Clinical trial NCT05289570
Conditions: Acute Lung Injury End Stage Lung Disease
Sponsor: Duke University
Start date: 2022-05-03; Completion date: 2023-07-04
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of the study is to evaluate the efficacy of voxelotor for increasing oxygen saturation in 20 patients with hypoxemia. Specifically, the SpO2/FiO2 ratio will be compared before and after voxelotor use at rest and during exercise (ambulatory patients only).

The primary study objective is to evaluate the efficacy of voxelotor for increasing oxygen saturation in patients with hypoxic hypoxemia as a result of end-stage lung disease or acute lung injury.

The secondary objective is to evaluate the efficacy of voxelotor on allowing de-escalation of supplemental oxygen support.

Detailed description:
Purpose of the study: Primary study objective is to evaluate the efficacy of voxelotor for increasing oxygen saturation in patients with hypoxic hypoxemia as a result of end-stage lung disease or acute lung injury.

Design and Procedures: The day after obtaining written informed consent, 20 patients will receive 500 mg of voxelotor two times a day (for a total daily dose of 1000 mg per day) for 5 days This dose may increase to a total maximum daily dose of 1500 mg (500 mg three times a day) if subject tolerates initial dose as determined by Principal Investigator (PI).

Physiological data at screening, baseline, study day 1 - 5, and up to two days post voxelotor administration will be recorded from standard of care with the only exception being SpO2/FiO2 (S/F) ratio measurements, which will be obtained at the same intervals but by the qualified and delegated study staff or medical team through the use of an FiO2 weaning maneuver.

Study subjects will be asked to rate their dyspnea symptoms daily to record their perceived shortness of breath.

Blood samples will be collected the day prior to voxelotor administration, on study days 1 - 5, and on the 2 wash-out days following voxelotor administration.

Arms: arm 1: 500 mg of Voxelotor two times a day (for a total daily dose of 1000 mg per day) for 5 days. This dose may increase to a total maximum daily dose of 1500 mg (500 mg three times a day), if subject tolerates the initial dose as determined by study doctor.
Interventions: intervention 1: Voxelotor
Intervention descriptions: intervention 1: 500 mg of voxelotor will be administered two times a day (for a total daily dose of 1000 mg per day) for 5 days. This dose may increase to a total maximum daily dose of 1500 mg (500 mg three times a day) if subject tolerates initial dose as determined by Principal Investigator (PI).

Protocol documents:
Prot_SAP_000.pdf: 
 
CONFIDENTIAL 
This document is confidential and the property of the Duke University.   
NCT05289570 
 
 
 
 
 
PROTOCOL TITLE  
 
 
A Phase 2b Open-Label, Single Arm Study to Evaluate the Efficacy of Voxelotor for 
Improving Oxygen Saturation and Reducing Ventilatory Support Requirements in Adult 
Patients with New or Increased Oxygen Requirement 
 
 
 
 
 
Protocol Number 
Pro00109353 
 
IND Number  
159999 
 
 
 
 
Version 2.0 
 
 
Date 
 
 18 May 2022 
 
 
 
 


 
 
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GBT_Voxelotor Protocol version 2.0_18MAY2022 
 
Regulatory Sponsor: 
Ian J. Welsby, MD  
Duke University Medical Center  
2301 Erwin Road,  
Durham, NC 27710 
919-681-6532 
 
 
Funding Sponsor: 
Global Blood Therapeutics 
181 Oyster Point Blvd. 
South San Francisco CA 94080 
+1 (650) 864-1754 
 
Study Product: 
2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl) 
methoxy)benzaldehyde [Voxelotor (GBT440)] 
 
 


 
 
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GBT_Voxelotor Protocol version 2.0_18MAY2022 
Table of Contents 
STUDY SUMMARY ................................................................................................................................................... 1 
1 
INTRODUCTION .............................................................................................................................................. 2 
1.1 
BACKGROUND ............................................................................................................................................. 2 
1.2 
INVESTIGATIONAL AGENT ........................................................................................................................... 2 
1.3 
PRECLINICAL DATA ..................................................................................................................................... 5 
1.4 
CLINICAL DATA TO DATE............................................................................................................................ 7 
1.5 
DOSE RATIONALE AND RISK/BENEFITS ....................................................................................................... 8 
2 
STUDY OBJECTIVES ...................................................................................................................................... 9 
3 
STUDY DESIGN ................................................................................................................................................ 9 
3.1 
GENERAL DESIGN........................................................................................................................................ 9 
3.2 
PRIMARY STUDY ENDPOINTS .................................................................................................................... 12 
3.3 
SECONDARY STUDY ENDPOINTS ............................................................................................................... 12 
3.4 
PRIMARY SAFETY ENDPOINTS ................................................................................................................... 12 
4 
SUBJECT SELECTION AND WITHDRAWAL.......................................................................................... 12 
4.1 
INCLUSION CRITERIA ................................................................................................................................. 12 
4.2 
EXCLUSION CRITERIA ............................................................................................................................... 13 
4.3 
SUBJECT RECRUITMENT AND SCREENING ................................................................................................. 13 
4.4 
EARLY WITHDRAWAL OF SUBJECTS .......................................................................................................... 14 
4.4.1 
When and How to Withdraw Subjects .................................................................................................. 14 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects ..................................................................... 14 
5 
STUDY DRUG ................................................................................................................................................. 15 
5.1 
DESCRIPTION ............................................................................................................................................. 15 
5.2 
TREATMENT REGIMEN .............................................................................................................................. 15 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS .................................................................. 15 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ............................................................................ 16 
5.5 
SUBJECT COMPLIANCE MONITORING ........................................................................................................ 16 
5.6 
PRIOR AND CONCOMITANT THERAPY ........................................................................................................ 17 
5.7 
PACKAGING ............................................................................................................................................... 17 
5.8 
BLINDING OF STUDY DRUG ....................................................................................................................... 17 
5.9 
RECEIVING, STORAGE, DISPENSING AND RETURN ..................................................................................... 18 
5.9.1 
Receipt of Drug Supplies ..................................................................................................................... 18 
5.9.2 
Storage ................................................................................................................................................. 18 
5.9.3 
Dispensing of Study Drug………………………………………………………………………………………18 
5.9.4 
Return or Destruction of Study Drug ................................................................................................... 18 
6 
STUDY PROCEDURES .................................................................................................................................. 19 
6.1 
SCREENING ................................................................................................................................................ 19 
6.2 
-1 DAY BEFORE VOXELOTOR ADMINISTRATION ......................................................................................... 19 
6.3 
 DAY 1  ...................................................................................................................................................... 20 
    6.4         DAY 2……………………………………………………………………………………………….......20   
    6.5         DAY 3-5…………………………………………………………………………...........21 
     6.6          DAY 6…………………………………………………………………………………………………   21 
     6.7          DAY 7……………………………………………………………………………………………. ….....22 
7 
STATISTICAL PLAN ..................................................................................................................................... 22 
7.1 
SAMPLE SIZE DETERMINATION ................................................................................................................. 22 
7.2 
STATISTICAL METHODS............................................................................................................................. 22 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS .................................................................................................. 23 


 
 
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8 
SAFETY AND ADVERSE EVENTS ............................................................................................................. 23 
8.1 
DEFINITIONS .............................................................................................................................................. 23 
8.2 
RECORDING OF ADVERSE EVENTS............................................................................................................. 25 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS ............................................................................................... 26 
8.3.1 
Study Sponsor Notification by Investigator ......................................................................................... 26 
8.3.2 
EC/IRB Notification by Investigator .................................................................................................... 26 
8.3.3 
FDA Notification by Sponsor ............................................................................................................... 26 
8.4 
STOPPING RULES ....................................................................................................................................... 27 
8.5 
MEDICAL MONITORING ............................................................................................................................. 27 
9 
DATA HANDLING AND RECORD KEEPING .......................................................................................... 27 
9.1 
CONFIDENTIALITY ..................................................................................................................................... 27 
9.2 
SOURCE DOCUMENTS ................................................................................................................................ 28 
9.3 
CASE REPORT FORMS ................................................................................................................................ 28 
9.4 
RECORDS RETENTION ................................................................................................................................ 28 
 
10 
STUDY MONITORING, AUDITING, AND INSPECTING ....................................................................... 28 
10.1 
STUDY MONITORING PLAN ....................................................................................................................... 28 
10.2 
AUDITING AND INSPECTING ....................................................................................................................... 28 
11 
ETHICAL CONSIDERATIONS .................................................................................................................... 29 
12 
STUDY FINANCES ......................................................................................................................................... 29 
12.1 
FUNDING SOURCE ..................................................................................................................................... 29 
12.2 
CONFLICT OF INTEREST ............................................................................................................................. 29 
13 
PUBLICATION PLAN .................................................................................................................................... 29 
14 
REFERENCES ................................................................................................................................................. 30 
 
 
List of Tables  
Table 1: Delay of Sickle Hemoglobin Polymerization by Voxelotor, and Fetal Hemoglobin…..5 
Table 2:.. Schedule of Activities and/or other clinical  outcomes.................................................10  
Table 3:...Volume of Liquid per Dose of Voxelotor Dispersible Tablet ..................................... 11  
Table 4  Dose Modification Guidelines for Study Drug Related Adverse Events ……………...15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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List of Abbreviations 
 
Abbreviation 
Definition 
AE 
Adverse event 
ALI 
Acute lung injury 
ARDS 
Acute Respiratory Distress Syndrome 
CAS 
Chemical abstract services 
CR 
Child-resistant 
CRF 
Case Report Form 
DPG 
Diphosphoglycerate 
ECG 
Electrocardiogram 
ECMO 
Extracorporeal membrane oxygenation 
eIND 
Exempt investigational new drug 
EMR 
Electronic medical record 
ESLD 
End -stage lung disease 
FDA 
Food and drug administration 
FEMA 
Flavor and Extract Manufacturers Association of the United States 
FiO2 
Fraction of inspired oxygen 
GBT 
Global Blood Therapeutics  
GMP 
Good manufacturing practice 
GRAS 
Generally recognized as safe 
Hb 
Hemoglobin 
HbF 
Fetal hemoglobin 
Hb-O2 
Hemoglobin-oxygen 
HbS 
Sickle hemoglobin 
Hct 
Hematocrit 
HR 
Heart rate 
ICU 
Intensive care unit 
IDS 
Investigational drug services 
IID 
Inactive Ingredients Database 
INN 
International nonproprietary name 
IPF 
Idiopathic pulmonary fibrosis  
LAR 
Legally Authorized Representative 
LPM 
Liters per minute 
NYHA 
New York Heart Association Functional Classification 
O2 
Oxygen  
OEC 
Oxygen equilibrium curve(s) 
ODC 
oxygen dissociation curve 
p20 
Partial pressure of oxygen resulting in 20% saturation of hemoglobin with oxygen 
p50 
Partial pressure of oxygen resulting in 50% saturation of hemoglobin with oxygen 


 
 
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PaCO2 
Partial pressure of carbon dioxide 
PaO2 
Partial pressure of oxygen 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PO2 
Partial pressure of oxygen 
PP 
Polypropylene 
RBC 
Red blood cells 
Abbreviation 
Definition 
RN 
Registered nurse 
SAE 
Serious Adverse event 
SaO2 
Oxygen saturation 
SCD 
Sickle cell disease 
S/F 
SpO2/FiO2 ; ratio of inspired oxygen needed to obtain a specific oxygen saturation 
SOC 
Standard of care 
SpO2 
Oxygen saturation 
SS 
Sickle cell 
SSRBC 
Sickle cell red blood cell 
STRT 
Study team respiratory therapist 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
VOC 
Vaso-occlusive crisis 
 
 
 
 
 
 
 
 
 


                                    
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CONFIDENTIAL 
This document is confidential and the property of the Duke University.   
Study Summary 
Title 
A Phase 2b Open-Label, Single Arm Study to Evaluate the Efficacy of 
Voxelotor for Improving Oxygen Saturation and Reducing Ventilatory 
Support Requirements in Adult Patients with New or Increased Oxygen 
Requirement 
Short Title 
GBT Voxelotor 
Protocol Number 
Pro00109353   
Phase 
Phase 2b 
Methodology 
Open label, single arm 
Study Duration 
24 months 
Study Center(s) 
Single-center  
Objectives 
Primary study objective - To evaluate the efficacy of voxelotor for 
increasing oxygen saturation in patients with hypoxic hypoxemia as a 
result of end-stage lung disease or acute lung injury. 
 
Secondary study objective - To evaluate the efficacy of voxelotor on 
allowing de-escalation of supplemental oxygen support. 
Number of Subjects 
20 
Diagnosis and Main 
Inclusion Criteria 
Oxygen dependency due to an end-staged lung disease (pre-lung 
transplant population) or ALI/acute lung injury (e.g. primary allograft 
dysfunction, infectious pneumonia, aspiration, non-cardiogenic 
pulmonary edema). 
Study Product, Dose, 
Route, Regimen 
2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl) 
methoxy)benzaldehyde [Voxelotor (GBT440)] 
Duration of 
administration 
500 mg of voxelotor two times a day (for a total daily dose of 1000 mg 
per day) for 5 days. This dose may increase to a total maximum daily 
dose of 1500 mg (500 mg three times a day), if subject tolerates the 
initial dose as determined by study doctor. 
Reference therapy 
Anecdotal evidence from an ECMO dependent Duke intensive care unit 
(ICU) patient who received Voxelotor on a compassionate use basis, 
after seeking an eIND from the FDA, who was rapidly weaned from 
ECMO and ventilatory support. 
Statistical 
Methodology 
Descriptive statistics for patient characteristics and baseline factors will 
be presented as median and interquartile range for continuous variables 
and number and percentage for categorical variables.   
 


 
 
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1 Introduction 
This document is a protocol for a human research study. This study is to be conducted according 
to US and international standards of Good Clinical Practice (FDA Title 21 part 312 and 
International Conference on Harmonization guidelines), applicable government regulations and 
Institutional research policies and procedures. 
 
Voxelotor (GBT440) is a small molecule inhibitor of sickle hemoglobin (HbS) polymerization 
which allosterically modifies hemoglobin-oxygen (Hb-O2) affinity that was developed by Global 
Blood Therapeutics (GBT) and is FDA-approved for the treatment of sickle cell disease in adults 
and pediatric patients 12 years of age and older.   
1.1 Background 
Treatment for decompensation of end-stage lung disease (ESLD) or acute lung injury (ALI) with 
hypoxemia may include disease modifying drugs (such as anti-fibrotic medications or steroids) 
and anti-viral/anti-microbial agents. However, escalation of the need for supplemental oxygen, 
complexity of modality of supplemental oxygen delivery, up to and including invasive 
mechanical ventilation, may still be required. Transfer to a monitored bed or an intensive care 
unit is typically triggered by the degree of arterial desaturation in a setting of escalating oxygen 
requirements, although ICU bed availability may be critically limited. The indication for 
intubation is typically refractory hypoxemia with falling levels of the saturation of hemoglobin 
(Hb) with oxygen (SaO2), yet mortality is high with recovery after intubation being slow and 
fraught with complications due to the need for heavy sedation and possible ventilator induced 
lung injury; avoiding intubation would be ideal. This is especially true for the pre-lung transplant 
population, where “pre-habilitation” is essential for a favorable outcome and loss of ambulatory 
status (as is often the case with escalating oxygen requirements and intubation) portends an 
increased mortality after lung transplantation. 
 
As an alternative, additive measure to escalating ventilation modality or the fraction of inspired 
oxygen (FiO2), increasing the affinity of hemoglobin for oxygen offers the ability to optimize the 
SaO2 for a given partial pressure of oxygen in the arteries (paO2, i.e. hypoxemia) and, by 
increasing the SaO2, postpone or avoid the need for ICU transfer and/or intubation, buying more 
time for the innate, or treatment induced, resolution of ALI or permitting continued ambulation 
pre-transplant. This concept is supported by anecdotal evidence from an ECMO dependent ICU 
patient who received voxelotor on a compassionate use basis, after seeking an eIND from the 
FDA, who was rapidly weaned from ECMO and ventilatory support. 
1.2 Investigational Agent 
 
PHYSICAL, CHEMICAL, AND PHARMACEUTICAL PROPERTIES AND 
FORMULATION 
 
Molecular Structure 
Chemical Name: 2-Hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl) 
methoxy)benzaldehyde  
Company Code: GBT440  


 
 
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GBT_Voxelotor Protocol version 2.0_18MAY2022 
Chemical Abstracts Service (CAS) registry number: 1446321-46-5  
International Nonproprietary Name (INN): Voxelotor 
 
Structure: 
 
 
 
Molecular Formula: C19H19N3O3 
 
 Molecular Weight: 337.4 
 
Physical Description Voxelotor is a synthetic small molecule bearing the chemical name 2-
hydroxy-6-((2-(1- isopropyl-1H-pyrazol-5-yl)pyridin-3-yl) methoxy)benzaldehyde. The 
chemical formula is C19H19N3O3 and the molecular weight is 337.4.  
 
Voxelotor is a white-to-yellow-to-beige compound in crystalline Form II of GBT440 free base. It 
is non-hygroscopic. It is highly soluble in common organic solvents such as acetone and toluene 
and insoluble in water (approximately 0.03 mg/mL). Voxelotor drug substance is manufactured 
in accordance with Good Manufacturing Practice (GMP). The chemistry used in the production 
of voxelotor drug substance is well established. The manufacturing process uses equipment 
commonly available in the industry. 
 
Nonclinical Pharmacology  
The pharmacology program established the mechanism of action by testing effects of  
voxelotor on HbS and by assessing the benefit on downstream inhibition of HbS  
polymerization both in vitro and in animal disease models 
 
Primary Pharmacology  
The in vitro primary pharmacology studies defined the mechanism of action of voxelotor and  
the in vivo studies determined the relationship between voxelotor blood concentration and ex  
vivo effects on Hb-O2 affinity as well as its physiologic and pathologic effects in a sickle cell 
mouse model. In addition, using a voxelotor analogue in C57BL/6 and sickle cell disease (SCD) 
mice, these studies also addressed its ability to preserve oxygen (O2) extraction in various 
organs, including the brain, ultimately translating to improved survival. Findings from the 
primary pharmacological studies demonstrated that voxelotor has the ability to:  
 
 bind specifically to Hb, 
 
 partition to red blood cells (RBCs),  
 
 increase Hb-O2 affinity and stabilize the oxyHb state,  
 
 inhibit HbS polymerization,  
 
 improve RBC rheology in human sickle cell (SS) blood,  
 
 exhibit ex vivo anti sickling activity in a SCD mouse model,  


 
 
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GBT_Voxelotor Protocol version 2.0_18MAY2022 
 
 increase RBC half-life and reduce reticulocyte counts in a SCD mouse model,  
 
in addition, a voxelotor analogue preserved O2 extraction in various organs and  
            improved brain oxygenation and survival in both normal and SCD mice.  
 
Furthermore, these studies showed that voxelotor-modified Hb can release O2 at lower pH,  
indicating that voxelotor binding to Hb does not interfere with the ability of Hb to deliver and  
offload O2 to metabolically active tissues. 
 
Binding of Voxelotor to Hemoglobin  
Crystallography studies of cocrystals of carbon monoxide-liganded Hb and voxelotor show  
that:  
 
Voxelotor binds to the N-terminal valine residue of an α chain; a single GBT440  
            molecule binding per Hb tetramer in a 1:1 stoichiometry (Study PRC-18-048;  
            Oksenberg D, 2016;1 Metcalf B, 2017).2  
 
The voxelotor binding site is distant from heme pockets and therefore does not  
            directly prevent release of O2 from Hb (Patel M, 2014,3 data on file).  
            Thus, voxelotor increases Hb-O2 affinity without sterically blocking the release of O2. 
 
Effect of Voxelotor on Hemoglobin-Oxygen Affinity  
The oxygen equilibrium curve (OEC) for whole blood relates the extent of Hb-O2 saturation to 
the partial pressure of oxygen (pO2) and measures the binding affinity of O2 to Hb. Blood OECs 
allow for the measurement of the partial pressure of oxygen resulting in 20% saturation of 
hemoglobin with oxygen (p20) or partial pressure of oxygen resulting in 50% saturation of 
hemoglobin with oxygen (p50) values, which are the pO2 at which Hb is 20% or 50% saturated 
with O2, respectively. Measurement of OECs using whole blood from patients with SCD (Figure 
2) shows a dose-dependent left-shift of the OEC and decrease in p50 and p20 values upon 
addition of voxelotor (Figure 1). 
 
Figure 1:            Effect of Voxelotor on Hemoglobin-Oxygen Affinity in Whole Blood from 
                            Patients with SCD 
 
 
Abbreviations: O2, oxygen; pO2, partial pressure of oxygen. 
Source: Study PRC-14-027-R 
 
 


 
 
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Stabilization of Hemoglobin in a High Oxygen Affinity State by Voxelotor  
Hb exists in both a R and a T state with high and low affinity for O2, respectively. Cooperativity 
arises from a shift in the population from the low affinity T structure to the high affinity R 
structure with increasing O2 affinity (Eaton WA, 1999).4 Using the oxygen dissociation assay (), 
voxelotor was shown to effectively maintain a high percent of Hb in the oxyhemoglobin 
conformation (associated with the R state) under hypoxic conditions (Study PRC-14-033-R; 
Patel MP, 2018)5 whilst maintaining the ability of O2 to offload from Hb. 
 
Voxelotor-modified Hb maintains the physiological mechanisms required for tissue O2 
extraction  
The ability of H+ ions and 2,3 diphosphoglycerate (DPG) to reduce Hb-O2 affinity are 2 of the 
key physiologic mechanisms that drive O2 offloading to metabolically active tissues. In vitro 
studies with voxelotor modified Hb and whole blood in the presence of H+ ions or DPG showed 
the expected increase in dissociation of O2. Therefore, physiologic mechanisms of augmenting 
tissue O2 extraction, including the Bohr effect and 2,3 DPG binding (Studies PRC-14-029-R and 
PRC-18-046) are preserved with voxelotor modified Hb. 
1.3 Preclinical Data 
Prevention of Sickle Hemoglobin Polymerization and Red Blood Cell Sickling In Vitro  
The intracellular polymerization of HbS upon deoxygenation is the primary pathogenic event in 
SCD (Noguchi CT, 1981).6 Delaying HbS polymerization long enough may prevent the RBCs 
from damage and sickling while transiting hypoxic tissue capillaries in patients with SCD. 
Therefore, the ability of voxelotor to delay HbS polymerization in vitro was evaluated (Study 
PRC-14-040-R). Voxelotor was shown to delay polymerization in a dose-dependent manner and 
mimicked the profile of polymerization delay afforded by the presence of 20% to 30% fetal 
hemoglobin (HbF) (Table 1). 
 
 
These data indicate that like HbF, voxelotor is a potent inhibitor of in vitro HbS polymerization 
and suggest that by delaying HbS polymerization, voxelotor may prevent RBC damage and 
sickling from patients with SCD.  
 
This decrease in polymerization causes a corresponding dose dependent decrease in the number 
of sickled RBCs (SS RBCs) in blood from patients with sickle cell disease under variable 
hypoxic conditions. The therapeutic target of 30% modification is sufficient to prevent in vitro 


 
 
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sickling of SS RBCs at an O2 tension typical of tissue capillaries (40 mmHg) (Study PRC-14-042 
R).  
 
Voxelotor dose-dependently reduced the number of sickled RBCs under hypoxic conditions (pO2 
of < 40 mmHg) (Figure 3), mimicking O2 tensions in tissue capillaries. 
Effect on Sickle Blood Viscosity and Deformability In Vitro Furthermore, by inhibiting HbS 
polymerization, voxelotor improves SS RBC deformability and decreases SS blood 
hyperviscosity in vitro under hypoxic conditions (Studies PRC-14-044-R and PRC-14-031-R, 
Dufu K, 2018).7 The effect of voxelotor on SCD blood viscosity was evaluated under 
deoxygenated conditions and compared to untreated SCD blood and blood from healthy subjects. 
Voxelotor reduced the viscosity of the deoxygenated SS blood when compared to untreated 
deoxygenated SCD blood (Figure 4A) and the viscosity of deoxygenated SCD blood improves 
with increasing voxelotor concentrations (Figure 2) 
 
Figure 2:       Voxelotor Prevents Red Blood Cell Sickling 
 
 
 
Abbreviations: RBC, red blood cell; pO2, partial pressure of oxygen. 
Source: Study PRC-14-042-R. 
 
Effect on Sickle Blood Viscosity and Deformability In Vitro  
Furthermore, by inhibiting HbS polymerization, voxelotor improves SS RBC deformability and 
decreases SS blood hyperviscosity in vitro under hypoxic conditions (Studies PRC-14-044-R and 
PRC-14-031-R, Dufu K, 2018).8 The effect of voxelotor on SCD blood viscosity was evaluated 
under deoxygenated conditions and compared to untreated SCD blood and blood from healthy 
subjects.  
 
Voxelotor reduced the viscosity of the deoxygenated SS blood when compared to untreated 
deoxygenated SCD blood (Figure 3A) and the viscosity of deoxygenated SCD blood improves 
with increasing voxelotor concentrations (Figure 3B). 
 
 
 
 
 


 
 
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GBT_Voxelotor Protocol version 2.0_18MAY2022 
Figure 3:     Voxelotor Reduces the Hyperviscosity Observed in SCD Blood 
 
               Source: Study PRC-14-044-R. 
 
Decreased RBC deformability and increased RBC rigidity in SCD have significant positive 
implications for microcirculatory blood flow and prevention of end-organ damage. 
Deformability experiments also showed that voxelotor restored deformability of human SS RBC 
under hypoxic conditions (Study PRC-14-031-R). In vitro results indicate that voxelotor reduces 
the blood hyperviscosity associated with deoxygenation of HbS. Since the viscosity of SCD 
blood under hypoxic conditions is primarily determined by polymer load, these data suggest that 
voxelotor decreased SS blood viscosity by reducing intracellular polymer load resulting from 
HbS polymerization. Consequently, this suggests a potential to improve the blood flow in the 
microcirculation, thus improving O2 delivery to peripheral tissues. As viscosity increases with 
hematocrit (Hct), and because sickle blood has an increased viscosity compared to normal blood 
for any given Hct, these results are important in supporting the potential for voxelotor to increase 
Hct and Hb in SCD patients without causing a clinically adverse worsening in blood viscosity. 
1.4 Clinical Data to Date 
GBT Sponsored Clinical Studies  
As of 05 November 2020, 28 clinical development studies (8 studies in SCD, 2 studies in 
idiopathic pulmonary fibrosis (IPF), 17 clinical pharmacology studies, and 1 study of healthy 
participants under hypoxic conditions, Study GBT440-0111) have enrolled an estimated 939 
participants who have been exposed to at least 1 dose of voxelotor. An additional 176 clinical 
study participants received placebo in the voxelotor development program. The 939 participants 
who received voxelotor consist of:  
 
430 participants with SCD: 276 adults and 154 pediatric participants (this includes 
participants enrolled in the expanded access program)  
 
404 healthy participants from the 17 clinical pharmacology studies (including participants 
with severe renal impairment [not on dialysis] and participants with hepatic impairment) 
 
62 healthy participants enrolled in studies other than clinical pharmacology (GBT440-
001 and GBT440-0111) 
 
43 adult participants with IPF 


 
 
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1.5 Dose Rationale and Risk/Benefits 
Based on the clinical studies safety data evaluated to date, voxelotor has an acceptable safety 
profile and has been well tolerated in adult and pediatric participants (aged 4 to < 18 years) with 
SCD. The most common adverse reactions in participants with SCD ≥ 12 years old were 
diarrhea, abdominal pain, nausea, rash, and pyrexia. Other clinically relevant and less frequent 
adverse reactions included drug hypersensitivity (< 1%). There were no reported events of 
anaphylaxis or anaphylactoid reactions. The majority of Treatment Emergent Adverse Event 
(TEAEs) were Grade1 to Grade 2 severity, clinically manageable, reversible or resolved. The 
TEAE profile of voxelotor for pediatric participants with SCD aged ≥ 4 to 11 years at a dose of 
1500 mg or equivalent weight-based dosing is acceptable with no new safety observations and is 
consistent with the data for adults and adolescent participants. 
 
Overall, the safety profile was similar between adults and pediatric participants aged ≥ 4 years 
and between participants who were or were not receiving hydroxyurea concomitantly.  
 
In the pivotal Study GBT440-031, over the 72-week treatment period, there was a trend towards 
a lower overall incidence of vaso-occulsive crisis (VOC) with numerically fewer VOC events in 
the voxelotor groups compared to the placebo group, although the differences did not reach 
statistical significance. No increase in the incidence of VOC was observed following 
discontinuation of voxelotor (up to 28 days after the last dose of study drug).  
 
No clinical safety concerns consistent with inadequate tissue oxygenation were identified in the 
voxelotor clinical development program, including in SCD study participants. 
 
The most common side effects of voxelotor include: 
• 
Headache 
• 
Diarrhea 
• 
Stomach (abdominal) pain 
• 
Nausea 
• 
Fatigue (Tiredness) 
• 
Rash 
• 
Fever 
 
Less common, but severe, side effects of voxelotor include: 
• 
Pulmonary embolism 
• 
Hypersensitivity reactions (occurring in <1% of patients treated), including the following    
symptoms: 
 
Generalized rash 
 
Urticaria (hives) 
 
Mild shortness of breath 
 
Mild facial swelling 
 
Eosinophilia (an increase in one of the white blood cells in your blood called eosinophils) 
 
As voxelotor increases the binding of oxygen to hemoglobin (providing the treatment effect of 
increased SpO2 for a given pO2), we will monitor for the possibility of inadequate oxygen being 
off-loaded to the tissues by measuring venous blood gases for evidence of metabolic acidosis 


 
 
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GBT_Voxelotor Protocol version 2.0_18MAY2022 
from tissue beds and tracking renal function as a reflection of adequacy of tissue oxygen during 
administration of Voxelotor. 
 
There may also be risks, discomforts, drug interactions, or side effects that are not yet known. 
2 Study Objectives 
The purpose of the study is to evaluate the efficacy of voxelotor for increasing oxygen saturation 
in patients with hypoxemia. Specifically, the SpO2/FiO2 ratio will be compared before and after 
voxelotor use at rest and during exercise (ambulatory patients only). 
 
Primary study objective  
To evaluate the efficacy of voxelotor for increasing oxygen saturation in patients with hypoxic 
hypoxemia as a result of end-stage lung disease or acute lung injury. 
 
Secondary study objective 
 To evaluate the efficacy of voxelotor on allowing de-escalation of supplemental oxygen support. 
 
 Exploratory endpoints: Pre and post Voxelotor use compare 
 
FiO2 requirements  
 
Oxygen delivery modality 
 
Combined end-point of de-escalation of FiO2 and/or oxygen delivery modality 
 
Nadir SpO2 
 
Oxygen flow 
 
Healthcare utilization 
 
Dyspnea scale 
3 Study Design 
3.1 General Design 
Following a screening period and observation that clinical status is stable and requiring 
substantial oxygen support for 48 hours, subjects with decompensation of ESLD or ALI with 
hypoxemia, will be approached for informed consent. The nature of the risks and benefits 
associated with participation in the study will be explained to all potential study subjects or 
legally authorized representative (LAR). Written informed consent must be obtained before the 
subject can begin any screening procedures that are not considered standard patient care.  
 
Physiological data: Physiological data at screening, baseline, study day 1 – 5, and up to two 
days post voxelotor administration will be recorded from standard of care with the only 
exception being SpO2/FiO2 (S/F) ratio measurements, which will be obtained at the same 
intervals but by the  qualified and delegated study staff or medical team through the use of an 
FiO2 weaning maneuver.  
 
Physiological measures to be recorded are detailed on the Schedule of Activities table 2. 


 
 
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GBT_Voxelotor Protocol version 2.0_18MAY2022 
FiO2 Weaning Maneuver: The process of titrating FiO2 down slowly until the study patient’s 
SpO2 measurement is approximately 88%. This will provide the study team with values for an 
S/F ratio that more closely represents the transition to the steepest part of the oxygen dissociation 
curve (ODC). Measurements that represent this transition on the ODC will allow for more 
precise comparison and provide more accurate trending data. Once completed, the oxygen 
delivery system will be titrated back to achieve SpO2 goals prescribed by the medical team.   
 
Modified Borg Dyspnea Scale: Study subjects will be asked to rate their dyspnea symptoms 
daily to record their perceived shortness of breath. 
 
Blood Sampling: Blood samples will be drawn as part of this study. Arterial blood gas samples 
will only be obtained for patients with an indwelling arterial line. Placement of an Aline is not a 
requirement for the study, but likely standard of care (SOC) for this patient population. The 
blood samples will be collected the day prior to voxelotor administration, on study day 1 – 5, and 
on the 2 wash out days following voxelotor administration. Blood will be collected and sent to a 
core laboratory for measurement of erythropoetin levels (for evidence of renal medullary 
hypoxia), drug trough level measurement via pharmacokinetics (PK), and P50.  Local lab will be 
used for Hematology and Chemistry.  A total of 109 mls of blood will be collected for this study. 
 
See Schedule of Activities Table 2. 
 
Central lab collection and processing: 
PK, P50, and erythropoetin labs will be collected, processed, and stored as described in Study 
Lab Manual. 
 
Voxelotor administration: The day after obtaining written, informed consent, 500 mg of 
voxelotor will be administered two times a day (for a total daily dose of 1000 mg per day) for 5 
days.  This dose may increase to a total maximum daily dose of 1500 mg (500 mg three times a 
day) if subject tolerates initial dose as determined by Principal Investigator (PI). Subjects will be 
dosed orally with approved tablets or recently approved dispersible tablet in water and given via 
feeding tube (when indicated). In the event the voxelotor administration needs to be modified 
during one of the study administration days for patient safety reasons, the PI will follow the dose 
modification guidelines for study related adverse events (Table 4). If the PI determines 
discontinuation of voxeletor is necessary for patient safety, then the protocol will progress to the 
wash out phase identified in the Schedule of Activities table 2.   
 
If a patient on the lung transplant list receives an “initiation call” from the lung transplant 
coordinators, study medication will be held until a determination is made to proceed with solid 
organ transplantation. In the event the study patient does not receive the solid organ transplant, 
study medication administration will be resumed as previously scheduled and missed doses will 
be not be considered protocol deviations as the PK and pharmacodynamics (PD) of Voxelotor in 
the setting of surgery, blood loss, and blood transfusion is unknown. In the event the study 
patient receives a “go call” for solid organ lung transplant then study medication will be 
discontinued and the subject will proceed to the study wash out phase. 
 


 
 
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GBT_Voxelotor Protocol version 2.0_18MAY2022 
Voxelotor is oral administration only and the effect of blood transfusion “diluting” the Voxelotor 
modified RBCs is unknown, so the effect of Voxelotor in this setting will be confounded by the 
common scenario of blood transfusion and/or hemodilution and they will enter the wash-out 
period. Also, the indication for Voxelotor, to maintain SaO2 in the face of a significant Alveolar-
arterial pO2 gradient, will have passed with the implantation of donor lungs. 
 
Study completion is at the end of 2 day wash out period defined by 2 days after the last 
administration of Voxelotor.  
 
Physiological measures and laboratory data to be recorded from electronic medical record 
(EMR) are detailed on the Schedule of Activities Table 2. 
 
Table 2: Schedule of Activities and/or other clinical outcomes 
 
Baseline 
Measurements 
Dosing Period 
Wash out Period 
Study Day 
D-2 
D-1 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
Screening 
x 
 
 
 
 
 
 
 
 
Consent 
x 
 
 
 
 
 
 
 
 
Voxelotor Dosing 
 
 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Physiological 
 
 
 
 
 
 
 
 
 
ESLD and ALI cohort 
(At rest and with exercise*) 
 
  
 
 
 
 
 
 
 
 
SpO2 
x 
x 
x 
x 
x 
x 
x 
x 
x 
FiO2 
x 
x 
x 
x 
x 
x 
x 
x 
x 
S/F ratio calculation 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HR 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ALI cohort 
 
 
 
 
 
 
 
 
 
paO2 
x 
x 
x 
x 
x 
x 
x 
x 
x 
SaO2 
x 
x 
x 
x 
x 
x 
x 
x 
x 
P/F ratio calculation 
x 
x 
x 
x 
x 
x 
x 
x 
x 
paCO2 
x 
x 
x 
x 
x 
x 
x 
x 
x 
A-a gradient calculation 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Borg Dyspnea Scale 
rating 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Laboratory 
 
 
 
 
 
 
 
 
 
Erythropoietin (5ml) 
 
x 
 
x 
 
 
 
x 
 
PK (2ml) 
 
x 
x 
x 
x 
x 
x 
x 
x 
P50 (3ml) 
 
x 
x 
x 
x 
x 
x 
x 
x 
BMP (4.5ml) 
 
 
x 
x 
x 
x 
x 
x 
 
CMP (4.5ml) 
 
x 
 
 
 
 
 
 
x 
CBC (3ml) 
 
x 
x 
x 
x 
x 
x 
x 
x 
Pregnancy test (2 ml) 
 
x 
 
 
 
 
 
 
 
Con meds 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse Events 
 
 
x 
x 
x 
x 
x 
x 
x 
*only if feasible, ambulatory patients only. Exercise protocol is SOC and data collected will be reviewed from medical 
record. 


 
 
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GBT_Voxelotor Protocol version 2.0_18MAY2022 
**  
3.2 Primary Study Endpoints 
The primary outcome will be change in S/F ratio from baseline to 2 days after initiation of 
Voxelotor treatment. 
3.3 Secondary Study Endpoints 
Secondary study endpoint is change in S/F ratio from baseline to 5 days after initiation of 
Voxelotor treatment. 
 
Exploratory endpoints: Pre and post Voxelotor use compare 
 
FiO2 requirements  
 
Oxygen delivery modality 
 
Combined end-point of de-escalation of FiO2 and/or oxygen delivery modality 
 
Nadir SpO2 
 
Oxygen flow 
 
healthcare utilization 
 
Dyspnea scale 
3.4 Primary Safety Endpoints 
Based on current knowledge of safety profiles, a primary safety end-point will not be specified. 
Safety will be assessed by tracking SOC clinical laboratory tests (hematology profile, serum 
chemistry, erythropoietin and urinalysis), physical examinations, vital signs, 12‐lead 
electrocardiogram (ECG) pre-administration and after Day 5. Hematology and chemistry labs 
will be screened before study drug administration and repeated daily until end of study. Vital 
signs will be monitored during study drug administration. Adverse events (AEs) and concomitant 
medications will be monitored and documented throughout the study. Of note, in a recent study 
in patients with impaired renal function, there was no deterioration of renal function. 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984382/ 
4 Subject Selection and Withdrawal 
4.1 Inclusion Criteria 
1. Oxygen dependency due to an end-stage lung disease (pre-lung transplant population) 
or ALI/acute lung injury (for example but not limited to primary allograft 
dysfunction, infectious pneumonia, aspiration, non-cardiogenic pulmonary edema). 
ALI will be defined as per Berlin criteria with a P/F ratio < 100 denoting severe acute 
respiratory distress syndrome (ARDS), < 200 denoting moderate and < 300 mild 
ARDS. ALI and mild ARDS are considered synonymous. In the event of inability to 
obtain arterial blood gas analysis to calculate a P/F ratio, we will consider a range of 
patients requiring standard nasal cannulae flowing at 6 LPM (liters per minute) to 
maintain SaO2 > 90% as ALI, and Salter High -Flow nasal cannulae at 12-15 LPM in 
order to maintain SaO2 > 85% as severe ARDS. 
2. At least 48 hours of stable, increased oxygen requirement or ventilatory support prior 
to the start of drug administration if consented. 


 
 
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GBT_Voxelotor Protocol version 2.0_18MAY2022 
4.2 Exclusion Criteria 
1. Minors (<18 years) 
2. Pre-existing congestive cardiac failure (NYHA III or IV) 
3. Medically significant, non-revascularized coronary artery disease 
4. Inability to obtain informed consent from LAR 
5. Pregnancy 
6. Incarcerated individual. 
7. Failure of another vital organ.  
8. Severe hepatic impairment (Childs-Pugh C) or liver enzymes > 4x upper limit of 
normal (ULN) at screening. 
9. Unstable acute kidney injury/rising creatinine. 
10. Chronic neuromuscular disease requiring mechanical ventilation 
11. Not anticipated to survive >48 hours 
12. Limited therapeutic goals (do not resuscitate, etc.) 
13. History of Pulmonary Embolism (PE) 
14. Requires treatment with Fluconazole or other moderate and strong CYP3A4 
inhibitors listed in section 5.6 
15. A patient with active bleeding complications requiring more than 1 unit of blood 
transfusion per day. 
16. Participated in another clinical trial of an investigational drug (or medical device) 
within 30 days or 5-half-lives, whichever is longer, prior to consent, or is currently 
participating in another trial of an investigational or marketed drug (or medical 
device) 
17. Any condition including the presence of laboratory abnormalities, which places the 
subject at unacceptable risk if he/she were to participate in the study 
18. Any condition or concomitant medication that confounds the ability to interpret data 
from the study or safely use Voxelotor.   
4.3 Subject Recruitment and Screening 
 A screening period and observation that subject’s clinical status is stable and requiring 
substantial oxygen support will be observed for 48 hours.  Research team will be informed of 
subjects meeting eligibility criteria and plan to approach. A member of the subject’s clinical care 
team will first approach an individual subject or LAR who is a potential candidate for 
participation. If the subject or LAR is interested in participating in the study, a study team 
member will explain the purpose, procedures, and intent of the study to each potential study 
subjects or LAR. Written informed consent must be obtained before the subject can begin any 
screening procedures that are not considered standard patient care.  
 
In the event a legal representative provides consent at the time of enrollment, the subject’s 
diminished capacity will be assessed throughout study enrollment, and they will be approached 
for consent if/when they regain the ability to make medical decisions for themselves. 
 
Subjects will not be compensated for participating in the study.  


 
 
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GBT_Voxelotor Protocol version 2.0_18MAY2022 
4.4 Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects. 
Study completion is at the end of 2 day wash out period defined by 2 days after the last 
administration of Voxelotor. If a patient withdraws informed consent, the patient will be 
withdrawn from Voxelotor study treatments and all study related assessments. 
 
A patient will be withdrawn from the study treatment if any of the events listed below occur but 
should continue to be followed according to the intervention table:  
• Decision by the Investigator that it is not in the best interest of a patient to continue 
treatment. 
• Subjects are free to withdraw their consent at any time; the PI will withdraw a subject if 
any adverse response is thought to be due to Voxelotor. 
• If a patient receives a “go call” for solid organ lung transplant then study medication will 
be discontinued and the subject will proceed to the study wash out phase, as the PK and 
PD of Voxelotor in the setting of surgery, blood loss, and blood transfusion is unknown. 
Voxelotor is oral administration only and the effect of blood transfusion “diluting” the 
Voxelotor modified RBCs is unknown, so the effect of Voxelotor in this setting will be 
confounded by the common scenario of blood transfusion and/or hemodilution. Also, the 
indication for Voxelotor, to maintain SaO2 in the face of a significant Alveolar-arterial 
pO2 gradient, will have passed with the implantation of donor lungs. 
• If a patient suffers bleeding complications requiring blood transfusion, as the PK and PD 
of Voxelotor in the setting of blood loss and blood transfusion is unknown. The effect of 
blood transfusion “diluting” the Voxelotor modified RBCs is unknown, so the effect of 
Voxelotor in this setting will be confounded and they will enter the wash-out period. 
• As Voxelotor increases the binding of oxygen to hemoglobin (providing the treatment 
effect of increased SpO2 for a given pO2), we will monitor for the possibility of 
inadequate oxygen being off-loaded to the tissues by tracking venous blood gases for 
evidence of metabolic acidosis from tissue beds and tracking renal function as a 
reflection of adequacy of tissue oxygen during administration of Voxelotor. 
 
To provide a complete safety review of each patient, participants will be enrolled and end study 
participation before the next subject is enrolled.  This will be done for the first five participants.  
For the remaining 15 participants, when an SAE occurs with a subject, enrollment of new 
participants will pause until the SAE is completely reviewed by the PI.  After three unexpected, 
related SAEs are reported in this study, the enrollment of new participants will be halted. 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
Patients enrolled in this study will receive 5 days of Voxelotor treatment, in the perioperative 
setting of lung transplantation for some subjects. In the event a patient receives a lung transplant 
during the 5-day treatment period, follow-up of survival status will continue through the 2 day 
wash out period post-transplant. Many confounding reasons related to the complexity of the 
recovery and the complication profile of lung transplantation render further follow-up unrealistic 
beyond the duration that subjects receive Voxelotor, as supported by few safety concerns despite 
administration to many patients with significant co-morbidities. 


 
 
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GBT_Voxelotor Protocol version 2.0_18MAY2022 
5 Study Drug  
5.1 Description 
Voxelotor (GBT440) is a small molecule inhibitor of HbS polymerization which allosterically 
modifies Hb-O2 affinity.  
 
Voxelotor is a white-to-yellow-to-beige compound in crystalline Form II of GBT440 free base. It 
is non-hygroscopic. It is highly soluble in common organic solvents such as acetone and toluene 
and insoluble in water (approximately 0.03 mg/mL). Voxelotor drug substance is manufactured 
in accordance with GMP. The chemistry used in the production of Voxelotor drug substance is 
well established. The manufacturing process uses equipment commonly available in the industry. 
 
Voxelotor will be supplied as 500 mg tablets, or as 100 mg and 300 mg dispersible tablets for a 
total daily dose of 1000 mg per day, which may be increased to a total maximum dose of 1500 
mg per day if subject tolerates initial dose as determined per PI.   
5.2 Treatment Regimen 
All participants will receive Voxelotor, administered orally as approved tablets or dispersible 
tablets for the duration of their enrollment in the study. Subjects will be dosed orally or given via 
feeding tube (when indicated). Voxelotor in all formulations, may be taken with or without food. 
Voxelotor dispersible tablets should be dispersed in clear liquid (e.g., water, apple juice).  
 
If the dispersible tablets are given, the instructions for preparation prior to administration are as 
follows: 
 
Table 3:  Volume of Liquid per Dose of Voxelotor Dispersible Tablet  
Voxelotor Dispersible Tablet Dose (mg)  
Volume of Water (cc)  
400 to 600  
No less than  
5  
700 to 900  
No less than  
7.5  
1000 to 1200  
No less than  
10  
1500  
No less than  
12.5  
Note:  one cubic centimeter (cc) is equivalent to one milliliter (mL)  
 
500 mg of voxelotor will be administered two times daily (for a total daily dose of 1000 mg per 
day) for 5 days. This dose may increase to a total maximum daily dose of 1500 mg (500 mg three 
times a day) if subject tolerates initial dose as determined by PI. In the event the voxelotor 
administration needs to be discontinued for patient safety reasons during one of the study 
administration days, further doses of voxelotor will be discontinued and the protocol will 
progress to the wash out phase identified in the schedule of activities (Table 2). 
5.3 Method for Assigning Subjects to Treatment Groups 
This is an open label single arm study. Subjects will not be randomized. 


 
 
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GBT_Voxelotor Protocol version 2.0_18MAY2022 
5.4 Preparation and Administration of Study Drug 
Voxelotor will be dispensed from IDS Pharmacy. Drug will be picked up by research team 
member and delivered to patient’s nurse.  
5.5 Subject Compliance Monitoring 
Voxelotor drug product must be administered orally daily. If a participant misses a dose, the 
participant should resume normal dosing next day (i.e., the dose on the day after a day of a 
missed dose should not be increased or decreased).  
 
The subjects will inpatient, and medications will be administered by the RN and noted in the 
record as given/not given. If study PI plans to dose modify/hold for AEs that affect safety and 
tolerability, a trial of reducing or holding (temporarily stopping) the dose may be used. In prior 
sickle cell disease (SCD) studies, modification of dose (or dosage hold) was utilized based upon 
the exact event and the grade of the event. Dose was reduced for Grade 2 AE and subject 
reassessed,  Dose was held or discontinued (for SAE) for Grade 3, as determined by PI.    
 
Table 4. Dose Modification Guidelines for Study Drug Related Adverse Events 
 
All instances of voxelotor dose modification (dose reduction, interruption, or discontinuation) 
will be documented in the participant’s medical record and study case report form (CRF). If the 
condition/event leading to the dose modification has resolved, the original dose level should be 
resumed, unless in the judgement of the Investigator this cannot be done safely.  
 


 
 
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GBT_Voxelotor Protocol version 2.0_18MAY2022 
Study personnel will review the EMR on a daily basis to ensure compliance or determine reasons 
for omission. 
5.6 Prior and Concomitant Therapy 
Prior medications taken within two days before study entry will be collected in CRF. 
Concomitant medications will be recorded through Study Day 7. 
 
Fluconazole will be prohibited as a concomitant medication and has been listed as an exclusion 
criterion. The focus on fluconazole is due to its relatively common usage in our patients but we 
will also censor concomitant use of all moderate and strong CYP3A4 inhibitors in this early 
stage pilot study. Specifically, we will avoid the following concomitant medications: 
 
▪ 
Moderate inhibitors of CYP3A4: amiodarone, erythromycin, fluconazole, 
miconazole, isavuconazole, diltiazem, verapamil, delavirdine, amprenavir, 
fosamprenavir, conivaptan. 
▪ 
Strong inhibitors of CYP3A4: Clarithromycin, telithromycin, nefazodone, 
itraconazole, ketoconazole, voriconazole/posaconazole, atazanavir, darunavir, 
indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir. 
 
Voxelotor is a weak 3A4 inhibitor so close monitoring of tacrolimus and/or cyclosprorine levels 
is needed if these drugs are concomitant medications. Daily levels are routine when used for in-
patients. 
 
There may also be risks, discomforts, drug interactions, or side effects that are not yet known. 
5.7 Packaging 
Voxelotor dispersible formulation will be dispensed. Voxelotor 100 mg and 300 mg dispersible 
tablets contain voxelotor drug substance along with formulation excipients. With the exception 
of artificial grape flavor, all excipients used in the dispersible tablets are listed in the FDA IID. 
The artificial grape flavor is listed under the Flavor and Extract Manufacturers Association 
(FEMA) guidelines and is considered a Generally Recognized as Safe (GRAS) material. All the 
excipients used in the formulation are either compendial per European Pharmacopoeia (Ph Eur) 
or are composed of mixtures that are compendial per Ph Eur or accepted by E number or 
European Commission regulation. 
 
Voxelotor tablets (500 mg) will be packaged in high-density polyethylene (HDPE) bottles with 
induction sealed polypropylene (PP) child-resistant (CR) caps. As an alternate packaging, tablets 
may be supplied in multilaminate blisters.  
5.8 Blinding of Study Drug 
This is an open –label study and subjects will not be randomized. There is no blinding. 


 
 
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GBT_Voxelotor Protocol version 2.0_18MAY2022 
5.9 Receiving, Storage, Dispensing and Return 
5.9.1 Receipt of Drug Supplies 
The initial shipment of voxelotor will be sent to Investigational Drug Services (IDS) Pharmacy  
once the site has met all requirements for activation by the Sponsor-Investigator and GBT. Initial 
quantity of study drug will be determined by study-specific forecasting criteria that includes, but not 
limited to the expected number of subject enrollment, treatment duration and dosing regimen. 
 
Investigational Drug Services (IDS) Pharmacy will receive study drug shipped from sponsor. 
Upon receipt of the study treatment supplies, an inventory must be performed, and a drug receipt 
log filled out and signed by the person accepting the shipment. It is important that the designated 
study staff counts and verifies that the shipment contains all the items noted in the shipment 
inventory. Any damaged or unusable study drug in a given shipment (active drug or comparator) 
will be documented in the study files.  The investigator must notify study sponsor of any 
damaged or unusable study treatments that were supplied to the investigator’s site. 
5.9.2 Storage 
Storage and Handling Procedure  
All study medications will be stored in IDS pharmacy at controlled room temperature between 
15°C to 25°C in the storage area of the investigational site pharmacy, which is a secure, 
temperature controlled, locked environment with restricted access. No special procedures for the 
safe handling of voxelotor drug products are required. 
5.9.3 Dispensing of Study Drug 
IDS pharmacy will maintain a Study Drug Dispensing Log. The following information will be 
recorded: 
• Total amount of study drug dispensed (quantity of tablets dispensed) 
• Identification (study number and initials) of the patient to whom the study drug was 
dispensed; 
• Initials of the person who dispensed the study drug; 
• Initials of the person who received the study drug for administration to the patient 
5.9.4 Return or Destruction of Study Drug 
The Investigator is responsible to ensure that all study drug is accurately accounted for. Any 
discrepancies must be described in writing. At the completion of the study, there will be a final 
reconciliation of drug shipped, drug consumed, and drug remaining.  This reconciliation will be 
logged on the drug reconciliation form, signed and dated.  Any discrepancies noted will be 
investigated, resolved, and documented prior to return or destruction of unused study drug.  Drug 
destroyed on site will be documented in the study files. Any unused voxelotor will be returned to 
the Sponsor at the conclusion of the study or destroyed according to clinical site’s SOP as 
mutually agreed upon by the Sponsor and the site. 


 
 
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GBT_Voxelotor Protocol version 2.0_18MAY2022 
6  Study Procedures 
6.1 Screening (2 days before Voxelotor administration) 
The following assessments will be performed during screening: 
• Determine eligibility based on inclusion/exclusion criteria 
• Obtain voluntarily given, written informed consent from subject or LAR 
• Record demographics  
• Record medical history  
• Collect baseline physiological data for ESLD and ALI at rest and with exercise*  
 
SpO2  
 
FiO2 
 
S/F ratio calculation 
 
Heart rate 
 
Modified Borg Dyspnea scale (MBDs) rating 
• Collect additional baseline physiological data with ALI group  
 
PaO2 
 
SaO2 
 
P/F ratio calculation 
 
PaCO2 
 
A-a gradient calculation                       
6.2 -1 day before Voxelotor administration          
The following assessments will be performed during Baseline: 
• Collect baseline physiological data for ESLD and ALI at rest and with exercise*  
 
SpO2  
 
FiO2 
 
S/F ratio calculation 
 
Heart rate 
 
MBDs rating 
• Collect additional baseline physiological data with ALI group  
 
Pa02 
 
SaO2 
 
P/F ratio calculation 
 
PaCO2 
 
A-a gradient calculation 
• Blood sampling for central lab 
 
Erythropoetin (5ml) 
 
P50  (3ml) 
 
PK (2ml) 
• Blood sampling for local lab 
o Pregnancy test for women of childbearing potential if not done as SOC (2ml) 
o CBC (3ml) 
o CMP (4.5ml) 


 
 
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GBT_Voxelotor Protocol version 2.0_18MAY2022 
6.3 Day 1 
• Blood sampling for central lab  
 
P50  (3ml) 
 
PK (2ml) 
• Blood sampling for local lab 
 
CBC (3ml) 
 
BMP (4.5ml) 
• Administer 500 mg Volexotor twice daily (or up to three times a day if patient 
tolerates initial dose per PI) 
• Collect daily physiological data for ESLD and ALI at rest and with exercise*  
 
SpO2  
 
FiO2 
 
S/F ratio calculation 
 
Heart rate 
 
MBDs rating 
• Collect additional daily physiological data with ALI group  
 
PaO2 
 
SaO2 
 
P/F ratio calculation 
 
PaCO2 
 
A-a gradient calculation 
• Record adverse events 
6.4 Day 2 
• Blood sampling for central lab  
 
P50  (3ml) 
 
PK (2ml) 
 
Erythropoietin (5ml) 
• Blood sampling for local lab 
 
CBC (3ml) 
 
BMP (4.5ml) 
• Administer 500 mg Volexotor twice daily (or up to three times a day if patient 
tolerates initial dose per PI) 
• Collect daily physiological data for ESLD and ALI at rest and with exercise*  
 
SpO2  
 
FiO2 
 
S/F ratio calculation 
 
Heart rate 
 
MBDs rating 
• Collect additional daily physiological data with ALI group  
 
PaO2 
 
SaO2 
 
P/F ratio calculation 


 
 
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GBT_Voxelotor Protocol version 2.0_18MAY2022 
 
PaCO2 
 
A-a gradient calculation 
• Record adverse events 
6.5 Day 3-5 
• Blood sampling for central lab 
 
P50  (3ml) 
 
PK (2ml) 
• Blood sampling for local lab 
 
CBC (3ml) 
 
BMP (4.5ml) 
• Administer 500 mg Volexotor twice daily (or up to three times a day if patient 
tolerates initial dose per PI) 
• Collect daily physiological data for ESLD and ALI at rest and with exercise*  
 
SpO2  
 
FiO2 
 
S/F ratio calculation 
 
Heart rate 
 
MBDs rating 
• Collect additional daily physiological data with ALI group  
 
PaO2 
 
SaO2 
 
P/F ratio calculation 
 
PaCO2 
 
A-a gradient calculation 
• Record adverse events 
6.6   Day 6 (Wash out period) 
• Collect daily physiological data for ESLD and ALI at rest and with exercise*  
 
SpO2  
 
FiO2 
 
S/F ratio calculation 
 
Heart rate 
 
MBDs rating 
• Collect additional daily physiological data with ALI group  
 
PaO2 
 
SaO2 
 
P/F ratio calculation 
 
PaCO2 
 
A-a gradient calculation 
• Blood sampling for central lab 
 
PK (2ml)  
 
P50  (3ml) 
 
Erythropoetin (5ml) 


 
 
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• Blood sampling for local lab 
 
CBC (3ml)  
 
BMP (4.5ml) 
• Record adverse event 
                                                    
6.7   Day 7 (Wash out period) 
• Collect daily physiological data for ESLD and ALI at rest and with exercise*  
 
SpO2  
 
FiO2 
 
S/F ratio calculation 
 
Heart rate 
 
MBDs rating 
• Collect additional daily physiological data with ALI group  
 
PaO2 
 
SaO2 
 
P/F ratio calculation 
 
PaCO2 
 
A-a gradient calculation 
• Blood sampling for central lab 
 
PK (2ml)  
 
P50  (3ml) 
• Blood sampling for local lab 
 
CBC (3ml)   
 
CMP (4.5ml) 
• Record adverse event 
 
*only if feasible/ ambulatory patients only. Exercise protocol is SOC and data collected will be reviewed from medical 
record. 
 
7 
**  Statistical Plan 
7.1 Sample Size Determination 
This is a pilot study and will be used to determine effect size for future prospective study  
7.2 Statistical Methods 
Descriptive statistics for patient characteristics and baseline factors will be presented as median 
and interquartile range for continuous variables and number and percentage for categorical 
variables.  The primary outcome will be change in S/F ratio from baseline to 2 days after 
initiation of voxelotor treatment, and the secondary outcome will be change in S/F ratio from 
baseline to 5 days after initiation of voxelotor treatment.  Each will be compared using the 
Wilcoxon Signed Rank test.  The baseline value will be defined as the median S/F ratio 
measurement during the 48-hour period before initiation of voxelotor treatment.  Similarly, the 


 
 
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day 2 and day 5 S/F ratio values will be defined as the median S/F ratio measurement on the 
second and fifth days after initiation of treatment. 
All S/F ratio values will also be analyzed using a mixed-effects model with a random intercept 
for each patient and time in hours (relative to initiation of voxelotor treatment) as a fixed effect.  
Quadratic and cubic terms for time will also be included to allow for flexible modeling of 
treatment effect over time.  We will tabulate and report all observed adverse events occurring 
during this trial. 
 
For the ALI group with an arterial line in place, the PaO2/FiO2 (P/F) ratio will also be compared 
in a similar manner to identify whether any improvement in S/F ratio is due to clinical 
improvement of ALI, as reflected in the P/F ratio. The concept of Voxelotor use is an 
improvement in the S/F ratio (the result of left-shift in p50) for a given P/F ratio (the result of 
pulmonary function limiting PaO2). This may be especially important for the ALI sub-study 
cohort, as ALI could improve during the 5 day dosing period. Realistically, however, such 
progress is typically slow and, in contrast, the end-stage lung disease cohort would not be 
expected to improve and S/F ratio alone would reflect voxelotor effect without the need to track 
P/F ratios. 
7.3 Subject Population(s) for Analysis 
• Protocol-compliant population:  Any subject who was randomized and received the 
protocol required study drug exposure and required protocol processing will be the 
primary analysis population.  
•  All-treated population:  Any subject randomized into the study that received at least one 
dose of study drug will be subject to secondary analyses. 
8 Safety and Adverse Events 
8.1 Definitions 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in 
severity during the course of the study.  Intercurrent illnesses or injuries should be regarded as 
adverse events.  Abnormal results of diagnostic procedures are considered to be adverse events if 
the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
 
AE Classification. The following definitions were based on guidelines provided by the Office for 
Human Research Protections (OHRP). The following URL provides useful examples to help 
clarify classification of adverse events https://www.hhs.gov/ohrp/regulations-and-
policy/guidance/reviewing-unanticipated-problems/index.html 
  


 
 
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An AE is deemed an unanticipated problem if it is not expected given (a) the known or 
foreseeable risk of the study procedures that are described in the informed consent document or 
study protocol, (b) the characteristics of the population being studied, (c) related or possibly 
related to participation in the study, and (d) suggests the research places subjects are greater risk 
of harm than previously known. 
Serious Adverse Event (SAE) 
Adverse events are classified as serious or non-serious. A serious adverse event is any AE that 
is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly 
of major clinical significance.   They may jeopardize the subject, and may require intervention to 
prevent one of the other serious outcomes noted above. For example, drug overdose or abuse, a 
seizure that did not result in in-patient hospitalization, or intensive treatment of bronchospasm in 
an emergency department would typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-
serious adverse events.  
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the period 
from the initiation of any study procedures to the end of the study treatment follow-up.  For this 
study, subjects will be followed for AEs from the time of voxelotor administration until 2 days 
after the last administration of voxelotor as defined by the wash out period.    
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition 
should be recorded as an adverse event if the frequency, intensity, or the character of the 
condition worsens during the study period. 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings/abnormalities that 
meet the definition of an adverse event must also be recorded and documented as an adverse 
event.  
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained.  At the last 
scheduled visit, the investigator should instruct each subject to report any subsequent event(s) 
that the subject, or the subject’s personal physician, believes might reasonably be related to 
participation in this study.  The investigator should notify the study sponsor of any death or 
adverse event occurring at any time after a subject has discontinued or terminated study 


 
 
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participation that may reasonably be related to this study.  The sponsor should also be notified if 
the investigator should become aware of the development of cancer or of a congenital anomaly 
in a subsequently conceived offspring of a subject that has participated in this study.  
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of the 
following conditions is met:  
• The laboratory abnormality is not otherwise refuted by a repeat test to confirm the 
abnormality 
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management; e.g. change of 
dose, discontinuation of the drug, more frequent follow-up assessments, further 
diagnostic investigation, etc. 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed otherwise in 
this protocol.  Any condition responsible for surgery should be documented as an adverse event 
if the condition meets the criteria for and adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 
adverse event in the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for a preexisting condition.  Surgery should not be reported as an 
outcome of an adverse event if the purpose of the surgery was elective or diagnostic 
and the outcome was uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the 
study, unless it is a worsening or increase in frequency of hospital admissions as 
judged by the clinical investigator. 
8.2 Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse events by 
specific questioning and, as appropriate, by examination.  Information on all adverse events 
should be recorded immediately in the source document of the case report form (CRF).  All 
clearly related signs, symptoms, and abnormal diagnostic procedures results should be recorded 
in the source document, though should be grouped under one diagnosis. 
 
All adverse events occurring during the study period must be recorded.  The clinical course of 
each event should be followed until resolution, stabilization, or until it has been determined that 
the study treatment or participation is not the cause.  Serious adverse events that are still ongoing 
at the end of the study period must be followed up to determine the final outcome.  Any serious 
adverse event that occurs after the study period and is considered to be possibly related to the 
study treatment or study participation should be recorded and reported immediately. 
 


 
 
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Requirements for reporting of an AE to various entities (IRB, FDA, and Sponsor) differ 
according to whether or not the AE represents an unanticipated problem.  This study will follow 
21 CFR 312.32 IND Safety Reporting guidelines and DUHS prompt reporting to the IRB policy 
for events that occur with this study.    
 
Subjects in this study will be followed for AEs from the time of voxelotor administration until 2 
days after the administration of voxelotor as defined by study wash out period. The PI will be 
responsible for ensuring participants’ safety.  
 
Dr. Ian Welsby will be the physician responsible for reviewing and evaluating all adverse events. 
Dr. Welsby will evaluate the safety of voxelotor treatment in all subjects by following adverse 
events and assigning likelihood of causality.  Related AEs will be reported to IRB.  Nonrelated 
AEs will be tracked by the study team.   
8.3 Reporting of Serious Adverse Events 
8.3.1 Study Sponsor Notification by Investigator 
A serious adverse event must be reported to GBT within 24 hours of the event. A Serious 
Adverse Event (SAE) form must be completed by the investigator and faxed to the study sponsor 
within 24 hours. The investigator will keep a copy of this SAE form on file at the study site.   
      Report serious adverse events by email or facsimile to: 
    globalbloodtx@primevigilance.com or 1-650-243-3433 
 
 At the time of the initial report, the following information should be provided: 
• Study identifier 
• Study Center 
• Subject number 
• A description of the event 
• Date of onset 
• Current status 
• Whether study treatment was 
discontinued 
• The reason why the event is 
classified as serious 
• Investigator assessment of the 
association between the event and 
study treatment 
 
Within the following 48 hours, the investigator must provide further information on the serious 
adverse event in the form of a written narrative.  This should include a copy of the completed 
Serious Adverse Event form, and any other diagnostic information that will assist the 
understanding of the event.  Significant new information on ongoing serious adverse events 
should be provided promptly to the study sponsor 
8.3.2  EC/IRB Notification by Investigator 
Reports of all serious adverse events (including follow-up information) must be submitted to the 
EC/IRB within 10 working days.  Copies of each report and documentation of EC/IRB 
notification and receipt will be kept in the Clinical Investigator’s binder. 


 
 
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8.3.3 FDA Notification by Sponsor 
The study sponsor shall notify the FDA by telephone or by facsimile transmission of any 
unexpected fatal or life-threatening experience associated with the use of the drug as soon as 
possible but no later than 7 calendar days from the sponsor’s original receipt of the information. 
Other serious, unexpected adverse events associated with the use of study drug shall be reported 
to the FDA no later than 15 calendar days from the sponsors’ original receipt of the information. 
 
If a previous adverse event that was not initially deemed reportable is later found to fit the 
criteria for reporting, the study sponsor will submit the adverse event in a written report to the 
FDA as soon as possible, but no later than 15 calendar days from the time the determination is 
made. 
8.4 Stopping Rules  
To provide a complete safety review of each patient, participants will be enrolled and end study 
participation before the next subject is enrolled.  This will be done for the first five participants.  
For the remaining 15 participants, when an SAE occurs with a subject, enrollment of new 
participants will pause until the SAE is completely review by the PI.  After three unexpected, 
related SAEs are reported in this study, the enrollment of new participants will be halted. 
 
 When an unexpected rate of expected SAEs occurs, the enrollment of new participants will be 
halted. 
8.5 Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her 
site.  This safety monitoring will include careful assessment and appropriate reporting of adverse 
events as noted above, as well as the construction and implementation of a site data and safety-
monitoring plan (see section 9 Auditing, Monitoring and Inspecting).  Medical monitoring will 
include a regular assessment of the number and type of serious adverse events. This study will be 
subject to Duke clinical quality management plan (CQMP) policy and will have designated 
review.   
9 Data Handling and Record Keeping 
9.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 


 
 
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should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at 
the end of their scheduled study period. 
9.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source 
data are contained in source documents   Examples of these original documents, and data records 
include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments involved 
in the clinical trial. 
9.3 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study.  All 
data requested on the CRF must be recorded.  All missing data must be explained.  If a space on 
the CRF is left blank because the procedure was not done or the question was not asked, write 
“N/D”.  If the item is not applicable to the individual case, write “N/A”.  All entries should be 
printed legibly in black ink.  If any entry error has been made, to correct such an error, draw a 
single straight line through the incorrect entry and enter the correct data above it.  All such 
changes must be initialed and dated.  DO NOT ERASE OR WHITE OUT ERRORS.  For 
clarification of illegible or uncertain entries, print the clarification above the item, then initial and 
date it. 
9.4 Records Retention 
It is the investigator’s responsibility to retain study essential documents for at least 2 years after 
the last approval of a marketing application in their country and until there are no pending or 
contemplated marketing applications in their country or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product.  These documents 
should be retained for a longer period if required by an agreement with the sponsor.  In such an 
instance, it is the responsibility of the sponsor to inform the investigator/institution as to when 
these documents no longer need to be retained.  
10  Study Monitoring, Auditing, and Inspecting 
10.1  Study Monitoring Plan 
This study will be monitored according to the monitoring plan in Duke CQMP.  The investigator 
will allocate adequate time for such monitoring activities.  The Investigator will also ensure that 
the monitor or other compliance or quality assurance reviewer is given access to all the above 
noted study-related documents and study related facilities (e.g. pharmacy, diagnostic laboratory, 
etc.), and has adequate space to conduct the monitoring visit. 


 
 
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10.2  Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, the 
sponsor, government regulatory bodies, and University compliance and quality assurance groups 
of all study related documents (e.g. source documents, regulatory documents, data collection 
instruments, study data etc.).  The investigator will ensure the capability for inspections of 
applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality assurance 
offices. 
11 Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
applicable government regulations and Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent 
Ethics Committee (EC) or Institutional Review Board (IRB), in agreement with local legal 
prescriptions, for formal approval of the study conduct.  The decision of the EC/IRB concerning 
the conduct of the study will be made in writing to the investigator and a copy of this decision 
will be provided to the sponsor before commencement of this study.  The investigator should 
provide a list of EC/IRB members and their affiliate to the sponsor. 
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study.  This consent form will be submitted with the protocol for review and approval by the 
EC/IRB for the study.  The formal consent of a subject, using the EC/IRB-approved consent 
form, must be obtained before that subject is submitted to any study procedure.  This consent 
form must be signed by the subject or legally acceptable surrogate, and the investigator-
designated research professional obtaining the consent.  
12 Study Finances 
12.1 Funding Source 
 This study is financed through a grant from the Global Blood Therapeutics (GBT). GBT will 
provide voxelotor to subjects free of charge. 
12.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the 
conflict reviewed by a properly constituted Conflict of Interest Committee with a Committee-
sanctioned conflict management plan that has been reviewed and approved by the study sponsor 
prior to participation in this study.  All University of Pennsylvania investigators will follow the 
University conflict of interest policy. 


 
 
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13 Publication Plan 
The intent is to publish our data in peer-reviewed scientific literature. GBT will have a courtesy 
review prior to publication. Affiliations and inclusions of study support will be transparent.  
Neither the complete nor any part of the results of the study carried out under this protocol, nor 
any of the information provided by the sponsor for the purposes of performing the study, will be 
published or passed on to any third party without the consent of the study sponsor. Any 
investigator involved with this study is obligated to provide the sponsor with complete test 
results and all data derived from the study.  
 
 
 
14 References 
 
1. 
Oksenberg D, Dufu K, Patel MP, et al. GBT440 increases haemoglobin oxygen affinity, 
reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease. 
British journal of haematology. 2016;175(1):141-153. 
2. 
Metcalf B, Chuang C, Dufu K, et al. Discovery of GBT440, an Orally Bioavailable R-
State Stabilizer of Sickle Cell Hemoglobin. ACS medicinal chemistry letters. 
2017;8(3):321-326. 
3. 
Patel MP, Cabrales P, Dufu K, Metcalf BW, Sinha U. GTx011, an Anti-Sickling 
Compound, Improves SS Blood Rheology By Reduction of HbS polymerization Via 
Allosteric Modulation of O2 Affinity. Blood. 2014;124:1370-1370. 
4. 
Eaton WA, Henry ER, Hofrichter J, Mozzarelli A. Is cooperative oxygen binding by 
hemoglobin really understood? Nature Structural Biology. 1999;6(4):351-358. 
5. 
Patel MP, Siu V, Silva-Garcia A, Xu Q, Li Z, Oksenberg D. Development and validation 
of an oxygen dissociation assay, a screening platform for discovering, and characterizing 
hemoglobin-oxygen affinity modifiers. Drug design, development and therapy. 
2018;12:1599-1607. 
6. 
Noguchi CT, Schechter AN. The intracellular polymerization of sickle hemoglobin and 
its relevance to sickle cell disease. Blood. 1981;58(6):1057-1068. 
7. 
Dufu K, Patel M, Oksenberg D, Cabrales P. GBT440 improves red blood cell 
deformability and reduces viscosity of sickle cell blood under deoxygenated conditions. 
Clin Hemorheol Microcirc. 2018;70:95-105. 
8. 
Dufu K, Oksenberg D. GBT440 reverses sickling of sickled red blood cells under 
hypoxic conditions in vitro. Hematology reports. 2018;10(2):7419-7419. 
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