Clinical trial NCT02846324
Conditions: Idiopathic Pulmonary Fibrosis Hypoxemia
Sponsor: Global Blood Therapeutics
Start date: 2016-06-01; Completion date: 2017-11-01
Enrollment: 39 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a randomized, double-blind, placebo-controlled trial in which eligible IPF subjects will be randomized to receive GBT440 or Placebo orally daily.

Detailed description:

Arms: arm 1: Parts A and B arm 2: Part A arm 3: Part B arm 4: Parts A and B
Interventions: intervention 1: GBT440 intervention 2: Placebo
Intervention descriptions: intervention 1: Capsules which contain GBT440 drug substance in Swedish orange intervention 2: Placebo capsules

Protocol documents:
Prot_000.pdf: 
 
CLINICAL STUDY PROTOCOL 
GBT440-006 
Study Number 
GBT440-006 
Study Title 
A Phase II randomized, placebo-controlled study of GBT440 to 
evaluate the safety, tolerability, pharmacokinetics and effect on 
hypoxemia in subjects with Idiopathic Pulmonary Fibrosis (IPF) 
Investigational Product 
GBT440 
IND Number 
128319 
Sponsor 
400 East Jamie Court, Suite 101 
South San Francisco,  
CA 94080 
United States of America 
Sponsor’s Medical 
Director 
Nicholas Vlahakis, M.D. 
Senior Medical Director  
Global Blood Therapeutics  
400 East Jamie Court, Suite 101  
South San Francisco, CA 94080  
(650) 741-7730 (Office Telephone No.)  
nvlahakis@globalbloodtx.com 
Medical Monitor 
Toni Bransford, M.D. 
Senior Medical Director 
Worldwide Clinical Trials 
973-420-6236 
toni.bransford@worldwide.com 
Version / Date 
Amendment 3, 21 December, 2016 
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 treatment. Once the protocol is 
signed, its terms are binding for all parties. 
 




Protocol Number GBT440-006 
 
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Final 21 December 2016 
Amendment 3 
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CONFIDENTIAL 
 
INVESTIGATOR STATEMENT OF APPROVAL AND COMPLIANCE 
A Phase II randomized, placebo-controlled study of GBT440 to evaluate the safety, 
tolerability, pharmacokinetics and effect on hypoxemia in subjects with Idiopathic 
Pulmonary Fibrosis (IPF) 
Protocol Number: GBT440-006, Amendment 3 
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:  
Date:  
Title:  
 


Protocol Number GBT440-006 
 
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CONFIDENTIAL 
 
SPONSOR CONTACT INFORMATION 
 
Sponsor’s Medical Director 
Nicholas 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, M.P.H. 
Director, Clinical Operations 
 (650) 351-4758 
boguno@globalbloodtx.com 
 
 
 
 


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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ............................................................................................1 
GBT440-006 ..............................................................................................................................1 
SPONSOR CONTACT INFORMATION .................................................................................4 
TABLE OF CONTENTS ...........................................................................................................5 
LIST OF TABLES .....................................................................................................................9 
LIST OF APPENDICES ............................................................................................................9 
LIST OF ABBREVIATIONS ..................................................................................................10 
PROTOCOL SYNOPSIS ........................................................................................................13 
1. 
INTRODUCTION ................................................................................................21 
1.1. 
Disease Background .............................................................................................21 
1.2. 
GBT440 ................................................................................................................21 
1.3. 
Rationale for Study ...............................................................................................22 
1.4. 
Nonclinical Data ...................................................................................................22 
1.4.1. 
Nonclinical Pharmacology ....................................................................................23 
1.4.2. 
Safety Pharmacology ............................................................................................23 
1.4.3. 
Pharmacokinetics ..................................................................................................23 
1.4.4. 
Metabolism and Potential Drug Interactions ........................................................24 
1.4.5. 
Toxicology ............................................................................................................24 
1.5. 
Clinical Development of GBT440 ........................................................................24 
1.5.1. 
Safety Findings in Study GBT440-001 ................................................................25 
1.5.2. 
Pharmacokinetic Parameters .................................................................................25 
1.5.3. 
Dose Rationale ......................................................................................................26 
1.5.4. 
Potential Risk of GBT440 Treatment ...................................................................26 
1.5.5. 
Conclusions Based on Clinical Study Data ..........................................................27 
2. 
STUDY OBJECTIVES ........................................................................................28 
2.1. 
Primary Objective .................................................................................................28 
2.2. 
Secondary Objectives ...........................................................................................28 
2.3. 
Exploratory Objectives .........................................................................................28 
3. 
INVESTIGATIONAL PLAN ...............................................................................29 
3.1. 
Study Design .........................................................................................................29 
3.2. 
Endpoints ..............................................................................................................32 
3.2.1. 
Primary Endpoint ..................................................................................................32 


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3.2.2. 
Secondary Endpoints ............................................................................................32 
3.2.3. 
Exploratory Endpoints ..........................................................................................32 
4. 
STUDY POPULATION .......................................................................................33 
4.1. 
Inclusion Criteria ..................................................................................................33 
4.2. 
Exclusion Criteria .................................................................................................33 
5. 
STUDY PROCEDURES AND EVALUATIONS ...............................................36 
5.1. 
Subject Screening .................................................................................................36 
5.2. 
Avoidance of Pregnancy .......................................................................................36 
5.3. 
Clinical Assessments ............................................................................................37 
5.3.1. 
Medical History and Demographic Data ..............................................................37 
5.3.2. 
Physical Examination ...........................................................................................37 
5.4. 
Laboratory Examination .......................................................................................37 
5.4.1. 
Clinical Laboratory Studies ..................................................................................37 
5.5. 
Disease Related Evaluations .................................................................................39 
5.5.1. 
Spirometry and Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) ..39 
5.5.2. 
Oxygen Saturation ................................................................................................39 
5.5.3. 
6-Minute Walk Test (6MWT) ..............................................................................39 
5.5.4. 
Cardiopulmonary Exercise Testing (CPET) .........................................................40 
5.5.5. 
Patient Reported Outcome (PRO) Measures ........................................................40 
5.6. 
Pharmacokinetic Samples .....................................................................................42 
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 Treatment Discontinuation .........................................................................43 
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 


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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 ..................................................................................................48 
8.3.3. 
Pirfenidone or Nintedanib Background Therapy ..................................................48 
8.4. 
Treatment Overdose ..............................................................................................49 
8.5. 
Concomitant Medications .....................................................................................49 
8.5.1. 
Permitted therapy ..................................................................................................49 
8.5.2. 
Restricted Therapies .............................................................................................49 
8.5.3. 
Therapies for Treatment of IPF ............................................................................50 
8.6. 
Fertility/Contraceptive Requirements ...................................................................50 
8.6.1. 
Acceptable Forms of Contraception .....................................................................50 
9. 
RANDOMIZATION PROCEDURE ....................................................................52 
9.1. 
Blinding ................................................................................................................52 
10. 
SAFETY ASSESSMENTS ..................................................................................53 
10.1. 
Safety Monitoring Committee (SMC) ..................................................................53 
10.2. 
Adverse Events (AE) ............................................................................................53 
10.3. 
Recording Adverse Events ...................................................................................54 
10.4. 
Assessment of Adverse Events .............................................................................54 
10.4.1. 
Serious Adverse Event (SAE) ..............................................................................54 
10.4.2. 
Protocol-Defined Events of Special Interest .........................................................55 
10.4.3. 
Severity of Adverse Events ..................................................................................55 
10.4.4. 
Relationship to Study Drug ..................................................................................55 
10.4.5. 
Unexpected Adverse Reactions ............................................................................56 
10.5. 
Reporting Adverse Events ....................................................................................56 
10.5.1. 
Diagnosis versus Signs and Symptoms ................................................................56 
10.5.2. 
Adverse Events Occurring Secondary to Other Events ........................................56 
10.5.3. 
Persistent or Recurrent Adverse Events ...............................................................57 
10.5.4. 
Abnormal Laboratory Values ...............................................................................57 
10.6. 
Discontinuation due to Adverse Events ................................................................57 
10.7. 
Reporting Serious Adverse Events and Adverse Events of Special Interest ........57 
10.8. 
Choosing Adverse Event Terms ...........................................................................58 


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10.9. 
Pregnancy .............................................................................................................58 
11. 
DATA ANALYSIS AND STATISTICAL PLANS .............................................60 
11.1. 
Sample Size ..........................................................................................................60 
11.2. 
Populations for Analysis .......................................................................................60 
11.2.1. 
Primary Endpoint ..................................................................................................60 
11.2.2. 
Secondary endpoints .............................................................................................60 
11.2.3. 
Pharmacokinetics ..................................................................................................61 
11.3. 
Analyses ................................................................................................................61 
11.3.1. 
Safety Data ............................................................................................................61 
11.3.2. 
Efficacy Data ........................................................................................................61 
11.3.3. 
PK Data .................................................................................................................61 
12. 
REGULATORY, ETHICAL AND LEGAL OBLIGATIONS ............................63 
12.1. 
Ethical Consideration ............................................................................................63 
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 .................................................................................................63 
12.6. 
Confidentiality ......................................................................................................64 
12.7. 
Trial Documentation and Data Storage ................................................................64 
12.8. 
Study Record Retention ........................................................................................64 
12.9. 
Disclosure of Information .....................................................................................65 
12.9.1. 
Publication ............................................................................................................65 
13. 
ADMINSTRATIVE OBLIGATIONS ..................................................................66 
13.1. 
Source Data ...........................................................................................................66 
13.2. 
Data Collection .....................................................................................................66 
13.3. 
Monitoring ............................................................................................................66 
13.4. 
Quality Control and Quality Assurance ................................................................66 
14. 
REFERENCES .....................................................................................................67 
15. 
APPENDICES ......................................................................................................69 
Appendix A SCHEDULE OF STUDY ASSESSMENTS ....................................................70 
Appendix B Strong Inducers of cyp ISOenzymes ................................................................73 


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LIST OF TABLES 
Table 1 
CYP Substrates with Narrow Therapeutic Range ................................................50 
Table 2 
Grading for Adverse Events not Covered in the NCI-CTCAE ............................55 
 
LIST OF APPENDICES 
Appendix A SCHEDULE OF STUDY ASSESSMENTS ....................................................70 
Appendix B Strong Inducers of CYP ISOenzymes ..............................................................73 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AT 
Anaerobic threshold 
ATS  
American Thoracic Society 
ATAQ 
A Tool to Assess Quality of Life (ATAQ) in IPF 
AUC 
Area under the concentration time curve 
AUC(0-inf) 
Area under the concentration-time curve from zero extrapolated to infinity 
AUC(0-inf)/D 
Dose-normalized AUC(0-inf) 
AUC(0-last) 
Area under the concentration-time curve from time zero to the time of last 
quantifiable analyte concentration 
AUC(0-tau) 
Area under the concentration-time curve during a dosing interval 
AUC(0-tau)/D 
Dose-normalized AUC(0-tau) 
BP 
Blood Pressure  
BUN 
Blood urea nitrogen 
CL 
Clearance 
Cmax 
Maximum concentration 
Cmax/D 
Dose-normalized Cmax 
Cmin 
Minimum concentration 
CNS 
Central nervous system 
CPET 
Cardiopulmonary Exercise Testing 
CRA 
Clinical research associate 
CRF 
Case Report Form 
CrCl 
Creatinine clearance 
CRO 
Contract research organization 
CV 
Coefficient of variation 
CYP 
Cytochrome 
DLCO 
Diffusing Capacity of the Lung for Carbon Monoxide 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
FEV1 
Forced expiratory volume in 1 second 


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FVC 
Forced vital capacity 
GBT 
Global Blood Therapeutics 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase 
Hb 
Hemoglobin 
HbA 
Adult hemoglobin 
HbS 
Hemoglobin S 
HbsAg 
Hepatitis B surface antigen 
β HCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C virus 
hERG 
Human Ether-à-go-go-Related Gene 
HIV 
Human immunodeficiency virus 
HV 
Healthy volunteers 
HR 
Heart rate 
HRR 
Heart rate recovery 
HRRes 
Heart rate reserve 
IB 
Investigator Brochure 
ICF 
Informed consent form 
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 
LC-MS 
Liquid chromatography-tandem mass spectrometry 
MDRD eGFR 
Modification of diet in renal disease estimate glomerular filtration rate 
MedDRA 
Medical dictionary for regulatory activities 
6MWT 
6-minute walk test 
NAC 
N-acetylcysteine 
OEC 
Oxygen equilibrium curve 
P20 
Partial pressure of oxygen at which hemoglobin is 20% saturated 


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p50 
Partial pressure of oxygen at which hemoglobin is 50% saturated 
PD 
Pharmacodynamic 
PDE 
phosphodiesterase  
PK 
Pharmacokinetic 
PRO 
Patient reported outcome 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
ODC 
Oxy-hemoglobin dissociation curve 
QTcF 
Corrected QT interval using the Fridericia formula 
RBC 
Red blood cell 
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 
SMC 
Safety Monitoring Committee 
SpO2 
Peripheral capillary oxygen saturation 
t1/2 
Apparent terminal half life 
tmax 
Time of maximum concentration 
tmin 
Time of minimum concentration 
UCSD SOBQ 
University of California, San Diego Shortness of Breath Questionnaire 
ULN 
Upper limit of normal 
VAS 
Visual analog scale 
VE/VCO2 slope 
Slope of relation between minute ventilation and CO2 production 
VO2 peak 
Peak oxygen consumption 
VO2 peak/kg 
Peak oxygen consumption/kg 
Vss 
Volume at steady state 
WBC 
White blood cell 
z 
Apparent terminal rate constant 
 


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PROTOCOL SYNOPSIS 
Protocol Title 
A Phase II randomized, placebo-controlled study of GBT440 to evaluate 
the safety, tolerability, pharmacokinetics and effect on hypoxemia in 
subjects with Idiopathic Pulmonary Fibrosis (IPF) 
Protocol Number 
GBT440-006 
Sponsor  
Global Blood Therapeutics 
400 East Jamie Court Suite #101 
South San Francisco, CA 94080 
Study Drug 
GBT440 capsules: 300 mg strength, administered orally.  
Matching placebo, administered orally. 
Objectives 
Primary 
 
To evaluate the safety and tolerability of multiple doses of GBT440 
administered to subjects with IPF.  
Secondary 
 
To evaluate the effect of GBT440 on oxygen saturation at Days 15 
and 28 compared to baseline during 6-minute walk testing 
(6MWT).  
 
To evaluate the pharmacokinetic (PK) parameters of GBT440 in 
plasma and whole blood. 
Exploratory 
 
To evaluate the effect of GBT440 on distance walked during the 
6MWT at Days 15 and 28 compared to baseline. 
 
To evaluate the effect of GBT440 on IPF-related symptoms using 
patient reported outcomes (PROs) at Day 28 compared to baseline. 
 
To evaluate the effect of GBT440 on cardiopulmonary exercise 
testing (CPET) parameters at Day 29 compared to baseline. 
 
To evaluate pulmonary function, including assessment of 
spirometry and Diffusing Capacity of the Lung for Carbon 
Monoxide (DLco) at Day 28 compared to baseline. 
 
To evaluate the PK-pharmacodynamic (PD) relationship of 
GBT440 at Days 15 and 28 compared to baseline. 
Study Design 
This study is a randomized, placebo-controlled trial that will be conducted 
in two parts. Together, Parts A and B will provide safety and efficacy data 
across a range of GBT440 doses that are expected to improve oxygen 
saturation in the enrolled subjects. 
 
In Part A, eligible IPF subjects will be randomized 1:1:1 to receive 
GBT440 900 mg (n = 6) or 600 mg (n = 6), or placebo (n = 6) 
administered orally as 300 mg capsules once daily for 28 days. The 
study site, subjects and Sponsor will be blinded to study treatment.  
 
In Part B eligible IPF subjects will be randomized 3:1:1 to receive 
GBT440 1500 mg (n = 9) or 600 mg (n = 3), or placebo (n = 3) 
administered orally as 300 mg capsules once daily for 28 days in 


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which the study site and subjects are blinded to study treatment. The 
Sponsor will be unblinded to study treatment. 
Subjects will participate in the study for approximately 79 days: screening 
(up to 21 days), treatment period (28 days) and follow-up period (30 days) 
with a total of 9 study site visits.  
The screening period for each subject commences when the subject 
undergoes the first study-specific screening assessment and must be 
completed and evaluated before randomization (Day 1).  
Subjects may be rescreened up to two times, if deemed appropriate by the 
Principal investigator. The rescreening visit should not occur sooner than 
10 calendar days after the failed screening visit. 
Patients on a stable dose of pirfenidone or nintedanib and/or N-acetyl 
cysteine at screening are eligible for entry into the study. 
A Safety Monitoring Committee (SMC) is planned to review all safety 
data on an ongoing basis throughout the study. If the SMC does not 
identify any clinically significant safety concerns in Part A, following 
review of data from approximately 18 subjects who have completed Day 
15, the Sponsor will initiate Part B of the study and randomise up to an 
additional 15 subjects, to the three study treatment arms to better 
characterize the safety, tolerability and/or potential treatment response of 
GBT440 in subjects with IPF. 
The dose levels predicted to achieve the hemoglobin (Hb) modification 
targets of ~20% to ~50% in IPF subjects are based on clinical PK and PD 
data from study GBT440-001. Dose levels of 600 mg or 900 mg per day 
administered to healthy subjects for 15 days resulted in a mean Hb 
modifications of 24% and 38%, respectively. A dose level of 300 mg per 
day resulted in a mean Hb modification of 11%, which is below the PD 
effect that showed benefit in animal models of hypoxemia. A dose of 
1500 mg is expected to achieve a Hb modification target of ~50%.  
Part A Treatment: 
• GBT440 900 mg: 3 GBT440 300 mg capsules. 
• GBT440 600 mg: 2 GBT440 300 mg capsules and 1 placebo 
capsule.  
• Placebo: 3 placebo capsules. 
Part B Treatment: 
• GBT440 1500 mg: 5 GBT440 300 mg capsules 
• GBT440 600 mg: 2 GBT440 300 mg capsules and 3 placebo 
capsules.  
• Placebo: 5 placebo capsules. 
In Part A two unblinded interim analyses of the primary and secondary 
endpoints are planned: i) when approximately 9 subjects have completed 
their Day 28 study visit and ii) when approximately 18 subjects have 
completed their Day 15 study visit. 


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Number of 
Subjects 
In Part A, a total of approximately 18 subjects will be randomized 1:1:1 to 
either: 900 mg GBT440, 600 mg GBT440 or placebo.  
In Part B, up to an additional 15 subjects will be randomized 3:1:1 to 
either: 1500 mg GBT440, 600 mg GBT440 or placebo.  
Replacement of 
Subjects 
Subjects who do not complete at least 10 days of dosing for reasons 
unrelated to toxicity may be replaced. 
Number of Centers 
The study will be conducted at approximately 10–15 clinical sites in the 
United States 
Duration of Study 
Participation 
Approximately 79 days, including screening, treatment and follow-up 
periods 
Study Population 
Inclusion Criteria 
1. Able and willing to provide signed informed consent to participate in 
this study. 
2. Documented diagnosis of IPF, as indicated in the 
ATS/ERS/JRS/ALAT 2011 guidelines. 
3. Adult males or females aged 45-80 years inclusive at randomization 
4. Oxygen saturation (SpO2) ≥ 88 % by pulse oximetry while breathing 
room air at rest 
5. Oxygen saturation (SpO2) <88% and at least a 5% absolute decrease 
during the baseline 6-minute walk test (6MWT) which is sustained for 
at least 10 seconds 
6. Able to walk at least 100 meters at completion of the baseline 6 MWT 
7. Weight ≥ 40 kg 
8. Subject is seronegative for recent hepatitis A (IgM anti-HAV), 
hepatitis B surface antigen (HBsAg), hepatitis C (HCV) antibody 
(anti-HCV), and human immunodeficiency virus antibody (anti-HIV) 
within 3 months of screening. 
9. Able, in the Investigator’s opinion, to complete the 6MWT unassisted 
at baseline and Day 15 and Day 28 and comply with the study 
procedures, including attending all assessment visits and adhering to 
all study requirements and restrictions. 
10. Male or female of child bearing potential willing and able to use 
highly effective methods of contraception from study start to 3 months 
after the last dose of study drug. 
Exclusion Criteria 
1. FEV1/FVC <70%. 
2. Requires supplemental oxygen therapy at rest.  
3. History of other interstitial lung diseases including but not limited to 
radiation, drug toxicity, sarcoidosis, hypersensitivity pneumonia, 
bronchiolitis obliterans, organizing pneumonia. 
4. History of clinically significant environmental exposure known to 
cause pulmonary fibrosis including but not limited to drugs (e.g., 
methotrexate or amiodarone), asbestos, beryllium, radiation and 
domestic birds. 


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5. History of other medical conditions that are known or may result in 
interstitial lung disease. For example, any connective tissue disease 
including but not limited to scleroderma, 
polymyositis/dermatomyositis, systemic lupus erythematosus and 
rheumatoid arthritis. 
6. AST, ALT or total Bilirubin >2 × ULN.  
7. Creatinine Clearance (CrCl) <30 mL/min/1.73 m2, calculated using 
the Modification of Diet in Renal Disease estimated Glomerular 
Filtration Rate (MDRD eGFR). 
8. Significant polycythemia defined as hemoglobin value >18 mg/dL.  
9. ECG with a QTcF >450 ms (males) or QTcF >470 ms (females). If 
ventricular pacing is noted on ECG, then QTcF intervals will not be 
calculated.  
10. Family or personal history of congenital long QT syndrome. 
11. Female who is breast-feeding or pregnant. 
12. 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, or Stage 1 uterine cancer.  
13. Subject has used any of the following therapies within 30 days of 
screening: 
 
Any cytotoxic, immunosuppressive or cytokine-modulating 
therapy including but not limited to: azathioprine, bosentan, 
ambrisentan, cyclophosphamide, cyclosporine, etanercept, 
iloprost, infliximab, leukotriene antagonists, methotrexate, 
mycophenolate, tacrolimus  
 
Imatinib mesylate, interferon gamma-1b, tyrosine kinase 
inhibitors (excluding nintedanib) 
14. Pulmonary hypertension requiring active therapy including but not 
limited to endothelin receptor inhibitors or PDE inhibitors (e.g., 
sildenafil, tadalafil).  
 
Note: intermittent use of a PDE inhibitor for erectile dysfunction 
may be allowed after approval by the Medical Monitor. 
15. Hospitalization due to an exacerbation of IPF within 30 days of 
screening 
16. Subject plans to begin or has commenced pulmonary rehabilitation 
within 30 days of screening 
 
Subjects 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 
17. Corticosteroids (>10 mg per day of prednisone or an equivalent) 
within 30 days of screening. 


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18. Current smoker (including use of eCigarettes or vaporizing) or history 
of smoking within 3 months from screening. 
19. Clinical evidence of active infection, including but not limited to 
bronchitis, pneumonia, sinusitis, urinary tract infection or cellulitis, 
within 14 days of screening 
20. Active tuberculosis requiring treatment within the last 12 months 
 
Testing for latent tuberculosis is not required 
21. Currently or, in the opinion of the investigator, soon to be listed for 
lung transplant.  
22. History of unstable or deteriorating cardiac or pulmonary disease 
(other than IPF) within 6 months of screening including but not 
limited to the following: 
 
Unstable angina pectoris or myocardial infarction or elective 
coronary intervention 
 
Congestive heart failure requiring hospitalization 
 
Uncontrolled clinically significant arrhythmias 
23. Any condition possibly affecting drug absorption, such as previous 
surgery on the stomach or small intestine. 
24. 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). 
25. Known hypersensitivity to any component of the study drug. 
26. Subject who, for any reason, is deemed by the investigator to be 
inappropriate for this study; or has any condition (such as addictive or 
psychosocial issues) which would confound or interfere with the 
evaluation of the safety, tolerability, or PK of the investigational drug; 
or is unable to comply with the study protocol. 
27. 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 
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 (collected in triplicate), safety labs, urinalysis, concomitant 
medication usage and adverse event monitoring.  


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Safety laboratory assessments include: hematology, serum chemistry, 
urinalysis, coagulation panel, Hepatitis A, B, C and HIV serologies and 
pregnancy tests. 
Clinical Assessments 
Spirometry and Diffusing Capacity of the Lung for Carbon Monoxide 
(DLco) Measurements 
All equipment, procedures, and personnel qualifications for the assessment 
of lung function are based on the recommendations of the American 
Thoracic Society (ATS 2005) and will be performed at each site using 
local equipment. Spirometry measurements will include FVC, FEV1 and 
flow-volume loops. Pre and 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 
Oxygen Saturation 
During screening and with all scheduled vital sign assessments resting, 
room air oxygen saturation (SpO2) will be measured by pulse oximetry 
(provided by the Sponsor) whilst the subject is seated and resting for at 
least 5 minutes. 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 resting.  
SpO2 will be also be collected as part of the 6MWT and during cardio-
pulmonary exercise testing. 
6-Minute Walk Test (6MWT) and Borg Scale of Perceived Exertion 
Functional exercise capacity will be evaluated at baseline, Days 15, 28 and 
58 using the 6-minute walk test. The 6MWT will be performed without 
the subject using supplementary oxygen. Oxygen may be used at any time 
during the 6MWT, if in the opinion of the Investigator or testing 
technician it is required for safety reasons. The 6MWT should then be 
stopped. 
Guidelines developed by the ERS/ATS will be used for conducting the test 
and interpreting the results (ATS 2002 and Holland 2014).  
As part of the 6MWT SpO2, heart rate and the Borg dyspnea scale will be 
measured prior to starting the test, during the test, at completion of the 
test, 1 minute and 2 minutes after test completion.  
Cardiopulmonary Exercise Testing (CPET) 
Symptom-limited cardiopulmonary exercise testing using a bicycle 
ergometer will be performed at baseline and Day 29. At baseline and 
during the exercise period the collected data will include but is not limited 
to: SpO2 and arterial blood gases, VO2 max, ventilation and lactate 
thresholds. Guidelines developed by ATS and American College of Chest 
Physicians will be used for conducting the test and interpreting the results 
(ATS 2003). 
St George’s Respiratory Questionnaire (SGRQ) 
The SGRQ is a symptom-specific 2-part, subject self-administered 
questionnaire that assesses shortness of breath while doing a variety of 
activities of daily living. This questionnaire comprises three domains: 
symptoms, activity and impact. Paper questionnaires will be provided to 


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sites prior to subject enrollment 
University of California, San Diego Shortness of Breath Questionnaire 
(UCSD) 
The UCSD is a 24-item assessment of breathlessness associated with 
various activities of daily living. The response for each item is measured 
on a 5-point Likert scale from 0 (none at all) to 5 (maximal or unable to 
perform). Refer to the Procedure Manual for a copy of the questionnaire. 
Paper questionnaires will be provided to sites prior to subject enrollment. 
Borg Dyspnea Scale 
The Borg Dyspnea scale is a one-item assessment, self-administered by 
the patient administered as part of the 6 MWT. The instrument will be 
used to assess dyspnea from the patient’s perspective. The Scale ranges 
from 0 (Nothing at all) to 10 (Absolute maximum/Highest possible). See 
Procedure Manual for a copy of the assessment. A paper scale will be 
supplied to sites prior to subject enrollment. 
A Tool to Assess Quality of Life (ATAQ) in IPF 
ATAQ questionnaires (IPF Symptoms Questionnaire and IPF Impacts 
Questionnaire) will be administered in Part B of this study. 
End of Study Questionnaire 
The end of study questionnaire is an 8-item 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 58 visit. The survey is to be completed by subjects enrolled 
under Part B of the trial. 
Visual Analog Scale (VAS) for Cough Severity 
Cough will be assessed using a VAS in which the subject will indicate the 
severity of their cough by drawing a mark on a 100 mm scale, which 
ranges from 0 - “no cough” to 100 mm - “worst cough severity”. A paper 
scale will be supplied to sites prior to subject enrollment.  
Pharmacokinetic Assessments 
Plasma and whole blood concentrations of GBT440 will be measured. PK 
samples will be collected at the following times: on Days 1 and 28: 
pre-dose, and 2 hours post dose (+/- 15 minutes); Day 2: 24 hours (+/- 2 
hours) after the Day 1 dose and prior to receiving the Day 2 dose; Days 8 
and 15: pre-dose only; during follow-up on Days 45 and 58. 
Restricted 
Concomitant 
Therapy 
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 (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 (e.g., 
alfentanil, dihdroergotamine, ergotamine, fentanyl, pimozide, 
quindine; GBT440 may increase the plasma concentration of these 
medications) 


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Note: based on results from the drug-drug interaction studies, 
co-administration of GBT440 with pirfenidone or nintedanib is considered 
to be acceptable. 
Statistical Methods 
Sample Size 
The sample size in this study was not selected based on statistical 
considerations but to determine preliminary safety, tolerability, PK, 
laboratory and clinical effects of GBT440 in IPF subjects.  
Study Endpoints 
Primary Endpoint 
 
Treatment-emergent adverse events and tolerability. 
Secondary Endpoints 
 
Change and percentage change from baseline in resting SpO2 at Days 
15 and 28 measured prior to beginning the 6MWT.  
 
Change and percentage change from baseline in end-of-6MWT SpO2 
at Days 15 and 28.  
 
Change and percentage change from baseline in lowest SpO2 value 
measured during the 6MWT at Days 15 and 28. 
 
Pharmacokinetic (PK) parameters of GBT440 in plasma and whole 
blood, including but not limited to maximum concentration (Cmax), 
minimum concentration (Cmin) at steady state in GBT440 treated 
subjects. 
Exploratory Endpoints 
 
Change and percentage change from baseline in distance walked 
during the 6MWT at Days 15 and 28. 
 
Time to first SpO2 <88% that is sustained for at least 10 seconds 
during the 6MWT at Days 15 and 28.  
 
Area under the SpO2 curve (AUC) during the 6MWT measured at 
baseline, Day 15 and Day 28. 
 
Change from baseline in PRO scores using SGRQ, UCSD, ATAQ 
(only subjects enrolled in Part B) and the Borg Scale of Perceived 
Exertion questionnaires and cough VAS at Days 15 and 28. 
 
Change and percentage change from baseline in cardiopulmonary 
exercise testing parameters at Day 29.  
 
Change and percentage change from baseline in lung function, 
including FVC and DLCO at Day 28. 
 PK/PD relationship in subjects receiving GBT440 from Baseline to 
Day 15 and Day 28. 


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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 
3-5 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 50-80 years, with a median age of 65 at diagnosis [Raghu 2006]. The 
natural course of IPF is variable. As the interstitial fibrosis and architectural distortion 
advance, the lung becomes increasingly non-compliant, and the work of breathing and 
dyspnea increase. The lungs lose their ability to transfer oxygen into the bloodstream 
resulting in hypoxemia, tissue hypoxia, and ultimately organ dysfunction and symptoms. 
Subjects with IPF typically experience slowly progressive worsening of lung function over 
time, with the development of significant co-morbidities, the use of supplemental oxygen and 
frequent hospitalizations in the late stage of the disease [Raghu 2011]. Supplemental oxygen 
relieves dyspnea, prevents secondary pulmonary hypertension and improves functional 
status, but requires equipment for oxygen administration which can limit patient mobility and 
quality of life. 
There are two marketed products available for the treatment of IPF, nintedanib and 
pirfenidone which were added to the American Thoracic Society treatment recommendations 
in 2015 [Raghu 2015]. In clinical studies, these products demonstrated an effect on forced 
vital capacity and decline in lung function, but did not show an effect on survival or disease 
modification. Furthermore, these therapies do not improve hypoxemia nor did they clearly or 
consistently improve disease symptoms such as dyspnea [Richeldi 2014, King 2014]. IPF 
remains a disease with high unmet medical need requiring novel therapies that address not 
only the underlying fibrosis but also secondary co-morbidities and that provide improvement 
in the 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 Hb α chain, and thus has the 
same pharmacodynamics effect on normal adult hemoglobin (HbA) than on sickle 
hemoglobin (HbS). In SCD, GBT440’s effect on HbS was expected to decrease red blood 
cell sickling, which was confirmed in preliminary Phase I/II data [Lehrer-Graiwer 2015]. 
Likewise for IPF, GBT440’s effect on HbA is expected to increase oxygen uptake in the 
lungs, improve hypoxemia and oxygen delivery to tissues and in turn provide significant 
benefit to IPF patients. 
In IPF, hypoxemia results from ventilation-perfusion mismatch and inefficient gas exchange 
at the alveolar-capillary barrier. The resultant reduced oxygen saturation (SpO2) leads to 


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insufficient oxygen delivery to tissues and tissue hypoxia, and in turn numerous adverse 
systemic effects including exercise intolerance with associated desaturation and pulmonary 
hypertension. As demonstrated by the use of supplemental oxygen therapy, improving 
oxygenation clearly provides clinical benefit; with improvement in dyspnea, functional 
capacity, quality of life, and prevention of disease associated complications. [Eaton. 2004] 
Based on it’s mechanism of action, GBT440 is expected to increase Hb-O2 saturation at low 
alveolar oxygen tensions and provide similar benefit to patients with IPF. 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. [Eaton 1974, 
Yalcin and Cabrales 2012] Based on these observations and its ability to safely increase Hb 
oxygen affinity in humans (both healthy subjects and patients with SCD in the ongoing 
GBT440-001 study), GBT440 may improve arterial oxygenation, tissue oxygen delivery, 
symptoms and functional status in subjects with IPF.  
1.3. 
Rationale for Study 
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 O2 
saturation, resulting in improved oxygen delivery to tissues. A key therapeutic goal for IPF 
patients with GBT440 is to reduce hypoxemia and improve the associated debilitating 
symptoms and functional impairment. Supplemental oxygen therapy is a well-established 
treatment in IPF and other chronic hypoxemic pulmonary diseases where it improves 
symptoms, functional status and (in the case of Chronic Obstructive Pulmonary Disease) 
improves survival. Supplemental oxygen therapy has disadvantages, however, which can 
negatively impact patient quality of life including the burden and decreased mobility from 
the required oxygen delivery devices, local complications, poor compliance and inadequate 
symptomatic relief. GBT440 therapy may be able to provide many of the same clinical 
benefits of oxygen therapy without the negative aspects of oxygen supplementation. GBT440 
could also be useful as an adjunct to oxygen therapy in more severe subjects who are not 
adequately oxygenated despite noninvasive oxygen therapy or to allow the use of lower flow, 
more convenient oxygen equipment for the same clinical benefit. This study will gather 
preliminary data, across a range of GBT440 doses, to determine whether GBT440 could 
improve: oxygen saturation at rest and with exercise, IPF-related symptoms and exercise 
capacity. 
GBT440 has been administered to healthy subjects and subjects with SCD. Overall, multiple 
doses of GBT440 have been well tolerated across a broad range of doses (300 mg–1000mg) 
for up to 90 days. Results from this study will inform future development of GBT440 in IPF 
subjects. 
1.4. 
Nonclinical Data 
An overview of the key nonclinical data is provided below. For a more detailed discussion of 
the nonclinical pharmacology, pharmacokinetic (PK) and toxicology studies conducted to 
date, please refer to the GBT440 Investigator’s Brochure (IB). 


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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 hemoglobin 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. These in vivo studies demonstrated that 
pharmacologically increasing Hb-O2 affinity in these mouse models of pulmonary 
hypoxemia resulted in improved O2 saturation, translating into improved physiologic 
endpoints and survival. 
1.4.2. 
Safety Pharmacology 
Safety assessments of GBT440 in three 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. 
Pharmacokinetics 
Pharmacokinetic (PK) evaluation 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.  


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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. 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 to date have been conducted primarily in healthy subjects and subjects with 
SCD. They include an ongoing Phase I/II study (GBT440-001), Phase II adolescent SCD 
study (GBT440-007) and 8 (4 complete and 4 ongoing) Phase I clinical pharmacology 
studies in healthy subjects. GBT440 is also being evaluated in an ongoing Phase II study in 
IPF subjects using oxygen at rest (GBT440-026). 
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 of GBT440 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 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.  
The eight clinical pharmacology studies (GBT440-002, GBT440-003, GBT440-004, 
GBT440-005, GBT440-008, GBT440-017, GBT440-018 and GBT440-019) are evaluating 
the absorption, metabolism, excretion, food effect, relative bioavailability and drug-
drug- interactions (DDI) of GBT440. 
The Phase II IPF study (GBT440-026) is an open label trial evaluating the safety of GBT440 
and its effects on oxygen saturation and supplemental oxygen requirements in IPF subjects 
who use oxygen at rest. GBT440 is being dosed at 900 mg orally daily for 90 days.  
Please refer to the GBT440 IB for additional details regarding GBT440 development and all 
clinical studies. 


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1.5.1. 
Safety Findings in Study GBT440-001 
To date, GBT440 has been well tolerated over a range of doses administered to healthy and 
SCD subjects, for up to 90 days.  
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.  
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); one event of presumed infection with hemolysis (Grade 2) 
(GBT440); one event of an ovarian cyst (Grade 3), occurring after the last dose of study drug 
(GBT440) and one 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 Cmax and AUC increased proportionally with 
study drug dose for both single or multiple doses. 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 GBT440 doses for investigation in IPF patients is based on 
pharmacodynamic (PD) targets that are expected to correspond to an increase in Hb-O2 
affinity which may result in a clinically significant increase in oxygenation. These PD targets 
are derived from data from three nonclinical pharmacology studies that included a hypoxia 
challenge model and two models of pulmonary hypoxemia (refer to the IB for details of these 
studies). Based on the in vivo data the lower limit for treatment response during exercise-
induced desaturation is expected to be ~20% Hb occupancy by GBT440.  
The dose levels predicted to achieve the Hb modification targets of ~20% to ~50% in IPF 
subjects are based on clinical PK and PD data from study GBT440-001. Dose levels of 
600 mg or 900 mg per day administered to healthy subjects for 15 days resulted in a mean Hb 
modifications of 24% and 38%, respectively. A dose level of 300 mg per day resulted in a 
mean Hb modification of 11%, which is below the PD effect that showed benefit in animal 
models of hypoxemia.  
The safety of the proposed doses of 600 mg and 900 mg in the initial cohort (Part A) of 
approximately 18 subjects and the safety of pursuing parallel dosing in this study are based 
on the totality of available nonclinical and clinical safety data. The expansion Cohort (Part B) 
of 15 subjects will have 3 dose arms: 1500 mg, 600 mg and placebo. Addition of a higher 
dose is supported by: the acceptable safety profile collected from the Part A subjects dosed to 
date in this study; review by the Safety Monitoring Committee of safety data from 
12 subjects who completed up to 28 days and 16 subjects who completed 15 days of dosing 
in Part A and Safety Monitoring Committee agreement to proceed with the evaluation of 
GBT440 1500 mg; continued favorable safety profile in ongoing studies evaluating GBT440 
in subjects with SCD, including continued dosing for up to 6 months; and an anticipated 
dose-dependent improvement in oxygen saturation. Guidelines for the safety review of Part 
A and Part B of the trial are outlined in the Safety Monitoring Committee section (Section 
10.1). 
1.5.4. 
Potential Risk of GBT440 Treatment 
1.5.4.1. 
Tissue Hypoxia 
There is a theoretical risk of tissue hypoxia in subjects treated with GBT440 based on the 
mechanism of action and potential associated 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 as measured by erythrocytosis, increased resting heart rate and erythropoietin 
and laboratory tests indicating organ injury (e.g. liver aminotransferases). To date, none of 
these findings have been documented in Part A subjects dosed in this study. 


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1.5.5. 
Conclusions Based on Clinical Study Data 
The emerging experience from clinical studies in healthy volunteers, SCD and approximately 
16 IPF subjects from Part A of this study (reviewed by the SMC), having received GBT440 
across a wide range of doses, has shown that GBT440 is well tolerated and no clinically 
significant safety signal has been identified. Based on these results it is anticipated that 
GBT440 will have favorable benefit-to-risk profile in IPF subjects, enrolled in both Parts A 
and B of this study. 
The steady-state exposure and PD effect, which are predicted for the 600 mg and 900 mg 
dose levels in Part A, have been demonstrated to be safe and tolerated in the healthy subjects 
treated with GBT440 for 15 days in the Phase I/II study (GBT440-001). The 1500 mg dose to 
be included in Part B is supported by the safety profile of the subjects in the 600 mg and 900 
mg dose arms in this study and an anticipated dose-dependent improvement in oxygen 
saturation. Furthermore, safety experience in SCD subjects treated for 90 days supports the 
proposed 28 day treatment duration in IPF subjects. 
 


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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
To evaluate the safety and tolerability of multiple doses of GBT440 administered to subjects 
with IPF  
2.2. 
Secondary Objectives 
• To evaluate the effect of GBT440 on oxygen saturation at Days 15 and 28 compared to 
baseline during the 6-minute walk testing (6MWT). 
• To evaluate the pharmacokinetic (PK) parameters of GBT440 in plasma and whole 
blood. 
2.3. 
Exploratory Objectives 
 To evaluate the effect of GBT440 on distance walked during the 6MWT at Days 15 and 
28 compared to baseline. 
 To evaluate the effect of GBT440 on IPF-related symptoms using patient reported 
outcomes (PROs) at Day 28 compared to baseline. 
 To evaluate the effect of GBT440 on cardiopulmonary exercise testing parameters at 
Day 29 compared to baseline. 
 To evaluate pulmonary function, including assessment of spirometry and Diffusing 
Capacity of the Lung for Carbon Monoxide (DLco) at Day 28 compared to baseline. 
 To evaluate the PK-PD relationship of GBT440 at Days 15 and 28 compared to baseline. 


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3. 
INVESTIGATIONAL PLAN 
3.1. 
Study Design 
This study is a randomized, placebo-controlled trial that will be conducted in two parts. 
Together, Parts A and B will provide safety and efficacy data across a range of GBT440 
doses that are expected to improve oxygen saturation in the enrolled subjects. 
 In Part A (Figure 1) eligible IPF subjects will be randomized 1:1:1 to receive GBT440 
900 mg (n = 6) or 600 mg (n = 6), or placebo (n = 6) administered orally as 300 mg 
capsules once daily for 28 days. The study site, subjects and Sponsor will be blinded to 
study treatment.  
 In Part B (Figure 2) eligible IPF subjects will be randomized 3:1:1 to receive GBT440 
1500 mg (n = 9) or 600 mg (n = 3), or placebo (n = 3) administered orally as 300 mg 
capsules once daily for 28 days in which the study site and subjects are blinded to study 
treatment. The Sponsor will be unblinded to study treatment. 
A signed and dated informed consent form (ICF) must be obtained before any screening 
procedures or 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 
randomization (Day 1). Subjects may be rescreened up to two times, if deemed appropriate 
by the Principal investigator. The rescreening visit should not occur sooner than 10 calendar 
days after the failed screening visit. 
Patients on a stable dose of pirfenidone or nintedanib and/or N-acetyl cysteine are eligible for 
entry into the study. 
After the Screening visit the study includes the following study periods:  
• Treatment period (28 days): subjects will be randomized (1:1:1) to one of three treatment 
groups in Part A (Figure 1) and randomized (3:1:1) to one of three treatment groups in 
Part B (Figure 2); subjects will receive:  
Part A: 
- 
Group 1: GBT440 900 mg; three 300 mg GBT440 capsules, daily orally.  
- 
Group 2: GBT440 600 mg; two 300 mg GBT440 capsules and one placebo capsule, 
daily orally. 
- 
Group 3: Placebo: three placebo capsules, daily orally. 
Part B: 
- 
Group 1: GBT440 1500 mg; five, 300 mg GBT440 capsules, daily orally.  
- 
Group 2: GBT440 600 mg; two 300 mg GBT440 capsules and three placebo capsule, 
daily orally. 
- 
Group 3: Placebo: five placebo capsules, daily orally. 
• Safety follow up (30 days): safety will be assessed for at least 5 half-lives after the last 
dose of GBT440. 


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Figure 1 
Study Design – Part A 
 
Figure 2 
Study Design – Part B 
 
Subjects who do not complete at least 10 days of dosing for reasons unrelated to toxicity may 
be replaced. 
In Part A, two unblinded interim analyses of the primary and secondary endpoints are 
planned: i) when approximately 9 subjects have completed their Day 28 study visit and ii) 
when approximately 18 subjects have completed their Day 15 study visit.  
A Safety Monitoring Committee (SMC) is planned to review all safety data on an ongoing 
basis throughout the study (refer to Section 10.1). If the SMC does not identify any clinically 
significant safety concerns in Part A, following review of data from approximately 18 
subjects who have completed Day 15, the Sponsor will initiate Part B of the study and 
randomise up to an additional 15 subjects, to the three study treatment arms to better 


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characterize the safety, tolerability and/or potential treatment response of GBT440 in subjects 
with IPF.  
In the eventuality that one treatment arm is discontinued, subjects may be randomised 1:1 to 
the remaining study drug treatment group or placebo. Therefore, the trial size is 
approximately 33 subjects. 
The end of the study is defined as the date when the last patient last visit occurs, which is 
expected to be approximately 58 days after the last patient is randomised. 
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. 
 
 


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3.2. 
Endpoints 
3.2.1. 
Primary Endpoint 
The primary endpoint is treatment-emergent adverse events and tolerability. 
3.2.2. 
Secondary Endpoints 
• Change and percentage change from baseline in resting SpO2 at Days 15 and 28 
measured prior to beginning the 6MWT.  
• Change and percentage change from baseline in end-of-6MWT SpO2 at Days 15 and 28.  
• Change and percentage change from baseline in lowest SpO2 value measured during the 
6MWT at Days 15 and 28.  
• Pharmacokinetic (PK) parameters of GBT440 in plasma and whole blood, including but 
not limited to maximum concentration (Cmax), minimum concentration (Cmin) at steady 
state in GBT440 treated subjects. 
3.2.3. 
Exploratory Endpoints 
• Change and percentage change from baseline in distance walked during the 6MWT at 
Days 15 and 28. 
• Time to first SpO2 <88% that is sustained for at least 10 seconds during the 6MWT at 
Days 15 and 28.  
• Area under the SpO2 curve (AUC) during the 6MWT measured at baseline, Day 15 and 
Day 28. 
• Change from baseline in PRO scores using SGRQ, UCSD, A Tool to Assess Quality of Life 
(ATAQ) in IPF (only subjects enrolled in Part B), and the Borg Scale of Perceived 
Exertion questionnaires and cough VAS at Days 15 and 28. 
• Change and percentage change from baseline in cardiopulmonary exercise testing 
parameters at Day 29.  
• Change and percentage change from baseline in lung function, including FVC and DLCO 
at Day 28.  
• PK/PD relationship in subjects receiving GBT440 from Baseline to Days 15 and 28 
 


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4. 
STUDY POPULATION 
4.1. 
Inclusion Criteria 
All subjects must meet the following inclusion criteria: 
1. Able and willing to provide signed informed consent to participate in this study. 
2. Documented diagnosis of IPF, as indicated in the ATS/ERS/JRS/ALAT 2011 guidelines. 
3. Adult males or females aged 45–80 years inclusive at randomization. 
4. Oxygen saturation (SpO2) ≥88 % by pulse oximetry while breathing room air at rest. 
5. Oxygen saturation (SpO2) <88% and at least a 5% absolute decrease during the baseline 
6MWT which is sustained for at least 10 seconds. 
6. Able to walk a total of at least 100 meters at completion of the baseline 6MWT. 
7. Weight ≥ 40 kg 
8. Subject is seronegative for hepatitis A (IgM anti-HAV), hepatitis B surface antigen 
(HBsAg), hepatitis C antibody (anti-HCV), and human immunodeficiency virus antibody 
(anti-HIV) within 3 months of screening. 
9. Able, in the Investigator’s opinion, to complete the 6MWT unassisted at baseline and 
Day 15 and Day 28 and comply with the study procedures, including attending all 
assessment visits and adhering to all study requirements and restrictions. 
10. Male or female of child bearing potential willing and able to use highly effective methods 
of contraception from study start to 3 months after the last dose of study drug. 
4.2. 
Exclusion Criteria 
Any subject who meets one or more of the following criteria will be excluded from 
participation: 
1. 
FEV1/FVC <70% 
2. 
Requires supplemental oxygen therapy at rest. 
3. 
History of other interstitial lung diseases including but not limited to radiation, drug 
toxicity, sarcoidosis, hypersensitivity pneumonia, bronchiolitis obliterans or organizing 
pneumonia. 
4. 
History of clinically significant environmental exposure known to cause pulmonary 
fibrosis, including but not limited to drugs (e.g. methotrexate or amiodarone), asbestos, 
beryllium, radiation and domestic birds. 
5. 
History of other medical conditions that are known or may result in interstitial lung 
disease. For example, any connective tissue disease including but not limited to 
scleroderma, polymyositis/dermatomyositis, systemic lupus erythematosus and 
rheumatoid arthritis. 
6. 
AST, ALT or total Bilirubin >2 × ULN 


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7. 
Creatinine Clearance (CrCl) <30 mL/min/1.73 m2, calculated using the Modification of 
Diet in Renal Disease estimated Glomerular Filtration Rate (MDRD eGFR). 
8. 
Significant polycythemia defined as hemoglobin value >18 mg/dL.  
9. 
ECG with a QTcF >450 ms (males) or QTcF >470 ms (females).  
 If ventricular pacing is noted on ECG, then QTcF intervals will not be calculated 
10. Family or personal history of congenital long QT syndrome. 
11. Female who is breast-feeding or pregnant. 
12. 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, or Stage 1 uterine 
cancer. 
13. Subject has used any of the following therapies within 30 days of screening: 
 Any cytotoxic, immunosuppressive or cytokine-modulating therapy including but 
not limited to: azathioprine, bosentan, ambrisentan, cyclophosphamide, 
cyclosporine, etanercept, iloprost, infliximab, leukotriene antagonists, methotrexate, 
mycophenolate, tacrolimus  
 Imatinib mesylate, Interferon gamma-1b, tyrosine kinase inhibitors (excluding 
nintedanib) 
14. Pulmonary hypertension requiring active therapy including but not limited to endothelin 
receptor inhibitors or PDE inhibitors (e.g., sildenafil, tadalafil).  
 Note: intermittent use of a PDE inhibitor for erectile dysfunction may be allowed 
after approval by the Medical Monitor. 
15. Hospitalization due to an exacerbation of IPF within 30 days of screening. 
16. Subject plans to begin or has commenced pulmonary rehabilitation within 30 days of 
screening 
 Subjects 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 
17. Corticosteroids (>10 mg per day of prednisone or an equivalent) within 30 days of 
screening. 
18. Current smoker (including use of eCigarettes or vaporizing) or history of smoking 
within 3 months from screening. 
19. Clinical evidence of active infection, including but not limited to bronchitis, pneumonia, 
sinusitis, urinary tract infection or cellulitis, within 14 days of screening. 
20. Active tuberculosis requiring treatment within the last 12 months. 
 Testing for latent tuberculosis is not required 
21. Currently or, in the opinion of the investigator, soon to be listed for lung transplant.  


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22. History of unstable or deteriorating cardiac or pulmonary disease (other than IPF) within 
6 months of screening including but not limited to the following: 
 Unstable angina pectoris or myocardial infarction or elective coronary intervention 
 Congestive heart failure requiring hospitalization 
 Uncontrolled clinically significant arrhythmias 
23. Any condition possibly affecting drug absorption, such as previous surgery on the 
stomach or small intestine. 
24. 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). 
25. Known hypersensitivity to any component of the study drug. 
26. Subject who, for any reason, is deemed by the investigator to be inappropriate for this 
study; or has any condition (such as addictive or psychosocial issues) which would 
confound or interfere with the evaluation of the safety, tolerability, or PK of the 
investigational drug; or is unable to comply with the study protocol. 
27. 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 
 


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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 informed consent form (ICF) before 
any screening procedures or study-specific tests may be performed. The baseline 6MWT 
performed at screening must be performed within 7 days of the Day 1 visit. If the 6MWT 
falls outside of the 7-day window, it must be repeated (the repeat may occur at the time of the 
Day 1 visit prior to any Day 1 visit assessments). 
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 
(refer to Appendix A), prior to any Day 1 visit assessments. 
Subjects may be rescreened up to two 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 
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 3 months 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). 
Women of Non Child-Bearing Potential 
Female subjects of non-child-bearing potential are defined as; bilateral oophorectomy, 
hysterectomy or post-menopausal females being amenorrhoeic for at least 2 years. 
For female subjects who report surgical sterilization (i.e., hysterectomy and/or bilateral 
oophorectomy), surgical sterilization procedures should be supported with clinical 
documentation and noted in the Relevant Medical History/Current Medical Conditions 
section of the CRF. 
Instructions for Male Subjects 
There is no information about effects that 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 3 months after the male subject has taken the 
last dose of GBT440.  
All male subjects should use the methods of contraception as outlined in Section 8.6).  


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5.3. 
Clinical Assessments  
Screening assessments must be performed and evaluated prior to randomization on Day 1. 
This study has nine visits in total including the screening visit and patients will be enrolled 
for approximately 58 days from the time of randomization until the last study visit. The 
timing of the visits, associated visit windows and all assessments are outlined in Appendix A: 
Schedule of Study Assessments. 
5.3.1. 
Medical History and Demographic Data 
Medical history includes clinically significant diseases, surgeries, cancer history (including 
prior cancer therapies and procedures), inflammatory/autoimmune disease, smoking history, 
use of alcohol and drugs of abuse within the previous year, and IPF-associated conditions 
including but not limited to pulmonary hypertension, familial IPF and gastroesophageal 
reflux disease. Medical conditions that are a result of side effects from concomitant 
medications 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 adverse event if 
deemed clinically significant by the investigator (refer to Section 10). 
All concomitant medications (e.g., prescription drugs, over-the-counter drugs, 
herbal/homeopathic remedies, nutritional supplements) used by the patient within 30 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. 
Demographic data will include age (date of birth), sex, and self-reported race/ethnicity. 
5.3.2. 
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 patient notes. New or 
worsened abnormalities should be recorded as adverse events on the Adverse Event eCRF. 
Vital signs will include measurements of respiratory rate, pulse rate, body temperature, 
systolic and diastolic blood pressure and SpO2 by pulse oximetry. Blood pressure and SpO2 
measurements should be taken while the patient 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 


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laboratory. All clinically significant laboratory value abnormalities are to be recorded as 
AEs. 
For the purpose of this study, a clinically significant laboratory value will be any abnormal 
result that, in the judgment of the Investigator, is an unexpected or unexplained laboratory 
value or if medical intervention or corrective action is required. Any abnormal values that 
persist should be followed at the discretion of the Investigator. 
Please refer to Appendix A Schedule of Study Assessments for all time points. 
5.4.1.1. 
Hematology 
Hematology assessments will include red blood cells (RBCs), hematocrit, hemoglobin, 
platelets and white blood cells (WBCs) with differential (basophils, eosinophils, neutrophils, 
monocytes and lymphocytes). Reticulocyte count and serum erythropoietin will also be 
collected.  
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 alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), alkaline phosphatase, gamma glutamyl transferase 
(GGT), and total bilirubin (direct and indirect).  
5.4.1.4. 
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. 
5.4.1.5. 
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. The 
ECGs will be collected in triplicate. Three separate recordings approximately 1 minute apart 
should be performed. All three tracings must be stored at the study site. If ventricular pacing 
is noted on ECG, then QTcF intervals will not be calculated. 
5.4.1.6. 
Other Clinical Laboratory Tests 
Screening tests will include serology for hepatitis A (IgM anti-HAV), hepatitis B surface 
antigen (HBsAg), hepatitis C (HCV) and HIV-1/0/2 antibodies if there is no documented 
testing results within 3 months of screening. 


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For women of child bearing potential, a pregnancy test (serum HCG) will be performed at 
screening and urine pregnancy testing will be performed during the study. If the urine 
pregnancy test is positive the result must be confirmed with a serum pregnancy test. 
Coagulation (Panel) including PT, PTT and INR will be collected at screening and Day 28. 
5.5. 
Disease Related Evaluations 
5.5.1. 
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 2005) 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.  
Spirometry and DLCO should be performed at each scheduled visit at approximately the same 
time of day (e.g. in the morning) and before the 6MWT, if scheduled on the same visit day. 
Local reports from the spirometry and DLCO testing will be stored on site. 
5.5.2. 
Oxygen Saturation 
During screening and with all scheduled vital sign assessments resting, room air oxygen 
saturation (SpO2) will be measured by pulse oximetry (provided by the Sponsor) whilst the 
subject is seated and resting for at least 5 minutes. 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 resting.  
SpO2 will be also be collected at baseline, during and following completion of the 6MWT 
and cardio-pulmonary exercise testing. 
5.5.3. 
6-Minute Walk Test (6MWT)  
Functional exercise capacity will be evaluated at Baseline and Days 15, 28 and 58 using the 
6-minute walk test. The 6MWT will be performed without the subject using supplementary 
oxygen. Oxygen may be used at any time during the 6MWT, if in the opinion of the 
Investigator or testing technician it is required for safety reasons. The 6MWT should then be 
stopped. 
The baseline 6MWT performed at screening must be performed within 7 days of the Day 1 
visit. If the 6MWT falls outside of the 7-day window, it must be repeated (the repeat may 
occur at the time of the Day 1 visit prior to any Day 1 visit assessments). 
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, 
1 minute and 2 minutes after test completion. 
For safety reasons, all patients should be clinically stable prior to performing the 6MWT. 
Absolute contraindications to the 6MWT include unstable angina or myocardial infarction 
during the previous month. 
Relative contraindications to participation in the 6MWT include: 
• Resting heart rate >120 or <60 beats per minute 
• Systolic blood pressure >180 mmHg 
• Diastolic blood pressure >100 mmHg 
5.5.4. 
Cardiopulmonary Exercise Testing (CPET) 
Symptom-limited cardiopulmonary exercise testing using a bicycle ergometer will be 
performed on Day 2 and Day 29. At baseline and during the exercise period the collected 
data will include but is not limited to: SpO2 and arterial blood gases, VO2 max, ventilation 
and lactate thresholds. Guidelines developed by ATS and American College of Chest 
Physicians will be used for conducting the test and interpreting the results (ATS 2003). 
Instructions for the conduct of the CPET will be provided in a separate manual. An arterial 
line placement will be part of the CPET procedure. If the subject refuses arterial line 
placement they may still undergo the CPET assessments without the arterial line. 
Agreement to undergo the CPET is not required for entry into the study; but participation is 
strongly encouraged.  
5.5.5. 
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 
(except in cases when the screening 6MWT is being repeated on Day 1 prior to any Day 1 
visit assessments) and before the patient receives any disease-status information during that 
assessment. They will be administered as indicated in the schedule of assessments (Appendix 
A).  
5.5.5.1. 
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 
comprises 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 
specification of 4 weeks. Paper questionnaires will be provided to sites prior to subject 
enrollment. 


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5.5.5.2. 
University of California, San Diego Shortness of Breath Questionnaire 
(UCSD) 
The UCSD is a 24-item assessment of breathlessness associated with various activities of 
daily living. The response for each item is measured on a 5-point Likert scale from 0 (none at 
all) to 5 (maximal or unable to perform). Paper questionnaires will be provided to sites prior 
to subject enrollment. 
5.5.5.3. 
Borg Dyspnea Scale 
The Borg Dyspnea scale is a 1-item assessment, self-administered by the patient 
administered as part of the 6 MWT. The instrument will be used to assess dyspnea from the 
patient’s perspective. The Scale ranges from 0 (Nothing at all) to 10 (Absolute 
maximum/Highest possible). Refer to the Procedure Manual for a copy of the assessment. A 
paper scale will be provided to sites prior to subject enrollment. 
5.5.5.4. 
A Tool to Assess Quality of Life (ATAQ) in IPF 
ATAQ questionnaires will be administered in Part B of this study. Paper questionnaires will 
be provided to sites prior to subject enrollment in Part B of the trial. 
5.5.5.4.1. 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 oxygen use. Items are assessed using a 
Likert scale with a 24-hr recall period.  
5.5.5.4.2. 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 one week recall period. 
5.5.5.5. 
Visual Analog Scale (VAS) for Cough Severity 
Cough will be assessed using a VAS in which the subject will indicate the severity of their 
cough by drawing a mark on a 100 mm scale, which ranges from 0 - “no cough” to 100 m - 
“worst cough severity”. A paper scale will be provided to sites prior to subject enrollment. 
5.5.5.6. 
End of Study Questionnaire 
The End of Study Questionnaire is an 8-item 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 58 visit. The survey is to be completed 
by subjects enrolled under Part B of the trial. A paper End of Study Questionnaire will be 
provided to the sites prior to subject enrollment in Part B. Subject responses will be entered 
in the eCRF by the site. At completion of the study the paper questionnaires will be returned 
to the Sponsor. 


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5.6. 
Pharmacokinetic Samples 
Plasma and whole blood concentrations of GBT440 will be measured using validated LCMS 
methods. Instructions for sample collection, processing and shipment are described in a 
separate lab manual. Up to nine PK samples will be collected at the following times (also 
refer to the Schedule of Assessments, Appendix A): 
 
During Treatment Period 
Pre-dose 
2 hrs ± 15 min post -dose 
Day 1 (Visit 2) 
X 
X 
Day 2 (Visit 3) 
X*  
 
Day 8 (Visit 4) 
X  
 
Day 15 (Visit 5) 
X  
 
Day 28 (Visit 6) 
X  
X 
 
During Follow-Up Period 
Day 45 (Visit 8) 
X 
Day 58 (Visit 9) 
X 
* On Day 2 the PK sample should be drawn 24 hours (± 2 hours) after the Day 1 dose and prior to receiving 
the Day 2 dose. 


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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 adverse events 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 Harmonisation (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 
• SMC recommendation 
• 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 Visit 8 (Day 45) 
assessments within 2 weeks (± 7 days) from the date of discontinuation. 
6.3. 
Study Treatment 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 
• Use of any medication (refer to Section 8.5), intended to chronically treat IPF, other 
than those documented at screening 
• Adverse event 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 


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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 study assessments, 
should return to the study site 2 weeks (+ 7 days) after the last dose of study drug to complete 
the Visit 8 (Day 45) assessments. 
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 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 
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 FDA IID (Inactive Ingredients Database) listed. 
Placebo Capsules: The placebo capsules contain microcrystalline cellulose in Swedish 
orange, opaque, size 0, hypromellose capsules. All the excipients used for the formulation are 
FDA IID (Inactive Ingredients Database) listed. The placebo capsules do not contain any 
GBT440 drug substance. 
7.1.3. 
Packaging and Labeling  
GBT440 and placebo capsules will be supplied to the site in 100 mL high-density 
polyethylene (HDPE) bottles induction sealed with child-resistant polypropylene (PP) screw 
caps bottles of 30 capsules. 
An unblinded study pharmacist will prepare daily doses of study drug dispensed into 30 mL 
high-density polyethylene (HDPE) bottles with child-resistant polypropylene (PP) screw 
caps. Packaging and labeling of each bottle and its contents are specific to each subject in the 
study and is based on the treatment group assignment at randomization. 
Each 30 mL bottle (or dose) is packaged individually with 3 capsules of active or placebo or 
both specific to each subject’s assigned treatment group. 
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 or placebo are required. The Sponsor 
will be permitted upon request to audit the supplies, storage, dispensing procedures and 
records provided that the blind of the study is not compromised. 


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7.2. 
Drug Accountability 
In accordance with GCP, the Investigational Site will account for all supplies of GBT440 and 
placebo. Details of receipt, storage, assembly and return will be recorded.  
All unused supplies of GBT440 and placebo will either be destroyed by the investigational 
site or returned to the study Sponsor or 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 and placebo will be administered orally each day for 28 days. GBT440 will be 
administered as 300 mg capsules. Placebo will be provided as capsules matching the 
GBT440 capsules. Subjects randomized to the following treatment groups will receive: 
Part A: 
• GBT440 900 mg: 3 GBT440 300 mg capsules. 
• GBT440 600 mg: 2 GBT440 300 mg capsules and 1 placebo capsule.  
• Placebo: 3 placebo capsules. 
Part B: 
• GBT440 1500 mg: 5 GBT440 300 mg capsules 
• GBT440 600 mg: 2 GBT440 300 mg capsules and 3 placebo capsule.  
• Placebo: 5 placebo capsules. 
Instructions for Administration of Study Drug: 
• Self-administered by subject in the morning 
- 
except on study visit days when the subject must not take study drug. It will be 
administered at the site after completion of scheduled assessments. 
• May be taken with or without food 
• May be taken with water or other non-alcoholic beverage 
Subjects must be instructed not to take study drug the day of their scheduled visits (refer to 
Appendix A). Study drug will be administered at the site on these days, after completion of 
all the assessments scheduled for that visit. 
8.2. 
Study Drug Dispensing 
Study drug will be dispensed to subjects on study Days 2, 8 and 15 as indicated in the 
schedule of assessments (refer to Appendix A). Each daily dose will be dispensed into 
separate containers and provided to the subject at the study site. 
If a dose reduction is required subjects must return to the study site for study drug to be 
re-dispensed. Subjects must return any remaining study drug and all study drug containers to 
the site where they will be destroyed as instructed by the Sponsor. 
8.3. 
Dose Modification 
Modification of study drug dosing may be considered if, in the opinion of the study 
Investigator, the AE may be 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. 
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 and in discussion with the Sponsor’s 
Medical Director. 
The Investigator, in discussion with the Sponsor’s Medical Director, may choose to: 
• Change dosing frequency, to one capsule 3 times per day  
• Reduce the total daily dose  
A reduction in dose should be by one active study drug capsule. Dose reductions will require 
the subject to return to the study site for the unblinded pharmacist to dispense new study drug 
capsules. Subjects will continue to take 3 capsules per day if in Part A and 5 capsules per day 
if in Part B of the study. 
A second dose reduction by another one active study drug capsule 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 
discussion with the Sponsor’s Medical Director.  
The Investigator must make every effort to restart the dosing regimen assigned to the subject 
at randomization, as soon as it is safe to do so.  
8.3.2. 
Dose Interruption 
Dose interruption may be initiated by the Investigator based on their assessment of the 
associated AE severity and overall subject safety and in discussion with the Sponsor’s 
Medical Director.  
Re-initiation of dosing will be based on the Investigator’s clinical assessment and in 
discussion with the Sponsor’s Medical Director. Dosing should be restarted at the dose 
assigned to the subject at randomization. 
The Investigator must make every effort to restart the dosing regimen assigned to the subject 
at randomization as soon as it is safe to do so.  
Study treatment 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. Patients 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 


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the study, taking in to account the Prescriber Information (USPI) of the drugs and past 
history of care from the subject’s IPF health care provider and must be entered into the 
eCRF. 
8.4. 
Treatment 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 adverse events 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 randomized subjects, 
all administered concomitant medications from signing the informed consent until the last 
study visit must be recorded in the subjects’ eCRF. 
All prior and concomitant medications that have been reported, will be coded using the 
current version of 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  
- 
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:  
- 
if the dose at screening is ≤10 mg per day of prednisone (or an equivalent) and 
has been stable for at least 2 weeks prior to screening and with no anticipated 
need for dose adjustments, including reductions in dose, during the study.  
- 
Use of corticosteroids for other non-IPF related reasons, including but not limited 
to intra-articular or intramuscular delivery, should be discussed with the medical 
monitor before administering.  
- 
Maintenance therapy for other medical conditions listed in the subject’s medical 
history at the time of screening. 
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:  


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 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 1; GBT440 may 
increase the plasma concentration of these medications) 
Table 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, see the following link: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabelin
g/ucm093664.htm#4 
Substrates with 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 
8.6.1. 
Acceptable Forms of Contraception 
Highly effective methods of birth control are defined as those which result in a low failure 
rate (i.e. less than 1% per year) when used consistently and correctly.  
• 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). 


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• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Vasectomised partner. Note that vasectomised 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 vasectomised partner has received 
medical assessment of the surgical success. 
• Sexual abstinence. Sexual abstinence is considered a highly effective method only if 
the subject is refraining from heterosexual intercourse during the entire period of risk 
associated with the study treatments. 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. 
For male subjects: 
• Men must agree to use two acceptable methods of contraception, 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 3 months following last study drug administration. 


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9. 
RANDOMIZATION PROCEDURE 
Subject randomization will be carried out centrally through an Interactive Response System 
(IxRS). 
In Part A, eligible subjects will be randomized 1:1:1 to either: 900 mg GBT440, 600 mg 
GBT440 or placebo, respectively. A total of approximately 18 subjects will be randomized.  
In Part B, up to an additional 15 subjects will be enrolled and randomized 3:1:1 to either: 
1500 mg GBT440, 600 mg GBT440 or placebo to further characterize the safety, tolerability 
and potential treatment response of GBT440. In the eventuality that one treatment arm is 
discontinued subjects may be randomised 1:1 to the remaining study treatment group or 
placebo. 
Randomization will be stratified by background IPF therapy used at the time of entry into the 
study, that is pirfenidone or nintedanib. 
9.1. 
Blinding 
The GBT440 and placebo oral capsules will be matched for shape, size and color. 
If at any time during the study a decision about a subject’s medical condition requires 
knowledge of the treatment assignment, the study blind may be broken (through IxRS) for 
that specific subject only. If in the opinion of the Investigator, there is no impact on patient 
safety, the Investigator is encouraged to contact the Sponsor’s Medical Director prior to 
unblinding. The reason for unblinding must be documented in the appropriate section of the 
eCRF.  
At the study site, only the Principal Investigator should be unblinded. If, in the Investigator’s 
opinion, and for the safety of the subject other study site personnel are required to be aware 
of the treatment assignment, the Investigator will ensure that the minimum number of 
personnel are informed.  
The SMC must be informed by the Sponsor’s Medical Director of any case of unblinding. 
Additionally, the SMC may unblind individual treatment assignment for further safety 
evaluation at their discretion. 


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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 II study will contribute to the understanding of the safety profile for 
GBT440 and for its use in IPF patients. 
10.1. 
Safety Monitoring Committee (SMC) 
The Safety Monitoring Committee (SMC) consisting of the Sponsor’s Medical Director, one 
Independent Physician with clinical IPF expertise and one Independent Physician with 
clinical trial experience. The SMC, along with the CRO’s statistician and data manager, will 
review the safety data throughout the study.  
The SMC may meet at any time during the study to review blinded or unblinded data when 
deemed necessary by the SMC.  
In Part A, the SMC will initially convene to review all available safety data after 
approximately 9 randomized subjects have completed the Day 15 visit. The SMC will also 
convene to review all available safety data after approximately 18 subjects have completed 
the Day 15 visit. If the SMC does not identify any clinically significant safety concerns the 
Sponsor will randomise up to an additional 15 subjects, to three study treatment arms (1500 
mg GBT440, 600 mg GBT440 or placebo) to better characterize the safety, tolerability 
and/or potential treatment response of GBT440.  
In Part B, the SMC will initially convene to review all available safety data after 
approximately 9 randomized subjects have completed the Day 15 visit. The SMC will also 
convene to review all available safety data after approximately 15 subjects have completed 
the Day 28 visit. At this time, the SMC will review safety data from all subjects, in Parts A 
and B, who have received at least one dose of study drug. 
Details of the SMC are described in a separate charter. 
10.2. 
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 therefore 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 58). Reporting of AEs prior to randomization should only include SAEs or AEs 
resulting from any protocol related interventions.  
Adverse events 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 nonserious) 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.  


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All reported AEs will be coded using the current version of the Medical Dictionary for 
Regulatory Activities (MedDRA). 
The procedures specified in Section 10.7 are to be followed for reporting SAEs. 
10.3. 
Recording Adverse Events 
Adverse events are to be recorded on the AE eCRF. The following information will be 
recorded: 
• Whether or not the AE is an SAE (Section 10.4.1) 
• AE severity (Section 10.4.2) 
• AE relationship to investigational product (Section 10.4.4) 
• 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. 
10.4. 
Assessment of Adverse Events 
The investigator will assess each AE for seriousness, severity, and relationship to study drug. 
10.4.1. 
Serious Adverse Event (SAE) 
The investigator is responsible for determining whether an AE meets the definition of an 
SAE. An SAE is any AE occurring from signing of the informed consent form (ICF) until the 
end of the study (Day 58) 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 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” (Section 10.7) for details. 
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 


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during the study, it must be reported as an AE (or SAE, if the event/ condition results in a 
serious outcome such as hospitalization). 
10.4.2. 
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: 
 
An allergic reaction/hypersensitivity: Grade 2 or higher (as defined by NCICTC 
Version 4.03) 
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. Refer to Section 10.7 for 
details. 
10.4.3. 
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. Adverse events reported for subjects participating 
in this study will be graded using the National Cancer Institute’s (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE), Version 4.03 
The Investigator will grade the severity of each AE using, when applicable, the NCI CTCAE, 
version 4.03. For AEs not included in the NCI-CTCAE Version 4.03, the criteria outlined in 
Table 2 should be used as a general guideline.  
Table 2 
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. 
10.4.4. 
Relationship to Study Drug 
The relationship of an AE to the investigational product should be determined by the 
Investigator according to the following definitions: 


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• Not Related: Evidence exists that the adverse event has an etiology other than the 
study drug (such as a preexisting condition, underlying disease, intercurrent illness, or 
concomitant medication). 
• Possibly/Probably Related: A temporal relationship exists between the event onset 
and administration of the study drug. It cannot be readily explained by the subject’s 
clinical state or concomitant therapies and appears with some degree of certainty to 
be related based on the known therapeutic and pharmacologic actions of the drug. In 
case of cessation or reduction of the dose, the event abates or resolves and reappears 
upon rechallenge. It should be emphasized that ineffective treatment should not be 
considered as causally related in the context of adverse event 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. 
10.4.5. 
Unexpected Adverse Reactions 
An adverse reaction is ‘unexpected’ if its nature and severity are not consistent with the 
information about the study drug: 
• In the case of a product with a marketing authorization, in the summary of product 
characteristics for that product. 
• In the case of any other IMP, in the Investigator’s Brochure relating to the trial in 
question.  
10.5. 
Reporting Adverse Events 
10.5.1. 
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, it should be reported as follow-up information and the diagnosis 
entered in the eCRF. 
10.5.2. 
Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (e.g., cascade 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. 


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10.5.3. 
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 their 
severity increases. If a persistent AE becomes more severe, it should be recorded again on 
the Adverse Event eCRF.  
A recurrent AE is one that occurs and resolves between subject evaluation time points and 
subsequently recurs. All recurrent AEs should be recorded on an Adverse Event eCRF. 
10.5.4. 
Abnormal Laboratory Values 
Only clinically significant laboratory abnormalities that require active management will be 
recorded as AEs or SAEs on the eCRF (e.g. abnormalities that require study drug dose 
modification, discontinuation of study treatment, more frequent follow-up assessments, 
further diagnostic investigation, etc.). 
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, seriousness, or etiology changes.  
10.6. 
Discontinuation due to Adverse Events 
Any subject who experiences an AE, serious or nonserious, 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’ Medical Director and the CRO 
medical monitor must be notified. If the AE relates to overdose of study treatment, the 
Investigator’s Brochure 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. 
10.7. 
Reporting Serious Adverse Events and Adverse Events of Special Interest 
SAEs/AESIs occurring in this study 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. 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. 


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Follow-up reports must be submitted in a timely fashion as additional information becomes 
available. 
The Investigator is responsible for notifying the Institutional Review Board (IRB) or 
Independent Ethics Committees (IEC) in accordance with local regulations, of all SAEs. The 
Sponsor or designee may request additional source documentation pertaining to the SAE 
from the investigational site. If a subject is permanently withdrawn from the study due to an 
SAE, this information must be included in the initial or follow-up SAE report in the eCRF. 
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. 
10.8. 
Choosing Adverse Event Terms 
Whenever possible, reported event terms for AEs (including SAEs) should be the names of 
medical events, not lists of symptoms or event outcomes. Below are some examples of terms 
to avoid and more accurate alternatives. 
Examples of Terms to Avoid 
Examples of More Accurate Terms 
Death (this is an outcome) 
Fatal myocardial infarction (best choice) 
Death due to unknown cause, autopsy results 
pending (if no other information is available) 
Hospitalized (this is a serious criterion) 
Myocardial infarction (best choice) 
Hospitalized with chest pain, rule out myocardial 
infarction (if no other information is available) 
Chest pain, shortness of breath, 
diaphoresis, anxiety, left arm pain 
Myocardial infarction (best choice) 
Hospitalized, rule out myocardial infarction (if no 
other information is available) 
10.9. 
Pregnancy 
Pregnancies occurring in a female subject or in a male subject’s partner while enrolled in this 
clinical study through 3 months 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 
(refer to Section 10.5). 
If a subject becomes pregnant while taking study drug, the study treatment will be 
immediately discontinued and the pregnancy must be reported within 24 hours. The 
investigator will discuss the risks and concerns of investigational drug exposure to a 
developing fetus and counsel the subject and/or pregnant partner (or ensure such counselling 
is provided). 
An uncomplicated pregnancy will not be considered an AE or SAE; however, all pregnancies 
will be followed through birth and 3 months post-delivery. 


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Any congenital abnormalities in the offspring of a subject who received investigational 
product will be reported as 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. 
The investigator will complete a Pregnancy Monitoring Form and report the information 
regarding the pregnancy, outcome, and status of the newborn, as appropriate.  


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Final 21 December 2016 
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11. 
DATA ANALYSIS AND STATISTICAL PLANS 
Details of all planned analyses will be specified in a separate statistical analysis plan. 
The study data will be reported using summary tables, figures and data listings. 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 from Parts A and B of the study will be pooled across the common treatment arms, i.e., 
GBT440 600 mg and placebo arms. 
11.1. 
Sample Size 
The sample size in this initial study was not selected based on statistical considerations but to 
determine preliminary safety, tolerability, PK, laboratory and clinical effects of GBT440 in 
IPF subjects.  
The study will enroll approximately 33 subjects: approximately 18 subjects in Part A and 
approximately 15 subjects in Part B.  
11.2. 
Populations for Analysis 
The following populations will be considered in the analysis of data for this study. 
Assignment or exclusion of subjects from the analysis populations will be performed prior to 
study unblinding. 
• Safety population: All subjects who receive any amount of study medication will be 
included in the safety population. Subjects will be analyzed based on medication 
received. This is the primary population for all safety analyses performed for this 
study. 
• Efficacy evaluable population: All randomized subjects who received at least 15 days 
of study drug treatment will be included in the Efficacy evaluable population. The 
Efficacy evaluable population will be used for analysis of all secondary and 
exploratory efficacy endpoints, and subjects will be analyzed as treated. 
• PK population: All subjects who receive investigational treatment and provide 
adequate data to evaluate the relevant PK parameter.  
11.2.1. 
Primary Endpoint 
The primary endpoint for this study is the safety and tolerability of GBT440.  
Analysis will be based on data from all subjects who were randomized and received at least 
one dose of study drug. Safety will be assessed by AEs, laboratory evaluations, vital signs 
and ECGs. Data from these subjects will be used for analysis of all baseline demographics 
and safety summaries. 
11.2.2. 
Secondary endpoints 
Analysis of data for secondary efficacy endpoints will be based on all randomized subjects 
who received at least 15 days of study drug treatment.  


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The treatment group for these analyses will be based on the treatment received at 
randomization. 
11.2.3. 
Pharmacokinetics 
Analysis of data for PK will be based on data from all subjects who received at least 1 dose 
of GBT440 and have sufficient PK data to derive at least 1 PK parameter. 
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. 
Analyses 
Demographic and baseline characteristics, primary and secondary endpoints, and safety 
parameters will be summarized using descriptive statistics and presented in individual 
listings. 
AEs will be reported by severity and relatedness to study treatment and classified according 
to the current version of MedDRA. 
11.3.1. 
Safety Data 
Safety data analysis will be performed on all randomized subjects who have received at least 
1 dose of study drug. Individual and summary blood pressures, heart rate, ECG parameters, 
exercise testing endpoints and clinical laboratory data (hematology, serum biochemistry and 
coagulation) will be summarized. 
For the laboratory safety data, out of range values will be flagged in the data listings and a 
list of clinically significantly abnormal values will be presented. 
Adverse events and medical history will be tabulated and summarized according to the 
current version of MedDRA. 
11.3.2. 
Efficacy Data 
For secondary and exploratory endpoints, binary data will be analyzed via Fisher’s exact test. 
Data for other endpoints will be analyzed with Wilcoxon’s test or analysis of covariance 
(ANCOVA) with baseline value as covariate. Full details of analysis methods, including how 
missing data will be handled, will be provided in the SAP which will be finalized prior to 
study unblinding.  
11.3.3. 
PK Data 
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.  


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Amendment 3 
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CONFIDENTIAL 
 
Steady state of GBT440 will be assessed graphically. 
Exploration of exposure-response relationships of GBT440 to exploratory efficacy data, and 
safety data (described below) will be performed as data permits. 


Protocol Number GBT440-006 
 
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Final 21 December 2016 
Amendment 3 
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CONFIDENTIAL 
 
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 current country and local regulations, FDA, ICH GCP, the Declaration of Helsinki, and 
Good Clinical Practice. 
The study will be conducted according to the protocol, and guidelines established by the ICH 
for GCP in clinical trials.  
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, and 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 
between the Sponsor and CRO, and then submitted to the IRB/IEC for approval. 
Amendments may be implemented only after a copy of the local IRB 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, 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.  
Financial Disclosure statements will be handled in a separate agreement apart from the 
protocol, kept on file and submitted as applicable with any subsequent license application. 
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. 
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. The subject should be given a 


Protocol Number GBT440-006 
 
Global Blood Therapeutics 
Final 21 December 2016 
Amendment 3 
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CONFIDENTIAL 
 
copy of the Informed Consent Form (ICF) in their native language. The informed consent 
process should be recorded in the source documentation. The original copy of the signed and 
dated informed consent must be retained in the institution’s records, and is subject to 
inspection by representatives of the Sponsor, or representatives from regulatory agencies. 
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 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. 
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. 


Protocol Number GBT440-006 
 
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Final 21 December 2016 
Amendment 3 
Page 65 
 
CONFIDENTIAL 
 
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. 
12.9.1. 
Publication 
The Sponsor intends to publish the results of the study as a whole once all subjects have 
completed the study and the study has been analyzed. 
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 GBT440-006 
 
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Final 21 December 2016 
Amendment 3 
Page 66 
 
CONFIDENTIAL 
 
13. 
ADMINSTRATIVE OBLIGATIONS 
13.1. 
Source Data 
Original documents, data, records (e.g., clinic records, laboratory notes, memoranda, subject 
diaries or evaluation checklists, pharmacy dispensing 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, 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 CRF 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 CRFs 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 CRFs and compare data to that contained in clinic notes and subjects’ source 
documents/medical records. 
Data collected for each subject will be entered into the CRF. The investigator will be 
responsible for the timeliness, completeness, and accuracy of the documentation entered into 
the CRFs. 
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 (CRFs and other pertinent data), provided that subject confidentiality is 
maintained, and that the monitoring is conducted in accordance with local regulations. 
It is the monitor’s responsibility to inspect the CRFs 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. 
13.4. 
Quality Control and Quality Assurance 
Quality Control will be performed according to the Sponsor 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. 


Protocol Number GBT440-006 
 
Global Blood Therapeutics 
Final 21 December 2016 
Amendment 3 
Page 67 
 
CONFIDENTIAL 
 
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. 2005. 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, 183 
(February 1974). 
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 
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, Puhan MA, Pepin V, 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. 
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. 
Procedure Manual [Manual on CD-ROM]. 2nd ed. 
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. 


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Final 21 December 2016 
Amendment 3 
Page 68 
 
CONFIDENTIAL 
 
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. 
Yalcin O, Cabrales P. Increased hemoglobin O2 affinity protects during acute hypoxia. Am J 
Physiol Heart Circ Physiol. 2012 Aug 1;303(3):H271-81. 
 


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CONFIDENTIAL 
 
15. 
APPENDICES


Protocol Number GBT440-006 
 
Global Blood Therapeutics 
Final 21 December 2016 
 
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APPENDIX A 
SCHEDULE OF STUDY ASSESSMENTS 
Study Day (Window) 
Screeninga 
 
Treatment Period 
Follow-up Visits 
Day -21 to 
Day -1 
Day 1 
Day 2 
Day 8 
(+/- 2) 
Day 15 
(+/- 2) 
Day 28 
(+/- 2) 
Day 29 
(+3) 
Day 45b 
(+/- 3) 
Day 58 
(+/- 3) 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Informed Consentc 
X 
 
 
 
 
 
 
 
 
Eligibility Assessment 
X 
X 
 
 
 
 
 
 
 
Demographic data 
X 
Xd 
 
 
 
 
 
 
 
Medical History and baseline conditions 
X 
Xd 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete Physical Examinatione 
X 
 
 
 
 
 
 
 
X 
Limited Physical Examinationf 
 
X 
 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
X 
 
 
 
Vital Signsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SpO2h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG (12-lead)i 
X 
 
 
X 
X 
X 
 
X 
X 
Adverse Eventsj 
Xj 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Pregnancy Test (females only)k 
X 
 
 
 
 
 
 
 
 
Urine Pregnancy Test (females only)l 
 
 
 
X 
X 
X 
 
X 
X 
Hematology 
X 
 
 
X 
X 
X 
 
X 
X 
Serum Chemistry 
X 
 
 
X 
X 
X 
 
X 
X 
Urinalysis 
X 
 
 
 
X 
X 
 
X 
X 


Protocol Number GBT440-006 
 
Global Blood Therapeutics 
Final 21 December 2016 
 
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CONFIDENTIAL 
 
Study Day (Window) 
Screeninga 
 
Treatment Period 
Follow-up Visits 
Day -21 to 
Day -1 
Day 1 
Day 2 
Day 8 
(+/- 2) 
Day 15 
(+/- 2) 
Day 28 
(+/- 2) 
Day 29 
(+3) 
Day 45b 
(+/- 3) 
Day 58 
(+/- 3) 
Coagulation Panel (PT, PTT, INR) 
X 
 
 
 
 
X 
 
 
 
Serum Erythropoietin 
X 
 
 
 
 
X 
 
X 
X 
Serology (Hepatitis A, B, C, and HIV) 
X 
 
 
 
 
 
 
 
 
PK Blood Samplesm 
 
X 
X 
X 
X 
X 
 
X 
X 
Spirometry and DLCO 
X 
 
 
 
 
X 
 
 
X 
6 Minute Walk Testn 
Xn 
 
 
 
X 
X 
 
 
X 
Cardiopulmonary Exercise Testingn  
 
 
X 
 
 
 
X 
 
 
Randomization (IxRS) 
 
X 
 
 
 
 
 
 
 
Study Drug Dispensing to Subjecto 
 
 
X 
X 
X 
 
 
 
 
Study Drug Administration at sitep 
 
X 
X 
X 
X 
X 
 
 
 
St. George’s Respiratory Questionnaireq 
 
X 
 
 
 
X 
 
 
X 
UCSD Shortness of Breath Questionnaireq 
 
X 
 
X 
X 
X 
 
X 
X 
ATAQ-IPF Symptomsq 
 
X 
 
X 
X 
X 
 
X 
X 
ATAQ-IPF Impactsq 
 
X 
 
X 
X 
X 
 
X 
X 
End of Study Questionnairer 
 
 
 
 
 
 
 
 
X 
Cough Visual Analogue Scaleq 
 
X 
 
X 
X 
X 
 
X 
X 
Abbreviations: ATAQ = A Tool to Assess Quality of Life; DLCO = lung diffusing capacity measured using carbon monoxide; ECG = electrocardiogram; 
HIV = human immunodeficiency virus; INR = international normalized ratio; PK = pharmacokinetic; PRO = patient reported outcome; PT = prothrombin time; 
PTT = partial thromboplastin time; SGRQ = St. George’s Respiratory Questionnaire; SpO2 = oxygen saturation measured by pulse oximetry; UCSD = University 
of California San Diego. 
Note: All assessments should be performed within the number of days (Window) as indicated for each scheduled visit day. All assessments should be performed 
prior to receiving study drug during the treatment period unless otherwise indicated. SGRQ, ATAQ, UCSD, Cough VAS should be performed before all other 
non-PRO assessments, followed by 12-lead ECG and then vital sign assessments. 


Protocol Number GBT440-006 
 
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Final 21 December 2016 
 
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CONFIDENTIAL 
 
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 randomization 
to the treatment period. In cases when the screening 6MWT is done more than 7 days prior to Visit 2, it must be repeated, up and through Day 1, prior to any 
Day 1 assessments. 
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 Day 45 (Visit 8) 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 at this visit and any changes since screening updated 
in the eCRF 
e 
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 
f 
Perform a limited, symptom-directed examination as clinically indicated. Record new or worsened clinically significant findings in the eCRF. 
g 
Includes heart rate, respiratory rate, systolic and diastolic blood pressure and temperature measured whilst in a semi-recumbent or supine position and resting 
for at least 5 minutes.  
h 
Performed while the subject is seated and resting for at least 5minutes. 
i 
Perform 12-lead ECG in triplicate; three separate tracings with approximately 1 minute between each tracing, after resting in a semi-recumbent or supine 
position for at least 5 minutes. 
j 
After informed consent but prior to randomization only serious adverse events (SAEs) resulting from a protocol-mandated intervention should be reported. 
After randomization, all adverse events will be reported until study completion (Day 58).  
k 
Performed for all female patients who are not post-menopausal or surgically sterile 
l 
If a urine pregnancy test is positive the result must be confirmed with a serum pregnancy test 
m 
PK blood samples during the treatment period should be collected on Days 1 and 28: Pre-dose and 2 hours post dose (+/- 15 minutes); Day 2: 24 hours 
(+/-2 hours) after the Day 1 dose and prior to receiving the Day 2 dose; Days 8 and 15: Pre-dose only.  
n 
Instructions for per-protocol performance of the 6-minute walk (and Borg dyspnea scale) and cardio-pulmonary exercise tests are provided in the procedure 
manual. Note: The baseline 6MWT performed during screening must be performed within 7 days of the Day 1 visit. 
o 
An unblinded study pharmacist will prepare daily doses of study drug, dispensed into 30 mL high-density polyethylene (HDPE) bottles. Each bottle (or dose) 
is packaged individually with 3 capsules of active or placebo or both specific to each subject’s assigned treatment group. Subjects who have their dose 
modified during the study must return to the site to have the modified dose of study drug dispensed by the unblinded pharmacist. 
p 
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.  
q 
The SGRQ, ATAQ and UCSD questionnaires and cough VAS 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 patient receives any disease-status information during that assessment. ATAQ questionnaires should 
be administered to subjects enrolled in Part B of the study. 
r 
The End of Study Questionnaire should be administered to subjects enrolled in Part B of the study. 


Protocol Number GBT440-006 
 
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Final 21 December 2016 
Amendment 3 
Page 73 
 
CONFIDENTIAL 
 
APPENDIX B 
STRONG INDUCERS OF CYP ISOENZYMES 
 
CYP Enzymes 
Medications 
CYP3A4/3A5 
Avasimibe, carbamazepine, phenytoin, rifampin, St. John’s 
wort 
CYP2B6, CYP2C9, CYP2C19 
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/ucm08
0499.htm. 
   
 
 
 

SAP_001.pdf: 
 
 
STATISTICAL ANALYSIS PLAN  
PROTOCOL TITLE 
A Phase II randomized, placebo-controlled study of GBT440 to 
evaluate the safety, tolerability, pharmacokinetics and effect on 
hypoxemia in subjects with Idiopathic Pulmonary Fibrosis (IPF) 
 
Sponsor:   
 
Global Blood Therapeutics, Inc. 
 
 
 
400 East Jamie Court, Suite 101 
 
 
 
South San Francisco, CA  94080 
 
Protocol Number: 
GBT440-006 
 
 
Author:   
 
Kalyani Kothapalli, MS 
 
 
 
Principal Biostatistician 
Statistics & Data Corporation 
 
Date:    
 
06Jul2017 
Version:  
 
1.0 




Protocol GBT440-006 SAP, Version 1.0 
 
06Jul2017 
Confidential & Proprietary 
Page 3 of 33 
 
 
Table of Contents 
1. 
Introduction .............................................................................................................................. 7 
2. 
Study Objectives ...................................................................................................................... 7 
3. 
Study Endpoints ....................................................................................................................... 8 
3.1 
Primary Endpoint ..................................................................................................................... 8 
3.2 
Secondary Endpoints ............................................................................................................... 8 
3.3 
Exploratory Endpoints .............................................................................................................. 8 
3.4 
Statistical Hypotheses .............................................................................................................. 8 
4. 
General Study Design .............................................................................................................. 9 
5. 
Schedule of Visits and Assessments ..................................................................................... 11 
5.1 
Schedule of Assessments ...................................................................................................... 12 
6. 
Study Treatments ................................................................................................................... 14 
6.1 
Method of Assigning Subjects to Treatment Groups ............................................................. 14 
6.2 
Dose Modifications and Adjustments ..................................................................................... 14 
6.3 
Blinding and Unblinding ......................................................................................................... 15 
7. 
Sample Size and Power Considerations ............................................................................... 15 
8. 
Data Preparation .................................................................................................................... 16 
9. 
Analysis Populations .............................................................................................................. 16 
9.1 
Safety Population ................................................................................................................... 16 
9.2 
Efficacy-Evaluable Population ............................................................................................... 16 
9.3 
PK Population ........................................................................................................................ 16 
10. 
General Statistical Considerations ......................................................................................... 16 
10.1 
Missing or Inconclusive Data Handling .................................................................................. 16 
10.1.1 
Start dates (e.g., AE onset date or start date of medication) ..................................... 17 
10.1.2 
Stop dates (e.g., AE resolution date or stop date of medication) .............................. 17 
10.2 
Definition of Baseline ............................................................................................................. 17 
10.3 
Data Analysis Conventions .................................................................................................... 17 
10.4 
Adjustments for Multiplicity .................................................................................................... 18 
11. 
Disposition of Subjects ........................................................................................................... 18 
12. 
Demographic and Baseline Characteristics ........................................................................... 19 
13. 
Targeted Medical History, Other Medical History, and Concomitant Medications ................ 19 
13.1 
Targeted Medical History ....................................................................................................... 19 
13.2 
Prior and Concomitant Medications ....................................................................................... 20 
14. 
Study Drug Administration, Extent of Exposure, and Dosing Compliance ............................ 20 


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14.1 
Study Drug Administration ..................................................................................................... 20 
14.2 
Extent of Exposure ................................................................................................................. 20 
14.3 
Dosing Compliance ................................................................................................................ 21 
15. 
Primary Analysis .................................................................................................................... 21 
15.1 
Analyses of Treatment-emergent Adverse Events and Serious Adverse Events ................. 21 
15.2 
Analyses of Other Safety Measures ...................................................................................... 22 
15.2.1 
Physical Examination ................................................................................................. 22 
15.2.2 
Vital Signs and Pulse Oximetry .................................................................................. 22 
15.2.3 
Electrocardiogram (ECG) ........................................................................................... 23 
15.2.4 
Clinical Laboratory Results ........................................................................................ 23 
16. 
Secondary Analyses of 6-Minute Walk Test .......................................................................... 23 
17. 
Exploratory Analyses ............................................................................................................. 24 
17.1 
6-Minute Walk Test ................................................................................................................ 24 
17.2 
Saint George’s Respiratory Questionnaire ............................................................................ 25 
17.3 
UCSD Shortness of Breath Questionnaire ............................................................................ 26 
17.4 
Borg Dyspnea Score during the 6-Minute Walk Test............................................................. 27 
17.5 
Cough Visual Analog Scale ................................................................................................... 27 
17.6 
A Tool to Assess Quality of Life (ATAQ) ................................................................................ 28 
17.6.1 
ATAQ Symptoms Domains ........................................................................................ 28 
17.6.2 
ATAQ Impacts Domains ............................................................................................ 29 
17.6.3 
Analysis of ATAQ Data .............................................................................................. 29 
17.7 
Cardiopulmonary Exercise Testing (CPET) ........................................................................... 30 
17.8 
Spirometry and DLco ............................................................................................................. 31 
17.9 
End of Study Questionnaire ................................................................................................... 31 
18. 
Interim Analyses .................................................................................................................... 32 
19. 
Changes from Protocol-Stated Analyses ............................................................................... 33 
20. 
References ............................................................................................................................. 33 
21. 
Appendices ............................................................................................................................ 33 
 
 
 


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List of Abbreviations 
6MWT 
6-Minute Walk Test 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Aminotransferase 
ATAQ 
A Tool to Assess Quality of Life 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Curve 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
CI 
Confidence Interval 
CPET 
Cardiopulmonary Exercise Test 
CRF 
Case Report Form 
CS 
Clinically Significant 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBP 
Diastolic Blood Pressure 
DLco 
Diffusing Capacity of the Lung for Carbon Monoxide 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ETCO2 
End Tidal Carbon Dioxide 
ETO2 
End Tidal Oxygen 
FEV1 
Forced Expiratory Volume in 1 second 
FVC 
Forced Vital Capacity 
GGT 
Gamma Glutamyl-transferase 
HR 
Heart Rate 
ICH 
International Conference on Harmonisation 
INR 
International Normalized Ratio 
IQR 
Interquartile Range 
IPF 
Idiopathic Pulmonary Fibrosis 
IxRS 
Interactive Response System 
LactThrsh 
Lactic Acid Threshold 
LFT 
Liver Function Tests 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCS 
Not clinically significant 
PDF 
Portable Document Format 
PK 
Pharmacokinetics 
PP 
Per-protocol 
PPT 
Partial Prothrombin Time 
PR 
Pulse Rate 
PRO 
Patient-Reported Outcomes 


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PT 
Preferred Term 
RBC 
Red Blood Cells 
RER 
Respiratory Exchange Ratio 
RR 
Respiratory Rate 
RTF 
Rich Text Format 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SDC 
Statistics and Data Corporation, Incorporated 
SGRQ 
Saint George’s Respiratory Questionnaire 
SMC 
Safety Monitoring Committee 
SOC 
System Organ Class 
SpO2 
Peripheral Oxygen Saturation 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-Emergent Adverse Event 
TIBC 
Total Iron Binding Capacity 
TVOL 
Tidal Volume 
UCSD 
University of California San Diego 
VAS 
Visual Analog Scale 
VentThrsh 
Ventilatory Threshold 
VCO2 
Carbon Dioxide Production 
VO2 
Oxygen Production 
WBC 
White Blood Cells 
WCT 
Worldwide Clinical Trials 
WHO DDE 
World Health Organization Drug Dictionary Enhanced 
 
 
 


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1. Introduction 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and reporting for 
protocol GBT440-006, version Amendment 3, dated December 21, 2016. 
This SAP is being written with due consideration of the recommendations outlined in the most recent 
International Conference on Harmonization (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials and the most recent ICH E3 Guideline, entitled Guidance for Industry: 
Structure and Content of Clinical Study Reports. 
This SAP describes the data that will be analyzed and the subject characteristics, efficacy, and safety 
assessments that will be evaluated.  This SAP provides details of the specific statistical methods that 
will be used.  The statistical analysis methods presented in this document will supersede the statistical 
analysis methods described in the clinical protocol.  If additional analyses are required to supplement 
the planned analyses described in this SAP they may be completed and will be identified in the clinical 
study report (CSR). 
Planned pharmacokinetic (PK) analyses will be described in a separate analysis plan. 
2. Study Objectives 
Primary Objective: 
To evaluate the safety and tolerability of multiple doses of GBT440 administered to subjects with 
IPF. 
Secondary Objectives: 
• 
To evaluate the effect of GBT440 on oxygen saturation at Days 15 and 28 compared to baseline 
during the 6-minute walk testing (6MWT). 
• 
To evaluate the pharmacokinetic (PK) parameters of GBT440 in plasma and whole blood. 
Exploratory Objectives: 
• 
To evaluate the effect of GBT440 on distance walked during the 6MWT at Days 15 and 28 
compared to baseline.  
• 
To evaluate the effect of GBT440 on IPF-related symptoms using patient reported outcomes 
(PROs) at Day 28 compared to baseline. 
• 
To evaluate the effect of GBT440 on cardiopulmonary exercise testing (CPET) parameters at 
Day 29 compared to baseline. 
• 
To evaluate pulmonary function, including assessment of spirometry and Diffusing Capacity of 
the Lung for Carbon Monoxide (DLco) at Day 28 compared to baseline. 


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• 
To evaluate the PK-PD relationship of GBT440 at Days 15 and 28 compared to baseline. 
3. Study Endpoints 
3.1 
Primary Endpoint 
The primary endpoint is treatment-emergent adverse events (TEAE) and tolerability. 
3.2 
Secondary Endpoints 
• 
Change and percentage change from baseline in resting peripheral oxygen saturation (SpO2) at 
Days 15 and 28 measured prior to beginning the 6MWT. 
• 
Change and percentage change from baseline in end-of-6MWT SpO2 at Days 15 and 28. 
• 
Change and percentage change from baseline in lowest SpO2 value measured during the 6MWT at 
Days 15 and 28. 
• 
Pharmacokinetic (PK) parameters of GBT440 in plasma and whole blood, including but not limited 
to maximum concentration (Cmax), minimum concentration (Cmin) at steady state in GBT440 
treated subjects. 
3.3 
Exploratory Endpoints 
• 
Change and percentage change from baseline in distance walked during the 6MWT at Days 15 and 
28. 
• 
Time to first SpO2 < 88% that is sustained for at least 10 seconds during the 6MWT at Days 15 and 
28. 
• 
Area under the SpO2 curve (AUC) during the 6MWT measured at baseline, Day 15 and Day 28. 
• 
Change from baseline in PRO scores using Saint George’s Repiratory Questionnaire (SGRQ), 
University of California, San Diego (UCSD) Shortness of Breath Questionnaire, A Tool to Assess 
Quality of Life (ATAQ) in IPF (only subjects enrolled in Part B), and the Borg Scale of Perceived 
Exertion questionnaires and cough visual analog scale (VAS) at Days 15 and 28. 
• 
Change and percentage change from baseline in cardiopulmonary exercise testing parameters at 
Day 29. 
• 
Change and percentage change from baseline in lung function, including forced vital capacity (FVC) 
and DLco at Day 28. 
• 
PK/PD relationship in subjects receiving GBT440 from Baseline to Days 15 and 28 
3.4 
Statistical Hypotheses 
This phase 2 study is designed to evaluate the safety and tolerability of multiple doses of GBT440 
administered to subjects with IPF.  No formal hypotheses are specified for this study. 


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4. General Study Design 
This study is a randomized, placebo-controlled trial that will be conducted in two parts. Together, Parts 
A and B will provide safety and efficacy data across a range of GBT440 doses that are expected to 
improve oxygen saturation in the enrolled subjects. 
• 
In Part A (Figure 1), eligible IPF subjects will be randomized 1:1:1 to receive GBT440 900 mg 
(n = 6) or 600 mg (n = 6), or placebo (n = 6) administered orally as 300 mg capsules once daily for 
28 days.  The study site, subjects, CRO statistician and Sponsor will be blinded to study treatment.  
• 
In Part B (Figure 2), eligible IPF subjects will be randomized 3:1:1 to receive GBT440 1500 mg 
(n = 9) or 600 mg (n = 3), or placebo (n = 3) administered orally as 300 mg capsules once daily for 
28 days in which the study site and subjects are blinded to study treatment.  The Sponsor and 
CRO statistician will be unblinded to study treatment. 
Subjects on a stable dose of pirfenidone or nintedanib and/or N-acetyl cysteine are eligible for entry into 
the study. 
After the Screening visit, the study includes the following study periods: 
• 
Treatment period (28 days): subjects will be randomized (1:1:1) to one of three treatment groups in 
Part A and randomized (3:1:1) to one of three treatment groups in Part B; subjects will receive:  
Part A: 
• 
Group 1: GBT440 900 mg; three 300 mg GBT440 capsules, daily orally.  
• 
Group 2: GBT440 600 mg; two 300 mg GBT440 capsules and one placebo capsule, daily orally. 
• 
Group 3: Placebo: three placebo capsules, daily orally. 
Part B: 
• 
Group 1: GBT440 1500 mg; five, 300 mg GBT440 capsules, daily orally.  
• 
Group 2: GBT440 600 mg; two 300 mg GBT440 capsules and three placebo capsule, daily 
orally. 
• 
Group 3: Placebo: five placebo capsules, daily orally. 
• 
Safety follow-up (30 days): safety will be assessed for at least 5 half-lives after the last dose of 
GBT440. 
 
 


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Figure 1 
Study Design – Part A 
 
Figure 2 
Study Design – Part B 
 
Subjects who do not complete at least 10 days of dosing for reasons unrelated to toxicity may be 
replaced. 
In Part A, two unblinded interim analyses of the primary and secondary endpoints are planned: i) when 
approximately 9 subjects have completed their Day 28 study visit and ii) when approximately 18 
subjects have completed their Day 15 study visit.  
A Safety Monitoring Committee (SMC) is planned to review all safety data on an ongoing basis 
throughout the study (refer to Protocol Section 10.1).  If the SMC does not identify any clinically 


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significant safety concerns in Part A, following review of data from approximately 18 subjects who 
have completed Day 15, the Sponsor will initiate Part B of the study, and randomize up to an 
additional 15 subjects to the three study treatment arms to better characterize the safety, tolerability, 
and potential treatment response of GBT440 in subjects with IPF.  
In the eventuality that one treatment arm is discontinued, subjects may be randomized 1:1 to the 
remaining study drug treatment group or placebo.  Therefore, the trial size is approximately 33 
subjects. 
The end of the study is defined as the date when the last subject completes the last visit, which is 
expected to occur approximately 58 days after the last subject is randomized. 
5. Schedule of Visits and Assessments 
The schedule of visits and assessments and PK sampling timepoints are provided below. 
 


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5.1 
Schedule of Assessments 
Study Day (Window) 
Screeninga 
 
Treatment Period 
Follow-up Visits 
Day -21 to 
Day -1 
Day 1 
Day 2 
Day 8 
(+/- 2) 
Day 15 
(+/- 2) 
Day 28 
(+/- 2) 
Day 29 
(+3) 
Day 45b 
(+/- 3) 
Day 58 
(+/- 3) 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Informed Consentc 
X 
 
 
 
 
 
 
 
 
Eligibility Assessment 
X 
X 
 
 
 
 
 
 
 
Demographic data 
X 
Xd 
 
 
 
 
 
 
 
Medical History and baseline conditions 
 
Xd 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete Physical Examinatione 
X 
 
 
 
 
 
 
 
X 
Limited Physical Examinationf 
 
X 
 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
X 
 
 
 
Vital Signsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SpO2h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG (12-lead)i 
X 
 
 
X 
X 
X 
 
X 
X 
Adverse Eventsj 
Xj 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Pregnancy Test (females only)k 
X 
 
 
 
 
 
 
 
 
Urine Pregnancy Test (females only)l 
 
 
 
X 
X 
X 
 
X 
X 
Hematology 
X 
 
 
X 
X 
X 
 
X 
X 
Serum Chemistry 
X 
 
 
X 
X 
X 
 
X 
X 
Urinalysis 
X 
 
 
 
X 
X 
 
X 
X 
Coagulation Panel (PT, PTT, INR) 
X 
 
 
 
 
X 
 
 
 
Serum Erythropoietin 
X 
 
 
 
 
X 
 
X 
X 
Serology (Hepatitis A, B, C, and HIV) 
X 
 
 
 
 
 
 
 
 
PK Blood Samplesm 
 
X 
X 
X 
X 
X 
 
X 
X 
Spirometry and DLCO 
X 
 
 
 
 
X 
 
 
X 
6-Minute Walk Testn 
Xn 
 
 
 
X 
X 
 
 
X 
Cardiopulmonary Exercise Testingn 
 
 
X 
 
 
 
X 
 
 
Randomization (IxRS) 
 
X 
 
 
 
 
 
 
 
Study Drug Dispensing to Subjecto) 
 
 
X 
X 
X 
 
 
 
 
Study Drug Administration at sitep 
 
X 
X 
X 
X 
X 
 
 
 
St. George’s Respiratory Questionnaireq 
 
X 
 
X 
X 
X 
 
X 
X 


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UCSD Shortness of Breath Questionnaireq 
 
X 
 
X 
X 
X 
 
X 
X 
ATAQ-IPF Symptomsq 
 
X 
 
X 
X 
X 
 
X 
X 
ATAQ-Impactsq 
 
X 
 
X 
X 
X 
 
X 
X 
End of Study Questionnairer 
 
 
 
 
 
 
 
 
X 
Cough Visual Analog Scaleq 
 
X 
 
X 
X 
X 
 
X 
X 
Abbreviations: ATAQ = A Tool to Assess Quality of Life; DLco = lung diffusing capacity measured using carbon monoxide; ECG = electrocardiogram; HIV = human immunodeficiency virus; 
INR = international normalized ratio; PK = pharmacokinetic; PRO = patient reported outcome; PT = prothrombin time; PTT = partial thromboplastin time; SGRQ = St. George’s Respiratory 
Questionnaire, SpO2 = oxygen saturation measured by pulse oximetry; UCSD = University of California San Diego. 
Note: All assessments should be performed within the number of days (Window) as indicated for each scheduled visit day. All assessments should be performed prior to receiving study drug 
during the treatment period unless otherwise indicated. SGRQ, UCSD, Cough VAS should be performed before all other non-PRO assessments, followed by 12-lead ECG and then vital sign 
assessments 
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 randomization to the treatment period.  In 
cases when the screening 6MWT is done more than 7 days prior to Visit 2, it must be repeated, up and through Day 1, prior to any Day 1 assessments. 
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 Day 45 (Visit 8) assessments (refer to Protocol 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 at this visit and any changes since screening updated in the eCRF. 
e 
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 
f 
Perform a limited, symptom-directed examination as clinically indicated.  Record new or worsened clinically significant findings in the eCRF. 
g 
Includes heart rate, respiratory rate, systolic and diastolic blood pressure and temperature measured whilst in a semi-recumbent or supine position and resting for at least 5 minutes. 
h 
Performed while the subject is seated and resting for at least 5 minutes. 
i 
Perform 12-lead ECG in triplicate; three separate tracings with approximately 1 minute between each tracing, after resting in a semi-recumbent or supine position for at least 5 
minutes. 
j 
After informed consent but prior to randomization only serious adverse events (SAEs) resulting from a protocol-mandated intervention should be reported. After randomization all 
adverse events will be reported until study completion (Day 58). 
k 
Performed for all female patients who are not post-menopausal or surgically sterile 
l 
If a urine pregnancy test is positive the result must be confirmed with a serum pregnancy test. 
m 
PK blood samples during the treatment period should be collected on Days 1 and 28: pre-dose, and 2 hours post dose (+/- 15 minutes); Day 2: 24 hours (+/- 2 hours) after the Day-1 
dose and prior to receiving the Day-2 dose; Days 8 & 15: pre-dose only.  Also see Protocol Section 5.6. 
n 
Instructions for per-protocol performance of the 6-minute walk (and Borg dyspnea scale) and cardio-pulmonary exercise tests are provided in the procedure manual.  Note: The 
baseline 6MWT performed during screening must be performed within 7 days of the Day-1 visit. 
o 
An unblinded study pharmacist will prepare daily doses of study drug, dispensed into 30 mL high-density polyethylene (HDPE) bottles.  Each bottle (or dose) is packaged individually 
with 3 capsules of active or placebo or both specific to each subject’s assigned treatment group.  Subjects who have their dose modified during the study must return to the site to 
have the modified dose of study drug dispensed by the unblinded pharmacist. 
p 
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. 
q 
The SGRQ, ATAQ, and UCSD questionnaires and cough VAS 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 patient receives any disease-status information during that assessment.  ATAQ questionnaires should be administered to subjects enrolled in Part b of 
the study. 
r 
The End of Study Questionnaire should be administered to subjects enrolled in Part B of the study. 
 


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6. Study Treatments 
The study drug is GBT440 300 mg capsules or placebo. 
Subjects randomized to the following treatment groups in Part A will receive: 
• 
GBT440 900 mg -- 3 GBT440 300 mg capsules 
• 
GBT440 600 mg -- 2 GBT440 300 mg capsules and 1 placebo capsule. 
• 
Placebo -- 3 placebo capsules. 
Subjects randomized to the following treatment groups in Part B will receive: 
• 
GBT440 1500 mg -- 5 GBT440 300 mg capsules 
• 
GBT440 600 mg -- 2 GBT440 300 mg capsules and 3 placebo capsules. 
• 
Placebo -- 5 placebo capsules. 
Study drug is to be dosed orally once daily for a total of 28 days. 
6.1 
Method of Assigning Subjects to Treatment Groups 
Subject randomization will be carried out centrally through an IxRS.  Eligible subjects in Part A will be 
randomized 1:1:1 to receive 900 mg GBT440, 600 mg GBT440, or Placebo. Eligible subjects in Part B 
will be randomized 3:1:1 to receive 1500 mg GBT440, 600 mg GBT440, or placebo respectively. 
The randomization will be stratified by background IPF therapy (pirfenidone/nintedanib or no 
pirfenidone/nintedanib) use at the time of entry into the study. 
6.2 
Dose Modifications and Adjustments 
Modification of study drug dosing may be considered if, in the opinion of the study Investigator, an AE 
may be related to study drug and it would be unsafe for the subject to continue receiving their current 
dose of study drug. 
Dose adjustments may be initiated by the Investigator based on their assessment of the associated AE 
severity and overall subject safety and in discussion with the Sponsor’s Medical Director. 
The Investigator, in discussion with the Sponsor’s Medical Director, may choose to: 
• 
Change dosing frequency, to one capsule 3 times per day 
• 
Reduce the total daily dose 
A reduction in dose should be by one active study drug capsule.  Dose reductions will require the subject 
to return to the study site for the unblinded pharmacist to dispense new study drug capsules.  Subjects 
in Part A will continue to take 3 capsules per day.  Subjects in Part B will continue to take 5 capsules 
per day. 


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A second dose reduction by one active study drug capsule 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 discussion with the Sponsor’s Medical 
Director. 
The Investigator must make every effort to restart the dosing regimen assigned to the subject at 
randomization when, in the investigator’s opinion, it is safe to do so. 
6.3 
Blinding and Unblinding 
An independent biostatistician who is not otherwise involved in the trial will generate the randomized 
study drug assignment list for Part A of the study.  The subject, study team, Investigators, and study 
staff will be blinded during the randomization process and throughout the duration of the study.  The 
Sponsor and CRO statistician will be unblinded to the treatment assignments when a minimum of 18 
treated subjects in Part A complete at least 28 days of study.  Sponsor representatives not involved in 
the conduct of the study will have access to unblinded treatment data throughout the conduct of the 
study. 
The CRO statistician will generate the randomized study drug assignment list for Part B of the study.  
The Investigators, study staff, and CRO data manager will remain blinded to treatment assignments in 
Part B of the study.  The Sponsor and CRO statistician will not be blinded to treatment assignments in 
Part B of the study. 
The randomization lists will reside on a secure server to which members of the study team will not have 
access until the study is unblinded per the protocol. 
If at any time during the study a decision about a subject’s medical condition requires knowledge of the 
treatment assignment, the study blind may be broken (through the interactive response system [IxRS]) 
for that specific subject only.  If, in the opinion of the Investigator, there is no impact on subject safety, 
the Investigator is encouraged to contact the Sponsor’s Medical Director prior to unblinding.  The reason 
for unblinding must be documented in the appropriate section of the case report form (eCRF). 
The SMC must be informed by the Sponsor’s Medical Director of any case of unblinding.  Additionally, 
the SMC may unblind any individual treatment assignment for further safety evaluation at their 
discretion. 
7. Sample Size and Power Considerations 
The sample size in this study was not selected based on statistical considerations but to determine 
preliminary safety, tolerability, PK, laboratory and clinical effects of GBT440 in IPF subjects. 
The study will enroll approximately 33 subjects: approximately 18 subjects in Part A and approximately 
15 subjects in Part B. 


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8. Data Preparation 
All reported study data will be recorded on the eCRFs supplied by Worldwide Clinical Trials (WCT) using 
eClincialOSTM, version 2016.5.0.  All data collected on the eCRF will be mapped from the clinical 
database to the appropriate Clinical Data Interchange Standards Consortium (CDISC) Study Data 
Tabulation Model (SDTM) domains (Implementation Guide version 3.2).  Analysis datasets will be 
mapped to the CDISC analysis data model (ADaM) using the ADaM Implementation Guide (version 1.1) 
for all data presented in summary tables and figures.  Listings will generated from SDTM domains or 
ADaM datasets as appropriate. 
The final analyses for this study will be carried out after the following have occurred: 
• 
All data management requirements are met according to WCT standard operating procedures, 
including data entry, performance of edit and validation checks, documentation and resolution 
of data queries, and database lock with written authorization provided by appropriate WCT 
and Sponsor personnel; 
• 
Protocol deviations have been identified and status defined (major/minor deviations); and 
• 
Analysis populations have been determined 
9. Analysis Populations 
9.1 
Safety Population 
All subjects who receive any amount of study drug will be included in the Safety population.  Subjects 
will be analyzed based on study drug received.  This is the primary population for all safety analyses 
performed for this study. 
9.2 
Efficacy-Evaluable Population 
All randomized subjects who received at least 14 days of study drug treatment will be included in the 
Efficacy-Evaluable population.  The Efficacy-Evaluable population will be used for analysis of all 
secondary and exploratory efficacy endpoints, and subjects will be analyzed as treated. 
9.3 
PK Population 
All subjects who receive investigational treatment and provide adequate data to evaluate the relevant 
PK parameter will be included in the PK population.  The PK population will not be used for analyses 
described in this statistical analysis plan (SAP). 
10. General Statistical Considerations 
10.1 
Missing or Inconclusive Data Handling 
If only a partial date is available and is required for a calculation of whether a medication is concomitant 
or an AE is treatment-emergent, the following standards will be applied: 


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10.1.1 Start dates (e.g., AE onset date or start date of medication) 
• 
For missing start day only - Day will be imputed as the first day of the month (i.e., 1) with the 
following exception: if the partial date falls in the same month and year as the date being used 
in the calculation (e.g., first dose date, informed consent date), then the partial date will be 
imputed to equal the date being used for the calculation. 
• 
For missing start day and month - Day and month will be imputed as the first day of the year 
(i.e., 1 January) with the following exception: if the partial date falls in the same year as the date 
being used in the calculation (e.g., first dose date, informed consent date), then the partial date 
will be imputed to equal the date being used for the calculation. 
10.1.2 Stop dates (e.g., AE resolution date or stop date of medication) 
• 
For missing stop day only - Day will be imputed as the last day of the month (i.e., 28, 29, 30, or 
31) 
• 
For missing stop day and month - Day and month will be imputed as the last day of the year 
(i.e., 31 December) 
Any partial dates will be displayed in data listings without imputation of missing days and/or months 
(e.g., MAR2011, 2009).  No other imputation of missing data will be performed. 
No imputation methods will be used for analysis of missing efficacy data in this study. 
10.2 
Definition of Baseline 
For all endpoints, baseline is defined as the last non-missing measure or the average of the non-missing 
measures before the first dose of study drug.  Change from baseline to follow-up visit will be calculated 
as the baseline measurement subtracted from the follow-up measurement for all assessments with the 
exception of the CPET endpoints.  The first measurements for CPET endpoints occur at Study Day 2.  
The change from Day 2 to Day 29 will be calculated as the Day-2 measurement subtracted from the 
Day-29 measurement for all CPET endpoints. 
The percent change from baseline values to post-baseline values will be calculated using the following 
formula where applicable: 
([post-baseline value – baseline value] / baseline value) × 100% 
10.3 
Data Analysis Conventions 
Analyses for SMC meetings, interim analyses, and final data analysis will be performed by Statistics & 
Data Corporation (SDC).  The final data analyses will be performed after Part B of the study is completed 
and the database has been locked.  Data from Parts A and B of the study will be pooled across the 
common treatment arms (GBT440 600 mg and placebo arms).  Statistical programming and analyses 
will be performed using SAS® Version 9.4 or higher.  All study data will be listed by subject, study drug, 


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and visit (as applicable) based on randomized and treated subjects unless otherwise specified.  
Summary statistics will be presented by treatment group including all GBT440, and will include a total 
column where appropriate. 
Study visits will be referred to in all tables and listings as the visit name corresponding to the planned 
study visit. 
Summaries for continuous and ordinal variables will include the number of observations (n), arithmetic 
mean, standard deviation (SD), median, minimum, and maximum).  Minima and maxima will be reported 
with the same precision as the raw values; means and medians will be presented to one additional 
decimal place than reported in the raw values.  Standard deviations will be presented to two additional 
decimal places than reported in the raw values.  Summaries for discrete variables will include frequency 
counts and percentages.  All percentages will be rounded to one decimal place (i.e., XX.X%). 
All statistical tests will be two-sided with a significance level of 0.05 (α = 0.05) unless otherwise specified.  
Confidence intervals (CI) for differences between treatment groups will be two-sided at 95% confidence.  
All p values will be rounded to four decimal places; p-values less than 0.0001 will be presented as 
“<0.0001”; p-values greater than 0.9999 will be presented as “>0.9999”.   
All summary tables will be supported with subject listings. 
10.4 
Adjustments for Multiplicity 
As this is a phase 2 study for which there is no pre-determined power to show a difference to a control, 
there will be no multiplicity adjustments in this study. 
11. Disposition of Subjects 
Subject disposition will be presented in terms of the numbers and percentages of subjects who were 
randomized and completed study treatment, completed the study, and discontinued from the study.  
Subjects who are not discontinued from the study will be considered study completers.  The number of 
subjects in the Safety and Efficacy-Evaluable populations will be displayed by study drug, and 
percentages will be calculated using subjects in the Safety population as the denominator. 
The number and percentage of subjects prematurely discontinued from the study and the reasons for 
study discontinuation will be summarized by treatment group for all subjects in the Safety population.  
The reasons for study discontinuation that will be summarized include: subject withdrawal of consent, 
discretion of the investigator, SMC recommendation, subject is lost to follow up, and other. 
Other subject listings will include a listing of inclusion and exclusion criteria violations, a listing of major 
protocol deviations, and a listing of screen failures with the reasons for screen failure. 


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12. Demographic and Baseline Characteristics 
The demographic variables collected in this study include age, gender, race, and ethnicity.  Subjects 
who record more than one race will be grouped into a single category denoted as multiple.  Additionally, 
the number and percentage of subjects in each treatment group who are on background pirfenidone or 
nintedanib will be included.  Demographic variables will be summarized for the Safety population.  
Age (years) will be summarized by study drug, using continuous descriptive statistics.  Age will be 
reported in years and calculated using the following formula: 
Age = ((consent date – date of birth) / 365.25) truncated as an integer 
The number and percentage of subjects will be presented by treatment group, all GBT440, and all 
subjects. 
The subject listing will include all demographic variables including the non-childbearing potential for 
female subjects. 
13. Targeted Medical History, Other Medical History, and Concomitant Medications 
13.1 
Targeted Medical History 
Medical history events identified as targeted medical history will be summarized with the number and 
percent of subjects in each treatment group, and for all GBT 440 subjects, who experienced each event.  
The targeted medical history events that will be summarized are as follows: 
• 
Cancer (including cancer therapies and procedures) 
• 
Inflammatory/Autoimmune Disorders 
• 
Primary Hypertension (including grade of severity and medications taken) 
• 
Pulmonary Rehabilitation 
• 
Gastroesophageal Reflux (including medications taken) 
• 
Sleep-Disordered Breathing/Sleep Apnea (including use of non-invasive ventilation, surgeries, and 
medications taken) 
• 
Pulmonary Embolism (including medications taken) 
• 
Lactose Intolerance (including medications taken) 
Other medical history will be summarized using discrete summary statistics and will be presented by 
study drug at the subject and event level by System Organ Class (SOC) and Preferred Term (PT) using 
the Safety population.  If a subject reports the same PT multiple times within the same SOC, that PT will 
only be reported once within that SOC.  As with the PT, if a subject reports multiple conditions within the 
same SOC, that SOC will only be reported once.  Other medical history will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA), version 19.0. 


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All medical history data will be listed. 
13.2 
Prior and Concomitant Medications 
Concomitant medications will be coded using the World Health Organization (WHO) Drug Dictionary 
(Enhanced B2, March, 2016) and summarized to the therapeutic drug class (Anatomical Therapeutic 
Chemical (ATC) 4 classification) and preferred name.  Medications with missing ATC codes will be 
classified as “uncoded”. 
Concomitant medications are defined as those medications having been taken 1) prior to initiation of 
study drug administration and continuing for any period of time following the first administration of study 
drug or 2) at any time following the first administration of study drug and within 30 days of last dose. 
14. Study Drug Administration, Extent of Exposure, and Dosing Compliance 
14.1 
Study Drug Administration 
The number and percent of subjects who completed study administration will be summarized with the 
number and percentage of subjects in each treatment group and for all GBT440 using the Safety 
population.  A subject will be defined to have “Completed Study Drug Administration” if the subject has 
a record for study drug administration corresponding to the Day-28 visit (Visit 6) and a response of “No” 
has been entered for the question, “Was study drug permanently discontinued?” on the Study Drug CRF 
for the same visit. 
The number and percentage of subjects who permanently discontinued study drug, and the reason for 
discontinuation (adverse event (AE) or other) will be summarized by study drug and for all GBT440.  
The number and percentage of subjects who missed at least 1 dose of study drug, had at least 1 dose 
reduction, or had at least 1 dose interruption will be summarized by study drug and for all GBT440.  The 
summary will include the number and percentage of subjects who had a dose reduction or dose 
interruption due to an adverse event.  Additionally, the number and percentage of subjects grouped by 
number of doses missed, number of dose reductions, and number of dose interruptions will be 
summarized by study drug and all GBT440. 
14.2 
Extent of Exposure 
Extent of treatment exposure for completed or discontinued subjects will be calculated in days using the 
following: 
Extent of Exposure (days) = (Date of last dose – date of first dose [Day 1]) + 1 – (Number of Missed 
Doses + Number of Days with Dose Interruption) 
Extent of exposure (days) will be summarized with continuous descriptive statistics using the Safety 
population. 


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14.3 
Dosing Compliance 
Dosing compliance will be calculated using the following: 
Dosing Compliance (%) = 
Sum of the Actual Days Dosed (days) 
x 100% 
Sum of Expected Days Dosed 
The actual days dosed is defined as the sum of the days a subject was dosed. The number of expected 
days dosed that will be used for calculating dosing compliance will be calculated as (date of last dose – 
date of Day1 dosing +1) for all subjects, regardless of study completion status.  
Dosing compliance will be summarized with continuous descriptive statistics for each treatment group, 
using the Safety population.   
Study drug administration (including extent of exposure and dosing compliance) will be listed for all 
subjects who received at least 1 dose of study drug. 
15. Primary Analysis 
The primary endpoint in this study is treatment-emergent adverse events and tolerability.  All safety 
analyses will be conducted using the Safety population. 
15.1 
Analyses of Treatment-emergent Adverse Events and Serious Adverse Events 
TEAEs are defined as any event that occurs or worsens on or after the first dose of study drug and 
within 30 days after the last dose.  Adverse events recorded in the eCRF which began prior to first dose 
of study drug will not be included in the summary tables but will be included in the AE data listings. 
Adverse events reported for subjects participating in this study will be graded using the National Cancer 
Institute’s (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03.  All AEs will 
be coded using the using MedDRA, version 19.0. 
An overall summary will be presented that includes the number of TEAEs and the number and 
percentage of subjects who experienced at least one TEAE, by study drug and all GBT440.  This 
summary will also include the number of Grade 3 or greater TEAEs, the number and percentage of 
subjects with at least 1 TEAE ≥ Grade 3, the number of possibly/probably related TEAEs, the number 
and percentage of subjects with at least 1 possibly/probably related TEAE,  the number of serious 
adverse events (SAEs), the number and percentage of subjects with at least 1 SAE, the number of 
TEAEs leading to study drug discontinuation, the number and percentage of subjects who discontinued 
study drug due to TEAEs, and the number and percentage of deaths. 
Additional summaries of TEAEs by study drug and all GBT440 will include the following: 
• 
Incidence of TEAEs by SOC and PT 


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• 
Incidence of TEAEs by SOC and PT by antifibrotic use 
• 
Incidence of TEAEs of Special Interest by SOC and PT 
o 
(If less than 5 events occur in each treatment group, then only a listing will be created) 
• 
Incidence of TEAEs by SOC, PT, and Maximum Severity 
• 
Incidence of TEAEs by SOC, PT, and Maximum Severity by antifibrotic use 
• 
Incidence of TEAEs Resulting in Discontinuation of Study Drug 
• 
Incidence of TEAEs Possibly/Probably Related to Study Drug 
o 
(If less than 5 events occur in each treatment group, then only listing will be created) 
• 
Incidence of SAEs 
All summaries will be provided showing the number and percentage of subjects who experienced at 
least one TEAE.  TEAEs will be summarized using discrete summary statistics (number and percentage 
of subjects) and will be presented by study drug and total GBT 440 by SOC and PT.  If a subject reports 
the same PT multiple times within the same SOC, that PT will only be reported once within that SOC.  
As with the PT, if a subject reports multiple conditions within the same SOC, that SOC will only be 
reported once.  Summaries will list SOC in ascending alphabetical order, and PTs will be listed in order 
of descending frequency for all GBT440 subjects within each SOC.   
Separate subject listings of AEs will be provided for all AEs, TEAEs Resulting in Discontinuation of Drug, 
SAEs, and Deaths. 
15.2 
Analyses of Other Safety Measures 
15.2.1 Physical Examination 
The physical examination results, height (cm), weight (kg), and body mass index (BMI) (kg/m2) will be 
summarized by study drug and all GBT 440 using summary statistics (number of subjects, mean, 
standard deviation, median, minimum, and maximum) by each applicable visit (Screening [Baseline], 
and Day 28, ) in the Safety population.  Height will be summarized only for Screening, and the screening 
height will be used for the calculation of BMI at Day 28.  Weight collected at visits other than those 
specified in the protocol will be included in the summary for completeness.  A subject listing of all 
physical exam results will be generated. 
15.2.2 Vital Signs and Pulse Oximetry 
Vital signs, including systolic blood pressure (SBP [millimeters of mercury (mmHg)]), diastolic blood 
pressure (DBP [mmHg]), heart rate (HR [beats per minute (bpm)]), respiratory rate (RR [bpm]), body 
temperature (degrees Celsius), and SpO2 (%), will be summarized with continuous descriptive statistics 
at each visit by study drug and for all GBT 440 subjects in the Safety population.  Change from baseline 
and percent change from baseline to each post-baseline visit also will be summarized.   


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15.2.3 Electrocardiogram (ECG) 
HR (bpm), PR interval (milliseconds [ms]), QRS interval (ms), QT interval (ms), and QT interval with 
Fridericia’s correction (QTcF [ms]) will be summarized using descriptive statistics by study drug and all 
GBT440 by visit in the Safety population.  When all electrocardiogram (ECG) parameters, except for the 
QTcF interval, are collected at the site, the QTcF interval will be calculated using the following formula: 
QTcF = QT / (60/HR)1/3 
Change from baseline to each post-baseline visit also will be summarized by study drug and all GBT 
440.  ECG triplicates will be averaged for summary tables.  Each triplicate and the average of triplicates 
will be provided in a subject listing for Baseline, Day 8, Day 15, Day 28, Day 45, and Day 58. 
Additionally, the number and percentage of subjects with QTcF > 450 ms, > 480 ms, and > 500 ms at 
baseline and as the maximum post-baseline measurement will be summarized.  The number and 
percentage of subjects with maximum increase from baseline where increase in QTcF > 30 ms and  
> 60 ms will be included in the summary. 
A subject listing of ECG parameters will include each triplicate and the average of triplicates for each 
visit. 
15.2.4 Clinical Laboratory Results 
Clinical laboratory data including serum chemistry, liver function tests, serum hematology, serum 
erythropoietin, coagulation panel, and urinalysis are collected at specified visits.  The quantitative 
variables will be summarized by study drug and all GT440 with continuous descriptive statistics for each 
visit in the Safety population.  Urinalysis results will be presented only as a subject listing.  Change from 
baseline and the percent change from baseline will also be summarized by study drug and all GBT 440.  
Units for laboratory results will be converted from reported units to SI units in the SDTM datasets.  
Reported results and units will be used for the summary tables. 
Subject listings of laboratory data will include a separate listing for clinically significant laboratory values 
in addition to subject listings of all laboratory values.  Listings will be presented with reported units and 
SI units.  Pregnancy test results for both serum and urinalysis sampling will be provided in a separate 
listing. 
16. Secondary Analyses of 6-Minute Walk Test 
The 6-Minute Walk Test is a multiple period assessment that includes a resting period (first minute 
before the walking portion), the 6-minute walking period, and a post-walking period that includes results 
at each minute for 2 minutes upon completion of walking.  End of exercise is defined as last SpO2 
immediately at end of 6MWT (not including the post-walking period).  Blood pressure is collected at rest 


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and at each minute post walking.  The distance walked (meters) is recorded at the end of the walking 
period. 
Results of the 6-Minute Walk test (6MWT) will be summarized by study drug and all GBT440 at the 
following visits: Baseline (Screening or repeat at Day 1 if applicable), Day 15, Day 28, and Day 58.  The 
number and percentage of subjects in each treatment group and all GBT 440 who completed the 6MWT, 
experienced myocardial infarction (MI) or unstable angina in the previous 30 days before the 6MWT, 
and utilized oxygen during the 6MWT will be summarized.  Summary statistics (N, mean, SD, median, 
min, and max) will be displayed for systolic and diastolic blood pressure collected at rest and at each 
minute post-walking. 
Subject listings will be provided for all 6MWT data collected on the eCRF. 
Summary statistics for resting SpO2, SpO2 at end of the 6MWT (last available result) and lowest SpO2 
collected during the 6MWT will be summarized at each visit by study drug and all GBT440 in the 
Efficacy-Evaluable population.  Summary statistics for the change and percent change from baseline to 
Day 15, Day 28, and Day 58 also will be displayed. 
Analysis of covariance models (ANCOVA) will be used to analyze the effect of treatment on the change 
from baseline and the percent change from baseline for each secondary endpoint with baseline value 
as a covariate.  Least squares (LS) means and SEs will be displayed for the change and percent change 
from baseline in each treatment group and for all GBT440. 
LS means (95% CI) and p-values from the models will be used to make the following comparisons: 
• 
GBT440 600 mg – Placebo 
• 
GBT440-900 mg – Placebo 
• 
GBT440-1500 mg – Placebo 
• 
All GBT 440 – Placebo 
17. Exploratory Analyses 
17.1 
6-Minute Walk Test 
Summary statistics for the distance walked (meters) during the 6MWT, time to the first SpO2 < 88%, and 
AUC of SpO2 will be summarized by study drug and all GBT 440, and visit in the Efficacy-Evaluable 
population.  The change and percent change from baseline to Day 15, Day 28, and Day 58 in distance 
walked also will be summarized and displayed. 
The AUC of SpO2 measurements will be calculated for each subject’s data at baseline, Day 15, Day 28, 
and Day 58.  The AUC will be estimated using the trapezoid rule for data collected on the eCRF as 
follows: 


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AUC= {∑1
2 [(Time𝑡−Time𝑡−1)×(SpO2𝑡+ SpO2𝑡−1)]
n
𝑡=1
} 
where n is the is the number of measurements of SpO2 collected during the 6MWT, t is the elapsed time 
in minutes (nominal time) and SpO2 is the measurement of SpO2 level at the respective timepoint, and 
Time is the timepoint.  If a SpO2 measurement is missing during the 6MWT, then that timepoint is 
removed from the calculation, such that the AUC is calculated using the trapezoid rule from the 2 
timepoints surrounding the missing SpO2 measurement. 
Additional exploratory endpoints include the change from rest to end of 6MWT  and change from rest to 
lowest SpO2 .  Both endpoints will be summarized by study drug and all GBT440. 
ANCOVA models will be used to analyze the effect of treatment on the change from baseline for each 
exploratory endpoint with baseline value as a covariate.  Least squares (LS) means and SEs will be 
displayed for the change from baseline in each treatment group and for all GBT440.  Similar ANCOVA 
models will be constructed for percent change from baseline for AUC and distance walked. 
LS means (95% CI) and p-values from the models will be used to make the following comparisons: 
• 
GBT440 600 mg – Placebo 
• 
GBT440-900 mg – Placebo 
• 
GBT440-1500 mg – Placebo 
• 
All GBT 440 – Placebo 
All exploratory efficacy data will be provided in subject listings. 
17.2 
Saint George’s Respiratory Questionnaire 
The Saint George’s Respiratory Questionnaire (SGRQ) is completed at baseline (Day 1), Day 8, Day 15, 
Day 28, Day 45, and Day 58.  The SGRQ is a component-based questionnaire with 3 component scores 
(Symptoms, Activity, and Impacts) and a total score for all components.  The method of calculating all 
component scores and total score is detailed in the SGRQ manual provided in the Appendix to this SAP. 
The questions and response weights used in the scoring algorithm are presented in Section 7 of the 
SGRQ manual.  The responses to Questions 1-8 are used to calculate the Symptoms component score.  
The Symptoms questions are designed to assess subjects’ perception of their respiratory problems over 
the preceding 3 months.  The Activity component score is calculated from the responses to Questions 
11 and 15, which measure disturbances to subjects’ daily physical activity.  The Impacts component 
score is calculated from the responses to Questions 9-10, 12-14, and 16-17.  The Impacts component 
score assesses disturbances of psycho-social function resulting from subjects’ respiratory problems.  
Subjects who are not receiving respiratory treatment are scored weight values corresponding to a 


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response of “False” for Question 14.  A Total score that summarizes the impact of the disease on overall 
health status also is calculated.  Each component score and the total score are expressed as a 
percentage of overall impairment where 100 represents the worst possible health status and 0 indicates 
the best possible health status.  No imputation for missing values will be performed.  The scoring 
algorithms account for unanswered questions. 
Summary statistics for each component score and total score will be displayed by study drug and all 
GBT440, and by visit for the Efficacy-Evaluable population.  The change from baseline to each post-
baseline visit also will be summarized.  Self-described current health status (very poor, poor, fair, good, 
or very good) at each visit will be summarized with the number and percent of subjects in each category.  
Additionally, subjects receiving respiratory treatment and those who reported other activities stopped by 
respiratory problems at each visit will be summarized with the number and percent of subjects by study 
drug and overall.   
ANCOVA models will be used to analyze the effect of treatment on the change from baseline with 
baseline value as a covariate.  Least squares (LS) means and SEs will be displayed for the change from 
baseline in each treatment group and for all GBT440. 
LS means (95% CI) and p-values from the models will be used to make the following comparisons: 
• 
GBT440 600 mg – Placebo 
• 
GBT440-900 mg – Placebo 
• 
GBT440-1500 mg – Placebo 
• 
All GBT 440 – Placebo 
Component scores and total score, self-described health status, receiving respiratory treatment, and 
other activities stopped by respiratory problems will be provided in a subject listing of SGRQ results. 
17.3 
UCSD Shortness of Breath Questionnaire 
The UCSD Shortness of Breath Questionnaire is completed at Baseline (Day 1), Day 8, Day 15, Day 
28, Day 45, and Day 58.  The questionnaire is comprised of 24 questions each scored on a scale of 0 
to 5.  Total score ranges from 0 to 120 where higher scores indicate worse severity due to shortness of 
breath.  Scores for each question answered will be summed to provide a total score.  Missing responses 
are not included in the calculation of the total score. 
Summary statistics for the UCSD Shortness of Breath Questionnaire total score will be displayed by 
study drug and all GBT440, and by visit for the Efficacy-Evaluable population using actual data collected 
at the site.  The change and percent change from baseline to each post-baseline visit also will be 
summarized and displayed.   


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ANCOVA models will be used to analyze the effect of treatment on the change from baseline with 
baseline value as a covariate.  Least squares (LS) means and SEs will be displayed for the change from 
baseline in each treatment group and for all GBT440. 
LS means (95% CI) and p-values from the models will be used to make the following comparisons: 
• 
GBT440 600 mg – Placebo 
• 
GBT440-900 mg – Placebo 
• 
GBT440-1500 mg – Placebo 
• 
All GBT 440 – Placebo 
Total scores will be provided in a subject listing of UCSD Shortness of Breath Questionnaire results. 
17.4 
Borg Dyspnea Score during the 6-Minute Walk Test 
The Borg dyspnea score will be assessed as the subject performs the 6MWT at the beginning of the 
rest period, at minute 3 during the walking period, at post-walking minute 1, and at post-walking minute 
2.  The Borg dyspnea score ranges from 0 to 10 with 0 being no breathing difficulty and 10 being maximal 
breathing difficulty.  Summary statistics for the Borg dyspnea score will be presented by study drug and 
all GBT440 for each visit and timepoint for the Efficacy-Evaluable population.  Summary statistics for 
the change from baseline to Day 15, Day 28, and Day 58 will also be summarized.   
ANCOVA models will be used to analyze the effect of treatment on the change from baseline with 
baseline value as a covariate.  Least squares (LS) means and SEs will be displayed for the change from 
baseline in each treatment group and for all GBT440. 
LS means (95% CI) and p-values from the models will be used to make the following comparisons: 
• 
GBT440 600 mg – Placebo 
• 
GBT440-900 mg – Placebo 
• 
GBT440-1500 mg – Placebo 
• 
All GBT 440 – Placebo 
Borg dyspnea scores will be provided in subject listings of the 6MWT for each visit and timepoint. 
17.5 
Cough Visual Analog Scale 
The Cough VAS is completed at Baseline (Day 1), Day 8, Day 15, Day 28, Day 45, and Day 58.  The 
VAS is scored from 0 to 100 where 0 represents no symptom and 100 represents the worst symptom.   
Summary statistics for the Cough VAS will be displayed by study drug and all GBT440, and by visit for 
the Efficacy-Evaluable population using actual data collected at the site.  The change from baseline to 
each post-baseline visit also will be summarized.  


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ANCOVA models will be used to analyze the effect of treatment on the change from baseline with 
baseline value as a covariate.  Least squares (LS) means and SEs will be displayed for the change from 
baseline in each treatment group and for all GBT440. 
LS means (95% CI) and p-values from the models will be used to make the following comparisons: 
• 
GBT440 600 mg – Placebo 
• 
GBT440-900 mg – Placebo 
• 
GBT440-1500 mg – Placebo 
• 
All GBT 440 – Placebo 
17.6 
A Tool to Assess Quality of Life (ATAQ) 
For Part B of the study only, the ATAQ questionnaires (ATAQ Symptoms and ATAQ Impacts) will be 
self-administered at Baseline (Day 1), Day 8, Day 15, Day 28, Day 45, and Day 58 to assess subjects’ 
disease symptoms across three domains (dyspnea, cough, and energy level), impact on quality of life 
across 4 domains (dyspnea, cough, energy level, and global impact), and a set of questions pertaining 
to oxygen use. 
17.6.1 ATAQ Symptoms Domains 
The ATAQ Symptoms questionnaire contains 3 domains (dyspnea, cough, and energy level).  The 
dyspnea domain (Questions 1-12) assesses subjects’ ability to perform physical activities in the 
previous 24 hours.  Responses are measured using a Likert scale (0-4) as applicable to subjects who 
completed the activities assessed.  Subjects who found the assessed activity for Questions 1, 2, 4-10, 
and 12 too difficult to perform due to their disease symptoms receive a score of 5 for the question, and 
subjects who did not complete the activity for other reasons receive no score.  The cough domain 
(Questions 13-18) measures subjects’ cough symptoms in the previous 24 hours, and the energy level 
domain (Questions 19-23) measures subjects’ energy level in the previous 24 hours.  Responses to 
questions within the cough and energy level symptoms domains measured on a Likert scale (0-4). 
Questions 19, 20, and 21 require reverse mapping for scoring and will be mapped as follows:  
• 
0 mapped to 4 
• 
1 mapped to 3 
• 
2 mapped to 2 
• 
3 mapped to 1 
• 
4 mapped to 0 


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Each domain score ranges from 0 to 100%.  Higher scores indicate worse health status in terms of 
subjects’ symptoms.  The Symptoms total score is an average of the domain scores.  Details of the 
scoring algorithm are provided in the Appendix to the SAP. 
17.6.2 ATAQ Impacts Domains 
All questions within the Impact domains are assessed using a Likert scale (0-4).  The impact of 
disease is assessed through subjects’ recall of events during the previous week.  Each domain 
(dyspnea, cough, energy level, and global impact) is scored on a scale of 0 to 100%, where 100% 
indicates worse health status in terms of the impact of disease on subjects’ quality of life.  The 
dyspnea domain is defined for Questions 1-6.  The cough domain is defined for Questions 7-11.  The 
energy domain is defined for Questions 13-14.  The global impact domain is defined for Questions 12 
and 15-21.  The Impacts total score is an average of the ATAQ Impacts domain scores. The same 
reverse mapping as described in the previous section is required for Questions 3, 17, 18, 19, 20, and 
21. 
Scoring for both ATAQ questionnaires will be based only on observed data.  No imputation for missing 
values will be used to calculate ATAQ scores. 
17.6.3 Analysis of ATAQ Data 
Summary statistics for each ATAQ domain will be displayed by study drug and all GBT440, and by 
visit for the Efficacy-Evaluable population.  The change from baseline to each post-baseline visit also 
will be summarized.  
ANCOVA models will be used to analyze the effect of treatment on the change from baseline with 
baseline value as a covariate.  Least squares (LS) means and SEs will be displayed for the change 
from baseline in each treatment group and for all GBT440. 
LS means (95% CI) and p-values from the models will be used to make the following comparisons: 
• 
GBT440 600 mg – Placebo 
• 
GBT440-900 mg – Placebo 
• 
GBT440-1500 mg – Placebo 
• 
All GBT 440 – Placebo 
Responses to questions regarding supplemental oxygen use will be summarized with the number and 
percentage of subjects in each treatment group and for all GBT440 at each visit.  Flow rates of oxygen 
during sleep, during physical activity, and during rest also be summarized with continuous descriptive 
statistics if at least 2 subjects in each treatment group are on supplemental oxygen.  The change from 
baseline to each post-baseline visit in flow rates will be included as applicable. 


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17.7 
Cardiopulmonary Exercise Testing (CPET) 
Cardiopulmonary exercise testing (CPET) parameters are computed using data collected on the CRF 
from all treated subjects at Day 2 and Day 29.  The following CPET parameters by stage include: 
Stage 
CPET Parameters 
Rest 
HR, Extime, VCO2, VO2, RER, SpO2, Art_O2, Art_O2Sat, Art_CO2, Lactate 
VentThrsh 
HR, Extime, VCO2, RER, SpO2, Art_O2, Art_O2Sat, Art_CO2, Lactate, VENT/ VO2 
LactThrsh 
HR, Extime, VCO2, VO2, RER, SpO2, Art_O2, Art_O2Sat, Art_CO2, Lactate, Watts 
Max 
HR, Extime, VCO2, VO2, RER, SpO2, Art_O2, Art_O2Sat, Art_CO2, Lactate, Watts 
HR = Heart Rate (bpm) 
Extime = Exercise time (elapsed time from start to end of stage) 
VCO2 = Carbon Dioxide Excretion (mls/min) 
VO2 = Oxygen Consumption (ml/min) 
RER = Respiratory Exchange Ratio (VCO2/VO2) 
SpO2 = Oxygen Saturation (%) 
Art_O2 = Arterial Oxygen (mmHg) 
Art_O2Sat = Arterial Oxygen Saturation (%) 
Art_CO2 = Arterial Carbon Dioxide (mmHg) 
Lactate = Lactate Concentration (mmol/L) 
Watts = Exercise Output (Watts) 
VentThrsh = Ventilatory Threshold 
LactThrsh = Lactic Acid Threshold 
Summary statistics for the CPET parameters at the following endpoints will be displayed by study drug 
and for all GBT440 by visit using the Efficacy-Evaluable population.  Summary statistics for the change 
from Day 2 to Day 29 will be included in the summary. 
Parameter 
Endpoint 
Exercise Time (Minutes) 
Max – Rest 
Watts 
Max 
VO2 (ml/min/kg) 
Max 
SpO2 (%) 
Max – Rest 
Arterial Oxygen (mmHg) 
Max – Rest 
Arterial Oxygen Saturation (%) 
Max – Rest 
Lactate (mmol/L) 
Max – Rest 
VO2 (ml/min/kg) 
VentThrsh / Max 
Watts 
VentThrsh / Max 
Heart Rate (bpm) 
Rest 
Heart Rate (bpm) 
Max – Rest 
RER 
Max 
Arterial Carbon Dioxide (mmHg) 
Max – Rest 
Heart Rate (bpm) 
VentThrsh – Rest 
Exercise Time (Minutes) 
VentThrsh – Rest 
VENT/VO2 (ml/min/kg) 
VentThrsh 
SpO2 (%) 
VentThrsh – Rest 
Arterial Oxygen (mmHg) 
VentThrsh – Rest 
Arterial Carbon Dioxide (mmHg) 
VentThrsh – Rest 
Arterial Oxygen Saturation (%) 
VentThrsh – Rest 
VO2 (ml/min) will be divided by the subject’s last non-missing body weight measurement before each 
analysis timepoint (ie Day 2 or Day 29) to obtain VO2 (ml/min/kg). 


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ANCOVA models will be used to analyze the effect of treatment on the change from Day 2 with the 
Day-2 value as a covariate.  Least squares (LS) means and SEs will be displayed for the change from 
Day 2 in each treatment group and for all GBT440. 
LS means (95% CI) and p-values from the models will be used to make the following comparisons: 
• 
GBT440 600 mg – Placebo 
• 
GBT440-900 mg – Placebo 
• 
GBT440-1500 mg – Placebo 
• 
All GBT 440 – Placebo 
17.8 
Spirometry and DLco 
Spirometry and DLco are assessed at Screening (Baseline), Day 28, and Day 58.  Spirometry and DLco 
parameters include forced expiratory volume in 1 second (FEV1) actual (L) and predicted (%), FVC 
actual (L) and predicted (%), FEV1/FVC (actual and predicted), DLco actual (ml/mmHg/min), and DLco 
adjusted (%). 
Summary statistics for the spirometry and DLco parameters will be displayed by study drug and all 
GBT440, and by visit for the Efficacy-Evaluable population.  The change and percent change from 
baseline to each post-baseline visit also will be summarized. 
Analysis of covariance models (ANCOVA) will be used to analyze the effect of treatment on the change 
from baseline and the percent change from baseline for each parameter with the baseline value as a 
covariate.  Least squares (LS) means and SEs will be displayed for the change and percent change 
from baseline in each treatment group and for all GBT440. 
LS means (95% CI) and p-values from the models will be used to make the following comparisons: 
• 
GBT440 600 mg – Placebo 
• 
GBT440-900 mg – Placebo 
• 
GBT440-1500 mg – Placebo 
• 
All GBT 440 – Placebo 
17.9 
End of Study Questionnaire 
The End of Study Questionnaire is an 8-item survey to evaluate the subjects' experience while on the 
study including symptoms, changes in oxygen saturation and use.  The questionnaire is a 
self-administered survey to be completed during the Day-58 visit.  The survey is to be completed by 
subjects enrolled under Part B of the trial.  All responses will be summarized with the number and 
percentage of subjects in the Safety population by study drug and all GBT440. 


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18. Interim Analyses 
In Part A of the study, two unblinded interim analyses of the primary and secondary endpoints are 
planned: i) when approximately 9 subjects have completed their Day-28 study visit and ii) when 
approximately 18 subjects have completed their Day-15 study visit. 
 
 


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19. Changes from Protocol-Stated Analyses 
Protocol 
SAP Change 
Rationale 
Exploratory endpoint: Time to 
first SpO2 < 88% that is 
sustained for at least 10 seconds 
during the 6MWT at days 15 and 
28. 
Exploratory endpoint: Time to 
first SpO2 < 88% during the 
6MWT at days 15 and 28. 
Did not collect SpO2 in 
seconds on CRF therefore 
cannot confirm “at least 10 
seconds” as per the protocol 
definition. 
 
Inclusion of additional 
exploratory endpoints: change 
from end of 6MWT to rest and 
change from lowest SpO2 to rest 
Not specified in protocol. 
Efficacy-Evaluable Population: 
All randomized subjects who 
received at least 15 days of 
study drug treatment will be 
included in the Efficacy-
Evaluable population. 
Efficacy-Evaluable Population: 
All randomized subjects who 
received at least 14 days of 
study drug treatment will be 
included in the Efficacy-
Evaluable population. 
Half of 28 days (complete 
dosing) is 14.  
 
20. References 
Not Applicable. 
21. Appendices 
Saint George’s Respiratory Questionnaire Manual 
ATAQ Scoring Algorithm