Clinical trial NCT04400487
Conditions: Sickle Cell Disease Sickle Cell Anemia
Sponsor: Pfizer
Start date: 2020-12-21; Completion date: 2022-09-13
Enrollment: 25 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a study to evaluate the effect of voxelotor on daily physical activity and sleep quality, as measured by a wrist-worn device in participants with sickle cell disease (SCD) and chronic moderate anemia.

Detailed description:
All participants will receive Voxelotor as treatment. There will be approximately 13 sites in the US.

Participant safety and tolerability will be monitored during the study using standard measures, including physical examinations, vital signs (including temperature, blood pressure, pulse rate, respiratory rate and peripheral oxygen saturation \[SpO2\]), clinical laboratory tests, and adverse event (AE) monitoring.

Screening Period (up to 4 weeks in duration): During this period, participants will sign the informed consent form (ICF), after which they will complete the screening assessments as detailed in the Schedule of Assessments (SOA).

Run-in Period (2 weeks in duration): During this period, participants will enter a 2-week run-in period (Day -14 to Day -1) during which baseline actigraphy measures of physical activity and sleep quality, overnight pulse oximetry assessments of oxygen saturation, and Patient-Reported Outcome (PRO) assessments will be collected before initiating treatment with voxelotor.

Treatment Period (24 weeks in duration): After completion of the 14-day Run-in Period, participants will enter the open label treatment period and receive voxelotor 1500 mg once daily for 24 weeks. Repeat actigraphy assessments of physical activity and sleep quality, and overnight pulse oximetry will be performed during the treatment period (Weeks 10 to 12 and Weeks 22 to 24). PRO and Clinical Global Impression (CGI) assessments will be completed at scheduled study visits. The open-label treatment period is considered the continuous 24 weeks of voxelotor treatment from date of first dose (Day 1).

Follow-up Period (4 weeks in duration): Immediately following the 24-week treatment period, participants will enter a 4-week Follow-up Period.

Arms: arm 1: Participants will receive voxelotor at 1500 mg
Interventions: intervention 1: Voxelotor
Intervention descriptions: intervention 1: 500 mg Tablet, Oral, With or Without Food

Protocol documents:
Prot_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
GBT440-039 
Study Number 
GBT440-039 
Study Title 
A Phase 4, Multicenter, Open-label Study to Evaluate the Treatment 
Effect of Voxelotor on Physical Activity in Adolescents and Adults with 
Sickle Cell Disease 
Study Drug 
Voxelotor 
IND Number 
121,691 
Sponsor 
Global Blood Therapeutics, Inc. 
181 Oyster Point Blvd 
South San Francisco, CA 94080 
United States of America 
Study Director 
, PharmD, MBA 
Senior Medical Science Director, Medical Evidence, Medical Affairs 
Global Blood Therapeutics, Inc. 
181 Oyster Point Blvd 
South San Francisco, CA 94080 
United States of America 
Telephone: 
 (office); 
 (mobile) 
Email: 
 
Protocol Amendment 2 
28 April 2021 
Protocol Amendment 1 
18 May 2020 
Original Protocol 
29 January 2020 
CONFIDENTIALITY STATEMENT 
The information in this study protocol is strictly confidential and is available for review to investigators, 
study center personnel, the ethics committee and the health authorities. It will not be disclosed to third 
parties without written authorization from the Sponsor, except to obtain informed consent from persons 
receiving the study treatment. Once the protocol is signed, its terms are binding for all parties. 
PPD
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STATEMENT OF APPROVAL AND COMPLIANCE 
A Phase 4, Multicenter, Open-label Study to Evaluate the Treatment Effect of Voxelotor on 
Physical Activity in Adolescents and Adults with Sickle Cell Disease 
SPONSOR APPROVAL 
The signature of the Sponsor representative below represents that the above-referenced clinical 
trial is being conducted under United States (US) Food and Drug Administration (FDA) 
Investigational New Drug (IND) Number 121691 GBT440 for the treatment of sickle cell disease. 
This IND application is held by Global Blood Therapeutics (GBT). The protocol is being 
conducted in accordance with International Council on Harmonisation (ICH) Good Clinical 
Practice (GCP) and all applicable federal, state and local regulations governing the conduct of this 
research, including the Department of Health and Human Services 45 Code of Federal Regulations 
(CFR) Part 46, FDA 21 CFR Parts 50, 54, 56, 312 and 812. GBT will provide the investigator with 
all information including safety information pertinent to the conduct of the study. 
Sponsor Representative 
(Signature):  
Name: 
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 the Declaration 
of Helsinki. All data obtained during the study will be provided to GBT. GBT requires that any 
presentation or publication of study data by an investigator be reviewed by GBT, before release. 
Principal Investigator (Print): 
 
Signature:  
 
 
 
 
Date: 
 
 
Senior Medical Science Director
29-Apr-2021 | 05:11 PDT
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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL GBT440-039 ............................................................................... 1 
STATEMENT OF APPROVAL AND COMPLIANCE ................................................................... 2 
TABLE OF CONTENTS ..................................................................................................................... 3 
LIST OF TABLES................................................................................................................................ 5 
LIST OF FIGURES .............................................................................................................................. 5 
SYNOPSIS ............................................................................................................................................ 6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................... 11 
1.
INTRODUCTION .......................................................................................................... 13 
1.1. 
Disease Background ....................................................................................................... 13 
1.2. 
Voxelotor ......................................................................................................................... 15 
1.3. 
Summary of Relevant Nonclinical Data and Clinical Data ......................................... 15 
1.4. 
Rationale for the Study ................................................................................................... 16 
1.5. 
Dose Rationale ................................................................................................................ 17 
2.
STUDY OBJECTIVES .................................................................................................. 17 
2.1. 
Safety ............................................................................................................................... 17 
3.
INVESTIGATIONAL PLAN ........................................................................................ 17 
3.1. 
Study Design ................................................................................................................... 17 
3.2. 
Duration of Study Participation and Duration of the Study ......................................... 19 
3.3. 
Stopping Rules ................................................................................................................ 19 
4.
SELECTION OF STUDY POPULATION .................................................................. 20 
4.1. 
Inclusion Criteria ............................................................................................................ 20 
4.2. 
Exclusion Criteria ........................................................................................................... 21 
5.
TREATMENTS ADMINISTERED .............................................................................. 22 
5.1. 
Treatment Regimen ........................................................................................................ 22 
5.2. 
Dose Frequency .............................................................................................................. 22 
5.3. 
Dose Modification .......................................................................................................... 22 
5.4. 
Physical Description ....................................................................................................... 23 
5.5. 
Formulation ..................................................................................................................... 23 
5.6. 
Packaging and Labeling ................................................................................................. 23 
5.7. 
Study Drug Supply ......................................................................................................... 24 
5.8. 
Storage and Handling Procedure ................................................................................... 24 


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5.9. 
Drug Accountability and Retention ............................................................................... 24 
5.10. 
Treatment of Overdose ................................................................................................... 24 
5.11. 
Concomitant Medications .............................................................................................. 25 
5.12. 
Fertility/Contraceptive Requirements ........................................................................... 26 
5.13. 
Assessment of Treatment Compliance .......................................................................... 28 
6. 
STUDY PROCEDURES AND EVALUATIONS ....................................................... 28 
6.1. 
Informed Consent/Assent ............................................................................................... 28 
6.2. 
Unique Participant Number............................................................................................ 28 
6.3. 
Demographics and Medical History .............................................................................. 28 
6.4. 
Physical Examination ..................................................................................................... 29 
6.5. 
Vital Signs ....................................................................................................................... 29 
6.6. 
Actigraphy Assessments ................................................................................................ 29 
6.7. 
Nocturnal Pulse Oximetry .............................................................................................. 29 
6.8. 
Patient-Reported Outcomes ........................................................................................... 29 
6.9. 
Clinical Global Impression of Change (CGIC) ............................................................ 30 
6.10. 
Adverse Events and Concomitant Medications ............................................................ 30 
6.11. 
Laboratory Assessments ................................................................................................. 30 
7. 
ADVERSE AND SERIOUS ADVERSE EVENTS..................................................... 31 
7.1. 
Adverse Events ............................................................................................................... 32 
7.2. 
Adverse Event Reporting ............................................................................................... 34 
7.3. 
Serious Adverse Events and Requirements for Immediate Reporting ........................ 35 
7.4. 
Reporting Pregnancy ...................................................................................................... 36 
7.5. 
Reporting Overdose ........................................................................................................ 36 
8. 
DATA ANALYSIS AND STATISTICAL PLANS..................................................... 37 
8.1. 
Endpoints ......................................................................................................................... 37 
8.2. 
Sample Size ..................................................................................................................... 37 
8.3. 
Populations for Analysis ................................................................................................ 37 
8.4. 
Analyses .......................................................................................................................... 37 
9. 
REGULATORY, ETHICAL AND LEGAL OBLIGATIONS.................................... 38 
9.1. 
Ethical Conduct of the Study ......................................................................................... 38 
9.2. 
Good Clinical Practice.................................................................................................... 38 
9.3. 
Written Informed Consent and Assent .......................................................................... 38 
9.4. 
Institutional Review Board and Regulatory Approval ................................................. 39 


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9.5. 
Essential Documentation Requirements........................................................................ 39 
9.6. 
Confidentiality ................................................................................................................ 39 
9.7. 
Regulatory, Ethical, and Legal Obligations .................................................................. 40 
9.8. 
Study Documentation and Data Storage ....................................................................... 40 
10. 
DATA HANDLING AND RECORDKEEPING ......................................................... 40 
10.1. 
Inspection of Records ..................................................................................................... 40 
10.2. 
Retention of Records ...................................................................................................... 41 
10.3. 
Disclosure of Information .............................................................................................. 41 
11. 
INSURANCE AND FINANCIAL DISCLOSURE ..................................................... 42 
12. 
PUBLICATION POLICY .............................................................................................. 42 
13. 
ADMINISTRATIVE OBLIGATIONS ......................................................................... 42 
13.1. 
Source Data ..................................................................................................................... 42 
13.2. 
Data Collection ............................................................................................................... 43 
13.3. 
Monitoring....................................................................................................................... 43 
13.4. 
Quality Control, Quality Assurance and Regulatory Inspections ................................ 43 
14. 
REFERENCES ............................................................................................................... 44 
APPENDIX 1. SCHEDULE OF ASSESSMENTS ....................................................................... 47 
 
LIST OF TABLES 
Table 1: 
Dose Modification Guidelines for Study Drug–Related Adverse Events ............................. 23 
Table 2: 
Sensitive CYP3A4 Substrates with a Narrow Therapeutic Range ....................................... 25 
Table 3: 
Examples of Strong CYP3A4 Inhibitors ............................................................................ 26 
Table 4: 
Examples of Moderate and Strong CYP3A4 Inducers ........................................................ 26 
Table 5: 
Clinical Laboratory Tests................................................................................................... 31 
Table 6: 
Grading for Adverse Events not Covered in the NCI CTCAE ............................................ 33 
 
LIST OF FIGURES 
Figure 1: 
Study Schematic ................................................................................................................ 49 


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SYNOPSIS 
Title 
A Phase 4, Multicenter, Open-label Study to Evaluate the Treatment Effect of 
Voxelotor on Physical Activity in Adolescents and Adults with Sickle Cell Disease 
Short Title 
Actigraphy Improvement with Voxelotor (ActIVe) Study 
Protocol Number 
GBT440-039 
Sponsor  
Global Blood Therapeutics, Inc. 
181 Oyster Point Blvd 
South San Francisco, CA 94080 
United States of America 
Study Drug 
Voxelotor, 1500 mg administered orally (three 500 mg tablets) 
Study 
Description 
This study is a Phase 4 multicenter, open-label, single-arm study to evaluate the 
effect of voxelotor on daily physical activity and sleep quality, as measured by 
actigraphy in participants with sickle cell disease (SCD) and chronic moderate 
anemia. Actigraphy assessments will be performed using wrist-worn tri-axial 
accelerometry device.  
Objectives 
The objectives of this study are to explore the effect of voxelotor on the below and 
are considered exploratory:  
• 
Change in physical activity as measured by actigraphy in adolescent and 
adult participants with SCD and chronic moderate anemia  
• 
Change in sleep quality as measured by overnight actigraphy 
• 
Change in peripheral oxygen saturation (SpO2) as measured by overnight 
monitoring  
• 
Change in hemoglobin (Hb) response, as defined by > 1 g/dL increase from 
baseline 
• 
Patient-reported outcome (PRO) measures of physical activity, fatigue, 
sleep quality, pain interference, depression, anxiety, and overall function 
(Patient-Reported Outcome Measurement Information System 
[PROMIS®], PROMIS Pediatric Profile-37 v2.0/PROMIS-43 V2.1 and 
Patient Global Impression of Change [PGIC]) 
• 
Clinician global impression of change (CGIC) 
• 
Safety and tolerability of voxelotor 


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Study Design 
The study is divided into a Screening Period, a Run-in Period, an Open-label 
Treatment Period and a Follow-up Period.  
Participant safety and tolerability will be monitored during the study using standard 
measures, including physical examinations, vital signs (including temperature, 
blood pressure, pulse rate, respiratory rate, and SpO2, clinical laboratory tests, and 
adverse event [AE] monitoring). 
Screening Period (up to 4 weeks in duration):  
During this period, participants will sign the informed consent form (ICF), after 
which they will complete the screening assessments as detailed in the Schedule of 
Assessments (SOA). 
Run-in Period (2 weeks in duration): 
During this period, participants will enter a 2-week Run-in Period (Day 14 to Day -1) 
during which baseline actigraphy measures of physical activity and sleep quality, 
overnight pulse oximetry assessments of oxygen saturation, and PRO assessments 
will be collected before initiating treatment with voxelotor.  
Treatment Period (24 weeks in duration): 
After completion of the 14-day Run-in Period, participants will enter the open-label 
Treatment Period and receive voxelotor 1500 mg once daily for 24 weeks. Repeat 
actigraphy assessments of physical activity and sleep quality, and overnight pulse 
oximetry will be performed during the Treatment Period (Weeks 10 to 12 and 
Weeks 22 to 24). PRO and CGIC assessments will be completed at scheduled study 
visits. The open-label Treatment Period is considered the continuous 24 weeks of 
voxelotor treatment from date of first dose (Day 1).  
Follow-up Period (4 weeks in duration): 
Immediately following the 24-week Treatment Period, participants will enter a 
4-week Follow-up Period.  
Dose 
During the open-label Treatment Period, all participants will receive 1500 mg of 
voxelotor once daily (administered as three 500 mg tablets) for 24 weeks 
Number of 
Participants 
Approximately 50 eligible participants will initiate treatment in this study.  
Number of 
Centers 
The study will be conducted at approximately 10 clinical sites in the United States 
(US). 
Duration of 
Study 
Participation 
The total duration of the study will be approximately 34 weeks. 


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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 sickle cell anemia (SCA) (sickle hemoglobin 
with two sickle cell genes [HbSS] or sickle hemoglobin (S) and one beta 
thalassemia gene [HbS β0] thal genotype)  
2. Between 12 to 55 years of age (inclusive)  
3. Screening Hb level ≤ 8.0 g/dL 
4. Treatment with hydroxyurea (HU) therapy on study is permitted if the 
participant has been on a stable dose for at least 90 days before enrollment with 
no dose modifications planned or anticipated by the investigator 
5. Treatment with glutamine is permitted 
6. Treatment with erythropoiesis-stimulating agents (ESAs) is permitted if the 
participant has been on a stable dose for at least 12 weeks before enrollment 
with no dose modifications planned or anticipated by the investigator  
7. Female participants of child-bearing potential must use highly effective 
methods of contraception to 30 days after the last dose of study drug. 
Male participants must use barrier methods of contraception to 30 days after the 
last dose of study drug 
8. Females of child-bearing potential and postmenopausal females are required to 
have a negative pregnancy test before the administration of study drug 
9. Written informed consent and/or parental/guardian consent and participant 
assent per Institutional Review Board (IRB) policy and requirements, consistent 
with International Council on Harmonisation (ICH) guidelines 
Exclusion Criteria: 
Participants meeting any of the following exclusion criteria will not be eligible for 
study enrollment: 
1. Red blood cell (RBC) transfusion within 3 months before initiation of study 
drug  
2. Planned initiation of regularly scheduled RBC transfusion therapy (also termed 
chronic, prophylactic, or preventive transfusion) during the study 
3. Hospitalization for vaso-occlusive crisis (VOC) or acute chest syndrome (ACS) 
within 30 days prior to informed consent/assent.  
4. More than 10 VOCs requiring hospitalization, emergency department or clinic 
visit within the past 12 months 
5. Planned elective surgery within the next 6 months 
6. Physical inactivity attributable to clinically significant musculoskeletal, 
cardiovascular, or respiratory comorbidities 
7. Anemia due to bone marrow failure (eg, myelodysplasia) 
8. Absolute reticulocyte count (ARC) < 100 × 109/L 
9. Screening alanine aminotransferase (ALT) > 4 × upper limit of normal (ULN) 
10. Severe renal dysfunction (estimated glomerular filtration rate < 30 mL/min/1.73 
m2 by Schwartz formula) or is on chronic dialysis 


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11. Known active hepatitis A, B, or C or known to be human immunodeficiency 
virus (HIV)-positive. 
12. Females who are breast-feeding or pregnant 
13. Major surgery within 8 weeks before enrollment. Participants must have 
completely recovered from any previous surgery before enrollment 
14. History of hematopoietic stem cell transplant or gene therapy 
15. Received an investigational drug within 30 days or 5-half-lives, whichever is 
longer, prior to consent, or is currently participating in another trial of an 
investigational or marketed drug (or medical device) 
16. Use of concomitant medications (eg, crizanlizumab) that confound the ability to 
interpret data from the study 
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; or, render the participant unable/unlikely to comply with the 
study procedures 
18. Use of herbal medications (eg, St. John’s Wort), sensitive cytochrome P450 
(CYP) 3A4 substrates with a narrow therapeutic index, strong CYP3A4 
inhibitors, fluconazole, or moderate or strong CYP3A4 inducers 
19. Symptomatic coronavirus disease of 2019 (COVID-19) infection 
Concomitant 
Medications and 
Restrictions 
The following concomitant medications are allowed:  
• HU (stable dose for at least 3 months before signing the ICF and with no dose 
modifications planned or anticipated and no sign of hematological toxicity) 
• Glutamine 
• ESAs (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 inhibitors or fluconazole  
• Moderate and strong CYP3A4 inducers 
• Crizanlizumab (Adakveo®) 
• Other experimental SCD therapy  
Study Endpoints 
All endpoints in this study are exploratory and include: 
• 
Change in total daily physical activity (expressed in counts per minute) from 
baseline to Week 10-12 and to Week 22-24 
• 
Categorical change from baseline in total daily physical activity as: light (LPA), 
moderate (MPA), and vigorous (VPA) physical activity from baseline to Week 
12 and Week 24 
• 
Change in total nocturnal sleep time from baseline to Week 10-12 and to 
Week 22-24 


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• 
Change in wake time after sleep onset from baseline to Week 10-12 and to 
Week 22-24 
• 
Change in sleep efficiency from baseline to Week 10-12 and to Week 22-24 
• 
Change in mean overnight SpO2 (%) and median number of overnight 
SpO2 dips > 3% per hour from baseline to Week 2 and to Week 12 and to 
Week 22-24 
• 
Proportion of participants with a > 1 g/dL increase in Hb from baseline to Week 
10-12 and to Week 22-24 
• 
Change in PRO measures (PROMIS Pediatric Profile-37 v2.0/PROMIS-43 
V2.1) 
• 
PGIC score at Week 24  
• 
CGIC score at Week 24 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Description 
ACS 
acute chest syndrome 
AE 
adverse event 
ALT 
alanine aminotransferase 
ARC 
absolute reticulocyte count 
AST 
aspartate aminotransferase 
CFR 
(United States) Code of Federal Regulations 
CGIC 
Clinician Global Impression of Change 
COVID-19 
coronavirus disease of 2019 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOS 
end of study 
ESA 
erythropoiesis-stimulating agents 
GBT 
Global Blood Therapeutics 
GCP 
Good Clinical Practice 
Hb 
hemoglobin 
HbF 
fetal hemoglobin  
HbS 
sickle hemoglobin 
HbS β0 thal 
sickle cell disease due to inheritance of one sickle hemoglobin (S) allele and one 
beta zero thalassemia (β0 thal) allele 
HbSS 
sickle cell disease due to inheritance of two sickle hemoglobin (S) alleles 
HU 
Hydroxyurea 
IB 
Investigator's Brochure 
ICF 
informed consent form 
ICH 
International Council on Harmonisation  
IND 
Investigational New Drug 
IID 
Inactive Ingredient Database 
IRB 
Institutional Review Board 
NCI 
National Cancer Institute 
oxyHb 
oxyhemoglobin 


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Abbreviation 
Description 
PD 
pharmacodynamic(s) 
PE 
physical examination 
PGIC 
Patient Global Impression of Change 
PRO 
patient-reported outcome(s) 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
QOL 
quality of life 
RBC 
red blood cell 
RSI 
Reference Safety Information 
SAE 
serious adverse event 
SCA 
sickle cell anemia 
SCD 
sickle cell disease 
SOA 
schedule of assessments 
SpO2 
peripheral oxygen saturation 
SUSAR 
suspected unexpected serious adverse reactions 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
US(A) 
United States (of America) 
VOC 
vaso-occlusive crisis 


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1. 
INTRODUCTION 
1.1. 
Disease Background 
Sickle cell disease (SCD) is an inherited blood disorder caused by a point mutation in the 
βglobin gene resulting in the formation of sickle hemoglobin (HbS). The disease is marked by 
the pathophysiologic features of hemolytic anemia, microvascular occlusion, and progressive 
end-organ damage, with a clinical course characterized by life-long disability and early death.1, 2 
In addition to unpredictable and recurrent vaso-occlusive pain episodes, hemolytic anemia 
directly damages blood vessels, resulting in a systemic vasculopathy that leads to progressive 
tissue and organ injury.3, 4 Cumulative injury to multiple organ systems from repeated episodes 
of red blood cell (RBC) sickling, vaso-occlusion, and chronic hemolytic anemia detrimentally 
affects patients’ quality of life (QOL) and overall functioning.5 
1.1.1. 
Impact of Anemia on Physical Activity and Sleep Quality in Sickle Cell Disease  
Moderate-to-severe anemia is a common feature of SCD. In individuals with the more severe 
form (sickle hemoglobin with two sickle cell genes [HbSS] or sickle hemoglobin (S) and one 
beta thalassemia gene [HbS/β0] thalassemia), referred to as sickle cell anemia (SCA), average 
hemoglobin (Hb) concentrations range from 6 to 8 g/dL.6  
Anemia is a well-established risk factor for cerebrovascular, cardiopulmonary, and renal 
complications in SCD.2, 7, 8, 9, 10 Chronic anemia in SCD and other hemolytic disorders is also 
associated with lower physical activity levels and symptoms of fatigue, shortness of breath, sleep 
disturbance, and reduced QOL.11, 12, 13, 14 Similar associations of anemia with impaired physical 
functioning and limited daily activities have been reported in adults with renal failure.7  
Impaired exercise performance and overall diminution of activity have been observed in both 
adults and adolescent patients with SCD.15 Exercise limitation may be related to the anemia 
directly or to chronic complications such as pulmonary vascular disease, congestive heart failure, 
and chronic parenchymal lung disease.16, 17, 11 Chronically low Hb levels are associated with 
decreased aerobic capacity and exercise performance in individuals with beta thalassemia.18 
Pre-transfusion Hb level and functional status are the leading indications for RBC transfusion in 
these patient populations. 
There is growing evidence that SCD pathophysiology is associated with Hb oxygen desaturation 
at rest and during exercise.19 Approximately 50% of children with SCA have mild or moderate 
oxygen desaturation at rest that is independently associated with hemolysis. Exercise-induced Hb 
oxygen desaturation is observed in 34% of children with SCA. Low Hb oxygen saturation is 
associated with severity of anemia and markers of hemolysis.20  
Sleep disordered breathing and nocturnal oxygen desaturation events are common in SCD with a 
reported prevalence of 69% in children and adolescents and 50% in adults.21, 22,23 Nocturnal 
hypoxemia is also associated with reduced exercise capacity, poor sleep quality, diminished 
self-reported QOL and is a risk factor for stroke, cardiopulmonary complications, and death.23, 24, 
25 In individuals with SCD, lower baseline oxygen saturation signiﬁcantly correlates with anemia 
and worsening neurocognitive performance.26, 27 Hydroxyurea and blood transfusions are 
therapies used to improve oxygen saturation and alleviate associated complications.28  


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1.1.2. 
Relationship Between Anemia and Fatigue  
Although pain is the most frequent symptom reported by individuals living with SCD, fatigue is 
an increasingly recognized symptom that interferes with the ability to carry out daily activities.29 
Adolescents with SCD report lower levels of general, sleep/rest, cognitive, and total fatigue 
compared to healthy peers,30 and young adults with SCD report significantly lower levels of 
vitality (energy) than the general population.14  
Despite the known pathophysiologic effects of chronic hemolytic anemia on tissue oxygenation, 
there has been little research examining the association between anemia and fatigue in SCD. 
Anemia is a significant contributor to fatigue in diseases such as cancer31, 32 and chronic kidney 
disease.33 In patients receiving transfusion for anemia related to other causes, an average increase 
in Hb of 1 g/dL was associated with a significant reduction in fatigue.34  
In a recent study examining biologic and behavioral correlates of fatigue in adolescents with 
SCD, lower Hb levels were associated with higher scores on Patient Reported Outcomes 
Measurement Information System (PROMIS®) measures of fatigue and sleep interference.35 
Moreover, fatigue interfered with mood and daily activities such as school, work, and exercise. 
The relationship between anemia, physical activity, sleep quality, and fatigue symptoms in the 
SCD population suggests that therapeutic interventions to improve anemia may be an effective 
strategy to impact these outcomes.  
1.1.3. 
Actigraphy Measures of Physical Activity  
Actigraphy makes use of wearable digital movement sensors, such as accelerometers, 
for continuous activity monitoring to capture objective real-world data that correlates to patient 
functional abilities and health outcomes. As an accepted methodology for tracking activity 
levels, time spent in moderate and vigorous physical activity, step counts, and energy 
expenditure, actigraphy is being increasingly utilized to identify clinically meaningful activity 
parameters and has even been incorporated as a primary endpoint in clinical trials for 
cardiopulmonary indications.  
A recent cross-sectional study using actigraphy to evaluate physical activity in SCD found that 
children and adolescents with SCD took fewer steps, spent significantly less time in 
moderate-to-vigorous daily activity, and burned fewer calories compared with healthy controls.36 
Moreover, among the participants in this study, the time spent in vigorous physical activity was 
significantly lower in those with a Hb level less than 8 g/dL compared to those with higher Hb 
levels. 
The specific impact of chronic anemia on physical activity, sleep patterns, and QOL in SCD 
merits further investigation. Therapeutic agents with the potential to improve daily activity, 
sleep, and overall well-being in children and adults with SCD are needed. Voxelotor, an inhibitor 
of HbS polymerization, has recently been approved for the treatment of anemia in SCD.37 
This exploratory study aims to evaluate the therapeutic potential of voxelotor to improve 
physical activity levels, sleep quality, and other patient-reported QOL measures, by targeting 
anemia. 


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1.2. 
Voxelotor 
Voxelotor (previously GBT440) is a 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 
(O2) affinity,38 stabilizing the oxyhemoglobin (oxyHb) state and inhibiting polymerization.39 The 
voxelotor binding site is distant from heme pockets and it can therefore increase O2 affinity 
without sterically blocking the release of O2.  
A primary and obligatory event in the molecular pathogenesis of SCD is the polymerization of 
deoxygenated HbS. Because oxyHb is a potent inhibitor of HbS polymerization, increasing the 
proportion of oxyHb in all RBCs with voxelotor can reduce HbS polymerization, decrease RBC 
membrane damage and destruction, and potentially achieve long-term disease modification. 
This principle is supported by the finding that in patients with in patients with coinherited HbS 
and hereditary persistence of fetal hemoglobin (HbS/HPFH), the dilution of HbS by 20% to 30% 
fetal hemoglobin (HbF) in all RBCs is sufficient to inhibit HbS polymerization, preventing RBC 
damage and SCD clinical sequelae. This suggests that pharmacologically maintaining 
approximately 20% to 30% of Hb in the nonpolymerizing oxygenated state in all RBCs may be 
an effective approach for the treatment of SCD. This therapeutic effect was demonstrated in the 
pivotal Phase 3 study (GBT440-031) where 1500 mg of voxelotor, achieving Hb modification of 
20-30%, administered daily orally for 24 weeks showed a significant and clinically meaningful 
increase in Hb and decrease in hemolysis.37  
Voxelotor was approved for use in the United States (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.  
Voxelotor continues to be evaluated in ongoing clinical studies exploring the safety, tolerability, 
pharmacokinetics, pharmacodynamics (PD), and treatment response in pediatric and adult 
participants with SCD as well as in clinical pharmacology studies in healthy adult participants. 
1.3. 
Summary of Relevant Nonclinical Data and Clinical Data 
1.3.1. 
Nonclinical Data 
Primary 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 HbO2 via 
hemoximetry, quantifying stabilization of the oxyhemoglobin state conformation, delaying HbS 
polymerization at low oxygen tension, preventing in vitro sickling induced by a low oxygen 
environment, decreasing viscosity, and improving deformability of RBCs in blood from patients 
with SCD. In addition, these studies show that voxelotor-modified Hb retains the Bohr Effect, 
which is the ability to augment oxygen delivery in metabolically active (low pH) tissues. 
Collectively, these studies demonstrate that voxelotor potently increases HbO2 affinity with high 
specificity of binding to Hb; stabilizes the oxygenated or relaxed-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 
lifespan, 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 and 
metabolism) and toxicology is provided in the most current version of the Investigator's 
Brochure (IB) for voxelotor. 
1.3.2. 
Clinical Data 
Global Blood Therapeutics’ (GBT’s) clinical development program for voxelotor and the results 
of clinical studies in participants with SCD are detailed in the current version of the IB. 
1.3.2.1. 
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 increase 
Hb, improve anemia, and reduce clinical measures of hemolysis in adult and pediatric 
participants 12 years of age and older with SCD.  
There have been no major safety findings arising from the ongoing studies or any pattern of 
adverse events (AEs) that would raise concerns or alter the benefit-risk profile of voxelotor. 
Clinical data to date support further development of voxelotor in adult and pediatric SCD 
populations. 
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. 
1.4. 
Rationale for the Study 
Sickle cell disease is a chronic debilitating disease characterized by vaso-occlusive episodes, 
hemolytic anemia, and progressive vascular injury to multiple organ systems.22 Chronic anemia 
is associated with decreased physical activity, poor sleep quality, cognitive impairment, fatigue 
and reduced QOL in patients with SCD. Given the negative impact of anemia on physical 
activity, sleep, and QOL in SCD and other hemolytic disorders, treatment of anemia represents a 
rational approach to improve measures of daily functioning. Voxelotor has been well tolerated in 
adult and pediatric participants aged ≥ 4 years and has shown rapid, significant, and sustained 
improvement in Hb and hemolysis measures over that achieved from standard-of-care therapy 
including HU;37 therefore, exploration of the effect of voxelotor in participants who may have 
the greatest potential to benefit from a disease-modifying therapy is warranted. Actigraphy 
provides an objective measure of physical function and has been successfully used in prospective 
interventional studies to assess the impact of pharmacologic treatments on physical activity, 
sleep, and QOL measures. The rationale for this study is based on the potential for voxelotor, 
through its effects on anemia and hemolysis, to improve measures of daily functioning, as 
assessed by actigraphy in participants with SCD and moderate anemia. 


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1.5. 
Dose Rationale 
Voxelotor is indicated for the treatment of SCD in adults and pediatric patients 12 years of age 
and older. This indication was approved under accelerated approval based on increase in Hb. The 
approved dose of 1500 mg taken orally once daily is supported by results of the pivotal Phase 3 
Study GBT440-031 in adults and adolescents with SCD demonstrating: (1) a statistically 
significant and clinically meaningful increase in mean Hb level of 1.1 g/dL and reductions in 
clinical markers of hemolysis observed with voxelotor 1500 mg compared to placebo and which 
were more robust than those observed with voxelotor 900 mg; (2) a favorable safety profile with 
absence of concerning exposure-related safety findings37; 3) the efficacy of the 1500 mg dose in 
adolescents is supported by similar improvements Hb and hemolysis measures observed in the 
Phase 2a Study GBT440-00740; 4) exposure-response analyses using data from both 
Study GBT440-031 and Study GBT440-007 demonstrating dose-dependent treatment effects of 
voxelotor on Hb and hemolysis measures; and 5) the majority of adult and adolescent 
participants receiving voxelotor 1500 mg in the GBT440-031 study achieved the intended 
therapeutic target of 20% to 30% mean % Hb occupancy. 
2. 
STUDY OBJECTIVES 
The objectives of this study are to evaluate the effect of voxelotor on the outcomes listed below 
and are considered exploratory: 
• 
Change in daily physical activity as measured by actigraphy in adolescent and adult 
participants with SCD and chronic moderate anemia  
• 
Change in sleep quality as measured by overnight actigraphy monitoring 
• 
Change in peripheral oxygen saturation (SpO2) as measured by overnight SpO2 
monitoring 
• 
Change in Hb response, as defined by > 1 g/dL increase from baseline 
• 
Change in nocturnal oxygen saturation as assessed by overnight pulse oximetry 
• 
Patient-reported outcome (PRO) measures of physical activity, fatigue, sleep quality, 
pain interference, depression, anxiety, and overall function (PROMIS), and Patient 
Global Impression of Change (PGIC) 
• 
Clinician global impression of change (CGIC) 
2.1. 
Safety 
The safety and tolerability of voxelotor will be evaluated. 
3. 
INVESTIGATIONAL PLAN 
3.1. 
Study Design  
This study is a Phase 4, multicenter, open-label, single-arm study to evaluate the effect of 
voxelotor on daily physical activity, measured by actigraphy, in participants with SCD and 


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chronic moderate anemia. The study is composed of a 28-day Screening Period, a 14-day Run-in 
Period, a 24-week Treatment Period, and a 28-day (4-week) Follow-up Period after last dose. 
This study will be conducted at approximately 10 clinical trial sites in the US. The overall study 
design is illustrated in the Study Schematic provided in Figure 1. 
Screening Period (28 days prior to Run-in) 
After signed informed consent and/or assent form has been provided, all eligibility criteria are 
met, and screening assessments have been completed, participants (12 to 55 years of age 
[inclusive]) will enter the Run-in Period.  
Run-in Period (14 days) 
During the Run-in Period, participants will be given a wrist-worn actigraphy device (eg, tri-axial 
accelerometer) to be worn continuously throughout the Run-in and Treatment Periods. Baseline 
measurements of physical activity, sleep parameters, and nocturnal oxygen saturations (SpO2) 
will be established during the Run-in Period.  
Participants will also be given a home pulse oximeter to record continuous overnight oxygen 
saturation during a scheduled overnight evaluation to establish baseline nocturnal SpO2. 
Additionally, QOL PRO assessments for measures of fatigue, sleep interference, pain 
(PROMIS), and depression (Patient Healthy Questionnaire-9 [PHQ-9]) will be completed during 
the Run-in Period. 
Treatment Period (24 weeks) 
Participants will be given a wrist-worn actigraphy device (eg, tri-axial accelerometer) to be worn 
continuously throughout the Run-in and Treatment Periods. During the Treatment Period, 
actigraphy assessments of physical activity and sleep quality, and overnight pulse oximetry 
assessments will be performed at scheduled time points. PRO and CGIC will be assessed at 
scheduled study visits. The open-label Treatment Period is considered the continuous 24 weeks 
of voxelotor treatment from date of first dose (ie, Day 1). 
Follow-up Period (28 days) 
Safety assessments including the collection of AE data, vital sign measurements, physical 
examinations, and laboratory evaluations will be collected at scheduled study visits.  
3.1.1. 
Study Treatment 
Dosage and treatment administration are described in Section 5. 
3.1.2. 
Study Assessments 
Study procedures and assessments are described in Section 6. The timing of the scheduled 
procedures and assessments are provided in Appendix 1. 
Safety will be assessed during the study using standard measures, including AE monitoring, 
clinical laboratory tests, vital sign measurements, physical examinations (PEs), and concomitant 
medication use. SCD-related complications will also be monitored. 


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3.1.3. 
Study Endpoints 
Study endpoints are described in Section 8.1. 
3.1.4. 
COVID-19 Risk Evaluation and Action Plan 
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 coronavirus disease 
of 2019 (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. 
3.2. 
Duration of Study Participation and Duration of the Study 
Participation is expected to last up to 34 weeks, including a 4-week Screening Period, a 2-week 
Run-in Period, a 24-week Treatment Period and a 4-week Follow-up Period. 
The study will end when the last participant’s last visit occurs. 
3.3. 
Stopping Rules 
3.3.1. 
Early Discontinuation of the Study 
The Sponsor has the right to terminate the study at any time. Reasons for terminating the study 
may include, but are not limited to, the incidence or severity of TEAEs in this or other studies 
indicating a potential health hazard to participants.  
In any instance of early termination of the study, the Sponsor will notify, in writing, the 
investigators, regulatory authorities, and Institutional Review Boards (IRBs) and will specify the 
reason(s) for termination.  
3.3.2. 
Discontinuation of Individual Participants 
3.3.2.1. 
Withdrawal of Consent 
Participants and/or their caregiver/legal representative will be informed that participation  
is voluntary and that they may withdraw from 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. 
Discontinuation of Study Treatment 
Participants may be discontinued from study treatment for any of the following reasons: 
• 
Participant is lost to follow-up. 
Every effort should be made for the participant to return to the clinic to complete the 
scheduled study visits. If the participant fails to return for the scheduled study visit, a 
documented effort must be made to determine the reason. If the participant cannot be 
reached by telephone after 2 attempts, a certified letter will be sent to the participant 
(or participant’s legally authorized representative, if appropriate) requesting the 
participant to contact the investigator. This information will be recorded in the study 


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records. Only after the documented efforts are conducted and the participant is still 
unresponsive will the participant be considered lost to follow-up. 
• Adverse event(s) 
• Discretion of the investigator 
• Discretion of the Sponsor 
• Pregnancy 
The participant should return to the investigational site for an End of Study (EOS) visit 
approximately 28 days after the last dose of study treatment as indicated in Appendix 1.  
4. 
SELECTION OF STUDY POPULATION 
Eligibility will be based on assessments performed prior to receiving study drug on Day 1 in this 
study. 
A participant will be enrolled after signing the informed consent form (ICF) or the assent form 
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 inclusion criteria will be eligible for study enrollment:  
1. Male or female with SCA (HbSS or [HbS β0]thal genotype) 
2. Age 12 to 55 years, inclusive 
3. Hb ≤ 8.0 g/dL during screening  
4. Treatment with HU therapy on study is permitted if the participant has been on a stable 
dose for at least 90 days before enrollment with no dose modifications planned or 
anticipated by the investigator 
5. Treatment with glutamine is permitted 
6. Treatment with erythropoiesis-stimulating agents (ESAs) is permitted if the participant 
has been on a stable dose for at least 12 weeks before enrollment with no dose 
modifications planned or anticipated by the investigator  
7. Female participants of child-bearing potential must use highly effective methods of 
contraception to 30 days after the last dose of study drug. Male participants must use 
barrier methods of contraception to 30 days after the last dose of study drug. 
8. Females of child-bearing potential and postmenopausal females are required to have a 
negative pregnancy test before the administration of study drug 
9. Written informed consent and participant assent per IRB policy and requirements, 
consistent with International Council and Harmonisation (ICH) guidelines 


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4.2. 
Exclusion Criteria 
Participants meeting any of the following exclusion criteria will not be eligible for study 
enrollment: 
1. RBC transfusion within 3 months before initiation of study drug  
2. Planned initiation of regularly scheduled RBC transfusion therapy (also termed chronic, 
prophylactic, or preventive transfusion) during the study 
3. Hospitalization for VOC or acute chest syndrome (ACS) within 30 days prior to informed 
consent/assent.  
4. More than 10 VOCs requiring hospitalization, emergency department or clinic visit 
within the past 12 months 
5. Planned elective surgery within the next 6 months 
6. Physical inactivity attributable to clinically significant musculoskeletal, cardiovascular, 
or respiratory comorbidities 
7. Anemia due to bone marrow failure (eg, myelodysplasia) 
8. Absolute reticulocyte count (ARC) < 100 × 109/L 
9. Screening alanine aminotransferase (ALT) > 4 × upper limit of normal (ULN)  
10.  Severe renal dysfunction (estimated glomerular filtration rate < 30 mL/min/1.73 m2 by 
Schwartz formula) or is on chronic dialysis  
11. Known active hepatitis A, B, or C or who are known to be human immunodeficiency 
virus (HIV) positive. 
12. Females who are breast-feeding or pregnant 
13. Major surgery within 8 weeks before enrollment. Participants must have completely 
recovered from any previous surgery before enrollment 
14. History of hematopoietic stem cell transplant or gene therapy  
15. Received an investigational drug within 30 days or 5-half-lives, whichever is longer, 
prior to consent, or is currently participating in another trial of an investigational or 
marketed drug (or medical device) 
16. Use of concomitant medications (eg, crizanlizumab) that confound the ability to interpret 
data from the study 
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, or render the 
participant unable/unlikely to comply with the study procedures 
18. Use of herbal medications (eg, St. John’s Wort), sensitive cytochrome P450 (CYP) 3A4 
substrates with a narrow therapeutic index, strong CYP3A4 inhibitors, or fluconazole 
19. Symptomatic COVID-19 infection 


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5. 
TREATMENTS ADMINISTERED  
5.1. 
Treatment Regimen 
Participants will be instructed to take 1500 mg of voxelotor (three 500 mg tablets) orally once 
daily for 24 weeks (168 days).  
Instructions for administration of voxelotor tablets: 
• 
Details regarding oral administration of the voxelotor tablets are provided in the 
Pharmacy Manual (provided separately). 
• For younger participants, voxelotor administration should be supervised by a parent 
or guardian. Detailed instructions will be provided to participants and their 
caregivers/legal guardians prior to the first dose of study drug. 
Treatment compliance will be based on comparison of the dispensed versus returned study drug.  
At assigned visits, participants will be supplied a sufficient quantity of voxelotor to ensure 
continuous dosing through to the next dispensing visit. All study drug packaging must be 
returned at designated visits, regardless of whether it is empty or contains unused study drug.  
5.2. 
Dose Frequency 
Participants will receive a 1500 mg dose of voxelotor as three 500 mg tablets 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 a day of a missed dose should not be increased or 
decreased).  
5.3. 
Dose Modification 
Participants should adhere to their assigned dose level. However, dose modification may be 
considered if warranted as outlined in Table 1.  
All instances of study drug modification (dose reduction, interruption, or discontinuation) should 
be documented in the participants’ medical record and recorded in the electronic case report form 
(eCRF). If the condition/event leading to the dose modification has resolved, the original dose 
level should be resumed, unless in the judgment of the investigator this cannot be done safely.  
 


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Table 1: 
Dose Modification Guidelines for Study Drug–Related Adverse Events 
Dose Reduction 
Event 
Recommended Action 
Grade ≥ 2 (NCI grading scale) AE deemed 
considered related to study drug by the Investigator  
AND  
Precludes continued dosing at the current dose level 
due to safety concern or lack of tolerability (in the 
Investigator’s judgment)  
Study drug: May be reduced by one (1) tablet.  
If, in the opinion of the Investigator, a Grade 2 AE has 
resolved to ≤ Grade 1, participant may resume study drug 
at the original dose. 
If, in the opinion of the Investigator, the AE poses a 
significant safety concern such that a dose hold is 
considered, the Investigator should contact the Medical 
Monitor. 
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 
Event 
Recommended Action 
Grade ≥ 3 study drug-related AE that, at the 
discretion of the Investigator, warrants 
discontinuation of study drug (eg, has not improved 
or resolved after dose hold). 
Study drug: Discontinue study drug. If the Investigator 
considers that the participant would benefit from 
continuing treatment, the Medical Monitor should be 
contacted. 
Abbreviations: AE, adverse event; SAE, serious adverse event. 
 
5.4. 
Physical Description 
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. 
5.5. 
Formulation 
Voxelotor (500 mg) tablets contain voxelotor drug substance along with several formulation 
excipients. All excipients used for the formulation are listed in the US FDA Inactive Ingredient 
Database (IID) or are pharmaceutical excipient mixtures entirely composed of FDA IID listed 
components.  
5.6. 
Packaging and Labeling 
Voxelotor tablets will be supplied to clinical sites in high-density polyethylene bottles with 
induction-sealed polypropylene child-resistant caps. Additional details are provided in the 
Pharmacy Manual. 


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5.7. 
Study Drug Supply 
The Sponsor or its representative will supply the packaged and labeled drug product to the 
clinical sites. Study drug will be dispensed at the Day 1 visit and at the Week 12 visit. 
Participants will receive a 3-month (90-day) supply of study drug at each dispensation visit. 
Additional details are provided in the Pharmacy Manual. 
5.8. 
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 the storage area of the investigational site pharmacy, which must be a secure, 
temperature-controlled, locked environment with restricted access. 
No special procedures are required for the safe handling of the study drug. The Sponsor (or its 
representatives) will be permitted (upon request) to audit the supplies, storage, dispensing 
procedures, and records. 
5.9. 
Drug Accountability and Retention 
In accordance with Good Clinical Practice (GCP), the investigational site will account for all 
supplies of the study drug. Details of receipt, storage, assembly, and return will be recorded. The 
lot numbers for the study drug will be provided to the site by the supplier/manufacturer as soon 
as they are available. 
The investigator (or designee) will maintain an accurate record of the receipt of the study drug as 
shipped by the Sponsor (or designee), including the date received and storage 
conditions/location. In addition, an accurate drug disposition record will be kept, specifying 
amount dispensed to each participant, the date of dispensation, the date of return, the number of 
tablets returned, and destruction records. A copy of this record will be returned to the Sponsor 
when the contents and condition of the study drug shipment have been verified. 
Current dispensing records will also be maintained, including the date and amount of study drug 
dispensed and the participant receiving the drug. This drug accountability record will be 
available for inspection at any time. 
All unused supplies of voxelotor will either be destroyed by the investigational site or returned to 
the Sponsor’s designated location throughout and at the end of the study in accordance with 
instruction by the Sponsor.  
Additional details are provided in the Pharmacy Manual (provided separately). 
5.10. 
Treatment of Overdose 
Based on the mechanism of action of voxelotor, an extreme overdose might decrease oxygen 
delivery to tissues. Transfusion, exchange transfusion, and/or hyperbaric oxygen therapy may be 
administered in the event of a medical emergency due to a suspected voxelotor overdose. 
Guidelines for reporting a suspected treatment overdose are provided in Section 7.5.  


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5.11. 
Concomitant Medications 
A concomitant medication is defined as any prescription or over-the-counter preparation, 
including vitamins and supplements.  
In the interests of participant safety and acceptable standards of medical care, the investigator 
will be permitted to prescribe treatment(s) at his/her discretion. For all participants who initiate 
treatment, all administered concomitant medications from signing the informed consent until 
28 days after the participant’s last dose of study drug, must be recorded in the participants’ eCRF 
(medication, dose, treatment duration, and indication).  
Penicillin prophylaxis and vaccinations (including the COVID-19 vaccine) are allowed in 
accordance with standard of care. 
All reported prior and concomitant medications will be coded using the current version of the 
World Health Organization Drug Dictionary. 
5.11.1. 
Restrictions Regarding Usage of Concomitant Medications 
Concurrent treatment with HU is allowed if the dose and regimen have been stable for at least 
3 months prior to signing the ICF and with no anticipated need for dose adjustments during the 
study and no sign of hematological toxicity. Concurrent treatment with ESAs is allowed if the 
dose and regimen have been stable for at least 4 weeks with no dose modifications planned or 
anticipated by the investigator.  
5.11.1.1. Prohibited Concomitant Medications 
Any experimental SCD therapy is not allowed during the entire study period. Any medication 
which is not approved for the indication of SCD and is not suggested in the current guidelines for 
the treatment of SCD is considered “experimental.” Additionally, concomitant medications 
(eg, crizanlizumab) that confound the ability to interpret data from the study are prohibited. 
Voxelotor is a moderate CYP3A4 inhibitor and should be not be coadministered with sensitive 
CYP3A4 substrates with a narrow therapeutic index (refer to Table 2 for examples). 
 
Table 2: 
Sensitive CYP3A4 Substrates with a Narrow Therapeutic Range 
Sensitive CYP3A4 Substrates with Narrow Therapeutic Range 
Alfentanil, sirolimus, and tacrolimus 
Abbreviation: CYP, cytochrome P450. 
Please note: This is not an exhaustive list. Substrates with a “narrow therapeutic range” refers to drugs whose 
exposure-response relationship indicates that small increases in their exposure levels by the concomitant use of CYP 
inhibitors may lead to serious safety concerns. Adapted from: FDA DRAFT Guidance for Industry: Drug 
Interactions Studies-Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations. 
February 2012. 
 
Avoid coadministration of strong CYP3A4 inhibitors (refer to Table 3 for examples) or 
fluconazole with voxelotor. If coadministration is unavoidable, the Sponsor’s Medical Monitor 
should be contacted. 


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Table 3: 
Examples of Strong CYP3A4 Inhibitors 
CYP Enzyme 
Strong Inhibitors 
CYP3A4 
Boceprevir, ceritinib, clarithromycin, cobicistat, conivaptan, 
danoprevir/ritonavir, elvitegravir/ritonavir, grapefruit juice, idelalisib, 
indinavir/ritonavir, itraconazole, ketoconazole, lopinavir/ritonavir, 
mibefradil, mifepristone, nefazodone, nelfinavir, posaconazole, ribociclib, 
ritonavir, saquinavir/ritonavir, telaprevir, telithromycin, tipranavir/ritonavir, 
troleandomycin, Viekira Pak, voriconazole 
Abbreviation: CYP, cytochrome P450. 
Please note: this is not an exhaustive list. For an updated list, refer to the following link: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm#ta 
ble 3-2. 
Since CYP3A4 is a primary CYP responsible for the metabolism of voxelotor, concomitant use 
of moderate or strong inducers of CYP3A4 with voxelotor is not allowed (refer to Table 4 for 
examples). 
Table 4: 
Examples of Moderate and Strong CYP3A4 Inducers 
CYP3A4 Inducer 
Examples 
Moderate 
Ritonavir, St. John’s wort, semagacestat, efavirenz, tipranavir/ritonavir, dabrafenib, 
lesinurad, bosentan, genistein, thioridazine, rifabutin, lorlatinib, nafcillin, talviraline, 
lopinavir, daclatasvir/asunaprevir/beclabuvir, modafinil, etravirine, elagolix, lersivirine, 
telotristat ethyl 
Strong 
Rifampin, mitotane, avasimbe, rifapentine, apalutamide, ivosidenib, phenytoin, 
carabamazepine, enzalutamide, St. John’s wort extract, lumacaftor, phenobarbital 
Abbreviation: CYP, cytochrome P450. 
Please note: this is not an exhaustive list. For an updated list, refer to the following link: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm#ta
ble3-3. 
5.12. 
Fertility/Contraceptive Requirements 
All female participants of child-bearing potential should avoid pregnancy and all sexually active 
male participants should avoid fathering a child.  
5.12.1. 
Instructions for Female Participants of Child-Bearing Potential 
For female participants of child-bearing potential who are 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 5.12.4 and pregnancy reporting requirements are outlined in Section 7.4. Female 
participants who become pregnant during the study will be withdrawn from the study. 


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5.12.2. 
Female Participants of Non-Child-Bearing Potential 
Female participants of non-child-bearing potential are defined as either (1) those who have not 
started their menarche; or (2) bilateral oophorectomy/hysterectomy/postmenopausal females 
being amenorrhoeic for greater than 2 years with an appropriate clinical profile, eg, age 
appropriate, history of vasomotor symptoms.  
5.12.3. 
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. 
5.12.4. 
Acceptable Forms of Contraception 
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. Effective methods of birth 
control are as follows: 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation: 
− Oral 
− Intravaginal 
− Transdermal 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation: 
− Oral 
− Injectable 
− Implantable 
• 
Hormonal contraception must be supplemented with a barrier method (preferably a 
male condom) 
• 
Intrauterine device  
• 
Intrauterine hormone-releasing system  
• 
Bilateral tubal occlusion 
• 
Vasectomized partner: Note that a vasectomized partner is a highly effective birth 
control method provided that the partner is the sole sexual partner of the woman of 
child-bearing potential trial participant and that the vasectomized partner has received 
medical assessment of the surgical success. 
• 
Sexual abstinence: Sexual abstinence is considered a highly effective method only if 
the participant is refraining from heterosexual intercourse during the entire period of 


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risk associated with the study treatments. The reliability of sexual abstinence needs to 
be evaluated in relation to the duration of the clinical trial and the preferred and usual 
lifestyle of the participant. 
For male participants with female partners capable of reproduction: 
• 
Barrier methods of contraception: Condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository. The use of 
barrier contraceptives should always be supplemented with the use of a spermicide.  
5.13. 
 Assessment of Treatment Compliance 
Drug disposition records will be maintained, specifying the amount of study drug dispensed to 
each participant and the date of dispensation. This record will be available for Sponsor review at 
any time. Compliance will be determined by returned tablet/packet count. 
6. 
STUDY PROCEDURES AND EVALUATIONS 
6.1. 
Informed Consent/Assent 
A signed and dated ICF and/or assent form 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 clinical site policy) or the participant’s legal representative. Care will be taken to 
avoid coercion of this vulnerable population of parents of children with SCD. 
Evaluations obtained as part of routine medical care and performed during the Screening Period 
may be used in place of the study-specific evaluations, provided they meet the time windows 
described below. Participants will acknowledge and agree to the possible use of this information 
for the study by giving informed consent. 
The Screening Period for a participant commences at the point at which the participant 
undergoes the first study-specific screening assessment and must be completed within 28 days 
after signing the ICF. Details of the assessments to be performed during the Screening Period are 
provided on the Schedule of Study Assessments (SOA) (Appendix 1).  
6.2. 
Unique Participant Number 
Upon execution of informed consent/assent, all participants will be given a unique participant 
number. This participant number will be used to identify the participant throughout the study and 
must be used on all study documentation related to that participant. 
6.3. 
Demographics and Medical History 
Demographic and baseline characteristics of sex, race, ethnicity, age, weight, and height of the 
participant will be collected at time of screening.  
Clinically significant medical history (as determined by the investigator) will be recorded at the 
time of the screening. 


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Medical history includes clinically significant disease manifestations, comorbid conditions, 
surgeries, and all medications used by participant within 30 days prior to screening. 
6.4. 
Physical Examination  
The PE will be a complete PE according to the standard at the site for this age group at screening 
and an abbreviated, symptom-directed examination at the scheduled study visits. 
• 
A complete PE should include, at a minimum, the following: height, weight, general 
appearance, examination of head, eyes, ears, nose, and throat, skin, cardiovascular 
and respiratory systems, abdominal examination, neurological, musculoskeletal, and 
symptom-directed examination 
• 
An abbreviated PE should include the following: general appearance; examination of 
eyes (including presence of scleral icterus), skin, cardiovascular system, and 
respiratory system; abdominal examination; and a symptom-directed examination. 
The physical examination will be completed at the time points indicated in the Schedule of 
Assessments (SOA) (Appendix 1).  
6.5. 
Vital Signs 
Vital signs (temperature, blood pressure, heart rate, respiratory rate, SpO2 [pulse oximetry], and 
body temperature) will be measured at the time points indicated in the SOA (Appendix 1). 
Blood pressure and heart rate measurements will be performed after the participant has rested 
comfortably for at least 5 minutes in the supine or sitting position, as age appropriate and 
feasible. If the first vital sign measurement is outside of the normal range and deemed clinically 
significant, the measurement will be repeated within 5 minutes. 
6.6. 
Actigraphy Assessments 
Actigraphy assessments of physical activity and sleep quality will be performed per the SOA 
(Appendix 1. Actigraphy assessments will be performed using a wrist-worn actigraphy device 
(eg, tri-axial accelerometer) that will be provided to the participant and will be worn 
continuously throughout the Run-in and Treatment Periods.  
6.7. 
Nocturnal Pulse Oximetry  
Nocturnal oxygen saturation will be assessed using a wearable home pulse oximeter to record 
continuous overnight oxygen saturation during sleep at a scheduled two-night evaluation; 
procedures will be performed according to standard protocols which will be provided in a 
manual to each site.  
Refer to the SOA in Appendix 1 for details of when these measures will be conducted throughout 
the study.  
6.8. 
Patient-Reported Outcomes 
Patient-reported outcomes will be evaluated using the National Institute of Health Patient 
Reported Outcome Measurement Information System (PROMIS) short forms and the PGIC 


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survey provided by the Sponsor. The following assessments will be used to collect QOL 
measures: 
• 
PROMIS Pediatric Profile-37 v2.0 (for pediatric participants) 
• 
PROMIS-43 V2.1 (for adult participants) 
• 
PGIC  
PRO assessments will be self-administered by study participants at scheduled study visits, 
as specified in the SOA. 
6.9. 
Clinical Global Impression of Change (CGIC) 
The investigator’s assessment of a participant’s overall health condition will be measured using 
the CGIC assessment, which is a 7-point scale used to assess how much the participant’s SCD has 
improved or worsened relative to baseline.  
Refer to the SOA in Appendix 1 for details of when these measures will be conducted throughout 
the study.  
6.10. 
Adverse Events and Concomitant Medications 
AEs and concomitant medications will be recorded throughout the study. See Section 7.2.1 for 
details regarding AE reporting period for this study. AEs and serious adverse events (SAEs) will 
be recorded from the time the study participant signs the ICF/assent form until 28 days after the 
last dose of study drug (EOS). See Section 7 for details regarding the definitions of and reporting 
requirements for AEs and SAEs. 
6.11. 
 Laboratory Assessments  
It is the responsibility of the investigator to assess the clinical significance of all abnormal 
clinical laboratory values, as defined by the list of normal values on file for the local clinical 
laboratory. All clinically significant laboratory value abnormalities are to be recorded as AEs. 
For the purpose of this study, a clinically significant laboratory value 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.  
Additional and repeat laboratory safety testing for the evaluation of abnormal results and/or AEs 
during the study may be performed at the discretion of the investigator or upon request of the 
Sponsor. Repeat laboratory testing of abnormal potentially clinically significant or clinically 
significant results for the screening evaluation of the participant may be repeated once at the 
discretion of the investigator. 
All laboratory safety testing will be performed by the local laboratory. The clinical laboratory 
tests that will be performed are listed in Table 5. Refer to Appendix 1 (SOA), for all time points. 


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Table 5: 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Urine 
Other 
• 
Hematocrit 
• 
Hemoglobin 
• 
%HbF (Screening only) 
• 
MCV 
• 
MCH 
• 
MCHC 
• 
Platelet count 
• 
RBC count 
• 
RDW 
• 
Reticulocyte count (percent) 
• 
Reticulocyte count (absolute) 
• 
WBC count with differential 
(basophils, eosinophils, 
neutrophils, monocytes, 
lymphocytes) 
• 
Albumin 
• 
Alkaline 
phosphatase 
• 
ALT 
• 
AST 
• 
Bicarbonate 
• 
Bilirubin (total, 
direct, and 
indirect) 
• 
BUN 
• 
Calcium 
• 
Chloride 
• 
Creatinine 
• 
Glucose 
• 
LDH 
• 
Phosphorus 
• 
Potassium 
• 
Serum 
erythropoietin 
• 
Sodium 
• 
Total protein 
• 
pH 
• 
Specific gravity 
• 
Blood 
• 
Glucose 
• 
Protein 
• 
Ketones 
• 
Bilirubin 
• 
Urobilinogen 
• 
Nitrite 
• 
Leukocytes 
• 
 Microscopic 
examination of 
sediment, if clinically 
indicated 
• 
Pregnancy 
test a 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; 
HbF, fetal hemoglobin; LDH, lactate dehydrogenase; MCH, mean cell hemoglobin; MCHC, mean corpuscular 
hemoglobin concentration; MCV, mean corpuscular volume; RBC, red blood cell; RDW, RBC distribution width; 
WBC, white blood cell. 
a Pregnancy tests will be performed for female participants who are postmenarche, including those who are 
postmenopausal. A serum β-human chorionic gonadotropin pregnancy test will be performed at screening and 
urine pregnancy tests will be performed prior to the first dose of study drug and at other times during the study. 
7. 
ADVERSE AND SERIOUS ADVERSE EVENTS 
Safety assessments will consist of AE and SAE monitoring, protocol-specified hematology and 
serum chemistry tests, abbreviated PEs, protocol-specified vital sign measurements, 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 
this section. 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 physical examination findings, weight, 
vital signs, and clinical laboratory test results will be recorded as AEs or SAEs, as appropriate.  


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7.1. 
Adverse Events 
7.1.1. 
Definition of Adverse Events 
An AE is defined as any untoward medical occurrence in a participant administered a 
pharmaceutical product during the course of a clinical investigation. 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. 
In addition to new events, any increase in the severity or frequency of a pre-existing condition 
that occurs after the participant signs the ICF for participation 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 Sponsor, 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 to be “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 Sponsor, results in any of the following 
outcomes: 
• 
Death  
• 
A life-threatening AE  
• 
Inpatient hospitalization or prolongation of existing hospitalization  
• 
Persistent or significant incapacity or disability (substantial disruption of the ability 
to conduct normal life functions)  
• 
A congenital anomaly/birth defect  
• 
Important medical events 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) is not 
considered to be an SAE. Any complications arising from a planned hospitalization may be 
considered an AE and should be reported, as applicable. Hospitalizations that occur for 
pre-existing conditions that are scheduled after study enrollment are considered SAEs.  
The investigator will assess each AE for seriousness, severity, and relationship to the study drug.  


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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.  
For AEs not adequately addressed in the NCI CTCAE, Version 5, the criteria presented in Table 6 
should be used.  
Table 6: 
Grading for Adverse Events not Covered in the NCI CTCAE 
Severity 
Description 
Grade 1 – mild 
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated  
Grade 2 – moderate 
Minimal, local or 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 that 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 pose a threat to a participant’s life or 
functioning. Seriousness (not severity) serves as a guide for defining regulatory reporting 
obligations.  
7.1.3. 
Relationship to Study Drug 
The relationship of an AE to the study drug 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 study drug administration
makes the relationship unlikely. If an SAE is not considered to be related to the 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 and 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.


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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 form until 
28 days after the last dose of study drug (EOS). All SAEs, regardless of causal attribution, must 
be reported within 24 hours of SAE awareness in the SAE eCRF via the electronic data capture 
(EDC) system. The investigator is responsible for evaluating all AEs, obtaining supporting 
documents, and ensuring that documentation of the event is complete. Details of each reported 
AE must include at a minimum severity, relationship to study treatment, duration, and outcome. 
All AEs (both serious and nonserious) must be followed until they are resolved or stabilized, 
or until reasonable attempts to determine resolution of the event are exhausted.  
Any participant who experiences an AE may be discontinued from study drug at any time, at 
the discretion of the investigator. The Sponsor and the Contract Research Organization (CRO) 
Medical Monitors 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 eCRF 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 eCRF. If a diagnosis is subsequently established, it should 
be reported as follow-up information.  
7.2.3. 
Abnormal Laboratory Values 
Only clinically significant laboratory abnormalities will be recorded in the AE eCRF 
(eg, abnormalities that have clinical sequelae, require study drug dose modification, 
discontinuation of study treatment, more frequent follow-up assessments, or further diagnostic 
investigation). If the clinically significant laboratory abnormality is a sign of a disease or 
syndrome (eg, alkaline phosphatase and bilirubin 5 × the ULN associated with cholecystitis), 
only the diagnosis (eg, cholecystitis) needs to be recorded on the eCRF.  
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the eCRF. 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 in the AE eCRF, unless the severity, seriousness, or etiology changes.  


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7.2.4. 
Worsening of Sickle Cell Disease 
SCD-related AEs that are common complications associated with the study participant’s SCD 
may not be considered to be related to voxelotor unless judged by the investigator to have 
worsened in severity and/or frequency or changed in nature during the study. SCD-related AEs 
include the following: SCA with crisis, ACS, pneumonia, priapism, and osteonecrosis.14 These 
events will be recorded on the AE eCRF.  
Vaso-occlusive Crisis 
VOC is defined as a composite of acute painful crisis and/or ACS. To allow for an assessment of 
VOC events, while minimizing variability in reporting and assessment, additional data will be 
collected for SCD-related AEs (eg, acute painful crisis, ACS events).  
7.3. 
Serious Adverse Events and Requirements for Immediate Reporting 
All SAEs, regardless of causal attribution, must be reported by the investigator (or designee) or 
site personnel within 24 hours of SAE awareness. The SAE will be reported by completing the 
AE CRF via the EDC system. 
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 participant identifier information (eg, name, medical record number) must be redacted in the 
hospital discharge summaries, autopsy reports, and/or death certificates.  
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 or 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 designee is responsible for reporting suspected unexpected serious adverse 
reactions (SUSARs) to regulatory agencies, competent authorities, IRBs, and investigators as per 
local laws and regulations. Fatal and life-threatening SUSARs will be submitted no later than 
7 calendar days of the Sponsor’s or 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 designee’s first knowledge of the event. The investigator is responsible for 
notifying the local IRBs of all SAEs that occur at his or her site, as required by local regulations 
or IRB policies, if this responsibility resides with the site.  
Investigators are required to report any urgent safety matters to the Sponsor or designee within 
24 hours of awareness. The Sponsor or designee will inform regulatory authorities, IRBs, and 
investigators, as applicable, of any events (eg, change to the safety profile of voxelotor, major 
safety findings that may place study participants at risk) that may occur during the clinical trial 
that do not fall within the definition of a SUSAR but may adversely affect the safety of study 
participants.  


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7.4. 
Reporting Pregnancy 
If a participant becomes pregnant while taking study drug, the study drug will be immediately 
discontinued and the pregnancy must be reported to the Sponsor or designee 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 counselling 
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).  
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 that an elective abortion is not considered an 
SAE. Pregnancy and pregnancy outcomes must be reported on a Pregnancy Notification Form or 
Pregnancy Outcome Form, respectively, and sent to the Sponsor or designee within 24 hours of 
the investigational site personnel learning of the pregnancy or pregnancy outcome.  
The child born to a female participant or partner of a male participant exposed to study drug will 
be followed for 3 months after delivery. The outcome of any pregnancy and the presence or 
absence of any congenital abnormality will be recorded in the Pregnancy Outcome Form and 
reported to the Sponsor or designee. 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 is provided in Section 6.11. Females of 
non-child-bearing potential are defined in Section 5.12.2. Highly effective means of 
contraception are listed in Section 5.12.4.  
7.5. 
Reporting Overdose 
If a participant takes more than the protocol-defined dose of study drug in a day and experiences 
a study drug-related AE, this will be reported as an overdose (AEs must be recorded in the AE 
eCRF) 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. 
Participants are to be instructed to contact their investigational site immediately if an overdose of 
study drug is suspected. An overdose with associated AEs must be reported within 24 hours of the 
investigator, designee, or site personnel learning of the overdose and reported 
to the Study Director/Medical Monitor. An overdose must be followed until any 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 
8.1. 
Endpoints 
All endpoints in this study are exploratory and include: 
• 
Change in total daily physical activity (expressed in counts per minute) from baseline 
to Week 10-12 and to Week 22-24 
• 
Categorical change from baseline in total daily physical activity as: light (LPA), 
moderate (MPA), and vigorous (VPA) physical activity from baseline to Week 10-12 
and Week 22-24 
• 
Change in total nocturnal sleep time from baseline to Week 10-12 and to Week 22-24 
• 
Change in wake time after sleep onset from baseline to Week 10-12 and to 
Week 22-24 
• 
Change in sleep efficiency from baseline to Week 10-12 and to Week 22-24 
• 
Proportion of participants with a > 1 g/dL increase in Hb from baseline from baseline 
to Week 10-12 and to Week 22-24 
• 
Change in mean overnight SpO2 (%) and median number of overnight SpO2 dips 
> 3% per hour from baseline to Week 12 and to Week 24 
• 
Change in PRO measures (PROMIS Pediatric Profile-37 v2.0/PROMIS-43 V2.1) 
• 
PGIC score at Week 24 
• 
CGIC score at Week 24  
8.2. 
Sample Size 
Approximately 50 participants who are 12 through 55 years of age (inclusive) with SCD and 
chronic moderate anemia will be enrolled and treated with voxelotor in this study.  
8.3. 
Populations for Analysis 
All participants who receive at least 1 dose of study treatment will be included in the safety 
population. This is the analysis population used to summarize all efficacy and safety data. 
8.4. 
Analyses 
Demographic and baseline characteristics, efficacy, PRO, and safety parameters will be 
summarized using descriptive statistics and presented in select individual listings.  
8.4.1. 
Efficacy 
Actigraphy assessments will be averaged over the 14-day period during the Run-in Period, 
Weeks 10 to 12, and Weeks 22 to 24.  
Change in actigraphy, SpO2, and PRO endpoints will be summarized for observed values and 
changes from baseline using appropriate descriptive statistics.  


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Hemoglobin response, defined as an increase in Hb of > 1 g/dL compared with baseline, will be 
summarized.  
8.4.2. 
Safety  
TEAEs, defined as an event that occurs on or after Day 1 of treatment with study drug or the 
worsening of a pre-existing condition on or after Day 1 of study treatment, will be classified 
according to the Medical Dictionary for Regulatory Activities. The incidence of TEAEs will be 
tabulated by System Organ Class, Preferred Term, severity, and relatedness to study treatment as 
assessed by the investigator. 
Clinical laboratory results and vital sign measurements, over time, will be descriptively 
summarized at each visit for observed values and changes from baseline.  
9. 
REGULATORY, ETHICAL AND LEGAL OBLIGATIONS 
9.1. 
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 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 eCRFs. 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 prior to implementation (refer to Section 9.4). 
9.2. 
Good Clinical Practice 
The study will be conducted according to the protocol; guidelines established by ICH GCP in 
clinical studies; and US regulations (21 Code of Federal Regulations [CFR] Parts 50, 54, 56, and 
312). 
9.3. 
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 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 assent form, according to local institution/IRB guidelines. The parent or legal 
guardian for participants under 18 years of age will also sign and date an authorization form 


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required under the Health Insurance Portability and Accountability Act, if applicable, that 
authorizes the use and disclosure of the participant’s protected health information. Participants 
who initially sign the assent form 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.  
Participants unable to sign the ICF may participate in the study if a legal representative or 
witness provides the consent (in accordance with the procedures of ICH GCP and local 
regulations) and the participant confirms his/her interest in study participation. The participant 
will be informed that he/she can freely withdraw consent and stop participation in the study at 
any time with no prejudice to further treatment. It is the participant’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. 
The participant should be given a copy of the ICF in their native language. The informed consent 
process should be recorded in the source documentation. The original copy of the signed and 
dated informed consent must be retained in the institution’s records and is subject to inspection 
by representatives of the Sponsor, or representatives from regulatory agencies. 
9.4. 
Institutional Review Board and Regulatory Approval 
The investigator must inform, and obtain approval from, the IRB for the conduct of the study at 
named sites, for the protocol, the participant ICF, and any other written information that will be 
provided to the participants and any advertisements that will be used. Written approval must be 
obtained prior to recruitment of participants into the study and shipment of study drug. 
Proposed amendments to the protocol and documents must be discussed with the Sponsor and 
CRO, and then submitted to the IRB for approval as well as submitted to regulatory authorities 
for approval prior to implementation. Amendments that are intended to eliminate an apparent 
immediate hazard to participants may be implemented prior to receiving Sponsor or IRB 
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 to 
facilitate their continuing review of the study (if needed) and that the IRB is informed about the 
end of the study. Copies of the update, subsequent approvals, and final letter must be sent to the 
Sponsor. The investigator will inform the IRB of any reportable AEs. 
9.5. 
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. 
9.6. 
Confidentiality 
The investigator must ensure that the participant’s privacy is maintained. In the eCRF or 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) should be kept in a 
strictly confidential file by the investigator. 
The investigator shall permit authorized representatives of the Sponsor, regulatory agencies, and 
IRBs to review the portion of the participant’s medical record that is directly related to the study. 
As part of the required content of informed consent, the participant must be informed that his/her 
records will be reviewed in this manner.  
9.7. 
Regulatory, Ethical, and Legal Obligations 
The study will comply with 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 number only in 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/ICF for the study will inform the participant of their rights and 
provide appropriate contact details of the Data Protection Officer. 
9.8. 
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 10.2. Participant files and 
other source data (including copies of protocols, original reports of test results, study drug 
dispensing logs, correspondence, records of informed consent, 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. 
10. 
DATA HANDLING AND RECORDKEEPING 
10.1. 
Inspection of Records 
GBT will be allowed to conduct site visits to the investigation facilities for the purpose of 
monitoring any aspect of the study. The investigator agrees to allow the monitor to inspect the 
drug storage area, study drug stocks, drug accountability records, participant charts, study source 
documents, and other records relative to study conduct. 
The investigator agrees to maintain a Regulatory Binder in a current, organized fashion; this 
Binder will contain documentation supportive of the protocol- and GCP-compliance of the study. 
The contents of the Binder will be organized according to the standards of ICH E6, Section 8 


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(Essential Documents). The investigator agrees to make this Binder accessible to the monitor, 
auditor, and representatives of regulatory agencies and the IRB. 
10.2. 
Retention of Records 
The investigator will maintain adequate records, including participants’ medical records, 
laboratory reports, signed consent forms, drug accountability records, safety reports, information 
regarding participants who discontinued the protocol, and any other pertinent data. All study 
records must be retained for at least 2 years after the last approval of a marketing application in 
the US or an ICH region and until (1) there are no pending or contemplated marketing 
applications in the US or an ICH region or (2) at least 2 years have elapsed since the formal 
discontinuation of clinical development of the study drug. 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. GBT must be notified with retention should the investigator/institution become 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 approvals, copies of Form FDA 1572, 
signed and dated consent forms, medical records, eCRFs, drug accountability records, 
all correspondence, and any other documents pertaining to the conduct of the study. 
If the 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. 
10.3. 
Disclosure of Information 
Participants’ medical information obtained as a result of this study is considered confidential, 
and disclosure to third parties, other than those noted in this protocol, is prohibited. Subject to 
any applicable authorization(s), all reports and communications relating to participants in this 
study will identify participants only by initials and number. Medical information resulting from a 
participant’s participation in this study may be given to the participant’s personal physician, 
other authorized parties, or to the appropriate medical personnel responsible for the participant’s 
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; 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 not to 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 


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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. 
11. 
INSURANCE AND FINANCIAL DISCLOSURE 
The Sponsor has subscribed to an insurance policy covering, in its terms and provisions, its legal 
liability for injuries caused to participating persons and arising out of this research performed 
strictly in accordance with the scientific protocol as well as with applicable law and professional 
standards.  
Financial Disclosure statements will be handled in a separate agreement apart from the protocol, 
kept on file and submitted as applicable with any subsequent license application. 
12. 
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 pre-publication 
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. 
13. 
ADMINISTRATIVE OBLIGATIONS 
13.1. 
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, 
X-rays, participant files, and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical trial) and all relevant sections of the 
participant’s medical records and all other data collection made specific to this trial constitute 
source documents. 
The completed eCRF is not a source document. The investigator/institution will permit 
trial--related monitoring, audits, IRB review and regulatory inspection by providing direct access 
to source documents. 


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13.2. 
Data Collection 
All participant data relating to the study will be recorded on electronic CRFs unless transmitted 
to the Sponsor or designee electronically (eg, actigraphy data).  
The investigator will be responsible for maintaining accurate and adequate case records (source 
documents) from which data will be transcribed (or if EDC, source data, transferred) to eCRFs 
designed to record data pertinent to this study. All relevant observations and data related to the 
study will be recorded. This will include medical and medication history, PEs, a checklist of 
inclusion and exclusion criteria, study drug administration, a record of sample collection, clinical 
assessments, AEs and final evaluation. The clinical site Clinical Research Associate will review 
all eCRFs and compare data to that contained in clinic notes and participants’ source 
documents/medical records. 
Data collected regarding each participant will be entered into the eCRF in a timely manner 
(generally within 5 business days of data capture). The investigator will be responsible for the 
timeliness, completeness, and accuracy of the documentation entered into the eCRFs. 
13.3. 
Monitoring 
It is understood that monitors, and any authorized personnel contracted to Sponsor may contact 
and visit the investigator, and that they will be allowed to inspect the various records of the trial 
on request (original source records and other pertinent trial data), provided that participant 
confidentiality is maintained, and that the inspection is conducted in accordance with local 
regulations. 
It is the monitor’s responsibility to inspect the eCRFs at regular intervals throughout the trial to 
verify adherence to the protocol, the completeness, accuracy and consistency of the data, and 
adherence to GCP regulations and guidelines.  
The investigator agrees to cooperate with the monitor to ensure that any problems detected 
during the course of these monitoring visits are resolved. 
13.4. 
Quality Control, Quality Assurance and Regulatory Inspections 
Quality Control will be performed according to Sponsor and CRO internal procedures. A Quality 
Assurance representative of the Sponsor and/or CRO may audit the study. In addition, the 
investigative site may be inspected by a representative of a regulatory authority. The investigator 
commits to making all necessary data/documents and key personnel available to support the 
inspection or audit. 


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14. 
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cell disease in the United States and United Kingdom. PLoS ONE. 2014;9(7):e99489. 
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2. Nouraie M, Lee JS, Zhang Y, et al. 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. 
3. 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;21:37-47. 
4. Kato GJ, McGowan V, Machado RF, et al. Lactate dehydrogenase as a biomarker of 
hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary 
hypertension, and death in patients with sickle cell disease. Blood. 2006;107:2279-85. 
5. Swanson ME, Grosse SD, Kulkami R. Disability among individuals with sickle cell 
disease: literature review from a public health perspective. Am J Prev Med. 
2011;41(6S4):S390-S397. 
6. Brown AK, Sleeper LA, Miller ST, et al. Reference values and hematologic changes 
from birth to 5 years in patients with sickle cell disease. Arch Pediatr Adolesc Med. 
1994;148(8):796-804. 
7. Powars DR, Elliott-Mills DD, Chan L, et al. Chronic renal failure in sickle cell disease: 
risk factors, clinical course, and mortality. Ann Intern Med. 1991;115:614-20. 
8. Hijmans CT, Grootenhuis MA, Oosterlaan J, et al. Neurocognitive deficits in children 
with sickle cell disease are associated with the severity of anemia. Pediatr Blood Cancer. 
2011;57:297-302. 
9. Bernaudin F, Verlhac S, Fréard F, et al. Multicenter prospective study of children with 
sickle cell disease: radiographic and psychometric correlation. J Child Neurol. 
2000;15:333-43. 
10. Kral MC, Brown RT, Connelly M, et al. Radiographic predictors of neurocognitive 
functioning in pediatric sickle cell disease. J Child Neurol. 2006;21:37-44. 
11. Liem RI, Nevin MA, Prestridge A, et al. Functional capacity in children and young adults 
with sickle cell disease undergoing evaluation for cardiopulmonary disease. Am J 
Hematol. 2009;84:645-649.  
12. Liem RI, Reddy M, Pilligra SA, et al. Reduced fitness and abnormal cardiopulmonary 
responses to maximal exercise testing in children and young adults with sickle cell 
anemia. Physiol Rep. 2015;3(4):e12338. doi: 10.14814/phy2.12338. 
13. Badawy SM, Thompson AA, Lai J-S, et al. Health-related quality of life and adherence to 
hydroxyurea in adolescents and young adults with sickle cell disease. Pediatr Blood 
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14. Dampier C, LeBeau P, Rhee S, et al. Health-related quality of life in adults with sickle 
cell disease (SCD): a report from the Comprehensive Sickle Cell Centers Clinical Trial 
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15. Badawy SM, Payne AB, Rodeghier MJ, Liem RI. Exercise capacity and clinical 
outcomes in adults followed in the Cooperative Study of Sickle Cell Disease (CSSCD). 
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16. Woodson RD, Wilks RE, Lenfant C. Effect of acute and established anemia on O2 
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17. Callahan LA, Woods KF, Mensah GA, et al. Cardiopulmonary responses to exercise in 
women with sickle cell anemia. Am J Respir Crit Care Med. 2002;165:1309-16. 
18. Marinov BI, Terziyski KV, Sapunarova KG, Kostianev SS. Exercise performance in 
children with severe beta thalassemia before and after transfusion. Folia Med (Plovdiv). 
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19. Waltz X, Romana M, Lalanne-Mistrih ML, et al. Hematologic and hemorheological 
determinants of resting and exercise-induced hemoglobin oxygen desaturation in children 
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20. Rackoff WR, Kunkel N, Silber JH, et al. Pulse oximetry and factors associated with 
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21. LeBourgeois MK, Giannotti F, Cortesi F, et al. The relationship between reported sleep 
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22. Kato GJ, Piel FB, Reid CD, et al. Sickle cell disease. Nature Rev Dis Primers. 2018 Mar 
15;4:18010. doi: 10.1038/nrdp.2018.10.  
23. Samuels C. Sleep, recovery, and performance: the new frontier in high-performance 
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24. Whitesell PL, Owoyemi O, Oneal P, et al. Sleep disordered breathing and nocturnal 
hypoxemia in young adults with sickle cell disease. Sleep Med. 2016 June;22:47-9.  
25. Kaleyias J, Cruz M, Goraya JS, et al. Spectrum of polysomnographic abnormalities in 
children with epilepsy. Pediatr Neurol. 2008 Sep;3:170-76. 
26. Hill CM, Hogan AM, Omugha N, et al. Increased cerebral blood flow velocity in children 
with mild sleep-disordered breathing: a possible association with abnormal 
neuropsychological function. Pediatrics. 2006;118(4):e1100-8. 
27. Hollocks MJ, Kok TB, Kirkham FJ, et al. Nocturnal oxygen desaturation and disordered 
sleep as a potential factor in executive dysfunction in sickle cell anemia. J Int 
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28. Pashankar F, Manwani D, Lee MT, Green NS. Hydroxyurea improves oxygen saturation 
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29. While AE, Mullen J. Living with sickle cell disease: the perspective of young people. 
Br J Nurs. 2004;13(6):320-5. 
30. Dampier C, Lieff S, LeBeau P, et al. Health-related quality of life in children with sickle 
cell disease: a report from the Comprehensive Sickle Cell Centers Clinical Trial 
Consortium. Pediatr Blood Cancer. 2010 Sep;55(3):485-94. doi: 10.1002/pbc.22497. 
31. Cella D, Lai J-S, Chang C-H, et al. Fatigue in cancer patients compared with fatigue in 
the general United States population. Cancer. 2002;94(2):528-38. 
32. Yeh C-H, Chiang Y-C, Lin L, et al. Clinical factors associated with fatigue over time in 
paediatric oncology patients receiving chemotherapy. Brit J Cancer. 2008;99:23-9. 
33. Lasch KF, Evans CJ, Schatell D. A qualitative analysis of patient-reported symptoms of 
anemia. Nephrol Nurs J. 2009;36(6):621-4,631-2; quiz 633. 
34. Prochaska MT, Newcomb R, Jiang D, Meltzer DO. The effect of red blood cell 
transfusion on fatigue in hospitalized patients with anaemia. Vox Sang. 2018 
Oct;113(7):669-77. 
35. Ameringer S, Elswick RK, Smith W. Fatigue in adolescents and young adults with sickle 
cell disease: biological and behavioral correlates and health-related quality of life. J 
Pediatr Oncol Nurs. 2014;31(1):6-17. 
36. Melo HN, Stoots SJM, Pool MA, et al. Objectively measured physical activity levels and 
sedentary time in children and adolescents with sickle cell anemia. PLoS One. 
2018;13(12):e208916. 
37. Vichinsky E, Hoppe CC, Ataga KI, et al. A phase 3 randomized trial of voxelotor in 
sickle cell disease. N Engl J Med. 2019;381(6):509-19. 
38. Eaton WA, Henry ER, Hofrichter J, Mozzarelli A. Is cooperative oxygen binding by 
hemoglobin really understood? Nat Struct Biol. 1999 Apr;6(4):351-8. 
39. Oksenberg D, Dufu K, Patel MP, et al. GBT440 increases haemoglobin oxygen affinity, 
reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease. Br J 
Haematol; 2016;175:141-53.  
40. Brown C, Hoppe C, Inati A, et al. Efficacy and safety of 1500 mg voxelotor in a phase 2a 
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509. 


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APPENDIX 1. SCHEDULE OF ASSESSMENTS 
Period 
Screening 
Run-in 
Open-label Treatment 
Follow-up 
Week 
Week -6 
Week -2 
Week 1 
Week 2 
Week 12 
Week 24 
Week 28 
Visit Day 
Day -42  
Day -14 
Day 1 
Day 14  
Day 84 
Day 168 
Day 196 
Visit Window 
 
 
(±3 days) 
(±3 days) 
(±3 days) 
(±3 days) 
(±3 days) 
Informed consent/assent  
X 
 
 
 
 
 
 
Inclusion/exclusion a 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Physical examination b 
X 
 
X 
 
X 
X 
X 
Body weight 
X 
 
X 
 
X 
X 
 
Height 
X 
 
 
 
 
 
 
Vital signs c 
X 
 
X 
 
X 
X 
X 
Serum pregnancy test d 
X 
 
 
 
 
 
 
Urine pregnancy test e 
 
 
X 
 
X 
X 
X 
Hematology, serum chemistry, liver 
function, urinalysis f 
X 
 
X 
X 
X 
X 
 
CGIC/PGIC assessments 
 
 
 
X 
X 
X 
X 
PRO assessments  
 
X g 
 
X 
X 
X 
 
Measure nocturnal SpO2 h 
 
X 
 
X 
X 
X 
 
Dispense actigraphy device 
 
X 
 
 
 
 
 
Return actigraphy device 
 
 
 
 
 
X 
 
Dispense study drug 
 
 
X 
 
X 
 
 
Collect study drug 
 
 
 
 
X 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CGIC, Clinician Global Impression of Change; Hb, 
hemoglobin; HbF, fetal hemoglobin; LDH, lactate dehydrogenase; MCH, mean cell hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MCV, 
mean corpuscular volume; PGIC, Patient Global Impression of Change; PRO, patient-reported outcome; RBC, red blood cell; RDW, red blood cell distribution 
width; SpO2, peripheral oxygen saturation; WBC, white blood cell. 
a All screening evaluations must be completed and reviewed before the Run-in Visit to confirm all eligibility criteria are met before dosing. 
b Physical examinations after the Screening Period may be abbreviated, focusing on abnormalities identified on the screening examination and as related to 
adverse events. 
c Vital signs (heart rate, blood pressure, respiratory rate, SpO2 [pulse oximetry], and body temperature) will be measured after a participant has rested for at least 
5 minutes in the supine or sitting position. Pulse oximetry, on room air, will be performed with vital signs. 


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d Females of child-bearing potential and postmenopausal females will have a serum pregnancy test at screening.  
e Urine pregnancy tests will be performed at scheduled visits for females of child-bearing potential and postmenopausal females. If a urine pregnancy test is 
positive the result must be confirmed with a serum pregnancy test. 
f Hematology assessments will include %HbF (screening only), WBC (with differential), RBC count, Hb, hematocrit, RDW, MCH, MCHC, MCV, platelet 
count, reticulocyte percentage, and absolute reticulocyte count. Serum chemistry will include sodium, potassium, bicarbonate, chloride, calcium, phosphorus, 
BUN, creatinine, glucose, bilirubin (total, direct, and indirect), total protein, albumin, ALT, alkaline phosphatase, AST, LDH, and serum erythropoietin. 
g PRO assessments to be completed during Run-in Period prior to start of treatment on Day 1. 
h Nocturnal SpO2 device will be dispensed at Week -2 (Run-in Period) and at Weeks 2, 12, and 24. Measurements will be performed for 2 consecutive nights and 
the device should be returned within 48 hours after the measurements have been performed. 


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Figure 1: 
Study Schematic