Clinical trial NCT02983227
Conditions: Rheumatoid Arthritis
Sponsor: Genentech, Inc.
Start date: 2016-11-30; Completion date: 2019-07-17
Enrollment: 496 participants; Allocation: ; Intervention model: PARALLEL

Brief summary:
A study to evaluate the long-term safety and efficacy of GDC-0853 in participants with moderate to severe active Rheumatoid Arthritis (RA) who have completed 12 weeks of study treatment in Study GA29350. Eligible participants from Study GA29350 who elect to participate will receive treatment with GDC-0853 twice daily (BID) in an open-label fashion for 52 weeks, followed by a safety follow-up period of 8 weeks.

Detailed description:

Arms: arm 1: Participants received GDC-0853 orally twice daily (BID) for 52 weeks, after completing 12 weeks in Cohort 1 of Study GA29350. Cohort 1 participants in GA29350 were enrolled with moderate to severe active Rheumatoid Arthritis (RA) and an inadequate response to previous methotrexate (MTX) therapy and then randomized to 12 weeks of GDC-0853 (50 mg daily, 150 mg daily, or 200 mg BID), adalimumab, or placebo. arm 2: Participants received GDC-0853 orally twice daily (BID) for 52 weeks, after completing 12 weeks in Cohort 2 of Study GA29350. Cohort 2 participants in GA29350 were enrolled with moderate to severe active Rheumatoid Arthritis (RA) and an inadequate response to one or two tumor necrosis factor (TNF) inhibitors and methotrexate (MTX) therapy, and then randomized to 12 weeks of GDC-0853 (200 mg BID) or placebo.
Interventions: intervention 1: GDC-0853
Intervention descriptions: intervention 1: GDC-0853 was administered orally at a dose of 200mg, as per the dosing schedules described above.

Protocol documents:
Prot_SAP_000.pdf: 
 
Official Title: A Phase II Open-Label Extension Study of Patients Previously 
Enrolled in Study GA29350 to Evaluate the Long-Term Safety and 
Efficacy of GDC-0853 in Patients With Moderate to Severe 
Rheumatoid Arthritis 
NCT Number: 
NCT02983227 
Document Date: 
Protocol Version 2: 08-August-2016 
 
 
 


 
Title
08-Aug-2016 17:39:29
Date and Time (UTC)
Company Signatory
Approver's Name
PROTOCOL AMENDMENT 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The information contained in this document, especially any unpublished data, is the property of 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. 
Protocol GA30067, Version 2 
PROTOCOL 
TITLE: 
A PHASE II OPEN-LABEL EXTENSION STUDY OF 
PATIENTS PREVIOUSLY ENROLLED IN 
STUDY GA29350 TO EVALUATE THE LONG-TERM 
SAFETY AND EFFICACY OF GDC-0853 IN PATIENTS 
WITH MODERATE TO SEVERE RHEUMATOID 
ARTHRITIS  
PROTOCOL NUMBER: GA30067 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
2016-000498-19 
IND NUMBER: 
120,162 
TEST PRODUCT: 
GDC-0853 (RO7010939) 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
Genentech, Inc. 
DATE FINAL: 
Version 1:  18 February 2016 
DATE AMENDED: 
Version 2:  See electronic date stamp below. 


GDC-0853—Genentech, Inc. 
2/Protocol GA30067, Version 2 
PROTOCOL AMENDMENT, VERSION 2 
RATIONALE 
Changes to the protocol, along with a rationale for each change, are summarized as 
follows and are reflected as applicable in the Schedule of Assessments (Appendix 1): 
• 
Background and nonclinical experience with GDC-0853 had been updated to 
include no observed adverse effect levels from 9-month study in dogs and chronic 
toxicity findings in rats and dogs that support multiple-dose exposures in patients 
with rheumatoid arthritis at the proposed clinical doses (Sections 1.2, 1.3, 
and 5.1.1.1). 
• 
The secondary efficacy objective to assess Boolean- and SDAI-based remission 
has been clarified.   
• 
Week 2 assessments have been removed throughout the protocol to reduce patient 
burden.  
• 
The rationale for GDC-0853 dose and schedule has been updated to reflect results 
from the available clinical and nonclinical data. 
• 
The inclusion criterion for completion of Study GA29350 has been clarified 
(Section 4.1.1). 
• 
Temperature for GDC-0853 storage has been updated to be between 2°C and 8°C 
(Section 4.2.1.). 
• 
Dosing for Day 1 has been clarified (Section 4.2.2). 
• 
Labeling of dates on the blister wallets and bottles has been changed to be 
prepopulated by the sites, with the time of dosing to be recorded by the patient for 
ease of labeling (Appendix 10). 
• 
The male-specific Informed Consent has been removed now that additional 
nonclinical toxicology results suggest lower testicular toxicity risk (Section 4.4.1).  
Upon completion of the nonclinical chronic duration dog toxicity study for GDC-0853, 
the potential risk of testicular toxicity has been reduced since similar effects were 
observed in both GDC-0853−treated and vehicle-treated dogs, and the only 
testicular effects considered GDC-0853 related occurred at a very high dose in rats. 
• 
The method of patient-reported (via electronic device) and clinician-reported 
outcomes (paper based) has been clarified (Section 4.4.6). 
• 
Updated nonclinical information has been added regarding immune function, 
hepatotoxicity, and vascular inflammation, and pancreatic effects have been 
removed on the basis of U.S. Food and Drug Administration agreement that this 
was a rat species−specific finding (Section 5.1.1). 
• 
Management guidelines have been updated to reflect changes in text, and the 
hepatotoxicity wording has been clarified (Table 3).  
 
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. 


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3/Protocol GA30067, Version 2 
PROTOCOL AMENDMENT, VERSION 2: 
SUMMARY OF CHANGES 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
SECTION 1.2.1:  Bruton’s Tyrosine Kinase 
…Affected male patients have a primary immune deficiency called X-linked 
agammaglobulinemia (XLA) and are susceptible to recurrent infections starting shortly 
after birth.  Intravenous immunoglobulin (IVIg) replacement therapy lowers the rate of 
infection, reduces hospitalization rates for patients with XLA, and has greatly improved 
the long term prognosis of these patients. Patients with XLA 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. 
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. 
SECTION 1.2.2:  Nonclinical Experience with GDC-0853 
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 (Segment II) studies in rats and rabbits.  Overall, 
GDC-0853 was well tolerated for 6 months in rats (up to 104 μM • h) and 9 months in 
dogs (up to 37 36 μM • h).  To date, the nNotable findings identified in nonclinical 
toxicology studies include effects to the male reproductive organs (≥ 37 μM • h) in dog 
and rats, vascular inflammation (≥ 56 μM • h) in dogs, and hepatotoxicity (180 μM • h) in 
dogs and rats, and a minimal increase in corrected QT interval (QTc; 7 ms or 3%; 
extrapolated unbound maximum observed concentration [Cmax] of 3.17 μM) in dogs.  
The projected mean exposure for the highest dose in this clinical study, GA29530, is 
anticipated to not exceed 10 μM • h area under the concentration time curve from time 
0 to 24 hours (AUC0-24) and 0.150 μM unbound Cmax, which is below the corresponding 
exposures at which the above adverse effects occurred in dogs, the most sensitive 
species.  Fetal malformations and ossification site changes in rats (≥ 190 μM • h) and 
fetal malformations in rabbits (≥ 10.6 μM • h) warrant the continued use of highly effective 
contraception in clinical trials.  Additionally, pancreatic findings have been observed in 
rats administered GDC 0853 (and other BTK inhibitors) and are considered to be a 
species specific effect (see the GDC 0863 Investigator’s Brochure).  On the basis of the 


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4/Protocol GA30067, Version 2 
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, GA30067.   
SECTION 1.2.3:  Clinical Experience with GDC-0853 
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 (U.S.) and Europe for use in patients with mantle cell 
lymphoma, chronic lymphocytic leukemia (CLL), and Waldenstrom’s macroglobulinemia. 
SECTION 1.3:  STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
In non clinical studies with GDC 0853, the no observed adverse effect levels (NOAELs) 
determined in the repeat dose, 6 month Wistar Han rat (20 mg/kg; 104 μM • h) and 
4 week dog (3 mg/kg; 10 μM • h) studies support multiple dose exposures in healthy 
subjects and RA patients up to 10 μM • h.  The 9 month dog study recovery phase is 
ongoing, and the final report is expected in May 2016.  The no-observed-adverse-effect 
levels (NOAELs) determined in the repeat-dose, 6-month Wistar Han rat (20 mg/kg; 
104 μM • h) and 9-month dog (10 mg/kg; 36 μM • h) studies support multiple-dose 
exposures in patients with RA at the proposed clinical doses,
 The primary toxicities identified in animals include the 
following (see Section 5.1 and the GDC-0853 Investigator’s Brochure for details): 
• 
Effects on lymphocytes and immunoglobulins in rats and dogs were reversible and 
considered to be related to pharmacological activity involving BTK inhibition.  
In  rats, after 4 weeks of dosing, elevated circulating total lymphocyte counts were 
observed at ≥ 20 mg/kg/day (≥ 104 μM • h).  In dogs, after 4 months of dosing, 
decreased circulating total lymphocytes were observed at ≥ 10 mg/kg/day 
(≥ 36 μM • h).  Peripheral blood immunophenotyping showed decreased circulating 
B-cell counts in male rats at 20 mg/kg/day and in dogs at ≥ 1 mg/kg/day 
(≥ 2.1 μM • h); there were no GDC-0853−related effects on total T, helper T, or 
cytotoxic T cells.  Ig isotyping in high-dose dogs (36 μM • h) and rats (104 μM • h) 
showed decreased IgG concentration; mid- and high-dose rats (≥ 17 μM • h) also 
had decreased IgM.  Histopathology in rats and dogs showed a decrease in the 
number of lymphocytes in follicular germinal centers in the spleen, mesenteric and 
mandibular lymph nodes, and/or Peyer's patches. 
• 
Hepatotoxicity in dogs, consisting of increases in ALT, AST, alkaline phosphatase 
(ALP), gamma-glutamyl transpeptidase, and/or total bilirubin levels correlated with 
microscopic findings of minimal hepatocyte degeneration/disorganization, Kupffer 
cell hypertrophy/hyperplasia and pigment, and perivascular mixed cell infiltrates.  
Serum chemistry and histopathology findings were observed in the 4-week toxicity 
study at ≥ 56 μM • h and 180 μM • h, respectively (considered monitorable with liver 
function tests; details below).  No adverse liver findings were observed in the 
chronic toxicity studies in rats (≤ 104 μM•h) and dogs (≤ 36 μM•h). 
• 
Effects to the male reproductive organs in rats (observed at 1438 μM • h) and dogs 
(findings in one animal observed at 37 μM • h) included seminiferous tubule 


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5/Protocol GA30067, Version 2 
degeneration/atrophy and associated hypospermia in the epididymis.  These 
findings did not reverse in the 1 month recovery period in rats.  A more robust 
evaluation of reversibility is ongoing in the recovery phase of the 9 month dog study 
as well as in a male rat Segment I study.  Thus, the informed consent will include 
male reproductive risks and a mandatory male specific informed consent. 
• 
Pancreatic findings observed in rats administered GDC-0853 (and other BTK 
inhibitors) are considered to be an on target, species-specific effect supported by a 
number of investigative studies and the lack of associated findings in humans with 
X linked agammaglobulinemia (XLA; (see the GDC-0853 Investigator’s Brochure for 
details).   
 
Infections 
GDC-0853 is a targeted immunomodulator; however, as a reversible inhibitor, 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, patients will be excluded initially from 
Study GA29350 if they have a history of hospitalization due to an infection in the 
8 weeks before screening for Study GA29350, evidence of active or latent or 
inadequately treated infection with mycobacterium tuberculosis (TB), any known 
immunodeficiency, including IgG < 500 mg/dL, or if they have experienced a serious 
infection or an infection requiring treatment with an IV antimicrobial agent during 
participation in Study GA29350.  Total Ig, IgG, IgM, IgA, and IgE concentrations will 
also be measured regularly throughout both studies. Patients should be carefully 
monitored throughout both the blinded Study GA29350 and the open-label Study 
GA30067 for infections.  GDC-0853 will be discontinued in any patient who develops a 
serious infection or any infection requiring treatment with an IV antimicrobial agent.  In 
addition, any serious infection, any infection requiring IV antimicrobials (i.e., Grade 3 
infection), or any opportunistic infection is considered an adverse event of special 
interest with expedited reporting requirements to the Sponsor. 
Hepatotoxicity  
Evidence of hepatobiliary injury was observed in animals administered relatively high 
doses of GDC-0853 in repeat-dose toxicity studies.…  
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 before screening will be excluded 
initially from participation in Study GA29350 (and therefore from Study GA30067), 
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 considered 
adverse events of special interest with expedited reporting requirements to the Sponsor.   


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6/Protocol GA30067, Version 2 
Pancreatic Effects: No significant changes in amylase, lipase, or serum glucose levels 
have been observed in patients with cancer or after single dose and multi dose 
administration in healthy subjects.  However, as a precautionary safety monitoring 
measure, amylase, lipase, and serum glucose levels will be monitored in patients during 
the study.   
Vasculitis 
The risk to human safety based on toxicological findings of vascular inflammation in 
animal studies is uncertain.  As a safety risk-mitigation measure, patients with a history 
of vasculitis, including RA associated vasculitis, will be excluded initially from 
Study GA29350 (and therefore from Study GA30067 and complete blood counts (CBCs), 
creatinine levels, and urinalysis findings will be monitored in all patients during both 
studies:  Studies GA29350 and GA30067.  Study drug should be discontinued in any 
patient who develops an adverse event of vasculitis, and the patient should enter the 
safety follow-up period. 
SECTION 3.1:  DESCRIPTION OF THE STUDY 
At Week 12, if there has not been at least a 20% improvement in the swollen joint count 
(SJC) and tender joint count (TJC) relative to the patient’s baseline joint counts in the 
blinded Study GA29350, then therapy should be escalated or substituted per the 
investigator’s judgment.  Such changes may include an increase in the dose of MTX, 
addition of other DMARDs (e.g., hydroxychloroquine or sulfasalazine), substitution of 
MTX with leflunomide, and/or an increase in the dose of corticosteroids (see Section 5.1).  
The investigator may adjust the therapy (e.g., escalate or reduce) on the basis of his or 
her overall clinical assessment of the patient.  However, certain medications, including 
but not limited to azathioprine, mycophenolate, biologics, Janus kinase (JAK) inhibitors, 
and calcineurin inhibitors, are prohibited throughout the OLE Study (see Section 4.3.2).  
Adjustment of MTX, other DMARDs, or corticosteroids for safety reasons is allowed 
throughout the trial (see Section 4.3.1.1).   
Since patients enrolling in this study may be receiving GDC-0853 for the first time, all 
patients will be monitored closely with more frequent visits at the beginning of this OLE 
study (i.e., more frequent visits up to Week 12 with a visit frequency similar to 
Study GA29350 and then every 3 months, thereafter).  Patients will have safety and 
clinical efficacy assessments at Weeks 0, 2, 4, 8, 12, 24, 36, and 52 (see Figure 1). 
SECTION 3.1.1:  Internal Monitoring Committee 
Periodic safety reviews for this OLE will also be performed by the Sponsor’s IMC as 
outlined in the IMC Charter.  If necessary, cumulative unblinded data for patients remaining in 
the parent study may also be made available to IMC members.…  
SECTION 3.3.5.1:  Efficacy Measurements 
Efficacy based on SJC and TJC will be assessed at Weeks 12 and 24, and improvement 
will be calculated using formulas provided in Appendix 9.  If a 20% improvement in 


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7/Protocol GA30067, Version 2 
SJC and TJC (relative to baseline values in the blinded Study GA29350) is not 
observed by Week 12, concomitant therapy will be escalated (e.g., adjusting the dose 
of corticosteroids, MTX, or both as well as the possible addition or substitution of other 
DMARDs; see Section 4.3.1.1.3).  If a 20% improvement in SJC and TJC (relative to 
baseline values in the blinded Study GA29350) is not observed by Week 24, the patient 
will be discontinued from this study because of lack of efficacy.  Confirmation of efficacy 
at these prescribed intervals will help to ensure that patients are not kept on an 
ineffective treatment for a prolonged period of time.   
SECTION 4.1.1:  Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Completion of treatment period through Day 84 as specified in Study GA29350, 
including completion of the Day 84 study visit assessments 
• 
If receiving oral corticosteroids (≤ 10 mg/day prednisone or equivalent) and/or 
NSAIDs (up to the maximum recommended dose), doses have remained stable for 
the duration (i.e., since the first administration of study drug) of Study GA29350.  If 
a change in dose was needed during Study GA29350, discuss with the Medical 
Monitor.  
• 
For men:  Agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, and agreement to refrain from donating sperm, as 
defined below (also see Appendix 4) 
Men with female partners of childbearing potential (including those who have had 
a tubal ligation) 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. 
SECTION 4.2.1:  Formulation, Packaging, and Handling 
Tablets will be supplied in bottles, which will be appropriately labeled for this study.  
GDC-0853 tablets should be stored at or below between 2°C and 8°C. 
SECTION 4.2.2.1:  GDC-0853 Dose and Administration 
The GDC-0853 dose regimen is oral 200 mg BID.  Patients will receive GDC-0853 
approximately every 12 hours for 52 weeks.  Patients should be directed to take one 
dose (a total of 4 tablets) BID (total of 8 tablets each day).  On clinic visit days during 
the first 12 weeks of the study, patients should be instructed that the a.m. dose of 
GDC-0853 will be administered in the clinic, except for Day 1, since the last dose of 
GDC-0853 for Study GA29350 is the a.m. dose on Day 84 for all patients.  For patients 
continuing into the OLE Study GA30067, the first open-label dose of GDC-0853 should 
be the p.m. dose (may be taken at home) on Day 84 (which is Day 1 of Study GA30067).  
After Week 12, GDC-0853 administration in the clinic is not required.   


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8/Protocol GA30067, Version 2 
Guidelines for dose reduction and treatment interruption or discontinuation are 
provided in Section 5.1. 
GDC-0853 may be orally administered with or without food.  The dates and times of the 
most recent prior meal, last dose of GDC-0853 (prior to clinic visit), and timing of 
GDC-0853 administration in clinic should be recorded at each clinic visit.  In addition, 
any use of PPIs, H2-receptor antagonists (H2RAs), and/or other antacids (e.g., Maalox®, 
Pepto-Bismol®, Rolaids®) should be recorded as concomitant medications, including time 
and date of last administration.  Administration of GDC-0853 should be staggered with 
antacid use (i.e., GDC-0853 should be taken 2 hours before or 2 hours after the antacid). 
At study visits, sufficient GDC-0853 tablets will be dispensed to complete dosing until the 
next scheduled visit.  When GDC-0853 is administered at the site, it will be administered 
under supervision of study personnel, and the amount of GDC-0853 dispensed must be 
recorded.  Patients will be instructed to return used and unused bottles of GDC 0853 at 
each clinic visit where GDC 0853 is administered in order to calculate the number of 
tablets and compliance.   
SECTION 4.2.2.2:  GDC-0853 Compliance 
The following measure will be taken to assess patient compliance with study drug:  
patients will be directed to bring any used and unused bottles to each visit.   
Sites will be responsible for prepopulating the dates on the dosing label (that should be 
affixed to the bottle) 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 on the affixed label.  (Refer to Appendix 10 for the bottle and label 
configuration.)  The number of tablets issued minus the number of tablets returned will 
be used to calculate the number of tablets taken and compliance.   
Guidelines for dosage reduction and treatment interruption or discontinuation are 
provided in Section 5.1. 
SECTION 4.3.1.1.3:  Other DMARDs 
Treatment with certain medications, including but not limited to azathioprine, 
mycophenolate, calcineurin inhibitors, biologic agents (e.g., anti-TNF, anti-IL-6 or 
anti-IL6 receptor, anti-IL-1, T-cell costimulation modulator agents, anti-CD20), and JAK 
inhibitors (e.g., tofacitinib), is prohibited throughout this study (see Section 4.3.2). 
SECTION 4.3.1.3:  Acid-Reducing Agents 
At visits with scheduled PK assessments (see Appendix 1), any use of PPIs, H2RAs, 
and/or other antacids (e.g., Maalox®, Pepto-Bismol®, Rolaids®) should be recorded as 
concomitant medications, including the date and time of last administration. 


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9/Protocol GA30067, Version 2 
SECTION 4.4.1:  Informed Consent Forms and Screening Log 
Written informed consent for participation in this study must be obtained before 
performing any study-related procedures.  Male patients will be required to sign the 
“Mandatory Consent for Males Participating in the Study” Informed Consent Form.   
All screening evaluations must be completed and reviewed to confirm that pPatients 
must meet all eligibility criteria before the receiving their first open-label dose in this study.  
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. 
SECTION 4.4.3:  Physical Examinations 
A complete physical examination should be performed at Day 1 (which is Day 84 of 
Study GA29350) and should include an evaluation of the head, eyes, ears, nose, and 
throat and the cardiovascular, dermatological, musculoskeletal, respiratory, GI, 
genitourinary, and neurological systems.  Any abnormality identified at baseline should 
be recorded on the General Medical History and Baseline Conditions eCRF. 
SECTION 4.4.5:  Efficacy Assessments 
The sequence of assessments where efficacy is assessed (see Appendix 1 for Schedule 
of Assessments) will be standardized as follows: 
• 
Administration of GDC-0853 in clinic (only at the indicated visits, per Appendix 1) 
• 
Post dose vital signs, post dose PK samples (only at the indicated visits, per 
Appendix 1), adverse events 
 
SECTION 4.4.5.1.1:  Swollen and Tender Joint Count (66/68) 
…A joint assessment training module will may be used as a tool to facilitate consistency 
in performing the joint counts.  
SECTION 4.4.5.1.2:  Tender/Painful Joint Count (68) 
Sixty-eight (68) joints will be assessed by a joint assessor (not blinded), and it is 
recommended that this assessor be the same as from the blinded Study GA29350 (for 
consistency), to determine the number of joints that are considered tender or painful.  
The response to pressure/motion on each joint will be assessed using the following 
scale:  Present/Absent/Not Done/Not Applicable (to be used for artificial joints). 
SECTION 4.4.6:  Patient-Reported and Clinician-Reported Outcomes 
Patients and clinicians will use an electronic device to capture PRO data, and clinicians 
will use a paper-based ClinRO for data collection.… 
SECTION 4.4.7:  Laboratory, Biomarker, and Other Biological Samples 
Samples for the following laboratory tests will be sent to one or several central 
laboratories for analysis: 
• 
Quantitative immunoglobulins:  Total Ig, IgA, IgG, IgM, IgE 
 


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Unless the patient gives specific consent for the leftover samples to be stored for 
optional exploratory research (see Sections 4.4.9 and 4.4.10), biological samples will be 
destroyed when the final clinical study report has been completed, with the following 
exception: 
SECTION 4.4.8:  Electrocardiograms 
When triplicate ECGs are indicated, three interpretable ECG recordings (e.g., without 
artifacts) must be obtained.  The average of the three readings will be used to determine 
ECG intervals (e.g., PR, QRS, and QT, QTc, and RR) and heart rate from these three ECGs 
(or single ECG, if indicated) will be entered into the eCRF; in addition, these triplicate readings 
will be stored for future analysis, if needed.  
SECTION 5.1.1:  Safety Plan for Potential Risks Associated with GDC-0853 
SECTION 5.1.1.1:  Infections 
Effects on lymphocytes and immunoglobulins in rats and dogs were reversible and 
considered to be related to pharmacological activity involving BTK inhibition.  See 
Section 1.2.2 for related primary nonclinical toxicity findings and the GDC-0853 
Investigator’s Brochure for further details. 
To date, no immune-challenge experiments (e.g., T-dependent antigen response test) 
have been conducted in animals.  It is not known whether these effects on B cells and 
IgG concentrations in animals will translate to humans or whether such changes would 
have functional or deleterious impact on immune function. 
Total Ig, IgG, IgM, IgA, and IgE 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 Centers for Disease Control and Prevention 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, 
systemic viral infections, and episodes of suspicious or febrile diarrhea, should be 
evaluated using serology or PCR if available and cultured if feasible and any identified 
organisms noted in the eCRF.  Any serious infection, infection requiring IV antimicrobials 
(i.e., any Grade 3 infection) or any opportunistic infection is considered as an adverse 
event of special interest and should be reported to the Sponsor in an expedited manner 
as outlined in Section 5.2.3.  
SECTION 5.1.1.3:  Bleeding 
Bleeding was not No decrease in platelets, changes in coagulation parameters, or 
bleeding events were observed in nonclinical studies with GDC-0853.… 




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May 2016; see the GDC 0853 Investigator’s Brochure for further details).  The risk to 
human safety based on toxicological findings of vascular inflammation in animal studies 
is uncertain.  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 2011).  
SECTION 5.1.1.9:  Malignancy 
Discussion of malignancy was moved to later in Section 5.1.1 (previously 
Section 5.1.1.6).  No change has been made to the text of this Malignancy section. 
SECTION 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, of which at least 35% is direct bilirubin) 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).… 
SECTION 5.4.1:  Emergency Medical Contacts 
Medical Monitor Contact Information  
 Medical Monitor contact information: 
Medical Monitors: 
 Medical Monitor (Primary) 
 
, M.D. 
, M.D. 
 
Argentina:  
 
 
Rest of World:  
 
 
United States:  
 
 
Alternate Medical Monitor contact information for all sites: 
Medical Monitor: 
, M.D. 
Telephone Nos.: 
 
Emergency Telephone Nos. 
 
 
 
 
SECTION 7.4:  SOURCE DATA DOCUMENTATION 
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, patient-reported outcomes, 
ClinROs, 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. 


GDC-0853—Genentech, Inc. 
13/Protocol GA30067, Version 2 
FIGURE 1:  Study Schema 
Figure 1 has been revised to reflect the changes in the protocol. 
TABLE  1:  OBJECTIVES AND ENDPOINTS 
Secondary Efficacy Objective: 
• To assess ACR/EULAR remission according to the Boolean-based remission, defined 
asdefinition (tender joint count ≤ 1, swollen joint count ≤ 1, CRP ≤ 1, and patient global 
assessment ≤ 1) 
• To assess SDAI-based remission (defined as ≤ 3.3 for ACR/EULAR remission) and 
CDAI-based remission 
 
Corresponding Endpoint(s) for Exploratory Pharmacokinetic Objectives: 
• Presence of genetic polymorphisms and/or genotype(s) 
 
TABLE  3:  Guidelines for Management of GDC-0853 in Patients Who 
Experience Specific Adverse Events 
Table 3 has been revised to reflect changes in the protocol. 
APPENDIX 1:  Schedule of Assessments 
The schedule of assessments has been revised to reflect the changes to the protocol. 
APPENDIX 9:  Joint Count Improvement Formula 
Appendix 9 has been added to the protocol. 
APPENDIX 10:  Bottle and Label Configuration for GDC-0853 Administration 
Appendix 10 has been added to the protocol. 
SAMPLE INFORMED CONSENT FORM 
The sample Informed Consent Form has been revised to reflect the changes to the 
protocol. 


GDC-0853—Genentech, Inc. 
14/Protocol GA30067, Version 2 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 21 
PROTOCOL SYNOPSIS .................................................................................... 22 
1. 
BACKGROUND .......................................................................................... 32 
1.1 
Background on Rheumatoid Arthritis ..................................... 32 
1.2 
Background on Bruton’s Tyrosine Kinase and 
GDC-0853 ............................................................................. 32 
1.2.1 
Bruton’s Tyrosine Kinase....................................................... 32 
1.2.2 
Nonclinical Experience with GDC-0853................................. 33 
1.2.3 
Clinical Experience with GDC-0853....................................... 34 
1.3 
Study Rationale and Benefit-Risk Assessment...................... 35 
2. 
OBJECTIVES AND ENDPOINTS ............................................................... 40 
3. 
STUDY DESIGN ......................................................................................... 42 
3.1 
Description of the Study......................................................... 42 
3.1.1 
Internal Monitoring Committee............................................... 44 
3.2 
End of Study and Length of Study......................................... 44 
3.2.1 
Length of Study ..................................................................... 44 
3.2.2 
End of Study.......................................................................... 45 
3.3 
Rationale for Study Design.................................................... 45 
3.3.1 
Rationale for GDC-0853 Dose and Schedule........................ 45 
3.3.2 
Rationale for Open-Label Design .......................................... 46 
3.3.3 
Rationale for Biomarker Assessments................................... 47 
3.3.4 
Rationale for PK Sample Collection Schedule....................... 47 
3.3.5 
Rationale for Other Study Design Elements .......................... 47 
3.3.5.1 
Efficacy Measurements ......................................................... 47 
3.3.5.2 
Clinical Outcomes Assessments ........................................... 48 
3.3.5.3 
Concomitant Medications ...................................................... 48 
4. 
MATERIALS AND METHODS .................................................................... 48 
4.1 
Patients.................................................................................. 48 
4.1.1 
Inclusion Criteria.................................................................... 48 
4.1.2 
Exclusion Criteria................................................................... 49 


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4.2 
Study Treatment.................................................................... 51 
4.2.1 
Formulation, Packaging, and Handling.................................. 51 
4.2.2 
Dosage, Administration, and Compliance.............................. 51 
4.2.2.1 
GDC-0853 Dose and Administration ..................................... 51 
4.2.2.2 
GDC-0853 Compliance.......................................................... 52 
4.2.3 
Investigational Medicinal Product Accountability ................... 52 
4.2.4 
Post-Trial Access to GDC-0853............................................. 52 
4.3 
Concomitant Therapy, Prohibited Food, and 
Additional Restrictions ........................................................... 53 
4.3.1 
Permitted Therapy ................................................................. 53 
4.3.1.1 
Use of Treatments for Rheumatoid Arthritis........................... 53 
4.3.1.2 
Dietary Supplements ............................................................. 55 
4.3.1.3 
Acid-Reducing Agents ........................................................... 55 
4.3.2 
Prohibited Therapy ................................................................ 56 
4.3.2.1 
Live or Attenuated Vaccinations ............................................ 57 
4.3.2.2 
CYP3A Inhibition ................................................................... 57 
4.3.3 
Prohibited Food ..................................................................... 58 
4.4 
Study Assessments ............................................................... 58 
4.4.1 
Informed Consent Forms and Screening Log........................ 59 
4.4.2 
Medical History and Demographic Data ................................ 59 
4.4.3 
Physical Examinations........................................................... 59 
4.4.4 
Vital Signs.............................................................................. 59 
4.4.5 
Efficacy Assessments............................................................ 60 
4.4.5.1 
ACR Assessments................................................................. 60 
4.4.5.2 
DAS Assessments................................................................. 62 
4.4.6 
Patient-Reported and Clinician-Reported 
Outcomes .............................................................................. 62 
4.4.6.1 
Patient’s Assessment of Arthritis Pain ................................... 63 
4.4.6.2 
Patient’s Global Assessment of Arthritis................................ 63 
4.4.6.3 
Physician’s Global Assessment of Arthritis............................ 63 
4.4.6.4 
Health Assessment Questionnaire⎯Disability 
Index...................................................................................... 64 
4.4.6.5 
Short-Form 36 Health Survey Questionnaire, 
Version 2 ............................................................................... 64 


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4.4.6.6 
Functional Assessment of Chronic Illness 
Therapy-Fatigue Scale .......................................................... 64 
4.4.7 
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 64 
4.4.8 
Electrocardiograms................................................................ 66 
4.4.9 
Optional Samples for Whole-Genome 
Sequencing............................................................................ 67 
4.4.10 
Samples for Roche Clinical Repository.................................. 68 
4.4.10.1 
Overview of the Roche Clinical Repository............................ 68 
4.4.10.2 
Sample Collection.................................................................. 69 
4.4.10.3 
Confidentiality........................................................................ 69 
4.4.10.4 
Consent to Participate in the Roche Clinical 
Repository ............................................................................. 70 
4.4.10.5 
Withdrawal from the Roche Clinical Repository..................... 70 
4.4.10.6 
Monitoring and Oversight....................................................... 70 
4.4.11 
Assessments at Unscheduled Visits...................................... 71 
4.5 
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 71 
4.5.1 
Patient Discontinuation.......................................................... 71 
4.5.2 
Study Treatment Discontinuation........................................... 71 
4.5.3 
Study and Site Discontinuation.............................................. 72 
5. 
ASSESSMENT OF SAFETY....................................................................... 72 
5.1 
Safety Plan ............................................................................ 72 
5.1.1 
Safety Plan for Potential Risks Associated with 
GDC-0853 ............................................................................. 73 
5.1.1.1 
Infections ............................................................................... 73 
5.1.1.2 
Vaccinations .......................................................................... 74 
5.1.1.3 
Bleeding................................................................................. 75 
5.1.1.4 
Cytopenias............................................................................. 76 
5.1.1.5 
Gastrointestinal Effects.......................................................... 76 
5.1.1.6 
Hepatotoxicity........................................................................ 77 
5.1.1.7 
Cardiovascular Effects........................................................... 77 
5.1.1.8 
Vascular Inflammation ........................................................... 78 
5.1.1.9 
Malignancy ............................................................................ 79 


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17/Protocol GA30067, Version 2 
5.1.2 
Management of GDC-0853 in Patients Who 
Experience Specific Adverse Events ..................................... 79 
5.2 
Safety Parameters and Definitions ........................................ 83 
5.2.1 
Adverse Events ..................................................................... 83 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 83 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 84 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 85 
5.3.1 
Adverse Event Reporting Period ........................................... 85 
5.3.2 
Eliciting Adverse Event Information ....................................... 85 
5.3.3 
Assessment of Severity of Adverse Events ........................... 85 
5.3.4 
Assessment of Causality of Adverse Events ......................... 86 
5.3.5 
Procedures for Recording Adverse Events............................ 87 
5.3.5.1 
Diagnosis versus Signs and Symptoms................................. 87 
5.3.5.2 
Adverse Events that are Secondary to Other 
Events.................................................................................... 88 
5.3.5.3 
Persistent or Recurrent Adverse Events................................ 88 
5.3.5.4 
Abnormal Laboratory Values ................................................. 88 
5.3.5.5 
Abnormal Vital Sign Values ................................................... 89 
5.3.5.6 
Abnormal Liver Function Tests.............................................. 90 
5.3.5.7 
Deaths ................................................................................... 90 
5.3.5.8 
Preexisting Medical Conditions.............................................. 90 
5.3.5.9 
Lack of Efficacy or Worsening of Rheumatoid 
Arthritis .................................................................................. 91 
5.3.5.10 
Hospitalization or Prolonged Hospitalization.......................... 91 
5.3.5.11 
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 91 
5.3.5.12 
Patient-Reported Outcome Data ........................................... 92 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 92 
5.4.1 
Emergency Medical Contacts................................................ 92 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 93 
5.4.2.1 
Events that Occur prior to Study Drug Initiation..................... 93 


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18/Protocol GA30067, Version 2 
5.4.2.2 
Events that Occur after Study Drug Initiation......................... 93 
5.4.3 
Reporting Requirements for Pregnancies.............................. 93 
5.4.3.1 
Pregnancies in Female Patients............................................ 93 
5.4.3.2 
Pregnancies in Female Partners of Male Patients................. 94 
5.4.3.3 
Congenital Anomalies/Birth Defects and 
Abortions ............................................................................... 94 
5.5 
Follow-Up of Patients after Adverse Events .......................... 94 
5.5.1 
Investigator Follow-Up........................................................... 94 
5.5.2 
Sponsor Follow-Up ................................................................ 95 
5.6 
Post-Study Adverse Events................................................... 95 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 95 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 96 
6.1 
Determination of Sample Size ............................................... 96 
6.2 
Summaries of Conduct of Study............................................ 96 
6.3 
Summaries of Demographic and Baseline 
Characteristics....................................................................... 96 
6.4 
Safety Analyses..................................................................... 96 
6.5 
Efficacy Analyses .................................................................. 96 
6.6 
Pharmacokinetic Analyses..................................................... 97 
6.7 
Biomarker Analyses............................................................... 97 
6.8 
Interim Analysis ..................................................................... 97 
7. 
DATA COLLECTION AND MANAGEMENT ............................................... 97 
7.1 
Data Quality Assurance......................................................... 97 
7.2 
Electronic Case Report Forms............................................... 98 
7.3 
Electronic Patient Reported Outcome ................................... 98 
7.4 
Source Data Documentation.................................................. 98 
7.5 
Use of Computerized Systems .............................................. 99 
7.6 
Retention of Records............................................................. 99 
8. 
ETHICAL CONSIDERATIONS.................................................................. 100 
8.1 
Compliance with Laws and Regulations .............................. 100 
8.2 
Informed Consent ................................................................ 100 


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19/Protocol GA30067, Version 2 
8.3 
Institutional Review Board or Ethics Committee.................. 101 
8.4 
Confidentiality...................................................................... 101 
8.5 
Financial Disclosure ............................................................ 102 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 102 
9.1 
Study Documentation .......................................................... 102 
9.2 
Protocol Deviations.............................................................. 102 
9.3 
Site Inspections ................................................................... 102 
9.4 
Administrative Structure....................................................... 102 
9.5 
Publication of Data and Protection of Trade 
Secrets ................................................................................ 103 
9.6 
Protocol Amendments ......................................................... 103 
10. REFERENCES ......................................................................................... 105 
 
LIST OF TABLES 
Table 1 
Primary (Safety), Efficacy, Pharmacokinetic, and Exploratory 
Objectives with Corresponding Endpoints .................................. 40 
Table 2 
Proposed Biomarkers for Exploratory Research......................... 66 
Table 3 
Guidelines for Management of GDC-0853 in Patients Who 
Experience Specific Adverse Events .......................................... 80 
Table 4 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 86 
Table 5 
Causal Attribution Guidance ....................................................... 87 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema............................................................................. 44 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments......................................................... 109 
Appendix 2 
Appropriate Equivalent Morphine Doses of Opioid 
Analgesics Common Opioid Analgesics ................................... 114 
Appendix 3 
Concomitant Medications (Including Foods and Herbal 
Products)................................................................................... 115 
Appendix 4 
Childbearing Potential, Pregnancy Testing, and 
Contraception............................................................................ 117 


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20/Protocol GA30067, Version 2 
Appendix 5 
Health Assessment Questionnaire⎯Disability Index 
(HAQ-DI)................................................................................... 119 
Appendix 6 
The Short-Form 36 Version 2 Health Survey (SF-36v2) ........... 122 
Appendix 7 
Functional Assessment of Chronic Illness Therapy Fatigue 
(FACIT-Fatigue) Scale .............................................................. 129 
Appendix 8 
Disease Activity Score 28 ......................................................... 130 
Appendix 9 
Joint Count Improvement Formula............................................ 131 
Appendix 10 Bottle and Label Configuration for GDC-0853 Administration... 132 


 
GDC-0853—Genentech, Inc. 
21/Protocol GA30067, Version 2 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE II OPEN-LABEL EXTENSION STUDY OF 
PATIENTS PREVIOUSLY ENROLLED IN 
STUDY GA29350 TO EVALUATE THE LONG-TERM 
SAFETY AND EFFICACY OF GDC-0853 IN PATIENTS 
WITH MODERATE TO SEVERE RHEUMATOID 
ARTHRITIS 
PROTOCOL NUMBER: GA30067 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
2016-000498-19 
IND NUMBER: 
120,162 
TEST PRODUCT: 
GDC-0853 (RO7010939) 
MEDICAL MONITOR: 
, M.D. 
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. 
22/Protocol GA30067, Version 2 
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE II OPEN-LABEL EXTENSION STUDY OF PATIENTS 
PREVIOUSLY ENROLLED IN STUDY GA29350 TO EVALUATE 
THE LONG-TERM SAFETY AND EFFICACY OF GDC-0853 IN 
PATIENTS WITH MODERATE TO SEVERE RHEUMATOID 
ARTHRITIS 
PROTOCOL NUMBER: 
GA30067 
VERSION NUMBER: 
2 
EUDRACT NUMBER: 
2016-000498-19 
IND NUMBER: 
120,162 
TEST PRODUCT: 
GDC-0853 (RO7010939) 
PHASE: 
Phase II 
INDICATION: 
Rheumatoid Arthritis 
SPONSOR: 
Genentech, Inc. 
 
Objectives and Endpoints 
This open-label extension (OLE) study will evaluate the long-term safety and efficacy of 
GDC-0853 in patients with rheumatoid arthritis (RA).  Specific objectives and corresponding 
endpoints and analyses for the study are outlined below. 
Objectives 
Corresponding Endpoint(s) 
Primary Objective (Safety) 
• To evaluate the long-term safety of 
GDC-0853 over an extended treatment 
period of up to 52 weeks 
• The nature, frequency, severity, and timing of 
adverse events 
• Changes in vital signs, physical findings, ECGs, 
and clinical laboratory results during and 
following GDC-0853 administration 
Primary Efficacy Objective 
• To evaluate the efficacy of GDC-0853 
(analyzed separately for MTX-IR and 
TNF-IR patients) at Week 52 relative to 
baseline in Study GA29350 
• ACR50 response at Week 52 
Secondary Efficacy Objective 
• To determine the improvement in disease 
activity through 52 weeks of treatment 
(analyzed separately for MTX-IR and 
TNF-IR patients) relative to baseline in 
Study GA29350 
• ACR50 response up to Week 12  
• ACR20, ACR70, DAS 28-3 (CRP), DAS 28-4 
(CRP), DAS 28-3 (ESR), and DAS 28-4 (ESR) 
response up to Week 52 
• To assess DAS28 remission (< 2.6) and 
LDA (< 3.2) state  
• States up to Week 52 


 
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23/Protocol GA30067, Version 2 
Objectives 
Corresponding Endpoint(s) 
• To assess ACR/EULAR remission 
according to the Boolean-based 
definition (tender joint count ≤ 1, swollen 
joint count ≤ 1, CRP ≤ 1, and patient global 
assessment ≤ 1) 
• Remission status up to Week 52 
• To assess SDAI-based remission (defined 
as ≤ 3.3 for ACR/EULAR remission) and 
CDAI-based remission 
• Remission status up to Week 52 
• To assess efficacy based on the individual 
components of the ACR relative to 
baseline in Study GA29350 
Response status up to Week 52 for:  
• 
Tender/Painful Joint Count (68) 
• 
Swollen Joint Count (66) 
• 
Patient’s Assessment of Arthritis Pain 
• 
Patient’s Global Assessment of Arthritis 
• 
Physician’s Global Assessment of Arthritis 
• 
CRP 
• 
HAQ-DI 
• To evaluate the effect of GDC-0853 on 
health-related quality of life  
• SF-36, standard, Version 2, questionnaire 
through 52 weeks 
• To evaluate the effect of GDC-0853 on 
fatigue 
• FACIT-Fatigue Scale up to Week 52 
Pharmacokinetic Objectives 
• To characterize the pharmacokinetics of 
GDC-0853 in patients using a population 
PK approach 
• Steady-state PK parameters (AUC0-t, Ctrough, t1/2, 
apparent CL/F)  
Exploratory Pharmacokinetic Objectives: 
• To evaluate the relationship between 
measures of drug exposure and PD 
effect(s), efficacy, and safety of GDC-0853
• Exploratory biomarker measures  
• ACR50, DAS28, and other measures of efficacy 
or clinical activity 
• The nature, frequency, severity, and timing of 
adverse events 
• Changes in vital signs, physical findings, ECGs, 
and clinical laboratory results following 
GDC-0853 administration 
• To evaluate the impact of selected 
baseline covariates on measures of 
GDC-0853 exposure and/or response 
• Steady-state PK parameters (AUC0-t, Ctrough, t1/2, 
apparent CL/F) 
• ACR50, DAS28, and other measures of efficacy 
or clinical activity 
• To evaluate the impact of genetic 
polymorphisms of on measures of 
GDC-0853 exposure 
• Steady-state PK parameters (AUC0-t, Ctrough, t1/2, 
apparent CL/F)  


 
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Objectives 
Corresponding Endpoint(s) 
Exploratory Biomarker Objectives 
• To evaluate the effect of GDC-0853 on 
biomarkers to aid in defining the MOA 
• To evaluate the relationship between 
changes in biomarkers and efficacy 
• To evaluate whether biomarkers, 
measured at baseline, identify a subset of 
patients with enhanced clinical benefit to 
GDC-0853. 
• Lymphoid, myeloid, and other potential 
inflammatory biomarkers (e.g., including but not 
limited to CXCL13 and sICAM) 
• ACR50, DAS28, and other measures of efficacy 
ACR = American College of Rheumatology; AUC0-t = area under the concentration time-curve from 
time 0 to time t; Ctrough = minimum observed plasma concentration; Cmax = maximum observed 
plasma concentration; CDAI = Clinical Disease Activity Index; CL/F = clearance following oral 
dosing; CRP = C-reactive protein; DAS = Disease Activity Score; ESR = erythrocyte sedimentation 
rate; EULAR = European League Against Rheumatism; FACIT = Functional Assessment of 
Chronic Illness Therapy; HAQ-DI = Health Assessment Questionnaire⎯Disability Index; 
IR = inadequate responder; LDA = low disease activity; MOA = mechanism of action; 
MTX = methotrexate; PD = pharmacodynamic; PK = pharmacokinetic; t1/2 = half-life; tmax = time to 
maximum concentration; TNF = tumor necrosis factor. 
 
Study Design 
Description of Study 
This is a Phase II, multicenter, OLE study to evaluate the long-term safety and efficacy of 
GDC-0853 in patients with RA who have completed 12 weeks of study treatment in 
Study GA29350.  The population for this study consists of patients with RA who have had an 
inadequate response to previous MTX therapy (Cohort 1 of Study GA29350) or previous TNF 
and MTX therapy (Cohort 2 of Study GA29350).   
This OLE study will be conducted in centers that have participated in the double-blind, Phase II 
Study GA29350.  The maximum number of patients potentially enrolling in this study will be 
approximately 580 patients.  Patients will be assigned the same patient number they had in 
Study GA29350. 
Eligible patients from Study GA29350 who elect to participate will receive treatment with 
GDC-0853 at 200 mg BID in an open-label fashion for 52 weeks, followed by a safety follow-up 
period of 8 weeks.  Dose reductions of GDC-0853 to 200 mg once daily are allowed for specific 
safety reasons and may be allowed on the basis of clinical safety concerns of the investigator, 
only after discussion with the Medical Monitor.  Eligible patients will be enrolled directly into 
Study GA30067 following treatment completion at Week 12 of Study GA29350 (e.g., they will 
not undergo the 8 weeks of safety follow-up in Study GA29350).  The dose and route of 
administration of methotrexate (MTX) at the end of the blinded Study GA29350 should be 
continued and held stable for the first 12 weeks of the OLE study.  Discontinuation of MTX or 
alteration of the MTX dose prior to Week 12 is discouraged.  Use of additional 
disease-modifying anti-rheumatic drugs (DMARDs) other than MTX is discouraged prior to 
Week 12.   
At Week 12, if there has not been at least a 20% improvement in the swollen joint count (SJC) 
and tender joint count (TJC) relative to the patient’s baseline joint counts in the blinded Study 
GA29350, then therapy should be escalated or substituted per the investigator’s judgment.  Such 
changes may include an increase in the dose of MTX, addition of other DMARDs (e.g., 
hydroxychloroquine or sulfasalazine), substitution of MTX with leflunomide, and/or an increase 
in the dose of corticosteroids.  The investigator may adjust the therapy (e.g., escalate or reduce) 
on the basis of his or her overall clinical assessment of the patient.  However, certain 
medications, including but not limited to mycophenolate, biologics, Janus kinase (JAK) inhibitors, 
and calcineurin inhibitors, are prohibited throughout the OLE Study.  Adjustment of MTX, other 
DMARDs, or corticosteroids for safety reasons is allowed throughout the trial.   


 
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At Week 24 in Study GA30067, if there has not been at least a 20% improvement in the SJC 
and TJC relative to the patient’s baseline joint counts in the blinded Study GA29350, the patient 
should be discontinued from this study due to lack of efficacy of GDC-0853.  See the protocol 
for adverse event reporting in the event of an unanticipated worsening of SJC and TJC. 
Patients who are receiving concomitant MTX will also receive a stable dose of folic acid given 
as either a single dose or divided into daily doses to achieve at least 5 mg of folic acid per week. 
Stable oral corticosteroids (i.e., ≤ 10 mg/day prednisone equivalent) are allowed at entry into the 
study.  Maintaining a stable dose of oral corticosteroids between the time of entry up to 
Week 12 is encouraged.  However, at any time during the study, patients who have worsening 
RA may receive concomitant therapy with oral or intra-articular corticosteroids at the discretion 
of the investigator.  Starting at Week 12, doses of corticosteroid, MTX, or both may be modified 
(e.g., increased or tapered) based on the investigator’s clinical assessment of the patient.  It is 
strongly encouraged that the corticosteroid dose not exceed 10 mg/day of prednisone or 
equivalent.  Adjustment for safety reasons is allowed throughout the trial. 
Since patients enrolling in this study may be receiving GDC-0853 for the first time, all patients 
will be monitored closely with more frequent visits at the beginning of this OLE study (i.e., more 
frequent visits up to Week 12 and then every 3 months, thereafter).  Patients will have safety and 
clinical efficacy assessments at Weeks 0, 4, 8, 12, 24, 36, and 52. 
Following completion of the 52-week treatment period, there will be an 8-week safety follow-up 
visit.  
Throughout this OLE study, patients will be monitored for safety by recording adverse events, 
ECGs, and clinical laboratory evaluations.  Efficacy and safety data will be collected at least 
every 4 weeks for the first 3 months and then approximately every 12 weeks thereafter until the 
safety follow-up visit.  Safety monitoring will also be performed routinely by the Internal 
Monitoring Committee. 
Number of Subjects 
The maximum number of patients potentially enrolling in this study will be approximately 
580 patients.   
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Age 18 to 76 years 
• 
Able and willing to provide written informed consent and to comply with the requirements of 
the protocol 
• 
Completion of treatment period through Day 84 as specified in Study GA29350 
• 
Acceptable safety and tolerability during Study GA29350 as determined by the investigator 
or Medical Monitor 
• 
Have not received any prohibited medications in Study GA29350   
• 
While taking MTX, must be willing to receive oral folic acid (at least 5 mg/week)  
• 
If receiving oral corticosteroids (≤ 10 mg/day prednisone or equivalent) and/or NSAIDs (up 
to the maximum recommended dose), doses have remained stable for the duration (i.e., 
since the first administration of study drug) of Study GA29350.  If a change in dose was 
needed during Study GA29350, discuss with the Medical Monitor.  
• 
Women of childbearing potential must test negative for pregnancy prior to enrollment  
• 
For women of childbearing potential (including those who have had a tubal ligation):  
Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive 
methods that result in a failure rate of < 1% per year during the treatment period and for at 
least 60 days after the last dose of study drug  
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). 


 
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Examples of contraceptive methods with a failure rate of < 1% per year include bilateral 
tubal ligation, male sterilization, established proper use of hormonal contraceptives 
that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices.  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 (including those who have had a tubal 
ligation) 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. 
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 fetus. 
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: 
• 
Met protocol defined treatment stopping criteria during Study GA29350 
• 
Treatment with any investigational agent (i.e., other than study drug) or live/attenuated 
vaccine during Study GA29350 or since the last administration of study drug in 
Study GA29350 
• 
Treatment with any of the following prohibited medications during Study GA29350 or since 
the last administration of study drug in Study GA29350: 
TNF inhibitors (except adalimumab for patients from Cohort 1), anti-IL-6 or anti-IL-6 
receptor antagonists, anti-CD20, abatacept, anakinra, all biosimilar agents 
JAK inhibitors 
Azathioprine, chlorambucil, cyclophosphamide, cyclosporine, gold, immunosorbent 
column, mycophenolate mofetil, mycophenolic acid sodium, penicillamine, sirolimus, 
tacrolimus 
Oral anticoagulants (including but not limited to warfarin, dabigatran, rivoxaban, 
apixaban), anti-platelet agents (e.g., clopidogrel; note:  non-steroidal 
anti-inflammatory drugs and aspirin of 162 mg/day or less are acceptable), heparin, 
low-molecular-weight heparin 
• 
In the opinion of the investigator, any new (since initially enrolling in the Phase II 
Study GA29350), significant, uncontrolled comorbidity, such as neurological, cardiac 
(e.g., moderate to severe heart failure New York Heart Association Class III/IV), pulmonary, 
renal, hepatic, endocrine, or GI disorders (excluding RA) that would increase the risk to the 
patient in Study GA30067 
• 
Pregnant or lactating or intending to become pregnant during the study 
• 
Any uncontrolled or clinically significant laboratory abnormality that would affect safety, 
interpretation of study data, or the patient’s participation in the study in the opinion of the 
investigator 
• 
Patients who experienced a de novo or reactivated serious viral infection such as 
hepatitis B virus, hepatitis C virus, or HIV during the Phase II Study GA29350 


 
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• 
Any major episode of infection requiring hospitalization or treatment with IV antibiotics 
during the Phase II Study GA29350 
• 
Patients who developed a malignancy (with the exception of non-serious local and 
resectable basal or squamous cell carcinoma of the skin) during the Phase II 
Study GA29350 
• 
12-lead ECG on Day 84 in Study GA29350 that demonstrates clinically relevant 
abnormalities that may affect patient safety or interpretation of study results, including  
QT interval corrected using Fridericia’s formula (QTcF) > 440 msec demonstrated by at 
least two ECGs > 30 minutes apart 
• 
Current treatment with medications that are well known to prolong the QT interval 
• 
Laboratory values from the Day 56 visit of Study GA29350 (which may be repeated once at 
an unscheduled visit, if necessary) that meet the following criteria: 
Creatinine > 1.5 × ULN 
ALT or AST > 1.5 × ULN 
Total bilirubin > ULN  
Hemoglobin < 8.5 g/dL 
ANC < 1.5 × 109/L 
Platelet count < 100 × 109/L  
 
End of Study 
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs or the 
date at which the last data point required for statistical analysis or safety follow-up is received 
from the last patient, whichever occurs later.  LPLV is expected to occur approximately 
60 weeks after the last patient is enrolled. 
Length of Study 
The maximum time in the study for a patient is 60 weeks, including treatment for 52 weeks and 
an 8-week safety follow-up period after the last dose of GDC-0853. 
Investigational Medicinal Product 
The investigational medicinal product (IMP) for this study is GDC-0853. 
The GDC-0853 dose regimen is oral 200 mg BID.  Patients will receive GDC-0853 
approximately every 12 hours for 52 weeks.  Patients should be directed to take one dose (a 
total of 4 tablets) BID (total of 8 tablets each day).  On clinic visit days during the first 12 weeks 
of the study, patients should be instructed that the a.m. dose of GDC-0853 will be administered 
in the clinic, except for Day 1, since the last dose of GDC-0853 for Study GA29350 is the a.m. 
dose on Day 84 for all patients.  For patients continuing into the OLE Study GA30067, the 
first open-label dose of GDC-0853 should be the p.m. dose (may be taken at home) on Day 84 
(which is Day 1 of Study GA30067).  After Week 12, GDC-0853 administration in the clinic is 
not required.   
Non-Investigational Medicinal Products 
From the beginning of the study until Week 12, patients should continue to receive the same 
dose of MTX that they were receiving at the end of Study GA29350, which should be between 
15 and 25 mg/week (doses as low as 7.5 mg/week are allowed only in the case of documented 
MTX intolerance).  Dose reductions for MTX or a change of route of administration are allowed 
prior to Week 12 only for safety reasons. 
After Week 12, patients may change (i.e., increase, decrease, or discontinue) their dose of MTX 
and/or add other permitted DMARDs as clinically indicated and tolerated by the patient, 
according to the investigator’s judgment. 
To prevent adverse events associated with MTX, patients are required to take folic acid or 
equivalent (e.g., 1 mg/day) at a stable dose of at least 5 mg/week (or equivalent) while they are 
receiving MTX.  This can be administered as either a single weekly dose or a daily dose per the 
discretion of the investigator. 


 
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Starting at Week 12, concomitant DMARDs in addition to MTX that may be used during the 
study include hydroxychloroquine, chloroquine, sulfasalazine, and leflunomide, as clinically 
indicated and tolerated by the patient, according to the investigator’s judgment.   
Statistical Methods 
Primary Analysis 
Patient efficacy data will be summarized separated by treatment cohorts during the blinded 
study (GA29350).  Efficacy summary will be based on the intent-to-treat population, defined as 
all eligible patients enrolled into this OLE study.  Analyses of additional study populations (e.g., 
completers, and per protocol [excluding major protocol violators]) will be performed as 
supportive evaluations.  Additional subgroup analyses may be conducted on an exploratory 
basis.  Details will be provided in the Data Analysis Plan. 
Determination of Sample Size 
No formal sample size calculations were performed for this OLE study.  The maximum number 
of patients eligible for enrollment is approximately 580 (i.e., all patients enrolled in 
Study GA29350). 
Interim Analysis 
No formal interim analysis is planned.  Data cuts may be performed at appropriate time points 
for inclusion in the submission with the main studies to support the safety profile. 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ACR 
American College of Rheumatology 
ALP 
alkaline phosphatase 
AUC 
area under the concentration time-curve  
AUC0-24 
area under the concentration time-curve from time 0 to 24 hours 
AUC0-t 
area under the concentration time-curve from time 0 to time t 
BCR 
B cell−antigen receptor 
BID 
twice daily 
BTK 
Bruton’s tyrosine kinase 
Cmax 
maximum observed plasma concentration 
CBC 
complete blood count 
CDAI 
Clinical Disease Activity Index 
CIA 
collagen-induced arthritis 
ClinRO 
clinician-reported outcome 
CLL 
chronic lymphocytic leukemia 
CRP 
C-reactive protein 
DAS 
Disease Activity Score 
DIP 
distal interphalangeal 
DLAE 
dose-limiting adverse event 
DMARD 
disease-modifying anti-rheumatic drug 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ESR 
erythrocyte sedimentation rate 
FACIT 
Functional Assessment of Chronic Illness Therapy 
FACS 
fluorescence activated cell sorting 
FDA 
U.S. Food and Drug Administration 
GI 
gastrointestinal 
H2RA 
H2 receptor antagonist 
HAQ-DI 
Health Assessment Questionnaire – Disability Index 
HIPAA 
U.S. Health Insurance Portability and Accountability Act 
 
 
 
 
ICH 
International Conference on Harmonisation 
IL 
Interleukin 
IMC 
Internal Monitoring Committee 


 
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Abbreviation 
Definition 
IMP 
investigational medicinal product 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
intravenous 
JAK 
Janus kinase 
LMWH 
low molecular weight heparin 
LPLV 
last patient, last visit 
MAD 
multiple-ascending dose 
MCP 
metacarpophalangeal 
MOA 
mechanism of action 
MTP 
metatarsophalangeal 
MTX 
methotrexate 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
NOAEL 
no-observed-adverse-effect level 
NSAID 
non-steroidal anti-inflammatory drug 
OLE 
open-label extension 
PBMC 
peripheral blood mononuclear cell 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PIP 
proximal interphalangeal 
PO 
orally 
PPI 
proton pump inhibitor 
PRN 
as needed 
PRO 
patient-reported outcome 
QD 
once daily 
QTcF 
QT interval corrected using Fridericia’s formula 
RA 
rheumatoid arthritis 
RCR 
Roche Clinical Repository 
SAD 
single-ascending dose 
SDAI 
Simplified Disease Activity Index 
SF-36 
Short-Form 36 Health Survey 
SJC 
swollen joint count 
TB 
tuberculosis 
TJC 
tender joint count 
TLR 
toll-like receptor 
TNF 
tumor necrosis factor 


 
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Abbreviation 
Definition 
ULN 
upper limit of normal 
VAS 
Visual Analog Scale 
WGS 
whole-genome sequencing 
XLA 
X-linked agammaglobulinemia 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON RHEUMATOID ARTHRITIS  
Rheumatoid arthritis (RA) is an autoimmune disorder characterized by progressive 
synovitis, systemic inflammation, and the production of characteristic autoantibodies 
(e.g., rheumatoid factor, anti-citrullinated peptide antibodies) that can lead to progressive 
damage to the joints, arthropathy, and impaired joint-dependent movement leading to 
significant reduction in quality of life, unemployment, and premature death 
(Lundkvist et al. 2008).  Current hypotheses on the pathogenesis of RA have focused on 
autoantibody production, immune complex formation in the synovium, pro-inflammatory 
cytokine production (especially interleukin [IL]-6 and tumor necrosis factor−alpha 
[TNF-α]), and the role of B cells and myeloid cells in inflamed synovium 
(Martin and Chan 2004; Looney 2006; Shlomchik 2008; Goronzy and Weyand 2009; 
Scott et al. 2010).  B cell−depletion therapy has provided evidence of the important role 
of B cells in the pathogenesis of RA and other inflammatory diseases 
(Eisenberg and Albert 2006; Hauser et al. 2008).  Although there are many medications 
available for the pharmacotherapy of RA, there remains an unmet need for safer therapy 
with improved efficacy, especially in the signs and symptoms of disease leading to full 
remission (Kjeken et al. 2006; Montag et al. 2011). 
Targeted B-cell treatments have become a focus of development as immunomodulators 
in autoimmune disorders and for B-cell neoplasms (Swanson et al. 2009; 
Robak and Robak 2012; Puri et al. 2013; Vargas et al. 2013).  One novel class of 
these immunomodulatory agents is inhibitors of Bruton’s tyrosine kinase (BTK) 
(Kelly and Genovese 2013; Tan et al. 2013).  BTK is a member of the TEC family of 
non-receptor or cytoplasmic tyrosine kinases, with expression restricted largely to the 
hematopoietic system (Rawlings and Witte 1995).  BTK is a key kinase in signaling 
cascades following B cell−antigen receptor (BCR) activation in B cells, in Fc receptor 
binding of immune complexes in myeloid cells and some toll-like receptor (TLR) signaling 
events in B cells, myeloid cells, and dendritic cells (Satterthwaite and Witte 2000; 
Brunner et al. 2005; Sochorová et al. 2007).  Autoimmune disorders marked by 
prominent B-cell and immune complex-mediated activities, such as RA and systemic 
lupus erythematous, may benefit from targeted antagonism of BTK signaling. 
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, mutations in the gene for 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 


 
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immunoglobulin levels due to a defect in B-cell differentiation at the pro- to pre-B cell 
stage that precludes assembly of the BCR complex and immunoglobulin 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.  Patients with XLA 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 essential for the differentiation and activity of B cells during immune system 
ontology and normal adaptive immune responses.  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 PLCγ2- 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, 
such as RA.  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 for further details). 
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 TNF-α, IL-1, and IL-6) by preventing signaling through the 
FCγRIII 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-α, which contributes to disease pathogenesis in RA.  In 
dendritic cells, BTK contributes to TLR8-mediated cytokine production (TNF-α and IL-6) 
(Sochorová et al. 2007).  In basophils, BTK-dependent activation of the FcεR leads to 
activation and up-regulation of CD63.   
The efficacy of GDC-0853 on inflammatory arthritis was investigated in female Lewis 
rats with developing Type II collagen-induced arthritis (CIA).  GDC-0853 treatment was 


 
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well tolerated and resulted in significant and dose-dependent beneficial effects.  
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.   
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 (Segment II) studies in rats and rabbits.  Overall, 
GDC-0853 was well tolerated for 6 months in rats (up to 104 μM • h) and 9 months in 
dogs (up to 36 μM • h).  Notable findings identified in nonclinical toxicology studies 
include vascular inflammation (≥ 56 μM • h) in dogs, hepatotoxicity (180 μM • h) in dogs 
and rats, and a minimal increase in corrected QT interval (QTc; 7 ms or 3%; 
extrapolated unbound maximum observed concentration [Cmax] of 3.17 μM) in dogs.  
Fetal malformations and ossification site changes in rats (≥ 190 μM • h) and fetal 
malformations in rabbits (≥ 10.6 μM • h) warrant the continued use of highly effective 
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, GA30067.   
1.2.3 
Clinical Experience with GDC-0853 
Study GO29089 is a Phase I, open-label study in which GDC-0853 has been evaluated 
in patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma or CLL.  In this 
study, 24 patients received study drug at 100, 200, or 400 mg orally (PO) once per day 
and preliminary analysis shows anti-tumor activity at all dose levels of GD-0853 tested.  
Nine patients received 400 mg of GDC-0853 PO daily for over 12 months.  GDC-0853 
was well tolerated with no dose-limiting toxicities, and adverse events have been 
generally non-serious Grade 1 or Grade 2 events that have been clinically manageable.  
The adverse events regardless of causality reported in ≥ 15% of patients include fatigue, 
nausea, diarrhea, headache, abdominal pain, dizziness, cough, and thrombocytopenia.  
Nine serious adverse events have been reported in 5 patients, of whom 2 had a fatal 
outcome (i.e., complications of H1N1 influenza and influenza pneumonia).  Refer to the 
GDC-0853 Investigator’s Brochure for further information on Study GO29089, including 
long-term safety.   
Study GP29318 was a two-part, single-ascending dose (SAD) study to assess the safety, 
tolerability, and pharmacokinetics of GDC-0853 administered to 93 healthy subjects.  In 
Part 1, the single-dose escalation portion, 71 subjects were randomized to panels of 
8 subjects (6:2 active:placebo ratio) per dose group (0.5 to 600 mg) with 53 subjects 
receiving active GDC-0853.  In Part 2, 100 mg GDC-0853 was administered to 
40 subjects in the open-label food and pilot rabeprazole effect study.  There were no 


 
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serious adverse events and no withdrawals due to adverse events during the conduct of 
Study GP29318.  In Part 1 of the study, there were no dose-limiting adverse events 
(DLAEs) at single doses up to 600 mg GDC-0853.  All adverse events were mild in 
intensity (Grade 1; Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials) and transient.  No adverse events 
increased in intensity or frequency with dose escalation.  There were two 
treatment-emergent adverse events of mild self-limited headache reported as related to 
GDC-0853 administration.  There were no trends in safety laboratory findings, vital sign 
changes, physical examination findings, or ECG changes.  There were no trends in 
hepatic laboratory changes following single doses of GDC-0853 in healthy subjects.  
Refer to the GDC-0853 Investigator’s Brochure for further information on Study GP29318, 
including pharmacokinetics. 
Study GA29347 was a multiple-ascending dose (MAD) study to assess the safety, 
tolerability, and pharmacokinetics of multiple doses of GDC-0853 administered to 
30 healthy subjects for 14 days.  Subjects were randomized to panels of 8 subjects 
(6:2 active:placebo) per dose group, at doses of 20 mg twice daily (BID), 60 mg BID, 
150 mg BID, 250 mg BID, or 500 mg QD for 14 days.  The study drug was well tolerated.  
There were no serious adverse events and no withdrawals due to adverse events during 
the conduct of the study.  All adverse events were mild in intensity (Grade 1) and 
transient, with no relationship to dose.  Adverse events included skin reactions (i.e., 
rash, contact dermatitis, and skin irritation from ECG leads), nausea, headache, 
insomnia, toothache, tinnitus, and asymptomatic bacteriuria.  There were no trends in 
safety laboratory, vital sign, physical examination, or ECG findings.   
Study GP29832 is a Phase Ia, randomized, open-label study investigating the effect of 
food, rabeprazole, and formulation on the pharmacokinetics of GDC-0853.  GDC-0853 
was well tolerated when administered to 32 healthy subjects at the 200-mg dose level in 
Parts 1 and 2 of the study. 
Refer to the GDC-0853 Investigator’s Brochure for detailed background information on 
GDC-0853 as well as for additional details on nonclinical and clinical studies. 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
The results from the Phase I studies, nonclinical toxicology studies, and studies in 
nonclinical models of RA support further evaluation of GDC-0853 as a potential 
treatment for RA.  The goal of this Phase II, open-label extension (OLE) Study GA30067 
is to evaluate the long-term safety and efficacy of GDC-0853 in combination with 
methotrexate (MTX) and/or other disease-modifying anti-rheumatic drugs (DMARDs) in 
patients with active RA.  Participation in Study GA30067 is optional and is based on the 
patient’s preference, the investigator’s clinical judgment, and meeting the eligibility 
requirements for this protocol.  Eligible patients will have participated in Study GA29350, 
which comprises of 2 cohorts.  In Cohort 1, three doses of GDC-0853 will be compared 
with placebo and HUMIRA® (adalimumab) in patients with an inadequate response to 


 
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MTX).  In Cohort 2, one dose of GDC-0853 will be compared with placebo in patients 
with an inadequate response to TNF inhibitors).  Study GA30067 is designed with 
safeguards in place to optimize clinical efficacy and minimize safety risks.  Patients who 
do not derive clinical benefit from GDC-0853, based on at least a 20% improvement in 
both SJCs and TJCs, relative to baseline values in the blinded Study GA29350, should 
not continue in the study past Week 24 of Study GA30067.  In addition, safety in both 
the blinded Study GA29350 and the open-label Study GA30067 will be monitored at 
regular intervals by the Internal Monitoring Committee (IMC).  If there are any 
concerning safety issues that arise, either as specified in Section 5.1.2 or based on the 
investigator’s judgment and discussion with the Medical Monitor, dose reductions and 
dose interruptions will be allowed in Study GA30067.  The blinded Study GA29350 is 
designed with an interim analysis at approximately 150 patients (i.e., 30 patients per 
arm), at which point the IMC will evaluate the unblinded efficacy and safety.  If the 
benefit-risk assessment is not deemed to be favorable, based on safety concerns and/or 
suboptimal efficacy, then a futility decision will be triggered to minimize patients’ 
exposure to GDC-0853.  
Inhibition of BTK offers a promising mechanism for the treatment of autoimmune 
diseases such as RA and lupus (see Section 1.2); however, data from clinical studies 
are lacking.  Humans with a mutation in the XLA gene and who therefore lack functional 
BTK can live relatively normal lives on a standard therapy of IVIg (Kaveri et al. 2011), 
suggesting that BTK can be safely inhibited in patients with RA who have functional 
immune systems to explore this hypothesis.  Clinical experience with GDC-0853 to date 
has not generated safety concerns that would preclude further evaluation in patients with 
autoimmune diseases.  GDC-0853 has been administered to 179 subjects to date (i.e., 
155 healthy subjects and 24 patients with hematological malignancies) at doses from 
0.5 to 600 mg and has been well tolerated with no safety signals.  In the SAD 
(Study GP29318), MAD (Study GA29347), relative bioavailability (Study GP29832), and 
oncology (Study GO29089) studies, GDC-0853 was well tolerated with no DLAEs or 
dose-limiting toxicities.  In the oncology study, there were two deaths due to 
complications of confirmed influenza (i.e., H1N1 influenza and influenza pneumonia).   
The no-observed-adverse-effect levels (NOAELs) determined in the repeat-dose, 
6-month Wistar Han rat (20 mg/kg; 104 μM • h) and 9-month dog (10 mg/kg; 36 μM • h) 
studies support multiple-dose exposures in patients with RA at the proposed clinical 
doses, 
 
 The primary 
toxicities identified in animals include the following (see Section 5.1 and the GDC-0853 
Investigator’s Brochure for details): 
• 
Vascular inflammation in dogs, characterized by endothelial necrosis, proliferation 
and hypertrophy, vascular/perivascular lymphocyte and macrophage infiltrates, and 
occasional necrosis of the medial smooth-muscle cells, was observed in a 4-week 


 
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toxicity study at ≥ 56 μM • h but not in the ongoing 9-month chronic toxicity study at 
the terminal necropsy (≤ 37 μM • h).   
• 
Effects on lymphocytes and immunoglobulins in rats and dogs were reversible and 
considered to be related to pharmacological activity involving BTK inhibition.  
In  rats, after 4 weeks of dosing, elevated circulating total lymphocyte counts were 
observed at ≥ 20 mg/kg/day (≥ 104 μM • h).  In dogs, after 4 months of dosing, 
decreased circulating total lymphocytes were observed at ≥ 10 mg/kg/day 
(≥ 36 μM • h).  Peripheral blood immunophenotyping showed decreased circulating 
B-cell counts in male rats at 20 mg/kg/day and in dogs at ≥ 1 mg/kg/day 
(≥ 2.1 μM • h); there were no GDC-0853−related effects on total T, helper T, or 
cytotoxic T cells.  Ig isotyping in high-dose dogs (36 μM • h) and rats (104 μM • h) 
showed decreased IgG concentration; mid- and high-dose rats (≥ 17 μM • h) also 
had decreased IgM.  Histopathology in rats and dogs showed a decrease in the 
number of lymphocytes in follicular germinal centers in the spleen, mesenteric and 
mandibular lymph nodes, and/or Peyer's patches. 
• 
Hepatotoxicity in dogs, consisting of increases in ALT, AST, alkaline phosphatase 
(ALP), gamma-glutamyl transpeptidase, and/or total bilirubin levels correlated with 
microscopic findings of minimal hepatocyte degeneration/disorganization, Kupffer 
cell hypertrophy/hyperplasia and pigment, and perivascular mixed cell infiltrates.  
Serum chemistry and histopathology findings were observed in the 4-week toxicity 
study at ≥ 56 μM • h and 180 μM • h, respectively (considered monitorable with liver 
function tests; details below).  No adverse liver findings were observed in the 
chronic toxicity studies in rats (≤ 104 μM•h) and dogs (≤ 36 μM•h). 
• 
Fetal malformations were observed in rats (i.e., cleft palate observed at 627 μM • h) 
and rabbits (i.e., domed-shaped heads with enlarged lateral/third ventricles at 
≥ 10.6 μM • h).  Thus, highly effective contraception will be mandatory for trial 
participation, and pregnancy monitoring will be performed at least monthly during 
the study. 
• 
Pancreatic findings observed in rats administered GDC-0853 (and other BTK 
inhibitors) are considered to be a species-specific effect supported by a number of 
investigative studies (see the GDC-0853 Investigator’s Brochure for details).   
 
Several measures will be taken to ensure the safety of patients participating in this study 
on the basis of potential risks from nonclinical and clinical studies and published 
literature (see Section 5.1 for details).  Eligibility criteria in both the blinded and 
open-label studies have been designed to exclude patients at higher risk for potential 
toxicities.   
Infections 
GDC-0853 is a targeted immunomodulator; however, as a reversible inhibitor, 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, patients will be excluded initially from 
Study GA29350 if they have a history of hospitalization due to an infection in the 


 
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8 weeks before screening for Study GA29350, evidence of active or latent or 
inadequately treated infection with mycobacterium tuberculosis (TB), any known 
immunodeficiency, including IgG < 500 mg/dL, or if they have experienced a serious 
infection or an infection requiring treatment with an IV antimicrobial agent during 
participation in Study GA29350.  Total Ig, IgG, IgM, IgA, and IgE concentrations will 
also be measured regularly throughout both studies. Patients should be carefully 
monitored throughout both the blinded Study GA29350 and the open-label Study 
GA30067 for infections.  GDC-0853 will be discontinued in any patient who develops a 
serious infection or any infection requiring treatment with an IV antimicrobial agent.  In 
addition, any serious infection, any infection requiring IV antimicrobials (i.e., Grade 3 
infection), or any opportunistic infection is considered an adverse event of special 
interest with expedited reporting requirements to the Sponsor. 
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; clinically, there is no reported bleeding propensity of 
patients with XLA.  In the GDC-0853 clinical study involving oncology patients, 2 patients 
experienced Grade ≥ 3 gastrointestinal (GI) bleeding.  These events were not dose 
related and occurred in patients on non-steroidal anti-inflammatory drugs 
(NSAIDs)/acetylsalicylic acid with a history of gastroesophageal or peptic ulcer disease. 
It is unknown whether GDC-0853 will increase the risk of bleeding in patients with RA 
receiving antiplatelet or anticoagulant therapies.  Therefore, the eligibility criteria of the 
blinded Study GA29350 will exclude patients at high risk for bleeding complications, and 
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 adverse event of special interest 
with expedited reporting requirements to the Sponsor. 
Cytopenias 
Neutropenia, anemia, and thrombocytopenia have been observed in patients with 
hematologic malignancies who received GDC-0853.  Events have been monitorable and 
clinically manageable.  The eligibility criteria for this study exclude patients with 
cytopenias (see Section 4.1.2).  Cell counts will be monitored regularly throughout this 
study.  
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 toward elevations in laboratory evaluations.  For 


 
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inclusion in this study, AST and ALT levels should be no more than 1.5 times the upper 
limit of normal (ULN) and total bilirubin levels should be normal at screening.  Baseline 
and routine evaluations of AST/ALT and total bilirubin will be performed throughout the 
study.  Laboratory results of AST or ALT elevations of Grade ≥ 3 (> 5 × ULN) are 
considered adverse events of special interest with expedited reporting requirements to 
the Sponsor.  The criteria for stopping GDC-0853 in the event of elevated transaminases 
are presented in Table 3.  
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.  
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. 
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 before screening will be excluded 
initially from participation in Study GA29350 (and therefore from Study GA30067), 
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 considered 
adverse events of special interest with expedited reporting requirements to the Sponsor.   
Vasculitis 
The risk to human safety based on toxicological findings of vascular inflammation in 
animal studies is uncertain.  As a safety risk-mitigation measure, patients with a history 
of vasculitis, including RA associated vasculitis, will be excluded initially from 
Study GA29350 (and therefore from Study GA30067 and complete blood counts (CBCs), 
creatinine levels, and urinalysis findings will be monitored in all patients during both 
studies:  Studies GA29350 and GA30067.  Study drug should be discontinued in any 
patient who develops an adverse event of vasculitis, and the patient should enter the 
safety follow-up period. 
Overall, GDC-0853 has been well tolerated in Phase I healthy subjects and in patients 
with hematological malignancies.  On the basis of the compelling mechanism for BTK 
inhibition in RA, the risk-benefit ratio for this study is deemed acceptable.  The long-term 
safety profile of GDC-0853 will be further characterized in this open-label 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.   


 
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Please refer to the most recent GDC-0853 Investigator’s Brochure for additional details 
on clinical and nonclinical studies and additional safety information. 
2. 
OBJECTIVES AND ENDPOINTS 
This OLE study will evaluate the long-term safety and efficacy of GDC-0853 in patients 
with RA.  Specific objectives and corresponding endpoints and analyses for the study 
are outlined in Table 1. 
Table 1 
Primary (Safety), Efficacy, Pharmacokinetic, and Exploratory 
Objectives with Corresponding Endpoints  
Objectives 
Corresponding Endpoint(s) 
Primary Objective (Safety) 
• To evaluate the long-term safety of 
GDC-0853 over an extended treatment 
period of up to 52 weeks 
• The nature, frequency, severity, and timing of 
adverse events 
• Changes in vital signs, physical findings, ECGs, 
and clinical laboratory results during and 
following GDC-0853 administration 
Primary Efficacy Objective 
• To evaluate the efficacy of GDC-0853 
(analyzed separately for MTX-IR and 
TNF-IR patients) at Week 52 relative to 
baseline in Study GA29350 
• ACR50 response at Week 52 
Secondary Efficacy Objective 
• To determine the improvement in disease 
activity through 52 weeks of treatment 
(analyzed separately for MTX-IR and 
TNF-IR patients) relative to baseline in 
Study GA29350 
• ACR50 response up to Week 12  
• ACR20, ACR70, DAS 28-3 (CRP), DAS 28-4 
(CRP), DAS 28-3 (ESR), and DAS 28-4 (ESR) 
response up to Week 52 
• To assess DAS28 remission (< 2.6) and 
LDA (< 3.2) state  
• States up to Week 52 
• To assess ACR/EULAR remission 
according to the Boolean-based 
definition (tender joint count ≤ 1, swollen 
joint count ≤ 1, CRP ≤ 1, and patient global 
assessment ≤ 1) 
• Remission status up to Week 52 
• To assess SDAI-based remission (defined 
as ≤ 3.3 for ACR/EULAR remission) and 
CDAI-based remission 
• Remission status up to Week 52 
• To assess efficacy based on the individual 
components of the ACR relative to 
baseline in Study GA29350 
Response status up to Week 52 for:  
• 
Tender/Painful Joint Count (68) 
• 
Swollen Joint Count (66) 
• 
Patient’s Assessment of Arthritis Pain 
• 
Patient’s Global Assessment of Arthritis 
• 
Physician’s Global Assessment of Arthritis 
• 
CRP 
• 
HAQ-DI 


 
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Objectives 
Corresponding Endpoint(s) 
• To evaluate the effect of GDC-0853 on 
health-related quality of life  
• SF-36, standard, Version 2, questionnaire 
through 52 weeks 
• To evaluate the effect of GDC-0853 on 
fatigue 
• FACIT-Fatigue Scale up to Week 52 
Pharmacokinetic Objectives 
• To characterize the pharmacokinetics of 
GDC-0853 in patients using a population 
PK approach 
• Steady-state PK parameters (AUC0-t, Ctrough, t1/2, 
apparent CL/F)  
Exploratory Pharmacokinetic Objectives: 
• To evaluate the relationship between 
measures of drug exposure and PD 
effect(s), efficacy, and safety of GDC-0853
• Exploratory biomarker measures  
• ACR50, DAS28, and other measures of efficacy 
or clinical activity 
• The nature, frequency, severity, and timing of 
adverse events 
• Changes in vital signs, physical findings, ECGs, 
and clinical laboratory results following 
GDC-0853 administration 
• To evaluate the impact of selected 
baseline covariates on measures of 
GDC-0853 exposure and/or response 
• Steady-state PK parameters (AUC0-t, Ctrough, t1/2, 
apparent CL/F) 
• ACR50, DAS28, and other measures of efficacy 
or clinical activity 
• To evaluate the impact of genetic 
polymorphisms of on measures of 
GDC-0853 exposure 
• Steady-state PK parameters (AUC0-t, Ctrough, t1/2, 
apparent CL/F)  
Exploratory Biomarker Objectives 
• To evaluate the effect of GDC-0853 on 
biomarkers to aid in defining the MOA 
• To evaluate the relationship between 
changes in biomarkers and efficacy 
• To evaluate whether biomarkers, 
measured at baseline, identify a subset of 
patients with enhanced clinical benefit to 
GDC-0853. 
• Lymphoid, myeloid, and other potential 
inflammatory biomarkers (e.g., including but not 
limited to CXCL13 and sICAM) 
• ACR50, DAS28, and other measures of efficacy 
ACR = American College of Rheumatology; AUC0-t = area under the concentration time-curve from 
time 0 to time t; Ctrough = minimum observed plasma concentration; Cmax = maximum observed 
plasma concentration; CDAI = Clinical Disease Activity Index; CL/F = clearance following oral 
dosing; CRP = C-reactive protein; DAS = Disease Activity Score; ESR = erythrocyte sedimentation 
rate; EULAR = European League Against Rheumatism; FACIT = Functional Assessment of 
Chronic Illness Therapy; HAQ-DI = Health Assessment Questionnaire⎯Disability Index; 
IR = inadequate responder; LDA = low disease activity; MOA = mechanism of action; 
MTX = methotrexate; PD = pharmacodynamic; PK = pharmacokinetic; t1/2 = half-life; tmax = time to 
maximum concentration; TNF = tumor necrosis factor. 
 


 
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3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This is a Phase II, multicenter, OLE study to evaluate the long-term safety and efficacy 
of GDC-0853 in patients with RA who have completed 12 weeks of study treatment in 
Study GA29350.  The population for this study consists of patients with RA who have 
had an inadequate response to previous MTX therapy (Cohort 1 of Study GA29350) or 
previous TNF and MTX therapy (Cohort 2 of Study GA29350).   
This OLE study will be conducted in centers that have participated in the double-blind, 
Phase II Study GA29350.  The maximum number of patients potentially enrolling in this 
study will be approximately 580 patients.  Patients will be assigned the same patient 
number they had in Study GA29350. 
Eligible patients from Study GA29350 who elect to participate will receive treatment with 
GDC-0853 at 200 mg BID in an open-label fashion for 52 weeks, followed by a safety 
follow-up period of 8 weeks.  Dose reductions of GDC-0853 to 200 mg QD are allowed 
for specific safety reasons (see Section 5.1.2) and may be allowed on the basis of 
clinical safety concerns of the investigator, only after discussion with the Medical Monitor.  
Eligible patients will be enrolled directly into Study GA30067 following treatment 
completion at Week 12 of Study GA29350 (e.g., they will not undergo the 8 weeks of 
safety follow-up in Study GA29350).  The dose and route of administration of MTX at the 
end of the blinded Study GA29350 should be continued and held stable for the first 
12 weeks of the OLE study.  Discontinuation of MTX or alteration of the MTX dose prior 
to Week 12 is discouraged.  Use of additional DMARDs other than MTX is discouraged 
prior to Week 12.   
At Week 12, if there has not been at least a 20% improvement in the swollen joint count 
(SJC) and tender joint count (TJC) relative to the patient’s baseline joint counts in the 
blinded Study GA29350, then therapy should be escalated or substituted per the 
investigator’s judgment.  Such changes may include an increase in the dose of MTX, 
addition of other DMARDs (e.g., hydroxychloroquine or sulfasalazine), substitution of 
MTX with leflunomide, and/or an increase in the dose of corticosteroids (see Section 5.1).  
The investigator may adjust the therapy (e.g., escalate or reduce) on the basis of his or 
her overall clinical assessment of the patient.  However, certain medications, including 
but not limited to mycophenolate, biologics, Janus kinase (JAK) inhibitors, and 
calcineurin inhibitors, are prohibited throughout the OLE Study (see Section 4.3.2).  
Adjustment of MTX, other DMARDs, or corticosteroids for safety reasons is allowed 
throughout the trial (see Section 4.3.1.1).   
At Week 24 in Study GA30067, if there has not been at least a 20% improvement in the 
SJC and TJC relative to the patient’s baseline joint counts in the blinded Study GA29350, 
the patient should be discontinued from this study due to lack of efficacy of GDC-0853.  


 
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See Section 5.3.5.9 for adverse event reporting in the event of an unanticipated 
worsening of SJC and TJC. 
Patients who are receiving concomitant MTX will also receive a stable dose of folic acid 
given as either a single dose or divided into daily doses to achieve at least 5 mg of folic 
acid per week. 
Stable oral corticosteroids (i.e., ≤ 10 mg/day prednisone equivalent) are allowed at entry 
into the study.  Maintaining a stable dose of oral corticosteroids between the time of 
entry up to Week 12 is encouraged.  However, at any time during the study, patients 
who have worsening RA may receive concomitant therapy with oral or intra-articular 
corticosteroids (see Section 4.3.1.1) at the discretion of the investigator.  Starting at 
Week 12, doses of corticosteroid, MTX, or both may be modified (e.g., increased or 
tapered) based on the investigator’s clinical assessment of the patient.  It is strongly 
encouraged that the corticosteroid dose not exceed 10 mg/day of prednisone or 
equivalent.  Adjustment for safety reasons is allowed throughout the trial (see 
Section 4.3.1.1.4). 
Since patients enrolling in this study may be receiving GDC-0853 for the first time, all 
patients will be monitored closely with more frequent visits at the beginning of this OLE 
study (i.e., more frequent visits up to Week 12 and then every 3 months, thereafter).  
Patients will have safety and clinical efficacy assessments at Weeks 0, 4, 8, 12, 24, 36, 
and 52 (see Figure 1). 
Following completion of the 52-week treatment period, there will be an 8-week safety 
follow-up visit.  
Throughout this OLE study, patients will be monitored for safety by recording adverse 
events, ECGs, and clinical laboratory evaluations.  Efficacy and safety data will be 
collected at least every 4 weeks for the first 3 months and then approximately every 
12 weeks thereafter until the safety follow-up visit.  Safety monitoring will also be 
performed routinely by the IMC.  


 
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Figure 1 Study Schema 
 
 
BID = twice daily; IR = inadequate response; MTX = methotrexate; OLE = open-label extension; 
TNF = tumor necrosis factor. 
Eligible patients from the blinded study (GA29350) will be enrolled to receive GDC-0853 in this 
OLE study (GA30067).  This study consists of 2 parts:  A 52-week open-label treatment period 
and an 8-week safety follow-up period. 
At study visits during the OLE treatment period, the morning dose of oral GDC-0853 will be 
administered in the clinic on Weeks 0, 4, 8, and 12 after pre-dose study assessments. 
 
3.1.1 
Internal Monitoring Committee 
Periodic safety reviews for this OLE will also be performed by the Sponsor’s IMC as 
outlined in the IMC Charter.  If necessary, cumulative unblinded data for patients remaining in 
the parent study may also be made available to IMC members.  This committee will be 
unblinded to treatment assignments from the parent Study GA29350 and will include a 
clinical scientist, drug safety scientist, biostatistician, and statistical programmer from the 
Sponsor.  The IMC members will not have direct contact with investigational staff or site 
monitors.  The IMC may request that additional Sponsor scientists participate in the data 
analyses and review.   
3.2 
END OF STUDY AND LENGTH OF STUDY 
3.2.1 
Length of Study 
The maximum time in the study for a patient is 60 weeks, including treatment for 
52 weeks and an 8-week safety follow-up period after the last dose of GDC-0853.  


 
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3.2.2 
End of Study 
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs 
or the date at which the last data point required for statistical analysis or safety follow-up 
is received from the last patient, whichever occurs later.  LPLV is expected to occur 
approximately 60 weeks after the last patient is enrolled.  
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for GDC-0853 Dose and Schedule 
The GDC-0853 dose of 200 mg BID is the highest dose under evaluation in 
Study GA29350 and was selected in order to characterize its efficacy, safety, and 
tolerability profile in a larger patient population and for a longer treatment period.  
 
 
 
 
 
 
 
 
 
  This study will be discontinued if Study GA29350 is stopped at the interim 
analysis. 
In the event of a safety issue, dose reduction to 200 mg QD is permitted (see 
Section 5.1.2).  This dose was selected because it is expected to reflect what may be a 
physician-initiated dose reduction in a real-world clinical setting (i.e., changing the 
dosing interval from BID to QD).  
 
 
No safety or tolerability issues were identified in healthy subjects receiving GDC-0853 up 
to 600 mg in the single-dose Study GP29318 (SAD) and up to 250 mg BID and 500 mg 
QD for 14 days in the multiple-dose study GA29347 (MAD).  No maximum tolerated 
dose was identified, and there were no dose-limiting adverse events; all adverse events 
were Grade 1 (mild) and transient.  
Data from experiments evaluating the PD effects and anti-inflammatory activity of a tool 
BTK inhibitor compound (GDC-0834) in the rat model of CIA suggest that the amount of 
BTK inhibition anticipated in this study may be sufficient to achieve meaningful 
anti-inflammatory activity.  These studies suggest that 70% BTK inhibition, as measured 
by phospho-BTK inhibition, is required for half-maximal activity (Liu et al. 2011).  
However, it is not known whether BTK inhibition in the rat CIA model accurately predicts 
efficacy in human RA.  


 
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Dose levels in this study are anticipated to result in exposures below 10 μM • h (mean 
AUC0-24), which is the NOAEL from nonclinical toxicology studies.  The NOAEL 
(10 μM • h) was defined in the 4-week dog study by vasculitis at higher doses 
(≥ 56 μM • h).  In the ongoing 9-month dog study, no vasculitis was observed up to the 
highest dose tested (37 μM • h); however, 1 of 4 dogs at the highest dose had 
seminiferous tubule degeneration in the testis; a 4-month recovery phase is in progress.  
No testicular findings have been observed at lower doses (≤ 10 μM • h).  For further 
details, see the GDC-0853 Investigator’s Brochure. 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
• 
 
 
 
 
 
 
 
 
• 
 
 
3.3.2 
Rationale for Open-Label Design 
The primary objective of Study GA30067 is to understand the long-term safety of 
GDC-0853 over an extended treatment period of up to 52 weeks.  The open-label study 
design will allow all eligible patients originating from the blinded Study GA29350 to be 
treated with GDC-0853.  


 
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3.3.3 
Rationale for Biomarker Assessments  
Biomarker assessments, before and at various timepoints after treatment, will be used to 
advance the understanding of the mechanism of action (MOA) of GDC-0853 in patients 
with RA, define PK/PD relationships, and aid dose regimen selection for future studies.  
A biomarker that predicts response to GDC-0853 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.  
3.3.4 
Rationale for PK Sample Collection Schedule 
The PK sampling schedule consists of predose assessments at multiple visits, which will 
enable the estimation of GDC-0853 exposure as well as an evaluation of intrapatient 
variability over the 52-week dosing period.  In addition, these results will contribute to the 
understanding of the GDC-0853 exposure-response analysis, which will assist in 
characterizing how safety and efficacy are impacted by drug exposure. 
3.3.5 
Rationale for Other Study Design Elements 
3.3.5.1 
Efficacy Measurements 
The American College of Rheumatology (ACR) response criteria are commonly used in 
RA studies and accepted by health authorities to measure reduction in RA disease 
activity; ACR50 has been chosen as the primary efficacy endpoint because it measures 
a more robust response with a lower placebo response rate than ACR20, which has 
traditionally been used by most pivotal trials in RA.  In addition, several other clinically 
meaningful aspects of RA will be evaluated, including Disease Activity Score (DAS) 28 
remission and low disease activity, Boolean remission, Simplified Disease Activity Index 
(SDAI), Clinical Disease Activity Index (CDAI), and patient-reported outcome (PRO) 
measures (i.e., Health Assessment Questionnaire⎯Disability Index [HAQ-DI], 
Short-Form 36 Health Survey [SF-36] v2, and Functional Assessment of Chronic Illness 
Therapy [FACIT]-Fatigue Scale [see Appendix 5, Appendix 6, and Appendix 7, 
respectively]).  Each of these measures has been well established and validated in 
previous studies.  The kinetics of response to GDC-0853 will be carefully evaluated 
throughout the course of this study at regular intervals.   
Efficacy based on SJC and TJC will be assessed at Weeks 12 and 24, and improvement 
will be calculated using formulas provided in Appendix 9.  If a 20% improvement in 
SJC and TJC (relative to baseline values in the blinded Study GA29350) is not 
observed by Week 12, concomitant therapy will be escalated (e.g., adjusting the dose of 
corticosteroids, MTX, or both as well as the possible addition or substitution of other 
DMARDs; see Section 4.3.1.1.3).  If a 20% improvement in SJC and TJC (relative to 
baseline values in the blinded Study GA29350) is not observed by Week 24, the patient 
will be discontinued from this study because of lack of efficacy.  Confirmation of efficacy 
at these prescribed intervals will help to ensure that patients are not kept on an 
ineffective treatment for a prolonged period of time.   


 
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3.3.5.2 
Clinical Outcomes Assessments  
PRO and clinician-reported outcome (ClinRO) 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.  In cases where this is logistically 
challenging, potentially painful procedures will be performed at least 15 minutes prior to 
initiation of the PRO measures. 
3.3.5.3 
Concomitant Medications 
Patients in this study will be able to continue on their background MTX therapy, because 
this represents a common treatment paradigm for patients who initiate additional 
therapies following an inadequate response to MTX and/or TNF inhibitors.  Stability of 
MTX and other concomitant medications will be encouraged for the first 12 weeks of this 
study, in order to assess efficacy at Week 12, which represents a total of 24 weeks of 
treatment for a proportion of patients coming from the blinded Study GA29350.  In 
addition, there will be more flexibility in the dosing of specified concomitant DMARDs 
and corticosteroids after Week 12 to optimize patient care, which will also enable a 
better understanding of the long-term safety and efficacy of GDC-0853 in a real-world 
context.  
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Up to 580 patients from Study GA29350 will be enrolled in this study. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Age 18 to 76 years 
• 
Able and willing to provide written informed consent and to comply with the 
requirements of the protocol 
• 
Completion of treatment period through Day 84 as specified in Study GA29350 
• 
Acceptable safety and tolerability during Study GA29350 as determined by the 
investigator or Medical Monitor 
• 
Have not received any prohibited medications in Study GA29350   
• 
While taking MTX, must be willing to receive oral folic acid (at least 5 mg/week)  
• 
If receiving oral corticosteroids (≤ 10 mg/day prednisone or equivalent) and/or 
NSAIDs (up to the maximum recommended dose), doses have remained stable for 
the duration (i.e., since the first administration of study drug) of Study GA29350.  If 
a change in dose was needed during Study GA29350, discuss with the Medical 
Monitor.  
• 
Women of childbearing potential must test negative for pregnancy prior to 
enrollment  


 
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• 
For women of childbearing potential (including those who have had a tubal ligation):  
Agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive methods that result in a failure rate of < 1% per year during the 
treatment period and for at least 60 days after the last dose of study drug (see 
Appendix 4)  
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, established proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, 
and copper intrauterine devices.  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 (also see Appendix 4) 
Men with female partners of childbearing potential (including those who have had 
a tubal ligation) 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. 
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 fetus. 
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: 
• 
Met protocol-defined treatment-stopping criteria during Study GA29350 
• 
Treatment with any investigational agent (i.e., other than study drug) or 
live/attenuated vaccine during Study GA29350 or since the last administration of 
study drug in Study GA29350 


 
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• 
Treatment with any of the following prohibited medications during Study GA29350 or 
since the last administration of study drug in Study GA29350:  
TNF inhibitors (except adalimumab for patients from Cohort 1), anti-IL-6 or 
anti-IL-6 receptor antagonists, anti-CD20, abatacept, anakinra, all biosimilar 
agents 
JAK inhibitors 
Azathioprine, chlorambucil, cyclophosphamide, cyclosporine, gold, 
immunosorbent column, mycophenolate mofetil, mycophenolic acid sodium, 
penicillamine, sirolimus, tacrolimus 
Oral anticoagulants (including but not limited to warfarin, dabigatran, rivoxaban, 
apixaban), anti-platelet agents (e.g., clopidogrel; note:  NSAIDs and aspirin of 
162 mg/day or less are acceptable), heparin, low-molecular-weight heparin 
(LMWH) 
• 
In the opinion of the investigator, any new (since initially enrolling in the Phase II 
Study GA29350), significant, uncontrolled comorbidity, such as neurological, cardiac 
(e.g., moderate to severe heart failure New York Heart Association Class III/IV), 
pulmonary, renal, hepatic, endocrine, or GI disorders (excluding RA) that would 
increase the risk to the patient in Study GA30067 
• 
Pregnant or lactating or intending to become pregnant during the study 
• 
Any uncontrolled or clinically significant laboratory abnormality that would affect 
safety, interpretation of study data, or the patient’s participation in the study in the 
opinion of the investigator 
• 
Patients who experienced a de novo or reactivated serious viral infection such as 
hepatitis B virus, hepatitis C virus, or HIV during the Phase II Study GA29350 
• 
Any major episode of infection requiring hospitalization or treatment with IV 
antibiotics during the Phase II Study GA29350 
• 
Patients who developed a malignancy (with the exception of non-serious local and 
resectable basal or squamous cell carcinoma of the skin) during the Phase II 
Study GA29350 
• 
12-lead ECG on Day 84 in Study GA29350 that demonstrates clinically relevant 
abnormalities that may affect patient safety or interpretation of study results, 
including  
QT interval corrected using Fridericia’s formula (QTcF) > 440 msec 
demonstrated by at least two ECGs > 30 minutes apart 
• 
Current treatment with medications that are well known to prolong the QT interval 
• 
Laboratory values from the Day 56 visit of Study GA29350 (which may be repeated 
once at an unscheduled visit, if necessary) that meet the following criteria: 
Creatinine > 1.5 × ULN 
ALT or AST > 1.5 × ULN 
Total bilirubin > ULN  


 
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Hemoglobin < 8.5 g/dL 
ANC < 1.5 × 109/L 
Platelet count < 100 × 109/L  
 
4.2 
STUDY TREATMENT  
The investigational medicinal product (IMP) for this study is GDC-0853. 
4.2.1 
Formulation, Packaging, and Handling 
GDC-0853 will be provided by the Sponsor as 50-mg dose strength tablets.    
Tablets will be supplied in bottles, which will be appropriately labeled for this study.  
GDC-0853 tablets should be stored between 2°C and 8°C. 
For information on the formulation and handling of GDC-0853, see the GDC-0853 
Investigator’s Brochure and pharmacy manual. 
4.2.2 
Dosage, Administration, and Compliance 
4.2.2.1 
GDC-0853 Dose and Administration 
The GDC-0853 dose regimen is oral 200 mg BID.  Patients will receive GDC-0853 
approximately every 12 hours for 52 weeks.  Patients should be directed to take one 
dose (a total of 4 tablets) BID (total of 8 tablets each day).  On clinic visit days during the 
first 12 weeks of the study, patients should be instructed that the a.m. dose of 
GDC-0853 will be administered in the clinic, except for Day 1, since the last dose of 
GDC-0853 for Study GA29350 is the a.m. dose on Day 84 for all patients.  For patients 
continuing into the OLE Study GA30067, the first open-label dose of GDC-0853 should 
be the p.m. dose (may be taken at home) on Day 84 (which is Day 1 of Study GA30067).  
After Week 12, GDC-0853 administration in the clinic is not required.   
A dose reduction of GDC-0853 for specific safety events is permitted (see Table 3).  For 
a potential dose reduction for other adverse events not listed in the table, please consult 
the Medical Monitor.  If dose reduction is indicated, the dose of GDC-0853 may be 
reduced from 200 mg BID to 200 mg QD.  In this case, patients should be directed to 
take one dose (a total of 4 tablets) QD in the morning (total of 4 tablets each day). 
Guidelines for dose reduction and treatment interruption or discontinuation are 
provided in Section 5.1. 
GDC-0853 may be orally administered with or without food.  The dates and times of the 
most recent prior meal, last dose of GDC-0853 (prior to clinic visit), and timing of 
GDC-0853 administration in clinic should be recorded at each clinic visit.  In addition, 
any use of PPIs, H2-receptor antagonists (H2RAs), and/or other antacids (e.g., Maalox®, 
Pepto-Bismol®, Rolaids®) should be recorded as concomitant medications, including time 
and date of last administration.  Administration of GDC-0853 should be staggered with 
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At study visits, sufficient GDC-0853 tablets will be dispensed to complete dosing until the 
next scheduled visit.  When GDC-0853 is administered at the site, it will be administered 
under supervision of study personnel, and the amount of GDC-0853 dispensed must be 
recorded.   
4.2.2.2 
GDC-0853 Compliance 
The following measure will be taken to assess patient compliance with study drug:  
patients will be directed to bring any used and unused bottles to each visit.   
Sites will be responsible for prepopulating the dates on the dosing label (that should be 
affixed to the bottle) 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 on the affixed label.  (Refer to Appendix 10 for the bottle and label 
configuration.)  The number of tablets issued minus the number of tablets returned will 
be used to calculate the number of tablets taken and compliance.   
Compliance will be documented on the source record.   
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.  If compliance is ≤ 80%, the investigator or designee is to counsel 
the patient and ensure steps are taken to improve compliance.  
4.2.3 
Investigational Medicinal Product Accountability 
The IMP required for completion of this study (GDC-0853 tablet) will be provided by the 
Sponsor.  The study site will acknowledge receipt of the IMP using the Interactive 
Voice/Web Response System (IxRS) to confirm the shipment condition and content.  
Any damaged shipments will be replaced.  
The IMP will either be disposed of at the study site according to the study site’s 
institutional standard operating procedure or 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. 
4.2.4 
Post-Trial Access to GDC-0853  
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 Study GA30067.  The Sponsor may evaluate whether to continue 


 
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providing GDC-0853 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 
 
4.3 
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 the start of the OLE Study GA30067 (Day 1) until the study completion visit.  
A patient who is receiving an allowed concomitant medication for any reason must be on 
a locally approved medication and dose that is considered standard of care for the 
treated indication.  All concomitant medication taken during the study must be recorded 
with indication, daily dose, and start and stop dates of administration must be recorded 
on the appropriate pages of the eCRF.  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. 
If possible, it is recommended that patients avoid changing other prescription or 
non-prescription drugs, vitamins, and dietary supplements during the study. 
4.3.1 
Permitted Therapy  
4.3.1.1 
Use of Treatments for Rheumatoid Arthritis 
The investigator must use the procedures outlined below in making modifications to 
these medications and document all changes in the eCRF.  If necessary, unscheduled 
safety laboratory samples may be collected at the discretion of the investigator to 
monitor for toxicity from concomitant medications (e.g., DMARDs, NSAIDs, steroids). 
4.3.1.1.1 
Methotrexate 
From the beginning of the study until Week 12, patients should continue to receive the 
same dose of MTX that they were receiving at the end of Study GA29350, which should 
be between 15 and 25 mg/week (doses as low as 7.5 mg/week are allowed only in the 
case of documented MTX intolerance).  Dose reductions for MTX or a change of route of 
administration are allowed prior to Week 12 only for safety reasons.  If dose reduction of 
MTX is a result of intolerance, such intolerance must be recorded as an adverse event 
and the dose modification must be recorded in the eCRF.  
After Week 12, patients may change (i.e., increase, decrease, or discontinue) their dose 
of MTX and/or add other permitted DMARDs as clinically indicated and tolerated by the 
patient, according to the investigator’s judgment (see Section 4.3.1.1.3).  
4.3.1.1.2 
Folic Acid 
To prevent adverse events associated with MTX, patients are required to take folic acid 
or equivalent (e.g., 1 mg/day) at a stable dose of at least 5 mg/week (or equivalent) 


 
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while they are receiving MTX.  This can be administered as either a single weekly dose 
or a daily dose per the discretion of the investigator.  
4.3.1.1.3 
Other DMARDs 
At Week 12, if there has not been at least a 20% improvement in the SJC and TJC 
relative to the patient’s baseline joint counts in the blinded Study GA29350, then therapy 
should be escalated per the investigator’s judgment.  
Starting at Week 12, concomitant DMARDs in addition to MTX that may be used during 
the study include hydroxychloroquine, chloroquine, sulfasalazine, and leflunomide, as 
clinically indicated and tolerated by the patient, according to the investigator’s judgment.  
Allowable DMARDs can be used alone or in combination, except for the combination of 
MTX and leflunomide, which is not allowed.  Dose reductions or discontinuations of 
DMARDs may be performed at any time for safety or for clinical improvement, per the 
investigator’s judgment.  If a dose reduction is a result of intolerance, such intolerance 
must be recorded as an adverse event and the dose modification must be recorded in 
the eCRF.   
Treatment with certain medications, including but not limited to mycophenolate, 
calcineurin inhibitors, biologic agents (e.g., anti-TNF, anti-IL-6 or anti-IL6 receptor, 
anti-IL-1, T-cell costimulation modulator agents, anti-CD20), and JAK inhibitors (e.g., 
tofacitinib), is prohibited throughout this study (see Section 4.3.2). 
4.3.1.1.4 
Corticosteroids 
Oral corticosteroids (≤ 10 mg/day) will be permitted during this study.  If a patient was 
receiving background oral corticosteroids in Study GA29350, he or she should continue 
this same dose (≤ 10 mg/day prednisone or equivalent), which should remain stable for 
the first 12 weeks of the study.  Starting at Week 12, corticosteroid doses may be 
modified (e.g., increased, tapered) on the basis of the investigator’s clinical assessment 
of the patient.  It is strongly encouraged that the dose not exceed 10 mg/day of 
prednisone or equivalent.  Adjustment for safety reasons is allowed throughout the trial 
(see Section 4.3).  
The use of IV or intramuscular corticosteroids is not permitted in this study.   
Starting at Week 12 of this study, up to 3 intra-articular corticosteroid injections are 
permitted.  No single injection should exceed 40 mg of triamcinolone or equivalent, and 
the total annual dose of intra-articular corticosteroid should not exceed 80 mg of 
triamcinolone or equivalent. 
4.3.1.1.5 
Non-Steroidal Anti-inflammatory Drugs 
Patients may be treated with NSAIDs at up to the maximum recommended dose 
according to local labeling (including COX-2 inhibitors).  Dose adjustments, including 
discontinuation, are permitted throughout the study.  Dose adjustments may be made for 


 
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safety reasons at any time and if required to treat disease flares.  If possible, dose 
adjustments should be avoided within 24 hours before a visit where clinical efficacy 
assessments are scheduled to be performed and recorded.   
Topical NSAIDs are allowed. 
Patients should receive NSAIDs only on an as needed (PRN) basis if absolutely required 
to treat RA disease flares, on the basis of the investigator’s judgment; however, PRN 
use 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 
162 mg/day.   
In order to prevent NSAID-related GI complications in high-risk patients, concomitant 
agents (e.g., PPIs) should be used according to local guidelines (see Section 5.1.1.3). 
4.3.1.1.6 
Analgesics (Other than NSAIDs) 
Analgesics (e.g. acetaminophen, opioids) up to the maximum recommended doses may 
be used for pain as required.  However, patients should not take analgesics within 
24 hours prior to a visit where clinical efficacy assessments are to be performed and 
recorded.  The total daily dose of acetaminophen may not exceed 2.6 g/day, and the 
total daily dose of opioid must not exceed the potency equivalent of 30 mg of orally 
administered morphine (see Appendix 2). 
4.3.1.2 
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 effects (such as hypervitaminosis).  Herbals with 
pharmaceutical properties are allowed only if there is acceptable evidence of no CYP3A 
inhibition or induction (refer to Appendix 3 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 first dose of study 
medication, unless there are 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. 
4.3.1.3 
Acid-Reducing Agents 
Patients who use antacids (e.g., Maalox®, Pepto-Bismol®, Rolaids®) for symptomatic 
relief of heartburn should take GDC-0853 at least 2 hours before or 2 hours after antacid 
administration because GDC-0853 requires an acidic gastric environment in order to be 
absorbed.   


 
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Patients may be treated with PPIs or H2RAs, but should remain on a stable regimen 
throughout the study.   
At visits with scheduled PK assessments (see Appendix 1), any use of PPIs, H2RAs, 
and/or other antacids (e.g., Maalox®, Pepto-Bismol®, Rolaids®) should be recorded as 
concomitant medications, including the date and time of last administration. 
4.3.2 
Prohibited Therapy 
A listing of concomitant medications that is prohibited or should be used with caution 
because of potential drug-drug interactions is provided in Appendix 3.  
Intravenous, intra-articular, or intramuscular corticosteroids; biologic response modifiers; 
tofacitinib or other JAK inhibitors; and medications listed below are not allowed during 
this study and any use will require discontinuation of GDC-0853.  
Use of the following therapies is prohibited during the study, unless otherwise specified 
below: 
• 
Investigational therapy other than study drug 
• 
Abatacept 
• 
Adalimumab  
• 
Anakinra 
• 
Anti-TNF inhibitors (infliximab, etanercept, golimumab, certolizumab, or biosimilar 
equivalents) 
• 
Chlorambucil 
• 
Cyclophosphamide 
• 
Cyclosporine 
• 
Immunosorbent column 
• 
Intravenous or intramuscular steroids 
• 
Mycophenolate mofetil 
• 
Mycophenolic acid sodium 
• 
Oral anticoagulants, including but not limited to warfarin, dabigatran, rivaroxaban, 
apixaban  
• 
Anti-platelet agents, e.g. clopidogrel (Note:  NSAIDs and low-dose aspirin are 
acceptable.) 
• 
Heparin, LMWH 
• 
Penicillamine 
• 
Rituximab (or biosimilar equivalent) 
• 
Sirolimus 
• 
Tacrolimus 


 
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• 
Tocilizumab and other anti-IL6R or anti-IL6 agents 
• 
Tofacitinib and other JAK inhibitors 
• 
All biosimilar agents 
 
4.3.2.1 
Live or Attenuated Vaccinations 
Immunization with a live or attenuated vaccine is prohibited for the duration of study 
participation, including the 8-week follow-up period after the administration of the last 
dose.  See Section 5.1.1.1 for further details and precautions around vaccinations. 
4.3.2.2 
CYP3A Inhibition 
In vitro studies suggest that GDC-0853 is a time-dependent inhibitor of CYP3A with 
inhibitory constant (Ki) values of approximately 10 μM (Study 13-0384).  Although peak 
plasma concentrations are anticipated to be much lower than 10 μM (preliminary results 
from Study GA29347 indicate that a BID dose of 250 mg powder in capsule resulted in a 
mean steady-state Cmax of approximately 849 nM), it is possible that GDC-0853 inhibition 
of CYP3A may alter the metabolism of CYP3A substrates, including estrogen derivatives 
such as ethinylestradiol, subsequently leading to an increase in plasma concentrations 
of these drugs (see below and the GDC-0853 Investigator’s Brochure).  Medications that 
are sensitive substrates of CYP3A or substrates of CYP3A with a narrow therapeutic 
window should be used with caution during this study (refer to Appendix 3 for a list of 
relevant medications). 
Ethinylestradiol is metabolized by CYP3A; therefore, plasma concentrations may 
increase in the presence of GDC-0853.  The use of hormone-replacement therapy 
containing ethinylestradiol or hormonal contraceptives containing ethinylestradiol, with 
the concomitant use of a barrier method, is permitted during this study (see Appendix 4); 
however, these agents should be used with caution and 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 because CYP-mediated oxidation appears to be a relatively minor 
component of orally administered ethinylestradiol (Zhang et al. 2007).  Although 
contraceptive efficacy is not expected to be impacted, increased ethinylestradiol plasma 
concentrations may lead to an increase in common side effects, such as nausea, breast 
tenderness, and headaches, and to a theoretical increase in rare dose-related events 
such as thromboembolism (Inman et al. 1970).   


 
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In vitro data suggest that GDC-0853 is metabolized by CYP3A, and there is a moderate 
to high 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 3) 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.  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. 
• 
Moderate or strong CYP3A inhibitors 
• 
Moderate or strong CYP3A inducers  
 
Data also suggest that GDC-0853 inhibits CYP3A, and there is a moderate to high 
potential for a drug-drug interaction with any medication that is metabolized by CYP3A.  
Plasma concentrations of the medications in the following categories (listed in detail in 
Appendix 3) may increase; therefore, they should be used with caution: 
• 
Sensitive CYP3A substrates 
• 
CYP3A substrates with a narrow therapeutic index  
 
The medications listed above and in Appendix 3 are not necessarily comprehensive.  
Thus, the investigator should consult the prescribing information for any concomitant 
medication as well as the Internet references provided below when determining whether 
a certain medication is metabolized by or strongly inhibits or induces CYP3A.  The 
investigator should contact the Medical Monitor if questions arise regarding medications 
not listed above.   
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/G
uidances/UCM292362.pdf 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx 
 
4.3.3 
Prohibited Food  
Use of the following foods is prohibited during the study and for at least 7 days prior to 
initiation of study treatment:  furanocoumarin derivatives as found in grapefruit, Seville 
orange, pomegranate, or star fruit juice or products. 
4.4 
STUDY ASSESSMENTS  
Please see Appendix 1 for the schedule of assessments to be performed during this 
study. 
The following results, collected at the final Day 84 study visit in the blinded 
Study GA29350, will be used as baseline assessments in Study GA30067: 
• 
Pregnancy test, ECGs, vital signs, physical examination 
• 
Joint counts, Patient Global Assessment of Disease Activity, Patient Assessment of 
Arthritis Pain, Physician’s Global Assessment of Arthritis 
• 
HAQ-DI, FACIT-Fatigue Scale, SF-36v2 


 
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• 
Laboratory tests 
• 
Concomitant medications 
• 
PK/PD assessments 
 
4.4.1 
Informed Consent Forms and Screening Log 
Patients will be screened on Day 84 of the blinded Study GA29350 to confirm that they 
meet the entrance criteria for this study.  The study investigator or subinvestigator will 
discuss with each patient the nature of the study, its requirements, and its restrictions.  
Written informed consent for participation in this 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. 
Patients must meet all eligibility criteria before receiving their first open-label dose in this 
study.  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. 
4.4.2 
Medical History and Demographic Data 
Any adverse events that commenced during and are still ongoing at the end of the 
blinded Study GA29350 will be recorded as “unresolved” and reopened in 
Study GA30067 with the start date, adverse event term, and initial intensity of the 
adverse event being identical to those in the Study GA29350.  Adverse events that 
occurred during the core study and resolved before the patient’s enrollment into 
Study GA30067 will be reported in the patient’s medical history according to their 
medical relevance.  
4.4.3 
Physical Examinations 
A complete physical examination should be performed at Day 1 (which is Day 84 of 
Study GA29350) and should include an evaluation of the head, eyes, ears, nose, and 
throat and the cardiovascular, dermatological, musculoskeletal, respiratory, GI, 
genitourinary, and neurological systems.  Any abnormality identified at baseline should 
be recorded on the General Medical History and Baseline Conditions eCRF. 
At subsequent visits or as clinically indicated, limited, symptom-directed physical 
examinations should be performed.  Changes from baseline abnormalities should be 
recorded in the patient notes.  New or worsened clinically significant abnormalities 
should be recorded as adverse events on the Adverse Event eCRF. 
4.4.4 
Vital Signs  
Vital signs will include measurements of pulse rate, systolic and diastolic blood 
pressures while the patient is in a seated position for at least 5 minutes, and temperature. 


 
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4.4.5 
Efficacy Assessments  
Questionnaires will be self-administered before the patient receives any information on 
disease status, prior to the performance of non-PRO assessments and prior to the 
administration of study treatment.  In cases where this is logistically challenging, 
potentially painful procedures will be performed no less than 15 minutes prior to initiation 
of the PRO measures. 
The sequence of assessments where efficacy is assessed (see Appendix 1 for Schedule 
of Assessments) will be standardized as follows: 
• 
Patient-Reported Outcome Measures: 
Patient’s Assessment of Arthritis Pain (see Section 4.4.6.1) 
Patient’s Global Assessment of Arthritis (see Section 4.4.6.2) 
HAQ-DI (see Appendix 5) 
SF-36v2 (see Appendix 6) 
FACIT-Fatigue Scale (see Appendix 7) 
• 
Laboratory samples for safety, efficacy, biomarkers, and pharmacokinetics should 
be drawn after patient self-assessments are completed 
• 
Investigators 
Joint counts 
Physician’s Global Assessment of Arthritis Visual Analog Scale (VAS), safety 
assessments (adverse events, vital signs, concomitant medications, review of 
laboratory data) 
• 
Administration of GDC-0853 in clinic (only at the indicated visits, per Appendix 1) 
 
4.4.5.1 
ACR Assessments 
The ACR’s definition for calculating improvement in RA (ACR20) is calculated as a 
20% improvement in TJCs and SJCs and a 20% improvement in 3 of the 5 remaining 
ACR-core set measures: patient and physician global assessments, pain, disability, and 
an acute-phase reactant.  Similarly, ACR50 and ACR70 are calculated with the 
respective percent improvements.  The Sponsor, on the basis of the component parts, 
will calculate the ACR score.   
The specific components of the ACR Assessments that will be used in this study are as 
follows: 
• 
Tender/Painful Joint Count (68) (see Section 4.4.5.1.1) 
• 
Swollen Joint Count (66) (see Section 4.4.5.1.2) 
• 
Patient’s Assessment of Arthritis Pain (see Section 4.4.6.1) 
• 
Patient’s Global Assessment of Arthritis (see Section 4.4.6.2) 
• 
Physician’s Global Assessment of Arthritis (see Section 4.4.6.3) 


 
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• 
C-reactive protein (CRP) (see Section 4.4.7) 
• 
HAQ-DI (see Appendix 5) 
 
These clinical assessments will be performed according to the Schedule of Assessments 
(see Appendix 1) and are detailed in Sections 4.4.5.1.1−4.4.5.1.3.   
4.4.5.1.1 
Swollen and Tender Joint Count (66/68) 
An assessment of 66 joints for swelling and 68 joints for tenderness will be made.  Joints 
will be assessed and classified as swollen/not swollen and tender/not tender by pressure 
and joint manipulation on physical examination.  Joint prosthesis, arthrodesis, or fused 
joints will not be taken into consideration for swelling or tenderness.  A joint assessment 
training module may be used as a tool to facilitate consistency in performing the joint 
counts.  
For clarification of how to assess joints which have undergone a procedure, please see 
below: 
• 
Surgery:  Joints that have been replaced or fused at any time prior to or at any time 
during the study should be documented as not done for the duration of the study.  
Any joints that have undergone synovectomy at any time prior to or at any time 
during the study (including chemical and radiation synovectomy) should be 
documented as not done for the duration of the study. 
• 
Intraarticular injection:  Any joint that has received a steroid intra-articular injection 
should be documented as “not done” for the following 12 weeks.  After this time, the 
joint may be assessed again. 
• 
Arthrocentesis:  Any joint that has fluid drained (and no steroid injected) will not be 
assessed at the next scheduled visit and will be graded as not done.  After this time, 
the joint may be assessed again. 
 
4.4.5.1.2 
Tender/Painful Joint Count (68) 
Sixty-eight (68) joints will be assessed by a joint assessor (not blinded), and it is 
recommended that this assessor be the same as from the blinded Study GA29350 (for 
consistency), to determine the number of joints that are considered tender or painful.  
The response to pressure/motion on each joint will be assessed using the following 
scale:  Present/Absent/Not Done. 
The 68 joints to be assessed are as follows: 
• 
Upper body:  Temporomandibular, sternoclavicular, acromioclavicular; 
• 
Upper extremity:  Shoulder, elbow, wrist (includes radiocarpal, carpal, and 
carpometacarpal considered as one unit), metacarpophalangeals (MCP I, II, III, IV, 
V), thumb interphalangeal, proximal interphalangeals (PIP II, III, IV, V), distal 
interphalangeals (DIP II, III, IV, V); 
• 
Lower extremity:  Hip, knee, ankle, tarsus (includes subtalar, transverse tarsal and 
tarsometatarsal considered as one unit), metatarsophalangeals (MTP I, II, III, IV, V), 


 
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great toe interphalangeal, proximal and distal interphalangeals combined (PIP II, III, 
IV, V) 
 
4.4.5.1.3 
Swollen Joint Count (66) 
The joint assessor will also assess joints for swelling using the following scale:  Present, 
Absent, Not Done, or Not Applicable (to be used for artificial joints). 
Sixty-six (66) joints will be assessed for swelling, the same as those listed above for 
tenderness/pain except that the right and left hip joints are not included in the swollen 
joint count.  Artificial joints will not be assessed. 
4.4.5.2 
DAS Assessments 
The DAS assessment is a derived measurement with differential weighting given to each 
component (Prevoo et al. 1995).  The DAS 28-4 (CRP), the DAS 28-3 (CRP), the 
DAS 28-4 (erythrocyte sedimentation rate [ESR]), and the DAS 28-3 (ESR) will be 
calculated.  The calculations for the DAS 28-4 (CRP) and the DAS 28-4 (ESR) are 
presented in Appendix 8. 
The components of the DAS 28 arthritis assessment are as follows: 
• 
Tender/Painful Joint Count (28) (see Section 4.4.5.2.1) 
• 
Swollen Joint Count (28) (see Section 4.4.5.2.2) 
• 
CRP or ESR (see Section 4.4.7) 
• 
Patient’s Global Assessment of Arthritis (included in the DAS 28-4 only) (see 
Section 4.4.6.2)  
 
4.4.5.2.1 
Tender/Painful Joint Count (28) 
Twenty-eight tender/painful joint count includes the following joints:  shoulders, elbows, 
wrists, metacarpophalangeal joints, proximal interphalangeal joints, and knees.  This 
count will be calculated by the Sponsor from the 68 tender/painful joint count assessed 
by the joint assessor as described in Section 4.4.5.1. 
4.4.5.2.2 
Swollen Joint Count (28) 
This measurement will include the same joints as described for the Tender/Painful Joint 
Count and will be calculated by the Sponsor from the 66 swollen joint count assessed by 
the joint assessor as described in Section 4.4.5.1. 
4.4.6 
Patient-Reported and Clinician-Reported Outcomes  
PRO (Patient’s Assessment of Arthritis Pain, Patient’s Global Assessment of Arthritis, 
HAQ-DI, SF-36v2, and FACIT-Fatigue Scale [see Appendix 5, Appendix 6, and 
Appendix 7, respectively]) and ClinRO (Physician’s Global Assessment of Arthritis) 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 
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questionnaires will be self-administered before the patient receives any information on 
disease status, prior to the performance of non-PRO and ClinRO assessments, and prior 
to the administration of study treatment, unless otherwise specified. 
Patients will use an electronic device to capture PRO data, and clinicians will use a 
paper-based ClinRO for data collection.  The electronic device and instructions for 
completing the questionnaires electronically will be provided by the investigator staff.  
The data will be transmitted to a centralized database maintained by the electronic 
device vendor.  The data will be available for access by appropriate study personnel. 
4.4.6.1 
Patient’s Assessment of Arthritis Pain 
Patients will assess the severity of their arthritis pain using a 100 mm VAS placing a 
mark on the scale between 0 (No Pain) and 100 (Most Severe Pain), which corresponds 
to the magnitude of their RA pain, as follows: 
My pain due to my rheumatoid arthritis at this time is: 
No______________________________________________________Most Severe 
Pain 
Pain 
 
4.4.6.2 
Patient’s Global Assessment of Arthritis 
Patients will answer the following question: “Considering all the ways your rheumatoid 
arthritis affects you, how are you feeling today?”  The patient’s response will be recorded 
using a 100 mm VAS (0 = Very well and 100 = Very poorly), as follows:  
Considering all the ways your rheumatoid arthritis affects you, how are you 
feeling today? 
Very well_______________________________________________Very poorly 
 
4.4.6.3 
Physician’s Global Assessment of Arthritis 
The investigator will assess how the patient’s overall RA appears at the time of the visit.  
This is an evaluation based on the patient’s disease signs, functional capacity, and 
physical examination and should be independent of the Patient’s Global Assessment of 
Arthritis and Patient’s Assessment of Arthritis Pain.  The investigator’s response will be 
recorded using a 100 mm VAS (0 = Very good and 100 = Very poor), as follows:  
The patient’s rheumatoid arthritis at this time is: 
Very good_______________________________________________Very poor 
 


 
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4.4.6.4 
Health Assessment Questionnaire⎯Disability Index  
The HAQ-DI will be used to assess patient’s physical functioning.  The HAQ-DI is a 
20-item, validated questionnaire used to assess difficulty in performing activities of daily 
living (Fries 1983) on a scale of 0 “without any difficulty” to 3 “unable to do.”  The 
HAQ-DI refers to the previous week and assesses eight domains of physical functioning: 
Dressing and Grooming (2 items), Hygiene (3 items), Arising (2 items), Reach (2 items), 
Eating (3 items), Grip (3 items), Walking (2 items), Common Daily Activities (3 items).  A 
lower HAQ-DI score indicates better quality of life.  See Appendix 5 for a review copy of 
the HAQ-DI questions. 
4.4.6.5 
Short-Form 36 Health Survey Questionnaire, Version 2  
The SF-36v2 will be used to assess health-related quality of life 
(Ware and Sherbourne 1992).  The 36-item questionnaire consists of 8 domains: 
Physical Functioning (10 items), Role-Physical (4 items), Bodily Pain (2 items), General 
Health (5 items), Vitality (4 items), Social Functioning (2 items), Role-Emotional (3 items), 
Mental Health (5 items), and an additional item on reported health transition.  The 
SF-36v2 has a recall specification of 4 weeks and items are assessed on Yes/No and 
5- to 6-point Likert scales.  A higher score indicates better health.  The SF-36v2 health 
survey will be used in this study to assess health-related quality of life and for economic 
modeling.  See Appendix 6 for a sample version of the SF-36v2 questionnaire. 
4.4.6.6 
Functional Assessment of Chronic Illness Therapy-Fatigue 
Scale 
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 RA 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.  See Appendix 7 for a list of questions in the FACIT-Fatigue 
Scale. 
4.4.7 
Laboratory, Biomarker, and Other Biological Samples  
Laboratory assessments will be performed as indicated on the Schedule of Assessments 
(see Appendix 1).  All laboratory tests will be sent to one or more central laboratories for 
analysis, with the exception of serum and urine pregnancy tests and ESR which will be 
conducted locally. 
On days of study drug administration, laboratory samples should be drawn before the 
administration of study drug and after the administration of patient reported PRO 
assessments (e.g., pain questionnaires). 


 
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Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis: 
• 
Pregnancy test 
All women of childbearing potential (including those who have had a tubal 
ligation) will have a urine pregnancy test at entry into the OLE and at monthly 
intervals (see Appendix 1).  If a urine pregnancy test result is positive, it must 
be confirmed by a serum pregnancy test.  Should a positive pregnancy result 
be recorded at any time, the procedures detailed in Section 5.4.3 should be 
followed. 
• 
ESR:  Can be performed at local laboratory or as point-of-care test in the clinic 
 
Samples for the following laboratory tests will be sent to one or several central 
laboratories for analysis: 
• 
Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, 
other cells) 
• 
Chemistry panel (serum or plasma):  Sodium, potassium, chloride, bicarbonate, 
glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total 
and direct bilirubin, ALP, ALT, AST, uric acid, LDH, amylase, and lipase 
• 
CRP:  CRP performed at the central lab  
• 
Urinalysis including dipstick (pH, specific gravity, glucose, protein, ketones, blood) 
and microscopic examination (sediment, RBCs, WBCs, casts, crystals, epithelial 
cells, bacteria) 
• 
Coagulation:  INR, activated partial thromboplastin time (aPTT), PT 
• 
Lipids (fasting not required):  Cholesterol, LDL cholesterol, HDL cholesterol 
• 
Quantitative immunoglobulins:  Total Ig, IgA, IgG, IgM, IgE 
• 
T, B, and natural killer cells 
• 
Rheumatoid factor 
• 
Anti-cyclic-citrullinated peptide antibody or anti-citrullinated protein/peptide antibody  
 
The following will be sent to the Sponsor or a designee for analysis:   
• 
Serum, plasma, cells, and RNA from blood for exploratory PD markers (lymphoid, 
myeloid and other inflammatory markers as well as other markers potentially related 
to disease, drug, or clinical response; see Table 2). 
• 
Plasma samples for PK analysis 
• 
Whole blood sample for DNA extraction for exploratory research on inherited 
biomarkers (including but not limited to genes that express proteins that may 
influence GDC-0853 pharmacokinetics) 
 
Exploratory biomarker research may include but will not be limited to the biomarkers 
listed in Table 2.  Given the complexity and exploratory nature of biomarker analyses, 


 
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results from the analyses will not be shared with investigators or study participants, 
unless required by law. 
Table 2 
Proposed Biomarkers for Exploratory Research 
Sample Type  
Proposed Biomarkers 
Whole blood for FACS 
Cells and markers including but not limited to 
monocytes, B cells, and B cell subsets 
Plasma 
Markers including but not limited to CCL3, CCL4 
Serum 
Markers including but not limited to sICAM1, 
CXCL13, CCL20 
Blood for PBMC cell lysate 
Markers including but not limited to phosphorylated 
and total BTK protein 
RNA extracted from blood 
Markers including but not limited to myeloid RNA 
markers 
BTK = Bruton’s tyrosine kinase; FACS = flow cytometry; PBMC = peripheral blood 
mononuclear cell. 
Note:  Biomarkers will be assessed at baseline and at subsequent timepoints during and 
after treatment, 
 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Unless the patient gives specific consent for the leftover samples to be stored for 
optional exploratory research (see Sections 4.4.9 and 4.4.10), biological samples will be 
destroyed when the final clinical study report has been completed, with the following 
exception: 
• 
Blood, plasma, and serum samples collected for biomarker analyses will be 
destroyed no later than 15 years after the final clinical study report has been 
completed. 
 
4.4.8 
Electrocardiograms 
Triplicate ECG recordings will be obtained at specified timepoints up to Week 12, as 
outlined in the schedule of assessments.  After Week 12, single ECGs will be obtained 
(see Appendix 1). 
When triplicate ECGs are indicated, three interpretable ECG recordings (e.g., without 
artifacts) must be obtained.  The ECG intervals (e.g., PR, QRS, QT, QTc, and RR) and 
heart rate from these three ECGs (or single ECG, if indicated) will be entered into the eCRF; in 
addition, these triplicate readings will be stored for future analysis, if needed.  
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  
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obtained from the same machine whenever possible.  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 are to be obtained prior to other 
procedures scheduled at that same time (e.g., vital sign measurements, blood draws) 
and should not be obtained within 3 hours after any meal, if possible.  Body position 
should be consistently maintained for each ECG evaluation to prevent changes in heart 
rate.  Circumstances that may induce changes in heart rate, including environmental 
distractions (e.g., television, radio, and conversation) should be avoided during the 
pre-ECG resting period and during ECG recording. 
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 
the next 5 minutes, and triplicate ECG monitoring should continue at least hourly until 
QTcF has stabilized on two successive ECGs.  The Medical Monitor should be notified.  
Standard-of-care 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). 
4.4.9 
Optional Samples for Whole-Genome Sequencing  
An optional whole blood sample will be collected for DNA extraction to enable whole 
genome sequencing (WGS) and may be sent to one or more laboratories for analysis. 
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS provides a comprehensive characterization of the genome and, 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 identification of important pathways, guiding the development of new targeted agents. 
Collection and submission of WGS samples is contingent upon the review and approval 
of the exploratory research and the WGS portion of the Informed Consent Form by each 
site's Institutional Review Board/Ethics Committee (IRB/EC) and, if applicable, an 


 
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appropriate regulatory body.  If a site has not been granted approval for WGS sampling, 
this section of the protocol (i.e., Section 4.4.9) will not be applicable at that site. 
WGS data and associated clinical data may be shared with researchers who are not 
participating in the study or submitted to government or other health research databases 
for broad sharing with other researchers.  Patients will not be identified by name or any 
other personally identifying information.  Given the complexity and exploratory nature of 
these analyses, WGS data and analyses will not be shared with investigators or patients 
unless required by law. 
WGS samples are to be stored until they are no longer needed or until they are 
exhausted.  The storage period will be in accordance with the IRB/EC-approved 
Informed Consent Form and applicable laws (e.g., health authority requirements). 
4.4.10 
Samples for Roche Clinical Repository  
Genentech is a member of the Roche group and participates in the collection and/or 
submission of biological samples to the Roche Clinical Repository (RCR).  Collection 
and submission of biological samples to the RCR is contingent upon the review and 
approval of the RCR portion of the Informed Consent Form by each site's IRB/EC and, if 
applicable, an appropriate regulatory body.  If a site is not granted the necessary 
approval for RCR sampling, this section of the protocol will not be applicable at that site. 
4.4.10.1 
Overview of the Roche Clinical Repository 
The RCR 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 and analysis of RCR 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 RCR will be collected from patients who give specific consent to 
participate in this optional research.  RCR 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 
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4.4.10.2 
Sample Collection 
The following samples will be collected for research purposes, including but not limited 
to research on biomarkers related to GDC-0853 and RA: 
• 
Leftover plasma samples 
• 
Leftover serum samples 
• 
Leftover blood RNA and/or protein samples 
• 
Leftover blood DNA samples 
 
For all samples, dates of consent should be recorded on the associated RCR page of 
the eCRF.  For sampling procedures, storage conditions, and shipment instructions, see 
the laboratory manual.   
RCR specimens will be destroyed no later than 15 years after the date of final closure of 
the associated clinical database.  The RCR storage period will be in accordance with the 
IRB/EC−approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
4.4.10.3 
Confidentiality 
4.4.10.3.1 
Confidentiality for All RCR Specimens 
Specimens and associated data will be labeled with a unique patient identification 
number. 
Patient medical information associated with RCR 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. 
Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities and Roche monitors, 
representatives, and collaborators, as appropriate. 
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  The 
aggregate results of any research conducted using RCR specimens will be available in 
accordance with the effective Roche policy on study data publication. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RCR data will become and remain the exclusive and unburdened property 
of Roche, except where agreed otherwise. 
4.4.10.3.2 
Additional Confidentiality for Specimens Used for Genetic 
Research 
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens collected for genetic research.  


 
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Upon receipt by the RCR, specimens for genetic research are "double-coded" by 
replacing the patient identification number with a new independent number.  Data 
generated from the use of these specimens and all clinical data transferred from the 
clinical database and considered relevant are also labeled with this same independent 
number.  A "linking key" between the patient identification number and this new 
independent number is stored in a secure database system.  Access to the linking key is 
restricted to authorized individuals and is monitored by audit trail.  Legitimate operational 
reasons for accessing the linking key are documented in a standard operating procedure.  
Access to the linking key for any other reason requires written approval from the Pharma 
Repository Governance Committee and Roche's Legal Department, as applicable. 
4.4.10.4 
Consent to Participate in the Roche Clinical Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RCR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RCR.  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 RCR specimens.  
Patients who decline to participate will not provide a separate signature. 
The investigator should document whether the patient has given consent to participate 
by completing the RCR Research Sample Informed Consent eCRF. 
In the event of an RCR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RCR research. 
4.4.10.5 
Withdrawal from the Roche Clinical Repository 
Patients who give consent to provide RCR specimens have the right to withdraw their 
specimens from the RCR 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 RCR Patient Withdrawal 
Form and, if the trial is ongoing, must enter the date of withdrawal on the RCR 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 GA30067 does not, by itself, constitute withdrawal of specimens from the 
RCR.  Likewise, a patient's withdrawal from the RCR does not constitute withdrawal from 
Study GA30067. 
4.4.10.6 
Monitoring and Oversight 
RCR 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.  Roche monitors and auditors will have direct access to 


 
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appropriate parts of records relating to patient participation in the RCR for the purposes 
of verifying the data provided to Roche.  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 RCR samples. 
4.4.11 
Assessments at Unscheduled Visits 
An unscheduled visit may occur at any time during the study (i.e., due to flare of disease 
activity or due to an adverse event).  Patients who are seen by the investigator or site 
staff at a timepoint not required by the protocol may undergo any of the assessments 
indicated (see Appendix 1), based on the reason for the unscheduled visit.  These 
assessments may include collection of PK and PD, to assess drug exposure and/or PD 
measures of drug activity. 
4.5 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.5.1 
Patient Discontinuation 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
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 a patient discontinues the study prior to the Week 52 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). 
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 (see Appendix 1). 
4.5.2 
Study Treatment Discontinuation 
Patients must discontinue study treatment if they experience any of the following: 
• 
Pregnancy 
• 
Anaphylaxis or other severe hypersensitivity reaction 


 
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• 
Malignancy (with the exception of non-serious local and resectable basal or 
squamous cell carcinoma of the skin) 
• 
Any serious infection or infection requiring treatment with an IV antimicrobial agent 
• 
Any prohibited medication as defined in Section 4.3  
• 
Any Grade 3 or greater thrombocytopenia (National Cancer Institute Common 
Terminology Criteria for Adverse Events [NCI CTCAE v4.0])   
• 
Any Grade 4 neutropenia (NCI CTCAE v4.0) 
• 
Failure to achieve a 20% improvement in both SJC and TJC (relative to baseline 
values in Study GA29350) at Week 24 
 
Patients who discontinue study treatment prematurely for the reasons listed above will 
be asked to return to the clinic for an early termination visit (see Section 4.5.1) followed 
by 8 weeks of safety follow-up. 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced. 
4.5.3 
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.   
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 
The safety plan for patients in this study is based on nonclinical and clinical experience 
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other BTK inhibitors.  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 the patients participating in this 
study.  Eligibility criteria in both the controlled and open-label studies have been 
designed to exclude patients at a 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, dose reduction, and enhanced safety reporting 
are provided below.   
Dose reduction from 200 mg BID to 200 mg QD for safety events is permitted for specific 
events as detailed in Table 3 of Section 5.1.2.  For adverse events not listed in the table 
where the investigator thinks a dose reduction may be indicated, please consult with the 
Medical Monitor. 
5.1.1 
Safety Plan for Potential Risks Associated with GDC-0853  
5.1.1.1 
Infections 
GDC-0853 is a reversible inhibitor of BTK, and the degree to which GDC-0853 
antagonism of BTK signaling may suppress immune activity is unknown.  On the basis 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 cleared primarily by B-cell adaptive immune 
responses.  This risk is likely independent of sex for patients exogenously administered 
GDC-0853.   
Effects on lymphocytes and immunoglobulins in rats and dogs were reversible and 
considered to be related to pharmacological activity involving BTK inhibition.  See 
Section 1.2.2 for related primary nonclinical toxicity findings and the GDC-0853 
Investigator’s Brochure for further details. 
To date, no immune-challenge experiments (e.g., T-dependent antigen response test) 
have been conducted in animals.  It is not known whether these effects on B cells and 
IgG concentrations in animals will translate to humans or whether such changes would 
have functional or deleterious impact on immune function. 
Infections, including pneumonia and fatal influenza infections, have occurred in patients 
with B-cell malignancies treated with GDC-0853.  In studies with healthy subjects with 


 
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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. 
Total Ig, IgG, IgM, IgA, and IgE 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 Centers for Disease Control and Prevention 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, including but not limited to 
respiratory infections, cutaneous infections, urinary tract infections, systemic viral 
infections, and episodes of suspicious or febrile diarrhea, should be evaluated using 
serology or PCR if available and cultured if feasible and any identified organisms noted 
in the eCRF.  Any serious infection, infection requiring IV antimicrobials (i.e., any 
Grade 3 infection) or any opportunistic infection is considered as 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 GDC-0853 in the event that infections are observed in 
patients are provided in Table 3.   
Please also refer to the GDC-0853 Investigator’s Brochure for further details. 
5.1.1.2 
Vaccinations 
The effect of GDC-0853 upon the efficacy of vaccinations is unknown.  It is 
recommended that appropriate vaccinations per ACR (Singh 2016) or European League 
Against Rheumatism (EULAR; van Assen 2010) recommendations or local guidelines be 
up to date before entry into the blinded study.  Immunization with a live or attenuated 
vaccine is prohibited for the duration of study participation, including the 8-week 
follow-up period after the administration of the last dose of GDC-0853.   
In addition, current routine household contact with children or others who have been 
vaccinated with live vaccine components may pose a 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; 


 
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• 
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. 
 
Please refer to the GDC-0853 Investigator’s Brochure for further details. 
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 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 activation in response to 
submaximal collagen stimulation but normal response to thrombin; clinically, there is no 
reported bleeding propensity in patients with XLA. 
Bruising or bleeding events related to GDC-0853 have not been reported in healthy 
subjects. 
It is unknown whether GDC-0853 will increase the risk of bleeding in patients, especially 
in those receiving anti-platelet or anti-coagulant therapies.  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 
whether 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 PPIs should be considered (Scheiman 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: 
• 
Patients using both aspirin and an NSAID 
• 
Patients with a history of ulcer disease 


 
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• 
Patients with one or more of the following: 
Age ≥ 60years 
High-dose NSAID use 
Concurrent corticosteroid use 
Dyspepsia or gastroesophageal reflux disease symptoms 
 
Any bleeding event Grade 2 or above 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 GDC-0853 in the event that bleeding is observed in 
patients are provided in Table 3.  Please refer to the GDC-0853 Investigator’s Brochure 
for further details.   
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 GDC-0853 in the event of cytopenias in patients are 
provided in Table 3.  Please refer to the GDC-0853 Investigator’s Brochure for further 
details. 
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 μM • h) for 6 months, and significant reductions in rats administered 100 mg/kg/day 
(1438 μM • h) and dogs administered 25 mg/kg (180 μM • h) 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 in patients with 
B-cell malignancies; however, the events have resolved and have not led to study drug 
discontinuation.  Healthy subjects in the MAD Study GA29347 reported events of mild 
self-limited nausea.  
Throughout the study, patients will be monitored for GI effects.   


 
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Guidelines for management GDC-0853 in the event of GI side effects in patients are 
provided in Table 3.  Please refer to the GDC-0853 Investigator’s Brochure for further 
details. 
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.  Dose-dependent increases in ALT, 
AST, and/or bilirubin have been observed in rats administered ≥ 6 mg/kg/day (≥ 17 μM • h) 
and dogs administered ≥ 10 mg/kg/day (≥ 36 μM • h) with corresponding microscopic 
changes in the liver of dogs administered 25 mg/kg/day (180 μM • h).  The hepatotoxicity 
findings in dogs were associated with moribundity in two high-dose animals.  The 
NOAEL for these findings was considered to be 10 mg/kg (36 μM•h) in dogs, the most 
sensitive species, given the absence of GDC-0853−related hepatotoxicity at this dose 
when administered for 9 months.  These findings were fully reversible and considered 
monitorable by changes in plasma transaminases and bilirubin that occurred at doses 
lower than those producing histopathology findings (see GDC-0853 Investigator’s 
Brochure for further details).  
In clinical studies to date including single dosing 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 nor trends 
toward 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 × ULN and total bilirubin levels should be normal at Day 56 
or Day 84 of Study GA29350 prior to entering Study GA30067 (see Section 4.1.2 for 
details).  Safety monitoring for potential hepatotoxicity includes baseline and routine 
evaluations of AST/ALT and total bilirubin levels throughout the study as outlined in the 
schedule of assessments.  The local prescribing information for MTX should also be 
consulted. 
Laboratory results of AST or ALT elevations of Grade ≥ 3 (i.e., > 5× ULN) are considered 
adverse events of special interest and should be reported to the Sponsor in an expedited 
manner as outlined in Section 5.2.3.   
Guidelines for the management of GDC-0853 in the event of hepatotoxicity in patients 
are provided in Table 3.  Please refer to the GDC-0853 Investigator’s Brochure for 
further details. 
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.  


 
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Based on extrapolated/interpolated toxicokinetic data, the unbound Cmax at 45 mg/kg 
(considered a NOAEL) and no-observable-effect level of 15 mg/kg 
 
 
  There have been no GDC-0853-related changes in ECG parameters in the 
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 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 
triplicate ECGs with PK-matched timepoints for cardiac interval analysis as outlined in 
the schedule of assessments, routine safety ECGs, 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 resolution 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 4.4.8). 
Guidelines for management of GDC-0853 in the event of cardiovascular effects in 
patients are provided in Table 3.  Please refer to the GDC-0853 Investigator’s Brochure 
for further details. 
5.1.1.8 
Vascular Inflammation 
Vascular inflammation (vasculitis) was observed in dogs administered GDC-0853 at 
≥ 10 mg/kg/day (≥ 56 μM • h) in the 4-week toxicity study, and these changes were not 
completely reversed by the end of the 4-week recovery period.  There was no consistent 
correlation with any clinical biomarkers.  However, in the 9-month toxicity study in 
dogs, no GDC-0853−related vascular inflammation was observed up to the highest dose 
of 10 mg/kg/day (36 μM•h), which is considered to be the NOAEL (AUC) for the canine 
vascular inflammation findings.  
 
 The translatability of 
these findings to 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 2011).  


 
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As a safety risk-mitigation measure, patients with a history of vasculitis, including 
RA-associated vasculitis, will be excluded from the study, and CBC, creatinine, and 
urinalysis will be monitored in all patients during the study.  Study drug should be 
discontinued in any patient who develops an adverse event of vasculitis, and the patient 
should enter safety follow-up. 
Guidelines for management of GDC-0853 in the event of vasculitis in patients are 
provided in Table 3.  Please refer to the GDC-0853 Investigator’s Brochure for further 
details. 
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 before screening will be excluded from the blinded Study GA29350.  
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 in the blinded study are not exclusionary. 
All malignancies are considered adverse events 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 GDC-0853 in the event of malignancies in patients are 
provided in Table 3.  Please refer to the GDC-0853 Investigator’s Brochure for further 
details. 
5.1.2 
Management of GDC-0853 in Patients Who Experience Specific 
Adverse Events 
Guidelines for management of GDC-0853 in patients who experience specific adverse 
events are provided in Table 3.  For a potential dose reduction for other adverse events 
not listed in the table, please consult the Medical Monitor.   
 


 
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Table 3 
Guidelines for Management of GDC-0853 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 
Discontinue GDC-0853 and report event as adverse event of special interest. 
Self-limited non-serious 
infections that require treatment 
Withhold GDC-0853 during antimicrobial therapy.  GDC-0853 may be resumed after consultation with the Medical 
Monitor. 
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 serious (Grade 3 or above) bleeding events, withhold GDC-0853 and consult with the Medical Monitor. 
Neutropenia c 
 
Grade 2:  ANC >1000-1500/mm3 
Maintain GDC-0853 dosing. 
Grade 3:  ANC 500−1000/mm3 
For the first occurrence of a Grade 3 neutrophil count decreased, withhold GDC-0853 and recheck the CBC in 
7 days.  If the neutrophil count has recovered to Grade 1 (> 1500/mm3) or normal range, resume dosing at 200 mg 
BID.  If the Grade 3 neutropenia persists, discontinue GDC-0853. 
Second occurrence of Grade 3 neutrophil count decreased:  Withhold GDC-0853, recheck CBC in 7 days. If the 
neutrophil count has recovered to Grade 1 (> 1500/mm3) or normal range, restart GDC-0853 at the lower dose of 
200 mg QD.  If the Grade 3 neutrophil count decreased persists, discontinue GDC-0853. 
Third occurrence of Grade 3 neutrophil count decreased:  Discontinue GDC-0853. 
Grade 4:  ANC < 500/mm3 
For Grade 4 neutrophil count decreased: discontinue GDC-0853. 
Thrombocytopenia d 
 
Grade 1:  PLT > 75,000/mm3 
In the absence of bleeding event(s), maintain GDC-0853 dosing. 
Grade 2:  PLT 50,000−75,000/mm3 
First occurrence of Grade 2 platelet count decreased: withhold GDC-0853, recheck CBC in 7 days.  If 
platelet count has recovered to Grade 1 or has returned to the normal range, and in the absence of bleeding 
resume dosing at 200 mg BID.   
Second occurrence of Grade 2 platelet count decreased: withhold GDC-0853, recheck CBC in 7 days. If 
platelet count has recovered to Grade 1 or has returned to the normal range and in the absence of bleeding 
restart GDC-0853 at the lower dose of 200mg QD. 
Third occurrence of Grade 2 platelet count decreased: Discontinue GDC-0853. 


Table 3 
Guidelines for Management of GDC-0853 in Patients Who Experience Specific Adverse Events (cont.) 
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Event 
Action to Be Taken a 
Grade ≥ 3:  PLT < 50,000/mm3 
For Grade 3 or greater platelet count decreased: discontinue GDC-0853. 
Gastrointestinal effects 
 
Nausea, vomiting, and/or diarrhea 
Manage according to site institutional guidelines.  Consider administration of GDC-0853 with food as 
possible mitigation strategy. 
Consider reducing GDC-0853 dose to 200 mg QD and discuss with Medical Monitor.   
Malignancy 
 
Any malignancy (with the exception of 
non-serious local and resectable basal 
or squamous cell carcinoma of the 
skin). 
Discontinue GDC-0853.  Report event as an adverse event of special interest to the Sponsor in an 
expedited manner. 
Hepatotoxicity 
 
Any AST or ALT > 3.0-5.0 × ULN  
Withhold GDC-0853 and consult with the Medical Monitor. 
AST or ALT elevation  > 3 × ULN in 
combination with total bilirubin 
> 2 × ULN, of which at least 35% is 
direct bilirubin, or clinical jaundice  
Discontinue GDC-0853. 
Report event as adverse event of special interest to the Sponsor in an expedited manner. 
Any AST or ALT > 5 × ULN 
Discontinue GDC-0853. 
Elevations of AST or ALT of > 5 × ULN should be reported as adverse event(s) 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
Unless there is a clear alternative cause other than study drug, discontinue GDC-0853 e 


Table 3 
Guidelines for Management of GDC-0853 in Patients Who Experience Specific Adverse Events (cont.) 
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Event 
Action to Be Taken a 
Sustained absolute QTcF that is 
> 515 msec 
Unless there is a clear alternative cause other than study drug, discontinue GDC-0853 e 
An episode of torsades de pointes or a 
new ECG finding of clinical concern 
Unless there is a clear alternative cause other than study drug, discontinue GDC-0853 e 
Vascular Inflammation 
 
Vasculitis 
Consult with the Medical Monitor  
Hypersensitivity reactions 
 
Fever, chills, pruritis, urticaria, 
angioedema, and skin rash 
Treat patient according to the standard of care for management of anaphylaxis/anaphylactoid or a 
hypersensitivity reaction.   
Cardiopulmonary reactions, including 
chest pain, dyspnea, hypotension, or 
hypertension 
Discontinue GDC-0853.   
Persistent gastrointestinal symptoms 
(e.g., crampy abdominal pain, vomiting) 
 
CBC = complete blood count; IV = intravenous; MTX = methotrexate; PLT = platelet count; ULN = upper limit of normal. 
a Any patient who discontinues GDC-0853 should enter safety follow-up if possible. 
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 because of a reduced neutrophil count must be followed closely for signs of infection, with treatment as deemed appropriate by the 
investigator, including discontinuation of MTX if indicated, and must have a repeat WBC count with differential performed weekly until the ANC is above 1000 
cells/mm³ (1.0 × 109/L).  If the ANC does not return to above 1000 cells/mm³ (1.0 × 109/L) within 2 months (or sooner if deemed necessary by the investigator), a 
hematology referral is recommended. 
d Patients withdrawn from the study because of a reduced platelet count must have a repeat platelet count weekly until the count is above 100,000 cells/mm³ 
(100 × 109/L); additional management and treatment should be as deemed appropriate by the investigator, including discontinuation of MTX if indicated.  If the 
platelets do not return to above 100,000 cells/mm³ (100 × 109/L) within 2 months (or sooner if deemed necessary by the investigator), a hematology referral is 
recommended. 
e In rare circumstances, it may be acceptable to resume GDC-0853, provided that any ECG abnormalities have resolved and that the patient is appropriately 
monitored.  Clinical judgment should be applied and discussion with the Medical Monitor should occur. 
 


 
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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 patient 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 
• 
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 5.3.5.10 
• 
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 5.3.5.11) 


 
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• 
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). 
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 (i.e., Grade 3 
infection) and any opportunistic infections 
• 
Any bleeding event Grade 2 or above 
• 
All malignancies 
• 
A laboratory result of an AST or ALT elevation of Grade ≥ 3 (i.e., AST or ALT 
> 5 × ULN) 
 
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 


 
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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 Sections 5.4−5.6.   
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 
procedures such as biopsy sample collections, 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.  After this period, the investigator should 
report any serious adverse events that are believed to be related to prior study drug 
treatment (see 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 4 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 


 
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Table 4 
 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 5): 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, considering especially 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 
occurrence of the event 
 


 
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Table 5 
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. 


 
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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. 
• 
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 be recorded only 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) 


 
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• 
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. 
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 be recorded only once on the Adverse Event eCRF (see Section 5.3.5.4 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 be recorded only once on the Adverse Event eCRF (see Section 5.3.5.4 for 
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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, of which at least 35% is direct bilirubin) 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, in addition to the 
protocol defined adverse events of special interest for GDC-0853 of elevations of AST or 
ALT of Grade ≥ 3 (> 5 × ULN), investigators must report as an adverse event the 
occurrence of either of the following: 
• 
Treatment-emergent ALT or AST > 3 × ULN (i.e., Grade ≥ 2) in combination with total 
bilirubin > 2 × ULN (of which 35% is direct bilirubin) 
• 
Treatment-emergent ALT or AST > 3 × ULN (i.e., Grade ≥ 2) 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 5.3.5.2) 
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 condition being studied  
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.  The term "sudden death" should be used only for the occurrence of an 
abrupt and unexpected death due to presumed cardiac causes in a patient with or 
without preexisting heart disease, within 1 hour after the onset of acute symptoms or, in 
the case of an unwitnessed death, within 24 hours after the patient was last seen alive 
and stable.  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. 
If the death is attributed to progression of RA, "Rheumatoid arthritis progression" should 
be recorded on the Adverse Event eCRF.  
5.3.5.8 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening for 
Study GA29350.  Such conditions should be recorded on the General Medical History 
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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 
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 Rheumatoid Arthritis  
Medical occurrences or symptoms of deterioration that are anticipated as part of 
condition being studied 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 RA 
on the Adverse Event eCRF, it is important to convey the concept that the condition has 
changed by including applicable descriptors (e.g., "accelerated rheumatoid arthritis"). 
5.3.5.10 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., in-patient 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.   
The following hospitalization scenarios are not considered to be adverse events: 
• 
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 
 
The following hospitalization scenarios are not considered to be serious adverse events, 
but should be reported as adverse events 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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Alternate Medical Monitor contact information for all sites: 
Medical Monitor: 
, M.D. 
Telephone Nos.: 
 
Emergency Telephone Nos. 
 
 
 
 
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 scanning 
and emailing the form to 
 (U.S. and ex-U.S. sites) or by 
faxing using the contact information 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 patient 
receives either in Study GA29350 or in this study.  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 scanning and emailing the form to 
 (U.S. and ex-U.S. sites) or by faxing using the contact 
information provided to investigators (see “Protocol Administrative and Contact 
Information & List of Investigators”).  Once the EDC system is available, all information 
will need to be entered and submitted via the EDC system.   
Instructions for reporting post-study adverse events 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 8 weeks after the last 
dose of study drug in this study.  A paper Pregnancy Reporting Form should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 


 
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24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 
the form to 
 (U.S. and ex-U.S. sites) or by faxing using 
the contact information provided to investigators (see “Protocol Administrative and 
Contact Information & List of 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 paper 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.  The pregnant partner will need to sign an Authorization for Use and Disclosure of 
Pregnancy Health Information to allow for follow-up on her pregnancy.  After the 
authorization has been signed, the investigator will 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 (because 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 


 
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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. 
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 
POST-STUDY ADVERSE EVENTS 
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 in this study) if the event 
is believed to be related to prior study drug treatment.   
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 following reference documents: 
• 
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. 


 
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Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
Because of the non-comparative nature of the study, no statistical tests are planned.  All 
efficacy parameters will be summarized descriptively.  Demographic and baseline 
characteristics will be summarized descriptively. 
6.1 
DETERMINATION OF SAMPLE SIZE 
No formal sample size calculations were performed for this OLE study.  The maximum 
number of patients eligible for enrollment is approximately 580 (i.e., all patients enrolled 
in Study GA29350). 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
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. 
6.3 
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
Demographic and baseline characteristics such as age, sex, weight, and disease activity 
will be summarized using means or medians for continuous variables and proportions for 
categorical variables.  Medical history including diagnoses and treatment will be 
tabulated.  
6.4 
SAFETY ANALYSES 
The safety analyses will include all patients who received at least one dose of study drug, 
during this OLE study.  Safety will be analyzed on the basis of reported/documented 
adverse events, laboratory results, and vital signs, including adverse events of special 
interest, separated by treatment cohorts during the blinded study (GA29350).  
6.5 
EFFICACY ANALYSES 
Patient efficacy data will be summarized separated by treatment cohorts during the 
blinded study (GA29350).  Efficacy summary will be based on the intent-to-treat 
population, defined as all eligible patients enrolled into this OLE study.  Analyses of 
additional study populations (e.g., completers, and per protocol [excluding major protocol 
violators]) will be performed as supportive evaluations.  Additional subgroup analyses 
may be conducted on an exploratory basis.  Details will be provided in the Data Analysis 
Plan. 


 
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6.6 
PHARMACOKINETIC ANALYSES  
Systemic GDC-0853 exposures will be evaluated using a population PK approach, and 
estimates of PK parameters (including total exposure [AUC] and clearance following oral 
dosing) will be generated and summarized by PK parameter (mean, SD, coefficient of 
variation, median, minimum, and maximum).  The extent of interpatient variability will be 
evaluated, and potential sources of variability will be assessed.  Relationships between 
exposures, biomarkers, and efficacy endpoints will be characterized.   
Additional PK analyses will be conducted during and/or at the end of the study as 
appropriate. 
6.7 
BIOMARKER ANALYSES  
PD biomarker analyses will include patients with at least one predose and post-dose 
biomarker assessment.  Descriptive statistics in PD biomarkers will be listed by dose, 
cohort, and response status.  Data will be analyzed by absolute levels of the biomarker 
as well as normalized to baseline levels.  Additional PD analyses will be conducted as 
appropriate.  The ability of biomarkers (e.g., but not limited to CXCL13 and sICAM1) 
measured at baseline to identify a subset of patients with enhanced clinical benefit to 
GDC-0853 will also be evaluated. 
6.8 
INTERIM ANALYSIS 
No formal interim analysis is planned.  Data cuts may be performed at appropriate time 
points for inclusion in the submission with the main studies to support the safety profile.  
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 will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data and other 
additional non-eCRF data will be sent directly to the Sponsor, using 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 through the use of an electronic device provided by a vendor.  
The device is designed for entry of data in a way that is attributable, secure, and 


 
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accurate, in compliance with U.S. Food and Drug Administration (FDA) regulations for 
electronic records (21 CFR Part 11).  The electronic data are available for view access 
only via secure access to a web server.  Only identified and trained users may view the 
data, and their actions become part of the audit trail.  The Sponsor will have view access 
only.  System backups for data stored by the Sponsor and records retention for the study 
data will be consistent with the Sponsor’s standard procedures. 
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 
ELECTRONIC PATIENT REPORTED OUTCOME  
Patients will use an electronic device to capture PRO data.  The data will be transmitted 
wirelessly automatically after entry to a centralized database maintained by the 
electronic device vendor. 
Once the study is complete, the data, audit trail, and trial and system documentation will 
be archived.  The investigator will receive patient data for the site in both human- and 
machine-readable formats on an archival-quality compact disc that must be kept with the 
study records as source data.  Acknowledgement of receipt of the compact disc is 
required.  In addition, the Sponsor will receive all data in a machine-readable format on a 
compact disc. 
7.4 
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, patient-reported outcomes, 
ClinROs, evaluation checklists, pharmacy dispensing records, recorded data from 
automated instruments, copies of transcriptions that are certified after verification as 
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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. 
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 7.6. 
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. 
7.5 
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. 
7.6 
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. 


 
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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 U.S. 
Investigational New Drug (IND) application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the 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 Home 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 or the patient’s legally 
authorized representative 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 


 
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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. 
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 


 
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102/Protocol GA30067, Version 2 
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. 
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., 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. 
9.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ 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. 
9.4 
ADMINISTRATIVE STRUCTURE 
The study will be conducted globally.  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.   


 
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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.rochetrials.com/pdf/RocheGlobalDataSharingPolicy.pdf 
 
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 clinical study report.  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. 
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. 


 
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104/Protocol GA30067, Version 2 
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 Assessments 
 
Treatment Visits 
Week 
0 a 
4 
8 
12
16 b 
20 b
24 
28 b 
32 b 
36 
40 b
44 b 
48 b
52 
Day (± days) 
1 c 
28
(± 4)
56
(± 4)
84
(± 4)
112 
(± 3) 
140
(± 3)
168
(± 7)
196
(± 7) 
224 
(± 7) 
252 
(± 7) 
280
(± 7)
308
(± 7) 
336
(± 7)
365
(± 7) 
SC/
SFU d 
(± 7) 
ET 
UV e
Informed consent f 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General medical history and 
baseline conditions  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
x g 
x 
x 
x 
 
 
x 
 
 
x 
 
 
 
x 
x 
x 
x 
Adverse events  
x g 
x 
x 
x 
 
 
x 
 
 
x 
 
 
 
x 
x 
x 
x 
Vital signs h 
x g 
x 
x 
x 
 
 
x 
 
 
x 
 
 
 
x 
x 
x 
x 
Weight 
x g 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
Complete physical examination i 
x g 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Limited physical examination j 
 
x 
x 
x 
 
 
x 
 
 
x 
 
 
 
x 
x 
x 
x 
ECG k 
x g 
x 
x 
x 
 
 
x 
 
 
x 
 
 
 
x 
x 
x 
x 
GDC-0853 administration in clinic l 
x m 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology n 
x g 
x 
x 
x 
 
 
x 
 
 
x 
 
 
 
x 
x 
 
x 
Chemistry o 
x g 
x 
x 
x 
 
 
x 
 
 
x 
 
 
 
x 
x 
 
x 
Coagulation studies PT/PTT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Pregnancy test (urine) women p 
x g 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Drug dispensing 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
Urinalysis q 
x g 
x 
x 
x 
 
 
x 
 
 
x 
 
 
 
x 
x 
x 
x 
Quantitative Ig r 
x g 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
 
x 
Lipid panel s 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
Rheumatoid Factor/anti-CCP 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 


Appendix 1  
Schedule of Assessments (cont.) 
GDC-0853—Genentech, Inc. 
110/Protocol GA30067, Version 2 
 
Treatment Visits 
Week 
0 a 
4 
8 
12
16 b 
20 b
24 
28 b 
32 b 
36 
40 b
44 b 
48 b
52 
Day (± days) 
1 c 
28
(± 4)
56
(± 4)
84
(± 4)
112 
(± 3) 
140
(± 3)
168
(± 7)
196
(± 7) 
224 
(± 7) 
252 
(± 7) 
280
(± 7)
308
(± 7) 
336
(± 7)
365
(± 7) 
SC/
SFU d 
(± 7) 
ET 
UV e
TBNK  
x g 
 
 
x 
 
 
x 
 
 
 
 
 
 
x 
x 
x 
x 
ACR/DAS: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CRP 
x g 
x 
x 
x 
 
 
x 
 
 
x 
 
 
 
x 
x 
x 
x 
ESR (on site or at local 
laboratory) 
x g 
x 
x 
x 
 
 
x 
 
 
x 
 
 
 
x 
x 
x 
x 
Tender/painful joint count (68), 
swollen joint count (66) 
x g 
x 
x 
x t 
 
 
x t 
 
 
x 
 
 
 
x 
x 
x 
x 
Patient’s Assessment of Arthritis 
Pain (VAS)u 
x g 
x 
x 
x 
 
 
x 
 
 
x 
 
 
 
x 
x 
x 
x 
Patient Global Assessment of 
Arthritis (VAS) u 
x g 
x 
x 
x 
 
 
x 
 
 
x 
 
 
 
x 
x 
x 
x 
Physician’s Global Assessment 
of Arthritis (VAS) v 
x g 
x 
x 
x 
 
 
x 
 
 
x 
 
 
 
x 
x 
x 
x 
HAQ-DI u 
x g 
x 
x 
x 
 
 
x 
 
 
x 
 
 
 
x 
x 
x 
x 
SF-36v2 u 
x g 
 
 
x 
 
 
x 
 
 
 
 
 
 
x 
x 
 
 
FACIT-Fatigue Scale u 
x g 
 
 
x 
 
 
x 
 
 
 
 
 
 
x 
x 
 
 
Blood for PK assessment  x 
x g 
 
 
x 
 
 
 
 
 
 
 
 
 
x 
 
x 
x 
PBMC protein lysate u 
(U.S. sites only) 
x g 
 
 
x 
 
 
 
 
 
 
 
 
 
x 
x 
 
 
Blood for FACS (U.S. sites only) w 
x g 
 
 
x 
 
 
 
 
 
 
 
 
 
x 
x 
 
 
Serum biomarkers  
x g, x 
 
 
x x 
 
 
 
 
 
 
 
 
 
x 
x 
 
 
Plasma biomarkers  
x g, x 
 
 
x x
 
 
 
 
 
 
 
 
 
x 
x 
 
 


Appendix 1  
Schedule of Assessments (cont.) 
GDC-0853—Genentech, Inc. 
111/Protocol GA30067, Version 2 
 
Treatment Visits 
Week 
0 a 
4 
8 
12
16 b 
20 b
24 
28 b 
32 b 
36 
40 b
44 b 
48 b
52 
Day (± days) 
1 c 
28
(± 4)
56
(± 4)
84
(± 4)
112 
(± 3) 
140
(± 3)
168
(± 7)
196
(± 7) 
224 
(± 7) 
252 
(± 7) 
280
(± 7)
308
(± 7) 
336
(± 7)
365
(± 7) 
SC/
SFU d 
(± 7) 
ET 
UV e
PAXgene RNA blood  
x g, x 
 
 
x x
 
 
 
 
 
 
 
 
 
x 
x 
 
 
Optional blood sample for 
genotyping y 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ACR = American College of Rheumatology; CCP = cyclic citrullinated protein; CRP = C-reactive protein; DAS = DAS = Disease Activity Score; 
eCRF = Electronic Case Report Form; ESR =  erythrocyte sedimentation rate; ET = early termination; HAQ-DI =  Health Assessment 
Questionnaire⎯Disability Index; OLE = open-label extension; PD = pharmacodynamics; PK = pharmacokinetic; PPI = proton pump inhibitor; SC = study 
completion; SFU = safety follow-up; TBNK = T, B, and natural killer cells; UV = unscheduled visit; VAS = visual analog scale. 
a Day 1 OLE assessments that overlap with Day 84 assessments in the main Study GA29350 do not need to be repeated. 
b This clinical visit is required only for women of childbearing potential for their monthly urine pregnancy testing.   
c Day 1 of Study GA30067 should be Day 84 in the blinded Study GA29350. 
d Safety follow-up should occur 8 weeks (± 7 days) after last dose. 
e An unscheduled visit represents a visit that is not as per Schedule of Assessments and is required for an adverse event or for potential relapse 
assessment.  All indicated assessments do NOT need to be performed at each unscheduled visit.  Assessments should be based on the reason for 
the unscheduled visit.  These assessments may include collection of PK and PD, to assess drug exposure and/or PD measures of drug activity.  
Assessments performed during unscheduled visits should be recorded on the corresponding eCRF(s). 
f Patients who wish to enroll in this OLE study must complete up to Day 84 of Study GA29350 (but should not take blinded study drug on Day 84) prior 
to signing OLE Informed Consent Form. 
g Day 84 assessments in Study GA29350 should be used as the Day 1 assessments of Study GA30067.  
h Includes pulse rate, systolic and diastolic blood pressures while the patient is in a seated position, and temperature. 
i Includes evaluation of the head, eyes, ears, nose, and throat and the cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurological systems.  Record abnormalities observed at baseline on the General Medical History and Baseline Conditions 
eCRF.  At subsequent visits, record new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
j Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated.  Record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF. 
 


Appendix 1  
Schedule of Assessments (cont.) 
GDC-0853—Genentech, Inc. 
112/Protocol GA30067, Version 2 
k Triplicate digital ECG recordings will be obtained at weeks 0 (collected on Day 84 of Study GA29350), 4, 8 and 12, single ECG recording 
otherwise.  The  ECG intervals (e.g., PR, QRS, QT, QTcF, and RR) and heart rate will be entered into the eCRF; in addition, ECG readings will be stored 
for future analysis, if needed.  ECGs for each patient should be obtained from the same machine whenever possible.  To minimize variability, it is 
important that patients be in a resting position for ≥ 10 minutes prior to each ECG evaluation.  Body position should be consistently maintained 
for each ECG evaluation to prevent changes in HR.  Environmental distractions (e.g., television, radio, conversation) should be avoided during 
the pre-ECG resting period and during ECG recording. 
l Patients will receive oral GDC-0853 200 mg twice daily (unless dose reduction is indicated) approximately every 12 hours starting on Day 1 
(starting with the a.m. dose) and ending on Day 365 (52 weeks).  GDC-0853 should be taken with water by mouth.  The dates and times of the 
most recent prior meal, last dose of oral study drug (prior to clinic visit), and timing of study drug administration in clinic should be recorded at 
each clinic visit.  At the indicated clinic visits during the first 12 weeks of the study, patients should be instructed that the first (a.m.) dose of 
GDC-0853 will be administered in the clinic.  After Week 12, GDC-0853 administration in the clinic is not required. 
m The last dose of blinded study drug in Study GA29350 is the p.m. dose on the day before the Week 12 (Day 84) visit for all patients.  For 
patients continuing into the OLE Study GA30067, the first open label dose of GDC-0853 should be the a.m. dose on Day 84 (which is Day 1 
of Study GA30067). 
n Includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, eosinophils, basophils, monocytes, 
lymphocytes, other cells). 
o Includes sodium, potassium, chloride, bicarbonate, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total and 
direct bilirubin, ALP, ALT, AST, uric acid, LDH, lipase and amylase 
p During this study, monthly urine pregnancy testing is required for women of childbearing potential.  Tests will be performed locally at specified 
clinic visits.  If a urine pregnancy test result is positive, it must be confirmed by a serum pregnancy test (performed locally).   
q Includes dipstick (pH, specific gravity, glucose, protein, ketones, blood) and microscopic examination (sediment, RBCs, WBCs, casts, crystals, 
epithelial cells, bacteria). 
r Includes IgM, IgA, IgG, and IgE. 
s Fasting sample not necessary. 
t Tender and Swollen Joint Count improvement should be calculated at Week 12 and 24 of OLE with use of formula provided in Appendix 9. 
u Questionnaires will be self-administered before the patient receives any information on disease status, prior to the performance of non-PRO 
assessments, and prior to the administration of study treatment. 
v The same clinician should complete the Physician’s Global Assessment of Arthritis throughout the study. 
u Collect prior to drug administration.  Blood for PBMCs will be shipped overnight to central laboratory for processing.  
 
 


Appendix 1  
Schedule of Assessments (cont.) 
GDC-0853—Genentech, Inc. 
113/Protocol GA30067, Version 2 
v The dates and times of the most recent prior meal and most recent prior dose of PPI, H2-RA, or other antacid (e.g., Maalox®, Pepto-Bismol®, 
Rolaids®) last dose of oral study drug (prior to clinic visit), and timing of study drug administration in clinic (on Days 1 and 84) should be 
recorded at clinic visits at which PK samples are collected. 
w Collect prior to drug administration.  Blood for flow cytometry analysis (e.g., B cell and monocyte subsets).  To be performed at select centers in 
the United States where samples can be shipped to FACS laboratory within 24 hours.  
x Sample to be collected prior to drug administration. 
y Not applicable if optional WGS sample was collected in Study GA29350.  WGS is contingent upon the review and approval by each site's 
IRB/EC and, if applicable, an appropriate regulatory body.  If a site has not been granted approval for WGS, this assessment will not be 
applicable at that site.  A single blood sample will be collected for WGS and may be sent to one or more laboratories for analysis. 
 


 
GDC-0853—Genentech, Inc. 
114/Protocol GA30067, Version 2 
Appendix 2  
Appropriate Equivalent Morphine Doses of Opioid Analgesics 
Common Opioid Analgesics 
Drug 
Maximum Allowed 
Total Daily Dose 
Relative Potency to 
Oral Morphine 
Half-Life 
Morphine 
30 mg 
1 
1.5−4 hours 
Hydrocodone (Vicodin, 
Lortab) 
30 mg 
1 
3.8−4.5 hours 
Hydromorphone (Dilaudid) 
7.5 mg 
4 
2.5 hours 
Meperidine (Demerol, 
Pethidine) 
300 mg 
0.1 
3.2−3.7 hours 
Methadone (Dolophine, 
Methadose, Physeptone) 
10 mg 
3.0 
23 hours 
Codeine (Paveral, Tylenol #2 
and #3) 
200 mg 
0.15 
2.5−3.5 hours 
Oxycodone [Roxicodone; 
Percocet, Tylox] 
15 mg 
~2 
3.2 hours 
Tramadol [Ultram, Zydol; 
Zamadol, Ultracet, Tramal] 
300 mg 
~0.1 
4.7−5.1 hours 
Propoxyphene HCl (Darvon, 
Darvocet, Doloxene) 
Propoxyphene napsylate 
(Darvon-N, Darvocet-N 100) 
300 mg propoxyphene
HCl 
400 mg propoxyphene
napsylate 
~0.1 
6−12 hours; 
30−36 hours for 
active metabolite 
(norpropoxyphene) 
Note:  Sites should contact the project team for acceptable alternative preparations and related 
data. 
 
 


 
GDC-0853—Genentech, Inc. 
115/Protocol GA30067, Version 2 
Appendix 3  
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® 
Moderate or 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 
• Antimicrobials (clarithromycin, erythromycin, 
itraconazole, ketoconazole, telithromycin, 
troleandamycin, voriconazole, posaconazole) 
• Antidepressants (nefazodone) 
• Antihypertensive/cardiac (verapamil, diltiazem) 
• 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 
• Antimicrobials (rifampin, rifapentine, rifabutin) 
• Antidepressants (St. John’s wort, hyperforin) 
• Antiepileptics (carbamazepine, phenytoin, 
phenobarbital, hyperforin) 
• Diabetes (pioglitazone, troglitazone) 
• Other (modafinil, bosentan) 


Appendix 3  
Concomitant Medications (Including Foods and Herbal Products) (cont.) 
GDC-0853—Genentech, Inc. 
116/Protocol GA30067, Version 2 
Class 
Expected Interaction 
Recommendation 
Examples of Drugs in this Class a 
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 
• 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, lovastatin) 
• Migraine (eletriptan, ergotamine) 
• Steroids (budesonide, fluticasone) 
• Other (alfentanil, buspirone, conivaptan, 
darifenacin, dasatinib, dihydroergotamine, 
fentanyl, lurasidone, pimozide, quetiapine, 
sildenafil, tolvaptan, triazolam) 
a The following list is not comprehensive.  Please refer to the following Web sites for additional information and consult the Medical 
Monitor if necessary: 
U.S. FDA Table of Substrates, Inhibitors, and Inducers 
(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm); 
Indiana University Department of Medicine P450 Interaction Table (http://medicine.iupui.edu/clinpharm/ddis). 
 
 


 
GDC-0853—Genentech, Inc. 
117/Protocol GA30067, Version 2 
Appendix 4  
Childbearing Potential, Pregnancy Testing, and Contraception 
For Women 
All women of childbearing potential (including those who have had a tubal ligation) will 
have a urine pregnancy test on Study Day 1 prior to administration of study drug and at 
monthly intervals throughout the study.  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 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 postovulation 
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) 
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. 
• 
Hormonal vaginal device 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
• 
Implants for contraception 
• 
Injections for contraception (with prolonged release) 


 
GDC-0853—Genentech, Inc. 
118/Protocol GA30067, Version 2 
• 
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. 
 
For Men  
All men must agree to remain abstinent (i.e., refrain from heterosexual intercourse) or 
use contraceptive measures and agreement to refrain from donating sperm, as 
defined below: 
• 
With female partners of childbearing potential, 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 fetus. 
 
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 postovulation methods) and withdrawal are not 
acceptable methods of contraception. 


 
GDC-0853—Genentech, Inc. 
119/Protocol GA30067, Version 2 
Appendix 5  
Health Assessment Questionnaire⎯Disability Index (HAQ-DI) 
 
 


 
120/Protocol GA30067, Version 2 


 
121/Protocol GA30067, Version 2 


 
Appendix 6  
The Short-Form 36 Version 2 Health Survey (SF-36v2) 
 
 
 
 
122/Protocol GA30067, Version 2 
















 
Appendix 8  
Disease Activity Score 28 
The DAS 28-4 (CRP) and the DAS 28-4 (ESR) will be calculated as follows. 
Assessments 
• 
Tender joint count of 28 joints (TJC28), square-root transformed 
• 
Swollen joint count of 28 joints (SJC28), square-root transformed 
• 
Acute-phase reactant (erythrocyte sedimentation rate [ESR] or C-reactive protein 
[CRP]), log transformed 
• 
Patient’s global assessment of disease activity on visual analog scale (0−100 mm) 
 
Calculations 
The DAS 28 is calculated according to the following formulas: 
• 
DAS 28(4)-ESR = 0.56 × SQRT(TJC28) + 0.28SQRT(SJC28) + 0.70 × ln(ESR) + 0.014 
× GH 
• 
DAS 28(4)-CRP = 0.56 × SQRT(TJC28) + 0.28SQRT(SJC28) + 0.36 × ln(CRP + 1) 
+ 0.014  × GH + 0.96 
• 
Total score:  Range, 0.49−9.07 
 
Scoring 
• 
Disease remission ≤ 2.6 
• 
Low disease activity ≤ 3.2 
• 
Moderate disease activity > 3.2 and ≤ 5.1 
• 
High disease activity > 5.1 
 
GH = general health; ln = natural logarithm; SQRT = square root. 
 
130/Protocol GA30067, Version 2 


 
Appendix 9  
Joint Count Improvement Formula 
The following formulas should be used to calculate T/S Joint Count Improvement for 
Weeks 12 and 24 of this study. Refer to Section 3.3.5.1 for details on patient 
management based on improvement calculation at each timepoint. 
 
 
To calculate joint count improvement at Week 12 or 24, follow the steps below: 
 
Step 1:  Begin by calculating the fraction inside the inner most brackets (see below):  
 
 
 
 
 
 
Step 2:  Subtract this result from 1: 
1−  (Insert value calculated in Step 1 above.) 
Step 3: Multiply the result you obtained from Step 2 above by 100%: 
(Insert value calculated in Step 2 above)  × 100%.)   
For Tender Joints  Æ 
For Swollen Joints  Æ 
 
131/Protocol GA30067, Version 2 


 
Appendix 10  
Bottle and Label Configuration for GDC-0853 Administration  
Label to be affixed on the study drug bottle shows a.m. (sun) versus p.m. (moon) dose.  
Site will be responsible for prepopulating the dates on the label and affixing the label to the bottle. 
Patients should record the time (in military time) of each dose on label.   
 
 
 
 
132/Protocol GA30067, Version 2