A Phase 3b, Randomized, Double-blind, Placebo-controlled, Multicenter Study to Evaluate the Treatment Effect of Voxelotor on Neurocognitive Function in Pediatric Participants 8 to < 18 Years of Age With Sickle Cell Disease
Phase: PHASE3
Conditions: Sickle Cell Disease
Sponsor: Pfizer

Global Blood Therapeutics, Inc.
Protocol Amendment 1
GBT440-044
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CLINICAL STUDY PROTOCOL
Study Number
GBT440-044
Study Title
A Phase 3b, Randomized, Double-blind, Placebo-controlled, Multicenter Study 
to Evaluate the Treatment Effect of Voxelotor on Neurocognitive Function in 
Pediatric Participants 8 to < 18 Years of Age with Sickle Cell Disease 
Short Title
Voxelotor Neurocognitive Function Study
Investigational 
Product
Voxelotor (GBT440)
IND Number
121691
Sponsor
Global Blood Therapeutics, Inc.
181 Oyster Point Blvd
South San Francisco, CA 94080
United States of America
Telephone: 
email: 
Original Protocol
28 April 2021
Amendment 1
10 December 2021 Version 2.0
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/assent from persons receiving the study treatment. Once the protocol is signed, its terms are 
binding for all parties.
PPD
PPD
PPD
PPD

Global Blood Therapeutics, Inc.
Protocol Amendment 1
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STATEMENT OF APPROVAL AND COMPLIANCE
Study Title: A Phase 3b, Randomized, Double-blind, Placebo-controlled, Multicenter Study to 
Evaluate the Treatment Effect of Voxelotor on Neurocognitive Function in Pediatric 
Participants 8 to < 18 Years of Age with Sickle Cell Disease
Short Title: Voxelotor Neurocognitive Function Study
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 
Independent Ethics Committee (IEC) will approve any changes to the protocol in writing before 
implementation. Global Blood Therapeutics will provide the Investigator with all information, 
including safety information, pertinent to the conduct of the study.
Sponsor Representative
Signature:
Date:
Title:
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. Global Blood Therapeutics requires that any 
presentation or publication of study data by an Investigator be reviewed by GBT, before release.
Principal Investigator 
(Print):
Signature:
Date:
Title:
PPD
PPD

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TABLE OF CONTENTS
CLINICAL STUDY PROTOCOL ..................................................................................................1
STATEMENT OF APPROVAL AND COMPLIANCE.................................................................2
TABLE OF CONTENTS.................................................................................................................3
LIST OF TABLES...........................................................................................................................7
LIST OF FIGURES .........................................................................................................................7
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................8
PROTOCOL SYNOPSIS ..............................................................................................................11
1.
INTRODUCTION......................................................................................................18
1.1.
Disease Background ...................................................................................................18
1.1.1.
Sickle Cell Disease .....................................................................................................18
1.1.2.
Rationale for This Study.............................................................................................18
1.2.
Voxelotor....................................................................................................................19
1.3.
Summary of Relevant Nonclinical Data and Clinical Data........................................19
1.3.1.
Nonclinical Data .........................................................................................................19
1.3.2.
Clinical Data...............................................................................................................20
1.4.
Summary of the Known and Potential Risks and Benefits of Voxelotor ...................20
1.5.
Description of and Justification for the Route of Administration, Dosage, 
Dosage Regimen, and Treatment Period(s)................................................................20
1.5.1.
Dose Rationale for Voxelotor.....................................................................................21
1.5.2.
Use of a Placebo Control............................................................................................21
2.
STUDY OBJECTIVES, ENDPOINTS, AND PURPOSE.........................................22
3.
INVESTIGATIONAL PLAN.....................................................................................23
3.1.
Study Design...............................................................................................................23
3.1.1.
Study Treatment..........................................................................................................24
3.1.2.
Study Assessments......................................................................................................24
3.1.3.
Study Endpoints..........................................................................................................24
3.1.4.
Minimization of Bias..................................................................................................24
3.2.
Duration of Study Participation and of the Study.......................................................25
3.3.
Stopping Rules............................................................................................................25
3.3.1.
Early Termination of the Study ..................................................................................25
3.3.2.
Discontinuation of Individual Participants .................................................................25
3.3.2.1.
Withdrawal of Consent/Assent...................................................................................25

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3.3.2.2.
Early Discontinuation from Study..............................................................................25
3.3.2.3.
Early Discontinuation of Study Treatment.................................................................26
4.
SELECTION OF STUDY PARTICPANTS ..............................................................27
4.1.
Inclusion Criteria ........................................................................................................27
4.2.
Exclusion Criteria.......................................................................................................27
5.
TREATMENTS OF SUBJECTS................................................................................29
5.1.
Treatment Regimen ....................................................................................................29
5.1.1.
Dose Frequency ..........................................................................................................29
5.1.2.
Dose Modification ......................................................................................................29
5.2.
Physical Description of Voxelotor..............................................................................31
5.3.
Dosage Forms .............................................................................................................31
5.3.1.
Voxelotor....................................................................................................................31
5.3.2.
Placebo........................................................................................................................31
5.4.
Randomization and Unblinding..................................................................................31
5.4.1.
Randomization............................................................................................................31
5.4.1.1.
Preventing Unblinding due to Laboratory Assessments.............................................31
5.4.1.2.
Unblinding for Medical Need.....................................................................................32
5.5.
Packaging and Labeling..............................................................................................32
5.6.
Investigational Product Supply...................................................................................32
5.7.
Storage and Handling Procedure ................................................................................32
5.8.
Concomitant and Prohibited Medications ..................................................................33
5.8.1.
Concomitant Medications...........................................................................................33
5.8.2.
Restrictions Regarding Usage of Concomitant Medications......................................33
5.8.3.
Transfusion .................................................................................................................33
5.8.4.
Other Therapies ..........................................................................................................33
5.8.5.
Prohibited Concomitant Medications .........................................................................33
5.9.
Fertility/Contraceptive Requirements.........................................................................35
5.9.1.
Instructions for Female Participants of Child-Bearing Potential................................35
5.9.2.
Female Participants of Non-Child-Bearing Potential.................................................35
5.9.3.
Instructions for Male Participants Capable of Fathering a Child ...............................35
5.10.
Acceptable Forms of Contraception for Sexually Active Participants.......................35
5.11.
Assessment of Treatment Compliance .......................................................................36
6.
STUDY PROCEDURES AND ASSESSMENTS......................................................37

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6.1.
Informed Consent/Assent ...........................................................................................37
6.2.
Participant ID Number................................................................................................37
6.3.
Eligibility Assessment, Inclusion/Exclusion Review.................................................37
6.4.
Medical History/Demographics..................................................................................37
6.5.
Physical Examination .................................................................................................38
6.6.
Vital Signs ..................................................................................................................38
6.7.
NIH Toolbox Assessments .........................................................................................38
6.8.
Adverse Events and Concomitant Medications..........................................................38
6.9.
Laboratory Assessments .............................................................................................39
6.9.1.
Hematology.................................................................................................................39
6.9.2.
Serum Chemistry ........................................................................................................40
6.9.3.
Pregnancy Testing ......................................................................................................40
6.10.
Patient/Caregiver-Reported Outcomes .......................................................................40
6.11.
Clinical Global Impression of Change .......................................................................41
6.12.
Missed Assessments ...................................................................................................41
7.
ADVERSE AND SERIOUS ADVERSE EVENTS...................................................42
7.1.
Adverse Events ...........................................................................................................42
7.1.1.
Definition of Adverse Events .....................................................................................42
7.1.2.
Severity of Adverse Events ........................................................................................43
7.1.3.
Relationship to Investigational Product......................................................................44
7.1.4.
Unexpected Adverse Reactions..................................................................................44
7.2.
Adverse Event Reporting............................................................................................44
7.2.1.
General........................................................................................................................44
7.2.2.
Diagnosis Versus Signs and Symptoms .....................................................................44
7.2.3.
Abnormal Laboratory Values .....................................................................................45
7.2.4.
Pre-existing Medical Conditions ................................................................................45
7.2.5.
Worsening of Sickle Cell Disease ..............................................................................45
7.3.
Serious Adverse Events, Serious Adverse Drug Reactions, and Requirements 
for Immediate Reporting.............................................................................................45
7.3.1.
Reporting Suspected Unexpected Serious Adverse Reactions and Urgent 
Safety Issues ...............................................................................................................46
7.4.
Reporting Pregnancy ..................................................................................................46
7.5.
Reporting Overdose....................................................................................................47

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8.
DATA ANALYSIS AND STATISTICAL PLANS...................................................48
8.1.
Analysis Populations ..................................................................................................48
8.2.
Summary of Study Conduct........................................................................................48
8.3.
Summary of Demographics, Baseline Characteristics, and Concomitant 
Medications.................................................................................................................48
8.4.
Efficacy Analysis........................................................................................................49
8.4.1.
Primary Endpoint........................................................................................................49
8.4.2.
Secondary Endpoints ..................................................................................................49
8.4.3.
Exploratory Endpoints................................................................................................49
8.5.
Safety Analysis ...........................................................................................................49
8.6.
Determination of Sample Size....................................................................................50
8.7.
Missing Data Handling...............................................................................................50
8.8.
Adjustment for Multiple Comparisons.......................................................................50
9.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................51
9.1.
Source Data.................................................................................................................51
9.2.
Data Collection...........................................................................................................51
10.
QUALITY CONTROL AND QUALITY ASSURANCE .........................................52
10.1.
Monitoring..................................................................................................................52
10.2.
Quality Control and Quality Assurance......................................................................52
10.3.
Laboratory Accreditation............................................................................................52
11.
REGULATORY, ETHICAL, AND LEGAL OBLIGATIONS .................................53
11.1.
Ethical Conduct of the Study......................................................................................53
11.2.
Good Clinical Practice................................................................................................53
11.3.
Written Informed Consent and Assent .......................................................................53
11.4.
Independent Ethics Committee and Regulatory Approval .........................................54
11.5.
Essential Documentation Requirements.....................................................................54
11.6.
Confidentiality............................................................................................................54
11.7.
Study Documentation and Data Storage.....................................................................55
12.
DATA HANDLING AND RECORDKEEPING.......................................................56
12.1.
Inspection of Records .................................................................................................56
12.2.
Retention of Records ..................................................................................................56
12.3.
Disclosure of Information...........................................................................................56
13.
INSURANCE AND FINANCIAL DISCLOSURE....................................................58

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14.
PUBLICATION POLICY ..........................................................................................59
15.
REFERENCES ...........................................................................................................60
APPENDIX 1.
SCHEDULE OF ASSESSMENTS ....................................................................62
LIST OF TABLES
Table 1:
Voxelotor Weight-based Doses for Participants Less than 12 Years of Age.............21
Table 2:
Objectives and Endpoints ...........................................................................................22
Table 3:
Dose Modification Guidelines for Study Drug-related Adverse Events 
(12-17 years)...............................................................................................................30
Table 4:
Voxelotor Weight-based Dose Reduction for Participants Less than 12 Years 
of Age .........................................................................................................................30
Table 5:
Sensitive CYP3A4 Substrates with Narrow Therapeutic Range................................34
Table 6:
Examples of Strong CYP Inducers.............................................................................34
Table 7:
Additional Prohibited Medications.............................................................................34
Table 8:
Grading for Adverse Events Not Covered in the NCI CTCAE..................................43
LIST OF FIGURES
Figure 1:
Study Schema .............................................................................................................24

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation
Description
ADHD
attention deficit hyperactivity disorder
ADL
activities of daily living
AE(s)
adverse event(s)
AF
assent form
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ARC
absolute reticulocyte count
AST
aspartate aminotransferase
AUC
area under curve
BUN
blood urea nitrogen
CFR
Code of Federal Regulations
CGI-C
Clinician Global Impression of Change
COVID-19
coronavirus disease of 2019
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
CRF
case report form
EDC
electronic data capture
eGFR
estimated glomerular filtration rate
EOS
end of study
ESA
erythropoietin-stimulating agents 
ET
early termination
FDA
Food and Drug Administration
FDA IID
Food and Drug Administration Inactive Ingredient Database
GBT
Global Blood Therapeutics, Inc.
GCP
Good Clinical Practice
GDPR
General Data Protection Regulation
Hb
hemoglobin
HbF
fetal hemoglobin
HbS
sickle hemoglobin
HbS/β0
sickle hemoglobin and one beta thalassemia gene
HbSS
sickle hemoglobin with 2 sickle cell genes
HC
hydroxycarbamide
HIPAA
health insurance portability and accountability act

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Abbreviation
Description
HIV
human immunodeficiency virus
HRQOL
health-related quality of life
HU
hydroxyurea
IB
Investigator's Brochure
ICF
informed consent form
ICH
International Council for Harmonisation 
ID
identifier 
IEC
Independent Ethics Committee
IID
Inactive Ingredient Database
IME
important medical events
IRB
Institutional Review Board 
ITT
intent-to-treat
IQ
intelligence quotient
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IxRS
Interactive Response System
LDH
lactate dehydrogenase
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MedDRA
medical Dictionary for Regulatory Activities
MMRM
mixed effect for repeated measures
MRA
magnetic resonance angiography
MRI
magnetic resonance imaging
NCI
National Cancer Institute 
Neuro-QOL
Quality of Life in Neurological Disorders
NIH
National Institute of Health
O2
oxygen
oxyHb
oxyhemoglobin
PBPK
physiologically-based pharmacokinetics
PD
pharmacodynamics
PE
physical examination
PfOS
powder for oral suspension
PGI-C
Patient Global Impression of Change
Ph Eur
European Pharmacopoeia
PI
Prescribing Information 
PP
per protocol population
PPK
population pharmacokinetics 
PRO
patient-reported outcome

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Abbreviation
Description
QD
once daily
QOL
quality of life
RBC
red blood cell
RSI
Reference Safety Information
SAE
serious adverse event
SAP
statistical analysis plan
SCA
sickle cell anemia
SCD
sickle cell disease
SOA
schedule of assessments
SOC
standard of care (for SCD)
SUSAR
suspected unexpected serious adverse reaction
TCD
transcranial Doppler
TEAE
treatment-emergent adverse event
TIA
transient ischemic attack
USPI
United States Prescribing Information
ULN
upper limit of normal 
US (A)
United States (of America)
WBC(s)
White blood cell(s)
WHO
World Health Organization

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PROTOCOL SYNOPSIS
Study Number
GBT440-044
Study Title
A Phase 3b, Randomized, Double-blind, Placebo-controlled, Multicenter Study to 
Evaluate the Treatment Effect of Voxelotor on Neurocognitive Function in Pediatric 
Participants 8 to < 18 Years of Age with Sickle Cell Disease (SCD)
Short Title
Voxelotor Neurocognitive Function Study
Sponsor
Global Blood Therapeutics, Inc.
181 Oyster Point Blvd
South San Francisco, CA 94080
United States of America (USA)
Study 
Description
This is a Phase 3b, randomized, double-blind, placebo-controlled, multicenter study 
to assess the treatment effect of voxelotor on neurocognitive function as assessed by 
the National Institute of Health (NIH) Toolbox Cognition Module of executive 
abilities in pediatric participants (8 to < 18 years) with SCD.
Number of 
Clinical Sites
The study will be conducted at approximately 15 clinical trial sites globally 
including United States of America (USA) and Europe.
Number of 
Study 
Participants
Approximately 80 participants will participate in this study.
Investigational 
Products
Voxelotor tablets, administered orally as 3 × 500-mg tablets, weight-adjusted 
equivalent dose of powder for oral suspension (PfOS) (300 mg, 400 mg, 600 mg, 
and 900 mg). 
Matching placebo, administered orally as 3 matching tablets or PfOS packet.
Treatment
During the Randomized Treatment Period, participants will be randomized in a 
1:1 ratio to receive 1500 mg of voxelotor, (or the weight-adjusted equivalent dose 
for participants < 12 years old), once daily (administered orally as tablets/PfOS) or 
matching placebo for 12 weeks in addition to ongoing standard of care (SOC) 
treatment.
Voxelotor, in all dosage forms, may be taken with or without food. Voxelotor 
tablets should be swallowed whole. The PfOS dosage form should be mixed with 
liquid. Details regarding preparation of voxelotor for administration are provided in 
the Pharmacy Manual (provided separately).
Objectives
OBJECTIVES
ENDPOINTS
Primary
To assess the effect of voxelotor 
compared with placebo on 
neurocognitive functions in 
pediatric participants (8 to < 18 
years of age) with SCD.
Change from baseline at Week 12 in the 
executive abilities composite score (using 
Dimensional Change Card Sort Test, 
Flanker Inhibitory Control and Attention 
Test, and List Sorting Test) as assessed by 
the NIH Toolbox Cognition Module. 

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Study Number
GBT440-044
Secondary
To assess the effect of voxelotor 
compared with placebo on 
processing speed.
Change from baseline at Week 12 in 
processing speed as measured by Pattern 
Comparison Test score as assessed by the 
NIH Toolbox Cognition Module.
To assess the effect of voxelotor 
compared with placebo in 
nonexecutive cognitive abilities 
composite score.
Change from baseline to Week 12 in 
nonexecutive cognitive abilities (Picture 
Vocabulary Test, Oral Reading 
Recognition Test, and Picture Sequence 
Memory Test) composite score as assessed 
by the NIH Toolbox Cognition Module. 
To evaluate the effect of voxelotor 
compared with placebo on changes 
in hemoglobin (Hb), and clinical 
measures of hemolysis.

Change from baseline in Hb level 
over time up to Week 12

Change and percent change from 
Baseline over time up to Week 12 in 
clinical measures of hemolysis, 
including unconjugated bilirubin, 
absolute reticulocyte, % reticulocytes, 
and lactate dehydrogenase (LDH)
Exploratory
To assess the relationship between 
Hb levels and the executive abilities 
composite score.
Correlation between change from baseline 
in Hb level and change from baseline in 
executive abilities composite score
To assess health-related quality of 
life (HRQOL) measures (patient-
and clinician-reported).
HRQOL scores using:

Patient Global Impression of Change 
(PGI-C) at Week 12

Change from baseline to Week 12 in 
Pediatric quality of life in 
neurological disorders (Neuro-QOL) 
score 

Clinician Global Impression of 
Change (CGI-C) at Week 12
Safety
To assess the safety and tolerability 
of voxelotor.
Incidence and severity of treatment 
emergent adverse events (AEs)
Study Design
The study is divided into a Screening Period, a Randomized Treatment Period, and 
follow-up:
Screening Period (within 2 weeks prior to randomization): 
During this period (Day -14 to Day -1), participants will sign the informed consent 
form (ICF)/assent form (AF), after which they will complete the screening and 
Baseline assessments. All Screening and Baseline assessments must be completed 
within 2 weeks before the Randomized Treatment Period. 

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Study Number
GBT440-044
Randomized Treatment Period (12 weeks [±3 day window for each visit after 
Day 1 Visit]): Eligible participants will be randomized 1:1 to receive voxelotor or 
placebo once daily for 12 weeks. This period will be comprised of three clinical 
visits at Day 1 (Randomization day), Week 6, and Week 12. The first dose of study 
treatment is intended to be on Day 1, and as soon as possible after randomization. 
At the time of randomization, participants will be stratified by concurrent 
hydroxyurea (HU) therapy (yes, no).
The Randomized Treatment Period is the continuous 12 weeks of voxelotor or 
placebo treatment from the date of randomization (Day 1).
Follow-up/End of Study (EOS) Period (4 weeks after last dose [± 7-day window 
for EOS visit]):
Following completion of the Randomized Treatment Period in this study, 
participants will be evaluated for an additional for 4 weeks after the last dose of 
treatment and instructed to return to the site to complete the EOS Visit.
Safety and tolerability will be monitored during the entire study using standard 
measures, including the assessment of AEs, clinical laboratory tests, physical 
examinations (PEs), and vital signs.
Duration of 
Study 
Participation
The approximate study duration for an individual participant includes the Screening 
Period (within 2 weeks), Randomized Treatment Period of 12 weeks, and a 
Follow-up Period/EOS visit at 4 weeks [± 7 days] after the last dose of study drug). 
From screening through follow-up/EOS, total participation in this study for an 
individual participant is up to 18 weeks. Participants will continue to be followed 
for efficacy and safety, when possible, through at least the endpoint visit (treatment 
Week 12) regardless of treatment discontinuation. The study will end when the last 
participant’s last visit occurs.
Study 
Population
Inclusion Criteria: 
Participants who meet all the following criteria will be eligible for enrollment in this 
study:
1.
Male or female participants with confirmed diagnosis of SCD (all 
genotypes).Documentation of SCD genotype is required and may be based on 
documented history of laboratory testing or confirmed by laboratory testing 
during Screening.
2.
Aged 8 to < 18 years.
3.
Screening Hb level 5.5 to 10.5 g/dL.
4.
Able to answer NIH Toolbox Module questions validated and normed based on 
age and maternal education on tablet.
5.
If participant is receiving HU they must have been on a stable dose for at least 
90 days prior to signing the ICF/AF, with no dose modifications or initiation of 
HU planned or anticipated by the Investigator.
6.
If participant is receiving erythropoiesis-stimulating agents (ESAs) they must 
have been on a stable dose for at least 12 weeks before enrollment with no dose 
modifications planned or anticipated by the Investigator.

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Study Number
GBT440-044
7.
Participants, who if female and of child-bearing potential, agree to use highly 
effective methods of contraception from study start to 30 days after the last dose 
of study drug and who if male, agree to use barrier methods of contraception 
and refrain from donating sperm from study start to 30 days after the last dose 
of study drug.
8.
Females of child-bearing potential must have a negative pregnancy test before 
the administration of study drug.
9.
Parental/guardian consent and participant assent per Institutional Review Board 
(IRB)/Independent ethics committee (IEC) policy and requirements, consistent 
with International Council for Harmonisation (ICH) guidelines.
10. Capable of complying with the requirements and restrictions in the protocol, 
and willing to participate in the study.
Exclusion Criteria:
Participants meeting any of the following exclusion criteria will not be eligible for 
study enrollment:
1.
Receiving chronic transfusion therapy.
2.
Red blood cell (RBC) transfusion within 3 months before initiation of study 
drug or receives scheduled RBC transfusion therapy (also termed chronic, 
prophylactic, or preventive transfusion).
3.
History of overt stroke including hemorrhagic stroke or transient ischemic 
attack (TIA) or spinal cord injury, magnetic resonance angiography (MRA)-
defined vasculopathy, or magnetic resonance imaging (MRI)/transcranial 
doppler (TCD)-documented silent cerebral infarcts. 
4.
Congenital brain malformation, previously diagnosed severe developmental 
disability (eg, autism and/or intelligence quotient [IQ] < 60, and/or severe 
attention deficit hyperactivity disorder [ADHD]), or impairment that would 
prevent the use of a computer tablet.
5.
Participant is taking or has received voxelotor (Oxbryta®) within 90 days prior 
to the Screening Visit.
6.
Surgery within 8 weeks before Day 1 or planned elective surgery during the 
study.
7.
Anemia due to bone marrow failure (eg, myelodysplasia).
8.
Absolute reticulocyte count (ARC) < 100 × 109/L.
9.
Screening alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
> 4× upper limit of normal (ULN).
10. Severe renal dysfunction (estimated glomerular filtration rate [eGFR] 
< 30 mL/min/1.73 m2) or is on chronic dialysis.

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Study Number
GBT440-044
11. Clinically significant bacterial, fungal, parasitic, or viral infection which 
requires therapy.
a.
Participants with acute bacterial infection requiring antibiotic use should 
delay screening/enrollment until the course of antibiotic therapy has been 
completed.
b.
Participants with known active hepatitis A, B, or C or who are known to be 
human immunodeficiency virus (HIV) positive.
12. Symptomatic coronavirus disease of 2019 (COVID-19) infection. 
13. Females who are breast-feeding or pregnant.
14. History of hematopoietic stem cell transplant or gene therapy.
15. Participants taking concomitant medications such as sensitive cytochrome 
P450 (CYP)3A4 substrates with a narrow therapeutic range, or strong CYP3A4 
inducers 
16. Participated in another clinical trial of an investigational product (or medical 
device) within 30 days or 5 half-lives of date of informed consent/assent, 
whichever is longer, or is currently participating in another trial of an 
investigational product (or medical device).
17. Medical, psychological, or behavioral condition that, in the opinion of the 
Investigator, would confound or interfere with evaluation of safety and/or 
efficacy of the study drug, prevent compliance with the study protocol; preclude 
informed consent/assent; or, render the participant unable/unlikely to comply 
with the study procedures.
Concomitant 
Medications 
and 
Restrictions
The following concomitant medications are allowed: 

Hydroxyurea/hydroxycarbamide (HC) (stable dose for at least 90 days prior 
to signing the ICF/AF and with no dose modifications planned or anticipated 
by the Investigator and no sign of hematological toxicity)

L-glutamine, over-the-counter analgesics, and opioids

Erythropoietin-stimulating agents (stable dose for at least 4 weeks with no 
dose modifications planned or anticipated by the Investigator)
The following concomitant medications are prohibited: 

Sensitive CYP3A4 substrates with a narrow therapeutic range

Strong CYP3A4 inducers

Crizanlizumab (Adakveo®)

Cisapride 

Other experimental SCD therapy

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Study Number
GBT440-044

Cannabis, alcohol and opioids that can interfere with neurocognitive testing 
must not be consumed within 24 hours prior to NIH Toolbox Cognition 
Module assessment at Baseline and Week 12 Visit 
Statistical 
Methods
This is a 2-arm, 3-period study: Screening, 12-week placebo-controlled 
Randomized Treatment Period with 1:1 randomization (voxelotor: placebo), and a 
Follow-up/EOS period.
Randomization will be stratified by concurrent HU therapy (yes, no).
Analysis Population
Three main analyses populations defined for this study are: the intent-to-treat (ITT), 
the per protocol (PP) population, and the safety-evaluable population. 
Efficacy analyses will be conducted on the ITT population, defined as all 
randomized participants. This will be the primary population for all efficacy 
analysis. Participants will be grouped by the treatment group to which they are 
randomized.
The PP population will include all participants who complete study treatment with 
no important protocol deviations which would impact the evaluation of efficacy. 
This analysis population may be used for sensitivity analyses of the primary and key 
secondary efficacy endpoints.
Safety analysis will be based on the safety-evaluable population, defined as 
randomized participants who received at least 1 dose of study treatment. 
Participants will be grouped by the actual study treatment they received.
Sample Size
Sample size determination is based on statistical power considerations for the 
primary efficacy endpoint, change from baseline in executive abilities composite 
score at Week 12.
A sample size of approximately 80 participants (40 participants per treatment arm 
voxelotor and placebo) provides approximately 80% power to detect a difference in 
mean change in executive abilities composite score from baseline to Week 12 
between the voxelotor arm and the placebo arm of 5 points with a common standard 
deviation of 7.5 points, using a 2-sided test at an overall α = 0.05 level. For the 
purposes of sample size calculation, a drop-out rate of 5% by Week 12 was 
assumed.
Primary Analysis
The executive abilities composite score will be measured using the NIH Toolbox 
Cognition Module. The primary endpoint will be the change from baseline in 
executive abilities composite score at Week 12 which will be summarized by 
treatment group using mean, SD, median, minimum and maximum. The analysis of 
the primary endpoint will compare voxelotor with placebo using analysis of 
covariance (ANCOVA) controlling for the baseline composite score, and HU use. 
Secondary Analysis
Changes from baseline to Week 12 in processing speed and nonexecutive cognitive 
abilities composite score will be summarized using mean, SD, median, minimum 
and maximum. The analyses of these endpoints will compare voxelotor with 
placebo using ANCOVA and controlling for the corresponding baseline scores and 
HU use.

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Study Number
GBT440-044
Changes from baseline in Hb and clinical measures of hemolysis (unconjugated 
bilirubin, % reticulocytes, absolute reticulocyte, and LDH) over time up to Week 12 
will be analyzed using a mixed effect for repeated measures (MMRM) model. The 
fixed effect terms include treatment, study visit, treatment by visit interaction. 
Within-subject variability will be modeled using an unstructured covariance matrix.
Exploratory Analysis
Exploratory endpoints will be summarized by descriptive statistics. Details will be 
provided in the statistical analysis plan (SAP).
Safety Analysis
Safety analysis will be performed on all participants receiving at least 1 dose of 
study drug.
Adverse Events will be classified according to the Medical Dictionary for 
Regulatory Activities (MedDRA). The number and percentage of participants with 
treatment emergent adverse events (TEAEs) will be tabulated by system organ class 
and preferred term. Treatment-emergent adverse events will also be presented by 
severity and relationship to study treatment.
Changes in laboratory parameters and vital signs will be summarized descriptively.

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1.
INTRODUCTION
1.1.
Disease Background
1.1.1.
Sickle Cell Disease 
Sickle cell disease is an inherited blood disorder caused by a point mutation in the β globin gene 
resulting in the formation of “sickle hemoglobin (HbS)”, which polymerizes in the deoxygenated 
state and leads to red blood cell (RBC) sickling. The disease is 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 (Gladwin, 2014; Nouraie, 2013). In 
addition to unpredictable and recurrent vaso-occlusive pain episodes, hemolytic anemia directly 
damages blood vessels, resulting in a systemic vasculopathy that leads to chronic and progressive 
tissue and organ injury (Kato, 2007). With improved survival in children, the natural history of 
SCD has shifted from a disease of childhood to a chronic, debilitating disease of young and 
middle-aged adults. Cumulative injury to multiple organ systems from repeated episodes of RBC 
sickling, vaso-occlusion, and chronic hemolytic anemia exact a high clinical burden in the aging 
adult, significantly impacting quality of life (QOL) and overall functioning (Swanson, 2011). 
1.1.2.
Rationale for This Study
There is well-established evidence that children with SCD have cognitive impairment with 
varying degrees of deficit. While the neurocognitive deficits are caused by neurologic damage 
from cerebral vascular accidents is consistently documented, the causes of cognitive deficits in 
children with no history of overt neurologic are not yet clear (Schatz, 2002; Wang, 1998). One of 
the direct potential causes suggested includes chronic brain hypoxia related to severe anemia 
(Schatz, 2002). There are several studies that support the hypothesis that neurocognitive deficits 
are associated with the severity of anemia (Bernaudin, 2000; Kral, 2003; Steen, 2003). Patients 
with SCD appear to have a decreased cerebral vascular reserve and may have a state of chronic 
cerebral ischemia resulting in neurocognitive dysfunction (Vichinsky, 2010). This is supported 
by the studies that find that blood transfusion and hydroxyurea (HU) may improve disease 
symptoms and reduce anemia severity, and may improve neurocognition in patients with SCD 
than in control group (Hood, 2019; Puffer, 2007). Similarly, in studies of healthy controls and 
other chronic diseases, anemia is associated with poorer neurocognitive performance, and 
increasing hemoglobin (Hb) levels improves test results (Weiskopf, 2000; Stivelman, 2000). 
Voxelotor was approved in 2019 for use in the US under the tradename Oxbryta® by the Food 
and Drug Administration (FDA), and is indicated for the treatment of SCD in adults and 
pediatric patients 12 years of age and older. Since voxelotor increases Hb concentration, it is 
speculated that improvement in anemia improves cerebral oxygen delivery and consequently, 
may enhance cognitive functions. Hence, study GBT440-044 hypothesizes that a disease 
modifying treatment, such as voxelotor may improve the executive abilities (a cognitive domain 
in which patients with SCD experience particular difficulty), by improving Hb, and cerebral 
oxygen delivery to the brain in pediatric participants 8 to < 18 years of age with SCD (see 
(Oxbryta USPI, 2019).

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1.2.
Voxelotor
Voxelotor (previously GBT440) is an HbS polymerization inhibitor that binds to HbS with a 
1:1 stoichiometry and exhibits preferential partitioning to RBCs. Voxelotor binds covalently and 
reversibly to the N-terminal valine of the Hb α chain and allosterically increases HbS-oxygen 
affinity (Eaton, 1999), stabilizing the oxyhemoglobin (oxyHb) state and inhibiting 
polymerization (Oksenberg, 2016). The voxelotor binding site (Kato, 2007) is distant from heme 
pockets and it can therefore increase oxygen (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% fetal 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 
(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. 
Voxelotor was approved in 2019 for use in the US under the tradename Oxbryta® by the FDA 
and is indicated for the treatment of SCD in adults and pediatric patients 12 years of age and 
older. Voxelotor is considered an investigational drug for this study. 
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 O2 tension, preventing in vitro sickling 
induced by a low O2 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 O2 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-oxygen affinity and RBC half-life, while 
decreasing ex vivo sickling and reticulocyte count in a SCD mouse model.

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Additional information regarding nonclinical pharmacology (including safety pharmacology, 
pharmacokinetics, and metabolism) and toxicology is provided in the most current version of the 
voxelotor Investigator's Brochure (IB).
1.3.2.
Clinical Data
Data from the Phase 3 randomized controlled trial (GBT440-031, HOPE ClinicalTrials.gov 
number, NCT03036813) demonstrated that administration of voxelotor in participants with SCD 
resulted in a statistically significant and clinically meaningful improvement in Hb (> 1 g/dL 
increase) at 24 weeks compared to placebo (Vichinsky, 2019). Concomitant with the improved 
anemia there was a reduction in laboratory measures of hemolysis, including reticulocytes, 
lactate dehydrogenase (LDH), and indirect bilirubin. Additionally, in the Phase 1/2 study 
(GBT440-001) and extension study (GBT440-024), treatment with voxelotor led to reductions in 
the percentage of sickled red cells in the peripheral blood (Howard, 2019). 
Additional information regarding the safety and tolerability, and efficacy of voxelotor is 
provided in Section 1.4 of this protocol, in the most current version of the voxelotor IB, provided 
separately, and voxelotor PI (Oxbryta® USPI, 2021).
1.4.
Summary of the Known and Potential Risks and Benefits of 
Voxelotor
Voxelotor is well tolerated in adult and pediatric participants 4 years of age and older with SCD. 
Adverse events, primarily associated with underlying disease and gastrointestinal events, were 
generally low-grade in severity, were managed by dose reduction and/or symptomatic treatment, 
and seldom resulted in discontinuation of therapy. Identified risks, which include the ADRs of 
diarrhea, abdominal pain, nausea, rash, and drug hypersensitivity, were low grade in severity and 
clinically manageable. 
In the pivotal Phase 3 study, Study GBT440-031, voxelotor was shown to significantly improve 
anemia and reduce clinical measures of hemolysis in adult and pediatric participants 12 years of 
age and older with SCD. 
In conclusion, voxelotor has a favorable benefit-risk profile based on clinical data from studies 
enrolling participants 4 years of age and older with SCD. Overall, by inhibiting HbS 
polymerization voxelotor has the potential to alter the clinical course of the disease by improving 
anemia and hemolysis in SCD disease.
Further information regarding the potential benefits and risks of voxelotor and guidance for the 
investigator are provided in the current version of the IB.
1.5.
Description of and Justification for the Route of Administration, 
Dosage, Dosage Regimen, and Treatment Period(s)
During the Randomized Treatment Period, participants will be randomized in a 1:1 ratio to 
receive voxelotor once daily or matching placebo for 12 weeks, in addition to ongoing current 
standard of care (SOC) for SCD. The SOC selected for any given participant is determined by 
the Investigator and may vary among participants. Participants ≥12 years old will receive a 
voxelotor dose of 1500 mg once daily, administered orally as tablets, while participants 
< 12 years old will receive a weight-adjusted equivalent dose.

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1.5.1.
Dose Rationale for Voxelotor
Voxelotor is available in an oral form and is intended for once daily administration. See 
Section 5.1 for additional information regarding the dose to be used in this study. 
The voxelotor dose of 1500 mg orally once daily is the currently approved dose for the treatment 
of SCD in the US in adults and pediatric patients 12 years of age and older (see
Oxbryta® USPI, 2021).
The recommended dosage of voxelotor for pediatric participants 12 to 17 years is 1500 mg taken 
orally once daily (QD) with or without food. Population pharmacokinetic (PPK) modeling, 
physiologically-based PK (PBPK) modeling and allometric scaling (Washington, 2018) were 
used to estimate weight-based equivalent of 1500 mg for the pediatric population. These 
weight-based doses are outlined in (Table 1) and are anticipated to provide PK exposures similar 
to those observed in pediatric participants 12 to 17 years of age and adults receiving voxelotor 
1500 mg. Weight-based dosing for voxelotor is being evaluated in an ongoing pediatric study 
(Study GBT440-007) and clinical efficacy, safety and PK results from this study support the 
continued evaluation of these doses.
Table 1:
Voxelotor Weight-based Doses for Participants Less than 12 Years of Age
Population
Voxelotor Doses (1500 mg Equivalent)
5 to < 10 kg
400 mg (PfOS packet only)
10 to < 20 kg
600 mg (PfOS packet only)
20 to < 40 kg
900 mg (PfOS packet only)
≥ 40 kg
1500 mg (3× 500 mg Tablets only)
Abbreviations: PfOS, powder for oral suspension.
1.5.2.
Use of a Placebo Control
This study will use placebo as a comparator on the background of SOC treatment. Placebo was 
chosen as the control because it is necessary to determine the effect of voxelotor on 
neurocognition while controlling for background changes with SOC. The use of a placebo 
control will also allow safety signals to be distinguished from AEs occurring due to SCD.
Randomization to placebo treatment in this study does not place study participants at increased 
risk, as the SOC treatment for SCD will be provided during the study.

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2.
STUDY OBJECTIVES, ENDPOINTS, AND PURPOSE
Table 2:
Objectives and Endpoints
OBJECTIVES
ENDPOINTS
Primary
To assess the effect of voxelotor compared 
with placebo on neurocognitive functions in 
pediatric participants (8 to < 18 years of age) 
with SCD. 
Change from baseline at Week 12 in the executive 
abilities composite score (using Dimensional Change 
Card Sort Test, Flanker Inhibitory Control and 
Attention Test, and List Sorting Test) as assessed by 
the NIH Toolbox Cognition Module. 
Secondary
To assess the effect of voxelotor compared 
with placebo on processing speed.
Change from baseline at Week 12 in processing speed 
as measured by Pattern Comparison Test score as 
assessed by the NIH Toolbox Cognition Module.
To assess the effect of voxelotor compared 
with placebo in nonexecutive cognitive 
abilities composite score.
Change from baseline to Week 12 in nonexecutive 
cognitive abilities (Picture Vocabulary Test, Oral 
Reading Recognition Test, and Picture Sequence 
Memory Test) composite score as assessed by the 
NIH Toolbox Cognition Module.
To evaluate the effect of voxelotor compared 
with placebo on changes in Hb, and clinical 
measures of hemolysis.
Change from baseline in Hb level over time up to 
Week 12 
Change and percent change from Baseline over time 
up to Week 12 in clinical measures of hemolysis, 
including unconjugated bilirubin, absolute 
reticulocyte, % reticulocytes, and LDH
Exploratory
To assess the relationship between Hb levels 
and the executive abilities composite score. 
Correlation between the change in Hb level and 
change in executive abilities composite score.
To assess health-related quality of life 
(HRQOL) measures (patient- and clinician-
reported).
HRQOL scores using:
Patient Global Impression of Change (PGI-C) at 
Week 12 Change from baseline to Week 12 in 
Pediatric Neuro-QOL score 
Clinician Global Impression of Change (CGI-C) at 
Week 12
Safety
To assess the safety and tolerability of 
voxelotor.
Incidence and severity of treatment emergent AEs

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3.
INVESTIGATIONAL PLAN
3.1.
Study Design
This study is a Phase 3b, randomized, double-blind, placebo-controlled, multicenter study 
evaluating the impact of voxelotor treatment on neurocognitive functions in pediatric participants 
with SCD aged between 8 to < 18 years. The study is divided into 3 study periods: Screening, 
Randomized Treatment, and Follow-up/End of Study (EOS).
The study will include approximately 80 eligible participants at approximately 15 clinical trial 
sites globally including United States of America (USA)and Europe. The overall study design is 
illustrated in the Study Schema provided in Figure 1.
Safety and tolerability will be monitored during the entire study using standard measures, 
including the assessment of AEs, clinical laboratory tests, physical examinations (PEs), and vital 
signs.
Screening Period (within 2 weeks prior to the Randomization)
During this period (Day -14 to Day -1), participants will sign the informed consent form 
(ICF)/assent form (AF), after which they will complete the Screening assessments, as detailed in 
the Schedule of Assessments (SOA) in Appendix 1. All Screening assessments must be 
completed within 2 weeks before the start of the Randomized Treatment Period. 
Randomized Treatment Period (12 weeks [± 3-day window for each visit after Day 1 Visit])
Eligible participants will be randomized 1:1 to receive voxelotor or placebo once daily for 
12 weeks. At the time of randomization, participants will be stratified by concurrent HU therapy 
(yes, no).
This period will be comprised of 3 clinical visits at Day 1 (Randomization day), Week 6, and 
Week 12. 
The first dose of study treatment is intended to be on Day 1, and as soon as possible after 
randomization. The randomized treatment period is the continuous 12 weeks of voxelotor or 
placebo treatment from the date of randomization (Day 1).
Follow-up Period/EOS (4 weeks after last dose [± 7-day window for EOS Visit])
Following completion of the Randomized Treatment Period in this study, participants will be 
evaluated for an additional 4 weeks after the last dose for safety and tolerability including PE, 
vital signs, hematology and AEs as detailed in the SOA (Appendix 1).

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Figure 1:
Study Schema
Abbreviations: SOC, standard of care (as determined by the investigator for an individual participant);
SOC treatment will be ongoing throughout all phases of study.
a Randomization will be stratified by concurrent HU use (yes, no).
3.1.1.
Study Treatment 
See Section 5 for dosage and treatment administration of voxelotor and placebo.
3.1.2.
Study Assessments 
Study procedures and assessments are described in Section 6. The timing for the study 
procedures and assessments is provided in the SOA (Appendix 1). 
Participant safety and tolerability will be monitored during the entire study using standard 
measures, including PEs, vital signs (including blood pressure, heart rate, oxygen saturation, and 
temperature), clinical laboratory tests, and AE monitoring.
3.1.3.
Study Endpoints
See Table 2 for details.
3.1.4.
Minimization of Bias
This study uses a double-blind, randomized, multicenter design to minimize bias in treatment 
assignment, participant monitoring, and assessment of efficacy. Participants will be randomized 
1:1 using an Interactive Response System (IxRS). Laboratory results that may suggest the 
treatment assignment will be redacted to the Investigator (see Section 5.4.1.1). Participants and 
Study site personnel will be blinded to treatment assignment throughout the study.

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3.2.
Duration of Study Participation and of the Study
The approximate study duration for an individual participant includes the Screening Period (within 
2 weeks), a Randomized Treatment Period of 12 weeks, and a Follow-up Period/EOS visit 
(4 weeks [± 7 days] after the last dose of study drug). From Screening through Follow-up/EOS, 
total participation in this study for an individual participant is up to 18 weeks. Participants will 
continue to be followed for efficacy and safety, when possible, through the endpoint visit 
(Week 12), and subsequent Follow-up Visit regardless of treatment discontinuation.
The study will end when the last participant’s last visit occurs.
3.3.
Stopping Rules 
3.3.1.
Early Termination of the Study
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 
with voxelotor indicating a potential health risk to participants.
In any instance of early termination (ET) of the study, the Sponsor will notify, in writing, the 
Investigators, regulatory authorities, and Independent Review Boards (IRBs)/Independent Ethics 
Committees (IECs) and will specify the reason(s) for termination.
3.3.2.
Discontinuation of Individual Participants
Participants who withdraw or are discontinued from the study should return to the study site for 
an ET Visit as soon as possible after the last dose of study treatment, as indicated in the SOA and 
if possible complete and EOS visit 28 days after the ET visit.
3.3.2.1.
Withdrawal of Consent/Assent
Participants and/or their caregiver/legal representative will be informed that participation is 
voluntary and that they may discontinue treatment or withdraw from the study at any time and 
for any reason. Any participant who requests to be withdrawn or whose caregiver/legal guardian 
requests withdrawal will be withdrawn from the study by the Investigator.
3.3.2.2.
Early Discontinuation from Study 
Participants may be discontinued from the study for any of the following reasons:

Any serious adverse event (SAE), clinically significant AE, severe laboratory 
abnormality, intercurrent illness, or other medical condition that indicates that 
continuation in the study is not in the best interest of participants

Participant is lost to follow-up

Participant failure to comply with protocol requirements including the requirement of 
prohibited concomitant medications or study related procedure

Withdrawal of participant consent/assent

Pregnancy: study treatment will be discontinued immediately (see also Section 7.4)

Discretion of the Investigator

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3.3.2.3.
Early Discontinuation of Study Treatment
Participants may be discontinued from study treatment for any of the following reasons:

Any SAE, clinically significant AE, severe laboratory abnormality, intercurrent 
illness, or other medical condition that indicates that continuation of study treatment 
is not in the best interest of participants

Participant failure to comply with protocol requirements including the requirement of 
prohibited concomitant medications or study related procedure

Withdrawal of participant consent/assent 

Pregnancy: study treatment will be discontinued immediately (see also Section 7.4)

Discretion of the Investigator
For participants discontinuing the study treatment, every attempt should be made to keep the 
participant in the study and continue to perform the required study-related follow-up and 
procedures even after pre-mature discontinuation of treatment. Participants discontinuing the 
study early should return to the study site for an EOS/ET visit approximately 28 days (± 7 days) 
after the last dose of study treatment, as indicated in the SOA.

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4.
SELECTION OF STUDY PARTICPANTS
Eligibility will be based on assessments performed during the Screening Period. A participant 
will be enrolled after signing the ICF/AF for this study. Informed consent/assent must be 
properly executed prior to the performance of any protocol-required assessments or procedures.
4.1.
Inclusion Criteria
Participants who meet all of the following criteria will be eligible for study enrollment:
1. Male or female participants with confirmed diagnosis of SCD (all genotypes).
Documentation of SCD genotype is required and may be based on documented history of 
laboratory testing or confirmed by laboratory testing during Screening.
2. Aged 8 to < 18 years. 
3. Screening Hb level 5.5 to 10.5 g/dL.
4. Able to answer NIH Toolbox Module questions validated and normed based on age and 
maternal education on tablet.
5. If participant is receiving HU, they must have been on a stable dose for at least 90 days 
prior to signing the ICF/AF, with no dose modifications or initiation of HU planned or 
anticipated by the Investigator.
6. If participant is receiving erythropoiesis-stimulating agents (ESAs) they must have been 
on a stable dose for at least 12 weeks before enrollment with no dose modifications 
planned or anticipated by the Investigator.
7. Participants, who if female and of child-bearing potential, agree to use highly effective 
methods of contraception from study start to 30 days after the last dose of study drug and 
who if male, agree to use barrier methods of contraception and refrain from donating 
sperm from study start to 30 days after the last dose of study drug.
8. Females of child-bearing potential must have a negative pregnancy test before the 
administration of study drug.
9. Parental/guardian consent and participant assent per IRB/IEC’s policy and requirements, 
consistent with International Council for Harmonisation (ICH) guidelines.
10. Capable of complying with the requirements and restrictions in the protocol, and willing 
to participate in the study.
4.2.
Exclusion Criteria 
Participants meeting any of the following exclusion criteria will not be eligible for study 
enrollment:
1. Receiving chronic transfusion therapy.
2. RBC transfusion within 3 months before initiation of study drug or receives scheduled 
RBC transfusion therapy (also termed chronic, prophylactic, or preventive transfusion).
3. History of overt stroke including hemorrhagic stroke or transient ischemic attack (TIA) or 
spinal cord injury, magnetic resonance angiogram (MRA)-defined vasculopathy, or 

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magnetic resonance imaging (MRI)/transcranial doppler (TCD)-documented silent 
cerebral infarcts.
4. Congenital brain malformation, previously diagnosed severe developmental disability 
(eg, autism and/or IQ < 60, and/or severe attention deficit hyperactivity disorder
[ADHD]), or impairment that would prevent the use of a computer tablet.
5. Participant is taking or has received voxelotor (Oxbryta®) within 90 days prior to the 
Screening Visit.
6. Surgery within 8 weeks before Day 1 or planned elective surgery during the study. 
7. Anemia due to bone marrow failure (eg, myelodysplasia).
8. Absolute reticulocyte count (ARC) < 100 × 109/L.
9. Screening alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
> 4× upper limit of normal (ULN).
10. Severe renal dysfunction (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 
m2) or is on chronic dialysis.
11. Clinically significant bacterial, fungal, parasitic, or viral infection which requires therapy:
a.
Participants with acute bacterial infection requiring antibiotic use should delay 
screening/enrollment until the course of antibiotic therapy has been completed.
b. Participants with known active hepatitis A, B, or C or who are known to be human 
immunodeficiency virus (HIV) positive.
12. Symptomatic COVID-19 infection.
13. Females who are breast-feeding or pregnant.
14. History of hematopoietic stem cell transplant or gene therapy.
15. Participants taking concomitant medications such as sensitive CYP3A4 substrates with a 
narrow therapeutic range, strong CYP3A4 inducers
16. Participated in another clinical trial of an investigational product (or medical device) 
within 30 days or 5 half-lives of date of informed consent/assent, whichever is longer, or 
is currently participating in another trial of an investigational product (or medical device).
17. Medical, psychological, or behavioral condition that, in the opinion of the Investigator, 
would confound or interfere with evaluation of safety and/or efficacy of the study drug, 
prevent compliance with the study protocol; preclude informed consent/assent; or render 
the participant unable/unlikely to comply with the study procedures.

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5.
TREATMENTS OF SUBJECTS
5.1.
Treatment Regimen
During the Randomized Treatment Period, participants will be randomized in a 1:1 ratio to 
receive voxelotor once daily or matching placebo for 12 weeks. Participant ≥12 years old will 
receive a voxelotor dose of 1500 mg once daily, administered orally as tablets, while participants 
< 12 years old will receive a weight-adjusted equivalent dose. In this study, all participants will 
receive the SOC for SCD during the Randomized Treatment Period and throughout all phases of 
the study. 
Voxelotor, in all dosage forms, may be taken with or without food. Voxelotor tablets should be 
swallowed whole. The PfOS dosage form should be mixed with liquid. Details regarding 
preparation of voxelotor for administration are provided in the Pharmacy Manual (provided 
separately).
5.1.1.
Dose Frequency
Participants will receive a voxelotor or matching placebo administered orally, once daily. 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). 
5.1.2.
Dose Modification
Participants should adhere to their assigned dose level. However, reducing or holding the dose 
for a short period of time during the study may be used for AEs that impact the participant’s 
safety and tolerability. All instances of study drug dose modification (dose reduction, 
interruption, or discontinuation) should be documented in the participants’ medical record and 
recorded in the CRF. If the conditions/event leading to the dose modification have resolved, the 
original dose level should be resumed unless, in the judgment of the Investigator, this cannot be 
done safely. Dose modifications may be determined by the Investigator in consultation with the 
Sponsor’s Medical Monitor (Table 3 and Table 4). 

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Table 3:
Dose Modification Guidelines for Study Drug-related Adverse Events 
(12-17 years)
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.
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.
Drug Discontinuation
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.
Abbreviations: AE, adverse event; NCI, National Cancer Institute. 
Table 4:
Voxelotor Weight-based Dose Reduction for Participants Less than 12 Years 
of Age
Population
Voxelotor Doses 
(1500 mg Equivalent)
Dose Reduction 1 -
New Dose
5 to < 10 kg
400 mg (PfOS packet only)
300 mg (PfOS packet only)
10 to < 20 kg
600 mg (PfOS packet only)
400 mg (PfOS packet only)
20 to < 40 kg
900 mg (PfOS packet only)
600 mg (PfOS packet only)
≥ 40 kg
1500 mg (3X 500 mg Tablets only) 
1000 mg (2X 500 mg Tablets only)
Abbreviations: PfOS, powder for oral suspension.

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5.2.
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.
5.3.
Dosage Forms
5.3.1.
Voxelotor
Voxelotor 500 mg tablets contain voxelotor drug substance along with several dosage form
excipients. In this study, voxelotor will be administered as tablets for participants ≥ 12 years old. 
Participants < 12 years old receiving voxelotor will be administeredas a powder for oral 
suspension (PfOS) (packaged as stick packets) at a dose based on their body weight. The 
participant’s weight will be measured according to the SOA (Appendix 1), and dose adjustments 
made as needed and as indicated in Table 1. While the dose should be adjusted if the 
participant’s weight changes, the PfOS dosage form of voxelotor administered to participants 
< 12 years old need not be changed if the participant crosses the cut-off age of 12 years during 
the consecutive 12-week Randomized Treatment visit.
All of the excipients used in the dosage forms are listed in the FDA Inactive Ingredient Database 
(IID) or are pharmaceutical excipient mixtures entirely composed of FDA IID components). All 
of the excipients used in the dosage forms are either compendial per European Pharmacopoeia 
(Ph Eur) or are composed of mixtures which are compendial per Ph Eur or accepted by E number
or European Commission regulation.
Additional details are provided in the Pharmacy Manual.
5.3.2.
Placebo
The matching placebo tablets, and PfOS, dosage form contain several formulation excipients. All 
of the excipients used in the dosage forms are listed in the FDA IID or are pharmaceutical 
excipient mixtures entirely composed of FDA IID components.
All of the excipients used in the dosage form s are either compendial per Ph Eur or are composed 
of mixtures which are compendial per Ph Eur or accepted by E number or European Commission 
regulation. The matching placebos do not contain any voxelotor drug substance.
5.4.
Randomization and Unblinding
5.4.1.
Randomization
Randomization will be carried out through an IxRS. Permuted blocks within randomization strata 
will be used. Eligibility of the participant will be confirmed by the Investigator prior to 
randomization.
5.4.1.1.
Preventing Unblinding due to Laboratory Assessments
Because knowledge of certain laboratory assessments (Hb, hematocrit, RBC count, total and 
unconjugated bilirubin, or absolute and % reticulocyte count) may suggest the treatment 

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assignment in the Randomized Treatment Period, these measurements will be redacted to the 
Investigator. 
Results of redacted laboratory tests will be communicated to the Investigator if a participant’s 
ARC declines to < 80 × 109/L, or Hb declines to < 5.0 g/dL, or if the Hb declines ≥2 g/dL from 
Screening. This does not require breaking of the treatment assignment blind. This is to ensure 
participant safety by allowing the Investigator to monitor for potential bone marrow suppression, 
as described in HU monitoring guidelines (McGann, 2015; Yawn, 2014. De-identified laboratory 
results will be available to the Sponsor.
5.4.1.2.
Unblinding for Medical Need
The Investigator and site personnel will remain blinded to the treatment assignment during the 
study. Treatment assignment for a study participant may be unblinded by the Investigator only in 
an emergency, and only if knowledge of the treatment assignment is urgently needed for the 
clinical management or welfare of the participant. The Investigator should contact the medical 
monitor or project manager before unblinding, when possible, but priority should be given to 
treatment of the participant. The Investigator should promptly document and explain to the 
Sponsor any premature unblinding (eg, accidental unblinding, unblinding due to an SAE) of the 
study participant. Pregnancy is considered a medical condition that requires unblinding. 
Unblinding procedures will be followed as outlined in the IxRS Manual and documented in the 
Investigator site file and the CRF.
5.5.
Packaging and Labeling 
Voxelotor tablets, and placebo tablets will be supplied to clinical sites in high-density 
polyethylene bottles with induction sealed polypropylene child resistant caps. Voxelotor PfOS 
(packaged as stick packets) and matching placebo dosage forms will be supplied to clinical sites 
in a tamper-sealed carton. Bottles and/or cartons will be labeled according to applicable 
regulations. All study drug packaging must be returned at each visit, regardless of whether they 
are empty or contain unused study drug (voxelotor).
Additional details are provided in the Pharmacy Manual.
5.6.
Investigational Product Supply 
Global Blood Therapeutics, Inc. (GBT) or their representative will supply the packaged and 
labeled drug product to the investigational sites. Participants will receive either 60-days or 
70 days supply of voxelotor 1500 mg tablet or voxelotor PfOS, respectively, at the Randomized 
Day 1 (Visit 2) and Week 6 (Visit 3). Additional details are provided in the Pharmacy Manual.
5.7.
Storage and Handling Procedure
All study drug will be stored at controlled room temperature between 15°C to 25°C (59°F to 
77°F), in a secure, temperature-controlled and locked environment with restricted access 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, provided that the blind of the study is not compromised.

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5.8.
Concomitant and Prohibited Medications
5.8.1.
Concomitant Medications
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 who 
initiate study treatment, all medications administered from signing the consent/assent until 
14 days (2 weeks) after the participant’s last dose of study drug are considered concomitant 
medications and, must be recorded on the participant’s case record form (CRF).
A concomitant medication is defined as any prescription or over-the-counter preparation, 
including vitamins and supplements.
All reported prior and concomitant medications will be coded using the current version of the 
World Health Organization (WHO) Drug Dictionary.
5.8.2.
Restrictions Regarding Usage of Concomitant Medications
Concomitant treatment with HU/hydroxycarbamide (HC) is allowed, provided that the dose has 
been stable for at least 90 days prior to signing the ICF/AF. Participants who are on HU/HC may 
have their dose adjusted (based on change in their weight) if the mg/kg dose is stable, in the 
opinion of the Investigator. If HU/HC treatment is initiated after a participant has been screened 
or after being randomized, the eligibility of the participant to continue in the study must be 
discussed with the Sponsor’s Medical Monitor. 
5.8.3.
Transfusion
Participants who require a transfusion (either for acute treatment or the start of a chronic 
transfusion program) during the study will continue with study drug treatment after their 
transfusion. However, the final assessments (Day 85) must be conducted a minimum of 30 days 
after a transfusion. If a transfusion occurs within 30 days of the scheduled Day 85 Visit, the 
Investigator will contact the Sponsor to determine when the Day 85 assessments will be 
conducted. These participants will be monitored for safety through the Day 113 EOS Visit.
5.8.4.
Other Therapies
Vaccinations, including those for COVID-19, are allowed in accordance with SOC. 
Other concomitant medications are allowed, unless the restrictions in Section 5.8.5 apply. 
Permitted concomitant medications include L-glutamine, over-the-counter analgesics, and opioids, 
which are among the chronic medications commonly taken by participants with SCD. 
Erythropoietin-stimulating agents (stable dose for at least 4 weeks with no dose modifications 
planned or anticipated by the Investigator) are allowed.
5.8.5.
Prohibited Concomitant Medications
Use of an investigational product other than voxelotor in this study, regardless of its intended 
use, is prohibited throughout the trial and for 28 days after the last dose. Additionally, 
concomitant medications (eg, crizanlizumab [Adakveo®]) that confound the ability to interpret 
data from the study are prohibited.

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Voxelotor is a moderate cytochrome P450 (CYP)3A4 inhibitor and should be not be 
coadministered with sensitive CYP3A4 substrates with a narrow therapeutic index (refer to 
Table 5 for examples).
Table 5:
Sensitive CYP3A4 Substrates with Narrow Therapeutic Range
Alfentanil, sirolimus, and tacrolimus
Abbreviation: 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/ucm
093664.htm#table 3-2.
Since concomitant use of voxelotor with rifampin (a strong CYP3A4 inducer) is predicted to 
decrease voxelotor area under curve (AUC) in participants by up to 40%, concomitant use of 
voxelotor with rifampin or other strong CYP3A4 inducers is not allowed (refer to Table 6 for 
examples).
Table 6:
Examples of Strong CYP Inducers
CYP3A4
Examples
Strong CYP3A4 inducers
Rifampin, apalutamide, phenytoin, carbamazepine, enzalutamide, 
St John’s wort, and mitotane
Abbreviation: 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/ucm
093664.htm#table3-3.
Additional prohibited medications are shown in Table 7.
Table 7:
Additional Prohibited Medications

Cisapride

Crizanlizumab (Adakveo®)

Cannabis, alcohol and opioids that can interfere with neurocognitive testing must not be 
consumed within 24 hours prior to NIH Toolbox Cognition Module assessment at Baseline and 
Week 12 Visit.

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5.9.
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. Pregnancy is considered a 
medical condition that requires unblinding (for details refer to Section 7.4).
5.9.1.
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 5.10. Pregnancy reporting requirements are outlined in Section 7.4.
Female participants who become pregnant during the study will be withdrawn from the study.
5.9.2.
Female Participants of Non-Child-Bearing Potential
Female study participants who have not experienced menarche will not be assessed for 
pregnancy. However, if a female participant experiences menarche during the study, the 
participant will be considered as a female of child-bearing potential and will undergo urine 
pregnancy testing as per the SOA, (Appendix 1).
5.9.3.
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 (Section 5.9).
5.10.
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 (must be supplemented with a barrier method, preferably male 
condom).
a.
Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation:
o
Oral
o
Intravaginal
o
Transdermal

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b. Progestogen-only hormonal contraception associated with inhibition of ovulation:
o
Oral
o
Injectable
o
Implantable
2. Intrauterine device (IUD)
3. Intrauterine hormone-releasing system (IUS)
4. Bilateral tubal occlusion
5. Sexual abstinence: 
a.
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 treatments. 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.
5.11.
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 tablets/ packets and participant dosing diaries. 
Details regarding dosing, including the dose administered (number of tablets/packets) and the 
date of dosing, will be recorded by the participant/caregiver daily between study visits. The date 
and reasons(s) for missed doses will also be recorded by the participant.

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6.
STUDY PROCEDURES AND ASSESSMENTS
The timing for the required study procedures and assessments are outlined in the SOA 
(Appendix 1).
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 2 weeks before the start of the Randomized Treatment Period. Randomization 
takes place on Day 1 of the study and the first dose of study treatment is intended to be on Day 1, 
and as soon as possible after randomization.
6.1.
Informed Consent/Assent
A signed and dated ICF and/or AF will be obtained before any protocol-specified screening 
procedures are performed. 
For pediatric participants, consent should be obtained from at least one parent (or both if it is 
required per Investigational Site policy) or the participant’s legal representative. Guidelines for 
the informed consent/assent process are outlined in Section 11.3.
6.2.
Participant ID Number
Upon execution of consent/assent, all participants will be given a unique participant identifier 
(ID) 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.
Interactive Response System user manual contains the information needed for registering 
participant status (eg, assigning participant numbers, indicating screen failure, temporary 
suspension of treatment, and end of treatment).
6.3.
Eligibility Assessment, Inclusion/Exclusion Review
Eligibility assessment will be conducted during Screening and, prior to receiving study drug on 
treatment Day 1. Both at Screening and prior to randomization, the Investigator should determine 
that the participant is in stable clinical condition at their steady state. 
The first dose of study treatment is intended to be on Day 1, and as soon as possible after 
randomization which occurs on study Day 1. If a participant is randomized and withdrawn from 
the study prior to the first dose of study drug, a reason must be provided
Re-screening may be considered at the discretion of the Investigator and in consultation with the 
Sponsor, if it is likely the previously screened participant will be eligible. Participants who re-
screen will have all assessments redone and a new participant ID assigned.
6.4.
Medical History/Demographics 
Clinically significant medical history (as determined by the Investigator), will be recorded at the 
time of the Screening. 
Demographics and baseline characteristics (including age, sex, race, ethnicity, and participant’s 
and maternal/primary caregiver’s level of education) will also be recorded at the time of the 
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6.5.
Physical Examination 
The PE will be a complete PE according to the standard at the site performed at the Screening 
Visit. Physical examinations after the Screening Visit may be abbreviated PEs driven by signs 
and symptoms. An abbreviated PE will be conducted at the scheduled study visits: Day 1 
(Week 1), Week 6, Week 12, and EOS/ET, as detailed in the SOA (Appendix 1).

The complete PE will include at a minimum: height, weight, general appearance, 
examination of head, eyes, ears, nose, and throat, skin, cardiovascular and respiratory 
systems, abdominal examination, neurologic, and musculoskeletal.

An abbreviated PE will be driven by signs and symptoms.
6.6.
Vital Signs
Vital signs (blood pressure, heart rate, oxygen saturation, and temperature) will be measured at 
every visit during the study, as outlined in SOA (Appendix 1), after a participant has rested 
comfortably for at least 5 minutes in the supine or sitting position, as feasible. A repeated 
measurement of any of the vital signs parameters will be taken within 5 minutes if the first 
reading is outside the normal range and deemed clinically significant.
6.7.
NIH Toolbox Assessments
The NIH Toolbox Cognition Module is a standardized cognitive battery comprising of executive 
function, episodic memory, language, processing speed, working memory, and attention as 
subdomains. Seven tests are designed within these subdomains that are validated and normed 
based on age and maternal education (Hood, 2019). Using standardized procedures, instructions 
will be presented visually on a tablet computer using a tablet app.
Cannabis, alcohol and opioids that can interfere with neurocognitive testing must not be 
consumed within 24 hours prior to NIH Toolbox Cognition Module assessment at Baseline and 
Week 12 Visit. 
Further details on the NIH Toolbox Module will be provided in NIH Toolbox assessment and 
Measurement Manual. Assessment timepoints are specified in the SOA (Appendix 1).
For analysis purpose, tests of the NIH Toolbox have been categorized as executive abilities 
(Dimensional Change Card Sort Test, Flanker Inhibitory Control and Attention Test, and List 
Sorting Test) and nonexecutive abilities (Picture Vocabulary Test, Oral Reading Recognition 
Test, and Picture Sequence Memory Test). The Pattern Comparison Test, which measures 
processing speed will be assessed separately. (Hood, 2019). 
6.8.
Adverse Events and Concomitant Medications
Adverse events and concomitant medications will be recorded at every visit during the study, as 
detailed in the SOA (Appendix 1). See Section 7.2 for details regarding AE reporting period for 
this study. 

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6.9.
Laboratory Assessments
All laboratory assessments will be performed through a central laboratory. Hematology will be 
collected at the Screening Visit, Week 6, Week 12, and Follow-up/EOS Visit (See Section 6.9.1
and Section 6.9.2) and Serum chemistry will be collected only at Screening and Week 12 Visit. 
A serum pregnancy test will be performed at the Screening Visit, and urine pregnancy tests will 
be performed at Baseline (Day 1), Week 6, Week 12, and EOS for female participants of 
childbearing potential (see Section 6.9.3 for more information on pregnancy testing). The serum 
pregnancy test will be done only if the urine pregnancy outcome is positive. Refer to the SOA 
(Appendix 1) for the additional details of laboratory tests.
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 or central laboratory).
For the purpose of this study, a clinically significant laboratory value will be any abnormal result 
that, in the judgment of the Investigator, is an unexpected or unexplained laboratory value or if 
medical intervention or corrective action (transfusion, hydration, initiation of antibiotics, or other 
concomitant medication) is required. Any abnormal values that persist should be followed at the 
discretion of the Investigator. 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; it is preferred for the analyses to be conducted by the central laboratory unless medical 
need necessitates urgent results reporting. Repeat laboratory testing of abnormal potentially 
clinically significant or clinically significant results for the screening evaluation of the 
participant may be repeated at the discretion of the Investigator.
If blood specimens collected at the Day 1 visit and Week 12 visit are found to be inadequate for 
laboratory testing, the blood sample must be redrawn and submitted for laboratory testing within 
7 days of the study visit.
6.9.1.
Hematology
Hematology assessments include the following:

RBCs

Hematocrit

Hb

Platelets

White blood cells (WBCs) with differential (basophils, eosinophils, neutrophils, 
monocytes, and lymphocytes)

% and absolute reticulocytes count (ARC)

Mean corpuscular volume (MCV)

Mean corpuscular hemoglobin concentration (MCHC)

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
Sickle cell genotype (sickle hemoglobin with 2 sickle cell genes [HbSS], and sickle 
hemoglobin and one beta thalassemia gene [HbS/β0 thalassemia]) test at Screening 
only if the SCD genotype is not known
6.9.2.
Serum Chemistry
Chemistry assessments include the following:

AST and ALT

Albumin

Alkaline phosphatase (ALP)

Bicarbonate

Blood urea nitrogen (BUN)

Chloride

Calcium

Creatinine

Glucose

LDH

Sodium

Potassium

Bilirubin (total, direct, and indirect)
6.9.3.
Pregnancy Testing
Female study participants who have not experienced menarche will not undergo pregnancy 
testing. Should a female participant experience menarche during the study, the participant will be 
considered a female of child-bearing potential and will undergo urine pregnancy testing as per 
the SOA (Appendix 1).
If a urine pregnancy test is positive, the result must be confirmed per local standards at each site 
(eg, ultrasound, serum pregnancy test). See Section 7.4 for reporting a pregnancy.
6.10.
Patient/Caregiver-Reported Outcomes
Patient reported outcomes (PROs) will be evaluated by the following measures:

The PGI-C assessment will be performed using a 7-point scale to measure the 
participant’s overall improvement at Week 12.

Change from baseline to Week 12 in Pediatric quality of life in neurological disorders 
(Neuro-QOL) score.

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These assessments will be self-administered by study participants at visits specified in the SOA
(Appendix 1).
6.11.
Clinical Global Impression of Change
The CGI-C is the Investigator’s assessment of change in the overall health condition of the 
participant. The CGI-C assessment will be administered by the Investigator using a 7-point scale 
to measure the participant’s overall improvement at Week 12 as specified in the SOA 
(Appendix 1).
6.12.
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.

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7.
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 7.1. 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 7.2 for details regarding the required time periods for AE reporting.
Clinically significant changes from study baseline in PE findings, weight, vital signs, and clinical 
laboratory parameters will be recorded as AEs or SAEs, as appropriate.
7.1.
Adverse Events
7.1.1.
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) or SOC procedures, 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 preexisting condition that occurs after the participant signs the ICF/AF 
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 judgment, 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 preexisting conditions that are scheduled after 
study enrollment are considered SAEs.
The Investigator will assess each AE for seriousness, severity, and relationship to investigational 
product.
7.1.2.
Severity of Adverse Events
Whenever possible, the severity of all AEs will be graded using the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0.
For AEs not adequately addressed in the NCI CTCAE Version 5.0, the following criteria should 
be used (Table 8).
Table 8:
Grading for Adverse Events Not Covered in the NCI CTCAE
Severity
Description
Grade 1—Mild
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated
Grade 2—Moderate
Minimal, local or noninvasive intervention indicated; limited age-appropriate 
instrumental 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
Abbreviations: ADL, activities of daily living; 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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7.1.3.
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 judgment 
should be used for determining causal assessment.
7.1.4.
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.
7.2.
Adverse Event Reporting
7.2.1.
General
All AEs will be recorded from the time the study participant signs the ICF/assent until the EOS 
or Early Termination (ET) visit. 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 
treatment, 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 treatment at any time, 
at the discretion of the Investigator. The Sponsor and the contract research organization’s (CRO) 
Medical Monitor must be notified of the study participant discontinuation.
7.2.2.
Diagnosis Versus Signs and Symptoms
If known, a diagnosis should be recorded in 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 in the CRF. If a diagnosis is subsequently established, it should be 
reported as follow-up information.

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7.2.3.
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 treatment, 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 5 × the ULN associated with cholecystitis), only the diagnosis 
(eg, cholecystitis) needs to be recorded in the CRF.
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded in 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.
7.2.4.
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”).
7.2.5.
Worsening of Sickle Cell Disease
Sickle cell disease-related AEs that are common complications associated with the study 
participant’s SCD may 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 
disease- related AEs include: SCD with vaso-occlusive pain crisis, acute chest syndrome, 
pneumonia, priapism, and osteonecrosis (Kato, 2018). 
7.3.
Serious Adverse Events, Serious Adverse Drug Reactions, and 
Requirements for Immediate Reporting
All SAEs, regardless of causal attribution, must be reported by the Investigator/designee or site 
personnel within 24 hours of SAE awareness on the AE CRF via the EDC system. In the event 
that 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 resolution of the SAE are 
performed.
7.3.1.
Reporting Suspected Unexpected Serious Adverse Reactions and Urgent Safety 
Issues
The Sponsor or its designee is responsible for reporting suspected unexpected serious adverse 
reactions (SUSARs) to regulatory agencies, competent authorities, IRBs/IECs, 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’s 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’s first knowledge of the event. The Investigator is responsible 
for notifying the local IRB/IECs of all SAEs that occur at his/her site as required by local 
regulations or IRB/IEC 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, 
IRB/IECs, 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.
7.4.
Reporting Pregnancy
If a participant becomes pregnant while taking study drug, the study treatment 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 study drug 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, 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, 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 7.3. 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 
Pharmacovigilance 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 7.3.
Information regarding pregnancy testing (including definition of females of child-bearing 
potential) is provided in Section 5.9.1. Highly effective means of contraception are listed 
in Section 5.10.
7.5.
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 study drug exposure with the participant. 
Parents, guardians, or 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.

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8.
DATA ANALYSIS AND STATISTICAL PLANS
The primary study analysis will be based on data from the complete study (including the 4-week 
Follow-up Period), and will be performed after all participants have completed the study or 
discontinued early and all data from the study are in the database and the database is locked.
A statistical analysis plan (SAP) will be developed and finalized before database lock and will 
describe in more detail procedures for accounting for missing data, additional sensitivity 
analyses of the primary and secondary variables as well as the analyses of the exploratory 
endpoints.
8.1.
Analysis Populations
Three main analyses populations are defined for this study: the intent-to-treat (ITT) population, 
the per protocol (PP) population, and the safety-evaluable population.
The ITT population includes all randomized participants. For analyses based on this population, 
participants will be grouped according to the treatment assigned at randomization. This is the 
primary analysis population for efficacy, demographics, and baseline characteristics data.
The PP population will include all participants who complete study treatment with no important 
protocol deviations which would impact the evaluation of efficacy. This analysis population may 
be used for sensitivity analyses of the primary and key secondary efficacy endpoints.
The safety-evaluable population includes all participants who receive at least 1 dose of study 
drug. For analyses based on this population, participants will be grouped according to the actual 
study treatment received. This is the primary analysis population for safety and exposure data.
8.2.
Summary of Study Conduct
The number of participants randomized will be tabulated by country, study site, and treatment 
group. Participant disposition (the number of participants randomized, receiving at least 1 dose 
of study treatment, completing the study through the 12-week blinded Randomized Treatment 
Period and Follow-up Visit) will be summarized by treatment group. Reasons for early 
discontinuation from study treatment and early discontinuation from the study will be 
summarized. Major protocol deviations will be listed and evaluated for potential impact on the 
interpretation of study results.
8.3.
Summary of Demographics, Baseline Characteristics, and 
Concomitant Medications
Demographic and baseline characteristics such as age, sex, race, ethnicity, and participant’s and 
maternal/ primary caregiver’s level of education along with baseline disease characteristics 
(including sickle cell genotype, Hb levels, clinical measures of hemolysis, and HU use). Baseline 
will be defined as the last assessment performed prior to receiving the first dose of study 
treatment. Concomitant medications will be coded using the WHO Drug Dictionary and 
summarized.

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8.4.
Efficacy Analysis
8.4.1.
Primary Endpoint 
The executive abilities composite score will be measured using the NIH Toolbox Cognition 
Module. The primary endpoint will be the change from baseline in executive abilities composite 
score at Week 12 which will be summarized by treatment group using mean, SD, median, 
minimum and maximum. The analysis of the primary endpoint will compare voxelotor with 
placebo using analysis of covariance (ANCOVA) controlling for the baseline composite score, 
and HU use.
8.4.2.
Secondary Endpoints
The secondary endpoints are:

Change from baseline at Week 12 in processing speed as measured by Pattern 
Comparison Test score

Change from baseline at Week 12 in nonexecutive cognitive abilities (Picture 
Vocabulary Test, Oral Reading Recognition Test, and Picture Sequence Memory 
Test) composite score

Change from baseline in Hb over time up to Week 12 

Change and percent change from baseline over time up to Week 12 in clinical 
measures of hemolysis, including unconjugated bilirubin, absolute reticulocyte, 
reticulocytes %, and LDH
Changes from baseline at Week 12 in processing speed and nonexecutive cognitive abilities 
composite score will be summarized using mean, SD, median, minimum and maximum. The 
analyses of these endpoints will compare voxelotor with placebo using ANCOVA controlling for 
the corresponding baseline scores and HU use.
Changes from baseline in Hb and clinical measures of hemolysis (unconjugated bilirubin, 
% reticulocytes, absolute reticulocyte, and LDH) over time up to Week 12 will be analyzed using 
a mixed effect for repeated measures (MMRM) model. The fixed effect terms include treatment, 
study visit, treatment by visit interaction. Within-subject variability will be modeled using an 
unstructured covariance matrix.
8.4.3.
Exploratory Endpoints
Exploratory endpoints will be summarized by descriptive statistics. Details will be provided in 
the SAP.
8.5.
Safety Analysis
Safety analysis will be performed on all participants receiving at least 1 dose of study drug.
Adverse events will be classified according to Medical Dictionary for Regulatory Activities 
(MedDRA). The number and percentage of participants with treatment emergent AEs will be 
tabulated by system organ class and preferred term. Treatment-emergent adverse events will also 
be presented by severity and relationship to study treatment.

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Changes in laboratory parameters and vital signs will be summarized descriptively.
8.6.
Determination of Sample Size 
Sample size determination is based on statistical power considerations for the primary efficacy 
endpoint, change from baseline in executive abilities composite score at Week 12.
A sample size of approximately 80 participants (40 participants per treatment arm [voxelotor and 
placebo]) provides approximately 80% power to detect a difference in mean change in executive 
abilities composite score from baseline at Week 12 between the voxelotor arm and the placebo 
arm of 5 points with a common standard deviation of 7.5 points, using a 2-sided test at an overall 
α = 0.05 level. For the purposes of sample size calculation, a drop-out rate of 5% by Week 12 
was assumed.
8.7.
Missing Data Handling
Detailed considerations of missing data handling will be described in the SAP.
8.8.
Adjustment for Multiple Comparisons
A fixed sequence hierarchical test procedure will be used to control Type I error when evaluating 
the treatment effect of voxelotor compared with placebo for the primary and secondary efficacy 
endpoints. The endpoints will be tested sequentially based on the following prespecified order:

Change from baseline in executive abilities composite score at Week 12 (primary 
endpoint)

Change from baseline in processing speed at Week 12

Change from baseline in nonexecutive cognitive composite score at Week 12

Change from baseline in Hb over time up to Week 12
Each endpoint will be tested at a 2-sided alpha level of 0.05. Formal testing of endpoints will 
continue until the first nonsignificant result. Testing of endpoints subsequent to a nonsignificant 
result will be considered exploratory in nature.

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9.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
9.1.
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 medico-technical 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, IRB/IEC review, and regulatory inspection by providing direct 
access to source documents.
9.2.
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, PEs, a checklist of inclusion and exclusion criteria, 
investigational treatment administration, a record of sample collection, clinical assessments, AEs, 
and final evaluation(s). The monitor (clinical research associate [CRA]) 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 in the CRF except when provided electronically, 
eg, central laboratories, NIH output. 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 (or Investigator’s Agreement if applicable) will apply his/her signature in the 
CRF indicating he/she has reviewed and approves of the data collected in the CRF.

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10.
QUALITY CONTROL AND QUALITY ASSURANCE
10.1.
Monitoring
Site personnel will be provided with training on how to collect quality data for the study, and a 
Sponsor monitor (CRA) 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 to 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 deviations or if other factors appear to 
jeopardize the validity of the study.
The Investigator agrees to cooperate with the monitor (CRA) to ensure that any problems 
detected during the course of these monitoring visits are resolved.
The Sponsor, or designee, will determine a risk evaluation plan and implement an action plan 
considering the need to reduce unnecessary contacts in the context of the COVID-19 pandemic 
or other epidemiological emergency. Site visits may be replaced by enhanced centralized 
monitoring or local visits may be postponed. These methods will be described in a monitoring 
plan by the Sponsor, or designee.
10.2.
Quality Control and Quality Assurance
Global Blood Therapeutics 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/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/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.
10.3.
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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11.
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 and/or assent form for the study will inform the 
participant of their rights and provide appropriate contact details of the Data Protection Officer.
11.1.
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 IRB/IEC 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 in 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 IRB/IEC prior to implementation (refer to 
Section 11.4).
11.2.
Good Clinical Practice
The study will be conducted according to the protocol; guidelines established by ICH-GCP in 
clinical studies; US regulations (21 Code of Federal Regulations [CFR] Parts 50, 54, 56, and 
312); and country-specific requirements, as applicable.
11.3.
Written Informed Consent and Assent
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. It is the 
Investigator’s responsibility to obtain written informed consent/assent 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.
Prior to initiation of any study-related procedures, participants (and/or their parent or legal 
guardian for participants under 18 years of age) will sign and date the ICF/AF to participate in 
the study. Participants under 18 years of age (and their parent or legal guardian) will review the 
ICF and sign a Child AF, according to local institution/IEC guidelines. The parent or legal 
guardian for participants under 18 years of age will also sign and date an authorization form 
required under the Health Insurance Portability and Accountability Act (HIPAA), if applicable, 
that authorizes the use and disclosure of the participants’ protected health information.

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Participants who initially sign the AF and subsequently legally become an adult while actively 
participating in the study (before the EOS visit) should be re-consented using the adult ICF soon 
after their status changes.
The participant should be given a copy of the ICF (and the AF, if applicable) in their native 
language. The informed consent and assent processes should be recorded in the source 
documentation. The original copies of the signed and dated ICF (and AF, if applicable), must be 
retained in the institution’s records and are participant to inspection by representatives of the 
Sponsor, or representatives from regulatory agencies.
Participants unable to sign the ICF may participate in the study if a legal representative or 
witness provides the consent/assent (in accordance with the procedures of ICH-GCP and local 
regulations) and the participant confirms his/her interest in study participation. The participant, 
parent, or legal guardian will be informed that he/she can freely withdraw consent/assent and 
stop participation in the study at any time with no prejudice to further treatment. It is the parent 
or legal guardian’s responsibility to communicate this decision to the Investigator.
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.
11.4.
Independent Ethics Committee and Regulatory Approval
The Investigator must inform, and obtain approval from, the IRB/IEC for the conduct of the 
study at named sites, for the protocol, the Participant ICF/AF, 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 
study drug.
Proposed amendments to the protocol and documents must be discussed with the Sponsor and 
CRO, and then submitted to the IRB/IEC for approval as well as submitted to regulatory 
authorities for approval prior to implementation. Amendments may be implemented only after a 
copy of the 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 IRB/IEC approval. However, in this case, approval must be obtained as 
soon as possible after implementation.
The Investigator will be responsible for ensuring that an annual update is sent to the IRB/IEC to 
facilitate their continuing review of the study (if needed) and that the IRB/IEC is informed about 
the end of the study. Copies of the update, subsequent approvals and final letter must be sent to 
the Sponsor. The Investigator will inform the IRB/IEC of any reportable AEs.
11.5.
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.
11.6.
Confidentiality
The Investigator must ensure that the participant’s privacy is maintained. In the CRF and other 
documents submitted to the Sponsor, participants will be identified by a participant study number 

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only. Documents that are not submitted to the Sponsor (eg, signed ICF/AF) should be kept in a 
strictly confidential file by the Investigator.
The Investigator shall permit authorized representatives of the Sponsor, regulatory agencies, and 
IRB/IECs 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/assent, the participant must be 
informed that his/her records will be reviewed in this manner.
11.7.
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 12.2. Participant files and 
other source data (including copies of protocols, original reports of test results, study drug 
dispensing logs, correspondence, records of informed consent/assent, 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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12.
DATA HANDLING AND RECORDKEEPING
12.1.
Inspection of Records
Global Blood Therapeutics 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 Sponsor’s 
monitor (CRA) 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 11.5
(Essential Documents). The Investigator agrees to make this binder accessible to the monitor 
(CRA), auditor, and representatives of regulatory agencies and the IRB/IEC.
12.2.
Retention of Records
The Investigator will maintain adequate records, including participants’ medical records, 
laboratory reports, signed consent/assent 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 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. Global Blood Therapeutics must be notified with 
retention if the Investigator/institution is 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, IRB/IEC approvals, copies of the 
Form FDA 1572 (or Investigator’s Agreement if applicable), signed and dated consent/assent 
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.
12.3.
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. Participant 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 

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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 
participation in this clinical study. Data generated in this study will be available for inspection on 
request by the FDA or other government regulatory agency auditors, the Sponsor, the Sponsor’s 
Medical Monitor (or designee), and their designated representatives, the IRB/IEC, and other 
authorized parties. All information concerning the study drug 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 government 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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13.
INSURANCE AND FINANCIAL DISCLOSURE
The Sponsor has subscribed to an insurance policy covering, in its terms and provisions, its legal 
liability for injuries caused to participating persons and arising out of this research performed 
strictly in accordance with the scientific protocol as well as with applicable law and professional 
standards.
Financial Disclosure statements will be handled in a separate agreement apart from the protocol, 
kept on file and submitted, as applicable, with any subsequent license application.

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14.
PUBLICATION POLICY
It is intended 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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15.
REFERENCES
Bernaudin F, Verlhac S, Freard F, Foudot-Thoraval F, Benkerrou M, Thuret I, et al. Multicenter 
prospective study of children with sickle cell disease: Radiographic and psychometric correlation. Journal 
of Child Neurology. 2000;15:333–43.
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.
Eaton WA, Henry ER, Hofrichter J, Mozzarelli A. Is cooperative oxygen binding by hemoglobin really 
understood? Nat Struct Biol. 1999;6(4):351-58.
Gladwin MT, Barst RJ, Gibbs JSR, Hildesheim M, Sachdev V, Nouraie M, et al. Risk factors for death in 
632 patients with sickle cell disease in the United States and United Kingdom. PLoS ONE. 
2014;9(7):e99489. 
Hood AM, King AA, Fields ME, Ford AL, Guilliams KP, Hulbert ML, Lee JM, White DA. Higher 
executive abilities following a blood transfusion in children and young adults with sickle cell disease. 
Pediatr Blood Cancer. 2019.
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.
Kato GJ, Gladwin MT, Steinberg MH. Deconstructing sickle cell disease: reappraisal of the role of 
hemolysis in the development of clinical subphenotypes. Blood Rev. 2007;21(1):37-47.
Kato GJ, Piel FB, Reid CD, Gaston MH, Ohene-Frempong K, Krishnamurti L, et al. Sickle cell disease. 
Nat Rev Dis Primers. 2018;4:18010. doi: 10.1038/nrdp.2018.10.
Kral, MC, Brown, RT, Nietert PJ, Abboud MR, Jackson SM, Hynd GW. Transcranial Doppler 
ultrasonography and neurocognitive functioning in children with sickle cell disease. Pediatrics. 
2003;112:324–31.
McGann PT, Ware RE. Hydroxyurea therapy for sickle cell anemia. Expert Opin Drug Saf. 
2015;14(11):1749-58.
Nouraie M, Lee JS, Zhang Y, Kanias T, Zhao X, Xiong Z. The relationship between the severity of 
hemolysis, clinical manifestations and risk of death in 415 patients with sickle cell anemia in the US and 
Europe. Haematologica. 2013;98(3):464-72.
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.
Oxbryta® [prescribing information]. South San Francisco, CA: Global Blood Therapeutics, Inc.; 2021. 
prescribing-information.pdf (oxbryta.com).
Puffer ES, Schatz J, Roberts CW. The association of oral hydroxyurea therapy with improved cognitive 
functioning in sickle cell disease. Child Neuropsychol. 2007;13(2):142-54.
Schatz J, Finke RL, Kellett JM, Kramer JH. Cognitive functioning in children with sickle cell disease: a 
meta-analysis. J Pediatr Psychol. 2002;27(8):739-48.

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Steen RG, Miles MA, Helton KJ, Strawn S, Wang W, Xiong X, et al. Cognitive impairment in children 
with hemoglobin SS sickle cell disease: Relationship to MR imaging findings and hematocrit. American 
Journal of Neuroradiology. 2003;24:382–89.
Stivelman JC. Benefits of anemia treatment on cognitive function. Nephrology, dialysis, transplantation: 
Official publication of the European Dialysis and Transplant Association -European Renal Association. 
2000;15:29–35.
Swanson ME, Grosse SD, Kulkarni R. Disability among individuals with sickle cell disease: literature 
review from a public health perspective. Am J Prev Med. 2011;41(6 Suppl 4):S390-97.
Vichinsky EP, Neumayr LD, Gold JI, Weiner MW, Rule RR, Truran D, et al. Neuropsychological 
Dysfunction and Neuroimaging Adult Sickle Cell Anemia Study Group. Neuropsychological dysfunction 
and neuroimaging abnormalities in neurologically intact adults with sickle cell anemia. JAMA. 
2010;303(18):1823–31. 
Vichinsky E, Hoppe C, Howard J, Ataga K, Nduba V, El-Beshlawy A, et al. HOPE Trial Investigators. A 
Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease. N Engl J Med. 2019 Aug 8; 
381(6):509-19.
Wang WC, Langston JW, Steen RG, Wynn LW, Mulhern RK, Wilimas JA, et al. Abnormalities of the 
central nervous system in very young children with sickle cell anemia. J Pediatr. 1998;132(6):994-98.
Washington C, Green M, Inati A, Estepp J, Brown, C, Abboud M, et al. Pharmacokinetics of voxelotor 
(GBT440) using population pharmacokinetic and physiologically-based pharmacokinetic modeling in 
pediatric subjects with sickle cell disease. European Hematology Association 2018. Poster Presentation.
Weiskopf RB, Kramer JH, Viele M, Neumann Mireille, Feiner John R, Watson Jessica J, et al. Acute 
Severe Isovolemic Anemia Impairs Cognitive Function and Memory in Humans. Anesthesiology.
2000;92:1646–52.
Yawn BP, Buchanan GR, Afenyi-Annan AN, Ballas SK, Hassell KL, James AH, et al. Management of 
sickle cell disease. Summary of the 2014 evidence-based report by expert panel memers. JAMA. 
2014;312(10):1033-48.

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APPENDIX 1.
SCHEDULE OF ASSESSMENTS
Abbreviations: CGI-C, Clinician Global Impression of Change; EOS, End of study; EOT, End of treatment; ET, Early termination; NIH toolbox, National 
institutes of Health Toolbox; QOL, Quality of Life; PGI-C, Patient Global Impression of Change.
Period
Screening
12-week Randomized Treatment
Follow-up/EOS Visit
Visit Number (Week)
Visit 1
(Week -2 to -1)
Screening
Visit 2
(Week 1)
Visit 3
(Week 6)
Visit 4
(Week 12)
(EOT/ET)h
Visit 5
(Week 16)a
Visit Day
-14 to -1
1
43 ± 3
85 ± 3
113 ± 7
Visit Window
± 3 days
± 3 days
± 7 days
Informed consent/assent
X
Inclusion/exclusionb
X
X
-
-
-
Medical historyc
X
Physical examinationd
X
X
X
X
X
Vital signse
X
X
X
X
X
Serum pregnancy testf
X
Urine pregnancy testg
X
X
X
X
Hematologyh
X
X
X
X
Serum chemistryi
X
X
NIH Toolboxj
X
X
PGI-C/CGI-C
X
Neuro-QOL
X
X
Randomization
X
Dispense study drugk and 
participant dosing diaryl
X
X
Collect study drugk and 
participant dosing diaryl
X
X
Concomitant medications
X
X
X
X
X
Adverse events
X
X
X
X
X

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Footnotes for Appendix I: Schedule of Assessments
a Participants who discontinue study early will undergo the EOT evaluations at an ET Visit and when possible, a subsequent Follow-up Visit.
b All Screening evaluations must be completed and reviewed before Visit 2 (Randomization) to confirm all eligibility criteria are met. Inclusion and exclusion 
criteria should be reviewed at Screening and just prior to randomizing each participant to ensure study eligibility is met.
c If the SCD genotype is unknown, genotype testing should be performed at Screening.
d Physical examinations after the Screening Period may be abbreviated, focused on abnormalities identified on the Screening examination and as related to 
adverse events.
e Vital signs (blood pressure, heart rate, oxygen saturation, and temperature) will be measured after a participant has rested for at least 5 minutes in the supine or 
sitting position. A repeated measurement of any of the vital signs parameters will be taken within 5 minutes if the first reading is outside the normal range and 
deemed clinically significant.
f Females of child-bearing potential females will have a serum pregnancy test at Screening.
g Urine pregnancy tests will be performed at scheduled visits for females of child-bearing potential. If a urine pregnancy test is positive, the result must be 
confirmed with a serum pregnancy test. See Section 6.9.3.
h Hematology assessments will include WBC (with differential), RBC count, Hb, hematocrit, MCHC, MCV, platelet count, reticulocyte percentage, and ARC. 
Blood specimens collected at the Day 1 visit and Week 12 visit and found to be inadequate for laboratory testing will be redrawn and submitted for laboratory 
testing within 7 days of the study visit. See Section 6.9.1.
i Serum chemistry will include sodium, potassium, bicarbonate, chloride, calcium, BUN, creatinine, glucose, bilirubin (total, direct, and indirect), albumin, 
ALT/AST, ALP, and LDH. See Section 6.9.2.
j Cannabis, alcohol and opioids that can interfere with neurocognitive testing must not be consumed within 24 hours prior to NIH Toolbox Cognition Module 
assessment at Baseline and Week 12 Visit.
k Study drug is dispensed at Day 1 (Week 1) and Week 6 of Randomized Treatment Period. Study drug administration occurs daily over the 12 weeks of 
randomized treatment, concurrently with the Investigator-designated standard of care for SCD.
l Participant dosing diary is dispensed starting at Day 1(Week 1) and Week 6. Participants/caregiver should be instructed to complete the diary each day and 
return it at the next visit for collection and site review. Reason(s) and dates for missed doses should be recorded by the participant.