A Phase IIa, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Crossover Study To Evaluate The Efficacy, Safety, Pharmacokinetics, And Pharmacodynamic Effects Of GDC-6599 In Patients With Chronic Cough
Phase: PHASE2
Conditions: Chronic Refractory Cough (CRC) With Non-atopic Asthma, CRC With Atopic Asthma, Unexplained Chronic Cough, CRC With Chronic Obstructive Pulmonary Disease, CRC With Chronic Obstructive Pulmonary Disease With Chronic Bronchitis
Sponsor: Genentech, Inc.

Official Title: 
A Phase IIa, Multicenter, Randomized, Double-Blind, Placebo-
Controlled, Crossover Study to Evaluate the Efficacy, Safety, 
Pharmacokinetics, and Pharmacodynamic Effects of GDC-6599 in 
Patients with Chronic Cough 
NCT Number: 
NCT05660850 
Document Date: 
Protocol Amendment Version 4: 03-May-2024 

CONFIDENTIAL 
The information contained in this document, especially any unpublished data, is the property of 
Genentech, Inc. (or under its control) and therefore is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Ethics Committee 
or Institutional Review Board.  It is understood that this information will not be disclosed to others 
without written authorization from Genentech except to the extent necessary to obtain informed 
consent from persons to whom the drug may be administered. 
GDC-6599—Genentech, Inc. 
Protocol GA43590, Version 4 
PROTOCOL 
TITLE: 
A PHASE IIa, MULTICENTER, RANDOMIZED, 
DOUBLE-BLIND, PLACEBO-CONTROLLED, 
CROSSOVER STUDY TO EVALUATE THE 
EFFICACY, SAFETY, PHARMACOKINETICS, AND 
PHARMACODYNAMIC EFFECTS OF GDC-6599 IN 
PATIENTS WITH CHRONIC COUGH   
PROTOCOL NUMBER: GA43590 
VERSION NUMBER: 
4 
REGULATORY 
AGENCY IDENTIFIER 
NUMBERS: 
IND Number:  154293 
EU CT Number:  Not applicable 
TEST PRODUCT: 
GDC-6599 (RO7441345) 
SPONSOR NAME AND 
ADDRESS: 
Genentech, Inc. 
1 DNA Way 
South San Francisco, CA  94080 
APPROVAL: 
See electronic signature and date stamp on the final 
page of this document. 

GDC-6599—Genentech, Inc. 
2/Protocol GA43590, Version 4 
PROTOCOL HISTORY 
Protocol 
Associated Country-Specific Protocol 
Version 
Date Final 
Country 
Version 
Date Final 
4 
See electronic date 
stamp on final page. 
3 
13 April 2023 
2 
17 September 2022 
United Kingdom 
1 
22 June 2023 
1 
2 March 2022 

GDC-6599—Genentech, Inc. 
3/Protocol GA43590, Version 4 
PROTOCOL AMENDMENT, VERSION 4: 
RATIONALE 
Protocol GA43590 has been amended to reduce patient burden, add clarity on study 
conduct, and to incorporate changes made to the United Kingdom-specific version of the 
protocol.  Protocol GA43590 Version 4 represents a merging of the global protocol 
(previously Version 3) and region-specific Version 1 (United Kingdom), and includes 
changes specific to this Version 4 amendment.  The changes, along with a rationale for 
each change, are summarized below. 
Changes specific to protocol GA43590 Version 4 are as follows: 
 
Background information on GDC-6955 has been updated with the most recent 
clinical data (Sections 1.2, 1.3 and 5.1) to align with the now completed Phase Ia/b 
study (GA43010).  
 
Sections 2, 4.5, and Appendices 1 and 2 have been updated to remove the mannitol 
challenge test from Study Visits 2 and 5 and to make this test optional for 
Study Visits 4 and 7 to reduce participants’ burden.  In accordance with this change, 
the study objectives (Sections 2 [Table 1], 3.3.1, and 3.3.5) have been modified to 
indicate that the evaluation of treatment effect of GDC-6599 on cough 
hypersensitivity, as measured by mannitol induced cough-dose ratio, and airway 
hyperresponsiveness, as measured by mannitol induced PD15 and response-dose 
ratio, are now exploratory rather than secondary objectives.  In making the mannitol 
challenge test optional, requirements for 
 
 (Sections 3.3.4, 3.3.5, and 4.5.5, and 4.5.10; 
Appendix 1, footnote l, and 
).  Section 4.5.9, Sputum Collection and 
Processing, has been removed, new Section 4.5.14, Optional Mannitol Challenge 
Tests, has been added, and subsequent sections renumbered. 
 
In Sections 3.1.1, 4.1, and 6.1, the total study recruitment has been revised to enroll 
approximately 30 patients with chronic refractory cough (CRC) with asthma with or 
without atopy, approximately 30 patients with unexplained chronic cough (UCC) in 
Cohort A (formerly 20 each), and approximately 20 patients with CRC from chronic 
obstructive pulmonary disease (COPD) with or without chronic bronchitis (CB) in 
Cohort B.  This change is made because of study objective reprioritization.  
 
In Section 3.1.1, the requirement to repeat the mannitol challenge test has been 
removed during re-screening within 6 weeks of initial screening if the patients have 
screen failed for any reason other than the mannitol challenge test.  

GDC-6599—Genentech, Inc. 
4/Protocol GA43590, Version 4 
 
In Section 4.1, eligibility criteria have been amended to better define the patient 
population and to be consistent with the American College of Chest 
Physicians/European Respiratory Society (ERS) guidelines on CRC diagnosis: 
– 
The requirement treatment for asthma, COPD, gastroesophageal reflux disease 
(GERD) and/or UCC has been reduced from 1 year to a minimum of 12 weeks 
while maintaining the requirement of a CRC diagnosis for at least 1 year 
(Section 4.1.1.1).  Section 4.4.1, Permitted Therapy, has been updated to align 
with this change. 
– 
The requirement for male contraception has been removed (see the updated 
GDC-6599 Investigator's Brochure dated May 2024) (Section 4.1.1.1). 
– 
For patients with asthma (Section 4.1.1.2), the duration of both diagnosis and 
stable background therapy have been reduced from 12 months to a minimum 
of 12 weeks.  
 
The language regarding single-patient emergency and non-emergency unblinding 
requested by the investigator has been updated to align with internal procedures 
(Section 4.2.2). 
 
Text has been modified to align with updates to the Roche Global Policy on 
Continued Access to Investigational Medicinal Products (Section 4.3.5). 
 
In Sections 4.4.2 and 4.4.4 treatment with xanthines (e.g., theophylline, oxtriphylline) 
is now prohibited within 24 hours prior to mannitol challenge tests to be consistent 
with the testing manual.  
 
In Section 4.5.6,
 
 
In Section 4.5.7 and Appendix 1, language has been updated to be consistent with 
the American Thoracic Society (ATS)/ERS guidelines for spirometry defining 
“usability” criteria, which allow the use of spirometry measurements where curves do 
not meet the acceptability/reproducibility criteria but represent the patient’s best 
efforts.  The Investigator may discuss these data with the Medical Monitor as 
applicable. Accordingly, the repeatability criterion for pre-bronchodilator spirometry 
(Appendix 1, footnote s) now defines the maximum difference between two largest 
acceptable forced vital capacity (FVC) and forced expiratory volume in 1 second 
(FEV1) measurements as 0.15 L (150 mL) (Appendix 1). 
 
In Appendices 1 and 2, the following modifications have been made to improve 
flexibility for sites, reduce patient burden, and clarify timing of assessments: 
– 
The window from screening to randomization has been expanded from 14 to 
21 days and must last a minimum of 7 days. To reduce participant burden, 
screening visits may occur during a single visit day or over a maximum of 
3 days.  Clarification has been added to indicate that the VitaloJAK cough 
monitoring should start at least 30 minutes after the mannitol challenge tests if 
performed during a single screening visit (Appendix 1 footnote a). 

GDC-6599—Genentech, Inc. 
5/Protocol GA43590, Version 4 
–
The window from the end of washout to second treatment period has been
expanded from 3 to 7 days and a clarification has been added to accordingly
shift subsequent visit days to ensure 14 days of study treatment for the second
treatment period (Appendix 1, Table and footnotes f).
–
During the screening period, urine samples are now specified to be collected
before mannitol challenge testing.  The timing of pharmacokinetic and
biomarker samples has been updated in line with aforementioned modifications
(
).
Protocol GA43590 Version 1 (United Kingdom) was generated to address feedback from 
the Medicines and Healthcare products Regulatory Agency.  The following changes 
specific to Version 1 (United Kingdom), which were implemented at sites in the United 
Kingdom only, will now be implemented at all sites: 

The inclusion criterion pertaining to body mass index (BMI) has been amended to
remove an allowance for BMI values outside the specified range if considered not
clinically significant by the investigator (Section 4.1.1.1).

For consistency with the study design, the inclusion criterion pertaining to chest
X-ray or computed tomography scan for all patients has been updated to clarify that
this criterion does not apply to COPD, for patients with CRC COPD with or without
chronic bronchitis (Section 4.1.1.1).

The exclusion criterion prohibiting clinical laboratory values outside the reference
range for the test laboratory at screening (Study Visit 1) unless the value is deemed
not clinically significant by the investigator, with Medical Monitor informed, has been
removed (Section 4.1.2).

Patients with hypomagnesemia will not be excluded from the study.  As such, for
clarity the examples “hypokalemia, hypomagnesemia, hypocalcemia” have been
removed from the exclusion criterion pertaining to history of ventricular dysrhythmias
or risk factors for ventricular dysrhythmias (Section 4.1.2).
Protocol GA43590 Version 3 was amended primarily to clarify details of the study 
design.  The following changes specific to the Version 3 protocol, which were not 
previously implemented at sites in the United Kingdom, will now be 
implemented at those sites: 

In Section 2 (Table 1) and Section 4.5.5, to clarify the exploratory endpoint of change
in mannitol-induced airway hyperresponsiveness (AHR), AHR has been defined as
follows:  AHR is expressed as response-dose ratio (calculated as maximum percent
decrease in FEV1 [relative to baseline of mannitol challenge] after the last dose of
mannitol divided by cumulative dose of mannitol, and PD15 (defined as provoking
dose of mannitol that induces a 15% decrease in FEV1). In this table, change in FEV1
from baseline to Day 14 has been added as an exploratory endpoint to better
evaluate the efficacy of GDC-6599, as compared with placebo, across each chronic
cough disease subgroup. To support the new exploratory endpoint, the timing of
spirometry has been clarified and an assessment of pre-bronchodilator spirometry
has been added on Day 29 (Appendix 1, footnote s).

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6/Protocol GA43590, Version 4 
 
In Section 3.1, Appendix 1, and 
 the washout periods in the schedule of 
activities have been updated to a minimum of 14 days (Days 15−28) to allow for 
cough and inflammation to return to baseline prior to initiating the second treatment 
period, including the 24-hr objective cough count−assessment at the pretreatment 
visit (Day 29), to provide a baseline prior to initiating treatment on Day 30.  This 
change aligns with the original intent of the protocol. Subsequent timepoints have 
been adjusted accordingly. 
 
In Sections 3.1.1 and 4.5.5 and in Appendix 1 mention of the recording of acute 
coughs induced during the mannitol challenge using the VitaloJAK system has been 
removed as manual cough counts during the mannitol challenge cannot be validated 
in this manner.  Details on cough counting during the mannitol challenge are 
provided in the mannitol challenge test guidance document. 
 
In Sections 3.1.2 and 6.8, clarification has been provided regarding the structure, 
roles, and responsibilities of the Internal Monitoring Committee. 
 
In Figure 1 the coughs-per-dose ratio (CDR) inclusion criterion in the Study Schema 
has been amended for consistency with the CDR-related inclusion criterion in 
Section 4.1.1. 
 
In Sections 4.1.1 and 4.1.2, eligibility criteria have been amended to better define the 
patient population and reflect the underlying patient population that may eventually 
benefit from the investigational drug as follows: 
– 
The inclusion criterion requiring stable background therapy for primary chronic 
lung disease or gastroesophageal reflux disease has been removed as it was 
duplicative of the exclusion criterion related to initiation of proton-pump inhibitor 
therapy within 8 weeks of screening.  
– 
An inclusion criterion related to smoking history has been added for patients 
with UCC.  
– 
The definition of smoking has been clarified as use of inhaled tobacco 
or cannabis products (e.g., cigarettes, cigars, electronic cigarettes, vaporizing 
devices, or pipes).  
– 
The exclusion criterion pertaining to use of oral or systemic corticosteroids has 
been revised to prohibit these medications for the treatment of respiratory 
diseases, including cough, within 8 weeks prior to screening. It has been 
clarified that continued, chronic use of oral or systemic corticosteroids for non-
respiratory conditions is permitted, provided patient has been receiving a stable 
treatment regimen for at least 8 weeks prior to screening and is likely to remain 
on the stable treatment regimen through completion of the study.  
– 
The exclusion criteria around respiratory infection (including upper 
respiratory infection), known coronavirus disease 2019 (COVID-19) infection, 
persistent symptoms of known prior COVID-19 infection, and/or known positive 
COVID-19 test have been consolidated; these conditions may not be present 
within 8 weeks prior to screening.   
– 
The exclusion criterion of blood transfusion within 8 weeks of screening has 
been removed. 

GDC-6599—Genentech, Inc. 
7/Protocol GA43590, Version 4 
– 
History of recurrent pneumonia has been removed as an exclusion criterion.  
– 
The exclusionary timeframe around treatment with angiotensin-converting 
enzyme inhibitor has been reduced from 12 to 8 weeks prior to screening. 
– 
The exclusion criterion pertaining to treatment with opioids (including codeine), 
pregabalin, gabapentin, amitriptyline, and nortriptyline has been revised to 
indicate that treatment with these medications for indications other than chronic 
cough is permitted, provided patients are receiving a stable treatment regimen 
for at least 2 weeks prior to screening and, in the opinion of the investigator, are 
likely to remain on the stable treatment regimen through completion of the 
study. 
– 
A criterion excluding treatment with dextromethorphan, guaifenesin, 
benzonatate, and any other over-the-counter or prescription medication 
containing an anti-tussive or expectorant for the treatment of cough within 
2 weeks prior to screening has been added for consistency with prohibited 
therapy in Section 4.4.2. 
 
Sections 4.1.1.2, 4.5.10, and Appendix 1 have been updated to provide operational 
flexibility such that patients with asthma who do not have confirmed atopic versus 
non-atopic status in their medical records may undergo either the ImmunoCAP 
Specific IgE test, skin prick test, or radioallergosorbent test for determination of 
atopic status at screening. 
 
In Sections 4.1.2, 4.4.1, and 4.4.2, the use of oral or systemic corticosteroids for the 
treatment of respiratory diseases, including cough, within 8 weeks prior to screening 
through completion of the end of the second treatment period has been added to 
prohibited therapy and aligned with the applicable exclusion criterion. Oral 
corticosteroids as rescue therapy for the treatment of acute exacerbations has been 
added as permitted therapy during the study. 
 
In Sections 4.1.2, 4.4.2, and Appendix 12, treatment with medications that are well 
known to prolong the QT interval within 1 month prior to screening through 
completion of the study at Visit 8 has been added to prohibited therapy and aligned 
with the applicable exclusion criterion. A reference list of drugs associated with QT 
prolongation has been appended to the protocol. 
 
In Section 4.3.2, details on GDC-6599 dosage, administration, and compliance have 
been added for clarity. 
 
In Sections 4.4.1 and 4.4.2 the timeframe for prohibition of the use of opioids 
(including codeine), pregabalin, gabapentin, amitriptyline, or nortriptyline for the 
treatment of cough has been modified to last through the end of the second 
treatment period. In addition, language has been added regarding permitted 
treatment with these medications for indications other than chronic cough for 
consistency with language added to the associated exclusion criterion. 
 
In Section 4.4.2, details regarding treatment with cough-suppressant medication, 
use of proton-pump inhibitor therapy, and 
 
 have been added to prohibited therapy for alignment with associated 
exclusion criteria. 

GDC-6599—Genentech, Inc. 
8/Protocol GA43590, Version 4 
 
In Section 4.5.5 and Appendix 1, the criteria for discontinuing mannitol doses during 
the mannitol challenge test have been clarified. 
 
In Section 4.5.10 and Appendix 1, the IgE f24 (shrimp) test screens for food 
allergies are no longer required for determining atopic status. As such, these 
screens have been replaced at screening with the ImmunoCAP Specific IgE test 
panel, which will be limited to specific IgE against standard allergens including cat 
dander, dog dander, cockroach, dust mite, mold, and relevant local allergens. To 
provide operational flexibility, the ImmunoCAP Specific IgE test may be analyzed at 
the study site’s local laboratory or at a central laboratory. 
 
In Section 5.1.2.1, language has been corrected to indicate that bronchial challenge 
testing with mannitol should not be performed in any patient with very low baseline 
pulmonary function tests (e.g., FEV1  1−1.5 liters or  60% of the predicted values) 
for consistency with the mannitol challenge guidance. 
 
In Section 8.4, a description of the technical and organizational security measures 
taken to protect personal data has been added (Section 8.4). 
 
In Section 9.5, text has been modified to clarify that summaries of clinical study 
results may be available for public access in health authority databases. 
 
In Appendix 1, given that patients are to visit the clinic at Study Visit 3 and Study 
Visit 6 solely for the purpose of blood chemistry testing (i.e., no pharmacokinetic 
sample collection at those timepoints), language has been modified to indicate that 
in-clinic dosing is not required at every clinic visit; patients may self-administer study 
drug at home on these days. 
 
In Appendix 1, to clarify timing of VitaloJAK cough recording performed after the 
optional mannitol challenge test during the treatment periods, the end of the 
mannitol challenge test has been defined as immediately after spirometry after the 
last dose of mannitol, or after the final spirometry following the recovery period (if 
required). 
 
In Appendix 1, the timing of (patient) administration of the Visual Analog Scale and 
Numeric Response Scale questionnaires has been clarified.  
 
In Section 4.5.13, Appendix 1, and 
 language has been revised to clarify 
that the blood sample collection for whole genome sequencing (WGS) or whole 
exome sequencing (WES) is not applicable for a site that has not been granted 
approval for WGS/WES, and if the sample is not collected at the specified timepoint, 
it may be collected at any future timepoint during the study. 
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics. This amendment represents cumulative 
changes to the original protocol. 
 
 

GDC-6599—Genentech, Inc. 
9/Protocol GA43590, Version 4 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 16
PROTOCOL SYNOPSIS .................................................................................... 17
1.
BACKGROUND ............................................................................ 22
1.1
Background on Chronic Cough ................................................ 22
1.2
Background on GDC-6599 ...................................................... 23
1.3
Study Rationale and BenefitRisk Assessment ....................... 24
2.
OBJECTIVES AND ENDPOINTS ................................................. 25
3.
STUDY DESIGN ........................................................................... 28
3.1
Description of the Study ........................................................... 28
3.1.1
Overview of Study (Part A and Part B) .................................... 28
3.1.2
Internal Monitoring Committee ................................................. 30
3.2
End of Study and Length of Study ........................................... 31
3.3
Rationale for Study Design ...................................................... 31
3.3.1
Rationale for Patient Population .............................................. 31
3.3.2
Rationale for GDC-6599 Dose and Schedule .......................... 32
3.3.3
Rationale for Control Group ..................................................... 34
3.3.4
Rationale for Biomarker Assessments ..................................... 34
3.3.5
Rationale for Mannitol Challenge Test ..................................... 35
3.3.6
Rationale for 24-Hour Cough Monitoring and Continuous 
Digital Cough Assessment ....................................................... 36
4.
MATERIALS AND METHODS ...................................................... 37
4.1
Patients .................................................................................... 37
4.1.1
Inclusion Criteria ...................................................................... 37
4.1.1.1
General Inclusion Criteria for All Patients ................................ 37
4.1.1.2
Inclusion Criteria for Patients with CRC with Atopic Asthma 
or Patients with CRC with Non-Atopic Asthma (Part A) ........... 39
4.1.1.3 
Inclusion Criteria for Patients with UCC (Part A) ................. 39
4.1.1.4
Inclusion Criteria for Patients with CRC COPD-CB or 
Patients with CRC COPD (Part B) ........................................... 40
4.1.2
Exclusion Criteria ..................................................................... 40

 
GDC-6599—Genentech, Inc. 
10/Protocol GA43590, Version 4 
4.2 
Method of Treatment Assignment and Blinding ....................... 43 
4.3 
Study Treatment and Other Treatments Relevant to the 
Study Design ........................................................................... 44 
4.3.1 
Study Treatment Formulation and Packaging .......................... 44 
4.3.1.1 
GDC-6599 and Placebo ........................................................... 44 
4.3.2 
Study Treatment Dosage, Administration, and Compliance .... 44 
4.3.3 
Mannitol Challenge Test .......................................................... 45 
4.3.4 
Investigational Medicinal Product Handling and 
Accountability ........................................................................... 45 
4.3.5 
Continued Access to GDC-6599 .............................................. 46 
4.4 
Concomitant Therapy, Prohibited Food, and Additional 
Restrictions .............................................................................. 46 
4.4.1 
Permitted Therapy ................................................................... 46 
4.4.2 
Prohibited Therapy .................................................................. 47 
4.4.3 
Prohibited Food ....................................................................... 49 
4.4.4 
Additional Restrictions ............................................................. 49 
4.5 
Study Assessments ................................................................. 50 
4.5.1 
Informed Consent Forms and Screening Records ................... 50 
4.5.2 
Medical History, Baseline Conditions, Concomitant 
Medication, and Demographic Data ......................................... 51 
4.5.3 
Physical Examinations ............................................................. 51 
4.5.4 
Vital Signs ................................................................................ 52 
4.5.5 
Mannitol Challenge Test .......................................................... 52 
4.5.6 
Cough Monitoring .................................................................... 52 
4.5.7 
Spirometry ............................................................................... 53 
4.5.8 
Fractional Exhaled Nitric Oxide ................................................ 54 
......................................................................... 54 
4.5.10 
Laboratory, Biomarker, and Other Biological Samples ............ 54 
4.5.11 
Electrocardiograms .................................................................. 57 
4.5.12 
Clinical Outcome Assessments ............................................... 58 
4.5.12.1 
Data Collection Methods for Clinical Outcome 
Assessments ........................................................................... 58 
4.5.12.2 
Description of Clinical Outcome Assessment Instruments ....... 59 
4.5.13 
Blood Samples for Whole Genome Sequencing or Whole 
Exome Sequencing (Patients at Participating Sites) ................. 60 

 
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11/Protocol GA43590, Version 4 
4.5.14 
Optional Mannitol Challenge Tests ......................................... 61 
4.5.15 
Optional Samples for Research Biosample Repository ........... 62 
4.5.15.1 
Overview of the Research Biosample Repository .................... 62 
4.5.15.2 
Approval by the Institutional Review Board or Ethics 
Committee ............................................................................... 62 
4.5.15.3 
Sample Collection .................................................................... 62 
4.5.15.4 
Data Protection, Use, and Sharing .......................................... 63 
4.5.15.5 
Consent to Participate in the Research Biosample 
Repository................................................................................ 64 
4.5.15.6 
Withdrawal from the Research Biosample Repository ............. 64 
4.5.15.7 
Monitoring and Oversight ......................................................... 65 
4.6 
Treatment, Patient, Study, and Site Discontinuation ................ 65 
4.6.1 
Study Treatment Discontinuation ............................................. 65 
4.6.2 
Patient Discontinuation from the Study .................................... 66 
4.6.3 
Study Discontinuation .............................................................. 67 
4.6.4 
Site Discontinuation ................................................................. 67 
5. 
ASSESSMENT OF SAFETY ......................................................... 67 
5.1 
Safety Plan .............................................................................. 67 
5.1.1 
Risks Associated with GDC-6599 ............................................ 68 
................................................................................ 68 
5.1.1.2 
Impaired Cough Reflex ............................................................ 69 
......................................................................... 70 
5.1.2 
Potential Risks Associated with Mannitol Challenge Test ........ 70 
5.1.2.1 
Severe Bronchospasm ............................................................ 70 
5.1.2.2 
Potential Effects in Patients with Comorbid Conditions ........... 71 
5.1.3 
Management of Patients Who Experience Specific 
Adverse Events ........................................................................ 71 
5.1.3.1 
Dose Modifications and Treatment Interruption ....................... 71 
5.1.3.2 
Management Guidelines .......................................................... 71 
5.1.3.3 
Management of Increases in QT Interval ................................. 73 
5.2 
Safety Parameters and Definitions .......................................... 73 
5.2.1 
Adverse Events ........................................................................ 74 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) .................................................................................. 74 

 
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12/Protocol GA43590, Version 4 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ...................................................... 75 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................... 75 
5.3.1 
Adverse Event Reporting Period .............................................. 76 
5.3.2 
Eliciting Adverse Event Information ......................................... 76 
5.3.3 
Assessment of Severity of Adverse Events ............................. 76 
5.3.4 
Assessment of Causality of Adverse Events............................ 77 
5.3.5 
Procedures for Recording Adverse Events .............................. 78 
5.3.5.1 
Diagnosis versus Signs and Symptoms ................................... 78 
5.3.5.2 
Adverse Events That Are Secondary to Other Events ............. 78 
5.3.5.3 
Persistent or Recurrent Adverse Events .................................. 79 
5.3.5.4 
Abnormal Laboratory Values ................................................... 79 
5.3.5.5 
Abnormal Vital Sign Values ..................................................... 80 
5.3.5.6 
Abnormal Liver Function Tests ................................................ 81 
5.3.5.7 
Deaths ..................................................................................... 81 
5.3.5.8 
Preexisting Medical Conditions ................................................ 81 
5.3.5.9 
Lack of Efficacy or Worsening of Chronic Cough ..................... 82 
5.3.5.10 
Hospitalization or Prolonged Hospitalization ............................ 82 
5.3.5.11 
Cases of Overdose, Medication Error, Drug Abuse, or 
Drug Misuse ............................................................................. 83 
5.3.5.12 
Patient-Reported Outcome Data .............................................. 85 
5.3.5.13 
Safety Biomarker Data ............................................................. 85 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................... 85 
5.4.1 
Emergency Medical Contacts .................................................. 85 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest .......................................... 86 
5.4.2.1 
Events That Occur prior to Study Drug Initiation ...................... 86 
5.4.2.2 
Events That Occur after Study Drug Initiation .......................... 86 
5.4.3 
Reporting Requirements for Pregnancies ................................ 86 
5.4.3.1 
Pregnancies in Female Patients .............................................. 86 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ................... 87 
5.4.3.3 
Abortions.................................................................................. 88 

 
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5.4.3.4 
Congenital Anomalies/Birth Defects ........................................ 88 
5.4.4 
Reporting Requirements for Medical Device Complaints ......... 88 
5.5 
Follow-Up of Patients after Adverse Events............................. 89 
5.5.1 
Investigator Follow-Up ............................................................. 89 
5.5.2 
Sponsor Follow-Up .................................................................. 89 
5.6 
Adverse Events That Occur after the Adverse Event 
Reporting Period ...................................................................... 89 
5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ............... 89 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ......... 90 
6.1 
Determination of Sample Size ................................................. 90 
6.2 
Summaries of Conduct of Study .............................................. 90 
6.3 
Summaries of Demographic and Baseline Characteristics ...... 90 
6.4 
Efficacy Analyses ..................................................................... 91 
6.5 
Safety Analyses ....................................................................... 91 
6.6 
Pharmacokinetic Analyses ....................................................... 91 
6.7 
Biomarker Analyses ................................................................. 92 
6.8 
Optional Interim Analysis ......................................................... 92 
7. 
DATA COLLECTION AND MANAGEMENT ................................. 92 
7.1 
Data Quality Assurance ........................................................... 92 
7.2 
Electronic Case Report Forms ................................................. 92 
7.3 
Electronic Patient-Reported Outcome Data ............................. 93 
7.4 
Source Data Documentation .................................................... 93 
7.5 
Use of Computerized Systems ................................................ 94 
7.6 
Retention of Records ............................................................... 94 
8. 
ETHICAL CONSIDERATIONS ...................................................... 94 
8.1 
Compliance with Laws and Regulations .................................. 94 
8.2 
Informed Consent .................................................................... 95 
8.3 
Institutional Review Board or Ethics Committee ...................... 96 
8.4 
Confidentiality .......................................................................... 96 
8.5 
Financial Disclosure ................................................................. 97 

 
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9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ....................................................................... 97 
9.1 
Study Documentation .............................................................. 97 
9.2 
Protocol Deviations .................................................................. 98 
9.3 
Site Inspections ....................................................................... 98 
9.4 
Administrative Structure ........................................................... 98 
9.5 
Dissemination of Data and Protection of Trade Secrets .......... 98 
9.6 
Protocol Amendments ............................................................. 99 
10. 
REFERENCES............................................................................ 100 
 
 
LIST OF TABLES 
Table 1 
Objectives and Corresponding Endpoints ................................... 26 
Table 2 
Planned Study Enrollment........................................................... 37 
Table 3 
Treatment for Comorbid Conditions of Chronic Chough ............. 47 
Table 4 
Guidelines for Management of Patients Who Experience 
Adverse Events ........................................................................... 71 
Table 5 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in DAIDS Toxicity Grading Scale ................... 77 
Table 6 
Causal Attribution Guidance ....................................................... 78 
 
LIST OF FIGURES 
...... 30 
...... 33 
 
LIST OF APPENDICES 
 
Appendix 1 
Schedule of Activities for Part A and Part B .............................. 106 
............ 113 
............ 115 
............ 117 
............ 119 
Appendix 6 
Visual Analog Scale .................................................................. 120 
Appendix 7 
Numeric Response Scale.......................................................... 121 
.................................. 122 
Appendix 9 
Anaphylaxis Precautions ........................................................... 126 

 
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Appendix 10 
Division of AIDS (DAIDS) Table for Grading the Severity of 
Adult and Pediatric Adverse Events .......................................... 127 
Appendix 11 
Investigational Medicinal Product and Non-Investigational 
Medicinal Product Designations (for Use in European 
Economic Area and United Kingdom) ....................................... 158 
Appendix 12 Drugs Associated with QT Prolongation .................................. 159 
 
 
 

 
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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE IIa, MULTICENTER, RANDOMIZED, 
DOUBLE-BLIND, PLACEBO-CONTROLLED, 
CROSSOVER STUDY TO EVALUATE THE 
EFFICACY, SAFETY, PHARMACOKINETICS, AND 
PHARMACODYNAMIC EFFECTS OF GDC-6599 IN 
PATIENTS WITH CHRONIC COUGH 
PROTOCOL NUMBER: GA43590 
VERSION NUMBER: 
4 
REGULATORY 
AGENCY IDENTIFIER 
NUMBERS: 
IND Number:  154293 
EU CT Number:  Not applicable 
TEST PRODUCT: 
GDC-6599 (RO7441345) 
SPONSOR: 
Genentech, Inc. 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by the contract research organization. 
 

 
GDC-6599—Genentech, Inc. 
17/Protocol GA43590, Version 4 
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE IIa, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, CROSSOVER STUDY TO EVALUATE 
THE EFFICACY, SAFETY, PHARMACOKINETICS, AND 
PHARMACODYNAMIC EFFECTS OF GDC-6599 IN PATIENTS 
WITH CHRONIC COUGH 
PROTOCOL NUMBER: 
GA43590 
VERSION NUMBER: 
4 
REGULATORY 
AGENCY IDENTIFIER 
NUMBERS: 
IND Number:  154293 
EU CT Number:  Not applicable  
TEST PRODUCT: 
GDC-6599 (RO7441345) 
PHASE: 
Phase IIa  
INDICATION: 
Chronic cough 
SPONSOR: 
Genentech, Inc. 
 
OBJECTIVES AND ENDPOINTS 
This Phase IIa, multicenter, randomized, double-blind, placebo-controlled, crossover study will 
evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamic (PD) effects of 
GDC-6599 compared with placebo in patients with a history of chronic cough.   
Specific objectives and corresponding endpoints for the study are outlined below. 
Primary Objective 
Corresponding Endpoint 
 To evaluate the efficacy of GDC-6599, 
as compared with placebo, in patients 
with CRC with asthma or UCC  
 Change in cough frequency per hour, assessed 
objectively over 24 hours (24-hour OCC) using 
VitaloJAK cough recorder, from baseline to Day 14 
Secondary Objective 
Corresponding Endpoints 
 To evaluate the efficacy of GDC-6599, 
as compared with placebo, in patients 
with CRC with asthma or UCC  
 Change in the severity of cough, as assessed 
through the use of the patient-reported cough 
severity VAS and NRS scores, from baseline to 
Day 14 
24-hour OCC  objective cough count over 24 hours; CRC   chronic refractory cough; 
NRS   Numeric Response Scale; UCC  unexplained chronic cough; VAS  visual analog scale. 
 
 

 
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OVERALL DESIGN AND STUDY POPULATION 
This Phase IIa, multicenter, randomized, double-blind, placebo-controlled, crossover study is 
designed to evaluate the efficacy, safety, pharmacokinetics, and PD effects of GDC-6599 
across three cohorts in patients with chronic cough.  In the main study (Part A), approximately 
60 patients with chronic cough will be enrolled across two cohorts:  chronic refractory cough 
(CRC) with asthma with or without atopy (n  approximately 30), and unexplained chronic 
cough (UCC) (n  approximately 30).  In the substudy (Part B), an additional 20 patients with a 
diagnosis of CRC with chronic obstructive pulmonary disease (CRC COPD) with or without 
chronic bronchitis (CB) (n= approximately 20) will be enrolled. 
Several key aspects of the study design and study population are summarized below. 
Phase: 
IIa 
Population Type: 
Adult patients 
Control Method: 
Placebo 
Population 
Diagnosis or 
Condition: 
Chronic cough 
Interventional 
Model: 
Crossover 
Population Age: 
1880 years,  
For patients with 
COPD:   40 years 
old  
Test Compounds: 
GDC-6599 (RO7441345) 
Mannitol 
(Aridol/Osmohale) 
Site Distribution: 
Multi-site and 
multi-region 
Active 
Comparator: 
Not applicable 
Study Intervention 
Assignment 
Method: 
Randomized 
Number of Arms: 
Two 
Number of 
Participants to Be 
Enrolled: 
Approximately 80 
 
STUDY TREATMENT 
During Treatment Period 1, patients will receive
GDC-6599 or placebo 
 
for 14 days.  Following a 
14-day washout period, patients will cross over to the second study period (Treatment Period 2, 
Study Visits 57) and will receive the alternate treatment (
mg GDC-6599 or placebo)
for 
14 days starting at Study Visit 5. 
 
DURATION OF PARTICIPATION 
The study will consist of a screening period of approximately 21 days, followed by a 14-day 
treatment period.  After a 14-day washout, patients will begin another 14-day treatment period 
during which time the opposite treatment will be administered.  A 14-day washout period and 
safety follow-up period will follow.  The total duration of study participation for each 
patient is expected to be approximately 1213 weeks. 
 
COMMITTEES 
Independent Committees: 
Not applicable 
Other Committees: 
Internal Monitoring Committee 
 
 

 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AITC 
allyl isothiocyanate 
AHR 
airway hyperresponsiveness 
ATS 
American Thoracic Society 
AUC 
area under the concentrationtime curve 
AUCINF 
area under the concentrationtime curve from Time 0 
to infinity 
BMI 
body mass index 
BP 
blood pressure 
CB 
chronic bronchitis 
CDR 
coughs-per-dose ratio 
CE 
Conformité Européenne 
CHEST 
American College of Chest Physicians 
CHS 
cough hypersensitivity syndrome 
Cmax 
maximum concentration observed 
COPD 
chronic obstructive pulmonary disease 
COVID-19 
coronavirus disease 2019 
CRC 
chronic refractory cough 
CT 
computed tomography (scan) 
Ctrough 
trough concentration 
DAIDS 
Division of AIDS 
DBF 
dermal blood flow 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ePRO 
electronic patient-reported outcome 
ERS 
European Respiratory Society 
FDA 
(U.S.) Food and Drug Administration 
FeNO 
fractional exhaled nitric oxide 
FEV1 
forced expiratory volume in 1 second 
FSH 
follicle-stimulating hormone 
FVC 
forced vital capacity 
GERD 
gastroesophageal reflux disease 
GINA 
Global Initiative for Asthma 
GLI 
Global Lung Function Initiative 

 
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Abbreviation 
Definition 
GOLD 
Global Initiative for Chronic Obstructive Lung Disease 
HbsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HRQoL 
health-related quality of life 
ICH 
International Council for Harmonisation 
ICS 
inhaled corticosteroid 
IMC 
Internal Monitoring Committee 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
LABA 
long-acting -agonist 
LLN 
lower limit of normal 
MAD 
multiple ascending dose 
MN 
mobile nursing 
NGS 
next-generation sequencing 
NRS 
Numeric Response Scale 
OCC 
objective cough count 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PPI 
proton-pump inhibitor 
PRO 
patient-reported outcome 
QD 
once a day 
QTc 
corrected QT (interval) 
QTcF 
QT interval corrected through use of Fridericia’s 
formula 
RAST 
radioallergosorbent test 
RBR 
Research Biosample Repository 
RDR 
response-dose ratio 
SABA 
short-acting -agonist 
SAD 
single ascending dose 
SMC 
Safety Monitoring Committee 
tmax 
time to maximum concentration 
TRP 
transient receptor potential 
TRPA1 
TRP ankyrin 1  

 
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Abbreviation 
Definition 
TRPV1 
TRP subfamily V, member 1 
UCC 
unexplained chronic cough 
ULN 
upper limit of normal 
VAS 
Visual Analog Scale 
WES 
whole exome sequencing 
WGS 
whole genome sequencing 
 

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1.
BACKGROUND
1.1 
BACKGROUND ON CHRONIC COUGH 
Chronic cough is common, affecting at least 10% of the global population (Song et al. 
2015) and representing significant physical and psychosocial burden.  Chronic cough is 
defined as daily cough lasting for more than 8 weeks.  Chronic cough, despite 
investigation and standard-of-care medical management in patients, is termed chronic 
refractory cough (CRC).  CRC is secondary to chronic diseases such as asthma or 
chronic obstructive pulmonary disease (COPD), whereas unexplained chronic cough 
(UCC) does not have an identified underlying cause.  
Asthma patients specify cough as a bothersome symptom and key aspect of disease 
burden (Polley et al. 2008; Globe et al. 2015; Gater et al. 2016) and is among the 
symptoms most frequently reported to clinicians with prominence from the patient 
perspective (Revicki et al. 1998; Osman et al. 2001; Irwin et al. 2006).  Cough is 
frequently a neglected symptom in uncontrolled asthma and is a major contributor to 
poor asthma control (Mincheva et al. 2014; Çolak et al. 2019).  The burden of cough is 
reflected in clinical guidelines citing perceived symptoms as a component of severity 
classification, and symptom reduction a goal of disease management (National Heart, 
Lung, and Blood Institute 2007; GINA 2016).  Cough that persists despite 
guideline-based treatment in the background of asthma has been referred to as both 
refractory chronic cough and CRC in consensus guidelines and literature.  Within this 
protocol, chronic cough secondary to asthma will be referred to as CRC. 
Cough is also a cardinal symptom of COPD, most frequently reported by patients along 
with dyspnea and breathlessness, and it is a fundamental component of symptom 
burden (van der Molen et al. 2003; Arne et al. 2007; Jones et al. 2009; Miravitlles et al. 
2014).  In patients with COPD, symptom burden, rather than pulmonary function, is more 
strongly associated with poor health-related quality of life (HRQoL) and more predictive 
of other negative outcomes such as acute exacerbations (Mahler 1992; Hajiro 1999; van 
der Molen 2013), as reflected in Global Initiative for Chronic Obstructive Lung Disease 
(GOLD) clinical staging and management guidelines (Vestbo et al. 2013; GOLD 2019).  
Cough is a commonly reported symptom of COPD, with 60% to 80% of patients 
reporting having had a cough within the past 7 days (Kessler et al. 2011; de Oliveira et 
al. 2013).  Cough and mucus disrupt COPD patients’ lives at a functional, emotional, 
social, and economic level (Cook et al. 2019).  
Despite the high unmet need, there are currently no approved drugs for the treatment of 
CRC with asthma, CRC with COPD, or UCC.  
The chronic cough that persists in patients with both asthma and COPD, despite 
standard of care, is postulated to be a consequence of airway afferent nerves activated 
by bronchial hyperresponsiveness, inflammation, and mucus.  Both peripheral and 
central neural pathways contribute to the regulation of cough and understanding which 

 
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24/Protocol GA43590, Version 4 
GDC-6599, administered orally (PO), was well tolerated in both rats and cynomolgus 
monkeys at doses up to 50 mg/kg/day for 4 weeks.  The most significant 
GDC-6599related finding was a dose-dependent, reversible prolongation of the 
coagulation parameters aPTT and PT in both rats and monkeys. 
GDC-6599 has been investigated in a completed Phase Ia/b single ascending dose 
(SAD) and multiple ascending dose (MAD) study (GA43010) in approximately 81 healthy 
volunteers to explore safety, and the pharmacokinetic and pharmacodynamic profile of 
the agent.  Pharmacodynamic target (TRPA1) inhibition has been evaluated using the 
AITC dermal challenge model (Joseph et al. 2021).  No significant clinical, laboratory, or 
ECG findings have been observed in the initial six dosing cohorts of the SAD portion and 
three cohorts of the MAD portion of Study GA43010.  Based upon the available clinical 
data, the clinical dose for the current Phase IIa protocol (GA43590) is 
 
(
; see Section 3.3.2).  No prior clinical experience with GDC-6599 exists in patients.  
Refer to the GDC-6599 Investigator’s Brochure for details on nonclinical and clinical 
studies. 
1.3 
STUDY RATIONALE AND BENEFITRISK ASSESSMENT   
This Phase IIa cough profiling study will be conducted to evaluate potential inhibition of 
cough by GDC-6599, a small molecule inhibitor of TRPA1, and its effects on 
mannitol-induced cough and airway hypersensitivity in a subset of patients with CRC 
with asthma or UCC.  The effects of GDC-6599 on cough and airway inflammation will 
also be assessed in a subgroup of patients with CRC who have a history of COPD. 
The rationale for targeting TRPA1 for the treatment of chronic cough, asthma, and 
COPD is driven by the potential role of TRPA1 in contributing to airway smooth 
muscle contraction, sensory hypersensitivity, and neurogenic inflammation, which may 
lead to bronchoconstriction, AHR, and symptoms such as cough.  Anticipated beneficial 
effects of targeting TRPA1 with GDC-6599 include reduction in bronchoconstriction 
and cough hypersensitivity in asthma and COPD and a reduction of cough 
hypersensitivity-associated CRC with asthma or UCC.  

 
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25/Protocol GA43590, Version 4 
GDC-6599 has been tested in healthy volunteers in a completed Phase Ia/b SAD/MAD 
Study GA43010.  No prior clinical experience with GDC-6599 exists in patients.  The 
rationale for conducting the current study in patients with chronic cough is to evaluate 
the efficacy, safety, pharmacokinetics, and organ-specific pharmacodynamics (target 
inhibition in lung) in a relevant patient population.   
An assessment has been conducted to determine whether the coronavirus disease 2019 
(COVID-19) pandemic has any impact on the benefit-risk assessment of this study 
including, but not limited to, the patient population under study and study treatment.  
Review of the summary safety data generated in the initial six dosing cohorts of the SAD 
portion and three cohorts of the MAD portion of the Phase Ia/b SAD/MAD study 
GA43010 of the potent TRPA1-inhibitor GDC-6599 suggests that inhibition of the TRPA1 
receptor is not associated with a higher frequency of infections or clinically significant 
findings in hematology parameters.  Combined with further review of the toxicology data 
and the mechanism of action of GDC-6599, no impact is anticipated.  The safety 
monitoring and management guidelines and risk mitigation measures provided in the 
study are considered adequate. 
2. 
OBJECTIVES AND ENDPOINTS 
This Phase IIa, multicenter, randomized, double-blind, placebo-controlled, crossover 
study will evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamic (PD) 
effects of GDC-6599 compared with placebo in patients with a history of chronic cough.  
It will assess the potential benefit of GDC-6599 to reduce cough frequency and severity 
in patients with a diagnosis of CRC with asthma, UCC, or CRC with COPD.  The study 
will also explore the effects of GDC-6599 on mannitol-induced cough and/or AHR and 
the value of mannitol-induced cough hypersensitivity and/or AHR as a prognostic tool in 
patients with CRC with asthma, UCC, or CRC with COPD as a measure of TRPA1 
airway activity.  Specific objectives and corresponding endpoints for the study are 
outlined in Table 1 below. 

 
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Table 1 
Objectives and Corresponding Endpoints 
Primary Objective 
Corresponding Endpoint 
 To evaluate the efficacy of GDC-6599, 
as compared with placebo, in patients 
with CRC with asthma or UCC  
 Change in cough frequency per hour, assessed 
objectively over 24 hours (24-hour OCC) using 
VitaloJAK cough recorder, from baseline to Day 14 
Secondary Objective 
Corresponding Endpoints 
 To evaluate the efficacy of GDC-6599, 
as compared with placebo, in patients 
with CRC with asthma or UCC  
 Change in the severity of cough, as assessed 
through the use of the patient-reported cough 
severity VAS and NRS scores, from baseline to 
Day 14 
Safety Objective 
Corresponding Endpoints 
 To evaluate the safety of GDC-6599 
compared with placebo 
 Incidence and severity of adverse events, with 
severity determined according to the DAIDS toxicity 
grading scale a  
 Change from baseline in targeted vital signs 
 Change from baseline in targeted clinical laboratory 
test results 
Pharmacokinetic Objective 
Corresponding Endpoints 
 To characterize the PK profile of 
GDC-6599 
 Plasma concentration of GDC-6599 at specified 
timepoints 
Exploratory Objectives 
Corresponding Endpoints 
 To evaluate mannitol-induced cough 
response as a measure of TRPA1 
airway activity and treatment benefit 
of GDC-6599, as compared with 
placebo, in patients with CRC with 
asthma or UCC 
 Change in cough hypersensitivity to mannitol, 
measured as the CDR to mannitol, from baseline to 
Day 14 
24-hour OCC  objective cough count over 24 hours; AHR  airway hyperresponsiveness, 
expressed as RDR (calculated as maximum percent decrease in FEV1 [relative to baseline of 
mannitol challenge] after the last dose of mannitol divided by cumulative dose of mannitol, and 
PD15 (defined as provoking dose of mannitol that induces a 15% decrease in FEV 1); 
CDR  coughs-per-dose ratio, calculated as total number of provoked coughs divided by 
cumulative dose of mannitol and expressed as coughs per 100 mg of mannitol; CRC   chronic 
refractory cough; DAIDS  Division of AIDS; FEV1  forced expiratory volume in 1 second; 
NRS   Numeric Response Scale; PK  pharmacokinetic; RDR  response-dose ratio; 
UCC  unexplained chronic cough; TRP  transient receptor potential; TRPA1  TRP ankyrin 1; 
VAS  visual analog scale. 
a Adverse events will be graded according to the DAIDS Table for Grading the Severity of Adult 
and Pediatric Adverse Events (HSS 2017), with slight modifications for clarity and for alignment 
with internal practices (see Section 5.3.3 and Appendix 10). 
 

(n = approximately 30).  In the substudy (Part B), approximately an additional 20 patients 
with a diagnosis of CRC with COPD with or without chronic bronchitis (CRC 
COPD ± CB) despite standard-of-care treatment will be enrolled. 
The study will consist of a screening period of approximately 21 days, followed by a 14-
day treatment period.  After a 14-day washout, patients will begin another 14-day 
treatment period during which time the opposite treatment will be administered.  A
14-day washout period and 
 safety follow-up period will follow.
Patients who meet all eligibility criteria (see Section 4.1) will be randomized in a 1:1 ratio 
to receive
mg GDC-6599 or placebo 
 
 
 for 14 days during the first study period (Treatment Period 
1, Study Visits 2−4).  Following a 14-day washout period, patients will cross over to the 
second study period (Treatment Period 2, Study Visits 5−7) and will receive the alternate 
treatment (
mg GDC-6599 or placebo) 
 for 14 days starting at Study Visit 5.  
VitaloJAK cough recorder (Vitalograph Inc., Maids Moreton, U.K.) will be used to 
monitor spontaneous cough frequency at screening and throughout the study.  
 
 
 
 
To characterize the pharmacokinetic (PK) properties of GDC-6599, blood samples will be 
taken at various timepoints before and after dosing.  
To characterize the PD effects of GDC-6599, 
 
 
 [collected under prior 
versions of this protocol]) will be collected at timepoints indicated in 
 
A safety follow-up assessment (Study Visit 8) will be scheduled 
 after the last 
dose of study treatment to ensure patient safety.   
At applicable sites, certain study assessments may be performed by a trained nursing 
professional at the patient’s home or another suitable location, if the patient has given 
written informed consent to participate in mobile nursing (MN) visits and mobile nursing 
is available. 
Figure 1 presents an overview of the study design.  A schedule of activities is provided in 
Appendix 1. 
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Patients who are not able to complete the assessments or are unable to meet eligibility 
requirements during the screening period (screen failure) will be permitted to be 
re-screened once (for a total of two screenings per patient) at the investigator’s 
discretion.  Patients who re-screen  6 weeks after Informed Consent Form completion 
must repeat the assessments that triggered the screen failure.  Patients who re-screen 
 6 weeks after Informed Consent Form completion are required to repeat the consent 
process and all assessments.  The investigator will maintain a record of reasons for 
screen failure (see Section 4.5.1). 
3.1.2 
Internal Monitoring Committee 
An Internal Monitoring Committee (IMC) will monitor patient safety throughout the study.  
Members from the IMC will be unblinded to treatment assignment and include 
representatives from clinical science, clinical safety, and biostatistics from the Sponsor.  
The IMC may invite representatives from other functional areas (e.g., clinical 
pharmacology) or external experts on an ad hoc basis when additional expertise is 
required.  Further details regarding roles and responsibilities will be outlined in the IMC 
Charter. 
Periodic safety reviews of cumulative data will be performed by the Sponsor’s IMC as 
outlined in the IMC Charter.  Ad hoc meetings may be held at the request of the IMC or 
Sponsor at any time to address potential safety concerns.  The data to be reviewed will 
include, but will not be limited to, demographics, concomitant medications, study drug 
administration, adverse events, serious adverse events, adverse events of special 
interest, ECGs, and relevant laboratory results. 

 
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At the time of each review, the IMC may make recommendations such as the following:  
the trial continues as planned, the trial is stopped for safety reasons, the dose level or 
frequency is changed, additional analyses need to be performed, or enrollment will be 
held pending further safety evaluations.  The IMC may also provide recommendations on 
amending the protocol.  Decisions will be made in consideration of the totality of the 
available data.  Final decisions will rest with the Sponsor’s study team. 
A detailed description of the procedures, data flow, and meeting schedule of the IMC will 
be provided in the IMC Charter.  
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of this study is defined as the date when the last patient, last visit occurs or the 
date at which the last data point required for statistical analysis or safety follow-up is 
received from the last patient, whichever occurs later.  Each patient is expected to 
remain in the study for a maximum of approximately 12 weeks.  The end of the study is 
expected to occur approximately 12 weeks after the last patient is enrolled. 
In addition, the Sponsor may decide to terminate the study at any time. 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 18 months. 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Patient Population 
Three cohorts of chronic cough patients with different disease backgrounds (CRC 
asthma with or without atopy, UCC, or CRC COPD) will be enrolled in this study to 
assess the potential heterogeneity of treatment effects on cough frequency across 
disease backgrounds.  The study will also explore potential heterogeneity of baseline 
cough hypersensitivity to inhaled mannitol and the relationship with baseline cough 
frequency. 
Cough is an important symptom of chronic lung disorders and is often cited by patients 
with CRC with asthma, CRC with COPD, or idiopathic pulmonary fibrosis as the most 
bothersome of respiratory symptoms having an adverse impact on HRQoL (Polley et al. 
2008) and is a key aspect of disease burden and control (Marsden et al. 2016).  Despite 
the high unmet need, there are currently no approved drugs for the treatment of CRC 
with asthma, UCC, or CRC with COPD. 
Chronic cough, despite adherence to guideline-based standard-of-care treatment, 
represents high unmet medical need in patients with CRC with asthma, UCC, or CRC 
with COPD.  Cough hypersensitivity to inhaled irritants is a key feature of chronic cough.  
This study will target patients with CRC with atopic asthma, CRC with non-atopic 
asthma, UCC, and CRC COPD.  Patients must have a diagnosis of chronic cough based 
upon consensus guidelines (American College of Chest Physicians [CHEST] 2018; 

 
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European Respiratory Society [ERS] 2020).  A mannitol CDR of at least 
12 coughs/100 mg is required for inclusion in this study (see Section 4.1.1) in order to 
identify patients with cough hypersensitivity and avoid including patients with very low 
mannitol-evoked cough responses, in whom a treatment effect would be difficult to 
demonstrate. 
Heightened and exaggerated cough responses to tussive stimuli is recognized as a 
unifying feature of patients with chronic cough (Hilton et al. 2013; Canning et al. 2014).  
However, in the clinical setting, it is clear that the processes regulating cough are 
heterogeneous across different patient subgroups.  Disease-specific profiles of neuronal 
sensitivity have been demonstrated in the cough responses to inhaled tussive stimuli in 
patients with COPD, healthy smokers, CRC, asthma, compared with healthy volunteers 
(Belvisi et al. 2016).  The extent to which this may be a consequence of increased 
activation of vagal afferents by pathology in the airways (e.g., inflammatory mediators, 
excessive mucus) or an altered neuronal phenotype is unknown.  There is recent 
evidence illustrating distinct patterns of neuronal dysfunction within subsets of UCC 
patients.  A recent study has identified four phenotypes of cough hypersensitivity in 
patients with UCC based upon activation of the TRPA1 and TRPV1 channels using 
selective agonists (Long et al. 2019).  Data from two recent studies assessing cough 
hypersensitivity to capsaicin, a TRPV1-specific irritant, in asthma patients suggest that 
heightened sensitivity to inhaled capsaicin in non-atopic asthma patients relative to 
atopic patients reflects greater neuronal dysfunction associated with poor asthma control 
and worse outcomes. (Satia et al. 2017; Kanemitsu et al. 2020). This supports the 
existence of heterogeneity in cough pathways and an approach for developing 
personalized anti-tussive therapies. 
Understanding the basis for this heterogeneity is key to the development of personalized 
treatments for cough.  This study is designed to profile cough hypersensitivity to inhaled 
mannitol and the relationship to cough frequency and cough severity across four 
distinct subsets of patients with chronic cough (CRC with atopic asthma, CRC with 
non-atopic asthma, UCC, and CRC COPD).  Treatment with GDC-6599 and placebo 
across two treatment periods will inform the relative contribution of TRPA1 airway 
activity to the cough profiles. 
3.3.2 
Rationale for GDC-6599 Dose and Schedule  
The selected dose of GDC-6599 is 
.  Based on PK/PD results from the 
 
 of the Phase Ia/b Study GA43010, this dose is expected to 
 
  

 
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3.3.3 
Rationale for Control Group 
The placebo-controlled crossover design of this study removes patient variation by 
allowing the patient to serve as their own control.  As a result of the inherent variability in 
cough and other symptoms, the use of a placebo period is necessary to assess safety 
and efficacy signals that may be attributable to GDC-6599.  Patients will not be at 
increased risk during the placebo period as they will be on standard background therapy 
for their primary disease and will have access to rescue medication. The addition of a 
washout period between the two treatment periods is incorporated to prevent the 
carryover effect of the study drug.  
3.3.4 
Rationale for Biomarker Assessments  
To demonstrate evidence of the biological activity of GDC-6599, biomarker 
assessments, before (i.e., randomization, pretreatment, baseline) and at various 
timepoints after treatment, will be used to identify biomarkers that may be predictive of 
response to GDC-6599 and/or demonstrate PD activity of GDC-6599, define PK/PD 
relationships, support selection of a recommended dosing regimen, and/or advance the 
understanding of the mechanism of action of GDC-6599 in patients on the basis of the 
following endpoints:  
 
Change from the baseline visit in biomarker levels in 
 
. 
 
Relationship among biomarker levels in 
 
. 
 
Relationship between biomarkers in 
 
 
During this study, 
 
 
 [collected under prior versions of this protocol]) will 
be collected.  
 
  
 
   
Additionally, blood samples will be collected for DNA extraction (optional) to enable 
identification of mutations in genes encoding that are associated with chronic cough and 
activity of TRPA1 in the airway or can increase the knowledge and understanding of 
disease biology. 
Exploratory research on safety biomarkers may be conducted to support future drug 
development.  Research may include further characterization of a safety biomarker or 
identification of safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation.  

 
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Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this 
study.  In addition, safety biomarker data will not inform decisions on patient 
management. 
3.3.5 
Rationale for Mannitol Challenge Test 
Inhaled cough challenge models with agents that safely activate sensory neuron 
receptors such as TRPV1 and P2X3 are commonly performed to assess neuronal 
hypersensitivity, a hallmark of chronic cough and cough hypersensitivity syndrome, and 
to evaluate the mechanism of action of investigational therapeutics for these diseases 
(Morice et al. 2007; Song and Morice 2017).  Activation of c-fibers with inhaled capsaicin 
evokes cough via TRPV1 in humans without significant bronchoconstriction, and 
therefore has been the most common cough challenge agent (Koskela et al. 2021; Mai 
et al. 2021).  Activating TRPA1 ion channels in humans is more limited. TRPA1 can be 
stimulated by wide variety of natural products and environmental irritants but these are 
pungent to inhale, can cause occupational asthma, and/or are carcinogenic; acrolein in 
cigarette smoke, mustard oil (i.e., isothiocyanate), garlic, formalin, wasabi, and 
cinnamaldehyde (Belvisi et al. 2011).  Due to the hydrophobic properties of TRPA1 
agonists, they require dissolution in high amounts of ethanol and these amounts would 
be intolerable to patients with chronic cough. Cinnamaldehyde has been administered to 
healthy volunteers and guinea pigs, but has never been attempted in patients with 
asthma or chronic cough (Birrell et al. 2009).  An alternative approach to stimulate 
TRPA1 would be to induce a change in osmolarity (e.g., with mannitol) and/or pH 
(e.g., with citric acid), though specificity of these challenges agents for TRPA1 is less 
understood.  Changes in pH are known to activate TRPV1 and other acid sensing ion 
channels in addition to TRPA1 (Gu and Lee 2011; Mukhopadhyay et al. 2014; Joseph et 
al. 2021). 
AHR is a key pathophysiological feature in asthma and eosinophilic COPD and is related 
to an increased airway smooth muscle contractility due to mast cell infiltration and 
eosinophilic airway inflammation.  The mannitol challenge test is a clinical, indirect, 
osmotic bronchial challenge test using inhaled dry powder mannitol to assess the 
severity of AHR, a measure of asthma control, and is often used to aid the diagnosis of 
asthma (Sverrild et al. 2009) that correlates with the level of eosinophilic and mast cell 
airway inflammation that is highly predictive of the response to anti-inflammatory 
therapies such as inhaled corticosteroid (ICS) treatment (Lipworth et al. 2012; Anderson 
et al. 2016) or biologic therapies recently developed for the treatment of moderate 
severe asthma (Sverrild et al. 2021).   

 
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Inhaled mannitol has been shown to induce dose-dependent AHR in patients with 
asthma and COPD, but not in healthy volunteers (Koskela et al. 2004; Leuppi et al. 
2005; Backer et al. 2020).  Several studies have also demonstrated that inhalation of 
mannitol elicits cough in a dose-response manner and differentiates patients with 
CRC/UCC hypersensitivity syndrome in a disease population (Koskela et al. 2018; Nurmi 
et al. 2019).   
The mechanism of mannitol-induced bronchoconstriction is not clearly understood.  It is 
unknown whether mannitol-induced bronchoconstriction is due to direct activation of 
TRPA1 by mannitol as an irritant to sensory neurons or indirect activation due to the 
hyper-osmolar effect of mannitol causing mast cell degranulation and releasing 
inflammatory mediators (histamine, tryptase, prostaglandins) and immunomodulators, 
such as PGD2, capable of smooth muscle contraction and activation of TRPA1.  In 
addition, coughing when inhaling mannitol is thought to occur due to i) dry powder 
inhalation stimulating mechanosensors; ii) changes in osmolarity; iii) 
bronchoconstriction; and iv) the release of histamine, prostaglandins from mast cells in 
the airways which can all directly sensitize and/or activate airway nerves and TRPA1 
(Koskela et al. 2004; Anderson et al. 2016; Koskela et al. 2020).  Thus, mannitol 
challenge could be a relevant disease model to explore the mechanism of action and 
efficacy of novel anti-tussive compounds. 
This is relevant for TRPA1 antagonist because the TRPA1 receptor is sensitive to 
changes in osmolarity (Zhang et al. 2008) and blocking TRPA1 has shown to be reduce 
inflammation and bronchoconstriction in nonclinical models (Balestrini et al. 2021).  
This study will test whether mannitol-induced AHR and cough are TRPA1 dependent 
and will explore mannitol-induced AHR and cough in different respiratory disease 
subsets.  If mannitol is a TRPA1-responsive challenge agent, it may have utility in future 
clinical studies as a PD biomarker of TRPA1 activity.  Furthermore, this study will 
instigate the relationship of baseline cough hypersensitivity, measured by mannitol-
induced cough, with efficacy endpoints (e.g., 24-hour cough count) and inform the use of 
mannitol-induced AHR or cough as prognostic biomarkers for a personalized approach 
to treatment with a TRPA1-specific therapy such as GDC-6599.  
3.3.6 
Rationale for 24-Hour Cough Monitoring and Continuous 
Digital Cough Assessment  
Cough will be assessed by the VitaloJAK semi-automated cough counting system.  
VitaloJAK is the only clinically validated, 510K-cleared, and Conformité 
Européenne-marked medical device system for the objective measurement of cough 
(Birring et al. 2008; Barton et al. 2012; Smith et al. 2021).  VitaloJAK has been used to 
measure cough frequency as either a primary or secondary endpoint in several Phase II 
and III programs, including gefapixent, BAY1817080, and BLU-5937, targeting patients 
with UCC or CRC.  The treatment effect in this study will be analyzed on the basis of 
cough frequency data (24-hour OCC) collected via VitaloJAK.  

 
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While VitaloJAK is the current gold standard for measuring cough frequency, it is limited 
to a maximum of 24-hour recordings.  Previous placebo-controlled studies suggest there 
is significant day-to-day variability in 24-hour OCC that reduces the probability of 
detecting treatment differences based upon a single 24-hour data collection.  
 
  
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Approximately 80 patients with five distinct subsets of chronic cough will be enrolled in 
this study (Part A and Part B).   Potential patients are eligible to be included in the study 
only if all of the general inclusion criteria (Section 4.1.1.1) and the criteria for their 
respective disease background (Section 4.1.1.2 or Section 4.1.1.4) are met. 
Table 2 
Planned Study Enrollment 
 
Study 
 
Cohort 
 
Approximate No. of 
Patients per Cohort 
Part A 
 
CRC with asthma  atopy 
 
30 
 
 
UCC 
 
30 
Part B 
 
CRC COPD  CB 
 
20 
Total enrollment 
 
 
 
80 
COPD  chronic obstructive pulmonary disease; COPD  CB  chronic obstructive pulmonary 
disease with or without chronic bronchitis; CRC  chronic refractory cough; UCC  unexplained 
chronic chough. 
 
4.1.1 
Inclusion Criteria 
4.1.1.1 
General Inclusion Criteria for All Patients 
Patients must meet the following criteria for study entry: 
 
Signed Informed Consent Form 
 
Age 1880 years at time of signing Informed Consent Form (except patients with 
COPD  40 years old) 

 
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 
Ability to comply with the study protocol 
 
Body mass index (BMI) of 1735 kg/m2 at screening  
 
A Persistent cough that has lasted for at least 1 year, and refractory despite 
optimized treatment for asthma, COPD, GERD, or UCC for at least 12 weeks 
(see CHEST 2018/ERS 2020 guidelines [Irwin et al. 2018; Morice et al. 2020]. 
 
Chest X-ray or computed tomography (CT) scan thorax within 5 years prior to 
screening visits that confirms, in the opinion of the investigator, the absence of 
any clinically significant abnormality contributing to the chronic cough, with the 
exception of COPD for patients with CRC COPD with or without CB (see 
Section 4.1.1.4)  
 
Cough severity VAS score  40 at screening  
 
Pre-bronchodilator forced expiratory volume in 1 second (FEV1)  60% of predicted 
value at screening 
 
Mannitol CDR  12 coughs per 100 mg of mannitol determined at screening 
mannitol challenge test, based on manual cough counting 
 
Demonstrated ability to use and comply with electronic patient-reported outcome 
(ePRO) requirements, defined as completion of all questions on at least 2 out of 
7 consecutive days within the 14 days during screening  
Patients unable to demonstrate compliance with completing the electronic daily 
assessments (Numeric Response Scale [NRS] and VAS on ePRO) within the 
first 2 weeks of screening will be screen failed.  Patients will have the 
opportunity to demonstrate ePRO compliance if re-screened. 
 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, as defined below: 
Women must remain abstinent or use contraceptive methods with a failure rate 
of  1% per year during the treatment period and for 
 after the final dose 
of study drug, or for the period required by local guidelines or regulations, 
whichever is longer. 
A woman is considered to be of childbearing potential if she is postmenarchal, 
has not reached a postmenopausal state ( 12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  Per this definition, a woman with a tubal ligation is 
considered to be of childbearing potential.  The definition of childbearing 
potential may be adapted for alignment with local guidelines or regulations. 
Examples of contraceptive methods with a failure rate of  1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices. 

 
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The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not adequate methods of contraception.  
If required per local guidelines or regulations, locally recognized adequate 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form. 
 
4.1.1.2 
Inclusion Criteria for Patients with CRC with Atopic Asthma or 
Patients with CRC with Non-Atopic Asthma (Part A) 
Patients with CRC with atopic asthma or patients with CRC with non-atopic asthma 
must meet the following criteria for study entry: 
 
Physician diagnosis of asthma for  12 weeks based upon GINA STEP 25  
 
Stable treatment with ICS therapy (GINA STEP 2) or ICS therapy and at least one 
additional controller (GINA STEP 35) for  12 weeks  
 
Patients with atopic asthma, based upon historic record of positive test for atopy (if 
available), or confirmed at screening by any positive test result from a panel of 
standard allergens including cat dander, dog dander, cockroach, dust mite, mold, 
and relevant local allergens, as determined through use of ImmunoCAP Specific 
IgE test, skin prick test, or radioallergosorbent test (RAST) 
 
Patients with non-atopic asthma, based upon historic record of negative test for 
atopy (if available), or confirmed at screening by negative test result across chosen 
atopy testing panel and no history or symptoms suggesting atopy 
 
No history of smoking or former smoker with smoking history of  20 pack-years or 
equivalent history  
Smoking is defined as use of inhaled tobacco or cannabis products 
(e.g., cigarettes, cigars, electronic cigarettes, vaporizing devices, or pipes). 
A former smoker is defined as someone with smoking history who has not used 
inhaled tobacco or cannabis products within 6 months prior to screening. 
 
4.1.1.3 
Inclusion Criteria for Patients with UCC (Part A) 
Patients with UCC must meet the following criteria for study entry: 
 
Diagnosis of UCC 
 
No history of smoking or former smoker with smoking history of  20 pack-years or 
equivalent history 
Smoking is defined as use of inhaled tobacco or cannabis products 
(e.g., cigarettes, cigars, electronic cigarettes, vaporizing devices, or pipes). 
A former smoker is defined as someone with smoking history who has not used 
inhaled tobacco or cannabis products within 6 months prior to screening. 
 

 
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4.1.1.4 
Inclusion Criteria for Patients with CRC COPD-CB or Patients 
with CRC COPD (Part B) 
Patients with CRC COPD must meet the following criteria for study entry: 
 
Diagnosis of COPD GOLD III  CB  
CB assessed by single question:  Have you had productive cough 
(sputum/mucus) daily for the past 4 weeks or longer? 
 
Stable background treatment for  12 weeks prior to screening 
On an eligible bronchodilator medication (long-acting -agonists [LABAs], 
long-acting muscarinic antagonists, or both)  12 weeks prior to screening 
and/or on stable ICS therapy for  12 weeks prior to screening  
 
Former smoker with  10 pack-years or equivalent history who has not used inhaled 
tobacco or cannabis products (e.g., cigarettes, cigars, electronic cigarettes, 
vaporizing devices, or pipes) within 6 months prior to screening  
 
Post-bronchodilator FEV1/forced vital capacity (FVC) ratio  0.70 at screening  
 
Chest X-ray or CT scan within 6 months prior to screening visit or during the 
screening period (prior to randomization [Study Visit 2]), that confirms the absence 
of clinically significant lung disease besides COPD 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 
Pregnant or breastfeeding, or intention of becoming pregnant during the study or 
within 
 after the final dose of GDC-6599 
Women of childbearing potential must have a negative serum pregnancy test 
result at screening and a negative urine pregnancy test within 1 day prior to 
initiation of study drug. 
 
History of diagnosed bleeding diathesis or easy bruising or bleeding (i.e., bruising or 
bleeding out of proportion to the degree of trauma) 
 
Post-bronchodilator FEV1/FVC ratio  0.60 at screening (patients with CRC asthma 
and UCC only: Part A) 
 
Acute exacerbations of asthma or COPD within 8 weeks prior to screening 
 
Use of oral or systemic corticosteroids for the treatment of respiratory diseases, 
including cough, within 8 weeks prior to screening 
Continued, chronic use of oral or systemic corticosteroids for non-respiratory 
conditions is permitted, provided patient has been receiving a stable treatment 
regimen for at least 8 weeks prior to screening and, in the opinion of the 
investigator, is likely to remain on the stable treatment regimen through 
completion of the study. 
 
 
 
Initiation of proton-pump inhibitor (PPI) therapy within 8 weeks prior to screening  

 
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 
History of significant hepatic impairment, defined as Child-Pugh Class B or C, 
corresponding to a Child-Turcotte-Pugh Score  7 
 
History of aspiration pneumonia 
 
Respiratory infection (including upper respiratory infection), known COVID-19 
infection, persistent symptoms of known prior COVID-19 infection, and/or known 
positive COVID-19 test within 8 weeks prior to screening and randomization 
COVID-19 testing is not required for participation in the study unless required 
by local regulations or institutional policies. 
 
Positive HIV antibody test at screening 
 
Positive hepatitis B surface antigen (hBsAg) at screening  
 
Positive hepatitis C virus (HCV) antibody test followed by a positive HCV RNA test 
at screening 
The HCV RNA test must be performed if a patient has a positive HCV antibody 
test at screening to determine if the patient has an HCV infection. 
 
Treatment with investigational therapy within 28 days or 5 drug-elimination half-lives 
(if known), whichever is longer, prior to initiation of study drug 
 
Treatment with any strong inhibitor or inducer of CYP3A within 28 days or 
5 drug-elimination half-lives, whichever is longer, prior to initiation of study drug 
 
 
 
Treatment with any vaccine within 7 days prior to initiation of study drug or a 
scheduled vaccination during study period (through follow-up/early termination visit)  
 
Treatment with angiotensin-converting enzyme (ACE) inhibitor within 8 weeks prior 
to screening  
 
Treatment with opioids (including codeine), pregabalin, gabapentin, amitriptyline, or 
nortriptyline for the treatment of cough within 2 weeks prior to screening  
Treatment with any of these medications for indications other than chronic 
cough is permitted, provided the patient is receiving a stable treatment 
regimen for at least 2 weeks prior to screening and, in the opinion of the 
investigator, is likely to remain on the stable treatment regimen through 
completion of the study. 
 
Treatment with dextromethorphan, guaifenesin, benzonatate, and any other over-
the-counter or prescription medication containing an anti-tussive or expectorant 
for the treatment of cough within 2 weeks prior to screening  
 
History of serious adverse reaction or serious hypersensitivity to any drug or the 
study drug formulation excipients 
 
Malabsorption syndrome or other condition that would interfere with 
enteral absorption 
 
Planned major surgical intervention that may require general anesthetic and/or 
hospital stay during the study 

 
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 
Serious infection requiring oral or IV antibiotics within 14 days prior to screening or 
randomization 
 
Any serious medical condition or abnormality in clinical laboratory tests that, in the 
investigator's judgment, precludes the patient's safe participation in and completion 
of the study 
 
History of malignancy within 5 years prior to screening, except for appropriately 
treated carcinoma in situ of the cervix or non-melanoma skin carcinoma 
 
Any of the following clinical laboratory values at screening (even if not considered 
clinically significant): 
– 
PT (INR)  upper limit of normal (ULN), PTT  ULN or platelet  lower limit of 
normal (LLN) 
– 
ALT or AST  ULN 
– 
Total bilirubin  ULN; patients with Gilbert syndrome may enroll provided total 
bilirubin  1.5  ULN and direct (conjugated) bilirubin is  ULN 
Laboratory testing may be repeated one time during screening if the initial results 
are outside the normal range specified by the laboratory performing the test or 
outside the ranges specified above. 
 
QT interval corrected through use of Fridericia's formula (QTcF)  450 ms 
If the initial QTcF  450 ms, the ECG should be repeated at least 30 minutes 
after the first ECG.  The patient may be enrolled if second QTcF  450 ms. 
 
History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such 
as structural heart disease (e.g., severe left ventricular systolic dysfunction, left 
ventricular hypertrophy), unstable coronary heart disease (symptomatic or with 
ischemia demonstrated by diagnostic testing) within last 12 months, clinically 
significant electrolyte abnormalities, or family history of sudden unexplained death 
or long QT syndrome 
 
Current treatment with medications that are well known to prolong the QT interval 
within 1 month prior to screening 
Refer to Appendix 12 for a list of drugs associated with QT prolongation. 
 
If stipulated by local or national laws:  employed by the site, the Sponsor, or 
Sponsor representatives or financially dependent on, or related to, an employee of 
the site, the Sponsor, or Sponsor representatives 
 
History or presence of an abnormal ECG that is clinically significant in the 
investigator's opinion, including complete left bundle branch block, second- or 
third-degree atrioventricular heart block, or evidence of prior myocardial infarction 
within last 12 months 
 
Known allergic sensitivity or reaction to adhesives, such as those used for VitaloJAK 
chest sensor application, that in the opinion of the investigator may impact the ability 
of the patient to complete the study 
 

 
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4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
This is a randomized, double-blind, crossover study.  After initial written informed 
consent has been obtained, all screening procedures and assessments have been 
completed, and eligibility has been established for a patient, the study site will obtain the 
patient's identification number and treatment assignment from an interactive voice or 
web-based response system (IxRS).  Patients will be randomized in a 1:1 ratio to receive 
mg GDC-6599 or placebo 
 in Treatment Period 1.  After a 14-day washout period, 
patients will begin Treatment Period 2, during which the opposite treatment received in 
Treatment Period 1 will be administered. 
Study site personnel and patients will be blinded to treatment assignment during the 
study.  The Sponsor and its agents will also be blinded to treatment assignment, with the 
exception of individuals who require access to patient treatment assignments to fulfill 
their job roles during a clinical trial.  These roles include the unblinding group 
responsible, clinical supply chain managers, sample handling staff, operational assay 
group personnel, IxRS service provider, and members of the IMC as specified in the 
IMC Charter. 
While PK samples must be collected during both treatment periods to maintain the 
blinding of treatment assignment, PK assay results for the placebo treatment period are 
generally not needed for the safe conduct or proper interpretation of the study data.  
Laboratories responsible for performing study drug PK assays will be unblinded to 
patient treatment assignments to identify appropriate samples for analysis.  PK samples 
from the placebo treatment period will not be analyzed for study drug PK concentration 
except by request (e.g., to evaluate a possible error in dosing).   
If unblinding becomes necessary because of a medical emergency (e.g., serious adverse 
event for which management might be affected by knowledge of the participant's 
treatment assignment), the investigator will be able to break the treatment code via the 
IxRS.  The investigator is not required to contact the Medical Monitor prior to breaking 
the treatment code in an emergency situation.  However, the Medical Monitor should be 
informed that the treatment code has been broken. 
The investigator will also be able to break the treatment code to determine the 
suitability of subsequent medical care for a participant.  However, approval must be 
obtained from the Sponsor Medical Monitor if the investigator wants to break the 
treatment code to determine a participant's eligibility for a subsequent clinical trial 
testing investigational medicinal products or procedures.  The investigator must 
contact the Sponsor Medical Monitor prior to breaking the treatment code for any 
reason other than a medical emergency.  The investigator should document and 
provide an explanation for any non-emergency unblinding. 

 
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As per health authority reporting requirements, the Sponsor's Drug Safety representative 
will break the treatment code for all serious, unexpected suspected adverse reactions 
(see Section 5.7) that are considered by the investigator or Sponsor to be related to an 
investigational medicinal product (IMP; defined in Section 4.3).   
4.3 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN 
The investigational medicinal products (IMPs) for this study are GDC-6599 and mannitol, 
provided in the form of a manufactured kit by the name of Aridol/Osmohale.   
Appendix 11 identifies all IMP and NIMP for this study.  
4.3.1 
Study Treatment Formulation and Packaging 
4.3.1.1 
GDC-6599 and Placebo 
GDC-6599 and matching placebo will be supplied and formulated by the Sponsor as 
film-coated tablets, with GDC-6599 provided in 
 dose.  For information 
on the GDC-6599 formulation, see the pharmacy manual and GDC-6599 Investigator’s 
Brochure. 
4.3.2 
Study Treatment Dosage, Administration, and Compliance 
The treatment regimens are summarized in Section 3.1.  
GDC-6599 or placebo will be administered orally at a dose of 
.  
GDC-6599 or placebo tablets should be taken approximately 
 
.  For Visit 2 (Day 1), Visit 4 (Day 14), 
Visit 5 (Day 30), and Visit 7 (Day 43), 
 
  Patients may self-administer 
 
 for Visit 3 (Day 7) and Visit 6 (Day 36).  Patients will self-administer all 
other doses of study drug at home. 
All active and placebo tablets will be administered by mouth, followed immediately with 
water.  The tablets should be swallowed whole; they should not be chewed, cut, broken, 
or crushed.  Study drug may be taken with or without food.  If a dose of study drug is 
missed (i.e. delayed by more than 4 hours) or if vomiting occurs when the dose is taken, 
the patient should resume dosing with the next scheduled dose without compensating 
for the missed dose. 
For doses administered in the clinic, compliance will be assessed by a visual check of the 
mouth and hand performed by site staff.  For self-administered doses, patients will be 
required to record the time they took each dose every day in a study drug compliance 
electronic diary; missed doses will also be recorded.  Patients will be instructed to bring 
all unused study medication and their study drug compliance diaries to the clinic at 
specified study visits (see schedule of activities in Appendix 1).  Compliance will be 
assessed by reviewing diaries and counting returned tablets. 

 
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Refer to the pharmacy manual for detailed instructions on drug preparation and 
administration. 
Details on treatment administration (e.g., dose and timing) should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Cases of overdose, 
medication error, drug abuse, or drug misuse, along with any associated adverse 
events, should be reported as described in Section 5.3.5.11. 
Guidelines for treatment interruption or discontinuation for patients who experience 
adverse events are provided in Section 5.1.3.1. 
4.3.3 
Mannitol Challenge Test 
The mannitol challenge test (Aridol/Osmohale) is a commercially approved bronchial 
challenge test kit containing prefilled mannitol capsules and a handheld dry powder 
inhaler device.  For additional information on the formulation, packaging, and handling of 
mannitol dry inhalation powder, see the local prescribing information. 
4.3.4 
Investigational Medicinal Product Handling and Accountability 
All IMPs required for completion of this study will be provided by the Sponsor.  The study 
site (i.e., investigator or other authorized personnel [e.g., pharmacist]) is responsible for 
maintaining records of IMP delivery to the site, IMP inventory at the site, IMP use by 
each patient, and disposition or return of unused IMP, thus enabling reconciliation of all 
IMP received, and for ensuring that patients are provided with doses specified by the 
protocol. 
The study site should follow all instructions included with each shipment of IMP.  The 
study site will acknowledge receipt of IMPs supplied by the Sponsor, using the IxRS to 
confirm the shipment condition and content.  Any damaged shipments will be replaced.  
The investigator or designee must confirm that appropriate temperature conditions have 
been maintained during transit, either by time monitoring (shipment arrival date and 
time) or temperature monitoring, for all IMPs received and that any discrepancies have 
been reported and resolved before use of the IMPs.  All IMPs must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions, with access limited to the investigator 
and authorized staff. 
Only patients enrolled in the study may receive IMPs, and only authorized staff may 
supply or administer IMPs. 

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IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor with the appropriate 
documentation.  The site's method of destroying Sponsor-supplied IMPs must be agreed 
to by the Sponsor.  The site must obtain written authorization from the Sponsor before 
any Sponsor-supplied IMP is destroyed, and IMP destruction must be documented on 
the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the drug accountability log. 
Refer to the GDC-6599 Investigator's Brochure for information on IMP handling.  Tablets 
should not be stored above 30°C.  Accountability will be secured according to local work 
instructions. 
4.3.5 
Continued Access to GDC-6599 
Currently, the Sponsor (Genentech, a member of the Roche Group) does not have any 
plans to provide Genentech IMP (GDC-6599) or any other study treatments to patients 
who have completed the study.  The Sponsor may evaluate whether to continue 
providing GDC-6599 in accordance with the Roche Global Policy on Continued Access 
to Investigational Medicinal Product, available at the following website: 
https://assets.cwp.roche.com/f/176343/x/92d6b13ee6/policy continued access to invest
igational medicines.pdf 
4.4 
CONCOMITANT THERAPY, PROHIBITED FOOD, AND 
ADDITIONAL RESTRICTIONS 
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from 14 days 
prior to initiation of study drug to the safety follow-up Visit 8/early termination visit.  All 
such medications should be reported to the investigator and recorded on the 
Concomitant Medication eCRF or Adverse Event or Intercurrent Illness eCRF. 
4.4.1 
Permitted Therapy 
Patients are permitted to use the following therapies during the study: 

Oral contraceptives with a failure rate of  1% per year (see Section 4.1.1)

Hormone-replacement therapy

Medications necessary to treat underlying disease (asthma/COPD) except those that
are restricted prior to mannitol challenge test (see Section 4.4.4)

 
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 
Opioids (including codeine), pregabalin, gabapentin, amitriptyline, or nortriptyline 
for indications other than chronic cough are permitted, provided patients are 
receiving a stable treatment regimen for at least 2 weeks prior to screening and, in 
the opinion of the investigator, are likely to remain on the stable treatment regimen 
through completion of the study 
 
Oral or systemic corticosteroids for non-respiratory conditions is permitted, 
provided patients have been receiving a stable treatment regimen for at least 
8 weeks prior to screening and, in the opinion of the investigator, are likely to 
remain on the stable treatment regimen through completion of the study 
 
Oral corticosteroids as rescue therapy for the treatment of acute exacerbations is 
permitted 
 
PPI therapy is permitted, provided treatment was initiated at least 8 weeks prior to 
screening 
 
Treatments for conditions associated with chronic cough, such as GERD, asthma, 
upper airway cough syndrome (formerly called post-nasal drip) are permitted, if 
patients have been treated for at least 12 weeks for these comorbid conditions and 
are receiving a stable treatment regimen for at least 2 weeks prior to screening and, 
in the opinion of the investigator, are likely to remain on the stable treatment regimen 
through completion of the study   
 
Possible treatment options for comorbid conditions are provided in Table 3.  As this list 
in not meant to be comprehensive, consult Sponsor for additional information. 
Table 3 
Treatment for Comorbid Conditions of Chronic Chough 
Condition 
Treatment 
GERD 
Anti-reflux therapy (PPI or H2 blocker) and/or pro-kinetic agents 
Asthma 
Bronchodilators, ICS  
COPD 
Bronchodilators, ICS 
COPD  chronic obstructive pulmonary disease; GERD  gastroesophageal reflux disease; 
ICS  inhaled corticosteroid; PPI   proton-pump inhibitor. 
 
In general, investigators should manage a patient's care with supportive therapies as 
clinically indicated, per local standard practice.   
4.4.2 
Prohibited Therapy 
Use of the following concomitant therapies is prohibited as described below: 
 
Investigational therapy (other than protocol-mandated study treatment) is prohibited 
within 28 days or 5 drug-elimination half-lives (if known), whichever is longer, prior 
to initiation of study treatment and during study treatment 

 
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 
Treatment with any strong inhibitor or inducer of CYP3A within 28 days or 
5 drug-elimination half-lives, whichever is longer, prior to initiation of study drug is 
prohibited.  The use of any strong CYP3A inhibitor or inducer during the study is 
prohibited. 
Known strong CYP3A inducers: rifampin (also known as rifampicin), mitotane, 
avasimibe, rifapentine, apalutamide, phenytoin, carbamazepine, enzalutamide, 
ivosidenib, St John's wort, lumacaftor 
Known strong CYP3A inhibitors:  Please refer to the Indiana University Drug 
Interactions Flockhart Table (Flockhart et al. 2021)   
 
ACE inhibitors are prohibited within 8 weeks prior to screening through completion 
of the study at Visit 8. 
 
Use of opioids (including codeine), pregabalin, gabapentin, amitriptyline, or 
nortriptyline for the treatment of cough is prohibited within 2 weeks prior to 
screening through the end of the second treatment period. 
Treatment with any of these medications for indications other than chronic 
cough is permitted, provided patients are receiving a stable treatment regimen 
for at least 2 weeks prior to screening and, in the opinion of the investigator, 
are likely to remain on the stable treatment regimen through completion of the 
study. 
 
Use of dextromethorphan, guaifenesin, benzonatate, and any other over-the-counter 
cough-suppressant or prescription medication containing an anti-tussive or 
expectorant for the treatment of cough is prohibited within 2 weeks prior to 
screening through the end of the second treatment period. 
 
Use of oral or systemic corticosteroids for the treatment of respiratory disease, 
including cough, is prohibited within 8 weeks prior to screening through the end of 
the second treatment period. 
Continued, chronic use of oral or systemic corticosteroids for non-respiratory 
conditions is permitted, provided treatment was initiated at least 8 weeks prior 
to screening. 
Oral corticosteroids as rescue therapy for the treatment of acute exacerbations 
is permitted during the study. 
 
 
 
 
Initiation of proton-pump inhibitor (PPI) therapy is prohibited within 8 weeks 
prior to screening and is prohibited through the end of the second treatment period. 
Continued use of PPI therapy during the study is permitted, provided 
treatment was initiated at least 8 weeks prior to screening. 
 
Treatment with medications that are well known to prolong the QT interval is 
prohibited from within 1 month prior to screening through the completion of the 
study at Visit 8.   
Refer to Appendix 12 for a list of drugs associated with QT prolongation. 

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
Treatment with xanthines (e.g., theophylline, oxtriphylline) is prohibited within
24 hours prior to mannitol challenge tests.

Initiation of new dietary and herbal remedies which do not contain an active
anti-tussive or expectorant (e.g., lozenges, drops, teas, drinks, and similar
treatments) is prohibited, unless the supplement is not expected to interfere with the
study, as determined by the investigator in consultation with the Sponsor.
Patients who have been using such dietary and herbal remedies on a regular 
basis for at least 2 weeks prior to screening are eligible to enroll. 
Patients requiring a prohibited therapy will be discontinued from study treatment and 
will undergo follow-up assessments as described in Appendix 1 . 
4.4.3 
Prohibited Food 
Use of the following foods is prohibited for all patients as described below: 

Consumption of liquid or food containing grapefruit, Seville orange, pomelo, or
tangelo from 10 days prior to the first study visit until 72 hours after the final dose of
study drug

Consumption of alcohol from 24 hours prior to and 24 hours following each study
visit
4.4.4 
Additional Restrictions 
Activity restrictions: 

Patients should abstain from strenuous exercise and avoid noisy environments
(e.g., hair dryer, lawn equipment, open windows while driving, cinemas, listening to
music, etc.) while the VitaloJAK cough monitor is attached over a 24-hour period.
However, patients may participate in light recreational activities (e.g., watching
television at a low volume, reading).

Patients should not allow the VitaloJAK cough monitor, microphone, or chest
sensor to get wet.  Thus, they must avoid bathing or showering for the duration of the
24-hour recording.
The VitaloJAK chest sensor will be applied to the patient’s chest with an
adhesive (sticky pad).  If the patient has a known allergic sensitivity or reaction 
to adhesives, and in the opinion of the investigator the sensitivity or reaction is 
severe enough to impact the ability of the patient to complete the study, the 
patient should not be enrolled in this study. 
See the VitaloJAK site manual for further details. 

Patients should avoid vigorous exercise on the day of mannitol challenge test prior to
administration.

Patients should not consume caffeine within 12 hours prior to each mannitol
challenge test.

 
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Medication restrictions before provocation with mannitol: 
 
SABAs (short-acting -agonists) within 8 hours prior to each mannitol challenge 
 
ICS within 12 hours prior to each mannitol challenge 
 
Ipratropium bromide within 12 hours prior to each mannitol challenge 
 
Non-steroidal anti-inflammatory medications within 12 hours prior to each mannitol 
challenge test. 
 
Twice daily LABAs or ICS/LABAs within 24 hours prior to each mannitol challenge 
 
Xanthines (e.g., theophylline, oxtriphylline) within 24 hours prior to each mannitol 
challenge 
 
Tiotropium bromide within 72 hours prior to each mannitol challenge 
 
Oral antihistamines within 72 hours prior to each mannitol challenge 
 
Leukotriene-Modifiers within 4 days prior to each mannitol challenge 
 
4.5 
STUDY ASSESSMENTS  
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities should be performed and documented for each patient.   
Patients will be closely monitored for safety and tolerability throughout the study.  
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable. 
At applicable sites, certain study assessments such as blood draws may be performed 
by an MN professional at the patient's home or another suitable location to improve 
access and convenience for patients participating in the study.  The Sponsor will select a 
healthcare company that will be responsible for providing MN services for participating 
sites (the MN vendor).  The MN vendor is responsible for ensuring that all MN 
professionals are licensed, qualified, and in good standing, as per applicable regulations, 
and that appropriate background checks have been performed.  If the investigator at a 
participating site determines that MN services are appropriate for a patient and the 
patient gives written informed consent to participate in MN visits, the MN network will 
communicate with the patient and the patient's site.  MN visits will be scheduled on 
specified visit days, to allow for relevant assessments to be performed by the MN 
professional.  The schedule of activities (see Appendix 1) will specify the assessments 
that may be performed by an MN professional. 
4.5.1 
Informed Consent Forms and Screening Records 
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site. 

 
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All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a detailed record of 
all patients screened, to document eligibility or record reasons for screening failure, as 
applicable. 
4.5.2 
Medical History, Baseline Conditions, Concomitant Medication, 
and Demographic Data 
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), historical record of 
post-bronchodilator reversibility of FEV1 or documented methacholine positive test, 
history of acute exacerbations (asthma or COPD), reproductive status, smoking 
history, and use of alcohol and drugs of abuse, will be recorded at baseline.  In addition, 
all medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or 
homeopathic remedies, nutritional supplements) used by the patient within 14 days prior 
to initiation of study treatment will be recorded.  At the time of each follow-up physical 
examination, an interval medical history should be obtained and any changes in 
medications and allergies should be recorded. 
Demographic data, including age and sex, will be also recorded at baseline, along with 
self-reported race/ethnicity, sexual orientation, and gender identity for patients willing to 
provide this information (U.S. sites only). 
4.5.3 
Physical Examinations 
A complete physical examination, performed at screening and other specified visits, 
should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, and 
neurologic systems.  Any abnormality identified at baseline should be recorded on the 
General Medical History and Baseline Conditions eCRF. 
Limited, symptom-directed physical examinations should be performed at specified 
postbaseline visits and as clinically indicated.  Changes from baseline abnormalities 
should be recorded in patient notes.  New or worsened clinically significant abnormalities 
should be recorded as adverse events on the Adverse Event eCRF. 
Sensory neurologic examinations, including assessment of light touch, pain, vibration, 
temperature, and two-point discriminative sensations, will be performed at screening and 
other specified timepoints to identify potential changes in the peripheral sensory system.  
TPRA1 is expressed on peripheral terminals of nociceptive primary sensory neurons, 
where it is involved in the transduction of potentially harmful stimuli.  In addition, TRPA1 
is involved in amplification of nociceptive transmission in the central terminals of 
nociceptive primary sensory neurons.   
New or worsened clinically significant abnormalities should be recorded as adverse 
events on the Adverse Event eCRF.   

 
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4.5.4 
Vital Signs  
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressure (BP) while the patient is in a seated position, and temperature.  
Record abnormalities observed at baseline on the General Medical History and Baseline 
Conditions eCRF.  At subsequent visits, record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF. 
4.5.5 
Mannitol Challenge Test 
The mannitol challenge test is a commercially approved bronchial challenge test kit 
containing pre-filled mannitol capsules and a handheld dry powder inhaler device.  
During a mannitol challenge test, patients will orally inhale increasing doses of mannitol.  
After each dose, airway parameters will be measured by spirometry.  Inhalation of 
mannitol doses will continue until all doses (cumulative 635 mg) are inhaled, there is a 
 15% decrease in FEV1 relative to baseline, or there is a  10% decrease in FEV1 
between two successive doses.  The mannitol challenge test is required at Study 
Visit 1 (screening) and optional at Study Visits 4 and 7 (see Section 4.5.14).  Details 
regarding conduct of mannitol challenge are provided in the mannitol challenge test 
guidance. 
4.5.6 
Cough Monitoring 
Objective cough counting will be conducted as per the study’s pulmonary function and 
cough monitoring guidance documents, in addition to standard manual methods of 
counting during the mannitol challenge tests (Koskela et al. 2004; Koskela et al. 2018). 
Cough numbers will be assessed by the VitaloJAK (Vitalograph Inc.) semi-automated 
cough-monitoring system.  The VitaloJAK device will record ambulatory audio for 
24 hours from two channels, a lapel microphone (air) and a chest-facing sensor 
(skin).  A software algorithm will remove non-cough sounds from the 24-hour audio 
recordings, compressing the files to less than 10% (on average) of the original length 
enabling manual analysis to be completed more quickly.  The recordings will be 
reviewed by trained Vitalograph analysts who will count individual explosive cough 
sounds, yielding hourly and 24-hour OCCs.  
The VitaloJAK counting device will be provided to all study sites.  The VitaloJAK device 
will be used to record spontaneous coughs during for 24 hours on the first day of 
screening, for 24 hours prior to the first dose of study drug of each treatment period, 
and for 24 hours following each optional mannitol challenge test during each treatment 
period (or for 24 hours beginning approximately 3 hours after study drug 
administration, if mannitol challenge test is not performed), as outlined in the schedule 
of assessments (Appendix 1).  The pulmonary function and cough monitoring guidance 
documents will include information on equipment, procedures, patient instructions, and 
precautions regarding the use of the VitaloJAK.  Cough monitoring will be performed per 
the study’s cough monitoring guidance documents.  Required training on equipment use 
and data transfer methods will be provided. 

 
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4.5.7 
Spirometry 
Spirometry, including the procedure for mannitol challenge testing, will be conducted as 
per the study’s pulmonary function testing manual which is based on the American 
Thoracic Society (ATS)/European Respiratory Society (ERS) Consensus Statement 
“Standardization of Spirometry 2019 Update” (Graham et al. 2019).  The guidance will 
include information on equipment, procedures, patient instructions, and precautions.  
Spirometry will be performed on a centralized spirometry system (provided to all sites 
by the spirometry vendor), configured to the requirements of the study, and in 
accordance with ATS/ERS guidelines.  Spirometric measures to be collected will include 
FEV1 and FVC values as well as flow−volume and volume-time curves. The Global Lung 
Function Initiative (GLI) dataset (Quanjer et al. 2012) will be used to calculate 
percent-predicted FEV1 and FVC values.  The GLI data sets have been standardized 
on the basis of key demographic information that includes ethnicity and race.  It is 
therefore necessary to collect patient race/ethnicity to ensure that the most appropriate 
reference equation is used to establish the predicted values. 
Acceptability or usability of the spirometry data from the computerized configured 
system, including the graphic representations of the maneuvers, will be determined by 
over-readers blinded to study drug treatment.  Calculations for the reproducibility of the 
acceptable maneuvers will be performed and reviewed centrally by over-readers and/or 
the Medical Monitor blinded to study drug treatment and/or the Medical Monitor.  

 
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Spirometry data may be used if it does not meet the acceptability and reproducibility 
criteria but represents the patients’ best efforts and meets the ATS/ERS usability 
criterion, after discussion between the investigator and the Medical Monitor, as 
applicable.  
Patients must be aware that medications containing bronchodilators may affect 
spirometry and must be withheld until assessments are completed on the day of the 
study visits.  The last dose of SABAs must be administered at least 8 hours before 
testing and the last dose of LABAs must administered at least 24 hours prior to testing. 
Pre- and post-bronchodilator spirometry will be assessed during screening and at 
subsequent visits according to the schedules of assessments in Appendix 1.  
Study-specific training on equipment use, system calibration, and data storage and 
transfer will be provided by the Sponsor. 
4.5.8 
Fractional Exhaled Nitric Oxide  
Fractional exhaled nitric oxide (FeNO) is a volatile marker of airway inflammation and 
has been demonstrated to decrease with ICS treatment.  Measurement of FeNO will be 
performed through the use of a standard nitric oxide machine, in accordance with 
guidelines published by the ATS (training and guidance to be provided separately) 
(Dweik et al. 2011).  FeNO measurement must be performed before spirometry testing.  
To minimize the effect of diurnal variation, FeNO measurements should be performed at 
approximately the same time of day ( 2 hours) as the first measurement.  Patients 
should avoid consumption of nitrate-rich foods (such as processed meats [bacon, lunch 
meat, hot dog, and sausage], spinach, green beans, broccoli, and cauliflower) for at 
least 8 hours prior to FeNO measurement and avoid all food or drink and strenuous 
exercise at least 1 hour before FeNO measurement.  
 
 
 
 
4.5.10 
Laboratory, Biomarker, and Other Biological Samples  
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis:  
 
Urine pregnancy test 
 

 
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Samples for the following laboratory tests will be sent to the study site's local 
laboratory or to one or several central laboratories for analysis: 
 
ImmunoCAP Specific IgE test panel, skin prick test, or RAST for specific IgE 
against standard allergens for cat dander, dog dander, cockroach, dust mite, mold, 
and relevant local allergens  
The ImmunoCAP Specific IgE test panel, skin prick test, or RAST is required 
only for patients with asthma who do not have confirmed atopic versus non-
atopic status in their medical records.  Patient eligibility may be determined by 
medical history alone (see Section 4.1.1.2). 
 
Samples for the following laboratory tests will be sent to one or several central 
laboratories or to the Sponsor or a designee for analysis: 
 
Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
percentage and absolute differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells) 
 
Chemistry panel (serum or plasma):  bicarbonate, sodium, potassium, chloride, 
glucose, urea, creatinine, total protein, albumin, phosphate, calcium, total and direct 
bilirubin, ALP, ALT, AST, urate, and LDH 
 
Coagulation:  INR, aPTT, and PT  
 
Vitamin Kdependent coagulation factors:  Factors II, VII, IX, X, and protein C and S 
 
HIV serology:  HIV-1/2 antibody 
 
Hepatitis B virus serology:  HBsAg 
 
HCV serology:  HCV antibody for all patients; HCV RNA for patients with a positive 
HCV antibody test 
If a patient has a positive HCV antibody test at screening, an HCV RNA test 
must also be performed to determine if the patient has an HCV infection. 
 
Follicle-stimulating hormone (FSH) at screening to confirm postmenopausal state, 
if required per local guidelines. 
 
Serum pregnancy test 
All women of childbearing potential will have a serum pregnancy test at 
screening.  Urine or serum pregnancy tests will be performed at specified 
subsequent visits.  If a urine pregnancy test is positive, it must be confirmed by 
a serum pregnancy test. 
Test for FSH may be performed at screening to confirm postmenopausal state, 
if required per local guidelines. 
 
Urinalysis, including dipstick (pH, specific gravity, glucose, protein, ketones, blood), 
and urine creatinine 
Microscopic examination (sediment, RBCs, WBCs, casts, crystals, epithelial 
cells, bacteria) should be performed if the dipstick is abnormal.  

 
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 
COVID-19 testing at screening 
COVID-19 testing is to be performed as per local regulations or institutional 
policies. 
 
 
 for exploratory research on 
biomarkers and biomarker assay development.  Exploratory biomarker research may 
include, but will not be limited to 
 
.  Research may involve whole genome sequencing (WGS) or whole 
exome sequencing (WES) of blood samples, but only at participating sites (see 
Section 4.5.13). 
Venous blood samples will be collected for measurement of plasma concentrations of 
GDC-6599 (by validated assay), as specified in the schedule of activities.  The actual 
date and time (24-hour clock time) of each sample will be recorded.  Plasma samples 
collected for PK analysis may be needed for PK assay development and validation and 
evaluation of metabolites; therefore, these samples will be destroyed no later than 
5 years after the final Clinical Study Report has been completed.  Previously collected 
sputum samples may also be analyzed for GDC-6599 concentration. 
including those collected from patients who do not enroll in the study, may be used for 
research related to the development of disease-related tests or tools. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.15), biological samples will be destroyed 
no later than the time of completion of the final Clinical Study Report, with the following 
exceptions: 
 
collected for biomarker research and biomarker assay development will be 
destroyed no later than 5 years after the final Clinical Study Report has been 
completed, with the exception of tissue samples that undergo WGS or WES, which 
will be stored until they are no longer needed or until they are exhausted.  However, 
the storage period will be in accordance with the IRB/ECapproved Informed 
Consent Form and applicable laws (e.g., health authority requirements). 
 
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 

 
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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. 
Data arising from sample analysis, including data on genomic variants, will be subject to 
the confidentiality standards described in Section 8.4. 
Data generated from samples collected for exploratory biomarker research will be 
analyzed in aggregate rather than on an individual patient basis. Thus, there will be no 
identification and reporting of incidental findings to investigators or patients.  In addition, 
given the complexity and exploratory nature of biomarker analyses, data derived from 
these analyses will generally not be provided to investigators or patients unless required 
by law. The aggregate results of any conducted research will be available in accordance 
with the effective Sponsor policy on study data publication. 
4.5.11 
Electrocardiograms 
A single 12-lead ECG will be performed at screening to confirm eligibility.  If the initial 
QTcF  450 ms, the ECG should be repeated at least 30 minutes after the first ECG.  
The patient may be enrolled if second QTcF  450 ms.  Thereafter, a single 12-lead ECG 
recording must be obtained for each specified timepoint.  Single 12-lead ECG recordings 
may also be obtained at unscheduled timepoints.  Triplicate ECGs are not required; 
however, ECGs with artifacts that may interfere with interpretation should be repeated. 
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting in a supine position for at least 10 minutes.  
All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws) and should not be obtained within 3 hours 
after any meal.  Circumstances that may induce changes in heart rate, including 
environmental distractions (e.g., television, radio, conversation) should be avoided 
during the pre-ECG resting period and during ECG recording. 
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site. Digital recordings will be stored at the site. The following should be 
recorded in the appropriate eCRF:  heart rate, RR interval, QRS interval, PR duration, 
uncorrected QT interval, and QTcF based on the machine readings of the individual 
ECG tracings.  Any morphologic waveform changes or other ECG abnormalities must be 
documented on the eCRF.  If considered appropriate by the Sponsor, ECGs may be 
analyzed retrospectively at a central laboratory. 
If at a particular timepoint the mean QTcF is  500 ms and/or  60 ms longer than the 
baseline value, another ECG must be recorded, ideally within the next 5 minutes, and 

 
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ECG monitoring should continue until QTcF has stabilized on two successive ECGs.  
The Medical Monitor should be notified.  Standard-of-care treatment may be instituted 
per the discretion of the investigator.  If a PK sample is not scheduled for that timepoint, 
an unscheduled PK sample should be obtained.  A decision on study drug 
discontinuation should be made, as described in Section 5.1.3.3.  The investigator 
should also evaluate the patient for potential concurrent risk factors (e.g., electrolyte 
abnormalities, co-medications known to prolong the QT interval, severe bradycardia). 
4.5.12 
Clinical Outcome Assessments 
The following PRO instruments will be completed to characterize the patient-reported 
symptoms and impact associated with chronic cough in patients with CRC with asthma, 
CRC with COPD, or UCC and to assess the treatment benefit across the study 
populations and patient experience of GDC-6599:  
 
 VAS, and NRS.  The 
 will be completed to characterize patient-reported symptoms in patients 
with CRC asthma.  On days when multiple PRO assessments are scheduled, the order 
of questionnaire completion is the following:  
, VAS, and NRS. 
4.5.12.1 
Data Collection Methods for Clinical Outcome Assessments 
The 
, and VAS will be self-administered at the clinic at specified 
timepoints during the study (see schedule of activities in Appendix 1).  The NRS and 
VAS will be self-administered at home via ePRO on a daily basis according to the 
schedule of assessments.  At the clinic, PRO assessments will be administered before 
the patient receives any information on disease status, prior to the performance of 
non-PRO assessments, and prior to the administration of study treatment unless 
otherwise specified. 
PRO instruments, translated into the local language as appropriate, will be completed 
through use of an electronic device provided by the Sponsor (note that 
 will be 
completed on paper with responses captured in the ePRO database).  The device will be 
pre-programmed to enable the appropriate instruments to be administered in the correct 
order at each specified timepoint.  The electronic device and instructions for completing 
the instruments electronically will be provided by the site staff.  The data will be 
transmitted to a centralized database maintained by the electronic device vendor.  The 
data will be available for access by appropriate study personnel.  
Patients should be given the following instructions for completing PRO instruments at 
home: 
 
Patients should complete the instruments in a quiet area with minimal distractions 
and disruptions. 
 
Patients should answer questions to the best of their ability; there are no right or 
wrong answers. 

 
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 
Patients should not obtain advice or help from others (e.g., family members or 
friends) when completing the instruments. 
During clinic visits, PRO instruments should be administered as outlined below: 
 
Patients' health status should not be discussed prior to administration of the 
instruments. 
 
Sites must administer the official version of each instrument, as provided by the 
Sponsor.  Instruments must not be copied from the protocol. 
 
Sites should allow sufficient time for patients to complete the instruments, estimated 
to be 10 minutes at each specified visit. 
 
Sites should administer the instruments in a quiet area with minimal distractions and 
disruptions. 
 
Patients should be instructed to answer questions to the best of their ability; there 
are no right or wrong answers. 
 
Site staff should not interpret or explain questions, but may read questions verbatim 
upon request. 
 
Patients should not obtain advice or help from others (e.g., family members or 
friends) when completing the instruments. 
  
4.5.12.2 
Description of Clinical Outcome Assessment Instruments 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 

 
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. 
Visual Analog Scale  
The VAS is a single-item rating used for the subjective assessment of cough severity.  
Patients will be asked to indicate the severity of their cough by marking a line on a scale 
between anchor statements of ‘no cough’ and ‘worst cough’ using a recall period of 
‘today’.  A copy of the VAS is provided in Appendix 6. 
Numeric Response Scale 
The NRS is a single-item measure of cough severity.  Patients will be asked to rate the 
severity of their cough from 0 (no cough) to 10 (worst cough) using a recall period of 
‘today’.  A copy of the NRS is provided in Appendix 7.  
4.5.13 
Blood Samples for Whole Genome Sequencing or Whole 
Exome Sequencing (Patients at Participating Sites) 
At participating sites, blood samples will be collected for DNA extraction to enable WGS 
or WES to identify variants that are predictive of response to study drug, are associated 
with progression to a more severe disease state, are associated with susceptibility to 
developing adverse events, can lead to improved adverse event monitoring or 
investigation, or can increase the knowledge and understanding of disease biology and 
drug safety.  Research will include exploration of germline variants.  The samples may 
be sent to one or more laboratories for analysis. 
Collection and submission of blood samples for WGS or WES is contingent upon the 
review and approval of the exploratory research by each site's Institutional Review Board 
or Ethics Committee (IRB/EC) and, if applicable, an appropriate regulatory body.  If a 
site has not been granted approval for WGS or WES, this section of the protocol 
(Section 4.5.13) will not be applicable at that site. 
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS and WES provide a comprehensive characterization of the genome and exome, 
respectively, and, along with clinical data collected in this study, may increase the 
opportunity for developing new therapeutic approaches or new methods for monitoring 
efficacy and safety or predicting which patients are more likely to respond to a drug or 
develop adverse events.  Data will be analyzed in the context of this study but may also 
be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.   

 
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Blood samples collected for WGS or WES are to be stored until they are no longer 
needed or until they are exhausted.  However, the storage period will be in accordance 
with the IRB/ECapproved Informed Consent Form and applicable laws (e.g., health 
authority requirements). 
Refer to Section 4.5.10 for details on use of samples after patient withdrawal and 
confidentiality standards for data. 
Data generated from blood samples collected for WGS or WES will be analyzed in 
aggregate rather than on an individual patient basis.  Thus, there will be no identification 
and reporting of incidental findings to investigators or patients.   
If permitted by local law, a patient may request access to uninterpreted WGS or WES 
data derived from analysis of his or her blood sample.  If a patient wishes to access 
these data, the investigator must inform the Sponsor, using the following email address:  
global.return-genomics-results@roche.com.  The Sponsor will provide available data to 
the investigator in the form of a raw genomic sequencing data file, but will not provide 
any interpretation of the data.  The investigator should not include the data file in the 
patient's medical record.  Samples may be stored and analyzed in the future, and some 
samples may never be analyzed.  Thus, data may not be available at the time of the 
request or may never be available. 
The aggregate results of any conducted research will be available in accordance with 
the effective Sponsor policy on study data publication. 
4.5.14 
Optional Mannitol Challenge Tests 
Consenting patients will undergo optional mannitol challenge tests during each 
treatment period at Study Visits 4 and 7.  Each mannitol challenge test is to be 
performed at least 2.5 hours after study drug administration.  Details on the mannitol 
challenge test are provided in Section 4.5.5 and in the mannitol challenge test 
guidance.  See Section 4.5.6 for details on cough monitoring during the challenges.  
Medication restrictions prior to the mannitol challenge are provided in Section 4.4.4.  
The Informed Consent Form will contain a separate section that addresses the optional 
mannitol challenge tests.  A separate, specific signature will be required to document a 
patient's agreement to undergo the optional mannitol challenge tests.  The investigator 
should document whether or not the patient has given consent to participate and (if 
applicable) the date of consent, by completing the Sample Informed 
Consent/Withdrawal eCRF. 
Samples may be used for exploratory biomarker research as described in Section 4.5.10.  
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  Refer to Section 4.5.10 for details on duration of sample storage, 

 
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use of samples after subject withdrawal, confidentiality standards for data, 
and availability of data from biomarker analyses.  
4.5.15 
Optional Samples for Research Biosample Repository  
4.5.15.1 
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 biological specimens, including body fluids, 
solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The 
collection, storage, and analysis of RBR samples will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future. 
Samples for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR samples will be analyzed to achieve one or 
more of the following objectives: 
 
To study the association of biomarkers with efficacy or disease progression 
 
To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation 
 
To increase knowledge and understanding of disease biology and drug safety 
 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
4.5.15.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the Informed Consent Form 
by each site's IRB/EC and, if applicable, an appropriate regulatory body.  If a site has not 
been granted approval for RBR sampling, this section of the protocol (Section 4.5.15.2) 
will not be applicable at that site. 
4.5.15.3 
Sample Collection 
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to GDC-6599 or TRPA1, 
diseases, or drug safety: 
 
and any derivatives thereof (e.g., DNA, RNA, proteins, peptides); see 
 for 
schedule of sample collection. 
 
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic variants via WGS, WES, or other genomic analysis methods.  Genomics is 

 
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increasingly informing researcher's understanding of disease pathobiology.  WGS and 
WES provide a comprehensive characterization of the genome and exome, respectively, 
and, along with clinical data collected in this study, may increase the opportunity for 
developing new therapeutic approaches or new methods for monitoring efficacy and 
safety or predicting which patients are more likely to respond to a drug or develop 
adverse events. 
Data generated from RBR samples will be analyzed in the context of this study but may 
also be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.   
RBR samples are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/ECapproved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
4.5.15.4 
Data Protection, Use, and Sharing 
RBR samples and associated data will be labeled with a unique patient identification 
number. 
Patient medical information associated with RBR samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Data generated from RBR samples will be analyzed in aggregate rather than on an 
individual patient basis.  Thus, there will be no identification and reporting of incidental 
findings to investigators or patients.  In addition, given the complexity and exploratory 
nature of the analyses of RBR samples, data derived from these analyses will generally 
not be provided to study investigators or patients, unless required by law, with the 
exception of data generated from blood samples collected for WGS or WES as 
described below. 
If permitted by local law, a patient may request access to uninterpreted WGS or WES 
data derived from analysis of his or her blood sample.  If a patient wishes to access 
these data, the investigator must inform the Sponsor, using the following email address:  
global.return-genomics-results@roche.com.  The Sponsor will provide available data to 
the investigator in the form of a raw genomic sequencing data file, but will not provide 
any interpretation of the data.  The investigator should not include the data file in the 
patient's medical record.  Samples may be stored and analyzed in the future, and some 

 
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samples may never be analyzed.  Thus, data may not be available at the time of 
the request or may never be available.  
The aggregate results of any conducted research will be available in accordance with 
the effective Sponsor policy on study data publication. 
Data generated from RBR samples 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. 
4.5.15.5 
Consent to Participate in the Research Biosample Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR samples.  Patients 
who decline to participate will not provide a separate signature.  The investigator should 
document whether or not the patient has given consent to participate and (if applicable) 
the date of consent, by completing the Sample Informed Consent/Withdrawal eCRF. 
In the event of an RBR participant's death or loss of competence, the participant's 
samples and data will continue to be used as part of the RBR research. 
4.5.15.6 
Withdrawal from the Research Biosample Repository 
Patients who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed.  However, if RBR samples have been tested prior to withdrawal of 
consent, results from those tests will remain as part of the overall research data.  If a 
patient wishes to withdraw consent to the testing of his or her RBR samples during the 
study, the investigator must inform the Medical Monitor in writing of the patient's wishes 
through use of the appropriate RBR Subject Withdrawal Form and must enter the date of 
withdrawal on the Sample Informed Consent/Withdrawal eCRF.  If a patient wishes to 
withdraw consent to the testing of his or her RBR samples after closure of the site, the 
investigator must inform the Sponsor by emailing the study number and patient number 
to the following email address: 
global_rcr-withdrawal@roche.com 

 
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A patient's withdrawal from this study does not, by itself, constitute withdrawal of consent 
for testing of RBR samples.  Likewise, a patient's withdrawal of consent for testing of 
RBR samples does not constitute withdrawal from this study. 
4.5.15.7 
Monitoring and Oversight 
RBR samples will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of samples as specified in this protocol and in the Informed 
Consent Form.  Sponsor monitors and auditors will have direct access to appropriate 
parts of records relating to patient participation in the RBR for the purposes of verifying 
the data provided to the Sponsor.  The site will permit monitoring, audits, IRB/EC review, 
and health authority inspections by providing direct access to source data and 
documents related to the RBR samples. 
4.6 
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Study Treatment Discontinuation 
A patient must permanently discontinue study treatment if any of the following criteria 
are met: 
 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient's safety if he or she continues to receive study treatment 
 
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient 
 
Pregnancy 
 
Serious adverse event related to study drug in the opinion of the investigator and 
Sponsor 
 
Clinically significant Grade  3 adverse event, as determined by the investigator, 
related to study drug 
 
Persistent ( 2 hours) Grade 1 bleeding 
 
 
– 
– 
– 
 
 
INR  4 and Grade 3 or Grade 4 bleeding 
 
 
ALT or AST elevation  3  ULN in combination with either total bilirubin  2  ULN or 
clinical jaundice (Hy’s Law; see Section 5.3.5.6) 
 
Episode of torsades de pointes (unless there is a clear alternative cause for the 
changes) 

 
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 
Sustained (at least two ECG measurements  30 minutes apart) QTcF that is 
 500 ms and  60 ms longer than the baseline value or sustained QTcF  515 ms 
(unless there is a clear alternative cause for the changes) 
 
Patient requirement for a prohibited therapy (see Section 4.4.2) 
 
The IMC will review any event suggestive of a significant safety risk to patients.  Study 
treatment for all enrolled patients may be paused or discontinued pending IMC review if 
any of the following criteria are met in two or more patients: 
 
Elevated ALT or AST in combination with either an elevated bilirubin or clinical 
jaundice as defined by Hy’s law (see Section 5.3.5.6) 
 
Sustained (at least two ECG measurements  30 minutes apart) QTcF that is 
 500 ms and  60 ms longer than the baseline value or sustained QTcF  515 ms 
(unless there is a clear alternative cause for the changes) 
 
Episode of torsades de pointes (unless there is a clear alternative cause for the 
changes)  
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced. 
Patients will return to the clinic for a treatment completion or treatment discontinuation 
days after the final dose of study drug. 
Refer to the schedule of activities (see Appendix 1) for details on follow-up assessments 
to be performed for patients who permanently discontinue study treatment.  If a patient 
requests to be withdrawn from treatment or follow-up assessments, this request must be 
documented in the source documents and signed by the investigator. 
4.6.2 
Patient Discontinuation from the Study 
Patients will return to the clinic for a study completion or study discontinuation visit at 
 after the last dose of study drug. 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time. 
Reasons for patient discontinuation from the study may include, but are not limited to, 
the following: 
 
Patient withdrawal of consent 
 
Study termination or site closure 
 
Adverse event 
 
Loss to follow-up 

 
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 
Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor 
 
Every effort should be made to obtain a reason for patient discontinuation from the 
study.  The primary reason for discontinuation from the study should be documented on 
the appropriate eCRF.  If a patient requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator.  Patients 
who withdraw from the study will not be replaced. 
4.6.3 
Study Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients 
 
Any event or scenario leading to permanent cessation of dosing in all patients 
(Section 4.6.1) and for which the IMC (in consultation with the investigator) cannot 
identify an adequate risk mitigation measure or therapeutic margin 
 
Patient enrollment is unsatisfactory 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.   
4.6.4 
Site Discontinuation 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
 
Excessively slow recruitment 
 
Poor protocol adherence 
 
Inaccurate or incomplete data recording 
 
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice 
 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
GDC-6599 is not approved, and clinical development is ongoing.  The safety plan for 
patients in this study is based on nonclinical data and clinical experience with GDC-6599 
in the completed first-in-human Phase Ia/b SAD and MAD study in healthy volunteers 
(Study GA43010).   
However, the full spectrum of risks in humans has not yet been fully characterized.  
Therefore, the anticipated potential/theoretical risks for GDC-6599 outlined below are 
based on the anticipated mechanism of action and results from nonclinical studies.  

 
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Please refer to GDC-6599 Investigator's Brochure for a complete summary of safety 
information.  
The mannitol challenge test is a commercially approved bronchial challenge test kit 
containing prefilled mannitol capsules and a handheld dry powder inhaler device.  
Please refer to local prescribing information for a complete summary of safety 
information. 
Several measures will be taken to ensure the safety of patients participating in this 
study.  Eligibility criteria have been designed to exclude patients at higher risk for 
toxicities (see Section 4.1).  Patients will undergo safety monitoring during the study, 
including assessment of the nature, frequency, and severity of adverse events.  In 
addition, guidelines for managing adverse events, including criteria for treatment 
interruption or discontinuation, are provided below. 
5.1.1 
Risks Associated with GDC-6599 
 
 
 

 
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5.1.1.2 
Impaired Cough Reflex 
Ion channels of the TRP class are important in the afferent sensory loop of the cough 
reflex and in the heightened cough sensitivity seen in disease.  There is growing 
evidence for both TRPV1 and TRPA1 in peripheral sensitization and cough (Morice et al. 
2014).  Specifically, TRPA1 is expressed in small diameter, nociceptive neurons in the 
airways, where its activation by cold temperatures and environmental irritants may 
contribute to the perception of noxious stimuli and the stimulation of vagal sensory 
afferent neurons leading to central reflexes including cough, which is necessary to 
remove the foreign material from the respiratory tract (Grace et al. 2011).  For this 
reason, there is a theoretical risk that inhibition of TRPA1 may impair normal cough 
reflexes. 
As a result, antagonists of TRPA1, such as GDC-6599, may reduce sensitivity to foreign 
material in the airways, which may increase the risk of aspiration pneumonitis and lower 
respiratory tract infections.  Individuals with a history of recurrent lower respiratory tract 
infections, such as pneumonia, have been shown to have a decreased response to 
capsaicin, an agonist of TRPV1 (Niimi et al. 2003).  It is unknown whether this 
association is unique to TRPV1 or generalizable to other TRP-class ion channels.  
Conversely, in patients with a history of severe asthma, increased sensitivity to capsaicin 
was associated with poorer asthma control, suggesting that in pathogenic processes 
such as asthma, the cough reflex is maladaptive (Kanemitsu et al. 2020). 
Animal studies of GDC-6599 found no evidence of impairment in cough or increased risk 
of lower respiratory tract infections.  However, animals included in toxicity studies are 
healthy, are prescreened for certain infectious agents with negative test results before 
study start, and are housed in a controlled laboratory environment that limits the risks of 
infections.  Thus, the absence of findings may not be predictive of the risk for human 
subjects. 
Patients with a history of aspiration will be excluded from participating in the study 
(see Section 4.1.2), and patients will be closely monitored for respiratory tract infections. 
Guidelines for management of patients who develop lower respiratory tract infections are 
provided in Section 5.1.3.2.  

 
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5.1.2 
Potential Risks Associated with Mannitol Challenge Test  
Investigators should be aware of the risks associated with the mannitol challenge test 
and guidelines for managing those risks.  Please refer to the local prescribing guidelines 
for the mannitol challenge test (Aridol/Osmohale) for full information.  
5.1.2.1 
Severe Bronchospasm 
Mannitol acts as a bronchoconstrictor and may cause severe bronchospasms in 
susceptible patients.  The test should only be conducted by trained professionals under 
the supervision of a physician familiar with all aspects of the bronchial challenge test and 
the management of acute bronchospasm.  Patients should not be left unattended during 
the bronchial challenge test.  Medications and equipment to treat severe bronchospasm 
must be present in the testing area.  If severe bronchospasm occurs, it should be treated 
immediately by administration of a SABA.  Because of the potential for severe 
bronchoconstriction, the bronchial challenge testing with mannitol should not be 
performed in any patient with very low baseline pulmonary function tests (e.g., 
FEV1  11.5 liters or  60% of the predicted values)  
If a patient has a  10% reduction in FEV1 (from pre-challenge FEV1) on administration of 
the 0 mg capsule, the mannitol challenge test should be discontinued and the patient 
should be given a dose of an inhaled SABA and monitored accordingly.  

 
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Table 4 
Guidelines for Management of Patients Who Experience Adverse 
Events (cont.) 
Event 
Action to Be Taken 
Coagulation abnormalities 
INR  4 without evidence of 
bleeding 
 
Contact Medical Monitor. 
 
Administer Vitamin K (10 mg PO daily) until INR 
 1.5 and at least 5 GDC-6599 drug-elimination 
half-lives have elapsed (estimated to be 4 days). 
 
If no response to Vitamin K, consider administering 
PCC or FFP. 
 
Consider subspecialist (hematology) consultation. 
INR  4 and Grade 3 or Grade 4 
bleeding  
 
Discontinue study drug. 
 
Administer 4-factor PCC or FFP. 
Impaired cough reflex 
FFP  fresh frozen plasma; GGT   gamma-glutamyl transferase; IDSA  Infectious Diseases 
Society of America; PCC  prothrombin complex concentrate; ULN  upper limit normal; 
PO  by mouth. 
a https://www.idsociety.org/practice-guideline/practice-guidelines/#/date_na_dt/DESC/0/+/). 
 

 
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5.1.3.3 
Management of Increases in QT Interval   
Study drug should be discontinued in patients who develop any of the following, unless 
there is a clear alternative cause for the changes: 
 
Sustained (at least two ECG measurements  30 minutes apart) QTcF that is 
 500 ms and  60 ms longer than the baseline value 
 
Sustained absolute QTcF that is  515 ms  
 
An episode of torsades de pointes or a new ECG finding of clinical concern 
 
Of note, if there is a new intraventricular conduction block, the increase in QRS complex 
duration should be subtracted from the QTcF change, because this represents an 
increase in QTcF unrelated to alterations in repolarization.  Also of note, it is not 
uncommon to record arrhythmias such as non-sustained ventricular tachycardia, 
supraventricular tachycardia, pauses, or atrial fibrillation in healthy volunteers receiving 
placebo during periods of extended ECG monitoring.  Therefore, it is critical that expert 
cardiology advice be sought to confirm any ECG changes and to ascertain the likelihood 
of a drug-induced arrhythmia versus the background occurrence of this arrhythmia.  
In such a situation, saving all available ECG data is highly suggested. 
Management of patients with sustained QTcF prolongation should include close 
monitoring, with ECGs repeated at least hourly until two successive ECGs show 
resolution of the findings, correction of any electrolyte abnormalities, and possible 
discontinuation of other concomitant medications that are known to prolong the QT 
interval.  Consultation with a cardiologist or electrophysiologist is recommended, to help 
in the management of such patients. 
In rare circumstances, it may be acceptable to resume study drug, at a lower dose, 
provided that any ECG abnormalities have resolved and the patient is appropriately 
monitored.  Clinical judgment should be applied. 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 

 
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5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation patient administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.9 
and 5.3.5.10 for more information) 
 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
 
Is fatal (i.e., the adverse event actually causes or leads to death) 
 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death. 
 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.10) 
 
Results in persistent or significant disability/incapacity (i.e., the adverse event results 
in substantial disruption of the patient's ability to conduct normal life functions) 
 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to 
DAIDS Table v2.1 toxicity scale; see Section 5.3.3); the event itself may be of relatively 
minor medical significance (such as severe headache without any further findings). 

 
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Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows: 
 
 
Clinically significant Grade  3 adverse event, as determined by the investigator 
 
 
– 
– 
– 
 
 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.6) 
 
Suspected transmission of an infectious agent by the study drug, as defined below 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected. 
 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6. The 
investigator is also responsible for reporting medical device complaints (see 
Section 5.4.4). 

 
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For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).   
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events). 
After initiation of study drug, all adverse events will be reported until 28 days after the 
final dose of study drug. 
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6. 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
 
5.3.3 
Assessment of Severity of Adverse Events 
The investigator will use the DAIDS toxicity grading scale (HHS 2017), with slight 
modifications for clarity and for alignment with internal practices (see Appendix 10), for 
assessing the severity of each adverse event reported during the study.  The 
investigator will use the grading scale in Table 5 for assessing the severity of adverse 
events that are not specifically listed in the DAIDS toxicity grading scale. 

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Table 5 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in DAIDS 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 
DAIDS  Division of AIDS. 
Notes:  Developed by the Division of AIDS, National Institute of Allergy and Infectious Diseases, 
National Institutes of Health, U.S. Department of Health and Human Services. 
Regardless of severity, some events may also meet seriousness criteria.  Refer to definition of a 
serious adverse event (see Section 5.2.2). 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see also 
Table 6): 

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction,
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the
occurrence of the event

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Table 6 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug). 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
5.3.5.2 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 

If vomiting results in mild dehydration with no additional treatment in a healthy adult,
only vomiting should be reported on the eCRF.

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

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

 
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5.3.5.6 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST ( 3  ULN) in combination with either an elevated 
total bilirubin ( 2  ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
 
Treatment-emergent ALT or AST  3  ULN in combination with total bilirubin 
 2  ULN 
 
Treatment-emergent ALT or AST  3  ULN in combination with clinical jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2). 
5.3.5.7 
Deaths 
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).This 
includes death attributed to progression condition being studied. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
If the death is attributed solely to progression of chronic cough, "chronic cough 
progression" should be recorded on the Adverse Event eCRF. 
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6. 
5.3.5.8 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 

 
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A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
5.3.5.9 
Lack of Efficacy or Worsening of Chronic Cough 
Medical occurrences or symptoms of deterioration that are anticipated as part of chronic 
cough should not be recorded as adverse events.  However, deterioration that is judged 
by the investigator to have unexpectedly worsened in severity or frequency or changed 
in nature at any time during the study should be recorded as an adverse event.  When 
recording an unanticipated worsening of chronic cough on the Adverse Event eCRF, it is 
important to convey the concept that the condition has changed by including applicable 
descriptors (e.g., "accelerated worsening of chronic cough”). 
5.3.5.10 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.   
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
 
Hospitalization for respite care 
 
Planned hospitalization required by the protocol (e.g., for study drug administration 
or insertion of access device for study drug administration) 
 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
The patient has not experienced an adverse event. 
 
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead: 
 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 

 
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5.3.5.11 
Cases of Overdose, Medication Error, Drug Abuse, or Drug 
Misuse 
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse 
(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 
 
Intentional overdose:  intentional 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. 
 
Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm 
 
Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse 
In cases where drug is to be self-administered by the patient, drug misuse 
could involve the drug being administered to someone other than the patient. 
 
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria or qualifies as an adverse event of special interest, the event should 
be reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).  For GDC-6599 (or matching placebo), adverse events 
associated with special situations should be recorded as described below for each 
situation: 
 
Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes. 
 
Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug 
abuse is not suspected, check the "Drug misuse" box. 
 
Medication error that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Accidental overdose" and "Medication error" boxes. 
 
Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box. 
 
Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes. 

 
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 
Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box. 
 
Drug misuse that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Intentional overdose" and "Drug misuse" boxes. 
 
In addition, all special situations associated with GDC-6599 (or matching placebo), 
regardless of whether they result in an adverse event, should be recorded on the 
Adverse Event eCRF as described below: 
 
Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes. 
 
Intentional overdose:  Enter the drug name and "intentional overdose" as the event 
term.  Check the "Intentional overdose" box.  If drug abuse is suspected, check the 
"Drug abuse" box.  If drug abuse is not suspected, check the "Drug misuse" box. 
 
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. 
 
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. 
 
Drug abuse that does not qualify as an overdose:  Enter the drug name and "drug 
abuse" as the event term.  Check the "Drug abuse" box. 
 
Drug abuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug abuse" 
boxes. 
 
Drug misuse that does not qualify as an overdose:  Enter the drug name and "drug 
misuse" as the event term.  Check the "Drug misuse" box. 
 
Drug misuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug misuse" 
boxes. 
 
Drug administered to someone other than the patient:  Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Drug misuse" 
box. 
 
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries. 

 
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5.3.5.12 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO data by the Sponsor.  Sites are not 
expected to review PRO data for adverse events. 
5.3.5.13 
Safety Biomarker Data  
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this 
study.  In addition, safety biomarker data will not inform decisions on patient 
management. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
 
Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements) 
 
Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements) 
 
Pregnancies (see Section 5.4.3 for details on reporting requirements) 
 
Medical device complaints (see Section 5.4.4 for details on reporting requirements) 
 
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information to the Sponsor immediately (i.e., no more 
than 24 hours after becoming aware of the information).  New significant information 
includes the following: 
 
New signs or symptoms or a change in the diagnosis 
 
Significant new diagnostic test results 
 
Change in causality based on new information 
 
Change in the event's outcome, including recovery 
 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
To ensure the safety of study participants, access to the Medical Monitors is available 
24 hours per day, 7 days per week.  Details will be provided separately. 

 
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5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators. 
5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 28 days after the final dose of study drug.  Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to Safety 
Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.   
Instructions for reporting serious adverse events that occur  28 days after the final dose 
of study treatment are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed through the Informed Consent 
Form to immediately inform the investigator if they become pregnant during the study or 
within 
 after the final dose of study drug. A paper Clinical Trial Pregnancy 
Reporting Form should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the pregnancy), either by 
faxing or by scanning and emailing the form using the fax number or email address 
provided to investigators.  Pregnancy should not be recorded on the Adverse Event 
eCRF.  The investigator should discontinue study drug and counsel the patient, 
discussing the risks of the pregnancy and the possible effects on the fetus.  Monitoring 
of the patient should continue until conclusion of the pregnancy.  Any serious adverse 
events associated with the pregnancy (e.g., an event in the fetus, an event in the mother 
during or after the pregnancy, or a congenital anomaly/birth defect in the child) should be 

 
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reported on the Adverse Event eCRF.  In addition, the investigator will submit a Clinical 
Trial Pregnancy Reporting Form when updated information on the course and outcome 
of the pregnancy becomes available.   
Attempts should be made to collect and report infant health information.  When permitted 
by the site, an Authorization for the Use and Disclosure of Infant Health Information 
would need to be signed by one or both parents (as per local regulations) to allow for 
follow-up on the infant.  If the authorization has been signed, the infant's health status at 
birth should be recorded on the Clinical Trial Pregnancy Reporting Form.  In addition, the 
Sponsor may collect follow-up information on the infant's health status at 6 and 
12 months after birth. 
5.4.3.2 
Pregnancies in Female Partners of Male Patients  
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
 after the final dose of study drug.  The investigator should report the pregnancy 
on the paper Clinical Trial Pregnancy Reporting Form and submit the form to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy), either by faxing or by scanning and emailing the form using the fax number 
or email address provided to investigators.  Attempts should be made to collect and 
report details of the course and outcome of any pregnancy in the partner of a male 
patient exposed to study drug.  When permitted by the site, the pregnant partner would 
need to sign an Authorization for the Use and Disclosure of Pregnancy Health 
Information to allow for follow-up on her pregnancy.  If the authorization has been 
signed, the investigator should submit a Clinical Trial Pregnancy Reporting Form with 
additional information on the pregnant partner and the course and outcome of the 
pregnancy as it becomes available.   
Attempts should be made to collect and report infant health information.  When permitted 
by the site, an Authorization for the Use and Disclosure of Infant Health Information 
would need to be signed by one or both parents (as per local regulations) to allow for 
follow-up on the infant.  If the authorization has been signed, the infant's health status at 
birth should be recorded on the Clinical Trial Pregnancy Reporting Form.  In addition, the 
Sponsor may collect follow-up information on the infant's health status at 6 and 
12 months after birth. 
An investigator who is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, to 
support an informed decision in cooperation with the treating physician and/or 
obstetrician. 

 
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5.4.3.3 
Abortions 
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2). 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event. 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.  
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2). 
5.4.4 
Reporting Requirements for Medical Device Complaints  
In this study, VitaloJAK is considered a medical device.  The investigator must report all 
medical device complaints to the Sponsor.  The investigator should document as much 
information as possible on the IMP Deviation Form, including the product batch number, 
and forward the form to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event) (refer to the pharmacy manual for further details).  If the medical 
device results in an adverse event to the study patient, the event must be reported on 
the Adverse Event eCRF and submitted through the EDC system.  If the event is 
serious, the Adverse Event eCRF must be completed immediately (i.e., no more than 
24 hours after learning of the event), as outlined in Section 5.4.2. 
Although the digital cough counting device is not considered a medical device in this 
study, the investigator must follow the same reporting procedures for device complaints 
and adverse events as outlined above.  

 
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5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study treatment or trial-related 
procedures until a final outcome can be reported. 
During the adverse event reporting period (defined in Section 5.3.1), resolution of adverse 
events (with dates) should be documented on the Adverse Event eCRF and in the patient's 
medical record to facilitate source data verification. 
All pregnancies reported during the study should be followed until pregnancy outcome, 
with follow-up information on the infant collected according to procedures outlined in 
Section 5.4.3. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, 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. 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
28 days after the final dose of study drug), if the event is believed to be related to prior 
exposure to study drug.  These events should be reported through use of the Adverse 
Event eCRF.  However, if the EDC system is not available, the investigator should report 
these events directly to the Sponsor or its designee, either by faxing or by scanning and 
emailing the paper Clinical Trial Serious Adverse Event/Adverse Event of Special 
Interest Reporting Form using the fax number or email address provided to investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 

 
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To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the document listed below: 
Drug 
Document 
GDC-6599 
GDC-6599 Investigator's Brochure  
Mannitol (Aridol/Osmohale) 
U.K. Summary of Product Characteristics 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The analysis of the data from the treatment period will be performed when all patients 
have either completed two treatment periods (Study Visit 7) or discontinued early from 
the study.   
The analysis of complete data from the study, including data from the treatment periods 
and the safety follow-up period, will be performed when all patients have either 
completed the treatment periods and the safety follow-up period or discontinued early 
from the study, all data from the study are in the database, and the database is locked. 
6.1 
DETERMINATION OF SAMPLE SIZE 
A sample size of approximately 20 to 30 patients per cohort (as specified in 
Sections 3.1.1 and 4.1) is expected to provide sufficient data to evaluate the primary 
objectives.  
6.2 
SUMMARIES OF CONDUCT OF STUDY 
The number of patients who enroll, discontinue, or complete the study will be 
summarized.  Reasons for premature study discontinuation will be listed and 
summarized.  Enrollment and major protocol deviations will be listed and evaluated for 
their potential effects on the interpretation of study results. 
6.3 
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
Demographic and baseline characteristics (including age, sex, weight, BMI, self-reported 
race/ethnicity) will be summarized using means, standard deviations, medians, and 
ranges for continuous variables and proportions for categorical variables, as appropriate.  
Summaries will be presented overall and by cohorts. 

 
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6.4 
EFFICACY ANALYSES 
The purpose of this study is estimation and hypothesis generation regarding efficacy and 
activity of GDC-6599, as compared with placebo, in patients with CRC with asthma or 
UCC.  The effects of GDC-6599 on cough will also be assessed in a subgroup of 
patients with CRC with COPD.  Statistical summaries will be descriptive in nature (e.g., 
incidence rates, means, standard deviations, and percentiles).  Any patients who 
received any amount of GDC-6599 or placebo will be included in the analyses.  Patients 
will be grouped according to the treatment received in a given period.  Final results will 
be summarized for GDC-6599 and for the placebo periods.  No formal hypothesis testing 
will be performed. 
6.5 
SAFETY ANALYSES 
The safety analysis population will consist of all randomized patients who received at 
least one dose of study drug, with patients grouped according to treatment received.  
Safety will be assessed through summaries of exposure to study treatment, adverse 
events, changes in laboratory test results, and changes in vital signs and ECGs.  All 
verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory 
Activities thesaurus terms, and adverse event severity will be graded according to 
DAIDS toxicity grading scale (see Section 5.3.3 and Appendix 10).  All adverse events, 
serious adverse events, adverse events leading to death, adverse events of special 
interest, and adverse events leading to study treatment discontinuation that occur on or 
after the first dose of study treatment (i.e., treatment-emergent adverse events) will be 
summarized by mapped term, appropriate thesaurus level, and severity grade.  Relevant 
laboratory, vital sign (pulse rate, respiratory rate, BP, pulse oximetry, and temperature), 
and ECG data will be displayed by time, with grades identified where appropriate.   
6.6 
PHARMACOKINETIC ANALYSES 
The PK analysis population will consist of patients with sufficient data to enable 
estimation of key parameters (e.g., area under the concentrationtime curve [AUC], time 
to maximum concentration [tmax], Cmax, half-life), with patients grouped according to 
treatment received.  
Individual and mean plasma GDC-6599 concentration-versus-time data will be tabulated 
and plotted.  The plasma pharmacokinetics of GDC-6599 may be analyzed via 
non-compartmental analysis and/or compartmental modeling as appropriate for the data 
collected. 
Additional PK analyses will be conducted as appropriate.  Exploratory analyses to 
assess relationships between plasma concentration or PK parameters of GDC-6599 and 
PD biomarkers, efficacy and/or activity outcomes, or safety outcomes may be conducted 
as appropriate. 

 
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6.7 
BIOMARKER ANALYSES  
Although no formal statistical analyses of exploratory biomarkers will be performed, data 
may be analyzed in the context of this study and in aggregate with data from other 
studies.   
6.8 
OPTIONAL INTERIM ANALYSIS 
Given the hypothesis-generating nature of this study, the Sponsor may choose to 
conduct interim safety and activity 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 by 
the IMC (see Section 3.1.2). 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data. Central laboratory data will be sent directly 
to the Sponsor, using the Sponsor's standard procedures to handle and process the 
electronic transfer of these data. 
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures. 
PRO data will be collected through the use of an electronic device provided by a vendor 
(see Section 7.3 for details). 
7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 

 
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At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required. 
7.3 
ELECTRONIC PATIENT-REPORTED OUTCOME DATA  
An electronic device will be used to capture PRO data, with the exception of the 
 
which will be collected in paper format.  The device is designed for entry of data in a way 
that is attributable, secure, and accurate, in compliance with U.S. Food and Drug 
Administration (FDA) regulations for electronic records (21 CFR Part 11).  The data will 
be transmitted to a centralized database maintained by the electronic device vendor. 
The electronic data will be available for view access only, via a secure web server.  Only 
identified and trained users may view the data, and their actions will become part of the 
audit trail.  The Sponsor will have view access only.  System backups for data stored by 
the Sponsor and records retention for the study data will be consistent with the 
Sponsor's standard procedures. 
Once the study is complete, the data, audit trail, and trial and system documentation will 
be archived.  The investigator will receive patient data for the site in both human- and 
machine-readable formats that must be kept with the study records as source data.  
Acknowledgement of receipt of the data is required.  In addition, the Sponsor will receive 
all data in a machine-readable format. 
7.4 
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 patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 

 
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Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6. 
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities. 
7.5 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 
7.6 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic or paper PRO data (if applicable), Informed Consent 
Forms, laboratory test results, medication inventory records, and images, must be 
retained by the Principal Investigator for 15 years after completion or discontinuation of 
the study or for the length of time required by relevant national or local health authorities, 
whichever is longer.  After that period of time, the documents may be destroyed, patient 
to local regulations.   
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
The Sponsor will retain study data for 25 years after the final study results have been 
reported or for the length of time required by relevant national or local health authorities, 
whichever is longer. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 

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

 
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A copy of each signed Consent Form must be provided to the patient or the patient's 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient's study file or in the site file and must be available for verification by study 
monitors at any time. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments 
(see Section 9.5). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety related- communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site's study file.  
8.4 
CONFIDENTIALITY 
Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect such 
data against accidental or unlawful loss, alteration, or unauthorized disclosure or 
access.  In the event of a data security breach, appropriate mitigation measures will be 
implemented. 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 

 
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Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law. The aggregate results of any conducted research will be 
available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.5). 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
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, data may be disseminated as described in Section 9.5 . 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data. 

 
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9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 
9.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored and managed by Genentech, Inc.  The Sponsor will provide 
clinical operations management, data management, and medical monitoring. 
Approximately 18 sites globally will participate to enroll approximately 80 patients.  
Enrollment will occur through an IxRS.   
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker and PK analyses), as specified in 
Section 4.5.10.  Accredited local laboratories will be used for routine monitoring; local 
laboratory ranges will be collected. 
An IMC will be employed to monitor and evaluate patient safety throughout the study. 
9.5 
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals.  The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and/or other summaries of clinical study results may be 
available in health authority databases for public access, as required by local regulation, 
and will be made available upon request.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Study Information at the following website: 
https://www.roche.com/innovation/process/clinical-trials/data-sharing/ 

 
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The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 

 
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10. 
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Balestrini A, Joseph V, Dourado M, et al. A TRPA1 inhibitor suppresses neurogenic 
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Belvisi MG, Dubuis E, Birrell MA. Transient receptor potential A1 channels: insights into 
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Belvisi MG, Birrell MA, Khalid S, et al. Neurophenotypes in airway diseases. Insights 
from translational cough studies. Am J Respir Crit Care Med 2016;193:136472. 
Belvisi MG, Birrell MA, Wortley MA, et al. XEN-D0501, a novel transient receptor 
potential vanilloid 1 antagonist, does not reduce cough in patients with refractory 
cough. Am J Respir Crit Care Med 2017;196:125563. 
Birrell MA, Belvisi MG, Grace M, et al. TRPA1 agonists evoke coughing in guinea pig 
and human volunteers. Am J Respir Crit Care Med 2009;180:10427. 
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Appendix 1: Schedule of Activities for Part A and Part B 
  
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110/Protocol GA43590, Version 4 
a Results of standard-of-care assessments performed prior to obtaining informed consent and within 21 days prior to Day 1 may be used; such 
assessments do not need to be repeated for screening.  Patients who do not meet the criteria for participation in this study may qualify for one 
re-screening opportunity (for a total of two screenings per patient) at the investigator’s discretion, as described in Section 3.1.1.  If a patient has 
completed all screening assessments and is eligible to enroll, randomization of the patient may begin as soon as 7 days into the screening 
period.  The screening visit may occur during a single day or over a maximum of 3 days.  If performed during a single screening visit, use of 
the VitaloJAK cough recorder should start at least 30 minutes after the mannitol challenge test . 
b Patients who complete both treatment periods will return to the clinic for a safety follow-up visit (Study Visit 8) at 
. 
c Visit not specified by the protocol.  Assessments (possibly including PK and biomarker sample collection; see 
 should be performed 
as clinically indicated.  Suggested safety assessments are outlined in this appendix table. 
d Patients who discontinue study drug prematurely will return to the clinic for a treatment discontinuation
days after their final dose of 
study drug. 
g Informed consent must be documented before any study-specific screening procedure is performed and may be obtained more than 21 days 
before initiation of study treatment. 
h 
Chemistry panel limited to liver function tests (ALP, ALT, AST, total and direct bilirubin).  If finding of an elevated ALT/AST ( 3  ULN 
and   5  ULN) and no other findings consistent with Hy's Law are observed, continue study drug and return to clinic for and unscheduled visit to 
repeat liver function tests (ALT, AST, GGT, alkaline phosphatase, total and direct bilirubin) within 48 hours.  
If finding of an elevated ALT/AST  5  ULN in isolation or   3  ULN in combination with other findings consistent with Hy's Law are observed, 
discontinue study drug, repeat liver function test within 72 hours, assess patient for signs/symptoms of hepatic failure, assess for other causes 
of liver dysfunction (e.g., viral hepatitis, concomitant medications, etc.), and continue to monitor liver function tests until abnormalities resolve 
(see Section 5.1.3.2). 
For patients at participating sites who have provided written informed consent to participate in mobile nursing visits, these assessments may 
be performed by a trained nursing professional at the patient’s home or another suitable location, if mobile nursing is available. 
i 
The ImmunoCAP Specific IgE test panel, skin prick test, or RAST is required only for patients with asthma who do not have confirmed 
atopic versus non-atopic status in their medical records.  Patient eligibility may be determined by medical history alone (see Section 
4.1.1.2). 

 
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Appendix 6  
Visual Analog Scale 
Do not reproduce or distribute.  The Sponsor will provide 
sites with all instruments to be completed in this study. 
 
 
 
 

 
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Appendix 7  
Numeric Response Scale 
 
Do not reproduce or distribute.  The Sponsor will provide 
sites with all instruments to be completed in this study. 

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Appendix 9  
Anaphylaxis Precautions 
These guidelines are intended as a reference and should not supersede pertinent local 
or institutional standard operating procedures. 
REQUIRED EQUIPMENT AND MEDICATION 
The following equipment and medication are needed in the event of a suspected 
anaphylactic reaction during study treatment administration in a clinical setting: 
 
Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer 
 
Oxygen 
 
Epinephrine for intramuscular (preferred route), subcutaneous, intravenous, or 
endotracheal administration in accordance with institutional guidelines 
 
Antihistamines 
 
Corticosteroids 
 
Intravenous infusion solutions, tubing, catheters, and tape 
 
PROCEDURES 
In the event of a suspected anaphylactic reaction during study treatment administration, 
the following procedures should be performed: 
1. 
Stop the study treatment administration, if possible.  
2. 
Call for additional medical assistance. 
3. 
Maintain an adequate airway. 
4. 
Ensure that appropriate monitoring is in place, with continuous ECG and pulse 
oximetry monitoring if possible. 
5. 
Administer antihistamines, epinephrine, or other medications and IV fluids as 
required by patient status and as directed by the physician in charge. 
6. 
Continue to observe the patient and document observations. 
 

 
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Appendix 10  
Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
The investigator will use the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
(HHS 2017), with slight modifications for clarity and for alignment with internal practices, for assessing the severity of each adverse 
event reported during the study. 
Table 1 
Severity Grading for Adult and Pediatric Adverse Events 
Parameter 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially Life-Threatening) 
Cardiovascular 
Arrhythmia (by ECG or 
physical examination) 
(Specify type if applicable) 
No symptoms and 
no intervention indicated 
No symptoms and 
non-urgent intervention 
indicated 
Nonlife-threatening 
symptoms and non-urgent 
intervention indicated 
Life-threatening arrhythmia or 
urgent intervention indicated 
Hypertension (with the 
lowest reading taken after 
repeat testing during a visit): 
 18 years of age  
140 to  160 mmHg systolic 
or  
90 to  100 mmHg diastolic a 
 160 to  180 mmHg systolic 
or  
 100 to  110 mmHg 
diastolic a 
 180 mmHg systolic or 
 110 mmHg diastolic a 
Life-threatening consequences in 
a participant not previously 
diagnosed with hypertension 
(e.g., malignant hypertension) or 
hospitalization indicated 
Hypertension (with the 
lowest reading taken after 
repeat testing during a visit): 
 18 years of age b 
 120 mmHg systolic or  
 80 mmHg diastolic, but 
systolic and diastolic  
 95th percentile adjusted 
for age, height, and sex 
 95th to  5 mmHg above 
the 99th percentile adjusted 
for age, height, and sex 
(systolic and/or diastolic) a 
 5 mmHg above the 
99th percentile adjusted 
for age, height, and sex 
(systolic and/or diastolic) a 
Life-threatening consequences in 
a participant not previously 
diagnosed with hypertension 
(e.g., malignant hypertension) or 
hospitalization indicated 
Hypotension 
No symptoms 
Symptoms corrected with 
oral fluid replacement 
Symptoms and IV fluids 
indicated 
Shock requiring use of 
vasopressors or mechanical 
assistance to maintain blood 
pressure 
a When systolic and diastolic blood pressures meet criteria for different grades, the higher grade should be used. 
b Blood pressure norms for children  18 years of age can be found in: Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk 
Reduction in Children and Adolescents; National Heart, Lung, and Blood Institute. Expert panel on integrated guidelines for cardiovascular health 
and risk reduction in children and adolescents: summary report. Pediatrics 2011;128(Suppl 5):S21356.   

Appendix 10: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
 
Table 1 
Severity Grading for Adult and Pediatric Adverse Events (cont.) 
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Parameter 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially Life-Threatening) 
Cardiovascular (cont.) 
Cardiac ischemia or 
infarction 
(Report the most 
appropriate term) 
 
 
New symptoms with 
ischemia (stable angina) 
or new testing consistent 
with ischemia 
Unstable angina or acute 
myocardial infarction 
Heart failure 
No symptoms and laboratory 
or cardiac imaging 
abnormalities 
Symptoms with mild to 
moderate activity or exertion 
Symptoms at rest or with 
minimal activity or 
exertion (e.g., hypoxemia) 
or intervention indicated 
(e.g., oxygen) 
Life-threatening consequences 
or urgent intervention indicated 
(e.g., vasoactive medications, 
ventricular assist device, 
heart transplant) 
Hemorrhage (with 
significant acute blood loss) 
 
Symptoms and no 
transfusion indicated 
Symptoms and 
transfusion of  2 units 
packed RBCs (for 
children, packed RBCs 
 10 cc/kg) indicated 
Life-threatening hypotension or 
transfusion of  2 units packed 
RBCs (for children, packed RBCs 
 10 cc/kg) indicated 
Prolonged PR interval or 
AV block:   16 years of age 
(Report the most 
appropriate term) 
PR interval 0.21 to 
 0.25 seconds 
PR interval  0.25 seconds or 
Type I second-degree AV 
block 
Type II second-degree AV 
block or ventricular pause 
 3.0 seconds 
Complete AV block 
Prolonged PR interval or 
AV block:   16 years of age 
(Report the most 
appropriate term) 
First-degree AV block 
(PR interval  normal for 
age and rate) 
Type I second-degree AV 
block 
Type II second-degree AV 
block or ventricular pause 
 3.0 seconds 
Complete AV block 
Prolonged QTc interval 
(corrected per Bazett's 
formula) 
0.45 to 0.47 seconds 
 0.47 to 0.50 seconds 
 0.50 seconds or 
 0.06 seconds above 
baseline 
Life-threatening consequences 
(e.g., torsade de pointes, other 
associated serious ventricular 
dysrhythmia) 
AV  atrioventricular. 
Parameter 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially Life-Threatening) 

Appendix 10: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
 
Table 1 
Severity Grading for Adult and Pediatric Adverse Events (cont.) 
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Cardiovascular (cont.) 
Thrombosis or embolism 
(Report the most 
appropriate term) 
 
Symptoms and no 
intervention indicated 
Symptoms and 
intervention indicated 
Life-threatening embolic event 
(e.g., pulmonary embolism, 
thrombus) 
Dermatologic 
Alopecia (scalp only) 
Detectable by study 
participant, caregiver, or 
physician and causing 
no or minimal interference 
with usual social and 
functional activities 
Obvious on visual inspection 
and causing greater than 
minimal interference with 
usual social and functional 
activities 
 
 
Bruising 
Localized to one area 
Localized to more than one 
area 
Generalized 
 
Cellulitis 
 
Non-parenteral treatment 
indicated (e.g., oral 
antibiotics, antifungals, 
antivirals) 
IV treatment indicated 
(e.g., IV antibiotics, 
antifungals, antivirals) 
Life-threatening consequences 
(e.g., sepsis, tissue necrosis) 
Hyperpigmentation 
Slight or localized causing 
no or minimal interference 
with usual social and 
functional activities 
Marked or generalized 
causing greater than minimal 
interference with usual social 
and functional activities 
 
 
Hypopigmentation 
Slight or localized causing 
no or minimal interference 
with usual social and 
functional activities 
Marked or generalized 
causing greater than minimal 
interference with usual social 
and functional activities 
 
 

Appendix 10: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
 
Table 1 
Severity Grading for Adult and Pediatric Adverse Events (cont.) 
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130/Protocol GA43590, Version 4 
Parameter 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially Life-Threatening) 
Dermatologic (cont.) 
Petechiae 
Localized to one area 
Localized to more than one 
area 
Generalized 
 
Pruritus c 
(without skin lesions) 
Itching causing no or 
minimal interference with 
usual social and 
functional activities 
Itching causing greater than 
minimal interference with 
usual social and functional 
activities 
Itching causing inability to 
perform usual social and 
functional activities 
 
Rash 
(Specify type, if applicable) 
Localized rash 
Diffuse rash or target lesions Diffuse rash and vesicles 
or limited number of 
bullae or superficial 
ulcerations of mucous 
membrane limited to 
one site 
Extensive or generalized bullous 
lesions or ulceration of mucous 
membrane involving two or more 
distinct mucosal sites or 
Stevens-Johnson syndrome or 
toxic epidermal necrolysis 
Endocrine and Metabolic 
Diabetes mellitus 
Controlled without 
medication 
Controlled with medication or 
modification of current 
medication regimen 
Uncontrolled despite 
treatment modification or 
hospitalization for 
immediate glucose 
control indicated 
Life-threatening consequences 
(e.g., ketoacidosis, hyperosmolar 
non-ketotic coma, end organ 
failure) 
Gynecomastia 
Detectable by study 
participant, caregiver, or 
physician and causing no or 
minimal interference with 
usual social and 
functional activities 
Obvious on visual inspection 
and causing pain with 
greater than minimal 
interference with usual social 
and functional activities 
Disfiguring changes and 
symptoms requiring 
intervention or causing 
inability to perform usual 
social and functional 
activities 
 
c For pruritus associated with injections or infusions, see "Site Reactions to Injections and Infusions" 

Appendix 10: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
 
Table 1 
Severity Grading for Adult and Pediatric Adverse Events (cont.) 
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Parameter 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially Life-Threatening) 
Endocrine and Metabolic (cont.) 
Hyperthyroidism 
No symptoms and abnormal 
laboratory value 
Symptoms causing greater 
than minimal interference 
with usual social and 
functional activities or thyroid 
suppression therapy 
indicated 
Symptoms causing 
inability to perform usual 
social and functional 
activities or uncontrolled 
despite treatment 
modification 
Life-threatening consequences 
(e.g., thyroid storm) 
Hypothyroidism 
No symptoms and abnormal 
laboratory value 
Symptoms causing greater 
than minimal interference 
with usual social and 
functional activities or thyroid 
replacement therapy 
indicated 
Symptoms causing 
inability to perform usual 
social and functional 
activities or uncontrolled 
despite treatment 
modification 
Life-threatening consequences 
(e.g., myxedema coma) 
Lipoatrophy (disorder 
characterized by fat loss in 
the face, extremities, and 
buttocks) 
Detectable by study 
participant, caregiver, or 
physician and causing 
no or minimal interference 
with usual social and 
functional activities 
Obvious on visual inspection 
and causing greater than 
minimal interference with 
usual social and functional 
activities 
Disfiguring changes 
 
Lipohypertrophy (disorder 
characterized by abnormal 
fat accumulation on the 
back of the neck, breasts, 
and abdomen) 
Detectable by study 
participant, caregiver, or 
physician and causing 
no or minimal interference 
with usual social and 
functional activities 
Obvious on visual inspection 
and causing greater than 
minimal interference with 
usual social and functional 
activities 
Disfiguring changes 
 

Appendix 10: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
 
Table 1 
Severity Grading for Adult and Pediatric Adverse Events (cont.) 
GDC-6599—Genentech, Inc. 
132/Protocol GA43590, Version 4 
Parameter 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially Life-Threatening) 
Gastrointestinal 
Anorexia 
Loss of appetite without 
decreased oral intake 
Loss of appetite associated 
with decreased oral intake 
without significant 
weight loss 
Loss of appetite  
associated with 
significant weight loss 
Life-threatening consequences or 
aggressive intervention 
indicated (e.g., tube feeding, 
total parenteral nutrition) 
Ascites 
No symptoms 
Symptoms and intervention 
indicated (e.g., diuretics, 
therapeutic paracentesis) 
Symptoms recur or persist 
despite intervention 
Life-threatening consequences 
Bloating or distension 
(Report the most 
appropriate term) 
Symptoms causing 
no or minimal interference 
with usual social and 
functional activities 
Symptoms causing greater 
than minimal interference 
with usual social and 
functional activities 
Symptoms causing 
inability to perform usual 
social and functional 
activities 
 
Cholecystitis 
 
Symptoms and medical 
intervention indicated 
Radiologic, endoscopic, 
or operative intervention 
indicated 
Life-threatening consequences 
(e.g., sepsis, perforation) 
Constipation 
 
Persistent constipation 
requiring regular use of 
dietary modifications, 
laxatives, or enemas 
Obstipation with manual 
evacuation indicated 
Life-threatening consequences 
(e.g., obstruction) 
Diarrhea:   1 year of age 
Transient or intermittent 
episodes of unformed stools 
or increase of  3 stools 
over baseline per 
24-hour period 
Persistent episodes of 
unformed to watery stools or 
increase of 4 to 6 stools over 
baseline per 24-hour period 
Increase of  7 stools over 
baseline per 24-hour 
period or IV fluid 
replacement indicated 
Life-threatening consequences 
(e.g., hypotensive shock) 

Appendix 10: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
 
Table 1 
Severity Grading for Adult and Pediatric Adverse Events (cont.) 
GDC-6599—Genentech, Inc. 
133/Protocol GA43590, Version 4 
Parameter 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially Life-Threatening) 
Gastrointestinal (cont.) 
Diarrhea:   1 year of age 
Liquid stools (more 
unformed than usual) but 
usual number of stools 
Liquid stools with increased 
number of stools or mild 
dehydration 
Liquid stools with 
moderate dehydration 
Life-threatening consequences 
(e.g., liquid stools resulting in 
severe dehydration, 
hypotensive shock) 
Dysphagia or odynophagia 
(Report the most 
appropriate term and 
specify location) 
Symptoms but able to eat 
usual diet 
Symptoms causing altered 
dietary intake with no 
intervention indicated 
Symptoms causing 
severely altered dietary 
intake with intervention 
indicated 
Life-threatening reduction in 
oral intake 
Gastrointestinal bleeding 
Not requiring intervention 
other than iron supplement 
Endoscopic intervention 
indicated 
Transfusion indicated 
Life-threatening consequences 
(e.g., hypotensive shock) 
Mucositis or stomatitis 
(Report the most 
appropriate term and 
specify location) 
Mucosal erythema 
Patchy pseudomembranes 
or ulcerations 
Confluent 
pseudomembranes or 
ulcerations or mucosal 
bleeding with minor 
trauma 
Life-threatening consequences 
(e.g., aspiration, choking) or 
tissue necrosis or diffuse 
spontaneous mucosal bleeding 
Nausea 
Transient ( 24 hours) or 
intermittent nausea and 
no or minimal interference 
with oral intake 
Persistent nausea resulting 
in decreased oral intake for 
2448 hours 
Persistent nausea 
resulting in minimal oral 
intake for  48 hours or 
rehydration indicated 
(e.g., IV fluids) 
Life-threatening consequences 
(e.g., hypotensive shock) 
Pancreatitis 
 
Symptoms with 
hospitalization not indicated 
Symptoms with 
hospitalization indicated 
Life-threatening consequences 
(e.g., circulatory failure, 
hemorrhage, sepsis) 

Appendix 10: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
 
Table 1 
Severity Grading for Adult and Pediatric Adverse Events (cont.) 
GDC-6599—Genentech, Inc. 
134/Protocol GA43590, Version 4 
Parameter 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially Life-Threatening) 
Gastrointestinal (cont.) 
Perforation 
(colon or rectum) 
 
 
Intervention indicated 
Life-threatening consequences 
Proctitis 
Rectal discomfort with no 
intervention indicated 
Symptoms causing greater 
than minimal interference 
with usual social and 
functional activities or 
medical intervention 
indicated 
Symptoms causing 
inability to perform usual 
social and functional 
activities or operative 
intervention indicated 
Life-threatening consequences 
(e.g., perforation) 
Rectal discharge 
Visible discharge 
Discharge requiring the use 
of pads 
 
 
Vomiting 
Transient or intermittent 
vomiting and no or minimal 
interference with oral intake 
Frequent vomiting episodes 
and no or mild dehydration 
Persistent vomiting 
resulting in orthostatic 
hypotension or aggressive 
rehydration indicated 
(e.g., IV fluids) 
Life-threatening consequences 
(e.g., hypotensive shock) 
Musculoskeletal 
Arthralgia 
Joint pain causing no or 
minimal interference with 
usual social and functional 
activities 
Joint pain causing greater 
than minimal interference 
with usual social and 
functional activities 
Joint pain causing inability 
to perform usual social 
and functional activities 
Disabling joint pain causing 
inability to perform basic 
self-care functions 
Arthritis 
Joint stiffness or swelling 
causing no or minimal 
interference with usual 
social and functional 
activities 
Joint stiffness or swelling 
causing greater than minimal 
interference with usual social 
and functional activities 
Joint stiffness or swelling 
causing inability to 
perform usual social and 
functional activities 
Disabling joint stiffness or 
swelling causing inability to 
perform basic self-care functions 

Appendix 10: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
 
Table 1 
Severity Grading for Adult and Pediatric Adverse Events (cont.) 
GDC-6599—Genentech, Inc. 
135/Protocol GA43590, Version 4 
Parameter 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially Life-Threatening) 
Musculoskeletal (cont.) 
Myalgia (generalized) 
Muscle pain causing no or 
minimal interference with 
usual social and functional 
activities 
Muscle pain causing greater 
than minimal interference 
with usual social and 
functional activities 
Muscle pain causing 
inability to perform usual 
social and functional 
activities 
Disabling muscle pain causing 
inability to perform basic self-
care functions 
Osteonecrosis 
 
No symptoms but with 
radiographic findings and no 
operative intervention 
indicated 
Bone pain with 
radiographic findings 
or operative intervention 
indicated 
Disabling bone pain with 
radiographic findings causing 
inability to perform basic 
self-care functions 
Osteopenia:   
 30 years of age 
BMD t-score 2.5 to 1 
 
 
 
Osteopenia:   
 30 years of age 
BMD z-score 2 to 1 
 
 
 
Osteoporosis:   
 30 years of age 
 
BMD t-score   2.5 
Pathologic fracture 
(e.g., compression 
fracture causing loss 
of vertebral height) 
Pathologic fracture causing 
life-threatening consequences 
Osteoporosis:   
 30 years of age 
 
BMD z-score  2 
Pathologic fracture 
(e.g., compression 
fracture causing loss 
of vertebral height) 
Pathologic fracture causing 
life-threatening consequences 
BMD  bone mineral density. 
 

Appendix 10: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
 
Table 1 
Severity Grading for Adult and Pediatric Adverse Events (cont.) 
GDC-6599—Genentech, Inc. 
136/Protocol GA43590, Version 4 
Parameter 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially Life-Threatening) 
Neurologic 
Acute CNS ischemia 
 
 
Transient ischemic attack 
Cerebral vascular accident (e.g., 
stroke with neurological deficit) 
Altered mental status 
(for dementia, see cognitive, 
behavioral, or attentional 
disturbance below) 
Changes causing no or 
minimal interference with 
usual social and functional 
activities 
Mild lethargy or 
somnolence causing 
greater than minimal 
interference with usual 
social and functional 
activities 
Confusion, memory 
impairment, lethargy, or 
somnolence causing 
inability to perform usual 
social and functional 
activities 
Delirium or obtundation or coma 
Ataxia 
Symptoms causing no or 
minimal interference with 
usual social and functional 
activities or no symptoms 
with ataxia detected on 
examination 
Symptoms causing 
greater than minimal 
interference with usual 
social and functional 
activities 
Symptoms causing 
inability to perform usual 
social and functional 
activities 
Disabling symptoms causing 
inability to perform basic 
self-care functions 
Cognitive, behavioral, or 
attentional disturbance 
(includes dementia and 
attention deficit disorder) 
(Specify type, if applicable) 
Disability causing no or 
minimal interference with 
usual social and functional 
activities or specialized 
resources not indicated 
Disability causing greater 
than minimal interference 
with usual social and 
functional activities or 
specialized resources on 
part-time basis indicated 
Disability causing inability 
to perform usual social and 
functional activities or 
specialized resources on 
a full-time basis indicated 
Disability causing inability to 
perform basic self-care functions 
or institutionalization indicated 

Appendix 10: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
 
Table 1 
Severity Grading for Adult and Pediatric Adverse Events (cont.) 
GDC-6599—Genentech, Inc. 
137/Protocol GA43590, Version 4 
Parameter 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially Life-Threatening) 
Neurologic (cont.) 
Developmental delay 
 18 years of age  
(Specify type, if applicable) 
Mild developmental delay, 
either motor or cognitive, 
as determined by 
comparison with a 
developmental screening 
tool appropriate for the 
setting 
Moderate developmental 
delay, either motor or 
cognitive, as determined 
by comparison with a 
developmental screening 
tool appropriate for the 
setting 
Severe developmental 
delay, either motor or 
cognitive, as determined 
by comparison with a 
developmental screening 
tool appropriate for the 
setting 
Developmental regression, either 
motor or cognitive, as determined 
by comparison with a 
developmental screening tool 
appropriate for the setting 
Headache 
Symptoms causing no 
or minimal interference 
with usual social and 
functional activities 
Symptoms causing 
greater than minimal 
interference with usual 
social and functional 
activities 
Symptoms causing 
inability to perform usual 
social and functional 
activities 
Symptoms causing inability to 
perform basic self-care functions 
or hospitalization indicated 
or headache with significant 
impairment of alertness or other 
neurologic function 
Neuromuscular weakness 
(includes myopathy and 
neuropathy) 
(Specify type, if applicable) 
Minimal muscle weakness 
causing no or minimal 
interference with usual 
social and functional 
activities or no symptoms 
with decreased strength on 
examination 
Muscle weakness 
causing greater than 
minimal interference with 
usual social and 
functional activities 
Muscle weakness 
causing inability to 
perform usual social and 
functional activities 
Disabling muscle weakness 
causing inability to perform basic 
self-care functions or respiratory 
muscle weakness impairing 
ventilation 

Appendix 10: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
 
Table 1 
Severity Grading for Adult and Pediatric Adverse Events (cont.) 
GDC-6599—Genentech, Inc. 
138/Protocol GA43590, Version 4 
Parameter 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially Life-Threatening) 
Neurologic (cont.) 
Neurosensory alteration 
(includes paresthesia and 
painful neuropathy) 
(Specify type, if applicable) 
Minimal paresthesia 
causing no or minimal 
interference with usual 
social and functional 
activities or no symptoms 
with sensory alteration 
on examination 
Sensory alteration or 
paresthesia causing 
greater than minimal 
interference with usual 
social and functional 
activities 
Sensory alteration or 
paresthesia causing 
inability to perform usual 
social and functional 
activities 
Disabling sensory alteration or 
paresthesia causing inability to 
perform basic self-care functions 
Seizure, new onset:  
 18 years of age 
 
 
13 seizures 
Prolonged and repetitive seizures 
(e.g., status epilepticus) or difficult 
to control (e.g., refractory epilepsy) 
Seizure, new onset:  
 18 years of age (includes 
new or preexisting febrile 
seizures) 
Seizure lasting  5 minutes 
with  24 hours postictal 
state 
Seizure lasting 5 to 
 20 minutes with 
 24 hours postictal state 
Seizure lasting 
 20 minutes or  24 hours 
postictal state 
Prolonged and repetitive seizures 
(e.g., status epilepticus) 
or difficult to control 
(e.g., refractory epilepsy) 
Seizure, preexisting 
(excludes preexisting febrile 
seizures) 
 
Increased frequency 
from previous level of 
control without change 
in seizure character 
Change in seizure 
character either in 
duration or quality 
(e.g., severity or focality) 
Prolonged and repetitive seizures 
(e.g., status epilepticus) or 
difficult to control 
(e.g., refractory epilepsy) 
Syncope 
Near syncope without loss 
of consciousness 
(e.g., pre-syncope) 
Loss of consciousness 
with no intervention 
indicated 
Loss of consciousness 
and hospitalization or 
intervention required 
 
Pregnancy, Puerperium, and Perinatal 
Stillbirth 
 
 
Fetal death occurring at 
 20 weeks gestational age 
 

Appendix 10: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
 
Table 1 
Severity Grading for Adult and Pediatric Adverse Events (cont.) 
GDC-6599—Genentech, Inc. 
139/Protocol GA43590, Version 4 
Parameter 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially Life-Threatening) 
Pregnancy, Puerperium, and Perinatal (cont.) 
Preterm birth 
Live birth at 
34 to  37 weeks 
gestational age 
Live birth at 
28 to  34 weeks 
gestational age 
Live birth at 
24 to  28 weeks 
gestational age 
Live birth at  24 weeks 
gestational age 
Spontaneous abortion (a 
pregnancy loss occurring at 
 20 weeks gestational age; 
also known as miscarriage) 
Chemical pregnancy 
Uncomplicated 
spontaneous abortion 
Complicated 
spontaneous abortion 
 
Psychiatric 
Insomnia 
Mild difficulty falling asleep 
or staying asleep or 
mild difficulty caused by 
early morning awakening, 
causing no or minimal 
interference with usual 
social and functional 
activities 
Moderate difficulty falling 
asleep or staying asleep, 
or moderate difficulty 
caused by early morning 
awakening, causing 
greater than minimal 
interference with usual 
social and functional 
activities 
Severe difficulty falling 
asleep or staying asleep or 
severe difficulty caused by 
early morning awakening, 
causing inability to perform 
usual social and functional 
activities and requiring 
intervention or 
hospitalization 
 
Psychiatric disorder (includes 
anxiety, depression, mania, 
and psychosis) 
(Specify disorder) 
Symptoms with 
intervention not indicated 
or behavior causing 
no or minimal interference 
with usual social and 
functional activities 
Symptoms with 
intervention indicated or 
behavior causing greater 
than minimal interference 
with usual social and 
functional activities 
Symptoms with 
hospitalization indicated 
or behavior causing 
inability to perform 
usual social and 
functional activities 
Threatens harm to self or others 
or acute psychosis or behavior 
causing inability to perform basic 
self-care functions 

Appendix 10: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
 
Table 1 
Severity Grading for Adult and Pediatric Adverse Events (cont.) 
GDC-6599—Genentech, Inc. 
140/Protocol GA43590, Version 4 
Parameter 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially Life-Threatening) 
Psychiatric (cont.) 
Suicidal ideation or suicide 
attempt 
(Report the most appropriate 
term) 
Preoccupied with thoughts 
of death and no wish to 
kill oneself 
Preoccupied with 
thoughts of death and 
wish to kill oneself with 
no specific plan or intent 
Thoughts of killing oneself 
with partial or complete 
plans but no attempt to do 
so or hospitalization 
indicated 
Suicide attempted 
Respiratory 
Acute bronchospasm 
Forced expiratory volume in 
1 second or peak flow 
reduced to  70 to  80% of 
predicted or mild symptoms 
with intervention not 
indicated 
Forced expiratory volume 
in 1 second or peak flow 
50% to  70% of 
predicted or symptoms 
with intervention indicated 
or symptoms causing 
greater than minimal 
interference with usual 
social and functional 
activities 
Forced expiratory 
volume in 1 second or 
peak flow 25% to  50% of 
predicted or symptoms 
causing inability to perform 
usual social and functional 
activities 
Forced expiratory 
volume in 1 second or 
peak flow  25% of predicted or 
life-threatening respiratory or 
hemodynamic compromise or 
intubation 
Dyspnea or respiratory 
distress 
(Report the most appropriate 
term) 
Dyspnea on exertion with 
no or minimal interference 
with usual social and 
functional activities 
or wheezing 
or minimal increase in 
respiratory rate for age 
Dyspnea on exertion 
causing greater than 
minimal interference 
with usual social and 
functional activities or 
nasal flaring or intercostal 
retractions or pulse 
oximetry 90% to  95% 
Dyspnea at rest causing 
inability to perform usual 
social and functional 
activities or pulse 
oximetry  90% 
Respiratory failure with ventilator 
support indicated (e.g., CPAP, 
BPAP, intubation) 

Appendix 10: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
 
Table 1 
Severity Grading for Adult and Pediatric Adverse Events (cont.) 
GDC-6599—Genentech, Inc. 
141/Protocol GA43590, Version 4 
BPAP  bilevel positive airway pressure; CPAP  continuous positive airway pressure. 
Parameter 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially Life-Threatening) 
Sensory 
Hearing loss (based on a 1, 
2, 3, 4, 6 and 8 kHz 
audiogram):   
 12 years of age 
 
Hearing aid or 
intervention not indicated 
Hearing aid or 
intervention indicated 
Profound bilateral hearing loss 
( 80 dB at 2 kHz and above) or 
non-serviceable hearing 
(i.e.,  50 dB audiogram and 
 50% speech discrimination) 
Hearing loss (based on a 1, 
2, 3, 4, 6 and 8 kHz 
audiogram):   
 12 years of age 
 20 dB hearing loss at 
 4 kHz 
 20 dB hearing loss at 
 4 kHz 
 20 dB hearing loss at 
 3 kHz in one ear with 
additional speech 
language related services 
indicated (where available) 
or hearing loss sufficient 
to indicate therapeutic 
intervention, including 
hearing aids 
Audiologic indication for 
cochlear implant and additional 
speech-languagerelated 
services indicated 
(where available) 
Tinnitus 
Symptoms causing no or 
minimal interference with 
usual social and functional 
activities and intervention 
not indicated 
Symptoms causing 
greater than minimal 
interference with usual 
social and functional 
activities or intervention 
indicated 
Symptoms causing inability 
to perform usual social and 
functional activities 
 
Uveitis 
No symptoms and 
detectable uveitis on 
examination 
Anterior uveitis with 
symptoms or medical 
intervention indicated 
Posterior uveitis or 
panuveitis or operative 
intervention indicated 
Uveitis with disabling visual loss 
in affected eye(s) 

Appendix 10: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
 
Table 1 
Severity Grading for Adult and Pediatric Adverse Events (cont.) 
GDC-6599—Genentech, Inc. 
142/Protocol GA43590, Version 4 
Parameter 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially Life-Threatening) 
Sensory (cont.) 
Vertigo 
Vertigo causing no 
or minimal interference 
with usual social and 
functional activities 
Vertigo causing greater 
than minimal interference 
with usual social and 
functional activities 
Vertigo causing inability 
to perform usual social 
and functional activities 
Disabling vertigo causing 
inability to perform basic  
self-care functions 
Visual changes (assessed 
from baseline) 
Visual changes causing no 
or minimal interference 
with usual social and 
functional activities 
Visual changes causing 
greater than minimal 
interference with usual 
social and functional 
activities 
Visual changes causing 
inability to perform usual 
social and functional 
activities 
Visual changes with disabling 
visual loss in affected eye(s) 
Systemic 
Acute allergic reaction 
Localized urticaria (wheals) 
with no intervention 
indicated 
Localized urticaria with 
intervention indicated or 
mild angioedema with no 
intervention indicated 
Generalized urticaria 
or angioedema with 
intervention indicated 
or symptoms of mild 
bronchospasm 
Acute anaphylaxis or 
life-threatening bronchospasm 
or laryngeal edema 
Chills 
Symptoms causing no 
or minimal interference 
with usual social and 
functional activities 
Symptoms causing 
greater than minimal 
interference with usual 
social and functional 
activities 
Symptoms causing inability 
to perform usual social 
and functional activities 
 

Appendix 10: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
 
Table 1 
Severity Grading for Adult and Pediatric Adverse Events (cont.) 
GDC-6599—Genentech, Inc. 
143/Protocol GA43590, Version 4 
Parameter 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially Life-Threatening) 
Systemic (cont.) 
Cytokine-release syndrome 
(disorder characterized by 
nausea, headache, 
tachycardia, hypotension, 
rash, and/or shortness of 
breath) 
Mild signs and symptoms 
and therapy (i.e., antibody 
infusion) interruption not 
indicated 
Therapy (i.e., antibody 
infusion) interruption 
indicated and responds 
promptly to symptomatic 
treatment or prophylactic 
medications indicated 
for  24 hours 
Prolonged severe signs 
and symptoms or 
recurrence of symptoms 
following initial 
improvement 
Life-threatening consequences 
(e.g., requiring pressor or 
ventilator support) 
Fatigue or malaise 
(Report the most appropriate 
term) 
Symptoms of fatigue or 
malaise causing no or 
minimal interference 
with usual social and 
functional activities 
Symptoms of fatigue or 
malaise causing greater 
than minimal interference 
with usual social and 
functional activities 
Symptoms of fatigue or 
malaise causing inability 
to perform usual social 
and functional activities 
Incapacitating symptoms of 
fatigue or malaise causing 
inability to perform basic 
self-care functions 
Fever (non-axillary 
temperatures only) 
38.0 to  38.6C or 
100.4 to  101.5°F 
 38.6 to  39.3C or 
 101.5 to  102.7F 
 39.3 to  40.0C or 
 102.7 to  104.0F 
 40.0C or  104.0F 
Pain (not associated with 
study agent injections and 
not specified elsewhere) 
(Specify location) 
Pain causing no or 
minimal interference 
with usual social and 
functional activities 
Pain causing greater than 
minimal interference 
with usual social and 
functional activities 
Pain causing inability to 
perform usual social and 
functional activities 
Disabling pain causing inability to 
perform basic self-care functions 
or hospitalization indicated 
Serum sickness (disorder 
characterized by fever, 
arthralgia, myalgia, skin 
eruptions, lymphadenopathy, 
marked discomfort, and/or 
dyspnea) 
Mild signs and symptoms 
Moderate signs and 
symptoms and 
intervention indicated 
(e.g., antihistamines) 
Severe signs and 
symptoms and higher level 
intervention indicated 
(e.g., corticosteroids 
or IV fluids) 
Life-threatening consequences 
(e.g., requiring pressor or 
ventilator support) 

Appendix 10: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
 
Table 1 
Severity Grading for Adult and Pediatric Adverse Events (cont.) 
GDC-6599—Genentech, Inc. 
144/Protocol GA43590, Version 4 
Parameter 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially Life-Threatening) 
Systemic (cont.) 
Underweight:   
 5 to 19 years of age 
WHO BMI z-score d 
 1 to 2 
WHO BMI z-score d 
 2 to 3 
WHO BMI z-score d  3 
WHO BMI z-score d  3 with 
life-threatening consequences 
Underweight:   
2 to 5 years of age 
WHO weight-for-height 
z-score e  1 to 2 
WHO weight-for-height 
z-score e  2 to 3 
WHO weight-for-height 
z-score e  3 
WHO weight-for-height 
z-score e  3 with  
life-threatening consequences 
Underweight:   
 2 years of age 
WHO weight-for-length 
z-score e  1 to 2 
WHO weight-for-length 
z-score e  2 to 3 
WHO weight-for-length 
z-score e  3 
WHO weight-for-length 
z-score e  3 with  
life-threatening consequences 
Unintentional weight loss 
(excludes postpartum weight 
loss) 
 
5% to  9% loss in body 
weight from baseline 
 9% to  20% loss in body 
weight from baseline 
 20% loss in body weight from 
baseline or aggressive intervention 
indicated (e.g., tube feeding, 
total parenteral nutrition) 
Urinary 
Urinary tract obstruction 
 
Signs or symptoms of 
urinary tract obstruction 
without hydronephrosis or 
renal dysfunction 
Signs or symptoms of 
urinary tract obstruction 
with hydronephrosis or 
renal dysfunction 
Obstruction causing 
life-threatening consequences 
BMI  body mass index; WHO  World Health Organization. 
d WHO reference tables for participants  5 to 19 years of age:  http://www.who.int/growthref/who2007_bmi_for_age/en/. 
e WHO reference tables for participants  5 years of age:  http://www.who.int/childgrowth/standards/chart_catalogue/en/. 
 
 

Appendix 10: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
 
Table 1 
Severity Grading for Adult and Pediatric Adverse Events (cont.) 
GDC-6599—Genentech, Inc. 
145/Protocol GA43590, Version 4 
Parameter 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially Life-Threatening) 
Site Reactions to Injections and Infusions f 
Injection-site pain or 
tenderness f 
Pain or tenderness 
causing no or minimal 
limitation of use of limb 
Pain or tenderness 
causing greater than 
minimal limitation of 
use of limb 
Pain or tenderness 
causing inability to 
perform usual social 
and functional activities 
Pain or tenderness causing 
inability to perform basic 
self-care function or 
hospitalization indicated 
Injection-site erythema, 
redness, induration, or 
swelling: f   15 years of age 
(Report the most appropriate 
term; report multiple events 
if appropriate) 
2.5 to  5 cm in diameter 
or 6.25 to  25 cm2 
surface area g and 
symptoms causing no 
or minimal interference 
with usual social and 
functional activities 
 5 to  10 cm in diameter 
or  25 to  100 cm2 
surface area g or 
symptoms causing 
greater than minimal 
interference with usual 
social and functional 
activities 
 10 cm in diameter or 
 100 cm2 surface area g 
or ulceration or secondary 
infection or phlebitis or 
sterile abscess or drainage 
or symptoms causing 
inability to perform usual 
social and functional 
activities 
Potentially life-threatening 
consequences (e.g., abscess, 
exfoliative dermatitis, necrosis 
involving dermis or deeper tissue) 
Injection-site erythema, 
redness, induration, or 
swelling: f   15 years of age 
(Report the most appropriate 
term; report multiple events 
if appropriate) 
 2.5 cm in diameter g 
 2.5 cm in diameter 
with  50% surface 
area g of the extremity 
segment involved 
(e.g., upper arm or thigh) 
 50% surface area g of 
the extremity segment 
involved (e.g., upper arm 
or thigh) or ulceration or 
secondary infection or 
phlebitis or sterile abscess 
or drainage 
Potentially life-threatening 
consequences (e.g., abscess, 
exfoliative dermatitis, necrosis 
involving dermis or deeper tissue) 
f Refer to Section 5.3.5.1 for instructions on reporting injection-site reactions to study treatment (if applicable).  For reactions to drugs other than 
study treatment, report the most appropriate term and report multiple events, if applicable. 
g Grading should be based on the greatest single diameter or measured surface area. 
 
 

Appendix 10: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
 
Table 1 
Severity Grading for Adult and Pediatric Adverse Events (cont.) 
GDC-6599—Genentech, Inc. 
146/Protocol GA43590, Version 4 
Parameter 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially Life-Threatening) 
Site Reactions to Injections and Infusions (cont.) f 
Injection-site pruritus f 
Itching localized to the 
injection site that is 
relieved spontaneously 
or requires treatment 
for  48 hours 
Itching beyond the 
injection site that is not 
generalized or itching 
localized to the injection 
site that requires 
treatment for  48 hours 
Generalized itching 
causing inability to 
perform usual social 
and functional activities 
 
Chemistries 
Acidosis 
 
pH  7.3 to  LLN 
pH  7.3 without 
life-threatening 
consequences 
pH  7.3 with  
life-threatening  
consequences 
Albumin, low 
3.0 g/dL to  LLN 
(30 g/L to  LLN) 
 2.0 to  3.0 g/dL 
( 20 to  30 g/L) 
 2.0 g/dL 
( 20 g/L) 
 
Alkaline phosphatase, high 
1.25 to  2.5  ULN 
2.5 to  5.0  ULN 
5.0 to  10.0  ULN 
 10.0  ULN 
Alkalosis 
 
pH  ULN to  7.5 
pH  7.5 without 
life-threatening 
consequences 
pH  7.5 with  
life-threatening 
consequences 
ALT or SGPT, high 
(Report the most 
appropriate term) 
1.25 to  2.5  ULN 
2.5 to  5.0  ULN 
5.0 to  10.0  ULN 
 10.0  ULN 
Amylase (pancreatic) or 
amylase (total), high 
(Report the most 
appropriate term) 
1.1 to  1.5  ULN 
1.5 to  3.0  ULN 
3.0 to  5.0  ULN 
 5.0  ULN 
LLN  lower limit of normal; ULN  upper limit of normal. 
f Refer to Section 5.3.5.1 for instructions on reporting injection-site reactions to study treatment (if applicable).  For reactions to drugs other than 
study treatment, report the most appropriate term and report multiple events, if applicable. 

Appendix 10: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
 
Table 1 
Severity Grading for Adult and Pediatric Adverse Events (cont.) 
GDC-6599—Genentech, Inc. 
147/Protocol GA43590, Version 4 
Parameter 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially Life-Threatening) 
Chemistries (cont.) 
AST or SGOT, high 
(Report the most 
appropriate term) 
1.25 to  2.5  ULN 
2.5 to  5.0  ULN 
5.0 to  10.0  ULN 
 10.0  ULN 
Bicarbonate, low 
16.0 mEq/L to  LLN 
(16.0 mmol/L to  LLN) 
11.0 to  16.0 mEq/L 
(11.0 to  16.0 mmol/L) 
8.0 to  11.0 mEq/L 
(8.0 to  11.0 mmol/L) 
 8.0 mEq/L 
( 8.0 mmol/L) 
Bilirubin (direct), high: 
 28 days of age 
 
 
 ULN with other signs 
and symptoms of 
hepatotoxicity 
 ULN with life-threatening 
consequences (e.g., signs and 
symptoms of liver failure) 
Bilirubin (direct), high:  
 28 days of age 
ULN to  1 mg/dL 
 1 to  1.5 mg/dL 
 1.5 to  2 mg/dL h 
 2 mg/dL h 
Bilirubin (total), high:  
 28 days of age 
1.1 to  1.6  ULN 
1.6 to  2.6  ULN 
2.6 to  5.0  ULN 
 5.0  ULN 
Bilirubin (total), high:  
 28 days of age 
See Table 7 
Calcium, high:   
 7 days of age  
10.6 to  11.5 mg/dL 
(2.65 to  2.88 mmol/L) 
11.5 to  12.5 mg/dL 
(2.88 to  3.13 mmol/L) 
12.5 to  13.5 mg/dL 
(3.13 to  3.38 mmol/L) 
 13.5 mg/dL 
( 3.38 mmol/L) 
Calcium, high:   
 7 days of age  
11.5 to  12.4 mg/dL 
(2.88 to  3.10 mmol/L) 
12.4 to  12.9 mg/dL 
(3.10 to  3.23 mmol/L) 
12.9 to  13.5 mg/dL 
(3.23 to  3.38 mmol/L) 
 13.5 mg/dL 
( 3.38 mmol/L) 
Calcium (ionized), high 
 ULN to  6.0 mg/dL 
( ULN to  1.5 mmol/L) 
6.0 to  6.4 mg/dL 
(1.5 to  1.6 mmol/L) 
6.4 to  7.2 mg/dL 
(1.6 to  1.8 mmol/L) 
 7.2 mg/dL 
( 1.8 mmol/L) 
LLN  lower limit of normal; ULN  upper limit of normal. 
h Direct bilirubin  1.5 mg/dL in a participant  28 days of age should be graded as Grade 2, if  10% of the total bilirubin. 

Appendix 10: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
 
Table 1 
Severity Grading for Adult and Pediatric Adverse Events (cont.) 
GDC-6599—Genentech, Inc. 
148/Protocol GA43590, Version 4 
Parameter 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially Life-Threatening) 
Chemistries (cont.) 
Calcium, low:   
 7 days of age  
7.8 to  8.4 mg/dL 
(1.95 to  2.10 mmol/L) 
7.0 to  7.8 mg/dL 
(1.75 to  1.95 mmol/L) 
6.1 to  7.0 mg/dL 
(1.53 to  1.75 mmol/L) 
 6.1 mg/dL 
( 1.53 mmol/L) 
Calcium, low:   
 7 days of age  
6.5 to  7.5 mg/dL 
(1.63 to  1.88 mmol/L) 
6.0 to  6.5 mg/dL 
(1.50 to  1.63 mmol/L) 
5.50 to  6.0 mg/dL 
(1.38 to  1.50 mmol/L) 
 5.50 mg/dL 
( 1.38 mmol/L) 
Calcium (ionized), low  
 LLN to 4.0 mg/dL 
( LLN to 1.0 mmol/L) 
3.6 to  4.0 mg/dL 
(0.9 to  1.0 mmol/L) 
3.2 to  3.6 mg/dL 
(0.8 to  0.9 mmol/L) 
 3.2 mg/dL 
( 0.8 mmol/L) 
Cardiac troponin I, high  
 
 
 
Levels consistent with myocardial 
infarction or unstable angina as 
defined by the local laboratory  
Creatine kinase, high  
3 to  6  ULN 
6 to  10  ULN 
10 to  20  ULN 
 20  ULN 
Creatinine, high 
1.1 to 1.3  ULN 
 1.3 to 1.8  ULN 
or increase to 
1.3 to  1.5  baseline i 
 1.8 to  3.5  ULN 
or increase to 
1.5 to  2.0  baseline i 
 3.5  ULN or increase to 
 2.0  baseline i 
Creatinine clearance or 
eGFR, low 
(Report the most 
appropriate term) 
 
 90 to 60 mL/min or 
mL/min/1.73 m2 or 
10% to  30% decrease 
from baseline j 
 60 to 30 mL/min or 
mL/min/1.73 m2 or 
30% to  50% decrease 
from baseline j 
 30 mL/min or mL/min/1.73 m2 or 
 50% decrease from baseline j 
or dialysis needed  
eGFR  estimated glomerular filtration rate; LLN  lower limit of normal; ULN  upper limit of normal. 
i For participant with normal baseline value, grade should be based on current value relative to ULN.  For participant with elevated baseline 
value, grade should be based on current value relative to baseline value. 
j For participant with normal baseline value, grade should be based on current value.  For participant with elevated baseline value, grade should 
be based on current value relative to baseline value. 

Appendix 10: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
 
Table 1 
Severity Grading for Adult and Pediatric Adverse Events (cont.) 
GDC-6599—Genentech, Inc. 
149/Protocol GA43590, Version 4 
Parameter 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially Life-Threatening) 
Chemistries (cont.) 
Glucose (fasting), high 
110 to 125 mg/dL 
(6.11 to  6.95 mmol/L) 
 125 to 250 mg/dL 
(6.95 to  13.89 mmol/L) 
 250 to 500 mg/dL 
(13.89 to  27.75 mmol/L) 
 500 mg/dL 
( 27.75 mmol/L) 
Glucose (non-fasting), high  
116 to 160 mg/dL 
(6.44 to  8.89 mmol/L) 
 160 to 250 mg/dL 
(8.89 to  13.89 mmol/L) 
 250 to 500 mg/dL 
(13.89 to  27.75 mmol/L) 
 500 mg/dL 
( 27.75 mmol/L) 
Glucose, low:   
28 days of age 
55 to 64 mg/dL 
(3.05 to  3.55 mmol/L) 
40 to  55 mg/dL 
(2.22 to  3.05 mmol/L) 
30 to  40 mg/dL 
(1.67 to  2.22 mmol/L) 
 30 mg/dL 
( 1.67 mmol/L) 
Glucose, low:   
 28 days of age 
50 to 54 mg/dL 
(2.78 to  3.00 mmol/L) 
40 to  50 mg/dL 
(2.22 to  2.78 mmol/L) 
30 to  40 mg/dL 
(1.67 to  2.22 mmol/L) 
 30 mg/dL 
( 1.67 mmol/L) 
Lactate, high 
ULN to  2.0  ULN 
without acidosis 
 2.0  ULN 
without acidosis 
Increased lactate with 
pH  7.3 without 
life-threatening 
consequences 
Increased lactate with pH  7.3 
with life-threatening  
consequences 
Lipase, high 
1.1 to  1.5  ULN 
1.5 to  3.0  ULN 
3.0 to  5.0  ULN 
 5.0  ULN 
Lipid disorder:   
cholesterol (fasting), high:  
 18 years of age 
200 to  240 mg/dL 
(5.18 to  6.19 mmol/L) 
240 to  300 mg/dL 
(6.19 to  7.77 mmol/L) 
 300 mg/dL 
( 7.77 mmol/L) 
 
Lipid disorder:   
cholesterol (fasting), high:  
 18 years of age 
170 to  200 mg/dL 
(4.40 to  5.15 mmol/L) 
200 to  300 mg/dL 
(5.15 to  7.77 mmol/L) 
 300 mg/dL 
( 7.77 mmol/L) 
 
Lipid disorder:   
LDL (fasting), high:  
 18 years of age 
130  to  160 mg/dL 
(3.37 to  4.12 mmol/L) 
160 to  190 mg/dL 
(4.12 to  4.90 mmol/L) 
 190 mg/dL 
( 4.90 mmol/L) 
 
ULN  upper limit of normal. 

Appendix 10: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
 
Table 1 
Severity Grading for Adult and Pediatric Adverse Events (cont.) 
GDC-6599—Genentech, Inc. 
150/Protocol GA43590, Version 4 
Parameter 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially Life-Threatening) 
Chemistries (cont.) 
Lipid disorder:   
LDL (fasting), high:  
 2 to  18 years of age 
110 to  130 mg/dL 
(2.85 to  3.34 mmol/L) 
130 to  190 mg/dL 
(3.34 to  4.90 mmol/L) 
 190 mg/dL 
( 4.90 mmol/L) 
 
Lipid disorder:   
triglycerides (fasting), high 
150 to 300 mg/dL 
(1.71 to 3.42 mmol/L) 
 300 to 500 mg/dL 
( 3.42 to 5.7 mmol/L) 
 500 to  1,000 mg/dL 
( 5.7 to 11.4 mmol/L) 
 1,000 mg/dL 
( 11.4 mmol/L) 
Magnesium, low 
1.2 to  1.4 mEq/L 
(0.60 to  0.70 mmol/L) 
0.9 to  1.2 mEq/L 
(0.45 to  0.60 mmol/L) 
0.6 to  0.9 mEq/L 
(0.30 to  0.45 mmol/L) 
 0.6 mEq/L 
( 0.30 mmol/L) 
Phosphate, low:   
 14 years of age 
2.0 mg/dL to  LLN 
(0.65 mmol/L to  LLN) 
1.4 to  2.0 mg/dL 
(0.45 to  0.65 mmol/L) 
1.0 to  1.4 mg/dL 
(0.32 to  0.45 mmol/L) 
 1.0 mg/dL 
( 0.32 mmol/L) 
Phosphate, low:   
1 to 14 years of age 
3.0 to  3.5 mg/dL 
(0.97 to  1.13 mmol/L) 
2.5 to  3.0 mg/dL 
(0.81 to  0.97 mmol/L) 
1.5 to  2.5 mg/dL 
(0.48 to  0.81 mmol/L) 
 1.5 mg/dL 
( 0.48 mmol/L) 
Phosphate, low:   
 1 year of age 
3.5 to  4.5 mg/dL 
(1.13 to  1.45 mmol/L) 
2.5 to  3.5 mg/dL 
(0.81 to  1.13 mmol/L) 
1.5 to  2.5 mg/dL 
(0.48 to  0.81 mmol/L) 
 1.5 mg/dL 
( 0.48 mmol/L) 
Potassium, high 
5.6 to  6.0 mEq/L or 
mmol/L 
6.0 to  6.5 mEq/L or 
mmol/L 
6.5 to  7.0 mEq/L or 
mmol/L 
 7.0 mEq/L or mmol/L 
Potassium, low 
3.0 to  3.4 mEq/L or 
mmol/L 
2.5 to  3.0 mEq/L or 
mmol/L 
2.0 to  2.5 mEq/L or 
mmol/L 
 2.0 mEq/L or mmol/L 
Sodium, high 
146 to  150 mEq/L or 
mmol/L 
150 to  154 mEq/L or 
mmol/L 
154 to  160 mEq/L or 
mmol/L 
 160 mEq/L or mmol/L 
Sodium, low 
130 to  135 mEq/L or 
mmol/L 
125 to  130 mEq/L or 
mmol/L 
121 to  125 mEq/L or 
mmol/L 
 121 mEq/L or mmol/L 
Uric acid, high 
7.5 to  10.0 mg/dL 
(0.45 to  0.59 mmol/L) 
10.0 to  12.0 mg/dL 
(0.59 to  0.71 mmol/L) 
12.0 to  15.0 mg/dL 
(0.71 to  0.89 mmol/L) 
 15.0 mg/dL 
( 0.89 mmol/L) 
LLN  lower limit of normal. 

Appendix 10: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
 
Table 1 
Severity Grading for Adult and Pediatric Adverse Events (cont.) 
GDC-6599—Genentech, Inc. 
151/Protocol GA43590, Version 4 
Parameter 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially Life-Threatening) 
Hematology 
Absolute CD4+ count, low 
(not HIV infected):   
 5 years of age 
300 to  400 cells/mm3 
(0.300  109 to 
 0.400  109 cells/L) 
200 to  300 cells/mm3 
(0.200  109 to 
 0.300  109 cells/L) 
100 to  200 cells/mm3 
(0.100  109 to 
 0.200  109 cells/L) 
 100 cells/mm3 
(0.100  109 cells/L) 
Absolute lymphocyte count, 
low (not HIV infected):   
 5 years of age 
600 to  650 cells/mm3 
(0.600  109 to 
 0.650  109 cells/L) 
500 to  600 cells/mm3 
(0.500  109 to 
 0.600  109 cells/L) 
350 to  500 cells/mm3 
(0.350  109 to 
 0.500  109 cells/L) 
 350 cells/mm3 
( 0.350  109 cells/L) 
Absolute neutrophil count, 
low:   7 days of age 
800 to 1000 cells/mm3 
(0.800  109 to 
1.000  109 cells/L) 
600 to 799 cells/mm3 
(0.600  109 to 
0.799  109 cells/L) 
400 to 599 cells/mm3 
(0.400  109 to  
0.599  109 cells/L) 
 400 cells/mm3 
( 0.400  109 cells/L) 
Absolute neutrophil count, 
low:  2 to 7 days of age 
1250 to 1500 cells/mm3 
(1.250  109 to 
1.500  109 cells/L) 
1000 to 1249 cells/mm3 
(1.000  109 to 
1.249  109 cells/L) 
750 to 999 cells/mm3 
(0.750  109 to  
0.999  109 cells/L) 
 750 cells/mm3 
( 0.750  109 cells/L) 
Absolute neutrophil count, 
low:   1 day of age 
4000 to 5000 cells/mm3 
(4.000  109 to 
5.000  109 cells/L) 
3000 to 3999 cells/mm3 
(3.000  109 to 
3.999  109 cells/L) 
1500 to 2999 cells/mm3 
(1.500  109 to  
2.999  109 cells/L) 
 1500 cells/mm3 
( 1.500  109 cells/L) 
Fibrinogen, decreased 
100 to  200 mg/dL 
(1.00 to  2.00 g/L) 
or 
0.75 to  1.00  LLN 
75 to  100 mg/dL 
(0.75 to  1.00 g/L) 
or 
 0.50 to  0.75  LLN 
50 to  75 mg/dL 
(0.50 to  0.75 g/L) 
or 
0.25 to  0.50  LLN 
 50 mg/dL 
( 0.50 g/L) 
or 
 0.25  LLN 
or associated with gross bleeding 
LLN  lower limit of normal. 

Appendix 10: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
 
Table 1 
Severity Grading for Adult and Pediatric Adverse Events (cont.) 
GDC-6599—Genentech, Inc. 
152/Protocol GA43590, Version 4 
Parameter 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially Life-Threatening) 
Hematology (cont.) 
Hemoglobin, low: 
 13 years of age  
(male only) k 
10.0 to 10.9 g/dL 
(6.19 to 6.76 mmol/L) 
9.0 to  10.0 g/dL 
(5.57 to  6.19 mmol/L) 
7.0 to  9.0 g/dL 
(4.34 to  5.57 mmol/L) 
 7.0 g/dL 
( 4.34 mmol/L) 
Hemoglobin, low: 
 13 years of age 
(female only) k 
9.5 to 10.4 g/dL 
(5.88 to 6.48 mmol/L) 
8.5 to  9.5 g/dL 
(5.25 to  5.88 mmol/L) 
6.5 to  8.5 g/dL 
(4.03 to  5.25 mmol/L) 
 6.5 g/dL 
( 4.03 mmol/L) 
Hemoglobin, low: 
57 days to  13 years of age 
(male and female) k 
9.5 to 10.4 g/dL 
(5.88 to 6.48 mmol/L) 
8.5 to  9.5 g/dL 
(5.25 to  5.88 mmol/L) 
6.5 to  8.5 g/dL 
(4.03 to  5.25 mmol/L) 
 6.5 g/dL 
( 4.03 mmol/L) 
Hemoglobin, low: 
36 to 56 days of age 
(male and female) k 
8.5 to 9.6 g/dL 
(5.26 to 5.99 mmol/L) 
7.0 to  8.5 g/dL 
(4.32 to  5.26 mmol/L) 
6.0 to  7.0 g/dL 
(3.72 to  4.32 mmol/L) 
 6.0 g/dL 
( 3.72 mmol/L) 
Hemoglobin, low: 
22 to 35 days of age 
(male and female) k 
9.5 to 11.0 g/dL 
(5.88 to 6.86 mmol/L) 
8.0 to  9.5 g/dL 
(4.94 to  5.88 mmol/L) 
6.7 to  8.0 g/dL 
(4.15 to  4.94 mmol/L) 
 6.7 g/dL 
( 4.15 mmol/L) 
Hemoglobin, low: 
8 to 21 days of age 
(male and female) k 
11.0 to 13.0 g/dL 
(6.81 to 8.10 mmol/L) 
9.0 to  11.0 g/dL 
(5.57 to  6.81 mmol/L) 
8.0 to  9.0 g/dL 
(4.96 to  5.57 mmol/L) 
 8.0 g/dL 
( 4.96 mmol/L) 
Hemoglobin, low: 
 7 days of age 
(male and female) k 
13.0 to 14.0 g/dL 
(8.05 to 8.72 mmol/L) 
10.0 to  13.0 g/dL 
(6.19 to  8.05 mmol/L) 
9.0 to  10.0 g/dL 
(5.59 to  6.19 mmol/L) 
 9.0 g/dL 
( 5.59 mmol/L) 
k Male and female sex are defined as sex at birth.  For transgender participants  13 years of age who have been on hormone therapy for more 
than 6 consecutive months, hemoglobin grade should be based on values for the gender with which they identify (e.g., grade for a transgender 
female should be based on hemoglobin laboratory values for females). 

Appendix 10: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
 
Table 1 
Severity Grading for Adult and Pediatric Adverse Events (cont.) 
GDC-6599—Genentech, Inc. 
153/Protocol GA43590, Version 4 
Parameter 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially Life-Threatening) 
Hematology (cont.) 
INR, high (not on 
anticoagulation therapy) 
1.1 to  1.5  ULN 
1.5 to  2.0  ULN 
2.0 to  3.0  ULN 
 3.0  ULN 
Methemoglobin 
(% hemoglobin) 
5.0% to  10.0% 
10.0% to  15.0% 
15.0% to  20.0% 
 20.0% 
PTT, high (not on 
anticoagulation therapy) 
1.1 to  1.66  ULN 
1.66 to  2.33  ULN 
2.33 to  3.00  ULN 
 3.00  ULN 
Platelets, decreased 
100,000 to  
 125,000 cells/mm3 
(100.000  109 to 
 125.000  109 cells/L) 
50,000 to  
 100,000 cells/mm3 
(50.000  109 to 
 100.000  109 cells/L) 
25,000 to  
 50,000 cells/mm3 
(25.000  109 to  
 50.000  109 cells/L) 
 25,000 cells/mm3 
( 25.000  109 cells/L) 
PT, high (not on 
anticoagulation therapy 
1.1 to  1.25  ULN 
1.25 to  1.50  ULN 
1.50 to  3.00  ULN 
 3.00  ULN 
WBC, decreased:   
 7 days of age 
2000 to 2499 cells/mm3 
(2.000  109 to  
2.499  109 cells/L) 
1500 to 1999 cells/mm3 
(1.500  109 to  
1.999  109 cells/L) 
1000 to 1499 cells/mm3 
(1.000  109 to  
1.499  109 cells/L) 
 1000 cells/mm3 
( 1.000  109 cells/L) 
WBC, decreased:   
 7 days of age 
5500 to 6999 
(5.500  109 to  
6.999  109 cells/L) 
4000 to 5499 
(4.000  109 to  
5.499  109 cells/L) 
2500 to 3999 
(2.500  109 to  
3.999  109 cells/L) 
 2500 
( 2.500  109 cells/L) 
ULN  upper limit of normal. 

Appendix 10: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
 
Table 1 
Severity Grading for Adult and Pediatric Adverse Events (cont.) 
GDC-6599—Genentech, Inc. 
154/Protocol GA43590, Version 4 
Parameter 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially Life-Threatening) 
Urinalysis 
Glycosuria (random 
collection tested by dipstick) 
Trace to 1+ or 
 250 mg 
2+ or  250 to 
 500 mg 
 2+ or  500 mg 
 
Hematuria (not to be reported 
based on dipstick findings or 
on blood believed to be of 
menstrual origin) 
6 to  10 RBCs per high 
power field 
 10 RBCs per high 
power field 
Gross, with or without clots 
or with RBC casts 
or intervention indicated 
Life-threatening consequences 
Proteinuria (random 
collection tested by dipstick) 
1+ 
2+ 
3+ or higher 
 
 
 

Appendix 10: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
 
GDC-6599—Genentech, Inc. 
155/Protocol GA43590, Version 4 
Table 7 
Severity Grading for Elevated Total Bilirubin in Neonates 
Parameter 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially Life-Threatening) 
Neonates  35 Weeks Gestational Age 
 24 hours of age  
4 to  7 mg/dL 
(68.4 to  119.7 mol/L) 
7 to  10 mg/dL 
(119.7 to  171 mol/L) 
10 to  17 mg/dL 
(171 to  290.7 mol/L) 
 17 mg/dL 
( 290.7 mol/L) 
24 to  48 hours of age  
5 to  8 mg/dL 
(85.5 to  136.8 mol/L) 
8 to  12 mg/dL 
(136.8 to  205.2 mol/L) 
12 to  19 mg/dL 
(205.2 to  324.9 mol/L) 
 19 mg/dL 
( 324.9 mol/L) 
48 to  72 hours of age  
8.5 to  13 mg/dL 
(145.35 to  222.3 mol/L) 
13 to  15 mg/dL 
(222.3 to  256.5 mol/L) 
15 to  22 mg/dL 
(256.5 to  376.2 mol/L) 
 22 mg/dL 
( 376.2 mol/L) 
72 hours to  7 days of age  
11 to  16 mg/dL 
(188.1 to  273.6 mol/L) 
16 to  18 mg/dL 
(273.6 to  307.8 mol/L) 
18 to  24 mg/dL 
(307.8 to  410.4 mol/L) 
 24 mg/dL 
( 410.4 mol/L) 
7 to 28 days of age (breast 
feeding)  
5 to  10 mg/dL 
(85.5 to  171 mol/L) 
10 to  20 mg/dL 
(171 to  342 mol/L) 
20 to  25 mg/dL 
(342 to  427.5 mol/L) 
 25 mg/dL 
( 427.5 mol/L) 
7 to 28 days of age (not 
breast feeding)  
1.1 to  1.6 ULN 
1.6 to  2.6 ULN 
2.6 to  5.0 ULN 
 5.0 ULN 
ULN  upper limit of normal. 
 
 
 

Appendix 10: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
 
Table 2 
Severity Grading for Elevated Total Bilirubin in Neonates (cont.) 
 
GDC-6599—Genentech, Inc. 
156/Protocol GA43590, Version 4 
 
Parameter 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially Life-Threatening) 
Neonates  35 Weeks Gestational Age 
32 to  35 weeks gestational 
age and  7 days of age  
 
 
10 to  14 mg/dL 
(171 to  239.4 mol/L) 
 14 mg/dL 
( 239.4 mol/L) 
28 to  32 weeks gestational 
age and  7 days of age  
 
 
6 to  10 mg/dL 
(102.6 to  171 mol/L) 
 10 mg/dL 
( 171 mol/L) 
 28 weeks gestational age 
and  7 days of age  
 
 
5 to  8 mg/dL 
(85.5 to  136.8 mol/L) 
 8 mg/dL 
( 136.8 mol/L) 
7 to 28 days of age 
(breast feeding)  
5 to  10 mg/dL 
(85.5 to  171 mol/L) 
10 to  20 mg/dL 
(171 to  342 mol/L) 
20 to  25 mg/dL 
(342 to  427.5 mol/L) 
 25 mg/dL 
( 427.5 mol/L) 
7 to 28 days of age 
(not breast feeding)  
1.1 to  1.6  ULN 
1.6 to  2.6 ULN 
2.6 to  5.0 ULN 
 5.0 ULN 
ULN  upper limit of normal. 
 

Appendix 10: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
 
GDC-6599—Genentech, Inc. 
157/Protocol GA43590, Version 4 
Table 3  
Severity Grading for Events Not Specifically Listed in Tables 1 and 2 
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 
 
REFERENCE 
[HHS] U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and Infectious 
Diseases, Division of AIDS. Division of AIDS (DAIDS) table for grading the severity of adult and pediatric adverse events, corrected 
version 2.1 [resource on the Internet]. 2017 [cited: 12 October 2021]. Available from: 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf. 
 

 
GDC-6599—Genentech, Inc. 
158/Protocol GA43590, Version 4 
Appendix 11  
Investigational Medicinal Product and Non-Investigational 
Medicinal Product Designations (for Use in European Economic 
Area and United Kingdom) 
 
Product Name 
IMP/NIMP 
Designation 
Marketing Authorization 
Status in EEA/and/ /U.K. 
Used within Marketing 
Authorization 
GDC-6599 
IMP (test product) 
Not approved 
Not applicable 
GDC-6599 Placebo 
IMP (Placebo) 
Not approved 
Not applicable 
Mannitol 
(Aridol/Osmohale) 
IMP (challenge agent) 
Approved 
Yes 
EEA    European Economic Area; IMP    investigational medicinal product; U.K.  United Kingdom.  
 

 
GDC-6599—Genentech, Inc. 
159/Protocol GA43590, Version 4 
Appendix 12  
Drugs Associated with QT Prolongation 
Drugs associated with QT prolongation are prohibited within 1 month prior to 
screening (Study Visit 1) through the completion of the study at Visit 8.  A list of 
drugs with known risk of QT prolongation is shown in Table 1.  This list is subject to 
change (output date 15 November 2022); please consult crediblemeds.org for updated 
information and information on additional drugs with possible or conditional risk of 
QT prolongation. 
Table 1 
Drugs with a Known Risk of QT Prolongation 
Generic Name 
Brand Names (Partial List) 
Aclarubicin (Only on Non-U.S. 
Market) 
Aclacin, Aclacinomycine, Aclacinon, Aclaplastin, 
Jaclacin 
Amiodarone  
Cordarone, Pacerone, Nexterone 
Anagrelide  
Agrylin, Xagrid 
Arsenic trioxide  
Trisenox 
Astemizole (Removed from U.S. 
Market) 
Hismanal 
Azithromycin  
Zithromax, Zmax 
Bepridil  
Vascor 
Cesium Chloride  
Energy Catalyst 
Chloroquine  
Aralen 
Chlorpromazine  
Thorazine, Largactil, Megaphen 
Chlorprothixene (Only on Non-U.S. 
Market) 
Truxal 
Cilostazol  
Pletal 
Ciprofloxacin  
Cipro, Cipro-XR, Neofloxin 
Cisapride (Removed from US Market) 
Propulsid 
Citalopram  
Celexa, Cipramil 
Clarithromycin  
Biaxin, Prevpac 
Cocaine 
Cocaine 
Disopyramide  
Norpace 
Dofetilide 
Tikosyn 
Domperidone (Only on Non-US 
Market) 
Motilium, Motillium, Motinorm Costi, Nomit 
Donepezil  
Aricept 
Dronedarone  
Multaq 
Droperidol 
Inapsine, Droleptan, Dridol, Xomolix 

Appendix 12: Drugs Associated with QT Prolongation 
  
GDC-6599—Genentech, Inc. 
160/Protocol GA43590, Version 4 
Table 1 
Drugs with a Known Risk of QT Prolongation (cont.) 
Erythromycin 
E.E.S., Robimycin, EMycin, Erymax, Ery-Tab, Eryc 
Ranbaxy, Erypar, Eryped, Erythrocin Stearate Filmtab, 
Erythrocot, E-Base, Erythroped, Ilosone, MY-E, 
Pediamycin, Abboticin, Abboticin-ES, Erycin, PCE 
Dispertab, Stiemycine, Acnasol, Tiloryth 
Escitalopram 
Cipralex, Lexapro, Nexito, Anxiset-E, Exodus, Esto, 
Seroplex, Elicea, Lexamil, Lexam, Entact, Losita, 
Reposil, Animaxen, Esitalo, Lexamil 
Flecainide 
Tambocor, Almarytm, Apocard, Ecrinal, Flécaine 
Fluconazole  
Diflucan, Trican 
Gatifloxacin (Removed from U.S. 
Market) 
Tequin 
Grepafloxacin (Removed from U.S. 
Market)  
Raxar 
Halofantrine (Only on Non-U.S. 
Market) 
Halfan 
Haloperidol 
Haldol, Aloperidin, Bioperidolo, Brotopon, Dozic, 
Duraperidol, Einalon S, Eukystol, Halosten, Keselan, 
Linton, Peluces, Serenace, Serenase, Sigaperidol 
Hydroquinidine (Dihydroquinidine) 
(Only on Non-U.S. Market)  
Serecor 
Hydroxychloroquine  
Plaquenil, Quineprox 
Ibogaine (Only on Non-U.S. Market) 
 
Ibutilide  
Corvert 
Levofloxacin  
Levaquin, Tavanic 
Levomepromazine (Methotrimeprazine) 
(Only on Non-U.S. Market) 
Nosinan, Nozinan, Levoprome 
Levomethadyl acetate (Removed from 
U.S. Market) 
Orlaam 
Levosulpiride (Only on Non-US 
Market) 
Lesuride, Levazeo, Enliva 
Meglumine antimoniate 
Glucantime 
Mesoridazine (Removed from US 
Market) 
Serentil 
Methadone  
Dolophine, Symoron, Amidone, Methadose, Physeptone, 
Heptadon 
Mobocertinib 
Exkivity 
Moxifloxacin  
Avelox, Avalox, Avelon 
Nifekalant (Only on Non-US Market) 
Shinbit 
Ondansetron 
Zofran, Anset, Ondemet, Zuplenz, Emetron, Ondavell, 
Emeset, Ondisolv, Setronax 

Appendix 12: Drugs Associated with QT Prolongation 
  
GDC-6599—Genentech, Inc. 
161/Protocol GA43590, Version 4 
Table 1 
Drugs with a Known Risk of QT Prolongation (cont.) 
Oxaliplatin  
Eloxatin 
Papaverine HCl (Intracoronary) 
 
Pentamidine 
Pentam 
Pimozide  
Orap 
Probucol (Removed from US Market)  
Lorelco 
Procainamide  
Pronestyl, Procan 
Propofol  
Diprivan, Propoven 
Quinidine  
Quinaglute, Duraquin, Quinact, Quinidex, Cin-Quin, 
Quinora 
Roxithromycin (Only on Non-US 
Market) 
Rulide, Xthrocin, Roxl-150, Roxo, Surlid, Rulide, 
Biaxsig, Roxar, Roximycinv, Roxomycin, Rulid, 
Tirabicin, Coroxin 
Sertindole 
Serdolect, Serlect 
Sevoflurane  
Ultane, Sojourn 
Sotalol  
Betapace, Sotalex, Sotacor 
Sparfloxacin (Removed from US 
Market)  
Zagam 
Sulpiride (Only on Non-US Market) 
Dogmatil, Dolmatil, Eglonyl, Espiride, Modal, Sulpor 
Sultopride (Only on Non-US Market) 
Barnetil, Barnotil, Topral 
Terfenadine (Removed from US 
Market) 
Seldane 
Terlipressin (Only on Non-US Market) 
Teripress, Glypressin, Terlipin, Remestyp, Tresil, 
Teriss 
Terodiline (Only on Non-US Market) 
Micturin, Mictrol 
Thioridazine  
Mellaril, Novoridazine, Thioril 
Vandetanib  
Caprelsa 
TdP  torsades de pointes. 
Note:  All drugs listed above are: 
Known risk of TdP:  Substantial evidence supports the conclusion that these drugs prolong the QT 
interval AND are clearly associated with a risk of TdP, even when taken as directed in official 
labeling. 
Drugs to avoid in congenital long QT:  Substantial evidence supports the conclusion that these 
drugs pose a risk of TdP for patients with congenital long QT.  Drugs on this list include those in 
the above risk category and other drugs that do not prolong the Qt interval per se, but they have a 
theoretical risk of causing arrhythmia that is based on their known stimulant actions on the heart. 
 
REFERENCE 
Woosley RL, Heise CW , Gallo T, et al., QTdrugs List, [resource on the Internet]. 2023 
[updated: 15 November 2022; cited: 2 February 2023]. Available from: 
https://crediblemeds.org/. 

Signature Page for Protocol - GA43590 - TRPA1 INHIBITOR (2) - v4 - Published
System identifier: RIM-CLIN-532976
Approval Task
Company Signatory
03-May-2024 15:42:47 GMT+0000