A Phase 1, Open-Label, Two-Part, Fixed-Sequence, Drug-Drug Interaction Study to Evaluate the Effect of Voxelotor on the Pharmacokinetics of Selected CYP and Transporter Probe Substrates in Healthy Participants
Phase: PHASE1
Conditions: Sickle Cell Disease
Sponsor: Pfizer

Title 
A Phase 1, Open-Label, Two-Part, Fixed-Sequence, Drug-Drug 
Interaction Study to Evaluate the Effect of Voxelotor on the 
Pharmacokinetics of Selected CYP and Transporter Probe 
Substrates in Healthy Participants 
Brief Title/Acronym
Voxelotor CYP and Transporter Cocktail Interaction Study
Active Substance 
Voxelotor 
Study Phase 
I 
IND Number 
121,691 
Agency Product Number 
EMEA/H/C/004869 
Marketing Authorization 
Holder 
Global Blood Therapeutics Netherlands B.V. 
Strawinskylaan 3051 
1077ZX Amsterdam 
The Netherlands 
Sponsor 
Global Blood Therapeutics, Inc.; a wholly owned subsidiary of 
Pfizer 
181 Oyster Point Blvd,  
South San Francisco, CA 94080 
United States of America 
Sponsor Contact  
 
Global Blood Therapeutics, Inc. 
181 Oyster Point Blvd. 
South San Francisco, CA 94080 
United States of America 
Email: 
 
Protocol Amendment 1 
02 March 2023 
Original Protocol 
10 June 2022  
CONFIDENTIALITY STATEMENT 
The information in this protocol is strictly confidential and is available for review to Investigator, 
study center personnel, the ethics committee, and health authorities. It will not be disclosed to third 
parties without written authorization from the Sponsor, except to obtain informed consent from 
persons receiving study treatment. Once the protocol is signed, its terms are binding for all parties. 
CLINICAL STUDY PROTOCOL 
PPD
PPD

Global Blood Therapeutics, Inc
Voxelotor
GBT440-0122 Protocol Amendment 1
02 March 2023
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STATEMENT OF APPROVAL AND COMPLIANCE
A Phase 1, Open-Label, Two-Part, Fixed-Sequence, Drug-Drug Interaction Study to 
Evaluate the Effect of Voxelotor on the Pharmacokinetics of Selected CYP and 
Transporter Probe Substrates in Healthy Participants
Protocol Amendment 1 02 March 2023
SPONSOR APPROVAL
The signature of the Sponsor representative below represents that the above-referenced clinical 
trial is being conducted under FDA IND Number 121,691 voxelotor for the treatment of sickle 
cell disease. This IND application is held by the Sponsor. The protocol is being conducted in 
accordance with ICH GCP and all applicable federal, state, and local regulations governing the 
conduct of this research, including DHHS 45 CFR Part 46, FDA 21 CFR Parts 50, 54, 56, 312,
and 812. The Sponsor will provide the Investigator with all information including safety 
information pertinent to the conduct of the study.
Sponsor Representative (Print):
Clark Brown, MD, PhD
Title:
Executive Director, Global Clinical Lead, Rare Diseases
Signature:
Date:
02 March 2023
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.
Principal Investigator (Print):
Cassandra Key, MD
Title:
Principle Investigator
Signature:
Date:
02 March 2023
PPD
PPD

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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................................8
1.
PROTOCOL SUMMARY..........................................................................................11
1.1.
Protocol Synopsis .......................................................................................................11
1.2.
Study Schema .............................................................................................................22
1.3.
Schedules of Assessments and Procedures.................................................................23
2.
INTRODUCTION......................................................................................................38
2.1.
Background .................................................................................................................38
2.2.
Summary of Findings to Date .....................................................................................38
2.2.1. 
Nonclinical Experience...............................................................................................38
2.2.2. 
Clinical Experience.....................................................................................................38
2.3.
Benefit/Risk Assessment ............................................................................................39
2.4.
Study Rationale...........................................................................................................39
2.4.1. 
Rationale for Study Design.........................................................................................39
2.4.1.1. 
Part A ..........................................................................................................................39
2.4.1.2. 
Part B ..........................................................................................................................39
2.4.2. 
Dose Rationale ............................................................................................................39
2.4.2.1. 
Part A ..........................................................................................................................39
2.4.2.2. 
Part B ..........................................................................................................................40
3.
OBJECTIVES .............................................................................................................41
4.
STUDY DESIGN .......................................................................................................42
4.1.
Overall Design ............................................................................................................42
4.1.1.
Part A..........................................................................................................................42
4.1.2. 
Part B ..........................................................................................................................43
4.2.
Scientific Rationale for Study Design ........................................................................43
4.3.
Dose Justification........................................................................................................43
4.4.
End of Study Definition ..............................................................................................43
5.
STUDY POPULATION.............................................................................................45
5.1.
Inclusion Criteria ........................................................................................................45
5.2.
Exclusion Criteria.......................................................................................................46
5.3.
Lifestyle Considerations .............................................................................................48
5.3.1. 
Dietary ........................................................................................................................48

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5.3.2.
Caffeine, Alcohol, and Tobacco .................................................................................48
5.3.3. 
Activity .......................................................................................................................48
5.4.
Screen Failures............................................................................................................48
6.
STUDY TREATMENT AND CONCOMITANT THERAPY..................................49
6.1.
Study Treatments Administered .................................................................................49
6.2.
Preparation, Handling, Storage, and Accountability ..................................................50
6.3.
Randomization and Blinding ......................................................................................51
6.4.
Study Treatment Compliance .....................................................................................51
6.5.
Concomitant Therapy .................................................................................................51
6.5.1.
Restrictions Regarding Concomitant Medications .....................................................52
6.5.1.1. 
Prohibited Concomitant Medications and Therapies..................................................52
6.5.2. 
Concomitant Procedures.............................................................................................52
7.
DISCONTINUATION OF STUDY TREATMENT AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................53
7.1.
Early Discontinuation of the Study.............................................................................53
7.2.
Discontinuation of Study Treatment...........................................................................53
7.2.1. 
Discontinuation due to Adverse Events......................................................................53
7.2.2. 
Liver Chemistry Stopping Criteria .............................................................................54
7.3.
Discontinuation/Withdrawal from the Study ..............................................................54
7.4.
Lost to Follow up ........................................................................................................54
8.
STUDY ASSESSMENTS AND PROCEDURES......................................................56
8.1.
Demographic/Medical History ...................................................................................56
8.2.
Pharmacokinetics........................................................................................................56
8.3.
Safety Assessments.....................................................................................................57
8.3.1. 
Physical Examination .................................................................................................57
8.3.2. 
Vital Signs ..................................................................................................................58
8.3.3. 
Oxygen Saturation (Part A only)................................................................................58
8.3.4. 
Electrocardiograms .....................................................................................................58
8.3.5. 
Clinical Laboratory Tests ...........................................................................................59
8.3.5.1. 
Other Tests ..................................................................................................................60
8.3.6. 
Pregnancy Testing ......................................................................................................61
8.4.
Adverse Events (AEs) Serious Adverse Events (SAEs), and Other Safety 
Reporting ....................................................................................................................61

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8.4.1.
Definition of Adverse Events .....................................................................................61
8.4.2. 
Definition of Serious Adverse Events or Serious Suspected Adverse 
Reactions.....................................................................................................................62
8.4.3.
Severity of Adverse Events ........................................................................................62
8.4.4.
Relationship to Investigational Product......................................................................63
8.4.5. 
Adverse Event Reporting ............................................................................................63
8.4.5.1. 
General........................................................................................................................63
8.4.5.2. 
Diagnosis Versus Signs and Symptoms .....................................................................63
8.4.5.3.
Abnormal Laboratory Values .....................................................................................64
8.4.6.
Serious Adverse Events, Serious Adverse Drug Reactions, and Requirements 
for Immediate Reporting.............................................................................................64
8.4.6.1. 
Reporting Suspected Unexpected Serious Adverse Reactions and Urgent 
Safety Issues ...............................................................................................................64
8.4.7. 
Reporting Pregnancy ..................................................................................................65
8.4.8. 
Reporting Overdose ....................................................................................................65
8.4.9. 
Time Period and Frequency for Collecting AE and SAE Information .......................66
8.4.10. 
Method of Detecting AEs and SAEs ..........................................................................66
8.4.11. 
Follow-up of AEs and SAEs.......................................................................................66
8.5.
Missed Assessments ...................................................................................................66
9.
STATISTICAL CONSIDERATIONS .......................................................................67
9.1.
Statistical Hypotheses .................................................................................................67
9.2.
Analysis Sets...............................................................................................................67
9.3.
Statistical Analyses.....................................................................................................67
9.3.1. 
General Considerations...............................................................................................67
9.3.1.1. 
Disposition..................................................................................................................67
9.3.2. 
Part A Pharmacokinetic Endpoints .............................................................................68
9.3.2.1. 
Primary Endpoint Analysis .........................................................................................68
9.3.2.2. 
Secondary Endpoints Analysis ...................................................................................68
9.3.2.3. 
Exploratory Endpoint Analysis...................................................................................68
9.3.3. 
Part B Pharmacokinetic Endpoints.............................................................................68
9.3.3.1. 
Primary Endpoint Analysis.........................................................................................68
9.3.3.2. 
Secondary Endpoints Analysis ...................................................................................68
9.3.3.3. 
Exploratory Endpoints Analysis.................................................................................68

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9.3.4.
Part A and B Safety Endpoints Analysis....................................................................68
9.3.5. 
Pharmacokinetic Analysis ..........................................................................................68
9.3.5.1. 
Part A Pharmacokinetic Analysis ...............................................................................69
9.3.5.2.
Part B Pharmacokinetic Analysis ...............................................................................69
9.3.6.
Part A and Part B Safety Analyses .............................................................................69
9.4.
Interim Analysis..........................................................................................................70
9.5.
Sample Size Determination ........................................................................................70
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..................................................................................................71
10.1.
Regulatory, Ethical, and Study Oversight Considerations .........................................71
10.1.1. 
Regulatory and Ethical Considerations ......................................................................71
10.1.2. 
Financial Disclosure ...................................................................................................71
10.1.3. 
Informed Consent Process..........................................................................................71
10.1.4. 
Committees Structure .................................................................................................72
10.1.5. 
Dissemination of Clinical Study Data ........................................................................72
10.1.6. 
Data Quality Assurance ..............................................................................................73
10.1.7. 
Source Documents ......................................................................................................74
10.1.8. 
Study Documentation and Data Storage.....................................................................74
10.1.8.1. 
Inspection of Records .................................................................................................74
10.1.8.2. 
Retention of Records ..................................................................................................74
10.1.9. 
Study and Site Start and Closure ................................................................................75
10.1.10. 
Publication Policy.......................................................................................................76
11.
REFERENCES ...........................................................................................................77
APPENDIX 1. CONTRACEPTIVE AND BARRIER GUIDANCE .........................................79
APPENDIX 2. GENETICS .........................................................................................................81
LIST OF TABLES 
Table 1: 
Schedule of Assessments – Part A, Period 1 ..............................................................23
Table 2: 
Schedule of Study Procedures - Part A, Period 1 .......................................................26
Table 3: 
Schedule of Assessments - Part A, Period 2...............................................................27
Table 4: 
Schedule of Study Procedures - Part A, Period 2 .......................................................30
Table 5: 
Schedule of Assessments - Part B, Period 1 ...............................................................32
Table 6: 
Schedule of Study Procedures - Part B, Period 1 .......................................................34

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Table 7: 
Schedule of Assessments - Part B, Period 2 ...............................................................35
Table 8: 
Schedule of Study Procedures - Part B, Period 2 .......................................................37
Table 9:
Study Objectives.........................................................................................................41
Table 10: Study Treatments Administered .................................................................................49
Table 11: Cocktail Drugs Administered .....................................................................................49
Table 12:
Clinical Laboratory Tests ...........................................................................................60
Table 13: Grading for Adverse Events not Covered in the NCI-CTCAE ..................................62
Table 14: Analysis Sets...............................................................................................................67
LIST OF FIGURES 
Figure 1: 
Part A Study Schema ..................................................................................................22
Figure 2: 
Part B Study Schema ..................................................................................................22
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Term 
Definition 
ADL 
activities of daily living 
AE 
adverse event 
AUC
area under the plasma concentration-time curve
AUC0-24
area under the plasma concentration-time curve from time 0 to 24 hours
AUCinf 
area under the plasma concentration-time curve from time 0 extrapolated to 
infinity 
AUClast 
area under the plasma concentration-time curve from time 0 to time of the 
last quantifiable concentration 
AUCt
area under the plasma concentration-time curve from time 0 to the time of 
the last quantifiable concentration 
AUCt M/P 
ratio of metabolite to parent AUCt corrected for molecular weight 
BMI 
body mass index 
BP 
blood pressure 
C(2hr) 
observed concentration at 2 hours 
CFR 
Code of Federal Regulations 
Clast
last measurable concentration 
CLcr
creatinine clearance 
Cmax
maximum observed plasma concentration 
Cmin 
minimum observed concentration 
COVID-19 
coronavirus disease 2019 
CP-I 
coproporphyrin I 
Cpredose
predose plasma concentration
CRU 
clinical research unit 
CV% 
percent coefficient of variation  
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DHHS 
Department of Health and Human Services
ECG 
electrocardiogram 
EMA 
European Medicines Agency 
eCRF 
electronic case report form 
ET 
early termination 
FDA 
(United States) Food and Drug Administration 

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Abbreviation or Term
Definition
FSH
follicle-stimulating hormone
GBT440 
voxelotor 
GCP 
Good Clinical Practice 
GM
geometric mean
GMR
geometric mean ration
HAV 
hepatitis A virus 
Hb-O2 
hemoglobin-oxygen 
HbS 
sickle hemoglobin 
HBsAg
hepatitis B surface antigen
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus
HR 
heart rate 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IPF 
idiopathic pulmonary fibrosis 
IRB 
institutional review board 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
MATE1 
multi-drug and toxin extrusion protein 1 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
OAT3
organic anion transporter
OATP1B1 
organic anion transporting polypeptide 1B1 
OTC 
over-the-counter 
Ph. Eur. 
European Pharmacopoeia 
PK 
pharmacokinetic(s) 
PR (interval) 
interval measured from the beginning of the P wave to the beginning of the 
QRS complex in the heart’s electrical cycle as measured by 
electrocardiogram 
PT 
prothrombin time 
PTT 
partial thromboplastin time 

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Abbreviation or Term
Definition
QRS (interval)
the interval between the Q wave and the S wave in the heart’s electrical 
cycle as measured by electrocardiogram; principal deflection in the 
electrocardiogram 
QT (interval) 
a measure of the time between the start of the Q wave and the end of the T 
wave in the heart’s electrical cycle as measured by electrocardiogram 
QTcF (interval) 
QT interval corrected for heart rate using Fridericia’s formula 
RR (interval) 
the time elapsed between 2 consecutive R waves as measured by 
electrocardiogram 
SAE 
serious adverse event 
SCD 
sickle cell disease 
SD
standard deviation
SoA 
schedule of assessments 
SUSAR 
suspected unexpected serious adverse reactions 
t½ 
terminal elimination half-life 
tmax
time at which the maximum plasma concentration was observed 
z
apparent terminal elimination rate constant 

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1. 
PROTOCOL SUMMARY 
1.1. 
Protocol Synopsis 
Study Number: GBT440-0122 
Active Substance: Voxelotor 
Study Title: A Phase 1, Open-Label, Two-Part, Fixed-Sequence, Drug-Drug Interaction Study to 
Evaluate the Effect of Voxelotor on the Pharmacokinetics of Selected CYP and Transporter Probe 
Substrates in Healthy Participants 
Brief Title: Voxelotor CYP and Transporter Cocktail Interaction Study 
Study Rationale: 
This study is comprised of 2 parts, Parts A and B. 
Part A is designed to determine whether voxelotor alters the plasma concentration profiles of the probe 
substrates for cytochrome P450s (CYPs) including CYP2B6, CYP2C8, CYP2C9, CYP2C19, and 
CYP3A4. In vitro data suggest that voxelotor may inhibit CYP2B6, CYP2C8, CYP2C9, CYP2C19, 
and CYP3A4 or induce CYP2B6. 
Part B is designed to determine whether voxelotor alters the plasma concentration profiles of the probe 
substrates for transporters including multi-drug and toxin extrusion protein 1 (MATE1), organic anion 
transporter 3 (OAT3), and organic anion transporting polypeptide 1B1 (OATP1B1). Furthermore, the 
study will assess the effect of voxelotor on plasma concentrations of coproporphyrin I (CP-I), a 
biomarker for OATP1B1 activity. In vitro data suggest that voxelotor may inhibit these transporters 
and could potentially cause drug-drug interactions (DDIs). 
The evaluation of the effects of these CYPs and transporters is relevant to the full characterization of 
the DDI potential of voxelotor. 
Number of Study Centers, Countries, and Regions: 
One site in the United States of America, North America 
Objectives and Endpoints: 
Objectives 
Primary Part A
To evaluate the effect of multiple doses of voxelotor on the plasma pharmacokinetics 
(PK) of a single dose of bupropion, repaglinide, flurbiprofen, omeprazole, and 
midazolam, which are probe substrates for CYP2B6, CYP2C8, CYP2C9, CYP2C19, 
and CYP3A4, respectively 
Exploratory Part A 
 To evaluate the effect of voxelotor on midazolam and 1-hydroxymidazolam PK 
stratified by CYP3A5 genotype
Safety Part A
 To evaluate the safety and tolerability of voxelotor when administered in combination 
with bupropion, repaglinide, flurbiprofen, omeprazole, and midazolam to healthy 
participants 

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Primary Part B 
 To evaluate the effect of multiple doses of voxelotor on the plasma PK of a single 
dose of metformin, furosemide, and rosuvastatin, probe substrates for MATE1, OAT3, 
and OATP1B1, respectively 
Exploratory Part B
To evaluate the effect of voxelotor on CP-I as a biomarker of OATP1B1 transport
Safety Part B
To evaluate the safety and tolerability of voxelotor when administered in combination 
with metformin, furosemide, and rosuvastatin to healthy participants 
Endpoints
Primary PK Part A 
 Maximum observed plasma concentration (Cmax), area under the plasma 
concentration-time curve (AUC) from time 0 to the time of the last quantifiable 
concentration (AUCt), and AUC from time 0 extrapolated to infinity (AUCinf) for 
bupropion, repaglinide, flurbiprofen, omeprazole, and midazolam 
Secondary PK Part A 
 Cmax, AUCt, and AUCinf for 6-hydroxybupropion, 5-hydroxyomeprazole, and 
1-hydroxymidazolam 
 The time that Cmax is observed (tmax), and terminal elimination half-life (t½) for 
bupropion, 6-hydroxybupropion, repaglinide, flurbiprofen, omeprazole, 
5-hydroxyomeprazole, midazolam, and 1-hydroxymidazolam in plasma. Ratio of 
metabolite to parent AUCt corrected for molecular weight (AUCt M/P) for bupropion, 
omeprazole, and midazolam
Exploratory PK Part A
 Cmax, AUCt, and AUCinf of midazolam and 1-hydroxymidazolam with and without 
voxelotor stratified by CYP3A5 genotype 
 Predose (Days 2-7, 12-13) and postdose observed concentration at 2 hours (Days 2, 4, 
6, and 12) for voxelotor in whole blood and plasma
Primary PK Part B 
 Cmax, AUCt, and AUCinf for metformin, furosemide, and rosuvastatin 
Secondary PK Part B 
 tmax and t½ for metformin, furosemide, and rosuvastatin in plasma 
 

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Exploratory PK Part B 
 Predose plasma concentration (Cpredose), Cmax, tmax, and AUC from time 0 to 24 hours 
(AUC0-24) for CP-I 
 Predose (Days 4, 5, 6) and postdose observed concentration at 2 hours (Day 4) for 
voxelotor whole blood and plasma concentration 
Safety Part A and Part B
Treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs)
Results of clinical laboratory tests, physical examination findings, and vital signs

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Overall Study Design: 
Part A 
This is an open-label, fixed-sequence, 2-period evaluation of the effect of concomitant administration 
of voxelotor on bupropion (a CYP2B6 probe substrate), repaglinide (a CYP2C8 probe substrate), 
flurbiprofen (a CYP2C9 probe substrate), omeprazole (a CYP2C19 probe substrate), and midazolam (a 
CYP3A4 probe substrate) plasma concentrations. Approximately 26 healthy participants (at least 
20% African Americans) will be enrolled and will be stratified by CYP3A5 expresser status 
(approximately 50% expressors). Treatment administration will be performed when participants are in 
a fasted state. 
Part A, Period 1: All participants will receive the following treatments: 
 
Treatment A: On Day 1, single oral doses of bupropion 150 mg, flurbiprofen 50 mg, 
omeprazole 20 mg, and midazolam 2 mg will be administered. 
 
Treatment B: On Day 4, a single oral dose of repaglinide 0.5 mg will be administered. 
Participants will be admitted to the clinical research unit (CRU) on Day -1 and will remain resident in 
the CRU until discharge on Day 5 of Period 1. 
There will be a washout (7 to 14 days) between the last probe substrate dose of Part A, Period 1 and 
dosing on Day 1 of Part A, Period 2. 
Part A, Period 2: All participants will receive the following treatments: 
 
Treatment C: On Day 1 to Day 13, oral doses of voxelotor 1500 mg will be administered 
daily for 13 days. 
 
Treatment D: On Day 2, a single oral dose of bupropion 150 mg will be administered 
immediately following voxelotor administration. 
 
Treatment E: On Day 4, single oral doses of flurbiprofen 50 mg, omeprazole 20 mg, and 
midazolam 2 mg will be administered immediately following voxelotor administration. 
 
Treatment F: On Day 6, a single oral dose of repaglinide 0.5 mg will be administered 
immediately following voxelotor administration. 
 
Treatment G: On Day 12, a single oral dose of bupropion 150 mg will be administered 
immediately following voxelotor administration. 
Participants will be admitted into the CRU on Day -1 and will remain resident in the CRU until 
discharge on Day 15 of Part A, Period 2. Subjects will return to the CRU for a Follow-up visit on 
Day 28 (± 1 day). 
Participants in Part A are ineligible to participate in Part B. 
A study schema is provided in Figure 1. 
 
Part B 
This is an open-label, fixed-sequence, 2-period evaluation of the effect of concomitant administration 
of voxelotor on metformin (a MATE1 probe substrate), furosemide (an OAT3 probe substrate), and 
rosuvastatin (an OATP1B1 probe substrate) plasma concentrations, as well as CP-I (an OATP1B1 
biomarker) plasma concentrations. Approximately 20 healthy participants (at least 20% African 
Americans) will be enrolled. Treatment administration will be performed when participants are in a 
fasted state. 

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Part B, Period 1: All participants will receive the following treatment: 
 
Treatment A: On Day 1, single oral doses of metformin hydrochloride 10 mg, furosemide 
1 mg, and rosuvastatin 10 mg will be administered. 
Participants will be admitted into the CRU on Day -1 and remain resident in the CRU until discharge 
on Day 4 of Part B, Period 1. 
There will be a washout (7 to 14 days) between the last probe substrate dose of Part B, Period 1 and 
dosing on Day 1 of Part B, Period 2. 
Part B, Period 2: All participants will receive the following treatments: 
 
Treatment B: On Day 1 to Day 3, oral doses of voxelotor 1500 mg will be administered 
daily for 3 days. 
 
Treatment C: On Day 4, single oral doses of metformin 10 mg, furosemide 1 mg, and 
rosuvastatin 10 mg will be administered immediately following a single oral dose of 
voxelotor 1500 mg. 
 
Treatment D: On Day 5, a single oral dose of voxelotor 1500 mg will be administered. 
Participants will be admitted into the CRU on Day -1 and will remain resident in the CRU until 
discharge on Day 7 of Period 2. Subjects will return to the CRU for a Follow-up visit on Day 18 
(± 1 day). 
Participants in Part B are ineligible to participate in Part A. 
A study schema is provided in Figure 2. 
Test Product, Dose, Route of Administration, and Duration of Treatment: 
In Part A, the study drugs are oral doses of voxelotor 1500 mg (Period 2 [Days 1-13]) and oral doses of 
the following cocktail drugs (probe substrates): 
 
bupropion 150 mg: Period 1 (Day 1) and Period 2 (Days 2 and 12) 
 
flurbiprofen 50 mg, omeprazole 20 mg, and midazolam 2 mg: Period 1 (Day 1) and 
Period 2 (Day 4) 
 
repaglinide 0.5 mg: Period 1 (Day 4) and Period 2 (Day 6) 
In Part B of this protocol, the study drugs are oral doses of voxelotor 1500 mg (Period 2 [Days 1-5]) 
and oral doses of the following cocktail drugs (probe substrates): 
 
metformin 10 mg, furosemide 1 mg, and rosuvastatin 10 mg: Period 1 (Day 1) and Period 2 
(Day 4) 
Duration of Study Participation: 
For Part A, participant involvement is expected to last approximately 81 days, including a 33-day 
screening period and a 48-day on study period (consisting of 2 treatment periods, a washout period 
lasting 7 to 14 days, and the Follow-up visit). 
For Part B, participant involvement is expected to last approximately 68 days, including a 33-day 
screening period and a 35-day on study period (consisting of 2 treatment periods, a washout period 
lasting 7 to 14 days, and the Follow-up visit). 

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Number of Study Participants:
Part A: Approximately 26 healthy male or female participants (at least 20% African Americans will be 
enrolled in this part). Participants will be stratified by CYP3A5 expresser status (approximately 
50% expressors) 
Part B: Approximately 20 healthy male or female participants (at least 20% African Americans will be 
enrolled in this part). 
In total, approximately 46 male or female participants will be enrolled in the study. 
Participant Selection Criteria: 
Inclusion Criteria: 
Participants must meet all inclusion criteria to be eligible for study participation. 
1.
Males o
consent. 
2. No clinically significant findings as assessed by review of medical and surgical history, vital 
signs assessments, 12-lead electrocardiograms (ECG), physical examination, and clinical 
laboratory evaluations conducted at screening and day of admission. A single repeat 
measurement/test may be performed to confirm eligibility based upon initial vital signs, ECG, 
or clinical laboratory tests abnormalities. 
3. Body mass Index (BMI) 
2
creening and 
Period 1 Day -1. 
BMI = weight (kg)/(height [m])2
4. Females of childbearing potential must agree to use a highly effective method of contraception 
or practice abstinence from 2 weeks prior to study start through 30 days after the last dose of 
study drug. A highly effective method of contraception is defined as one that results in a low 
documented failure rate when used consistently and correctly such as: condom plus use of an 
intrauterine device; intrauterine system or hormonal method of contraception (oral, injected, 
implanted, or transdermal) for their female partner; or sexual abstinence. Males must be 
surgically sterilized, or agree to practice true abstinence, or use acceptable contraception if 
sexually active with a female partner of childbearing potential, throughout the study, and for at 
least 30 days after the last dose of study drug. 
5. Males must agree not to donate sperm during the study and for 30 days following last dose of 
study drug. 
6. Participants must be able to communicate effectively in English with the study personnel. 
7. Participants must be nonsmokers, defined as having abstained from tobacco- or 
nicotine-containing products (eg, cigarettes, chewing tobacco, snuff, nicotine patches, and 
electronic cigarettes) in the 6 months prior to screening. 
8. Capable of providing signed informed consent, which includes compliance with the 
requirements and restrictions listed in the informed consent form and in this protocol. 
Exclusion Criteria: 
Participants meeting any of the following exclusion criteria will not be eligible for study enrollment: 
1. Positive pregnancy test or is lactating. 
2. History or presence of clinically significant allergic diseases (except for untreated, 
asymptomatic, seasonal allergies) at time of screening in the opinion of the Investigator. 

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3.
History or presence of conditions which, in the opinion of the Investigator, are known to 
interfere with the absorption, distribution, metabolism, or excretion of drugs, such as previous 
surgery on the gastrointestinal tract (including removal of parts of the stomach, bowel, liver, or 
pancreas). Participants who have a history of cholecystectomy and appendectomy are eligible 
for enrollment. 
4.
History of surgery or major trauma within 12 weeks of screening, or surgery planned during 
the study. 
5. Any signs and/or symptoms of acute illness at screening or Day -1. 
6. Abnormal ECG in any of the single ECGs collected at screening or Day -1, including 
QTcF > 430 msec for males and > 450 msec for females, or any cardiac rhythm other than 
sinus rhythm that is interpreted by the Investigator to be clinically significant. A single repeat 
measurement may be performed to re-evaluate ECG abnormalities (ie, to confirm that a 
participant is eligible). All the single ECGs must be not clinically significant to qualify for 
enrollment into the study. 
7. Known personal or family history of congenital long QT syndrome or known family history of 
sudden death. 
8. Resting bradycardia (HR < 45 bpm) or resting tachycardia (HR > 100 bpm) at screening or 
Day -1. A single repeat measurement may be performed to re-evaluate vital signs abnormalities 
(ie, to confirm that a participant is ineligible). Each of the readings must be not clinically 
significant to qualify for enrollment into the study. 
9. Hypertension, defined as resting (supine) systolic blood pressure (BP) > 140 mmHg or resting 
diastolic BP > 90 mmHg at screening or Day -1. A single repeat measurement may be 
performed to re-evaluate vital signs abnormalities (ie, to confirm that a participant is eligible). 
Each of the readings must be not clinically significant to qualify for enrollment into the study. 
10. History of alcohol abuse, illicit drug use, significant mental illness, or physical dependence to 
any opioid. 
11. Use of prescription medications (with the exception of contraception), any over the counter 
drugs including herbal preparations including St. John’s wort or dietary supplements, or any 
drugs that induce or inhibit study drug specific CYP450(s) within 14 days or 5 half-lives, 
whichever is longer, prior to Day -1, or requires continuing use during study participation. 
12. Consumption of more than 400 mg of caffeine (approximately 4 cups of coffee) per day or is 
unwilling to abstain from consumption of caffeine- or xanthine-containing products (eg, tea, 
coffee, chocolate, cola, etc.) from 48 hours prior to Day -1 until the end of the study 
(Follow-up visit). 
13. Unwilling to abstain from alcohol 48 hours prior to Day -1 until the end of the study 
(Follow-up visit). 
14. Consumption of Seville oranges and/or Seville orange juice, grapefruit and/or grapefruit juice 
within 14 days prior to Day -1 and is unwilling to abstain from consumption of Seville oranges 
and/or Seville orange juice, grapefruit and/or grapefruit juice until the end of the study 
(Follow-up visit). 
15. Unwilling to abstain from any strenuous physical exercise (such as weight training or aerobics) 
from 72 hours prior to Day -1 until the final PK sample is collected in the study. Participants 
are permitted to exercise following the screening visit until 72 hours prior to Day-1. 
16. Has participated in another clinical trial of an investigational drug (or medical device) within 
30 days or 5 half-lives, whichever is longer, prior to screening, or is currently participating in 
another trial of an investigational drug (or medical device). 
17. Prior exposure to voxelotor/Oxbryta® within the past month. 

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18. Clinically significant anemia, or has donated blood or blood components exceeding 400 mL 
within 90 days prior to screening. 
19. Positive urine test for drugs of abuse, alcohol, or cotinine at screening or Day -1. 
20. Positive screen for human immunodeficiency virus 1 (HIV-1) and HIV -2 antibodies, hepatitis 
A virus antibody, hepatitis B surface antigen, or hepatitis C virus antibody. 
21. Positive COVID-19 test at admit to CRU. 
22. Poor venous access as determined by the Investigator or study staff. 
23. Involved in the planning or conduct of this study. 
24. Any other condition or prior therapy that, in the Investigator’s opinion, would confound or 
interfere with the evaluation of safety, tolerability, or PK of the study drug, interfere with study 
compliance, or preclude informed consent. 
Part A only
25. History or presence of contraindication to the use of midazolam including but not limited to 
hypersensitivity to benzodiazepines or formulation ingredients, acute narrow-angle glaucoma, 
myasthenia gravis, severe respiratory insufficiency, or sleep apnea syndrome. 
26. Poor CYP2C9 or CYP2C19 metabolizer (determined at screening or available historical data). 
27. Participant has an allergy or sensitivity to voxelotor, bupropion, repaglinide, flurbiprofen, 
omeprazole, or midazolam. 
Part B only 
28. History of statin-induced myopathy or serious hypersensitivity reaction to other 
3-hydroxy-3-methylglutaryl coenzyme A, reductase inhibitors (statins). 
29. Heterozygous or homozygous variant allele carriers of SLCO1B1 (c.521T>C, rs4149056), 
encoding the hepatic uptake transporter OATP1B1, resulting in decreased transport activity. 
30. Participant has an allergy or sensitivity to voxelotor, metformin, furosemide, or rosuvastatin. 
Criteria for Evaluation:  
Pharmacokinetics: 
Part A 
 
Whole blood and plasma concentrations of voxelotor and plasma concentrations of 
bupropion, 6-hydroxybupropion, repaglinide, flurbiprofen, omeprazole, 
5-hydroxyomeprazole, midazolam, and 1-hydroxymidazolam will be determined using 
validated assays. 
 
Plasma PK samples following dosing of flurbiprofen, omeprazole, and midazolam will be 
collected predose and at approximately 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours 
postdose during Part A, Period 1 on Day 1 and during Period 2 on Day 4. 
 
Plasma PK samples following dosing of bupropion will be collected predose and at 
approximately 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours postdose during Part A, 
Period 1 on Day 1 and during Period 2 on Days 2 and 12. 
 
Plasma PK samples following dosing of repaglinide will be collected predose and at 
approximately 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose during Part A, Period 1 
on Day 4 and during Period 2 on Day 6. 

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Whole blood and plasma concentrations of voxelotor will be measured. Whole blood and 
plasma samples will be collected during Part A, Period 2 only on the following days: 
Days 2-7 and Days 12-13: predose
 
Days 2, 4, 6, and 12: 2 hours postdose 
Part B
 
Plasma concentrations of metformin, furosemide, and rosuvastatin will be measured. 
Plasma PK samples will be collected predose and at approximately 0.5, 1, 1.5, 2, 2.5, 3, 4, 
5, 6, 8, 10, 12, 24, and 48 hours postdose starting on Day 1 (Part B, Period 1) and Day 4 
(Part B, Period 2). Additionally, PK samples of rosuvastatin will be collected up to 
72 hours postdose on Day 1 (Part B, Period 1) and on Day 4 (Part B, Period 2). 
 
Whole blood and plasma concentrations of voxelotor will be measured. Whole blood and 
plasma samples will be collected during Part B, Period 2 only on the following days: 
 
Days 4, 5, and 6: predose 
 
Day 4: 2 hours postdose 
 
Plasma concentrations of CP-I will be measured. Samples will be collected predose and at 
approximately 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 hours postdose on Day 1 
(Part B, Period 1) and Day 4 (Part B, Period 2).  
Part A and B Safety: 
Participants will be monitored for adverse events (AE) from the time the informed consent is signed 
through Follow-up visit (Day 28 [Part A, Period 2] or Day 18 [Part B, Period 2]). Severity of AEs will 
be determined based on the Common Terminology Criteria for Adverse Events, Version 5.0. 
Safety assessments also include physical examinations, vital signs measurements (blood pressure, heart 
rate, respiratory rate, and oral temperature), oxygen saturation (Part A only), clinical laboratory 
evaluations (hematology, coagulation, serum chemistry, and urinalysis), pregnancy tests as appropriate, 
and concomitant medications. 
Statistical Methods:
Sample Size: 
Part A 
There will be 26 participants enrolled in Part A. A previous DDI cocktail study (GBT440-003) used 
several probe substrates including midazolam and omeprazole that are common with the current 
protocol. It was shown that voxelotor, at two 900 mg/day doses followed by a 600 mg/day dose, 
significantly decreased midazolam elimination in 24 healthy participants but had no effect on the PK of 
omeprazole. Thus, we anticipate that an approximately similar number of healthy participants (n = 24, 
adjusting for a potential 10% dropout rate, out of 26 enrolled participants) would facilitate 
characterization of the magnitude of DDI when 1500 mg voxelotor is administered for 4 days. 
 
Part B 
There will be 20 participants enrolled in Part B. Rosuvastatin is used as the probe substrate of choice 
for sample size estimation because robust information on the intrasubject variability is lacking at 
sub-clinical doses of metformin and furosemide. A previous study indicated an intrasubject coefficient 
of variation (intraCV%) of approximately 12.3% for rosuvastatin AUC0-t and 21.3% for rosuvastatin 
Cmax. Using the precision method and assuming the true GMR (geometric mean ratio) = 1, a sample 

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size of 17 subjects will provide the GMR of Cmax, given alone versus given with voxelotor, to be within 
80% and 125% of the true value, with 90% confidence. Thus, approximately 17 subjects (adjusting for 
a potential 10% dropout rate, out of approximately 20 enrolled participants) will be sufficient to 
provide adequate insight into the potential effect of voxelotor on the PK of rosuvastatin. 
Pharmacokinetic Analysis: 
Whole blood and plasma concentrations of voxelotor (whole blood applicable only for voxelotor) and 
all probe substrates (alone and probe substrate administered with voxelotor) will be listed and 
summarized by dosing regimen and nominal sampling time with the number of nonmissing 
observations, arithmetic mean, standard deviation (SD), percent coefficient of variation (CV%), 
geometric mean (GM), geometric CV%, median, minimum, and maximum values at each sampling 
time. 
Part A 
Plasma PK parameters will be listed for bupropion, 6-hydroxybupropion, repaglinide, flurbiprofen, 
omeprazole, 5-hydroxyomeprazole, midazolam, and 1-hydroxymidazolam. 
Summary statistics of PK parameters (primary and secondary) will be presented for each treatment 
including mean, GM, SD, CV%, geometric CV%, median, and range. Whole blood and plasma PK 
parameters will be listed for voxelotor.
In addition, Cmax, AUCt, and AUCinf of midazolam and 1-hydroxymidazolam with and without 
voxelotor will be summarized by CYP3A5 genotype. 
To assess the effect of voxelotor on the PK of the probe substrates and their metabolites, a linear mixed 
effect model will be fitted to the log-transformed values of Cmax, AUCt, and AUCinf. The model will 
include treatment as a fixed effect and participant as a random effect. Point estimates and 
90% confidence intervals for treatment differences (probe substrate alone versus probe substrate 
administered with voxelotor) on the log scale will be exponentiated to obtain estimates for GM ratios 
on the original scale. For bupropion, both Day 2 and Day 12 in Period 2 will be compared separately to 
Period 1 data. 
Part B 
Plasma PK parameters will be listed for metformin, furosemide, rosuvastatin, and CP-I. Summary 
statistics of PK parameters (primary and secondary) will be presented for each treatment including 
mean, GM, SD, CV%, geometric CV%, median, and range. Whole blood and plasma PK parameters 
will be listed for voxelotor. 
To assess the effect of voxelotor on the PK of the probe substrates, a linear mixed effect model will be 
fitted to the log-transformed values of Cmax, AUCt, and AUCinf. The model will include treatment as a 
fixed effect and participant as a random effect. Point estimates and 90% confidence intervals for 
treatment differences (probe substrate alone versus probe substrate administered with voxelotor) on the 
log scale will be exponentiated to obtain estimates for GM ratios on the original scale. 
Safety Analysis Part A and Part B 
Demographics (age, sex, ethnicity, and race) and baseline characteristics (height, weight, and BMI) will 
be summarized by part and overall. Medical history will be provided in a data listing. 
All safety data will be presented in listings by part. Descriptive summaries will be provided for AEs, 
clinical laboratory tests (hematology, serum chemistry, and coagulation), and vital signs (heart rate, 
blood pressure, respiratory rate, and oral temperature). Urinalysis laboratory tests, concomitant 
medications, and physical examinations will be presented in data listings only. 
The number and percentage of participants reporting any treatment-emergent AE will be tabulated by 

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system organ class and preferred term (coded using Medical Dictionary for Regulatory Activities). 
Treatment-emergent AEs will be further classified by severity and relationship to treatment. 

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1.2.
Study Schema
Figure 1:
Part A Study Schema
Figure 2:
Part B Study Schema

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1.3.
Schedules of Assessments and Procedures
Table 1:
Schedule of Assessments – Part A, Period 1
Assessment 
Screening 
(Days -35 
to -2) 
Part A, Period 1 
Day -1 
Admission 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 / 
Discharge 
Informed Consent 
X 
 
 
 
 
 
 
Review Inclusion/Exclusion criteria
X
X
Medical and Surgical History 
X 
X a
 
 
 
 
 
Height/Weight/BMI b
X
X
Vital Signs c 
X 
X 
X 
X 
X 
X 
X 
Pulse Oximetry d
X
ECG (12-lead) e 
X 
X 
 
 
 
 
 
Physical Examination f
X
X
X
CYP2C9, CYP2C19, and CYP3A5 
genotyping 
X 
 
 
 
 
 
 
COVID-19 Test g
X
Pregnancy Test (all females) h
X
X
FSH (postmenopausal females only) i 
X
Hematology, Serum Chemistry, and 
Urinalysis 
X 
X 
 
X 
 
 
X 
Coagulation Panel (PT, PTT, INR)
X
X
Creatinine Clearance j
X
X
Serology Panel (Hepatitis A, B, C, and 
HIV) 
X 
 
 
 
 
 
 

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Assessment
Screening 
(Days -35 
to -2)
Part A, Period 1 
Day -1
Admission 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 / 
Discharge 
Screening for Drugs of Abuse, Alcohol, 
and Cotinine 
X 
X 
 
 
 
 
 
Overnight Stay 
 
X 
X 
X 
X 
X 
 
Bupropion, Flurbiprofen, Omeprazole, 
and Midazolam Administration k
 
 
X 
 
 
 
 
Flurbiprofen, Omeprazole, 
5-hydroxyomeprazole, Midazolam, and 
1-hydroxymidazolam PK Sampling 
(Plasma) l
 
 
X 
X
X
Bupropion, 6-hydroxybupropion PK 
Sampling (Plasma) l 
 
 
X 
X 
X 
X 
 
Repaglinide Administration k
X
Repaglinide PK Sampling (Plasma) l 
 
 
 
 
 
X 
X 
Concomitant Medications
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
Abbreviations: BMI = body mass index; CLcr = creatinine clearance; COVID-19 = coronavirus disease; CYP = cytochrome P450; ECG = electrocardiogram; 
FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; INR = international normalized ratio; PK = pharmacokinetic; PT = prothrombin 
time; PTT = partial thromboplastin time. 
a. 
Any updates to medical and surgical history will be recorded. 
b. Height will be performed at screening only. BMI will be calculated using the height obtained at screening. 
c. 
Vital signs (heart rate, blood pressure, respiratory rate, and oral temperature) will be measured after a participant has rested at least 5 minutes in the 
supine position. Vital signs will be collected as outlined in Table 2. 
d. Oxygen saturation will be measured by pulse oximetry prior to and following cocktail administration as outlined in Table 2. 
e. 
ECGs (12-lead) will be recorded after a participant has rested at least 5 minutes in the supine position. 
f. 
Physical examinations after the screening visit may be targeted at the discretion of the Investigator, focusing on specific organ systems, abnormalities 
identified on the screening examination, and abnormalities related to adverse events and screening for bupropion toxicity. 
g. Additional COVID-19-testing or procedures may be implemented based on the prevailing situation during study conduct, at the Investigator’s 
discretion. Any procedure implemented will be in accordance with the local regulations and shall be documented appropriately. 

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h. A serum pregnancy test will be conducted at screening and urine pregnancy test at Day -1. A serum pregnancy test will also be conducted for 
confirmation in the event of a positive urinary pregnancy test result. 
i. 
Postmenopausal is defined as having amenorrhea for 12 consecutive months or surgically sterile. 
j. 
CLcr will be calculated using the Cockcroft-Gault formula (CLcr [mL/min] = [(140-age [years]) × weight (kg) × (0.85 for female 
participants)]/[72 × serum creatinine (mg/dL)]). 
k. Participants must remain upright or semi-recumbent (head of bed > 45 degrees) for 4 hours postdose on days of probe substrate administration. 
l. 
Blood samples for plasma PK analysis of bupropion, 6-hydroxybupropion, flurbiprofen, omeprazole, 5-hydroxyomeprazole, midazolam, 
1-hydroxymidazolam, and repaglinide will be collected as outlined in Table 2. 
NOTE: If multiple postdose procedures are required to be conducted at the same nominal time point, the timing of PK blood sample collections will take priority 
over all other scheduled activities except for dosing. In practice, the following is the order of priority: (1) PK blood sampling; (2) clinical laboratory tests 
sampling; (3) ECG recording; (4) vital signs and pulse oximetry assessments; (5) physical examination and weight measurements. Electrocardiograms and vital 
signs may be conducted up to 15 and 10 minutes, respectively, prior to the nominal time to minimize the potential autonomic effects of blood draws on these 
measurements. 

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Table 2:
Schedule of Study Procedures - Part A, Period 1
Study 
Day 
Time 
Relative to 
Dosing a 
-Vital Signs 
Timepoints b
Time Relative to 
Dosing a
-Pulse Oximetry 
Timepoints c
Time Relative to 
Flurbiprofen, Omeprazole, 
Midazolam Dose a 
-PK Sampling Timepoints d
Time Relative to 
Bupropion a
-PK Sampling 
Timepoints e
Time Relative to 
Repaglinide Dose a 
-PK Sampling 
Timepoints f
1
0, 4 
0, 0.5, 1, 1.5, 2, 3, 4 
0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 
0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 
12 
 
2 
24 
 
24 
24 
 
3
48
48
48
4 
0, 4 
 
 
72 
0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 
12 
5 / 
Discharge 
24 
 
 
 
24 
Abbreviations: PK = pharmacokinetic.
a. 
Time relative to dosing in hours. 
b. Vital signs (heart rate, blood pressure, respiratory rate, and oral temperature) will be measured after a participant has rested at least 5 minutes in the 
supine position. Predose is at timepoint 0. 
c. 
Oxygen saturation will be measured by pulse oximetry. Predose is at timepoint 0. 
d. PK samples are to determine plasma flurbiprofen, omeprazole, 5-hydroxyomeprazole, midazolam, and 1-hydroxymidazolam concentrations. Predose PK 
blood sample (timepoint 0) will be collected within 60 minutes prior to dosing. Collection windows of ± 5 minutes through 8-hour sampling and 
± 15 minutes for samples drawn thereafter are acceptable. 
e. 
PK samples are to determine plasma bupropion and 6-hydroxybupropion concentrations. Predose PK blood sample (timepoint 0) will be collected 
within 60 minutes prior to dosing. Collection windows of ± 5 minutes through 8-hour sampling and ± 15 minutes for samples drawn thereafter are 
acceptable. 
f. 
PK samples are to determine plasma repaglinide concentrations. Predose PK blood sample (timepoint 0) will be collected within 60 minutes prior to 
dosing. Collection windows of ± 5 minutes through 8-hour sampling and ± 15 minutes for samples drawn thereafter are acceptable. 
NOTE: If multiple postdose procedures are required to be conducted at the same nominal time point, the timing of PK blood sample collections will take priority 
over all other scheduled activities except for dosing. In practice, the following is the order of priority: (1) PK blood sampling; (2) clinical laboratory tests 
sampling; (3) vital signs and pulse oximetry assessments; (4) physical examination and weight measurements. Vital signs may be conducted up to 10 minutes, 
prior to the nominal time to minimize the potential autonomic effects of blood draws on these measurements 

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Table 3:
Schedule of Assessments - Part A, Period 2
Assessment
Day
Part A, Period 2 
Follow-up / 
ET 
-1
Admit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 
Day 15 / 
Discharge 
28
(± 1 day) 
Review Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight/BMI a
X
X
Vital Signs b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse Oximetry 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ECG (12-lead) c
X
Physical Examination d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
COVID-19 e 
X
Urine Pregnancy Test (all 
females) f
X
 
X
Hematology, Serum 
Chemistry, and Urinalysis 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
Coagulation Panel (PT, PTT, 
INR) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Screening for Drugs of Abuse, 
Alcohol, and Cotinine 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Overnight Stay
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Voxelotor Administration g
X
X
X
X
X
X
X
X
X
X
X
X
X
Voxelotor PK Sampling 
(Whole Blood and Plasma) i
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
 
 
 
Bupropion Administration g, h
X
X

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Assessment 
Day 
Part A, Period 2 
Follow-up / 
ET 
-1
Admit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 
Day 15 / 
Discharge 
28
(± 1 day) 
Bupropion and 
6-hydroxybupropion PK 
Sampling (Plasma) i 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
 
Flurbiprofen, Omeprazole, and 
Midazolam Administration h
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Flurbiprofen, Omeprazole, 
5-hydroxyomeprazole, 
Midazolam, and 
1-hydroxymidazolam PK 
Sampling i
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Repaglinide Administration g, h
X
Repaglinide PK Sampling 
(Plasma) i
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviations: BMI = body mass index; COVID-19 = coronavirus disease; ECG = electrocardiogram; ET = early termination; INR = international normalized 
ratio; PK = pharmacokinetic; PT = prothrombin time; PTT = partial thromboplastin time. 
a. 
BMI will be calculated using the height obtained at screening. 
b. Vital signs (heart rate, blood pressure, respiratory rate, and oral temperature) will be measured after the participant has rested at least 5 minutes in the 
supine position. Vital signs will be measured following dosing and will be collected as outlined in Table 4. 
c. 
ECGs (12-lead) will be collected after the participant has rested at least 5 minutes in the supine position. 
d. Physical examinations after the screening visit may be targeted at the discretion of the Investigator, focusing on specific organ systems, abnormalities 
identified on the screening examination, and abnormalities related to adverse events and screening for bupropion toxicity. 
e. 
Additional COVID-19-testing or procedures may be implemented based on the prevailing situation during study conduct, at the Investigator’s 
discretion. Any procedure implemented will be in accordance with the local regulations and shall be documented appropriately. 
f. 
A urine pregnancy test will be conducted. A serum pregnancy test will also be conducted for confirmation in the event of a positive urinary pregnancy 
test result. 
g. On days when voxelotor is administered with a probe substrate, voxelotor will be administered first and will be immediately followed by the probe 
substrate administration. 

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h. Participants must remain upright or semi-recumbent (head of bed > 45 degrees) for 4 hours postdose on days of probe substrate administration. 
i. 
PK samples will be collected as outlined in Table 4. 
NOTE: If multiple postdose procedures are required to be conducted at the same nominal time point, the timing of PK blood sample collections will take priority 
over all other scheduled activities except for dosing. In practice, the following is the order of priority: (1) PK blood sampling; (2) clinical laboratory tests 
sampling; (3) ECG recording; (4) vital signs; (5) physical examination and weight measurements. Electrocardiograms and vital signs may be conducted up to 
15 and 10 minutes, respectively, prior to the nominal time to minimize the potential autonomic effects of blood draws on these measurements. 
 
 

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Table 4:
Schedule of Study Procedures - Part A, Period 2
Study Day
Time 
Relative to 
Dosing a 
-Vital Signs 
Timepoints b
Time Relative 
to Dosing a 
-Pulse 
Oximetry 
Timepoints c
Time Relative 
to Voxelotor 
Dose a 
-PK Sampling 
Timepoints d
Time Relative to 
Bupropion Dose a 
-PK Sampling 
Timepoints e
Time Relative to 
Flurbiprofen, 
Omeprazole, 
Midazolam Dose a 
-PK Sampling 
Timepoints f
Time Relative to 
Repaglinide Dose a
-PK Sampling 
Timepoints g
1
0, 4
2 
0, 4 
 
0, 2 
0, 0.5, 1, 1.5, 2, 3, 4, 
6, 8, 12 
 
 
3 
0, 4 
 
0 
24 
 
 
4 
0, 4 
0, 0.5, 1, 1.5, 2, 
3, 4 
0, 2 
48 
0, 0.5, 1, 1.5, 2, 3, 4, 6, 
8, 12 
 
5
0, 4
0
72
24
6
0, 4 
 
0, 2 
 
48 
0, 0.5, 1, 1.5, 2, 3, 4, 6, 
8, 12 
7 
0, 4 
 
0 
 
 
24 
8
0, 4
9
0, 4
10
0, 4
11
0, 4
12
0, 4 
 
0, 2 
0, 0.5, 1, 1.5, 2, 3, 4, 
6, 8, 12 
 
 
13
0, 4
0
24
14
24
48
15 / Discharge
48
72
Abbreviations: PK = pharmacokinetic.
a. 
Time relative to dosing in hours. 

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b. Vital signs (heart rate, blood pressure, respiratory rate, and oral temperature) will be measured after a participant has rested at least 5 minutes in the 
supine position. Predose (timepoint 0) will be collected within 20 minutes prior to dosing. 
c. 
Oxygen saturation will be measured by pulse oximetry. Predose is at timepoint 0. 
d. On days when voxelotor is administered with a probe substrate, voxelotor will be administered first and will be immediately followed by the probe 
substrate administration. PK samples are to determine whole blood and plasma of voxelotor. Predose PK blood samples (timepoint 0) will be collected 
within 15 minutes prior to dosing. Collection windows of ± 5 minutes are acceptable. 
e. 
PK samples are to determine plasma bupropion and 6-hydroxybupropion concentrations. Predose PK blood samples (timepoint 0) will be collected 
within 15 minutes prior to dosing. Collection windows of ± 5 minutes through 8-hour sampling and ± 15 minutes for samples drawn thereafter are 
acceptable. 
f. 
PK samples are to determine plasma flurbiprofen, omeprazole, 5-hydroxyomeprazole, midazolam, and 1-hydroxymidazolam concentrations. Predose PK 
blood sample (time point 0) will be collected within 15 minutes prior to dosing. Collection windows of ± 5 minutes through 8-hour sampling and 
± 15 minutes for samples drawn thereafter are acceptable. 
g. PK samples are to determine plasma repaglinide concentrations. Predose PK blood sample (timepoint 0) will be collected within 15 minutes prior to 
dosing. Collection windows of ± 5 minutes through 8-hour sampling and ± 15 minutes for samples drawn thereafter are acceptable. 
NOTE: If multiple postdose procedures are required to be conducted at the same nominal time point, the timing of PK blood sample collections will take priority 
over all other scheduled activities except for dosing. In practice, the following is the order of priority: (1) PK blood sampling; (2) clinical laboratory tests 
sampling; (3) vital signs and pulse oximetry assessments; (4) physical examination and weight measurements. Vital signs may be conducted up to 10 minutes, 
prior to the nominal time to minimize the potential autonomic effects of blood draws on these measurements. 

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Table 5:
Schedule of Assessments - Part B, Period 1
Assessment 
Screening 
(Day -35 to 
Day -2) 
Part B, Period 1 
Day -1 
Admission 
Day 1 
Day 2 
Day 3 
Day 4 / 
Discharge 
Informed Consent
X
Review Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
Medical and Surgical History
X
X a
Height/Weight/BMI b 
X 
X 
 
 
 
 
Vital Signs c
X
X
X
X
X
X
ECG (12-lead) d 
X 
X 
 
 
 
 
Physical Examination e
X
X
X
SLCO1B1 Genotyping 
X 
 
 
 
 
 
COVID-19 Test f
X
Pregnancy Test (all females) g 
X
X
FSH (postmenopausal females only) h
X
Hematology, Serum Chemistry, and 
Urinalysis 
X 
X 
 
X 
X 
 
Coagulation Panel (PT, PTT, INR)
X
X
Creatinine Clearance i
X
X
Serology Panel (Hepatitis A, B, C, and HIV)
X
Screening for Drugs of Abuse, Alcohol, and 
Cotinine 
X 
X 
 
 
 
 
Overnight Stay
X
X
X
X
Cocktail Administration j
X

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Assessment
Screening 
(Day -35 to 
Day -2)
Part B, Period 1 
Day -1
Admission 
Day 1 
Day 2 
Day 3 
Day 4 / 
Discharge 
Metformin and Furosemide PK Sampling 
(Plasma) k
 
 
X 
X 
X 
 
Rosuvastatin PK Sampling (Plasma) k 
 
 
X 
X 
X 
X 
Plasma CP-I Sampling k
X
X
Concomitant Medications 
X 
X 
X 
X 
X 
X 
Adverse Events
X
X
X
X
X
X
Abbreviations: BMI = body mass index; CLcr = creatinine clearance; COVID-19 = coronavirus disease; CP-I = coproporphyrin I; ECG = electrocardiogram; 
FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; INR = international normalized ratio; PK = pharmacokinetic; PT = prothrombin 
time; PTT = partial thromboplastin time. 
a. 
Any updates to medical and surgical history will be recorded. 
b. Height will be performed at screening only. BMI will be calculated using the height obtained at screening. 
c. 
Vital signs (heart rate, blood pressure, respiratory rate, and oral temperature) will be measured after a participant has rested at least 5 minutes in the 
supine position. Vital signs will be collected as outlined in Table 6. 
d. ECGs (12-lead) will be recorded after a participant has rested at least 5 minutes in the supine position. 
e. 
Physical examinations after the screening visit may be targeted at the discretion of the Investigator, focusing on specific organ systems, abnormalities 
identified on the screening examination, and abnormalities related to adverse events and screening for metformin, furosemide, and rosuvastatin toxicity. 
f. 
Additional COVID-19-testing or procedures may be implemented based on the prevailing situation during study conduct, at the Investigator’s 
discretion. Any procedure implemented will be in accordance with the local regulations and shall be documented appropriately. 
g. A serum pregnancy test will be conducted at screening and urine pregnancy test at Day-1. A serum pregnancy test will also be conducted for 
confirmation in the event of a positive urinary pregnancy test result. 
h. Postmenopausal is defined as having amenorrhea for 12 consecutive months or surgically sterile. 
i. 
CLcr will be calculated using the Cockcroft-Gault formula (CLcr [mL/min] = [(140-age [years]) × weight (kg) × (0.85 for female 
participants)]/[72 ×serum creatinine (mg/dL)]). 
j. 
Cocktail includes metformin 10 mg, furosemide 1 mg, and rosuvastatin 10 mg. Participants must remain upright or semi-recumbent (head of 
bed > 45 degrees) for 4 hours postdose on days of probe substrate administration. 
k. Blood samples for plasma CP-I and plasma PK analysis of metformin, furosemide, and rosuvastatin will be collected as outlined in Table 6. 
NOTE: If multiple postdose procedures are required to be conducted at the same nominal time point, the timing of PK blood sample collections will take priority 
over all other scheduled activities except for dosing. In practice, the following is the order of priority: (1) PK blood sampling; (2) clinical laboratory tests 
sampling; (3) ECG recording; (4) vital signs; (5) physical examination and weight measurements. Electrocardiograms and vital signs may be conducted up to 
15 and 10 minutes, respectively, prior to the nominal time to minimize the potential autonomic effects of blood draws on these measurements. 

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Table 6:
Schedule of Study Procedures - Part B, Period 1
Study Day 
Time Relative to 
Dosing a 
-Vital Signs 
Timepoints b
Time Relative to Metformin 
and Furosemide Dose a 
-PK Sampling Timepoints c
Time Relative to Rosuvastatin 
Dose a 
-PK Sampling Timepoints c 
Time Relative to Dosing a
-Plasma CP-I Sampling 
Timepoints d
1
0, 4 
0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 
10, 12 
0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 
10, 12 
0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 
10, 12 
2 
24 
24 
24 
24 
3
48
48
48
4 / 
Discharge 
72 
 
72 
 
Abbreviations: CP-I = coproporphyrin I; PK = pharmacokinetic. 
a. 
Time relative to dosing in hours. 
b. Vital signs (heart rate, blood pressure, respiratory rate, and oral temperature) will be measured after a participant has rested at least 5 minutes in the 
supine position. Predose is at timepoint 0. 
c. 
PK samples are to determine plasma metformin, furosemide, and rosuvastatin concentrations. Predose PK blood sample (timepoint 0) will be collected 
within 60 minutes prior to dosing. Collection windows of ± 5 minutes through 8-hour sampling and ± 15 minutes for samples drawn thereafter are 
acceptable. 
d. PK samples are to determine plasma concentrations of CP-I. Predose PK blood sample (timepoint 0) will be collected within 60 minutes prior to dosing. 
Collection windows of ± 5 minutes through 8-hour sampling and ± 15 minutes for samples drawn thereafter are acceptable. 
NOTE: If multiple postdose procedures are required to be conducted at the same nominal time point, the timing of PK blood sample collections will take priority 
over all other scheduled activities except for dosing. In practice, the following is the order of priority: (1) PK blood sampling; (2) clinical laboratory tests 
sampling; (3) vital signs and pulse oximetry assessments; (4) physical examination and weight measurements. Vital signs may be conducted up to 10 minutes, 
prior to the nominal time to minimize the potential autonomic effects of blood draws on these measurements. 

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Table 7:
Schedule of Assessments - Part B, Period 2
 
Part B, Period 2 
Follow-
up / 
ET 
Assessment
Day -1 
Admit
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7 / 
Discharge
Day 18 
(± 1 day)
Review Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
Weight/BMI a
X
X
Vital Signs b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG (12-lead) c
X
Physical Examination d
X
X
COVID-19 Test e
X
Urine Pregnancy Test (all females) f 
X
X
Hematology, Serum Chemistry, and Urinalysis
X
X
X
X
X
Coagulation Panel (PT, PTT, INR)
X
X
Screening for Drugs of Abuse, Alcohol, and Cotinine
X
 
X
Overnight Stay
X
X
X
X
X
X
X
Voxelotor Administration
X
X
X
X g
X
Voxelotor PK Sampling (Whole Blood and Plasma) h
X
X
X
Cocktail Administration i
X
Metformin and Furosemide PK Sampling (Plasma) h
X
X
X
Rosuvastatin PK Sampling (Plasma) h
X
X
X
X
Plasma CP-I Sampling j
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X

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Abbreviations: BMI = body mass index; COVID-19 = coronavirus disease; CP-I = coproporphyrin I; ECG = electrocardiogram; ET = early termination; 
INR = international normalized ratio; PK = pharmacokinetic; PT = prothrombin time; PTT = partial thromboplastin time. 
a. 
BMI will be calculated using the height obtained at screening. 
b. Vital signs (heart rate, blood pressure, respiratory rate, and oral temperature) will be measured after the participant has rested at least 5 minutes in the 
supine position. Vital signs will be measured and collected as outlined in Table 8. 
c. 
ECGs (12-lead) will be collected after the participant has rested at least 5 minutes in the supine position. 
d. Physical examinations after the screening visit may be targeted, focusing on specific organ systems, abnormalities identified on the screening and 
abnormalities related to adverse events and screening for metformin, furosemide, and rosuvastatin toxicity. 
e. 
Additional COVID-19-testing or procedures may be implemented based on the prevailing situation during study conduct, at the Investigator’s 
discretion. Any procedure implemented will be in accordance with the local regulations and shall be documented appropriately. 
f. 
A urine pregnancy test will be conducted. A serum pregnancy test will also be conducted for confirmation in the event of a positive urinary pregnancy 
test result. 
g. Voxelotor will be administered first and immediately followed by administration of metformin, furosemide, and rosuvastatin.  
h. Blood samples for voxelotor, metformin, furosemide, and rosuvastatin PK analysis will be collected as outlined in Table 8. 
i. 
Cocktail includes metformin 10 mg, furosemide 1 mg, and rosuvastatin 10 mg. Participants must remain upright or semi-recumbent (head of 
bed > 45 degrees) for 4 hours postdose on days of probe substrate administration. 
j. 
Blood samples for plasma CP-I assessment will be collected as outlined in Table 8. 
NOTE: If multiple postdose procedures are required to be conducted at the same nominal time point, the timing of PK blood sample collections will take priority 
over all other scheduled activities except for dosing. In practice, the following is the order of priority: (1) PK blood sampling; (2) clinical laboratory tests 
sampling; (3) ECG recording; (4) vital signs; (5) physical examination and weight measurements. Electrocardiograms and vital signs may be conducted up to 
15 and 10 minutes, respectively, prior to the nominal time to minimize the potential autonomic effects of blood draws on these measurements. 

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Table 8:
Schedule of Study Procedures - Part B, Period 2
Study Day 
Time 
Relative to 
Dosing a 
-Vital Signs 
Timepoints b
Time Relative to 
Voxelotor Dose a
-PK Sampling 
Timepoints c
Time Relative to Metformin 
and Furosemide Dose a 
-PK Sampling Timepoints d
Time Relative to 
Rosuvastatin Dose a 
-PK Sampling 
Timepoints d
Time Relative to Dosing a 
-Plasma CP-I Sampling 
Timepoints e
1
0
2 
0 
 
 
 
3
0, 4
4 
0, 4 
0, 2 
0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 
8, 10, 12 
0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 
6, 8, 10, 12 
0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 
6, 8, 10, 12 
5
24
0
24
24
24
6 
48 
0 
48 
48
 
7 / 
Discharge 
72 
 
 
72 
 
Abbreviations: CP-I = coproporphyrin I; PK = pharmacokinetic.
a. 
Time relative to dosing in hours. 
b. Vital signs (heart rate, blood pressure, respiratory rate, and oral temperature) will be measured after a participant has rested at least 5 minutes in the 
supine position. Predose (timepoint 0) will be collected within 20 minutes prior to dosing. 
c. 
Voxelotor will be administered first and will be immediately followed by administration of metformin, furosemide, and rosuvastatin. PK samples are to 
determine whole blood and plasma of voxelotor. Predose PK blood samples (timepoint 0) will be collected within 15 minutes prior to dosing. Collection 
windows of ± 5 minutes are acceptable. 
d. PK samples are to determine plasma metformin, furosemide, and rosuvastatin concentrations. Predose PK blood sample (timepoint 0) will be collected 
within 15 minutes prior to dosing. Collection windows of ± 5 minutes through 8-hour sampling and ± 15 minutes for samples drawn thereafter are 
acceptable. 
e. 
PK samples are to determine plasma concentrations of CP-I. Predose PK blood sample (timepoint 0) will be collected within 15 minutes prior to dosing. 
Collection windows of ± 5 minutes through 8-hour sampling and ± 15 minutes for samples drawn thereafter are acceptable. 
NOTE: If multiple postdose procedures are required to be conducted at the same nominal time point, the timing of PK blood sample collections will take priority 
over all other scheduled activities except for dosing. In practice, the following is the order of priority: (1) PK blood sampling; (2) clinical laboratory tests 
sampling; (3) vital sign and pulse oximetry assessments; (4) physical examination and weight measurements. Vital signs may be conducted up to 10 minutes, 
prior to the nominal time to minimize the potential autonomic effects of blood draws on these measurements. 

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2. 
INTRODUCTION 
Voxelotor (formerly known as GBT440) is a small molecule inhibitor of HbS polymerization, 
which allosterically modifies Hb-O2 affinity and is being developed by the Sponsor for the 
treatment of SCD. 
Voxelotor increases Hb-O2 affinity and stabilizes hemoglobin in the oxyhemoglobin state,
thereby inhibiting the underlying mechanism of disease in SCD: the polymerization of HbS in 
red blood cells (Oksenberg et al, 2016). By addressing this underlying mechanism of SCD, 
voxelotor constitutes a disease-modifying therapy, improving anemia, and reducing hemolysis, 
and has the potential to reduce the end-organ damage resulting from hemolytic anemia. 
On 25 November 2019, accelerated approval the US FDA was granted for voxelotor, now known 
by the trade name Oxbryta® for the treatment of adolescents and adults with SCD 12 years of age 
and older. On 17 December 2021, accelerated approval was expanded to pediatric patients down 
to 4 years of age. Continued approval for this indication may be contingent upon verification and 
description of clinical benefit in confirmatory trial(s). Oxbryta also received marketing 
authorization valid throughout the European Union on 14 February 2022 for the treatment of 
hemolytic anemia due to SCD in adults and pediatric patients 12 years of age and older as 
monotherapy or in combination with hydroxycarbamide. This study is being conducted at the 
request of the EMA.
The recommended dosage of Oxbryta® is 1500 mg (three 500 mg film-coated tablets) taken 
orally once daily (Oxbryta, EMA Prescribing Information)
2.1. 
Background 
Voxelotor is currently being investigated for the treatment of SCD. 
2.2. 
Summary of Findings to Date 
2.2.1.
Nonclinical Experience
The nonclinical safety pharmacology, PK, metabolism, and toxicity are summarized in the 
Voxelotor Investigator’s Brochure (Version 9.0, 17 December 2021).
2.2.2.
Clinical Experience
As of 05 November 2021, approximately 1083 participants (of which 264 were pediatric 
participants) have received single or multiple doses of voxelotor in 30 clinical development 
studies (10 studies in SCD, 2 studies in IPF, 17 clinical pharmacology studies, and 1 study of 
healthy participants under hypoxic conditions). 
Voxelotor has been well tolerated over a range of doses administered to healthy participants (up 
to 1800 mg) for up to 15 days, and participants with SCD (up to 1500 mg) for up to 18 months. 
The safety data have not shown clinically significant findings in 12-lead ECGs, vital sign 
measurements, or safety laboratory values. There were no deaths and no treatment related SAEs 
or severe AEs reported in healthy participants. 

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The most common treatment emergent AEs in healthy participants
participants, included Grade 1 or 2 headache and gastrointestinal events (including diarrhea, 
abdominal pain, and gastroenteritis) and dizziness. All events of diarrhea and abdominal pain 
were Grade 1. 
For additional information on voxelotor clinical trials in healthy participants and patients refer to 
the Voxelotor Investigator’s Brochure (Version 9.0, 17 December 2021; Sections 5 and 6).
2.3. 
Benefit/Risk Assessment 
Voxelotor is an EMA and FDA approved drug with an established safety profile and therefore 
the potential risks to healthy participants are minimal. 
More detailed information about the known and expected benefits and risks and expected AEs of 
voxelotor may be found in the Voxelotor Investigator’s Brochure (Version 9.0, 17 December 
2021). 
2.4. 
Study Rationale 
2.4.1. 
Rationale for Study Design 
2.4.1.1. 
Part A 
Part A is designed to determine whether voxelotor alters the plasma concentration profiles of the 
probe substrates for CYPs including CYP2B6, CYP2C9, CYP2C8, CYP2C19, and CYP3A4. In 
vitro data suggest that voxelotor may inhibit a number of CYP enzymes. Voxelotor is approved 
for the treatment of SCD and evaluation of the effects of induction or inhibition of CYPs is 
relevant to the full description of the DDI potential of voxelotor.
2.4.1.2. 
Part B 
Part B is designed to determine whether voxelotor alters the plasma concentration profiles of 
MATE1, OAT3, and OATP1B1 probe substrates. Furthermore, this part will assess the effect of 
voxelotor on plasma concentrations of CP-I, a biomarker for OATP1B1 activity. In vitro data 
suggest that voxelotor may inhibit these transporters and could potentially cause DDIs. 
Voxelotor is approved for the treatment of SCD and evaluation of the effects of inhibition of 
transporters may be relevant to the full description of the DDI potential of voxelotor.
2.4.2.
Dose Rationale
2.4.2.1.
Part A
To determine the likelihood of observing an effect of voxelotor on selected CYPs at therapeutic 
exposures, the highest approved dose of voxelotor (1500 mg) will be dosed orally daily for 
14 days. Maximum CYP inhibition by voxelotor is likely to occur within 2 to 4 days and 
expected plasma voxelotor exposures are approximately 14 –
4
(GBT440-0115), which is equivalent to plasma Cmax exposures observed in patients with 
SCD (Savic et al, 2022). The induction of CYP2B6 by voxelotor will likely take longer; thus 
voxelotor will be dosed to steady-state for 13 days. 

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Single doses of CYP probe substrates, bupropion 150 mg (CYP2B6), flurbiprofen 50 mg 
(CYP2C9), omeprazole 20 mg (CYP2C19), midazolam 2 mg (CYP3A4), and repaglinide 
0.25 mg (CYP2C8) were selected based on a previously conducted modified Geneva cocktail 
study (Dai et al, 2021). However, since repaglinide 0.25 mg is not commercially available in the 
United States or the European Union, after consultation with EMA, it was decided to administer 
repaglinide at 0.5 mg. Since repaglinide is administered at least 48 hours after probe substrates 
for other CYP pathways, it is unlikely that this higher dose would interfere with the PK of other 
substrates. In vitro data suggest that voxelotor may inhibit and induce CYP2B6, so the effect of 
voxelotor on the CYP2B6 probe substrate, bupropion 150 mg will be assessed on Day 2 and Day 
12. Co-administration of voxelotor and bupropion on Day 2 was selected to assess voxelotor’s 
potential to inhibit CYP2B6 because no induction is expected to be present. Co-administration of 
voxelotor and bupropion on Day 12 was selected to assess whether voxelotor has the potential to 
induce CYP2B6. The assessment of voxelotor’s potential impact on the CYP2C8 probe 
substrate, repaglinide, is separated from the other CYP probe substrates by 3 days (Period 1) and 
2 days (Period 2) to avoid the potential for drug interaction between repaglinide and the other 
probe substrates. The doses of these probe substrates have been shown to be clinically tolerable 
and result in exposures from which PK parameters can be reliably calculated. 
2.4.2.2. 
Part B
To determine the likelihood of observing an inhibitory effect of voxelotor on selected 
transporters at therapeutic exposures, the highest approved dose of voxelotor (1500 mg) used in 
SCD clinical studies will be dosed orally daily for 5 days. This voxelotor dosing regimen is 
expected to result in target plasma voxelotor exposures of approximately 14 – 
Day 4 (GBT440-0115), which is equivalent to plasma Cmax exposures observed in patients with 
SCD (Savic et al, 2022). Single doses of the transporter probe substrates, metformin 
hydrochloride 10 mg (MATE1), furosemide 1 mg (OAT3), and rosuvastatin 10 mg (OAT1B1) 
are based on results from an optimized and validated cocktail study (Stopfer et al, 2018a; Wiebe
et al, 2020). Doses of metformin (10 mg) and furosemide (1 mg) are lower than the typical 
clinical or therapeutic doses due to the potential for a drug interaction with metformin and/or 
furosemide with rosuvastatin (Stopfer et al, 2018b). The lower doses of metformin and 
furosemide have been shown to not increase rosuvastatin PK exposures and are suitable for 
assessing the potential for drug interactions with voxelotor. 

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3. 
OBJECTIVES 
Table 9:
Study Objectives
Objectives
Primary Part A
 To evaluate the effect of multiple doses of voxelotor on the plasma PK of a single dose 
of bupropion, repaglinide, flurbiprofen, omeprazole, and midazolam, which are probe 
substrates for CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4, respectively 
Exploratory Part A 
 To evaluate the effect of voxelotor on midazolam and 1-hydroxymidazolam PK 
stratified by CYP3A5 genotype 
Safety Part A 
 To evaluate the safety and tolerability of voxelotor when administered in combination 
with bupropion, repaglinide, flurbiprofen, omeprazole, and midazolam to healthy 
participants
Primary Part B 
 To evaluate the effect of multiple doses of voxelotor on the plasma PK of a single dose 
of metformin, furosemide, and rosuvastatin, probe substrates for MATE1, OAT3, and 
OATP1B1, respectively 
Exploratory Part B
 To evaluate the effect of voxelotor on CP-I as a biomarker of OATP1B1 transport 
Safety Part B 
 To evaluate the safety and tolerability of voxelotor when administered in combination 
with metformin, furosemide, and rosuvastatin to healthy participants 

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4. 
STUDY DESIGN 
4.1. 
Overall Design 
4.1.1. 
Part A
This is an open-label, fixed-sequence, 2-period evaluation of the effect of concomitant 
administration of voxelotor on bupropion (a CYP2B6 probe substrate), repaglinide (a CYP2C8 
probe substrate), flurbiprofen (a CYP2C9 probe substrate), omeprazole (a CYP2C19 probe 
substrate), and midazolam (a CYP3A4 probe substrate) plasma concentrations. Figure 1
summarizes the design of Part A. Approximately 26 healthy participants (at least 20% African 
Americans) will be enrolled and will be stratified by CYP3A5 expresser status (approximately 
50% expressors). Treatment administration will be performed when participants are in a fasted 
state. 
Part A, Period 1: All participants will receive the following treatments: 
 Treatment A: On Day 1, single oral doses of bupropion 150 mg, flurbiprofen 50 mg, 
omeprazole 20 mg, and midazolam 2 mg will be administered. 
 Treatment B: On Day 4, a single oral dose of repaglinide 0.5 mg will be administered. 
Participants will be admitted to the CRU on Day -1 and will remain resident in the CRU until 
discharge on Day 5 of Period 1. 
There will be a washout (7 to 14 days) between the last probe substrate dose of Part A, Period 1 
and dosing on Day 1 of Part A, Period 2. 
Part A, Period 2: All participants will receive the following treatments: 
 Treatment C: On Day 1 to Day 13, oral doses of voxelotor 1500 mg will be 
administered daily for 13 days. 
 Treatment D: On Day 2, a single oral dose of bupropion 150 mg will be administered 
immediately following voxelotor administration. 
 Treatment E On Day 4, single oral doses of flurbiprofen 50 mg, omeprazole 20 mg, 
and midazolam 2 mg will be administered immediately following voxelotor 
administration. 
 Treatment F: On Day 6, a single oral dose of repaglinide 0.5 mg will be administered 
immediately following voxelotor administration.
 Treatment G: On Day 12, a single oral dose of bupropion 150 mg will be 
administered immediately following voxelotor administration. 
Participants will be admitted into the CRU on Day -1 and will remain resident in the CRU until 
discharge on Day 15 of Part A, Period 2. Subjects will return to the CRU for a Follow-up visit on 
Day 28 (± 1 day). 
For Part A, participant involvement is expected to last approximately 81 days. 
Participants in Part A are ineligible to participate in Part B. 

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4.1.2.
Part B
This is an open-label, fixed-sequence, 2-period evaluation of the effect of concomitant 
administration of voxelotor on metformin (a MATE1 probe substrate), furosemide (an OAT3 
probe substrate), and rosuvastatin (an OATP1B1 probe substrate) plasma concentrations, as well 
CP-I (an OATP1B1 biomarker) plasma concentrations. Figure 2 summarizes the design of the 
study. Approximately 20 healthy participants (at least 20% African Americans) will be enrolled. 
Treatment administration will be performed when participants are in a fasted state. 
Part B, Period 1: All participants will receive the following treatment: 
 Treatment A: On Day 1, single oral doses of metformin hydrochloride 10 mg, 
furosemide 1 mg, and rosuvastatin 10 mg will be administered.
Participants will be admitted into the CRU on Day -1 and remain resident in the CRU until 
discharge on Day 4 of Part B, Period 1. 
There will be washout (7 to 14 days) between the last probe substrate dose of Part B, Period 1 
and dosing on Day 1 of Part B, Period 2. 
Part B, Period 2: All participants will receive the following treatments: 
 Treatment B: On Day 1 to Day 3, oral doses of voxelotor 1500 mg will be 
administered daily for 3 days.
 Treatment C: On Day 4, single oral doses of metformin 10 mg, furosemide 1 mg, and 
rosuvastatin 10 mg will be administered immediately following a single oral dose of 
voxelotor 1500 mg. 
 Treatment D: On Day 5, a single oral dose of voxelotor 1500 mg will be 
administered.
Participants will be admitted into the CRU on Day -1 and will remain resident in the CRU until 
discharge on Day 7 of Period 2. Subjects will return to the CRU for a Follow-up visit on Day 18 
(± 1 day). 
For Part B, participant involvement is expected to last approximately 68 days. 
Participants in Part B are ineligible to participate in Part A. 
4.2. 
Scientific Rationale for Study Design 
Refer to Section 2.4.1.
4.3. 
Dose Justification 
Refer to Section 2.4.2.
4.4. 
End of Study Definition 
The end of the study is defined as the date of the last visit of the last participant in the study has 
completed all study procedures up to and including the Follow-up visit, as specified in the SoA 
(refer to Section 1.3).

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A participant is considered to have completed the study if they have completed all periods of the 
study in their part, including the Follow-up. 

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5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1.
Inclusion Criteria
Participants must meet all inclusion criteria to be eligible for study participation.
1. 
 55 years of age inclusive, at the time of signing the 
informed consent. 
2. No clinically significant findings as assessed by review of medical and surgical history, 
vital signs assessments, 12-lead ECGs, physical examination, and clinical laboratory 
evaluations conducted at screening and day of admission. A single repeat 
measurement/test may be performed to confirm eligibility based upon initial vital signs, 
ECG, or clinical laboratory tests abnormalities. 
3. 
2
at screening and Period 1 Day -1.
BMI = weight (kg)/(height [m])2 
4. Females of childbearing potential must agree to use a highly effective method of 
contraception or practice abstinence from 2 weeks prior to study start through 30 days 
after the final dose of study drug. A highly effective method of contraception is defined 
as one that results in a low documented failure rate when used consistently and correctly 
such as: condom plus use of an intrauterine device; intrauterine system or hormonal 
method of contraception (oral, injected, implanted, or transdermal) for their female 
partner; or sexual abstinence. Males must be surgically sterilized, or agree to practice true 
abstinence, or use acceptable contraception if sexually active with a female partner of 
childbearing potential, throughout the study, and for at least 30 days after the last dose of 
study drug. 
5. Males must agree not to donate sperm during the study and for 30 days following last 
dose of study drug. 
6. Participants must be able to communicate effectively in English with the study personnel.
7. Participants must be nonsmokers, defined as having abstained from tobacco- or 
nicotine-containing products (eg, cigarettes, chewing tobacco, snuff, nicotine patches, 
and electronic cigarettes) in the 6 months prior to screening.
8. Capable of providing signed informed consent as described in Section 10.1.3, which 
includes compliance with the requirements and restrictions listed in the ICF and in this 
protocol. 

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5.2.
Exclusion Criteria 
Participants meeting any of the following exclusion criteria will not be eligible for study 
enrollment: 
1. Positive pregnancy test or is lactating.
2. History or presence of clinically significant allergic diseases (except for untreated, 
asymptomatic, seasonal allergies) at time of screening in the opinion of the Investigator.
3. History or presence of conditions which, in the opinion of the Investigator, are known to 
interfere with the absorption, distribution, metabolism, or excretion of drugs, such as 
previous surgery on the gastrointestinal tract (including removal of parts of the stomach, 
bowel, liver, or pancreas). Participants who have a history of cholecystectomy and 
appendectomy are eligible for enrollment. 
4. History of surgery or major trauma within 12 weeks of screening, or surgery planned 
during the study. 
5. Any signs and/or symptoms of acute illness at screening or Day -1. 
6. Abnormal ECG in any of the single ECGs collected at screening or Day -1, including 
QTcF > 430 msec for males and > 450 msec for females, or any cardiac rhythm other 
than sinus rhythm that is interpreted by the Investigator to be clinically significant. A 
single repeat measurement may be performed to re-evaluate ECG abnormalities (ie, to 
confirm that a participant is eligible). All the single ECGs must be not clinically 
significant to qualify for enrollment into the study. 
7. Known personal or family history of congenital long QT syndrome or known family 
history of sudden death. 
8. Resting bradycardia (HR < 45 bpm) or resting tachycardia (HR > 100 bpm) at screening 
or Day -1. A single repeat measurement may be performed to re-evaluate vital signs 
abnormalities (ie, to confirm that a participant is ineligible). Each of the readings must be 
not clinically significant to qualify for enrollment into the study. 
9. Hypertension, defined as resting (supine) systolic BP > 140 mmHg or resting diastolic 
BP > 90 mmHg at screening or Day -1. A single repeat measurement may be performed 
to re-evaluate vital signs abnormalities (ie, to confirm that a participant is eligible). Each 
of the readings must be not clinically significant to qualify for enrollment into the study. 
10. History of alcohol abuse, illicit drug use, significant mental illness, or physical 
dependence to any opioid. 
11. Use of prescription medications (with the exception of contraception), any OTC drugs 
including herbal preparations including St. John’s wort or dietary supplements, or any 
drugs that induce or inhibit study drug specific CYP450(s) within 14 days or 5 half-lives, 
whichever is longer, prior to Day -1, or requires continuing use during study 
participation. 

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12. Consumption of more than 400 mg of caffeine (approximately 4 cups of coffee) per day 
or is unwilling to abstain from consumption of caffeine- or xanthine-containing products 
(eg, tea, coffee, chocolate, cola, etc.) from 48 hours prior to Day -1 until the end of the 
study (Follow-up visit). 
13. Unwilling to abstain from alcohol from 48 hours prior to Day -1 until the end of the study 
(Follow-up visit).
14. Consumption of Seville oranges and/or Seville orange juice, grapefruit and/or grapefruit 
juice within 14 days prior to Day -1 and is unwilling to abstain from consumption of 
Seville oranges and/or Seville orange juice, grapefruit and/or grapefruit juice until the 
end of the study (Follow-up visit).
15. Unwilling to abstain from any strenuous physical exercise (such as weight training or 
aerobics) from 72 hours prior to Day -1 until the final PK sample is collected in the study. 
Participants are permitted to exercise following the screening visit until 72 hours prior to 
Day -1.
16. Has participated in another clinical trial of an investigational drug (or medical device) 
within 30 days or 5 half-lives, whichever is longer, prior to screening, or is currently 
participating in another trial of an investigational drug (or medical device). 
17. Prior exposure to voxelotor/Oxbryta within the past month.
18. Clinically significant anemia or has donated blood or blood components exceeding 
400 mL within 90 days prior to screening. 
19. Positive urine test for drugs of abuse, alcohol, or cotinine at screening or Day -1.
20. Positive screen for HIV-1 and HIV-2 antibodies, HAV antibody, HBsAg, or HCV 
antibody. 
21. Positive COVID-19 test at admit to CRU.
22. Poor venous access as determined by the Investigator or study staff. 
23. Involved in the planning or conduct of this study. 
24. Any other condition or prior therapy that, in the Investigator’s opinion, would confound 
or interfere with the evaluation of safety, tolerability, or PK of the study drug(s), interfere 
with study compliance, or preclude informed consent. 
Part A only 
25. History or presence of contraindication to the use of midazolam including but not limited 
to hypersensitivity to benzodiazepines or formulation ingredients, acute narrow-angle 
glaucoma, myasthenia gravis, severe respiratory insufficiency, or sleep apnea syndrome. 
26. Poor CYP2C9 or CYP2C19 metabolizer (determined at screening or available historical 
data). 
27. Participant has an allergy or sensitivity to voxelotor, bupropion, repaglinide, flurbiprofen, 
omeprazole, or midazolam. 

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Part B only 
28. History of statin-induced myopathy or serious hypersensitivity reaction to other 
3-hydroxy-3-methylglutaryl coenzyme A, reductase inhibitors (statins).
29. Heterozygous or homozygous variant allele carriers of SLCO1B1 (c.521T>C, 
rs4149056), encoding the hepatic uptake transporter OATP1B1, resulting in decreased 
transport activity
30. Participant has an allergy or sensitivity to voxelotor, metformin, furosemide, or 
rosuvastatin. 
5.3. 
Lifestyle Considerations 
5.3.1. 
Dietary 
 Participants are not permitted to consume Seville oranges and/or Seville orange juice, 
grapefruit and/or grapefruit juice from 14 days prior to Day -1 of Period 1 until the 
end of the study (Follow-up visit). Participants must also refrain from the 
consumption of other fruit juices while in the clinic. 
 Participants are not permitted to consume any food and drink from outside of the 
CRU while residing at the CRU.
5.3.2. 
Caffeine, Alcohol, and Tobacco 
 Participants are not permitted to consume alcohol from 48 hours prior to Day -1 of 
Period 1 until the end of the study (Follow-up visit).
 Participants are not permitted to consume caffeine-containing food or beverages for 
48 hours prior to Day -1 of Period 1 until the end of the study (Follow-up visit).
5.3.3. 
Activity  
Strenuous activity (such as weight training or aerobics) is prohibited from 72 hours prior to 
Day -1 until the final PK sample is collected in the study.
5.4. 
Screen Failures 
Participants who are discontinued from the study prior to study drug administration will be 
considered screen failures.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened as long as the participant was not discontinued from the study due to noncompliance 
with the protocol (ie, positive urine drugs of abuse screen, etc.). Rescreened participants should 
be assigned a new participant number for every screening/rescreening event. 
Screen failure data will not be recorded in the eCRF. 

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6. 
STUDY TREATMENT AND CONCOMITANT THERAPY 
6.1. 
Study Treatments Administered 
Identity of voxelotor is presented in Table 10 and identity of cocktail drugs (probe substrates) is 
presented in Table 11.
Table 10: 
Study Treatments Administered 
Treatment Name 
Voxelotor 
Excipients 
All of the excipients used in the formulations are 
either compendial per Ph. Eur. or are composed of 
mixtures which are compendial per Ph. Eur. or 
accepted by E number or European Commission 
regulation. 
Dose Formulation 
Tablet 
Unit Dose Strength 
500 mg/tablet 
Dosage Level 
1500 mg 
Route of Administration 
Oral 
Packaging and Labeling 
Tablets are packaged in 150 cc white, high density 
polyethylene bottles. The bottles are closed with 
child-resistant polypropylene screw caps. 
Storage Conditions 
Controlled room temperature between 15°C and 
25°C 
Table 11: 
Cocktail Drugs Administered
Drug (Probe Substrate) 
Dose 
Part A
bupropion 
150 mg 
flurbiprofen a
50 mg 
omeprazole
20 mg
midazolam 
2 mg 
repaglinide 
0.5 mg 
Part B
metformin 
10 mg 
furosemide 
1 mg 
rosuvastatin 
10 mg 
a. Flurbiprofen (50 mg) is manufactured by Delpharm L’ Aigle and marketed in the United Kingdom. The marketing authorization holder is 
Mylan Products Ltd. 

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Eligible participants will receive the following treatments: 
Part A, Period 1: 
 Treatment A: On Day 1, single oral doses of bupropion 150 mg, flurbiprofen 50 mg, 
omeprazole 20 mg, and midazolam 2 mg will be administered. 
 Treatment B: On Day 4, a single oral dose of repaglinide 0.5 mg will be administered. 
Part A, Period 2: 
 Treatment C: On Day 1 to Day 13, oral doses of voxelotor 1500 mg will be 
administered daily for 13 days. 
 Treatment D: On Day 2, a single oral dose of bupropion 150 mg will be administered 
immediately following voxelotor administration. 
 Treatment E: On Day 4, single oral doses of flurbiprofen 50 mg, omeprazole 20 mg, 
and midazolam 2 mg will be administered immediately following voxelotor 
administration. 
 Treatment F: On Day 6, a single oral dose of repaglinide 0.5 mg will be administered 
immediately following voxelotor administration. 
 Treatment G: On Day 12, a single oral dose of bupropion 150 mg will be 
administered immediately following voxelotor administration. 
Part B, Period 1: 
 Treatment A: On Day 1, single oral doses of metformin hydrochloride 10 mg, 
furosemide 1 mg, and rosuvastatin 10 mg will be administered. 
Part B, Period 2: 
 Treatment B: On Day 1 to Day 3, oral doses of voxelotor 1500 mg will be 
administered daily for 3 days. 
 Treatment C: On Day 4, single oral doses of metformin 10 mg, furosemide 1 mg and 
rosuvastatin 10 mg will be administered immediately following a single oral dose of 
voxelotor 1500 mg. 
 Treatment D: On Day 5, a single oral dose of voxelotor 1500 mg will be 
administered. 
Study treatments will be administered with approximately 240 mL (8 fluid ounces) of 
nonrefrigerated, noncarbonated water following an overnight fast of at least 10 hours. No food 
will be allowed for at least 4 hours postdose. Water will be allowed as desired, except for 1 hour 
before and 2 hours following dosing. 
6.2. 
Preparation, Handling, Storage, and Accountability 
Details regarding preparation of study drugs for administration are provided in the Study 
Reference Manual (provided separately). 

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The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study drug received, and any discrepancies are reported and 
resolved before use of the study drug. 
Cocktail drugs (probe substrates) will be stored according to the package inserts. 
Only participants enrolled in the study may receive study drug, and only authorized site staff 
may supply or administer study drug. All study drug must be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the Investigator and authorized site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study drug accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records). 
A Drug Accountability Record will be used for the study drug. The record must be kept current 
and should contain the dates and quantities of study drug received, study number, lot or batch 
number(s), participants receiving study drug, the date and quantity of study drug dispensed and 
remaining, and the initials of the dispenser. 
All study drug inventory forms must be made available for inspection by an authorized 
representative of the Sponsor or designee. 
Further guidance and information for the final disposition of unused study drugs are provided in 
the Study Reference Manual.
6.3. 
Randomization and Blinding 
This is an open-label study. Randomization and blinding are not applicable. 
6.4. 
Study Treatment Compliance 
When participants are dosed at the site, they will receive study drug directly from the 
Investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents. The dose of study drug and 
study participant identification will be confirmed at the time of dosing by a member of the study 
site staff other than the person administering the study drug.
If a participant misses a dose, the participant should resume normal dosing the next day.
6.5. 
Concomitant Therapy 
A concomitant medication is defined as any prescription medication or vaccine (including over 
the counter or prescription medicines, recreational drugs, vitamins, and/or herbal supplements. 
In the interests of participant safety and acceptable standards of medical care, the Investigator
will be permitted to prescribe treatment(s) at their discretion. For all enrolled participants, all 
administered concomitant medications from signing the informed consent until 30 days after the 
participant’s last dose of study drug, must be recorded in the participants’ eCRF (medication, 
dose, treatment duration, and indication).  

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All reported prior and concomitant medications will be coded using the current version of the 
World Health Organization Drug Dictionary. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.5.1. 
Restrictions Regarding Concomitant Medications 
Participants must abstain from the use of prescription medications (with the exception of 
contraception), any OTC drugs including herbal preparations including St. John’s wort or dietary 
supplements, or any drugs that induce or inhibit study drug specific CYP450(s) within 14 days or 
5 half-lives, whichever is longer, prior to Day -1, or requires continuing use during study 
participation.
Other concomitant medications may be considered on a case-by-case basis by the Investigator in 
consultation with the Medical Monitor. 
Penicillin prophylaxis and vaccinations (including the COVID-19 vaccine) are allowed in 
accordance with standard of care. 
6.5.1.1. 
Prohibited Concomitant Medications and Therapies 
Treatment with any of the following is not allowed during the study: 
 Prescription medications with the exception of oral contraceptive agents taken by 
women of child-bearing age 
 OTC drugs (including herbal preparations and any dietary supplements) 
 Drugs that induce or inhibit study drug specific CYP450(s) 
6.5.2. 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (eg, surgery/biopsy, physical therapy) 
or diagnostic assessment (eg, chest x-ray, blood gas measurement, bacterial cultures) performed 
between the time the participant is enrolled in the study and the Follow-up/ET Visit. 
The use of concomitant therapies or procedures must be recorded on the participant’s eCRF, 
according to instructions for eCRF completion. Adverse events related to administration of these 
therapies or procedures must be documented in the appropriate eCRF. 

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7. 
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
Discontinuation of specific sites or of the study as a whole are detailed in Section 10.1.9.
7.1. 
Early Discontinuation of the Study 
The Sponsor has the right to terminate this study at any time. Reasons for terminating the study 
may include, but are not limited to, the incidence or severity of AEs in participants.
Participants will be informed that they are free to discontinue treatment or withdraw from the 
study at any time and for any reason. The Investigator must withdraw any participant from the 
study who requests to be withdrawn.  
Participants who ask to leave the study early (withdraw consent) should be encouraged to 
undergo the tests and evaluations listed for the ET Visit (ie, ET is intended for participants who 
withdraw consent). If a participant withdraws before completing the study, the date and reason 
for withdrawal is to be documented on the eCRF.
A participant who withdraws from the study or is lost to follow-up will not be replaced.
7.2. 
Discontinuation of Study Treatment 
Participants may discontinue study treatment for any of the following reasons:  
 Adverse event 
 Withdrawal of consent 
 Discretion of the Investigator
 Participant is lost to follow-up 
 Participant is noncompliant 
Pregnancy. Study drug must be discontinued immediately. Report the pregnancy 
according to the instructions in Section 8.4.7.
Participants who discontinue from study treatment will be encouraged to continue to participate 
in the study assessments, as applicable. Participants who are discontinued from study treatment 
due to pregnancy will also be discontinued from the study (Section 8.4.7). A participant may be 
discontinued from study treatment at any time at the discretion of the Investigator in accordance 
with his or her clinical judgment.
7.2.1.
Discontinuation due to Adverse Events
Any participant who experiences an AE may be withdrawn at any time from the study at the 
discretion of the Investigator. Participants withdrawn from the study due to an AE, whether 
serious or nonserious, should be followed by the Investigator until the clinical outcome of the AE 
is determined (ie, the event has resolved or has stabilized). The details of AE(s) should be noted 
on the appropriate eCRFs. The Sponsor and Medical Monitor must be notified of the study 
participant discontinuation. If the AE is due to overdose of study treatment, the most recent

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version of the voxelotor IB should be referred for further details on any specific actions to be 
taken.  
7.2.2. 
Liver Chemistry Stopping Criteria 
Participants will be monitored for signs of DILI. Study drug will be withheld in the event of 
potential DILI. 
Potential events of DILI will be defined as meeting all of the following criteria (as specified in 
the FDA Guidance for Industry Drug-induced Liver Injury: Premarketing Clinical Evaluation, 
2009): 
 Alanine aminotransferase or aspartate aminotransferase > 3 × ULN 
 Total bilirubin > 2 × ULN without initial findings of cholestasis (elevated serum 
alkaline phosphatase) 
 No other reason can be found to explain the combination of laboratory value 
increases (eg, acute viral hepatitis; alcoholic and autoimmune hepatitis; hepatobiliary 
disorders; nonalcoholic steatohepatitis; cardiovascular causes; concomitant 
treatments) 
Potential events of DILI will be reported as SAEs (Section 8.4). All participants with potential 
DILI will be closely followed until abnormalities return to normal or baseline or until reasonable 
attempts to determine resolution of the event are exhausted. 
7.3. 
Discontinuation/Withdrawal from the Study 
A participant may withdraw from the study at any time at their own request or may be 
discontinued at any time at the discretion of the Investigator for safety, behavioral, or compliance 
reasons. 
At the time of discontinuing from the study, if possible, an ET visit should be 
conducted, as shown in the SoA Section 1.3. The SoA details the data to be collected 
at the time of study discontinuation and follow-up and for any further evaluations that 
need to be completed.
The participant will be permanently discontinued from the study treatment and the 
study at the time of discontinuation.
If the participant withdraws consent for disclosure of future information, the Sponsor
may retain and continue to use any data collected before such a withdrawal of 
consent.
If a participant withdraws from the study, they may request destruction of any 
samples taken and not tested, and the Investigator must document this in the site 
study records.
7.4. 
Lost to Follow up 
A participant will be considered lost to follow-up if they repeatedly fail to return for scheduled 
visits and are unable to be contacted by the study site. 

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The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:
 The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible, counsel the participant on the importance of maintaining the 
assigned visit schedule, and ascertain whether the participant wishes to and/or should 
continue in the study. 
 Before a participant is deemed lost to follow-up, the Investigator or designee must 
make every effort to regain contact with the participant (where possible, a minimum 
of 2 telephone calls, and if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record. 
 Should the participant continue to be unreachable, they will be considered to have 
withdrawn from the study.  
 Site personnel will attempt to collect the vital status of the participant within legal and 
ethical boundaries for all participants randomized, including those who did not get 
study treatment. Public sources may be searched for vital status information. If vital 
status is determined as deceased, this will be documented, and the participant will not 
be considered lost to follow-up. Sponsor personnel will not be involved in any 
attempts to collect vital status information. 

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8. 
STUDY ASSESSMENTS AND PROCEDURES 
 Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.
 Immediate safety concerns should be discussed with the Sponsor/Medical Monitor
immediately upon occurrence or awareness to determine if the participant should 
continue or discontinue study drug. 
 Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. 
8.1. 
Demographic/Medical History 
Demographic information (sex, age, race/ethnicity, and height) will be recorded.
Participants will be asked to provide a thorough medical history. Moreover, weight will also be 
measured on Day -1 in both periods of Parts A and B.
8.2. 
Pharmacokinetics 
Whole blood and plasma PK samples will be collected at time points specified in the PK 
sampling schedule (Part A, Period 1: Table 2, Part A, Period 2: Table 4, Part B, Period 1: 
Table 6, and Part B, Period 2: Table 8). Blood sample collection, processing, and shipping details 
will be outlined in a separate study reference manual. 
Part A
 Whole blood and plasma concentrations of voxelotor, and plasma concentrations of 
bupropion, 6- hydroxybupropion, repaglinide, flurbiprofen, omeprazole, 
5-hydroxyomeprazole, midazolam, and 1-hydroxymidazolam will be determined 
using validated assays.
Part B
Whole blood and plasma concentrations of voxelotor, and plasma concentrations of 
metformin, furosemide, rosuvastatin, and CP-I will be determined using validated 
assays.

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The following PK parameters will be determined for Part A:
Cmax
Maximum observed plasma concentration (probe substrates only). 
tmax 
The time that Cmax was observed (probe substrates only). 
AUCt
Area under the plasma concentration-time curve from time 0 to the time of the 
last quantifiable concentration; calculated using the linear/log trapezoid rule
(probe substrates only).
AUCinf 
Area under the plasma concentration-time curve from time 0 extrapolated to 
infinity; calculated as AUClast + Clast/
z, where Clast is the last measurable 
concentration (probe substrates only). 
AUCt M/P
Ratio of metabolite to parent AUCt corrected for molecular weight for 
6-hydroxybupropion/ bupropion, 5-hydroxyomeprazole/omeprazole, and 
1-hydroxymidazolam/midazolam.
t½
Terminal elimination half-life; calculated as ln(2)/
z. 
The following PK parameters will be determined for Part B: 
Cmax
Maximum observed plasma concentration.
Cpredose 
Predose plasma concentration (CP-I only). 
tmax 
The time that Cmax was observed.
AUC0-24 
Area under the plasma concentration-time curve from time 0 to 24 hours 
(CP-I only).
AUCt 
Area under the plasma concentration-time curve from time 0 to the time of the 
last quantifiable concentration; calculated using the linear/log trapezoid rule.
AUCinf 
Area under the plasma concentration-time curve from time 0 extrapolated to 
infinity; calculated as AUClast + Clast/
z, where Clast is the last measurable 
concentration.
t½
Terminal elimination half-life; calculated as ln(2)/
z (metformin, furosemide,
and rosuvastatin).
Retained research samples will be collected and stored for further analyses which may, for 
example, provide greater understanding of the study intervention. 
8.3. 
Safety Assessments 
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3). 
8.3.1. 
Physical Examination 
 A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, and neurological systems. Height and 
weight will also be measured and recorded.
 Physical examinations after the screening visit will be performed at the discretion of 
the Investigator and may be targeted, focusing on specific organ systems, 

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abnormalities identified on the screening examination, and abnormalities related to 
adverse events and screening for drug toxicities. 
 An abnormal physical examination finding that is considered clinically significant 
and requires the participant to be discontinued from the study, requires the participant
to receive treatment, or requires a change or discontinuation of the study drug (if 
applicable) will be recorded as an AE. 
8.3.2. 
Vital Signs 
 Oral temperature (°C), heart rate, respiratory rate (breaths per minute), and blood 
pressure will be assessed. 
 Blood pressure and heart rate measurements will be assessed in a supine position with 
a completely automated device. 
 Blood pressure and heart rate measurements should be preceded by at least 5 minutes 
of rest for the participant in a quiet setting without distractions (eg, television, cell 
phones). 
 Vital signs (to be taken before blood collection for laboratory tests) will consist of 
heart rate, blood pressure measurement, oral temperature, and respiratory rate. 
 Any clinically significant abnormal vital sign assessment requires at least one repeat 
measurement. 
 A vital signs abnormality that is (1) considered clinically significant initially and on 
confirmation, (2) requires a participant to be discontinued from the study, (3) requires 
a participant to receive treatment, or (4) requires a change or discontinuation from the 
study drug (if applicable) will be recorded as an AE or SAE as applicable. 
8.3.3. 
Oxygen Saturation (Part A only) 
Oxygen saturation will be measured by pulse oximetry. 
Oxygen saturation abnormalities during the on-study period (ie, following dose administration) 
that (1) are considered clinically significant initially and on confirmation, (2) require a 
participant to be discontinued from the study, (3) require a participant to receive treatment, or 
(4) require a change or discontinuation from the study drug (if applicable) will be recorded as 
AEs. 
8.3.4. 
Electrocardiograms 
 Participants must be resting quietly in a supine position or in the most recumbent 
position possible for at least 5 minutes before the ECG is obtained. 
 12-lead ECG(s) will be obtained as outlined in the SoA (Section 1.3) using an ECG 
machine that automatically calculates the heart rate and measures at a minimum RR, 
PR, QRS, QT, and QTcF intervals. 
 Electrocardiogram assessment may include automated interpretation of the tracings 
(eg, rhythm, presence of arrhythmia or conduction defects, morphology, any evidence 

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of myocardial infarction, or ST segment, T-wave, and U-wave abnormalities). The 
Investigator or designee is responsible for reviewing and over-reading the ECG 
interpretation, for assessing whether the ECG machine interpretation findings are 
accurate, appropriate, normal or abnormal, and for providing corrected interpretations 
as appropriate. In addition, any abnormal ECGs will be assessed for clinical 
significance. 
 Additional ECGs may be obtained if clinically indicated and must be obtained if 
abnormal and clinically significant or thought to be an error (eg, lead placement error, 
movement artifact, etc.). Any additional relevant data obtained by the Investigator 
during the course of this study will be supplied to the Sponsor. 
For any ECG that the Investigator considers clinically significant, the Investigator will: 
 Repeat the ECG. 
 Follow-up ECG(s) will be obtained if any significant abnormalities are detected after 
dose administration to document resolution and as clinically indicated. 
 Record as an AE any ECG that is confirmed and the Investigator considers clinically 
significant, requires a participant to be discontinued from the study, requires a 
participant to receive treatment, or requires a change or discontinuation of the study 
drug (if applicable). 
8.3.5. 
Clinical Laboratory Tests 
See Table 12 for the list of clinical laboratory tests to be performed and the SoA (Section 1.3) for 
the timing and frequency. 
 Protocol-specific requirements for the determination of participant eligibility are 
detailed in Section 5 of the protocol. 
 It is the responsibility of the Investigator or designee to assess the clinical 
significance of all abnormal clinical laboratory values as defined by the applicable list 
of normal values on file (ie, local or central). All clinically significant laboratory 
value abnormalities should be recorded as AEs 
 Additional and repeat laboratory safety testing for the evaluation of abnormal results 
and/or AEs during the study may be performed at the discretion of the Investigator or 
upon request of the Sponsor; it is preferred for the analyses to be conducted by the 
central laboratory unless medical need necessitates urgent results reporting. Repeat 
laboratory testing of abnormal potentially clinically significant or clinically 
significant results for the screening evaluation of the participant may be repeated at 
the discretion of the Investigator 

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Table 12: 
Clinical Laboratory Tests
Hematology 
Hematocrit 
Hemoglobin 
Mean corpuscular volume
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration 
Platelet count (estimate not 
acceptable) 
Red blood cell count 
White blood cell count including 
differential count (percent and 
absolute): 
• 
Neutrophils 
• 
Lymphocytes 
• 
Monocytes 
• 
Basophils 
• 
Eosinophils 
Serum Chemistry 
Albumin 
Alkaline phosphatase 
Alanine aminotransferase 
Aspartate aminotransferase 
Total bilirubin (direct and 
indirect) 
Lactate dehydrogenase a 
Total protein 
Blood urea nitrogen 
Creatinine
Creatine phosphokinase a
Calcium 
Phosphorous 
Sodium 
Potassium 
Magnesium 
Bicarbonate 
Chloride 
Glucose a
 
Urinalysis 
Specific gravity
Ketones 
pH 
Protein 
Blood 
Glucose 
Bilirubin 
Urobilinogen 
Nitrite 
Leukocytes 
Microscopic examination 
of sediment, if clinically 
indicated 
Coagulation 
Prothrombin time 
Partial thromboplastin time 
International normalized ratio 
a. 
Fasting (8 hours) required at screening only 
8.3.5.1.
Other Tests
The following tests will be performed:
Urine drugs of abuse (at a minimum, cocaine, cannabinoids, amphetamines,
methylenedioxymethamphetamine, methamphetamines, opiates, methadone, 
barbiturates, and phencyclidine).
 Cotinine screen (urine) 
 Alcohol test (urine)
 Serology tests (ie, HIV-1 and HIV-2 antibodies, HAV antibody, HBsAg, and HCV 
antibody, and any confirmatory tests performed at the discretion of the Investigator) 
 Creatinine clearance (CLcr); calculated using the Cockcroft-Gault formula: 
CLcr (mL/min) = ([140-age (years)] × weight [kg] × [0.85 for female 
participants])/(72 × serum creatinine [mg/dL])
 Pregnancy test (females only) 

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FSH (females only; as needed to confirm postmenopausal status)
COVID-19 test
CYP2C9 Genotyping (Part A only)
 CYP2C19 Genotyping (Part A only)
 CYP3A5 Genotyping (Part A only)
 SLCO1B1 genotyping (Part B only) 
Tests for drugs of abuse and alcohol screens may not be repeated for eligibility at screening or 
Day -1.
8.3.6.
Pregnancy Testing
Pregnancy tests will be performed on all female participants as indicated in the SoA
(Section 1.3). A serum pregnancy test will be conducted at screening with urine pregnancy tests 
conducted thereafter as indicated in the SoA. If the Day-1 urine test is positive, a serum 
pregnancy test should be performed; if positive, the participant will be considered a screen 
failure. 
8.4. 
Adverse Events (AEs) Serious Adverse Events (SAEs), and Other 
Safety Reporting 
8.4.1. 
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 section of the current IB or is not listed at the specificity or 
severity that has been observed.

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The Investigator will assess each AE for seriousness, severity, and relationship to investigational 
product. 
8.4.2. 
Definition of Serious Adverse Events or Serious Suspected Adverse Reactions
An SAE or serious suspected adverse reaction is an AE or suspected adverse reaction that, at any 
dose, in the view of 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.
8.4.3. 
Severity of Adverse Events
Whenever possible, the severity of all AEs will be graded using the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 5.0. 
For AEs not adequately addressed in the NCI-CTCAE, Version 5.0, the criteria presented in 
Table 13 should be used.
Table 13:
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  

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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. 
8.4.4. 
Relationship to Investigational Product   
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 the investigational product administration makes the 
relationship unlikely. If an SAE is not considered to be related to study drug, then an alternative 
explanation should be provided. 
RELATED: A temporal relationship exists between the event onset and the administration of 
the study drug 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. 
8.4.5. 
Adverse Event Reporting 
8.4.5.1. 
General 
All AEs will be recorded from the time the study participant signs the ICF form obtained through 
the Follow-up visit (Day 28 [Part A, Period 2] or Day 18 [Part B, Period 2]). All SAEs must be 
reported within 24 hours of AE awareness on the AE eCRF via the electronic data capture 
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 (both 
serious and nonserious) AEs must be followed until they are resolved or stabilized, or until 
reasonable attempts to determine resolution of the event are exhausted.  
Any participant who experiences an AE may be discontinued from study treatment at any time at 
the discretion of the Investigator. The Sponsor and the contract research organization Medical 
Monitors must be notified of the study participant discontinuation. 
8.4.5.2. 
Diagnosis Versus Signs and Symptoms 
If known, a diagnosis should be recorded on 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 

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should be recorded separately on the eCRF. If a diagnosis is subsequently established, it should 
be reported as follow-up information. 
8.4.5.3. 
Abnormal Laboratory Values
Only clinically significant laboratory abnormalities will be recorded on 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 upper limit of normal 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 on the AE eCRF, unless their severity, seriousness, or etiology 
changes.  
8.4.6. 
Serious Adverse Events, Serious Adverse Drug Reactions, 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 
paper SAE report forms and faxed or emailed to the Sponsor or designee. 
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. 
8.4.6.1. 
Reporting Suspected Unexpected Serious Adverse Reactions and Urgent Safety 
Issues 
The Sponsor or designee is responsible for reporting SUSARs to regulatory agencies, competent 
authorities, IRBs/ECs, and the Investigator 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. 

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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.  
8.4.7. 
Reporting Pregnancy 
If a participant becomes pregnant while taking study drug, the study treatment will be 
immediately discontinued, and the pregnancy must be reported to the Sponsor or 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, or spontaneous or elective abortion).  
An uncomplicated pregnancy will not be considered an AE or SAE. Pregnancy complications 
such as spontaneous abortion/miscarriage and congenital anomalies are considered SAEs and 
must be reported as described in Section 8.4.6. 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 Investigator 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 may
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 8.4.6.  
Information regarding pregnancy testing (including definition of females of childbearing 
potential) is provided in Section 11. Highly effective means of contraception are listed in 
Appendix 1. 
8.4.8. 
Reporting Overdose 
If a participant takes more than the protocol-defined dose of study drug in a day and experiences 
a drug related AE, this will be reported as an overdose (AEs must be recorded on 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 investigational agent exposure with the 
participant. Participants are to be instructed to contact their study site immediately if an overdose 
of study drug is suspected. 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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8.4.9.
Time Period and Frequency for Collecting AE and SAE Information
All AEs and SAEs will be collected from the signing of the ICF until the Follow-up visit (Day 28 
[Part A, Period 2] or Day 18 [Part B, Period 2]) at the timepoints specified in the SoA 
(Section 1.3). 
Medical occurrences that begin before the start of study drug but after obtaining informed 
consent will be recorded as medical history/current medical conditions, not as AEs. 
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Section 8.4.6. The Investigator will 
submit any updated SAE data to the Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study drug or study participation, the Investigator must promptly notify 
the Sponsor. 
8.4.10. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
8.4.11. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, 
the event is otherwise explained, or the participant is lost to follow-up (as defined in 
Section 7.4). 
8.5. 
Missed Assessments 
Missed assessments should be rescheduled and performed as close to the original scheduled date 
as possible. An exception is made when rescheduling becomes, in the Investigator’s opinion, 
medically unnecessary or unsafe because it is too close in time to the next scheduled evaluation. 
In that case, the missed evaluation should be abandoned.

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9. 
STATISTICAL CONSIDERATIONS 
The statistical analysis will be conducted following the principles as specified in ICH Topic E9 
(CPMP/ICH/363/96). All statistical analyses will be described in a separate statistical analysis 
plan. The statistical analysis plan will be finalized prior to database lock, and it will include a 
more technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important endpoints 
including primary and key secondary endpoints. 
9.1. 
Statistical Hypotheses 
No formal hypotheses will be tested.
9.2. 
Analysis Sets 
For the purposes of analysis, the following analysis sets are defined:
Table 14:
Analysis Sets
Participant Analysis Set 
Description 
Pharmacokinetic Full 
Population 
All participants who received at least 1 dose of study drug (voxelotor 
or cocktail drugs [probe substrates]) and have at least 1 whole blood 
or plasma concentration data point. 
Pharmacokinetic Evaluable 
Population 
All participants who received at least 1 dose of study drug (voxelotor 
or cocktail drugs [probe substrates]) and have a sufficient PK profile 
to derive at least 1 PK parameter. 
Safety Population 
All participants who received any amount of study drug (voxelotor or 
cocktail drugs [probe substrates]). 
9.3. 
Statistical Analyses 
9.3.1.
General Considerations
Unless otherwise noted, continuous variables will be summarized by using the number of 
nonmissing observations, arithmetic mean, standard deviation, median, minimum, and maximum 
values as descriptive statistics; categorical variables will be summarized by using the frequency 
count and the percentage of study participants in each category as descriptive statistics. All 
safety and demographic analyses will be performed for each part of the study.
All analyses and tabulations will be performed by using SAS Version 9.4 or higher and PK 
parameters will be determined using WinNonlin Version 8.0.0 or higher.
9.3.1.1. 
Disposition
Among the study participants enrolled into the study, the number and percentage who complete 
the study and who prematurely discontinue from the study will be summarized. In addition, 
reasons leading to study discontinuation will be summarized. The number of study participants
included in each analysis population (PK Full Population, PK Evaluable Population, and Safety 
Population) will also be presented. 

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9.3.2.
Part A Pharmacokinetic Endpoints
9.3.2.1. 
Primary Endpoint Analysis 
Cmax, AUCt, and AUCinf for bupropion, repaglinide, flurbiprofen, omeprazole, and 
midazolam 
9.3.2.2. 
Secondary Endpoints Analysis
 Cmax, AUCt, and AUCinf for 6-hydroxybupropion, 5-hydroxyomeprazole, and 
1-hydroxymidazolam 
 tmax and t½ for bupropion, 6-hydroxybupropion, repaglinide, flurbiprofen, omeprazole, 
5-hydroxyomeprazole, midazolam, and 1-hydroxymidazolam in plasma. AUCt M/P
for bupropion, omeprazole, and midazolam 
9.3.2.3. 
Exploratory Endpoint Analysis 
 Cmax, AUCt, and AUCinf of midazolam and 1-hydroxymidazolam with and without 
voxelotor stratified by CYP3A5 genotype 
 Predose (Days 2-7, 12-13) and postdose observed concentration (Days 2, 4, 6, and 12) 
for voxelotor in whole blood and plasma 
9.3.3. 
Part B Pharmacokinetic Endpoints 
9.3.3.1. 
Primary Endpoint Analysis 
 Cmax, AUCt, and AUCinf for metformin, furosemide, and rosuvastatin 
9.3.3.2. 
Secondary Endpoints Analysis
 tmax and t½ for metformin, furosemide, and rosuvastatin in plasma 
9.3.3.3. 
Exploratory Endpoints Analysis 
 Cpredose, Cmax, tmax, and AUC0-24 for CP-I 
 Predose (Days 4, 5, 6) and postdose observed concentration (Day 4) for voxelotor in 
whole blood and plasma
9.3.4. 
Part A and B Safety Endpoints Analysis
 TEAEs and SAEs
 Results of clinical laboratory tests, physical examination findings, and vital signs
9.3.5. 
Pharmacokinetic Analysis 
Whole blood and plasma concentrations of voxelotor (whole blood applicable only for voxelotor) 
and all probe substrates (alone and probe substrate administered with voxelotor) will be listed 
and summarized by dosing regimen and nominal sampling time with the number of nonmissing 

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observations, arithmetic mean, SD, CV%, GM, geometric CV%, median, minimum, and 
maximum values at each sampling time. 
9.3.5.1. 
Part A Pharmacokinetic Analysis 
Plasma PK parameters will be listed for bupropion, 6-hydroxybupropion, repaglinide, 
flurbiprofen, omeprazole, 5-hydroxyomeprazole, midazolam, and 1-hydroxymidazolam. 
Summary statistics of PK parameters (primary and secondary) will be presented for each 
treatment including mean, GM, SD, CV%, geometric CV%, median, and range. Whole blood 
and plasma PK parameters and will be listed for voxelotor. 
In addition, Cmax, AUCt, and AUCinf of midazolam and 1-hydroxymidazolam with and without 
voxelotor will be summarized by CYP3A5 genotype.
To assess the effect of voxelotor on the PK of the probe substrates and their metabolites, a linear 
mixed effect model will be fitted to the log-transformed values of Cmax, AUCt, and AUCinf. The 
model will include treatment as a fixed effect and participant as a random effect. Point estimates 
and 90% confidence intervals for treatment differences (probe substrate alone versus probe 
substrate administered with voxelotor) on the log scale will be exponentiated to obtain estimates 
for GM ratios on the original scale. For bupropion, both Day 2 and Day 12 in Period 2 will be 
compared separately to Period 1 data.
9.3.5.2. 
Part B Pharmacokinetic Analysis 
Plasma PK parameters will be listed for metformin, furosemide, rosuvastatin, and CP-I. 
Summary statistics of PK parameters (primary and secondary) will be presented for each 
treatment including mean, GM, SD, CV%, geometric CV%, median, and range. Whole blood 
and plasma PK parameters will be listed for voxelotor.
To assess the effect of voxelotor on the PK of the probe substrates, a linear mixed effect model 
will be fitted to the log-transformed values of Cmax, AUCt, and AUCinf. The model will include 
treatment as a fixed effect and participant as a random effect. Point estimates and 
90% confidence intervals for treatment differences (probe substrate alone versus probe substrate 
administered with voxelotor) on the log scale will be exponentiated to obtain estimates for GM 
ratios on the original scale. 
9.3.6. 
Part A and Part B Safety Analyses 
Demographics (age, sex, ethnicity, and race) and baseline characteristics (height, weight, and 
BMI) will be summarized by part and overall. Medical history will be provided in a data listing.
All safety data will be presented in listings by part. Descriptive summaries will be provided for 
AEs, clinical laboratory tests (hematology, serum chemistry, and coagulation), and vital signs 
(HR, BP, respiratory rate, and oral temperature). Urinalysis laboratory tests, concomitant 
medications, and physical examinations will be presented in data listings only. 
The number and percentage of participants reporting any treatment-emergent AE will be 
tabulated by system organ class and preferred term (coded using Medical Dictionary for 
Regulatory Activities). Treatment-emergent AEs will be further classified by severity and 
relationship to treatment. 

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9.4. 
Interim Analysis 
No interim analysis is planned for the primary endpoint. 
9.5. 
Sample Size Determination 
Part A
There will be 26 participants enrolled in Part A. A previous DDI cocktail study (GBT440-003) 
used several probe substrates including midazolam and omeprazole that are common with the 
current protocol. It was shown that voxelotor, at two 900 mg/day doses followed by a 
600 mg/day dose, significantly decreased midazolam elimination in 24 healthy participants but 
had no effect on the PK of omeprazole. Thus, we anticipate that an approximately similar 
number of healthy participants (n=24, adjusting for a potential 10% dropout rate, out of 
26 enrolled participants) would facilitate characterization of the magnitude of DDI when 
1500 mg voxelotor is administered for 4 days. 
Part B
There will be 20 participants enrolled in Part B. Rosuvastatin is used as the probe substrate of 
choice for sample size estimation because robust information on the intrasubject variability is 
lacking at sub-clinical doses of metformin and frusemide. A previous study indicated an 
intrasubject coefficient of variation (intraCV%) of approximately 12.3% for rosuvastatin AUC0-t
and 21.3% for rosuvastatin Cmax. Using the precision method and assuming the true GMR = 1, a 
sample size of 17 subjects will provide the GMR of Cmax, given alone versus given with 
voxelotor, to be within 80% and 125% of the true value, with 90% confidence. Thus, 
approximately 17 subjects (adjusting for a potential 10% dropout rate, out of approximately 
20 enrolled participants) will be sufficient to provide adequate insight into the potential effect of 
voxelotor on the PK of rosuvastatin. 

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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Regulatory, Ethical, and Study Oversight Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
 This study will be conducted in accordance with the protocol and with the following: 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences international ethical guidelines 
Applicable ICH GCP guidelines
 Applicable local laws and regulations 
The protocol, protocol amendments, ICF, Investigator’s Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB by the Investigator and 
reviewed and approved by the IRB before the study is initiated.
Any amendments to the protocol will require IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants.  
 Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
 The Investigator will be responsible for the following: 
 Providing written summaries of the status of the study to the IRB annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB 
 Notifying the IRB of SAEs or other significant safety findings as required by IRB
procedures 
 Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB, European regulation 536/2014 
for clinical studies (if applicable), European Medical Device Regulation 2017/745 
for clinical device research (if applicable), and all other applicable local 
regulations 
10.1.2. 
Financial Disclosure 
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.
10.1.3. 
Informed Consent Process 
 The Investigator or their representative will explain the nature of the study, purpose 
and duration of the study, participation/termination conditions, and risks and benefits, 

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to the participant or their legally authorized representative and answer all questions 
regarding the study. 
 Participants must be informed that their participation is voluntary.  
 Prior to initiation of any study-related procedures, participants will sign and date the 
ICF that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
privacy and data protection requirements, where applicable, and the IRB or study 
center.  
 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 medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF.
 Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study. 
 A copy of the ICF(s) must be provided to the participant [or their legally authorized 
representative] in their native language.
Participants who are rescreened are required to sign a new ICF.
10.1.4. 
Committees Structure 
Not applicable. 
10.1.5. 
Dissemination of Clinical Study Data 
 Participants’ medical information obtained as a result of this study is considered 
confidential, and disclosure to third parties, other than those noted in this protocol, is 
prohibited. Participant to any applicable authorization(s), all reports and 
communications relating to participants in this study will identify participants only by 
initials and number.  
 Medical information resulting from a 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/EC, and other 
authorized parties.  
All information concerning the study medication and the Sponsor’s operations (such 
as patent applications, formulas, manufacturing processes, basic scientific data, or 
other information supplied by the Sponsor and not previously published) are 
considered confidential and shall remain the sole property of the Sponsor. The 

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Investigator agrees to use this information only in conducting this study and to not 
use it for other purposes without the Sponsor’s prior written consent.  
 The information developed in this clinical study will be used by the Sponsor in the 
clinical development of voxelotor and therefore, may be disclosed by the Sponsor as 
required, to authorized parties (including its corporate partners for the study drug, if 
any, and their designated representatives), other clinical Investigators, pharmaceutical 
companies, the FDA, and other government agencies.  
 Any information, inventions, discoveries (whether patentable or not), innovations, 
suggestions, ideas, and reports made or developed by the Investigator(s) as a result of 
conducting this study shall be promptly disclosed to the Sponsor and shall be the sole 
property of the Sponsor. The Investigator agrees, upon the Sponsor’s request and at 
the Sponsor’s expense, to execute such documents and to take such other actions as 
the Sponsor deems necessary or appropriate to obtain patents in the Sponsor’s name 
covering any of the foregoing. 
10.1.6. 
Data Quality Assurance 
 All participant data relating to the study will be recorded on printed or eCRFs unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the eCRF.
 Guidance on completion of eCRFs will be provided in the eCRF completion 
document. 
 The Investigator must permit study-related monitoring, audits, IRB review, and 
regulatory agency inspections and provide direct access to source data documents. 
 Monitoring details describing strategy, including definition of study critical data 
items and processes (eg, risk-based initiatives in operations and quality such as risk 
management and mitigation strategies and analytical risk-based monitoring), 
methods, responsibilities, and requirements, including handling of noncompliance 
issues and monitoring techniques (central, remote, or on-site monitoring) are provided 
in the monitoring plan. 
 The Sponsor or designee is responsible for the data management of this study, 
including quality checking of the data. 
 The Sponsor assumes accountability for actions delegated to other individuals (eg, 
contract research organizations). 
 Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the Investigator for at least 2 years after study completion 
unless local regulations or institutional policies require a longer retention period. No 
records may be destroyed during the retention period without the written approval of 
the Sponsor. No records may be transferred to another location or party without 
written notification to the Sponsor. 

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10.1.7.
Source Documents
Source documents (including copies of protocols, original reports of test results, 
investigational agent dispensing logs, correspondence, records of informed consent, 
and other documents pertaining to the conduct of the study) provide evidence for the 
existence of the participant and substantiate the integrity of the data collected. 
 The Investigator must retain a comprehensive and centralized filing system of all 
study-related source documents that is suitable for inspection by the Sponsor and 
representatives of regulatory authorities. 
 Data entered in the eCRF that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available. 
 The Investigator must maintain accurate documentation (source data) that supports 
the information entered in the eCRF. 
 Study monitors will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
10.1.8. 
Study Documentation and Data Storage
10.1.8.1. Inspection of Records 
 The Sponsor or designees will be allowed to conduct site visits to the investigation 
facilities for the purpose of monitoring any aspect of the study. The Investigator
agrees to allow the monitor to inspect the drug storage area, study drug stocks, drug 
accountability records, participant charts, study source documents, and other records 
relative to study conduct. 
 The Investigator agrees to maintain a Regulatory Binder in a current, organized 
fashion; this Binder will contain documentation supportive of the protocol- and 
GCP-compliance of the study. The contents of the Binder will be organized according 
to the standards of ICH E6, Section 8 (Essential Documents). The Investigator agrees 
to make this Binder accessible to the monitor, auditor, and representatives of 
regulatory agencies and the IRB/EC.
10.1.8.2. Retention of Records 
 All study records must be retained for at least 2 years after the last approval of a 
marketing application in the United States of America or an ICH region and until 
(1) there are no pending or contemplated marketing applications in the USA or an 
ICH region or (2) at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product under study.  

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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. The 
Sponsor must be notified with retention should the Investigator/institution are unable 
to continue with the maintenance of study participant files for the full 15 years. All 
study records must be stored in a secure and safe facility. 
 The Investigators must retain protocols, amendments, IRB approvals, copies of the 
Form FDA 1572, signed and dated consent forms, medical records, eCRFs, drug 
accountability records, all correspondence and any other documents pertaining to the 
conduct of the study. 
 If the 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 
10.1.9. 
Study and Site Start and Closure 
First Act of Recruitment
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
Study/Site Termination 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to:
For study termination: 
Discontinuation of further study intervention development 
For site termination:
Failure of the Investigator to comply with the protocol, the requirements of the IRB 
or local health authorities, the Sponsor’s procedures, or GCP guidelines 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator 
Total number of participants included earlier than expected

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If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IRBs, the regulatory authorities, and any contract research organization(s) used 
in the study of the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The Investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
10.1.10. 
Publication Policy 
 The results of this study may be published or presented at scientific meetings. If this 
is foreseen, the Investigator agrees to submit all manuscripts or abstracts to the 
Sponsor before submission. This allows the Sponsor to protect proprietary 
information and to provide comments. 
 The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
site data. In this case, a coordinating Investigator will be designated by mutual 
agreement. 
 Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 

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11. 
REFERENCES 
Common Terminology Criteria for Adverse Events, Version 5.0. National Cancer Institute. 2017. 
Available at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_50. Accessed 
05 April 2022. 
Dai X, Karol MD, Hitron M, Hard ML, Goulet MT, McLaughlin CF, Brantley SJ. Napabucasin 
Drug-Drug Interaction Potential, Safety, Tolerability, and Pharmacokinetics Following Oral 
Dosing in Healthy Adult Volunteers. Clin Pharmacol Drug Dev. 2021 Aug;10(8):824-839. doi: 
10.1002/cpdd.961. Epub 2021 Jun 9. PMID: 34107166; PMCID: PMC8453567. 
FDA Guidance for Industry Drug-induced Liver Injury: Premarketing Clinical Evaluation. 2009. 
Available at:https://www.fda.gov/regulatory-information/search-fda-guidance-documents/drug-
induced-liver-injury-premarketing-clinical-evaluation. Accessed 24 May 2022. 
Global Blood Therapeutics, Inc. Voxelotor (previously GBT440) Investigator’s Brochure. 
Version 9.0. Effective 17 December 2021. 
Oksenberg D, Dufu K, Patel MP, Chuang C, Li Z, Xu Q, Silva-Garcia A, Zhou C, Hutchaleelaha 
A, Patskovska L, Patskovsky Y, Almo SC, Sinha U, Metcalf BW, Archer DR. GBT440 increases 
haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of 
sickle cell disease. Br J Haematol. 2016 Oct;175(1):141-53. doi: 10.1111/bjh.14214. Epub 2016 
Jul 5. PMID: 27378309. 
OXBRYTA (voxelotor) European Medicines Agency. 
https://www.ema.europa.eu/en/documents/product-information/oxbryta-epar-product-
information_en.pdf. Accessed 01 June 2022. 
Savic RM, Green ML, Jorga K, Zager M, Washington CB. Model-informed drug development of 
voxelotor in sickle cell disease: Population pharmacokinetics in whole blood and plasma. CPT 
Pharmacometrics Syst Pharmacol. 2022 Apr 21. doi: 10.1002/psp4.12731. Epub ahead of print. 
PMID: 35447014. 
Stopfer P, Giessmann T, Hohl K, Sharma A, Ishiguro N, Taub ME, Jungnik A, Gansser D, Ebner 
T, Müller F. Effects of Metformin and Furosemide on Rosuvastatin Pharmacokinetics in Healthy 
Volunteers: Implications for Their Use as Probe Drugs in a Transporter Cocktail. Eur J Drug 
Metab Pharmacokinet. 2018a Feb;43(1):69-80. doi: 10.1007/s13318-017-0427-9. PMID: 
28685495; PMCID: PMC5794840. 
Stopfer P, Giessmann T, Hohl K, Hutzel S, Schmidt S, Gansser D, Ishiguro N, Taub ME, Sharma 
A, Ebner T, Müller F. Optimization of a drug transporter probe cocktail: potential screening tool 
for transporter-mediated drug-drug interactions. Br J Clin Pharmacol. 2018b Sep;84(9):1941-
1949. doi: 10.1111/bcp.13609. Epub 2018 Jun 21. PMID: 29665130; PMCID: PMC6089804. 
Study GBT440-0115. A Multiple-Dose, Randomized, Double-Blind, Placebo-Controlled, 
Active-Comparator, Parallel Study to Investigate the Effect of Voxelotor at a Projected 
Supratherapeutic Concentration on the QT/QTc Interval in Healthy Subjects with a Multiple 
Ascending Dose Run-In Phase. 
Wiebe ST, Giessmann T, Hohl K, Schmidt-Gerets S, Hauel E, Jambrecina A, Bader K, Ishiguro 
N, Taub ME, Sharma A, Ebner T, Mikus G, Fromm MF, Müller F, Stopfer P. Validation of a 

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Drug Transporter Probe Cocktail Using the Prototypical Inhibitors Rifampin, Probenecid, 
Verapamil, and Cimetidine. Clin Pharmacokinet. 2020 Dec;59(12):1627-1639. doi: 
10.1007/s40262-020-00907-w. PMID: 32504272; PMCID: PMC7716890. 

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APPENDIX 1. CONTRACEPTIVE AND BARRIER GUIDANCE 
Contraception Requirements 
All female participants of childbearing potential (post-menarche) should avoid pregnancy, and 
all sexually active male participants should avoid fathering a child.
Female participants will not be considered of childbearing potential if they are surgically sterile 
(hysterectomy, bilateral salpingectomy, tubal ligation, or bilateral oophorectomy) or 
postmenopausal (no menses for 12 months without an alternative medical cause, confirmed by 
FSH test results).
Highly Effective Methods of Birth Control for Female Participants 
Highly effective methods of birth control are defined as those that result in a low failure rate (ie, 
< 1% per year) when used consistently and correctly. Highly effective methods of birth control 
are as follows: 
 Hormonal contraceptives: 
 Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation: oral; intravaginal; injected; implanted; or 
transdermal. 
 Progestogen-only hormonal contraception associated with inhibition of ovulation: 
oral; injectable; or implantable. 
 Hormonal contraception must be supplemented with a barrier method (preferably 
male condom). 
 IUD. 
 IUS. 
 Bilateral tubal occlusion. 
 Sexual abstinence: 
 Sexual abstinence is a highly effective method only if the participant is refraining 
from heterosexual intercourse during the entire period of risk associated with the 
study treatment. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the clinical study and the preferred and usual lifestyle of 
the participant. 
 Male partner who has been vasectomized with confirmation of azoospermia (verbal 
confirmation is acceptable). 
Highly Effective Methods of Birth Control for Male Participants with Female Partners 
Capable of Reproduction
 For male participants who are not surgically sterile with confirmed absence of sperm, 
condom plus effective contraception for their female partners (ie, established use of 
oral, injected, or implanted hormonal contraception, or an IUD or IUS) must be used.

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Vasectomy at least 3 months prior to Day -1 with confirmation of azoospermia 
(verbal confirmation is acceptable).
Contraception Guidance 
Instructions for Female Participants of Childbearing Potential
For female participants of childbearing potential (post-menarche) who are sexually active, 
pregnancy should be avoided. Females must use a highly effective method of contraception 
consistently throughout the study and for at least 30 days after the last dose of study drug. 
Female participants who become pregnant during the study will be withdrawn from the study. 
Pregnancy reporting is described in Section 8.4.7. 
Instructions for Male Participants Capable of Fathering a Child 
No information is available about the effects that voxelotor may 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 received 
his last dose of voxelotor. Sperm donation should be avoided for this same period. 
Males must be surgically sterilized, or agree to practice true abstinence, or agree to use 
acceptable contraception if sexually active with a female partner of childbearing potential, 
throughout the study, and for at least 30 days after the last dose of study drug.  

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APPENDIX 2. GENETICS 
Use/Analysis of DNA
Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Variable response to study 
intervention may be due to genetic determinants that impact intervention absorption, 
distribution, metabolism, and excretion; mechanism of action of the intervention; 
disease etiology; and/or molecular subtype of the disease being treated. Therefore, 
where local regulations and IRB allow, a blood and/or saliva sample will be collected 
for DNA analysis from consenting participants.
 DNA samples will be used for determination of factors that may impact absorption, 
metabolism, transport, and elimination of drugs such as probe substrates used in this 
study. Genotyping may consist of the analysis of one or more candidate genes or the 
analysis of genetic markers throughout the genome or analysis of the entire genome
(as appropriate).
 DNA samples will be analyzed for CYP2C9 or CYP2C19 poor metabolizer status, or 
carrying SLCO1B1 (c.521T>C, rs4149056) variant allele, as well as CYP3A5 
expresser status. 
 The results of genotyping may be reported in the clinical study report or in a separate 
study summary. 
 The Sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
 The samples will be retained while the study continues but no longer than 10 years or 
other period as per local requirements.