Clinical trial NCT03807739
Conditions: Healthy Volunteers
Sponsor: Genentech, Inc.
Start date: 2019-02-01; Completion date: 2019-05-30
Enrollment: 38 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a two-part study to determine the relative bioavailability of two different prototype capsules of GDC-0134 to that of an existing reference capsule of GDC-0134 under both fed and fasted conditions. The study is open to healthy female participants of non-childbearing potential.

Detailed description:

Arms: arm 1: In Part 1 participants will receive single doses of either GDC-0134 F16 capsules (prototype) or GDC-0134 F09 capsules (reference) after having consumed a standard meal. arm 2: In Part 2, participants will receive a single dose of either GDC-0134 F15 capsules (prototype) or GDC-0134 F09 capsules (reference) after an overnight fast.
Interventions: intervention 1: GDC-0134 F09 Formulation intervention 2: GDC-0134 F15 Formulation intervention 3: GDC-0134 F16 Formulation
Intervention descriptions: intervention 1: Participants will receive a single oral dose of GDC-0134 reference capsule F09. intervention 2: Participants will receive a single oral dose of GDC-0134 prototype capsule F15. intervention 3: Participants will receive a single oral dose of GDC-0134 prototype capsule F16.

Protocol documents:
Prot_000.pdf: 
Clinical Protocol 
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CONFIDENTIAL 
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A Phase I Study to Determine the Relative Bioavailability of Various Formulations of 
GDC-0134 in Healthy Female Subjects of Non-Childbearing Potential 
 
 
 
 
 
Protocol GP40957 
 
Covance Study 8398091 
 
IND 125737 
 
Version Number 1 
 
for 
 
Genentech, Inc. 
1 DNA Way 
South San Francisco, California 94080-4990 
 
 
 
 
by 
 
Covance Early Clinical Segment 
3402 Kinsman Boulevard 
Madison, Wisconsin 53704 
 


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STUDY IDENTIFICATION 
Sponsor 
Genentech, Inc. 
 
1 DNA Way 
 
South San Francisco, California 94080-4990 
 
Sponsor’s Study Contact 
Sravanthi Cheeti, B.Pharm., MS,  
Clinical Pharmacologist 
 
Genentech, Inc. 
 
1 DNA Way 
 
South San Francisco, California 94080-4990 
 
Sponsor’s Medical Monitor William Cho, M.D., Ph.D. 
 
Genentech, Inc. 
 
1 DNA Way 
 
South San Francisco, California 94080-4990 
 
Study Site 
Covance Clinical Research Unit 
 
1900 Mason Ave, Suite 140 
 
Daytona Beach, Florida 32117 
 
 
Covance Clinical Research Unit 
 
1341 W. Mockingbird Lane, Suite 200 E, 
 
Dallas, Texas 75247 
 
Principal Investigator 
Hugh Coleman, D.O. 
 
Covance Clinical Research Unit 
 
Daytona Beach, Florida 
 
hugh.coleman@covance.com 
 
 
T. Alexander King, M.D. 
 
Covance Clinical Research Unit 
 
Dallas, Texas 
 
alex.king@covance.com 
 


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Study Institutional 
Review Board 
MidLands Independent Review Board 
8417 Santa Fe Drive, Suite 100 
Overland Park, Kansas 66212 
 
Main Clinical Laboratory 
Laboratory Corporation of America 
 
 
 
 
 
4200 N 29th Ave 
 
 
 
 
 
Hollywood, Florida 33020-1016 
 
 
 
 
 
 
Laboratory Corporation of America 
 
 
 
 
 
7777 Forest Lane Building C350 
 
 
 
 
 
Dallas, Texas 75230 
 
Bioanalytical Laboratory 
Covance Laboratories Inc. 
 
3402 Kinsman boulevard 
 
Madison, Wisconsin, 53704 
 
Protocol biostatistician 
Emma Warriner, M.Sc. 
 
Covance Early Clinical Biometrics 
 
emma.warriner@covance.com 
 
Protocol pharmacokineticist Sarah Thorn, B.S. 
 
Covance Clinical Pharmacology Services 
 
sarah.thorn@covance.com 
 
Protocol medical writer 
Edward Bowen, Ph.D. 
 
Covance Global Medical Writing 
 
edward.bowen@covance.com 


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TABLE OF CONTENTS 
 
1 
SYNOPSIS ........................................................................................................................ 11 
2 
INTRODUCTION ............................................................................................................ 13 
2.1 
BACKGROUND .................................................................................................. 13 
2.2 
OVERVIEW OF GDC-0134 CLINICAL DEVELOPMENT .............................. 14 
2.3 
CLINICAL PHARMACOKINETICS OF GDC-0134 ......................................... 15 
2.4 
STUDY RATIONALE ......................................................................................... 16 
2.5 
DOSE RATIONALE ............................................................................................ 16 
3 
STUDY OBJECTIVES AND CORRESPONDING ENDPOINTS ................................. 17 
3.1 
PRIMARY OBJECTIVE ...................................................................................... 17 
3.2 
SECONDARY OBJECTIVES.............................................................................. 17 
3.3 
EXPLORATORY OBJECTIVES ......................................................................... 17 
3.4 
ENDPOINTS ........................................................................................................ 17 
3.4.1 
PHARMACOKINETIC ENDPOINTS ............................................... 17 
3.4.2 
SAFETY ENDPOINTS ...................................................................... 18 
4 
STUDY DESIGN.............................................................................................................. 18 
4.1 
DESCRIPTION OF THE STUDY ....................................................................... 18 
4.2 
RATIONALE FOR STUDY DESIGN ................................................................. 22 
4.3 
RATIONALE FOR SUBJECT POPULATION ................................................... 22 
4.4 
RATIONALE FOR EXPLORATORY ASSESSMENTS .................................... 22 
4.5 
RATIONALE FOR PHARMACOKINETIC SAMPLING SCHEDULE ............ 22 
4.6 
RATIONALE FOR WHOLE GENOME SEQUENCING ................................... 23 
5 
SUBJECT SELECTION ................................................................................................... 23 
5.1 
SCREENING PROCEDURES ............................................................................. 23 
5.2 
CHECK-IN PROCEDURES ................................................................................ 23 
5.3 
INCLUSION CRITERIA ...................................................................................... 24 
5.4 
EXCLUSION CRITERIA .................................................................................... 25 


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5.5 
REMOVAL OF SUBJECTS FROM STUDY PARTICIPATION ....................... 27 
6 
ASSESSMENT OF SAFETY ........................................................................................... 28 
6.1 
SAFETY PLAN .................................................................................................... 28 
6.1.1 
RISKS ASSOCIATED WITH GDC-0134 ......................................... 28 
6.1.2 
CONTRAINDICATIONS WITH GDC-0134 .................................... 28 
6.1.3 
SERIOUS ADVERSE DRUG REACTIONS ..................................... 28 
6.1.4 
POTENTIAL RISKS .......................................................................... 29 
7 
STUDY PROCEDURES .................................................................................................. 32 
7.1 
SCHEDULE OF STUDY ACTIVITIES .............................................................. 32 
7.2 
STUDY TREATMENT ........................................................................................ 39 
7.2.1 
DRUG SUPPLIES AND ACCOUNTABILITY ................................ 39 
7.2.2 
DOSE PREPARATION AND ADMINISTRATION ........................ 41 
7.3 
REMOVAL OF STUDY BLIND ......................................................................... 41 
7.4 
DIET, FLUID, AND ACTIVITY CONTROL ..................................................... 42 
7.5 
CONCOMITANT MEDICATIONS .................................................................... 42 
7.6 
PHARMACOKINETIC BLOOD AND URINE SAMPLE COLLECTION AND 
PROCESSING ...................................................................................................... 44 
7.7 
ANALYTICAL METHODOLOGY ..................................................................... 44 
7.8 
CLINICAL LABORATORY EVALUATIONS .................................................. 44 
7.9 
SAMPLES FOR THE RESEARCH BIOSAMPLE REPOSITORY .................... 45 
7.9.1 
OVERVIEW OF THE RESEARCH BIOSAMPLE REPOSITORY . 45 
7.9.2 
APPROVAL BY THE INSTITUTIONAL REVIEW BOARD ......... 46 
7.9.3 
MANDATORY SAMPLES FOR WHOLE GENOME SEQUENCING 
SAMPLE COLLECTION ................................................................... 46 
7.9.4 
CONFIDENTIALITY......................................................................... 46 
7.9.5 
CONSENT TO PARTICIPATE IN THE RESEARCH BIOSAMPLE 
REPOSITORY .................................................................................... 47 
7.9.6 
WITHDRAWAL FROM THE RESEARCH BIOSAMPLE 
REPOSITORY .................................................................................... 47 


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7.9.7 
MONITORING AND OVERSIGHT ................................................. 48 
7.10 
12-LEAD ELECTROCARDIOGRAMS .............................................................. 48 
7.11 
VITAL SIGNS ...................................................................................................... 49 
7.12 
HOW DO YOU FEEL? INQUIRY ...................................................................... 49 
7.13 
PHYSICAL EXAMINATIONS ........................................................................... 49 
7.14 
OPHTHALMOLOGY ASSESSMENTS.............................................................. 49 
7.15 
CLINIC DISCHARGE PROCEDURES .............................................................. 50 
7.16 
STUDY COMPLETION/EARLY TERMINATION PROCEDURES ................ 50 
8 
ADVERSE EXPERIENCES ............................................................................................ 50 
8.1 
SAFETY PARAMETERS AND DEFINITIONS ................................................ 50 
8.1.1 
ADVERSE EVENTS .......................................................................... 50 
8.1.2 
SERIOUS ADVERSE EVENTS (IMMEDIATELY REPORTABLE 
TO THE SPONSOR) .......................................................................... 51 
8.1.3 
ADVERSE EVENTS OF SPECIAL INTEREST (IMMEDIATELY 
REPORTABLE TO THE SPONSOR) ............................................... 52 
8.2 
METHODS AND TIMING FOR CAPTURING AND ASSESSING SAFETY 
PARAMETERS .................................................................................................... 52 
8.2.1 
ADVERSE EVENT REPORTING PERIOD ..................................... 52 
8.2.2 
ELICITING ADVERSE EVENT INFORMATION .......................... 53 
8.2.3 
ASSESSMENT OF SEVERITY OF ADVERSE EVENTS ............... 53 
8.2.4 
ASSESSMENT OF CAUSALITY OF ADVERSE EVENTS ........... 54 
8.3 
PROCEDURES FOR RECORDING ADVERSE EVENTS ................................ 55 
8.3.1 
RECORDING ADVERSE EVENTS ON THE CASE REPORT 
FORM ................................................................................................. 55 
8.4 
IMMEDIATE REPORTING REQUIREMENTS FROM PRINCIPAL 
INVESTIGATOR TO SPONSOR ........................................................................ 60 
8.4.1 
REPORTING REQUIREMENTS FOR FATAL OR LIFE-
THREATENING SERIOUS ADVERSE EVENTS ........................... 61 
8.4.2 
REPORTING REQUIREMENTS FOR ALL SERIOUS ADVERSE 
EVENTS ............................................................................................. 61 


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8.4.3 
REPORTING REQUIREMENTS FOR CASES OF ACCIDENTAL 
OVERDOSE OR MEDICATION ERROR ........................................ 63 
8.4.4 
FOLLOW-UP OF SUBJECTS AFTER ADVERSE EVENTS .......... 64 
8.5 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE EVENT 
REPORTING PERIOD ......................................................................................... 64 
8.5.1 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
PRINCIPAL INVESTIGATORS, AND INSTITUTIONAL REVIEW 
BOARDS ............................................................................................ 65 
9 
STATISTICAL ANALYSES ........................................................................................... 65 
9.1 
SAFETY AND TOLERABILITY ANALYSIS ................................................... 66 
9.2 
PHARMACOKINETIC ANALYSIS ................................................................... 66 
9.3 
WHOLE GENOME SEQUENCING ANALYSIS ............................................... 67 
9.4 
INTERIM ANALYSIS ......................................................................................... 67 
9.4.1 
OPTIONAL INTERIM ANALYSIS .................................................. 68 
9.5 
STATISTICAL ANALYSIS OF PHARMACOKINETIC DATA ....................... 68 
9.6 
STATISTICAL ANALYSES OF SAFETY DATA ............................................. 68 
9.7 
SAMPLE SIZE ..................................................................................................... 69 
9.8 
QUALITY CONTROL AND QUALITY ASSURANCE .................................... 69 
10 
ADMINISTRATIVE ASPECTS ...................................................................................... 69 
10.1 
CHANGE IN PROTOCOL................................................................................... 69 
10.2 
PRINCIPAL INVESTIGATOR MEETING; SITE INITIATION ....................... 69 
10.3 
DISCLOSURE ...................................................................................................... 69 
10.4 
MONITORING (CLINICAL RESEARCH ASSOCIATE) ................................. 70 
10.5 
INSTITUTIONAL REVIEW BOARD ................................................................. 70 
10.6 
INFORMED CONSENT ...................................................................................... 70 
10.7 
RECORDS ............................................................................................................ 71 
10.7.1 
ELECTRONIC CASE REPORT FORMS ......................................... 71 
10.7.2 
SOURCE DATA DOCUMENTATION ............................................. 72 
10.7.3 
USE OF COMPUTERIZED SYSTEMS ............................................ 72 


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10.7.4 
STUDY MEDICATION ACCOUNTABILITY................................. 73 
10.7.5 
DISCLOSURE OF DATA .................................................................. 73 
10.7.6 
RETENTION OF RECORDS............................................................. 74 
10.8 
REFERENCE TO DECLARATION OF HELSINKI/BASIC PRINCIPLES ...... 74 
PRINCIPAL INVESTIGATOR AGREEMENT .......................................................................... 75 
PRINCIPAL INVESTIGATOR AGREEMENT .......................................................................... 76 
SPONSOR AGREEMENT ........................................................................................................... 77 
REFERENCES ............................................................................................................................. 78 
APPENDIX A – CLINICAL LABORATORY EVALUATIONS ............................................... 79 
APPENDIX B – APPROXIMATE MAXIMUM BLOOD VOLUME COLLECTED ................ 80 
 
TABLE OF TABLES 
 
Table 7-1 
Schedule of Activities – Part 1.............................................................................. 33 
Table 7-2 
Schedule of Activities – Part 2.............................................................................. 36 
Table 7-3 
Plasma Pharmacokinetic Sampling Scheme (All Study Periods) ......................... 39 
Table 7-4 
Study Drug ............................................................................................................ 40 
Table 8-1 
Adverse Event Severity Grading Scale for Events Not Specifically Listed in 
WHO Toxicity Grading Scale ............................................................................... 54 
Table 8-2 
Causal Attribution Guidance ................................................................................. 55 
 
TABLE OF FIGURES 
 
Figure 1 
Study Schematic of Crossover Design – Part 1 .................................................... 21 
Figure 2 
Study Schematic of Crossover Design – Part 2 .................................................... 21 
 


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ABBREVIATIONS 
Aeu 
amount excreted in urine over a sampling interval 
AE 
adverse event 
AESI 
adverse event of special interest 
ALS 
amyotrophic lateral sclerosis 
ALT 
alanine aminotransferase 
anti-HCV 
hepatitis C virus antibody 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-t 
area under the concentration-time curve from Hour 0 to the last measurable 
concentration 
AUC0-∞ 
area under the concentration-time curve extrapolated to infinity 
BMI 
body mass index 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cmax 
maximum observed concentration 
CL/F 
apparent systemic clearance 
CLR 
renal clearance 
CPET 
Clinical Pharmacology Protocol Execution Team 
CRU 
Clinical Research Unit 
Ct 
last measurable concentration 
Ctrough 
concentration at the end of a dosing interval at steady state 
DLK 
dual leucine zipper kinase 
ECG 
electrocardiogram 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ERG 
electroretinography 
ET 
Early Termination 
FDA 
Food and Drug Administration 
%Feu 
percentage of dose excreted in urine over a sampling interval 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HBsAg 
hepatitis B surface antigen 


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HDYF? 
How do you feel? 
HIV 
human immunodeficiency virus 
HRT 
hormone replacement therapy 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation/International Council for 
Harmonisation 
IND 
Investigational New Drug 
IOP 
intraocular pressure 
IRB 
Institutional Review Board 
JNK 
c-jun N-terminal kinase 
OSE 
open-label safety expansion 
PD 
pharmacodynamic(s) 
PI 
Principal Investigator 
PK 
pharmacokinetic(s) 
PPD 
purified protein derivative 
PPI 
proton pump inhibitor 
PPS 
peripapillary swelling 
QD 
once daily 
QTcF 
QT interval corrected through use of Fridericia’s formula 
RBC 
red blood cell 
RBR 
Research Biosample Repository 
RNFL 
retinal nerve fiber layer 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
TB 
tuberculosis 
TEM 
transmission electron microscopy 
t1/2 
apparent terminal elimination half-life 
tmax 
time to maximum observed concentration 
UA 
urinalysis 
ULN 
upper limit of normal 
Vz/F 
apparent volume of distribution during the terminal phase 
WBC 
white blood cell 
WGS 
whole genome sequencing 
λz 
apparent terminal elimination rate constant 


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1 SYNOPSIS 
Title of Study: 
A Phase I Study to Determine the Relative Bioavailability of Various Formulations  
GDC-0134 in Healthy Female Subjects of Non-Childbearing Potential 
Objectives: 
The primary objectives of this study are: 
• 
To determine the relative bioavailability of GDC-0134 F16 capsules (newly 
developed capsule formulation with GDC-0134 malate drug substance) with 
respect to the current clinical material, GDC-0134 F09 capsules, with a standard 
meal. 
• 
To determine the relative bioavailability of GDC-0134 F15 capsules (newly 
developed capsule formulation with GDC-0134 freebase) with respect to the 
current clinical material, GDC-0134 F09 capsules, under fasted conditions. 
A description of test products is provided below. 
 
The secondary objectives of this study are: 
• 
To determine the safety and tolerability of a single oral dose of GDC-0134 in 
healthy subjects. 
• 
To characterize the pharmacokinetics (PK) of GDC-0134 after oral 
administration in healthy subjects. 
 
The exploratory objective of this study is: 
• 
To determine the urinary elimination of GDC-0134 
Methodology/Study 
Design: 
This will be an open-label, randomized, 2-period crossover study consisting of two parts 
to determine:  
• 
Part 1 – the relative bioavailability of GDC-0134 F16 capsules (Ro 704-
0814/F16) and GDC-0134 F09 capsules (Ro 704-0814/F09) with a standard 
meal 
• 
Part 2 – the relative bioavailability of GDC-0134 F15 capsules (Ro 704-
0814/F15) and GDC-0134 F09 capsules (Ro 704-0814/F09) under fasted 
conditions 
In each part of the study, plasma PK samples will be collected through 21 days postdose 
and urine samples will be collected through 48 hours postdose.  The following safety 
assessments will be conducted at specific times during the study: physical examination, 
12-lead electrocardiogram (EGC), vital signs, “How do you feel” inquiries (to assess 
adverse events [AEs]), ophthalmology, and clinical laboratory evaluations.  
Number and General 
Description of Subjects: 
Twenty-two healthy female subjects of non-childbearing potential will be enrolled in 
each part of the study, in order for at least 18 subjects (9 per treatment sequence) to 
complete each part (Part 1 and Part 2).  If the two parts of the study are run sequentially, 
subjects will be encouraged to participate in both parts.  The maximum number of 
subjects enrolled into the study will be approximately 44. 
Diagnosis and Main 
Criteria for Inclusion: 
Female subjects of non-childbearing potential between 18 and 65 years of age, inclusive, 
and within body mass index range of 18.5 to 35 kg/m2, inclusive.  
Test Product(s), Dose, 
and Mode of 
Administration: 
Study Drug Product 
Description 
Study 
Designation 
GDC-0134 F09 capsule, 
200 mg (aka GDC-0134 
capsules, 200 mg in 
Investigational New Drug 
CMC dossier)  
Reference drug, current clinical 
material 
GDC-0134 F09 
capsule 
GDC-0134 F15 capsule, 
200 mg 
Test drug, newly developed 
capsule formulation with GDC-
0134 freebase 
GDC-0134 F15 
capsule 


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GDC-0134 F16 capsule, 
200 mg 
Test drug, newly developed 
capsule formulation with 
GDC-0134 malate drug 
substance 
GDC-0134 F16 
capsule 
Subjects will receive the following treatments, according to a randomization schedule 
generated by a Covance biostatistician: 
Part 1: 
• 
GDC-0134 F16 capsules (Ro 704-0814/F16) - 800 mg, oral, with a standard 
meal 
• 
GDC-0134 F09 capsules (Ro 704-0814/F09) - 800 mg, oral, with a standard 
meal 
Part 2: 
• 
GDC-0134 F15 capsules (Ro 704-0814/F15) - 800 mg, oral, fasted 
• 
GDC-0134 F09 capsules (Ro 704-0814/F09) - 800 mg, oral, fasted 
Duration of Treatment: 
Planned Enrollment/Screening Duration:  approximately 4 weeks 
Length of Each Confinement:  approximately 1 day predose until approximately 2 days 
postdose. 
Planned Individual Study Part Duration:  approximately 11 weeks 
Criteria for Evaluation:  
Safety 
Safety assessments will include clinical laboratory evaluations, physical examinations, 
ECGs, ophthalmology, and vital signs.  In addition, the nature, frequency and severity of 
treatment-emergent AEs  will be collected and summarized. 
Criteria for Evaluation:  
Pharmacokinetics 
The following PK parameters will be derived from the plasma concentrations of GDC-
0134 using the model independent approach: Maximum observed concentration (Cmax), 
time to maximum observed concentration (tmax), area under the concentration-time curve 
(AUC) from Hour 0 to the last measurable concentration (AUC0-t), AUC extrapolated to 
infinity (AUC0-∞), apparent terminal elimination rate constant (λz), terminal elimination 
half-life (t1/2), apparent systemic clearance (CL/F), and apparent volume of distribution 
during the terminal phase (Vz/F). 
The following PK parameters will be derived from the urine concentrations of 
GDC-0134: amount excreted in urine over a sampling interval (Aeu), cumulative amount 
excreted in urine (Total Aeu), percentage of dose excreted in urine over a sampling 
interval (%Feu), cumulative percentage of dose excreted in urine (Total %Feu), and renal 
clearance (CLR). 
Statistical Methods: 
The primary parameters for analysis will be AUC0-∞, and Cmax of GDC-0134. A linear 
mixed model will be applied to analyze the log-transformed primary PK parameters. The 
model assumes fixed effects for formulation, period, and sequence, and a random effect 
for subject within sequence. Estimates of geometric mean ratios on the original scale, 
together with the corresponding 90% CIs, will be derived for the comparisons between 
Test and Reference treatments.  
Descriptive statistics will be calculated on the PK data. No formal statistical analyses are 
planned for safety data. 
 


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2 INTRODUCTION 
2.1 BACKGROUND 
GDC-0134 (also known as G02792134 and RO7040814) is a potent, selective, orally available 
and brain-penetrant small molecule inhibitor of dual leucine zipper kinase (DLK) being 
developed as a therapeutic for amyotrophic lateral sclerosis (ALS).  Dual leucine zipper kinase 
has been identified as a central regulator of neuronal degeneration in a variety of settings, and 
regulates pathways active in chronic neurodegenerative diseases.  Both in vitro and nonclinical in 
vivo studies support the hypothesis that GDC-0134-mediated inhibition of DLK may benefit 
patients with both familial and sporadic ALS. 
 
ALS is a devastating, incurable neurodegenerative disease of upper and lower motor neurons that 
affects approximately three in every 100,000 adults in the United States, most commonly people 
between the ages of 40 and 70 years (1).  Degeneration of motor neurons leads to loss of motor 
control and strength (which affects the limbs, speech, swallowing, and respiration), resulting in 
the need for permanent respiratory support and ultimately death.  Although significant 
heterogeneity does exist in the rate of disease progression, the majority of patients with ALS die 
within 3 to 5 years after disease diagnosis (1). 
 
The mechanisms of motor neuron loss are currently unknown and a common pathophysiological 
mechanism has yet to be identified.  Despite numerous clinical trials exploring multiple 
interventions (2), there have been limited  successes, with riluzole and edaravone being the only 
medications approved in the United States for treatment of ALS.   Riluzole, a tetrodotoxin-
sensitive sodium channel antagonist confers only a modest (2-3 months)  survival benefit and has 
not consistently demonstrated functional benefit (3).  Edaravone, a free radical scavenger, was 
approved for the treatment of ALS in 2017 in the United States and in Canada in 2018. A 
survival benefit has not been established (Radicava® U.S. Package Insert).  While this recent 
approval brings one more treatment option to ALS patients, there remains a high unmet medical 
need for novel therapeutic approaches that could improve function and prolong survival. 
 
Dual leucine zipper kinase is a member of the mixed-lineage kinase family that is an upstream 
regulator of the c-jun N-terminal kinase (JNK) pathway. This pathway has been shown to 
contribute to axon degeneration and neuronal apoptosis following nerve injury and excitotoxic 
insult and in models of chronic neurodegenerative disease (4-6).  Motor neurons in particular 
appear to require DLK in order to degenerate, and loss of DLK signaling is potently 
neuroprotective in this cell type (4, 8).  Stress-induced activation of the DLK/JNK pathway is 
evident in motor neurons of a mouse model of ALS, and genetic reduction of DLK protects 


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motor neurons from degeneration, preserves motor function, and extends survival in the SOD1 
G93A mouse (9).   
 
Expression of DLK is limited largely to neurons of the central and peripheral nervous systems 
(7), and does not have an impact on normal physiological JNK activity (4, 5).  Inhibition of DLK 
by GDC-0134, therefore, provides a highly specific approach to preventing neurodegeneration.  
2.2 OVERVIEW OF GDC-0134 CLINICAL DEVELOPMENT 
There have been two recent clinical studies evaluating GDC-0134.  A randomized, double-blind 
Phase I study (Study GN29823) is ongoing in patients with ALS to evaluate the safety, 
tolerability and pharmacokinetics (PK) of GDC-0134.  An open-label, cross over clinical 
pharmacology study (Study GP39778) is completed and was conducted in healthy female 
subjects of non-childbearing potential to investigate the relative bioavailability of two 
formulations of GDC-0134 and to evaluate the effect of food, a proton pump inhibitor (PPI), and 
applesauce preparation on GDC-0134 absorption and disposition. 
 
As of 22 October 2018, Study GN29823 has enrolled 43 male and female patients with ALS who 
have received GDC-0134 or placebo.  GDC-0134 has had a favorable safety profile in all single 
dose, multiple-dose, and open-label safety expansion (OSE) cohorts evaluated in Study 
GN29823.  There have been no reported deaths; one serious adverse event (SAE) in the OSE 
stage at 400 mg once daily (QD) (life-threatening thrombocytopenia confounded by concomitant 
medications including cephalexin and ibuprofen), one dose-limiting AE (DLAE) in multiple 
ascending dose (MAD) stage at 800 mg (non-serious AE of blurred vision with no objective 
findings), and four withdrawals due to AEs have been observed (two in the single ascending dose 
[SAD] stage [one asymptomatic non-serious increase in intraocular pressure (IOP); and one non-
serious asymptomatic increase in blood bilirubin 161 days after last dose], one in the MAD [the 
DLAE described previously] and one in the OSE [the SAE described previously]) (see the 
Investigator Brochure [IB] for full details [10]). 
 
In the completed Study GP39778, a total of 18 healthy female subjects each have received four 
single doses (200 mg each) of GDC-0134, separated by approximately 3 weeks.  Overall, single 
doses of GDC-0134 were well tolerated.  There were no deaths, no SAEs, and no withdrawals 
due to AEs.  There was one severe AE of asymptomatic increased transaminases approximately 
2 days after dosing with formulated GDC-0134 with high-fat meal in combination with 20 mg 
rabeprazole following prior administration of rabeprazole for 3 days (see the IB for full details 
[10]).  
 


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2.3 CLINICAL PHARMACOKINETICS OF GDC-0134 
The clinical pharmacokinetics of GDC-0134 has been investigated in ongoing and completed 
clinical studies.  As of 15 September 2018, preliminary PK data from Study GN29823 are 
available from 17 patients receiving escalating single oral doses of GDC-0134 and from 
24 patients administered 100-1200 mg GDC-0134 QD for a planned treatment period of 28 
consecutive days in the MAD stage.  The PK data from completed Study GP39778 are available 
from 18 healthy volunteers who received 200 mg single oral doses of GDC-0134.  
In Study GN29823, following a single dose, GDC-0134 was rapidly absorbed with peak 
concentrations achieved at around 1.5 hours (median time to maximum observed concentration 
[tmax]) after dosing.  Biphasic elimination with a relatively rapid decline in drug concentration 
was observed right after tmax of up to 6−12 hours, followed by a slower decline of up to 
168 hours.  Mean apparent terminal elimination half-life (t1/2) of GDC-0134 following a single 
dose was approximately 89 hours.  GDC-0134 exposure in the fasted state increased with dose in 
an approximately dose-proportional manner across the dose range tested to date (20-640 mg). 
 
Following multiple doses (100-1200 mg QD) of GDC-0134 in the MAD stage of Study 
GN29823, plasma concentrations of GDC-0134 increased with dose after a single dose and at 
steady state in MAD (100-1200 mg); however, the increase was less than dose proportional 
within the MAD dose range tested.  Consistent with the long terminal elimination half-life, 
median accumulation following QD dosing was approximately 2 to 3-fold relative to single dose 
Cmax and area under the concentration-time curve from 0 to 6 hours (AUC0-6). 
 
In Study GP39778, following analysis of the plasma concentrations of GDC-0134 to determine 
the effect of formulation, food, and PPI use in healthy volunteers, no significant difference in 
GDC-0134 exposures between powder-in-capsule and formulated capsule were observed at 
200 mg.  Statistically significant increases in systemic exposure (Cmax and AUC) to GDC-0134 
were observed with a high-fat meal (1.1 to 1.4 fold) or applesauce preparation (1.4 − 2.8 fold) 
compared to fasted condition.  Systemic exposure (Cmax and AUC) to GDC-0134 significantly 
decreased (26%-60% of control) in the presence of a PPI, rabeprazole (administered to subjects 
after an overnight fast).  However, this effect was partially attenuated by the consumption of a 
high-fat meal (46%−99% of control). In addition, a reduction in inter-subject exposure variability 
was observed when GDC-0134 was administered with a high-fat meal, as an applesauce 
preparation, or with a PPI compared with when it was administered alone in the fasted condition. 


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2.4 STUDY RATIONALE 
GDC-0134 is a novel molecule being developed by Genentech as a therapeutic for the treatment 
of patients with ALS.  GDC-0134 is intended for oral administration, and the current formulation 
of the drug has been investigated in its free base form. 
 
In this study, the systemic exposure to GDC-0134 following oral administration of the current 
GDC-0134 formulation (GDC-0134 F09 capsule, Ro 704-0814/F09) and the newly developed 
capsule formulation with GDC-0134 malate drug substance (GDC-0134 F16 capsule) will be 
investigated to determine the relative bioavailability.  A newly developed capsule formulation 
with GDC-0134 free base (GDC-0134 F15 capsules) will also be compared against the current 
clinical material GDC-0134 F09 capsules. 
2.5 DOSE RATIONALE 
A maximum of 800 mg single dose is proposed for this study; this dose is considered safe based 
on clinical safety data. In the ongoing Phase I GN29823 study in patients with ALS, single doses 
of 20 mg through 640 mg and multiple doses of 100 mg through 1200 mg QD have been well 
tolerated to date (see Section 2.2). 
 
The highest dose tested in the Phase I study, 1200 mg QD dose, is expected to provide an 
exposure margin of >5-fold compared to 800 mg single dose of the current clinical material, 
GDC-0134 F09 capsules, in fasted condition (1200 mg once daily dosing in patients with ALS 
resulted in a steady state Cmax and AUC0-6 of 13.6 µM and 60.1 µM*hr, respectively compared to 
a single dose of 800 mg which resulted in a Cmax and AUC0-6 of 2.62 µM and 8.58 µM*hr, 
respectively).  The PK of single doses of GDC-0134 (200 mg) were shown to be comparable 
between healthy volunteers (study GP39778) and patients with ALS (study GN29823). 
 
In this study, the exposures with the GDC-0134 F16 and F15 are expected to be comparable with 
that of the current clinical material GDC-0134 F09 capsules.  Systemic exposure to GDC-0134 
administered with a meal is expected to be within 2-fold of the systemic exposure observed with 
current clinical material GDC-0134 F09 capsules in fasted condition.  This is based on the food 
effect observed in study GP39778 (1.1-1.4 fold; see Section 2.3), taking into account that the 
standard meal planned in this study is expected to have less of an effect than the high-fat meal in 
study GP39778. 
 
Doses between 600 mg per day and 1200 mg per day, administered QD or divided into two 
doses, are predicted to be clinically efficacious based on the preclinical PK/PD model and the 


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population PK model. Therefore, an 800 mg single dose of GDC-0134 is proposed to understand 
the effects of formulation and food at a clinically meaningful dose. 
3 STUDY OBJECTIVES AND CORRESPONDING ENDPOINTS 
3.1 PRIMARY OBJECTIVE 
The primary objectives of this study are: 
• 
To determine the relative bioavailability of GDC-0134 F16 capsules 
(newly developed capsule formulation with GDC-0134 malate drug 
substance) with respect to the current clinical material, GDC-0134 F09 
capsules, with a standard meal. 
• 
To determine the relative bioavailability of GDC-0134 F15 capsules 
(newly developed capsule formulation with GDC-0134 freebase) with 
respect to the current clinical material, GDC-0134 F09 capsules, under 
fasted conditions. 
 
A full description of study products is provided in Table 7-4. 
3.2 SECONDARY OBJECTIVES 
The secondary objectives of this study are: 
• To determine the safety and tolerability of a single oral dose of GDC-0134 in healthy 
subjects. 
• To characterize the PK of GDC-0134 after oral administration in healthy subjects. 
3.3 EXPLORATORY OBJECTIVES 
The exploratory objective of this study is: 
• To determine urinary elimination of GDC-0134 
 
3.4 ENDPOINTS 
3.4.1 PHARMACOKINETIC ENDPOINTS 
The primary PK endpoints of this study are:  
• maximum observed concentration (Cmax); 
• AUC extrapolated to infinity (AUC0-∞). 
 
The secondary PK endpoints of this study are: 


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• time to maximum observed concentration (tmax); 
• AUC from Hour 0 to the last measurable concentration (AUC0-t); 
• apparent terminal elimination rate constant (λZ); 
• apparent terminal elimination half-life (t1/2); 
• apparent systemic clearance (CL/F); 
• apparent volume of distribution during the terminal phase (Vz/F). 
 
The exploratory PK endpoints of this study are:  
• amount excreted in urine over a sampling interval (Aeu); 
• cumulative amount excreted in urine (Total Aeu); 
• percentage of dose excreted in urine over a sampling interval (%Feu); 
• cumulative percentage of dose excreted in urine (Total %Feu); 
• renal clearance (CLR). 
 
3.4.2 SAFETY ENDPOINTS 
The Safety endpoints of this study are: 
• Incidence, nature, and severity of AEs (assessed and graded according to the grading 
criteria in Section 8.2.3); 
• Changes in vital signs, electrocardiograms (ECGs), physical examination findings, 
ophthalmology assessment findings, and clinical laboratory results during and following 
GDC-0134 administration. 
4 STUDY DESIGN 
4.1 DESCRIPTION OF THE STUDY 
This will be an open-label, randomized, 2-period crossover study consisting of two parts to 
determine:  
• Part 1 – the relative bioavailability of GDC-0134 F16 capsules and the current clinical 
material, GDC-0134 F09 capsules; 
• Part 2 – the relative bioavailability of GDC-0134 F15 capsules and the current clinical 
material, GDC-0134 F09 capsules. 
 
Part 1 and Part 2 may occur in parallel or consecutively in either order (Part 1 followed by Part 2, 
or Part 2 followed by Part 1). 
 


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Approximately 22 female subjects of non-childbearing potential (11 per treatment sequence) 
between 18 and 65 years of age, inclusive, will be enrolled into each part of the study across two 
clinical research sites.  In each part, subjects will be randomized into one of two treatment 
sequences following a randomization schedule generated by Covance.  If the two parts are run 
sequentially subjects will be encouraged to enroll into more than one part of the study, and there 
will be a minimum of 22 days between dosing in different parts. A washout period of 21 days is 
considered to be sufficient based on the mean terminal elimination half-life of GDC-0134 in 
patients and healthy volunteers being <100 hours, and based on a negligible residual drug 
concentration of GDC-0134 on Day 21 in healthy volunteers (mean Cmax/ concentration at the 
end of a dosing interval at steady state [Ctrough] ratio >300-fold).  A maximum of approximately 
44 subjects will be enrolled into this study. The crossover design is presented in Figure 1 and 
Figure 2. 
 
In each part of the study, potential subjects will be screened to assess their eligibility to enter the 
study within 27 days prior to Check-in (Day -1) for their first treatment period.  Replacement 
subjects may be enrolled, only if deemed necessary by the Sponsor, to ensure that 18 subjects 
complete each part of the study (9 subjects per treatment sequence).  For all subjects, routine 
screening procedures, as outlined in Section 5.1, will be performed. 
 
In both parts of the study, eligible subjects will be admitted to the Clinical Research Units 
(CRUs) on the day prior to dosing for each period (Check-in; Day -1) to collect baseline data and 
to familiarize the subjects with study procedures that will be used during the rest of the study.  
Randomization will occur on Day 1 of Period 1. 
 
Part 1 
 
In Part 1, Periods 1 and 2, eligible subjects will receive 800 mg of either GDC-0134 F16 
capsules or the current clinical material, GDC-0134 F09 capsules (Ro 704-0814/F09), orally with 
a standard meal on Day 1 according to the randomization schedule.  Subjects will be confined to 
the CRU from Check-in (Day -1) until Discharge on Day 3.  Subjects will be required to return 
to the CRU for outpatient visits on Days 5, 7, and 15 (or at Early Termination [ET]).  Check-in 
(Day -1) for Period 2 will occur 20 days after dosing in Period 1. 
 
Part 2 
In Part 2, Periods 1 and 2, subjects will receive 800 mg of GDC-0134 F15 or the current clinical 
material, GDC-0134 F09 capsules, after an overnight fast according to the randomization 
schedule on Day 1. Subjects will not receive food for 4 hours postdose.  Part 2 may occur before, 
after, or in parallel with Part 1. 


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Subjects will be confined to the CRU from Check-in (Day -1) until Discharge on Day 3 during 
each period.  Subjects will be required to return to the CRU for outpatient visits on Days 5, 7, 
and 15 (or at ET). Check-in (Day -1) for Period 2 will occur 20 days after dosing in Period 1. 
 
A detailed list of assessments is included in Table 7-1 and Table 7-2. 


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Figure 1 
Study Schematic of Crossover Design – Part 1 
 
GDC-0134 F09 
capsule
GDC-0134 F16 
capsule
GDC-0134 F16 
capsule
GDC-0134 F09 
capsule
Period 1
Period 2
Sequence A
(n = 11)
Sequence B
(n = 11)
Standard meal
 
Note: F09 capsules = current clinical material of GDC-0134; F16 capsules = newly developed capsule formulation 
with GDC-0134 malate drug substance 
 
 
Figure 2 
Study Schematic of Crossover Design – Part 2 
 
GDC-0134 F09 
capsule
GDC-0134 F15 
capsule
GDC-0134 F15 
capsule
GDC-0134 F09 
capsule
Period 1
Period 2
Sequence A
(n = 11)
Sequence B
(n = 11)
Fasted
 
Note: F09 capsules = current clinical material of GDC-0134; F15 capsules = newly developed capsule formulation 
with GDC-0134 free base 


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In this study design, physical examinations, 12-lead ECGs, vital signs, “How do you feel?” 
(HDYF?) inquiries, ophthalmology assessments, and clinical laboratory evaluations 
(Appendix A) will be performed at Screening, at specified times during the study, and/or at 
Study Completion (for specific timepoints and details on each study variable, refer to Section 7).  
After informed consent has been obtained but prior to initiation of study drug administration 
(Day 1), only SAEs caused by protocol-mandated interventions will be reported.  After initiation 
of study drug administration on Day 1 of each study part, all AEs, whether volunteered, elicited, 
or noted upon physical examination, will be recorded throughout the study until 28 days after the 
last dose of the study (i.e., from Day 1 until Study Completion/ET).  Following administration of 
each treatment in each study part, plasma PK samples will be collected through 21 days postdose 
and urine PK samples will be collected through 48 hours postdose.   A Schedule of Activities is 
presented in Table 7-1 and Table 7-2. 
4.2 RATIONALE FOR STUDY DESIGN 
This study will assess the relative bioavailability of newly developed formulations of GDC-0134 
compared to the current clinical material in healthy females of non-childbearing potential.  A 
single dose, randomized, 2 part, 2-period crossover study design was considered acceptable to 
achieve the study objectives.  This study will not be blinded as the primary endpoints 
(GDC-0134 PK) are not subjective or able to be biased by knowledge of study sequence. 
4.3 RATIONALE FOR SUBJECT POPULATION 
The study will exclude women of childbearing potential and will be limited to healthy female 
subjects of non-childbearing potential based on findings of maternal toxicity and significant fetal 
malformations in nonclinical studies in pregnant rats and rabbits (see Section 2.1 and the IB [10] 
for further details).  Males are excluded based on findings of testicular toxicity observed in male 
rats (see Sections 6.1.4.10).  Clinical experience in humans is still limited to assess the 
translatability of these nonclinical findings to humans. 
4.4 RATIONALE FOR EXPLORATORY ASSESSMENTS 
Urine samples will be collected to determine urinary elimination of GDC-0134. 
4.5 RATIONALE FOR PHARMACOKINETIC SAMPLING SCHEDULE 
The frequent sampling schedule is designed to capture data at a sufficient number of timepoints 
to provide a detailed profile of the concentration-time curve, including maximum observed 
concentration (Cmax), time to maximum observed concentration (tmax), and apparent terminal 
elimination half-life (t1/2). 


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4.6 RATIONALE FOR WHOLE GENOME SEQUENCING 
A whole blood sample will be collected from all subjects for DNA extraction to enable whole 
genome sequencing (WGS). Genomics is increasingly informing researcher’s understanding of 
disease pathobiology.  Whole genome sequencing provides a comprehensive characterization of 
the genome and, through the generation of control data from healthy subjects along with clinical 
data collected in this study, may increase our understanding of PK, response, human diseases, 
and 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.  Given the complexity and exploratory nature of these 
analyses, WGS data and analyses will not be shared with the Principal Investigators (PIs) or 
study subjects unless required by law. 
5 SUBJECT SELECTION 
Twenty-two healthy volunteer female subjects of non-childbearing potential who meet all the 
protocol inclusion criteria and none of the exclusion criteria will be enrolled into each part of the 
study.  If the two parts of the study are run sequentially, subjects will be encouraged to 
participate in multiple parts of the study as long as they continue to meet the eligibility criteria.  
If the parts are conducted sequentially, any subjects discontinued may be replaced with new 
subjects prior to the start of each part.  The maximum possible number of subjects enrolled into 
the study will be approximately 44. 
5.1 SCREENING PROCEDURES 
Refer to Table 7-1 and Table 7-2 for procedures performed for all potential subjects at the 
Screening visit. 
 
If subjects are participating in multiple parts of the study, they will not be required to re-screen 
for the second part of the study as long as there are ≤28 days between Clinic Discharge in the 
first part and Check-in for the second part of the study. 
5.2 CHECK-IN PROCEDURES 
Refer to Table 7-1 and Table 7-2 for procedures performed at Check-in for Periods 1 and 2 when 
subjects will report to the study site. 
 
For subjects to continue their participation in the study, the drug screen and pregnancy test must 
be negative and the clinical laboratory evaluations must be within the normal laboratory range 


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(unless deemed not clinically significant by the PIs).  In addition, continued compliance with 
concomitant medication and other restrictions will be verified. 
5.3 INCLUSION CRITERIA 
Subjects who meet the following criteria may be included in the study: 
1. 
Females, between 18 and 65 years of age, inclusive; 
    within body mass index (BMI) range 18.5 to 35 kg/m2, inclusive; 
2. 
In good health, determined by no clinically significant findings from medical 
history, physical examination, 12-lead ECG, and vital signs; 
3. 
Clinical laboratory evaluations (including chemistry panel [fasted at least 8 
hours], complete blood count [CBC], and urinalysis [UA] with complete 
microscopic analysis (if indicated) within the reference range for the test 
laboratory, unless deemed not clinically significant by the PIs [Gilberts syndrome 
is acceptable]); 
4. 
A normal ophthalmology assessment; minor abnormalities or age-related changes 
are acceptable, if not considered clinically significant, as per the judgment of the 
ophthalmologist; 
5. 
Negative test for selected drugs of abuse at Screening (does not include alcohol) 
and at Check-in for each study period (does include alcohol; Appendix A); 
6. 
Negative for cannabinoids (tetrahydrocannabinol) at Screening and at Check-in 
for both study periods (Appendix A); 
7. 
Negative hepatitis panel (hepatitis B virus core antibody, hepatitis B surface 
antigen [HBsAg] and hepatitis C virus antibody [anti-HCV]) and negative HIV 
antibody screens (Appendix A); 
8. 
Females of non-childbearing potential only, defined as: 
- 
females who are permanently sterile via hysterectomy, bilateral 
salpingectomy, and/or bilateral oophorectomy by reported medical history 
and/or medical records. Surgical sterilization to have occurred a minimum of 
6 weeks prior to Screening  
- 
Females of at least 45 years of age with amenorrhea for 12 months without an 
alternative medical reason with confirmatory follicle-stimulating hormone 
(FSH) levels of ≥40 mIU/mL. The amenorrhea should not be induced by a 
medical condition such as anorexia nervosa, hypothyroid disease or polycystic 
ovarian disease, or by extreme exercise. It should not be due to concomitant 
medications that may have induced the amenorrhea such as oral 
contraceptives, hormones, gonadotropin-releasing hormones, anti-estrogens, 
or selective estrogen receptor modulators. Women aged > 60 years old whose 


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FSH values are not ≥40 mIU/L may be included at the discretion of the PIs 
and in consultation with the Sponsor  
9. 
Negative screening test for latent mycobacterium tuberculosis (TB) infection by 
QuantiFERON® TB Gold (Appendix A). Indeterminate results may be confirmed 
By repeat or by a purified protein derivative (PPD) skin test; 
10. 
Receive an explanation of the mandatory WGS component of the study; 
11. 
Able to comprehend and willing to sign an Informed Consent Form (ICF). 
5.4 EXCLUSION CRITERIA 
The following will exclude potential subjects from the study: 
1. 
Significant history or clinical manifestation of any metabolic, allergic, 
dermatological, hepatic, renal, hematological, pulmonary, cardiovascular 
(including left ventricular hypertension), gastrointestinal (GI), neurological, 
ophthalmologic, or psychiatric disorder, as determined by the PI (or designee); 
2. 
History of significant hypersensitivity, intolerance, or allergy to any drug 
compound, food, or other substance, unless approved by the PI (or designee); 
3. 
History of stomach or intestinal surgery or resection (including cholecystectomy) 
that would potentially alter absorption and/or excretion of orally administered 
drugs except that appendectomy and hernia repair will be allowed; 
4. 
History or presence of an abnormal ECG at Screening or Check-in (Day -1) for 
Period 1, which in the PIs opinion, is clinically significant (QTc interval >470 
msec, PR interval >210 msec, or QRS complex >120 msec; abnormal ECG 
findings will be confirmed by calculating the mean of the original value and 
2 repeats);  
5. 
History of alcoholism or drug addiction within 1 year prior to Check-in (Day -1) 
for their first treatment period; 
6. 
Participation in any other investigational study drug trial in which receipt of an 
investigational study drug occurred within five half-lives (if known) or 30 days 
(small molecule) or 90 days (biologic) for Check-in (Day -1) of their first 
treatment period, whichever is longer;  
7. 
Use of any prescription medications/products within 14 days prior to Check-in 
(Day -1) for their first treatment period and during the entire study duration, 
unless deemed acceptable by the PI (use of hormone replacement therapy [HRT], 
thyroid replacement therapy, ophthalmic drops, or other ophthalmic procedures as 
part of the fundoscopic exam is acceptable); 
8. 
Use of oral antibiotics within 4 weeks or intravenous antibiotics within 8 weeks 
prior to the Screening evaluation and during the entire study duration; 


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9. 
Use of any over-the-counter, non-prescription preparations (including vitamins; 
minerals; and phytotherapeutic-, herbal-, and plant-derived preparations) within 
14 days prior to Check-in (Day -1) for their first treatment period and during the 
entire study duration, unless deemed acceptable by the PI (acetaminophen 
[paracetamol] is acceptable [see Section 7.5]); 
10. 
Use of acid reducing medications (PPIs, H2 receptor antagonists, etc.) within 
14 days prior to Check-in (Day -1) for their first treatment period and during the 
entire study duration. As an alternative, antacids may be allowed at least 4 hours 
before or after dose; 
11. 
Use of strong inhibitors and inducers of CYP3A4/5 and UGT enzymes within 
14 days prior to Check-in (Day -1) for their first treatment period until the Study 
Completion/ET is prohibited, and alternate medications should be considered 
where possible; 
12. 
Use of any vaccines (including seasonal flu and H1N1 vaccines) within 14 days 
prior to Check-in (Day -1) for their first treatment period; 
13. 
Use of tobacco- or nicotine-containing products (including, but not limited to, 
cigarettes, e-cigarettes, pipes, cigars, chewing tobacco, nicotine patches, nicotine 
lozenges, or nicotine gum) within 6 months prior to Check-in (Day -1) for their 
first treatment period and during the entire study; 
14. 
Use of alcohol- or caffeine-containing foods or beverages within 72 hours prior to 
Check-in (Day -1) for their first treatment period until Study Completion/ET; 
15. 
Consumption of grapefruit, grapefruit-containing products, and pomegranate, 
pomelo, and star fruit juice/products within 7 days prior to Check-in (Day -1) for 
their first treatment period and during the entire study duration; 
16. 
strenuous exercise within 48 hours prior to Check-in (Day -1) for their first 
treatment period or during the period of confinement at the study site (e.g., 
subjects will not begin a new exercise program or participate in any unusually 
strenuous physical exertion); 
17. 
Poor peripheral venous access; 
18. 
History of malignancy, except for appropriately treated carcinoma in situ of the 
cervix, non-melanoma skin carcinoma, or Stage I uterine cancer; 
19. 
Donation of blood from 30 days prior to Screening through Study Completion, 
Clinic Discharge, or ET, inclusive, or of plasma from 2 weeks prior to Screening 
through Study Completion, Clinic Discharge, or ET, inclusive; 
20. 
Receipt of blood products within 2 months prior to Check-in (Day -1) for their 
first treatment period; 


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21. 
Subjects with best-corrected visual acuity worse than 20/40 in either eye, history 
of optic neuropathy, history of optic disc swelling or atrophy, and/or history of 
chronic eye disease (e.g., glaucoma, uveitis, diabetic retinopathy); 
22. 
Any acute or chronic condition or any other reason that, in the opinion of the PI, 
would limit the subject’s ability to complete and/or participate in this clinical 
study; 
23. 
Any condition that would preclude participants from receiving a lumbar puncture 
during the study. 
 
Subjects participating in multiple parts of the study: 
24. 
Subjects that have received GDC-0134 within <28 days prior to Day 1 
25. 
Subjects that have an ongoing AE which, in the opinion of the PI, prohibits them 
from further participation in the study 
 
5.5 REMOVAL OF SUBJECTS FROM STUDY PARTICIPATION 
Subjects will be informed that they are free to withdraw from the study at any time and for any 
reason.  The PI may remove a subject from the study if, in the PIs opinion, it is not in the best 
interest of the subject to continue the study.  Subjects may be discontinued due to the following:  
change in compliance with inclusion/exclusion criterion that is clinically relevant and affects 
subject safety, occurrence of AEs, occurrence of pregnancy, intake of non-permitted concomitant 
medication that might affect subject safety or study assessments/objectives, etc.  Notification of 
discontinuation will immediately be made to the Sponsor’s Study Monitor.  In case of premature 
discontinuation of study participation, efforts will be made to perform all final study day 
assessments (see Section 7.16).  The date the subject is withdrawn from the study and the reason 
for discontinuation will be recorded on the subject’s electronic Case Report Form (eCRF).  All 
dropouts will be followed until resolution of all their AEs or until the unresolved AEs are judged 
by the PI to have stabilized or returned to baseline. 
 
For subjects who are discontinued by the PI or who voluntarily withdraw prematurely from the 
study, replacement subjects may be enrolled only if deemed necessary by the Sponsor.  Except 
for replacements, the subjects will be assigned a number by study site staff.  Assignment of 
numbers will be in ascending order and no numbers will be omitted.  Subject numbers will be 
used on all study documentation.  Replacement subjects will be assigned a subject number by 
adding 100 or 1000 to the number of the subject they are replacing (e.g., Subject No. 105 
replaces Subject No. 005). 
 


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The entire study may be discontinued at the discretion of the PI, Sponsor, or Sponsor’s Medical 
Monitor based on the occurrence of, but not limited to, the following: 
• 
AEs unknown to date with respect to their nature, severity, and duration; 
• 
Increased frequency, and/or severity, and/or duration of known AEs; 
• 
Medical or ethical reasons affecting the continued performance of the 
study; 
• 
Difficulties in the recruitment of subjects;* 
• 
Cancellation of drug development.* 
* For reasons that are not related to subject safety, the PI will discuss discontinuation of 
the entire study with the Sponsor prior to making any decisions. 
6 ASSESSMENT OF SAFETY 
6.1 SAFETY PLAN 
GDC-0134 is not approved, and clinical development is ongoing.  The safety plan for subjects in 
this study is based on clinical experience with GDC-0134 in completed and ongoing studies.  
The anticipated important safety risks for GDC-0134 are outlined below.  Please refer to the IB 
(10) for more details on nonclinical studies in rats and cynomolgus monkeys, and preliminary 
clinical data 
 
Several measures will be taken to ensure the safety of subjects participating in this study.  
Eligibility criteria have been designed to exclude subjects at higher risk for toxicities.  Subjects 
will undergo safety monitoring during the study, including assessment of the nature, frequency, 
and severity of AEs. 
6.1.1 RISKS ASSOCIATED WITH GDC-0134 
There are no identified risks for GDC-0134. 
6.1.2 CONTRAINDICATIONS WITH GDC-0134 
There are no known contraindications for GDC-0134. 
6.1.3 SERIOUS ADVERSE DRUG REACTIONS 
No serious adverse drug reactions have been identified for GDC-0134. 


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6.1.4 POTENTIAL RISKS 
6.1.4.1 Phototoxicity  
A 3-day, multiple-dose phototoxicity study in rats showed no direct dermal effects, but ocular 
findings were observed in UVR-exposed rats and included inflammation and edema in the 
cornea and hyperplasia of the anterior lens epithelium.  These findings were considered 
consistent with phototoxicity. 
 
To prevent potential phototoxicity, subjects will be advised to avoid exposure to direct sunlight 
with the use of protective clothing, hats, sunglasses, and repeated application of sunscreen for 
19 days after last dosing. 
6.1.4.2 Skin Lesions 
Skin lesions (erosions/ulcerations/scabs/sores/red discharge/alopecia) were observed in rats and 
monkeys with a dose-related effect.  The tail was the most commonly affected area in monkeys, 
requiring amputation of the tail tip in some animals.  Therefore, complete physical examinations, 
including a complete examination of the skin, will be conducted throughout the study to monitor 
for skin ulcerations or discolorations that may be indicative of study drug-induced toxicity.  
Limited, symptom-directed physical examinations may also be performed.  In addition, subjects 
will be asked to do self-examinations on a daily basis. 
6.1.4.3 Hypothermia 
In repeat-dose toxicity studies in rats, mild reversible body temperature decreases of 
approximately 0.5oC were observed.  In single- and repeat-dose toxicity studies of GDC-0134 in 
monkeys, dose-dependent decrease in oral body temperature was noted at higher doses in the 4-
week study, but was not observed in the 39-week study.  Body temperature will be monitored at 
baseline and during the study.  
6.1.4.4 Retinal Toxicity 
Nonclinical toxicology studies with DLK inhibitors have identified reversible peripapillary 
swelling (PPS) or optic disc edema by ocular examination and retinal nerve fiber layer (RNFL) 
thickening by optical coherence tomography in cynomolgus monkeys after multiple days of 
dosing that returns to near baseline after continued drug exposure in the majority of animals.  
However, in two instances a moderate decrease in RNFL thickness was observed after the 
transient thickening, and in one instance a continued RNFL thinning was observed 8 weeks after 
the end of drug exposure.  The RNFL thickening was largely correlated with increased axon size.  


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In the two animals with thinning RNFL, increases in axon size were also noted by transmission 
electron microscopy (TEM) with one animal also observed to have minimally increased glial cell 
processes.  There was no evidence of axonal loss or degeneration by TEM.  On ophthalmic 
exams, no optic nerve head cupping was observed that would suggest elevated IOP as a factor 
for the RNFL thinning, and no GDC-0134-related effects were noted on IOP measurements, nor 
were any visual deficits detected in an animal, as assessed by electroretinography (full field and 
multi-focal ERGs) or visual evoked cortical potentials.  No GDC-0134-related ophthalmic 
abnormalities, IOP effects, fundus photographic observations, or effects on rod- and cone-driven 
retinal function, as assessed by scotopic and photopic ERGs, have been observed.  The 
functional consequences of this retinal change are unknown.  Patients with best-corrected visual 
acuity worse than 20/40 in either eye, history of optic neuropathy, history of optic disc swelling 
or atrophy, and/or history of chronic eye disease (e.g. glaucoma, uveitis, diabetic retinopathy) are 
excluded from the GDC-0134 studies.  Potential ocular toxicities will be evaluated at baseline 
and throughout GDC-0134 studies as shown in the Schedule of Activities (Table 7-1 and 
Table 7-2). 
6.1.4.5 Increased Intracranial Pressure 
As stated above, 4-week and 39-week nonclinical toxicology studies have identified reversible 
bilateral PPS or optic disc edema in cynomolgus monkeys.  One potential mechanism of PPS or 
optic disc edema is increased intracranial pressure. 
 
Any patient on active drug who experiences clinically significant optic disc edema on 
funduscopic examination, clinically significant functional visual change from baseline, or 
clinically significant RNFL thickening by SD-OCT that is deemed study drug related will 
undergo a lumbar puncture to rule out increased intracranial pressure and will be prohibited from 
receiving further doses of study medication. 
 
In addition, if clinical signs or symptoms (such as severe headache, dizziness, lethargy, vomiting, 
seizures, pulsatile tinnitus) raise the suspicion of increased intracranial pressure, a lumbar 
puncture will be performed.  Lumbar punctures should include measurement of opening pressure 
in the lateral decubitus position.  For all patients who undergo lumbar puncture, cerebrospinal 
fluid will be collected for analysis of glucose, protein, red blood cells (RBCs), white blood cells 
(WBCs), and differential and potentially cryptococcal antigen and bacterial culture. 
 


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6.1.4.6 Cardiac hypertrophy 
Increased heart weights were observed in rats with a corresponding slight to moderate increase in 
thickness (hypertrophy) of the left ventricular wall and interventricular septum of the heart in a 
26-week study.  In a 4-week study, increased heart weight without microscopic findings of 
hypertrophy were observed.  There were no changes in heart weight or findings of cardiac 
hypertrophy or other abnormal microscopic changes observed in the hearts of monkeys.  
However, transient non-adverse increases in heart rate were observed after single doses, with no 
observed effects on other hemodynamic parameters, blood pressures, or ECG assessments. 
6.1.4.7 Gastrointestinal Ulcerations 
Gastrointestinal toxicities characterized by the presence of bloody feces or vomit and 
microscopic findings of gastric erosions or ulcerations were observed in the 4-week toxicity 
study in monkeys but generally resolved during the 4-week recovery period.  GI toxicity was the 
cause of moribundity and early euthanasia in two animals.  In the 39-week study in monkeys, no 
GI toxicity was observed.  Potential GI toxicities will be evaluated regularly by assessing for 
adverse effects that may indicate intolerability, such as nausea, vomiting, or diarrhea. 
 
6.1.4.8 Glycemic Dysregulation 
In nonclinical studies, effects on glucose regulation (rat and monkey) and brown adipose tissue 
macrovesicular vacuolation (monkey) were consistent with GDC-0134 potentially interfering 
with glycemic regulation. Serum blood glucose and body temperature will be monitored.  
 
6.1.4.9 Hepatotoxicity 
Nonclinical studies with GDC-0134 showed an increase of unconjugated bilirubin (2-4x) in rats, 
in the absence of elevated liver enzymes.  No increases of unconjugated bilirubin or liver 
enzymes were observed in cynomolgus monkeys.  Patients with abnormal baseline clinical 
laboratory test results will be excluded from GDC-0134 study protocol(s), as will patients 
positive for anti-HCV or HBsAg. 
 
Liver function tests, including aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), alkaline phosphatase, and total and fractionated bilirubin, will be monitored closely.  
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, must be reported to 
Sponsor as an AE of special interest (AESI) within 24 hours (see Section 8.1.3). 


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6.1.4.10 
Reproductive Toxicity 
Nonclinical findings showed decreased weights of male and female reproductive organs (rat and 
monkey), and vacuolation of some cells of the anterior pituitary gland in males (rats) were seen. 
Men will be excluded from this GDC-0134 study.  
 
Maternal toxicity (e.g. excessive mortality, body weight loss, decreased activity) and multiple 
fetal malformations (e.g. malrotated hindlimbs, whole body subcutaneous edema, cleft snout, 
short tails, small mandible, absent tongue) were observed in nonclinical studies in rats and 
rabbits (see IB for further details).  Therefore, GDC-0134 should not be administered to pregnant 
women. Women of child bearing potential are excluded from this study. 
7 STUDY PROCEDURES 
7.1 SCHEDULE OF STUDY ACTIVITIES 
 


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Table 7-1 
Schedule of Activities – Part 1 
 
 
Period 1 
Cross 
over 
Period 2 
 
Study 
Procedures 
Part 1 Study 
Days 
Screeninga 
Day 
Study 
Completion/ 
ET 
Day 43 
Safety 
Follow-
Up 
 
Day 49 
Days -28 
to -2 
-1 
1 
2 
3 
5 
7 
15 
21 
22 
23 
24 
26 
28 
36 
Period 1 Days 
-1 
1 
2 
3 
5 
7 
15 
21 
22 
- 
- 
- 
- 
- 
 
 
Period 2 Days 
- 
- 
- 
- 
- 
- 
- 
-1 
1 
2 
3 
5 
7 
15 
22 
28 
Check-in to CRU 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Confined to the Study Site 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
 
 
 
 
Discharge from CRU 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
Outpatient Visit 
X 
 
 
 
 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Previous Medication and 
Compliance with 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medication 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical History 
X 
X b 
 
 
 
 
 
 
 
 
 
 
Height, Weight, and BMI c 
X 
X 
 
 
 
 
 
 
 
 
 
X 
Physical Examination d 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
12-Lead ECG 
X 
X 
 
 
 
X 
 
 
 
 
 
 
X 
Vital Signs e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fundoscopic Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visual acuity Assessments 
 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
Visual Field Examination 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 


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Period 1 
Cross 
over 
Period 2 
 
Study 
Procedures 
Part 1 Study 
Days 
Screeninga 
Day 
Study 
Completion/ 
ET 
Day 43 
Safety 
Follow-
Up 
 
Day 49 
Days -28 
to -2 
-1 
1 
2 
3 
5 
7 
15 
21 
22 
23 
24 
26 
28 
36 
Period 1 Days 
-1 
1 
2 
3 
5 
7 
15 
21 
22 
- 
- 
- 
- 
- 
 
 
Period 2 Days 
- 
- 
- 
- 
- 
- 
- 
-1 
1 
2 
3 
5 
7 
15 
22 
28 
AE Evaluations (HDYF? 
Inquiry) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
GDC-0134 Dosef 
X 
 
 
 
 
X 
 
 
 
 
 
 
PK Blood Samples g 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
PK Urine Samplesh 
 
 
X 
X 
X 
 
 
 
 
X 
X 
X 
 
 
 
 
 
Chemistry Panel, CBC, and 
UA i 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
Coagulation profile 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Hepatitis B, C, and HIV 
Screen i 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tuberculosis Testing j 
X 
 
 
 
 
 
 
 
 
 
Drug Screen (including 
cotinine) k 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Serum Pregnancy Test 
X 
X 
 
 
 
 
 
 
 
 
X 
FSH l 
X 
 
 
 
 
 
 
 
 
 
Blood Sample for WGSm 
X 
 
 
 
 
 
 
 
 
AE = adverse event; BMI = body mass index; CBC = complete blood count; ECG = electrocardiogram; ET = Early Termination; FSH = follicle-stimulating 
hormone; HDYF? = how do you feel?; HIV = human immunodeficiency virus; PK = pharmacokinetic; TB = tuberculosis; UA = urinalysis; WGS = whole 
genome sequencing. 
a.In the event of a subject agreeing to participate in both parts of the study and there being ≤28 days between Clinic Discharge for the first part that they 
participate in and Check-in for the second part that they participate in, subjects will not undergo re-screening for the second part. Inclusion/exclusion criteria 


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will be checked prior to completion of the first part. If there is > 28 days between Clinic Discharge for the first part the subject participates in and Check-in for 
the second part that they participate in, the subject will undergo re-screening and will sign a new ICF for the second part. 
b Interim medical history only. 
c Body weight recorded at Screening, Check-in (Day -1) for Period 1, and Study Completion, and height and BMI recorded at Screening only. 
d Routine physical examination (Section 7.13) to occur at scheduled timepoints. Unscheduled abbreviated physical examinations may occur at the discretion of 
the PI (or designee). 
e Vital signs include:  oral temperature, respiratory rate, and supine blood pressure and pulse. 
f GDC-0134 F09 or F16 capsules will be administered 30 minutes after starting a standard meal according to the randomization schedule. 
g For PK blood samples collected during the study, refer to Table 7-3. The predose blood sample for Period 2 (study Day 22) will also be used as the Day 22 
sample for Period 1.  
h Urine PK samples collected during the study will include: predose (single sample voided within 1 hour prior to dosing), and pooled samples voided over the 
following time periods: 0-12 hours, 12-24 hours, 24-36 hours, and 36-48 hours postdose.  
i Refer to Appendix A for a list of evaluations. 
j QuantiFERON TB Gold test. If positive, subject will be excluded. Indeterminate results may be confirmed by repeat or by a PPD skin test. If a negative TB 
screening test has been documented within 3 months of Screening, no new test is needed. 
k Includes alcohol testing at Check-in (Day -1) for each period only. 
l Follicle-stimulating hormone testing performed on postmenopausal females only. 
m Sample collected prior to the GDC-0134 dose on Day 1 of Period 1. If the subject participates in Part 1 and Part 2, a sample for WGS will only be taken during 
the first part of the study that the subject participates in. 
 
 


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Table 7-2 
Schedule of Activities – Part 2 
 
 
Period 1 
Cross 
over 
Period 2 
 
Study 
Procedures 
Part 2 Study 
Days 
Screeninga 
Day 
Study 
Completion/ 
ET 
Day 43 
Safety 
Follow-
Up 
 
Day 49 
Days -28 
to -2 
-1 
1 
2 
3 
5 
7 
15 
21 
22 
23 
24 
26 
28 
36 
Period 1 Days 
-1 
1 
2 
3 
5 
7 
15 
21 
22 
- 
- 
- 
- 
- 
 
 
Period 2 Days 
- 
- 
- 
- 
- 
- 
- 
-1 
1 
2 
3 
5 
7 
15 
22 
28 
Check-in to CRU 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Confined to the Study Site 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
 
 
 
 
Discharge from CRU 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
Outpatient Visit 
X 
 
 
 
 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Previous Medication and 
Compliance with 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medication 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical History 
X 
X b 
 
 
 
 
 
 
 
 
 
 
Height, Weight, and BMI c 
X 
X 
 
 
 
 
 
 
 
 
 
X 
Physical Examination d 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
12-Lead ECG 
X 
X 
 
 
 
X 
 
 
 
 
 
 
X 
Vital Signs e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fundoscopic Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visual acuity Assessments 
 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
Visual Field Examination 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 


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Period 1 
Cross 
over 
Period 2 
 
Study 
Procedures 
Part 2 Study 
Days 
Screeninga 
Day 
Study 
Completion/ 
ET 
Day 43 
Safety 
Follow-
Up 
 
Day 49 
Days -28 
to -2 
-1 
1 
2 
3 
5 
7 
15 
21 
22 
23 
24 
26 
28 
36 
Period 1 Days 
-1 
1 
2 
3 
5 
7 
15 
21 
22 
- 
- 
- 
- 
- 
 
 
Period 2 Days 
- 
- 
- 
- 
- 
- 
- 
-1 
1 
2 
3 
5 
7 
15 
22 
28 
AE Evaluations (HDYF? 
Inquiry) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
GDC-0134 Dosef 
X 
 
 
 
 
X 
 
 
 
 
 
 
PK Blood Samples g 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
PK Urine Samplesh 
 
 
X 
X 
X 
 
 
 
 
X 
X 
X 
 
 
 
 
 
Chemistry Panel, CBC, and 
UA i 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
Coagulation profile 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Hepatitis B, C, and HIV 
Screen i 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tuberculosis Testing j 
X 
 
 
 
 
 
 
 
 
 
Drug Screen (including 
cotinine) k 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Serum Pregnancy Test 
X 
X 
 
 
 
 
 
 
 
 
X 
FSH l 
X 
 
 
 
 
 
 
 
 
 
Blood Sample for WGSm 
X 
 
 
 
 
 
 
 
 
AE = adverse event; BMI = body mass index; CBC = complete blood count; ECG = electrocardiogram; ET = Early Termination; FSH = follicle-stimulating 
hormone; HDYF? = how do you feel?; HIV = human immunodeficiency virus; PK = pharmacokinetic; PPD = purified protein derivative; TB = tuberculosis; 
UA = urinalysis; WGS = whole genome sequencing. 
a. In the event of a subject agreeing to participate in both parts of the study and there being ≤28 days between Clinic Discharge for the first part that they 
participate in and Check-in for the second part that they participate in, subjects will not undergo re-screening for the second part. Inclusion/exclusion criteria 


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will be checked prior to completion of the first part. If there is > 28 days between Clinic Discharge for the first part the subject participates in and Check-in for 
the second part that they participate in, the subject will undergo re-screening and will sign a new ICF for the second part. 
b Interim medical history only. 
c Body weight recorded at Screening, Check-in (Day -1) for Period 1, and Study Completion, and height and BMI recorded at Screening only. 
d Routine physical examination (Section 7.13) to occur at scheduled timepoints. Unscheduled abbreviated physical examinations may occur at the discretion of 
the PI (or designee). 
e Vital signs include:  oral temperature, respiratory rate, and supine blood pressure and pulse. 
f GDC-0134 F09 or F15 capsules will be administered after an overnight fast according to the randomization schedule. 
g For PK blood samples collected during the study, refer to Table 7-3. The predose blood sample for Period 2 (study Day 22) will also be used as the Day 22 
sample for Period 1. 
h Urine PK samples collected during the study will include: predose (single sample voided within 1 hour prior to dosing), and pooled samples voided over the 
following time periods: 0-12 hours, 12-24 hours, 24-36 hours, and 36-48 hours postdose.  
i Refer to Appendix A for a list of evaluations. 
j QuantiFERON TB Gold test. If positive, subject will be excluded. Indeterminate results may be confirmed by repeat or by a PPD skin test. If a negative TB 
screening test has been documented within 3 months of Screening, no new test is needed. 
k Includes alcohol testing at Check-in (Day -1) for both periods only. 
l Follicle-stimulating hormone testing performed on postmenopausal females only. 
m Sample collected prior to the GDC-0134 dose on Day 1 of Period 1. If the subject participates in Part 1 and Part 2, a sample for WGS will only be taken during 
the first part of the study that the subject participates in. 
 


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Table 7-3 
Plasma Pharmacokinetic Sampling Scheme (All Study Periods) 
Period 
Day 
PK Sampling Timepoints (Hours Postdose) 
Window (+/-) 
Analyte (Matrix) 
Day 1 
Predose (0 Hour) any time prior to study drug 
administration 
NA 
GDC-0134 (Plasma) 
0.5 
3 minutes 
GDC-0134 (Plasma) 
1 
5 minutes 
GDC-0134 (Plasma) 
1.5 
5 minutes 
GDC-0134 (Plasma) 
2 
10 minutes 
GDC-0134 (Plasma) 
3 
10 minutes 
GDC-0134 (Plasma) 
4 
10 minutes 
GDC-0134 (Plasma) 
6 
10 minutes 
GDC-0134 (Plasma) 
8 
10 minutes 
GDC-0134 (Plasma) 
12 
10 minutes 
GDC-0134 (Plasma) 
Day 2 
24 
10 minutes 
GDC-0134 (Plasma) 
Day 3 
48 
30 minutes 
GDC-0134 (Plasma) 
Day 5 
96 
6 hours 
GDC-0134 (Plasma) 
Day 7 
144 
6 hours 
GDC-0134 (Plasma) 
Day 15 
336 
6 hours 
GDC-0134 (Plasma) 
Day 22 1 
504 
6 hours 
GDC-0134 (Plasma) 
NA = not applicable; PK = pharmacokinetic. 
1. The predose sample in the second period in each part (Period 2) will be used as the Day 22 PK sample for the 
first period in each part (Period 1).  
7.2 STUDY TREATMENT 
The Investigational Medicinal Product for this study is GDC-0134. For details on the drug 
products used in the study, refer to related Investigational New Drug (IND) quality information 
amendment. 
7.2.1 DRUG SUPPLIES AND ACCOUNTABILITY 
The Sponsor or designee will provide the PI with adequate quantities of the study drug (see 
Table 7-4). 


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Table 7-4 
Study Drug 
Study Drug 
GDC-0134 hemimalate 
GDC-0134 
GDC-0134 
Study Designation 
GDC-0134 F16 capsule 
GDC-0134 F15 capsule 
GDC-0134 F09 capsule 
Description 
Test drug, newly 
developed capsule 
formulation with 
GDC-0134 malate drug 
substance 
Test drug, newly 
developed capsule 
formulation with 
GDC-0134 freebase 
Reference drug, current 
clinical material 
Formulation a 
GDC-0134 Capsule, 
200 mg (freebase 
equivalent), Ro 704-
0814/F16 form 
GDC-0134 Capsule, 
200 mg, Ro 704-0814/F15 
GDC-0134 Capsule, 
200 mg, Ro 704-0814/F09 
Strength 
200 mg 
200 mg 
200 mg 
Manufacturer 
Shanghai STA  
Pharmaceutical Product 
Co. Ltd 
Roche Basel 
Patheon Inc. 
a Specific ingredients/purity will be identified on the Certificate of Analysis (or equivalent) that is supplied with the 
study drug(s). 
 
The lot numbers for the study drug will be provided to the study site by the 
supplier/manufacturer as soon as available. 
 
Study drug will be stored at temperatures below 25oC.  The study drug will be transferred from 
the bulk supplies into the subject’s dose container by qualified study site employees.  Each unit 
dose container will be appropriately labeled. 
 
The PI or designee will maintain an accurate record of the receipt of the test materials as shipped 
by the Sponsor or designee, including the date received.  One copy of this receipt will be 
returned to the Sponsor when the contents of the test material shipment have been verified. In 
addition, an accurate drug disposition record will be kept, specifying the amount dispensed to 
each subject and the date of dispensation.  This drug accountability record will be available for 
inspection at any time.  At the completion of the study, the original drug accountability record 
will be available for review by the Sponsor upon request. 
 
If deemed appropriate by the Sponsor, sufficient samples will be randomly selected from the 
supply provided by the Sponsor or designee and retained by the study site to meet the retention 
requirements described in U.S. Title 21 Code of Federal Regulations (CFR) 320.38 and 320.63. 
 
At the completion of the study, all unused drug supplies (except for retention supplies, if 
appropriate) will be returned to the Sponsor or designee or disposed of by the study site, per the 
Sponsor’s or designee’s written instructions. 


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7.2.2 DOSE PREPARATION AND ADMINISTRATION 
Each unit dose will be prepared by qualified clinical staff based on the study randomization that 
will be provided by a Covance biostatistician. 
 
Appropriate unit doses, as described above, will be administered to subjects in ascending order 
based on the subjects’ number.  Although the timing of events requires that each subject will be 
consistently administered the appropriate dose at specific times, the exact dose time of 
consecutive subjects may be staggered to obviate the need to have all subjects on precisely the 
same study schedule.  For each dose, the subject’s actual time will be recorded in the source 
documents and transcribed into the eCRFs. 
 
Except as part of dose administration or as part of a scheduled meal, subjects will restrict their 
consumption of water for 1 hour prior to dose and for 2 hours postdose; at all other times during 
the study, subjects may consume water ad libitum. 
 
7.2.2.1 Part 1 and Part 2 
In both parts of the study, each dose will be administered orally with approximately 240 mL 
room temperature water.  A hand and mouth check will be performed to verify that the dose 
administered was swallowed. 
 
In Part 1, subjects will receive a standard meal starting 30 minutes prior to dosing which must 
have been entirely consumed within 25 minutes.  In Part 2, doses will be preceded by an 
overnight fast (i.e., at least 8 hours) from food (not including water) and will be followed by a 
fast from food (not including water) for at least 4 hours postdose.  
 
Cases of GDC-0134 accidental overdose or medication error, along with any associated AEs, 
should be reported as described in Section 8.4.3. 
 
Details regarding standard meal administration in Part 1 (including, but not limited to, meal start 
date/time, meal completion date/time, and estimated percentage of meal consumed [if not 
entirely consumed]) will be recorded. 
7.3 REMOVAL OF STUDY BLIND 
Not applicable; this is an open-label study and will not be blinded. 


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7.4 DIET, FLUID, AND ACTIVITY CONTROL 
Subjects will refrain from use of tobacco- or nicotine-containing products (including, but not 
limited to, cigarettes, e-cigarettes, pipes, cigars, chewing tobacco, nicotine patches, nicotine 
lozenges, and nicotine gum) within 6 months prior to Check-in (Day -1) for their first treatment 
period and during the entire study. 
 
Subjects will abstain from consuming alcohol- or caffeine-containing foods and beverages for 
72 hours prior to their Check-in (Day -1) to their first study period until Study Completion/ET, 
unless deemed acceptable by the PI. 
 
Subjects will abstain from consuming grapefruit, grapefruit-containing products, and 
pomegranate, pomelo, and star fruit juice/products from 7 days prior to Check-in (Day -1) for 
their first treatment period and during the entire study duration. 
 
Subjects will refrain from strenuous exercise from 48 hours prior to Check-in (Day -1) for their 
first treatment period and during the period of confinement at the study site and will otherwise 
maintain their normal level of physical activity throughout the entire study (i.e., will not begin a 
new exercise program or participate in any unusually strenuous physical exertion). 
 
With the exception of dosing, as applicable, while confined at the study site, subjects will receive 
a standardized diet at scheduled times that do not conflict with other study-related activities. 
 
Doses will be preceded by an overnight fast (i.e., at least 8 hours) from food (not including 
water) and will be followed by a fast from food (not including water) for at least 4 hours 
postdose, or will be preceded by a standard meal prior to dosing, according to the randomization 
scheme and as detailed in Section 7.2.2.1.  Except as part of dose administration, subjects will 
restrict their consumption of water for 1 hour prior to dose and for 2 hours postdose; at all other 
times during the study, subjects may consume water ad libitum. 
 
Subjects will remain seated/standing upright for 1 hour following each dose administered, except 
as necessitated by the occurrence of an AE(s) and/or study procedures. 
7.5 CONCOMITANT MEDICATIONS 
Concomitant therapy consists of any prescription medications, herbal, vaccines, topical 
medications, or over-the-counter preparations, including herbal or dietary supplements taken by 
a subject in addition to protocol-mandated treatment at any time from Check-in (Day -1) for their 
first treatment period through Study Completion. 


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Subjects will not have received any investigational study drug within 5 half-lives (if known), or 
30 days (small molecule) or 90 days (biologic), whichever is longer, prior to their first treatment 
period. 
 
Subjects will refrain from the use of any prescription medications during the interval from 
14 days prior to Check-in (Day -1) for their first treatment period and for the entire study 
duration, unless deemed acceptable by the PI (use of HRT or thyroid replacement is acceptable).  
Subjects will refrain from the use of strong inhibitors and inducers of CYP3A4/5 and UGT 
enzymes within 14 days prior to Period 1 Check-in (Day -1) for their first treatment period until 
Study Completion, and alternate medications should be considered where possible. 
 
In addition, subjects will refrain from the use of any over-the-counter non-prescription 
medications (including vitamins; minerals; and phytotherapeutic-, herbal-, and plant-derived 
preparations) from 14 days prior to Check-in (Day -1) for their first treatment period and for the 
entire study duration, unless deemed acceptable by the PI (acetaminophen [paracetamol] is 
acceptable and may be administered as needed up to 0.5 to 1 g every 4 to 6 hours [maximum 
3 g/day] but should be avoided from Check-in [Day -1] for their first treatment period to the end 
of the study).  Use of thyroid medication or ophthalmic drops or other ophthalmic procedures (as 
part of the fundoscopic exam) is acceptable.  Subjects will not use acid reducing medications 
(PPIs, H2 receptor anatagonists, etc) within 14 days prior to Check-in (Day -1) for their first 
treatment period and during the entire study duration.  As an alternative, antacids may be 
allowed at least 4 hours before or after dose. 
 
Subjects will not have had any vaccines (including seasonal flu and H1N1 vaccines) within 
14 days prior to the Check-in (Day -1) for their first treatment period. 
 
Subjects will not take oral antibiotics within 4 weeks or intravenous antibiotics within 8 weeks 
prior to the Screening evaluation. 
 
Subjects who have taken drugs of abuse (including opioids) within 4 weeks of Screening or 
during the entire study will be excluded from this study. 
 
The administration of any other concomitant medications during the study is prohibited without 
prior approval of the PI, unless its use is deemed necessary in a medical emergency.  Any 
medication taken by a subject during the course of the study and the reason for its use will be 
documented in the source documents and the eCRF. 


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7.6 PHARMACOKINETIC BLOOD AND URINE SAMPLE COLLECTION AND 
PROCESSING 
Blood samples for PK analysis of GDC-0134 levels will be collected via an indwelling catheter 
and/or via direct venipuncture using Vacutainer evacuated collection tubes.  Blood samples will 
be collected at the timepoints listed in Table 7-1, Table 7-2, and Table 7-3. 
 
Processing, storage, and shipping instructions for these PK blood samples are presented in a 
separate Laboratory Manual. 
 
After the plasma and urine samples collected in the study are analyzed for GDC-0134 
concentrations, any residual samples may be used for analysis such as metabolite profiling and 
identification, interacting drug concentration measurements, ex vivo protein binding, or 
development of PK or PD assays.  Left over PK samples will be destroyed no later than 5 years 
after the final Clinical Study Report has been completed.  When a subject withdraws from the 
study, samples collected prior to the date of withdrawal may still be analyzed, unless the subject 
specifically requests in writing that the samples be destroyed or local laws require destruction of 
the samples.  However, if samples have been tested prior to withdrawal, results from those tests 
will remain as part of the overall research data.  
 
Urine samples for PK analysis will be collected at the time intervals indicated in Table 7-1 and 
Table 7-2. 
 
The weight of the pooled urine collected during each sampling interval will be recorded. Further 
details will be provided in the Laboratory Manual. 
7.7 ANALYTICAL METHODOLOGY 
Plasma and urine concentrations of GDC-0134 will be determined by Covance Laboratories 
using a validated (plasma) and qualified (urine) analytical procedure. 
 
7.8 CLINICAL LABORATORY EVALUATIONS 
Clinical laboratory evaluations (including chemistry panel fasted at least 8 hours, CBC, UA, and 
coagulation profile) will be collected at the timepoints listed in Table 7-1 and Table 7-2. 
 
Screens for a hepatitis panel and HIV antibody will be performed at Screening.  A drug screen 
for selected drugs of abuse (not including alcohol) will be performed at Screening and repeated 


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(but including an alcohol breath or urine test) at Check-in (Day -1) for each study period.  A 
serum qualitative pregnancy test (females only) and FSH test (postmenopausal females only) will 
be performed at the timepoints specified in Table 7-1 and Table 7-2. 
 
Tuberculosis testing will be performed for all subjects at Screening using the following criteria: 
• QuantiFERON TB Gold is an acceptable screening assay for latent mycobacterium 
tuberculosis infection; 
• An indeterminate QuantiFERON TB Gold test should be repeated. Indeterminate results 
may also be confirmed by a PPD skin test; 
o A positive PPD tuberculin skin test reaction is considered ≥10 mm (or ≥5 mm in 
subjects receiving the equivalent of >15 mg/day of prednisone); 
• A positive QuantiFERON TB Gold test should be considered a positive diagnostic TB 
test; 
• An indeterminate QuantiFERON TB Gold test followed by a negative QuantiFERON TB 
Gold test should be considered a negative diagnostic TB test; 
• If a negative TB screening test has been documented within 3 months of Screening, no 
new test is needed. 
7.9 SAMPLES FOR THE RESEARCH BIOSAMPLE REPOSITORY 
7.9.1 OVERVIEW OF THE RESEARCH BIOSAMPLE REPOSITORY 
The Research Biosample Repository (RBR) is a centrally administered group of facilities used 
for the long-term storage of human biologic specimens, including body fluids, solid tissues, and 
derivatives thereof (e.g., DNA, RNA, proteins, and/or peptides).  The collection, storage, and 
analysis of RBR specimens will facilitate the rational design of new pharmaceutical agents and 
the development of diagnostic tests, which may allow for individualized drug therapy for 
subjects in the future. 
 
Specimens for the RBR will be collected from subjects who give specific consent to participate 
in this research.  The RBR specimen will be used to achieve the following objectives: 
• To study the association of biomarkers with efficacy, AEs, or disease progression; 
• To increase knowledge and understanding of disease biology; 
• To study drug response, including drug effects and the processes of drug absorption and 
disposition; 
• To develop biomarker or diagnostic assays and establish the performance characteristics 
of these assays. 


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7.9.2 APPROVAL BY THE INSTITUTIONAL REVIEW BOARD 
Collection and submission of biological samples to the RBR is contingent upon the review and 
approval of the exploratory research and the RBR portion of the ICF by each site’s Institutional 
Review Board (IRB) and, if applicable, an appropriate regulatory body.  If a site has not been 
granted approval for RBR sampling, Sections 7.9 through 7.9.7 of this protocol will not be 
applicable at that site. 
7.9.3 MANDATORY SAMPLES FOR WHOLE GENOME SEQUENCING SAMPLE 
COLLECTION 
A mandatory whole blood sample will be collected for DNA extraction to enable WGS and may 
be sent to one or more laboratories for analysis.  The WGS sample is considered an RBR sample. 
 
For sampling procedures, storage conditions, and shipment instructions, see the Laboratory 
Manual. 
 
The RBR specimens will be stored until they are no longer needed or until they are exhausted.  
However, the RBR storage period will be in accordance with the IRB/EC-approved ICF and 
applicable laws (e.g., health authority requirements).  When a subject withdraws from the study, 
samples collected prior to the date of withdrawal may still be analyzed, unless the subject 
specifically requests in writing that the samples be destroyed or local laws require destruction of 
the samples.  However, if samples have been tested prior to withdrawal, results from those tests 
will remain as part of the overall research data. 
7.9.4 CONFIDENTIALITY 
Specimens and associated data will be labeled with a unique subject identification number. 
 
Subject medical information associated with RBR specimens is confidential and may be 
disclosed to third parties only as permitted by the ICF (or separate authorization for use and 
disclosure of personal health information) signed by the subject, unless permitted or required by 
law. 
 
Given the complexity and exploratory nature of the analyses, data derived from RBR specimens 
will generally not be provided to study PIs or subjects unless required by law.  The aggregate 
results of any conducted research will be available in accordance with the effective Sponsor 
policy on study data publication. 
 


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Data generated from RBR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, representatives, 
and collaborators, as appropriate. 
 
Any inventions and resulting patents, improvements, and/or know-how originating from the use 
of the RBR data will become and remain the exclusive and unburdened property of the Sponsor, 
except where agreed otherwise. 
7.9.5 CONSENT TO PARTICIPATE IN THE RESEARCH BIOSAMPLE 
REPOSITORY 
The ICF will contain a separate section that addresses participation in the RBR.  The PI or 
authorized designee will explain to each subject the objectives, methods, and potential hazards of 
participation in the RBR.  Subjects 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 (the 
withdrawal of their RBR specimen will coincide with withdrawal from the study).  A separate, 
specific signature will be required to document a subject’s agreement to provide RBR specimens 
for WGS. 
 
The PI (or designee) should document whether or not the subject has given consent to participate 
and (if applicable) the date(s) of consent, by completing the RBR Research Sample Informed 
Consent eCRF. 
 
In the event of an RBR participant’s death or loss of competence, the participant’s specimens and 
data will continue to be used as part of the RBR research. 
7.9.6 WITHDRAWAL FROM THE RESEARCH BIOSAMPLE REPOSITORY 
Subjects who give consent to provide RBR specimens have the right to withdraw their specimens 
from the RBR at any time and for any reason.  If a subject wishes to withdraw consent to the 
testing of their specimens, the PI must inform the Medical Monitor in writing of the subject’s 
wishes using the appropriate RBR Subject Withdrawal Form and, if the trial is ongoing, must 
enter the date of withdrawal on the RBR Research Sample Withdrawal of Informed Consent 
eCRF.  The subject will be provided with instructions on how to withdraw consent after the trial 
is closed.  A subject’s withdrawal from this study does not, by itself, constitute withdrawal of 
specimens from the RBR. 


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7.9.7 MONITORING AND OVERSIGHT 
The RBR specimens will be tracked in a manner consistent with Good Clinical Practice (GCP) 
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 ICF.  Sponsor monitors and 
auditors will have direct access to appropriate parts of records relating to subject participation in 
the RBR for the purposes of verifying the data provided to the Sponsor.  The site will permit 
monitoring, audits, IRB review, and health authority inspections by providing direct access to 
source data and documents related to the RBR samples. 
7.10 
12-LEAD ELECTROCARDIOGRAMS 
Resting 12-lead ECGs will be recorded after the subject has been supine and at rest for at least 5 
minutes at the times  Table 7-1 and Table 7-2. 
 
Single 12-lead ECGs will be repeated twice, and an average taken of the three readings, if any of 
the following criteria apply:  
• QT interval corrected through use of Fridericia’s formula (QTcF) value >470 msec 
• PR interval >210 msec 
• QRS complex >120 msec 
• QTcF change from the baseline (predose) is > 60 msec. 
 
Additional 12-lead ECGs may be performed at other times if judged to be clinically appropriate 
or if the ongoing review of the data suggests a more detailed assessment of ECGs is required.  
The PI (or designee) will perform a clinical assessment of each 12-lead ECG. 
 
To minimize variability in autonomic tone and heart rate, subjects will rest quietly and in a 
supine position for at least 5 minutes prior to recording the ECG. Blood draws, other procedures, 
activity, and environmental distractions (e.g., television, radio, conversation) should be avoided 
during the pre-ECG resting period and between ECG recordings, to minimize variability due to 
the effects of activity and stress on cardiac electrophysiology.  Whenever possible, ECG tracings 
for each subject should be obtained from the same type of machine throughout the study. 
 
When 12-lead ECGs are scheduled at the same time as blood draws and vital signs, the blood 
draws will be obtained at the scheduled timepoint, and the 12-lead ECGs and vital signs will be 
obtained as close to the scheduled blood draw as possible, but prior to the blood draw (order of 
assessments = ECGs, vital signs, blood samples). 


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7.11 
VITAL SIGNS 
Vital signs (including oral temperature, respiratory rate, and supine blood pressure and pulse) 
will be obtained at the timepoints specified in Table 7-1 and Table 7-2. 
 
Supine blood pressure and pulse will be obtained after the subject has been supine for at least 
5 minutes.  When vital signs are scheduled at the same time as blood draws, the blood draws will 
be obtained at the scheduled timepoint, and the vitals will be obtained as close to the scheduled 
blood draw as possible, but prior to the blood draw. 
7.12 
HOW DO YOU FEEL? INQUIRY 
Subjects will be asked a non-leading HDYF? question such as “Have there been any changes in 
your health status since Screening/since you were last asked?” once daily on the days specified 
in Table 7-1 and Table 7-2.  Subjects will also be encouraged to voluntarily report AEs occurring 
at any other time during the study.  See Section 8.3 and Section 8.4 for reporting requirements 
for AEs and SAEs, respectively. 
7.13 
PHYSICAL EXAMINATIONS 
A routine physical examination will be performed at the timepoints specified in Table 7-1 and 
Table 7-2. 
 
A routine physical examination will consist of an assessment of general appearance, skin, 
thorax/lungs, abdomen, lymph nodes, head, ears, eyes, nose, throat, neck (including thyroid); and 
cardiovascular, musculoskeletal, and neurological systems.  The PI or designee may conduct 
unscheduled abbreviated physical examinations if required. 
 
7.14 
OPHTHALMOLOGY ASSESSMENTS 
During the screening period, a fundoscopic examination will be performed by a qualified 
optician/ophthalmologist as per the local standard of care. 
 
The following assessments will be conducted at the times indicated in Table 7-1 and Table 7-2: 
• Best-corrected visual acuity at a distance of 4 meters 
• Near visual acuity using a card 
• Visual field examination 
 


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Subjects are allowed to use their own glasses for visual acuity and visual field assessments.  If a 
subject has a 2-line decrease in visual acuity, they will be referred for an ophthalmology 
assessment.  Additional ophthalmology assessments may be conducted during the study at the 
discretion of the PI. 
7.15 
CLINIC DISCHARGE PROCEDURES 
Refer to Table 7-1 and Table 7-2 for procedures performed on the days of Discharge. 
7.16 
STUDY COMPLETION/EARLY TERMINATION PROCEDURES 
Refer to Table 7-1 and Table 7-2 for procedures performed at Study Completion or at ET. 
8 ADVERSE EXPERIENCES 
8.1 SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording AEs, including SAEs and AESIs, 
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.  The Sponsor or its designee is responsible for reporting relevant SAEs 
to the competent authority, other applicable regulatory authorities, and participating PIs, in 
accordance with International Conference on Harmonisation/International Council for 
Harmonisation (ICH) guidelines, Food and Drug Administration (FDA) regulations, European 
Clinical Trials Directive (Directive 2001/20/EC), and/or local regulatory requirements.  
 
Certain types of events require immediate reporting to the Sponsor, as outlined in Section 8.4. 
8.1.1 ADVERSE EVENTS 
According to the ICH Guideline for GCP, an AE is any untoward medical occurrence in a 
clinical investigation subject administered a pharmaceutical product, regardless of causal 
attribution. An AE 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); 
• Recurrence of an intermittent medical condition (e.g., headache) not present at baseline; 


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• 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; 
• AE 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). 
8.1.2 SERIOUS ADVERSE EVENTS (IMMEDIATELY REPORTABLE TO THE 
SPONSOR) 
An SAE is any AE that meets any of the following criteria: 
• Is fatal (i.e., the AE actually causes or leads to death); 
• Is life-threatening (i.e., the AE, in the view of the PI, places the subject at immediate risk 
of death); this does not include any AE that had it occurred in a more severe form or was 
allowed to continue might have caused death; 
• Requires or prolongs inpatient hospitalization; 
• Results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the subject’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 PIs judgment (e.g., may jeopardize the subject or 
may require medical/surgical intervention to prevent one of the outcomes listed above). 
 
All AEs that do not meet any of the criteria for serious should be regarded as non-serious AEs. 
 
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of an AE 
(e.g., rated as mild, moderate, or severe, according to National Cancer Institute Common 
Terminology Criteria for Adverse Events); the event itself may be of relatively minor medical 
significance (such as severe headache) without any further findings.  An event should be 
considered “serious” only if it meets the regulatory criteria outlined in the above-mentioned 
paragraph outlining seriousness criteria. 
 
Seriousness (not severity) serves as the guide for defining regulatory reporting obligations. 
 
Severity and seriousness need to be independently assessed for each AEs recorded on the eCRF. 
 
Serious AEs are required to be reported by the PI to the Sponsor via the Covance project 
manager immediately (i.e., no more than 24 hours after learning of the event; see Section 8.4.2 
for reporting instructions). 


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8.1.3 ADVERSE EVENTS OF SPECIAL INTEREST (IMMEDIATELY REPORTABLE 
TO THE SPONSOR) 
Adverse events of special interest are required to be reported by the PI to the Sponsor via the 
Covance project manager immediately (i.e., no more than 24 hours after learning of the event; 
see Section 8.4.2 for reporting instructions).  The AESI for this study are as follows: 
 
• 
Clinically significant peripapillary or optic disc swelling on funduscopic 
examination, as determined by the local site PI/ophthalmologist 
• 
Clinically significant functional visual change from baseline, as 
determined by the local site PI/ophthalmologist 
 
• Cases of potential drug-induced liver injury that include an elevated alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) in combination with either 
an elevated bilirubin or clinical jaundice, as defined by Hy’s Law (see Section 8.3.1.6); 
• Suspected transmission of an infectious agent by the study drug as defined below: 
o Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an infection 
in a subject exposed to a medicinal product. The term applies only when a 
contamination of the study drug is suspected. 
 
8.2 METHODS AND TIMING FOR CAPTURING AND ASSESSING SAFETY 
PARAMETERS 
The PI is responsible for ensuring that all AEs (as defined in Section 8.1) are recorded on the AE 
eCRF and reported to the Sponsor via the Covance project manager in accordance with protocol 
instructions (see Section 8.4.2). 
 
For each AE recorded on the AE eCRF, the PI will make an assessment of seriousness (see 
Section 8.1.2 for seriousness criteria), severity, and causality (see Section 8.2.3). 
8.2.1 ADVERSE EVENT REPORTING PERIOD 
Principal Investigators will seek information on AEs at each subject contact.  All AEs, whether 
reported by the subject or noted by study personnel, will be recorded in the subject’s medical 
record and on the AE eCRF. 


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After informed consent has been obtained but prior to initiation of study drug, only SAEs 
caused by a protocol-mandated intervention (e.g., discontinuation of medications) will be 
reported (see Section 8.4.2 for instructions for reporting SAEs).  After initiation of study drug 
administration, all AEs will be reported until 28 days after the final dose. 
 
Instructions for reporting AEs that occur after the AE reporting period are provided in 
Section 8.5. 
 
The PI is not required to actively monitor subjects after the study has ended or for AEs after the 
end of the AE reporting period (defined as 28 days after the final dose of study drug, whichever 
is longer).  However, the Sponsor should be notified if the PI becomes aware of any death, other 
SAEs, or AESIs occurring after the end of the AE reporting period that are believed to be related 
to prior study drug treatment.  The Sponsor should also be notified if the PI becomes aware of 
the development of cancer or a congenital anomaly/birth defect in a subsequently conceived 
offspring of a female subject exposed to study drug. 
8.2.2 ELICITING ADVERSE EVENT INFORMATION 
A consistent methodology of non-directive questioning should be adopted for eliciting AE 
information at all subject 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?” 
8.2.3 ASSESSMENT OF SEVERITY OF ADVERSE EVENTS 
The World Health Organization (WHO) toxicity grading scale will be used for assessing AE 
severity. Table 8-1 will be used for assessing severity for AEs that are not specifically listed in 
the WHO toxicity grading scale. 


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Table 8-1 
Adverse Event Severity Grading Scale for Events Not Specifically Listed in 
WHO Toxicity Grading Scale 
Grade 
Severity 
1 
Mild; transient or mild discomfort (<48 hours); no medical intervention or therapy required 
2 
Moderate; mild to moderate limitation in activity; some assistance may be needed; no or 
minimal medical intervention or therapy required 
3 
Severe; marked limitation in activity; some assistance usually required; medical intervention or 
therapy required; hospitalization possible 
4 
Life-threatening; extreme limitation in activity; significant assistance required; significant 
medical intervention or therapy required, hospitalization or hospice care probable 
Notes:  Developed by the Division of Microbiology and Infectious Diseases. 
Regardless of severity, some events may also meet seriousness criteria. Refer to definition of an SAE (see 
Section 8.1.2). 
 
8.2.4 ASSESSMENT OF CAUSALITY OF ADVERSE EVENTS 
Principal Investigators should use their knowledge of the subject, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an AE 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 8-2): 
• Temporal relationship of event onset to the initiation of study drug; 
• Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable); 
• Known association of the event with the study drug or with similar treatments; 
• Known association of the event with the disease under study; 
• Presence of risk factors in the subject 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 8-2 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by the study drug based on 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 subject’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. 
Principal Investigators should apply facts, evidence, or rationales based on scientific principles and 
clinical judgment to support a causal/contributory association with a study drug. 
NO 
AE will be considered related, unless they fulfill the criteria as specified below. 
Evidence exists that the adverse event has an etiology other than the study drug (e.g., pre-existing 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). 
Note:  The PIs assessment of causality for individual adverse event reports is part of the study 
documentation process. Regardless of the “Yes” or “No” causality assessment for individual adverse event 
reports, the Sponsor will promptly evaluate all reported SAEs against cumulative product experience to 
identify and expeditiously communicate possible new safety findings to PIs and applicable regulatory 
authorities. Attribution of SAEs will be reviewed on an ongoing basis, and may be changed as 
additional clinical data emerges (e.g., reversibility of adverse event, new clinical findings in subject 
with adverse event, effects of re-treatment, and AE in other subjects). 
 
8.3 PROCEDURES FOR RECORDING ADVERSE EVENTS 
8.3.1 RECORDING ADVERSE EVENTS ON THE CASE REPORT FORM 
Principal Investigators should use correct medical terminology/concepts when recording AEs on 
the AE eCRF. Colloquialisms and abbreviations should be avoided. 
 
All AEs should be recorded on the AE eCRF page. If the AE qualifies as an SAE or non-serious 
AESI, the PI should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on a paper Clinical Trial SAE/AESI Reporting Form.  The completed 
paper Clinical Trial SAE/AESI Reporting Form and safety fax coversheet should be emailed to 
Roche Safety Risk Management via the Covance project manager within 24 hours of learning of 
the event (see Section 8.4.2).  The AE and SAE eCRF should also be completed within this 
timeframe.  It is important that the information on the SAE Reporting Form and AE and SAE 
eCRF is consistent and identical. 
 
Only one AE term should be recorded in the event field on the AE eCRF. 


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8.3.1.1 DIAGNOSIS VERSUS SIGNS AND SYMPTOMS 
If known, a diagnosis should be recorded on the AE 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 AE eCRF.  If a diagnosis is subsequently established, all previously 
reported AEs based on signs and symptoms should be nullified and replaced by one AE report 
based on the single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis. 
8.3.1.2 ADVERSE EVENTS THAT ARE SECONDARY TO OTHER EVENTS 
In general, AEs 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 AE that is separated in time from the initiating event 
should be recorded as an independent event on the AE 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 subsequent 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 AEs should be recorded separately on the AE eCRF if it is unclear as to whether the events 
are associated. 
8.3.1.3 PERSISTENT OR RECURRENT ADVERSE EVENTS 
A persistent AE is one that extends continuously, without resolution between subject evaluation 
timepoints.  Such events should only be recorded once in the AE eCRF.  The initial severity 
(intensity or grade) of the event will be recorded at the time the event is first reported.  If a 
persistent AE becomes more severe, the most extreme severity should also be recorded on the 
AE 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 8.4.2 for 


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reporting instructions).  The AE 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 SAEs. 
 
A recurrent AE is one that resolves between subject evaluation timepoints and subsequently 
recurs.  Each recurrence of an AE should be recorded as a separate event on the AE eCRF. 
8.3.1.4 ABNORMAL LABORATORY VALUES 
Not every laboratory abnormality qualifies as an AE.  A laboratory test result should be reported 
as an AE if it meets any of the following criteria: 
• Is accompanied by clinical symptoms; 
• Results in a change in study treatment (e.g., dosage modification, treatment interruption, 
or treatment discontinuation); 
• Results in a medical intervention (e.g., potassium supplementation for hypokalemia) or a 
change in concomitant therapy; 
• Is clinically significant in the PIs judgment. 
 
It is the responsibility of the PI to review all laboratory findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated laboratory abnormality should be 
classified as an AE. 
 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., alkaline 
phosphatase and bilirubin five times the upper limit of normal (ULN) associated with 
cholestasis), only the diagnosis (i.e., cholestasis) should be recorded on the AE eCRF. 
 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded on the AE 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 AE.  For 
example, an elevated serum potassium level of 7.0 mEq/L should be recorded as “hyperkalemia.” 
 
Observations of the same clinically significant laboratory abnormality from visit to visit should 
only be recorded once on the AE eCRF (see Section 8.3.1.3 for details on recording persistent 
AEs). 


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8.3.1.5 ABNORMAL VITAL SIGN VALUES 
Not every vital sign abnormality qualifies as an AE.  A vital sign result should be reported as an 
AE 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 judgment of the PI. 
 
It is the responsibility of the PI 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 AE. 
 
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 AE eCRF. 
 
Observations of the same clinically significant vital sign abnormality from visit to visit should 
only be recorded once on the AE eCRF (see Section 8.3.1.3 for details on recording persistent 
AEs). 
8.3.1.6 ABNORMAL LIVER FUNCTION TESTS 
The finding of an elevated ALT or AST (>3 × ULN) in combination with either an elevated total 
bilirubin (>2 × ULN) or clinical jaundice in the absence of cholestasis or other causes of 
hyperbilirubinemia is considered to be an indicator of severe liver injury (as defined by Hy’s 
Law).  Therefore, PIs must report as an AE the occurrence of either of the following: 
• Treatment-emergent ALT or AST >3 × ULN in combination with total bilirubin >2 × 
ULN; 
• Treatment-emergent ALT or AST >3 × ULN in combination with clinical jaundice. 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal laboratory 
values should be recorded on the AE eCRF (see Section 8.3.1) and reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event), either as an SAE or an 
AESI (see Section 8.4.2). 


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8.3.1.7 DEATHS 
All deaths that occur during the protocol-specified AE reporting period (see Section 8.2.1), 
regardless of relationship to study drug, will be recorded on the AE eCRF as well as on the paper 
Clinical Trial SAE Reporting Form and immediately reported to the Sponsor via the Covance 
project manager (see Section 8.4.2 for reporting instructions). 
 
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 AE 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 AE 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”). 
 
Deaths that occur after the AE reporting period should be reported as described in Section 8.5. 
8.3.1.8 PRE-EXISTING MEDICAL CONDITIONS 
A pre-existing 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 
page. 
 
A pre-existing medical condition should be recorded as an AE only if the frequency, severity, or 
character of the condition worsens during the study.  When recording such events on an AE 
eCRF, it is important to convey the concept that the pre-existing condition has changed by 
including applicable descriptors (e.g., “accelerated worsening of headaches”). 
8.3.1.9 HOSPITALIZATION OR PROLONGED HOSPITALIZATION 
Any AE that results in hospitalization (i.e., inpatient admission to a hospital) or prolonged 
hospitalization should be documented and reported as an SAE (per the definition of SAE in 
Section 8.1.2) except as outlined below.  
 
An event that leads to hospitalization under the following circumstances should not be reported 
as an AE or SAE: 
• Hospitalization for respite care; 


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• Hospitalization for a pre-existing condition, provided that all of the following criteria are 
met: 
o 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; 
o The subject has not experienced an AE. 
 
An event that leads to hospitalization under the following circumstances is not considered to be 
an SAE but should be reported as an AE instead: 
• Hospitalization that was necessary because of the subject’s requirement for outpatient 
care outside of normal outpatient clinic operation hours. 
8.4 IMMEDIATE REPORTING REQUIREMENTS FROM PRINCIPAL 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate measures to 
address potential new risks in a clinical trial.  The PI must report such events to the Sponsor 
immediately via the Covance project manager; under no circumstances should reporting take 
place more than 24 hours after the PI learns of the event.  The following is a list of events that 
the PI must report to the Sponsor within 24 hours (see Section 8.4.2) after learning of the event, 
regardless of relationship to study drug: 
• SAEs (see Section 8.4.2 for further details); 
• AESIs (see Section 8.1.3 for further details); 
• Pregnancies (see Section 8.4.2.3 for further details); 
• Accidental overdoses or medication errors (see Section 8.4.3 for details on reporting 
requirements); 
 
The PI must report new significant follow-up information for these events to the Sponsor 
immediately via the Covance project manager (i.e., no more than 24 hours after becoming aware 
of the information).  New significant information includes the following: 
• New signs or symptoms or a change in the diagnosis; 
• Significant new diagnostic test results; 
• Change in causality based on new information; 
• Change in the event’s outcome, including recovery; 
• Additional narrative information on the clinical course of the event. 
 
Principal Investigators must also comply with local requirements for reporting SAEs to the local 
health authority and IRB/EC. 


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8.4.1 REPORTING REQUIREMENTS FOR FATAL OR LIFE-THREATENING 
SERIOUS ADVERSE EVENTS 
Any life-threatening (e.g., imminent risk of death) or fatal AE that is attributed by the PI to study 
drug will be telephoned to the Medical Monitor immediately, followed by completion of the 
paper Clinical Trial SAE Reporting Form within 24 hours of learning of the event as described in 
Section 8.4.2. 
 
Medical Monitor:   
William Cho, M.D., Ph.D. 
 
Genentech, Inc. 
 
(650) 225-4087 (Office Telephone No.) 
 
((650) 302-3027 (Mobile Telephone No.) 
8.4.2 REPORTING REQUIREMENTS FOR ALL SERIOUS ADVERSE EVENTS 
8.4.2.1 EVENTS THAT OCCUR PRIOR TO STUDY DRUG INITIATION 
After informed consent has been obtained but prior to initiation of study drug, only SAEs caused 
by protocol-mandated intervention should be reported.  The completed paper Clinical Trial 
SAE/AESI Reporting Form provided to the PI should be completed and submitted to the Sponsor 
via the Covance project manager immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or email 
address provided below. 
 
The Covance project manager to receive the PI-generated SAE reports: 
Name:  Jaclyn Lowe 
Email Address:  Jaclyn.lowe@covance.com 
608-210-5359 (Office Telephone No.)  
214-502-8547 (Mobile Telephone No.) 
 
8.4.2.2 EVENTS THAT OCCUR AFTER STUDY DRUG INITIATION 
After initiation of study drug, SAEs and AESIs will be reported until 28 days after the final dose 
of study drug. Principal Investigators should record all case details that can be gathered 
immediately on a paper Clinical Trial SAE/AESI Reporting Form.  The completed paper Clinical 
Trial SAE/AESI Reporting Form should be completed and submitted to the Sponsor (via the 
Covance project manager) immediately (i.e., no more than 24 hours after learning of the event), 
either by faxing or by scanning and emailing the form using the fax number or email address 
provided in Section 8.4.2.1.  All information will also need to be entered into the AE eCRF. 


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Relevant follow-up information should be submitted to Roche Safety Risk Management via the 
Covance project manager on an updated paper Clinical Trial SAE/AESI Reporting Form as soon 
as it becomes available and/or upon request.  Any updates to the paper Clinical Trial SAE/AESI 
Reporting Form must also be updated in electronic data capture (EDC) on the AE eCRF. 
 
Relevant follow-up information should be submitted to Roche Safety Risk Management via the 
Covance project manager on an updated paper Clinical Trial SAE/AESI Reporting Form as soon 
as it becomes available and/or upon request.  Any updates to the paper Clinical Trial SAE/AESI 
Reporting Form must also be updated in EDC on the AE eCRF. 
8.4.2.3 REPORTING REQUIREMENTS FOR PREGNANCIES 
8.4.2.3.1 
PREGNANCIES IN FEMALE SUBJECTS 
Subjects should be females of non-childbearing potential in order to be eligible to enter this 
study.  However, the subject will be instructed to immediately inform the PI if they become 
pregnant during the study or within 28 days after the final dose of study drug.  A paper Clinical 
Trial Pregnancy Reporting Form should be completed by the PI immediately (i.e., no more than 
24 hours after learning of the pregnancy) and emailed to Roche Safety Risk Management via the 
Covance project manager (see Section 8.4.2 for reporting instructions).  Pregnancy should not be 
recorded on the AE eCRF.  The PI should discontinue study drug and counsel the subject, 
discussing the risks of the pregnancy and the possible effects on the fetus.  Monitoring of the 
subject should continue until conclusion of the pregnancy.  Any SAEs 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 AE eCRF.  In addition, 
the PI will submit a paper Clinical Trial Pregnancy Reporting Form when updated information 
on the course and outcome of the pregnancy becomes available. 
8.4.2.3.2 
CONGENITAL ANOMALIES/BIRTH DEFECTS AND ABORTIONS 
Any congenital anomaly/birth defect in a child born to a female subject exposed to the study 
drug should be classified as an SAE, recorded on the AE eCRF, and reported to the Sponsor 
immediately via the Covance project manager (see Section 8.4.2 for reporting instructions) (i.e., 
no more than 24 hours after learning of the event; see Section 8.4.2).  Any abortion should be 
reported in the same fashion (as the Sponsor considers abortions to be medically significant 
events). 


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8.4.3 REPORTING REQUIREMENTS FOR CASES OF ACCIDENTAL OVERDOSE 
OR MEDICATION ERROR 
Accidental overdose and medication error (hereafter collectively referred to as “special 
situations”), are defined as follows: 
• Accidental overdose:  accidental administration of a drug in a quantity that is higher than 
the assigned dose; 
• Medication error:  accidental deviation in the administration of a drug.  
 
In some cases, a medication error may be intercepted prior to administration of the drug. 
 
Special situations are not in themselves AEs, but may result in AEs.  Each AE associated with a 
special situation should be recorded separately on the AE eCRF.  If the associated AE 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 8.4.2).  For GDC-0134, AEs associated with 
special situations should be recorded as described below for each situation: 
• Accidental overdose:  Enter the AE term. Check the “Accidental overdose” and 
“Medication error” boxes. 
• Medication error that does not qualify as an overdose:  Enter the AE term. Check the 
“Medication error” box. 
• Medication error that qualifies as an overdose:  Enter the AE term. Check the “Accidental 
overdose” and “Medication error” boxes. 
 
In addition, all special situations associated with GDC-0134, regardless of whether they result in 
an AE, should be recorded on the AE eCRF and reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event).  Special situations should be recorded as 
described below: 
• Accidental overdose:  Enter the drug name and “accidental overdose” as the event term. 
Check the “Accidental overdose” and “Medication error” boxes. 
• Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong dosing 
schedule, incorrect route of administration, wrong drug, expired drug administered) as the 
event term. Check the “Medication error” box. 
• Medication error that qualifies as an overdose:  Enter the drug name and “accidental 
overdose” as the event term. Check the “Accidental overdose” and “Medication error” 
boxes. Enter a description of the error in the additional case details. 


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• Intercepted medication error:  Enter the drug name and “intercepted medication error” as 
the event term. Check the “Medication error” box. Enter a description of the error in the 
additional case details. 
 
As an example, an accidental overdose that resulted in a headache would require the completion 
of two AE eCRF pages, one to report the accidental overdose and one to report the headache.  
The “Accidental overdose” and “Medication error” boxes would need to be checked on both 
eCRF pages. 
8.4.4 FOLLOW-UP OF SUBJECTS AFTER ADVERSE EVENTS 
8.4.4.1 PRINCIPAL INVESTIGATOR FOLLOW-UP 
The PI should follow each AE until the event has resolved to baseline grade or better, the event 
is assessed as stable by the PI, the subject is lost to follow-up, or the subject withdraws consent.  
Every effort should be made to follow all SAEs considered to be related to study drug or trial-
related procedures until a final outcome can be reported.  During the study period, resolution of 
AEs (with dates) should be documented on the AE eCRF and in the subject’s medical record to 
facilitate source data verification. 
 
All pregnancies reported during the study should be followed until pregnancy outcome. 
8.4.4.2 SPONSOR FOLLOW-UP 
For SAEs, AESI, and pregnancies, the Sponsor or a designee may follow-up by telephone, fax, 
email, and/or a monitoring visit to obtain additional case details and outcome information (e.g., 
from hospital discharge summaries, consultant reports, autopsy reports) in order to perform an 
independent medical assessment of the reported case. 
8.5 ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE EVENT REPORTING 
PERIOD 
At the Study Completion/ET visit or at Clinic Discharge, the PI should instruct each subject to 
report to the PI any subsequent AEs that the subject’s personal physician believes could be 
related to prior study drug treatment or study procedures.  The Sponsor should be notified if the 
PI becomes aware of any SAE that occurs after the end of the AE reporting period (defined as 
28 days after the final dose of study drug) if the event is believed to be related to prior study drug 
treatment.  
 


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These events should be reported through the use of the AE eCRF.  However, if the EDC system 
is not available, the PI should report these events directly to the Sponsor or its designee, by 
faxing or by scanning and emailing the paper Clinical Trial SAE/AESI Reporting Form using the 
below fax number or email address provided to PIs. 
 
Genentech US Drug Safety 
Email Address: 
us_drug.safety@gene.com 
Fax No.: 
 
(650) 225-4682 
8.5.1 EXPEDITED REPORTING TO HEALTH AUTHORITIES, PRINCIPAL 
INVESTIGATORS, AND INSTITUTIONAL REVIEW BOARDS 
The Sponsor will promptly evaluate all SAEs and AESIs against cumulative product experience 
to identify and expeditiously communicate possible new safety findings to PIs, IRBs, and 
applicable health authorities based on applicable legislation. 
 
To determine reporting requirements for single AE cases, the Sponsor will assess the 
expectedness of these events using the following reference document(s): 
 
• GDC-0134 IB 
 
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 PIs assessment of causality and seriousness, 
with allowance for upgrading by the Sponsor as needed. 
 
The IRB will be notified by the investigative site in writing (e.g., email) within the timeframe 
required per local IRB regulations for when a reportable AE is first recognized or reported.  In 
addition, a copy of the written confirmation or summary of the AE, as submitted to the Sponsor, 
will also be submitted to the IRB within that same timeframe from when the AE is first 
recognized or reported.  The IRB Serious and Unexpected AE Submission Form will be 
completed and submitted with the copy of the written confirmation or summary of the AE. 
9 STATISTICAL ANALYSES 
The Safety Population will consist of all subjects who received the study drug and have at least 
one postdose safety assessment.  


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The PK Population will consist of all subjects who received the study drug and have at least 
one evaluable postdose PK sample.  A subject will be excluded from the PK summary statistics 
and statistical analysis (where applicable) if the subject has an AE of vomiting that occurs at or 
before 2 times median tmax. 
 
Baseline is defined as the last result prior to the study drug administration on Day 1.  As 
necessary, baseline will be further defined in the Statistical Analysis Plan (SAP). 
9.1 SAFETY AND TOLERABILITY ANALYSIS 
Safety will be assessed by a review of AEs, physical examinations, vital signs, clinical laboratory 
assessments, ophthalmologic assessments, and ECGs.  Clinical laboratory assessments, vital 
signs (including oral temperature, respiratory rate, and supine blood pressure and pulse), weight 
data, ophthalmologic assessments, and ECGs will be listed by subject number and scheduled 
time. Changes from baseline will be summarized. 
 
Verbatim descriptions of AEs will be coded according to current Medical Dictionary for 
Regulatory Activities version 20.0 (or higher) guidelines. Adverse events will be summarized. 
Adverse events of special interest that could indicate hypersensitivity reactions will be 
summarized separately. Enrollment and discontinuations from the study will be summarized 
overall. Demographics and baseline characteristics such as age, sex, and BMI will be 
summarized overall. 
9.2 PHARMACOKINETIC ANALYSIS 
The following PK parameters will be derived from the plasma concentrations of GDC-0134 
using the model independent approach:  
Cmax 
maximum observed concentration 
tmax 
time to maximum observed concentration 
AUC0-t 
area under the concentration-time curve from Hour 0 to the last 
measurable concentration, calculated using the linear trapezoidal 
rule for increasing concentrations and the logarithmic rule for 
decreasing concentrations 
AUC0-∞ 
area under the concentration-time curve extrapolated to infinity, 
calculated using the formula: 
AUC0-∞ = AUC0-t + 
z
t
λ
C  


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where Ct is the last measurable concentration and λz is the apparent 
terminal elimination rate constant 
λz 
apparent terminal elimination rate constant, where λz is the 
magnitude of the slope of the linear regression of the log 
concentration versus time profile during the terminal phase 
t1/2 
apparent terminal elimination half-life (whenever possible), where 
t1/2 = natural log (ln)2/λz 
CL/F 
apparent systemic clearance, calculated as dose/ AUC0-∞ 
Vz/F 
apparent volume of distribution during the terminal phase, 
calculated as CL/F/λz 
 
The following PK parameters will be derived from urine concentrations of GDC-0134:  
Aeu 
amount excreted in urine over a sampling interval 
Total Aeu 
cumulative amount excreted in urine 
%Feu 
percentage of dose excreted in urine over a sampling interval 
Total %Feu 
cumulative percentage of dose excreted in urine 
CLR 
renal clearance 
 
Pharmacokinetic calculations will be performed, if appropriate, using commercial software such 
as Phoenix WinNonlin (Certara Inc., Version 6.4 or higher). 
 
Other parameters may be added as appropriate. Final PK parameters reported will be detailed in 
the SAP. 
 
Pharmacokinetic analysis will use actual times as recorded on the eCRF. Other data handling 
procedures will be detailed in the SAP. 
9.3 WHOLE GENOME SEQUENCING ANALYSIS 
The WGS data will be analyzed in the context of this study and explored in aggregate with data 
from other studies to increase researcher’s understanding of disease pathobiology and guide the 
development of new therapeutic approaches. 
9.4 INTERIM ANALYSIS 
No interim analyses are planned for this study. 


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9.4.1 OPTIONAL INTERIM ANALYSIS 
Given the hypothesis-generating nature of this study, the Sponsor may choose to conduct interim 
analyses.  The decision to conduct an optional interim analysis and the timing of the analysis will 
be documented in the Sponsor’s trial master file prior to the conduct of the interim analysis.  The 
interim analysis will be performed and interpreted by Sponsor study team personnel. 
9.5 STATISTICAL ANALYSIS OF PHARMACOKINETIC DATA 
Descriptive statistics (mean, median, minimum, maximum, standard deviation, geometric mean, 
and geometric coefficient of variation) will be calculated for all PK parameters and PK 
concentration data. 
 
The primary parameters for analysis will be AUC0-∞ and Cmax of GDC-0134. A linear mixed 
model will be applied to analyze the log-transformed primary PK parameters. The model 
assumes fixed effects for formulation, period, and sequence, and a random effect for subject 
within sequence. Estimates of geometric mean ratios on the original scale, together with the 
corresponding 90% CIs, will be derived for the comparisons between Test and Reference 
treatments. 
 
Time to maximum observed concentration will be analyzed by using Wilcoxon signed-rank test, 
and Hodges-Lehmann estimate to generate the difference in medians between treatments (Test- 
Reference) and 90% CI of the median difference. 
 
All calculations will be performed using SAS® version 9.4 or greater. 
 
Specification of PK parameters for analysis; statistical level of significance to be used; criteria 
for study termination; procedures for accounting for missing, unused, or spurious data; 
procedures for reporting deviations from the original statistical plan; and selection of subjects to 
be included in the analyses population(s) will be presented in the Clinical Study Report and/or 
SAP as appropriate. 
 
Statistical analyses details will be included in the SAP. 
 
9.6 STATISTICAL ANALYSES OF SAFETY DATA 
Descriptive statistics will be used for the safety parameters.  No formal statistical analyses are 
planned. 


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9.7 SAMPLE SIZE 
The sample size chosen for this study was based upon precedent set by other PK studies of 
similar nature and was not based on power calculations. 
9.8 QUALITY CONTROL AND QUALITY ASSURANCE 
Quality control and quality assurance will be performed according to Covance Standard 
Operating Procedures or per client request and as applicable according to the contract between 
Covance and the Sponsor. 
10 ADMINISTRATIVE ASPECTS 
10.1 
CHANGE IN PROTOCOL 
There will be no alterations in the protocol without agreement between the Sponsor and the PI. 
 
There will be no alterations in the protocol affecting subject safety without the express written 
approval of the Sponsor, PI, and the IRB (see Form FDA 1572). 
10.2 
PRINCIPAL INVESTIGATOR MEETING; SITE INITIATION 
Prior to the start of the clinical study, the representative(s) of the Sponsor will meet with the 
PI(s) and appropriate clinical staff to familiarize the PI and clinical staff with the materials 
necessary for conducting the clinical study. 
10.3 
DISCLOSURE 
All information provided regarding the study, as well as all information collected and 
documented during the course of the study, will be regarded as confidential.  The PI agrees not to 
disclose such information in any way without prior written permission from the Sponsor. 
 
Any publication of the results, either in part or in total (e.g., articles in journals or newspapers, 
oral presentations, abstracts) by the PI(s) or their representative(s), shall require prior notification 
and review, within a reasonable timeframe, by the Sponsor, and cannot be made in violation of 
the Sponsor’s confidentiality restrictions or to the detriment of the Sponsor’s intellectual 
property rights. 


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10.4 
MONITORING (CLINICAL RESEARCH ASSOCIATE) 
The Sponsor will designate a Sponsor’s Study Monitor who will be responsible for monitoring 
this clinical trial.  The Sponsor’s Study Monitor will monitor the study conduct, proper eCRF 
and source documentation completion and retention, and accurate study drug accountability. To 
this end, the Sponsor’s Study Monitor will visit the study site at suitable intervals and be in 
frequent contact through verbal and written communication.  It is essential that the Sponsor’s 
Study Monitor have access to all documents, including study data, subject medical records, and 
eCRFs, at any time these are requested.  In turn, the Sponsor’s Study Monitor will adhere to all 
requirements for subject confidentiality as outlined in the ICF.  The PI and PIs staff will be 
expected to cooperate with the Sponsor’s Study Monitor, to be available during a portion of the 
monitoring visit to answer questions, and to provide any missing information. 
10.5 
INSTITUTIONAL REVIEW BOARD 
In accordance with 21CFR 56, the protocol, advertisement, and ICF will be reviewed and 
approved by the IRB. The Sponsor will supply relevant material for the PI to submit to the IRB 
for the protocol’s review and approval. Verification of the IRB unconditional approval of the 
protocol and the written ICF statement will be transmitted to the PI. 
 
The IRB will be informed by the PI of subsequent protocol amendments and of serious and 
unexpected AEs.  Approval for protocol amendments will be transmitted in writing to the PI.  If 
requested, the PI will permit audits by the IRB and regulatory inspections by providing direct 
access to source data and documents. 
 
The PI will provide the IRB with progress reports at appropriate intervals (not to exceed 1 year) 
and a Study Progress Report following the completion, termination, or discontinuation of the PIs 
participation in the study. 
10.6 
INFORMED CONSENT 
Written informed consent for the study will be obtained from all subjects before 
protocol-specific procedures are carried out.  The ICF will be approved (along with the protocol) 
by the IRB and will be acceptable to the Sponsor. 
 
The PI or designee will explain the nature of the study and the action of the test product.  The 
subjects will be informed that participation is voluntary and that they can withdraw from the 
study at any time.  In accordance with 21 CFR 50, the informed consent process shall be 


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documented by the use of a written ICF approved by the IRB and signed by the subject prior to 
protocol-specific procedures being performed. 
 
The subject will sign two copies of the ICF.  One copy will be given to the subject, and the other 
will be maintained with the subject’s records. 
10.7 
RECORDS 
The results from Screening and data collected during the study will be recorded in the subject’s 
eCRF. To maintain confidentiality, the subjects will be identified only by numbers. 
 
The completed eCRFs will be transferred to the Sponsor or designee. Copies of each eCRF will 
be retained by the PI. All source documents, records, and reports will be retained by the study 
site in accordance with 21 CFR 312.62(c). 
 
All primary data, or copies thereof (e.g., laboratory records, case report forms [CRFs], data 
sheets, correspondence, photographs, and computer records), which are a result of the original 
observations and activities of the study and are necessary for the reconstruction and evaluation of 
any study report, will be retained in the study site archives. 
10.7.1 ELECTRONIC CASE REPORT FORMS 
Electronic CRFs are to be completed using the Medidata RAVE EDC system. The site will 
receive training and have access to a manual for appropriate eCRF completion. Electronic CRFs 
will be submitted electronically to Covance and should be handled in accordance with 
instructions from Genentech/Covance.  All eCRFs should be completed by designated, trained 
examining personnel as appropriate. 
 
The results from Screening and data collected during the study will be recorded in the subject’s 
eCRF. To maintain confidentiality, the subjects will be identified only by numbers. The PI will 
ensure the accuracy, completeness, legibility, and timeliness of the data reported in the eCRF by 
providing an electronic signature. The completed eCRFs will be transferred to the Sponsor or 
designee. 
 
In addition, at the end of the study, the PI will receive subject data for the site in a readable 
format (e.g., a compact disc) that must be kept with the study records. 


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10.7.2 SOURCE DATA DOCUMENTATION 
Study Monitors will perform ongoing source data verification and review 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 subject 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, subject diaries or 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, subject files, and records kept at the pharmacy, 
laboratories, and medico-technical departments involved in a clinical trial.  Source documents 
that are required to verify the validity and completeness of data entered into the eCRFs must 
never be obliterated or destroyed.  To facilitate source data verification and review, the PI and 
institution(s) must provide the Sponsor direct access to applicable source documents and reports 
for trial-related monitoring, Sponsor audits, and IRB review.  The study site must also allow 
inspection by applicable health authorities. 
10.7.3 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 FDA requirements pertaining to 
computerized systems used in clinical research.  An acceptable computerized data collection 
system (for clinical research purposes) would be one that (1) allows data entry only by 
authorized individuals; (2) prevents the deletion or alteration of previously entered data and 
provides an audit trail for such data changes (e.g., modification of file); (3) protects the database 
from tampering; and (4) ensures data preservation. 
 
In collaboration with the Study Monitor, Genentech’s or Covance’s Quality Assurance group 
may assist in assessing whether electronic records generated from computerized medical record 
systems used at study sites can serve as source documents for the purposes of this protocol.  If a 
site’s computerized medical record system is not adequately validated for the purposes of clinical 
research (as opposed to general clinical practice), applicable hardcopy source documents must be 
maintained to ensure that critical protocol data entered into the eCRFs can be verified. 


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10.7.4 STUDY MEDICATION ACCOUNTABILITY 
The recipient of study medication will acknowledge receipt by returning the appropriate 
documentation form indicating shipment content and condition.  Damaged supplies will be 
replaced.  Accurate records of all study drug received at, dispensed from, returned to, and 
disposed of by the study site should be recorded by using the Drug Inventory Log. 
 
Study drug will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to Genentech with the appropriate documentation, as 
determined by the Sponsor.  If the study site is able to destroy study drug, the method of 
destruction must be documented. Genentech must evaluate and approve the study site’s drug 
destruction standard operating procedure prior to the initiation of drug destruction by the study 
site. 
10.7.5 DISCLOSURE OF DATA 
Subject medical information obtained by this study is confidential and may only be disclosed to 
third parties as permitted by the ICF (or separate authorization to use and disclose personal 
health information) signed by the subject or unless permitted or required by law.  Medical 
information may be given to a subject’s personal physician or other appropriate medical 
personnel responsible for the subject’s welfare for treatment purposes. 
 
Given the complexity and exploratory nature of the analyses, data derived from exploratory 
biomarker specimens will generally not be provided to study PIs or subjects unless required by 
law.  The aggregate results of any conducted research will be available in accordance with the 
effective Sponsor policy on study data publication. 
 
Data generated by this study must be available for inspection upon request by representatives of 
the U.S. FDA and other regulatory agencies, national and local health authorities, Genentech 
monitors/representatives and collaborators, and the IRB for the study site, if appropriate. 
 
Study data, may be submitted to government or other health research databases or shared with 
researchers, government agencies, companies, or other groups that are not participating in this 
study.  These data may be combined with or linked to other data and used for research purposes, 
to advance science and public health, or for analysis, development, and commercialization of 
products to treat and diagnose disease.  In addition, redacted clinical study reports and other 
summary reports will be provided upon request. 


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10.7.6 RETENTION OF RECORDS 
U.S. FDA regulations (21 CFR §312.62[c]) and the ICH Guideline for GCP require that records 
and documents pertaining to the conduct of this study and the distribution of investigational 
drug, including eCRFs, ICFs, laboratory test results, and medication inventory records, must be 
retained by the PI for 2 years after the last marketing application approval in an ICH region or 
after at least 2 years have elapsed since formal discontinuation of clinical development of the 
study drug.  All state and local laws for retention of records also apply.  No records should 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.  For studies conducted outside the United States under a U.S. IND, the PI must comply 
with the record retention requirements set forth in the U.S. FDA IND regulations and the 
relevant national and local health authorities, whichever is longer. 
 
All primary data, or copies thereof (e.g., laboratory records, eCRFs, data sheets, correspondence, 
photographs, and computer records), which are a result of the original observations and activities 
of the study and are necessary for the reconstruction and evaluation of any study report will be 
retained in the study site archives. 
10.8 
REFERENCE TO DECLARATION OF HELSINKI/BASIC PRINCIPLES 
The study procedures outlined in this protocol will be conducted in accordance with the U.S. 
CFR governing Protection of Human Subjects (21 CFR 50), Financial Disclosure by Clinical PIs 
(21 CFR 54), IRBs (21 CFR 56), IND Application (21 CFR 312), and Applications for FDA 
Approval to Market a New Drug (21 CFR 314), as appropriate.  As such, these sections of U.S. 
Title 21 CFR, along with the applicable ICH Guidelines, are commonly known as GCP, which 
are consistent with the Declaration of Helsinki. 






Clinical Protocol 
Covance Study 8398091 
SPONSOR AGREEMENT 
CONFIDENTIAL 
Protocol GP40957 
I have read the foregoing protocol and agree to the conduct of the study as described herein. 
Sravanthi Cheeti, B.Pharm., M.S. 
Clinical Pharmacologist 
Genentech, Inc. 
Final: 19 December 2018 
CPET Protocol Template, Version 11.0: 30 April2018 
Date 
Page 77 of80 


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REFERENCES  
1. Kiernan MC, Vucic S, Cheah BC, et al. Amyotrophic lateral sclerosis. Lancet 
2011;377:942-55. 
2. Bucchia M, Ramirez A, Parente V, et al. Therapeutic development in amyotrophic lateral 
sclerosis. Clin Ther 2015;37:668-80. 
3. Rilutek® Package Insert. Sanofi-Aventis Canada, Inc., 2016. Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020599s017lbl.pdf 
4. Ghosh AS, Wang B, Pozniak CD, et al. DLK induces developmental neuronal 
degeneration via selective regulation of proapoptotic JNK activity. J Cell Biol 
2011;194:751-64. 
5. Pozniak CD, Sengupta AS, Gogineni A,et al. Dual leucine zipper kinase is required for 
excitotoxicity-induced neuronal degeneration. J Exp Med 2013;210:2553-67. 
6. Watkins TA, Wang B, Huntwork-Rodriguez S, et al. DLK initiates a transcriptional 
program that couples apoptotic and regenerative responses to axonal injury. Proc Natl 
Acad Sci USA 2013;110:4039-44. 
7. Hirai S, Cui DF, Miyata T, et al. The c-Jun N-terminal kinase activator dual leucine 
zipper kinase regulates axon growth and neuronal migration in the developing cerebral 
cortex. J Neurosci 2006;26:1 1992-2002 
8. Itoh A, Horiuchi M, Wakayama K, et al. ZPK/DLK, a mitogen-activated protein kinase 
kinase kinase, is a critical mediator of programmed cell death of motoneurons. J Neurosci 
2011;31:7223-28. 
9. Le Pichon CE, Meilandt WJ, Domingues S, et al. Loss of dual leucine zipper kinase 
signaling is protective in animal models of neurodegenerative disease. Sci Transl Med 
2017;9:403. 
10. GDC-0134 Investigator Brochure (IB), December 2018. 


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APPENDIX A – CLINICAL LABORATORY EVALUATIONS 
Clinical Chemistry Panel 
(Fasted at least 8 hours): 
Complete Blood Count: 
Urinalysis: 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Blood urea nitrogen 
Calcium 
Chloride 
Cholesterol 
Creatinine 
Creatine kinase (CK)/Creatine 
phosphokinase (CPK) 
Direct bilirubin 
Glucose 
Potassium 
Sodium 
Total bilirubin 
Total protein 
Triglycerides 
Uric acid 
 
Hematocrit 
Hemoglobin 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration 
Mean corpuscular volume 
Platelet count 
Red blood cell (RBC) count 
RBC distribution width 
White blood cell (WBC) count 
WBC differential (absolute): 
Basophils 
Eosinophils 
Lymphocytes 
Monocytes 
Neutrophils 
Bilirubin 
Color and appearance 
Glucose 
Ketones 
Leukocyte esterase 
Nitrite 
Occult blood 
pH and specific gravity 
Protein 
Urobilinogen 
Microscopic exam including 
bacteria, casts, crystals, 
epithelial cells, RBCs, and 
WBCs (if protein, leukocyte 
esterase, nitrite, or blood is 
positive) a 
Drug Screen: 
Other Tests: 
Coagulation Profile 
Including but not limited to the following: 
Alcohol (ethanol) c 
Amphetamines 
Barbiturates 
Benzodiazepines 
Cannabinoids (THC) 
Cocaine (metabolite) 
Methadone 
Opiates 
Phencyclidine 
Cotinine 
Hepatitis B virus core antibody b 
Hepatitis B surface antigen b 
Hepatitis C virus antibody b 
Human Immunodeficiency Virus 
antibody b 
Pregnancy test (serum qualitative) 
Follicle-stimulating hormone (FSH) b 
QuantiFERON® TB Gold 
Tuberculosis test b 
Prothrombin time (PT) 
Activated partial 
thromboplastin time 
(aPTT)/Partial 
thromboplastin time 
(PTT) 
International normalized 
ratio (INR) 
Fibrinogen 
 
a A microscopic examination will be performed at Screening. During other scheduled urinalysis assessments, a 
microscopic examination will only be performed if protein, leukocyte esterase, nitrite, or blood is positive. 
b Measured at the Screening visit only. 
c Alcohol breath or urine testing will be performed at Check-in (Day -1) for both periods only. 
 


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APPENDIX B – APPROXIMATE MAXIMUM BLOOD VOLUME COLLECTED 
Number of samples collected in each part of the study 
 
Sample Volume 
(mL) 
Number of 
Samples 
Total Volume 
(mL) 
Serology 
7 
1 
7 
Clinical Laboratory Evaluations (including serum 
pregnancy and serum FSH) 
12.5 
5 
62.5 
Coagulation 
3 
3 
9 
Tuberculosis (Quantiferon® TB Gold) 
4 
1 
4 
PK Samples 
4 
31 
124 
WGS Sample 
6 
1 
6 
Total per part 
212.5 
FSH = follicle-stimulating hormone; PK = pharmacokinetic; TB = tuberculosis; WGS = whole genome sequencing. 
 
Note:  Additional samples may be drawn for safety purposes. 
 
If subjects participate in both parts of the study, the total blood volume will be approximately 
double that indicated in the table (~425 mL). 

SAP_001.pdf: 
Final V1: 01 March 2019 
 
Page 1 of 20 
 
STATISTICAL ANALYSIS PLAN 
A Phase I Study to Determine the Relative Bioavailability of Various Formulations of 
GDC-0134 in Healthy Female Subjects of Non-Childbearing Potential 
Statistical Analysis Plan Status: Final V1 
Statistical Analysis Plan Date: 01 March 2019 
Study Drug: GDC-0134 
Sponsor Reference Number: GP40957 
Covance Study Number: 8398091 
Clinical Phase 1 
 
 
Sponsor: 
 
Genentech, Inc. 
1 DNA Way 
South San Francisco,  
California, USA 94080-4990 
 
Study Site: 
Covance Clinical Research Unit 
1900 Mason Ave, Suite 140 
Daytona Beach, Florida USA 32117 
 
Covance Clinical Research Unit 
1341 West Mockingbird Lane, Suite 
200E 
Dallas, Texas USA 75247 
 
 
Sponsor Signatory: 
Chen Chen 
Statistician 
Principal Investigator: 
Hugh Coleman, D.O. 
Covance Clinical Research Unit 
Daytona Beach, Florida 
 
T. Alexander King, M.D. 
Covance Clinical Research Unit 
Dallas, Texas 
 
 
 
 


Statistical Analysis Plan 
CONFIDENTIAL
Covance Study: 8398091 
 
Sponsor Reference: GP40957 
 
Final V1: 01 March 2019 
 
Page 2 of 20 
 
1 STATISTICAL ANALYSIS PLAN APPROVAL SIGNATURES 
By signing this page when the Statistical Analysis Plan (SAP) is considered final, the signatories 
agree to the statistical and pharmacokinetic (PK) analyses to be performed for this study, and to 
the basic format of the tables, figures, and listings (TFLs). Once the SAP has been signed, 
programming of the TFLs based upon this document can proceed. Any modifications to the SAP 
and TFLs made after signing may result in a work-scope change. 
 
Covance approval: 
 
 


Statistical Analysis Plan 
CONFIDENTIAL
Covance Study: 8398091 
 
Sponsor Reference: GP40957 
 
Final V1: 01 March 2019 
 
Page 3 of 20 
 
2 TABLE OF CONTENTS 
1
STATISTICAL ANALYSIS PLAN APPROVAL SIGNATURES ................................... 2
2
TABLE OF CONTENTS ................................................................................................... 3
3
ABBREVIATIONS ............................................................................................................ 4
4
INTRODUCTION .............................................................................................................. 6
5
STUDY OBJECTIVES ...................................................................................................... 6
6
STUDY ENDPOINTS ........................................................................................................ 7
6.1
Pharmacokinetic Endpoints ......................................................................................... 7
6.2
Safety Endpoints .......................................................................................................... 7
7
STUDY DESIGN ............................................................................................................... 8
8
TREATMENTS .................................................................................................................. 9
9
SAMPLE SIZE JUSTIFICATION ................................................................................... 10
10
DEFINITION OF ANALYSIS POPULATIONS ............................................................ 10
11
STATISTICAL METHODOLOGY ................................................................................. 11
11.1 General ....................................................................................................................... 11
11.1.1
Definition of Baseline and Change from Baseline ........................................... 11
11.1.2
Repeat and Unscheduled Readings .................................................................. 11
11.2 Demographics and Subject Disposition ..................................................................... 12
11.3 Prior and Concomitant Medications .......................................................................... 12
11.4 Pharmacokinetic Assessment ..................................................................................... 12
11.4.1
Pharmacokinetic Analysis ................................................................................ 12
11.4.5
Pharmacokinetic Statistical Methodology ........................................................ 16
11.5 Safety and Tolerability Assessments ......................................................................... 17
11.5.1
Adverse Events ................................................................................................. 17
11.5.2
Clinical Laboratory Parameters ........................................................................ 18
11.5.3
Vital Signs ........................................................................................................ 18
11.5.4
Electrocardiogram ............................................................................................ 19
11.5.5
Ophthalmological Assessments ........................................................................ 19
11.5.6
Other Assessments ........................................................................................... 19
11.5.7
Safety and Tolerability Statistical Methodology .............................................. 19
12
INTERIM ANALYSES .................................................................................................... 19
13
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ....... 19
14
DATA PRESENTATION ................................................................................................ 19
14.1 Insufficient Data for Presentation .............................................................................. 19
15
REFERENCES ................................................................................................................. 20
 


Statistical Analysis Plan 
CONFIDENTIAL
Covance Study: 8398091 
 
Sponsor Reference: GP40957 
 
Final V1: 01 March 2019 
 
Page 4 of 20 
 
3 ABBREVIATIONS 
Abbreviations pertain to the SAP only (not the TFLs). 
ADaM 
Analysis Data Model 
Aeu 
amount excreted in urine over a sampling interval 
AE 
adverse event 
AESI 
Adverse events of special interest 
AUC0-  
area under the concentration-time curve extrapolated to infinity 
AUC0-48 
area under the concentration-time curve from Hour 0 to 48 hours 
postdose 
AUC0-t 
area under the concentration-time curve calculated from Hour 0 to 
the last measurable concentration 
BLQ 
below the limit of quantification 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
confidence interval 
CL/F 
apparent systemic clearance 
CLR 
renal clearance 
Cmax 
maximum observed concentration 
CSR 
Clinical Study Report 
CV 
coefficient of variation 
ECG 
electrocardiogram 
%Feu 
percentage of dose excreted in urine over a sampling interval 
ICH 
International Conference on Harmonisation 
z 
apparent terminal elimination rate constant 
NC 
not calculated 
NR 
no result 
PK 
pharmacokinetic 
QTc 
QT correction; QT interval corrected for heart rate 
QTcB 
QTc calculated using the Bazett correction 
QTcF 
QTc calculated using the Fridericia correction  
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
t1/2 
apparent terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
TFLs 
tables, figures, and listings 


Statistical Analysis Plan 
CONFIDENTIAL
Covance Study: 8398091 
 
Sponsor Reference: GP40957 
 
Final V1: 01 March 2019 
 
Page 5 of 20 
 
tmax 
time to maximum observed concentration 
Vz/F 
apparent volume of distribution during the terminal elimination 
phase 
WHO  
World Health Organization 
 


Statistical Analysis Plan 
CONFIDENTIAL
Covance Study: 8398091 
 
Sponsor Reference: GP40957 
 
Final V1: 01 March 2019 
 
Page 6 of 20 
 
4 INTRODUCTION 
This SAP has been developed after review of the clinical study protocol (Final Version 1.0 dated 
19 December 2018).  
This SAP describes the planned analysis of the safety, tolerability, and PK data from this study. 
A detailed description of the planned TFLs to be presented in the Clinical Study Report (CSR) is 
provided in the accompanying TFL shell document. 
The intent of this document is to provide guidance for the statistical analyses of PK data. In 
general, the analyses are based on information from the protocol, unless they have been modified 
by agreement between Error! Reference source not found., Inc. and Covance Clinical 
Development Services. A limited amount of information concerning this study (e.g., objectives, 
zed prior to the 
lock of the clinical database for this study. When the SAP and TFL shells are agreed upon and 
 
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon 
between Genentech, Inc. and Covance Clinical Development Services and identified in the CSR. 
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 guideline entitled, Guidance for Industry: Statistical 
Principles for Clinical Trials  and the ICH E3 guideline entitled, Guidance for Industry: 
Structure and Content of Clinical Study Reports. 1,2 
5 STUDY OBJECTIVES 
The primary objectives of this study are: 
 To determine the relative bioavailability of GDC-0134 F16 capsules (newly developed 
capsule formulation with GDC-0134 malate drug substance) with respect to the current 
clinical material, GDC-0134 F09 capsules, with a standard meal. 
 To determine the relative bioavailability of GDC-0134 F15 capsules (newly developed 
capsule formulation with GDC-0134 freebase) with respect to the current clinical 
material, GDC-0134 F09 capsules, under fasted conditions. 
The secondary objectives of this study are: 
 To determine the safety and tolerability of a single oral dose of GDC-0134 in healthy 
subjects. 
 To characterize the PK of GDC-0134 after oral administration in healthy subjects. 


Statistical Analysis Plan 
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Covance Study: 8398091 
 
Sponsor Reference: GP40957 
 
Final V1: 01 March 2019 
 
Page 7 of 20 
 
The exploratory objective of this study is: 
  To determine urinary elimination of GDC-0134. 
6 STUDY ENDPOINTS 
6.1 
Pharmacokinetic Endpoints 
The primary PK endpoints are: 
 Maximum observed concentration (Cmax) 
 Area under the concentration-time curve extrapolated to infinity (AUC0- ) 
The secondary PK endpoints are: 
 
 Time to maximum observed concentration (tmax) 
 Area under the concentration-time curve from Hour 0 to the last measurable concentration 
(AUC0-t) 
 Apparent terminal elimination rate constant ( Z) 
 Apparent terminal elimination half-life (t1/2) 
 Apparent systemic clearance (CL/F) 
 Apparent volume of distribution during the terminal elimination phase (Vz/F) 
The exploratory PK endpoints of this study are: 
 Amount excreted in urine over a sampling interval (Aeu) 
 Cumulative amount excreted in urine (Total Aeu) 
 Percentage of dose excreted in urine over a sampling interval (%Feu) 
 Cumulative percentage of dose excreted in urine (Total %Feu) 
 Renal clearance (CLR) 
6.2 
Safety Endpoints 
The safety endpoints of this study are: 
 Incidence, nature, and severity of adverse events (AEs) 


Statistical Analysis Plan 
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Covance Study: 8398091 
 
Sponsor Reference: GP40957 
 
Final V1: 01 March 2019 
 
Page 8 of 20 
 
 Changes in vital signs, electrocardiograms (ECGs), physical examination findings, 
ophthalmology assessment findings, and clinical laboratory results during and following 
GDC-0134 administration 
7 STUDY DESIGN 
This will be an open-label, randomized, 2-period crossover study consisting of two parts to 
determine: 
 Part 1  the relative bioavailability of GDC-0134 F16 capsules and the current clinical 
material, GDC-0134 F09 capsules; 
 Part 2  the relative bioavailability of GDC-0134 F15 capsules and the current clinical 
material, GDC-0134 F09 capsules. 
Part 1 and Part 2 may occur in parallel or consecutively in either order (Part 1 followed by Part 2, 
or Part 2 followed by Part 1). 
Approximately 22 female subjects of non-childbearing potential (11 per treatment sequence) 
between 18 and 65 years of age, inclusive, will be enrolled into each part of the study across two 
clinical research sites. 
In Part 1, Periods 1 and 2, eligible subjects will receive 800 mg of either GDC-0134 F16 
capsules or the current clinical material, GDC-0134 F09 capsules (Ro 704-0814/F09), orally with 
a standard meal on Day 1 according to the randomization schedule.   
In Part 2, Periods 1 and 2, subjects will receive 800 mg of GDC-0134 F15 or the current clinical 
material, GDC-0134 F09 capsules, after an overnight fast according to the randomization 
schedule on Day 1. Subjects will not receive food for 4 hours postdose. 
An overview of the study design is provided in Error! Reference source not found. and 2: 
Figure 1 Study Schematic of Crossover Design  Part 1
 


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Figure 2 Study Schematic of Crossover Design  Part 2 
 
8 TREATMENTS 
The following is a list of the study treatment abbreviations and ordering that will be used in the 
TFLs for Part 1. 
Study Treatment Name 
Abbreviation 
Treatment Order on TFLs 
GDC-0134 F16 capsule fed (Test) 
F16 fed 
1 
GDC-0134 F09 capsule fed 
(Reference)  
F09 fed 
2 
The following is a list of the study treatment abbreviations and ordering that will be used in the 
TFLs for Part 2. 
Study Treatment Name 
Abbreviation 
Treatment Order on TFLs 
GDC-0134 F15 capsule fasted 
(Test) 
F15 fasted 
1 
GDC-0134 F09 capsule fasted 
(Reference) 
F09 fasted 
2 
 


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The following is a list of the study treatment sequence abbreviations and ordering that will be 
used in the baseline TFLs for Part 1. 
Study Treatment Sequence 
Abbreviation 
Treatment Order on TFLs 
GDC-0134 F09 capsule fed (Reference)/ 
GDC-0134 F16 capsule fed (Test) 
F09 fed/F16 fed  
1 
GDC-0134 F16 capsule fed (Test)/ 
GDC-0134 F09 capsule fed (Reference) 
F16 fed/F09 fed  
2 
The following is a list of the study treatment sequence abbreviations and ordering that will be 
used in the baseline TFLs for Part 2. 
Study Treatment Sequence 
Abbreviation 
Treatment Order on TFLs 
GDC-0134 F09 capsule fasted (Reference)/ 
GDC-0134 F15 capsule fasted (Test)  
F09 fasted/F15 fasted 
1 
GDC-0134 F15 capsule fasted (Test)/ 
GDC-0134 F09 capsule fasted (Reference) 
F15 fasted/F09 fasted 
2 
9 SAMPLE SIZE JUSTIFICATION 
Twenty-two healthy volunteer female subjects of non-childbearing potential who meet all the 
protocol inclusion criteria and none of the exclusion criteria will be enrolled into each part of the 
study. 
If the two parts of the study are run sequentially, subjects will be encouraged to participate in 
both parts. The maximum number of subjects enrolled into the study will be approximately 44. 
The sample size chosen for this study was based upon precedent set by other PK studies of 
similar nature and was not based on power calculations. 
10 DEFINITION OF ANALYSIS POPULATIONS 
The Safety Population will consist of all subjects who received at least 1 dose of study drug.  
The PK Population will consist of all subjects who received at least 1 dose of study drug and 
have at least 1 evaluable postdose PK sample. A subject may be excluded from the PK summary 
statistics and statistical analysis if the subject has an AE of vomiting that occurs at or before 2 
times median tmax.  
All protocol deviations that occur during the study will be considered prior to database lock for 
their severity/impact and will be taken into consideration when subjects are assigned to analysis 
populations. Details of subject assignment to the analysis populations will be listed. 
The All Subjects Population will be consistent with the Safety Population. 


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11 STATISTICAL METHODOLOGY 
11.1 General 
Data listings will be provided for the All Subjects Population. Summary statistics and statistical 
analyses will be performed for subjects included in the relevant analysis populations 
(Safety/PK).  
For continuous data, summary statistics will include the arithmetic mean, arithmetic standard 
deviation (SD), median, minimum, maximum, and number. For log-normal data (e.g., the PK 
parameters: AUCs and Cmax), the geometric mean and geometric coefficient of variation (CV) 
will also be presented. For categorical data, frequency counts and percentages will be presented. 
Data listings will be provided for all subjects up to the point of withdrawal, with any subjects 
excluded from the relevant population highlighted. For the calculation of summary statistics and 
statistical analysis, unrounded data will be used. 
Missing values will not be imputed, with the possible exception of missing PK predose 
concentrations, as detailed in Section 11.4.2. 
Data analysis will be performed using SAS® Version 9.4. 
Analysis Data Model (ADaM) datasets will be prepared using Clinical Data Interchange 
Standards Consortium (CDISC) ADaM Version 2.1, and CDISC ADaM Implementation Guide 
Version 1.1. Pinnacle 21 Community Validator Version 2.2.0 will be utilized to ensure 
compliance with CDISC standards. 
11.1.1 Definition of Baseline and Change from Baseline 
Period specific baseline for each parameter is defined as the last value measured prior to dosing 
in each period, including repeat (vital signs and ECGs) and unscheduled (clinical laboratory 
parameters) readings (see Section 11.1.2 for definitions of repeat and unscheduled readings).   
Mean change from period specific 
baseline values. Each individual change from baseline will be calculated by subtracting the 
change from baseline values will be used to calculate the mean change from baseline using a 
SAS procedure such as Proc Univariate. 
11.1.2 Repeat and Unscheduled Readings 
Repeat readings occur when the original vital signs or ECG result requires confirmation. Repeat 
readings are labelled as 
epeat  in the listings and replace the original readings in all summaries 
and changes from baseline presentations and calculations. Prior to dosing, all readings taken in 
addition to the original reading are defined as predose repeats. Postdose repeat readings are 
defined as readings collected within 15 minutes of the actual time of the original reading. Where 
results are taken in triplicate and repeated, the last 3 readings are used in all subsequent 
calculations  


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With the exception of predose results described above, unscheduled readings for vital signs or 
ECGs are defined as readings collected >15 minutes from the actual time of the original reading. 
Where results are taken in triplicate, the original reading is defined as the first reading of the 
triplicate. All results not taken at a scheduled timepoint for other data types (e.g., clinical 
laboratory paramete
the listings. Because unscheduled readings are not associated with any scheduled timepoint, they 
are excluded from all summaries (with the exception that they may be used as baseline, as stated 
in Section 11.1.1). 
11.2 Demographics and Subject Disposition 
The demographic variables age, sex, race, ethnicity, body weight, height, and body mass index 
will be summarized and listed by study part. Subject disposition will be summarized and listed 
by study part. 
11.3 Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
Drug Dictionary (Version September 2018 Enhanced Dictionary Version B3 format [or higher if 
version is updated during the study]). Prior and concomitant medications will be listed separately 
by study part. 
11.4 Pharmacokinetic Assessment 
11.4.1  Pharmacokinetic Analysis 
The following PK parameters will be determined where possible from the plasma concentrations 
of GDC-0134 using non-compartmental methods performed using Phoenix WinNonlin (Certara 
USA, Inc., Version 6.4 or higher): 


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Parameter 
Definition 
Cmax 
maximum observed concentration 
tmax 
time to maximum observed concentration 
AUC0-48 
area under the concentration-time curve from Hour 0 to 48 hours postdose, 
calculated using the linear trapezoidal rule for increasing concentrations 
and the logarithmic rule for decreasing concentrations 
AUC0-t 
area under the concentration-time curve from Hour 0 to the last measurable 
concentration, calculated using the linear trapezoidal rule for increasing 
concentrations and the logarithmic rule for decreasing concentrations 
AUC0-  
area under the concentration-time curve extrapolated to infinity, calculated 
using the formula: 
AUC0-  = AUC0-t + (Ct
z) 
where Ct is the last measurable concentration and z is the apparent 
terminal elimination rate constant 
z 
apparent terminal elimination rate constant, where z is the magnitude of 
the slope of the linear regression of the log concentration versus time 
profile during the terminal phase 
t1/2 
apparent terminal elimination half-life (whenever possible),  
where t1/2 = natural log (ln)2
z 
CL/F 
apparent systemic clearance, calculated as dose/AUC0-  
Vz/F 
apparent volume of distribution during the terminal phase, calculated as 
z 
The following PK parameters will be determined where possible from the urine concentrations of 
GDC-0134: 
Parameter 
Definition 
Aeu 
amount excreted in urine over a sampling interval 
%Feu 
percentage of dose excreted in urine over a sampling interval 
Total Aeu 
cumulative amount excreted in urine 
Total %Feu 
cumulative percentage of dose excreted in urine 
CLR 
renal clearance 
Additional PK parameters may be determined where appropriate. 
The PK analysis will, where possible, be carried out using actual postdose times recorded in the 
raw data. If actual times are missing, nominal times may be used with sponsor approval.  
Concentrations will be used as supplied by the analytical laboratory for PK analysis. The units of 
concentration and resulting PK parameters, with amount or concentration in the unit, will be 
presented as they are received from the analytical laboratory.  
The Cmax and tmax will be obtained directly from the plasma concentration-time profiles.   


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For multiple peaks, the highest postdose concentration will be reported as Cmax. In the case that 
multiple peaks are of equal magnitude, the earliest tmax will be reported.  
The Aeu for each urine collection interval will be calculated as the product of urine concentration 
and urine weight (assuming a specific gravity of 1 g/mL); Total Aeu will be calculated by 
summing the Aeu values for each collection interval over the 0-12 h, 12-24 h, 24-36 h, and 
36-48 h time periods. 
The %Feu will be calculated for each collection interval (i) and the 0-x h time periods (Total 
%Feu) according to the following formula: 
 
The CLR will be calculated over 0-48 h according to the following formula: 
 
11.4.2 Criteria for Handling Concentrations that are Missing or Below the Limit of 
Quantification in Pharmacokinetic Analysis 
 Plasma concentration values that are below the limit of quantification (BLQ) will be set 
to zero, with defined exceptions as follows; 
 Any embedded BLQ value (between 2 quantifiable concentrations) and BLQ 
values following the last quantifiable concentration in a profile will be set to 
missing for the purposes of PK analysis. 
 If there are late positive concentration values following 2 BLQ concentration 
values in the apparent terminal phase, these values will be evaluated. If these 
values are considered to be anomalous, they will be set to missing. 
 If an entire concentration-time profile is BLQ, the profile will be excluded from 
the PK analysis. 
 If a predose concentration is missing, these values may be set to zero. 
 Urine concentrations that are BLQ will be set to zero. 
11.4.3 Criteria for the Calculation of an Apparent Terminal Half-Life 
11.4.3.1 Number of Data Points 
 At least 3 data points will be included in the regression analysis and preferably should 
not include Cmax. 


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11.4.3.2 Goodness of Fit 
 When assessing terminal elimination phases, the adjusted coefficient for determination 
of exponential fit (R2 adjusted) will be used as a measure of the goodness of fit of the 
data points to the determined line.  
 Regression-based parameters (i.e.
z, t1/2, AUC0- , CL/F, Vz/F) will only be calculated 
if the R2 
 
11.4.3.3 Period of Time Estimation 
 Apparent terminal elimination half-lives will be estimated over a time period of at least    
2 half-lives, where possible.  
 Where t1/2 is estimated over a time period of less than 2 half-lives, it will be flagged in 
the data listings at the discretion of the Pharmacokineticist, and the robustness of the 
value should be discussed in the study report. 
11.4.3.4 Calculation of AUC 
 The minimum requirement for the calculation of AUC will be the inclusion of at least 3 
consecutive plasma concentrations above the lower limit of quantification, with at least 
1 of these concentrations following Cmax. 
 For any partial AUC determination, nominal time will generally be used for the end of 
the interval. Actual times for partial AUC intervals may be used at the discretion of the 
Pharmacokineticist.  
 The AUC0-  values (and related parameters [CL/F, Vz/F]) where the percentage 
extrapolation is less than 30% will be reported and included in summary and inferential 
statistics. Any AUC0-  values (and related parameters) where the percentage 
extrapolation is 30% will be reported but flagged and excluded from summary and 
inferential statistics.   
11.4.3.5 Anomalous Values 
 If a value is considered to be anomalous due to being inconsistent with the expected PK 
profile, it may be appropriate to exclude this point from the PK analysis. However, the 
exclusion of data must have strong justification and will be documented in the raw data 
and study report. 
 Embedded BLQ values may be considered anomalous depending on the route of 
administration and the characteristics of the drug. 
 Positive predose value(s) greater than 5% of Cmax may be excluded from the summary 
statistics of PK tables and statistical analysis at the discretion of the Pharmacokineticist. 


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11.4.4 Presentation of Pharmacokinetic Data 
11.4.4.1 Presentation of Pharmacokinetic Concentration Data 
 The following rules will be applied if there are values that are BLQ or if there are 
missing values (e.g., no result [NR]) in a plasma concentration data series to be 
summarized. 
 For the calculation of summary statistics, BLQ values will be set to zero. 
 If an embedded BLQ value is considered anomalous within the 
concentration-time profile, this value will be excluded from the summary 
statistics. 
 Where there is NR, these will be set to missing. 
 If there are fewer than 3 values in the data series, only the minimum, maximum 
and number will be presented. The other summary statistics will be denoted as not 
calculated (NC). BLQ is considered a value. 
 If all the values are BLQ, then the arithmetic mean, arithmetic SD, median, 
minimum and maximum will be presented as zero, and the geometric mean and 
geometric CV will be denoted as NC. 
 If the value of the arithmetic mean or median is BLQ, it will be presented as zero 
and the geometric mean and geometric CV will be denoted as NC. 
11.4.4.2 Presentation of Pharmacokinetic Parameters 
 For the calculation of summary statistics of PK parameters, all NR and NC values in a 
data series will be set to missing. 
 The AUC values will be set to NC if they have been calculated using fewer than three 
concentrations, and/or three concentrations if the last is Cmax. 
11.4.5 Pharmacokinetic Statistical Methodology 
Descriptive statistics (mean, median, minimum, maximum, SD, geometric mean, 
and geometric CV) will be calculated for all PK parameters and PK 
concentration data. 
Plasma concentrations of GDC-0134, and derived plasma PK parameters, will be listed and 
summarized by study part and treatment using descriptive statistics. Individual and mean 
concentration versus time profiles will be plotted. The primary parameters for analysis will be 
AUC0-  and Cmax of GDC-0134. A linear mixed model will be applied to analyze the log-
transformed primary PK parameters. The model assumes fixed effects for formulation, period, 
and sequence, and a random effect for subject within sequence. Estimates of geometric mean 


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ratios on the original scale, together with the corresponding 90% confidence intervals (CIs), will 
be derived for the comparisons between Test and Reference treatments. All calculations will be 
performed using SAS® version 9.4 or greater. 
Example SAS code that will be used: 
Within-subject CV will be calculated for AUC0-  and Cmax based on the log-normal distribution 
using the following formula: 
CVW(%) = [exp(mse)  1]½ x 100 
where mse is the residual error from the mixed model. 
Residual plots will be produced to assess the adequacy of the model. 
The parameter tmax will be analyzed nonparametrically using the Wilcoxon signed-rank test. 
Hodges-Lehmann estimates of the median difference and the corresponding 90% CIs will be 
calculated for comparison between test and reference treatments. 
11.5 Safety and Tolerability Assessments 
11.5.1 Adverse Events 
A baseline sign and symptom is defined as an AE that starts after the subject has provided 
written informed consent and that resolves prior to the first dosing occasion, or an AE that starts 
prior to the first dosing occasion and does not increase in severity after dosing. A 
treatment-emergent AE (TEAE) is defined as an AE that occurs postdose or that is present 
predose and becomes more severe postdose. If the start date of an AE is incomplete or missing, it 
will be assumed to be a TEAE, except if the incomplete start date or the stop date indicates that 
the event started prior to the first dosing. The AE of special interest (AESI) for this study are 
defined as follows: 
 Clinically significant peripapillary or optic disc swelling on funduscopic examination, as 
determined by the local site principal investigator/ophthalmologist 


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 Clinically significant functional visual change from baseline, as determined by the local 
site principal investigator/ophthalmologist 
 Cases of potential drug-induced liver injury that include an elevated alanine 
aminotransferase or aspartate aminotransferase in combination with either an elevated 
bilirubin or clinical jaundice, as defined by Hy s Law 
 Suspected transmission of an infectious agent by the study drug as defined below: 
 Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be suspected 
from clinical symptoms or laboratory findings that indicate an infection in a subject 
exposed to a medicinal product. The term applies only when a contamination of the 
study drug is suspected. 
AEs occurring during administration of the Period 1 Day 1 dose up to the dose administration in 
Period 2 Day 1 will be assigned to Period 1. Any AEs occurring during administration of the 
Period 2 Day 1 dose and postdose from Period 2 Day 1 to Follow-up will be assigned to 
Period 2. 
All AEs will be listed by study part. The TEAEs will be summarized by study part, treatment, 
severity rated based on WHO Toxicity Grading Scale, and relationship to the study drug. The 
frequency (the number of TEAEs, the number of subjects experiencing a TEAE, and the 
percentage of subjects experiencing a TEAE) of TEAEs will be summarized by study part, 
treatment, and by Medical Dictionary for Regulatory Activities system organ class and preferred 
term. The summary and frequency TEAE tables will be presented for all causalities and for those 
TEAEs considered related to the study drug (those that have a relationship of suspected). Any 
severe or serious AEs or any AESIs or deaths will be tabulated by study part. For any AEs that 
change severity ratings the AE will be included only once under the maximum severity rating in 
the summaries.  
11.5.2 Clinical Laboratory Parameters 
All chemistry, hematology, coagulation and urinalysis data outside the clinical reference ranges 
will be listed by study part, parameter and treatment.   
11.5.3 Vital Signs 
Vital signs values outside the clinical reference ranges will be flagged on the individual subject 
data listings. 
The vital signs data will be summarized by study part and treatment, together with changes from 
baseline. Figures of mean vital signs and mean change from baseline profiles will be presented 
by study part and treatment.  


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11.5.4 Electrocardiogram 
The ECG data will be obtained directly from the 12-lead ECG traces. These data include the QT 
interval calculated using the Fridericia correction (QTcF), the PR and QT intervals, the QRS 
duration, and heart rate.  
Where ECGs are measured in triplicate (at approximately 2-minute intervals), the mean value 
will be used in all subsequent calculations.  
Values for ECG parameters outside the clinical reference ranges will be flagged on the individual 
subject data listings. 
11.5.5 Ophthalmological Assessments 
Ophthalmological assessments include fundoscopic examination, visual acuity assessment, and 
visual field examination. The ophthalmological data will be listed by study part. 
11.5.6 Other Assessments 
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed. 
Medical history data will be presented. 
11.5.7 Safety and Tolerability Statistical Methodology 
No inferential statistical analyses are planned. 
12 INTERIM ANALYSES 
Given the hypothesis-generating nature of this study, the sponsor may choose to conduct interim 
analyses. The decision to conduct an optional interim analysis and the timing of the analysis will 
interim analysis will be performed and interpreted by the sponsor study team personnel. 
13 CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES 
There were no changes from the protocol-specified statistical analyses. 
14 DATA PRESENTATION 
14.1 Insufficient Data for Presentation 
Some of the TFLs may not have a sufficient number of subjects or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the center of the table, 
 


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15 REFERENCES 
1. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998. 
2. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.