Clinical trial NCT02833350
Conditions: Rheumatoid Arthritis
Sponsor: Genentech, Inc.
Start date: 2016-09-09; Completion date: 2018-07-02
Enrollment: 578 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multicenter, Phase II, randomized, double-blind, placebo-controlled, active comparator (Cohort 1 only), parallel-group, dose-ranging study to evaluate the efficacy and safety of GDC-0853 in participants with moderate to severe active RA and an inadequate response to previous methotrexate (MTX) therapy (Cohort 1) or MTX and tumor necrosis factor (TNF) therapy who may have also had exposure to no more than one non-TNF inhibitor biologic (Cohort 2).

Detailed description:

Arms: arm 1: Participants of Cohort 1 will receive GDC-0853 high dose, orally once daily along with placebo matched to adalimumab, subcutaneously every 2 weeks (Q2W) starting on Day 1 for 12 weeks. Participants will remain on a stable background therapy of MTX 15-25 milligrams per week (mg/week) (oral or parenteral; for participants entering the trial on MTX doses 15 mg/week, doses as low as 7.5 mg/week are allowed only if there is clear documentation in the medical record that higher doses were not tolerated or that the dose of MTX is the highest acceptable dose based on local clinical practice guidelines) and folic acid of at least 5 mg total dose weekly (or equivalent) as per investigator's discretion. arm 2: Participants of Cohort 1 will receive GDC-0853 low dose, orally once daily along with placebo matched to adalimumab, subcutaneously Q2W starting on Day 1 for 12 weeks. Participants will remain on a stable background therapy of MTX 15-25 mg/week (oral or parenteral; for participants entering the trial on MTX doses 15 mg/week, doses as low as 7.5 mg/week are allowed only if there is clear documentation in the medical record that higher doses were not tolerated or that the dose of MTX is the highest acceptable dose based on local clinical practice guidelines) and folic acid of at least 5 mg total dose weekly (or equivalent) as per investigator's discretion. arm 3: Participants of Cohort 1 will receive GDC-0853 mid dose, orally twice daily along with placebo matched to adalimumab, subcutaneously Q2W starting on Day 1 for 12 weeks. Participants will remain on a stable background therapy of MTX 15-25 mg/week (oral or parenteral; for participants entering the trial on MTX doses 15 mg/week, doses as low as 7.5 mg/week are allowed only if there is clear documentation in the medical record that higher doses were not tolerated or that the dose of MTX is the highest acceptable dose based on local clinical practice guidelines) and folic acid of at least 5 mg total dose weekly (or equivalent) as per investigator's discretion. arm 4: Participants of Cohort 1 will receive placebo matched to GDC-0853, orally once daily along with adalimumab, subcutaneously Q2W starting on Day 1 for 12 weeks. Participants will remain on a stable background therapy of MTX 15-25 mg/week (oral or parenteral; for participants entering the trial on MTX doses 15 mg/week, doses as low as 7.5 mg/week are allowed only if there is clear documentation in the medical record that higher doses were not tolerated or that the dose of MTX is the highest acceptable dose based on local clinical practice guidelines) and folic acid of at least 5 mg total dose weekly (or equivalent) as per investigator's discretion. arm 5: Participants of Cohort 1 will receive placebo matched to GDC-0853, orally once daily along with placebo matched to adalimumab, subcutaneously Q2W starting on Day 1 for 12 weeks. Participants will remain on a stable background therapy of MTX 15-25 mg/week (oral or parenteral; for participants entering the trial on MTX doses 15 mg/week, doses as low as 7.5 mg/week are allowed only if there is clear documentation in the medical record that higher doses were not tolerated or that the dose of MTX is the highest acceptable dose based on local clinical practice guidelines) and folic acid of at least 5 mg total dose weekly (or equivalent) as per investigator's discretion. arm 6: Participants of Cohort 2 will receive GDC-0853 high dose, orally twice daily for 12 weeks. Participants will remain on a stable background therapy of MTX 15-25 mg/week (oral or parenteral; for participants entering the trial on MTX doses 15 mg/week, doses as low as 7.5 mg/week are allowed only if there is clear documentation in the medical record that higher doses were not tolerated or that the dose of MTX is the highest acceptable dose based on local clinical practice guidelines) and folic acid of at least 5 mg total dose weekly (or equivalent) as per investigator's discretion. arm 7: Participants of Cohort 2 will receive placebo matched to GDC-0853, orally twice daily for 12 weeks. Participants will remain on a stable background therapy of MTX 15-25 mg/week (oral or parenteral; for participants entering the trial on MTX doses 15 mg/week, doses as low as 7.5 mg/week are allowed only if there is clear documentation in the medical record that higher doses were not tolerated or that the dose of MTX is the highest acceptable dose based on local clinical practice guidelines) and folic acid of at least 5 mg total dose weekly (or equivalent) as per investigator's discretion.
Interventions: intervention 1: GDC-0853 intervention 2: Adalimumab intervention 3: Folic Acid intervention 4: MTX intervention 5: Placebo
Intervention descriptions: intervention 1: Participants will receive GDC-0853 at low, mid, or high doses, orally once or twice daily for 12 weeks in Cohort 1 or 2. intervention 2: Participants will receive adalimumab, subcutaneously Q2W starting on Day 1 for 12 weeks. intervention 3: Participants will receive stable background therapy of folic acid of at least 5 mg total dose weekly (or equivalent) as per investigator's discretion. intervention 4: Participants will receive stable background therapy of MTX 15-25 mg/week (oral or parenteral; for participants entering the trial on MTX doses 15 mg/week, doses as low as 7.5 mg/week are allowed only if there is clear documentation in the medical record that higher doses were not tolerated or that the dose of MTX is the highest acceptable dose based on local clinical practice guidelines). intervention 5: Participants will receive placebo matched to adalimumab, subcutaneously Q2W and/or placebo matched to GDC-0853, orally once or twice daily for 12 weeks in Cohort 1 or 2.

Protocol documents:
Prot_SAP_001.pdf: 
 
Official Title: A Two-Cohort Randomized Phase II, Double-Blind, Parallel Group 
Study in Patients With Active Rheumatoid Arthritis Evaluating the 
Efficacy and Safety of GDC-0853 Compared With Placebo and 
Adalimumab in Patients With an Inadequate Response to Previous 
Methotrexate Therapy (Cohort 1) and Compared With Placebo in 
Patients With an Inadequate Response or Intolerance to Previous TNF 
Therapy (Cohort 2) 
NCT Number: 
NCT02833350 
Document Date: 
Protocol Version 4: 10-March-2017 
 
 


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 GA29350, Version 4 
PROTOCOL 
TITLE: 
A TWO-COHORT RANDOMIZED PHASE II, 
DOUBLE-BLIND, PARALLEL GROUP STUDY IN 
PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS 
EVALUATING THE EFFICACY AND SAFETY OF 
GDC-0853 COMPARED WITH PLACEBO AND 
ADALIMUMAB IN PATIENTS WITH AN INADEQUATE 
RESPONSE TO PREVIOUS METHOTREXATE THERAPY 
(COHORT 1) AND COMPARED WITH PLACEBO IN 
PATIENTS WITH AN INADEQUATE RESPONSE OR 
INTOLERANCE TO PREVIOUS TNF THERAPY 
(COHORT 2) 
PROTOCOL NUMBER: GA29350 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2016-000335-40 
IND NUMBER: 
120,162 
TEST PRODUCT: 
GDC-0853 (RO7010939) 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
Genentech, Inc. 
DATE FINAL: 
Version 1:  29 January 2016 
DATES AMENDED: 
Version 2 (Korea): 22 July 2016 
Version 3:  5 August 2016 
Version 4:  See electronic date stamp below. 
 
10-Mar-2017 21:59:20
Title
Approver's Name
Company Signatory (Clinical)
Date and Time (UTC)


GDC-0853—Genentech, Inc. 
2/Protocol GA29350, Version 4 
PROTOCOL AMENDMENT, VERSION 4 
RATIONALE 
Changes to the protocol, along with a rationale for each change, are summarized as 
follows and are reflected as applicable in the Schedules of Assessments 
(Appendices 13): 
 
Clinical Disease Activity Index (CDAI)-based remission has been defined as  2.8 
(Table 1). 
 
The initiation of Cohort 2 will no longer be gated on the interim analysis.  The 
decision to open Cohort 2 now is based on evidence for activity of BTK inhibition in 
rheumatoid arthritis patients, as demonstrated by another BTK inhibitor (Section 3.1). 
 
The population for Cohort 2 has been broadened to also include those who may 
have had intolerance to 1 or 2 TNF inhibitors and who may have also had exposure 
to no more than one non-TNF inhibitor biologic (Section 3.1).   
 
For Cohort 2, the randomization will be stratified by geographic region and prior 
exposure to a non-TNF inhibitor biologic, in order to balance treatment assignments 
for the purpose of limiting any potential confounding of efficacy.  The Sponsor may 
choose to limit the percentage of patients enrolled that have had prior exposure to a 
non-TNF inhibitor biologic in order to minimize heterogeneity of the Cohort 2 
population (Section 3.1).  
 
The size of Cohort 2 has been expanded to include approximately 120 patients who 
will be randomized to placebo or 200 mg BID GDC-0853 (Figure 1 and Section 3.1)  
 
The definition of inadequate response to TNF inhibitors has been updated to allow 
exposure to TNF inhibitors at doses and durations that, in accordance with local 
clinical practice, are considered acceptable to assess clinical response 
(Section 4.1.1). 
 
The eligibility requirement based on high sensitivity C-reactive protein (hsCRP) has 
been lowered to  0.400 mg/dL for Cohort 1 at screening in order to broaden the 
eligible population for Cohort 1.  The Sponsor may choose to limit the percentage of 
patients enrolled who have a screening hsCRP of between 0.400 and 0.649 mg/dL 
in order to minimize confounding of efficacy, as patients with higher levels of 
inflammation might be expected to demonstrate an enhanced response to 
GDC-0853 based on mechanism of action (Section 3.1). 
 
The protocol has been updated to state that at any time during the study, the 
Sponsor may choose to inactivate and suspend enrollment and further dosing for a 
given treatment arm (in Cohort 1) due to safety concerns and as guided by the 
Internal Monitoring Committee (IMC), and that in Cohort 1, subsequently enrolled 
patients will be randomly allocated to the remaining active arms (Section 3.1). 
 
For patients entering the trial on methotrexate (MTX) doses  15 mg/week, the 
protocol has been clarified that for patients taking doses as low as 7.5 mg/week, 
there must be clear documentation that higher doses were not tolerated or that the 
dose of MTX is the highest acceptable dose based on local clinical practice 
guidelines (Section 4.1.1). 


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3/Protocol GA29350, Version 4 
 
Systemic involvement secondary to rheumatoid arthritis (RA) has been clarified, 
including specific examples (Section 4.1.1). 
 
Current treatment with medications that are well known to prolong the QT interval 
has been clarified to specify that this refers to use of medications at doses that have 
a clinically meaningful effect on the QT interval; a reference website for QT 
prolonging medications has been included (Section 4.1.2). 
 
Exclusion criteria of current liver disease and pancreatitis have been clarified 
(Section 4.1.2). 
 
Guidance on missed doses has been added (Section 4.3.2.1).  
 
Language around mandatory morning visits for clinic visits on Days 1, 28, and 84 
has been removed and logistics of study drug dosing have been clarified 
(Section 4.5).  
 
Grade 3 LFT abnormalities have been added, and use of prohibited medications has 
been removed from the reasons for permanent discontinuation of study treatment.  
In addition, patients will be asked to remain in the blinded study (off study treatment) 
through Week 12, instead of transferring to safety follow-up, in order to minimize 
missing data (Section 4.6.2). 
 
The reporting of the term “sudden death” has been clarified (Section 5.3.5.8). 
 
Event reporting for hospitalization has been clarified (Section 5.3.5.11). 
 
Language around the interim analysis has been clarified, including the case in which 
the IMC decides to unblind the study team to enable decision-making and potential 
interactions with regulatory bodies (Section 6.8.1.1). 
 
Updated language for the interim analysis includes the possibility of increasing 
enrollment by up to 20% to obtain greater precision for estimation of treatment 
differences (Section 6.8.1.1). 
 
Updated language for an optional interim analysis (for Cohort 2) has been added in 
order to guide internal decision making around issues such as the adequacy of dose 
ranging, the adequacy of sample sizes for safety and/or efficacy analyses, or to 
inform further development decisions (Section 6.8.1.2).  
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents 
cumulative changes to the original protocol. 


GDC-0853—Genentech, Inc. 
4/Protocol GA29350, Version 4 
PROTOCOL AMENDMENT, VERSION 4: 
SUMMARY OF CHANGES 
GLOBAL CHANGE 
The population for Cohort 2 has been broadened to also include those who may have 
had intolerance to 1 or 2 TNF inhibitors and who may have also had exposure to no 
more than one non-TNF inhibitor biologic. 
The number of patients has increased from approximately 580 to approximately 600. 
Use of antacids has been clarified that the protocol is referencing short-acting antacids. 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
TABLE 1:  Primary, Secondary, Safety, Pharmacokinetic, and Exploratory 
Objectives with Corresponding Endpoints 
Table 1 has been updated to reflect the broadening of Cohort 2 as well as to define 
CDAI-based remission. 
SECTION 3.1:  DESCRIPTION OF THE STUDY 
This is a multicenter, Phase II, randomized, double-blind, placebo-controlled, active 
comparator (Cohort 1 only), parallel-group, dose-ranging study to evaluate the efficacy 
and safety of GDC-0853 in patients with moderate to severe active RA and an 
inadequate response to previous MTX therapy (Cohort 1) or MTX and TNF therapy 
(Cohort 2).who may have also had exposure to no more than one non-TNF inhibitor 
biologic (Cohort 2).  Moderate to severe active RA is defined by  6 tender/painful joints 
on motion (68 joint count) and  6 swollen joints (66 joint count) at both screening and 
Day 1 (randomization), as well as a high sensitivity C-reactive protein (CRPhsCRP) 
 0.7 400 mg/dL for Cohort 1 and a hsCRP  0.650 mg/dL for Cohort 2 at screening.  
Improvement in disease activity will be measured using the American College of 
Rheumatology (ACR) response rate.   
This study will enroll approximately 580 600 patients.  Initially,In Cohort 1 will be opened 
and, approximately 480  MTX -IR patients will be randomized to placebo, ADA, or one of 
3 doses of GDC -0853 (50 mg QD, 150 mg QD, or 200 mg BID).  An interim analysis (IA) 
of data from the first approximately 150 patients (~30 patients per arm) will evaluate 
safety and efficacy, including exposure response relationships.  On the basis of the 
results of the Cohort 1 interim analysis,In Cohort 2 will be opened and, approximately 
100 approximately 120 TNF-IR patients will be randomized to placebo or 200 mg BID 
of GDC-0853; however, the selected dose may be lower than 200 mg BID, depending 
on the outcome of the IA(see Figure 1).  The randomization will be stratified by 
geographic region, and patients who withdraw or discontinue will not be replaced. 


GDC-0853—Genentech, Inc. 
5/Protocol GA29350, Version 4 
At any time during the study, the Sponsor may choose to inactivate and suspend 
enrollment and further dosing for a given treatment arm (Cohort 1) or reduce the dose 
in Arm F (Cohort 2) due to safety concerns, and as guided by the IMC.  In Cohort 1, 
subsequently enrolled patients will be randomly allocated to the remaining arms.  
FIGURE 1:  Study Schema 
Figure 1 has been updated to reflect the changes in the protocol. 
SECTION 3.1.1:  Cohort 1 (MTX-IR) 
Cohort 1 includes patients with active RA who have demonstrated an inadequate 
response to MTX.  An inadequate response to MTX is defined as meeting entry criteria 
for active disease despite having received MTX for at least 12 weeks immediately prior 
to randomization, of which the last 8 weeks prior to randomization must have been at a 
stable dose of between 15 and 25 mg/week (oral or parenteral; for patients entering the 
trial on MTX doses  15 mg/week, doses as low as 7.5  mg/week are allowed only if 
there is clear documentation in the casemedical record that higher doses were not 
tolerated or that the dose of documented MTX intoleranceMTX is the highest acceptable 
dose based on local clinical practice guidelines). 
At baseline (Day 1), patients in Cohort 1 will be randomly assigned in a 1:1:1:1:1 fashion 
to 1 of 5 parallel treatment arms:  
 
Arm A:  50 mg QD GDC-0853 (BID tablets)  SC placebo injections SC every 
2 weeks (Q2W)  (n  40) 
 
Arm B:  150 mg QD GDC-0853 (BID tablets)    SC placebo injections SC Q2W 
(n  110) 
 
Arm C:  200 mg BID GDC-0853 (BID tablets)    SC placebo injections SC Q2W 
(n  110) 
 
Arm D:  placebo (BID tablets)   SC placebo injections SC Q2W (n  110) 
 
Arm E:  placebo (BID tablets)   40 mg SC ADA injections SC Q2W (n  110) 
 
Once enrollment in Arm A has completedis complete, patients will be randomized 1:1:1:1 
across the 4 remaining treatment arms. 
For Cohort 1 the randomization will be stratified by geographic region.  The Sponsor 
may choose to limit the percentage of patients enrolled who have a screening hsCRP of 
between 0.400 and 0.649 mg/dL.   
Patients will be assessed at site visits on Days 1, 7, 14, 28, 42, 56, 70, and 84 during the 
treatment period and, if the patient does not enroll in OLE Study GA30067, on Day 140 
during the follow-up period.   
After 150 patients in Cohort 1 (~30 patients/arm) have completed 12 weeks of treatment, 
an IA andto evaluate safety assessmentand efficacy will be performed by the IMC.  


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6/Protocol GA29350, Version 4 
Cohort 1 will continue to enroll while the IA is being performed.  If the IA demonstrates 
that futility criteria are not met, as defined in the Data Analysis Plan (DAP), and safety 
data are acceptable, as determined by the IMC and Sponsor, the study will continue.  
The Sponsor will open enrollment into(see Section 6.8). at this time, if appropriate.  If the 
IA indicates that one or more dose levels of GDC 0853 in Cohort 1 do not have sufficient 
efficacy or safety/tolerability, the Sponsor may discontinue the dose arm(s) in this cohort 
and continue the study.  The Sponsor may also elect to amend the protocol to change 
the dose level of GDC 0853 in Arm F of Cohort 2. 
SECTION 3.1.2:  Cohort 2 (TNF-IR) 
Cohort 2 includes patients with active RA who must have demonstrated an inadequate 
response or intolerance to one or two TNF inhibitors and MTX and who may have also 
had exposure to no more than one non-TNF inhibitor biologic.  Cohort 2 is designed to 
assess the safety and efficacy of GDC-0853, administered orally at 1 dose level, in 
combination with MTX.   
At baseline (Day 1), patients in Cohort 2 will be randomly assigned in a 1:1 fashion to 
1 of 2 parallel treatment arms:  
 
Arm F:  200 mg BID GDC-0853 (BID tablets; approximately n  50  670) 
 
Arm G:  placebo (BID tablet; approximately n  50  7060) 
 
The dose for Arm F of Cohort 2 may be reduced, depending upon the results of the 
exposure response and efficacy analyses from the IA.  
For Cohort 2, the randomization will be stratified by geographic region and prior 
exposure to a non-TNF inhibitor biologic.  The Sponsor may choose to limit the 
percentage of patients enrolled who have had prior exposure to a non-TNF inhibitor 
biologic.  
SECTION 3.3.2:  Rationale for Patient Population 
This Phase II study will evaluate patients with unmet need due to an inadequate 
response to MTX (Cohort 1) or inadequate response or intolerance to TNF inhibitors and 
who may have been exposed to one other non-TNF inhibitor biologic agent (Cohort 2), 
given the greater unmet need in these populations of patients with RA. 
SECTION 3.3.3.2:  Active Control Group 
ADA is a biologic TNF inhibitor licensed for the treatment of RA at a dose of 40 mg Q2W 
and is considered the SOC in many countries, often in combination with MTX.  Refer to 
local ADA prescribing information and RA treatment guidelines for details.  ADA will be 
used as an internalactive control to assess relative differences in efficacy, safety, and 
tolerability of GDC-0853.  ADA will be provided by the Sponsor.  Refer to local ADA 
prescribing information and RA treatment guidelines for details. 


GDC-0853—Genentech, Inc. 
7/Protocol GA29350, Version 4 
SECTION 3.3.6.4:  Stratification and Enrollment Cap 
Patient randomization will be stratified by geographic region, because regional variation 
in the management of RA can manifest as variability in response rates, including 
differences in placebo response rates.  The stratification is intended to balance the 
proportion of patients from different regions across the study arms in order to limit any 
confounding of the study results.  In Cohort 1, the Sponsor may choose to limit the 
percentage of patients enrolled who have a screening hsCRP of between 0.400 and 0.649 
mg/dL in order to enrich for patients with higher levels of inflammation who might be 
expected to demonstrate an enhanced response to GDC-0853, based on mechanism of 
action. 
Patients in Cohort 2 will also be stratified based on whether or not they have had prior 
exposure to a non-TNF inhibitor biologic, in order to balance treatment assignment for 
the purpose of limiting any potential confounding of efficacy.  The Sponsor may choose 
to limit the percentage of patients enrolled who have had prior exposure to a non-TNF 
inhibitor biologic, in order to minimize heterogeneity of the Cohort 2 population.   
SECTION 3.3.6.5:  Interim Analysis 
The IA for Cohort 1, which will be conducted after 150 patients in Cohort 1 
(~30 patients/arm) have completed 12 weeks of treatment, is intended to minimize the number 
of patients exposed to GDC 0853, should a safety signal or a lack of meaningful efficacy 
be observed at one or multiple dose levels of GDC 0853.  In addition, the IA will be used 
to confirm the appropriateness of the dose used in Cohort 2. 
SECTION 4.1.1:  Inclusion Criteria 
 
At screening, must have hsCRP as follows: 
Cohort 1:   0.7400 mg/dL at screening(may be repeated once) 
Cohort 2:   0.650 mg/dL (may be repeated once) 
 
Have received MTX for at least 12 weeks immediately prior to randomization, of 
which the last 8 weeks prior to randomization must have been at a stable dose of 
between 157.5 and 25 mg/week (oral or parenteral); doses as low as 7.5 mg/week 
are allowed only in the case of documented MTX intolerance ) 
For patients entering the trial on MTX doses  15 mg/week, there must be 
clear documentation in the medical record that higher doses were not tolerated 
or that the dose of MTX is the highest acceptable dose based on local clinical 
practice guidelines. 
  
 
Willing to withdraw all non-biologic disease-modifying anti-rheumatic 
drugs  (DMARDs), other than MTX and leflunomide, at least 4 weeks prior to 
randomization;.  Patients previously on leflunomide should be must have either 
discontinued  2 8 weeks after standard (e.g., 11 day) cholestyramine or charcoal 
washout prior to randomization or discontinued with the following elimination 
procedure at least 28 days prior randomization: 


GDC-0853—Genentech, Inc. 
8/Protocol GA29350, Version 4 
Cholestyramine or activated charcoal should be taken at standard doses for a 
minimum of 6 days but ideally for the standard 11 days (Arava U.S. Package 
Insert; Arava Summary of Product Characteristics) 
 
Willing to receive treatment at an adequate and stable dose of folic acid (not less 
than 5 mg total dose weekly) during study 
 
Only for patients currently receiving NSAIDs: on a regular basis (e.g., not as needed):  
Treatment must be at a stable dose during the 2 weeks prior to randomization and 
with a plan to remain at a stable dose for the duration of the study. 
To be enrolled into Cohort 2, patients must also meet the following criteria:  
 
Experienced anan inadequate response for  3 months or intolerance to previous 
treatment with at least one and no more than 2 of the followingbiologic             
TNF inhibitors (e.g., infliximab, etanercept, adalimumab, golimumab, or 
certolizumab, or biosimilar equivalent) and in the opinion of the investigator either 
of the following (which must be documented in the eCRF):  
– 
Experienced insufficient efficacy or loss of efficacy at a dose and duration that, 
in accordance with local clinical practice, is considered acceptable to 
adequately assess clinical response  
– 
:Experienced intolerance of such treatment 
 
May have also been exposed to no more than one non-TNFα inhibitor biologic 
(e.g., abatacept, tocilizumab, sarilumab, sirukumab, anakinra, or any biologics or 
or biosimilar equivalents with the same mode of action to the listed agents, 
including investigational biosimilar agents).  Etanercept (or biosimilar equivalent) 
at 25 mg twice a week or 50 mg weekly 
At least 4 consecutive infusions of infliximab (or biosimilar equivalent) at 
 3 mg/kg 
ADA (or biosimilar equivalent) at 40 mg every other week 
At least 4 consecutive injections of golimumab  50 mg 
At least 5 consecutive injections of certolizumab  200 mg  
 
Prior to randomization, will have discontinued all biologic anti TNF therapies as 
follows: 
Etanercept for  2 weeks 
Infliximab, adalimumab, golimumab, or certolizumab for  8 weeks  
 
SECTION 4.1.2:  Exclusion Criteria 
Patients who meet any of the following criteria willmust be excluded from study entry: 
 
Significant systemicSystemic involvement secondary to RA, including but not limited 
to leading to clinically significant organ dysfunction or increased risk for 
participation in the study, in the opinion of the investigator. For example, patients 
with known RA vasculitis, pulmonary fibrosis, or Felty’s syndrome;  should be 
excluded.  Exceptions are as follows:; NB:  


GDC-0853—Genentech, Inc. 
9/Protocol GA29350, Version 4 
– 
Sjogren’s syndrome with RA is allowable 
– 
Aand anemia secondary to RA (if Hgb is greater than or equal to 8.5 mg/dL) 
isare allowable. 
– 
History of treatment with any non TNF inhibitor biologic DMARD cell-depleting 
therapy including B celldepleting therapy (e.g., anti-CD20directed therapy 
[e.g.,such as rituximab], anti IL6 directed therapy [e.g., tocilizumab], or T cell
directed therapy [e.g., abatacept]) including biosimilar equivalents) 
– 
History of treatment with any investigational biologics for the treatment of RA 
– 
AnyRAAny condition or medication that precludes the use of or is contraindicated 
with MTX or folic acid, according to the local prescribing label or the investigator 
(e.g., patients with pleural effusion, ascites, or who are on concomitant acitretin) 
 
For Cohort 1 only:   
– 
For Cohort 1 only:  For Cohort 1 only: 2: History of anaphylactic or other serious 
allergic reaction to ADAtreatment with anti CD20 directed therapy [e.g., rituximab] 
– 
History of treatment with tofacitinib or other Janus kinase (JAK) inhibitor(s) 
(approved or experimental) 
– 
Prior to randomization, must have discontinued all biologic anti TNF therapies as 
follows: 
Etanercept and etanercept biosimilar agents for  2 weeks 
Infliximab, adalimumab, golimumab, or certolizumabAll other biologic agents 
(including biosimilars and investigational biosimilars to approved agents) 
for  8 weeks28 days  
– 
Previous exposure to any cell depleting therapy or investigational agent (not 
including investigational biosimilars to approved therapies) within 12 weeks 
or 5 half-lives of the investigational agent, whichever is longer, prior to 
randomization 
 
Current treatment with medications that are well known to prolong the QT 
interval at doses that have a clinically meaningful effect on QT, as determined by 
the investigator.  The investigator may contact the Sponsor for confirmation if 
needed. The investigator may reference the website: 
https://www.crediblemeds.org/pdftemp/pdf/CompositeList.pdf. 
 
Current liver disease that is clinically significant, in the opinion of the investigator 
 
History of nongallstone-related pancreatitis or chronic pancreatitis that is judged 
to be clinically significant, in the opinion of the investigator (e.g., unexplained 
upper abdominal pain or malabsorptive diarrhea) 
 
Neuropathies or other painful conditions that might interfere with pain evaluation as 
determined by, in the opinion of the investigator 
 
History.  Aspirin at doses of non gallstone related pancreatitis or chronic 
pancreatitisup to 162 mg QD is allowed. 


GDC-0853—Genentech, Inc. 
10/Protocol GA29350, Version 4 
 
History of CV accident (CVA) within 10 years or, any history of hemorrhagic CVA, 
history of spontaneous intracranial hemorrhage, or history of traumatic 
intracranial hemorrhage within 10 years 
 
History of spontaneous intracranial hemorrhage or history of traumatic intracranial 
hemorrhage within 10 years 
 
Current treatment with medications that are well known to prolong the QT interval 
Additionally, patients who meet any of the following criteria will be excluded from 
Cohort 1: 
 
History of treatment with non-TNF inhibitor biologic for RA, including anti-IL6–
directed therapy (e.g., tocilizumab, sarilumab, sirukumab), anti-IL1-directed therapy 
(e.g., anakinra), or T cell–directed therapy (e.g., abatacept) including biosimilar 
equivalents 
SECTION 4.2:  METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
The Sponsor will provide the specifications of the randomization algorithm to the 
interactive voice and Web response system (IxRS) vendor.  TheFor Cohort 1 tThe 
randomization will be stratified by geographic region.  For Cohort 2, the randomization 
will be stratified by geographic region and prior exposure to a non-TNF inhibitor 
biologic. 
SECTION 4.3.2.1:  GDC-0853 and Placebo Dose and Administration 
The GDC-0853 dose levels are 50 mg QD, 150 mg QD, and 200 mg BID, with matching 
placebos (see Table 2).  Patients will receive GDC-0853/placebo BID, approximately 
every 12 hours starting on Day 1 and ending on Day 8483.  Patients should be directed 
to take one dose (a total of 4 tablets) BID (a total of 8 tablets each day).  On clinic visit 
days, patients should be instructed that study drug will be administered in the clinic.   
If a dose is missed, the patient should resume normal dosing with the next scheduled 
dose.  Missed doses should not be taken, as they result in doubling of the dose.  Patients 
should record on the blister wallet (Cohort 1) or bottle (Cohort 2) the dose that was 
missed and notify study staff of any missed doses.  Doses that are vomited will be 
considered missed doses. 
GDC-0853 or placebo may be orally administered with or without food, except on Days 1, 
28, and 84 (see Appendix 1 and Appendix 2), when the morningfor the dose of oral 
study drug taken at the clinic visit on Days 1 and 28 (see Appendix 1 and Appendix 2), 
which will be administered at the morning (mandatory) clinic visit while fasting.  The 
dates and times of the most recent prior meal, last dose of oral study drug (prior to clinic 
visit), and timing of oral study drug administration in clinic should be recorded at each 
clinic visit.  In addition, any use of PPIs, H2RAs, and/or othershort-acting antacids (e.g., 
Maalox, Pepto-Bismol, Rolaids) should be recorded as concomitant medications, 
including date and time of last administration. prior to the clinic visit.  Administration of 
study drug should be staggered with short-acting antacid use (i.e., oral study drug 
should be taken 2 hours before or 2 hours after the short-acting antacid). 


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SECTION 4.3.2.2:  GDC-0853 and Placebo Compliance 
The following measures will be taken to assess patient compliance with study drug:  
patients will receive Patient Dosing Instructions and be directed to bring any used and 
unused blister wallets (Cohort 1) or bottles (Cohort 2) to each visit after randomization.   
SECTION 4.3.3.1:  Methotrexate 
In order to minimize confounding of study assessments, MTX treatment must have been 
initiated for at least the last 12 weeks immediately before randomization, of which the 
last 8 weeks before randomization must have been at a stable dose between 15 and 
25 mg/week (oral or parenteral).  Doses as low as 7.5 mg/week are allowed only in 
cases of documented MTX intolerance.  Patients are required to be on a stable MTX 
dose of 157.525 mg/week (oral or parenteral) for the duration of their participation in 
this study.  For patients entering the trial on MTX doses  15 mg/week, there must be 
clear documentation in the medical record that higher doses were not tolerated or that 
the dose of MTX is the highest acceptable dose based on local clinical practice 
guidelines. (doses as low as 7.5 mg/week are allowed only in cases of documented 
MTX intolerance).   
SECTION 4.3.5:  Post-Trial Access to GDC-0853 
Patients who complete all study assessments may be eligible to screen for and enroll in 
the OLE Study GA30067, if considered appropriate according to the investigator. 
SECTION 4.4.1.2:   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.  TheFor patients who are 
receiving NSAID treatment on a regular basis (e.g., not as needed), the dose should 
remain stable for at least the 2 weeks before randomization and throughout the study.   
SECTION 4.5:  STUDY ASSESSMENTS 
Morning visits are strongly recommended for the clinic visits on Days 1, 28, and 84, 
particularly for the Day 28 visit at which post-dose PK blood samples will be collected.  
Patients should be fasting ( 48 hours) prior to these clinic visits.  Study drug will be 
administered at these visits after pre-dose blood samples are collected when applicable.  
If a morning visit is logistically challenging, then based on the timing of their 
scheduled visit and scheduled dose, patients may be asked to take their morning dose of 
study drug as scheduled, then fast ( 48 hours) prior to their clinic visit later in the 
day.  At the clinic visit, pre-dose blood samples will be collected and the evening dose of 
oral study drug will be administered if applicable (e.g., for the Day 28 visit when post -
dose blood samples are collected). 
SECTION 4.5.1.2:  Rescreening 
Rescreening refers to repeating the whole screening process.  Rescreening is required if 
a patient has not met all of the eligibility criteria within 28 days after the original 
screening visit.  (Note: patients who have failed two laboratory testing attempts as 


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described in Section 4.5.1.1 cannot be rescreened)., except in cases where eligibility 
criteria such as hsCRP have been updated).   
SECTION 4.5.2:  Medical History and Demographic Data 
 
Medical history:  The diagnosis of RA should be recorded on the medical history 
eCRF (and captured as “rheumatoid arthritis”), including the date of diagnosis.  
The history must include dates of previousthe most recent vaccinations (specifically 
influenza, pneumococcus, and zoster).) on the eCRF.  All medical history relevant to 
RA will be collected.  The medical history should include CHD risk factors per the 
National Cholesterol Education Program (NCEP) guidelines (e.g., smoking, 
hypertension, low HDL, family history of premature CHD - see Appendix 6).  
The medical history must also include clinically significant diseases, surgeries, 
procedures, cancer history (including prior cancer therapies and procedures), 
reproductive status, smoking history, and use of alcohol and drugs of abuse.  
A detailed history of medication used for RA is required.  This should include a 
complete history of all conventional synthetic DMARDs and biological DMARDs 
ever taken (those taken within 5 years before screening should include 
dose/duration, date of discontinuation, and reason for discontinuation).   
SECTION 4.5.3:  Physical Examinations 
A complete physical examination should be performed at screening and should include 
an evaluation of the head, eyes, ears, nose, and throat and the CV, 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., including assessment of rheumatoid nodules and other 
physical manifestations of RA (to be recorded in the eCRF). 
SECTION 4.5.5:  Chest Radiograph (Chest X Ray) 
Posterior anterior and lateral chest radiographsChest radiographs of appropriate quality 
(to adhere to local standards for the exclusion of active TB) and with formal readings by 
a radiologist will be obtained at screening.  If chest radiographs have been taken within 
90 days prior to screening and documented results (as read by a radiologist) show no 
clinically significant abnormality as readdetermined by a radiologistthe investigator, the 
chest radiograph does not need to be repeated. 
SECTION 4.5.6:  Efficacy Assessments 
 
The Efficacy Assessor (or designee) should be a rheumatologist or other skilled 
arthritis assessor.  The Efficacy Assessor cannot be the Principal Investigator.  The 
efficacy assessor will be responsible for completing the joint counts and the 
Physician’s Global Assessment of Arthritis VAS.  To ensure consistent joint 
evaluation throughout the trial, individual patients should be evaluated by the same 
efficacy assessor whenever possible for all study visits. 
 


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SECTION 4.5.6.1.1:  Swollen and Tender Joint Count 
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 which 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.  Surgery should not occur 
during the trial except in the case of a documented emergency. 
 
Arthrocentesis:  Any joint that had 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.  If arthrocentesis is necessary at a visit, it should 
only be performed after the joint assessment at the visit has been completed. 
 
SECTION 4.5.6.1.2:  Tender/Painful Joint Count (68) 
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 (MCPMCPs I, II, 
III, IV, V), thumb interphalangeal, proximal interphalangeals (PIPs II, III, IV, V), distal 
interphalangeals (DIPs II, III, IV, V) 
 
Lower extremity:  Hip, knee, ankle, tarsus (includes subtalar, transverse tarsal and 
tarsometatarsal considered as one unit), metatarsophalangeals (MTPs I, II, III, IV, V), 
great toe interphalangeal, PIP and DIP combinedPIPs (PIPs II, III, IV, V) 
 
SECTION 4.5.6.2:  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), DAS 28-3 (CRP), 
and DAS 28-3 (ESR)  are presented in Appendix 14.   
SECTION 4.5.8:  Laboratory, Biomarker, and Other Biological Samples 
 
ESR:  Can beShould be performed at local laboratory or as a point-of-care test in 
clinic (with kits provided) in accordance with test guidelines 
 
PPD (if QFT not available):  Should be read locally per local guidelines 
Samples for the following laboratory tests will be sent to one or several central 
laboratories for analysis: 
 
hsCRP:  performed at the central laboratory will be blinded after the baseline visit. 
 
Quantiferon as appropriate 
 


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SECTION 4.5.9:  Electrocardiograms 
Triplicate ECG recordings will be obtained at specified timepoints within approximately 
2-5 minutes of each other, as outlined in the Schedule of Assessments (see Appendix 1 
and Appendix 2).   
Predose ECGs acquired on Day 1 and Day 28 should be as closely time-matched as 
feasible (morning only, morning visit requiredvisits are strongly recommended), and the 
patient should be fasting. ( 48 hours).  
All ECGs are toshould 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. whenever possible.   
SECTION 4.6.1:  Patient Discontinuation 
These patients are not eligible to enter the OLE Study GA30067 and should return for 
the 8-week safety follow-up visit in this study (see Appendix 1 and Appendix 2).  If the 
patient is unable to return for a follow-up visit, the trial site may contact the patient by 
telephone to determine their clinical status. 
SECTION 4.6.2:  Study Treatment Discontinuation 
Patients must permanently discontinue study treatment (with both oral study drug and 
SC comparator drug) (however patients should be asked to remain in the blinded study 
through Week 12 even if their study treatment is discontinued in order to minimize 
missing data that limits study interpretability) if they experience any of the following: 
 
Pregnancy 
 
Pregnancy (the patient may still remain in the blinded study at the investigator’s 
discretion) 
 
Anaphylaxis or other severe hypersensitivity reaction 
 
Malignancy  
 
Any serious infection or infection requiring treatment with an IV antimicrobial agent 
 
Any prohibited medication as defined in Section 4.4.2  
 
Grade  2 AST or ALT elevation: (AST or ALT  3  ULN) in combination with 
total bilirubin  2  ULN or clinical jaundice as defined by Hy’s law 
 
Grade  3 AST or ALT elevation: (AST or ALT  5  ULN) 
 
Any Grade 3 or greater thrombocytopenia (National Cancer Institute Common 
Terminology Criteria for Adverse Events [NCI CTCAE v4.0])  ]): Platelets 
 50,000/mm3 
 
Any Grade 4 neutropenia (NCI CTCAE v4.0)):  ANC  500/mm3 
 
Patients who discontinue study treatment prematurely for the reasons listed above will 
be and who do not remain in the blinded study will be asked to return to the clinic for an 
early termination visit (see Section 4.6.1) followed by 8 weeks of safety follow-up. 


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SECTION 5.1.3:  Management of Study Treatment in Patients Who 
Experience Specific Adverse Events 
If there are any other situations where it seems appropriate to hold and/or discontinue 
study treatment, please discuss with the Medical Monitor before reinitiating treatment. 
TABLE 5:  Guidelines for Management of Study Treatment in Patients Who 
Experience Specific Adverse Events 
Table 5 has been updated to clarify study treatment discontinuation. 
SECTION 5.3.5.8:  Deaths 
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.  The term "sudden death" should not 
be used unless combined with the presumed cause of death (e.g., "sudden cardiac 
death"). 
SECTION 5.3.5.11:  Hospitalization or Prolonged Hospitalization 
The following An event that leads to hospitalization scenarios areunder the following 
circumstances should not considered to be reported as an adverse eventsevent or a 
serious adverse event: 
The following An event that leads to hospitalization scenariounder the following 
circumstances is not considered to be a serious adverse eventsevent, but should be 
reported as an adverse eventsevent instead: 
 
SECTION 5.4.1:  Emergency Medical Contacts 
Medical Monitor Contact Information  
 Medical Monitor contact information: 
Medical Monitors: 
 Medical Monitor (Primary) 
 
 M.D. 
 
Argentina:  
 
 
Rest of WorldOffice:  
  
 
Mobile: 
 
United States:  
 
 
Email: 
 
 
 


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Alternate Medical MonitorMonitors contact information for all sites: 
Medical Monitor: 
, M.D. 
Telephone No.: 
 
Office: 
  
 
Mobile
 
 
Email: 
 
Emergency Telephone Nos. 
 
 
 
Sponsor Medical Monitor: 
, M.D. 
Telephone No.: 
Office: 
 
 
Email:
 
SECTION 6.1.1:  Cohort 1:  MTX-IR (Arms AE) 
An IA will be performed after 150 patients (~30 patients per arm) have completed the 
12 week assessment.  A sample size of 30 patients per arm has 80% power to detect a 
difference of 30% between the placebo (Arm D) and a GDC 0853treated arm for an 
ACR50 response rate of up to 20% in the placebo arm, with a two sided type one error 
rate of 0.2 with use of Fisher’s exact test.  The minimally detectable difference for 
superiority at the interim is an improvement of 20%.  No adjustment for multiple 
comparisons will be made.   
The overall sample-size may be increased by up to 20% depending on the outcome of the 
IA (see Section 6.8). 
SECTION 6.1.2:  Cohort 2:  TNF-IR (Arms FG) 
The purpose of this cohort is estimation and hypothesis generation regarding the effects 
of GDC-0853 on ACR50 response relative to placebo.  A target of approximately 
100 120 patients will be enrolled and randomized with a 1:1 ratio to the two treatment 
groups:  200 mg BID GDC-0853 (Arm F) or placebo (Arm G).  The study is designed to 
detect a significant difference in ACR50 response rates between the active and placebo 
arms at Day 84.  A sample size of 50approximately 5060 patients per arm provides 
80% power, respectively, to detect a difference of 20% for an ACR50 response rate of 
up to 152015% in the placebo arm (Arm G) with a two-sided type one error rate of 0.2 
with use of Fisher’s exact test. 
SECTION 6.4.2:  Secondary Efficacy Endpoints 
The key secondary efficacy analysis for the MTX-IR population will compare the 
proportion of patients achieving an ACR50 response between each of two higher 
dose-levels (Arm B and Arm C) of GDC-0853treated patients and ADA-treated patients 
(Arm E).  The Cochran-Mantel Haenszel test will be used to assess the difference in the 
proportion of responders, adjusted for the randomization stratification factor, 
geographic region.  The key secondary efficacy analysis for the TNF-IR cohort will 
compare the proportion of patients achieving an ACR50 response between GDC-


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0853treated patients (Arm F) with the placebo-treated arm (Arm G).  The Cochran-
Mantel Haenszel test will be used to assess the difference in the proportion of 
responders, adjusted for the randomization stratification factor,factors geographic region 
and prior exposure to a non-TNF inhibitor biologic.  The details for other secondary 
efficacy analyses will be specified in the DAP. 
SECTION 6.8.1.1:  Cohort 1:  MTX-IR (Arms AE) 
An IA for futility will be performed after approximately 150 patients have completed their 
12-week evaluation (~30 patients/arm).  The purpose of this IA is to assess the efficacy 
of the GDC-0853treated arms compared with the placebo-treated arm and to determine 
whether to terminate the study and whether to open the TNF IR cohort.  The IA for futility 
will be prepared by an IMC with selected members with no direct contact with 
investigational staff and monitors.  . Summaries of safety and efficacy data by treatment 
group will be prepared for reviewand reviewed by members of the IMC.  ; the IMC 
consists of Sponsor’s members who do not have direct contact with investigational staff 
and monitors.  No unblinded individual patient data will be shared with the members of 
the Sponsor’s study team, who have direct contact with investigational staff and 
monitors except for the PK scientist, statistician,case in which the IMC decides to 
unblind the study team to enable decision-making and the statistical programming 
analystpotential interactions with regulatory bodies.  Recruitment of patients will 
continue during the conduct of the IA.  Further details of the IA, including the use of the 
IMC and decision criteria, will be specified in the DAP.  No further IAs are planned in 
Cohort 1; however, given the hypothesis-generating nature of this study, the Sponsor 
may choose to conduct one subsequent efficacy IA.  It should be noted that other 
Sponsor representatives (e.g., governance committee members) who are not associated 
with the study team may review unblinded interim data to enable decision making. 
If the results of the IA yield encouraging evidence of activity in one or more BTK 
containing treatment groups relative to placebo and is accompanied by an unexpected 
placebo response rate (for example), the Sponsor may opt to increase enrollment by up 
to 20% to obtain greater precision for estimation of treatment differences. 
SECTION 6.8.1.2:  Cohort 2:  TNF-IR (Arms FG) 
No IA is planned in Cohort 2; however, given the hypothesis-generating nature of this 
study, the Sponsor may choose to conduct one efficacy IA.optional efficacy IA in order 
to guide internal decision making around issues such as the adequacy of dose ranging, 
the adequacy of sample sizes for safety and/or efficacy analyses, or to inform further 
development decisions.  The IA plan will be detailed in an updated Data Analysis Plan 
prior to conducting the IA.  The decision to conduct this optional IA and the timing of 
the analysis will be documented in the Sponsor’s trial master file prior to the conduct of 
the IA.  TheThis optional IA will be performed and interpreted by an IMC with no; the 
IMC consists of Sponsor’s members who do not have direct contact with investigational 
staff and monitors.  No unblinded individual patient data will be shared with the 
Sponsor’s IMC may decide to unblind the study team, except for the statistician, the 


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statistical programming analyst, and the PK scientist.  It should be noted that other 
Sponsor representatives (e.g., governance committee members) who are not associated 
with the study team may review unblinded interim data to enable decision -making. and 
potential interactions with regulatory bodies. 
APPENDIX 1:  SCHEDULE OF ASSESSMENTS (COHORT 1:  MTX-IR) 
Appendix 1 has been updated to reflect the changes in the main protocol. 
APPENDIX 2:  SCHEDULE OF ASSESSMENTS (COHORT 2:  TNF-IR) 
Appendix 2 has been updated to reflect the changes in the main protocol. 
APPENDIX 3:  SCHEDULE OF PHARMACOKINETIC AND 
BIOMARKER SAMPLES 
Appendix 3 has been updated to reflect the changes in the main protocol. 
APPENDIX 14:  DISEASE ACTIVITY SCORE 28 
Appendix 14 has been updated to reflect the changes in the main protocol. 
APPENDIX 15:  BLISTER WALLET CONFIGURATION FOR 
GDC-0853/PLACEBO ADMINISTRATION (COHORT 1 ONLY) 
Appendix 15 has been updated to reflect the changes in the main protocol. 
APPENDIX 16:  BOTTLE AND LABEL CONFIGURATION FOR GDC-
0853/PLACEBO ADMINISTRATION (COHORT 2 ONLY) 
Appendix 16 has been updated to reflect the changes in the main protocol. 
SAMPLE INFORMED CONSENT FORMS 
The sample Informed Consent Forms have been revised to reflect the changes to the 
protocol. 


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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 27 
PROTOCOL SYNOPSIS .................................................................................... 28 
1. 
BACKGROUND .......................................................................................... 43 
1.1 
Background on Rheumatoid Arthritis ..................................... 43 
1.2 
Background on Bruton’s Tyrosine Kinase and 
GDC-0853 ............................................................................. 43 
1.2.1 
Bruton’s Tyrosine Kinase ....................................................... 43 
1.2.2 
Nonclinical Experience with GDC-0853 ................................. 44 
1.2.3 
Clinical Experience with GDC-0853 ....................................... 45 
1.3 
Study Rationale and Benefit-Risk Assessment ...................... 46 
2. 
OBJECTIVES AND ENDPOINTS ............................................................... 50 
3. 
STUDY DESIGN ......................................................................................... 53 
3.1 
Description of the Study......................................................... 53 
3.1.1 
Cohort 1 (MTX-IR) ................................................................. 54 
3.1.2 
Internal Monitoring Committee ............................................... 56 
3.2 
End of Study and Length of Study ......................................... 56 
3.2.1 
Length of Study ..................................................................... 56 
3.2.2 
End of Study .......................................................................... 56 
3.3 
Rationale for Study Design .................................................... 56 
3.3.1 
Rationale for GDC-0853 Dose and Schedule ........................ 56 
3.3.2 
Rationale for Patient Population ............................................ 58 
3.3.3 
Rationale for Control Groups ................................................. 59 
3.3.3.1 Placebo Control Groups ....................................................... 59 
3.3.3.2 Active Control Group ............................................................ 59 
3.3.4 
Rationale for Biomarker Assessments ................................... 59 
3.3.5 
Rationale for PK Sample Collection Schedule ....................... 59 
3.3.6 
Rationale for Other Study Design Elements .......................... 60 
3.3.6.1 Efficacy Measurements ........................................................ 60 
3.3.6.2 Blinding Strategy .................................................................. 60 
3.3.6.3 Clinical Outcomes Assessments .......................................... 60 


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3.3.6.4 Stratification and Enrollment Cap ........................................ 61 
3.3.6.5 Methotrexate Therapy .......................................................... 61 
4. 
MATERIALS AND METHODS .................................................................... 61 
4.1 
Patients .................................................................................. 61 
4.1.1 
Inclusion Criteria .................................................................... 61 
4.1.2 
Exclusion Criteria ................................................................... 64 
4.2 
Method of Treatment Assignment and Blinding ..................... 68 
4.3 
Study Treatment .................................................................... 69 
4.3.1 
Formulation, Packaging, and Handling .................................. 69 
4.3.1.1 GDC-0853 and Placebo Tablet ............................................ 69 
4.3.1.2 Adalimumab and Adalimumab Placebo ................................ 69 
4.3.2 
Dosage, Administration, and Compliance .............................. 70 
4.3.2.1 GDC-0853 and Placebo Dose and 
Administration ..................................................................................... 70 
4.3.2.2 GDC-0853 and Placebo Compliance ................................... 71 
4.3.2.3 Adalimumab and Placebo Dose and 
Administration ..................................................................................... 72 
4.3.3 
Required Background Treatment for Rheumatoid        
Arthritis            .......................................................................................... 73 
4.3.3.1 Methotrexate ........................................................................ 73 
4.3.3.2 Folic Acid .............................................................................. 73 
4.3.4 
Investigational Medicinal Product Accountability ................... 74 
4.3.5 
Post-Trial Access to GDC-0853 ............................................. 74 
4.4 
Concomitant Therapy, Prohibited Food, and 
Additional Restrictions ........................................................... 74 
4.4.1 
Permitted Therapy ................................................................. 75 
4.4.1.1 Corticosteroids ..................................................................... 75 
4.4.1.2 Non-Steroidal Anti-Inflammatory Drugs ................................ 75 
4.4.1.3 Analgesics Other than NSAIDs ............................................ 75 
4.4.1.4 Dietary Supplements ............................................................ 76 
4.4.1.5 Acid-Reducing Agents .......................................................... 76 
4.4.2 
Prohibited Therapy ................................................................ 76 
4.4.2.1 Live or Attenuated Vaccinations ........................................... 77 
4.4.2.2 CYP3A Inhibition .................................................................. 78 


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4.4.3 
Prohibited Food ..................................................................... 79 
4.4.4 
Additional Restrictions ........................................................... 79 
4.5 
Study Assessments ............................................................... 79 
4.5.1 
Informed Consent Forms and Screening Log ........................ 80 
4.5.1.1 Retesting: Laboratory Inclusion/Exclusion ............................ 80 
4.5.1.2 Rescreening ......................................................................... 81 
4.5.2 
Medical History and Demographic Data ................................ 81 
4.5.3 
Physical Examinations ........................................................... 81 
4.5.4 
Vital Signs .............................................................................. 82 
4.5.5 
Chest Radiograph .................................................................. 82 
4.5.6 
Efficacy Assessments ............................................................ 82 
4.5.6.1 ACR Assessments ............................................................... 84 
4.5.6.2 DAS Assessments ................................................................ 86 
4.5.7 
Patient-Reported and Clinician-Reported 
Outcomes   .............................................................................................. 86 
4.5.7.1 Patient’s Assessment of Arthritis Pain .................................. 87 
4.5.7.2 Patient’s Global Assessment of Arthritis ............................... 87 
4.5.7.3 Physician’s Global Assessment of Arthritis .......................... 87 
4.5.7.4 Health Assessment Questionnaire-Disability 
Index       ............................................................................................. 87 
4.5.7.5 Short-Form 36 Health Survey Questionnaire, 
Version 2 ............................................................................................ 88 
4.5.7.6 Functional Assessment of Chronic Illness 
Therapy-Fatigue Scale (FACIT-Fatigue) ............................................ 88 
4.5.8 
Laboratory, Biomarker, and Other Biological 
Samples      .............................................................................................. 88 
4.5.9 
Electrocardiograms ................................................................ 90 
4.5.10 
Optional Samples for Whole-Genome 
Sequencing .............................................................................................. 92 
4.5.11 
Samples for Roche Clinical Repository.................................. 92 
4.5.11.1 Overview of the Roche Clinical Repository ........................ 92 
4.5.11.2 Sample Collection .............................................................. 93 
4.5.11.3 Confidentiality ..................................................................... 93 
4.5.11.4 Consent to Participate in the Roche Clinical 
Repository .......................................................................................... 94 


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4.5.11.5 Withdrawal from the Roche Clinical Repository ................. 94 
4.5.11.6 Monitoring and Oversight ................................................... 95 
4.6 
Patient, Treatment, Study, and Site 
Discontinuation ...................................................................... 95 
4.6.1 
Patient Discontinuation .......................................................... 95 
4.6.2 
Study Treatment Discontinuation ........................................... 96 
4.6.3 
Study and Site Discontinuation .............................................. 96 
5. 
ASSESSMENT OF SAFETY ....................................................................... 97 
5.1 
Safety Plan ............................................................................ 97 
5.1.1 
Safety Plan for Potential Risks Associated with 
GDC-0853   .............................................................................................. 97 
5.1.1.1 Infections .............................................................................. 97 
5.1.1.2 Vaccinations ......................................................................... 98 
5.1.1.3 Bleeding ............................................................................... 99 
5.1.1.4 Cytopenias ......................................................................... 100 
5.1.1.5 Gastrointestinal Effects ...................................................... 101 
5.1.1.6 Hepatotoxicity ..................................................................... 101 
5.1.1.7 Cardiovascular Effects ....................................................... 102 
5.1.1.8 Vascular Inflammation ........................................................ 103 
5.1.1.9 Malignancy ......................................................................... 103 
5.1.2 
Potential Risks with Adalimumab ......................................... 104 
5.1.2.1 Hypersensitivity Reactions ................................................. 104 
5.1.2.2 Local Injection-Site Reactions ............................................ 104 
5.1.3 
Management of Study Treatment in Patients Who 
Experience Specific Adverse Events ..................................................... 104 
5.2 
Safety Parameters and Definitions ...................................... 108 
5.2.1 
Adverse Events ................................................................... 108 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor) ...................................................................................... 108 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .................................................................... 109 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters .............................................. 110 
5.3.1 
Adverse Event Reporting Period ......................................... 110 


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5.3.2 
Eliciting Adverse Event Information ..................................... 110 
5.3.3 
Assessment of Severity of Adverse Events ......................... 110 
5.3.4 
Assessment of Causality of Adverse Events ....................... 111 
5.3.5 
Procedures for Recording Adverse Events .......................... 112 
5.3.5.1 Injection-Site Reaction ....................................................... 112 
5.3.5.2 Diagnosis versus Signs and Symptoms ............................. 112 
5.3.5.3 Adverse Events That Are Secondary to Other 
Events     .......................................................................................... 113 
5.3.5.4 Persistent or Recurrent Adverse Events ............................ 113 
5.3.5.5 Abnormal Laboratory Values .............................................. 113 
5.3.5.6 Abnormal Vital Sign Values ................................................ 114 
5.3.5.7 Abnormal Liver Function Tests ........................................... 115 
5.3.5.8 Deaths ................................................................................ 115 
5.3.5.9 Preexisting Medical Conditions .......................................... 115 
5.3.5.10 Lack of Efficacy or Worsening of Rheumatoid 
Arthritis      ........................................................................................ 116 
5.3.5.11 Hospitalization or Prolonged Hospitalization .................... 116 
5.3.5.12 Adverse Events Associated with an Overdose 
or Error in Drug Administration ......................................................... 116 
5.3.5.13 Patient-Reported Outcome Data ...................................... 117 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor ........................................................ 117 
5.4.1 
Emergency Medical Contacts .............................................. 117 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest ..................................... 118 
5.4.2.1 Events That Occur prior to Study Drug Initiation ................ 118 
5.4.2.2 Events That Occur after Study Drug Initiation .................... 118 
5.4.3 
Reporting Requirements for Pregnancies ............................ 119 
5.4.3.1 Pregnancies in Female Patients ......................................... 119 
5.4.3.2 Pregnancies in Female Partners of Male 
Patients   .......................................................................................... 119 
5.4.3.3 Congenital Anomalies/Birth Defects and 
Abortions .......................................................................................... 119 
5.4.4 
Reporting Requirements for Medical Device 
Complaints  ............................................................................................ 120 


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5.5 
Follow-Up of Patients after Adverse Events ........................ 120 
5.5.1 
Investigator Follow-Up ......................................................... 120 
5.5.2 
Sponsor Follow-Up .............................................................. 120 
5.6 
Post-Study Adverse Events ................................................. 121 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees ............................................................... 121 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ..................... 121 
6.1 
Determination of Sample Size ............................................. 121 
6.1.1 
Cohort 1: MTX-IR (Arms AE) ............................................. 121 
6.1.2 
Cohort 2: TNF-IR (Arms FG) ............................................. 122 
6.2 
Summaries of Conduct of Study .......................................... 122 
6.3 
Summaries of Demographic and Baseline 
Characteristics ..................................................................... 122 
6.4 
Efficacy Analyses ................................................................ 122 
6.4.1 
Primary Efficacy Endpoint .................................................... 122 
6.4.2 
Secondary Efficacy Endpoints ............................................. 123 
6.5 
Safety Analyses ................................................................... 123 
6.6 
Pharmacokinetic Analyses ................................................... 123 
6.7 
Biomarker Analyses ............................................................. 123 
6.8 
Interim Analysis ................................................................... 124 
6.8.1 
Planned Interim Analysis ..................................................... 124 
6.8.1.1 Cohort 1: MTX-IR (Arms AE) ............................................ 124 
6.8.1.2 Cohort 2: TNF-IR (Arms FG) ............................................ 124 
7. 
DATA COLLECTION AND MANAGEMENT ............................................. 125 
7.1 
Data Quality Assurance ....................................................... 125 
7.2 
Electronic Case Report Forms ............................................. 125 
7.3 
Electronic Patient-Reported Outcome Data ......................... 125 
7.4 
Source Data Documentation ................................................ 126 
7.5 
Use of Computerized Systems ............................................ 126 
7.6 
Retention of Records ........................................................... 127 
8. 
ETHICAL CONSIDERATIONS .................................................................. 127 
8.1 
Compliance with Laws and Regulations .............................. 127 


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8.2 
Informed Consent ................................................................ 127 
8.3 
Institutional Review Board or Ethics Committee .................. 128 
8.4 
Confidentiality ...................................................................... 129 
8.5 
Financial Disclosure ............................................................ 129 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 129 
9.1 
Study Documentation .......................................................... 129 
9.2 
Protocol Deviations .............................................................. 130 
9.3 
Site Inspections ................................................................... 130 
9.4 
Administrative Structure....................................................... 130 
9.5 
Publication of Data and Protection of Trade 
Secrets ................................................................................ 130 
9.6 
Protocol Amendments ......................................................... 131 
10. REFERENCES ......................................................................................... 132 
 
 
LIST OF TABLES 
Table 1 
Primary, Secondary, Safety, Pharmacokinetic, and 
Exploratory Objectives with Corresponding Endpoints ............... 51 
Table 2 
GDC-0853 Dosing Regimen by Treatment Arm (Cohorts 1 
and 2) .......................................................................................... 71 
Table 3 
Roles and Data Access for Specific Site Personnel .................... 84 
Table 4 
Proposed Non-Inherited Biomarkers for Exploratory 
Research..................................................................................... 90 
Table 5 
Guidelines for Management of Study Treatment in Patients 
Who Experience Specific Adverse Events ................................ 105 
Table 6 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 111 
Table 7 
Causal Attribution Guidance ..................................................... 112 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 54 
 


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LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments (Cohort 1: MTX-IR) ......................... 136 
Appendix 2 
Schedule of Assessments (Cohort 2: TNF-IR) .......................... 141 
Appendix 3 
Schedule of Pharmacokinetic and Biomarker Samples ............ 147 
Appendix 4 
Appropriate Equivalent Morphine Doses 
of Common Opioid Analgesics .................................................. 150 
Appendix 5 
Concomitant Medications (Including Foods and Herbal 
Products)................................................................................... 151 
Appendix 6 
National Cholesterol Education Program (NCEP) Guidelines ... 153 
Appendix 7 
Clinical Criteria for Diagnosing Anaphylaxis.............................. 160 
Appendix 8 
Childbearing Potential, Pregnancy Testing, and 
Contraception ............................................................................ 161 
Appendix 9 
2010 American College of Rheumatology/European League 
Against Rheumatism Classification Criteria for Rheumatoid 
Arthritis ...................................................................................... 163 
Appendix 10 ACR Classification of Functional Capacity in Rheumatoid 
Arthritis ...................................................................................... 165 
Appendix 11 Health Assessment Questionnaire-Disability Index (HAQ-DI) ... 166 
Appendix 12 The Short-Form 36 Version 2 Health Survey (SF-36v2) ........... 169 
Appendix 13 Functional Assessment of Chronic Illness Therapy Fatigue 
(FACIT-Fatigue) Scale .............................................................. 176 
Appendix 14 Disease Activity Score 28 ......................................................... 177 
Appendix 15 Blister Wallet Configuration for GDC-0853/Placebo 
Administration (Cohort 1 Only) .................................................. 178 
Appendix 16 Bottle and Label Configuration for GDC-0853/Placebo 
Administration (Cohort 2 Only) .................................................. 179 


 
GDC-0853—Genentech, Inc. 
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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A TWO-COHORT RANDOMIZED PHASE II, 
DOUBLE-BLIND, PARALLEL GROUP STUDY IN 
PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS 
EVALUATING THE EFFICACY AND SAFETY OF 
GDC-0853 COMPARED WITH PLACEBO AND 
ADALIMUMAB IN PATIENTS WITH AN INADEQUATE 
RESPONSE TO PREVIOUS METHOTREXATE THERAPY 
(COHORT 1) AND COMPARED WITH PLACEBO IN 
PATIENTS WITH AN INADEQUATE RESPONSE OR 
INTOLERANCE TO PREVIOUS TNF THERAPY 
(COHORT 2) 
PROTOCOL NUMBER: GA29350 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2016-000335-40 
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. 
28/Protocol GA29350, Version 4 
PROTOCOL SYNOPSIS 
TITLE: 
A TWO-COHORT RANDOMIZED PHASE II, DOUBLE-BLIND, 
PARALLEL GROUP STUDY IN PATIENTS WITH ACTIVE 
RHEUMATOID ARTHRITIS EVALUATING THE EFFICACY AND 
SAFETY OF GDC-0853 COMPARED WITH PLACEBO AND 
ADALIMUMAB IN PATIENTS WITH AN INADEQUATE RESPONSE 
TO PREVIOUS METHOTREXATE THERAPY (COHORT 1) AND 
COMPARED WITH PLACEBO IN PATIENTS WITH AN 
INADEQUATE RESPONSE OR INTOLERANCE TO PREVIOUS 
TNF THERAPY (COHORT 2) 
PROTOCOL NUMBER: 
GA29350 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2016-000335-40 
IND NUMBER: 
120,162 
TEST PRODUCT: 
GDC-0853 (RO7010939) 
PHASE: 
II 
INDICATION: 
Rheumatoid Arthritis 
SPONSOR: 
Genentech, Inc. 
 
Objectives and Endpoints 
This study will evaluate the efficacy and safety of GDC-0853 compared with placebo (Cohorts 1 
and 2) and compared with ADA (Cohort 1), each in combination with methotrexate (MTX), in 
patients with moderate to severe active rheumatoid arthritis (RA).  Specific objectives and 
corresponding endpoints for the study are outlined below. 


 
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29/Protocol GA29350, Version 4 
Objective(s) 
Corresponding Endpoint(s) 
Primary Efficacy Objective 
• To evaluate the efficacy of GDC-0853 at three dose 
levels compared with placebo used in combination with 
stable doses of MTX in patients with active RA who 
have had an inadequate response to MTX and are 
naive to TNF therapy (Cohort 1: MTX-IR) 
• ACR50 response rates at Day 84 
Key Secondary Efficacy Objectives 
• To evaluate the efficacy of GDC-0853 compared with 
ADA used in combination with stable doses of MTX in 
patients with active RA who have had an inadequate 
response to MTX and who are naive to TNF therapy 
(Cohort 1: MTX-IR) 
• ACR50 response rates at Day 84 
• To evaluate the efficacy of GDC-0853 compared with 
placebo used in combination with stable doses of MTX 
in patients with active RA who have had an inadequate 
response or intolerance to 1 or 2 TNF inhibitors and 
may have been previously exposed to no more than 
one non-TNF biologic (Cohort 2:  TNF-IR) 
• ACR50 response rates at Day 84 
Secondary Efficacy Objectives 
• To evaluate the efficacy of GDC-0853 over time with 
multiple standardized assessments  
• ACR20, ACR70, DAS 28-3 (CRP), DAS 28-4 
(CRP), DAS 28-3 (ESR), and DAS 28-4 (ESR) 
response rates, change from baseline SDAI, and 
change from baseline CDAI at Days 7, 14, 28, 56, 
and 84 
• To assess the efficacy of GDC-0853 over time  
• ACR50 response rates at Days 7, 14, 28, and 56 
• To assess efficacy on the basis of the individual 
components of the ACR 
Response rates at Days 7, 14, 28, 56, and 84 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 assess DAS28 remission (< 2.6) and LDA (< 3.2) 
state 
• States at Days 7, 14, 28, 56, and 84 
• 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 at Days 7, 14, 28, 56, and 84 
• To assess SDAI-based remission (defined as ≤ 3.3 for 
ACR/EULAR remission) and CDAI-based remission 
(defined as ≤ 2.8) 
• Remission at Days 7, 14, 28, 56, and 84 
• To evaluate the effect of GDC-0853 compared with 
placebo on health-related quality of life 
• SF-36, standard, Version 2, questionnaire at 
Day 84 
• To evaluate the effect of GDC-0853 compared with 
placebo on fatigue 
• FACIT-Fatigue measure at Day 84 


 
GDC-0853—Genentech, Inc. 
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Safety Objective 
 To evaluate the safety of GDC-0853 given in 
combination with MTX in patients with moderate to 
severe RA 
 The nature, frequency, severity, and timing of 
adverse events 
 Changes in vital signs, physical findings, ECGs, 
and clinical laboratory results following GDC-0853 
administration 
Pharmacokinetic Objective: 
 To characterize the pharmacokinetics of GDC-0853 in 
patients using a population PK approach 
 Steady-state PK parameters (AUC0-t, Cmax, Tmax, 
Ctrough, t1/2, apparent CL/F)  
Exploratory Pharmacokinetic Objectives 
 To evaluate the relationship between measures of drug 
exposure and pharmacodynamic effect(s), efficacy, 
and safety of GDC-0853 
 Exploratory biomarker measures in Table 4 
 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 covariates on 
measures of GDC-0853 exposure and/or response 
 Steady-state PK parameters (AUC0-t, Cmax, Tmax, 
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, Cmax, Tmax, 
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 if 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; ADA  adalimumab; AUC0-t  area under the concentration 
time-curve from time 0 to time t; Cmax  maximum observed plasma concentration; Ctrough  minimum 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; 
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; PK  pharmacokinetic; RA  rheumatoid arthritis; SDAI  Simplified Disease Activity 
Index; SF-36  Short-Form 36 Health Survey; t1/2  half-life; Tmax  time to maximum concentration; TNF  tumor 
necrosis factor. 
 
Study Design 
Description of Study 
This is a multicenter, Phase II, randomized, double-blind, placebo-controlled, active comparator 
(Cohort 1 only), parallel-group, dose-ranging study to evaluate the efficacy and safety of GDC-
0853 in patients with moderate to severe active RA and an inadequate response to previous 
MTX therapy (Cohort 1) or MTX and TNF therapy who may have also had exposure to no more 
than one non-TNF inhibitor biologic (Cohort 2).  Moderate to severe active RA is defined by 
 6 tender/painful joints on motion (68 joint count) and  6 swollen joints (66 joint count) at both 
screening and Day 1 (randomization), as well as a high sensitivity C-reactive protein (hsCRP) 
 0. 400 mg/dL for Cohort 1 and a hsCRP  0.650 mg/dL for Cohort 2 at screening.  


 
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Improvement in disease activity will be measured using the American College of Rheumatology 
(ACR) response rate.   
This study will enroll approximately 600 patients.  In Cohort 1, approximately 480 MTX-IR 
patients will be randomized to placebo, ADA, or one of 3 doses of GDC-0853 (50 mg QD, 150 
mg QD, or 200 mg BID).  In Cohort 2, approximately 120 TNF-IR patients will be 
randomized to placebo or 200 mg BID GDC-0853 (see Figure 1).  
At any time during the study, the Sponsor may choose to inactivate and suspend enrollment 
and further dosing for a given treatment arm (Cohort 1) or reduce the dose in Arm F (Cohort 
2) due to safety concerns, and as guided by the IMC.  In Cohort 1, subsequently enrolled 
patients will be randomly allocated to the remaining arms. 
After the screening period (up to 28 days), patients in both cohorts will receive blinded study 
drug (oral GDC-0853 or matching placebo) for 12-weeks, after which they will have the option of 
either entering an 8-week follow-up period or enrolling into an open-label extension (OLE) study 
(Study GA30067).  In addition to study drug, patients in Cohort 1 will also be treated with the 
subcutaneous (SC) comparator drug (ADA or placebo). 
Cohort 1 treatment regimens:  Patients in Cohort 1 will be randomly assigned in a 
1:1:1:1:1 fashion to 1 of 5 parallel treatment arms; once enrollment in Arm A has completed, 
patients will be randomized 1:1:1:1 across the 4 remaining treatment arms: 
 
Arm A:  50 mg QD GDC-0853 (BID tablets)   placebo injections SC every 2 weeks (Q2W) 
(n  40) 
 
Arm B:  150 mg QD GDC-0853 (BID tablets)   placebo injections SC Q2W (n  110) 
 
Arm C:  200 mg BID GDC-0853 (BID tablets)   placebo injections SC Q2W (n  110) 
 
Arm D:  placebo (BID tablets)   placebo injections SC Q2W (n  110) 
 
Arm E:  placebo (BID tablets)   40 mg ADA injections SC Q2W (n  110) 
Cohort 2 treatment regimens:  Patients in Cohort 2 will be randomly assigned in a 1:1 fashion 
to 1 of 2 parallel treatment arms: 
 
Arm F:  200 mg BID GDC-0853 (BID tablets; approximately n  60) 
 
Arm G:  placebo (BID tablet; approximately n  60) 
Patients must enter and remain on stable MTX treatment and a stable dose of folic acid while in 
the study. 
For patients receiving chronic non-steroidal anti-inflammatory drug (NSAIDs) and/or 
corticosteroids, the continued use of stable (for at least 2 weeks prior to randomization) oral 
NSAIDs and/or stable (for at least 6 weeks prior to randomization) oral corticosteroid 
( 10 mg/day prednisone equivalent) doses is allowed and should be continued unchanged 
throughout the study, unless an adjustment is necessary for safety reasons.   
Patients receiving proton pump inhibitors (PPIs) or H2 receptor antagonists (H2RAs) should be 
stabilized on a regimen beginning at least 2 weeks prior to randomization and continuing 
throughout the study. 
Safety will be assessed at regular intervals by the Sponsor’s Internal Monitoring Committee for 
the duration of the study.   
Number of Subjects 
This study will enroll approximately 600 patients.  Approximately 480 patients will take part in 
Cohort 1, and approximately 120 patients will take part in Cohort 2. 
Target Population 
Inclusion Criteria 
All patients must meet the following criteria for study entry: 
 
Age 18 to 75 years at screening 
 
Able and willing to provide written informed consent and to comply with the requirements of 
the protocol 
 
Have a diagnosis of adult-onset RA as defined by the 2010 ACR/European League Against 
Rheumatism Classification Criteria for RA 


 
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 
RA disease activity by joint counts and laboratory markers of inflammation: 
 6 tender/painful joints on motion (68 joint count) and  6 swollen joints (66 joint count) 
at BOTH screening and Day 1 (randomization)  
 
At screening, must have hsCRP as follows: 
Cohort 1:   0.400 mg/dL (may be repeated once) 
Cohort 2:   0.650 mg/dL (may be repeated once) 
 
Positive for anti-cyclic citrullinated protein/peptide antibody (anti-CCP or ACPA), rheumatoid 
factor, or both (if based on historical data, need documentation of prior positive laboratory 
value in the electronic Case Report Form) 
 
Have received MTX for at least 12 weeks immediately prior to randomization, of which the 
last 8 weeks prior to randomization must have been at a stable dose of between 7.5 and 
25 mg/week (oral or parenteral)  
For patients entering the trial on MTX doses  15 mg/week, there must be clear 
documentation in the medical record that higher doses were not tolerated or that the 
dose of MTX is the highest acceptable dose based on local clinical practice guidelines.  
 
Willing to withdraw all non-biologic disease-modifying anti-rheumatic drugs (DMARDs), 
other than MTX and leflunomide, at least 4 weeks prior to randomization.  Patients 
previously on leflunomide must have either discontinued  8 weeks prior to randomization 
or discontinued with the following elimination procedure at least 28 days prior 
randomization: 
Cholestyramine or activated charcoal should be taken at standard doses for a 
minimum of 6 days but ideally for the standard 11 days (Arava U.S. Package Insert; 
Arava Summary of Product Characteristics) 
 
Willing to receive treatment at an adequate and stable dose of folic acid (not less than 5 mg 
total dose weekly) during study 
 
Only for patients currently receiving oral corticosteroids:  Treatment must be at a stable 
dose of  10 mg/d prednisone (or equivalent) during the 6 weeks prior to randomization and 
with a plan to remain at a stable dose for the duration of the study. 
 
Only for patients currently receiving NSAIDs on a regular basis (e.g., not as needed)::  
Treatment must be at a stable dose during the 2 weeks prior to randomization and with a 
plan to remain at a stable dose for the duration of the study. 
 
Only for patients currently receiving PPIs or H2RAs:  Treatment must be at a stable dose 
during the 2 weeks prior to randomization and with a plan to remain at a stable dose for the 
duration of the study. 
 
No evidence of active or latent or inadequately treated infection with Mycobacterium 
tuberculosis (TB) as defined by all of the following: 
A negative QuantiFERON TB-Gold (QFT) or, if QFT unavailable, a Mantoux Purified 
Protein Derivative (PPD) skin test (performed per Centers for Disease Control and 
Prevention guidelines with use of 5 tuberculin units per 0.1 mL) result of  5 mm of 
induration, performed at the screening visit or within the 3 months prior to screening 
Patients with a history of Bacille Calmette-Guérin vaccination should be screened 
using the QFT test only.  
An indeterminate QFT test should be repeated.  
A positive QFT test or two successive indeterminate QFT results should be 
considered a positive diagnostic TB test.  
An indeterminate QFT test followed by a negative QFT test should be considered a 
negative diagnostic TB test. 


 
GDC-0853—Genentech, Inc. 
33/Protocol GA29350, Version 4 
A chest radiograph taken at the screening visit or documented results within the 
3 months prior to screening (must be read by a radiologist), without changes 
suggestive of active TB infection 
If a patient has previously received an adequate documented course of therapy for 
either latent (9 months of isoniazid in a locale where rates of primary 
multidrug-resistant TB infection are  5% or an acceptable alternative regimen, 
according to local guidelines) or active (acceptable multidrug regimen, according to 
local guidelines) TB infection, neither a PPD test nor a QFT test need be obtained, but 
a chest radiograph must still be obtained if not done so within the prior 3 months; this 
chest radiograph must be without changes suggestive of active TB infection. 
 
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 or longer if required per the local prescribing 
label for ADA 
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 
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. 
 
To be enrolled into Cohort 2, patients must also meet the following criteria:  
 
Experienced an inadequate response or intolerance to previous treatment with at least one 
and no more than 2 biologic TNF inhibitors (e.g., infliximab, etanercept, adalimumab, 
golimumab, or certolizumab, or biosimilar equivalent) and in the opinion of the investigator either of 
the following (which must be documented in the eCRF):  
– 
Experienced insufficient efficacy or loss of efficacy at a dose and duration that, in 
accordance with local clinical practice, is considered acceptable to adequately assess 
clinical response  
– 
Experienced intolerance of such treatment 


 
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 
May have also been exposed to no more than one non-TNFα inhibitor biologic (e.g., 
abatacept, tocilizumab, sarilumab, sirukumab, anakinra, or any biologics or or biosimilar 
equivalents with the same mode of action to the listed agents, including investigational 
biosimilar agents).    
 
Exclusion Criteria 
Patients who meet any of the following criteria must be excluded from study entry: 
 
History of or current inflammatory joint disease other than RA (e.g., gout requiring current 
treatment, reactive arthritis, psoriatic arthritis, seronegative spondyloarthritis, Lyme disease) 
or other systemic autoimmune disorder (e.g., systemic lupus erythematosus, inflammatory 
bowel disease, scleroderma, inflammatory myopathy, mixed connective tissue disease, or 
other overlap syndrome) 
 
Systemic involvement secondary to RA leading to clinically significant organ dysfunction 
or increased risk for participation in the study, in the opinion of the investigator. For 
example, patients with known RA vasculitis, pulmonary fibrosis, or Felty’s syndrome should 
be excluded.  Exceptions are as follows:  
– 
Sjogren’s syndrome with RA is allowable 
– 
Anemia secondary to RA (if Hgb is greater than or equal to 8.5 mg/dL) is allowable. 
 
Functional Class IV, according to the ACR 1991 Revised Criteria for Global Functional 
Status in Rheumatoid Arthritis 
 
Major surgery, including bone/joint surgery (e.g., joint fusion) within 8 weeks prior to 
screening or joint surgery planned within 12 weeks following randomization 
 
Previous treatment with GDC-0853 or other BTK inhibitors 
 
History of treatment with cell-depleting therapy including B celldepleting therapy (e.g., 
anti-CD20directed therapy such as rituximab) 
 
History of treatment with any non-TNF inhibitor biologic DMARD (e.g., anti-CD20directed 
therapy [e.g., rituximab], anti-IL6–directed therapy [e.g., tocilizumab], or T cell–directed 
therapy [e.g., abatacept]) including biosimilar equivalents 
 
Any condition or medication that precludes the use of or is contraindicated with MTX or folic 
acid, according to the local prescribing label or the investigator (e.g., patients with pleural 
effusion, ascites, or who are on concomitant acitretin) 
 
History of treatment with tofacitinib or other Janus kinase (JAK) inhibitor(s) (approved or 
experimental) 
 
Prior to randomization, must have discontinued all biologic therapies as follows: 
Etanercept and etanercept biosimilar agents for  2 weeks 
All other biologic agents (including biosimilars and investigational biosimilars 
to approved agents) for  28 days  
 
Previous exposure to any investigational agent (not including investigational biosimilars 
to approved therapies) within 12 weeks or 5 half-lives of the investigational agent, 
whichever is longer, prior to randomization 
 
Previous treatment within 6 months of randomization with IV gamma globulin or the 
Prosorba Column 
 
History of treatment with alkylating agents such as cyclophosphamide or chlorambucil or 
with total lymphoid irradiation 
 
Require any prohibited concomitant medications (see Section 4.4.2).  
 
Current treatment with corticosteroids at doses  10 mg/d of prednisone (or equivalent)  
 
Intra-articular or parenteral corticosteroids within 4 weeks prior to and during screening  


 
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 
History of live attenuated vaccine within 6 weeks prior to randomization or requirement to 
receive these vaccinations at any time during study drug treatment 
Seasonal influenza and H1N1 vaccinations are permitted if the inactivated vaccine 
formulations are administered.  
 
Evidence of serious uncontrolled concomitant cardiac, neurologic, pulmonary (including 
obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes 
mellitus), metabolic, or GI disease that, in the investigator’s opinion, would preclude patient 
participation 
 
Patients meeting the New York Heart Association Class III and Class IV criteria for 
congestive heart failure: 
Class III:  Patients with marked limitation of activity; they are comfortable only at rest 
Class IV:  Patients who should be at complete rest, confined to bed or chair; any 
physical activity brings on discomfort and symptoms occur at rest 
 
Screening 12-lead ECG that demonstrates clinically relevant abnormalities that may affect 
patient safety or interpretation of study results, including 
QT interval corrected using Fridericia’s formula (QTcF)  440 ms demonstrated by at 
least two ECGs  30 minutes apart 
 
History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as long 
QT syndrome and other genetic risk factors (e.g., Brugada syndrome), structural heart 
disease (e.g., severe left ventricular systolic dysfunction, severe left ventricular hypertrophy), 
coronary heart disease (CHD; symptomatic, or with ischemia demonstrated by diagnostic 
testing, prior coronary artery bypass grafting, or coronary lesions  70% diameter stenosis 
that have not been or cannot be re-vascularized), clinically significant electrolyte 
abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of 
sudden unexplained death or cardiac ion channel mutations (e.g., congenital long QT 
syndrome) 
 
Current treatment with medications that are well known to prolong the QT interval at doses that 
have a clinically meaningful effect on QT, as determined by the investigator.  The investigator may 
contact the Sponsor for confirmation if needed. The investigator may reference the website: 
https://www.crediblemeds.org/pdftemp/pdf/CompositeList.pdf. 
 
Uncontrolled disease states, such as asthma, psoriasis, or inflammatory bowel disease, 
where flares are commonly treated with oral or parenteral corticosteroids 
 
History of vasculitis 
 
Current liver disease that is clinically significant, in the opinion of the investigator 
 
Evidence of chronic and/or active hepatitis B or C 
Positive hepatitis B surface antigen (HBsAg) or hepatitis C serology (regardless of 
treatment status) 
Positive hepatitis B core antibody (HBcAb) 
 
Abnormalities in hepatic synthetic function tests (e.g., prothrombin [PT], INR, PTT, albumin) 
judged by the investigator to be clinically significant 
 
History of alcohol, drug, or chemical abuse within the 12 months prior to screening as 
determined by the investigator 
 
History of nongallstone-related pancreatitis or chronic pancreatitis that is judged to be clinically 
significant, in the opinion of the investigator (e.g., unexplained upper abdominal pain or 
malabsorptive diarrhea)   
 
Any known active infection (with the exception of fungal nail infections or oral herpes) 


 
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• 
History of recurrent bacterial, viral, mycobacterial or fungal infections (defined as > 2 similar 
episodes requiring anti-microbial treatment within the previous 12 months), with the 
exception of recurrent oral or genital herpes (HSV1/HSV2) 
• 
Any history of opportunistic infections that, in the Investigator or Sponsor’s judgment, would 
raise safety concerns regarding the patient's participation in the study 
• 
Any major episode of infection requiring hospitalization or treatment with IV anti-microbials 
within 8 weeks prior to and during screening or treatment with oral anti-microbials within 
2 weeks prior to and during screening 
Antimicrobials include antifungal, antibacterial, and antiviral agents. 
• 
History of or currently active primary or secondary immunodeficiency, including known 
history of HIV infection 
• 
History of cancer, including hematologic malignancy and solid tumors, within 10 years 
before screening; 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 > 1 year prior to screening are not exclusionary. 
• 
Women who are pregnant, nursing (breastfeeding), or intending to become pregnant during 
the study or within 60 days after completion of the study 
• 
For women of childbearing potential (including those who have had a tubal ligation):  
Positive serum pregnancy test result at screening or on Day 1; a serum pregnancy test is 
needed on Day 1 ONLY if the urine pregnancy test is positive (see Appendix 8 for definition 
of “childbearing potential”). 
• 
Neuropathies or other painful conditions that might interfere with pain evaluation, in the 
opinion of the investigator 
• 
Need for systemic anti-coagulation with warfarin, other oral or injectable anti-coagulants, or 
anti-platelet agents other than NSAIDs, aspirin, and other salicylates 
Aspirin at doses of up to 162 mg QD is allowed. 
• 
History of hospitalizations or transfusion for a GI bleed 
• 
History of CV accident (CVA) within 10 years, any history of hemorrhagic CVA, history of 
spontaneous intracranial hemorrhage, or history of traumatic intracranial hemorrhage 
within 10 years 
• 
Known bleeding diathesis 
• 
Any condition possibly affecting oral drug absorption (e.g., gastrectomy, clinically significant 
diabetic gastroenteropathy, or certain types of bariatric surgery such as gastric bypass); 
procedures such as gastric banding, that simply divide the stomach into separate 
chambers, are not exclusionary 
• 
Any uncontrolled clinically significant laboratory abnormality that would affect safety, 
interpretation of study data, or the patient’s participation in the study 
 
The following exclusion criteria are based on screening laboratory tests.  Laboratory tests may be 
repeated once during the screening period unless otherwise indicated (see Section 4.5.1.1): 
• 
Creatinine > 1.5 times the ULN (may be repeated if 1.5−2 × ULN) 
• 
ALT or AST > 1.5 times ULN (may be repeated if 1.5−3 × ULN) 
• 
Total bilirubin > ULN (may be repeated if 1−3 × ULN) 
• 
Hemoglobin < 8.5 g/dL (may be repeated if 7−8.4 g/dL) 
• 
ANC < 1.5 × 109/L (may be repeated if 1.2−1.5 × 109/L) 
• 
Platelet count < 100 × 109/L (may be repeated if 80−100 × 109/L) 
• 
IgG < 500 mg/dL (should not be repeated) 
 


 
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Additionally, patients who meet any of the following criteria will be excluded from Cohort 1: 
 
History of treatment with non-TNF inhibitor biologic for RA, including anti-IL6–directed 
therapy (e.g., tocilizumab, sarilumab, sirukumab), anti-IL1-directed therapy (e.g., anakinra), 
or T cell–directed therapy (e.g., abatacept) including biosimilar equivalents 
 
History of treatment with any TNF inhibitor (e.g., infliximab, etanercept, ADA, golimumab, or 
certolizumab), including biosimilar equivalents and investigational biosimilars to approved 
agents 
 
Any condition that is a contraindication for treatment with ADA in accordance with the 
approved local label   
 
History of anaphylactic or other serious allergic reaction to ADA 
 
End of Study 
The end of study is defined as the last patient, last safety follow-up visit in this protocol or the 
last patient in this protocol enrolled into the OLE Study GA30067, whichever is later. 
Length of Study 
The maximum time in the study for a patient is 24 weeks, including screening for up to 28 days, 
treatment for 12 weeks, and the safety follow-up period for 8 weeks (after the last dose of study 
drug).  Patients enrolling in OLE Study GA30067 for GDC-0853 will not enter the safety 
follow-up period of Study GA29350.   
Investigational Medicinal Products 
Test Product (Investigational Drug) 
The GDC-0853 dose levels are 50 mg QD, 150 mg QD, and 200 mg BID, with matching 
placebos.  Patients will receive GDC-0853/placebo BID, approximately every 12 hours starting 
on Day 1 and ending on Day 84.  Patients should be directed to take one dose (a total of 
4 tablets) BID (a total of 8 tablets each day).  On clinic visit days, patients should be instructed 
that study drug will be administered in the clinic.   
Arm 
GDC-0853 Dose 
(mg) 
No. of Tablets 
GDC-0853 
(a.m./p.m.) 
Placebo 
(a.m./p.m.) 
A 
50 
1/0 
3/4 
B 
150 
3/0 
1/4 
C 
200 
4/4 
0/0 
D 
0 
0/0 
4/4 
E 
0 
0/0 
4/4 
F 
200 
4/4 
0/0 
G 
0 
0/0 
4/4 
BID  twice daily. 
Note:  All patients will take 4 tablets BID (i.e., 8 tablets daily) 
regardless of assigned GDC-0853 dose regimen; therefore, 
patients may be receiving some placebo tablets as part of their 
daily dose in order to maintain the blind. 
 
Comparator 
ADA is to be administered at a dose of 40 mg SC every other week (starting on Day 1).  In this 
study, the ADA and ADA placebo are not visually identical.  To maintain the ADA blind, all SC 
comparator drug administration will be administered by the unblinded health-care professional 
in a manner that prevents the patient from observing which study treatments he or she is 
receiving.    


 
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Non-Investigational Medicinal Products 
Patients must enter and remain on stable MTX treatment and a stable dose of folic acid while in 
the study. 
Statistical Methods 
Primary Analysis 
Efficacy analyses will be conducted for the intent-to-treat population, defined as all randomized 
patients.  Sensitivity analyses of additional study populations (e.g., completers and per protocol 
[excluding major protocol violators]) will also be performed.  Exploratory subgroup analyses 
(e.g., based on baseline biomarker characteristics) may be also be conducted.   
The primary efficacy analysis will compare the proportion of patients achieving an ACR50 
response between each of three dose-levels (Arms A to C) of GDC-0853treated patients and 
placebo-treated patients (Arm D) at Day 84 for patients who had an inadequate response to 
MTX and are naive to TNF therapy.  Non-responder imputation will be implemented in the event 
of missing data.  The Cochran-Mantel-Haenszel test will be used to assess the difference in the 
proportion of responders, adjusted for the randomization stratification factor, geographic region.   
Determination of Sample Size   
Cohort 1 
The purpose of this cohort is estimation and hypothesis generation regarding the effects of 
GDC-0853 on ACR50 response relative to placebo and relative to ADA as the active 
comparator.  Point and interval estimates of the ACR50 response rates will be obtained.  A 
target of approximately 480 patients will be enrolled and randomized.  The first 200 patients will 
be randomly allocated in a 1:1:1:1:1 ratio to the five treatment arms:  50 mg QD GDC-0853 
(Arm A), 150 mg QD GDC-0853 (Arm B), 200 mg BID GDC-0853 (Arm C), placebo (Arm D), or 
ADA (Arm E).  The remaining 280 patients will be randomly allocated in a 1:1:1:1 ratio to 
Arms BE.  The study is designed to estimate differences in ACR50 response rates between 
the active comparator Arm E and GDC-0853treated Arms B or C at Day 84.  A sample size of 
110 patients per arm has 80% power to detect a difference of 15% between Arm E and Arm B 
or C, for an ACR50 response rate of up to 50% in the active comparator arm (Arm E), with a 
two-sided type-one error rate of 0.2 with the 2 test with continuity correction.  No adjustment for 
multiple comparisons is made. 
Cohort 2 
The purpose of this cohort is estimation and hypothesis generation regarding the effects of 
GDC-0853 on ACR50 response relative to placebo.  A target of approximately 120 patients will 
be enrolled and randomized with a 1:1 ratio to the two treatment groups:  200 mg BID 
GDC-0853 (Arm F) or placebo (Arm G).  The study is designed to detect a significant difference 
in ACR50 response rates between the active and placebo arms at Day 84.  A sample size of 
approximately 60 patients per arm provides 80% power to detect a difference of 20% for an 
ACR50 response rate of up to 20% in the placebo arm (Arm G) with a two-sided type one error 
rate of 0.2 with use of Fisher’s exact test.   
Interim Analyses 
An IA will be performed after approximately 150 patients have completed their 12-week 
evaluation (~30 patients/arm).  The purpose of this IA is to assess the efficacy of the GDC-
0853treated arms compared with the placebo-treated arm. Summaries of safety and efficacy 
data by treatment group will be prepared and reviewed by members of the IMC; the IMC 
consists of Sponsor’s members who do not have direct contact with investigational staff and 
monitors.  No unblinded individual patient data will be shared with the members of the 
Sponsor’s study team who have direct contact with investigational staff and monitors except 
for the case in which the IMC decides to unblind the study team to enable decision-making 
and potential interactions with regulatory bodies.  Recruitment of patients will continue during 
the conduct of the IA.  Further details of the IA, including the use of the IMC and decision 
criteria, will be specified in the DAP.  No further IAs are planned in Cohort 1; however, given the 
hypothesis-generating nature of this study, the Sponsor may choose to conduct one subsequent 
efficacy IA. 


 
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If the results of the IA yield encouraging evidence of activity in one or more BTK containing 
treatment groups relative to placebo and is accompanied by an unexpected placebo response 
rate (for example), the Sponsor may opt to increase enrollment by up to 20% to obtain greater 
precision for estimation of treatment differences.   
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ACPA 
anti-citrullinated protein/peptide antibody 
ACR 
American College of Rheumatology 
ADA 
adalimumab 
ALP 
alkaline phosphatase 
ASA 
acetylsalicylic acid 
AUC 
area under the concentration time-curve  
 
 
BCG 
Bacille Calmette-Guérin 
BCR 
B cellantigen receptor 
BID 
twice daily 
BTK 
Bruton’s tyrosine kinase 
Cmax 
maximum observed plasma concentration 
Ctrough 
minimum observed plasma concentration 
CBC 
complete blood count 
CCP 
cyclic citrullinated protein 
CDAI 
Clinical Disease Activity Index 
CHD 
coronary heart disease 
CIA 
collagen-induced arthritis 
ClinRO 
clinician-reported outcome 
CLL 
chronic lymphocytic leukemia 
CRP 
C-reactive protein 
CV 
cardiovascular 
CVA 
cardiovascular accident 
DAP 
Data Analysis Plan 
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 
EULAR 
European League Against Rheumatism 
FACIT 
Functional Assessment of Chronic Illness Therapy 
FACS 
fluorescence-activated cell sorting 
FDA 
U.S. Food and Drug Administration 


 
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Abbreviation 
Definition 
GGT 
gamma-glutamyl transpeptidase 
GI 
gastrointestinal 
GMR 
geometric mean ratio 
H2RA 
H2 receptor antagonist 
HAQ-DI 
Health Assessment QuestionnaireDisability Index 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HCP 
health-care professional 
HIPAA 
U.S. Health Insurance Portability and Accountability Act 
HN 
home nurse 
hsCRP 
high sensitivity C-reactive protein 
IA 
interim analysis 
 
 
 
 
ICH 
International Conference on Harmonisation 
IL 
interleukin 
IMC 
internal monitoring committee 
IMP 
investigational medicinal product 
IND 
Investigational New Drug 
IR 
inadequate response 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IV 
intravenous 
IxRS 
interactive voice and Web response system 
JAK 
Janus kinase 
MAD 
multiple-ascending dose 
MCP 
metacarpophalangeal 
MOA 
mechanism of action 
MTX 
methotrexate 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
NHL 
non-Hodgkin’s lymphoma 
NOAEL 
no-observed-adverse-effect level 
NSAID 
non-steroidal anti-inflammatory drug 
OLE 
open-label extension 
PD 
pharmacodynamic 
PFS 
prefilled syringe 


 
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Abbreviation 
Definition 
PK 
pharmacokinetic 
PIP 
proximal interphalangeal 
PO 
orally 
PPD 
purified protein derivative 
PPI 
proton pump inhibitor 
PRN 
as needed 
PRO 
patient-reported outcome 
PT 
prothrombin time 
Q2W 
every 2 weeks 
QD 
once daily 
QFT 
QuantiFERON TB -Gold 
QoL 
quality of life 
QTcF 
QT interval corrected using Fridericia’s formula 
RA 
rheumatoid arthritis 
RCR 
Roche Clinical Repository 
RF 
rheumatoid factor 
SAD 
single-ascending dose 
SC 
subcutaneous 
SDAI 
Simplified Disease Activity Index 
SF-36 
Short-Form 36 Health Survey 
SOC 
standard of care 
TB 
tuberculosis 
TBNK 
T, B, and natural killer cells 
TLR 
toll-like receptor 
TNF 
tumor necrosis factor 
ULN 
upper limit of normal 
VAS 
visual analog scale 
WGS 
whole-genome sequence 
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 (QoL), 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-]), 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 in 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 


 
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(Bruton 1952; Tsukada et al. 1993; Vetrie et al. 1993; Conley et al. 2005) and very low 
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, 
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, which suggests that BTK can be safely inhibited, 
especially in people with established immune systems.  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. 
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 PLC2- and Ca2-dependent signaling, which leads to the activation of 
NF-κBand NFAT-dependent pathways leading to cellular activation and differentiation 
(Niiro and Clark 2002). 
The therapeutic potential of BTK inhibitors as anti-cancer agents has been established in 
clinical trials with agents including ibrutinib, a covalent inhibitor of BTK, which has been 
approved in the United States and Europe for use in patients with mantle-cell lymphoma, 
chronic lymphocytic leukemia (CLL), and Waldenstrom’s macroglobulinemia. 
1.2.2 
Nonclinical Experience with GDC-0853 
GDC-0853 is a highly selective, orally administered, reversible inhibitor of BTK that is 
being developed by Genentech, Inc. as a potential therapeutic for autoimmune diseases, 
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-, IL-1, and IL-6) by preventing signaling through the 
FCRIII receptor (Di Paolo et al. 2011; Liu et al. 2011).  GDC-0853 effectively blocks 
BCR- and CD40-mediated activation and proliferation of B cells.  BTK in B cells also 
plays a role in TLR4-mediated B-cell proliferation and class switching.  In monocytes, 
GDC-0853 inhibits TLR4- and immune complex-mediated inflammatory cytokine 
production, including TNF-, which contributes to disease pathogenesis in RA.  In 
dendritic cells, BTK contributes to TLR8-mediated cytokine production (TNF-and IL-6) 
(Sochorová et al. 2007).  In basophils, BTK-dependent activation of the FcR leads to 
activation and up-regulation of CD63.   


 
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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 
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 (QD 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 (CV) 
system; and embryo-fetal development (Seg II) studies in rats and rabbits.  Overall, 
GDC-0853 was well tolerated for 6 months in rats (up to 104 M  h) and 9 months in 
dogs (up to 36 M  h).  Notable findings identified in nonclinical toxicology studies 
include vascular inflammation ( 56 M  h) in dogs, hepatotoxicity (180 M  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 M) in dogs.  
Fetal malformations in rats (at 627 M  h) and rabbits ( 10.6 M  h) warrant the 
continued use of contraception in clinical trials.  On the basis of the nonclinical and 
clinical safety data to date, GDC-0853 is expected to be well tolerated at the doses and 
duration administered in the current study, Study GA29350.   
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 (NHL) or CLL.  In 
that study, 24 patients received study drug at 100, 200, or 400 mg orally (PO) QD.  Nine 
patients received 400 mg of GDC-0853 PO QD 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600 mg), 53 subjects received 
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 serious adverse 


 
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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.   
In Study GP29832, GDC-0853 was also well tolerated when administered to 32 healthy 
subjects at the 200-mg dose level.  This was a Phase Ia, randomized, open-label study 
investigating the effect of food, rabeprazole, and formulation on the pharmacokinetics of 
GDC-0853. 
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 study (GA29350) is to evaluate the clinical 
efficacy and safety of GDC-0853 in combination with methotrexate (MTX) in patients 
with active RA.  In Cohort 1, three dose levels of GDC-0853 will be compared with 
placebo and HUMIRA (adalimumab [ADA]) in patients with an inadequate response to 
methotrexate [MTX-IR].  In Cohort 2, one dose level of GDC-0853 will be compared with 
placebo in patients with an inadequate response or intolerance to 1 or 2 TNF inhibitors 
[TNF-IR] and who may have had exposure to no more than one non-TNF inhibitor 
biologic.  The study is powered to detect a meaningful clinical benefit and includes 




 
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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 (GGT), 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 M  h and 180 M  h, respectively (considered 
monitorable with liver function tests; details below).  No adverse liver findings were 
observed in the chronic toxicity studies in rats ( 104 Mh) and dogs ( 36 Mh). 
 
Fetal malformations were observed in rats (i.e., cleft palate observed at 627 M  h) 
and rabbits (i.e., domed-shaped heads with enlarged lateral/third ventricles at 
 10.6 M  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) were 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 
because 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 from the study if they have 
a history of hospitalization due to an infection in the 8 weeks before screening, evidence 
of active or latent or inadequately treated infection with Mycobacterium tuberculosis 
(TB), or any known immunodeficiency, including IgG  500 mg/dL.  Total Ig, IgM, IgG, 
IgA, and IgE will be measured regularly throughout the study.  Patients should be 
carefully monitored throughout the study 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 in 


 
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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 (ASA) 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 
who receive antiplatelet or anticoagulant therapies.  Therefore, the eligibility criteria 
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. 
Cytopenias 
Neutropenia, anemia, and thrombocytopenia have been observed in patients with 
hematologic malignancies who received GDC-0853.  Events have been monitorable 
and clinically manageable.  Cell counts will be monitored regularly throughout 
Study GA29350. 
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 QD 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 
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 adverse 
events of special interest with expedited reporting requirements to the Sponsor.   
Cardiovascular Effects 
GDC-0853 is considered to have a low potential to cause QT interval prolongation or to 
directly affect other CV parameters at therapeutic exposures.  A minimal increase in 
corrected QT (QTc; 7 ms or 3%) interval was noted at 45 mg/kg in the single-dose CV 
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.  


 
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Patients with a history of cancer within 10 years of screening will be excluded from study 
participation, except for basal or squamous cell carcinoma of the skin that has been 
excised and is considered cured and in situ carcinoma of the cervix treated with 
apparent success by curative therapy more than 1 year prior to screening.  All 
malignancies are 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 from the study, and 
complete blood counts (CBC), creatinine levels, and urinalysis findings 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 the safety follow-up 
period. 
Overall, GDC-0853 has been well tolerated in Phase I healthy subjects and oncology 
studies.  On the basis of the compelling mechanism for BTK inhibition in RA, the 
risk-benefit ratio for this study is deemed acceptable.  The safety profile of GDC-0853 
will be further characterized in this Phase II study, and a robust safety monitoring plan 
that describes the potential risks for GDC-0853 and the risk-mitigation strategies to 
minimize risks for the patients in this trial is provided in Section 5.1.   
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 study will evaluate the efficacy and safety of GDC-0853 compared with placebo 
(Cohorts 1 and 2) and compared with ADA (Cohort 1), each in combination with MTX, in 
patients with moderate to severe active RA.  Specific objectives and corresponding 
endpoints for the study are outlined in Table 1. 
 


 
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Table 1 
Primary, Secondary, Safety, Pharmacokinetic, and Exploratory 
Objectives with Corresponding Endpoints  
Objective(s) 
Corresponding Endpoint(s) 
Primary Efficacy Objective 
• To evaluate the efficacy of GDC-0853 at three dose 
levels compared with placebo used in combination with 
stable doses of MTX in patients with active RA who 
have had an inadequate response to MTX and are 
naive to TNF therapy (Cohort 1: MTX-IR) 
• ACR50 response rates at Day 84 
Key Secondary Efficacy Objectives 
• To evaluate the efficacy of GDC-0853 compared with 
ADA used in combination with stable doses of MTX in 
patients with active RA who have had an inadequate 
response to MTX and who are naive to TNF therapy 
(Cohort 1:  MTX-IR) 
• ACR50 response rates at Day 84 
• To evaluate the efficacy of GDC-0853 compared with 
placebo used in combination with stable doses of MTX 
in patients with active RA who have had an inadequate 
response or intolerance to 1 or 2 TNF inhibitors and 
may have been previously exposed to no more than 
one non-TNF biologic (Cohort 2:  TNF-IR) 
• ACR50 response rates at Day 84 
Secondary Efficacy Objectives 
• To evaluate the efficacy of GDC-0853 over time with 
multiple standardized assessments  
• ACR20, ACR70, DAS 28-3 (CRP), DAS 28-4 
(CRP), DAS 28-3 (ESR), and DAS 28-4 (ESR) 
response rates, change from baseline SDAI, and 
change from baseline CDAI at Days 7, 14, 28, 56, 
and 84 
• To assess the efficacy of GDC-0853 over time  
• ACR50 response rates at Days 7, 14, 28, and 56 
• To assess efficacy on the basis of the individual 
components of the ACR 
Response rates at Days 7, 14, 28, 56, and 84 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 assess DAS28 remission (< 2.6) and LDA (< 3.2) 
state 
• States at Days 7, 14, 28, 56, and 84 
• To assess ACR/EULAR remission according to the 
Boolean-based definition (tender joint count ≤ 1, 
swollen joint count ≤ 1, CRP ≤ 1 mg/dL, and patient 
global assessment ≤ 1)  
• Remission at Days 7, 14, 28, 56, and 84 
• To assess SDAI-based remission (defined as ≤ 3.3 for 
ACR/EULAR remission) and CDAI-based remission 
(defined as ≤ 2.8) 
• Remission at Days 7, 14, 28, 56, and 84 
• To evaluate the effect of GDC-0853 compared with 
placebo on health-related quality of life 
• SF-36, standard, Version 2, questionnaire at 
Day 84 
• To evaluate the effect of GDC-0853 compared with 
placebo on fatigue 
• FACIT-Fatigue measure at Day 84 
 


 
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Table 1 
Primary, Secondary, Safety, Pharmacokinetic, and Exploratory 
Objectives with Corresponding Endpoints (cont.)  
Safety Objective 
 To evaluate the safety of GDC-0853 given in 
combination with MTX in patients with moderate to 
severe RA 
 The nature, frequency, severity, and timing of 
adverse events 
 Changes in vital signs, physical findings, ECGs, 
and clinical laboratory results following GDC-0853 
administration 
Pharmacokinetic Objective: 
 To characterize the pharmacokinetics of GDC-0853 in 
patients using a population PK approach 
 Steady-state PK parameters (AUC0-t, Cmax, Tmax, 
Ctrough, t1/2, apparent CL/F)  
Exploratory Pharmacokinetic Objectives 
 To evaluate the relationship between measures of drug 
exposure and pharmacodynamic effect(s), efficacy, 
and safety of GDC-0853 
 Exploratory biomarker measures in Table 4 
 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 covariates on 
measures of GDC-0853 exposure and/or response 
 Steady-state PK parameters (AUC0-t, Cmax, Tmax, 
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, Cmax, Tmax, 
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 if 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; ADA  adalimumab; AUC0-t  area under the concentration 
time-curve from time 0 to time t; Cmax  maximum observed plasma concentration; Ctrough  minimum 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; 
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; PK  pharmacokinetic; RA  rheumatoid arthritis; SDAI  Simplified Disease Activity 
Index; SF-36  Short-Form 36 Health Survey; 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 multicenter, Phase II, randomized, double-blind, placebo-controlled, active 
comparator (Cohort 1 only), parallel-group, dose-ranging study to evaluate the efficacy 
and safety of GDC-0853 in patients with moderate to severe active RA and an 
inadequate response to previous MTX therapy (Cohort 1) or MTX and TNF therapy who 
may have also had exposure to no more than one non-TNF inhibitor biologic (Cohort 2).  
Moderate to severe active RA is defined by  6 tender/painful joints on motion (68 joint 
count) and  6 swollen joints (66 joint count) at both screening and Day 1 
(randomization), as well as a high sensitivity C-reactive protein (hsCRP)  0. 400 mg/dL 
for Cohort 1 and a hsCRP  0.650 mg/dL for Cohort 2 at screening.  Improvement in 
disease activity will be measured using the American College of Rheumatology (ACR) 
response rate.   
This study will enroll approximately 600 patients.  In Cohort 1, approximately 
480 MTX-IR patients will be randomized to placebo, ADA, or one of 3 doses of 
GDC-0853 (50 mg QD, 150 mg QD, or 200 mg BID).  In Cohort 2, approximately 
120 TNF-IR patients will be randomized to placebo or 200 mg BID GDC-0853 (see 
Figure 1).  
At any time during the study, the Sponsor may choose to inactivate and suspend 
enrollment and further dosing for a given treatment arm (Cohort 1) or reduce the dose 
in Arm F (Cohort 2) due to safety concerns, and as guided by the IMC.  In Cohort 1, 
subsequently enrolled patients will be randomly allocated to the remaining arms.  
After the screening period (up to 28 days), patients in both cohorts will receive blinded 
study drug (oral GDC-0853 or matching placebo) for 12-weeks, after which they will 
have the option of either entering an 8-week follow-up period or enrolling into an 
open-label extension (OLE) study (Study GA30067).  In addition to study drug, patients 
in Cohort 1 will also be treated with the subcutaneous (SC) comparator drug (ADA or 
placebo). 
Patients must enter and remain on stable MTX treatment while in the study (see 
Section 4.3.3.1).  In order to prevent adverse events associated with MTX treatment, 
patients are also required to be on a stable dose of folic acid while in the study (see 
Section 4.3.3.2).   
For patients receiving chronic NSAIDs and/or corticosteroids, the continued use of stable 
(for at least 2 weeks prior to randomization) oral NSAIDs and/or stable (for at least 
6 weeks prior to randomization) oral corticosteroid ( 10 mg/day prednisone equivalent) 
doses is allowed and should be continued unchanged throughout the study, unless an 
adjustment is necessary for safety reasons (see Section 4.4.1).   




 
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stable dose of between 15 and 25 mg/week (oral or parenteral; for patients entering the 
trial on MTX doses  15 mg/week, doses as low as 7.5 mg/week are allowed only if there 
is clear documentation in the medical record that higher doses were not tolerated or that 
the dose of MTX is the highest acceptable dose based on local clinical practice 
guidelines). 
Cohort 1 Arms AE are designed to assess the safety and efficacy of GDC-0853 
administered orally at 3 dose levels in combination with background MTX therapy.  
Comparisons will be made against placebo and ADA and among the 3 dose levels of 
GDC-0853.  Patients will receive both study drug (GDC-0853 and/or placebo tablets) 
BID and SC comparator drug (ADA or placebo injection) every 2 weeks in a 
double-dummy design.  No patient will receive both GDC-0853 and ADA. 
At baseline (Day 1), patients in Cohort 1 will be randomly assigned in a 1:1:1:1:1 fashion 
to 1 of 5 parallel treatment arms:  
 
Arm A:  50 mg QD GDC-0853 (BID tablets)   placebo injections SC every 2 weeks 
(Q2W) (n  40) 
 
Arm B:  150 mg QD GDC-0853 (BID tablets)   placebo injections SC Q2W (n  110) 
 
Arm C:  200 mg BID GDC-0853 (BID tablets)   placebo injections SC Q2W (n  110) 
 
Arm D:  placebo (BID tablets)   placebo injections SC Q2W (n  110) 
 
Arm E:  placebo (BID tablets)   40 mg ADA injections SC Q2W (n  110) 
 
Once enrollment in Arm A is complete, patients will be randomized 1:1:1:1 across the 4 
remaining treatment arms. 
For Cohort 1 the randomization will be stratified by geographic region.  The Sponsor 
may choose to limit the percentage of patients enrolled who have a screening hsCRP of 
between 0.400 and 0.649 mg/dL.   
Patients will be assessed at site visits on Days 1, 7, 14, 28, 42, 56, 70, and 84 during the 
treatment period and, if the patient does not enroll in OLE Study GA30067, on Day 140 
during the follow-up period.   
After 150 patients in Cohort 1 (~30 patients/arm) have completed 12 weeks of treatment, 
an IA to evaluate safety and efficacy will be performed by the IMC (see Section 6.8). 
Cohort 2 (TNF-IR) 
Cohort 2 includes patients with active RA who must have demonstrated an inadequate 
response or intolerance to one or two TNF inhibitors and MTX and who may have also 
had exposure to no more than one non-TNF inhibitor biologic.  Cohort 2 is designed to 
assess the safety and efficacy of GDC-0853, administered orally at 1 dose level, in 
combination with MTX.   


 
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At baseline (Day 1), patients in Cohort 2 will be randomly assigned in a 1:1 fashion to 
1 of 2 parallel treatment arms:  
 
Arm F:  200 mg BID GDC-0853 (BID tablets; approximately n  60) 
 
Arm G:  placebo (BID tablet; approximately n  60) 
 
For Cohort 2, the randomization will be stratified by geographic region and prior 
exposure to a non-TNF inhibitor biologic.  The Sponsor may choose to limit the 
percentage of patients enrolled who have had prior exposure to a non-TNF inhibitor 
biologic.  
Patients will be assessed at site visits on Days 1, 7, 14, 28, 56, and 84 during the 
treatment period and, if the patient does not enroll in OLE Study GA30067, on Day 140 
during the follow-up period.   
3.1.2 
Internal Monitoring Committee 
Periodic safety reviews and the IA will also be performed by the Sponsor’s IMC as 
outlined in the IMC Charter.  This committee will be unblinded to treatment assignments 
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 24 weeks, including screening for up to 
28 days, treatment for 12 weeks, and the safety follow-up period for 8 weeks (after the 
last dose of study drug).  Patients enrolling in OLE Study GA30067 for GDC-0853 will 
not enter the safety follow-up period of Study GA29350.   
3.2.2 
End of Study 
The end of study is defined as the last patient, last safety follow-up visit in this protocol 
or the last patient in this protocol enrolled into the OLE Study GA30067, whichever is 
later. 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for GDC-0853 Dose and Schedule 
The range of GDC-0853 dose levels in this study were determined on the basis of data 
from Phase I studies in healthy subjects and patients with hematologic malignancies as 
well as nonclinical toxicology studies and arthritis models.  Preliminary analysis in 
Study GO29089 found anti-tumor activity in patients with B-cell malignancies at all doses 
of GDC-0853 tested (i.e., 100 mg, 200 mg, and 400 mg PO QD).  No safety or 
tolerability issues were identified in healthy subjects receiving GDC-0853 up to 600 mg 
in the single-ascending-dose Study GP29318 and up to 250 mg BID and 500 mg QD for 




 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
It should be noted that the extent of target engagement required for clinical efficacy is 
unknown.  Consequently, doses were selected to evaluate a wide range of target 
engagement and to characterize dose response in order to select the optimal dose for 
further study. 
3.3.2 
Rationale for Patient Population 
Despite many advances in the treatment of RA, including the use of biologic agents, 
there remain a substantial number of patients with RA who do not achieve an adequate 
response, who lose response over time, or who cannot tolerate currently available 
therapies.  Given limitations with the current therapeutic options for RA, there remains a 
need for therapies that provide a higher degree of both efficacy and safety.  
This Phase II study will evaluate patients with unmet need due to an inadequate 
response to MTX (Cohort 1) or inadequate response or intolerance to TNF inhibitors and 
who may have been exposed to one other non-TNF inhibitor biologic agent (Cohort 2), 
given the greater unmet need in these populations of patients with RA.  Eligibility criteria 
for this study are similar to those of many Phase II proof-of-concept RA studies.  
Following demonstration of acceptable efficacy and safety in this Phase II program, the 
use of GDC-0853 may be subsequently considered for treatment-naive patients with RA 
and potentially as a monotherapy option.   
No adverse drug reactions for GDC-0853 have been established to date, and no 
patterns of adverse events have been identified that would preclude testing GDC-0853 
in patients with RA.  Patients with RA whose medical history or laboratory findings at 
screening might increase their risk of adverse events will be excluded from the study 


 
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(see Section 4.1.2 and Section 5.1.1).  Potential risks with GDC-0853, such as infections, 
will be monitored during the conduct of this study, and the study will be modified or 
terminated as appropriate to ensure the safety of the patients in the study (see 
Section 3.1.2).   
3.3.3 
Rationale for Control Groups  
3.3.3.1 
Placebo Control Groups 
Placebo-treated control groups, Arms D and G, are required for this study to achieve its 
efficacy and safety objectives.  Historical control groups are not sufficiently comparable 
given changes in RA populations and treatment patterns over time, inherent variability in 
the subjective assessments comprising the endpoint, and regional differences in the 
management of patients with RA.  Use of an active comparator only (e.g., ADA) could 
result in an underestimation of the safety or efficacy effects of GDC-0853.  Patients in 
the placebo arms will receive stable standard-of-care (SOC) MTX therapy throughout the 
study.  The placebo treatment period will be limited to 12 weeks, which is typically the 
minimum time necessary to establish the peak-level efficacy of RA therapeutics.  
Multiple recent Phase II and Phase III studies incorporate 12-week placebo comparator 
groups.   
Patients in the placebo-treated control groups will enter the study while on their stable 
background MTX treatment, low-dose corticosteroids ( 10 mg/day), and any other 
stable background medications (e.g., NSAIDs, PPIs, H2RAs).  
3.3.3.2 
Active Control Group 
ADA is a biologic TNF inhibitor licensed for the treatment of RA at a dose of 40 mg Q2W 
and is considered the SOC in many countries, often in combination with MTX.  ADA will 
be used as an active control to assess relative differences in efficacy, safety, and 
tolerability of GDC-0853.  ADA will be provided by the Sponsor.  Refer to local ADA 
prescribing information and RA treatment guidelines for details. 
3.3.4 
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.   
3.3.5 
Rationale for PK Sample Collection Schedule 
The sampling schedule is designed to capture data at several timepoints over the dosing 
interval (i.e., on Day 28) in order to provide information about the absorption, distribution, 
and elimination of GDC-0853 in patients with RA.  In addition, assessments will enable 
the evaluation of intrapatient variability over a 12-week dosing period.  Results will be 
used to select dosing regimens for future studies of GDC-0853.  In addition, these 


 
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results will enable a robust exposure-response analysis, which will help characterize 
how efficacy is impacted by drug exposure and, thus, inform the most appropriate dose 
for further study. 
3.3.6 
Rationale for Other Study Design Elements 
3.3.6.1 
Efficacy Measurements 
The 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 [see Appendix 11, 
Appendix 12, and Appendix 13, 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 the study at regular intervals (at least 
every month for a period of 12 weeks).   
3.3.6.2 
Blinding Strategy  
To minimize bias in efficacy and safety assessments, this study uses blinded, matching 
placebos for GDC-0853 and a double-dummy design for the SC comparator drug.  
Because ADA does not have a matching placebo SC injection, an unblinded health-care 
professional (HCP) will administer the SC comparator drug to maintain the blind.   
To prevent potential blind breaks due to observed efficacy or laboratory changes and to 
minimize bias in efficacy assessment, the “dual assessor” approach (i.e., an “efficacy 
assessor” and the treating physician; see Section 4.5.6) will be used to evaluate efficacy 
and safety.  Both efficacy assessor and treating physician will be blinded to treatment 
assignment.  The efficacy assessor, who will not have access to any other patient data, 
will perform the swollen and tender joint count and the Physician’s Global Assessment of 
Arthritis.  The investigator (treating physician) will have access to both safety and 
efficacy data and will make all treatment decisions based on the patient’s clinical 
response and laboratory parameters (see Section 4.5.6 for details).  If required for the 
safety of a patient, the investigator may break the blind and determine the treatment 
assignment of that patient (see Section 4.2).   
3.3.6.3 
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, 
SC administration of medication) should be performed after the pain assessment.  In 


 
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cases where this is logistically challenging (e.g., the visit of Day 28 with intensive PK 
assessments), potentially painful procedures will be performed at least 15 minutes prior 
to initiation of the PRO measures. 
3.3.6.4 
Stratification and Enrollment Cap 
Patient randomization will be stratified by geographic region because regional variation 
in the management of RA can manifest as variability in response rates, including 
differences in placebo response rates.  The stratification is intended to balance the 
proportion of patients from different regions across the study arms in order to limit any 
confounding of the study results.  In Cohort 1, the Sponsor may choose to limit the 
percentage of patients enrolled who have a screening hsCRP of between 0.400 and 0.649 
mg/dL in order to enrich for patients with higher levels of inflammation who might be 
expected to demonstrate an enhanced response to GDC-0853, based on mechanism of 
action. 
Patients in Cohort 2 will also be stratified based on whether or not they have had prior 
exposure to a non-TNF inhibitor biologic, in order to balance treatment assignment for 
the purpose of limiting any potential confounding of efficacy.  The Sponsor may choose 
to limit the percentage of patients enrolled who have had prior exposure to a non-TNF 
inhibitor biologic, in order to minimize heterogeneity of the Cohort 2 population.     
3.3.6.5 
Methotrexate Therapy 
Patients in this study will 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.  In addition, MTX is 
commonly prescribed with ADA to minimize the potential for immunogenicity with ADA.   
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Approximately 600 patients with moderate to severe active RA will be enrolled in this 
study. 
4.1.1 
Inclusion Criteria 
All patients must meet the following criteria for study entry: 
 
Age 18 to 75 years at screening 
 
Able and willing to provide written informed consent and to comply with the 
requirements of the protocol 
 
Have a diagnosis of adult-onset RA as defined by the 2010 ACR/European League 
Against Rheumatism (EULAR) Classification Criteria for RA (see Appendix 9) 
 
RA disease activity by joint counts and laboratory markers of inflammation: 
 6 tender/painful joints on motion (68 joint count) and  6 swollen joints (66 joint 
count) at BOTH screening and Day 1 (randomization)  


 
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 
At screening, must have hsCRP as follows: 
Cohort 1:   0.400 mg/dL (may be repeated once) 
Cohort 2:   0.650 mg/dL (may be repeated once) 
 
Positive for anti-cyclic citrullinated protein/peptide antibody (anti-CCP or ACPA), 
rheumatoid factor (RF), or both (if based on historical data, need documentation of 
prior positive laboratory value in the electronic Case Report Form [eCRF])  
 
Have received MTX for at least 12 weeks immediately prior to randomization, of 
which the last 8 weeks prior to randomization must have been at a stable dose of 
between 7.5 and 25 mg/week (oral or parenteral) 
For patients entering the trial on MTX doses  15 mg/week, there must be 
clear documentation in the medical record that higher doses were not tolerated 
or that the dose of MTX is the highest acceptable dose based on local clinical 
practice guidelines. 
  
 
Willing to withdraw all non-biologic disease-modifying anti-rheumatic 
drugs (DMARDs), other than MTX and leflunomide, at least 4 weeks prior to 
randomization.  Patients previously on leflunomide must have either discontinued 
 8 weeks prior to randomization or discontinued with the following elimination 
procedure at least 28 days prior randomization: 
Cholestyramine or activated charcoal should be taken at standard doses for a 
minimum of 6 days but ideally for the standard 11 days (Arava U.S. Package 
Insert; Arava Summary of Product Characteristics) 
 
Willing to receive treatment at an adequate and stable dose of folic acid (not less 
than 5 mg total dose weekly) during study 
 
Only for patients currently receiving oral corticosteroids:  Treatment must be at a 
stable dose of  10 mg/d prednisone (or equivalent) during the 6 weeks prior to 
randomization and with a plan to remain at a stable dose for the duration of the 
study. 
 
Only for patients currently receiving NSAIDs on a regular basis (e.g., not as needed):  
Treatment must be at a stable dose during the 2 weeks prior to randomization and 
with a plan to remain at a stable dose for the duration of the study. 
 
Only for patients currently receiving PPIs or H2RAs:  Treatment must be at a stable 
dose during the 2 weeks prior to randomization and with a plan to remain at a stable 
dose for the duration of the study. 
 
No evidence of active or latent or inadequately treated infection with TB as defined 
by all of the following: 
A negative QuantiFERON TB-Gold (QFT) or, if QFT unavailable, a Mantoux 
Purified Protein Derivative (PPD) skin test (performed per Centers for Disease 
Control and Prevention guidelines with use of 5 tuberculin units per 0.1 mL) 
result of  5 mm of induration, performed at the screening visit or within the 
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Patients with a history of Bacille Calmette-Guérin (BCG) vaccination should 
be screened using the QFT test only.  
An indeterminate QFT test should be repeated.  
A positive QFT test or two successive indeterminate QFT results should be 
considered a positive diagnostic TB test.  
An indeterminate QFT test followed by a negative QFT test should be 
considered a negative diagnostic TB test. 
A chest radiograph taken at the screening visit or documented results within the 
3 months prior to screening (must be read by a radiologist), without changes 
suggestive of active TB infection 
If a patient has previously received an adequate documented course of therapy 
for either latent (9 months of isoniazid in a locale where rates of primary 
multidrug-resistant TB infection are  5% or an acceptable alternative regimen, 
according to local guidelines) or active (acceptable multidrug regimen, 
according to local guidelines) TB infection, neither a PPD test nor a QFT test 
need be obtained, but a chest radiograph must still be obtained if not done so 
within the prior 3 months; this chest radiograph must be without changes 
suggestive of active TB infection. 
 
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 or longer if 
required per the local prescribing label for ADA (see Appendix 8)  
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 8): 
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 


 
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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. 
 
To be enrolled into Cohort 2, patients must also meet the following criteria:  
 
Experienced an inadequate response or intolerance to previous treatment with at 
least one and no more than 2 biologic TNF inhibitors (e.g., infliximab, 
etanercept, adalimumab, golimumab, or certolizumab, or biosimilar equivalent) and 
in the opinion of the investigator either of the following (which must be 
documented in the eCRF):  
– 
Experienced insufficient efficacy or loss of efficacy at a dose and duration that, 
in accordance with local clinical practice, is considered acceptable to 
adequately assess clinical response  
– 
Experienced intolerance of such treatment 
 
May have also been exposed to no more than one non-TNFα inhibitor biologic 
(e.g., abatacept, tocilizumab, sarilumab, sirukumab, anakinra, or any biologics or 
biosimilar equivalents with the same mode of action to the listed agents, including 
investigational biosimilar agents).   
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria must be excluded from study entry: 
 
History of or current inflammatory joint disease other than RA (e.g., gout requiring 
current treatment, reactive arthritis, psoriatic arthritis, seronegative spondyloarthritis, 
Lyme disease) or other systemic autoimmune disorder (e.g., systemic lupus 
erythematosus, inflammatory bowel disease, scleroderma, inflammatory myopathy, 
mixed connective tissue disease, or other overlap syndrome) 
 
Systemic involvement secondary to RA leading to clinically significant organ 
dysfunction or increased risk for participation in the study, in the opinion of the 
investigator. For example, patients with known RA vasculitis, pulmonary fibrosis, or 
Felty’s syndrome should be excluded.  Exceptions are as follows:  
– 
Sjogren’s syndrome with RA is allowable 
– 
Anemia secondary to RA (if Hgb is greater than or equal to 8.5 mg/dL) is 
allowable. 
 
Functional Class IV, according to the ACR 1991 Revised Criteria for Global 
Functional Status in Rheumatoid Arthritis (see Appendix 10) 


 
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 
Major surgery, including bone/joint surgery (e.g., joint fusion) within 8 weeks prior to 
screening or joint surgery planned within 12 weeks following randomization 
 
Previous treatment with GDC-0853 or other BTK inhibitors 
 
History of treatment with cell-depleting therapy including B celldepleting therapy 
(e.g., anti-CD20directed therapy such as rituximab) 
 
Any condition or medication that precludes the use of or is contraindicated with MTX 
or folic acid, according to the local prescribing label or the investigator (e.g., patients 
with pleural effusion, ascites, or who are on concomitant acitretin) 
 
History of treatment with tofacitinib or other Janus kinase (JAK) inhibitor(s) 
(approved or experimental) 
 
Prior to randomization, must have discontinued all biologic therapies as follows: 
Etanercept and etanercept biosimilar agents for  2 weeks 
All other biologic agents (including biosimilars and investigational biosimilars to 
approved agents) for  28 days  
 
Previous exposure to any investigational agent (not including investigational 
biosimilars to approved therapies) within 12 weeks or 5 half-lives of the 
investigational agent, whichever is longer, prior to randomization 
 
Previous treatment within 6 months of randomization with IV gamma globulin or the 
Prosorba Column 
 
History of treatment with alkylating agents such as cyclophosphamide or 
chlorambucil or with total lymphoid irradiation 
 
Require any prohibited concomitant medications (see Section 4.4.2).  
 
Current treatment with corticosteroids at doses  10 mg/d of prednisone (or 
equivalent)  
 
Intra-articular or parenteral corticosteroids within 4 weeks prior to and during 
screening  
 
History of live attenuated vaccine within 6 weeks prior to randomization or 
requirement to receive these vaccinations at any time during study drug treatment 
Seasonal influenza and H1N1 vaccinations are permitted if the inactivated 
vaccine formulations are administered.  
 
Evidence of serious uncontrolled concomitant cardiac, neurologic, pulmonary 
(including obstructive pulmonary disease), renal, hepatic, endocrine (including 
uncontrolled diabetes mellitus), metabolic, or GI disease that, in the investigator’s 
opinion, would preclude patient participation 
 
Patients meeting the New York Heart Association Class III and Class IV criteria for 
congestive heart failure: 
Class III:  Patients with marked limitation of activity; they are comfortable only at 
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Class IV:  Patients who should be at complete rest, confined to bed or chair; 
any physical activity brings on discomfort and symptoms occur at rest 
 
Screening 12-lead ECG that demonstrates clinically relevant abnormalities that may 
affect patient safety or interpretation of study results, including 
QT interval corrected using Fridericia’s formula (QTcF)  440 ms demonstrated 
by at least two ECGs  30 minutes apart 
 
History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such 
as long QT syndrome and other genetic risk factors (e.g., Brugada syndrome), 
structural heart disease (e.g., severe left ventricular systolic dysfunction, severe left 
ventricular hypertrophy), coronary heart disease (CHD; symptomatic, or with 
ischemia demonstrated by diagnostic testing, prior coronary artery bypass grafting, 
or coronary lesions  70% diameter stenosis that have not been or cannot be 
re-vascularized), clinically significant electrolyte abnormalities (e.g., hypokalemia, 
hypomagnesemia, hypocalcemia), or family history of sudden unexplained death or 
cardiac ion channel mutations (e.g., congenital long QT syndrome) 
 
Current treatment with medications that are well known to prolong the QT 
interval at doses that have a clinically meaningful effect on QT, as determined by 
the investigator.  The investigator may contact the Sponsor for confirmation if 
needed. The investigator may reference the website: 
https://www.crediblemeds.org/pdftemp/pdf/CompositeList.pdf. 
 
Uncontrolled disease states, such as asthma, psoriasis, or inflammatory bowel 
disease, where flares are commonly treated with oral or parenteral corticosteroids 
 
History of vasculitis 
 
Current liver disease that is clinically significant, in the opinion of the investigator 
 
Evidence of chronic and/or active hepatitis B or C 
Positive hepatitis B surface antigen (HBsAg) or hepatitis C serology (regardless 
of treatment status) 
Positive hepatitis B core antibody (HBcAb) 
 
Abnormalities in hepatic synthetic function tests (e.g., prothrombin [PT], INR, PTT, 
albumin) judged by the investigator to be clinically significant 
 
History of alcohol, drug, or chemical abuse within the 12 months prior to screening 
as determined by the investigator 
 
History of nongallstone-related pancreatitis or chronic pancreatitis that is judged 
to be clinically significant, in the opinion of the investigator (e.g., unexplained 
upper abdominal pain or malabsorptive diarrhea)   
 
Any known active infection (with the exception of fungal nail infections or oral 
herpes) 
 
History of recurrent bacterial, viral, mycobacterial or fungal infections (defined as 
 2 similar episodes requiring anti-microbial treatment within the previous 
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• 
Any history of opportunistic infections that, in the Investigator or Sponsor’s 
judgment, would raise safety concerns regarding the patient's participation in the 
study 
• 
Any major episode of infection requiring hospitalization or treatment with IV 
anti-microbials within 8 weeks prior to and during screening or treatment with oral 
anti-microbials within 2 weeks prior to and during screening 
Antimicrobials include antifungal, antibacterial, and antiviral agents. 
• 
History of or currently active primary or secondary immunodeficiency, including 
known history of HIV infection 
• 
History of cancer, including hematologic malignancy and solid tumors, within 
10 years before screening; 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 > 1 year prior to screening are not 
exclusionary. 
• 
Women who are pregnant, nursing (breastfeeding), or intending to become pregnant 
during the study or within 60 days after completion of the study 
• 
For women of childbearing potential (including those who have had a tubal ligation):  
Positive serum pregnancy test result at screening or on Day 1; a serum pregnancy 
test is needed on Day 1 ONLY if the urine pregnancy test is positive (see 
Appendix 8 for definition of “childbearing potential”). 
• 
Neuropathies or other painful conditions that might interfere with pain evaluation, in 
the opinion of the investigator 
• 
Need for systemic anti-coagulation with warfarin, other oral or injectable 
anti-coagulants, or anti-platelet agents other than NSAIDs, aspirin, and other 
salicylates 
Aspirin at doses of up to 162 mg QD is allowed. 
• 
History of hospitalizations or transfusion for a GI bleed 
• 
History of CV accident (CVA) within 10 years, any history of hemorrhagic CVA, 
history of spontaneous intracranial hemorrhage, or history of traumatic 
intracranial hemorrhage within 10 years 
• 
Known bleeding diathesis 
• 
Any condition possibly affecting oral drug absorption (e.g., gastrectomy, clinically 
significant diabetic gastroenteropathy, or certain types of bariatric surgery such as 
gastric bypass); procedures such as gastric banding, that simply divide the stomach 
into separate chambers, are not exclusionary 
• 
Any uncontrolled clinically significant laboratory abnormality that would affect safety, 
interpretation of study data, or the patient’s participation in the study 
 


 
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The following exclusion criteria are based on screening laboratory tests.  Laboratory 
tests may be repeated once during the screening period unless otherwise indicated (see 
Section 4.5.1.1): 
 
Creatinine  1.5 times the ULN (may be repeated if 1.52  ULN) 
 
ALT or AST  1.5 times ULN (may be repeated if 1.53  ULN) 
 
Total bilirubin  ULN (may be repeated if 13  ULN) 
 
Hemoglobin  8.5 g/dL (may be repeated if 78.4 g/dL) 
 
ANC  1.5  109/L (may be repeated if 1.21.5  109/L) 
 
Platelet count  100  109/L (may be repeated if 80100  109/L) 
 
IgG  500 mg/dL (should not be repeated) 
 
Additionally, patients who meet any of the following criteria will be excluded from 
Cohort 1: 
 
History of treatment with non-TNF inhibitor biologic for RA, including anti-IL6–
directed therapy (e.g., tocilizumab, sarilumab, sirukumab), anti-IL1-directed therapy 
(e.g., anakinra), or T cell–directed therapy (e.g., abatacept) including biosimilar 
equivalents 
 
History of treatment with any TNF inhibitor (e.g., infliximab, etanercept, ADA, 
golimumab, or certolizumab), including biosimilar equivalents and investigational 
biosimilars to approved agents 
 
Any condition that is a contraindication for treatment with ADA in accordance with 
the approved local label   
 
History of anaphylactic or other serious allergic reaction to ADA  
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
The Sponsor will provide the specifications of the randomization algorithm to the 
interactive voice and Web response system (IxRS) vendor.  For Cohort 1 the 
randomization will be stratified by geographic region.  For Cohort 2, the randomization 
will be stratified by geographic region and prior exposure to a non-TNF inhibitor 
biologic. 
To prevent potential blind breaks due to observed efficacy or laboratory changes, a dual 
assessor approach will be used to evaluate efficacy and safety (see Section 4.5.6). 
To maintain the blind, after screening, sites will not receive data related to selected 
laboratory parameters, including but not limited to TBNK (T, B, and natural killer cells) 
results (including CD19 counts) and CRP levels.   
PK samples will be collected from patients assigned to all arms in order to maintain the 
blinding of the treatment assignments.  Since PK assay results for patients in the 
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of this trial, samples from patients assigned to the comparator arm will not be analyzed 
except by request (i.e., to evaluate a possible error in dosing).  Sponsor personnel 
responsible for performing PK assays, which may include contracted laboratory 
personnel, will be unblinded to patients’ treatment assignments to identify appropriate 
PK samples to be analyzed. 
If unblinding is necessary for patient management (e.g., in the case of a serious adverse 
event for which patient management might be affected by knowledge of treatment 
assignment), the investigator will be able to break the treatment code by contacting the 
IxRS.  Treatment codes should not be broken except in emergency situations.  If the 
investigator wishes to know the identity of the study drug for any other reason, he or she 
should contact the Medical Monitor directly to discuss the rationale.  The investigator 
should document and provide an explanation for any premature unblinding (e.g., 
accidental unblinding, unblinding due to a serious adverse event), without disclosing the 
treatment assignment in the documentation. 
For regulatory reporting purposes and if required by local health authorities, the Sponsor 
will break the treatment code for all serious, unexpected suspected adverse reactions 
(SUSARs, see Section 5.7) that are considered by the investigator or Sponsor to be 
related to study drug. 
4.3 
STUDY TREATMENT 
The investigational medicinal products (IMPs) for this study are GDC-0853 and ADA. 
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
GDC-0853 and Placebo Tablet  
GDC-0853 will be provided by the Sponsor as 50-mg dose strength tablets with 
corresponding matching placebo tablets, which will be indistinguishable in appearance.    
Tablets will be supplied in blister wallets (Cohort 1) and bottles (Cohort 2) as appropriate 
for the treatment arm to which the patient is randomized.  Blister wallets and bottles will 
be appropriately labeled for this study.  GDC-0853 and placebo 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. 
4.3.1.2 
Adalimumab and Adalimumab Placebo 
For Cohort 1 only, SC comparator drug will be provided by the Sponsor in two, 
non-matching prefilled syringes (PFSs):  one for ADA and one for placebo.  Because of 
the different appearance of the syringes, they will need to be administered by an 
unblinded HCP in a manner that does not unblind the patient or blinded study staff.   


 
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ADA will be supplied by the Sponsor for use as a single-use, 1-mL, glass PFS with a 
fixed 27-gauge 1/2-inch needle, providing 40 mg (0.8 mL) of ADA.  ADA is supplied as a 
preservative-free, sterile solution for SC administration.  
ADA placebo will be supplied by the Sponsor as a liquid formulation in PFSs to be 
administered as an SC injection.  Each 1-mL PFS will contain 0.7 mL of a solution of 
20 mM histidine, 0.2 M arginine succinate, and 0.04% polysorbate 20, pH 5.8.  Each 
syringe is for single-dose SC administration and contains no preservatives.  
Study drug packaging will be overseen by the Sponsor’s Clinical Trial Supplies 
Department and bear a label with the identification required by local law, the protocol 
number, drug identification, and dosage.  The packaging and labeling of the SC 
comparator drug will be in accordance with the Sponsor’s standards and local 
regulations. 
Upon arrival of investigational products at the site, the unblinded HCP (e.g., pharmacist 
or pharmacy staff) should check for damage and verify proper identity, quantity, integrity 
of seals, and temperature conditions and report any deviations or product complaints to 
the monitor upon discovery. 
The SC comparator drug must be stored according to the details on the product label.  
The drug label indicates the storage temperature.  PFSs of the SC comparator drug 
should be refrigerated at 2C8C and protected from excessive light and heat.  PFSs 
should not be frozen, shaken, or stored at room temperature. 
For further details, see the ADA Summary of Product Characteristics (SmPC) or 
United States Package Insert (USPI). 
4.3.2 
Dosage, Administration, and Compliance 
4.3.2.1 
GDC-0853 and Placebo Dose and Administration 
The GDC-0853 dose levels are 50 mg QD, 150 mg QD, and 200 mg BID, with matching 
placebos (see Table 2).  Patients will receive GDC-0853/placebo BID, approximately 
every 12 hours starting on Day 1 and ending on Day 83.  Patients should be directed to 
take one dose (a total of 4 tablets) BID (a total of 8 tablets each day).  On clinic visit 
days, patients should be instructed that study drug will be administered in the clinic.   
If a dose is missed, the patient should resume normal dosing with the next scheduled 
dose.  Missed doses should not be taken, as they result in doubling of the dose.  Patients 
should record on the blister wallet (Cohort 1) or bottle (Cohort 2) the dose that was 
missed and notify study staff of any missed doses.  Doses that are vomited will be 
considered missed doses. 
GDC-0853 or placebo may be orally administered with or without food, except for the 
dose of oral study drug taken at the clinic visit on Days 1 and 28 (see Appendix 1 and 


 
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Appendix 2), which will be administered at the clinic visit while fasting.  The dates and 
times of the most recent prior meal, last dose of oral study drug (prior to clinic visit), and 
timing of oral study drug administration in clinic should be recorded at each clinic visit.  
In addition, any use of PPIs, H2RAs, and/or short-acting antacids (e.g., Maalox, 
Pepto-Bismol, Rolaids) should be recorded as concomitant medications, including 
date and time of last administration prior to the clinic visit.  Administration of study drug 
should be staggered with short-acting antacid use (i.e., oral study drug should be taken 
2 hours before or 2 hours after the short-acting antacid). 
Table 2 
GDC-0853 Dosing Regimen by Treatment Arm (Cohorts 1 and 2) 
Arm 
GDC-0853 Dose 
(mg) 
No. of Tablets 
GDC-0853 
(a.m./p.m.) 
Placebo 
(a.m./p.m.) 
A 
50 
1/0 
3/4 
B 
150 
3/0 
1/4 
C 
200 
4/4 
0/0 
D 
0 
0/0 
4/4 
E 
0 
0/0 
4/4 
F 
200 
4/4 
0/0 
G 
0 
0/0 
4/4 
BID  twice daily. 
Note:  All patients will take 4 tablets BID (i.e., 8 tablets daily) 
regardless of assigned GDC-0853 dose regimen; therefore, 
patients may be receiving some placebo tablets as part of their 
daily dose in order to maintain the blind. 
 
At study visits, sufficient study medication tablets will be dispensed to complete dosing 
until the next scheduled visit.  When study medication is administered at the site, it will 
be administered under supervision of study personnel, and the amount of study 
medication dispensed must be recorded.   
4.3.2.2 
GDC-0853 and Placebo Compliance 
The following measures will be taken to assess patient compliance with study drug:  
patients will receive Patient Dosing Instructions and be directed to bring any used and 
unused blister wallets (Cohort 1) or bottles (Cohort 2) to each visit after randomization.  
For Cohort 1, sites will be responsible for prepopulating the dates on the blister wallets 
for when patients are scheduled to take study drug.  Under the corresponding dates 
listed, the patients will record the times (a.m. or p.m.) that they take each dose on the 
blister wallet (refer to Appendix 15 for Blister Wallet configuration).  Patients will be 
instructed to return all blister wallets (used and unused) at each study visit for 
assessment of compliance and for medication disposal.   


 
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For Cohort 2, 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 16 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 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.   
4.3.2.3 
Adalimumab and Placebo Dose and Administration  
During this study, the SC comparator drug is intended for use under the guidance and 
supervision of a physician.  The SC comparator drug will be administered by the 
unblinded HCP using the provided PFS (to be supplied by the Sponsor).  Prior to use, 
the solution in the PFS must be carefully inspected for particulate matter and 
discoloration.  If particulates and discolorations are noted, the product should not be 
used.   
ADA is to be administered at a dose of 40 mg SC every other week (starting on Day 1).  
In this study, the ADA and ADA placebo are not visually identical.  To maintain the ADA 
blind, all SC comparator drug administration will be administered by the unblinded HCP 
in a manner that prevents the patient from observing which study treatments he or she is 
receiving.  The unblinded HCP will not be involved in safety and efficacy assessments 
and will not be involved with or have access to patient data.   
There are two recommended injection sites for the SC comparator drug:  the front of the 
middle thighs and the lower part of the abdomen below the navel except for the 2-inch 
area directly around the navel. 
Injections should never be given into areas where the skin is not intact or is tender, 
bruised, red, or hard.  The injection sites will be inspected by the site personnel at each 
clinic visit.  Local injection-site reactions should be reported as described in 
Section 5.1.2.2. 
For all administrations, the SC comparator drug is to be administered by the unblinded 
HCP in a setting where medications and resuscitation facilities are available.  Following 
each SC comparator drug administration, patients should be monitored for acute 
hypersensitivity reactions as indicated in the local label.  Epinephrine and parenteral 
diphenhydramine must be readily available for immediate use if required to treat a 


 
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hypersensitivity reaction; site personnel must be able to detect and treat such reactions.  
Patients with severe hypersensitivity reactions (e.g., stridor, angioedema, life-threatening 
change in vital signs) must be withdrawn from study treatment and complete the 8-week 
safety follow-up phase in this study (See Appendix 7 for Sampson’s Criteria). 
All adverse events of systemic hypersensitivity reactions or anaphylactoid or anaphylaxis 
reactions must be reported as outlined in Section 5.1.2.1. 
If the unblinded HCP cannot administer the SC comparator drug on the scheduled 
dosing day, the SC comparator drug is to be administered within a window of  2 days 
from the scheduled dosing date.  If the patient experiences a minor illness (e.g., minor 
infection), at the discretion of the investigator, the SC comparator drug may be delayed 
for a maximum period of 1 week.  Following the delay, the SC comparator drug dosing is 
to be resumed in accordance with the original dosing schedule.  Any potential deviation 
from this window is to be discussed with the Medical Monitor for the study. 
Any overdose or incorrect administration of SC comparator drug should be noted on the 
Study Drug Administration eCRF.  Adverse events associated with an overdose or 
incorrect administration of study drug should be recorded on the Adverse Event eCRF.   
4.3.3 
Required Background Treatment for Rheumatoid Arthritis 
4.3.3.1 
Methotrexate  
In order to minimize confounding of study assessments, MTX treatment must have been 
initiated for at least the last 12 weeks immediately before randomization, of which the 
last 8 weeks before randomization must have been at a stable dose between 15 and 
25 mg/week (oral or parenteral).  Patients are required to be on a stable MTX dose of 
7.525 mg/week (oral or parenteral) for the duration of their participation in this study.  
For patients entering the trial on MTX doses  15 mg/week, there must be clear 
documentation in the medical record that higher doses were not tolerated or that the 
dose of MTX is the highest acceptable dose based on local clinical practice guidelines. 
Adjustments to this dose or a change in route of administration will not be allowed 
except in the case of MTX intolerance or toxicity; this must be discussed in advance with 
the Medical Monitor unless medically emergent.  If dose reduction is a result of 
intolerance, such intolerance must be recorded as an adverse event and the dose 
modification recorded in the eCRF. 
4.3.3.2 
Folic Acid 
To prevent adverse events associated with MTX, all patients are required to take folic 
acid or equivalent (e.g., 1 mg/day) at a stable dose of at least 5 mg/week total dose (or 
equivalent).  This can be administered as either a single weekly dose or a QD dose per 
the discretion of the investigator.  


 
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4.3.4 
Investigational Medicinal Product Accountability 
All IMPs required for completion of this study (i.e., GDC-0853 tablet, GDC-0853 placebo 
tablet, ADA, and ADA placebo) will be provided by the Sponsor.  The study site will 
acknowledge receipt of IMPs using the IxRS to confirm the shipment condition and 
content.  Any damaged shipments will be replaced.  
IMPs 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. 
4.3.5 
Post-Trial Access to GDC-0853  
Patients may be eligible to screen for and enroll in the OLE Study GA30067, if 
considered appropriate according to the investigator. 
Currently, the Sponsor (Genentech, a member of the Roche Group) does not have any 
plans to provide GDC-0853 or any other study treatments or interventions to patients 
who have completed the study and are not qualified or elect not to enter OLE 
Study GA30067, in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, available at the following Web site: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
 
4.4 
CONCOMITANT THERAPY, PROHIBITED FOOD, AND 
ADDITIONAL RESTRICTIONS 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient from 12 weeks prior to initiation of study drug through 8 weeks after the last dose 
of study drug or entrance into the OLE, whichever occurs first.  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.  The concomitant medication must be documented on 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. 
A description of the type of medication, the amount, duration, and reason for 
administration of drug or procedure must also be documented.   


 
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It is recommended that patients avoid changing other prescription or non-prescription 
drugs, vitamins, and dietary supplements within 7 days or 5 half-lives, whichever is 
longer, prior to the first dose of study medication and throughout the study. 
All concomitant medication taken during the study must be recorded along with 
indication, daily dose, and start and stop dates of administration.  Adverse events related 
to the administration of a concomitant medication or the performance of a procedure 
must also be documented on the appropriate adverse event page of the eCRF. 
4.4.1 
Permitted Therapy  
4.4.1.1 
Corticosteroids 
During the study, patients may continue to receive background oral corticosteroids at a 
dose of  10 mg/day prednisone (or equivalent) that remains stable for the 6 weeks prior 
to randomization and throughout the study.  If a dose  10 mg/day prednisone (or 
equivalent) is needed to manage an adverse event (e.g., a flare of RA disease activity or 
other clinical condition requiring steroids), this must first be discussed with the Medical 
Monitor (unless urgent) and the event must be documented on the appropriate eCRF as 
an adverse event. 
4.4.1.2 
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.  For patients who are receiving 
NSAID treatment on a regular basis (e.g., not as needed), the dose should remain 
stable for at least the 2 weeks before randomization and throughout the study.  Dose 
adjustments may be made for safety reasons and if absolutely 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, based on 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 CV 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). 
4.4.1.3 
Analgesics Other than NSAIDs 
Analgesics (e.g., acetaminophen, opioids) up to their 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 


 
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recorded.  The total daily dose of acetaminophen may not exceed 2.6 g per day, and the 
total daily dose of opioid must not exceed the potency equivalent of 30 mg of orally 
administered morphine (see Appendix 4). 
4.4.1.4 
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 (e.g., hypervitaminosis).  Herbals with 
pharmaceutical properties are allowed only if there is acceptable evidence of no CYP3A 
inhibition or induction (refer to Appendix 5 for a list of prohibited concomitant 
medications, including herbal products).  Otherwise, herbals with pharmaceutical 
properties must be discontinued for at least 4 weeks prior to the first dose of study 
medication, unless there 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. 
4.4.1.5 
Acid-Reducing Agents 
Patients who use short-acting antacids (e.g., Maalox®, Pepto-Bismol®, Rolaids®) for 
symptomatic relief of heartburn should take GDC-0853 or matching placebo 2 hours 
before or 2 hours after short-acting antacid administration because gastric acid 
improves GDC-0853 absorption.   
Patients may be treated with PPIs or H2RAs at up to the maximum recommended dose 
according to local labeling.  The dose should remain stable for at least the 2 weeks 
before randomization and throughout the study.   
At visits with scheduled PK assessments (see Appendix 1 and Appendix 2), any use of 
PPIs, H2RAs, and/or other short-acting antacids (e.g., Maalox, Pepto-Bismol, 
Rolaids) should be recorded as concomitant medications, including the date and time of 
last administration prior to the clinic visit. 
4.4.2 
Prohibited Therapy 
A listing of concomitant medications that is prohibited or should be used with caution due 
to potential drug-drug interactions is provided in Appendix 5.  
IV, intra-articular, intramuscular corticosteroids, biologic response modifiers, tofacitinib or 
other JAK inhibitors, and DMARDs other than MTX are not allowed during this study and 
any use will require discontinuation of study treatment.   
Use of the following therapies is prohibited while the patient is receiving study 
treatment, unless otherwise specified below: 
 
Investigational therapy other than study drug 


 
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 
Abatacept 
 
Adalimumab (ADA) (prohibited for Cohort 2) 
 
Anakinra 
 
Anti-TNF inhibitors (e.g., infliximab, etanercept, golimumab, certolizumab, or 
biosimilar equivalents) 
 
Azathioprine 
 
Chlorambucil 
 
Chloroquine 
 
Cyclophosphamide 
 
Cyclosporine 
 
Gold 
 
Hydroxychloroquine 
 
Immunosorbent column 
 
IV, intramuscular, or intra-articular steroids 
 
Leflunomide 
 
Mycophenolate mofetil 
 
Mycophenolic acid sodium 
 
Oral anticoagulants, including but not limited to warfarin, dabigatran, rivaroxaban, 
apixaban  
 
Anti-platelet agents, such as clopidogrel (Note:  NSAIDs and low-dose aspirin are 
acceptable.) 
 
Heparin, low molecular weight heparin (LMWH) 
 
Penicillamine 
 
Rituximab (or biosimilar equivalent) 
 
Sirolimus 
 
Sulfasalazine 
 
Tacrolimus 
 
Tocilizumab and other anti-IL6R or anti-IL6 agents  
 
Tofacitinib and other JAK inhibitors 
 
All biosimilar agents 
 
4.4.2.1 
Live or Attenuated Vaccinations 
Immunization with a live or attenuated vaccine is prohibited within 6 weeks prior to 
baseline and for the duration of study participation, including the 8-week follow-up period 
after the administration of the last dose.  See Section 5.1.1.2 for further details and 
precautions around vaccinations. 


 
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4.4.2.2 
CYP3A Inhibition 
In vitro studies suggest that GDC-0853 is a time-dependent inhibitor of CYP3A with 
inhibitory constant (Ki) values of approximately 10 M (Study 13-0384).  Although peak 
plasma concentrations are anticipated to be much lower than 10 M (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 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 5 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 8); 
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).   
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 5) 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 5) may increase; therefore, they should be used with caution: 
 
Sensitive CYP3A substrates 
 
CYP3A substrates with a narrow therapeutic index  


 
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The medications listed above and in Appendix 5 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 
 
4.4.3 
Prohibited Food  
Use of the following foods is prohibited during the study and for at least 7 days prior to 
initiation of study treatment:  furanocoumarin derivatives as found in grapefruit, Seville 
orange, pomegranate, or star fruit juice or products.  
4.4.4 
Additional Restrictions  
Patients should be fasting for  48 hours prior to first PK draw at Days 1, 28, and 84.  
On Day 28, patients should also remain fasting for the 2-hour post-dose PK timepoint 
(see Appendix 3). 
4.5 
STUDY ASSESSMENTS  
Please see Appendix 1 and Appendix 2 for the schedules of assessments to be 
performed during this study.   
The screening visit can occur up to 28 days prior to the first dose of study drug.  The 
Day 1 (baseline and randomization) visit occurs on the first day of study drug 
administration.   
Morning visits are strongly recommended for the clinic visits on Days 1, 28, and 84, 
particularly for the Day 28 visit at which post-dose PK blood samples will be collected.  
Patients should be fasting ( 48 hours) prior to these clinic visits.  Study drug will be 
administered at these visits after pre-dose blood samples are collected when applicable.  
If a morning visit is logistically challenging, then based on the timing of their 
scheduled visit and scheduled dose, patients may be asked to take their morning dose of 
study drug as scheduled, then fast ( 48 hours) prior to their clinic visit later in the 
day.  At the clinic visit, pre-dose blood samples will be collected and the evening dose of 
oral study drug will be administered if applicable (e.g., for the Day 28 visit when post-
dose blood samples are collected). 
Patients who complete the treatment period should complete the Day 84 treatment 
completion visit (see Appendix 1 and Appendix 2).  After the Day 84 visit is completed, 
patients who are eligible and consent are to enroll into the OLE Study GA30067 directly; 
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or who choose not to enroll in the OLE study should return for the 8-week safety 
follow-up visit in this study. 
At applicable sites (U.S. only), if the patient is unable to return to the clinic on Day 28 for 
the PK blood draw at the 810 hour timepoint (see Appendix 3), then this sample may 
be collected by a home nurse (HN) professional at the patient's home or another suitable 
location to improve access and convenience for patients participating in the study.  If a 
home visit is needed, the Sponsor will select and provide a health-care company that will 
be responsible for providing HN services (the HN vendor).  The HN vendor is 
responsible for ensuring that all HN professionals are licensed, qualified, and in good 
standing, as per applicable regulations, and that appropriate background checks have 
been performed.  If the investigator at a participating site determines that HN services 
are appropriate for a patient and the patient gives written informed consent to participate 
in HN visits, the HN network will communicate with the patient and the patient’s site.  HN 
visits will be scheduled on specified visit days, to allow for relevant assessments to be 
performed by the HN professional.  The schedule of assessments (see Appendix 3) 
specifies the assessment that may be performed by an HN professional. 
4.5.1 
Informed Consent Forms and Screening Log 
Patients will be screened within a period of up to 28 days prior to administration of study 
medication to confirm that they meet the entrance criteria for the 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 the study must be obtained before 
performing any study-related procedures. 
Informed Consent Forms for enrolled patients and for patients who are not subsequently 
enrolled will be maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before randomization.  The investigator will maintain a screening log 
to record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
4.5.1.1 
Retesting:  Laboratory Inclusion/Exclusion 
If a patient does not meet certain laboratory inclusion/exclusion criteria at screening, the 
investigator may repeat the test once within the screening period (see Section 4.1.2 for a 
list of laboratory tests and levels that can be retested).  If the patient meets the 
laboratory eligibility criteria on the second assessment, he or she will be permitted to 
enter the study.  It will not be considered a retesting if blood samples have to be redrawn 
because of sample handling problems, breakage, sample integrity, or laboratory error. 


 
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4.5.1.2 
Rescreening 
Rescreening refers to repeating the whole screening process.  Rescreening is required if 
a patient has not met all of the eligibility criteria within 28 days after the original 
screening visit.  (Note: patients who have failed two laboratory testing attempts as 
described in Section 4.5.1.1 cannot be rescreened, except in cases where eligibility 
criteria such as hsCRP have been updated).  Patients are allowed to be rescreened only 
once.  Each patient must be re-consented before rescreening occurs.  It will not be 
considered a rescreening if blood samples have to be redrawn because of sample 
handling problems, breakage, sample integrity, or laboratory error.   
4.5.2 
Medical History and Demographic Data 
At screening, the following information will be collected: 
 
Confirmation of rheumatoid arthritis (RA) diagnosis:  The patient must have a 
diagnosis of RA based upon the 2010 ACR/EULAR Criteria for RA Diagnosis (see 
Appendix 9).   
 
Medical history:  The diagnosis of RA should be recorded on the medical history 
eCRF (and captured as “rheumatoid arthritis”), including the date of diagnosis.  
The history must include dates of the most recent vaccinations (specifically influenza, 
pneumococcus, and zoster) on the eCRF.  All medical history relevant to RA will be 
collected.  The medical history should include CHD risk factors per the National 
Cholesterol Education Program (NCEP) guidelines (e.g., smoking, hypertension, 
low HDL, family history of premature CHD - see Appendix 6).  
The medical history must also include clinically significant diseases, surgeries, 
procedures, cancer history (including prior cancer therapies and procedures), 
reproductive status, smoking history, and use of alcohol and drugs of abuse.  
A detailed history of medication used for RA is required.  This should include a 
complete history of all conventional synthetic DMARDs and biological DMARDs 
ever taken (those taken within 5 years before screening should include 
dose/duration, date of discontinuation, and reason for discontinuation).   
All medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or 
homeopathic remedies, vitamins, and nutritional or dietary supplements) used by 
the patient within 12 weeks prior to initiation of study drug are to be recorded.   
 
Demographic data:  This data will include age, sex, and self-reported race/ethnicity. 
 
4.5.3 
Physical Examinations 
A complete physical examination should be performed at screening and should include 
an evaluation of the head, eyes, ears, nose, and throat and the CV, 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, including assessment of rheumatoid nodules and other 
physical manifestations of RA (to be recorded in the eCRF). 


 
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At subsequent visits or as clinically indicated, limited, symptom-directed physical 
examinations should be performed.  Changes from baseline abnormalities should be 
recorded in patient notes.  New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF. 
4.5.4 
Vital Signs  
Vital signs will include measurements of respiratory rate, pulse rate, temperature, and 
systolic and diastolic blood pressures while the patient is in a seated position for at least 
5 minutes. 
4.5.5 
Chest Radiograph 
Chest radiographs of appropriate quality (to adhere to local standards for the exclusion 
of active TB) and with formal readings by a radiologist will be obtained at screening.  If 
chest radiographs have been taken within 90 days prior to screening and documented 
results (as read by a radiologist) show no clinically significant abnormality as determined 
by the investigator, the chest radiograph does not need to be repeated. 
4.5.6 
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 because 
of a long visit duration (e.g., the visit on Day 28 with intensive PK assessments), 
potentially painful procedures will be performed no less than 15 minutes prior to initiation 
of the PRO measures. 
Except for the Day 28 visit, the sequence of assessments where efficacy is assessed 
(see Appendix 1 and Appendix 2 for Schedules of Assessments) will be standardized as 
follows: 
 
PRO Measures: 
Patient’s Assessment of Arthritis Pain  
Patient’s Global Assessment of Arthritis  
HAQ-DI (see Appendix 11) 
SF-36v2 (see Appendix 12) 
FACIT-Fatigue (see Appendix 13) 
 
Laboratory samples for safety, efficacy, biomarkers, and pharmacokinetics must be 
drawn after patient self-assessments are completed (except where specified) 
 
Investigators 
Efficacy assessor:  Joint counts and Physician’s Global Assessment of Arthritis 
visual analog scale (VAS) 
Treating physician:  Safety assessments (adverse events, vital signs, 
concomitant medications, review of laboratory data) 


 
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 
For Cohort 1 only:  SC comparator drug injection 
 
For Cohorts 1 and 2:  Administration of oral study drug 
 
Post-dose vital signs, post-dose PK sample (at the indicated visits per Appendix 1 
and Appendix 2), adverse events 
 
To prevent potential unblinding due to observed efficacy or laboratory changes, a dual 
assessor approach (see Section 3.3.6.2) will be used to evaluate efficacy and safety as 
described below: 
 
The Efficacy Assessor (or designee) should be a rheumatologist or other skilled 
arthritis assessor.  The Efficacy Assessor cannot be the Principal Investigator.  The 
efficacy assessor will be responsible for completing the joint counts and the 
Physician’s Global Assessment of Arthritis VAS.  To ensure consistent joint 
evaluation throughout the trial, individual patients should be evaluated by the same 
efficacy assessor whenever possible for all study visits. 
 
The treating physician (or designee) should be a rheumatologist (or other medically 
qualified physician) and will have access to both safety and efficacy data.  The 
treating physician may be the Principal Investigator.  The treating physician will have 
access to source documents, laboratory results, and the eCRFs and will be 
responsible for completing safety assessments (e.g., adverse events, vital signs, 
concomitant medications, and review of laboratory data).   
 
It is essential that assessments completed by the patient and the Efficacy Assessor are 
made before those by the treating physician so that the treating physician has the data 
needed for his or her assessment.   
Table 3 describes the roles and access to data for specific site personnel. 


 
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Table 3 
Roles and Data Access for Specific Site Personnel 
 
Medication Allocation 
Efficacy 
Assessment(s) 
Safety Data 
Study Coordinator 
No access to SC 
medication 
assignment 
Access to patient 
efficacy data a 
Access to patient 
safety data 
Treating Physician 
and Principal 
Investigator 
No access to SC 
medication 
assignment 
Access to patient 
efficacy data a 
Access to patient 
safety data 
Efficacy Assessor 
No access to SC 
medication 
assignment 
Will perform joint 
counts and 
Physician’s Global 
Assessment of 
Arthritis but have no 
access to other 
patient efficacy data 
No access to any 
patient safety data 
Pharmacist or 
pharmacy staff (if 
available at the site) 
Access to SC 
medication 
assignment 
Cannot participate in 
patient care or data 
collection from 
patient 
Cannot participate in 
patient care or data 
collection from 
patient  
Medication HCP  
Access to SC 
medication 
assignment and 
administration of 
unblinded study 
medication 
Cannot participate in 
patient care or data 
collection from 
patient 
Cannot participate in 
patient care or data 
collection from 
patient 
CRP  C-reactive protein; HCP  health-care professional; SC  subcutaneous. 
a Efficacy data will not include CRP. 
  
4.5.6.1 
ACR Assessments 
The ACR’s definition for calculating improvement in RA (ACR20) is calculated as a 
20% improvement in tender and swollen joint counts 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 4.5.6.1.2) 
 
Swollen Joint Count (66) (see Section 4.5.6.1.3) 
 
Patient’s Assessment of Arthritis Pain (see Section 4.5.7.1) 
 
Patient’s Global Assessment of Arthritis (see Section 4.5.7.2) 
 
Physician’s Global Assessment of Arthritis (see Section 4.5.7.3) 


 
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 
CRP (see Section 4.5.8) 
 
HAQ-DI (see Section 4.5.7.4) 
 
The following clinical assessments will be performed according to the Schedule of 
Assessments (see Appendix 1 and Appendix 2).  
4.5.6.1.1 
Swollen and Tender Joint Count  
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 which 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.  Surgery should not occur 
during the trial except in the case of a documented emergency. 
 
Arthrocentesis:  Any joint that had 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.  If arthrocentesis is necessary at a visit, it should 
only be performed after the joint assessment at the visit has been completed. 
 
4.5.6.1.2 
Tender/Painful Joint Count (68) 
Sixty-eight (68) joints will be assessed by an efficacy assessor who is blinded to the 
patient’s safety data and randomization, 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, or 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 (MCPs I, II, III, IV, 
V), thumb interphalangeal, proximal interphalangeals (PIPs II, III, IV, V), distal 
interphalangeals (DIPs II, III, IV, V) 
 
Lower extremity:  Hip, knee, ankle, tarsus (includes subtalar, transverse tarsal and 
tarsometatarsal considered as one unit), metatarsophalangeals (MTPs I, II, III, IV, V), 
great toe interphalangeal, PIPs (PIPs II, III, IV, V) 
 


 
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4.5.6.1.3 
Swollen Joint Count (66) 
The blinded efficacy assessor will also assess joints for swelling using the following 
scale:  Present, Absent, or Not Done. 
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. 
4.5.6.2 
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), DAS 28-4 (ESR), DAS 28-3 (CRP), and DAS 
28-3 (ESR) are presented in Appendix 14.   
The components of the DAS 28 arthritis assessment are as follows: 
 
Tender/Painful Joint Count (28) (see Section 4.5.6.2.1) 
 
Swollen Joint Count (28) (see Section 4.5.6.2.2) 
 
CRP or ESR (see Section 4.5.8) 
 
Patient’s Global Assessment of Arthritis (included in the DAS 28-4 only) (see 
Section 4.5.7.2) 
 
4.5.6.2.1 
Tender/Painful Joint Count (28) 
The 28 tender/painful joint count includes the following joints:  shoulders, elbows, wrists, 
MCP joints, PIP joints, and knees.  This count will be calculated by the Sponsor from the 
68 tender/painful joint count assessed by the blinded efficacy assessor as described in 
Section 4.5.6. 
4.5.6.2.2 
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 blinded efficacy assessor as described in Section 4.5.6. 
4.5.7 
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 11, Appendix 12, and 
Appendix 13, 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 
instrument validity and that data standards meet health authority requirements, 
questionnaires will be self-administered before the patient receives any information on 


 
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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. 
4.5.7.1 
Patient’s Assessment of Arthritis Pain 
Patients will assess the severity of their arthritis pain using a 100-mm VAS by placing a 
mark on the scale between 0 (no pain) and 100 (most severe pain) that 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 
 
4.5.7.2 
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, as follows:  
Considering all the ways your rheumatoid arthritis affects you, how are you 
feeling today? 
Very well_______________________________________________Very poorly 
 
4.5.7.3 
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 (see 
Appendix 10), 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, as follows:  
The patient’s rheumatoid arthritis at this time is: 
Very good_______________________________________________Very poor 
 
4.5.7.4 
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).  The HAQ-DI refers to the previous week and assesses eight 


 
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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).  The questions assess usual abilities ranging from 
0 “without any difficulty” to 3 “unable to do.”  A lower HAQ-DI score indicates better QoL.  
See Appendix 11 for a review copy of the HAQ-DI questions. 
This questionnaire should be completed by the patient prior to any procedures being 
performed at the visit, if possible.  
4.5.7.5 
Short-Form 36 Health Survey Questionnaire, Version 2  
The SF-36v2 will be used to assess health-related QoL (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 QoL and for economic modeling.  See Appendix 12 for a sample 
version of the SF-36v2 questionnaire. 
4.5.7.6 
Functional Assessment of Chronic Illness Therapy-Fatigue 
Scale (FACIT-Fatigue) 
The FACIT-Fatigue scale will be used to assess patients’ fatigue (Cella et al. 2005).  The 
13-item questionnaire has been validated for use with 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 13 for a list of questions in the FACIT-Fatigue.  
4.5.8 
Laboratory, Biomarker, and Other Biological Samples  
Laboratory assessments will be performed as indicated on the Schedule of Assessments 
(see Appendix 1, Appendix 2, and Appendix 3).  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 clinic visits at which study drug is administered, laboratory samples should 
generally be drawn before the administration of study drug (and SC comparator drug for 
Cohort 1) and after the administration of patient reported PRO assessments (e.g., pain 
questionnaires).  An exception is on Day 28, where indicated PK samples should also be 
collected at timepoints following study treatment administration (see Appendix 3). 


 
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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 serum pregnancy test at screening.  Urine pregnancy tests 
will be performed at specified subsequent visits.  If a urine pregnancy test result 
is positive, it must be confirmed by a serum pregnancy test.  Should a positive 
result be recorded at any time, the procedures detailed in Section 5.4.3 should 
be followed. 
 
ESR:  Should be performed as a point-of-care test in clinic (with kits provided) in 
accordance with test guidelines 
 
PPD (if QFT not available):  Should be read locally  
 
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, alkaline phosphatase, ALT, AST, uric acid, LDH, amylase, and 
lipase 
 
hsCRP:  performed at the central laboratory will be blinded after the baseline visit. 
 
Urinalysis including dipstick (pH, specific gravity, glucose, protein, ketones, blood) 
and microscopic examination (sediment, RBCs, WBCs, casts, crystals, epithelial 
cells, bacteria) 
 
Coagulation:  INR, activated PTT, PT 
 
Viral serology 
Hepatitis B:  HBsAg, total HBcAb, and hepatitis B surface antibody  
Hepatitis C antibody 
 
Fasting lipids:  Cholesterol, LDL cholesterol, HDL cholesterol, triglycerides 
 
Quantitative immunoglobulins:  Total Ig, IgA, IgG, IgM, IgE 
 
TBNKs:  Once treatment with study medication begins, TBNK results will be blinded. 
 
RF  
 
Anti-CCP antibody (or ACPA) 
 
Quantiferon as appropriate 
 


 
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The following will be sent to the Sponsor or a designee for analysis:   
 
Serum, plasma, cells, and RNA from blood for exploratory non-inherited PD markers 
(lymphoid, myeloid, and other inflammatory markers as well as other markers 
potentially related to disease, drug, or clinical response; see Table 4). 
 
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 4.  Given the complexity and exploratory nature of biomarker analyses, 
results from the analyses will not be shared with investigators or study participants, 
unless required by law. 
Table 4 
Proposed Non-Inherited Biomarkers for Exploratory Research 
Sample Type  
Proposed Non-Inherited Biomarkers 
Whole blood for FACS 
(United States only) 
Cells and markers, including but not limited to basophil CD63, 
monocytes, B cells, and B cell subsets 
Plasma 
Markers, including but not limited to CCL3 and CCL4 
Serum 
Markers, including but not limited to sICAM, CXCL13, CCL20 
Blood for PBMC cell lysate 
(United States only) 
Markers including but not limited to phosphorylated and total BTK 
protein 
RNA extracted from blood 
Markers including but not limited to myeloid RNA markers 
FACS  fluorescence-activated cell sorting; PBMC  peripheral blood mononuclear cell. 
Note:  The timing for all samples is 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 4.5.10 and 4.5.11), 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. 
 
4.5.9 
Electrocardiograms 
Triplicate ECG recordings will be obtained at specified timepoints within approximately 
2-5 minutes of each other, as outlined in the Schedule of Assessments (see Appendix 1 
and Appendix 2).   


 
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Predose ECGs acquired on Day 1 and Day 28 should be as closely time-matched as 
feasible (morning visits are strongly recommended), and the patient should be fasting 
( 48 hours).  
The post-dose ECGs on Day 28 should occur 2 hours ( 30 minutes) after oral study 
medication is administered, and the patient should be fasting.   
ECGs obtained at all other timepoints can be performed without specific restrictions (e.g., 
may be any time of day, before or after dosing, fasting or fed).  
Three interpretable ECG recordings (e.g., without artifacts) must be obtained.  The ECG 
intervals (e.g., PR, QRS, QT, QTcF, and RR) and heart rate from these three ECGs will 
be entered into the eCRF; in addition, these triplicate readings will be stored for future 
analysis, if needed.  
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  
Lead placement should be as consistent as possible.  ECGs for each patient should be 
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 should be obtained prior to other 
procedures scheduled at that same time (e.g., vital sign measurements, blood draws) 
whenever 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 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 ms and/or 60 ms longer 
than the baseline value, another triplicate ECG must be recorded, ideally within the next 
5 minutes, and triplicate ECG monitoring should continue 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 4.6.2.  The 
investigator should also evaluate the patient for potential concurrent risk factors 


 
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(e.g., electrolyte abnormalities, co-medications known to prolong the QT interval, severe 
bradycardia). 
4.5.10 
Optional Samples for Whole-Genome Sequencing  
An optional 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 or Ethics Committee (IRB/EC) and, if applicable, an 
appropriate regulatory body.  If a site has not been granted approval for WGS sampling, 
this section of the protocol (i.e., Section 4.5.10) 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 will 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). 
4.5.11 
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 or 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. 
4.5.11.1 
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 


 
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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. 
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 
characteristics of these assays 
 
4.5.11.2 
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 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). 
4.5.11.3 
Confidentiality 
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. 


 
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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. 
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.  
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. 
4.5.11.4 
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. 
4.5.11.5 
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 


 
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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 GA29350 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 GA29350. 
4.5.11.6 
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 
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. 
4.6 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Patient Discontinuation 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
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 Day 84 treatment completion visit, an early 
termination visit should be conducted.   
These patients are not eligible to enter the OLE Study GA30067 and should return for 
the 8-week safety follow-up visit in this study (see Appendix 1 and Appendix 2).  If the 
patient is unable to return for a follow-up visit, the trial site may contact the patient by 
telephone to determine their clinical status. 
Patients who discontinue the study during the safety follow-up period but prior to 
completion of the 8-week safety follow-up will be asked to return to the clinic within 


 
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30 days ( 7 days) after the last dose of study drug or last scheduled visit for an early 
termination visit (see Appendix 1 and Appendix 2). 
4.6.2 
Study Treatment Discontinuation 
Patients must permanently discontinue study treatment with both oral study drug and SC 
comparator drug (however patients should be asked to remain in the blinded study 
through Week 12 even if their study treatment is discontinued in order to minimize 
missing data that limits study interpretability) if they experience any of the following: 
 
Pregnancy (the patient may still remain in the blinded study at the investigator’s 
discretion) 
 
Anaphylaxis or other severe hypersensitivity reaction 
 
Malignancy  
 
Any serious infection or infection requiring treatment with an IV antimicrobial agent 
 
Grade  2 AST or ALT elevation: (AST or ALT  3  ULN) in combination with 
total bilirubin  2  ULN or clinical jaundice as defined by Hy’s law 
 
Grade  3 AST or ALT elevation: (AST or ALT  5  ULN) 
 
Any Grade 3 or greater thrombocytopenia (National Cancer Institute Common 
Terminology Criteria for Adverse Events [NCI CTCAE v4.0]): Platelets 
 50,000/mm3 
 
Any Grade 4 neutropenia (NCI CTCAE v4.0):  ANC  500/mm3 
 
Patients who discontinue study treatment and who do not remain in the blinded study 
will be asked to return to the clinic for an early termination visit (see Section 4.6.1) 
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. 
4.6.3 
Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include but are not limited to the following: 
 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients 
 
Patient enrollment is unsatisfactory 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.   
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 


 
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 
Poor protocol adherence 
 
Inaccurate or incomplete data recording 
 
Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice 
 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
To protect patient safety, an unblinded IMC will monitor safety throughout the study (see 
Section 3.1.2). 
The safety plan for patients in this study is based on nonclinical and clinical experience 
with GDC-0853 in completed and ongoing studies as well as published literature on 
other BTK inhibitors.  The important potential safety risks for GDC-0853 are outlined 
below.  Please refer to the GDC-0853 Investigator’s Brochure for a complete summary 
of safety information.   
Several measures will be taken to ensure the safety of patients participating in this study.  
Eligibility criteria have been designed to exclude patients at higher risk for potential 
toxicities.  Patients will undergo safety monitoring during the study, including monitoring 
of vital signs, physical examination, ECGs, and routine laboratory safety assessments 
(hematology, chemistry, and urinalysis) and assessment of the nature, frequency, and 
severity of adverse events.  In addition, guidelines for managing potential adverse 
events, including criteria for treatment interruption or discontinuation, and enhanced 
safety reporting are provided below.   
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 


 
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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 
single doses and with dosing for 14 days, self-limited Grade 1 events of nasopharyngitis 
were reported but did not lead to any change in study drug dosing.  One subject had 
asymptomatic bacteriuria, which resolved while study drug dosing continued. 
Patients will be excluded from the study if they have a history of hospitalization due to an 
infection in the 8 weeks before screening, evidence of active or latent or inadequately 
treated infection with Mycobacterium TB, known active infection (current) or history of 
recurrent infection, or any known immunodeficiency including IgG  500 mg/dL. 
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 TB, and should be evaluated 
promptly.  Physicians or an HCP 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 an adverse event of special interest and should be 
reported to the Sponsor as outlined in Section 5.2.3. 
Guidelines for management of study treatment in the event that infections are observed 
are provided in Table 5. 
Please 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 et al. 2016) or EULAR 
(van Assen et al. 2011) recommendations or local guidelines be up to date before study 
participation.  Patients will be excluded from study participation and will not be dosed 


 
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with GDC-0853 if they have been vaccinated with live, attenuated vaccines (e.g., the 
intranasal live attenuated influenza vaccines, BCG, varicella) within 6 weeks before 
planned dosing.  In addition, immunization with a live or attenuated vaccine is prohibited 
for the duration of study participation, including the 8-week safety follow-up period after 
the administration of the last dose.   
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 
 
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 
NCI 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 of 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 antiplatelet or anticoagulant therapies.  As a precautionary safety 
measure, patients will be excluded from study participation if they have a need for 


 
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systemic anticoagulation with warfarin or other oral or injectable anti-coagulants or 
anti-platelet agents (other than NSAIDs, aspirin, and other salicylates), any history of 
hospitalizations or transfusion for a GI bleed, any history of a hemorrhagic CVA, any 
history of spontaneous intracranial hemorrhage, traumatic intracranial hemorrhage within 
10 years prior to the study, or a known bleeding diathesis.  Patients should be advised to 
seek immediate medical attention if they develop signs and symptoms suggestive of 
clinically significant bleeding.   
Several risk factors, including patient age, co-morbidities, concurrent medications, prior 
medical history, and Helicobacter pylori infection, have been demonstrated in a variety of 
studies to increase the risk of NSAID-related GI injury (Lanza et al. 2009).  It is unknown 
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 PPI should be considered (Bhatt et al. 2008) and used according to 
local or recognized guidelines (e.g., ACCF/ACG/AHA 2008 Expert Consensus 
Document). 
Patients at high risk for NSAID-related GI toxicity include: 
 
Patients using both aspirin and an NSAID 
 
Patients with a history of ulcer disease 
 
Patients with one or more of the following: 
Age  60 years 
High-dose NSAID use 
Concurrent corticosteroid use 
Dyspepsia or gastroesophageal reflux disease symptoms 
 
Any bleeding event of Grade  2 is considered an adverse event of special interest and 
should be reported to the Sponsor in an expedited manner as outlined in Section 5.2.3.   
Guidelines for management of study treatment in the event that bleeding is observed in 
patients are provided in Table 5.  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 


 
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they develop signs and symptoms suggestive of cytopenias (e.g., persistent fever, 
bruising, bleeding, pallor).  
Guidelines for the management of study treatment in the event of cytopenias in patients 
are provided in Table 5.  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 M  h) for 6 months, and significant reductions in rats administered 100 mg/kg/day 
(1438 M  h) and dogs administered 25 mg/kg (180 M  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 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 side effects.   
Guidelines for management of study treatment in the event of GI side effects in patients 
are provided in Table 5.  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 M  h) 
and dogs administered  10 mg/kg/day ( 36 M  h), with corresponding microscopic 
changes in the liver of dogs administered 25 mg/kg/day (180 M  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 M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 the 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 QD 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.   


 
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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 
screening.  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 Grade  3 ( 5  ULN) AST or ALT elevation are 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 study treatment in the event of hepatotoxicity in 
patients are provided in Table 5.  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 CV parameters, at therapeutic exposures.  A minimal increase 
in QTc (7 ms or 3%) interval was noted at 45 mg/kg in the single-dose CV safety 
pharmacology study in telemetry-instrumented dogs.  Based on 
extrapolated/interpolated toxicokinetic data, the unbound Cmax at 45 mg/kg (considered a 
NOAEL) and no-observed-effect level of 15 mg/kg were 
 
  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, routine safety ECGs, and collection of 
adverse events (see Appendix 1 and Appendix 2). 
Management of patients with sustained QTcF prolongation (QTcF that is  500 ms 
and/or  60 ms 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. 
Guidelines for management of study treatment in the event in the event of CV effects in 
patients are provided in Table 5. 


 
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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 M  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 M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).  
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 study treatment in the event of vasculitis in patients are 
provided in Table 5. 
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 study.  Basal or squamous 
cell carcinoma of the skin that has been excised and is considered cured and in situ 
carcinoma of the cervix treated with apparent success by curative therapy more than 
1 year prior to screening are not exclusionary. 
All malignancies are adverse events of special interest and should be reported to the 
Sponsor in an expedited manner as outlined in Section 5.2.3.   


 
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Guidelines for management of study treatment in the event of malignancies in patients 
are provided in Table 5.  Please refer to the GDC-0853 Investigator’s Brochure for 
further details. 
5.1.2 
Potential Risks with Adalimumab 
Investigators should be aware of the risks associated with ADA and their management, 
including serious infections, injection-site reactions, liver enzyme elevations, headache, 
and rash (for full details, see the local prescribing information). 
5.1.2.1 
Hypersensitivity Reactions 
Patients with a history of anaphylactic or other serious allergic reaction to ADA are 
excluded from study participation. 
Investigators and HCPs administering study injections should be trained to recognize 
and manage the signs and symptoms of a potential anaphylactic/anaphylactoid or 
hypersensitivity reaction and to accurately and appropriately report these events.   
HCPs should also instruct patients how to recognize the signs and symptoms of any 
anaphylactic/anaphylactoid or hypersensitivity reaction and to contact a health-care 
provider and/or seek emergency care in case of any such symptoms.  See Appendix 7 
for clinical criteria for diagnosing anaphylaxis (Sampson’s criteria). 
Guidelines for management of study treatment in the event of hypersensitivity reactions 
in patients are provided in Table 5.  
5.1.2.2 
Local Injection-Site Reactions 
A local injection-site reaction is any local cutaneous reaction occurring at the site of 
injection following SC comparator drug administration.  In the clinic setting, patients 
should be monitored for local injection-site reactions in the period immediately following 
injections and adverse events reported as outlined in Section 5.3.1. 
5.1.3 
Management of Study Treatment in Patients Who Experience 
Specific Adverse Events 
Guidelines for management of study treatment in patients who experience specific 
adverse events are provided in Table 5. 
If there are any other situations where it seems appropriate to hold and/or discontinue 
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Table 5 
Guidelines for Management of Study Treatment in Patients Who Experience Specific Adverse Events  
Event 
Action to Be Taken a 
Infection b 
 
Serious infection or any infection requiring 
treatment with an IV antimicrobial agent 
Discontinue study treatment and report event as an adverse event of special interest.     
Self-limited infections that require treatment 
Withhold study treatment during antimicrobial therapy.  Study treatment may resume 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) bleeding events, withhold study treatment and consult with the Medical 
Monitor. 
Neutropenia c 
 
Grade 2:  ANC  10001500/mm³ 
Maintain study treatment dosing. 
Grade 3:  ANC 5001000/mm³ 
For the first event, hold study treatment and recheck CBC in 7 days.  If neutrophil count has 
recovered to Grade 1 ( 1500/mm3) or has returned to the normal range, study treatment can be 
resumed.  If Grade 3 neutropenia persists or for recurrent Grade 3 neutropenia, discontinue 
study treatment. 
Grade 4 ANC  500 /mm³ 
Discontinue study treatment. 
Thrombocytopenia d 
 
Grade 1:  PLT  75,000/mm³ 
In the absence of bleeding event(s), maintain study treatment dosing. 
Grade 2:  PLT 50,00075,000/mm³ 
For the first event, hold study treatment and recheck CBC in 7 days.  If platelet count has 
recovered to Grade 1 or has returned to the normal range, study treatment can be resumed.  For 
recurrent Grade 2 thrombocytopenia and in the absence of bleeding events, discuss with the 
Medical Monitor (or discontinue study treatment). 
Grade  3:  PLT  50,000/mm³ 
Discontinue study treatment. 
Gastrointestinal effects 
 
Nausea, vomiting, and/or diarrhea 
Manage according to site institutional guidelines. 
Consider administration of GDC-0853 with food as a possible mitigation strategy. 


Table 5 
Guidelines for Management of Study Treatment in Patients Who Experience Specific Adverse Events 
(cont.) 
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Event 
Action to Be Taken a 
Malignancy 
 
Any malignancy  
Discontinue study treatment with the exception of non-serious local and resectable basal or 
squamous cell carcinoma of the skin.  Report event as an adverse event of special interest to 
the Sponsor in an expedited manner. 
Hepatotoxicity 
 
AST or ALT  3.0 5.0  ULN 
Withhold study treatment and consult with the Medical Monitor 
AST or ALT  3  ULN in combination with a 
total bilirubin  2  ULN, of which at least 35% is 
direct bilirubin, or clinical jaundice  
Discontinue study treatment.  Report event(s) as adverse event of special interest to the 
Sponsor in an expedited manner. 
AST or ALT  5  ULN 
Discontinue study treatment.  Any elevation of an AST or ALT  5  ULN should be reported as 
an adverse event of special interest to the Sponsor in an expedited manner.   
Cardiovascular effects  
 
Sustained (at least two ECG measurements 
 30 minutes apart) QTcF that is  500 ms 
and/or  60 ms longer than the baseline value 
Unless there is a clear alternative cause other than study drug, discontinue study treatment. e 
Sustained absolute QTcF that is  515 ms 
Unless there is a clear alternative cause other than study drug, discontinue study treatment. 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 study treatment. e 
Vascular inflammation 
 
Vasculitis 
Consult with the Medical Monitor.  
Hypersensitivity reactions 
 
Fever, chills, pruritis, urticaria, angioedema, 
and skin rash 
Cardiopulmonary reactions, including chest 
pain, dyspnea, hypotension, or hypertension 
Persistent gastrointestinal symptoms (e.g., 
crampy abdominal pain, vomiting) 
The patient should be treated according to the standard of care for management of 
anaphylaxis/anaphylactoid or a hypersensitivity reaction.  The patient must discontinue study 
treatment.   
 


Table 5 
Guidelines for Management of Study Treatment in Patients Who Experience Specific Adverse Events 
(cont.) 
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CBC  complete blood count; IV  intravenous; MTX  methotrexate; PLT  platelet count; QTcF  QT interval corrected using Fridericia’s formula ; 
SC  subcutaneous; ULN  upper limit of normal. 
Note:  “Study treatment” includes study drug (GDC-0853 or placebo) and SC comparator drug (ADA or placebo, applicable only to Cohort 1). 
a Any patient who must discontinue study treatment for safety reasons (where specified above) should be asked to stay in the blinded study 
through Week 12 if deemed appropriate by the investigator, however they must not receive study treatment. 
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 checked 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 study drug, provided that any ECG abnormalities have resolved and that the patient is 
appropriately monitored.  Clinical judgment should be applied. 
 


 
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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 5.3.5.11  
 
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 Grade  3 AST or ALT elevation 
 
Adverse events of special interest for general drug development 
Cases of potential drug-induced liver injury that include an elevated ALT or AST 
in combination with either an elevated bilirubin or clinical jaundice, as defined 
by Hy’s law (see Section 5.3.5.7) 
Suspected transmission of an infectious agent by the study drug, as defined 
below 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, 
is considered an infectious agent.  A transmission of an infectious agent 


 
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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.  The 
investigator is also responsible for reporting medical device complaints (see 
Section 5.4.4). 
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 collection, discontinuation of medications) should be 
reported (see Section 5.4.2 for instructions for reporting serious adverse events). 
After initiation of study drug, all adverse events will be reported until 8 weeks after the 
last dose of study drug the patients receives, either in this study or the OLE 
Study GA30067.  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 6 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 


 
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Table 6 
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 
an 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 7): 
 
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 7 
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 
Injection-Site Reaction 
Local cutaneous adverse events that occur at or around the injection site during or within 
24 hours following study drug injection should be captured as individual signs (e.g., 
erythema, induration/swelling at injection site) and symptoms (e.g., pain, pruritus at 
injection site) on the Adverse Event eCRF rather than a diagnosis of allergic reaction or 
injection-site reaction. 
5.3.5.2 
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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5.3.5.3 
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. 
5.3.5.4 
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. 
5.3.5.5 
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). 
5.3.5.6 
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 
details on recording persistent adverse events). 


 
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5.3.5.7 
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 an 
indicator of severe liver injury (as defined by Hy's law).  Therefore, in addition to the 
protocol defined adverse event of special interest of Grade  3 AST or ALT elevations, 
investigators must report as an adverse event the occurrence of either of the following: 
 
Treatment-emergent ALT or AST  3  ULN in combination with total bilirubin 
 2  ULN (of which at least 35% is direct bilirubin) 
 
Treatment-emergent ALT or AST  3  ULN in combination with clinical jaundice 
 
The most appropriate diagnosis or, if a diagnosis cannot be established, the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.3) 
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). 
5.3.5.8 
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.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not 
be used unless combined with the presumed cause of death (e.g., "sudden cardiac 
death"). 
If the death is attributed to progression of RA, "Rheumatoid arthritis progression" should 
be recorded on the Adverse Event eCRF.  
5.3.5.9 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 


 
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that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
5.3.5.10 
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”). 
5.3.5.11 
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.   
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
 
Hospitalization for respite care 
 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
The patient has not experienced an adverse event 
 
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead: 
 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
5.3.5.12 
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 Monitors contact information for all sites: 
Medical Monitor: 
 M.D. 
Telephone No.: 
Office: 
  
 
Mobile: 
 
 
Email:
Emergency Telephone Nos. 
 
 
 
Sponsor Medical Monitor: 
, M.D. 
Telephone No.: 
Office
 
 
Email:
 
 
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 patients 
receives, either in this study or the OLE Study GA30067.  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. 


 
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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, either in this study or the OLE Study GA30067.  A paper 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 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 


 
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Section 5.4.2).  Any abortion should be reported in the same fashion (because the 
Sponsor considers abortions to be medically significant). 
5.4.4 
Reporting Requirements for Medical Device Complaints 
In this study, ADA PFS is considered a medical device.  The investigator must report all 
medical device complaints to the Sponsor.  The investigator should document as much 
information as possible on the PD 103 IMP Deviation Form, including the product batch 
number and expiration date, and forward the form to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; refer to the pharmacy manual for further 
details).  The PD 103 IMP Deviation Form, together with pictures of the defective PFS, 
should be sent to kaiseraugst.global_impcomplaint_management@roche.com.  Where 
possible, the investigator will retrieve the PFS unit(s) involved in the complaint and 
attempt to return to the Sponsor for further assessment, if necessary. 
If the medical device results in an adverse event to the study patient, the event must be 
reported on the Adverse Event eCRF and submitted through the EDC system.  If the 
event is serious, the Adverse Event eCRF must be completed immediately (i.e., no more 
than 24 hours after learning of the event), as outlined in Section 5.4.2. 
If the medical device complaint results in an adverse event to an individual rather than 
the study patient, the device complaint must be reported on the PD 103 IMP Deviation 
Form and the adverse event must be reported as a spontaneous adverse event to 
Roche Safety Risk Management via telephone. 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported. 
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 
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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, either in this study or the 
OLE Study GA30067), 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 
 
Local prescribing information for ADA  
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
6.1 
DETERMINATION OF SAMPLE SIZE 
6.1.1 
Cohort 1:  MTX-IR (Arms AE) 
The purpose of this cohort is estimation and hypothesis generation regarding the effects 
of GDC-0853 on ACR50 response relative to placebo and relative to ADA as the active 
comparator.  Point and interval estimates of the ACR50 response rates will be obtained.  
A target of approximately 480 patients will be enrolled and randomized.  The first 
200 patients will be randomly allocated in a 1:1:1:1:1 ratio to the five treatment arms:  
50 mg QD GDC-0853 (Arm A), 150 mg QD GDC-0853 (Arm B), 200 mg BID GDC-0853 
(Arm C), placebo (Arm D), or ADA (Arm E).  The remaining 280 patients will be randomly 
allocated in a 1:1:1:1 ratio to Arms BE.  The study is designed to estimate differences 
in ACR50 response rates between the active comparator Arm E and GDC-0853treated 


 
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Arms B or C at Day 84.  A sample size of 110 patients per arm has 80% power to detect 
a difference of 15% between Arm E and Arm B or C, for an ACR50 response rate of up 
to 50% in the active comparator arm (Arm E), with a two-sided type-one error rate of 0.2 
with the 2 test with continuity correction.  No adjustment for multiple comparisons is 
made. 
The overall sample-size may be increased by up to 20% depending on the outcome of the 
IA (see Section 6.8). 
6.1.2 
Cohort 2:  TNF-IR (Arms FG) 
The purpose of this cohort is estimation and hypothesis generation regarding the effects 
of GDC-0853 on ACR50 response relative to placebo.  A target of approximately 
120 patients will be enrolled and randomized with a 1:1 ratio to the two treatment groups:  
200 mg BID GDC-0853 (Arm F) or placebo (Arm G).  The study is designed to detect a 
significant difference in ACR50 response rates between the active and placebo arms at 
Day 84.  A sample size of approximately 60 patients per arm provides 80% power to 
detect a difference of 20% for an ACR50 response rate of up to 20% in the placebo arm 
(Arm G) with a two-sided type one error rate of 0.2 with use of Fisher’s exact test.   
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 
Treatment group comparability will be analyzed.  Demographic and baseline 
characteristics such as age, sex, weight, and disease activity will be summarized by 
treatment group with use of means or medians for continuous variables and proportions 
for categorical variables.  Medical history, including diagnoses and treatment, will be 
tabulated.  
6.4 
EFFICACY ANALYSES 
Efficacy analyses will be conducted for the intent-to-treat (ITT) population, defined as all 
randomized patients.  Sensitivity analyses of additional study populations (e.g., 
completers and per protocol [excluding major protocol violators]) will also be performed.  
Exploratory subgroup analyses (e.g., based on baseline biomarker characteristics) may 
also be conducted.   
6.4.1 
Primary Efficacy Endpoint 
The primary efficacy analysis will compare the proportion of patients achieving an 
ACR50 response between each of three dose-levels (Arms A to C) of 


 
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GDC-0853treated patients and placebo-treated patients (Arm D) at Day 84 for 
patients who had an inadequate response to MTX and are naive to TNF therapy.  
Non-responder imputation will be implemented in the event of missing data.  The 
Cochran-Mantel-Haenszel test will be used to assess the difference in the proportion of 
responders, adjusted for the randomization stratification factor, geographic region.   
6.4.2 
Secondary Efficacy Endpoints 
The key secondary efficacy analysis for the MTX-IR population will compare the 
proportion of patients achieving an ACR50 response between each of two higher 
dose-levels (Arm B and Arm C) of GDC-0853treated patients and ADA-treated patients 
(Arm E).  The Cochran-Mantel Haenszel test will be used to assess the difference in the 
proportion of responders, adjusted for the randomization stratification factor, 
geographic region.  The key secondary efficacy analysis for the TNF-IR cohort will 
compare the proportion of patients achieving an ACR50 response between GDC-
0853treated patients (Arm F) with the placebo-treated arm (Arm G).  The Cochran-
Mantel Haenszel test will be used to assess the difference in the proportion of 
responders, adjusted for the randomization stratification factors geographic region and 
prior exposure to a non-TNF inhibitor biologic.  The details for other secondary efficacy 
analyses will be specified in the DAP. 
6.5 
SAFETY ANALYSES 
The safety analyses will include all randomized patients who received at least one dose 
of study drug, with patients grouped according to treatment received.  Safety will be 
analyzed on the basis of reported/documented adverse events, laboratory results, and 
vital signs, including adverse events of special interest.  
6.6 
PHARMACOKINETIC ANALYSES  
The PK analyses will include patients with sufficient data to enable estimation of key 
parameters (e.g., AUC, predose concentrations [Ctrough], and half-life), with patients 
grouped according to treatment received.   
Systemic GDC-0853 exposure will be evaluated using a population PK approach, and 
estimates of PK parameters will be generated.  The extent of interpatient variability will 
be evaluated, and potential sources of variability will be assessed.  Relationships 
between exposure and PD, efficacy, and safety endpoints will be explored. 
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 


 
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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 
6.8.1 
Planned Interim Analysis 
6.8.1.1 
Cohort 1:  MTX-IR (Arms AE) 
An IA will be performed after approximately 150 patients have completed their 12-week 
evaluation (~30 patients/arm).  The purpose of this IA is to assess the efficacy of the 
GDC-0853treated arms compared with the placebo-treated arm. Summaries of safety 
and efficacy data by treatment group will be prepared and reviewed by members of the 
IMC; the IMC consists of Sponsor’s members who do not have direct contact with 
investigational staff and monitors.  No unblinded individual patient data will be shared 
with the members of the Sponsor’s study team who have direct contact with 
investigational staff and monitors except for the case in which the IMC decides to 
unblind the study team to enable decision-making and potential interactions with 
regulatory bodies.  Recruitment of patients will continue during the conduct of the IA.  
Further details of the IA, including the use of the IMC and decision criteria, will be 
specified in the DAP.  No further IAs are planned in Cohort 1; however, given the 
hypothesis-generating nature of this study, the Sponsor may choose to conduct one 
subsequent efficacy IA. 
If the results of the IA yield encouraging evidence of activity in one or more BTK 
containing treatment groups relative to placebo and is accompanied by an unexpected 
placebo response rate (for example), the Sponsor may opt to increase enrollment by up 
to 20% to obtain greater precision for estimation of treatment differences. 
6.8.1.2 
Cohort 2:  TNF-IR (Arms FG) 
No IA is planned in Cohort 2; however, given the hypothesis-generating nature of this 
study, the Sponsor may choose to conduct one optional efficacy IA in order to guide 
internal decision making around issues such as the adequacy of dose ranging, the 
adequacy of sample sizes for safety and/or efficacy analyses, or to inform further 
development decisions.  The IA plan will be detailed in an updated Data Analysis Plan 
prior to conducting the IA.  The decision to conduct this optional IA and the timing of 
the analysis will be documented in the Sponsor’s trial master file prior to the conduct of 
the IA.  This optional IA will be performed and interpreted by an IMC; the IMC consists 
of Sponsor’s members who do not have direct contact with investigational staff and 
monitors. IMC may decide to unblind the study team to enable decision-making and 
potential interactions with regulatory bodies.  


 
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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, with use of 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 
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 DATA 
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. 


 
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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, PROs, 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. 
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. 


 
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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. 
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 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 
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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 
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 


 
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or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file.  
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., last patient last 
safety follow-up visit in this protocol or the last patient in this protocol enrolled into the 
OLE Study GA30067). 
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. 


 
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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 and include approximately 600 patients.  The 
contract research organization 
 will be responsible for submission to IRB/ECs 
for approval of the study protocol, patient recruitment, study conduct, data collection, 
and reporting.   
9.5 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to HCPs 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. 


 
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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. 
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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GDC-0853—Genentech, Inc. 
136/Protocol GA29350, Version 4 
Appendix 1  
Schedule of Assessments (Cohort 1:  MTX-IR) 
Week 
Screening 
Period 
Treatment Period 
SFU 
ET 
UV 
0 
1 
2 
4 
6 
8 
10 
12 
8 weeks 
after last 
dose 
( 4) 
Day ( days) 
 28 to 
 1 
Day 1 a 
Day 7 
( 1) 
Day 14 
( 1) 
Day 28 a 
( 2) 
Day 42 
( 2) 
Day 56 
( 2) 
Day 70 
( 2) 
Day 84 a,b 
( 2) 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
 
 
 
 
 
General medical history and baseline conditions c 
x 
x 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
x 
 
 
 
 
 
 
 
 
 
 
Concomitant medications d 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x  
Adverse events  
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x  
Vital signs e 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x f 
Height 
x 
 
 
 
 
 
 
 
 
 
 
 
Weight 
x 
x 
 
 
x 
 
x 
 
x 
x 
x 
 
Complete physical examination g 
x 
 
 
 
 
 
 
 
x 
x 
x 
 
Limited physical examination h 
 
x 
x 
x 
x 
x 
x 
x 
 
 
 
x f 
Triplicate ECG i 
x j 
x k 
x j 
 
x k 
 
x j 
 
x j 
x j 
x j 
x f, j 
HBsAg, HBsAb, Hep B cAb, HCV Ab 
x 
 
 
 
 
 
 
 
 
 
 
 
QFT or PPD l 
x 
 
 
 
 
 
 
 
 
 
 
 
Chest radiograph m 
x 
 
 
 
 
 
 
 
 
 
 
 
GDC-0853/placebo administration in clinic n 
 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
Drug dispensing 
 
x 
 
x 
x 
x 
x 
x 
 
 
 
 
ADA/placebo SC administration o 
 
x 
 
x 
x 
x 
x 
x 
 
 
 
 
Hematology p 
x 
x 
x 
 
x 
 
x 
 
x 
x 
x 
x f 


Appendix 1  
Schedule of Assessments (Cohort 1:  MTX-IR) (cont.) 
GDC-0853—Genentech, Inc. 
137/Protocol GA29350, Version 4 
Week 
Screening 
Period 
Treatment Period 
SFU 
ET 
UV 
0 
1 
2 
4 
6 
8 
10 
12 
8 weeks 
after last 
dose 
( 4) 
Day ( days) 
 28 to 
 1 
Day 1 a 
Day 7 
( 1) 
Day 14 
( 1) 
Day 28 a 
( 2) 
Day 42 
( 2) 
Day 56 
( 2) 
Day 70 
( 2) 
Day 84 a,b 
( 2) 
Chemistry q 
x 
x 
x 
 
x 
 
x 
 
x 
x 
x 
x f 
Coagulation studies PT/PTT 
x 
 
 
 
 
 
 
 
 
 
 
x f 
Pregnancy test r 
x 
x 
 
 
x 
 
x 
 
x 
x 
x 
x f 
Urinalysis s 
x 
x 
 
 
x 
 
x 
 
x 
x 
x 
x f 
Quantitative Ig t  
x 
x 
 
 
x 
 
x 
 
x 
x 
x 
x f 
Lipid panel  
 
x 
 
 
x 
 
 
 
x 
x 
x 
 
Rheumatoid factor and anti-CCP/ACPA 
x 
 
 
 
 
 
 
 
x 
x 
x 
 
TBNK 
x 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x f 
ACR/DAS: 
 
 
 
 
 
 
 
 
 
 
 
 
CRP 
x 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x f 
ESR (on site or at local laboratory) 
x 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x f 
Tender/painful joint count (68), swollen joint count 
(66) 
x 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x f 
Patient’s Assessment of Arthritis Pain u 
 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x f 
Patient Global Assessment of Arthritis u 
 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x f 
Physician’s Global Assessment of Arthritis v 
 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
 x f 
HAQ-DI u  
 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x f 
SF-36v2 u  
 
x 
 
 
 
 
x 
 
x 
x 
x 
 
FACIT-Fatigue u 
 
x 
 
x 
x 
 
x 
 
x 
x 
x 
 
PK assessment w  
 
x 
x 
 
x 
 
x 
 
x  
 
x 
x f 
PBMC protein lysate x (U.S. sites only) 
x 
x 
 
 
x 
 
 
 
x 
x 
x 
 


Appendix 1  
Schedule of Assessments (Cohort 1:  MTX-IR) (cont.) 
GDC-0853—Genentech, Inc. 
138/Protocol GA29350, Version 4 
Week 
Screening 
Period 
Treatment Period 
SFU 
ET 
UV 
0 
1 
2 
4 
6 
8 
10 
12 
8 weeks 
after last 
dose 
( 4) 
Day ( days) 
 28 to 
 1 
Day 1 a 
Day 7 
( 1) 
Day 14 
( 1) 
Day 28 a 
( 2) 
Day 42 
( 2) 
Day 56 
( 2) 
Day 70 
( 2) 
Day 84 a,b 
( 2) 
Blood for FACS (U.S. sites only) y 
x 
x 
 
 
x 
 
 
 
x 
x 
x 
x f 
PD blood sample for FACS/basophils (U.S. sites 
only) z 
x 
x 
x 
 
x 
 
 
 
x 
 
x 
x f 
Serum biomarkers aa 
x 
x 
x 
 
x 
 
 
 
x 
x 
x 
x f 
Plasma biomarkers  bb 
x 
x 
x 
 
x 
 
 
 
x 
x 
x 
x f 
PAXgene RNA blood biomarkers cc 
x 
x 
x 
 
x 
 
 
 
x 
x 
x 
x 
Whole blood PG sample 
 
x 
 
 
 
 
 
 
 
 
 
 
Whole blood sample for genotyping (optional) dd 
 
x 
 
 
 
 
 
 
 
 
 
 
ACPA  anti-citrullinated protein/peptide antibody; ACR  American College of Rheumatology; ADA  adalimumab; BID  twice daily; CCP  cyclic citrullinated 
protein; CRP  C-reactive protein; DAS  Disease Activity Score; eCRF  electronic Case Report Form; ESR  erythrocyte sedimentation rate; ET  early 
termination; FACIT  Functional Assessment of Chronic Illness Therapy; FACS  fluorescence-activated cell sorting; HAQ-DI  Health Assessment 
QuestionnaireDisability Index; HBsAg  hepatitis B core antibody; HBsAb  hepatitis B surface antigen; HCP  health-care professional; HCV  hepatitis C 
virus; IRB/EC  Institutional Review Board/Ethics Committee; MTX-IR  patients who had an inadequate response to methotrexate; OLE  open-label 
extension; PBMC  peripheral blood mononuclear cell; PD  pharmacodynamic; PG  pharmacogenomic; PK  pharmacokinetic; PPD  purified protein derivate; 
PPI  proton pump inhibitor; PRO  patient reported outcome; QFT  QuantiFERON-TB Gold; RA  rheumatoid arthritis; SC  subcutaneous; SF-36  Short-
Form 36 Health Survey; SFU  safety follow-up; SST  serum separator tube; TB  tuberculosis; TBNK  T, B, and natural killer cells; UV  unscheduled visit; 
WGS  whole-genome sequencing. 
a A morning clinic visit (fasting) is strongly recommended for visits on Days 1, 28, and 84, and particularly on Day 28 (for intensive PK sampling).  When 
morning visits are strongly recommended, the patient should be fasting ( 48 hours) prior to the first PK blood draw and fasting lipid panel.  
b Day 84 is the last day of the study treatment period (however, no blinded study drug will be given on Day 84; the last dose of blinded study drug is the PM 
dose of Day 83).  If eligible, patients may enroll into the OLE Study GA30067 to receive their first open-label dose of GDC-0853 on Day 1 of 
Study GA30067 (after a trough PK level is drawn) or they will proceed to the SFU period and return for the SFU visit on Day 140 (8 weeks after last 
dose of study drug). 
c   Medical history will include the diagnosis of rheumatoid arthritis and date of RA diagnosis, all history relevant to RA, including a detailed history of RA 
medications taken within 5 years before screening, with dose(s)/duration(s), date(s) of discontinuation, and reason(s) for discontinuation; coronary heart 
disease risk factors; dates of previous vaccinations, if applicable (including influenza, pneumococcus, zoster); other clinically significant diseases; 
reproductive status; smoking history; and use of alcohol and drugs of abuse.  The evaluation on Day 1 should only include any updates from screening. 


Appendix 1  
Schedule of Assessments (Cohort 1:  MTX-IR) (cont.) 
GDC-0853—Genentech, Inc. 
139/Protocol GA29350, Version 4 
 
d Includes any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, vitamins, and nutritional or 
dietary supplements) used by a patient from 12 weeks prior to initiation of study drug until 8 weeks after the last dose of study drug or entrance into the 
OLE, whichever occurs first.  In addition, at each clinic visit, any use of PPIs, H2 receptor antagonists, and/or other short-acting antacids (e.g., 
Maalox, Pepto-Bismol, Rolaids) should be recorded as concomitant medications, including the date and time of last administration prior to the 
clinic visit. 
e Includes respiratory rate, pulse rate, temperature, and systolic and diastolic blood pressures while the patient is in a seated position for at least 
5 minutes.  
 To be performed only if medically indicated on the basis of the reason for the UV. 
g 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. 
The baseline rheumatoid nodules assessment should be recorded in the Day 1 eCRF.  At subsequent visits, record new or worsened clinically 
significant abnormalities on the Adverse Event eCRF.  
h Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated.  After the baseline visit, any new or worsened 
clinically significant abnormalities should be recorded on the Adverse Event eCRF. 
i Triplicate interpretable digital ECG recordings (e.g., without artifacts) will be obtained within approximately 25 minutes of each other.  The ECG 
intervals (e.g., PR, QRS, QT, QTcF, and RR) and heart rate from these three ECGs will be entered into the eCRF; in addition, these triplicate readings 
will be stored for future analysis, if needed.  ECGs for each patient should be 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) whenever possible.  Body 
position should be consistently maintained for each ECG evaluation to prevent changes in heart rate.  Environmental distractions (e.g., television, 
radio, conversation) should be avoided during the pre-ECG resting period and during ECG recording.  
 ECGs at these specified timepoints can be performed without specific restrictions (e.g., can be any time of day, before or after dosing, fasting or fed).   
k Instructions for ECG collection at the indicated timepoints:  before dosing of the in-clinic dose on Days 1 and 28 (while patient is fasting) and at 
2 hours ( 30 minutes) after dosing of the in-clinic dose on Day 28 (while patient is fasting).   
 PPD should be performed only if QFT is not available.  Refer to the requirements for TB testing in Section 4.1.1 (may be performed within 3 months 
of screening, if indicated). 
m Not required if documented results of a chest radiograph (read by a radiologist) taken within the 3 months prior to screening is without changes 
suggestive of active TB infection. 
n Patients will receive GDC-0853/placebo BID approximately every 12 hours starting on Day 1 and ending on Day 83.  GDC-0853/placebo 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.  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). 


Appendix 1  
Schedule of Assessments (Cohort 1:  MTX-IR) (cont.) 
GDC-0853—Genentech, Inc. 
140/Protocol GA29350, Version 4 
o The SC comparator drug will be administered subcutaneously in the thigh region.  Alternatively, the injections can be administered subcutaneously in the 
abdomen.  Following each SC comparator drug administration, patients should be monitored for acute hypersensitivity reactions per the local label.  If the 
unblinded HCP cannot administer the SC comparator drug on the scheduled dosing day, the SC comparator drug is to be administered within a window of 
 2 days from the scheduled dosing date.  If the patient experiences a minor illness (e.g., minor infection), at the discretion of the investigator, the SC 
comparator drug may be delayed for a maximum period of 1 week.  Following the delay, the SC comparator drug dosing is to be resumed in accordance with 
the original dosing schedule.  Any potential deviation from this window is to be discussed with the Medical Monitor for the study. 
p Includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, other 
cells). 
q Includes sodium, potassium, chloride, bicarbonate, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total and direct bilirubin, 
alkaline phosphatase, ALT, AST, uric acid, LDH, lipase, and amylase. 
 All women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test at screening.  Urine pregnancy tests will 
be performed locally at specified subsequent visits.  If a urine pregnancy test result is positive, it must be confirmed by a serum pregnancy test (performed 
locally). 
s Includes dipstick (pH, specific gravity, glucose, protein, ketones, blood) and microscopic examination (sediment, RBCs, WBCs, casts, crystals, epithelial cells, 
bacteria). 
 Includes total Ig, IgM, IgA, IgG, and IgE. 
u Questionnaires will be self-administered on an electronic device (“ePRO”).  Patients will complete the ePRO assessments before receiving any information on 
disease status, prior to the performance of non-PRO assessments and prior to the administration of study treatment.  See Appendix 11, Appendix 12, 
Appendix 13, and Appendix 14 for sample questionnaires for the HAQ-DI, SF-36v2, FACIT-Fatigue, and DAS-28, respectively.   
v The same clinician who performs the joint counts (Efficacy Assessor, see Section 4.5.6) should complete the Physician’s Global Assessment of Arthritis 
throughout the study. 
w See Appendix 3 for detailed schedule.   
x Collect prior to drug administration.  Blood for PBMCs will be shipped overnight to a central laboratory for processing.  
y 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 (see Laboratory Manual) within 24 hours.  
z Collect prior to drug administration.  Blood for flow cytometry.  To be performed at selected centers in the United States where samples can be shipped to a 
FACS laboratory (see Laboratory Manual) within 24 hours. 
aa SST(s).  Collect prior to drug administration. 
bb Citrate plasma tube.  Collect prior to drug administration. 
cc Collection into two PaxGene blood tubes.  Collect prior to drug administration. 
dd Optional 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. 
141/Protocol GA29350, Version 4 
Appendix 2  
Schedule of Assessments (Cohort 2:  TNF-IR) 
Week 
Screening 
Period 
Treatment Period 
SFU 
ET 
UV 
0 
1 
2 
4 
8 
12 
8 Weeks 
after Last 
Dose 
( 4) 
Day 
 28 to  1 Day 1 a 
Day 7 
( 1) 
Day 14 
( 1) 
Day 28 a 
( 2) 
Day 56 
( 2) 
Day 84 a, b 
( 2) 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
 
 
 
General medical history and baseline conditions c  
x 
x 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
x 
 
 
 
 
 
 
 
 
Concomitant medications d 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x  
Adverse events 
 
x 
x 
x 
x 
x 
x 
x 
x 
x  
Vital signs e 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x f 
Height 
x 
 
 
 
 
 
 
 
 
 
Weight 
x 
x 
 
 
x 
x 
x 
x 
x 
 
Complete physical examination g 
x 
 
 
 
 
 
x 
x 
x 
 
Limited physical examination h 
 
x 
x 
x 
x 
x 
 
 
 
x f 
Triplicate ECG i 
x j 
x k 
x j 
 
x k 
x j 
x j 
x j 
x j 
x f 
HBsAg, HBsAb, Hep B cAb, HCV Ab 
x 
 
 
 
 
 
 
 
 
 
QFT or PPD l 
x 
 
 
 
 
 
 
 
 
 
Chest radiograph m 
x 
 
 
 
 
 
 
 
 
 
GDC-0853/placebo administration in clinic n 
 
x 
x 
x 
x 
x 
 
 
 
 
Drug dispensing 
 
x 
 
x 
x 
x 
 
 
 
 


Appendix 2  
Schedule of Assessments (Cohort 2:  TNF-IR) (cont.) 
GDC-0853—Genentech, Inc. 
142/Protocol GA29350, Version 4 
Week 
Screening 
Period 
Treatment Period 
SFU 
ET 
UV 
0 
1 
2 
4 
8 
12 
8 Weeks 
after Last 
Dose 
( 4) 
Day 
 28 to  1 Day 1 a 
Day 7 
( 1) 
Day 14 
( 1) 
Day 28 a 
( 2) 
Day 56 
( 2) 
Day 84 a, b 
( 2) 
Hematology o 
x 
x 
x 
 
x 
x 
x 
x 
x 
x f 
Chemistry p 
x 
x 
x 
 
x 
x 
x 
x 
x 
x f 
Coagulation studies PT/PTT 
x 
 
 
 
 
 
 
 
 
x f 
Pregnancy test q 
x 
x 
 
 
x 
x 
x 
x 
x 
x f 
Urinalysis r 
x 
x 
 
 
x 
x 
x 
x 
x 
x f 
Quantitative Ig s 
x 
x 
 
 
x 
x 
x 
x 
x 
x f 
Lipid panel  
 
x 
 
 
x 
 
x 
x 
x 
 
Rheumatoid factor and anti-CCP/ACPA 
x 
 
 
 
 
 
x 
x 
x 
 
TBNK 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x f 
ACR/DAS: 
 
 
 
 
 
 
 
 
 
 
CRP 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x f 
ESR (on site or at local laboratory) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x f 
Tender/painful joint count (68), swollen joint count (66) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x f 
Patient’s Assessment of Arthritis Pain (VAS) t 
 
x 
x 
x 
x 
x 
x 
x 
x 
x f 
Patient Global Assessment of Arthritis (VAS) t 
 
x 
x 
x 
x 
x 
x 
x 
x 
x f 
Physician’s Global Assessment of Arthritis (VAS) u 
 
x 
x 
x 
x 
x 
x 
x 
x 
x f 
HAQ-DI t 
 
x 
x 
x 
x 
x 
x 
x 
x 
x f 
SF-36v2 t 
 
x 
 
 
 
x 
x 
x 
x 
 
FACIT-Fatigue t 
 
x 
 
x 
x 
x 
x 
x 
x 
 
PK assessment v 
 
x 
x 
 
x 
x 
x  
 
x 
x f 


Appendix 2  
Schedule of Assessments (Cohort 2:  TNF-IR) (cont.) 
GDC-0853—Genentech, Inc. 
143/Protocol GA29350, Version 4 
Week 
Screening 
Period 
Treatment Period 
SFU 
ET 
UV 
0 
1 
2 
4 
8 
12 
8 Weeks 
after Last 
Dose 
( 4) 
Day 
 28 to  1 Day 1 a 
Day 7 
( 1) 
Day 14 
( 1) 
Day 28 a 
( 2) 
Day 56 
( 2) 
Day 84 a, b 
( 2) 
PBMC protein lysate w (U.S. sites only) 
x 
x 
 
 
x 
 
x 
x 
x 
 
Blood for FACS (U.S. sites only) x 
x 
x 
 
 
x 
 
x 
x 
x 
x f 
PD blood sample for FACS/basophils (U.S. sites only) y 
x 
x 
x 
 
x 
 
x 
 
x 
x f 
Serum biomarkers z 
x 
x 
x 
 
x 
 
x 
x 
x 
x f 
Plasma biomarkers aa 
x 
x 
x 
 
x 
 
x 
x 
x 
x f 
PAXgene RNA blood biomarkers bb 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
Whole blood PG sample 
 
x 
 
 
 
 
 
 
 
 
Whole blood sample for genotyping (optional) cc 
 
x 
 
 
 
 
 
 
 
 
ACPA  anti-citrullinated protein/peptide antibody; ACR  American College of Rheumatology; BID  twice daily; CCP  cyclic citrullinated protein; 
CRP  C-reactive protein; DAS  Disease Activity Score; eCRF  electronic Case Report Form; ESR  erythrocyte sedimentation rate; ET  early 
termination; FACIT  Functional Assessment of Chronic Illness Therapy; FACS  fluorescence-activated cell sorting; HAQ-DI  Health Assessment 
QuestionnaireDisability Index; HBsAg  hepatitis B core antibody; HBsAb  hepatitis B surface antigen; HCV  hepatitis C virus; IRB/EC  Institutional 
Review Board/Ethics Committee; OLE  open-label extension; PBMC  peripheral blood mononuclear cell; PK  pharmacokinetic; PPD  purified 
protein derivate; PPI  proton pump inhibitor; PRO  patient reported outcome; QFT  QuantiFERON-TB Gold; RA  rheumatoid arthritis; 
SF-36  Short-Form 36 Health Survey; SFU  safety follow-up; SST  serum separator tube; TB  tuberculosis; TBNK  T, B, and natural killer cells; 
TNF-IR  patients who had an inadequate response to tissue necrosis factor inhibitors; UV  unscheduled visit; VAS  visual analog scale; 
WGS  whole-genome sequencing. 
a A morning clinic visit is strongly recommended for visits on Days 1, 28, and 84, and particularly on Day 28 (for intensive PK sampling).  When 
morning visits are strongly recommended, the patient should be fasting ( 4-8 hours) prior to the first PK blood draw and fasting lipid panel. 
b Day 84 is the last day of the study treatment period (however, no blinded study drug will be given on Day 84; the last dose of blinded study 
drug is the PM dose of Day 83).  If eligible, patients may enroll into the OLE Study GA30067 to receive their first open-label dose of GDC-0853 
on Day 1 of Study GA30067 (after a trough PK level is drawn), or they will proceed to the SFU period and return for the SFU visit on Day 140 
(8 weeks after last dose of study drug). 
 


Appendix 2  
Schedule of Assessments (Cohort 2:  TNF-IR) (cont.) 
GDC-0853—Genentech, Inc. 
144/Protocol GA29350, Version 4 
c Medical history will include the diagnosis of rheumatoid arthritis and date of RA diagnosis, all history relevant to RA, including a detailed history of RA 
medications taken within 5 years before screening, with dose(s)/duration(s), date(s) of discontinuation, and reason(s) for discontinuation; coronary 
heart disease risk factors; dates of previous vaccinations, if applicable (including influenza, pneumococcus, zoster); other clinically significant 
diseases; reproductive status; smoking history; and use of alcohol and drugs of abuse.  The evaluation on Day 1 should only include any updates 
from screening.  
d Includes any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, vitamins, and nutritional or dietary 
supplements) used by a patient from 12 weeks prior to initiation of study drug until 8 weeks after the last dose of study drug or entrance into the OLE, 
whichever occurs first.  In addition, at each clinic visit, any use of PPIs, H2 receptor antagonists, and/or other short-acting antacids (e.g., Maalox, 
Pepto-Bismol, Rolaids) should be recorded as concomitant medications, including the date and time of last administration prior to the clinic visit. 
e Includes respiratory rate, pulse rate, temperature, and systolic and diastolic blood pressures while the patient is in a seated position for at least 5 
minutes. 
f To be performed only if medically indicated on the basis of the reason for the UV. 
g 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.  The baseline rheumatoid nodules assessment should be recorded in the Day 1 eCRF.  At subsequent visits, record new or worsened 
clinically significant abnormalities on the Adverse Event eCRF. 
h Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated.  After the baseline visit, any new or worsened 
clinically significant abnormalities should be recorded on the Adverse Event eCRF. 
i Triplicate interpretable digital ECG recordings (e.g., without artifacts) will be obtained within approximately 25 minutes of each other.  The ECG 
intervals (e.g., PR, QRS, QT, QTcF, and RR) and heart rate from these three ECGs will be entered into the eCRF; in addition, these triplicate readings 
will be stored for future analysis, if needed.  ECGs for each patient should be 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) whenever possible.  Body position should be 
consistently maintained for each ECG evaluation to prevent changes in heart rate.  Environmental distractions (e.g., television, radio, and conversation) 
should be avoided during the pre-ECG resting period and during ECG recording. 
j ECGs at these specified timepoints can be performed without specific restrictions (e.g., can be any time of day, before or after dosing, fasting or fed).   
k Instructions for ECG collection at the following timepoints:  screening, before dosing of the in-clinic dose on Days 1, 28, and 84 (while patient is fasting) and 
at 2 hours ( 30 minutes) after dosing of the in-clinic dose on Day 28 (while patient is fasting).   
l PPD should be performed only if QFT is not available.  Refer to the requirements for TB testing in Section 4.1.1 (may be performed within 3 months 
of screening, if indicated). 
 
 
 


Appendix 2  
Schedule of Assessments (Cohort 2:  TNF-IR) (cont.) 
GDC-0853—Genentech, Inc. 
145/Protocol GA29350, Version 4 
m Not required if documented results of a chest radiograph (read by a radiologist) taken within the 3 months prior to screening is without changes suggestive 
of active TB infection. 
n Patients will receive GDC-0853/placebo BID approximately every 12 hours starting on Day 1 and ending on Day 83.  GDC-0853/placebo 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.  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). 
o Includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, 
other cells). 
p Includes sodium, potassium, chloride, bicarbonate, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total and direct bilirubin, 
alkaline phosphatase, ALT, AST, uric acid, LDH, lipase, and amylase. 
q All women of childbearing potential (including those who have had a tubal ligation) will have a serum pregnancy test at screening.  Urine pregnancy tests will 
be performed locally at specified subsequent visits.  If a urine pregnancy test result is positive, it must be confirmed by a serum pregnancy test (performed 
locally). 
r Includes dipstick (pH, specific gravity, glucose, protein, ketones, blood) and microscopic examination (sediment, RBCs, WBCs, casts, crystals, epithelial 
cells, bacteria). 
s Includes total Ig, IgM, IgA, IgG, and IgE. 
t Questionnaires will be self-administered on an electronic device (“ePRO”).  Patients will complete the ePRO assessments before receiving any information 
on disease status, prior to the performance of non-PRO assessments, and prior to the administration of study treatment.  See Appendix 11, Appendix 12, 
Appendix 13 and Appendix 14 for sample questionnaires for the HAQ-DI, SF-36v2, FACIT-Fatigue, and DAS-28, respectively. 
u The same clinician who performs the joint counts (Efficacy Assessor, see Section 4.5.6) should complete the Physician’s Global Assessment of Arthritis 
throughout the study. 
v See Appendix 3 for detailed schedule. 
w Collect prior to drug administration:  blood for PBMCs will be shipped overnight to a central laboratory for processing.   
x Collect prior to drug administration:  blood for flow cytometry analysis of lymphocytes (e.g., B-cell and monocyte subsets).  To be performed at select 
centers in the United States where samples can be shipped to a FACS laboratory (see Laboratory Manual) within 24 hours. 
y Collect prior to drug administration.  Blood for flow cytometry.  To be performed at selected centers in the United States where samples can be shipped to a 
FACS laboratory (see Laboratory Manual) within 24 hours.  
z SST(s).  Collect prior to drug administration. 
 
 
 


Appendix 2  
Schedule of Assessments (Cohort 2:  TNF-IR) (cont.) 
GDC-0853—Genentech, Inc. 
146/Protocol GA29350, Version 4 
aa Citrate plasma tube.  Collect prior to drug administration. 
bb Collection into two PaxGene blood tubes.  Collect prior to drug administration. 
cc Optional 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. 
147/Protocol GA29350, Version 4 
Appendix 3  
Schedule of Pharmacokinetic and Biomarker Samples 
Visit 
Timepoint 
Sample Type 
Screening 
(Day  28 to Day  1) 
No timing restrictions PBMC protein lysate (U.S. sites only) 
Blood for FACS (U.S. sites only) 
Blood sample for FACS/basophils; (U.S. sites only) 
Serum biomarkers 
Plasma biomarkers 
PAXgene RNA blood 
Day 1 a 
Prior to the dose (to be 
administered in clinic if 
applicable), fasting 
GDC-0853 PK (plasma)  
PBMC protein lysate (U.S. sites only) 
Blood for FACS (U.S. sites only) 
Blood sample for FACS/basophils (U.S. sites only) 
Serum biomarkers  
Plasma biomarkers  
PAXgene RNA blood  
PG sample  
(Optional) WGS  
Day 7 
Prior to the dose (to be 
administered in clinic if 
applicable) 
 GDC-0853 PK (plasma)  
Blood sample for FACS/basophils (U.S. sites only) 
Serum biomarkers 
Plasma biomarkers 
PAXgene RNA blood 
Day 28 a 
Prior to the dose (must 
be administered in 
clinic), fasting 
GDC-0853 PK (plasma)  
PBMC protein lysate (U.S. sites only) 
Blood for FACS (U.S. sites only) 
Blood sample for FACS/basophils (U.S. sites only) 
Serum biomarkers  
Plasma biomarkers  
PAXgene RNA blood 
2 h ( 30 min) after 
dosing, fasting 
GDC-0853 PK (plasma)  
46 h after dosing 
GDC-0853 PK  (plasma) 
810 h after dosing 
(U.S. sites only) c 
GDC-0853 PK   (plasma) 
Days 56 
Prior to the dose (to be 
administered in clinic if 
applicable) 
GDC-0853 PK (plasma) 


Appendix 3 
 
Schedule of Pharmacokinetic and Biomarker Samples (cont.) 
GDC-0853—Genentech, Inc. 
148/Protocol GA29350, Version 4 
Visit 
Timepoint 
Sample Type 
Day 84 a, b 
No timing restrictions 
unless the patient is 
entering 
Study GA30067, in 
which case collection 
should occur prior to 
first dose on Day 1 of 
Study GA30067  
GDC-0853 PK (plasma) 
PBMC protein lysate (U.S. sites only) 
Blood for FACS (U.S. sites only) 
Blood sample for FACS/basophils (U.S. sites only) 
Serum biomarkers 
Plasma biomarkers 
PAXgene RNA blood 
Day 140  
(Safety follow up 
visit) 
No timing restrictions PBMC protein lysate (U.S. sites only)  
Blood for FACS (U.S. sites only) 
Serum biomarkers  
Plasma biomarkers  
PAXgene RNA blood 
Unscheduled visit 
No timing restrictions PAXgene RNA blood 
Only collect if 
medically indicated, 
based on the reason for 
the unscheduled visit: 
GDC-0853 PK (plasma) 
Blood for FACS (U.S. sites only) 
Serum biomarkers 
Plasma biomarkers 


Appendix 3 
 
Schedule of Pharmacokinetic and Biomarker Samples (cont.) 
GDC-0853—Genentech, Inc. 
149/Protocol GA29350, Version 4 
Visit 
Timepoint 
Sample Type 
Early termination 
visit 
No timing restrictions GDC-0853 PK (plasma) 
PBMC protein lysate (U.S. sites only) 
Blood for FACS (U.S. sites only) 
Blood sample for FACS/basophils (U.S. sites only) 
Serum biomarkers  
Plasma biomarkers  
PAXgene RNA blood 
FACS   fluorescence-activated cell sorting; H2RA  H2 receptor antagonist; PBMC   peripheral 
blood mononuclear cell; PG  pharmacogenomic; PK  pharmacokinetic; PPI  proton pump inhibitor; 
WGS  whole-genome sequencing. 
Notes:  Study assessments may be delayed or moved ahead of the window to accommodate 
holidays, vacations, and unforeseen delays. 
Morning clinic visits are preferred for all visits but are especially encouraged on Days 1, 28, and 84.  
Prior to each clinic visit, patients should be instructed not to take their dose and to bring their study 
medication with them to their clinic visit.  For all PK samples, the dates and times of the most 
recent prior meal and most recent prior dose of PPI, H2RA, or other short-acting 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 should be recorded at each clinic visit.  The procedures for 
collection, handling, and shipping of PK samples can be found in the study's Laboratory Manual. 
a Morning visit is strongly recommended.  Patients must be fasting ( 48 hours) prior to PK draw 
(trough level). 
b The last dose of blinded study drug in GA29350 is the PM dose on Day 83. For patients 
enrolling into the open-label Study GA30067, the Day 84 first dose will be the first dose (Day 1) 
of open-label GDC-0853, which should be administered after the trough PK sample has been 
obtained. 
c U.S. sites only:  If the patient is unable to stay or return to clinic for the post-dose 810-hour 
timepoint, this sample may be collected by a home nurse visit on Day 28. 


 
GDC-0853—Genentech, Inc. 
150/Protocol GA29350, Version 4 
Appendix 4  
Appropriate Equivalent Morphine Doses 
of Common Opioid Analgesics 
Drug 
Maximum Allowed, 
Total Daily Dose 
(mg) 
Relative Potency to 
Oral Morphine 
Half-Life 
(hours) 
Morphine 
30 
1 
1.54  
Hydrocodone (Vicodin, 
Lortab) 
30 
1 
3.84.5  
Hydromorphone (Dilaudid) 
7.5 
4 
2.5  
Meperidine (Demerol, 
Pethidine) 
300 
0.1 
3.23.7  
Methadone (Dolophine, 
Methadose, Physeptone) 
10 
3.0 
23  
Codeine (Paveral, Tylenol #2 
and #3) 
200 
0.15 
2.53.5  
Oxycodone (*Roxicodone; 
Percocet, Tylox) 
15 
~2 
3.2  
Tramadol (Ultram, Zydol; 
Zamadol, Ultracet, Tramal) 
300 
~0.1 
4.75.1  
Propoxyphene HCl (Darvon, 
Darvocet, Doloxene) 
Propoxyphene napsylate 
(Darvon-N, Darvocet-N 100) 
300 (propoxyphene 
HCl) 
400 (propoxyphene 
napsylate) 
~0.1 
612; 3036 for 
active metabolite 
(norpropoxyphene)  
Note:  Sites should contact the project team for acceptable alternative preparations and related 
data. 
 
 


 
GDC-0853—Genentech, Inc. 
151/Protocol GA29350, Version 4 
Appendix 5  
Concomitant Medications (Including Foods and Herbal Products) 
Class 
Expected Interaction 
Recommendation 
Examples of Drugs in this Class a 
Short-acting 
Antacids 
Decreased GDC-0853 
absorption due to 
increased gastric pH 
Take GDC-0853 2 hours 
before or 2 hours after 
short-acting 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 5  
Concomitant Medications (Including Foods and Herbal Products) (cont.) 
GDC-0853—Genentech, Inc. 
152/Protocol GA29350, Version 4 
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. 
153/Protocol GA29350, Version 4 
Appendix 6  
National Cholesterol Education Program (NCEP) Guidelines 
 
 














 
Appendix 7  
Clinical Criteria for Diagnosing Anaphylaxis 
These criteria are taken from a summary report from the second symposium on the 
definition and management of anaphylaxis, conducted by the National Institute of Allergy 
and Infectious Disease/Food Allergy and Anaphylaxis Network (Sampson et al. 20061).  
Anaphylaxis is highly likely when any one of the following three criteria is fulfilled: 
1. 
Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen 
lips-tongue-uvula)  
AND AT LEAST ONE OF THE FOLLOWING: 
 
Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced 
peak expiratory flow, hypoxemia) 
 
Reduced blood pressure or associated symptoms of end-organ dysfunction (e.g., 
hypotonia, syncope, incontinence) 
2. 
Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours): 
 
Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, 
swollen lips-tongue-uvula) 
 
Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced 
peak expiratory flow, hypoxemia) 
 
Reduced blood pressure or associated symptoms (e.g., hypotonia, syncope, 
incontinence) 
 
Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting) 
3. 
Reduced blood pressure after exposure to known allergen for that patient (minutes 
to several hours): 
 
Infants and children:  low systolic blood pressure (age specific)2 or greater than 
30% decrease in systolic blood pressure 
 
Adults:  systolic blood pressure of less than 90 mmHg or greater than 30% 
decrease from that person’s baseline 
 
                                            
 
1 Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second symposium on the definition and 
management of anaphylaxis: summary report—second National Institute of Allergy and 
Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin 
Immunol 2006;117:391397. 
2 Low systolic blood pressure for children is defined as less than 70 mmHg from 1 month to 
1 year, less than (70 mmHg  [2  age]) from 1 to 10 years, and less than 90 mmHg from 11 to 
17 years. 
GDC-0853—Genentech, Inc. 
160/Protocol GA29350, Version 4


 
Appendix 8  
Childbearing Potential, Pregnancy Testing, and Contraception 
For Women 
All women of childbearing potential (including those who have had a tubal ligation) will 
have a serum pregnancy test at screening and a urine pregnancy test on Study Day 1 
prior to administration of study drug and at subsequent clinic visits.  If a urine pregnancy 
test result is positive, study drug will not be administered until pregnancy is ruled out.  
The result must be confirmed by a serum pregnancy test (conducted by the local 
laboratory).  Refer to Section 5.4.3 of the protocol for management of a patient with a 
confirmed pregnancy. 
All female patients are considered to be of childbearing potential unless they meet one of 
the following criteria: 
 
The patient has been postmenopausal (non−therapy-induced amenorrhea) for at 
least 12 continuous months with no other identified cause 
 
The patient had a surgical bilateral oophorectomy (with or without hysterectomy) 
more than 6 weeks prior to enrollment 
 
The patient had a hysterectomy 
 
Female patients of reproductive or childbearing potential who are unwilling to use a 
method of contraception that results in a failure rate of  1 % per year or remain abstinent 
(refrain from heterosexual intercourse) during the treatment period and for at least 
60 days after the last dose of study drug or longer if required per the local prescribing 
label for adalimumab will be excluded from study participation. 
Abstinence is acceptable only if it is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. 
Examples of contraceptive methods with a failure rate of  1% per year include the 
following: 
 
Sterilization, bilateral surgical tubal ligation 
 
Intrauterine device 
 
Combined oral contraceptive pill1 
 
Contraceptive transdermal patch (estrogen and progestin containing)1 
 
 
 
1 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. 
GDC-0853—Genentech, Inc. 
161/Protocol GA29350, Version 4


Appendix 8  
Childbearing Potential, Pregnancy Testing, and Contraception 
(cont.) 
 
Hormonal vaginal device 
 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
 
Implants for contraception 
 
Injections for contraception (with prolonged release) 
 
Sole sexual partner consisting of surgically sterilized male partner with appropriate 
postsurgical verification of the absence of spermatozoa in the ejaculate.  Patients 
may provide verbal confirmation that the partner completed appropriate follow-up 
after vasectomy.  Sites are not required to obtain partner medical records. 
 
For Men 
All men must agree to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures and to refrain from donating sperm, as defined below: 
 
With female partners of childbearing potential (including those who have had a tubal 
ligation), men must remain abstinent or use a condom plus an additional 
contraceptive method that together result in a failure rate of  1% per year during the 
treatment period and for at least 120 days (4 months) after the last dose of study 
treatment.  Men must refrain from donating sperm during this same period. 
 
With pregnant female partners, men must remain abstinent or use a condom during 
the treatment period and for at least 28 days after the last dose of study treatment to 
avoid exposing the 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 post-ovulation methods) and withdrawal are not 
acceptable methods of contraception. 
 
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Appendix 9  
2010 American College of Rheumatology/European League 
Against Rheumatism Classification Criteria for Rheumatoid 
Arthritis 
Target population (Who should be tested?):  
1. 
Patients who have at least 1 joint with definite clinical synovitis (swelling) a 
2. 
Patients with synovitis not better explained by another disease b 
 
Classification criteria for RA) score-based algorithm:  add score of categories AD; 
a score of  6/10 is needed for classification of a patient as having definite RA) c 
Classification Criteria 
Score 
A. Joint involvement d 
 
1 large joint e 
0 
210 large joints 
1 
13 small joints (with or without involvement of large joints) f 
2 
410 small joints (with or without involvement of large joints) 
3 
 10 joints (at least 1 small joint) g 
5 
B. Serology (at least 1 test result is needed for classification) h 
 
Negative RF and negative ACPA 
0 
Low-positive RF or low-positive ACPA 
2 
High-positive RF or high-positive ACPA 
3 
C. Acute-phase reactants (at least 1 test result is needed for classification) i 
 
Normal CRP and normal ESR 
0 
Abnormal CRP or abnormal ESR 
1 
D. Duration of symptoms  j 
 
 6 weeks 
0 
 6 weeks 
1 
Source: Aletaha D, Neogi T, Silman AJ, et al.  Rheumatoid arthritis classification criteria: an 
American College of Rheumatology/European League Against Rheumatism collaborative 
initiative. Arthritis Rheum 2010;62:256981. 
ACPA  anti citrullinated protein antibody; CRP  C-reactive protein; ESR  erythrocyte 
sedimentation rate; IU  international units; RA  rheumatoid arthritis; RF  rheumatoid factor; 
ULN  upper limit of normal. 
a The criteria are aimed at classification of newly presenting patients.  In addition, patients with 
erosive disease typical of RA with a history compatible with prior fulfillment of the 2010 criteria 
should be classified as having RA.  Patients with longstanding disease, including those whose 
disease is inactive (with or without treatment), who, based on retrospectively available data, 
have previously fulfilled the 2010 criteria should be classified as having RA. 
b Differential diagnoses vary among patients with different presentations but may include 
conditions such as systemic lupus erythematosus, psoriatic arthritis, and gout.  If it is unclear 
about the relevant differential diagnoses to consider, an expert rheumatologist should be 
consulted. 
c Although patients with a score of  6/10 are not classifiable as having RA, their status can be 
reassessed and the criteria might be fulfilled cumulatively over time. 
 
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Appendix 9  
2010 American College of Rheumatology/European League 
against Rheumatism Classification Criteria for Rheumatoid 
Arthritis (cont.) 
d Joint involvement refers to any swollen or tender joint on examination, which may be 
confirmed by imaging evidence of synovitis.  Distal interphalangeal joints, first 
carpometacarpal joints, and first metatarsophalangeal joints are excluded from assessment.  
Categories of joint distribution are classified according to the location and number of involved 
joints, with placement into the highest category possible based on the pattern of joint 
involvement. 
e “Large joints” refers to shoulders, elbows, hips, knees, and ankles. 
f “Small joints” refers to the metacarpophalangeal joints, proximal interphalangeal joints, 
second through fifth metatarsophalangeal joints, thumb interphalangeal joints, and wrists. 
g In this category, at least 1 of the involved joints must be a small joint; the other joints can 
include any combination of large and additional small joints, as well as other joints not 
specifically listed elsewhere (e.g., temporomandibular, acromioclavicular, sternoclavicular). 
h Negative refers to IU values that are less than or equal to the ULN for the laboratory and 
assay; low-positive refers to IU values that are higher than the ULN but  3 times the ULN for 
the laboratory and assay; high-positive refers to IU values that are  3 times the ULN for the 
laboratory and assay.  Where RF information is available only as positive or negative, a 
positive result should be scored as low-positive for RF.  
i Normal/abnormal is determined by local laboratory standards.   
j Duration of symptoms refers to patient self-report of the duration of signs or symptoms of 
synovitis (e.g., pain, swelling, tenderness) of joints that are clinically involved at the time of 
assessment, regardless of treatment status. 
 
GDC-0853—Genentech, Inc. 
164/Protocol GA29350, Version 4


 
Appendix 10  
ACR Classification of Functional Capacity in Rheumatoid 
Arthritis 
Class I 
Complete functional capacity with ability to carry on all usual duties without 
handicaps 
Class II 
Functional capacity adequate to conduct normal activities despite handicap of 
discomfort or limited mobility of one or more joints 
Class III 
Functional capacity adequate to perform only few or none of the duties of usual 
occupation or of self-care 
Class IV 
Largely or whole incapacitated with patient bedridden or confined to wheelchair, 
permitting little or no self-care 
Source:  Hochberg MC, Chang RW, Dwosh I, et al. The American College of Rheumatology 
1991 Revised Criteria for the Classification of Global Functional Status in Rheumatoid Arthritis. 
Arthritis Rheum 1992;35:498502. 
 
 
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Appendix 11  
Health Assessment QuestionnaireDisability Index (HAQ-DI) 
 
 
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Appendix 12  
The Short-Form 36 Version 2 Health Survey (SF-36v2) 
 
 
 
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Appendix 14  
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 mm/hr] or high 
sensitivity C-reactive protein [hsCRP mg/L]), 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 
 PtGA 
 
DAS 28(4)-CRP  0.56  SQRT(TJC28)  0.28SQRT(SJC28)  0.36  ln(CRP  1)  
 0.014    PtGA  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 
 
PtGA  patient’s global assessment of disease activity; ln  natural logarithm; SQRT  square 
root. 
 
The DAS28(3) and DAS28-CRP(3) will be calculated as follows: 
Calculations 
DAS28(3)  [0.56  SQRT(TJC28)  0.28SQRT(SJC28)  0.70  ln(ESR)]  1.08  0.16 
 
DAS28-
CRP(3)  [0.56  SQRT(TJC28)  0.28SQRT(SJC28)  0.36  ln(CRP  1)]  1.10  1.15 
 


 
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Appendix 15  
Blister Wallet Configuration for GDC-0853/Placebo 
Administration (Cohort 1 Only) 
Cohort 1 only:  Blister Wallet configuration shown below denotes a.m. (sun) versus p.m. 
(moon) dose:   
Site will be responsible for prepopulating the dates on the blister wallets. 
Patients should record time (in military time) of each dose on blister wallets.   
 
Patient Dosing Instructions will be provided for guidance on dose administration at 
home, during clinic visits, and in the event if a dose is missed.  
 
 


 
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Appendix 16  
Bottle and Label Configuration for GDC-0853/Placebo 
Administration (Cohort 2 Only) 
Cohort 2 only:  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.   
 
Patient Dosing Instructions will be provided for guidance on dose administration at 
home, during clinic visits, and in the event if a dose is missed.