Clinical trial NCT04247594
Conditions: Sickle Cell Disease
Keywords: Sickle Cell Disease, SCD
Sponsor: Pfizer
Start date: 2020-01-09; Completion date: 2021-06-08
Enrollment: 6 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Study participants will undergo up to four periods of voxelotor administered orally at progressively higher dose levels from 1500 mg until either a maximum tolerated dose (MTD) or 3000 mg/day dose is reached, whichever occurs first

Detailed description:

Arms: arm 1: 1500 mg per day arm 2: 2000 mg per day arm 3: 2500 mg per day arm 4: 3000 mg per day
Interventions: intervention 1: Voxelotor
Intervention descriptions: intervention 1: synthetic small molecule supplied as 500 mg tablets

Protocol documents:
Prot_SAP_000.pdf: 
Global Blood Therapeutics, Inc. 
Protocol Amendment 2.0 
 
GBT440-029 
CONFIDENTIAL 
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Clinical Study Protocol 
Study Number 
GBT440-029 
Study Title 
A Phase 2, Open Label, Multiple Dose Escalation Study to 
Evaluate the Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics of Voxelotor in Patients with Sickle Cell 
Disease 
Investigational Product 
Voxelotor (GBT440) 
IND Number 
121,691 
EudraCT Number 
2019-001838-34 
Sponsor 
Global Blood Therapeutics, Inc. 
181 Oyster Point Blvd 
South San Francisco, CA 94080 
United States of America 
Study Director 
Will Tappe, MD, Senior Medical Director 
Global Blood Therapeutics, Inc. 
181 Oyster Point Blvd 
South San Francisco, CA 94080 
United States of America 
Email: wtappe@gbt.com  
Telephone (707) 321-0745 
Protocol Amendment 2.0 
05 October 2020 
Protocol Amendment 1.0 
13 September 2019 
Original Protocol 
11 July 2019 
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. 


Global Blood Therapeutics, Inc. 
Protocol Amendment 2.0 
 
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STATEMENT OF APPROVAL AND COMPLIANCE 
An Open Label, Multiple Dose Escalation Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of Voxelotor in Patients with Sickle Cell 
Disease  
SPONSOR APPROVAL 
The signature of the Sponsor (Global Blood Therapeutics, Inc., “GBT”) representative, below, 
signifies that the above-referenced clinical study is being conducted in accordance with 
applicable local regulatory requirements in all relevant jurisdictions where the study is being 
conducted. In addition, the study is being conducted in compliance with the procedures of 
International Council for Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use and Good Clinical Practice [ICH-GCP] and associated 
regulatory guidance. Furthermore, GBT, and the Institutional Review Board/Research Ethics 
Board/Independent Ethics Committee (IRB/REB/IEC) will approve any changes to the protocol 
in writing before implementation. GBT will provide the Investigator with all information, 
including safety information, pertinent to the conduct of the study.  
Sponsor Representative 
(Print): 
Rajiv Patni, MD 
Signature: 
 
 
 
Date: 
Title: 
Chief Medical Officer 
 
 
INVESTIGATOR 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 GCP guidelines and Declaration of 
Helsinki. All data obtained during the study will be provided to GBT. GBT requires that any 
presentation or publication of study data by an Investigator be reviewed by GBT, before release. 
Principal Investigator 
(Print): 
 
Signature: 
 
 
Date: 
 
Title: 
 
 


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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................7 
LIST OF FIGURES .........................................................................................................................7 
LIST OF ABBREVIATIONS ..........................................................................................................8 
PROTOCOL SYNOPSIS...............................................................................................................10 
1. 
INTRODUCTION ......................................................................................................14 
1.1. 
Disease Background ...................................................................................................14 
1.2. 
Voxelotor ....................................................................................................................14 
1.3. 
Summary of Relevant Nonclinical Data and Clinical Data ........................................15 
1.3.1. 
Nonclinical Data .........................................................................................................15 
1.3.2. 
Clinical Data ...............................................................................................................16 
1.4. 
Summary of the Known and Potential Risks and Benefits of Voxelotor ...................16 
1.5. 
Description of and Justification for the Route of Administration, Dosage, 
Dosage Regimen, and Treatment Period(s) ................................................................17 
1.5.1. 
Study Rationale ...........................................................................................................17 
1.5.2. 
Dose Rationale ............................................................................................................19 
2. 
STUDY OBJECTIVES ..............................................................................................20 
2.1. 
Primary Objective .......................................................................................................20 
2.2. 
Secondary Objectives .................................................................................................20 
2.3. 
Exploratory Objectives ...............................................................................................20 
3. 
INVESTIGATIONAL PLAN .....................................................................................21 
3.1. 
Study Endpoints ..........................................................................................................21 
3.2. 
Study Design ...............................................................................................................21 
3.3. 
Assessments ................................................................................................................22 
3.4. 
Safety Monitoring Committee ....................................................................................22 
3.5. 
Treatment ....................................................................................................................22 
3.6. 
Duration of Study Participation and of the Study .......................................................22 
3.7. 
Stopping Rules ............................................................................................................23 
3.7.1. 
Early Discontinuation of the Study/Study Stopping Rules .........................................23 
3.7.2. 
Cohort Dose Escalation Stopping Rules .....................................................................23 
3.7.3. 
Early Discontinuation of Individual Participants .......................................................23 


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3.7.3.1. 
Individual Dose-limiting Toxicity Definition: Dose Escalation Period .....................23 
3.7.3.2. 
Individual Early Discontinuation of Study Drug ........................................................24 
4. 
SELECTION OF STUDY POPULATION ................................................................25 
4.1. 
Inclusion Criteria ........................................................................................................25 
4.2. 
Exclusion Criteria .......................................................................................................25 
5. 
TREATMENTS ADMINISTERED ...........................................................................27 
5.1. 
Treatments Administered ............................................................................................27 
5.2. 
Dose Frequency ..........................................................................................................27 
5.3. 
Physical Description of Voxelotor ..............................................................................27 
5.4. 
Formulation .................................................................................................................27 
5.5. 
Packaging and Labeling ..............................................................................................27 
5.6. 
Investigational Product Supply ...................................................................................27 
5.7. 
Storage and Handling Procedure ................................................................................27 
5.8. 
Concomitant and Prohibited Medications ..................................................................28 
5.8.1. 
Prior and Concomitant Medications ...........................................................................28 
5.8.2. 
Hydroxyurea Therapy .................................................................................................28 
5.8.3. 
Transfusion .................................................................................................................28 
5.8.4. 
Other Therapies ..........................................................................................................28 
5.8.5. 
Concomitant Medications to Be Used with Caution ..................................................28 
5.8.6. 
Prohibited Concomitant Medications .........................................................................29 
6. 
FERTILITY/CONTRACEPTIVE REQUIREMENTS ..............................................31 
6.1. 
Instructions for Female Participants of Child-Bearing Potential ................................31 
6.2. 
Female Participants of Non-Child-Bearing Potential .................................................31 
6.3. 
Instructions for Male Participants Capable of Fathering a Child ...............................31 
6.4. 
Acceptable Forms of Contraception for Sexually Active Participants .......................31 
7. 
ASSESSMENT OF TREATMENT COMPLIANCE ................................................33 
8. 
STUDY PROCEDURES AND EVALUATIONS .....................................................34 
8.1. 
Informed Consent .......................................................................................................34 
8.2. 
Participant Study Number ...........................................................................................34 
8.3. 
Demographics and Medical and Medication History .................................................34 
8.4. 
Physical Examination .................................................................................................34 
8.5. 
Vital Signs ..................................................................................................................34 
8.6. 
Body Mass Index ........................................................................................................35 


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8.7. 
Electrocardiograms .....................................................................................................35 
8.8. 
Eligibility Assessment, Inclusion/Exclusion Review .................................................35 
8.9. 
Adverse Events and Concomitant Medications ..........................................................35 
8.10. 
Clinical Global Impression of Change .......................................................................35 
8.11. 
Patient Global Impression of Change .........................................................................35 
8.12. 
Safety Laboratory Assessments ..................................................................................35 
8.12.1. 
Screening ....................................................................................................................36 
8.12.2. 
Hematology .................................................................................................................36 
8.12.3. 
Serum Chemistry ........................................................................................................36 
8.13. 
Other Laboratory Assessments ...................................................................................37 
8.13.1. 
Effect on Hemoglobin Oxygen Equilibrium Curve ....................................................37 
8.13.2. 
Hemoglobin Genotype ................................................................................................37 
8.13.3. 
Serum Erythropoietin ..................................................................................................37 
8.13.4. 
Red Blood Cell Deformability and Dense Cells .........................................................37 
8.13.4.1. 
Pregnancy Test ............................................................................................................37 
8.13.5. 
Pharmacokinetic Sample Collection ...........................................................................38 
8.14. 
Phone Call ...................................................................................................................38 
8.15. 
Missed Assessments ...................................................................................................38 
8.16. 
End of Study Visit ......................................................................................................38 
8.17. 
Participant Discontinuation from the Study ...............................................................38 
8.18. 
Order of Assessments .................................................................................................38 
9. 
ADVERSE AND SERIOUS ADVERSE EVENTS ...................................................40 
9.1. 
Adverse Events ...........................................................................................................40 
9.1.1. 
Definition of Adverse Events .....................................................................................40 
9.1.2. 
Severity of Adverse Events ........................................................................................41 
9.1.3. 
Relationship to Investigational Product ......................................................................42 
9.1.4. 
Unexpected Adverse Reactions ..................................................................................42 
9.2. 
Adverse Event Reporting ............................................................................................42 
9.2.1. 
General ........................................................................................................................42 
9.2.2. 
Diagnosis Versus Signs and Symptoms .....................................................................42 
9.2.3. 
Abnormal Laboratory Values .....................................................................................43 
9.2.4. 
Pre-existing Medical Conditions ................................................................................43 
9.2.5. 
Worsening of Sickle Cell Disease ..............................................................................43 


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9.3. 
Serious Adverse Events, Serious Adverse Drug Reactions, and Requirements 
for Immediate Reporting .............................................................................................43 
9.3.1. 
Reporting Suspected Unexpected Serious Adverse Reactions and Urgent 
Safety Issues ...............................................................................................................44 
9.4. 
Reporting Pregnancy ..................................................................................................44 
9.5. 
Reporting Overdose ....................................................................................................45 
9.6. 
Safety Monitoring Committee ....................................................................................45 
10. 
DATA ANALYSIS AND STATISTICAL PLANS ...................................................46 
10.1. 
Endpoints ....................................................................................................................46 
10.1.1. 
Primary Endpoint ........................................................................................................46 
10.1.2. 
Secondary Endpoints ..................................................................................................46 
10.1.3. 
Exploratory Endpoints ................................................................................................46 
10.2. 
Determination of Sample Size ....................................................................................46 
10.3. 
Populations for Analysis .............................................................................................46 
10.4. 
Data Analysis ..............................................................................................................47 
11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................48 
11.1. 
Source Data .................................................................................................................48 
11.2. 
Data Collection ...........................................................................................................48 
11.3. 
Essential Documentation Requirements .....................................................................48 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................49 
12.1. 
Monitoring ..................................................................................................................49 
12.2. 
Quality Control and Quality Assurance ......................................................................49 
12.3. 
Laboratory Accreditation ............................................................................................49 
13. 
REGULATORY, ETHICAL AND LEGAL OBLIGATIONS ..................................50 
13.1. 
Ethical Conduct of the Study ......................................................................................50 
13.2. 
Good Clinical Practice ................................................................................................50 
13.3. 
Written Informed Consent ..........................................................................................50 
13.4. 
Independent Ethics Committee, Institutional Review Board, and Regulatory 
Approval .....................................................................................................................50 
13.5. 
Essential Documentation Requirements .....................................................................51 
13.6. 
Informed Consent .......................................................................................................51 
13.6.1. 
Participant ...................................................................................................................51 
13.6.2. 
Investigator Responsibilities .......................................................................................51 


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13.7. 
Confidentiality ............................................................................................................51 
13.8. 
Regulatory, Ethical and Legal Obligations .................................................................52 
13.9. 
Study Documentation and Data Storage .....................................................................52 
14. 
DATA HANDLING AND RECORDKEEPING .......................................................53 
14.1. 
Inspection of Records .................................................................................................53 
14.2. 
Retention of Records ..................................................................................................53 
14.3. 
Disclosure of Information ...........................................................................................53 
15. 
PUBLICATION POLICY ..........................................................................................55 
16. 
FINANCING AND INSURANCE .............................................................................56 
17. 
REFERENCES ...........................................................................................................57 
APPENDIX A. SCHEDULE OF ASSESSMENTS: DOSE ESCALATION PHASE ...............59 
APPENDIX B. SCHEDULE OF ASSESSMENTS: OBSERVATION PERIOD AND 
SAFETY FOLLOW-UP .............................................................................................61 
APPENDIX C. DOSE MODIFICATION GUIDELINES FOR STUDY DRUG-
RELATED ADVERSE EVENTS ..............................................................................63 
 
LIST OF TABLES 
Table 1: 
CYP Substrates with Narrow Therapeutic Range ......................................................29 
Table 2: 
Sensitive CYP3A4 Substrates with Narrow Therapeutic Range ................................29 
Table 3: 
Examples of Strong CYP3A4 Inhibitors ....................................................................29 
Table 4: 
Examples of Moderate and Strong CYP Inducers ......................................................30 
Table 5: 
Additional Prohibited Medications .............................................................................30 
Table 6: 
Grading for Adverse Events Not Covered in the NCI CTCAE ..................................41 
 
LIST OF FIGURES 
Figure 1: 
Relationships Between Change from Baseline in Hemoglobin at Week 24 
and Percent Hemoglobin Occupancy ..........................................................................18 
Figure 2: 
 Study Schema ............................................................................................................22 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
BID 
twice daily 
CGI-C 
Clinical Global Impression of Change 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EOS 
End of Study 
FDA 
(US) Food and Drug Administration 
GBT 
Global Blood Therapeutics  
GCP 
Good Clinical Practice 
Hb 
hemoglobin  
HbF 
fetal hemoglobin 
HbS 
hemoglobin S 
HIV 
human immunodeficiency virus 
HU 
hydroxyurea  
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IPF 
idiopathic pulmonary fibrosis 
IRB 
Institutional Review Board 
LDH 
lactate dehydrogenase 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
OxyHb 
oxyhemoglobin  
PD 
pharmacodynamic 
PE 
physical examination 


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Abbreviation 
Definition 
PGI-C 
Patient Global Impression of Change 
PK 
pharmacokinetic(s) 
QTcF 
QT interval corrected using Fridericia’s formula 
RBC 
red blood cell 
RSI 
Reference Safety Information 
SAE 
serious adverse event 
SCD 
sickle cell disease 
SMC 
Safety Monitoring Committee 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
US 
United States 
VOC 
vaso-occlusive crisis 
WBC 
white blood cells 
 


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PROTOCOL SYNOPSIS 
Study Number 
GBT440-029 
Study Title 
An Open Label, Multiple Dose Escalation Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics of Voxelotor in Patients 
with Sickle Cell Disease 
Investigational 
Product 
Voxelotor tablets, 500 mg tablets administered orally 
Sponsor 
Global Blood Therapeutics, Inc. 
181 Oyster Point Blvd 
South San Francisco, CA 94080 
United States of America 
Number of 
Clinical Sites 
The study will be conducted at up to approximately 10 clinical sites. 
Number of 
Study 
Participants 
Up to 40 participants. 
Treatment 
Voxelotor will be supplied as 500 mg tablets and will be administered at doses 
ranging from 1500 mg to up to 3000 mg. 
Objectives 
Primary Objective: 
• 
To evaluate the tolerability and safety of voxelotor at daily doses of 
> 1500 mg (2000 mg to 3000 mg) in participants with sickle cell disease 
(SCD) 
Secondary Objectives: 
• 
To evaluate the change in hemoglobin (Hb) and hemolysis measures  
• 
To evaluate the incidence rate of vaso-occlusive crises (VOCs) 
Exploratory Objectives: 
• 
To evaluate the PD properties (effect on Hb-oxygen equilibrium curve 
[OEC]) as measured by P50 and P20 
• 
To assess voxelotor pharmacokinetics (PK) as evaluated by population PK 
analysis and % Hb occupancy 
• 
To evaluate the PK-PD relationship of voxelotor at daily doses of 
>1500 mg 
• 
To evaluate the effects of voxelotor on Clinical Global Impression of 
Change (CGI-C) and Patient Global Impression of Change (PGI-C) 
Study Design 
This is an open-label, sequential period, within-participant dose escalation study. 
Up to 40 participants with SCD (HbSS or HbSB0) who are 18 to < 60 years of age, 
inclusive, will be enrolled.  


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Study Design 
(continued) 
Study participants will undergo up to four periods of voxelotor administered orally 
at progressively higher dose levels from 1500 mg until either a maximum tolerated 
dose (MTD) or 3000 mg/day dose is reached, whichever occurs first: 
• 
Period 1: 1500 mg per day: 1500 mg once daily (3 × 500 mg tablets) for 
3 weeks (± 3 days) 
• 
Period 2: 2000 mg per day: 1000 mg (2 × 500 mg) twice daily (BID) for 
3 weeks (± 3 days) 
• 
Period 3: 2500 mg per day: 1500 mg (3 × 500 mg) in morning and 1000 mg 
(2 × 500 mg) in evening daily for 3 weeks (± 3 days) 
• 
Period 4: 3000 mg per day: 1500 mg (3 × 500 mg) BID for 3 weeks 
(± 3 days) 
• 
Observation Period: MTD or 3000 mg daily for 24 weeks 
• 
Safety Follow-up Period: from day of last dose to 28 days postdose. 
If at any time a dose level > 1500 mg is not tolerated by a participant, the dose may 
be reduced to a previous level for the participant, which will then be administered 
for 24 additional consecutive weeks as an observation period.  
Dose modifications are allowed during the observation period in consultation with 
the Sponsor’s Medical Monitor. 
If 1500 mg daily is the MTD for a participant, then the participant may enter the 
observation period and continue to receive 1500 mg for up to 24 weeks until such 
time as they are able to roll over into the open-label extension study or receive 
commercial voxelotor, where available. If the participant discontinues early from 
the study, the participant will undergo an End of Study (EOS) visit approximately 
28 days after the last dose and will not be eligible for the open-label extension 
study. 
The safety of study participants will be closely monitored by the study team. In 
addition, a Safety Monitoring Committee (SMC) will review safety, tolerability, 
and available PK and PD data at regular intervals. Blood draws for PK and PD 
(including Hb and hemolysis markers), routine chemistry and hematology 
laboratory tests, and 12-lead electrocardiograms (ECGs) in triplicate will be 
obtained periodically as listed in the Schedule of Assessments.  
Upon completion of the observation period for individual participants or 
after study termination, eligible participants will be given the option to enroll 
in an open-label extension study. 
Duration of 
Study 
Participation 
Study participation will be for up to 44 weeks, which includes up to 30 days in 
Screening Period; 21 days (3 weeks) each in Periods 1, 2, 3, and 4; 168 days 
(24 weeks) in the Observation Period; and 28 days in the Safety Follow-up Period. 
Statistical 
Methods 
Primary Endpoints 
• 
Treatment-emergent adverse events (TEAEs) and serious adverse events 
(SAEs)  


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Statistical 
Methods 
(continued) 
Secondary Endpoints 
• 
Change in Hb and clinical measures of hemolysis (unconjugated bilirubin, 
% reticulocyte, absolute reticulocyte, and lactate dehydrogenase [LDH]) 
from Baseline 
• 
Proportion of participants with an Hb increase > 1 g/dL compared to 
Baseline 
• 
Incidence rate of VOCs 
Exploratory Endpoints 
• 
P50 and P20 at 8 hours and 24 hours postdose 
• 
PK of voxelotor as assessed by population PK analysis using nonlinear 
mixed-effect modeling 
• 
% Hb occupancy at 8 hours and 24 hours postdose  
• 
CGI-C  
• 
PGI-C 
Sample Size 
As this is an exploratory study to provide descriptive information on the tolerability, 
safety and efficacy of voxelotor at dose levels >1500 mg daily, the sample size 
chosen was based on previous experience in exploratory studies to support the 
assessment of a MTD based on descriptive summaries of safety and PK data. The 
sample size of up to 40 participants takes into account the differential tolerance in 
participants, some potentially tolerating 3000 mg daily, while others only tolerating 
lower dose levels An effort will be made to enroll a number of subjects sufficient to 
ensure that at least 6 participants are treated at the study level MTD. 
Populations for Analysis 
Safety Population: All participants who receive at least one dose of study drug will 
be included in the safety population.  
PK Population: The PK population will consist of all participants who receive any 
amount of study drug and have at least one measured concentration at a scheduled 
PK time point after the start of dosing.  
Analyses 
TEAEs, defined as events that occur on or after Day 1 of study drug or the 
worsening of a pre-existing condition on or after Day 1 of study drug, will be 
classified according to the Medical Dictionary for Regulatory Activities 
(MedDRA). The incidence of TEAEs and relatedness to study drug, as assessed by 
the Investigator, will be summarized descriptively by maximum dose level 
tolerated. 
Clinical laboratory tests, ECGs, and vital signs over time will be summarized by 
maximum dose level tolerated using descriptive statistics.  
An Hb responder endpoint, defined as an increase in Hb of > 1 g/dL compared to 
Baseline, will be summarized. Additionally, change from baseline in Hb and 
clinical measures of hemolysis (unconjugated bilirubin, % reticulocyte, absolute 
reticulocyte, and LDH) will be summarized by maximum dose level tolerated using 
descriptive statistics.  
The incidence of VOCs will be summarized by maximum dose tolerated. 


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Statistical 
Methods 
(continued) 
The CGI-C and PGI-C will be summarized by maximum dose level tolerated. 
Population PK analysis using nonlinear mixed-effect modeling will be performed to 
characterize voxelotor PK in plasma and whole blood. 
 


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1. 
INTRODUCTION 
1.1. 
Disease Background 
Sickle cell disease (SCD) is a rare and inherited disorder caused by a point mutation in the 
β-globin gene, leading to formation of hemoglobin S (HbS). It is a devastating and debilitating 
disease marked by the pathophysiologic features of hemolytic anemia, vaso-occlusion, and 
progressive end-organ damage, with a clinical course characterized by life-long disability and 
early death. A primary and obligatory event in the molecular pathogenesis of SCD is the 
polymerization of deoxygenated HbS, which leads to sickling of red blood cells (RBCs). The 
resulting hemolytic anemia is experienced to various degrees by all patients with SCD and is a 
defining and serious feature of the disease. Hemolytic anemia leads to reduced oxygen-carrying 
capacity, tissue hypoxia, and clinical manifestations of end-organ damage in patients with SCD. 
The disease course is also characterized by life-long pain and frequent healthcare interactions. 
Chronic hemolytic anemia, and its sequelae, have become the leading cause of mortality in adults 
with SCD and is recognized as a critical contributor to irreversible cumulative organ damage and 
dysfunction (Lanzkron, 2013; Vichinsky, 2018). Half of adult patients with SCD have 
irreversible organ damage, and presence of dysfunction in a single organ is an independent 
predictor of death and subsequent multiorgan dysfunction (Powars, 2005). 
Hemoglobin (Hb) concentration is an important indicator of disease severity, indicating not only 
the degree of anemia but also the degree of hemolysis that occurs in patients with SCD, as 
evidenced by the strong inverse correlation between Hb and clinical measures of RBC 
destruction, such as indirect bilirubin, reticulocyte count, and lactate dehydrogenase (LDH), and 
the association of low Hb and elevated hemolysis with increased risk of mortality (Taylor, 2008). 
It is well established that low Hb levels are associated with an increased risk for end-organ 
complications in SCD, including stroke/silent cerebral infarction, chronic kidney disease, leg 
ulcers, and pulmonary hypertension (Powars, 1991; Ohene-Frempong, 1998; Gladwin, 2004; 
Ataga, 2018). 
Therapies approved for the treatment of SCD in some regions include hydroxyurea (HU) (Smith, 
2011), L-glutamine (Emmaus Medical, 2018), and crizanlizumab (Novartis, 2019). Hydroxyurea 
is an established therapeutic option that is indicated to reduce the frequency of painful crisis and 
the need for blood transfusions in patients with recurrent moderate-to-severe sickle cell crises 
(E.R. Squibb, 2018). L-glutamine is an approved therapy in the United States (US) that is 
indicated to treat the acute complications of SCD in adult patients and pediatric patients five 
years of age and older (Emmaus Medical, 2018). Although shown to decrease vaso-occlusive 
crises (VOCs), L-glutamine has no demonstrated effect on hemolytic anemia. Despite the current 
standard of care, patients with SCD continue to suffer serious morbidity and premature mortality 
(Steinberg, 2003). Crizanlizumab is approved in the US to reduce the frequency of VOCs in 
adults and pediatric patients aged 16 years and older with SCD (Novartis, 2019).  
1.2. 
Voxelotor 
Voxelotor (formerly known as GBT440) is an orally administered small molecule that inhibits 
HbS polymerization by allosterically modifying Hb-O2 affinity and is being developed for the 
treatment of SCD. Voxelotor was designed to bind to HbS with preferential partitioning into 
RBCs. It binds covalently and reversibly via Schiff base to the N-terminal valine of the Hb 


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α chain (ie, a single voxelotor molecule binding per HbS tetramer in a 1:1 stoichiometry) and 
allosterically (Eaton, 1999) increases HbS-O2 affinity (Oksenberg, 2016), stabilizing the 
oxyhemoglobin (oxyHb) state and inhibiting polymerization (Oksenberg, 2016). The voxelotor 
binding site is distant from heme pockets and therefore it can increase O2 affinity without 
sterically blocking the release of O2. 
A primary and obligatory event in the molecular pathogenesis of SCD is the polymerization of 
deoxygenated HbS. Because oxyHb is a potent inhibitor of HbS polymerization, increasing the 
proportion of oxyHb in all RBCs with voxelotor can reduce HbS polymerization, decrease RBC 
membrane damage and destruction and has the potential to subsequently achieve long term 
disease modification. This principle is supported by the finding that in patients with sickle 
hereditary persistence of fetal hemoglobin (HbF), the dilution of HbS by 20% to 30% HbF in all 
RBCs is sufficient to inhibit HbS polymerization, preventing RBC damage and SCD clinical 
sequelae. This suggests that pharmacologically maintaining approximately 20% to 30% of Hb in 
the nonpolymerizing oxygenated state in all RBCs may be an effective approach for the 
treatment of SCD. This therapeutic effect was demonstrated in the pivotal Phase 3 study 
(GBT440-031) where 1500 mg of voxelotor, achieving Hb modification of 20% to 30%, 
administered daily orally for 24 weeks showed a significant and clinically meaningful increase in 
Hb, and decrease in hemolysis (Vichinsky, 2019).  
In November 2019, the US Food and Drug Administration (FDA) approved voxelotor, now 
known by the trade name Oxbryta™, for the treatment of SCD in adults and pediatric patients 
12 years of age and older. However, voxelotor remains an investigational drug outside of the US, 
and this study administers doses at and higher than the approved dose in the US. 
1.3. 
Summary of Relevant Nonclinical Data and Clinical Data 
1.3.1. 
Nonclinical Data 
Primary pharmacodynamics (PD) studies of voxelotor consisted of in vitro and in vivo studies to 
characterize (a) voxelotor binding and affinity for Hb, (b) the effect of voxelotor on HbS 
modification using purified Hb, washed RBCs, and whole blood, and (c) the efficacy of 
voxelotor in vivo in a mouse model of SCD. These in vitro assays of increasing complexity 
included measuring Hb-O2 via hemoximetry, quantifying stabilization of the oxyHb state 
conformation, delaying HbS polymerization at low oxygen tension, preventing in vitro sickling 
induced by a low oxygen environment, decreasing viscosity, and improving deformability of 
RBCs in blood from patients with SCD (Dufu, 2018). In addition, these studies show that 
voxelotor-modified Hb retains the Bohr Effect, which is the ability to offload oxygen from Hb in 
metabolically active (low pH) tissues. 
Collectively, these studies demonstrate that voxelotor increases Hb-O2 affinity with high 
specificity of binding to Hb, stabilizes the oxy or R-state conformation of Hb, prevents HbS 
polymerization and RBC sickling in vitro, and improves sickle blood viscosity and deformability 
in vitro. In addition, voxelotor increases HbS-O2 affinity and RBC half-life, while decreasing 
ex vivo sickling and reticulocyte count in a SCD mouse model. 
Additional information regarding nonclinical pharmacology (including safety pharmacology and 
metabolism) and toxicology is provided in the most current version of the Voxelotor 
Investigator’s Brochure (IB), provided separately. 


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1.3.2. 
Clinical Data 
As of 05 November 2019, approximately 823 participants have received single or multiple doses 
of voxelotor in 23 clinical development studies (five studies in SCD, two studies in idiopathic 
pulmonary fibrosis [IPF], 15 clinical pharmacology studies, and one physiology study of healthy 
participants exercising in hypoxic conditions).  
The 823 participants consist of:  
• 379 participants with SCD (122 pediatric and 257 adult participants) 
• 378 healthy participants (including participants with severe renal impairment [not on 
dialysis] and participants with hepatic impairment) 
• 43 adult participants with IPF 
• 23 participants from the expanded access program (6 adolescents and 17 adults) 
− 15 participants from the GBT-sponsored expanded access protocol 
− 8 participants from the single-patient Investigational New Drug (IND) program 
Information regarding the safety, tolerability, and efficacy of voxelotor is provided in 
Section 1.4. and can be found in the Voxelotor IB. 
1.4. 
Summary of the Known and Potential Risks and Benefits of 
Voxelotor 
Clinical data to date have shown that treatment with voxelotor results in a dose-dependent 
increase in Hb within 2 weeks that is maintained through 24 weeks, and with an associated 
decrease in clinical measures of hemolysis which correlates with drug exposure (Brown, 2018; 
Vichinsky, 2018). In a global, multicenter, Phase 3, double-blind, randomized, placebo-
controlled trial of voxelotor in participants with SCD (Study GBT440-031), the percentage of 
participants achieving an Hb response (> 1 g/dL Hb increase from Baseline at Week 24) was 
dose dependent: 51.1% for the voxelotor 1500 mg group, 32.6% for the voxelotor 900 mg group, 
and 6.5% for the placebo group (p < 0.001 for each voxelotor dose vs placebo). In the 1500 mg 
group, the mean Hb increase at Week 24 was 1.14 g/dL and in placebo -0.08 g/dL. Consistent 
with the improvement in Hb, the reductions in hemolysis measures (indirect bilirubin, absolute 
reticulocytes, percent reticulocytes, and LDH) were observed with both voxelotor 1500 mg and 
900 mg compared to placebo. These were significant for indirect bilirubin (-25.9%, p < 0.001) 
and percent reticulocytes (-24.5%, p < 0.001) (Vichinsky, 2019).  
Based on available data, voxelotor has been well tolerated in adult and adolescent patients with 
SCD. The most common adverse reactions in participants with SCD ≥ 12 years old in ≥ 10% of 
participants treated with voxelotor 1500 mg with a difference of > 3% compared to placebo 
included headache, diarrhea, abdominal pain, nausea, fatigue, rash, and pyrexia. Other clinically 
relevant and less frequent adverse reactions included drug hypersensitivity (< 1%). There were 
no reported events of anaphylaxis or anaphylactoid reactions in the clinical development 
program. The majority of treatment-emergent adverse events (TEAEs) were Grade 1 to Grade 2 
in severity, clinically manageable, and reversed or resolved. Overall, the safety profile was 
similar in participants who were or were not receiving HU concomitantly, and between adults 
and adolescents. In SCD studies with voxelotor, the incidence of VOCs was similar to placebo 


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regardless of the extent of Hb increase with voxelotor. No increase in incidence of VOC was 
observed following voxelotor discontinuation. In study participants with SCD, there has been no 
evidence of mechanism–related toxicity (ie, inadequate O2 offloading from voxelotor-bound Hb) 
as indicated by clinical observations, vital signs, electrocardiograms (ECGs), hematologic 
changes, or cardiopulmonary exercise testing (Howard, 2019; Stewart, 2018).  
Overall, no concerning safety findings have been identified in studies with voxelotor and there 
has been no pattern of adverse events (AEs) that would raise concerns or alter the benefit-risk 
profile of voxelotor.  
Additional information regarding safety is available in the Voxelotor IB (provided separately). 
1.5. 
Description of and Justification for the Route of Administration, 
Dosage, Dosage Regimen, and Treatment Period(s) 
Voxelotor is available in an oral form and is intended for once daily administration. See below, 
and Section 3.2 and Section 5.1 for additional information regarding the dose to be used in this 
study.  
1.5.1. 
Study Rationale  
In the pivotal Phase 3 Study GBT440-031, voxelotor was shown to have a dose-dependent 
(1500 mg > 900 mg orally daily), and clinically meaningful increase in Hb, as well as concurrent 
reductions in clinical measures of hemolysis. Study GBT440-029, is designed to assess 
tolerability, safety, and PD of voxelotor dose levels higher than 1500 mg daily (the maximum 
dose in the pivotal Phase 3 study) and to compare these results to the 1500 mg dose. The 
rationale for this study is based on an exposure-response analysis from the pivotal 
Study GBT440-031, which showed a linear relationship between whole blood voxelotor and 
%Hb occupancy and efficacy as measured by improvement in Hb (see Figure 1 below) and 
hemolysis markers. The 1500 mg dose led to a mean Hb occupancy of 29% and led to a mean Hb 
increase of 1.1 g/dL. At 3000 mg of voxelotor, assuming a linear relationship, the mean Hb 
occupancy is projected to be 49.3% with a Hb increase of 2.04 g/dL. Furthermore, no dose level 
has been associated with exposure-related concerning safety signals, and a maximum tolerated 
dose (MTD) has not been defined. Treatment-related AEs were mostly grade 1/grade 2 
gastrointestinal events. Given the predicted improved efficacy of higher doses, and lack of dose-
limiting safety concerns, this study will investigate the potential for a greater benefit/risk for 
higher doses in patients with SCD. 
In this study, baseline response will be characterized in participants receiving a 3-week treatment 
regimen with voxelotor 1500 mg and compared, within and across participants, to the response 
with the highest dose level tolerated at steady state. Dose escalation will be done in 3-week 
increments to assess tolerability at the escalated dose.  


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Figure 1: 
Relationships Between Change from Baseline in Hemoglobin at Week 24 and 
Percent Hemoglobin Occupancy 
 
 
Cmin, minimum plasma concentration at steady state; CFB, change from baseline; Hb, hemoglobin. 
Note: The vertical dashed lines indicate the median of % Hb occupancy for each dose group. The box plots describe the 
distribution of % Hb occupancy in each dose group. The left and right edges of the box correspond to the 25th and 75th 
percentiles, and the vertical line inside the box indicates the median. The solid blue line and gray shaded area represent a 
second-degree polynomial regression and 95% confidence interval through the data. The p-value for the polynomial relationship 
compared with the null model (no relationship) is shown on the plot. The black dashed line is a linear regression line through the 
data. 


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1.5.2. 
Dose Rationale 
The doses of voxelotor to be evaluated in this study are 1500 mg orally daily through 3000 mg 
administered by split dose twice daily (BID). This dose of voxelotor is supported by: 1) absence 
of concerning exposure-related safety findings with 1500 mg daily from the pivotal Phase 3 
Study GBT440-031 in adults and adolescents with SCD; 2) demonstrating dose-dependent 
treatment effects of voxelotor on PD and efficacy measures; and 3) not yet achieving MTD with 
dose levels up to 2800 mg to date as a single dose in healthy volunteers and 1500 mg daily for 
multiple doses in healthy volunteers and participants with SCD. A conservative dose-escalation 
approach is undertaken with increments of 500 mg at a time, representing 33% increase at the 
lowest dose level and 20% increase at the highest, with careful monitoring and assessments prior 
to escalation to the next dose level. It is perceived, based on prior data, that voxelotor 
administration twice rather than once daily may result in favorable gastrointestinal tolerability. 
See the IB for additional details.  


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2. 
STUDY OBJECTIVES 
See Section 3 for details regarding the investigational plan. 
2.1. 
Primary Objective 
• To evaluate the tolerability and safety of voxelotor at daily doses of > 1500 mg 
(2000 mg to 3000 mg) in participants with SCD  
2.2. 
Secondary Objectives 
• To evaluate the change in Hb and hemolysis measures  
• To evaluate the incidence of VOCs 
2.3. 
Exploratory Objectives 
• To evaluate the PD properties (effect on Hb-oxygen equilibrium curve [OEC]) as 
measured by P50 and P20 
• To assess voxelotor pharmacokinetics (PK) as evaluated by population PK analysis 
and % Hb occupancy 
•  To evaluate the PK-PD relationship of voxelotor at daily doses of >1500 mg 
• To evaluate the effects of voxelotor on Clinical Global Impression of Change 
(CGI-C) and Patient Global Impression of Change (PGI-C) 


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3. 
INVESTIGATIONAL PLAN 
This study is an open-label, Phase 2 study of the tolerability and safety of voxelotor 2000, 2500, 
and 3000 mg in adult participants with SCD ≥ 18 to < 60 years of age.  
3.1. 
Study Endpoints 
Study endpoints are described in Section 10. 
3.2. 
Study Design  
This is an open-label, sequential period, within-participant dose escalation study. Up to 
40 participants with SCD (HbSS or HbSB0) who are 18 to < 60 years of age, inclusive, will be 
enrolled.  
Study participants will undergo up to four periods of voxelotor administration at progressively 
higher dose levels from 1500 mg until either a MTD or 3000 mg daily dose is reached, 
whichever occurs first (Figure 2): 
• Period 1: 1500 mg per day: 1500 mg once daily (3 × 500 mg tablets) for 3 weeks 
(± 3 days) 
• Period 2: 2000 mg per day: 1000 mg (2 × 500 mg) BID for 3 weeks (± 3 days) 
• Period 3: 2500 mg per day: 1500 mg (3 × 500 mg) in morning and 1000 mg 
(2 × 500 mg) in evening daily for 3 weeks (± 3 days) 
• Period 4: 3000 mg per day: 1500 mg (3 × 500 mg) BID for 3 weeks (± 3 days) 
• Observation Period: MTD or 3000 mg daily for 24 weeks 
• Safety Follow-up Period: from day of last dose to 28 days postdose. 
If at any time a dose level > 1500 mg is not tolerated by a participant in the dose escalation 
period, the dose may be reduced to a previous level for the participant, which will then be 
administered for 24 additional consecutive weeks as an observation period. Dose modifications 
are allowed during the observation period in consultation with the Sponsor’s Medical Monitor 
(Appendix C). 
If 1500 mg daily is the MTD for a participant, then the participant may enter the observation 
period and continue to receive 1500 mg, for up to 24 weeks or until they are able to roll over into 
the open-label extension or receive commercial voxelotor, where available. If the participant 
discontinues early from the study, the participant will undergo an End of Study (EOS) visit 
approximately 28 days after the last dose and will not be eligible for the open-label extension 
study. 
The safety of study participants will be closely monitored by the study team. In addition, a Safety 
Monitoring Committee (SMC) will review safety, tolerability, and available PK and PD data at 
regular intervals (Section 3.4). Blood draws for PK and PD (including Hb and hemolysis 
markers), routine chemistry and hematology laboratory tests, and 12-lead ECGs in triplicate will 
be obtained periodically, as listed in the Schedule of Assessments (Appendix A, Appendix B).  


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Individual stopping rules are specified in Section 3.7. Upon completion of the observation period 
for individual participants or after study termination, eligible participants will be given the option 
to enroll in an open-label extension study. 
Figure 2: 
 
Study Schema 
Voxelotor
1500 mg
N ≥ 5
Voxelotor
2000 mg
N ≥ 5
Voxelotor
2500 mg
N ≥ 5
Voxelotor
3000 mg
N ≥ 5
24-week 
observation 
period
Voxelotor
highest 
tolerated 
dose level
Participant has the 
option to enroll in OLE
3-week 
safety 
evaluation 
period
3-week 
safety 
evaluation 
period
No study 
drug
3-week 
safety 
evaluation 
period
28-day 
safety 
follow-up
3-week 
safety 
evaluation 
period
Screening 
End of 
Study 
visit
30 days
  
OLE, open-label extension. 
 
3.3. 
Assessments  
Assessments and procedures are described in Section 8, Appendix A, and Appendix B. 
3.4. 
Safety Monitoring Committee  
The SMC will closely monitor the safety of the study participants throughout the duration of 
study. The SMC will review the totality of safety, tolerability, and available PK and PD data to 
monitor safety.  
The SMC will be composed of the Principal Investigator or designee and Sponsor 
representatives, including the Study Director/Medical Monitor, Clinician with disease expertise, 
Biostatistician, and Safety Scientist. Details of the scope, responsibilities, and frequency of the 
SMC will be provided in the SMC Charter. 
3.5. 
Treatment  
See Section 5 for voxelotor information. 
3.6. 
Duration of Study Participation and of the Study 
Study participation will be up to 44 weeks in duration, which includes up to 30 days in the 
Screening Period; 21 days (3 weeks) each in Periods 1, 2, 3, and 4; 168 days (24 weeks) in the 
Observation Period; and 28 days in the Safety Follow-up Period. See Section 3.2 for additional 
information regarding the study periods for this study. 
The study will end when the last participant’s last visit occurs. 


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3.7. 
Stopping Rules  
3.7.1. 
Early Discontinuation of the Study/Study Stopping Rules 
The Sponsor has the right to terminate this study at any time. Reasons for terminating the study 
may include, but are not limited to, the incidence or severity of TEAEs in this or other studies 
indicating a potential health risk to participants.  
The study will be put on hold immediately with the first fatal case reported in participants (at any 
dose level greater than 1500 mg/day) considered to be related to study drug, until SMC reviews 
the data and determines whether it is reasonable to proceed. 
In the instance of early termination of the study, the Sponsor will notify, in writing, the 
Investigators, regulatory authorities, and Independent Ethics Committees (IECs)/Institutional 
Review Boards (IRBs) and will specify the reason(s) for termination. 
3.7.2. 
Cohort Dose Escalation Stopping Rules 
• If ≥3 participants at a given dose level experience similar and related serious adverse 
events (SAEs), dose escalation will be paused until the SMC assesses the safety data 
and makes a recommendation. 
• Progression to the next higher dose level can also be stopped if the SMC recommends 
discontinuation of dose escalation based on the totality of safety data.  
3.7.3. 
Early Discontinuation of Individual Participants 
3.7.3.1. 
Individual Dose-limiting Toxicity Definition: Dose Escalation Period  
Criteria for individual dose-limiting toxicity at doses beyond 1500 mg/day include, but are not 
limited to, the following: 
• Any AE Grade ≥ 3 not clearly resulting from the underlying disease and deemed by 
the Investigator and/or Medical Monitor to be related to study drug.  
• Worsening of an ongoing, treatment-related AE by ≥ 1 grade as per Investigator 
assessment  
• Grade 3 nausea, vomiting, or diarrhea (deemed related to study drug) requiring 
hospitalization and/or intravenous fluids and parenteral tube feeding, total parenteral 
nutrition 
• Study drug-related SAE 
If any of these criteria is met, the Investigator should consider temporary dose reduction and/or 
study drug discontinuation for the individual participant after discussing with the Sponsor. If a 
subject discontinues early due to AEs, the subject will not be eligible for the open-label 
extension study.  


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3.7.3.2. 
 Individual Early Discontinuation of Study Drug 
Participants will be discontinued from study drug for any of the following reasons:  
• Participant is lost to follow-up 
• Discretion of the Investigator 
• Participant is noncompliant 
• Pregnancy 
• Withdrawal of consent (participants are free to discontinue treatment or withdraw 
from the study at any time and for any reason. The Investigator must withdraw 
participants from the study who request to be withdrawn). 
The participant should return to the study site for an EOS visit approximately 28 days after the 
last dose of study drug as indicated in Section 8.16. Subjects who discontinue study drug early 
will not be eligible for the open-label extension study.  


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4. 
SELECTION OF STUDY POPULATION 
If a participant is found to meet inclusion/exclusion criteria at Screening but then has a clinically 
significant change in status prior to dosing (eg, hospitalized for sickle cell VOC, acute infection 
with drop in hemoglobin from participant’s baseline), the participant should be withdrawn from 
screening and not administered study drug. The participant may be rescreened once at the 
Investigator’s discretion and in consultation with the Sponsor. Participants who are rescreened 
will have all assessments repeated except for Hb genotyping. 
4.1. 
Inclusion Criteria 
Participants who meet all the following criteria will be eligible for enrollment in the study:  
1. Male or female with SCD 
2. Documentation of SCD genotype HbSS or HbSB0  
3. Age 18 to < 60 years, inclusive  
4. Hemoglobin ≥ 5.5 and ≤ 10.5 g/dL during Screening, and considered stable and close to 
Baseline by the Investigator 
5. For participants taking HU, the dose in mg/kg must be stable for at least 90 days prior to 
signing the informed consent form (ICF) and with no anticipated need for dose 
adjustments during the study, in the opinion of the Investigator. 
6. Participants, who if female and of child-bearing potential, agree to use highly effective 
methods of contraception or practicing abstinence from study start to 30 days after the 
last dose of study drug, and who if male, agree to use barrier methods of contraception or 
practice abstinence from study start to 30 days after the last dose of study drug  
7. Participant has provided documented informed consent 
4.2. 
Exclusion Criteria  
Participants meeting any of the following exclusion criteria will not be eligible for study 
enrollment: 
1. More than 10 VOCs within 12 months of screening that required a hospital, emergency 
room, or clinic visit 
2. Female participant who is breast feeding or pregnant 
3. Receiving regularly scheduled blood (RBC) transfusion therapy (also termed chronic, 
prophylactic, or preventive transfusion) or have received an RBC transfusion for any 
reason within 60 days of signing the ICF or at any time during the Screening Period 
4. Hospitalized for sickle cell crisis or other vaso-occlusive event within 30 days prior to 
dosing (ie, a vaso-occlusive event cannot be within 30 days prior to dosing) 
5. Screening laboratory test of alanine aminotransferase (ALT) > 4 × upper level of normal 
(ULN)  
6. Clinically significant bacterial, fungal, parasitic, or viral infection which requires therapy, 
including acute bacterial infection requiring antibiotics 


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7.  Known to be COVID-19 positive from within 3 weeks of screening through Day 1 
8. Participants with active hepatitis A, B, or C or who are known to be human 
immunodeficiency virus (HIV) positive 
9. Severe renal dysfunction (estimated glomerular filtration rate < 30 mL/min/1.73 m2 at the 
Screening visit; calculated by the local laboratory to assess safety) or is on chronic 
dialysis  
10. History of malignancy within the past 2 years prior to treatment Day 1 requiring 
chemotherapy and/or radiation (with the exception of local therapy for non-melanoma 
skin malignancy) 
11. History of unstable or deteriorating cardiac or pulmonary disease within 6 months prior 
to consent including but not limited to the following:  
a. Unstable angina pectoris or myocardial infarction or elective coronary intervention 
b. Congestive heart failure requiring hospitalization 
c. Uncontrolled clinically significant arrhythmias 
d. Pulmonary hypertension 
12. Criteria related to ECG parameters: 
a. PR interval > 220 msec in any participant 
b. QRS interval > 120 msec or QT interval corrected using Fridericia’s formula (QTcF) 
> 480 msec (both genders) in participants without bundle branch block 
c. QRS interval > 120 msec in participants with newly (within 3 months) emerged 
bundle branch block 
d. A participant with stable bundle branch block with or without stable cardiac disease 
may be enrolled; QRS interval > 120 msec and QTcF interval > 480 msec are 
acceptable in these participants. 
13. Any condition affecting drug absorption, such as major surgery involving the stomach or 
small intestine (prior cholecystectomy is acceptable) 
14. Participated in another clinical trial of an investigational agent or medical device within 
30 days or 5 half-lives of date of informed consent, whichever is longer, or is currently 
participating in another trial of an investigational agent or medical device 
15. Inadequate venous access as determined by the Investigator/site staff 
16. Medical, psychological, or behavioral conditions, which, in the opinion of the 
Investigator, may preclude safe participation, confound study interpretation, interfere 
with compliance, or preclude informed consent 
17. Received erythropoietin or other hematopoietic growth factor treatment within 28 days of 
signing ICF or is anticipated to require such agents during the study  
18. Ongoing or recent (within 2 years) substance abuse 
19. Known allergy to voxelotor  
20. Use of herbal medications (eg, St. John’s Wort), sensitive cytochrome P450 (CYP) 3A4 
substrates with a narrow therapeutic index, strong CYP3A4 inhibitors, fluconazole, or 
moderate or strong CYP3A4 inducers. 


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5. 
TREATMENTS ADMINISTERED 
5.1. 
Treatments Administered 
Participants will receive voxelotor as 500 mg tablets. Detailed instructions will be provided to 
participants prior to the first dose of study drug. 
5.2. 
Dose Frequency 
Participants will receive voxelotor tablets administered orally, once or twice daily, as outlined in 
Section 3.2. If a participant misses a dose, the participant should resume normal dosing the next 
day (ie, the dose, on the day after the day of a missed dose, should not be increased or 
decreased).  
5.3. 
Physical Description of Voxelotor 
Voxelotor is a synthetic small molecule bearing the chemical name 2-hydroxy-6-((2-(1-
isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde. The chemical formula is 
C19H19N3O3 and the molecular weight is 337.4 g/mol.  
5.4. 
Formulation 
Voxelotor will be supplied as 500 mg tablets.  
Details regarding drug administration will be provided in the Pharmacy Manual. 
5.5. 
Packaging and Labeling  
Voxelotor drug product will be supplied to clinical sites in high-density polyethylene bottles with 
induction sealed polypropylene child-resistant caps. At each visit (except for End of Treatment 
and EOS), participants will be supplied a sufficient quantity of study drug to ensure continuous 
dosing through to the next clinic visit. All study drug packaging must be returned at each visit, 
regardless if they are empty or contain unused study drug. 
5.6. 
Investigational Product 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. 
5.7. 
Storage and Handling Procedure 
All study medications will be stored at controlled room temperature between 15°C to 25°C 
(59°F to 77°F), in the storage area of the investigational site pharmacy, which is a secure, 
temperature controlled, locked environment with restricted access. The Sponsor or its 
representatives will be permitted upon request to audit the supplies, storage, dispensing 
procedures, and records. 


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5.8. 
Concomitant and Prohibited Medications 
5.8.1. 
Prior and Concomitant Medications 
A concomitant medication is defined as any prescription or over-the-counter preparation, 
including vitamins and supplements. 
In the interests of participant safety and acceptable standards of medical care, the Investigator 
will be permitted to prescribe treatment(s) at his/her discretion. For all study participants, 
all administered concomitant medications from signing the ICF until 28 days (4 weeks) after the 
participant’s last dose of study drug, must be recorded on the participant’s case report form 
(CRF). 
All reported prior and concomitant medications will be coded using the current version of the 
World Health Organization (WHO) Drug Dictionary. 
5.8.2. 
Hydroxyurea Therapy 
Hydroxyurea therapy is allowed, provided that the dose has been stable for at least 90 days prior 
to signing the ICF. Participants who start chronic therapy with HU any time after enrollment will 
be discontinued from the study.  
Participants who are on HU may have their dose adjusted (based on change in their weight) if 
the mg/kg dose is stable.  
5.8.3. 
Transfusion 
Participants who require chronic transfusion will be discontinued from study drug and 28 days 
later undergo the EOS visit. 
5.8.4. 
Other Therapies 
Penicillin prophylaxis and vaccinations are allowed as per standard of care. 
Other concomitant medications are allowed, unless the restrictions in Section 5.8.5 and 
Section 5.8.6 apply. Permitted concomitant medications include folic acid, L-glutamine, over-the-
counter analgesics, and opioids. 
The use of erythropoietin is prohibited during the study.  
5.8.5. 
Concomitant Medications to Be Used with Caution 
Voxelotor may increase the plasma concentrations of CYP3A4 substrates with a narrow 
therapeutic index and should be used with caution with these medications. See Table 1 for 
examples. 


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Table 1: 
CYP Substrates with Narrow Therapeutic Range 
CYP Enzymes 
Substrates with Narrow Therapeutic Range 
CYP3A4 
Alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, 
quinidine, sirolimus, and tacrolimus, 
CYP, cytochrome P450; FDA, Food and Drug Administration. 
Note that this is not an exhaustive list; country specific lists may be used if available. Decision can be made in 
consultation with the Sponsor’s Medical Monitor.  
Substrates with a “narrow therapeutic range” refers to drugs whose exposure-response relationship indicates that 
small increases in their exposure levels by the concomitant use of CYP inhibitors may lead to serious safety 
concerns. Adapted from: FDA DRAFT Guidance for Industry: Drug Interactions Studies-Study Design, Data 
Analysis, Implications for Dosing, and Labeling Recommendations. February 2012. Restrictions. 
5.8.6. 
Prohibited Concomitant Medications 
Use of an investigational product other than that under study in this trial, regardless of its 
intended use, is prohibited throughout the trial and for 28 days after the last dose. Additionally, 
concomitant medications (eg, crizanlizumab) that confound the ability to interpret data from the 
study are prohibited. 
Voxelotor is a moderate CYP3A4 inhibitor and should not be coadministered with sensitive 
CYP3A4 substrates with a narrow therapeutic index (refer to Table 2 for examples). 
Table 2: 
Sensitive CYP3A4 Substrates with Narrow Therapeutic Range 
Sensitive CYP3A4 Substrates with Narrow Therapeutic Range 
Alfentanil, sirolimus, and tacrolimus 
CYP, cytochrome P450. 
Note: This is not an exhaustive list. Country-specific lists may be used if available. 
For an updated list, refer to the following link: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm0
93664.htm#table 3-2. 
Voxelotor should not be coadministered with strong CYP3A4 inhibitors (refer to Table 3 for 
examples) or fluconazole. 
Table 3: 
Examples of Strong CYP3A4 Inhibitors 
CYP 
Strong Inhibitors 
CYP3A4 
Boceprevir, ceritinib, clarithromycin, cobicistat, conivaptan, danoprevir/ritonavir, 
elvitegravir/ritonavir, grapefruit juice, idelalisib, indinavir/ritonavir, itraconazole, ketoconazole, 
lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, posaconazole, ribociclib, 
ritonavir, saquinavir/ritonavir, telaprevir, telithromycin, tipranavir/ritonavir, troleandomycin, 
Viekira Pak®, voriconazole 
CYP, cytochrome P450. 
Note: This is not an exhaustive list. Country-specific lists may be used if available. 
For an updated list, refer to the following link: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm0
93664.htm#table 3-2. 
Since CYP3A4 is a primary CYP responsible for the metabolism of voxelotor, concomitant use 
of voxelotor and moderate or strong inducers of CYP3A4 is not allowed (refer to Table 4 for 
examples). 


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Table 4: 
Examples of Moderate and Strong CYP Inducers 
CYP3A4 
Examples 
Moderate CYP3A4 inducers 
Efavirenz, bosentan, etravirine, phenobarbital, and primidone 
Strong CYP3A4 inducers 
Rifampin, apalutamide, phenytoin, carbamazepine, enzalutamide, 
St John’s wort, and mitotane 
CYP, cytochrome P450. 
Note: This is not an exhaustive list. Country-specific lists may be used if available. 
For an updated list, refer to the following link: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm0
93664.htm#table3-3. 
Additional prohibited medications are shown in Table 5. 
Table 5: 
Additional Prohibited Medications 
Prohibited Medications 
Astemizole, cisapride, terfenadine, crizanlizumab 
 


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6. 
FERTILITY/CONTRACEPTIVE REQUIREMENTS 
All female participants of child-bearing potential (post menarche) should avoid pregnancy, and 
all sexually active male participants should avoid fathering a child.  
6.1. 
Instructions for Female Participants of Child-Bearing Potential 
For female participants of child-bearing potential (post menarche) and sexually active, pregnancy 
should be avoided by either abstinence from sex/sexual intercourse or the use of highly effective 
means of contraception for the duration of the study, and for a total period of 30 days after the 
participant has taken her last dose of voxelotor. Highly effective means of contraception are 
listed below in Section 6.4. Pregnancy reporting requirements are outlined in Section 9.4. 
Female participants who become pregnant during the study will be withdrawn from the study. 
6.2. 
Female Participants of Non-Child-Bearing Potential 
Female participants of non-child-bearing potential are defined as: bilateral oophorectomy/ 
hysterectomy/postmenopausal females being amenorrheic for greater than 2 years with an 
appropriate clinical profile, eg, age appropriate, history of vasomotor symptoms.  
6.3. 
Instructions for Male Participants Capable of Fathering a Child 
There is no information about effects that voxelotor could have on the development of the fetus 
in humans. Therefore, it is important that the partners of male participants do not become 
pregnant during the study and for a total period of 30 days after the male participant has taken 
the last dose of voxelotor. 
As a precaution, all male participants who are sexually active should avoid fathering a child by 
either true abstinence or the use of barrier methods of contraception. 
6.4. 
Acceptable Forms of Contraception for Sexually Active Participants 
For female participants:  
Highly effective methods of birth control are defined as those which result in a low failure rate 
(ie, less than 1% per year) when used consistently and correctly. Highly effective methods of 
birth control are as follows: 
1. Hormonal contraceptives  
a. Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
o Oral 
o Intravaginal 
o Transdermal 
b. Progestogen-only hormonal contraception associated with inhibition of ovulation: 
o Oral 
o Injectable 
o Implantable 


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c. Hormonal contraception must be supplemented with a barrier method (preferably 
male condom). 
2. Intrauterine device (IUD) 
3. Intrauterine hormone-releasing system (IUS) 
4. Bilateral tubal occlusion 
5. Sexual abstinence:  
Sexual abstinence is considered a highly effective method only if the participant is 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study drug. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the clinical study and the preferred and usual lifestyle of the 
participant. 
For male participants with female partners capable of reproduction: 
Barrier methods of contraception: 
• Condom with occlusive cap (diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository for female partner. The use of barrier contraceptives 
should always be supplemented with the use of a spermicide. 


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7. 
ASSESSMENT OF TREATMENT COMPLIANCE 
Drug disposition records will be maintained, specifying the amount dispensed to each participant 
and the date of dispensation. This record will be available for Sponsor review at any time. 
Compliance will be determined by returned tablet count.  


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8. 
STUDY PROCEDURES AND EVALUATIONS 
The Screening Period for a participant commences at the point at which the participant 
undergoes the first study-specific screening assessment. All screening assessments must be 
completed within 30 days before the first dose of study drug. 
The required study procedures, and timing that they need to occur, are outlined in the Schedule 
of Assessments (Appendix A, Appendix B). 
8.1. 
Informed Consent 
A signed and dated consent form will be obtained before any protocol-specified screening 
procedures are performed. 
Guidelines for the informed consent process are outlined in Section 13.6. 
8.2. 
Participant Study Number 
Upon execution of consent, all participants will be given a unique study number. This number 
will be used to identify the participant throughout the clinical study and must be used on all 
study documentation related to that participant. A new participant number will be assigned to 
rescreened participants.  
8.3. 
Demographics and Medical and Medication History 
Demographic and baseline characteristics of sex, race, ethnicity, age, weight, and height of the 
participant will be collected at the time of Screening.  
Medical history includes clinically significant diseases, surgeries, all medications (eg, 
prescription drugs, over-the-counter drugs, herbal/homeopathic remedies, nutritional 
supplements) used by the participant within 30 days prior to the first dose will be recorded. 
8.4. 
Physical Examination  
The physical examination (PE) will be a complete PE according to the standard at the site for this 
age group at Screening and an abbreviated, symptom-directed examination at the scheduled 
clinic visits. 
• Complete PE should include at a minimum: Examination of head, eyes, ears, nose, 
and throat, skin, cardiovascular and respiratory systems, abdominal examination, 
neurologic, musculoskeletal, and symptom-directed examination. 
• Abbreviated PE should include at a minimum: Examination of skin, cardiovascular 
and respiratory systems, abdominal examination, and symptom-directed examination. 
8.5. 
Vital Signs 
Vital signs (blood pressure, heart rate, and temperature will be measured, as outlined in Schedule 
of Assessments (Appendix A, Appendix B), after a participant has rested comfortably for at least 
5 minutes in the supine or sitting position, as age appropriate and feasible. A repeated 
measurement of any of the vital signs parameters will be taken within 5 minutes if the first 
reading is outside of the normal range and deemed clinically significant. 


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8.6. 
Body Mass Index 
Height and weight will be measured, and body mass index (BMI) will be calculated.  
8.7. 
Electrocardiograms  
Electrocardiograms (12-lead) will be recorded after 10 minutes of rest in the supine position. 
ECGs recorded at Screening, on Days 1 and 7 of each period, and Day 21 in Period 4 will be 
recorded in triplicate for evaluation at a central ECG laboratory (refer to the Schedule of 
Assessments, Appendix A, Appendix B). Other ECGs will be recorded as singles. 
8.8. 
Eligibility Assessment, Inclusion/Exclusion Review 
Eligibility assessments will be conducted during screening and prior to receiving study drug on 
treatment Day 1. If a participant is found to meet the inclusion/exclusion criteria, but then has a 
clinically significant change in status prior to administration of the first dose of study drug (eg, is 
hospitalized for sickle cell crisis), the participant should be considered a screen failure. 
Participants who have not been enrolled or dosed may be rescreened once at the Investigator’s 
discretion and in consultation with the Sponsor. Participants who rescreen will have 
all SCREENING assessments redone, except for Hb genotyping.  
8.9. 
Adverse Events and Concomitant Medications 
AEs and concomitant medications will be recorded throughout the study. See Section 9.2 for 
details regarding AE reporting period for this study.  
8.10. 
Clinical Global Impression of Change 
Investigator’s assessment of change in the overall health condition of the participant. The CGI-C 
assessment will be performed using a 7-point scale to assess how much the participant’s SCD 
has improved or worsened relative to Baseline.  
8.11. 
Patient Global Impression of Change 
The participant’s assessment of change in their overall health condition. The PGI-C assessment 
will be performed using a 7-point scale to assess how much the participant’s SCD has improved 
or worsened relative to Baseline. 
8.12. 
Safety Laboratory Assessments 
Refer to the Schedule of Assessments (Appendix A, Appendix B) for the specific timing that 
laboratory tests are to occur and refer to the Laboratory Manual for details. 
It is the responsibility of the Investigator or designee to assess the clinical significance of all 
abnormal clinical laboratory values as defined by the applicable list of normal values on file 
(ie, local laboratory). All clinically significant laboratory value abnormalities are to be recorded 
as AEs. 
Additional and repeat laboratory safety testing for the evaluation of abnormal results and/or AEs 
during the study may be performed at the discretion of the Investigator or upon request of the 
Sponsor. Repeat laboratory testing of abnormal potentially clinically significant or clinically 


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significant results for the screening evaluation of the participant may be repeated at the discretion 
of the Investigator. 
8.12.1. 
Screening 
In addition to screening laboratory tests that are also conducted throughout the study, the 
following laboratory assessments will be conducted at Screening only: 
• Follicle-stimulating hormone (FSH) (postmenopausal females only)  
• Coagulation panel (prothrombin time [PT], partial thromboplastin time [PTT], 
international normalized ratio [INR])  
• Serology panel: Serum virology (hepatitis A, B, C, and, if clinically indicated, HIV) 
• Hemoglobin genotyping (only if no documentation of hemoglobin genotype is 
available) 
• Fetal hemoglobin 
• Urinalysis: urine will be assessed for color and appearance. Dipstick analysis will be 
conducted for specific gravity, pH, protein, glucose, ketones, leucocytes, bilirubin, 
urobilinogen, nitrite, and occult blood. Microscopic analysis (RBCs, white blood cells 
[WBCs], bacteria, and casts) will be collected as clinically indicated. 
8.12.2. 
Hematology 
Hematology assessments include the following: 
• RBCs  
• Hematocrit  
• Hb  
• Platelets  
• WBCs with differential (basophils, eosinophils, neutrophils, monocytes, and 
lymphocytes)  
• Percent and absolute reticulocytes  
• Mean corpuscular volume (MCV)  
• Mean corpuscular hemoglobin concentration (MCHC)  
8.12.3. 
Serum Chemistry 
Chemistry assessments include the following: 
• ALT 
• Albumin 
• Alkaline phosphatase (ALP) 
• Aspartate aminotransferase (AST) 


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• Bicarbonate 
• Blood urea  
• Chloride 
• Calcium 
• Creatinine  
• Glucose 
• LDH 
• Sodium 
• Potassium 
• Bilirubin (total, direct, and indirect) 
8.13. 
Other Laboratory Assessments 
8.13.1. 
Effect on Hemoglobin Oxygen Equilibrium Curve 
Assessments of P50 and P20 will be conducted by hemoximetry as indicated in the Schedule of 
Assessments (Appendix A, Appendix B).  
8.13.2. 
Hemoglobin Genotype 
Unless documented in their medical record, participants will be tested for hemoglobin genotype 
at Screening. 
8.13.3. 
Serum Erythropoietin  
Serum erythropoietin will be measured as indicated in the Schedule of Assessments 
(Appendix A, Appendix B). 
8.13.4. 
Red Blood Cell Deformability and Dense Cells 
Assessments will be conducted as indicated in the Schedule of Assessments (Appendix A, 
Appendix B). 
8.13.4.1. Pregnancy Test 
Pregnancy tests will be performed on female participants who are post menarche; a serum 
pregnancy test (human chorionic gonadotropin in serum) will be performed at Screening. Urine 
pregnancy tests will be performed in females who are post menarche as outlined in the Schedule 
of Assessments (Appendix A and Appendix B). If a urine test is positive, the result must be 
confirmed with a serum pregnancy test.  
Information regarding fertility and contraceptive requirements is provided in Section 6; highly 
effective means of contraception are listed in Section 6.4. Instructions for 
reporting pregnancy are provided in Section 9.4.  


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8.13.5. 
Pharmacokinetic Sample Collection 
Blood samples for whole blood and plasma PK assessments will be collected according to the 
Schedule of Assessments (Appendix A, Appendix B). Whole blood and plasma concentrations of 
voxelotor will be measured using a validated liquid chromatography mass spectrometry (LCMS) 
assay. 
8.14. 
Phone Call 
Follow-up phone calls will be conducted on Day 3 of each study period (Appendix A, 
Appendix B). These phone calls will be used to confirm compliance, ask for concomitant 
medications, and check for participant wellbeing by asking open ended questions (eg, How are 
you feeling?). 
8.15. 
Missed Assessments 
Missed assessments should be rescheduled and performed as close to the originally scheduled 
date as possible. An exception is made when rescheduling becomes, in the Investigator’s 
opinion, medically unnecessary or unsafe because it is too close in time to the next scheduled 
evaluation. In that case, the missed evaluation should be abandoned. 
8.16. 
End of Study Visit 
The EOS is defined as the visit that occurs 28 days after the last dose of study drug. Assessments 
for this visit are outlined in the Schedule of Assessments (Appendix A, Appendix B). 
If the participant terminates study drug early, every effort should be made to collect the 
Day 168/End-of-Treatment assessments. The participant should also be asked to attend the 
Safety Follow-up visit 28 days later.  
8.17. 
Participant Discontinuation from the Study  
The reasons for a participant's discontinuation from the study may include but are not limited to 
the following: 
• Patient withdrawal of consent 
• Study termination 
• Adverse event 
• Loss to follow-up 
• Participant non-compliance, defined as failure to comply with protocol requirements, 
as determined by the Investigator or Sponsor 
If a participant requests to be withdrawn from the study, this information should be documented 
and signed by the Investigator. No further data will be collected from the signed date onwards. 
8.18. 
Order of Assessments 
Visits should take place in the morning. Participants are instructed to hold study drug until a 
predose blood sample for PK is obtained at the investigational site.  


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For procedures scheduled to be performed at the same timepoint, the order of assessments is as 
follows: vital signs, PK sample collection, blood draw for PD/safety laboratory assessments, 
ECGs. If times are delayed due to technical difficulties, this will be noted but not considered a 
protocol violation.  
The predose PK sample should be collected within 30 min prior to dosing.  
On Day 1 in Period 1: 
• Triplicate ECGs should be recorded at 3 timepoints prior to dosing 
(-45 min, -30 min, -15 min). 
• Postdose triplicate ECGs (after the morning dose) should be recorded within 15 min 
following the 2-hour PK sample collection.  
On Day 1 in Periods 2, 3, and 4, on Day 7 in all periods, and on Day 21 in Period 4: 
• Predose triplicate ECGs should be recorded within 15 min following the predose PK 
sample collection.  
• Postdose triplicate ECGs (after the morning dose) should be recorded within 15 min 
following the 2-hour PK sample collection.  
All PD assessments should be performed after the PK assessments. RBC deformability and dense 
cells will be tested, if feasible, by the local or collaborating lab at the time of collection.  


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9. 
ADVERSE AND SERIOUS ADVERSE EVENTS 
Safety assessments will consist of recording all AEs and SAEs, protocol-specified hematology 
and clinical chemistry variables, clinical examination findings, measurement of protocol-
specified vital signs, and the results from other protocol-specified tests that are deemed critical to 
the safety evaluation of voxelotor. 
The determination, evaluation, reporting, and follow-up of AEs will be performed as outlined in 
Section 9.1. At each visit, the study participant or participant caregiver will be asked about any 
new or ongoing AE since the previous visit. Assessments of AEs will occur at each study visit. 
See Section 9.2 for details regarding the required time periods for AE reporting. 
Clinically significant changes from study baseline in physical examination findings, weight, 
vital signs, and clinical laboratory parameters will be recorded as AEs or SAEs, as appropriate. 
9.1. 
Adverse Events 
9.1.1. 
Definition of Adverse Events 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. An AE can therefore be any unfavorable and 
unintended sign, symptom, or disease temporally associated with the use of an investigational 
product, whether or not thought to be related to the investigational product. An AE may also 
constitute complications occurring as a result of protocol-mandated interventions (eg, invasive 
procedures such as biopsies), including the period prior to receiving the first dose of the study 
drug (eg, medication wash out). In addition to new events, any increase in the severity or 
frequency of a pre-existing condition that occurs after the participant signs the ICF is considered 
an AE. This includes any side effect, injury, toxicity, or sensitivity reaction. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the drug 
caused the AE. For the purposes of expedited safety reporting, “Reasonable possibility” means 
there is evidence to suggest a causal relationship between the drug and the AE. Suspected 
adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which 
means any AE caused by a drug. 
Life-threatening AE or life-threatening suspected adverse reaction is an AE or suspected adverse 
reaction that, in the view of either the Investigator or GBT, places the study participant at 
immediate risk of death. It does not include an AE or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. 
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the 
Reference Safety Information (RSI) section of the current IB or is not listed at the specificity or 
severity that has been observed. 
An SAE or serious suspected adverse reaction is an AE or suspected adverse reaction that at any 
dose, in the view of the either the Investigator or GBT, results in any of the following outcomes: 
• Death 
• A life-threatening AE 
• Inpatient hospitalization or prolongation of existing hospitalization 


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• Persistent or significant incapacity or disability (substantial disruption of the ability to 
conduct normal life functions) 
• A congenital anomaly/birth defect 
• Important medical events (IME) that may not result in death, be immediately 
life-threatening, or require hospitalization may be considered serious when based 
upon medical judgement, they may jeopardize the study participant and may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition 
NOTE: Hospitalization planned prior to study enrollment (eg, for elective surgeries) are not 
considered SAEs. Hospitalizations that occur for pre-existing conditions that are scheduled after 
study enrollment are considered SAEs. 
The Investigator will assess each AE for seriousness, severity, and relationship to investigational 
product. 
9.1.2. 
Severity of Adverse Events 
Whenever possible, the severity of all AEs will be graded using the National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. 
For AEs not adequately addressed in the NCI CTCAE Version 5.0, the following criteria should 
be used (Table 6). 
Table 6: 
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 non-invasive 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 
NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events.  
To make sure there is no confusion or misunderstanding between the terms “serious” and 
“severe”, which are not synonymous, the following note of clarification is provided. The term 
“severe” is often used to describe the intensity (severity) of a specific event (ie, mild, moderate, 
or severe); the event itself, however, may be of relatively minor medical significance (eg, severe 
headache). This is not the same as “serious” which is based on the study participant / event 
outcome or action criteria associated with events that post a threat to a participant’s life or 
functioning. Seriousness (not severity) serves as a guide for defining regulatory reporting 
obligations. 


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9.1.3. 
Relationship to Investigational Product 
The relationship of an AE to the investigational product should be determined by the Investigator 
according to the following definitions: 
• NOT RELATED: Evidence exists that the AE has an etiology other than the study 
drug and/or the temporal relationship of the AE/SAE to the investigational product 
administration makes the relationship unlikely. If an SAE is not considered related to 
study drug, then an alternative explanation should be provided. 
• RELATED: A temporal relationship exists between the event onset and the 
administration of the study drug makes a causal relationship possible or probable. 
It cannot be readily explained by the participant’s clinical state or concomitant 
therapies and may appear, with some degree of certainty, to be related based on the 
known therapeutic and pharmacologic actions of the drug. Good clinical judgement 
should be used for determining causal assessment. 
9.1.4. 
Unexpected Adverse Reactions 
An AE is ”unexpected” if its nature and severity are not consistent with the information about the 
study drug provided in the RSI in the Voxelotor IB. 
9.2. 
Adverse Event Reporting  
9.2.1. 
General 
All AEs will be recorded from the time the study participant signs the ICF until 28 days after the 
last dose of study drug. After this period, the Investigator should report only SAEs that are 
assessed as related to study drug until the EOS visit occurs. All SAEs must be reported within 24 
hours of SAE awareness on the AE CRF via the electronic data capture (EDC) system. The 
Investigator is responsible for evaluating all AEs, obtaining supporting documents, and ensuring 
documentation of the event is complete. Details of each reported AE must include at minimum 
severity, relationship to study drug, duration and outcome. 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. 
Any participant who experiences an AE may be discontinued from study drug at any time at the 
discretion of the Investigator. The Sponsor and the CRO’s Medical Monitors must be notified of 
the study participant’s discontinuation. 
9.2.2. 
Diagnosis Versus Signs and Symptoms 
If known, a diagnosis should be recorded on the CRF rather than individual signs and symptoms 
(eg, 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 separately on the CRF. If a diagnosis is subsequently established, it should be 
reported as follow-up information. 


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9.2.3. 
Abnormal Laboratory Values 
Only clinically significant laboratory abnormalities will be recorded on the AE 
CRF (eg, abnormalities that have clinical sequelae, require study drug dose modification, 
discontinuation of study drug, more frequent follow-up assessments, further diagnostic 
investigation). If the clinically significant laboratory abnormality is a sign of a disease or 
syndrome (eg, ALP and bilirubin above the ULN associated with cholecystitis), only the 
diagnosis (eg, cholecystitis) needs to be recorded on the CRF.  
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the CRF. If the laboratory abnormality can 
be characterized by a precise clinical term, the clinical term should be recorded. 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 on the AE CRF, unless their severity, seriousness, or etiology 
changes. 
9.2.4. 
Pre-existing Medical Conditions 
A pre-existing medical condition is one that is present at the start of the study. Such conditions 
should be recorded on the Medical History and Baseline Conditions CRF. 
If a pre-existing medical condition increases in frequency or severity, or if the character of the 
condition worsens during the study, the condition should be recorded as an AE or SAE. When 
recording such events on the AE CRF, it is important to convey the concept that the pre-existing 
condition has changed by including applicable descriptors (eg, “more frequent headaches”). 
9.2.5. 
Worsening of Sickle Cell Disease 
Sickle cell anemia-related AEs that are common complications associated with the study 
participant’s SCD should not be considered related to voxelotor unless judged by the Investigator 
to have worsened in severity and/or frequency or changed in nature during the study. Sickle cell 
anemia-related AEs include: sickle cell anemia with crisis, acute chest syndrome, pneumonia, 
priapism, and osteonecrosis (Kato, 2018).  
9.3. 
Serious Adverse Events, Serious Adverse Drug Reactions, and 
Requirements for Immediate Reporting 
All SAEs, regardless of causal attribution, occurring on this study will be reported to the 
Sponsor’s designated CRO’s Drug Safety Department within 24 hours of the Investigator, 
designee, or site personnel’s knowledge of the event. The SAE will be reported via the EDC 
system. If the EDC system is not available, paper SAE report forms will be used to report the 
SAE and faxed or emailed to GBT Pharmacovigilance or CRO designee. The information 
reported on the paper SAE report form should be entered into the EDC once available. 
The Sponsor or designee may request additional source documentation pertaining to the SAE 
from the investigational site. Follow-up reports must be submitted within 24 hours of awareness 
and ensure that participant identifier information (eg, name, medical record number) are redacted 
in the hospital discharge summaries, autopsy reports, and/or death certificates. 


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Follow-up SAE information must be submitted within 24 hours of awareness as additional 
information becomes available. All SAEs, regardless of causal attribution, must be followed to 
resolution, stabilization or until reasonable attempts to determine that resolution of the SAEs are 
performed. 
9.3.1. 
Reporting Suspected Unexpected Serious Adverse Reactions and Urgent Safety 
Issues 
The Sponsor or its designee is responsible for reporting serious suspected unexpected serious 
adverse reactions (SUSARs) to regulatory agencies, competent authorities, IECs/IRBs, and 
Investigators as per local laws and regulations. Fatal and life-threatening SUSARs will be 
submitted no later than 7 calendar days of the Sponsor’s or CRO designee first knowledge of the 
event and follow-up information submitted within an additional 8 calendar days, or as otherwise 
required per local laws and regulations. All other SUSARs will be submitted within 15 calendar 
days of the Sponsor’s or CRO designee first knowledge of the event. The Investigator is 
responsible for notifying the local IECs/IRBs of all SAEs that occur at his or her site, as required 
by local regulations or IEC/IRB policies, if this responsibility resides with the site. 
Investigators are required to report any urgent safety matters to the Sponsor or its designee 
within 24 hours of awareness. The Sponsor or its designee will inform regulatory authorities, 
IECs/IRBs, and Investigators, as applicable, of any events (eg, change to the safety profile of 
voxelotor, major safety findings that may place study participants at risk) that may occur during 
the clinical trial that do not fall within the definition of a SUSAR but may adversely affect the 
safety of study participants. 
9.4. 
Reporting Pregnancy 
If a participant becomes pregnant while taking study drug, the study drug will be immediately 
discontinued, and the pregnancy must be reported to the Sponsor or designated Drug Safety CRO 
within 24 hours of awareness. The Investigator will discuss the risks and concerns of 
investigational agent exposure to a developing fetus and counsel the participant and/or pregnant 
partner (or ensure such counseling is provided). 
Reported pregnancy of a participant or a participant’s partner while participating in this study 
will be monitored for the full duration of the pregnancy, and/or followed through a definitive 
outcome (ie, birth, or spontaneous or elective abortion). Pregnancies in partners of male study 
participants will similarly be monitored for the full duration of the pregnancy and/or followed 
through a definitive outcome (ie, birth, or spontaneous or elective abortion). 
An uncomplicated pregnancy will not be considered an AE or SAE. Pregnancy complications 
such as spontaneous abortion/miscarriage and congenital anomalies are considered SAEs and 
must be reported as described in Section 9.3. Note: an elective abortion is not considered an 
SAE. Pregnancy and pregnancy outcomes must be reported on a Pregnancy Notification or 
Pregnancy Outcome Form, respectively, and sent to the Sponsor or designated Drug Safety CRO 
within 24 hours of the Investigator, designee, or site personnel learning of the pregnancy or 
pregnancy outcome.  
The child born to a female participant or participant’s partner exposed to study drug will be 
followed for 3 months after delivery. The outcome of any pregnancy and the presence or absence 


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of any congenital abnormality will be recorded in the Pregnancy Outcome Form and reported to 
the Sponsor or designated Drug Safety CRO. Any congenital abnormalities in the offspring will 
be reported as an SAE and must be reported as described in Section 9.3. 
Information regarding pregnancy testing (including definition of females of child-bearing 
potential) is provided in Section 6. Highly effective means of contraception are listed 
in Section 6.4. 
9.5. 
Reporting Overdose 
If a participant takes more than the protocol-defined dose in a day and experiences a drug-related 
AE, this will be reported as an overdose and a protocol deviation. However, if the participant did 
not experience any AEs, this will only be reported as a protocol deviation. 
The Investigator will discuss the risks and concerns of investigational agent exposure with the 
participant. Participants are to be instructed to contact their study site immediately if an overdose 
of study drug is suspected. A suspected overdose with AEs should be reported to the Sponsor’s 
designated CRO’s Drug Safety Department within 24 hours of the Investigator, designee, or site 
personnel’s knowledge of the event. An overdose with AEs must be followed until the adverse 
effects are resolved or stabilized, or until reasonable attempts to determine resolution of the 
event are exhausted. 
9.6. 
Safety Monitoring Committee 
See Section 3.4 for information regarding the SMC. 


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10. 
DATA ANALYSIS AND STATISTICAL PLANS 
10.1. 
Endpoints 
10.1.1. 
Primary Endpoint 
The primary endpoints are: 
• TEAEs and SAEs 
10.1.2. 
Secondary Endpoints 
The secondary endpoints are: 
• Change in Hb and clinical measures of hemolysis (unconjugated bilirubin, 
% reticulocyte, absolute reticulocyte, and LDH) from Baseline  
• Proportion of participants with an Hb increase > 1 g/dL compared to Baseline 
• Incidence rate of VOCs 
10.1.3. 
Exploratory Endpoints 
The exploratory endpoints are: 
• P50 and P20 at 8 hours and 24 hours postdose 
• PK of voxelotor as assessed by population PK analysis using nonlinear mixed-effect 
modeling 
• % Hb occupancy at 8 hours and 24 hours postdose  
• CGI-C 
• PGI-C 
10.2. 
Determination of Sample Size 
As this is an exploratory study to provide descriptive information on the tolerability, safety, and 
efficacy of voxelotor at dose levels > 1500 mg daily, the sample size chosen was based on 
previous experience in exploratory studies to support the assessment of a MTD based on 
descriptive summaries of safety and PK data. The sample size of up to 40 participants takes into 
account the differential tolerance in participants, some potentially tolerating 3000 mg daily, 
while others only tolerating lower dose levels. An effort will be made to enroll a number of 
subjects sufficient to ensure that at least 6 participants are treated at the study level MTD. 
10.3. 
Populations for Analysis 
Safety Population: All participants who receive at least one dose of study drug will be included 
in the safety population.  
Pharmacokinetic Population: The PK population will consist of all participants who receive any 
amount of study drug and have at least one measured concentration at a scheduled PK time point 
after the start of dosing.  


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10.4. 
Data Analysis 
Data will be presented by maximum dose level. 
A TEAE, defined as an event that occurs on or after Day 1 of study drug or the worsening of a 
pre-existing condition on or after Day 1 of study drug, will be classified according to the Medical 
Dictionary for Regulatory Activities (MedDRA). The incidence of TEAEs and relatedness to 
study drug, as assessed by the Investigator, will be summarized descriptively by maximum dose 
level tolerated. 
Clinical laboratory tests, ECGs, and vital signs over time will be summarized by maximum dose 
level tolerated using descriptive statistics. Change from baseline in ECG intervals will be 
evaluated using descriptive statistics. If an effect on mean change from baseline in QTc interval 
exceeding 10 msec is observed, concentration-QTc analysis may be explored. Results from the 
diagnostic interpretation will be summarized by maximum dose tolerated. 
An Hb responder endpoint, defined as an increase in Hb of > 1 g/dL compared to Baseline, will 
be summarized. Additionally, change from baseline in hemoglobin and clinical measures of 
hemolysis (unconjugated bilirubin, % reticulocyte, absolute reticulocyte, and LDH) will be 
summarized by maximum dose level tolerated using descriptive statistics.  
The incidence of VOCs will be summarized by maximum dose tolerated. 
The CGI-C and PGI-C will be summarized by maximum dose level tolerated. 
Population PK analysis using nonlinear mixed-effect modeling will be performed to characterize 
voxelotor PK in plasma, and whole blood. 


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11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
11.1. 
Source Data 
Original documents, data, records (eg, clinic records, laboratory notes, memoranda, participant 
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, participant files, and 
records kept at the pharmacy, at the laboratories, and at medicotechnical departments involved in 
the clinical study), and all relevant sections of the participant’s medical records and all other data 
collection made specific to this study constitute source documents. 
The completed CRF is not a source document. The Investigator/institution will permit 
study-related monitoring, audits, IEC/IRB review and regulatory inspection by providing direct 
access to source documents. 
11.2. 
Data Collection 
The Investigator will be responsible for maintaining accurate and adequate case records 
(source documents) from which data will be transcribed to CRFs designed to record data pertinent 
to this study. All relevant observations and data related to the study will be recorded. This will 
include medical and medication history, physical examinations, a checklist of inclusion and 
exclusion criteria, investigational treatment administration, a record of sample collection, clinical 
assessments, AEs, and final evaluation(s). The monitor will review all CRFs and compare data to 
that contained in clinic notes and participants’ source documents/medical records. 
Data for each participant will be recorded on the CRF unless transmitted to the sponsor or 
designee electronically, eg, laboratory data. A CRF must be completed for every participant 
enrolled in the study. When data are complete, the Investigator or medically qualified 
Sub-Investigator listed on Form FDA 1572 will apply his/her signature on the CRF indicating 
he/she has reviewed and approves of the data collected on the CRF. 
11.3. 
Essential Documentation Requirements 
The Sponsor or Sponsor’s representative will collect from the investigational site the required 
essential regulatory documents per International Council for Harmonisation (ICH) guidance prior 
to voxelotor shipment to the site. 


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12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
12.1. 
Monitoring 
Site personnel will be provided with training on how to collect quality data for the study, and a 
Sponsor monitor will be contacting the site periodically to review study conduct and data recorded 
at the site. At the Sponsor’s discretion, on-site monitoring visits may be conducted prestudy, 
during the study, and following study completion. These visits are to provide the Sponsor with the 
opportunity to evaluate study progress; verify the accuracy and completeness of source data and 
CRFs; and ensure that all protocol and Good Clinical Practice (GCP) requirements, applicable US 
FDA or country-specific regulations, and Investigator obligations are being fulfilled. The Sponsor 
may terminate study participation by a clinical study site if study-site personnel do not follow the 
protocol or GCPs. Additionally, individual participants may be excluded if a medical records 
review indicates protocol violations or if other factors appear to jeopardize the validity of the 
study. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected 
during the course of these monitoring visits are resolved. 
12.2. 
Quality Control and Quality Assurance 
GBT may conduct a quality assurance audit(s) of this study. If such an audit occurs, the 
Investigator agrees to allow the auditor direct access to all relevant documents (eg, all participant 
records, medical records and CRFs) and access to all corresponding portions of the office, clinic, 
laboratory, or pharmacy which may have been involved with the study. The Investigator will 
allocate his or her time and that of the study-site personnel to the auditor to discuss findings and 
any relevant issues. In addition, regulatory agencies may conduct a regulatory inspection of this 
study. If such an inspection occurs, the Investigator agrees to notify GBT upon notification by 
the regulatory agency. The Investigator agrees to allow the inspector direct access to all relevant 
documents and to allocate his or her time and that of the study-site personnel to the inspector to 
discuss findings and any relevant issues. The Investigator will allow GBT personnel to be 
present as an observer during a regulatory inspection, if requested. 
12.3. 
Laboratory Accreditation 
The laboratory facility used for analysis of clinical laboratory samples must provide evidence of 
adequate licensure or accreditation. Copies of laboratory certification, licensure, and reference 
ranges (as appropriate) will be supplied to the Sponsor prior to study initiation. The Sponsor or 
designee should be notified of any changes in reference range values or certification/license 
renewal during the course of the study. 


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13. 
REGULATORY, ETHICAL AND LEGAL OBLIGATIONS  
13.1. 
Ethical Conduct of the Study 
The Investigator will ensure that this study is conducted in full conformity with the current 
revision of the 1964 Declaration of Helsinki. 
The Investigator is generally not to deviate from the protocol. In medical emergencies, the 
Investigator will use medical judgment and will remove the participant from immediate hazard. 
The Investigator will immediately notify the Sponsor and IEC/IRB regarding the nature of the 
emergency and the course of action taken. The Investigator is to notify the Sponsor of any 
inadvertent protocol deviations upon discovery and is to document the deviations appropriately in 
the study files or on the CRFs. The Sponsor assumes no responsibility or liability for any 
unapproved deviations. Major changes in the protocol initiated by the Sponsor will be provided as 
an amendment and will be approved by the IEC/IRB prior to implementation (refer to 
Section 13.4). 
13.2. 
Good Clinical Practice 
The study will be conducted according to the protocol; guidelines established by ICH for GCP in 
clinical studies; US regulations (21 CFR Parts 50, 54, 56, and 312); and country-specific 
requirements, as applicable. 
13.3. 
Written Informed Consent 
Each individual will be provided with oral and written information describing the nature, purpose 
and duration of the study, participation/termination conditions, and risks and benefits. Prior to 
initiation of any study-related procedures, participants will sign and date the ICF to participate in 
the study. In the event of a pregnancy in the female partner of a male participant, a pregnancy 
consent form will be provided to allow the follow-up of the pregnancy. 
13.4. 
Independent Ethics Committee, Institutional Review Board, and 
Regulatory Approval 
The Investigator must inform, and obtain approval from, the IEC/IRB for the conduct of the 
study at named sites, for the protocol, the Participant ICF, and any other written information that 
will be provided to the participants and any advertisements that will be used. Written approval 
must be obtained prior to recruitment of participants into the study and shipment of 
investigational agent. 
Proposed amendments to the protocol and documents must be discussed with the Sponsor and 
CRO, and then submitted to the IEC/IRB for approval as well as submitted to regulatory 
authorities for approval prior to implementation. Amendments may be implemented only after a 
copy of local IEC approval letter has been transmitted to the Sponsor. Amendments that are 
intended to eliminate an apparent immediate hazard to participants may be implemented prior to 
receiving Sponsor or IEC/IRB approval. However, in this case, approval must be obtained as 
soon as possible after implementation. 


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The Investigator will be responsible for ensuring that an annual update is sent to the EC to 
facilitate their continuing review of the study (if needed) and that the IEC/IRB is informed about 
the end of the study. Copies of the update, subsequent approvals, and final letter must be sent to 
the Sponsor. The Investigator will inform the IEC/IRB of any reportable AEs. 
13.5. 
Essential Documentation Requirements 
The Sponsor or Sponsor’s representative will collect from the investigational site the required 
essential regulatory documents per ICH guidance prior to voxelotor shipment to the site. 
13.6. 
Informed Consent 
13.6.1. 
Participant 
Each participant will be provided with oral and written information describing the nature, 
purpose and duration of the study, participation/termination conditions, and risks and benefits. 
Prior to initiation of any study-related procedures, participants will sign and date the ICF to 
participate in the study.  
Participants unable to sign the ICF may participate in the study if a legal representative or 
witness provides the consent (in accordance with the procedures of ICH-GCP and local 
regulations) and the participant confirms his/her interest in study participation. The participant 
will be informed that they can freely withdraw consent and stop participation in the study at any 
time with no prejudice post study care. 
13.6.2. 
Investigator Responsibilities 
It is the Investigator’s responsibility to obtain written informed consent from the participant after 
adequate explanation of the objectives, methods, anticipated benefits, and potential risks of the 
study and before any study procedures are commenced. The participant should be given a copy 
of the ICF in their native language. The informed consent processes should be recorded in the 
source documentation. The original copies of the signed and dated informed consent must be 
retained in the institution’s records and are subject to inspection by representatives of the 
Sponsor, or representatives from regulatory agencies. 
13.7. 
Confidentiality 
The Investigator must ensure that the participant’s privacy is maintained. On the CRF and other 
documents submitted to the Sponsor, participants will be identified by a participant study number 
only. Documents that are not submitted to the Sponsor (eg, signed ICF) should be kept in a 
strictly confidential file by the Investigator. 
The Investigator shall permit authorized representatives of the Sponsor, regulatory agencies, and 
IECs/IRBs to review the portion of the participant’s medical record that is directly related to the 
study. As part of the required content of informed consent, the participant must be informed that 
his/her records will be reviewed in this manner. 


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13.8. 
Regulatory, Ethical and Legal Obligations 
The study will comply with the General Data Protection Regulation (GDPR) 2018, and 
applicable local data protection regulations. Data collected will be pseudonymized.  
The processing of the personal data of participants will be minimized by making use of a unique 
participant study number only on study documents and electronic database(s). 
All study documents will be stored securely and only accessible by study staff and authorized 
personnel. The study staff will safeguard the privacy of participants’ personal data. The 
participant information sheet/informed consent for the study will inform the participant of their 
rights and provide appropriate contact details of the Data Protection Officer. 
13.9. 
Study Documentation and Data Storage 
The Investigator must retain a comprehensive and centralized filing system of all study-related 
documentation that is suitable for inspection by the Sponsor and representatives of regulatory 
authorities. 
The Investigator must retain essential documents as detailed in Section 14.2. Participant files and 
other source data (including copies of protocols, original reports of test results, investigational 
agent dispensing logs, correspondence, records of informed consent, and other documents 
pertaining to the conduct of the study) 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 study document will be destroyed without prior written agreement between the Sponsor and 
the Investigator. Should the Investigator wish to assign the study records to another party or 
move them to another location, written agreement must be obtained from the Sponsor. 


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14. 
DATA HANDLING AND RECORDKEEPING 
14.1. 
Inspection of Records 
GBT will be allowed to conduct site visits to the investigation facilities for the purpose of 
monitoring any aspect of the study. The Investigator agrees to allow the monitor to inspect the 
drug storage area, study drug stocks, drug accountability records, participant charts, study source 
documents, and other records relative to study conduct. 
The Investigator agrees to maintain a Regulatory Binder in a current, organized fashion; this 
Binder will contain documentation supportive of the protocol and GCP compliance of the study. 
The contents of the Binder will be organized according to the standards of ICH E6, Section 8 
(Essential Documents). The Investigator agrees to make this Binder accessible to the monitor, 
auditor, and representatives of regulatory agencies and the IEC/IRB. 
14.2. 
Retention of Records 
The Investigator will maintain adequate records, including participants’ medical records, 
laboratory reports, signed consent forms, drug accountability records, safety reports, information 
regarding participants who discontinued the protocol, and any other pertinent data. All study 
records must be retained for at least 2 years after the last approval of a marketing application in 
the US or an ICH region and until (1) there are no pending or contemplated marketing 
applications in the US or an ICH region or (2) at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product under study. 
The Investigator/institution should retain participant identifiers for at least 15 years after the 
completion or discontinuation of the study. Study participant files and other resource data must 
be kept for the maximum period of time permitted by the hospital/institution but not less than 
15 years. These documents should be retained for a longer period, if required by the applicable 
regulatory requirements or by the Sponsor. GBT must be notified with retention if the 
Investigator/institution are unable to continue with the maintenance of study participant files for 
the full 15 years. All study records must be stored in a secure and safe facility. 
The Investigators must retain protocols, amendments, IEC/IRB approvals, copies of the Form 
FDA 1572, signed and dated consent forms, medical records, CRFs, drug accountability records, 
all correspondence and any other documents pertaining to the conduct of the study. 
If the 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. The Investigator must notify the 
Sponsor immediately in the event of accidental loss or destruction of any protocol records. 
14.3. 
Disclosure of Information 
Participants’ medical information obtained as a result of this study is considered confidential, 
and disclosure to third parties, other than those noted in this protocol, is prohibited. Subject to 
any applicable authorization(s), all reports and communications relating to participants in this 
study will identify participants only by initials and number. Medical information resulting from a 
participant’s participation in this study may be given to the participant’s personal physician, 
other authorized parties, or to the appropriate medical personnel responsible for the participant’s 


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participation in this clinical study. Data generated in this study will be available for inspection on 
request by the FDA or other governmental regulatory agency auditors, the Sponsor, the 
Sponsor’s Medical Monitor (or designee), and their designated representatives, the IEC/IRB, and 
other authorized parties. All information concerning the study medication and the Sponsor’s 
operations (such as patent applications, formulas, manufacturing processes, basic scientific data, 
or other information supplied by the Sponsor and not previously published) are considered 
confidential and shall remain the sole property of the Sponsor. The Investigator agrees to use this 
information only in conducting this study and to not use it for other purposes without the 
Sponsor’s prior written consent. The information developed in this clinical study will be used by 
the Sponsor in the clinical development of voxelotor and, therefore, may be disclosed by the 
Sponsor as required, to authorized parties (including its corporate partners for the study drug, if 
any, and their designated representatives), other clinical Investigators, pharmaceutical 
companies, the FDA, and other governmental agencies. Any information, inventions, discoveries 
(whether patentable or not), innovations, suggestions, ideas, and reports made or developed by 
the Investigator(s) as a result of conducting this study shall be promptly disclosed to the Sponsor 
and shall be the sole property of the Sponsor. The Investigator agrees, upon the Sponsor’s 
request and at the Sponsor’s expense, to execute such documents and to take such other actions 
as the Sponsor deems necessary or appropriate to obtain patents in the Sponsor’s name covering 
any of the foregoing. 


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15. 
PUBLICATION POLICY 
The Sponsor intends to publish the results of the study once all participants have completed the 
study and the study has been analyzed. 
The Investigator or the Sponsor may not submit for publication or present the results of this 
study without allowing each of the other parties to review and comment on the prepublication 
manuscript, as defined in the site’s clinical trial agreement. 
The Investigator may not submit any of the results of the study for publication without the prior 
consent of the Sponsor. 


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16. 
FINANCING AND INSURANCE 
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. 


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17. 
REFERENCES 
1. Ataga KI. New and experimental agents for sickle cell disease. Clin Adv Hematol Oncol. 
2018;16(7):476-9. 
2. Brown C, Hoppe C, Inati A, Abboud MR, Wang W, Liem R, et al. Efficacy and safety of 
1500 mg voxelotor in a Phase 2a study (GBT440-007) in adolescents with sickle cell 
disease. Blood. 2018;132(Suppl 1):509. 
3. Dufu K, Patel M, Oksenberg D, Cabrales P. GBT440 improves red blood cell 
deformability and reduces viscosity of sickle cell blood under deoxygenated conditions. 
Clin Hemorheol Microcirc. 2018;70(1):95-105. 
4. E.R. Squibb & Sons, L.L.C. (2018). Droxia® (hydroxyurea) Prescribing Information. 
Plainsboro, NJ. 
5. Eaton WA, Henry ER, Hofrichter J, Mozzarelli A. Is cooperative oxygen binding by 
hemoglobin really understood? Nat Struct Biol. 1999;6(4):351-8. 
6. Emmaus Medical Inc (2018). ENDARITM (L-glutamine oral powder) Prescribing 
Information. Torrance, CA. 
7. Gladwin MT, Sachdev V, Jison ML, Shizukuda Y, Plehn JF, Minter K, et al. Pulmonary 
hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med. 
2004;350(9):886-95. 
8. Howard J, Hemmaway CJ, Telfer P, Layton DM, Porter J, Awogbade M, et al. A phase 
1/2 ascending dose study and open-label extension study of voxelotor in patients with 
sickle cell disease. Blood. 2019;133(17):1865-75. 
9. Kato GJ, Piel FB, Reid CD, Gaston MH, Ohene-Frempong K, Krishnamurti L, et al. 
Sickle cell disease. Nat Rev Dis Primers. 2018;15(4):18010.  
10. Lanzkron S, Carroll CP, Haywood C Jr. Mortality rates and age at death from sickle cell 
disease: U.S., 1979-2005. Public Health Rep. 2013;128(2):110-6. 
11. Novartis (2019). Advakeo® (crizanlizumab) Prescribing Information. East Hanover, NJ. 
12. Ohene-Frempong K, Weiner SJ, Sleeper LA, Miller ST, Embury S, Moohr JW, et al. 
Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood. 
1998;91:288-94. 
13. Oksenberg D, Dufu K, Patel MP, Chuang C, Li Z, Xu Q, et al. GBT440 increases 
hemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine 
model of sickle cell disease. Br J Haematol. 2016;175(1):141-53. 
14. Powars DR, Chan LS, Hiti A, Ramicone E, Johnson C. Outcome of sickle cell anemia: a 
4-decade observational study of 1056 patients. Medicine (Baltimore). 2005;84(6):363-76. 
15. Powars DR, Elliott-Mills DD, Chan L, Niland J, Hiti AL, Opas LM, et al. Chronic renal 
failure in sickle cell disease: risk factors, clinical course, and mortality. Ann Intern Med. 
1991;115(8):614-20.  
16. Smith WR, Jordan LB, Hassell KL. Frequently asked questions by hospitalists managing 
pain in adults with sickle cell disease. J Hosp Med. 2011;6(5):297-303.  


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17. Steinberg MH, Barton F, Castro O, Pegelow CH, Ballas SK, Kutlar A, et al. Effect of 
hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up 
to 9 years of treatment. JAMA. 2003;289(13):1645-51. 
18. Stewart G, Chase S, Cross T, Ziegler B, Joyner M, Curry T, et al. Effect of GBT440, an 
R-state stabilizer of hemoglobin, on hypoxic maximal exercise. Am J Respir Crit Care 
Med. 2018;197:A2367.  
19. Taylor JG, Nolan VG, Mendelsohn L, Kato GJ, Gladwin MT, Steinberg MH. Chronic 
hyper-hemolysis in sickle cell anemia: Association of vascular complications and 
mortality with less frequent vasoocclusive pain. PLoS One. 2008;3(5):e2095. 
20. Vichinsky E, Hoppe C, Ataga KI, Ware RE, Nduba V, El-Beshlawy A, et al. A phase 3 
randomized trial of voxelotor in sickle cell disease. N Engl J Med. 2019;381(6):509-19. 
21. Vichinsky E, Hoppe C, Howard J, Ataga KI, Nduba V, El-Beshlawy A, et al. Results 
from Part A of the Hemoglobin Oxygen Affinity Modulation to Inhibit HbS 
Polymerization (HOPE) Trial (GBT440-031), a placebo-controlled randomized study 
evaluating voxelotor (GBT440) in adults and adolescents with sickle cell disease. Blood. 
2018;132(Suppl 1):505. 


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APPENDIX A. SCHEDULE OF ASSESSMENTS: DOSE ESCALATION 
PHASE 
Visit (days) 
Screening 
Periods 1, 2, 3, and 4 
Period 4 
Only 
Day -21 to 
Day -1 
Day 1 
Day 2 
Day 3 
Day 7 ± 1 Day 14 ± 2 Day 21 
Visit to investigational site 
X 
X 
X 
 
X 
X 
X 
Phone call 
 
 
 
X 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
Review inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
Medication and medical history 
X 
X 
 
 
 
 
 
Heighta/weight/BMI 
X 
X 
 
 
 
 
X 
Vital signsb 
X 
X 
X 
 
 
X 
 
ECG (12-lead) in triplicatec 
X 
X 
 
 
X 
 
X 
Physical examinationd 
X 
X 
 
 
 
 
 
Serum pregnancy test (females of 
child-bearing potential only) 
X 
 
 
 
 
 
 
Urine pregnancy test (females of 
child-bearing potential only)e 
 
X 
 
 
 
 
 
FSH (postmenopausal females 
only) 
X 
 
 
 
 
 
 
Coagulation panel (PT, PTT, INR) 
X 
 
 
 
 
 
 
Serology panel (Hepatitis A, B, C, 
and HIVf) 
X 
 
 
 
 
 
 
Blood for hematology and 
chemistry 
X 
X 
X 
 
 
X 
X 
Hemoglobin genotype testing (if 
not already available)  
X 
 
 
 
 
 
 
Fetal hemoglobin  
X 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
Erythropoietin 
 
X 
 
 
 
 
 
RBC deformability, dense cells (if 
feasible) 
 
X 
 
 
 
 
 
Hemoximetry (P50 and P20)g 
 
X 
X 
 
X 
 
X 
Study drug administrationh,i 
 
 
Blood for PK assessmentj 
 
X 
X 
 
X 
 
X 
CGI-C and PGI-C 
 
Xk 
 
 
 
 
X 


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Visit (days) 
Screening 
Periods 1, 2, 3, and 4 
Period 4 
Only 
Day -21 to 
Day -1 
Day 1 
Day 2 
Day 3 
Day 7 ± 1 Day 14 ± 2 Day 21 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
BID, twice daily; BMI, body mass index; CGI-C, Clinical Global Impression of Change; ECG, electrocardiogram; 
FSH, follicle-stimulating hormone; HIV, human immunodeficiency virus; INR, international normalized ratio; P20, 
partial pressure at which hemoglobin is 20% saturated with oxygen; P50, partial pressure at which hemoglobin is 
50% saturated with oxygen; PGI-C, Patient Global Impression of Change; PK, pharmacokinetic; PT, prothrombin 
time; PTT, partial thromboplastin time; RBC, red blood cell. 
Note: For procedures scheduled to be performed at the same timepoint, the order of assessments is as follows: vital 
signs, PK sample collection, blood draw for PD/safety laboratory assessments, ECGs. If times are delayed due to 
technical difficulties, this will be noted but not considered a protocol violation. RBC deformability and dense cells 
will be tested if feasible by the local or collaborating lab at the time of collection.  
a Height to be assessed at Screening only. 
b Vital signs (heart rate, blood pressure, and body temperature [only on Day 1] will be measured after a participant 
has rested for at least 5 minutes in the seated or supine position. While at the investigational site, vital signs will be 
obtained in the morning prior to dosing and other planned assessments. 
c Triplicate ECGs should be recorded at screening. On Day 1 of Period 1 only, triplicate ECGs should be recorded at 
3 timepoints prior to dosing (-45 min, -30 min, and -15 min); the predose PK sample should be collected 
immediately prior to the -30-minute ECGs; and postdose triplicate ECGs (after the morning dose) should be 
recorded within 15 min following the 2-hour PK sample collection. On Day 1 in Periods 2, 3, and 4, on Day 7 in 
all periods, and on Day 21 in Period 4, predose triplicate ECGs should be recorded within 15 minutes following 
the predose PK sample collection. Postdose triplicate ECGs (after the morning dose) should be recorded within 
15 min following the 2-hour PK sample collection. All triplicate ECGs will be centrally read. Participants should 
rest supinely for at least 10 min prior to ECGs.  
d A compete physical examination should be performed at the Screening visit; Physical examinations after the 
Screening visit may be abbreviated. Abbreviated physical examination should include at a minimum: Examination 
of skin, cardiovascular and respiratory systems, abdominal examination, and symptom-directed examination. 
e  If positive urine test, serum pregnancy test will be done to confirm result. 
f A test for HIV will be performed only if clinically indicated. 
g On Day 1, samples for hemoximetry will be obtained predose (within 30 minutes prior to dosing) and at 8 hours 
postdose. Samples will only be predose on all other scheduled days. The predose sample will be obtained prior to 
dosing at the investigational site.  
h Visits should take place in the morning. Participants are instructed to hold study drug until a predose blood sample 
for PK is obtained at the investigational site.  
i During Period 1 (1500 mg daily), study drug will be administered as 3 × 500 mg tablets once daily. During 
Periods 2, 3, and 4, study drug will be administered BID (Period 2: 2000 mg daily, 2 × 500 mg BID; Period 3: 
2500 mg daily, 3 × 500 mg in morning and 2 × 500 mg in evening); Period 4: 3000 mg daily, 3 × 500 mg BID). 
j On Day 1, blood samples for PK will be obtained predose (within 30 minutes prior to dosing) and at 2 hours 
(± 15 min) and 8 hours (± 15 min) postdose. On Day 2, blood samples for PK will be obtained predose only, and 
on Day 7, will be obtained predose and 2 hours postdose. The predose sample will be obtained prior to morning 
dosing at the investigational site.  
k Periods 2, 3, and 4 only (equivalent to Day 21 for Periods 1, 2, and 3, respectively). 


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APPENDIX B. SCHEDULE OF ASSESSMENTS: OBSERVATION 
PERIOD AND SAFETY FOLLOW-UP 
 
Observation Period 
Safety 
Follow-upa  
Visit (weeks) 
Week 1 
Week 3 
Week 6 
Week 12 
Week 18 
Week 24/ 
EOT 
Week 28/ 
EOS 
Visit (days) 
Day 
1b 
Day 
7 
Day 21 
Day 42 
Day 84 
Day 126 
Day 168 
Day 196 
Visit to investigational site 
X 
X 
X 
X 
X 
X 
X 
X 
Weight/BMI 
 
 
 
 
 
 
X 
X 
Vital signsc 
 
X 
X 
X 
X 
X 
X 
X 
ECG (12-lead) in triplicated 
 
 
 
 
X 
 
X 
X 
Physical examinatione 
 
 
 
 
 
 
X 
X 
Urine pregnancy test 
(females of child-bearing 
potential only)f 
 
X 
 
 
X 
 
X 
 
Blood for hematology and 
chemistry 
 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
 
 
 
 
 
 
X 
 
Erythropoietin 
 
 
 
 
 
 
X 
 
RBC deformability, dense 
cells (if feasible) 
 
 
 
 
X 
 
X 
 
Hemoximetry (P50 and 
P20)g 
 
X 
X 
 
X 
 
X 
 
Study drug administrationh,i 
 
 
Blood for PK assessmentj 
 
X 
X 
 
X 
 
X 
 
CGI-C and PGI-C 
 
 
 
 
X 
 
X 
 
Concomitant medications 
 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
X 
X 
X 
X 
X 
 
 X 
X 
BMI = body mass index; CGI-C, Clinical Global Impression of Change; ECG, electrocardiogram; EOS, End of 
Study; EOT, End of Treatment; P20, partial pressure at which hemoglobin is 20% saturated with oxygen; P50, 
partial pressure at which hemoglobin is 50% saturated with oxygen; PGI-C, Patient Global Impression of Change; 
PK, pharmacokinetic; RBC, red blood cell. 
Note: For procedures scheduled to be performed at the same timepoint, the order of assessments is as follows: vital 
signs, PK sample collection, blood draw for PD/safety laboratory assessments, ECGs. If times are delayed due to 
technical difficulties, this will be noted but not considered a protocol violation. RBC deformability and dense cells 
will be tested if feasible by the local or collaborating lab at the time of collection.  
a Safety Follow-up visit will take place 28 days post final dose. 
b Day 1 of the observation period is the same as the last day of the dose escalation period. If the participant begins 
the observation period after a dose reduction, a Day 1 clinical visit is needed, which would collect the same 
assessments as the Day 21 visit in the Dose Escalation Period (Appendix A). 
c Vital signs (heart rate and blood pressure) will be obtained in the morning prior to dosing and other planned 
assessments. 
 


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Protocol Amendment 2.0 
 
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d Single safety ECG at Week 12, Week 24/ET, and Week 196 (EOS). 
e Physical examinations may be abbreviated. Abbreviated physical examination should include at a minimum: 
Examination of skin, cardiovascular and respiratory systems, abdominal examination, and symptom-directed 
examination. 
f  If positive urine test, serum pregnancy test will be done to confirm result. 
g Samples for hemoximetry will be obtained predose (within 30 minutes prior to dosing) at the investigational site.  
h Visits should take place in the morning. Participants are instructed to hold study drug until a predose blood sample 
for PK is obtained at the investigational site.  
i During the observation period, the participant will receive their maximum tolerated dose or 3000 mg daily. 
j During the observation period, blood samples for PK will be obtained predose (within 30 minutes prior to dosing) 
at the investigational site.  


Global Blood Therapeutics, Inc. 
Protocol Amendment 2.0 
 
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CONFIDENTIAL 
63 
APPENDIX C. DOSE MODIFICATION GUIDELINES FOR STUDY 
DRUG-RELATED ADVERSE EVENTS 
Dose Reduction 
Event 
Recommended Action 
Grade ≥ 2 (NCI grading scale) AE deemed 
considered related to study drug by the Investigator  
AND  
Precludes continued dosing at the current dose level 
due to safety concern or lack of tolerability (in the 
Investigator’s judgment)  
Study drug: May be reduced by one (1) tablet.  
If, in the opinion of the Investigator, a Grade 2 AE has 
resolved to ≤ Grade 1, participant may resume study drug 
at the original dose. 
If, in the opinion of the Investigator, the AE poses a 
significant safety concern such that a dose hold is 
considered, the Investigator should contact the Medical 
Monitor. 
ALT ≥ 3 × ULN if ALT within normal limits at 
baseline OR > 3 × ULN AND a ≥ 2-fold increase 
above baseline value if elevated ALT value at 
baseline in the absence of additional signs of 
compromised liver function such as elevated PT, 
PTT, INR, elevated conjugated bilirubin, jaundice, 
or hepatic pain 
Study drug: Confirm by repeat testing within 48 to 
72 hours if possible, then repeat liver panel at least weekly 
until ALT level improves.  
Additional Actions: If ALT level continues to increase, 
reduce dose by one tablet and notify the Medical Monitor. 
ALT ≥ 5 × and < 8 × ULN (confirmed by repeat 
testing within 48 to 72 hours) in the absence of 
additional signs of compromised liver function such 
as elevated PT, PTT, elevated conjugated bilirubin, 
jaundice, or hepatic pain 
Study drug: Reduce dose by one tablet. 
Additional actions: Repeat liver panel test within 48 to 
72 hours if possible and then at least weekly until 
resolution to < 5 × ULN; if ALT does not improve within 
2 weeks of dose reduction, the Medical Monitor should be 
notified. If ALT continues to increase within 1 week after 
a dose reduction, dose should be interrupted and the 
Medical Monitor should be notified. 
Dose Interruption (Hold) 
Event 
Recommended Action 
Grade ≥ 3 (NCI grading scale) AE deemed 
considered related to study drug by the Investigator  
AND  
Precludes continued dosing at the current or at a 
reduced dose level due to safety concern or lack of 
tolerability in the Investigator’s judgment 
Study drug: Hold dose until ≤ Grade 2, then resume study 
drug at original dose. If, in the opinion of the Investigator, 
dosing should be resumed at a lower dose, contact the 
Medical Monitor for further discussion.  
If the AE recurs or worsens, reduce dose by one tablet. 
Maximum dose hold is 5 continuous days. If, in the 
opinion of the Investigator, a longer dose hold is clinically 
needed, the Medical Monitor should be contacted for 
discussion. 
 


Global Blood Therapeutics, Inc. 
Protocol Amendment 2.0 
 
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Dose Interruption (Hold) (continued) 
Event 
Recommended Action 
NOTE: Study drug-related rash 
Grade 2 study drug-related rash that persists after a 
dose reduction 
Management: Consider antihistamines, topical steroids, as 
clinically indicated. 
Study Drug: If rash does not resolve or improve to 
Grade 1 after a dose reduction, consider a dose hold. Once 
the rash has resolved or improved, dosing may be resumed 
at the reduced level or if, in the opinion of the Investigator, 
participant may resume study drug at the original dose. 
The Medical Monitor may be contacted for further 
discussion. 
Maximum dose hold is 5 continuous days. If, in the 
opinion of the Investigator, a longer dose hold is clinically 
needed, the Medical Monitor should be contacted for 
discussion. 
Drug Discontinuation 
Event 
Recommended Action 
Grade ≥ 3 study drug-related AE that, at the 
discretion of the Investigator, warrants 
discontinuation of study drug (eg, has not improved 
or resolved after dose hold). 
Study drug: Discontinue study drug. If the Investigator 
considers that the participant would benefit from 
continuing treatment, the Medical Monitor should be 
contacted. 
Consider drug discontinuation if:  
• 
ALT > 8 × ULN  
• 
ALT > 3 × ULN or ≥ 2-fold increase 
above baseline value if elevated ALT 
value at baseline with additional signs of 
compromised liver function such as 
elevated PT, PTT, INR, elevated 
conjugated bilirubin, jaundice, or hepatic 
pain, appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or 
tenderness, fever, rash, and/or eosinophilia. 
Study drug: Hold dose, confirm by repeat testing within 
48 to 72 hours if possible, and assess potential reversible 
causes of liver function test abnormalities. Contact the 
Medical Monitor for discussion of study drug 
discontinuation. 
AE, adverse event; ALT, alanine aminotransferase; INR, international normalized ratio; NCI, National Cancer 
Institute; PT, prothrombin time; PTT, partial thromboplastin time; ULN, upper limit of normal.