuse or patchy) hair loss 
with scalp inflammation (redness over scalp)
16. Mild alopecia
diffuse or patchy hair loss without scalp 
inflammation (clinically detectable or by history)
17. Peri-ungual erythema or chilblains
chilblains are localised inflammatory lesions 
                                                                        
(may ulcerate) which are precipitated by 
exposure to cold
18. Splinter haemorrhages
NEUROPSYCHIATRIC
19. Aseptic meningitis
criteria (all): acute/subacute onset
headache
fever
abnormal CSF (raised protein &/or 
   lymphocyte predominance) but negative       
cultures
preferably photophobia, neck stiffness and 
meningeal irritation should be present as well 
but are not essential for diagnosis
exclude CNS/meningeal infection, intracranial   
haemorrhage
20. Cerebral vasculitis
should be present with features of vasculitis 
in another system 
supportive imaging &/or biopsy findings
21. Demyelinating syndrome
discrete white matter lesion with associated  
neurological deficit not recorded elsewhere
ideally there should have been at least one 
previously recorded event
supportive imaging required
exclude multiple sclerosis


Appendix 9
BILAG-2004 Index Glossary (cont.)
GDC-0853—Genentech, Inc.
158/Protocol GA30044, Version 3
22. Myelopathy
acute onset of rapidly evolving paraparesis or 
quadriparesis and/or sensory level
exclude intramedullary and extramedullary 
space occupying lesion
23. Acute confusional state
acute disturbance of consciousness or level of 
arousal with reduced ability to focus, maintain 
or shift attention
includes hypo- and hyperaroused states and
encompasses the spectrum from delirium to 
coma
24. Psychosis
delusion or hallucinations
does not occur exclusively during course of a 
delirium
exclude drugs, substance abuse, primary 
psychotic disorder
25. Acute inflammatory demyelinating
Criteria:
polyradiculoneuropathy
    
progressive polyradiculoneuropathy
loss of reflexes
symmetrical involvement
increased CSF protein without pleocytosis
supportive electrophysiology study
26. Mononeuropathy (single/multiplex)
supportive electrophysiology study required
27. Cranial neuropathy
except optic neuropathy which is classified 
under ophthalmic system
28. Plexopathy
disorder of brachial or lumbosacral plexus 
resulting in neurological deficit not 
corresponding to territory of single root or nerve
supportive electrophysiology study required
29. Polyneuropathy
acute symmetrical distal sensory and/or motor 
                                                                        
deficit
supportive electrophysiology study required


Appendix 9
BILAG-2004 Index Glossary (cont.)
GDC-0853—Genentech, Inc.
159/Protocol GA30044, Version 3
30. Seizure disorder
independent description of seizure by reliable 
witness
31. Status epilepticus
a seizure or series of seizures lasting ≥ 30 
minutes without full recovery to baseline
32. Cerebrovascular disease
any one with supporting imaging:
       (not due to vasculitis)
  
   stroke syndrome
   
   transient ischaemic attack
  
   intracranial haemorrhage
exclude hypoglycaemia, cerebral sinus 
thrombosis, vascular malformation, tumour, 
abscess
cerebral sinus thrombosis not included as 
definite thrombosis not considered part of lupus 
activity
33. Cognitive dysfunction
significant deficits in any cognitive functions:
simple attention (ability to register & 
maintain                                                                         
information)
complex attention
memory (ability to register, recall & recognise 
information eg learning, recall)
visual-spatial processing (ability to analyse, 
synthesize & manipulate visual-spatial 
information)
language (ability to comprehend, repeat & 
   produce oral/written material eg verbal 
   fluency, naming)
reasoning/problem solving (ability to reason & 
   abstract)
psychomotor speed
executive functions (eg planning, organising, 
     sequencing)
in absence of disturbance of consciousness or 
level of arousal
sufficiently severe to interfere with daily 
activities
neuropsychological testing should be done or 


Appendix 9
BILAG-2004 Index Glossary (cont.)
GDC-0853—Genentech, Inc.
160/Protocol GA30044, Version 3
corroborating history from third party if 
possible 
exclude substance abuse
34. Movement disorder
exclude drugs
35. Autonomic disorder
any one:
fall in blood pressure to standing > 30/15 mm 
Hg (systolic/diastolic)
increase in heart rate to standing ≥ 30 bpm
loss of heart rate variation with respiration  
(max – min < 15 bpm, expiration:inspiration 
ratio < 1.2, Valsalva ratio < 1.4)
loss of sweating over body and limbs 
(anhidrosis) by sweat test
exclude drugs and diabetes mellitus
36. Cerebellar ataxia
cerebellar ataxia in isolation of other CNS 
features
usually subacute presentation
37. Severe lupus headache (unremitting)
disabling headache unresponsive to narcotic 
analgesia & lasting ≥ 3 days
exclude intracranial space occupying lesion 
and CNS infection
38. Headache from IC hypertension
exclude cerebral sinus thrombosis
MUSCULOSKELETAL
39. Severe myositis
significantly elevated serum muscle enzymes 
with significant muscle weakness
exclude endocrine causes and drug-induced 
myopathy


Appendix 9
BILAG-2004 Index Glossary (cont.)
GDC-0853—Genentech, Inc.
161/Protocol GA30044, Version 3
electromyography and muscle biopsy are used 
for diagnostic purpose and are not required to 
determine level of activity
40. Mild myositis
significantly elevated serum muscle enzymes 
with myalgia but without significant muscle 
weakness
asymptomatic elevated serum muscle enzymes 
not included
exclude endocrine causes and drug-induced 
myopathy
electromyography and muscle biopsy are used 
for diagnostic purpose and are not required to 
determine level of activity
41. Severe arthritis
observed active synovitis ≥ 2 joints with marked  
loss of functional range of movements and 
significant impairment of activities of daily 
living, that has been present on several days 
(cumulatively) over the last 4 weeks
42. Moderate arthritis or Tendonitis
tendonitis/tenosynovitis or active synovitis ≥ 1 
       or Tenosynovitis 
joint (observed or through history) with some 
loss of functional range of movements, that has 
been present on several days over the last 4 
weeks
43. Mild arthritis or Arthralgia or Myalgia
inflammatory type of pain (worse in the 
morning with stiffness, usually improves with 
activity & not brought on by activity) over 
joints/muscle 
inflammatory arthritis which does not fulfil the 
above criteria for moderate or severe arthritis
CARDIORESPIRATORY
44. Mild myocarditis
inflammation of myocardium with raised 
cardiac enzymes &/or ECG changes and without 
resulting cardiac failure, arrhythmia or valvular 
dysfunction


Appendix 9
BILAG-2004 Index Glossary (cont.)
GDC-0853—Genentech, Inc.
162/Protocol GA30044, Version 3
45. Cardiac failure
cardiac failure due to myocarditis or non-
infective inflammation of endocardium or 
cardiac valves (endocarditis)
cardiac failure due to myocarditis is defined by 
left ventricular ejection fraction ≤ 40% & 
pulmonary oedema or peripheral oedema
cardiac failure due to acute valvular 
regurgitation (from endocarditis) can be 
associated with normal left ventricular ejection 
fraction
diastolic heart failure is not included
46. Arrhythmia
arrhythmia (except sinus tachycardia) due to 
myocarditis or non-infective inflammation of 
endocardium or cardiac valves (endocarditis)
confirmation by electrocardiogram required 
(history of palpitations alone inadequate)
47. New valvular dysfunction
new cardiac valvular dysfunction due to 
myocarditis or non-infective inflammation of 
endocardium or cardiac valves (endocarditis)
supportive imaging required
48. Pleurisy/Pericarditis
convincing history &/or physical findings that 
you would consider treating
in absence of cardiac tamponade or pleural 
effusion with dyspnoea
                                                                        
do not score if you are unsure whether or not it 
is pleurisy/pericarditis
49. Cardiac tamponade
supportive imaging required
50. Pleural effusion with dyspnoea
supportive imaging required
51. Pulmonary haemorrhage/vasculitis
inflammation of pulmonary vasculature with 
haemoptysis &/or dyspnoea &/or pulmonary 
hypertension
supportive imaging &/or histological diagnosis 
required


Appendix 9
BILAG-2004 Index Glossary (cont.)
GDC-0853—Genentech, Inc.
163/Protocol GA30044, Version 3
52. Interstitial alveolitis/pneumonitis
radiological features of alveolar infiltration not 
due to infection or haemorrhage required for 
diagnosis
corrected gas transfer Kco reduced to < 70% 
normal or fall of > 20% if previously abnormal
on-going activity would be determined by 
clinical findings and lung function tests, and 
repeated imaging may be required in those with 
deterioration (clinically or lung function tests) 
or failure to respond to therapy
53. Shrinking lung syndrome
acute reduction (>20% if previous measurement
available) in lung volumes (to < 70% predicted) 
in the presence of normal corrected gas transfer 
(Kco) & dysfunctional diaphragmatic 
movements
54. Aortitis
inflammation of aorta (with or without 
dissection) with supportive imaging 
abnormalities 
accompanied by > 10 mm Hg difference in BP 
between arms &/or claudication of extremities 
&/or vascular bruits
repeated imaging would be required to 
determine on-going activity in those with 
clinical deterioration or failure to respond to 
therapy
55. Coronary vasculitis
inflammation of coronary vessels with 
radiographic evidence of non-atheromatous 
narrowing, obstruction or aneurysmal changes
GASTROINTESTINAL
56. Lupus peritonitis
serositis presenting as acute abdomen with 
rebound/guarding
57. Serositis
not presenting as acute abdomen


Appendix 9
BILAG-2004 Index Glossary (cont.)
GDC-0853—Genentech, Inc.
164/Protocol GA30044, Version 3
58. Lupus enteritis or colitis
vasculitis or inflammation of small or large 
bowel with supportive imaging &/or biopsy 
findings
59. Malabsorption
diarrhoea with abnormal D- xylose absorption 
test or increased faecal fat excretion after 
exclusion of coeliac’s disease (poor response to 
gluten-free diet) and gut vasculitis
60. Protein-losing enteropathy
diarrhoea with hypoalbuminaemia or increased 
faecal excretion of iv radiolabeled albumin after 
exclusion of gut vasculitis and malabsorption
61. Intestinal pseudo-obstruction
subacute intestinal obstruction due to intestinal 
hypomotility
62. Lupus hepatitis
raised transaminases 
absence of autoantibodies specific to 
autoimmune hepatitis (eg: anti-smooth muscle, 
anti-liver cytosol 1) &/or biopsy appearance of 
chronic active hepatitis
hepatitis typically lobular with no piecemeal 
necrosis
exclude drug-induced and viral hepatitis
63. Acute lupus cholecystitis
after exclusion of gallstones and infection
64. Acute lupus pancreatitis
usually associated multisystem involvement
OPHTHALMIC
65. Orbital inflammation
orbital inflammation with myositis &/or extra-
ocular muscle swelling &/or proptosis
supportive imaging required
66. Severe keratitis 
sight threatening
includes:  corneal melt
    peripheral ulcerative keratitis
67. Mild keratitis
not sight threatening


Appendix 9
BILAG-2004 Index Glossary (cont.)
GDC-0853—Genentech, Inc.
165/Protocol GA30044, Version 3
68. Anterior uveitis
69. Severe posterior uveitis &/or retinal 
sight-threatening &/or retinal vasculitis
       vasculitis
not due to vaso-occlusive disease
70. Mild posterior uveitis &/or retinal
not sight-threatening
       vasculitis
not due to vaso-occlusive disease
71. Episcleritis
72. Severe scleritis
necrotising anterior scleritis
anterior &/or posterior scleritis requiring 
systemic steroids/immunosuppression &/or not 
responding to NSAIDs
73. Mild scleritis
anterior &/or posterior scleritis not requiring 
systemic steroids
excludes necrotising anterior scleritis
74. Retinal/choroidal vaso-occlusive 
includes: retinal arterial & venous occlusion
disease
  
serous retinal &/or retinal pigment 
  epithelial detachments secondary to   
     choroidal vasculopathy
75. Isolated cotton-wool spots
also known as cytoid bodies
76. Optic neuritis
excludes anterior ischaemic optic neuropathy
77. Anterior ischaemic optic neuropathy
visual loss with pale swollen optic disc due to 
occlusion of posterior ciliary arteries
RENAL
78. Systolic blood pressure
79. Diastolic blood pressure
80. Accelerated hypertension
blood pressure rising to > 170/110 mm Hg 
within 1 month with grade 3 or 4 Keith-
Wagener-Barker retinal changes (flame-shaped 
haemorrhages or cotton-wool spots or 
papilloedema)
81. Urine dipstick
82. Urine albumin-creatinine ratio
on freshly voided urine sample


Appendix 9
BILAG-2004 Index Glossary (cont.)
GDC-0853—Genentech, Inc.
166/Protocol GA30044, Version 3
conversion: 1 mg/mg = 113 mg/mmol
it is important to exclude other causes 
(especially infection) when proteinuria is present
83. Urine protein-creatinine ratio
on freshly voided urine sample
conversion: 1 mg/mg = 113 mg/mmol
it is important to exclude other causes 
(especially infection) when proteinuria is present
84. 24 hour urine protein
it is important to exclude other causes 
(especially infection) when proteinuria is present
85. Nephrotic syndrome
criteria:
heavy proteinuria ( 3.5 g/day or protein-
creatinine ratio 350 mg/mmol or albumin-
creatinine ratio 350 mg/mmol)
hypoalbuminaemia 
oedema
86. Plasma/Serum creatinine
exclude other causes for increase in creatinine 
(especially drugs)
87. GFR 
MDRD formula:
GFR = 170 x [serum creatinine (mg/dl)]-0.999 x  
              [age]-0.176 x [serum urea (mg/dl]-0.17 x  
              [serum albumin (g/dl)]0.318 x [0.762 if 
              female] x [1.180 if African ancestry]
units = ml/min per 1.73 m2
normal: male = 130 ± 40
     female = 120 ± 40
conversion:
serum creatinine  - mg/dl = (mol/l)/88.5
serum urea          -   mg/dl = (mmol/l) x 2.8
serum albumin    -    g/dl    = (g/l)/10
creatinine clearance not recommended as it is 
not reliable


Appendix 9
BILAG-2004 Index Glossary (cont.)
GDC-0853—Genentech, Inc.
167/Protocol GA30044, Version 3
exclude other causes for decrease in GFR 
(especially drugs)
88. Active urinary sediment
pyuria (> 5 WCC/hpf or > 10 WCC/mm3 (l)) 
   OR
haematuria (> 5 RBC/hpf or > 10 RBC/mm3 (l))
   OR
red cell casts 
   OR
white cell casts
exclude other causes (especially infection, 
vaginal bleed, calculi)
89. Histology of active nephritis
WHO Classification (1995): (any one) 
   Class III – (a) or (b) subtypes
   Class IV – (a), (b) or (c) subtypes
   Class V – (a), (b), (c) or (d) subtypes
   Vasculitis
   OR
ISN/RPS Classification (2003): (any one)
   Class III – (A) or (A/C) subtypes
   Class IV – (A) or (A/C) subtypes
   Class V
   Vasculitis
within last 3 months
glomerular sclerosis without inflammation not 
included
HAEMATOLOGICAL
90. Haemoglobin
exclude dietary deficiency & GI blood loss
91. White cell count
exclude drug-induced cause
92. Neutrophil count
exclude drug-induced cause
93. Lymphocyte count


Appendix 9
BILAG-2004 Index Glossary (cont.)
GDC-0853—Genentech, Inc.
168/Protocol GA30044, Version 3
94. Platelet count
exclude drug-induced cause
95. TTP
thrombotic thrombocytopaenic purpura
clinical syndrome of micro-angiopathic 
haemolytic anaemia and thrombocytopenia in 
absence of any other identifiable cause
96. Evidence of active haemolysis
positive Coombs’ test & evidence of haemolysis 
(raised bilirubin or raised reticulocyte count or 
reduced haptoglobulins or fragmented RBC or 
microspherocytes)
97. Isolated positive Coombs’ test
ADDITIONAL ITEMS
These items are required mainly for calculation of GFR
      i. 
Weight
      ii. 
African ancestry 
      iii. 
Serum urea
      iv. 
Serum albumin
References:
Rule of nines diagram. Burn Center, University of Utah Health Sciences Center 
(http://uuhsc.utah.edu/burncenter/emergencycare/extent.html)
Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration 
rate from serum creatinine: a new prediction equation. Modification of Diet in Renal 
Disease Study Group. Ann Intern Med 1999;130:46170. 
Weening JJ, D'Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in 
systemic lupus erythematosus revisited. J.Am.Soc.Nephrol 2004;15:24150. 


GDC-0853—Genentech, Inc.
169/Protocol GA30044, Version 3
Appendix 10
Systemic Lupus Erythematosus Disease Activity Index 
(SLEDAI-2K)
(Circle in SLEDAI Score column if descriptor is present at the time of the visit or in the 
preceding 4 weeks) (The same instrument can also be used going back only ten days)
Item 
no.
SLEDAI 
SCORE
Descriptor
Definition
1
8
Seizure
Recent onset, exclude metabolic, infectious or drug 
causes
2
8
Psychosis
Altered ability to function in normal activity due to 
severe disturbance in the perception of reality. Include 
hallucinations, incoherence, marked loose 
associations, impoverished thought content, marked 
illogical thinking, bizarre, disorganised, or catatonic 
behaviour. Exclude uraemia and drug causes
3
8
Organic brain 
syndrome
Altered mental function with impaired orientation, 
memory, or other intellectual function, with rapid onset 
and fluctuating clinical features, inability to sustain 
attention to environment, plus at least 2 of the 
following: perceptual disturbance, incoherent speech, 
insomnia or daytime drowsiness, or increased or 
decreased psychomotor activity. Exclude metabolic, 
infectious or drug causes
4
8
Visual disturbance
Retinal changes of SLE. Include cytoid bodies, retinal 
hemorrhages, serous exudates or hemorrhages in the 
choroid, or optic neuritis. Exclude hypertension, 
infection, or drug causes
5
8
Cranial nerve 
disorder
New onset of sensory or motor neuropathy involving 
cranial nerves
6
8
Lupus headache
Severe, persistent headache; may be migrainous, but 
must be non-responsive to narcotic analgesia THIS 
WOULD RARELY BE ATTRIBUTED TO 
SLE...ALMOST NEVER SCORED
7
8
CVA
New onset Cerebrovascular accident(s). Exclude 
arteriosclerosis
8
8
Vasculitis
Ulceration, gangrene, tender finger nodules, 
periungual infarction, splinter hemorrhages or biopsy 
or angiogram proof of vasculitis
9
4
Arthritis
>/= 2 joints with pain and signs of inflammation (i.e. 
tenderness, swelling or effusion)
10
4
Myositis
Proximal muscle aching/weakness, associated with 
elevated creatinine phosphokinase (CK)/aldolase, or 
EMG changes or a biopsy showing myositis
11
4
Urinary casts
Heme-granular or RBC casts
12
4
Hematuria
> 5 RBC/high power field. Exclude stone, infection or 
other cause
13
4
Proteinuria
> 0.5 gram/24 hours
14
4
Pyuria
> 5 WBC/high power field. Exclude infection
15
2
Rash
Inflammatory type rash
16
2
Alopecia
Abnormal, patchy or diffuse loss of hair


Appendix 10
Systemic Lupus Erythematosus Disease Activity Index 
(SLEDAI-2K) (cont.)
GDC-0853—Genentech, Inc.
170/Protocol GA30044, Version 3
Item 
no.
SLEDAI 
SCORE
Descriptor
Definition
17
2
Mucosal ulcers
Oral or nasal ulcerations
18
2
Pleurisy
Pleuritic chest pain or pleural rub with effusion, or 
pleural thickening (requires objective evidence)
19
2
Pericarditis
Classic pericardial pain and/or rub, effusion with ECG 
or echocardiogram confirmation (requires an objective 
component)
20
2
Low complement
Decrease in CH50, C3 or C4 below lower limit of 
normal for testing laboratory 
21
2
Increased DNA 
binding
Increased DNA binding above normal range for 
testing laboratory
22
1
Fever
> 38ºC. Exclude infectious cause
23
1
Thrombocytopenia
< 100 x 109 platelets/L, exclude drug causes
24
1
Leukopenia
< 3 x 109 WBC/L, exclude drug causes
SCORE:      


 
 
Appendix 10  
Systemic Lupus Erythematosus Disease Activity Index  
(SLEDAI-2K) (cont.) 
 
GDC-0853—Genentech, Inc. 
171/Protocol GA30044, Version 3 
GUIDELINES FOR USE OF SLEDAI-2K MODIFIED FOR ASSESSMENT OVER 
28 DAYS: TO ASSESS DISEASE ACTIVITY  
General guidelines for filling out the SLEDAI-2K: 
• 
The main principle to keep in mind is that this instrument is intended to 
evaluate current lupus activity and not chronic damage, severity is 
accounted for in part by the "weightedness" of the scale.  
• 
Points are given exactly as defined. 
• 
A descriptor is either scored the exact points allotted or not scored, i.e. 
given a zero. Descriptors are scored only if they are present at the time of 
the physician encounter or in the preceding 28 days. Windows acceptable 
in a clinical trial are acceptable in scoring the SLEDAI. However, it is 
never acceptable to fill in gaps which cover activity over 2-3 months or 
more. The reason for this is that disease activity at the visit might have 
changed several times in such intervals and the recording of distant 
activity becomes meaningless.  
 
Please note that in the original SLEDAI the disease activity being scored 
was meant to cover only a ten day period, the modification to 28 days is a 
more useful assessment for use in clinical trials, in order to capture 
disease activity between monthly visits. 
• 
The descriptor must be documented by the notes written in the physician 
encounter form and generally applies to the clinical data and not to the 
laboratory data. The laboratory data is strictly defined as per cutoffs and 
documentation is provided by the reports from the commercial laboratory.  
• 
Descriptors do not have to be new but can be. They can be ongoing, 
recurrent, or initial events. Each would be scored the same way. An 
example would be a malar rash or mucosal ulcer. In these situations a 
malar rash observed at the initial visit but which remains unchanged for 
the next six months, irrespective of any treatment, is scored 2 points each 
time the SLEDAI is completed. Since the nature of lupus is that 
manifestations are not usually fleeting it would be rare for descriptors to 
appear transiently during the month and not at the time of the encounter. 
This is discussed in more detail for each descriptor but is especially 
relevant for the neurologic (except for seizure or CVA), pulmonary, and 
cutaneous manifestations.  


 
 
Appendix 10  
Systemic Lupus Erythematosus Disease Activity Index  
(SLEDAI-2K) (cont.) 
 
GDC-0853—Genentech, Inc. 
172/Protocol GA30044, Version 3 
• 
In some descriptors the exclusions written may not be exhaustive. The 
intent of the SLEDAI is that the descriptor be attributed to SLE. If the 
physician does not attribute the descriptor to SLE it should not be scored, 
but full documentation must be provided. 
Written in italics is the definition for each descriptor precisely provided in the 
SLEDAI SCORE  
SEIZURE 
Definition: Recent onset (last 28 days). Exclude metabolic, infectious or drug 
cause, or seizure due to past irreversible CNS damage. 
This descriptor is scored if the patient has had a witnessed seizure or convincing 
description (such as tongue biting or incontinence) within 30 days of the current 
encounter. The patient need not have a positive EEG, CT scan, PET scan, 
QEEG, or MRI. The CSF may be totally normal. 
A seizure is also not counted: 
1. If a metabolic cause is determined. 
2. In the presence of a proven infectious meningitis, brain abscess, or fungal 
foci. 
3. If there is a history of recent head trauma. 
4. In the presence of an offending drug. 
5. In the presence of severe hyperthermia or hypothermia. 
6. If the patient has stopped taking anticonvulsant medication. 
7. If the patient has a documented sub-therapeutic anticonvulsant drug level. 
PSYCHOSIS 
Definition: Altered ability to function in normal activity due to severe disturbance 
in the perception of reality. Include hallucinations, incoherence, marked loose 
associations, impoverished thought content, marked illogical thinking, bizarre, 
disorganized, or catatonic behavior. Exclude uremia and drug causes. 
This descriptor is scored if any of the criteria above are met. 
With regard to drug causes the most problematic situation is glucocorticoids. If 
the treating physician attributes the psychosis to glucocorticoids this descriptor 
should not be counted. 


 
 
Appendix 10  
Systemic Lupus Erythematosus Disease Activity Index  
(SLEDAI-2K) (cont.) 
 
GDC-0853—Genentech, Inc. 
173/Protocol GA30044, Version 3 
ORGANIC BRAIN SYNDROME  
Definition: Altered mental function with impaired orientation, memory or other 
intellectual function, with rapid onset and fluctuating clinical features. Include 
clouding of consciousness with reduced capacity to focus, and inability to sustain 
attention to environment, plus at least two of the following: perceptual 
disturbance, incoherent speech, insomnia or daytime drowsiness, or increased or 
decreased psychomotor activity. Exclude metabolic, infectious or drug causes. 
a. reduced capacity to focus as exemplified by new inability to perform 
everyday mathematical computations or disorientation to person, place, 
time, or purpose 
 
OR 
b. inability to carry on a conversation 
 
OR 
c. reduction in short term memory 
PLUS: Documented abnormality on neuropsychiatric testing  
Neuropsychiatric testing may take the form of a "mini-mental-status exam" or a 
formal neuropsychiatric examination. The important aspect for scoring OBS is 
that it be reversible. Consideration should be given to the improvement of OBS 
after institution of glucocorticoids. 
This descriptor is not scored in the presence of a metabolic, infectious, or drug 
cause. If the problem is chronic this descriptor is not scored in SLEDAI but is 
scored on the damage index.  
VISUAL DISTURBANCE 
Definition: Retinal and eye changes of SLE. Include cytoid bodies, retinal 
hemorrhages, serous exudate or hemorrhages in the choroid, or optic neuritis. 
Exclude hypertension, infection or drug causes. 
This is scored exactly as defined with the understanding that it must be 
supported by objective evidence. 
CRANIAL NERVE DISORDER 
Definition: New onset of sensory or motor neuropathy involving cranial nerves. 
Include vertigo due to lupus. 


 
 
Appendix 10  
Systemic Lupus Erythematosus Disease Activity Index  
(SLEDAI-2K) (cont.) 
 
GDC-0853—Genentech, Inc. 
174/Protocol GA30044, Version 3 
This is scored exactly as defined with the understanding that it must be 
supported by objective evidence. However, it should be noted that 
hydroxychloroquine can affect the eighth cranial nerve. 
LUPUS HEADACHE 
Definition: Severe persistent headache: may be migrainous, but must be non-
responsive to narcotic analgesia. 
For this descriptor to be counted, the headache must be present for greater than 
24 hours and must not be responsive to narcotic analgesia. Objective 
documentation need not be present although it is expected that such a complaint, 
given the severity, would prompt formal testing such as MRI, CT, LP, etc. 
Furthermore, the headache should be of sufficient severity to warrant the 
initiation of glucocorticoids or additional immunosuppressive agents. Scoring of 
this descriptor means attribution of the headache to CNS lupus. 
Most headaches, including most severe and/or migrainous headaches are 
not attributable to lupus and this descriptor should only be scored very 
rarely. 
CVA 
Definition: New onset of cerebrovascular accident (s). Exclude arteriosclerosis or 
hypertensive causes. 
This descriptor is scored if the patient has had a CVA within 28 days of the 
current encounter. A patient recovering from a CVA that was documented more 
than 28 days prior to the current encounter is not given points for this descriptor. 
A patient may have had a previous CVA but to be scored the current CVA must 
be new. 
This descriptor is scored in the presence or absence of anti-phospholipid 
antibodies, i.e., the precise pathophysiologic mechanism need not be known. 
The CVA is scored even in the presence of a normal CT or MRI. A TIA is also 
scored if the patient gives a convincing history. To exclude atherosclerosis the 
patient has to have a normal carotid and/or vertebral Doppler and cannot have 
uncontrolled hypertension. 


 
 
Appendix 10  
Systemic Lupus Erythematosus Disease Activity Index  
(SLEDAI-2K) (cont.) 
 
GDC-0853—Genentech, Inc. 
175/Protocol GA30044, Version 3 
VASCULITIS: 
Definition: Ulceration, gangrene, tender finger nodules, periungual infarction, 
splinter hemorrhages, or biopsy or angiogram proof of vasculitis. 
To score this descriptor the above definitions must be present. For example, 
erythematous lesions on the hands or feet which may be characteristically 
considered "leukocytoclastic vasculitis" but do not fulfill at least one of the above 
definitions and if not biopsied, are not counted. Similarly livedo reticularis is not 
counted. Healed ulcers with residual scar are not to be counted, but be sure to 
count these in the damage index. A lesion consistent with erythema nodosum 
should be counted regardless of whether it is biopsied or not. Purpura in the 
presence of a normal platelet count should be counted regardless of whether it 
has been biopsied or not. 
ARTHRITIS 
Definition: Two or more joints with pain and signs of inflammation, i.e., 
tenderness, swelling, or effusion. 
Arthritis is scored if it is ongoing; it need not be new or recurrent. 
Arthritis is scored only if at least two joints manifest signs of inflammation. The 
rheumatologist must be convinced that this is active arthritis due to lupus. 
Inflammation of the tendons, ligaments, bursae, and other periarticular structures 
are not scored. For example subacromial bursitis and trochanteric bursitis are not 
scored. If further evaluation reveals osteonecrosis or osteoarthritis, this 
descriptor is not counted.  
MYOSITIS 
Definition: Proximal muscle aching/weakness, associated with elevated creatine 
phosphokinase/aldolase or electromyogram changes or a biopsy showing 
myositis. 
The patient complains of muscle aching and/or weakness in the proximal 
muscles PLUS one of the following must be present: 
1. elevated serum creatinine phosphokinase and/or aldolase 
2. abnormalities on electromyogram consistent with myositis 
3. biopsy-proven myositis 


 
 
Appendix 10  
Systemic Lupus Erythematosus Disease Activity Index  
(SLEDAI-2K) (cont.) 
 
GDC-0853—Genentech, Inc. 
176/Protocol GA30044, Version 3 
RENAL: Note that the following domains (urinary casts, hematuria, 
proteinuria, and pyuria) can only be evaluated on clean catch urinalysis 
specimens.   
URINARY CASTS 
Definition: Heme-granular or red blood cell casts. 
This is scored if red blood cell casts are seen, even if it is only one. Pigmented 
casts are counted but non-pigmented granular casts, hyaline or waxy casts are 
not counted. 
HEMATURIA 
Definition: >5 red blood cells/high power field. Exclude stone, infection or other 
cause. 
With regard to this descriptor, every attempt should be made to see patients 
when they are not menstruating. If this is not possible the urinalysis should be 
deferred until the next visit. 
This descriptor is not scored if there is documented renal calculi or infection. The 
latter must be confirmed by a positive urinary culture. However it is 
acknowledged that associated conditions such as chlamydia or urethral irritation 
may result in mild hematuria and the physician's best judgment is warranted. The 
important point is attribution: there must be other evidence of nephritis and 
other causes of hematuria must be excluded.  
In the complete absence of proteinuria, attribution of hematuria to active nephritis 
would be very unlikely unless pathology is limited to the mesangium. 
PROTEINURIA 
Definition: proteinuria of more than 0.5 g/24 hours (or equivalent by spot urine 
protein to creatinine ratio). 
Must be attributed to active lupus nephritis. 
PYURIA 
Definition: >5 white blood cells/high power field. Exclude infection. 


 
 
Appendix 10  
Systemic Lupus Erythematosus Disease Activity Index  
(SLEDAI-2K) (cont.) 
 
GDC-0853—Genentech, Inc. 
177/Protocol GA30044, Version 3 
This descriptor is not scored if there is evidence of vaginal contamination 
(presence of any squamous epithelial cells) or a documented infection. The latter 
must be confirmed by a positive urinary culture. However, it is acknowledged that 
associated conditions such as chlamydia, trichomonas or urethral irritation may 
result in mild pyuria and the physician's best judgment is warranted. The 
important point is attribution; there must be other evidence of nephritis, 
and other causes of pyuria should be excluded. In the complete absence of 
proteinuria, attribution of hematuria to active nephritis would be very unlikely 
unless pathology is limited to the interstitium. 
RASH 
Definition: Ongoing inflammatory lupus rash. 
A rash is scored if it is ongoing, new or recurrent. Even if it is identical in terms of 
distribution and character to that observed on the last visit and the intensity is 
improved, it is counted. Therefore, despite improvement in a rash, if it is still 
ongoing it represents disease activity. The rash must be attributable to SLE. A 
description of the rash must appear in the physical exam and should include 
distribution, characteristics such as macular or papular, and size.  
The following should not be scored: 
1. Chronic scarred discoid plaques in any location. 
2. Transient malar flush, i.e., it is not raised and is evanescent 
A common problem one may encounter is the differentiation between scoring a 
lesion as "rash" and/or "vasculitis". If a lesion meets the descriptive criteria of the 
latter it should not also be counted as rash, i.e., the score would be 8 points not 
10 points. If a separate rash characteristic of SLE is present only then would 
"rash" also be scored. 
ALOPECIA: 
Definition: Ongoing abnormal, patchy or diffuse loss of hair due to active lupus. 
This should be scored if any of the following conditions are present: 
1. There is temporal thinning which is newly present for less than six months 
(if temporal alopecia is present for more than six months with no change it 
should not be counted)  


 
 
Appendix 10  
Systemic Lupus Erythematosus Disease Activity Index  
(SLEDAI-2K) (cont.) 
 
GDC-0853—Genentech, Inc. 
178/Protocol GA30044, Version 3 
2. Areas of scalp with total bald spots if present for less than six months 
(does not need to have accompanying discoid lesion or follicular plugging) 
3. The presence of "lupus frizz" i.e., short of strands of unruly hair in the 
frontal or temporal area 
If a patient complains of hair loss and there is nothing apparent on exam this 
descriptor is not scored. 
MUCOSAL ULCERS: 
Definition: Ongoing oral or nasal ulcerations due to active lupus. 
An ulcer is scored if it is ongoing, it need not be new or recurrent. Ulcers can be 
present in either the nose or oral cavity. Erythema alone without frank ulceration 
is not sufficient to be scored, even if the erythema is present on the upper palate. 
Ulcers on the buccal mucosa and tongue are counted. 
Mucosal ulcers are not counted as vasculitis. 
PLEURISY 
Definition: Classic and severe pleuritic chest pain or pleural rub with effusion or 
new pleural thickening due to lupus. 
This descriptor is scored if the patient complains of pleuritic chest pain lasting 
greater than 12 hours. The pain should be classic, i.e., exacerbated by 
inspiration, to help distinguish it from musculoskeletal conditions such as 
costochondritis, which could be confused with pleurisy. The symptom must also 
be accompanied by objective findings.  
PERICARDITIS: 
Definition: Classic and severe pericardial pain with rub or effusion, or 
electrocardiogram or echocardiogram confirmation. 
The symptom must be accompanied by objective findings.  
LOW COMPLEMENT: 
Definition: Decrease in CH50, C3 or C4 below the lower limit of normal for testing 
laboratory. 


 
 
Appendix 10  
Systemic Lupus Erythematosus Disease Activity Index  
(SLEDAI-2K) (cont.) 
 
GDC-0853—Genentech, Inc. 
179/Protocol GA30044, Version 3 
Exclude a low C4 or CH50 in patients with known inherited deficiency of C4.  
INCREASED DNA BINDING 
Definition: >25% binding by Farr assay or above normal range for testing 
laboratory. 
FEVER: 
Definition: >38°C. Exclude infectious cause. 
This would be scored if one of the following conditions are present: 
1. A documented temperature elevation >100.4°F or >38°C at the time of the 
visit. 
2. A convincing history from the patient that she/he has been febrile within 
the preceding 10 days prior to the visit without any signs or symptoms 
suggestive of infection. Febrile is defined as above and not simply that the 
patient felt feverish. In this case the patient need not be febrile at the time 
of the visit for a score of 2 to be given. 
As stated in the SLEDAI, fever secondary to infection is not to be scored 
although it is acknowledged that concomitant lupus activity and infection can 
occur. Fever in the presence of infection should only be scored on the SLEDAI if 
other evidence of lupus activity is present.  
THROMBOCYTOPENIA: 
Definition: <100,000 platelets/mm3. 
LEUKOPENIA: 
Definition: <3,000 white blood cells/mm3. Exclude drug causes. 
This is exactly as described, WBC <3,000/mm3. The presence of an absolute 
lymphopenia does not count in the SLEDAI. A note of caution, do not confuse 
this WBC with that used to satisfy the ACR criteria for SLE which is WBC 
<3,500/mm3. 
With regard to current use of possible offending drugs, the following guidelines 
are to be considered: 


 
 
Appendix 10  
Systemic Lupus Erythematosus Disease Activity Index  
(SLEDAI-2K) (cont.) 
 
GDC-0853—Genentech, Inc. 
180/Protocol GA30044, Version 3 
1. The nadir after cyclophosphamide, i.e., low WBC at 10 days after 
receiving cyclophosphamide in a patient known to have a WBC ≥ 3,000 at 
the time of receiving cyclophosphamide should not be counted. 
2. Do not score leukopenia appearing after initiation of a new medication 
known to be associated with leukopenia, such as azathioprine or sulfa 
drugs. If the patient develops a WBC <3000 while taking drugs which may 
cause leukopenia, score this only if the dosage of medication is 
unchanged since the last WBC determination. 


 
GDC-0853—Genentech, Inc. 
181/Protocol GA30044, Version 3 
Appendix 11  
SELENA-SLEDAI FLARE INDEX (SFI) 
(Can be used with any version of the SLEDAI) 
Mild or Moderate Flare 
Severe Flare 
Increase in SLEDAI by ≥ 3 
New or worse: 
Rash (discoid, photosensitive, profundus, 
cutaneous vasculitis, bullous lupus) 
Nasopharyngeal ulcers 
Pleuritis 
Pericarditis 
Arthritis 
Fever (SLE) 
Increase in SLEDAI to > 12 
New or worse (requiring doubling of prednisone, 
prednisone > 0.5 mg/kg/day, or hospitalization): 
CNS-SLE 
Vasculitis 
Nephritis 
Myositis  
Platelets < 60,000/mm3 
Hemolytic anemia:  Hb < 7g/dL or decrease of 
Hb by > 3 g/dL 
Increase in Prednisone, but not 
to >0.5 mg/kg/day 
Prednisone > 0.5 mg/kg/day 
Added NSAID or hydroxychloroquine for 
disease activity 
New cyclophosphamide, azathioprine, 
methotrexate, mycophenolate mofetil, or 
hospitalization (for SLE) 
Increase in Physican’s Global Assessment 
by ≥ 1.0, but not to more than 2.5 
Increase in Physician’s Global Assessment to 
> 2.5 
 
Buyon JP et al. The Effect of Combined Estrogen and Progesterone Hormone 
Replacement Therapy on Disease Activity in Systemic Lupus Erythematosus: A 
Randomized Trial. Ann Internal Med 2005;142:953-62. 
Petri M, Buyon J, Kim M. Classification and definition of major flares in SLE clinical trials. 
Lupus 1999;8:685-91. 
Petri M, Kim MY, Kalunian KC, et al. Combined Oral Contraceptives in Women with 
Systemic Lupus Erythematosus. N Engl J Med 2005;353:2550-8. 


GDC-0853—Genentech, Inc.
182/Protocol GA30044, Version 3
Appendix 12
Glucocorticoid Toxicity Change Index
COMPOSITE GLUCOCORTICOID TOXICITY CHANGE INDEX
1.
Body mass index (BMI) (compared to baseline)
a)
Improvement (in either direction) by more than 2 BMI units toward normal BMI 
(normal range18.524.9 kg/m2)
b)
No significant change (BMI remains within 2 BMI units compared with baseline) 
or BMI remains within the normal range
c)
Moderate increase in BMI (increase by more than 2 but less than 5 BMI units to 
above the upper limit of normal BMI [24.9 kg/m2])
d)
Major increase in BMI (increase by more than 5 BMI units to above normal BMI 
[24.9 kg/m2])
2.
Glucose tolerance (compared to baseline)
a)
Improvement in glucose tolerance: 

HbA1c (glycosylated hemoglobin) declined 10% from baseline without 
medication increase
OR

Decrease in diabetic medication without an increase in HbA1c of 10% or 
HbA1c 5.7%
b)
No significant change in glucose tolerance:

HbA1c within 10% of baseline or HbA1c 5.7% and no change in 
medication 
OR 

HbA1c increased to 10% of baseline due to a decrease in medication 
OR 

Improvement in glucose tolerance 10% due to an increase in medication
c)
Worsening of glucose tolerance or medication status: 

HbA1c increased to 10% and HbA1c 5.7% without a change in 
medication 
OR

Increase in diabetic medication with 10% increase in HbA1c
d)
Worsening of glucose tolerance despite treatment:

HbA1c 5.7% and increased to 10% of baseline and an increase in 
diabetic medication


Appendix 12
Glucocorticoid Toxicity Change Index (cont.)
GDC-0853—Genentech, Inc.
183/Protocol GA30044, Version 3
3.
Blood pressure (BP) (compared to baseline)
a)
Improvement in BP: 

Decrease in BP of 10% of baseline without medication increase
OR

Decrease in medication without an increase in BP of 10% or systolic BP 
120 and diastolic BP 85
b)
No significant change in BP:

BP within 10% of baseline or systolic BP 120 and diastolic BP 85 and no 
change in medication 
OR

Deterioration in either systolic or diastolic BP 10% due to a decrease in 
medication
OR 

An improvement in either systolic or diastolic BP of 10% due to an 
increase in medication
c)
Worsening of hypertension: 

Increase in BP of 10% such that the systolic BP exceeds 120 mmHg or 
the diastolic BP exceeds 85 mmHg without a change in medication 
OR 

Increase in anti-hypertensive medication without an improvement in BP 
10%
d)
Worsening of hypertension despite treatment:

Increase in BP of 10% such that the systolic BP exceeds 120 mmHg or 
the diastolic BP exceeds 85 mmHg and an increase in medication
4.
Hyperlipidemia (compared to baseline)
a)
Improvement in lipids: 

Decrease in low-density lipoprotein (LDL) concentration 10% of baseline 
without medication increase toward the target range 
OR

Decrease in medication without an increase in LDL of 10% or LDL 
remains within target range


Appendix 12
Glucocorticoid Toxicity Change Index (cont.)
GDC-0853—Genentech, Inc.
184/Protocol GA30044, Version 3
b)
No significant change in LDL:

LDL within 10% of baseline or within the target range for patient and no 
change in medication 
OR 

Increase in LDL 10% due to a decrease in medication
OR 

Improvement in LDL of 10% due to an increase in medication
c)
Worsening of LDL or medication status: 

Increase in LDL of 10% to above target range without increase in 
medication
OR 

Increase in medication without 10% change in LDL
d)
Worsening of LDL despite treatment:

Increase in LDL of 10% and an increase in medication
5.
Steroid myopathy
a)
No steroid myopathy
b)
Mild steroid myopathy (weakness without functional limitation)
c)
Moderate steroid myopathy (weakness with functional limitation)
See steroid myopathy definitions below.
6.
Skin 
a)
No skin toxicity
b)
Mild 
c)
Moderate 
See skin definitions below.
7.
Neuropsychiatric 
a)
No neuropsychiatric symptoms
b)
Mild
c)
Moderate 
See neuropsychiatry definitions below.


Appendix 12
Glucocorticoid Toxicity Change Index (cont.)
GDC-0853—Genentech, Inc.
185/Protocol GA30044, Version 3
8.
Infection (since last assessment) 
a)
No significant infection
b)
Specific infections Grade 3 (oral or vaginal candidiasis, uncomplicated zoster)
c)
Grade 3 
See infection notes below.
9.
Bone mineral density (BMD) (compared to baseline)
a)
Improvementincrease in BMD by 3%
b)
No significant change (BMD between 3% and 3%)
c)
Deterioration decrease by 3% 
% refers to total BMD in gms/cm2
If BMD not evaluated, then option “b” should be selected.
GLUCOCORTICOID-INDUCED MYOPATHY DEFINITIONS

Glucocorticoid-induced myopathy is defined as mild symmetrical weakness of the 
proximal muscles and/or neck flexors associated with steroid therapy and not due to 
any other apparent cause.  Muscle enzymes are typically within normal limits.

Mild and moderate myopathy are defined by muscle strength of 4 on the standard 
Medical Research Council strength testing scale.  A 4 means weaker than normal 
but greater than anti-gravity strength. 

“Mild” is Grade 4 weakness that does not functionally limit the patient.

”Moderate” is Grade 4 weakness that does impose functional limitations on the 
patient, interfering with normal daily activities.

Note that inability to rise from a chair without assistance constitutes severe
glucocorticoid-induced myopathy (Specific Domain)
SEVERITY OF GLUCOCORTICOID TOXICITY IN THE SKIN
Manifestations to be considered:

Acneiform rash

Easy bruising

Hirsutism

Atrophy/striae

Erosions/tears/ulcerations


Appendix 12
Glucocorticoid Toxicity Change Index (cont.)
GDC-0853—Genentech, Inc.
186/Protocol GA30044, Version 3
Skin 6b. Mild
Skin 6c. Moderate
Severe (Specific Domain)
Acneiform rash (Grades 12)
Acneiform rash (Grade 3)
Acneiform rash (Grade 4)
Easy bruising (Grade 1)
Easy bruising (Grade 2)
Hirsutism (Grade 1)
Hirsutism (Grade 2)
Atrophy/striae (Grade 1)
Atrophy/striae (Grade 2)
Atrophy/striae (Grade 3)
Erosions/tears/ulcerations 
(Grade 1)
Erosions/tears/ulcerations 
(Grade 2)
Erosions/tears/ulcerations 
(Grade 3)
Acneiform rash

Grade 1:  Papules and/or pustules covering 10% body surface area (BSA), which 
may or may not be associated with symptoms of pruritus or tenderness

Grade 2:  Papules and/or pustules covering 10%30% BSA, which may or may not 
be associated with symptoms of pruritus or tenderness; associated with 
psychosocial impact; limiting instrumental activities of daily living (ADL)

Grade 3:  Papules and/or pustules covering 30% BSA, which may or may not be 
associated with symptoms of pruritus or tenderness; limiting self-care ADL; 
associated with local superinfection with oral antibiotics indicated

Grade 4:  Papules and/or pustules covering any % BSA, which may or may not be 
associated with symptoms of pruritus or tenderness and are associated with 
extensive superinfection with intravenous (IV) antibiotics indicated; life-threatening 
consequences
Easy bruising

Grade 1:  Localized or in a dependent area

Grade 2:  Generalized
Hirsutism:  In women, increase in length, thickness, or density of hair in a male 
distribution

Grade 1:  Hirsutism that the patient is able to camouflage by periodic shaving, 
bleaching, or removal of hair

Grade 2:  Hirsutism that requires daily shaving or consistent destructive means of 
hair removal to camouflage; associated with psychosocial impact
Atrophy/striae

Grade 1:  Covering 10% BSA; associated with telangiectasias or changes in skin 
color

Grade 2:  Covering 10%30% BSA; associated with striae or adnexal structure loss

Grade 3:  Covering 30% BSA; associated with ulceration


Appendix 12
Glucocorticoid Toxicity Change Index (cont.)
GDC-0853—Genentech, Inc.
187/Protocol GA30044, Version 3
Erosions/tears/ulcerations

Grade 1:  Combined area of ulcers 1 cm; non-blanchable erythema of intact skin 
associated with warmth or erythema

Grade 2:  Combined area of ulcers 12 cm; partial thickness skin loss involving skin 
or subcutaneous fat

Grade 3:  Combined area of ulcers 2 cm; full-thickness skin loss involving damage 
to or necrosis of subcutaneous tissue that may extend down to fascia
SEVERITY OF NEUROPSYCHIATRIC GLUCOCORTICOID TOXICITY
Manifestations to be considered: 

Insomnia

Mania

Cognitive impairment

Depression
7b. MildNo Functional 
Impairment
7c. ModerateFunctional 
Impairment
Severe (Specific Domain)
Insomnia
Insomnia
Mania (Grade 1)
Mania (Grade 2)
Mania (Grade 3)
Cognitive impairment 
(Grade 1)
Cognitive impairment (Grade 
2)
Cognitive impairment 
(Grade 3)
Depression (Grade 1)
Depression (Grade 2)
Depression (Grade 3)
DEFINITIONS OF SEVERITY WITHIN THE NEUROPSYCHIATRIC DOMAIN
Insomnia:  Dissatisfaction with sleep quality and difficulty initiating or maintaining 
sleep or early morning awakening

Grade 1:  Not associated with functional impairment

Grade 2:  Associated with functional impairment; recorded as moderate toxicity
Mania

Grade 1: Slightly or occasionally elevated or irritable mood and 01 mild or 
occasional additional symptoms of inflated self-esteem, decreased need 
for sleep, increased talkativeness, feeling that thoughts are faster than 
usual, distractibility, increased activity or agitation, and impulsive actions

Grade 2:  Frequent or moderately elevated or irritable mood and 23 mild additional 
symptoms of inflated self-esteem, decreased need for sleep, increased 


Appendix 12
Glucocorticoid Toxicity Change Index (cont.)
GDC-0853—Genentech, Inc.
188/Protocol GA30044, Version 3
talkativeness, feeling that thoughts are faster than usual, distractibility, 
increased activity or agitation, and impulsive actions

Grade 3:  Severe or constantly elevated or irritable mood and 4 or more additional 
symptoms of inflated self-esteem, decreased need for sleep, increased 
talkativeness, feeling that thoughts are faster than usual, distractibility, 
increased activity or agitation, and impulsive actions
Cognitive impairment

Grade 1:  Minor cognitive complaints, no objective findings on mental status 
examination (i.e., not apparent to the examiner) that were not present 
before initiating steroids

Grade 2:  New moderate cognitive deficits that were not present before initiating 
steroids

Grade 3:  Frank delirium 
Depression

Grade 1:  Feeling slightly down or depressed and 02 mild or occasional additional 
symptoms of loss of interest, low energy, guilt, poor concentration, 
insomnia, restlessness, or change in appetite

Grade 2:  Frequent or moderate feelings of being down or depressed and/or 34 
symptoms of loss of interest, low energy, guilt, poor concentration, 
insomnia, restlessness, or change in appetite

Grade 3: Severe constant feeling of being down or depressed and/or 5 or more 
symptoms of loss of interest, low energy, guilt, poor concentration, 
insomnia, restlessness, or change in appetite and/or suicidal thoughts
INFECTION NOTES

No significant infection:  No specific infections or serious infections Grade 3 or 
greater

Specific infections:  Oral or vaginal candidiasis or zoster infections without 
postherpetic neuralgia or eye involvement

Grade 3:  IV antibiotic, anti-fungal, or anti-viral intervention or hospitalization 
indicated or radiologic or operative intervention indicated or herpes zoster 
complicated by postherpetic neuralgia or eye involvement

Grade 4 or 5:  Life-threatening consequences; urgent intervention indicated or death 
from infection (Specific Domain)


GDC-0853—Genentech, Inc.
189/Protocol GA30044, Version 3
Appendix 13
28-Joint Count
The number of tender joints and the number of swollen joints will be assessed on any 
patient in whom arthritis is present at the current visit or in whom arthritis has been 
present at any previous visit during the study. 
The joint counts must be performed by an assessor with experience in performing these 
assessments; this may be the Principal Investigator, subinvestigator, the study 
coordinator, or another trained individual approved by the Sponsor.  The joint counts on 
a given patient should be performed by the same assessor at each study visit. 
The 28 joints to be assessed for tenderness and swelling are as follows:

Shoulders (2 joints)

Elbows (2 joints)

Wrists (2 joints)

Interphalangeal of each thumb (2 joints)

Proximal interphalangeal joints on fingers 25 (8 joints)

Metacarpophalangeal joints on digits 15 (10 joints)

Knees (2 joints)
The choice of joints included in this assessment is based on the 28-joint count 
performed as part of the Disease Activity Score (DAS)-28 for assessment of disease 
activity in rheumatoid arthritis. 


GDC-0853—Genentech, Inc.
190/Protocol GA30044, Version 3
Appendix 14
Cutaneous Lupus Erythematosus Disease Area and Severity 
Index (CLASI)
The Cutaneous Lupus Area and Severity Index (CLASI) comprises a score for the
activity of the disease and a score for the damage caused by the disease 
(see Scoresheet in this appendix).  The CLASI should be completed at intervals as
indicated in the SOA (Appendix 1) for any patient who has mucocutaneous 
manifestations of SLE at a given study visit and then at all subsequent visits. 
With the exception of alopecia, only skin lesions that are specific to SLE are included in 
this assessment.  The cutaneous manifestations of SLE (e.g., vasculitis) are not scored 
for the CLASI.
1.
localized and generalized manifestations of acute cutaneous lupus erythematosus 
(malar rash, maculopapular rash, photosensitive rash, bullous lupus erythematosus);
2.
subacute cutaneous lupus erythematosus (annular / polycyclic or papulosquamous / 
psoriasiform); and
3.
chronic cutaneous lupus erythematosus (localized and generalized discoid lupus, 
verruccous/hyperkeratotic discoid lupus, mucosal discoid lupus, tumid lupus, 
perniotic/chilblain lupus, and lupus profundus/lupus panniculitis). 
Training in the use of the CLASI will be provided to Investigators.
Activity 
Lesion activity is scored for 13 specified anatomical areas in terms of erythema 
(absent0; pink or faint erythema1; red2; dark red, purple, violaceous, crusted, or 
hemorrhagic 3) and scale/hypertrophy (absent0; scale1; verruccous or 
hypertrophic 2).  The severity score for each area is based on the worst lesion within 
that area.  
The patient is asked about mucous membrane involvement and if this is reported the 
affected areas are examined (absent0, present1). 
The patient is asked about hair loss in the past 30 days (patient-reported absence 0, 
presence1). Non-scarring alopecia on examination is scored by examining the scalp in 
quadrants (absent 0; diffuse, non-inflammatory1; focal or patchy in one quadrant2; 
focal or patchy in more than one quadrant3).  The scores for the various anatomical 
areas are summed.
The maximum possible score for the Activity component of the CLASI is 70. 


Appendix 14
Cutaneous Lupus Erythematosus Disease Area and Severity 
Index (CLASI) (cont.)
GDC-0853—Genentech, Inc.
191/Protocol GA30044, Version 3
Damage 
Skin damage is scored for 12 specified anatomical areas (as for the Activity score but 
excluding the scalp which is scored separately, see below).  Damage in each area is 
scored for dyspigmentation (absent0; present1) and for scarring, atrophy and 
panniculitis (absent0; scarring 1; severe atrophic scarring or panniculitis 2).  As for 
the Activity component of the index, the damage severity score for each area is based 
on the worst lesion within that area.  The scores for the various anatomical areas are 
then summed.
The patient is asked whether the dyspigmented cutaneous lesions usually remain visible 
for more than 12 months.  If so, this is taken to indicate that the lesions are permanent, 
and the dyspigmentation score is doubled. 
The scalp is examined for scarring, again by dividing into quadrants (absent 0; scarring 
in one quadrant3; two quadrants4; three quadrants5; whole skull scarred6). 
The maximum possible score for the Damage component of the CLASI is 56. 
Reference:
Albrecht J, Werth V. Development of the CLASI as an outcome instrument for cutaneous 
lupus erythematosus. Derm Ther. 2007:20; 93-101.


Appendix 14
Cutaneous Lupus Erythematosus Disease Area and Severity 
Index (CLASI) (cont.)
GDC-0853—Genentech, Inc.
192/Protocol GA30044, Version 3


GDC-0853—Genentech, Inc.
193/Protocol GA30044, Version 3
Appendix 15
Physician’s Global Assessment
The Investigator’s global assessment of the patient’s current disease activity (PGA) will 
be marked on a 100 mm horizontal visual analogue scale (VAS) marked from ‘none’ to 
‘severe’ and graded from 0 to 3 (see example of following page).  The Investigator 
should refer to assessments at prior visits and move the tick mark according to his or her 
assessment of the patient’s disease activity over the preceding 28 days.  The PGA 
should be done after the Investigator has done the clinical history and examination of the 
patient and has completed the BILAG-2004 and SLEDAI-2K indices and (where 
appropriate) the CLASI and 28-joint counts. 
Pertinent laboratory values should be taken into account before completing the PGA 
rating. If relevant laboratory results are pending, investigator may make a provisional 
marking on a local paper copy of the PGA case record form and finalize the assessment 
when all pertinent data are available.








GDC-0853—Genentech, Inc.
197/Protocol GA30044, Version 3
Appendix 18
Types and Doses of Standard Oral Treatments for Systemic 
Lupus Erythematosus Permitted in Study 
Oral corticosteroids a
Equivalent dose (mg)
Hydrocortisone
20
Cortisone acetate 
25
Prednisone
5
Prednisolone
5
Methylprednisolone
4
Dexamethasone 
0.75
Betamethasone 
0.75
Triamcinolone
4
Beclometasone 
0.75
Deflazacort
6
Other c

Oral Immunosuppression and anti-malarials b
Azathioprine 
1 to 2.5 mg/kg/day
Methotrexate
7.5 to 25 mg/week
Mycophenolate mofetil
500 to 3000 mg/day
Mycophenolic sodium
360 to 2160 mg/day
Hydroxychloroquine
200 to 400 mg/day
Chloroquine
100 to 250 mg/day
Quinacrine
100 to 200 mg/day
Other c       

a Cortisol (hydrocortisone) is the standard of comparison for glucocorticoid potency. 
Hydrocortisone is the name used for pharmaceutical preparations of cortisol.
b Any combination of azathioprine, methotrexate, mycophenolate mofetil, or mycophenolic 
sodium is prohibited.
c Other medications may apply based on region and should be consulted with the Medical 
Monitor.


GDC-0853—Genentech, Inc.
198/Protocol GA30044, Version 3
Appendix 19
Concomitant Medications (Including Foods and Herbal Products)
Class
Expected Interaction
Recommendation
Examples of Drugs in this Class a
Antacids
Decreased 
GDC-0853 
absorption due to 
increased gastric pH
Take GDC-0853 
2 hours before or 
2 hours after antacid
Maalox, Pepto-Bismol, Rolaids
Strong 
CYP3A 
inhibitors 
Increased 
GDC-0853 plasma 
concentrations due 
to inhibition of 
metabolism
Avoid for 7 days or 
5 half-lives 
(whichever is 
longer) prior to first 
dose of study drug 
and during the 
treatment period, 
unless otherwise 
advised by the 
Medical Monitor or 
delegateb
Antimicrobials (clarithromycin, 
erythromycin, itraconazole, 
ketoconazole, telithromycin, 
troleandamycin, voriconazole, 
posaconazole)
Antidepressants (nefazodone)
Other (grapefruit juice, Seville 
orange juice, pomegranate, star 
fruit)
CYP3A 
inducers 
Decreased 
GDC-0853 plasma 
concentrations due 
to increased 
metabolism
Avoid for 7 days or 
5 half-lives 
(whichever is 
longer) prior to first 
dose of study drug 
and during the 
treatment period, 
unless otherwise 
advised by the 
Medical Monitor or 
delegateb
Antimicrobials (rifampin, 
rifapentine, rifabutin)
Antidepressants (St. John’s wort, 
hyperforin)
Antiepileptics (carbamazepine, 
phenytoin, phenobarbital, 
hyperforin)
Diabetes (pioglitazone, 
troglitazone)
Other (modafinil, bosentan)
Sensitive 
and narrow 
therapeutic 
window 
CYP3A 
substrates
Potential for 
increased plasma 
concentrations of 
CYP3A substrates 
due to inhibition of 
metabolism by GDC-
0853
Use with caution 
and monitor for 
adverse events 
related to CYP3A 
substrates as 
directed by product 
labeling; consult 
with the Medical 
Monitor as neededb
Antiemetic/prokinetic (aprepitant, 
cisapride)
Anti-histamine (astemizole, 
terfenadine)
Anti-hypertensive/cardiac 
(dronedarone, eplerenone, 
felodipine, nisoldipine, quinidine, 
ticagrelor, vardenafil)
Benzodiazepines (alprazolam, 
diazepam, midazolam)
Lipid-lowering (simvastatin
[recommended maximum dose: 10 
mg/day], lovastatin [recommended 
maximum dose: 20 mg/day])
Migraine (eletriptan, ergotamine)
Steroids (budesonide, fluticasone)
Other (alfentanil, buspirone, 
conivaptan, darifenacin, dasatinib, 
dihydroergotamine, fentanyl, 
lurasidone, pimozide, quetiapine, 


Appendix 19
Concomitant Medications (Including Foods and Herbal Products) 
(cont.)
GDC-0853—Genentech, Inc.
199/Protocol GA30044, Version 3
sildenafil, tolvaptan, triazolam)
BCRP 
substrates 
with a 
narrow 
therapeutic 
index
Potential for 
increased plasma 
concentrations of 
BCRP substrates 
due to inhibition of 
transport by 
GDC-0853
Use with caution 
and monitor for 
adverse events 
related to BCRP 
substrates as 
directed by product 
labeling; consult 
with the Medical 
Monitor as neededb
Anti-hypertensive (prazosin)
Anti-inflammatory (sulfasalazine)
Lipid-lowering (rosuvastatin 
[recommended maximum dose: 10 
mg/day], atorvastatin 
[recommended maximum dose: 20 
mg/day]
Muscle relaxants (dantrolene)
Steroids (estrone-3-sulfate)
a The following list is not comprehensive.  Please refer to the following websites for additional 
information and consult the Medical Monitor if necessary:
U.S. FDA Table of Substrates, Inhibitors, and Inducers (Tables 3-1, 3-2, 3-3, and 5-1) 
(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteract
ionsLabeling/ucm093664.htm)
Indiana University Department of Medicine P450 Interaction Table 
(http://medicine.iupui.edu/clinpharm/ddis/clinical-table)
b 
Potential CYP3A- and BCRP-mediated interactions between GDC-0853 and concomitant 
medications will be reviewed by the Medical Monitor or delegate during the pre-enrolment 
adjudication process