A Phase II Open Label Study to Evaluate the Effect of GBT440 on Hypoxemia in Subjects With Idiopathic Pulmonary Fibrosis (IPF) Who Are Using Supplemental Oxygen at Rest (ZEPHYR)
Phase: PHASE2
Conditions: Idiopathic Pulmonary Fibrosis, Hypoxemia
Sponsor: Global Blood Therapeutics

Protocol Number GBT440-026, Amendment 2 
 
Global Blood Therapeutics 
Final June 5, 2017 
 
Page 1 of 77 
 
 
Clinical Study Protocol 
GBT440-026 
Study Number 
GBT440-026 
Study Title 
A Phase II open label study to evaluate the effect of GBT440 on 
hypoxemia in subjects with Idiopathic Pulmonary Fibrosis (IPF) who 
are using supplemental oxygen at rest (ZEPHYR) 
Investigational 
Product 
GBT440  
IND Number 
128319 
EudraCT Number 
2017-001276-27 
Sponsor 
400 East Jamie Court, Suite 101 
South San Francisco,  
CA 94080 
United States of America 
Sponsor’s Medical 
Director 
Nicholas Vlahakis, MD 
Senior Medical Director  
650 741-7730 (Office Telephone No.)  
nvlahakis@globalbloodtx.com 
Medical Monitor 
(US) 
Toni Bransford, MD 
Senior Medical Director 
Worldwide Clinical Trials 
973-420-6236 
toni.bransford@worldwide.com 
Medical Monitor 
(UK) 
Ruben Rosoky, MD, PhD, MFPM 
Medical Director 
UBC: An Express Scrips company 
+41 22 596 4410 
ruben.ayzinrosoky@ubc.com 
Version / Date 
Amendment 2 / 05 June 2017 
CONFIDENTIAL 
The information in this study protocol is strictly confidential and is available for review to 
Investigators, study center personnel, the ethics committee and the health authorities. It will 
not be disclosed to third parties without written authorization from the Sponsor, except to 
obtain informed consent from persons receiving the study drug. Once the protocol is signed, 
its terms are binding for all parties. 

Protocol Number GBT440-026, Amendment 2 
 
Global Blood Therapeutics 
Final June 5, 2017 
 
Page 3 of 77 
 
INVESTIGATOR STATEMENT OF APPROVAL AND COMPLIANCE 
A Phase II open label study of GBT440 to evaluate the effect on hypoxemia in subjects 
with Idiopathic Pulmonary Fibrosis (IPF) who are using supplemental oxygen at rest 
(ZEPHYR)  
Protocol Number: GBT440-026, Amendment 2 
APPROVAL 
The signature of the Investigator below constitutes approval of this protocol as written and 
reflects the Investigator’s commitment to conduct the study in accordance with the protocol, 
the applicable laws and regulations and in compliance with ICH Good Clinical Practice 
guidelines. 
Principal Investigator 
(signature): 
 
Principal Investigator 
(printed name) 
 
Date: 
 
Title: 
 
 

Protocol Number GBT440-026, Amendment 2 
 
Global Blood Therapeutics 
Final June 5, 2017 
 
Page 4 of 77 
 
SPONSOR CONTACT INFORMATION 
Sponsor’s Medical Director 
Nick Vlahakis, M.D. 
Senior Medical Director  
(650) 741-7730  
nvlahakis@globalbloodtx.com 
Clinical Trial Manager 
Aimee Enriquez 
Clinical Trial Manager 
(650) 741-7777  
aenriquez@globalbloodtx.com  
Clinical Operations Oversight 
Bella Oguno, MPH 
Director, Clinical Operations 
 (650) 351-4758 
boguno@globalbloodtx.com 
 

Protocol Number GBT440-026, Amendment 2 
Global Blood Therapeutics 
Final June 5, 2017 
Page 5 of 77 
TABLE OF CONTENTS 
SPONSOR STATEMENT OF APPROVAL AND COMPLIANCE ........................................2 
INVESTIGATOR STATEMENT OF APPROVAL AND COMPLIANCE .............................3 
SPONSOR CONTACT INFORMATION .................................................................................4 
TABLE OF CONTENTS ...........................................................................................................5 
LIST OF TABLES .....................................................................................................................8 
LIST OF FIGURES ...................................................................................................................8 
LIST OF APPENDICES ............................................................................................................8 
LIST OF ABBREVIATIONS ....................................................................................................9 
PROTOCOL SYNOPSIS.........................................................................................................11 
1 
INTRODUCTION .................................................................................................20 
1.1 
Disease Background.........................................................................................20 
1.2 
GBT440............................................................................................................20 
1.3 
Rationale for Study ..........................................................................................21 
1.4 
Nonclinical Data ..............................................................................................22 
1.4.1 
Nonclinical Pharmacology ...................................................................22 
1.4.2 
Nonclinical Pharmacology ...................................................................22 
1.4.3 
Nonclinical Pharmacokinetics .............................................................22 
1.4.4 
Metabolism and Potential Drug Interactions .......................................22 
1.4.5 
Toxicology ...........................................................................................23 
1.5 
Clinical Development of GBT440 ...................................................................23 
1.5.1 
Safety Findings ....................................................................................23 
1.5.2 
Pharmacokinetic Parameters ................................................................24 
1.5.3 
Dose Rationale .....................................................................................25 
1.5.4 
Potential Risk of GBT440 Treatment ..................................................25 
2 
STUDY OBJECTIVES ..........................................................................................26 
2.1 
Primary Objective ............................................................................................26 
2.2 
Secondary Objectives .......................................................................................26 
2.3 
Exploratory Objectives ....................................................................................26 
3 
INVESTIGATIONAL PLAN ................................................................................27 
3.1 
Study Design ....................................................................................................27 
3.2 
Endpoints .........................................................................................................29 
3.2.1 
Primary Endpoint .................................................................................29 
3.2.2 
Secondary Endpoints ...........................................................................29 
3.2.3 
Exploratory Endpoints .........................................................................29 
3.2.4 
Safety Endpoints ..................................................................................30 
3.2.5 
Pharmacokinetics Endpoints ................................................................30 
4 
STUDY POPULATION ........................................................................................31 

Protocol Number GBT440-026, Amendment 2 
 
Global Blood Therapeutics 
Final June 5, 2017 
 
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4.1 
Inclusion Criteria .............................................................................................31 
4.2 
Exclusion Criteria ............................................................................................31 
5 
STUDY PROCEDURES AND EVALUATIONS ................................................34 
5.1 
Subject Screening .............................................................................................34 
5.2 
Avoidance of Pregnancy ..................................................................................34 
5.3 
Clinical Assessments .......................................................................................35 
5.3.1 
Pregnancy .............................................................................................35 
5.3.2 
Medical History and Demographic Data .............................................35 
5.3.3 
Physical Examination...........................................................................36 
5.4 
Laboratory Examination ..................................................................................36 
5.4.1 
Clinical Laboratory Studies .................................................................36 
5.5 
Disease-Related Evaluations ............................................................................38 
5.5.1 
Oxygen Titration Test (OTT) ...............................................................38 
5.5.2 
Oxygen Saturation Measurement .........................................................38 
5.5.3 
Arterial Blood Gases (ABG) ................................................................39 
5.5.4 
6-Minute Walk Test (6MWT) ..............................................................39 
5.5.5 
Spirometry and Diffusing Capacity of the Lung for Carbon 
Monoxide (DLCO) ................................................................................40 
5.5.6 
Patient Reported Outcome (PRO) Measures .......................................40 
5.6 
Pharmacokinetic Samples ................................................................................41 
6 
EARLY DISCONTINUATION OF STUDY OR INDIVIDUAL SUBJECTS ....43 
6.1 
Early Discontinuation of the Study and/or Site ...............................................43 
6.2 
Early Discontinuation of Individual subjects ...................................................43 
6.3 
Study Drug Discontinuation ............................................................................44 
7 
STUDY DRUG AND ACCOUNTABILITY ........................................................45 
7.1 
Study Drug .......................................................................................................45 
7.1.1 
Physical Description ............................................................................45 
7.1.2 
Formulation ..........................................................................................45 
7.1.3 
Packaging and Labeling .......................................................................45 
7.1.4 
Supply ..................................................................................................45 
7.1.5 
Storage and Handling Procedure .........................................................45 
7.2 
Drug Accountability.........................................................................................46 
8 
DOSAGE AND TREATMENT ADMINISTRATION .........................................47 
8.1 
Treatment Regimen ..........................................................................................47 
8.2 
Study Drug Dispensing ....................................................................................47 
8.3 
Dose Modification ...........................................................................................47 
8.3.1 
Dose Adjustment ..................................................................................48 
8.3.2 
Dose Interruption .................................................................................49 

Protocol Number GBT440-026, Amendment 2 
 
Global Blood Therapeutics 
Final June 5, 2017 
 
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8.3.3 
Pirfenidone or Nintedanib Background Therapy .................................49 
8.4 
Study Drug Overdose .......................................................................................50 
8.5 
Concomitant Medications ................................................................................50 
8.5.1 
Permitted Therapy ................................................................................50 
8.5.2 
Restricted Therapies .............................................................................51 
8.5.3 
Therapies for treatment of IPF .............................................................51 
8.6 
Fertility/Contraceptive Requirements ..............................................................51 
8.6.1 
Acceptable Forms of Contraception ....................................................52 
9 
RANDOMIZATION PROCEDURE .....................................................................53 
9.1 
Blinding............................................................................................................53 
10 
SAFETY ASSESSMENTS ....................................................................................54 
10.1 
Adverse Events (AE) .......................................................................................54 
10.2 
Recording Adverse Events ...............................................................................54 
10.2.1 
Assessment of Adverse Events ............................................................55 
10.2.2 
Serious Adverse Event (SAE) ..............................................................55 
10.2.3 
Protocol-Defined Events of Special Interest ........................................55 
10.2.4 
Severity of Adverse Events ..................................................................56 
10.2.5 
Relationship to Study Drug ..................................................................56 
10.2.6 
Unexpected Adverse Events ................................................................57 
10.3 
Reporting Adverse Events ...............................................................................57 
10.3.1 
Diagnosis versus Signs and Symptoms................................................57 
10.3.2 
Adverse Events Occurring Secondary to Other Events .......................57 
10.3.3 
Persistent or Recurrent Adverse Events ...............................................57 
10.3.4 
Abnormal Laboratory Values ..............................................................58 
10.3.5 
Reporting Serious Adverse Events (SAEs) ..........................................58 
10.3.6 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
Reporting..............................................................................................59 
10.4 
Discontinuation due to Adverse Events ...........................................................59 
10.5 
Pregnancy .........................................................................................................59 
11 
DATA ANALYSIS AND STATISTICAL PLANS ..............................................61 
11.1 
Sample Size ......................................................................................................61 
11.2 
Analysis Populations ........................................................................................61 
11.3 
Statistical Analyses ..........................................................................................61 
11.3.1 
Efficacy Analyses ................................................................................61 
11.3.2 
Safety Analyses ....................................................................................62 
11.3.3 
PK and PK/PD Analyses ......................................................................62 
12 
REGULATORY, ETHICAL AND LEGAL OBLIGATIONS ..............................63 
12.1 
Ethical Consideration .......................................................................................63 

Protocol Number GBT440-026, Amendment 2 
 
Global Blood Therapeutics 
Final June 5, 2017 
 
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12.2 
Institutional Review Board (IRB) and Regulatory Approval ..........................63 
12.3 
Insurance and Financial Disclosure .................................................................63 
12.4 
Essential Documentation Requirements ..........................................................63 
12.5 
Informed Consent.............................................................................................64 
12.6 
Confidentiality .................................................................................................64 
12.7 
Trial Documentation and Data Storage............................................................64 
12.8 
Study Record Retention ...................................................................................65 
12.9 
Disclosure of Information ................................................................................65 
12.10 
Publication .......................................................................................................65 
13 
ADMINISTRATIVE OBLIGATIONS .................................................................66 
13.1 
Source Data ......................................................................................................66 
13.2 
Data Collection ................................................................................................66 
13.3 
Monitoring .......................................................................................................66 
13.4 
Quality Control and Quality Assurance ...........................................................67 
14 
REFERENCES ......................................................................................................68 
15 
APPENDICES .......................................................................................................70 
 
LIST OF TABLES 
Table 5-1 
PK Sample Collection Schedule ................................................................42 
Table 8-1 
CYP Substrates with Narrow Therapeutic Range ......................................51 
Table 10-1 
Grading for Adverse Events Not Covered in the NCI CTCAE .................56 
Table 15-1 
Schedule of Assessments: Part A — 900 mg Dose ...................................71 
Table 15-2 
Schedule of Assessments: Part B — 1500 mg Dose..................................74 
  
LIST OF FIGURES 
Figure 3-1 
Study Design ..............................................................................................28 
 
LIST OF APPENDICES 
Appendix A 
SCHEDULES OF STUDY ASSESSMENTS ...........................................71 
Appendix B 
STRONG INDUCERS OF CYP ISOENZYMES .....................................77 
 

Protocol Number GBT440-026, Amendment 2 
 
Global Blood Therapeutics 
Final June 5, 2017 
 
Page 9 of 77 
 
LIST OF ABBREVIATIONS 
ABG 
Arterial blood gases 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALAT 
Latin American Respiratory Society 
ALK 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATAQ 
A Tool to Assess Quality of Life 
ATS 
American Thoracic Society 
AUC 
Area under the concentration time curve 
BUN 
Blood Urea Nitrogen 
CL 
Clearance 
Cmax 
Maximum concentration 
Cmin 
Minimum concentration 
CNS 
Central nervous system 
CRA 
Clinical research associate 
CRF 
Case report form 
CRO 
Contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of variation 
CYP 
Cytochrome 
DDI 
Drug-drug interaction 
DLCO 
Diffusing capacity of the lung for carbon monoxide 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
EPO 
Serum erythropoietin 
ERS 
European Respiratory Society 
FEV1 
Forced expiratory volume in 1 second 
FVC 
Forced vital capacity 
GBT 
Global Blood Therapeutics 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase 
GMP  
Good Manufacturing Practices 
Hb 
Hemoglobin 
HbA 
Adult hemoglobin 
HbS 
Hemoglobin S 
hCG 
Human chorionic gonadotropin 
hERG 
Human Ether-à-go-go-Related Gene 
IB 
Investigator's Brochure 
ICF 
Informed consent form 

Protocol Number GBT440-026, Amendment 2 
 
Global Blood Therapeutics 
Final June 5, 2017 
 
Page 10 of 77 
 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IPF 
Interstitial pulmonary fibrosis 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IUS 
Intrauterine system 
JRS 
Japanese Respiratory Society 
MedDRA 
Medical dictionary for regulatory activities 
6MWD 
6-minute walk distance 
6MWT 
6-minute walk test 
MTD 
Maximum tolerated dose 
NAC 
N-acetylcysteine 
NCI 
National Cancer Institute 
NOAEL 
No observed adverse effect level 
ODC 
Oxy-hemoglobin dissociation curve 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PRO 
Patient reported outcome 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QTcF 
Corrected QT interval using the Fridericia formula 
OTT 
Oxygen titration test 
RBC 
Red blood cell 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SaO2 
Arterial oxygen saturation 
SCD 
Sickle cell disease 
SD 
Standard deviation 
SGRQ 
St George’s Respiratory Questionnaire 
SpO2 
Peripheral (resting) oxygen saturation 
SUSAR 
Suspected unexpected serious adverse reaction 
t1/2 
Apparent terminal half life 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
VS 
Vital signs 
Vss 
Volume at steady state 
WHO  
World Health Organization 
z 
Apparent terminal rate constant 
 

Protocol Number GBT440-026, Amendment 2 
 
Global Blood Therapeutics 
Final June 5, 2017 
 
Page 11 of 77 
 
PROTOCOL SYNOPSIS 
Protocol Title 
A Phase II open label study to evaluate the effect of GBT440 on 
hypoxemia in subjects with Idiopathic Pulmonary Fibrosis (IPF) 
who are using supplemental oxygen at rest (ZEPHYR) 
Protocol Number 
GBT440-026 
Sponsor 
Global Blood Therapeutics 
400 East Jamie Court Suite #101 
South San Francisco, CA  94080 
Study Drug 
GBT440 capsules or tablets: 300 mg strength, administered orally 
Objectives 
Primary 
To evaluate the effect of GBT440 on oxygen saturation at rest, breathing 
room air, on Days 30 and 90 compared to baseline 
Secondary 
• To evaluate the effect of GBT440 on the requirement for 
supplemental oxygen (O2) at rest and post-exercise at Days 30 and 
90 compared to baseline 
• To evaluate the effect of GBT440 on resting and post-exercise 
Alveolar-arterial O2 tension difference [P(A-a)O2] at Days 30 and 90 
compared to baseline 
• To evaluate the effect of GBT440 on 6-minute walk distance 
(6MWD) at Days 30 and 90 compared to baseline 
• To evaluate the effect of GBT440 on IPF-related symptoms, using 
patient reported outcomes (PROs), at Days 30 and 90 compared to 
baseline 
• To evaluate pulmonary function at Day 90 compared to baseline 
• To evaluate the safety and tolerability of 900 mg and 1500 mg 
GBT440 dosed daily for 90 days 
• To evaluate the pharmacokinetics (PK) of GBT440 
Exploratory 
 To evaluate the effect of GBT440 on the need for any O2 while 
at rest at Days 30 and 90 compared to baseline 
• To compare the change in O2 requirement between the two O2 flow 
rate allocation groups 
• To evaluate the effect of GBT440 on extent of activity during daily 
living at Days 30 and 90 compared to baseline 

Protocol Number GBT440-026, Amendment 2 
 
Global Blood Therapeutics 
Final June 5, 2017 
 
Page 12 of 77 
 
Study Design 
This is an open label study that will be conducted in two parts. Together, 
Parts A and B will provide safety and efficacy data across the two 
GBT440 doses that are expected to improve oxygen saturation in the 
enrolled subjects. Approximately up to 32 eligible subjects will be 
enrolled in the study. 
 In Part A, up to approximately 16 eligible IPF subjects will 
receive 900 mg of GBT440 administered orally as 3 × 300 mg 
capsules or tablets once daily for 90 days. 
 In Part B, up to approximately 16 eligible IPF subjects will 
receive 1500 mg of GBT440 administered orally as 5 × 300 
mg capsules or tablets once daily for 90 days. 
The screening period for each subject commences when the subject 
undergoes the first study-specific screening assessment and must be 
completed and tests evaluated before dosing (Day 1). Subjects may be 
rescreened up to 2 times, if deemed appropriate by the Principal 
Investigator. The rescreening visit should not occur sooner than 
10 calendar days after the failed screening visit.  
Subjects on a stable dose of pirfenidone or nintedanib and/or N-acetyl 
cysteine for the treatment of IPF are eligible for entry into the study. 
After the screening visit, the study includes the following study periods:  
 
Treatment period (90 days): subjects in Part A will receive 900 mg 
(3 × 300 mg) and subjects in Part B 1500 mg (5 × 300 mg) capsules 
or tablets daily 
 Safety follow up (30 days): safety will be assessed for at least 
5 half-lives after the last dose of GBT440 in both Parts A and 
B  
Number of Subjects 
Approximately up to 32 subjects will be enrolled in the study. 
Replacement of 
Subjects 
Subjects who discontinue for reasons unrelated to toxicity, may be 
replaced if: 
 
the subject does not take at least 80% of their daily doses of study 
drug, prior to Day 30 (24 days) or Day 90 (72 days) 
and/or 
 
the subject does not take study drug for at least 8 consecutive days 
prior to Days 30 or 90. 
Number of Centers 
The study will be conducted at up to 10 clinical sites in the United States 
and the United Kingdom. 
Duration of Study 
Participation 
Approximately up to 151 days, including screening, treatment and 
follow-up periods 

Protocol Number GBT440-026, Amendment 2 
 
Global Blood Therapeutics 
Final June 5, 2017 
 
Page 13 of 77 
 
Study Population 
Inclusion Criteria 
1) 45 to 85 years of age inclusive, at randomization 
2) Able and willing to provide signed informed consent to participate in 
this study 
3) Documented diagnosis of IPF, as indicated in the American Thoracic 
Society (ATS)/European Respiratory Society (ERS)/Japanese 
Respiratory Society (JRS)/Latin American Respiratory Society 
(ALAT) 2011 Guidelines 
4) Receiving supplemental O2 for use at rest. 
 
Subjects using O2 only with exercise will not be eligible.  
5) Resting oxygen saturation (SpO2) between 85 and 88% for at least 
30 consecutive seconds while breathing room air (refer to 
Section 5.1 and Section 5.5.2 for details on confirming eligibility) 
Or 
Resting SpO2 <85% for 10 consecutive seconds or, if in the opinion 
of the site staff, it is not safe or tolerable for the subject to continue 
without using their supplemental oxygen for 10 consecutive seconds 
whilst the SpO2 is <85%. 
Either of these 2 criteria should be met at both screening and Day 1 
visits. 
6) Able, in the Investigator’s opinion, to walk a total of at least 100 
meters at completion of the baseline 6-minute walk test (6MWT) 
7) Weight ≥40 kg 
8) Able, in the Investigator’s opinion, to complete the O2 titration study 
unassisted at baseline (Day 1) and Days 30, 90, and 120 
9) Able, in the Investigator’s opinion, to comply with the study 
procedures, including attending the assessment visits and adhering to 
study requirements and restrictions 
10) Male or female of childbearing potential willing and able to use 
highly effective methods of contraception from study start to 30 days 
after the last dose of study drug 
Exclusion Criteria 
1) Forced expiratory volume in 1 second (FEV1) / forced vital capacity 
(FVC) <70% 
2) History of interstitial lung diseases secondary to other medical 
conditions (e.g., scleroderma, sarcoidosis, or rheumatoid arthritis) or 
resulting from clinically significant environmental exposures 
including but not limited to, drug toxicity, hypersensitivity 
pneumonitis, or asbestos 
3) Hospitalization due to an exacerbation of IPF within 30 days of 
screening 
4) Documented pulmonary hypertension that is severe (World Health 
Organization [WHO] Functional Class IV) and/or clinically unstable, 
as determined by the study Investigator 

Protocol Number GBT440-026, Amendment 2 
 
Global Blood Therapeutics 
Final June 5, 2017 
 
Page 14 of 77 
 
 
Subjects with documented mild to moderate pulmonary 
hypertension on a stable regimen of therapy for at least 3 
months prior to screening will be eligible for the study 
5) Subject plans to begin, or has commenced, pulmonary rehabilitation 
within 30 days of screening 
 
Subject who is on a stable exercise regimen at screening or whose 
regimen, in the opinion of the Investigator, is not expected to change 
at any time during the entire study will be considered eligible for the 
study  
6) Corticosteroid therapy for the treatment of IPF, >10 mg per day of 
prednisone (or an equivalent), administered for 7 days or longer, 
within 30 days of screening. 
 
Subjects receiving a stable dose of ≤10 mg per day of prednisone 
(or an equivalent) for at least 14 days prior to screening, and in 
the opinion of the Investigator not anticipated to require a dose 
adjustment during the study, are eligible for the study 
7) Corticosteroid therapy for treatment of non-IPF diseases, unless: 
 
Receiving a stable dose of prednisone (or an equivalent) for at least 
14 days prior to screening, and in the opinion of the Investigator not 
anticipated to require a dose adjustment during the study 
8) Participated in another clinical trial of an investigational drug (or 
medical device) within 30 days or 5-half-lives, whichever is longer, 
prior to screening, or is currently participating in another trial of an 
investigational drug (or medical device). 
9) Aspartate aminotransferase (AST), alanine aminotransferase (ALT) 
or total bilirubin >2 × upper limit of normal (ULN) 
10) Serum creatinine >2.0 mg/dL 
11) Clinical evidence of active infection, within 14 days of screening, 
which may include but is not limited to bronchitis, pneumonia, 
urinary tract infection, or cellulitis. 
12) Active viral hepatitis within the last 6 months 
13) Active tuberculosis within the last 6 months 
 
Testing for latent tuberculosis is not required 
14) Electrocardiogram (ECG) with a corrected QT interval using the 
Fridericia formula (QTcF) >450 ms (males) or QTcF >470 ms 
(females) 
 
If ventricular pacing is noted on ECG, then QTcF intervals will 
not be calculated 
15) Family or personal history of congenital long QT syndrome 
16) Female who is breast-feeding or pregnant 
17) Known current malignancy or current evaluation for a potential 
malignancy or history of malignancy within the past 2 years prior to 
screening, except for appropriately treated non-melanoma skin 
carcinoma, carcinoma in situ of the cervix, Stage 1 uterine cancer 
18) Current smoker (including use of eCigarettes or vaporizing) or 
history of smoking within 3 months from screening 

Protocol Number GBT440-026, Amendment 2 
 
Global Blood Therapeutics 
Final June 5, 2017 
 
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19) History of unstable or deteriorating cardiac or pulmonary disease 
(other than IPF) within 3 months of screening, including but not 
limited to, congestive heart failure requiring hospitalization or 
uncontrolled clinically significant arrhythmias 
20) History of mental illness within the last 5 years, unless the subject 
fulfills one of the following conditions: 
 
The subject has not required or been prescribed any psychiatric 
medication (including but not limited to antidepressants or 
anxiolytics) within 12 months before screening and, in the 
opinion of the Investigator, the subject is able and safe to 
participate in the study 
 
The subject has been on a fixed regimen of psychiatric 
medications for at least 6 months before screening and displays 
no sign of acute mental illness and, in the opinion of the 
Investigator, the subject is able and safe to participate in the 
study 
21) Other clinically significant medical disease that is uncontrolled 
despite treatment and is likely, in the study Investigator’s opinion, to 
significantly impact the study’s efficacy and safety assessments 
22) Any condition affecting drug absorption, such as major surgery 
involving the stomach or small intestine (prior cholecystectomy is 
acceptable) 
23) Known hypersensitivity to any component of the study drug 
Study Evaluations 
Safety Assessments 
Subject safety and tolerability will be monitored throughout the study 
using standard measures, including physical examinations, vital signs 
(including blood pressure, pulse rate, body temperature, respiratory rate), 
12-lead ECGs, safety labs (hematology, serum chemistry, urinalysis, 
coagulation, and pregnancy tests), concomitant medication usage and 
adverse event (AE) monitoring. 
Clinical Assessments 
Oxygen Titration Test (OTT) 
The OTT will be used to assess the subjects’ O2 requirements at rest and 
with exercise, as measured by pulse oximetry and arterial blood gases 
(ABG). Subjects will exercise by walking along a 6MWT or equivalent 
course. 
Refer to the separate OTT manual for complete instructions on the 
conduct of the OTT. The flow of O2 will be titrated to maintain a stable 
SpO2 of 89 to 92%. 
Oxygen Saturation Measurement 
The measurement of peripheral oxygen saturation (SpO2) will be 
performed using the pulse oximeter provided by the Sponsor.  
Screening and Day 1 Visit 
SpO2 measured at these visits are to determine eligibility for inclusion 
into the study, and will be performed at rest, breathing room air.  

Protocol Number GBT440-026, Amendment 2 
 
Global Blood Therapeutics 
Final June 5, 2017 
 
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Prior to measuring SpO2 breathing room air, subjects must be rested for 
at least 10 minutes breathing their usually prescribed flow rate of O2. 
Then the subject’s supplemental O2 should be turned off to measure 
resting, room air SpO2 as noted below. 
 
Resting oxygen saturation (SpO2) between 85 and 88% for at 
least 30 consecutive seconds while breathing room air (refer to 
Section 4.1 Inclusion Criteria) 
Or 
 
Resting SpO2 <85% for 10 consecutive seconds or, if in the 
opinion of the site staff, it is not safe or tolerable for the subject 
to continue without using their supplemental oxygen for 10 
consecutive seconds whilst the SpO2 is <85%. 
Either of these 2 criteria should be met at both screening and Day 1 
visits. 
Arterial Blood Gases (ABG) 
Arterial blood samples will be taken at each scheduled OTT: Day 1 
(baseline), Days 30, 90, and 120. Two samples will be drawn at each 
test:  
 Prior to the beginning of the test (i.e., prior to beginning to 
walk) while resting and breathing room air (i.e., with no 
oxygen being delivered to the subject) and  
 Immediately after completion of the OTT while receiving 
oxygen at the flow rate being delivered at the end of the 
test 
An Allen’s test should be performed prior to the resting ABG at each 
OTT. 
The necessary equipment for performing the ABG should be prepared 
prior to beginning the OTT and readily available for both samples. 
Likewise, the necessary materials and equipment to transport the ABG 
samples for analysis should be readily available to ensure the integrity of 
the samples is not compromised. 
6-Minute Walk Test (6MWT) and Borg Scale of Perceived Exertion 
Functional exercise capacity will be evaluated at Day 1 (baseline) and 
Days 30, 90, and 120 using the 6MWT.  
Refer to the 6MWT manual for complete instructions. 
Guidelines developed by the ERS/ATS will be used for conducting the 
test and interpreting the results (ATS 2002 and Holland 2014). 
Instructions for the conduct of the 6MWT will be provided in a separate 
manual. 
Spirometry and Diffusing Capacity of the Lung for Carbon Monoxide 
(DLco) Measurements 
All equipment, procedures, and personnel qualifications for the 
assessment of lung function should be based on the recommendations of 
the American Thoracic Society (ATS 2003) and will be performed at 
each site using local equipment and procedures. 

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Spirometry measurements will include FVC, FEV1, DLCO and other 
measures per the site’s local practices. Post-bronchodilator assessments 
will not be performed. DLCO will be measured at each site by 
determining the diffusing/transfer capacity of the lung for carbon 
monoxide. DLCO adjusted for Hb will also be measured. 
Patient Reported Outcome (PRO)Measures 
PRO assessments should be self-administered by the subject, using the 
paper questionnaires provided by the Sponsor, at the investigational site 
prior to all other non-PRO assessments and before the subject receives 
any disease-status information during that assessment. They will be 
administered as indicated in the Schedules of Assessments in 
Appendix A (Table 15-1 for Part A; Table 15-2 for Part B). 
A Tool to Assess Quality of Life (ATAQ) in IPF – Symptoms 
Questionnaire 
The ATAQ-IPF Symptoms Questionnaire is an IPF-specific, 
self-administered questionnaire that assesses the subject’s disease 
symptoms across three domains (physical activity, cough, and energy 
level) and a set of questions pertaining to O2 use. Items are assessed 
using a Likert scale with a 24-hour recall period. 
A Tool to Assess Quality of Life (ATAQ) in IPF – Impacts 
Questionnaire 
The ATAQ-IPF Impact Questionnaire is an IPF-specific, self-
administered questionnaire that assesses how IPF affects the subjects’ 
quality of life. Items are assessed using a Likert scale with a 1-week 
recall period. 
St George’s Respiratory Questionnaire (SGRQ) 
The SGRQ is a symptom-specific 2-part, patient self-administered 
questionnaire that assesses shortness of breath while doing a variety of 
activities of daily living. This questionnaire is comprised of three 
domains: symptoms, activity and impact. Items are assessed on various 
response scales, including a 5-point Likert scale and True/False scale. 
The SGRQ has a recall period of 4 weeks. 
Borg Dyspnea Scale 
The Borg Dyspnea Scale is a 1-item assessment, self-administered by the 
subject as part of the 6MWT. The instrument will be used during the 
6MWT to assess dyspnea from the subject’s perspective. The Scale 
ranges from 0 (Nothing at all) to 10 (Absolute maximum/Highest 
possible. 
End of Treatment Questionnaire  
The End of Treatment Questionnaire is survey to evaluate the subjects' 
experience while on the study including symptoms, changes in oxygen 
saturation and use. This is a self-administered survey to be completed 
during the Day-90 visit. A paper version of the End of Treatment 
Questionnaire will be provided to the sites. Subject responses will be 
entered in the eCRF by the site. 
 

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Pharmacokinetic Assessments 
Plasma and whole blood concentrations of GBT440 will be determined 
using validated assays and collected pre and post drug administration 
(refer to Table 5-1 and Appendix A). 
Restricted Therapies 
Subjects should not take the following medications within 14 days prior 
to screening and during the entire study:  
•
Strong inducers of CYP3A4/CYP3A5, CYP2B6, CYP2C9 and
CYP2C19 (refer to Appendix B; these medications may decrease
the blood concentration of GBT440)
•
Herbal medications (e.g., St. John’s Wort)
The following medications should be used with caution: 
CYP3A4 substrates with a narrow therapeutic index (refer to Table 8-1; 
GBT440 may increase the plasma concentration of these medications). 
Note: based on results from the drug-drug interaction studies, 
co-administration of GBT440 with pirfenidone or nintedanib is 
considered to be acceptable and they are allowed in this study. 
Statistical Methods 
Sample Size 
The study will enroll up to approximately 32 subjects; up to 
approximately 16 subjects in Part A and up to approximately 16 subjects 
in Part B.  
Study Endpoints 
The primary endpoint is change and % change from baseline in oxygen 
saturation at rest (SpO2 or SaO2), measured while breathing room air, at 
Days 30 and 90. 
Secondary Endpoints 
•
Change and % change from baseline in O2 flow rate (L/min),
measured at rest, to maintain a target oxygen saturation (SpO2) of
89 to 92%, at Days 30 and 90.
•
Change and % change from baseline in O2 flow rate (L/min),
measured post-exercise to maintain a target oxygen saturation (SpO2
or SaO2) of 89 to 92%, at Days 30 and 90
•
Change and % change from baseline in resting P(A-a) O2 at Days 30
and 90
•
Change and % change from baseline in post-exercise P(A-a) O2 at
Days 30 and 90
•
Change and % change from baseline in 6MWD, at Days 30 and 90
•
Change in patient-reported IPF-related symptoms from baseline,
measured by ATAQ and SGRQ, at Days 30 and 90
•
Change from baseline in FVC and DLco at Day 90
Exploratory Endpoints
•
Number and % of total subjects no longer requiring O2 at rest, at
Days 30 or 90

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 
Difference between the two O2 allocation groups, in the change from 
baseline in resting O2 flow rate (L/min), to maintain a target oxygen 
saturation (SpO2 or SaO2) of 89 to 92%, at Days 30 and 90 
 
Change from baseline in daily activity, measured by a pedometer, at 
Days 30 and 90 
Safety Endpoint 
The frequency and severity of treatment-emergent adverse events 
(TEAEs) and tolerability of GBT440 administered daily orally for 90 
days. 
Pharmacokinetic Endpoints 
PK parameters of GBT440 administered daily orally for 90 days in 
plasma and whole blood, including but not limited to, minimum 
concentration (Cmin), at steady state. 
 

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1 
INTRODUCTION 
1.1 
Disease Background 
Idiopathic Pulmonary Fibrosis (IPF) is a chronic disease of unknown etiology that is 
characterized by progressive fibrotic destruction of the lung, resulting in worsening dyspnea 
and progressive loss of lung function (Raghu 2011). IPF is the most common type of 
interstitial lung disease with a high mortality rate (Michaelson 2000). While the course of the 
disease is variable, the prognosis is uniformly poor, with a median survival of about 3 to 
5 years after diagnosis (Raghu 2006, King 2001, Nicholson 2000). In the United States, it is 
estimated to affect up to 200,000 people with approximately 50,000 new cases diagnosed 
each year (Raghu 2006) and approximately 40,000 dying each year (Olson 2012). IPF is 
typically seen in older adults, more commonly in men than women, usually occurring 
between the ages of 50 to 80 years, with a median age of 65 at diagnosis (Raghu 2006). 
Nintedanib and pirfenidone were approved for the treatment of IPF (Raghu 2015) in 2015, 
specifically targeting the fibrotic process; demonstrating a reduction in the annual decrease in 
forced vital capacity. However, there was no observed effect on survival, nor an 
improvement in hypoxemia or a clear and consistent improvement in disease symptoms such 
as dyspnea (Richeldi 2014, King 2014). As the interstitial fibrosis and architectural distortion 
advance, the lung becomes increasingly non-compliant and diffusing capacity decreases 
ultimately leading to hypoxemia, tissue hypoxia, and end-organ dysfunction.  
Treatment of hypoxemia using supplemental oxygen (O2) remains an important part of IPF 
management with the therapeutic goal of increasing blood oxygenation and in turn reducing 
the potential detrimental effects of hypoxic tissue injury and dysfunction and patient 
symptoms. Supplemental oxygen relieves dyspnea and improves functional status, but 
requires burdensome equipment for oxygen administration. Although minimal data are 
available specifically for IPF, the clinical benefit of improved oxygenation, is based on 
strong physiologic rationale and ethical considerations (Raghu 2011). Increased oxygenation 
as a therapeutic goal in patients with IPF-associated pulmonary hypertension and/or sleep 
disordered breathing is inferred from the clinical benefit demonstrated in other hypoxemic 
pulmonary diseases. In addition, studies have shown that dyspnea can be reduced and 
6-minute walk distance (6MWD) increased with improved oxygenation from supplemental 
O2 (Visca 2011). However, the use of supplemental O2 comes with a cost to the patient who 
has to take on the physical burden of the oxygen delivery equipment, which can severely 
limit patient mobility and quality of life (FDA: The Voice of the Patient). 
IPF remains a disease with high-unmet medical need requiring novel therapies that address 
not only the underlying fibrosis but also the associated hypoxemia and patients’ quality of 
life. 
1.2 
GBT440 
Global Blood Therapeutics (GBT) has developed GBT440, a novel small molecule allosteric 
modulator of hemoglobin (Hb) oxygen affinity that is currently being investigated for the 
treatment of sickle cell disease (SCD). GBT440 binds to the N-terminal valine of a Hb 
α chain, and increases the affinity of Hb for oxygen resulting in a left shift in the 

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oxy-hemoglobin dissociation curve (ODC). It has the same pharmacodynamic effect on both 
mutated hemoglobin (HbS) and normal adult hemoglobin (HbA). Preliminary data from 
Phase 2 SCD trials (Lehrer-Graiwer 2015) showed reduction in red blood cell (RBC) sickling 
consistent with GBT440’s effect on maintaining more Hb in an oxygenated state. Based on 
GBT440’s similar effect on HbA it is expected, in IPF patients, to increase oxygen uptake in 
the lungs, improving hypoxemia and oxygen delivery to tissues. 
1.3 
Rationale for Study 
IPF is a severely debilitating disease characterized by progressive fibrosis, worsening 
hypoxemia, dyspnea and poor quality of life. Despite the recent approval of pirfenidone and 
nintedanib to treat IPF, these and other therapies have not demonstrated significant 
improvement in oxygenation, patient symptoms, functional status, or survival 
[Richeldi 2014, King 2014]. 
GBT440, a hemoglobin modifier that causes a left-shift in the oxy-hemoglobin dissociation 
curve (ODC) has the potential to enable increased oxygen uptake in the lungs and oxygen 
saturation, resulting in improved oxygen delivery to tissues. In support of this hypothesis, 
individuals with naturally occurring high affinity Hb mutations are physiologically adapted 
to the low oxygen tensions present at high altitude and are able to load and deliver more 
oxygen than normal controls (Hebbel 1978). Furthermore, numerous animal models have 
shown that increasing Hb oxygen affinity during acute and chronic hypoxia improves arterial 
oxygenation, cardiovascular function and survival (Xin 2016, Eaton 1974, Eaton 2004, 
Yalcin and Cabrales 2012).  
Based on these observations and its ability to safely increase Hb oxygen affinity in humans 
(including IPF patients in the ongoing GBT440-006 study, healthy subjects and patients with 
SCD in the ongoing GBT440-001 study), study GBT440-026 was initiated in IPF patients. 
Study GBT440-006 is investigating the effect of GBT440 on oxygen saturation in a 
sub-population of IPF patients who demonstrate exercise-induced oxygen desaturation. In the 
current study (GBT440-026 Zephyr), the efficacy and safety of GBT440 is being studied in a 
broader IPF population who have more severe hypoxemia and require supplemental O2 at 
rest. It is expected that GBT440 may demonstrate significant oxygenation improvement in 
these particular patients since a left shift in the ODC will provide a relatively large 
improvement in oxygenation since their room air SpO2 is on the steep segment of the ODC. 
Although supplemental O2 can successfully treat hypoxemia, it does have significant 
disadvantages which negatively impact patient quality of life including the burden and 
decreased mobility from the required oxygen delivery devices and local complications 
(FDA: The Voice of the Patient) which in turn leads to poor compliance. GBT440 therapy 
may be able to provide the clinical benefits of oxygen therapy without the burden of oxygen 
supplementation and avoiding the negative effects of poor patient compliance and associated 
intermittent hypoxemia. In some patients, GBT440 may obviate the need for oxygen therapy 
and in others may facilitate the use of lower flow O2 allowing patients to use more 
convenient oxygen equipment for the same clinical benefit. GBT440 could also be useful as 
an adjunct to oxygen therapy in more severe subjects who are not adequately oxygenated 
despite noninvasive oxygen therapy. 

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1.4 
Nonclinical Data 
An overview of the key nonclinical data is provided below. For additional details regarding 
the nonclinical pharmacology, pharmacokinetic (PK) and toxicology studies conducted to 
date, refer to the GBT440 Investigator’s Brochure (IB). 
1.4.1 
Nonclinical Pharmacology 
In vitro pharmacology studies were conducted to characterize the pharmacodynamic (PD) 
effects of GBT440. These studies demonstrated that GBT440 binds to Hb, modulates Hb-O2 
affinity and maintains the oxyHb state during deoxygenation. In addition, these studies 
showed that GBT440-modified Hb retains the Bohr Effect, which is the ability to augment 
oxygen delivery in metabolically active (low pH) tissues. This should preserve the ability of 
GBT440-modified Hb to off-load oxygen to metabolically active tissues, despite its increased 
affinity for oxygen. 
In vivo pharmacology studies were performed in murine models of acute hypoxia challenge 
and pulmonary hypoxemia (lipopolysaccharide [LPS]-induced acute lung injury [ALI] and 
bleomycin induced lung fibrosis and hypoxemia (Xin 2016). These in vivo studies 
demonstrated that pharmacologically increasing Hb-O2 affinity in these murine models of 
pulmonary hypoxemia resulted in improved O2 saturation, translating into improved 
physiologic endpoints and survival. 
1.4.2 
Nonclinical Pharmacology 
The safety pharmacology studies conducted with GBT440 are summarized in the GBT440 
Investigator’s Brochure. Safety assessments of GBT440 in 3 in vivo studies did not identify 
any biologically significant effects in the central nervous system (CNS) and respiratory 
system. There were minor effects in the cardiovascular (CV) safety pharmacology studies, 
with a mild increase in systolic BP at higher doses (1000 mg/kg) and a small decrease 
(15.3%) in hERG channel current at 10µM. Based on these results, there appears to be a low 
risk to humans for adverse effects on CNS, respiratory, or CV function. 
1.4.3 
Nonclinical Pharmacokinetics 
The PK studies conducted with GBT440 are summarized in the GBT440 Investigator’s 
Brochure. PK evaluations showed that GBT440 had low blood clearance (CL), low blood 
Vss, and long terminal t½ and was well absorbed in all animal species tested. GBT440 whole 
blood concentrations were much higher than plasma concentrations (calculated RBC: plasma 
ratio ~150:1), consistent with a high affinity and specificity of GBT440 for Hb. The PK 
properties of GBT440 in animals suggest that it will preferentially bind to Hb and be slowly, 
but completely eliminated from the body. With increasing doses in rats and dogs, the 
exposure with GBT440 is less than dose-proportional.  
1.4.4 
Metabolism and Potential Drug Interactions  
Metabolism was the major route of elimination of GBT440 in humans. Renal excretion was a 
minor elimination pathway.  

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In vitro metabolism studies indicate that GBT440 could be metabolized by several CYP 
enzymes, i.e., CYP1A1, 1B1, 2B6, 2C9, 2C19, 3A4, and 3A5. However, in total, the data 
show that the exposure of GBT440 is unlikely to dramatically increase (<1.7-fold) when 
coadministered with a CYP inhibitor. Refer to Section 8.5.2 for restricted therapies in this 
study. 
GBT440 has also been evaluated as a potential inhibitor/substrate of various membrane 
transporters. Refer to the GBT440 IB for further details of these studies. 
1.4.5 
Toxicology 
The toxicity of GBT440 has been evaluated in single dose, repeat dose and reproductive 
toxicity studies. The genotoxic potential of GBT440 has been evaluated in a battery of in 
vitro and in vivo assays. The details of the nonclinical toxicology program, including 
toxicokinetics, are provided in the GBT440 IB. 
1.5 
Clinical Development of GBT440 
Clinical studies have been conducted in healthy subjects (including 10 Phase I clinical 
pharmacology studies) and in patients with SCD and IPF.  
The Phase II IPF study (GBT440-006) is a randomized, controlled trial evaluating the safety 
and PK of GBT440 and its effects on oxygen saturation in IPF subjects who are hypoxemic 
with exercise. GBT440 is being dosed at 600 mg, 900 mg and 1500 mg orally daily for 
28 days.  
The Phase I/II study (GBT440-001) is a randomized, placebo-controlled, ascending dose 
study evaluating the safety, tolerability, PK, and PD effects of single and multiple doses of 
orally administered GBT440 in healthy subjects and subjects with SCD. Healthy subjects 
have received multiple doses of 300 mg to 900 mg/day for up to 15 days. SCD subjects have 
received multiple doses of 500 mg to 1000 mg/day for up to 28 days, and 700 mg or 
900 mg/day for up to 90 days; some subjects (900 mg) are continuing treatment for up to 
6 months under a separate protocol (GBT440-024).  
The Phase III study (GBT440-031) is a randomized, double-blind placebo-controlled study 
evaluating the efficacy and safety in SCD patients at GBT440 doses of 900 mg or 1500 mg 
for up to 72 weeks 
The Phase II study in adolescent subjects with SCD (GBT440-007) is an open label, single 
dose and multiple dose PK study of GBT440 in pediatric subjects, ages 12 to 17 years.  
Refer to the GBT440 IB for additional details regarding GBT440 development and all 
clinical studies. 
1.5.1 
Safety Findings  
To date, GBT440 has been well tolerated over a range of doses administered to healthy and 
SCD subjects, for up to 90 days.  

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As of 30 September 2016, a total of 259 subjects have received at least 1 dose of GBT440: 
205 healthy subjects, 47 adult SCD subjects and 7 pediatric SCD subjects.  
In Study GBT440-001, the majority of the adverse events (AEs) were mild or moderate 
(Grade 1 or Grade 2), most commonly headache or diarrhea, and no clinically significant 
findings in vital signs, 12-lead electrocardiograms (ECGs), or laboratory safety values were 
identified. 
In the SCD subjects dosed for 90 days, the majority of the AEs were also mild or moderate 
(Grade 1 or Grade 2). The most common AEs, occurring in ≥2 subjects and at a similar 
frequency in GBT440 and placebo-treated subjects, were headache, back pain, fatigue, and 
rhinitis.  
The AEs that occurred at a higher rate in subjects receiving GBT440 included cough, 
diarrhea, and rash, of which diarrhea and rash were considered treatment-related by the 
Investigator. No episodes of anaphylaxis, anaphylactoid, or hypersensitivity reactions were 
reported. 
Rashes were morbilliform in nature, typically involved the trunk or extremities, associated 
with mild pruritus, resolving within 2 to 5 days (in one case with continued dosing), and were 
not associated with any systemic features.  
Overall, 10 serious adverse events (SAEs) have been reported as of 30 September 2016, in 
10 subjects with SCD, considered by the Investigator to be not related to the study drug. 
There were 7 events of sickle cell crisis (Grade 3), all occurring off treatment during 
follow-up (1 placebo; 6 GBT440); 1 event of presumed infection with hemolysis (Grade 2) 
(GBT440); 1 event of an ovarian cyst (Grade 3), occurring after the last dose of study drug 
(GBT440) and 1 event of Grade 2 upper respiratory tract infection requiring hospitalization 
(GBT440). 
Please refer to the GBT440 IB for additional details on GBT440 safety findings.  
1.5.2 
Pharmacokinetic Parameters 
The mean PK results of GBT440 from analyzed samples to date derived from whole blood 
concentration-time profiles, shows that both maximum blood concentration (Cmax) and area 
under the curve (AUC) increases proportionally with study drug dose for both single or 
multiple doses in Study GBT440-001. The exposure of GBT440 at steady-state was 
consistent with accumulation predicted based on the single dose data. 
For the same dose, GBT440 exposure was lower and the T1/2 was significantly shorter in 
subjects with SCD compared with healthy subjects. At steady-state, the exposure in subjects 
with SCD was also lower than that observed in healthy subjects. Since IPF patients will most 
likely have hematocrit values within the normal range, PK of GBT440 in these patients are 
expected to be similar to that of healthy volunteers.  
Please refer to the GBT440 IB for additional details of GBT440 PK parameters. 

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1.5.3 
Dose Rationale 
The selection of the GBT440 doses for this study are based on a benefit risk profile that 
supports studying the potential efficacy and safety of GBT440 in a population of IPF subjects 
who have a high unmet medical need.  
Based on data from in vivo studies of hypoxemia (Section 1.4.1) demonstrating a 
dose-dependent increase in Hb-O2 affinity (PD effect of GBT440) and PK/PD data from 
study GBT440-001 the selected doses are expected to increase Hb-O2 affinity to an extent 
that will result in a clinically significant increase in oxygen saturation.  
The safety of the proposed doses is based on the overall favorable safety profile of GBT440 
in studies to date: 
• Study GBT440-006 in IPF subjects who desaturate with exercise. The safety findings 
from 16 subjects in Part A of the study who completed 28 days of dosing (900 mg and 
600 mg GBT440) were reviewed by the study’s Safety Monitoring Committee who 
endorsed continuing the study with the addition of a 1500 mg dose arm.  
• Safety findings from healthy volunteers, SCD patients and IPF patients have not 
demonstrated that a daily, oral 900 mg dose of GBT440 represents a maximum tolerated 
dose (MTD). 
• Continued favorable safety profile in ongoing studies evaluating GBT440 in subjects 
with SCD (refer to Section 1.5), including continued dosing for up to 6 months. 
 
The safety of the proposed doses is based on the totality of available nonclinical and clinical 
safety data from IPF and SCD patients. 
1.5.4 
Potential Risk of GBT440 Treatment 
Tissue Hypoxia 
There is a theoretical risk of tissue hypoxia in subjects treated with GBT440 based on the 
mechanism of action and the potential for impairment in O2 offloading at the tissues. 
However, in vitro data show that GBT440-modified Hb remains sensitive to the Bohr effect, 
and in vivo data from animal models of pulmonary hypoxemia are consistent with increased 
oxygen extraction and consumption by tissues. Furthermore, clinical data from subjects 
receiving study drug and those participating in maximal cardio-pulmonary exercise tests in 
the ongoing Phase I/II study, GBT440-001, have not identified a concern with tissue hypoxia. 
Please refer to the GBT440 IB for further details. 
IPF subjects in this study will be closely monitored for subclinical evidence of worsening 
tissue hypoxia including using assessments for erythrocytosis, increased resting heart rate 
and erythropoietin and laboratory tests indicating organ injury (e.g., liver aminotransferases).  
 

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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
To evaluate the effect of GBT440 on oxygen saturation at rest, breathing room air, on Days 
30 and 90 compared to baseline. 
2.2 
Secondary Objectives 
• To evaluate the effect of GBT440 on the requirement for supplemental O2 at rest and 
post-exercise at Days 30 and 90 compared to baseline  
• To evaluate the effect of GBT440 on resting and post-exercise Alveolar-arterial O2 
tension difference [P(A-a)O2] at Days 30 and 90 compared to baseline 
• To evaluate the effect of GBT440 on 6MWD at Days 30 and 90 compared to baseline 
• To evaluate the effect of GBT440 on IPF-related symptoms, using patient reported 
outcomes (PROs), at Days 30 and 90 compared to baseline 
• To evaluate pulmonary function at Day 90 compared to baseline 
• To evaluate the safety and tolerability of 900 mg and 1500 mg GBT440 dosed daily for 
90 days 
• To evaluate the PK of GBT440 
 
2.3 
Exploratory Objectives 
• To evaluate the effect of GBT440 on the need for any O2 while at rest at Days 30 and 
90 compared to baseline 
• To compare the change in O2 requirement between the two O2 flow rate allocation groups 
• To evaluate the effect of GBT440 on extent of activity during daily living at Days 30 and 
90 compared to baseline 
 

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3 
INVESTIGATIONAL PLAN 
3.1 
Study Design 
This is an open label study that will be conducted in two parts. Together, Parts A and B will 
provide safety and efficacy data across the two GBT440 doses that are expected to improve 
oxygen saturation in the enrolled subjects.  
Approximately up to 32 eligible subjects will be enrolled in the study.  
• In Part A (Figure 1), up to approximately 16 eligible IPF subjects will receive 900 mg of 
GBT440 administered orally as 3 × 300 mg capsules or tablets once daily for 90 days. 
• In Part B (Figure 1), up to approximately 16 eligible IPF subjects will receive 1500 mg of 
GBT440 administered orally as 5 × 300 mg capsules or tablets once daily for 90 days. 
 
Subjects enrolled in Part A will follow the GBT440 900 mg visit schedule. Subject enrolled 
in Part B will follow the GBT440 1500 mg visit schedule. Schedules of Assessments are 
provided in Appendix A (Table 15-1 for Part A; Table 15-2 for Part B). 
A signed and dated informed consent form (ICF) must be obtained before any study-specific 
tests may be performed.  
The screening period for each subject commences when the subject undergoes the first 
study-specific screening assessment and must be completed and tests evaluated before dosing 
(Day 1). Subjects may be rescreened up to 2 times, if deemed appropriate by the Principal 
Investigator. The rescreening visit should not occur sooner than 10 calendar days after the 
failed screening visit. 
After the screening visit, the study includes the following study periods (Figure 3-1):  
• Treatment period (90 days): subjects in Part A will receive 900 mg (3 × 300 mg) and 
subjects in Part B 1500 mg (5 × 300 mg) capsules or tablets daily 
• Safety follow up (30 days): safety will be assessed for at least 5 half-lives after the last 
dose of GBT440 in both Parts A and B 
 

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Figure 3-1 
Study Design 
Part A 
 
Part B 
 
 
Subjects, who discontinue for reasons unrelated to toxicity, may be replaced if: 
 the subject does not take at least 80% of their daily doses of study drug, prior to 
Day 30 (24 days) or Day 90 (72 days)  
and/or 
 the subject does not take study drug for at least 8 consecutive days prior to Days 30 or 
90 
 
The end of the study is defined as the date when the last subject last visit occurs, which is 
expected to be approximately 120 days after the last subject is enrolled. 

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This study will be performed in compliance with the protocol, ICH Good Clinical Practice 
(GCP), and applicable regulatory requirements. Aspects of the study concerned with the 
Investigational Medicinal Product (IMP) will meet the requirements of Good Manufacturing 
Practice. 
3.2 
Endpoints 
3.2.1 
Primary Endpoint 
The primary endpoint is change and % change from baseline in oxygen saturation at rest 
(SpO2 or SaO2), measured while breathing room air, at Days 30 and 90. 
3.2.2 
Secondary Endpoints 
• Change and % change from baseline in O2 flow rate (L/min), measured at rest, to 
maintain a target oxygen saturation (SpO2) of 89 to 92%, at Days 30 and 90  
• Change and % change from baseline in O2 flow rate (L/min), measured post-exercise to 
maintain a target oxygen saturation (SpO2 or SaO2) of 89 to 92%, at Days 30 and 90 
• Change and % change from baseline in resting P(A-a)O2 at Days 30 and 90  
• Change and % change from baseline in post-exercise P(A-a)O2 at Days 30 and 90 
• Change and % change from baseline in 6MWD, at Days 30 and 90 
• Change in patient-reported IPF-related symptoms from baseline, measured by ATAQ and 
SGRQ, at Days 30 and 90 
• Change from baseline in forced vital capacity (FVC) and diffusing capacity of the lung 
for carbon monoxide (DLco) at Day 90 
 
3.2.3 
Exploratory Endpoints 
• Number and % of total subjects no longer requiring O2 at rest, at Days 30 or 90  
• Difference between the two O2 allocation groups, in the change from baseline in resting 
O2 flow rate (L/min), to maintain a target oxygen saturation (SpO2 or SaO2) of 89 to 92%, 
at Days 30 and 90  
• Change from baseline in daily activity, measured by a pedometer, at Days 30 and 90  
 

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3.2.4 
Safety Endpoints 
The safety outcome measures for this study are the frequency and severity of treatment 
emergent adverse events (TEAEs) and tolerability of GBT440 administered daily orally for 
90 days. 
3.2.5 
Pharmacokinetics Endpoints 
Pharmacokinetic (PK) parameters of GBT440 in plasma and whole blood, including but not 
limited, minimum concentration (Cmin) at steady-state. 
 

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4 
STUDY POPULATION 
4.1 
Inclusion Criteria 
All subjects must meet all of the following inclusion criteria: 
1. 45 to 85 years of age inclusive, at randomization 
2. Able and willing to provide signed informed consent to participate in this study 
3. Documented diagnosis of IPF, as indicated in the American Thoracic Society 
(ATS)/European Respiratory Society (ERS)/Japanese Respiratory Society (JRS)/Latin 
American Respiratory Society (ALAT) 2011 Guidelines 
4. Receiving supplemental O2 for use at rest  
5. Subjects using O2 only with exercise will not be eligible  
6. Resting oxygen saturation (SpO2) between 85 and 88% for at least 30 consecutive 
seconds while breathing room air (refer to Section 5.1 and Section 5.5.2 for details 
regarding confirming eligibility) 
Or 
Resting SpO2 <85% for 10 consecutive seconds or, if in the opinion of the site staff, it is 
not safe or tolerable for the subject to continue without using their supplemental oxygen 
for 10 consecutive seconds whilst the SpO2 is <85%.  
Either of these 2 criteria should be met at both screening and Day 1 visits. 
7. Able, in the Investigator’s opinion, to walk a total of at least 100 meters at completion of 
the baseline 6-minute walk test (6MWT) 
8. Weight ≥40 kg 
9. Able, in the Investigator’s opinion, to complete the O2 titration study unassisted at 
baseline (Day 1) and Days 30, 90, and 120 
10. Able, in the Investigator’s opinion, to comply with the study procedures, including 
attending the assessment visits and adhering to study requirements and restrictions. 
11. Male or female of child-bearing potential willing and able to use highly effective 
methods of contraception from study start to 30 days after the last dose of study drug 
 
4.2 
Exclusion Criteria 
Any subject who meets any one of the following criteria will be excluded from participation: 
1. Forced expiratory volume in 1 second (FEV1) / forced vital capacity (FVC) <70% 
2. History of interstitial lung diseases secondary to other medical conditions (e.g., 
scleroderma, sarcoidosis or rheumatoid arthritis) or resulting from clinically significant 
environmental exposures including but not limited to, drug toxicity, hypersensitivity 
pneumonitis, or asbestos  

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3. Hospitalization due to an exacerbation of IPF within 30 days of screening 
4. Documented pulmonary hypertension that is severe (World Health Organization [WHO] 
Functional Class IV) and/or clinically unstable, as determined by the study Investigator 
- 
Subjects with documented mild to moderate pulmonary hypertension on a stable 
regimen of therapy for at least 3 months prior to screening will be eligible for the 
study 
5. Subject plans to begin, or has commenced, pulmonary rehabilitation within 30 days of 
screening 
- 
Subject who is on a stable exercise regimen at screening or whose regimen, in the 
opinion of the Investigator, is not expected to change at any time during the entire 
study will be considered eligible for the study 
6. Corticosteroid therapy, for treatment of IPF, >10 mg per day of prednisone (or an 
equivalent), administered for 7 days or longer, within 30 days of screening 
- 
Subjects receiving a stable dose of ≤10 mg per day of prednisone (or an equivalent) 
for at least 14 days prior to screening, and in the opinion of the Investigator not 
anticipated to require a dose adjustment during the study, are eligible for the study  
7. Corticosteroid therapy for treatment of non-IPF diseases, unless:  
- 
Receiving a stable dose of prednisone (or an equivalent) for at least 14 days prior to 
screening, and in the opinion of the Investigator not anticipated to require a dose 
adjustments during the study 
8. Participated in another clinical trial of an investigational drug (or medical device) within 
30 days or 5-half-lives, whichever is longer, prior to screening, or is currently 
participating in another trial of an investigational drug (or medical device) 
9. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) or total bilirubin 
>2 × upper limit of normal (ULN) 
10. Serum creatinine >2.0 mg/dL  
11. Clinical evidence of active infection, within 14 days of screening, which may include but 
is not limited to bronchitis, pneumonia, urinary tract infection, or cellulitis.  
12. Active viral hepatitis within the last 6 months  
13. Active tuberculosis within the last 6 months 
- 
Testing for latent tuberculosis is not required 
14. Electrocardiogram (ECG) with a corrected QT interval using the Fridericia formula 
(QTcF) >450 ms (males) or QTcF >470 ms (females)  
- 
If ventricular pacing is noted on ECG, then QTcF intervals will not be calculated 
15. Family or personal history of congenital long QT syndrome 
16. Female who is breast-feeding or pregnant 

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17. Known current malignancy or current evaluation for a potential malignancy or history of 
malignancy within the past 2 years prior to screening, except for appropriately treated 
non-melanoma skin carcinoma, carcinoma in situ of the cervix, Stage 1 uterine cancer  
18. Current smoker (including use of eCigarettes or vaporizing) or history of smoking within 
3 months from screening 
19. History of unstable or deteriorating cardiac or pulmonary disease (other than IPF) within 
3 months of screening, including but not limited to, congestive heart failure requiring 
hospitalization or uncontrolled clinically significant arrhythmias 
20. History of mental illness within the last 5 years, unless the subject fulfills one of the 
following conditions: 
- 
The subject has not required or been prescribed any psychiatric medication (including 
but not limited to antidepressants or anxiolytics) within 12 months before screening 
and, in the opinion of the Investigator, the subject is able and safe to participate in the 
study 
- 
The subject has been on a fixed regimen of psychiatric medications for at least 
6 months before screening and displays no sign of acute mental illness and, in the 
opinion of the Investigator, the subject is able and safe to participate in the study 
21. Other clinically significant medical disease that is uncontrolled despite treatment and is 
likely, in the study Investigator’s opinion, to significantly impact the study’s efficacy and 
safety assessments  
22. Any condition affecting drug absorption, such as major surgery involving the stomach or 
small intestine (prior cholecystectomy is acceptable) 
23. Known hypersensitivity to any component of the study drug 
 

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5 
STUDY PROCEDURES AND EVALUATIONS 
5.1 
Subject Screening 
The subject must be willing and able to sign and date the ICF before any screening 
procedures or study-specific tests may be performed. 
All subjects who sign the informed consent will be given a unique study number. This 
number will be used to identify the subject throughout the clinical study and must be used on 
all study documentation related to that subject. 
The screening period for a particular subject commences at the point at which the subject 
undergoes the first study-specific screening assessment and must be completed and evaluated 
within the screening period, prior to the first day of study drug dosing (Day 1). Schedules of 
Assessments are provided in Appendix A (Table 15-1 for Part A; Table 15-2 for Part B). 
SpO2 measurement for study eligibility: Assessment of resting, room air SpO2 for study 
eligibility (refer to Section 4.1, Inclusion Criteria 5) is to be performed on both the screening 
and Day 1 visits. If the criterion is not met on either study visit day, the subject is to be 
screen failed without completing the other study related assessments. If the criterion is met, 
then the subject should proceed with the remaining assessments scheduled for that visit.  
The same process is to be followed for the Day 1 visit. 
Subjects may be rescreened up to 2 times, if deemed appropriate by the Principal 
Investigator. The rescreening visit should not occur sooner than 10 calendar days after the 
failed screening visit. 
5.2 
Avoidance of Pregnancy 
Instructions for Male Subjects 
There is no information about the effects GBT440 could have on the development of the 
fetus in humans. Therefore, it is important that the partners of male subjects do not become 
pregnant during the entire study and for a total 30 days after the male subject has taken the 
last dose of GBT440.  
The methods of acceptable (highly effective) contraception that should be used by male 
subjects and their partners are outlined in Section 8.6.  
Women of Child-Bearing Potential 
Pregnancy should be avoided by either absolute abstinence or the use of highly effective 
means of contraception (refer to Section 8.6) for the duration of the study and a total period 
of 30 days after the subject has taken the last dose of GBT440. 
Female subjects who become pregnant during the study will have study drug discontinued 
but continue in the study to complete all safety follow-up assessments (refer to Section 6.3). 

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Women of Non Child-Bearing Potential 
Female subjects are considered to be of non-child-bearing potential if they have had surgical 
sterilization (i.e., hysterectomy and/or bilateral oophorectomy) or if post-menopausal, having 
been amenorrheic for at least 2 years. 
Surgical sterilization procedures should be supported with clinical documentation and noted 
in the relevant medical history/current medical conditions section of the eCRF. 
5.3 
Clinical Assessments  
Screening assessments must be performed and evaluated prior to dosing on Day 1. This study 
has 8 visits (including the screening visit), and subjects will be enrolled for approximately 
120 days from the time of first study drug dose until the last study visit. The timing of the 
visits, associated visit windows, and all assessments are outlined in the Schedules of 
Assessments provided in Appendix A (Table 15-1 for Part A; Table 15-2 for Part B). 
5.3.1 
Pregnancy 
In women of childbearing potential, pregnancy testing will be performed during Screening, 
Day 1, Day 30, Day 60, Day 90 and Day 120 visits. During the screening visit (Day -21 to 
Day -1) a serum pregnancy test will be performed. Serum pregnancy test results must be 
available and negative prior to Day 1 dosing. During Day 1, a urine pregnancy test will be 
performed and the pregnancy test must be negative prior to proceeding with other study 
related assessments and Day 1 dosing. 
5.3.2 
Medical History and Demographic Data 
Medical history includes currently active and past clinically significant diseases, surgeries, 
cancer history (including prior cancer therapies and procedures), smoking history, use of 
alcohol and drugs of abuse within the previous year, and IPF-associated conditions including 
but not limited to pulmonary hypertension, gastroesophageal reflux disease, and sleep 
disordered breathing.  
Medical conditions that are a result of side effects (e.g., rash or diarrhea) from concomitant 
medications (e.g., pirfenidone or nintedanib) should be clearly defined and entered into the 
eCRF.  
Any medical condition present at baseline should be followed during the study, and a change 
from the baseline status (intensity or frequency) should be reported as an AE by the 
Investigator (refer to Section 10.1). 
All concomitant medications (e.g., prescription drugs, over-the-counter drugs, 
herbal/homeopathic remedies, nutritional supplements) used by the subject within 14 days 
prior to the screening visit should be entered on the Concomitant Medications eCRF. A start 
date should be entered for all medication items entered into the Concomitant Medications 
eCRF, including those medications used chronically. 

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Demographic data will include age (date of birth), sex, and self-reported race/ethnicity. 
5.3.3 
Physical Examination 
A complete physical examination should include the following: an evaluation of the head, 
eyes, ears, nose, throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, and neurological systems. A rectal or pelvic examination is not required. 
Any abnormality identified during screening should be recorded on the eCRF. 
At subsequent visits, limited, symptom-directed physical examinations should be performed. 
Changes from baseline abnormalities should be recorded in the subject’s study source 
documents. New or worsened abnormalities should be recorded as AEs on the Adverse Event 
eCRF. 
Vital signs will include measurements of respiratory rate, heart rate, body temperature, 
systolic and diastolic blood pressure and oxygen saturation (SpO2) by pulse oximetry. Blood 
pressure and SpO2 measurements should be taken while the subject is in a seated or 
semi-recumbent position, and resting for at least 5 minutes. 
5.4 
Laboratory Examination 
5.4.1 
Clinical Laboratory Studies 
It is the responsibility of the Investigator to assess the clinical significance of all abnormal 
clinical laboratory values as defined by the list of normal values on file for the local clinical 
laboratory. All clinically significant laboratory value abnormalities are to be recorded as 
AEs. 
For the purpose of this study, a clinically significant laboratory value is any abnormal result 
that, in the judgment of the Investigator, is an unexpected or unexplained laboratory value 
and is accompanied by clinical symptoms and/or results in a medical intervention or 
corrective action (e.g., abnormalities that have clinical sequelae, require study drug dose 
modification, discontinuation of study drug, more frequent follow-up assessments or further 
diagnostic investigation). Any abnormal values that persist should be followed at the 
discretion of the Investigator.  
Laboratory assessment time points are outlined in the Schedules of Assessments provided in 
Appendix A (Table 15-1 for Part A; Table 15-2 for Part B). 
5.4.1.1 
Hematology 
Hematology assessments will include RBCs, hematocrit, Hb, platelets, and white blood cells 
(WBCs) with differential (basophils, eosinophils, neutrophils, monocytes, and lymphocytes). 
Reticulocyte count and serum erythropoietin (EPO) will also be collected.  

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5.4.1.2 
Blood Chemistries 
Blood chemistry assessments will include measurement of albumin, bicarbonate, blood urea 
nitrogen (BUN), calcium, chloride, creatinine, creatine kinase, glucose, lactate 
dehydrogenase, magnesium, phosphorus, potassium, sodium, total protein, and uric acid. 
5.4.1.3 
Liver Function 
Liver function assessments will include measurements of serum ALT, AST, alkaline 
phosphatase (ALK), gamma glutamyl transferase (GGT), and bilirubin (total, direct and 
indirect).  
5.4.1.4 
Plasma Protein Samples 
Blood samples for plasma protein binding assessment will be collected as indicated in the 
Schedules of Assessments provided in Appendix A (Table 15-1 for Part A; Table 15-2 for 
Part B). 
5.4.1.5 
Urinalysis 
Urine will be assessed for color and appearance. Dipstick analysis for specific gravity, pH, 
protein, glucose, ketones, and occult blood and microscopic analysis (RBCs, WBCs, bacteria 
and casts) will be performed. 
5.4.1.6 
Electrocardiograms 
12-lead ECGs should be performed after the subject has been resting in a supine or 
semi-recumbent position for at least 5 minutes and prior to all other non-PRO assessment. A 
single ECG tracing will be obtained at the indicated study visit, and must be stored at the 
study site. If in the opinion of the Investigator there is a clinically significant abnormality the 
ECG parameters should be entered into the eCRF as indicated.  
5.4.1.7 
Other Clinical Laboratory Tests 
For women of child-bearing potential, a pregnancy test (serum hCG) will be performed at 
screening, and a urine pregnancy test will be performed at Days 1, 30, 60, 90, 120 and early 
termination (if applicable) visits. The urine pregnancy test at Day 1 must be completed and 
confirmed negative before any other assessments are performed, including investigational 
product administration. If the urine pregnancy test is positive, the result must be confirmed 
with a serum pregnancy test and if positive, the subject is to be discontinued from the study.  
Coagulation (Panel) including PT, PTT, and INR will be collected at screening. 
 

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5.5 
Disease-Related Evaluations 
5.5.1 
Oxygen Titration Test (OTT) 
The OTT will be used to assess the subjects’ O2 requirements at rest and with exercise, as 
measured by pulse oximetry and arterial blood gases (ABG). Subjects will exercise by 
walking along a 6MWT or equivalent course. 
Refer to the separate OTT manual for complete instructions on the conduct of the OTT.  
ABGs will be performed twice during the OTT:  
1. Prior to the beginning of the test (i.e., prior to beginning to walk) while resting and 
breathing room air (i.e., with no oxygen being delivered to the subject) 
2. Immediately after completion of the OTT while receiving oxygen at the flow rate being 
delivered at the end of the test 
 
During the OTT, the flow of O2 will be titrated to maintain an SpO2 of 89 to 92%, using the 
lowest possible flow rate.  
The OTT should be performed at each of the scheduled visits (Days 1, 30, 90, and 120) at 
approximately the same time of day (e.g., in the morning) and prior to performing the 6MWT 
assessment (if scheduled on the same Visit day). For safety reasons, all subjects should be 
clinically stable, as assessed by the study Investigator or performing technician, prior to 
performing the OTT. 
5.5.2 
Oxygen Saturation Measurement 
The measurement of peripheral oxygen saturation (SpO2) will be performed using the pulse 
oximeter provided by the Sponsor.  
Screening and Day 1 Visit 
SpO2 measured at these visits are to determine eligibility for inclusion into the study, and will 
be performed at rest, breathing room air.  
Prior to measuring SpO2 breathing room air, subjects must be rested for at least 10 minutes 
breathing their usually prescribed flow rate of O2. Then the subject’s supplemental O2 should 
be turned off to measure resting, room air SpO2 as noted in Section 4.1 Inclusion Criteria and 
reproduced below. 
• Resting oxygen saturation (SpO2) between 85 and 88% for at least 30 consecutive 
seconds while breathing room air (refer to Section 4.1 Inclusion Criteria) 
Or 

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• Resting SpO2 <85% for 10 consecutive seconds or, if in the opinion of the site staff, it is 
not safe or tolerable for the subject to continue without using their supplemental oxygen 
for 10 consecutive seconds whilst the SpO2 is <85%. 
 
Either of these 2 criteria should be met at both screening and Day 1 visits. 
Vital Sign Assessments 
At all scheduled vital sign assessments, SpO2 will be measured with the subject breathing 
supplemental O2, set at their usual O2 flow rate, and after resting for at least 5 minutes. SpO2 
will be also be collected during conduct of the OTT and 6MWT (refer to the respective 
manuals for complete instructions).  
Before recording the SpO2 value in the eCRF, the study staff should ensure the measurement 
is stable, which may require continuous or repeated measurements and ensuring the subject is 
adequately rested.  
5.5.3 
Arterial Blood Gases (ABG) 
Arterial blood samples will be taken at each scheduled OTT: Day 1 (baseline), Days 30, 90, 
and 120. Two samples will be drawn at each test:  
• Prior to the beginning of the test (i.e., prior to beginning to walk) while resting and 
breathing room air (i.e., with no oxygen being delivered to the subject) and  
• Immediately after completion of the OTT while receiving oxygen at the flow rate being 
delivered at the end of the test 
 
An Allen’s test should be performed prior to the resting ABG at each OTT. 
The necessary equipment for performing the ABG should be prepared prior to beginning the 
OTT and readily available for both samples. Likewise, the necessary materials and 
equipment to transport the ABG samples for analysis should be readily available to ensure 
the integrity of the samples is not compromised.  
5.5.4 
6-Minute Walk Test (6MWT)  
Functional exercise capacity will be evaluated at Day 1 (baseline) and Days 30, 90, and 120 
using the 6MWT.  
Refer to the 6MWT manual for complete instructions. 
Guidelines developed by the ERS/ATS will be used for conducting the test and interpreting 
the results (ATS 2002 and Holland 2014). Instructions for the conduct of the 6MWT will be 
provided in a separate manual. 

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The 6MWT should be performed at each scheduled visit at approximately the same time of 
day (e.g., in the morning) and after spirometry and DLCO assessments (if scheduled on the 
same visit day). 
As part of the 6MWT, SpO2, heart rate, and the Borg Dyspnea Scale will be measured at the 
following time points: prior to starting the test, during the test, at completion of the test, and 
1 minute and 2 minutes after test completion.  
Refer to the 6MWT manual for complete instructions.  
For safety reasons, all subjects should be clinically stable, as determined by the study 
Investigator or the performing technician, prior to performing the 6MWT. 
5.5.5 
Spirometry and Diffusing Capacity of the Lung for Carbon Monoxide 
(DLCO)  
All equipment, procedures, and personnel qualifications for the assessment of lung function 
should be based on the recommendations of the American Thoracic Society (ATS 2003) and 
will be performed at each site using local equipment and procedures 
Spirometry measurements will include FVC, FEV1, DLCO and other measures per the site’s 
local practices. Post-bronchodilator assessments will not be performed. 
DLCO will be measured at each site by determining the diffusing/transfer capacity of the lung 
for carbon monoxide. DLCO adjusted for Hb will also be measured. 
Spirometry and DLCO should be performed at screening and Day 90 at approximately the 
same time of day (e.g., in the morning) and before the 6MWT, if scheduled on the same visit. 
Local reports from the spirometry and DLCO testing will be stored on site. 
5.5.6 
Patient Reported Outcome (PRO) Measures 
PRO assessments should be self-administered by the subject, using the paper questionnaires 
provided by the Sponsor, at the investigational site prior to all other non-PRO assessments 
and before the subject receives any disease-status information during that assessment. They 
will be administered as indicated in the Schedules of Assessments provided in Appendix A 
(Table 15-1 for Part A; Table 15-2 for Part B).  
5.5.6.1 
A Tool to Assess Quality of Life (ATAQ) in IPF Symptoms Questionnaire  
The ATAQ-IPF Symptoms Questionnaire is an IPF-specific, self-administered questionnaire 
that assesses the subject’s disease symptoms across three domains (physical activity, cough, 
and energy level) and a set of questions pertaining to O2 use. Items are assessed using a 
Likert scale with a 24-hr recall period.  

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5.5.6.2 
A Tool to Assess Quality of Life (ATAQ) in IPF Impacts Questionnaire 
The ATAQ-IPF Impact Questionnaire is an IPF-specific, self-administered questionnaire that 
assesses how IPF affects the subjects’ quality of life. Items are assessed using a Likert scale 
with a 1-week recall period.  
5.5.6.3 
St George’s Respiratory Questionnaire (SGRQ) 
The SGRQ is a symptom-specific 2-part, patient self-administered questionnaire that assesses 
shortness of breath while doing a variety of activities of daily living. This questionnaire is 
comprised of three domains: symptoms, activity and impact. Items are assessed on various 
response scales, including a 5-point Likert scale and True/False scale. The SGRQ has a recall 
period of 4 weeks. 
5.5.6.4 
Borg Dyspnea Scale 
The Borg Dyspnea Scale is a 1-item assessment, self-administered by the subject as part of 
the 6MWT. The instrument will be used during the 6MWT to assess dyspnea from the 
subject’s perspective. The Scale ranges from 0 (Nothing at all) to 10 (Absolute 
maximum/Highest possible 
5.5.6.5 
End of Treatment Period Questionnaire 
The End of Treatment Questionnaire is survey to evaluate the subjects' experience while on 
the study including symptoms, changes in oxygen saturation and use. This is a self-
administered survey to be completed during the Day-90 visit. A paper version of the End of 
Treatment Questionnaire will be provided to the sites. Subject responses will be entered in 
the eCRF by the site.  
5.6 
Pharmacokinetic Samples 
Plasma and whole blood concentrations of GBT440 will be determined using validated 
assays and collected pre and post drug administration (refer to Table 5-1).  
Pre-dose PK samples should be obtained as soon as possible after PROs, ECG, AEs and 
Concomitant Medications history and vitals have been obtained and before any other 
assessments are performed.  
Post-dose PK samples should be obtained following administration of study drug at the time 
points indicated in Table 5-1, below. Collection of these PK samples should occur after 
completion of all other scheduled assessments, including spirometry and DLco, OTT, 6MWT 
and investigational product dosing. 
Up to eleven PK samples will be collected at the following times outlined in Table 5-1 (also 
refer to the Schedules of Assessments provided in Appendix A [Table 15-1 for Part A; 
Table 15-2 for Part B]). 

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Table 5-1 
PK Sample Collection Schedule 
 
Pre-dose 
15 minutes 
Post-dose 
Between 2–4 
hours Post-dose 
During Study 
Visit 
Day 1 (Visit 2) 
 
X 
X* 
 
Day 15 (Visit 3) 
X* 
 
 
 
Day 30 (Visit 4) 
X 
 
 
 
Day 60 (Visit 5) 
X 
 
X 
 
Day 90 (Visit 6) 
X 
 
 
 
Day 105 (Visit 7) 
 
 
 
X 
Day 120 (Visit 8) 
 
 
 
X 
* Blood sample collection for protein binding assessment should also be collected at this time (refer to the 
Schedules of Assessments provided in Appendix A [Table 15-1 for Part A; Table 15-2 for Part B]).  
Instructions for sample collection, processing and shipment are described in a separate laboratory manual. 

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6 
EARLY DISCONTINUATION OF STUDY OR INDIVIDUAL 
SUBJECTS 
6.1 
Early Discontinuation of the Study and/or Site 
The Sponsor has the right to terminate this study at any time. Reasons for terminating the 
study may include, but are not limited to:  
• Incidence or severity of AEs in this or other studies indicating a potential health hazard to 
subjects. 
• Unsatisfactory subject recruitment e.g., excessively slow 
• Poor protocol adherence 
• Incomplete or inaccurate data recording 
• Poor compliance with the International Conference on Harmonization (ICH) guidelines 
for Good Clinical Practice (GCP) 
 
In any instance of early discontinuation of the study, the Sponsor will notify, in writing, the 
Investigators, regulatory authorities and ethics committees, and will specify the reason(s) for 
termination.  
6.2 
Early Discontinuation of Individual subjects 
Reasons for subject withdrawal from the study may include but are not limited to any of the 
following reasons: 
• Subject withdrawal of consent 
• Discretion of the Investigator, if it is deemed not safe, or in the subject’s best interest, to 
continue 
• Subject is lost to follow-up 
 
The date and reason for discontinuation should be documented in the eCRF.  
Subjects who discontinue the study should return to the site to complete the Early 
Termination visit assessments within 2 weeks (± 7 days) from the date of discontinuation. 

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6.3 
Study Drug Discontinuation 
Subjects should discontinue study drug for any of the following reasons: 
• Malignancy: not including local and non-serious basal or squamous cell skin cancer 
• Pregnancy 
• Anaphylaxis, anaphylactoid or serious hypersensitivity reaction 
• Grade 3 or higher rash 
• Use of any medication to treat IPF, other than those documented at screening. 
• AE, which in the opinion of the Investigator, precludes the subject from safely continuing 
in the study 
• Pulmonary rehabilitation started at any time from screening until the end of the study 
• Subject is noncompliant with study requirements 
 
The date and reason for discontinuation should be documented in the eCRF. 
Subjects who discontinue study drug should continue in the study to complete all scheduled 
assessments. 
Those subjects who are unwilling or unable to complete all remaining scheduled assessments 
should return to the site to complete the Early Termination visit assessments within 2 weeks 
(± 7 days) from the date of discontinuation. In this way, all subjects will be assessed at least 
5 half-lives after the last dose of study drug. 
 

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7 
STUDY DRUG AND ACCOUNTABILITY 
7.1 
Study Drug 
7.1.1 
Physical Description 
GBT440 is a synthetic small molecule bearing the chemical name 2-hydroxy-6-((2-(1-
isopropyl-1H-pyrazol-5-yl) pyridin-3-yl) methoxy) benzaldehyde. The chemical formula is 
C19H19N3O3 and the molecular weight is 337.38. 
7.1.2 
Formulation 
During this study GBT440 may be administered in the form of capsules or tablets as 
determined by the Sponsor 
GBT440 Capsules: GBT440 will be provided as 300 mg capsules which contain GBT440 
drug substance in Swedish orange, opaque, size 0, hypromellose capsules, along with several 
formulation excipients including hypromellose, microcrystalline cellulose, lactose 
monohydrate, croscarmellose sodium and magnesium stearate. All the excipients used for the 
formulation are also FDA IID (Inactive Ingredients Database) listed. 
GBT440 Tablets: The GBT440 300 mg tablets contain GBT440 drug substance along with 
several formulation excipients. All the excipients used for the formulation are FDA IID 
listed. 
7.1.3 
Packaging and Labeling  
GBT440 capsules will be supplied to the site in 100 mL bottles of 30 capsules. GBT440 
tablets will be supplied to the site in 60 mL bottles of 30 tablets.  
7.1.4 
Supply 
GBT or their representative will supply the packaged and labeled drug product to the 
investigational sites. Additional details are provided in the pharmacy manual. 
7.1.5 
Storage and Handling Procedure 
All study medications will be stored at controlled room temperature between 15°C to 25°C 
protected from light in the storage area of the investigational site pharmacy, which is a 
secure, temperature-controlled, locked environment with restricted access. 
No special procedures for the safe handling of GBT440 are required. The Sponsor will be 
permitted upon request to audit the supplies, storage, dispensing procedures and records. 

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7.2 
Drug Accountability 
In accordance with GCP, the Investigational Site will account for all supplies of GBT440. 
Details of receipt, storage, dispensing and return will be recorded. All drug received must be 
reconciled or explained. 
All unused supplies of GBT440 will either be destroyed by the investigational site or 
returned to the study Sponsor’s designee at the end of the study in accordance with 
instructions from the Sponsor. 
Additional details are provided in the pharmacy manual. 

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8 
DOSAGE AND TREATMENT ADMINISTRATION 
8.1 
Treatment Regimen 
GBT440 will be administered orally each day for 90 days. GBT440 will be administered as 
300 mg capsules or tablets.  
Part A: 
• GBT440 900 mg: three 300 mg capsules or tablets 
Part B: 
• GBT440 1500 mg: five 300 mg capsules or tablets  
Instructions for administration of study drug: 
• Self-administered by subject in the morning 
• May be taken with or without food  
• May be taken with water or another non-alcoholic beverage 
• Swallow the capsules or tablets whole 
 
Subjects must be instructed not to take study drug on the day of their scheduled visits (refer 
to the Schedules of Assessments provided in Appendix A [Table 15-1 for Part A; Table 15-2 
for Part B]).  
Study drug will be administered at the site on these days, after completion of all the 
assessments scheduled for that visit. The subject should be instructed to swallow the capsules 
or tablets whole. 
If a subject misses a dose of the study drug, they should resume normal dosing the next day; 
i.e., on the next day, the dose of study drug should be unchanged — not increased or 
decreased. 
8.2 
Study Drug Dispensing 
Study drug will be dispensed to subjects at each of the study visits (refer to the Schedules of 
Assessments provided in Appendix A [Table 15-1 for Part A; Table 15-2 for Part B]).  
8.3 
Dose Modification 
Modification of study drug dosing may be considered if, in the opinion of the study 
Investigator, an AE may be possibly/probably related to study drug, and it would be unsafe 
for the subject to continue receiving their current dose of study drug.  
The Investigator’s assessment of AE relatedness should take into account the toxicity profile 
of all concomitant medications including pirfenidone and nintedanib. 

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Not all AEs require study drug modifications and may be managed as determined by the 
Investigator and based on the clinical nature of the AE. 
The Sponsor’s Medical Director should be contacted prior to any change in dosing. 
8.3.1 
Dose Adjustment 
Dose adjustments may be initiated by the Investigator based on their assessment of the 
associated AE severity and overall subject safety. 
The Investigator, in discussion with the Sponsor’s Medical Director, may choose to reduce 
the total daily dose. 
• The initial reduction in dose should be by one (300 mg) study drug capsule or tablet.  
• A second dose reduction by another one (300 mg) capsule or tablet may be initiated, if 
deemed necessary by the Investigator and based on a safety assessment of the subject. 
The timing of the second dose reduction will be based on the Investigator’s clinical 
assessment and in prior discussion with the Sponsor’s Medical Director.  
• Any further dose reduction deemed necessary by the Investigator should be by one 
(300 mg) capsule at a time and based on a safety assessment of the subject. 
 
The Investigator must make every effort to return the subject to the dose level administered 
at the time of study enrollment. 
Once, in the opinion of the study Investigator, it is safe to increase dosing, this may be 
performed by: 
• Initiating the full dose, administered at study enrollment 
• Increasing the dose in a step-wise fashion by single capsule or tablet increments. The 
timing of the increase in dosing should be at the discretion of the Investigator. 
Instructions for increasing study drug dosing are listed below. 
 
Part A: If the subject is receiving a reduced dose of 300 mg (a total of 1 capsule or tablet) or 
600 mg (a total of 2 capsules or tablets), the dose may be increased by 1 capsule or tablet 
(300 mg) at a time up to 900 mg (a total of 3 capsules or tablets) or a dose best tolerated by 
the subject. 
Part B: If the subject is receiving a reduced dose of 300 mg, 600 mg, 900 mg or 1200 mg (a 
total of 1, 2, 3 or 4 capsules or tablets respectively), the dose may be increased by 1 capsule 
or tablet (300 mg) at a time up to 1500 mg (a total of 5 capsules or tablets) or a dose best 
tolerated by the subject. 

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Rash 
In the case that a subject develops a rash, the Investigator must assess whether the rash might 
be due to study drug or concomitant medications, in particular pirfenidone or nintedanib 
which may both cause rash. 
If, in the opinion of the Investigator, the rash may be possibly/probably related to study drug, 
the dose should be modified based on the instructions outlined in this section and in 
Section 8.3.2. 
An increase in dosing beyond the dose at the time of subject enrollment, is not allowed.  
8.3.2 
Dose Interruption 
Dose interruption may be initiated by the Investigator due to an AE, based on their 
assessment of the associated AE severity and overall subject safety and in discussion with the 
Sponsor’s Medical Director.  
Study drug should be restarted when, in the Investigator's opinion, it is safe to do so and in 
discussion with the Sponsor’s Medical Director.  
Part A 
Study drug may be restarted at 900 mg (3 capsules or tablets) or at a lower dose (600 mg or 
300 mg) as tolerated. If study drug is restarted at a lower dose the dose may be increased by 
300 mg (1 capsule or tablet) at a time to a total of 900 mg (3 capsules or tablets) or a dose 
best tolerated by the subject. Refer to Section 8.3.1 for instructions on dose escalation. 
Part B 
Study drug may be restarted at 1500 mg (5 capsules or tablets) or at a lower dose (900 mg, 
600 mg or 300 mg) as tolerated. If study drug is restarted at a lower dose the dose may be 
increased by 300 mg (1 capsule or tablet) at a time to a total of 1500 mg (5 capsules or 
tablets) or a dose best tolerated by the subject. 
For both Parts A and B, study drug may be discontinued due to an AE if, in the opinion of the 
Investigator, it is unsafe for the subject to continue receiving study drug. Subjects who 
discontinue study drug should remain in the study and complete all scheduled assessments 
(refer to Section 6).  
8.3.3 
Pirfenidone or Nintedanib Background Therapy 
If, in the opinion of the Investigator, the subject experiences significant side effects, judged 
to be related to pirfenidone or nintedanib therapy, treatment of symptoms and/or dose 
modifications of these medications are allowed.  
The decision to modify pirfenidone or nintedanib dosing is ultimately the responsibility of 
the Investigator. Any modifications to dosing will be managed by the Investigator throughout 
the study, taking in to account the United States Prescriber Information (USPI) of the drugs 

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and past history of care from the subject’s IPF health care provider and must be entered into 
the eCRF. 
8.4 
Study Drug Overdose 
To date, no events of overdose have been reported. Based on the mechanism of action of 
GBT440, the result of an overdose might include, but is not limited to, increased severity of 
previously reported associated AEs or decreased oxygen delivery to tissues (refer to 
Section 1). In the event of a medical emergency due to suspected GBT440 overdose, the 
Medical Monitor should be contacted as soon as possible.  
8.5 
Concomitant Medications 
A concomitant medication is defined as any prescription or over-the-counter preparation, 
including vitamins and supplements.  
In the interests of subject safety and acceptable standards of medical care the Investigator 
will be permitted to prescribe treatment(s) at his/her discretion. For all subjects, concomitant 
medications taken from signing of the informed consent until the last study visit must be 
recorded in the subjects’ eCRFs. 
All reported prior and concomitant medications will be coded using the WHO Drug 
Dictionary. 
8.5.1 
Permitted Therapy 
Use of the following therapies is allowed during the study: 
• Pirfenidone, nintedanib or N-acetylcysteine (NAC) for the treatment of IPF  
- 
Only if at the time of screening, the dose has been stable for at least 1 month prior to 
screening and with no anticipated need for dose adjustments during the study 
• Corticosteroids for the treatment of IPF  
- 
Only if the dose at screening is ≤ 10 mg per day of prednisone (or an equivalent) and 
has been stable for at least 14 days prior to screening and with no anticipated need for 
dose adjustments, including reductions in dose, during the study  
• Corticosteroids for the treatment of non-IPF conditions 
- 
Only if the dose of prednisone (or an equivalent) has been stable for at least 14 days 
prior to screening, and in the opinion of the Investigator not anticipated to require 
dose adjustments during the study 
• Maintenance therapy for other medical conditions listed in the subject’s medical history 
at the time of screening 
 

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Medications such as acetaminophen, non-steroidal anti-inflammatories and routinely-taken 
dietary supplements, including vitamins are allowed at the discretion of the Investigator and 
provided that the medications have no discernable impact on the study. 
8.5.2 
Restricted Therapies 
Subjects should not take the following medications within 14 days prior to screening and 
during the entire study:  
• Strong inducers of CYP3A4/CYP3A5, CYP2B6, CYP2C9 and CYP2C19 (refer to 
Appendix B; these medications may decrease the blood concentration of GBT440) 
• Herbal medications (e.g., St. John’s Wort) 
 
The following medications should be used with caution:  
• CYP3A4 substrates with a narrow therapeutic index (refer to Table 8-1; GBT440 may 
increase the plasma concentration of these medications) 
 
Table 8-1 
CYP Substrates with Narrow Therapeutic Range  
CYP Enzymes 
Substrates with Narrow Therapeutic Range 
CYP3A4 
Alfentanil, astemizole, cisapride, cyclosporine, dihdroergotamine, 
ergotamine, fentanyl, pimozide, quindine, sirolimus, tacrolimus, terfenadine 
Note that this is not an exhaustive list. For an updated listed, refer to the following link: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/
ucm093664.htm#4 
Substrates with a ‘narrow therapeutic range’ refers to drugs whose exposure-response relationship indicates 
that small increases in their exposure levels by the concomitant use of CYP inhibitors may lead to serious 
safety concerns.  
Adapted from: FDA DRAFT Guidance for Industry: Drug Interactions Studies-Study Design, Data Analysis, 
Implications for Dosing, and Labeling Recommendations. February 2012. 
 
8.5.3 
Therapies for treatment of IPF 
Therapies, other than those used at the time of screening, for the treatment of IPF are not 
allowed. 
If in the opinion of the Investigator an escalation in therapy for IPF is required, then study 
drug should be discontinued and the subject should complete all remaining scheduled 
assessments (refer to Section 6.3). 
8.6 
Fertility/Contraceptive Requirements 
Highly effective birth control should be used from the screening period until 30 days 
following the last study drug administration. 

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8.6.1 
Acceptable Forms of Contraception 
Highly effective methods of birth control are considered acceptable in this study. Highly 
effective is defined as those methods of birth control which result in a low failure rate (i.e., 
less than 1% per year) when used consistently and correctly.  
For female subjects: 
• Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: 
- 
Oral 
- 
Intravaginal 
- 
Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
- 
Oral 
- 
Injectable 
- 
Implantable 
◦ 
Note: Hormonal contraception must be supplemented with a barrier method 
(preferably male condom). 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Vasectomized partner. Note that vasectomized partner is a highly effective birth control 
method provided that partner is the sole sexual partner of the woman of child-bearing 
potential trial participant and that the vasectomized partner has received medical 
assessment of the surgical success.  
 
For male subjects: 
• Vasectomy 
• Two acceptable methods of contraception: Must agree to use, at least one of which must 
be a barrier method (e.g., spermicidal gel plus condom) for the entire duration of the 
study, and for 30 days following last study drug administration. 
• Sexual abstinence: 
This method of contraception is considered highly effective only if the subject is 
refraining from heterosexual intercourse during the entire period of risk associated with 
the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the subject. 

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9 
RANDOMIZATION PROCEDURE 
Subject randomization will not be carried out in this study. 
Approximately up to 32 subjects (up to approximately 16 subjects in Part A and 16 subjects 
in Part B) will be enrolled.  
9.1 
Blinding 
The study is open label. 
 

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10 
SAFETY ASSESSMENTS 
GBT440 is not an approved drug and, as a result, the entire safety profile is not known at this 
time. This Phase 2 study will contribute to the understanding of the safety profile for 
GBT440 and for its use in IPF patients. 
Safety assessments will consist of recording all AEs and SAEs, protocol-specified laboratory 
variables, vital signs, ECGs, and the results from other protocol-specified tests that are 
deemed critical to the safety evaluation of GBT440. Dedicated eCRFs will be used to collect 
information on specific AEs including SAEs, SUSARs, rashes and pregnancies. 
10.1 
Adverse Events (AE) 
An AE is defined as any untoward medical occurrence in any subject enrolled in a clinical 
investigation administered a pharmaceutical product, regardless of causal attribution.  
An AE can be any unfavorable and/or unintended sign, symptom, or disease temporally 
associated with the use of an investigational product, whether or not it is thought to be related 
to the investigational product. In addition to new events, any increase in the severity or 
frequency of a pre-existing condition that occurs is considered an AE. This includes any side 
effect, injury, toxicity or sensitivity reaction.  
Subjects will be monitored throughout the study for AEs, from the time informed consent is 
obtained until the last study visit (Day 120). Reporting of AEs prior to enrollment should 
only include SAEs or AEs resulting from any protocol-related interventions.  
AEs that are identified at the last assessment visit as specified in the protocol must be 
recorded in the eCRF. All events that are ongoing at this time will be recorded as ongoing on 
the eCRF. All (both serious and non-serious) AEs must be followed until they are resolved or 
stabilized, or until reasonable attempts to determine resolution of the event are exhausted. 
The Investigator should use his/her discretion in ordering additional tests as necessary to 
monitor the resolution of such events.  
All reported AEs will be coded using the current version of the Medical Dictionary for 
Regulatory Activities (MedDRA). 
All procedures specified in Section 10.3 are to be followed for reporting SAEs. 
10.2 
Recording Adverse Events 
Adverse events are to be recorded on the AE page of the eCRF. The following information 
will be recorded at the time the AE is reported and during follow up during the course of the 
AE: 
• Whether or not the AE is an SAE (Section 10.2.2) 
• AE severity using National Cancer Institute Common Terminology Criteria for Adverse 
Events, Version 4.03 (NCI CTCAE v4.03) (Section 10.2.3) 

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• AE relationship to investigational product (Section 10.2.4) 
• Action taken, including but not limited to: none, study drug dose modification or 
discontinuation, required concomitant medication, required procedure, or other 
• Outcome: recorded as event resolved, resolved with sequelae, ongoing, or death 
 
10.2.1 
Assessment of Adverse Events 
The Investigator will assess each AE for seriousness, severity, and relationship to study drug. 
10.2.2 
Serious Adverse Event (SAE) 
The Investigator is responsible for determining whether an AE meets the definition of an 
SAE. An SAE is any AE that results in any of the following outcomes: 
• Death 
• Life-threatening, i.e., an AE that places the subject at immediate risk of death  
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant disability or incapacity, i.e., a substantial disruption in the 
subject’s ability to conduct normal life functions 
• A congenital anomaly or birth defect in a neonate or infant born to a mother exposed to 
study drug 
• Significant medical events that, in the opinion of the Investigator, may jeopardize the 
subject or may require medical or surgical intervention to prevent any of the outcomes 
listed in this definition.  
 
SAEs will be reported to the Sponsor’s designated CRO’s Drug Safety Department within 
24 hours of the Investigator, designee, or site personnel’s knowledge of the event. Refer to 
“Reporting Serious Adverse Events” (details are provided in Section 10.3.4). 
Note: Hospitalization is not considered to be an SAE if a subject has a hospitalization or 
procedure (e.g., elective surgery) during the study, that was scheduled prior to the subject 
entering the study (i.e., before the subject signed the informed consent) for a pre-existing 
condition (i.e., one that occurred before the study). However, if the event/condition worsens 
during the study, it must be reported as an AE (or SAE, if the event/ condition results in a 
serious outcome such as hospitalization). 
10.2.3 
Protocol-Defined Events of Special Interest 
An adverse event of special interest (AESI) is any AE occurring from signing of the 
informed consent form (ICF) until the end of the study (Day 58) that results in: 

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•
An allergic reaction/hypersensitivity Grade 2 or higher (as defined by NCI CTCAE
v4.03)
AESIs will be reported to the CRO’s Drug Safety Department within 24 hours of the 
investigator, designee, or site personnel’s knowledge of the event. 
10.2.4 
Severity of Adverse Events 
The severity of an event describes the degree of impact upon the subject and/or the need for 
medical care necessary to treat the event. AEs reported for subjects participating in this study 
will be graded using the NCI CTCAE v4.03 (Table 10-1). 
The Investigator will grade the severity of each AE using, when applicable, the NCI CTCAE 
v4.03. For AEs not included in the NCI CTCAE v4.03, the criteria outlined in Table 10-1 
should be used as a general guideline.  
Table 10-1 
Grading for Adverse Events Not Covered in the NCI CTCAE 
Severity 
Description 
Grade 1 – Mild 
Asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
Grade 2 – Moderate 
Minimal, local or noninvasive intervention indicated; limited age-
appropriate instrumental activities of daily living (ADL) 
Grade 3 – Severe 
Medically significant but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self-care ADL. 
Grade 4 – Life-threatening 
Life-threatening consequences; urgent intervention indicated 
Grade 5 – Fatal 
Death 
ADL = activities of daily living; NCI CTCAE = National Cancer Institute-Common Terminology Criteria for 
Adverse Events 
10.2.5 
Relationship to Study Drug 
The relationship of an AE to the investigational product should be determined by the 
Investigator according to the following definitions: 
•
Not Related: Evidence exists that the AE has an etiology other than the study drug (such
as a preexisting condition, underlying disease, intercurrent illness, or concomitant
medication); and/ or the temporal relationship of the AE/SAE to the investigational
product administration makes the relationship unlikely.
•
Possibly/Probably Related: A temporal relationship exists between the event onset and
administration of the study drug; and it cannot be readily explained by the subject’s
clinical state or concomitant therapies; and it may appear with some degree of certainty to
be related based on the known therapeutic and pharmacologic actions of the drug.
Additional criteria to consider include in the case of cessation or reduction of the dose,

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the event abates or resolves and reappears upon re-challenge. It should be emphasized 
that ineffective treatment should not be considered as causally related in the context of 
AE reporting.  
 
These criteria, in addition to good clinical judgment, should be used as a guide for 
determining the causal assessment. If it is felt that the event is not related to study drug 
therapy, then an alternative explanation should be provided. 
10.2.6 
Unexpected Adverse Events  
An adverse reaction is ‘unexpected’ if its nature and severity are not consistent with the 
information contained within the current GBT440 IB. 
10.3 
Reporting Adverse Events 
Reporting of AEs prior to dosing should only include SAEs resulting from any protocol-
related interventions. 
10.3.1 
Diagnosis versus Signs and Symptoms 
If known, a diagnosis should be recorded on the 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 as an AE or SAE on the eCRF. If a diagnosis is 
subsequently established, all previously reported AEs based on signs and symptoms should 
be nullified and replaced by one AE report based on the single diagnosis, with a starting date 
that corresponds to the starting date of the first symptom or sign of the eventual diagnosis. 
10.3.2 
Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (e.g., cascade of events or clinical 
sequelae) should be identified by their primary cause. For example, if severe diarrhea is 
known to have resulted in dehydration, it is sufficient to record only diarrhea as an AE or 
SAE on the eCRF.  
However, medically significant AEs occurring secondary to an initiating event that are 
separated in time should be recorded as independent events on the eCRF. For example, if a 
severe gastrointestinal hemorrhage leads to renal failure, both events should be recorded 
separately on the eCRF. 
10.3.3 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution between subject 
evaluation time points. Such events should only be recorded once in the eCRF unless the 
severity changes (increases or decreases). If a persistent AE becomes more or less severe, the 
AE should be recorded as separate AEs for each Grade of severity.  

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If the event becomes serious, it should be reported to the Sponsor or the Sponsor’s designated 
CRO’s Drug Safety Department within 24 hours of the Investigator, designee, or site 
personnel’s knowledge of the event. The AE eCRF should be updated to add the SAE, 
providing the date that the event became serious. The updated eCRF should include both the 
non-serious and serious designated AEs. 
A recurrent AE is one that resolves between subject evaluation time points and subsequently 
recurs. All recurrent AEs should be recorded separately on an Adverse Event eCRF. 
10.3.4 
Abnormal Laboratory Values 
Only clinically significant laboratory abnormalities will be recorded as AEs or SAEs on the 
eCRF (e.g., abnormalities that require study drug dose modification, discontinuation of study 
drug, more frequent follow-up assessments, further diagnostic investigation). 
If the clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., 
increased alkaline phosphatase and bilirubin associated with cholecystitis), only the diagnosis 
(e.g., cholecystitis) needs to be recorded on the eCRF. 
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded as an AE or SAE on the eCRF. If the laboratory 
abnormality can be characterized by a precise clinical term, the clinical term should be 
recorded as the AE or SAE. 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 not be repeatedly recorded as AEs or SAEs on the Adverse Event eCRF, unless their 
severity increases or decreases, or the seriousness or etiology changes. 
10.3.5 
 Reporting Serious Adverse Events (SAEs) 
All SAEs and AESIs, regardless of causal attribution, that occur in this study will be reported 
to the Sponsor’s designated CRO’s Drug Safety Department within 24 hours of the 
Investigator, designee, or site personnel’s knowledge of the event. The SAE/AESI will be 
reported by completing the SAE/AESI eCRF in the EDC system. 
In the event that the EDC system is not available, a paper SAE/AESI report form must be 
submitted to the CRO’s Drug Safety Department (drugsafety@wwctrials.com or faxed to 
1-866-387-5539) within 24 hours of becoming aware of the event. The Principal Investigator 
or designee must complete the SAE/AESI eCRF page as soon as the EDC system becomes 
available. 
Follow-up reports must be submitted in a timely fashion as additional information becomes 
available. The Sponsor or designee may request additional source documentation pertaining 
to the SAE/AESI from the investigational site. If a subject is permanently withdrawn from 
the study due to a SAE, this information must be included in the initial or follow-up SAE 
report in the eCRF. 

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The Investigator is responsible for notifying the Institutional Review Board (IRB) or 
Independent Ethics Committees (IEC) of SAEs, in accordance with local regulations. The 
Sponsor or designee is responsible for reporting SAEs to the relevant regulatory authorities, 
and participating Investigators, in accordance with ICH guidelines, FDA regulations, and/or 
local regulatory requirements. 
Properly anonymized and de-identified documents (e.g., hospital discharge summaries, 
autopsy reports, and/or death certificates) as available will be provided to the CRO’s Drug 
Safety Department for all reported SAEs/AESIs. 
10.3.6 
Suspected Unexpected Serious Adverse Reaction (SUSAR) Reporting 
An SAE may qualify for mandatory expedited reporting to regulatory authorities if the SAE 
is attributable to the study drug and is not listed in the current IB (i.e., an unexpected event). 
The Sponsor or its designee is responsible for reporting SUSARs associated with the use of 
the study drug to the regulatory agencies and competent authorities after being notified of the 
event.  
10.4 
 Discontinuation due to Adverse Events 
Any subject who experiences an AE, serious or non-serious, may have study drug 
discontinued at any time at the discretion of the Investigator. The AE(s) should be noted on 
the appropriate eCRFs, and the subject’s progress should be followed until the AE is resolved 
or stabilized as determined by the Investigator. The Sponsor’s Medical Director and the CRO 
Medical Monitor must be notified. If the AE relates to overdose of study treatment, the IB 
should be consulted for details of any specific actions to be taken. 
Subjects should return to the study to complete assessments as outlined in Section 6. 
10.5 
 Pregnancy 
Pregnancies occurring in female subjects or in a male subject’s partner while enrolled in this 
clinical study through 30 days after the last dose of study drug administration, must be 
reported on a Pregnancy Monitoring Form and sent to the CRO’s Drug Safety Department 
within 24 hours of the Investigator, designee, or site personnel learning of the pregnancy (in 
accordance with Section 10.3). 
If a subject becomes pregnant while taking study drug, the study drug will be immediately 
discontinued, and the pregnancy must be reported to the CRO’s Drug Safety Department 
within 24 hours The Investigator will discuss with the subject the risks and concerns of 
investigational drug exposure to a developing fetus and counsel the subject and/or pregnant 
partner (or ensure such counseling is provided).  

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All pregnancies will be followed through to a definitive outcome (i.e., birth and 3 months 
post-delivery, spontaneous/elective abortion or miscarriage). An uncomplicated pregnancy 
will not be considered an AE or SAE. Pregnancy complications (e.g., spontaneous 
abortion/miscarriage or congenital anomalies) are considered an SAE. The outcome of any 
pregnancy and the presence or absence of any congenital abnormality will be recorded in the 
source documentation and reported to the CRO’s Drug Safety Department in accordance with 
Section 10.3. 
The Investigator will complete a Pregnancy Monitoring Form and report the information 
regarding the pregnancy, outcome, and status of the newborn and mother, as appropriate.  
 

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11 
 DATA ANALYSIS AND STATISTICAL PLANS 
This section describes the statistical methodology to be used in the analysis of the protocol 
endpoints. Details of all planned analyses will be specified in a separate Statistical Analysis 
Plan (SAP). 
Data will be summarized using descriptive statistics. Continuous variables will be 
summarized using mean, standard deviation (SD), coefficient of variation (CV%, as 
appropriate), median, minimum, maximum, and, as appropriate, geometric mean. Categorical 
variables will be summarized by presenting the number (frequency) and percentage in each 
category.  
Data will be summarized by dose level (900 mg, 1500 mg) and overall (total subjects). All 
collected data will be presented in data listings.  
11.1 
Sample Size  
The study will enroll up to approximately 32 subjects; up to approximately 16 subjects in 
Part A and up to approximately 16 subjects in Part B. 
11.2 
Analysis Populations  
The following populations will be considered in the analysis of data for this study.  
Efficacy Evaluable (EE) Population: All subjects who complete dosing for at least 20 days 
within the first 30 days of the treatment period or at least 60 days for the entire 90-day 
treatment period will be included in the EE Population. The EE Population will be the 
primary Population for all efficacy data presented. 
Safety Population: All subjects who receive any amount of study drug will be included in 
the Safety Population. The Safety Population will be the primary population for all safety 
data presented.  
PK Population: The PK Population will consist of all subjects who receive active study drug 
and have at least one measured concentration at a scheduled PK time point after start of 
dosing for at least one PK analyte. If any subjects are found to be noncompliant with respect 
to dosing or have incomplete data, protocol violations, or clinical events that affect PK, a 
decision will be made on a case-by-case basis as to their inclusion in the analysis. Subjects in 
this Population will be used for all PK summaries. 
11.3 
Statistical Analyses 
11.3.1 
Efficacy Analyses 
The analysis of the primary and secondary endpoints will be summarized descriptively. Each 
endpoint will be summarized by dose group and overall (total subjects). 
Full details of the analysis methods, including how missing data will be handled, will be 
provided in the SAP.  

Protocol Number GBT440-026, Amendment 2 
 
Global Blood Therapeutics 
Final June 5, 2017 
 
Page 62 of 77 
 
11.3.2 
Safety Analyses 
Safety and tolerability will be assessed by incidence, severity and changes from baseline of 
all relevant parameters including AEs, laboratory evaluations, vital signs, and ECGs. 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). The 
number and percentage of subjects experiencing 1 or more AEs will be summarized by dose 
group and overall, relationship to study drug and severity according to system organ class 
and preferred term. Additional summaries will be provided for SAEs and events resulting in 
permanent discontinuation of study drug.  
Laboratory parameters will be summarized using descriptive statistics and by post-dose shifts 
relative to baseline. Laboratory values outside normal limits will be identified in the subject 
listings and will include flags for high and low values.  
Vital sign results and ECGs will also be summarized descriptively for each scheduled 
protocol time point.  
11.3.3 
PK and PK/PD Analyses 
A listing of PK sample collection times as well as derived sampling time deviations will be 
provided. A subject listing of all concentration-time data for each treatment, and study day 
will be presented. PK variables will be summarized using appropriate descriptive statistics 
(e.g., n, mean, SD, CV%, minimum, median, and maximum, and/or geometric mean) by part, 
dose, and study day.  
Graphical presentations of key PK parameters and concentrations will be used as appropriate. 
Figures of individual concentrations versus time will be presented by subject.  
PK/PD analyses will be performed. 
 

Protocol Number GBT440-026, Amendment 2 
 
Global Blood Therapeutics 
Final June 5, 2017 
 
Page 63 of 77 
 
12 
REGULATORY, ETHICAL AND LEGAL OBLIGATIONS 
12.1 
Ethical Consideration 
It is the responsibility of the Investigator to assure that the study is conducted in accordance 
with the protocol, current country and local regulations, FDA regulations, ICH GCP 
guidelines, and the Declaration of Helsinki.  
12.2 
Institutional Review Board (IRB) and Regulatory Approval 
The Investigator must inform, and obtain approval from, the IRB/IEC for the conduct of the 
study at named sites, for the protocol, the Subject Informed Consent Form, any other written 
information that will be provided to the subjects, and any advertisements that will be used. 
Written approval must be obtained prior to recruitment of subjects into the study and 
shipment of investigational drug. 
Proposed amendments to the protocol and aforementioned documents must be discussed 
among the Sponsor and CRO, and then submitted to the IRB/IEC for approval. Amendments 
may be implemented only after a copy of the local EC approval letter has been transmitted to 
the Sponsor. Amendments that are intended to eliminate an apparent immediate hazard to 
subjects may be implemented prior to receiving Sponsor or IRB/IEC approval. However, in 
this case, notification to the Sponsor and IRB approval must be obtained as soon as possible 
after implementation. 
The Investigator will be responsible for ensuring that an annual update is sent to the IRB/IEC 
to facilitate their continuing review of the trial (if needed) and that the IRB/IEC is informed 
about the end of the study. Copies of the update, subsequent approvals and final letter must 
be sent to the Sponsor. 
12.3 
Insurance and Financial Disclosure 
The Sponsor has subscribed to an insurance policy covering, in its terms and provisions, its 
legal liability for injuries caused to participating persons and arising out of this research 
performed strictly in accordance with the scientific protocol as well as with applicable law 
and professional standards.  
The Investigator and sub Investigator(s) must complete, sign and date a Financial Disclosure 
Form prior to their participation in the study. This Form will be maintained with the study 
records. The Investigator and sub Investigator(s) will provide an updated Financial 
Disclosure Form if any of the factors change during the trial and for 1 year after the trial’s 
completion or termination. 
12.4 
Essential Documentation Requirements 
The Sponsor will collect from the investigational site the required essential regulatory 
documents per ICH guidance prior to GBT440 shipment to the site. 

Protocol Number GBT440-026, Amendment 2 
 
Global Blood Therapeutics 
Final June 5, 2017 
 
Page 64 of 77 
 
12.5 
Informed Consent 
It is the Investigator’s responsibility to obtain written informed consent from the subject after 
adequate explanation of the objectives, methods, anticipated benefits, and potential hazards 
of the study and before any study procedures are commenced. This information is contained 
within the informed consent form (ICF). 
The Investigator also commits to providing each subject with a copy of the revised ICF if any 
changes are made to the study. 
For both the original and all updated ICFs: (a) the subject and the person executing the 
informed consent process must personally sign and date the document, (b) a copy of the ICF 
in the subject’s native language must be provided to the subject, and (c) the informed consent 
process should be recorded in the source documentation. All original signed/dated ICFs must 
be retained with the study records.  
12.6 
Confidentiality 
The Investigator must ensure that the subject’s privacy is maintained. On the CRF or other 
documents submitted to the Sponsor, subjects will be identified by a subject study number 
only. Documents that are not submitted to the Sponsor (e.g., signed informed consent form) 
should be kept in a strictly confidential file by the Investigator. 
The Investigator shall permit authorized representatives of the Sponsor, regulatory agencies 
and IRBs/IECs to review the portion of the subject’s medical record that is directly related to 
the study. As part of the required content of informed consent, the subject must be informed 
that his/her records will be reviewed in this manner. 
12.7 
Trial Documentation and Data Storage 
The Investigator must retain a comprehensive and centralized filing system of all trial-related 
documentation that is suitable for inspection by the Sponsor and representatives of regulatory 
authorities. 
The Investigator must retain essential documents until at least 2 years after the last approval 
of a marketing application. Subject files and other source data (including copies of protocols, 
original reports of test results, investigational drug dispensing logs, correspondence, records 
of informed consent, and other documents pertaining to the conduct of the trial) must be kept 
for the maximum period of time permitted by the institution. Documents should be stored in 
such a way that they can be accessed/data retrieved at a later date. Consideration should be 
given to security and environmental risks. 
No trial document will be destroyed without prior written agreement between the Sponsor 
and the Investigator. Should the Investigator wish to assign the trial records to another party 
or move them to another location, written agreement must be obtained from the Sponsor. 

Protocol Number GBT440-026, Amendment 2 
 
Global Blood Therapeutics 
Final June 5, 2017 
 
Page 65 of 77 
 
12.8 
Study Record Retention 
In accordance with 21 CFR 312.62(c), the Investigators will retain records required to be 
maintained under this part for a period of 2 years following the date a marketing application 
is approved for the drug for the indication for which it is being investigated. If no application 
is to be filed or if the application is not approved for such indication, the Investigator will 
retain these records until 2 years after the investigation is discontinued and the US FDA or 
applicable regulatory authorities are notified. 
The Investigators must retain protocols, amendments, IRB/IEC approvals, copies of the Form 
FDA 1572, signed and dated consent forms, medical records, eCRFs, drug accountability 
records, all correspondence and any other documents pertaining to the conduct of the study. 
If the Principal Investigator moves, withdraws from an investigation or retires, the 
responsibility for maintaining the records may be transferred to another person who will 
accept responsibility. Notice of transfer must be made to and agreed by the Sponsor. 
12.9 
Disclosure of Information 
Information concerning the study, patent applications, processes, scientific data or other 
pertinent information is confidential and remains the property of the Sponsor. The 
Investigator may use this information for the purposes of the study only. 
It is understood by the Investigator that the Sponsor will use information developed in this 
clinical study in connection with the development of GBT440 and, therefore, may disclose it 
as required to other clinical Investigators and to regulatory agencies. In order to allow the use 
of the information derived from this clinical study, the Investigator understands that he/she 
has an obligation to provide complete test results and all data developed during this study to 
the Sponsor. 
Verbal or written discussion of results prior to study completion and full reporting should 
only be undertaken with written consent from the Sponsor. 
12.10 
Publication 
The Sponsor intends to publish the results of the study as a whole once all subjects have 
completed the study and the study results have been analyzed. 
If the publication includes study Investigators: 
• The Investigator may not submit the results of the study for publication without the prior 
consent of the Sponsor. 
• The Investigator or the Sponsor may not submit for publication or present the results of 
this study without allowing each of the other parties adequate time to review and 
comment on the pre-publication manuscript.  
Authorship will be determined by mutual agreement and in line with the International 
Committee of Medical Journal Editors authorship requirements. 

Protocol Number GBT440-026, Amendment 2 
 
Global Blood Therapeutics 
Final June 5, 2017 
 
Page 66 of 77 
 
13 
ADMINISTRATIVE OBLIGATIONS 
13.1 
Source Data 
Original documents, data, records (e.g., clinic records; laboratory reports; memoranda; 
subject diaries or evaluation checklists; study drug accountability records; recorded data from 
automated instruments; copies or transcriptions certified after verification as being accurate 
and complete; microfiches; photographic negatives; microfilm or magnetic media; X-rays; 
ECGs: questionnaires, subject files; and records kept at the pharmacy, at the laboratories, and 
at medico-technical departments involved in the clinical trial) and all relevant sections of the 
subject’s medical records and all other data collection made specific to this trial constitute 
source documents. 
The completed eCRF is not a source document. The Investigator/institution will permit 
trial-related monitoring, audits, IRB review and regulatory inspection by providing direct 
access to source documents. 
13.2 
Data Collection 
The Investigator will be responsible for maintaining accurate and adequate case records 
(source documents) from which data will be transcribed (or if electronically captured [EDC] 
source data, transferred) to eCRFs designed to record data pertinent to this study. All relevant 
observations and data related to the study will be so recorded. This will include medical and 
medication history, physical examinations, a checklist of inclusion and exclusion criteria, 
investigational treatment administration, and a record of sample collection, clinical 
assessments, AEs, and final evaluation. The clinical site Clinical Research Associate (CRA) 
will review all eCRFs and compare data to that contained in clinic notes and subjects’ source 
documents/medical records. 
Data collected regarding each subject will be entered into the eCRF. The Investigator will be 
responsible for the timeliness, completeness, and accuracy of the documentation entered into 
the eCRFs. 
13.3 
Monitoring 
It is understood that monitors and any authorized personnel contracted to Sponsor may 
contact and visit the Investigator, and that they will be allowed to inspect the various records 
of the trial on request (source documents and other pertinent data), provided that subject 
confidentiality is maintained, and that the inspection is conducted in accordance with local 
regulations. 
It is the monitor’s responsibility to inspect the source data at regular intervals throughout the 
trial to verify adherence to the protocol; the completeness, accuracy and consistency of the 
data and adherence to Good Clinical Practice guidelines. 
The Investigator agrees to co-operate with the monitor to ensure that any problems detected 
during the course of these monitoring visits are resolved. 

Protocol Number GBT440-026, Amendment 2 
 
Global Blood Therapeutics 
Final June 5, 2017 
 
Page 67 of 77 
 
13.4 
Quality Control and Quality Assurance 
Quality Control will be performed according to the Sponsor’s or Sponsor’s designee internal 
procedures. A Quality Assurance representative of the Sponsor may audit the study. All 
necessary data and documents will be made available for inspection, and the Investigator 
agrees to co-operate with the auditor to ensure that any issues detected during the course of 
audit are addressed. 

Protocol Number GBT440-026, Amendment 2 
 
Global Blood Therapeutics 
Final June 5, 2017 
 
Page 68 of 77 
 
14 
REFERENCES 
American Thoracic Society statement: guidelines for the six-minute walk test. Am J Respir 
Crit Care Med. 2002;166(1):111-117. 
American Thoracic Society. Pulmonary Function Laboratory Management and American 
Thoracic Society/ American College of Chest Physicians statement on cardiopulmonary 
exercise testing. Am J Respir Crit Care Med. 2003;167(2):211-277. 
Eaton JW. Extreme altitude: Protective effect of increased hemoglobin-oxygen. Science. 
1974;183. 
Eaton T, Lewis C, Young P, Kennedy Y, Garrett JE, et al. Long-term oxygen therapy 
improves health-related quality of life. Respir Med. 2004;98:285-293. 
FDA: The Voice of the Patient 
www.fda.gov/downloads/forindustry/userfees/prescriptiondruguserfee/ucm440829.pdf 
Hebbel RP, Eaton JW, Kronenberg RS, Zanjani ED. Adaptation to altitude in subjects with 
high hemoglobin oxygen affinity. J Clin Invest. 1978;62(3):593-600. 
Holland AE, Spruit MA, Troosters T, et al. An official European Respiratory 
Society/American Thoracic Society technical standard: field walking tests in chronic 
respiratory disease. Eur Respir J. 2014;44:1428-1446. 
King TE, Bradford WZ, Castro-Bernardini S, et al. A Phase 3 trial of pirfenidone in patients 
with idiopathic pulmonary fibrosis. NEJM. 2014;370 (22);2083-2092. 
King TE, Tooze JA, Schwarz MI, et al. Predicting survival in idiopathic pulmonary fibrosis: 
scoring system and survival model. Am J Respir Crit Care Med. 2001;164:1171-1181. 
Lehrer-Graiwer J, Howard J, Hemmaway CJ, Awogbade M, Telfer P, Layton M, et al. 
GBT440, a potent anti-sickling hemoglobin modifier reduces hemolysis, improves anemia 
and nearly eliminates sickle cells in peripheral blood of patients with sickle cell disease. Oral 
presentation: American Society of Hematology Annual Meeting; Orlando, FL. 2015. 
Michaelson JE, Aguayo SM, Roman J. Idiopathic pulmonary fibrosis; a practical approach 
for diagnosis and management. Chest. 2000;118:788-794. 
National Institute for Health Care and Excellence, nice.org.uk/guidance/cg163. 
Nicholson AG, Colby TV, du Bois RM, et al. The prognostic significance of the histologic 
pattern of interstitial pneumonia in patients presenting with the clinical entity of cryptogenic 
fibrosing alveolitis. Am J Respir Crit Care Med. 2000;162:2213-2217. 
Olson AL, Swigris JJ. Idiopathic pulmonary fibrosis; diagnosis and epidemiology. Clin Chest 
Med. 2012;33:41-50. 

Protocol Number GBT440-026, Amendment 2 
 
Global Blood Therapeutics 
Final June 5, 2017 
 
Page 69 of 77 
 
Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic 
pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir 
Crit Care Med. 2011;183:788-824. 
Raghu G, Rochwerg B, Zhang Y. An official ATS/ERS/JRS/ALAT clinical practice 
guideline: treatment of idiopathic pulmonary fibrosis. An update of the 2011 clinical practice 
guideline. Am J Respir Crit Care Med. 2015;192(2):e3-e19. 
Raghu G, Weycker D, Edelsberg, et al. Incidence and prevalence of Idiopathic pulmonary 
fibrosis. Am J Respir Crit Care Med. 2006;174:810-816. 
Richeldi L, du Bois Rm, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic 
pulmonary fibrosis. NEJM. 2014:370(22):2071-2082. 
Visca D, Montgomery A, de Lauretis A, et al. Ambulatory oxygen in interstitial lung disease. 
Eur Respir J. 2011;38:987. 
Xin G, Dufu K, Hutchaleelaha A, et al. Increased hemoglobin–oxygen affinity ameliorates 
bleomycin‐induced hypoxemia and pulmonary fibrosis. Physiological Reports Published 
13 September 2016 Vol. 4 no. e12965 DOI: 10.14814/phy2.12965 
Yalcin O, Cabrales P. Increased hemoglobin O2 affinity protects during acute hypoxia. Am J 
Physiol Heart Circ Physiol. 2012;303(3):H271-81. 
 

Protocol Number GBT440-026, Amendment 2 
 
Global Blood Therapeutics 
Final June 5, 2017 
 
Page 70 of 77 
 
15 
APPENDICES

Protocol Number GBT440-026, Amendment 2 
 
Global Blood Therapeutics 
Final June 5, 2017 
 
Page 71 of 77 
 
APPENDIX A 
SCHEDULES OF STUDY ASSESSMENTS  
Table 15-1 
Schedule of Assessments: Part A — 900 mg Dose  
  
Screeninga 
Treatment Phase 
End of Study (EOS) 
Early Term (ET)b 
Day -21 to 
Day -1 
Day 
1 
Day 
15 
±3 
Day 
30 ±3 
Day 
45 ±3 
Day 
60 ±5 
Day 90 ±5 
Day 120 ±5 
Procedures and Assessments 
Visit 1 
Visit 
2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 7 
Visit 8 
ET 
Informed consentc 
X 
Eligibility assessment 
X 
 
 
 
 
 
 
 
 
Medical history, demographics, and 
baseline conditions 
X 
Xd 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review adverse eventse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete physical examf 
X 
 
 
 
 
 
 
 
 
Limited physical examg 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
Weight 
X 
X 
X 
X 
X 
X 
Vital signsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SpO2i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGj 
X 
X 
X 
Urine pregnancy testk 
 
X 
 
X 
 
X 
X 
X 
X 
Serum pregnancy testl 
X 
 
 
 
 
 
 
 
 
Hematology, serum chemistry, liver 
function tests 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
Coagulation 
X 
Serum erythropoietin 
X 
X 
X 
X 
X 
PK Blood Samples 
X 
X 
X 
X 
X 

Protocol Number GBT440-026, Amendment 2 
 
Global Blood Therapeutics 
Final June 5, 2017 
 
Page 72 of 77 
 
  
Screeninga 
Treatment Phase 
End of Study (EOS) 
Early Term (ET)b 
Day -21 to 
Day -1 
Day 
1 
Day 
15 
±3 
Day 
30 ±3 
Day 
45 ±3 
Day 
60 ±5 
Day 90 ±5 
Day 120 ±5 
Procedures and Assessments 
Visit 1 
Visit 
2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 7 
Visit 8 
ET 
Spirometry  
X 
 
X 
DLco 
X 
 
X 
Oxygen titration testm 
 
X 
 
X 
 
 
X 
X 
 
Arterial blood gasm 
X 
X 
X 
X 
6 MWTm 
X 
X 
X 
X 
Borg scalem 
 
X 
 
X 
 
 
X 
X 
 
SGRQn 
X 
 
X 
 
X 
X 
X 
ATAQn 
X 
 
X 
 
X 
X 
X 
Study drug dispensing to subject 
 
X 
X 
X 
X 
X 
 
 
 
Study drug administration at site o 
X 
X 
X 
X 
X 
X 
 
Pedometer dispensing to subject 
 
X 
 
 
 
 
 
 
 
Abbreviations for Table and Footnotes: ATAQ = A Tool for Assessment of Quality of Life; DLco = lung diffusing capacity measured using carbon 
monoxide; ECG = electrocardiogram; eCRF = electronic Case Report Form; EOS = end of study; ET = early term; 6MWT = 6-minute walk test; PK 
= pharmacokinetic; PRO = patient reported outcome; SAE = serious adverse event; SGRQ = St. George’s Respiratory Questionnaire; SpO2 = oxygen 
saturation measured by pulse oximetry. 
Note: All assessments should be performed within the window indicated for each scheduled visit. All assessments should be performed prior to receiving 
study drug. SGRQ and ATAQ should be performed before all other assessments, followed by 12-lead ECG and then vital signs. 
a. 
All screening evaluations must be completed and reviewed prior to Day 1 (Visit 2) to confirm the subject meets all eligibility criteria prior to 
dosing. 
b. All subjects who discontinue study or study drug prior to study completion and who are unwilling or unable to complete the remaining scheduled 
visits should return to the study site to complete all ET assessments (see Section 6)  
c. 
Written informed consent must be obtained and documented prior to performing any study-specific screening procedure 
d. Demographics, medical history and baseline conditions obtained at screening should be reviewed again and any changes since screening noted in 
the eCRF 
e. 
After informed consent but prior to randomization only SAEs resulting from a protocol-mandated intervention should be reported. After 
randomization, all adverse events will be reported until study completion (Day 120).  

Protocol Number GBT440-026, Amendment 2 
 
Global Blood Therapeutics 
Final June 5, 2017 
 
Page 73 of 77 
 
f. 
Includes evaluation of the head, eyes, ears, nose and throat and cardiovascular, respiratory, musculoskeletal, gastrointestinal, neurological, 
dermatologic systems. No rectal or pelvic examination is required. Record any observed abnormalities in the eCRF. At subsequent visits record new 
or worsened clinically significant findings on the eCRF. 
g. Perform a limited, symptom-directed examination as clinically indicated. Record new or worsened clinically significant findings in the eCRF. 
h. Includes heart rate, respiratory rate, systolic and diastolic blood pressure and temperature measured in a semi-recumbent or supine position and 
resting for at least 5 minutes.  
i. 
Performed at the time of Vital Signs assessment, with the subject breathing their supplemental O2 delivered at the usual prescribed rate and after the 
subject has rested for at least 5 minutes. 
j. 
Perform 12-lead ECG after the subject has been resting in a semi-recumbent or supine position for at least 5 minutes. 
k. Perform for all female subjects who are not post-menopausal or surgically sterile. On Day 1, urine pregnancy must be performed before any other 
assessments. The Investigator is to ensure that the result is negative prior to completing any other study related assessments and prior to 
administering investigational product to the subject. 
l. 
If a urine pregnancy test on Day 1 is positive, confirm the result with a serum pregnancy test. The serum pregnancy test must be available (and 
negative) prior to Day 1 dosing. 
m. Instructions for per-protocol performance of the oxygen titration and 6-minute walk (and Borg dyspnea scale) tests are provided in the procedure 
manual. 
n. The ATAQ and SGRQ questionnaires should be self-administered by the subject, using the paper forms provided by the Sponsor prior to all other 
non-PRO assessments and before the subject receives any disease-status information during that assessment.  
o. Subjects should not administer study drug on the morning of these study visits. Study drug will be administered by the study staff after completion 
of all pre-dose assessments. 
Guidance for PK Sample Collection: 
Pre-dose PK samples should be obtained as soon as possible after PROs, ECG, AEs and Concomitant Medications history and vitals have been obtained and 
before any other assessments are performed.  
Post-dose PK samples should be obtained following administration of study drug. Collection of these PK samples should occur after completion of all other 
scheduled assessments, including spirometry and DLco, oxygen titration test, 6MWT and investigational product dosing. 
These samples may be drawn at the same time as the blood draw for other scheduled laboratory assessments during the visit.

Protocol Number GBT440-026, Amendment 2 
 
Global Blood Therapeutics 
Final June 5, 2017 
 
Page 74 of 77 
 
Table 15-2 
Schedule of Assessments: Part B — 1500 mg Dose  
  
Screeninga 
Treatment Phase 
End of 
Study 
(EOS) 
Early 
Term 
(ET)b 
Day -21 to 
Day -1 
Day 1 
Day 15 
±3 
Day 30 
±3 
Day 60 
±5 
Day 90 
±5 
Day 105 
±5 
Day 120 
±5 
Procedures and Assessments 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
ET 
Informed consentc 
X 
 
 
 
 
 
 
 
 
Eligibility assessment 
X 
 
Medical history, demographics, and 
baseline conditions 
X 
Xd 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review adverse eventse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete physical examf 
X 
 
Limited physical examg 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
 
X 
X 
Vital signsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SpO2i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGj 
X 
X 
 
X 
Urine pregnancy testk 
 
X 
 
X 
X 
X 
 
X 
X 
Serum pregnancy testl 
X 
 
 
 
 
 
 
 
 
Hematology, serum chemistry, liver 
function tests 
X 
X 
X 
X 
 
X 
X 
Urinalysis 
X 
X 
X 
 
X 
Coagulation 
X 
 
Serum erythropoietin 
X 
X 
X 
 
X 
X 
PK blood samples 
X 
X 
X 
X 
X 
X 
X 
Protein binding sample (plasma)  
 
X 
X 
 
 
 
 
 
 

Protocol Number GBT440-026, Amendment 2 
 
Global Blood Therapeutics 
Final June 5, 2017 
 
Page 75 of 77 
 
  
Screeninga 
Treatment Phase 
End of 
Study 
(EOS) 
Early 
Term 
(ET)b 
Day -21 to 
Day -1 
Day 1 
Day 15 
±3 
Day 30 
±3 
Day 60 
±5 
Day 90 
±5 
Day 105 
±5 
Day 120 
±5 
Procedures and Assessments 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
ET 
Spirometry  
X 
 
X 
 
DLco 
X 
 
X 
 
Oxygen titration testm 
 
X 
 
X 
 
X 
 
X 
 
Arterial blood gasm 
X 
X 
X 
 
X 
6MWTm 
X 
X 
X 
 
X 
Borg scalem 
 
X 
 
X 
 
X 
 
X 
 
SGRQn 
X 
 
X 
X 
X 
 
X 
ATAQn 
X 
 
X 
X 
X 
 
X 
End of Treatment Questionnaire n 
 
 
 
 
 
X 
 
 
 
Study drug dispensing to subject 
X 
X 
X 
X 
 
 
 
Study drug administration at site o 
X 
X 
X 
X 
X 
 
 
Pedometer dispensing to subject 
 
X 
 
 
 
 
 
 
 
Pedometer return 
 
 
 
 
 
 
 
X 
 
Abbreviations for Table and Footnotes: ATAQ = A Tool for Assessment of Quality of Life; DLco = lung diffusing capacity measured using carbon monoxide; 
ECG = electrocardiogram; eCRF = electronic Case Report Form; EOS = end of study; ET = early term; 6MWT = 6-minute walk test; PK = pharmacokinetic; 
PRO = patient reported outcome; SAE = serious adverse event; SGRQ = St. George’s Respiratory Questionnaire; SpO2 = oxygen saturation measured by pulse 
oximetry. 
Note: All assessments should be performed within the window indicated for each scheduled visit. All assessments should be performed prior to receiving study 
drug. SGRQ, ATAQ and End of Treatment questionnaires should be performed before all other assessments, followed by 12-lead ECG, AEs/concomitant 
medication changes, vital signs, bloodwork, pre-dose PK, OTT, 6MWT, study drug administration, and post dose PK. 
a 
All screening evaluations must be completed and reviewed prior to Day 1 (Visit 2) to confirm the subject meets all eligibility criteria prior to dosing. SpO2 
assessment for study eligibility (refer to Section 4.1, Inclusion Criteria 5) is to be performed on both the screening and Day 1 visits. If the criteria are not met 
at either study visit, the subject is to be screen failed without the completion of other study related assessments. If the criteria are met, then the subject should 
proceed with the remaining assessments. 

Protocol Number GBT440-026, Amendment 2 
 
Global Blood Therapeutics 
Final June 5, 2017 
 
Page 76 of 77 
 
b 
All subjects who discontinue study or study drug prior to study completion (Day 120) and who are unwilling or unable to complete the remaining scheduled 
visits should return to the study site to complete all Early Termination (ET) assessments (refer to Section 6).  
c 
Written informed consent must be obtained and documented prior to performing any study-specific screening procedure. 
d 
Demographics, medical history and baseline conditions obtained at screening should be reviewed again and any changes since screening noted in the eCRF 
e 
After informed consent but prior to randomization only serious adverse events (SAEs) resulting from a protocol-mandated intervention should be reported. 
After randomization, all AEs will be reported until study completion (Day 120).  
f 
Includes evaluation of the head, eyes, ears, nose and throat and cardiovascular, respiratory, musculoskeletal, gastrointestinal, neurological, dermatologic 
systems. No rectal or pelvic examination is required. Record any observed abnormalities in the eCRF. At subsequent visits, record new or worsened 
clinically significant findings on the eCRF. 
g 
Perform a limited, symptom-directed examination as clinically indicated. Record new or worsened clinically significant findings in the eCRF. 
h 
Includes heart rate, respiratory rate, systolic and diastolic blood pressure and temperature measured in a semi-recumbent or supine position and resting for at 
least 5 minutes.  
i 
Performed at the time of Vital Signs assessment, with the subject breathing their supplemental O2 delivered at the usual prescribed rate and after the subject 
has rested for at least 5 minutes. On Screening and Day 1 visits must be performed prior to other assessments to ensure eligibility. 
j 
Perform 12-lead ECG after the subject has been resting in a semi-recumbent or supine position for at least 5 minutes. 
k 
Perform for all female subjects who are not post-menopausal or surgically sterile. On Day 1, urine pregnancy must be performed before any other 
assessments. The Investigator is to ensure that the result is negative prior to completing any other study related assessments and prior to administering 
investigational product to the subject. 
l 
If a urine pregnancy test on Day 1 is positive, confirm the result with a serum pregnancy test. The serum pregnancy test must be available (and negative) 
prior to Day 1 dosing. 
m 
Instructions for per protocol performance of the oxygen titration, 6-minute walk (and Borg Dyspnea Scale) and ABG tests are provided in the procedure 
manual. 
n 
The ATAQ, SGRQ and End of Treatment questionnaires should be self-administered by the subject using the paper forms provided by the Sponsor prior to 
all other non-PRO assessments and before the subject receives any disease-status information during that assessment. The End of Treatment questionnaire is 
to be administered at the Day 120 visit, if it was not administered at the Day 90 visit.  
o 
Subjects should not administer study drug on the morning of these study visits. The study staff will administer study drug after completion of all pre-dose 
assessments.  
Guidance for PK Sample Collection: 
Pre-dose PK samples should be obtained as soon as possible after PROs, ECG, AEs and Concomitant Medications history and vitals have been obtained and 
before any other assessments are performed.  
Post-dose PK samples should be obtained following administration of study drug. Collection of these PK samples should occur after completion of all other 
scheduled assessments, including spirometry and DLco, oxygen titration test, 6MWT and investigational product dosing. 
Protein Binding samples should be obtained at Day 1 between 2-4 hours post-dose and Day 15 pre-dose. 
These samples may be drawn at the same time as the blood draw for other scheduled laboratory assessments during the visit. 

Protocol Number GBT440-026, Amendment 2 
 
Global Blood Therapeutics 
Final June 5, 2017 
 
Page 77 of 77 
 
APPENDIX B 
STRONG INDUCERS OF CYP ISOENZYMES 
CYP Enzymes 
Medications 
CYP3A4/3A5 
avasimibe, carbamazepine, phenytoin, rifampin, St. John’s 
wort, mitotane, enzalutamide 
CYP2B6 
Carbamazepine 
CYP2C19 
rifampin and ritonavir 
 CYP2C9  
Currently no known inducers 
Please note the following: This is not an exhaustive list. For an updated list, refer to the following link: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/uc
m080499.htm.