The Effect of Voxelotor on Cerebral Hemodynamic Response in Children With Sickle Cell Anemia
Phase: PHASE2
Conditions: Sickle Cell Anemia in Children
Sponsor: Emory University

Study Protocol 
 
TITLE: The Effect of Voxelotor on Cerebral Hemodynamic Response in 
Children with Sickle Cell Anemia (VoxSCAN) 
 
NCT NUMBER: NCT05018728 
 
Protocol Date: June 10, 2024 

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PROTOCOL TITLE: 
The Effect of Voxelotor on Cerebral Hemodynamic Response in Children with Sickle Cell Anemia 
Protocol Number: 
ESR-C007
SHORT TITLE: 
Voxelotor SCA NIRS Study (VoxSCAN)
PRINCIPAL INVESTIGATOR:  
CO-INVESTIGATOR:
Amy Tang, MD
Assistant Professor
Emory + Pediatric Institute
Children’s Healthcare of Atlanta
Erin M. Buckley, PhD 
Associate Professor
Emory University School of Medicine
Agent: 
Voxelotor
IND: 
155720
VERSION: 
2.4 dated 10JUN2024
Drug Supplier:
Global Blood Therapeutics, Inc. (GBT)
181 Oyster Point Boulevard
South San Francisco, CA 94080

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REVISION HISTORY
Revision #
Version 
Date
Summary of Changes
Consent 
Changes 
(Y/N)
1.0
18NOV2020
Original
N
1.1
9DEC2020
Original + Template Update
N
1.2
29DEC2020
Original + Updates from Team Review
N
1.3
3MAR2021
Original + Monitoring Plan Update
N
1.4
18MAR2021
Original + Updates from Emory Reviewer
N
1.5
8APR2021
Original + FDA requested update
Y
1.6
14MAY2021
Original + IRB pending approval request
Y
1.7
09MAR2022
Original + Updates from Team Review
Y
1.8
03Aug2022
Original + Changes in PI, enrollment target & study labs
Y
1.9 draft, not 
released
08Sept2023
Original + changes to study labs & subject payment
Y
2.0 draft, not 
released
28Sept2023
Original + Data Safety Monitoring Plan Requirements
N
2.1
25Oct2023
Original + Data Safety Monitoring Plan Monitoring Table 
edits
N
2.2
12Jan2024
Original + changes to study labs + SAE reporting changes
N
2.3
04MAR2024
Original + changes to assessments + endpoints
N
2.4
06Jun2024
Original + changes to assessments timepoints
List of Major Changes to Version 1.9: (draft, not released)
-
Change subject payment to $50/visit
-
In Schedule of Assessments, removed CMP & LDH assessments from the 4 and 8w time 
points, remove Hb electropheresis assessments from the 8 and 12w time points.
-
Removing Global Blood Therapeutics Laboratory as the source of analysis for RBC 
deformability and mitochondrial content assessments.  
List of Major Changes to Version 2.0 (draft, not released)
-
Addition of Data Safety Monitoring Plan Requirements table explaining new process
List of Major Changes to Version 2.1
-
Edits to Data Safety Monitoring Plan Requirements monitoring table
List of Major Changes to Version 2.2
-
Removing Global Blood Therapeutics Laboratory as the source of analysis for RBC 
deformability and mitochondrial content assessments. This change was intended in 
version 1.9, but some references were missed that have now been corrected.
-
Changing safety reporting to comply with Pfizer’s policies

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List of Major Changes to Version 2.3
- 
Removing Worldwide Therapeutics and Functional Fluidics assessments of some 
markers of RBC health and hemoglobin modification
-
Removing exploratory endpoints associated with RBC oxygen affinity and deformability, 
as these parameters will no longer be quantified
-
Adding 12w electrophoresis assessment
List of Major Changes to Version 2.4
-
Removing 4 and 8w timepoints for RBC health and clarified what will be measured to 
assess RBC health

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Table of Contents
REVISION HISTORY..........................................................................................................................2
STATEMENT OF COMPLIANCE ........................................................................................................5
PROTOCOL SIGNATURE PAGE.........................................................................................................6
1.
Study Summary.......................................................................................................................7
2.
Objectives and Endpoints.....................................................................................................10
3.
Background...........................................................................................................................12
4.
Study Intervention/Investigational Agent ............................................................................13
4.1
Dosing and Administration.........................................................................................13
4.2
Dose Justification .......................................................................................................14
4.3
Acquisition and Accountability...................................................................................14
4.4
Formulation, Appearance, Packaging, and Labeling...................................................15
4.5
Product Storage and Stability.....................................................................................15
4.6
Preparation.................................................................................................................15
4.7
Study Intervention Compliance..................................................................................15
4.8
Concomitant Therapy.................................................................................................15
5.
Procedures Involved.............................................................................................................15
5.1
Study Schema.............................................................................................................16
5.2
Schedule of Assessments (SoA)..................................................................................17
5.3
Efficacy, Safety, and Other Assessments....................................................................17
5.4
Adverse Events and Serious Adverse Events..............................................................19
5.5
Time Period and Frequency for Event Assessment and Follow-up ............................20
5.6
Adverse Event Reporting............................................................................................21
5.7
Serious Adverse Event Reporting ...............................................................................21
5.8
Reporting of Pregnancy..............................................................................................22
5.9
Unanticipated Problems.............................................................................................22
5.10
End of Study............................................................................................................23
6.
Data and Specimen Banking .................................................................................................23
7.
Sharing of Results with Participants .....................................................................................24
8.
Study Timelines.....................................................................................................................24
9.
Inclusion and Exclusion Criteria............................................................................................24
9.1
Inclusion Criteria.........................................................................................................24
9.2
Exclusion Criteria........................................................................................................25

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9.3
Lifestyle Considerations .............................................................................................26
10.
Vulnerable Populations .....................................................................................................26
11.
Local Number of Participants ............................................................................................26
12.
Recruitment Methods........................................................................................................26
12.1
Subject Identification..............................................................................................26
12.2
Screen Failures........................................................................................................27
13.
Withdrawal of Participants................................................................................................27
13.1
Discontinuation of Study Intervention ...................................................................27
13.2
Participant Discontinuation/Withdrawal from the Study.......................................27
13.3
Lost to Follow-Up....................................................................................................28
14.
Risks to Participants...........................................................................................................28
15.
Potential Benefits to Participants......................................................................................29
16.
Compensation to Participants ...........................................................................................30
17.
Statistical Considerations, Data Management and Confidentiality...................................30
17.1
Statistical Considerations........................................................................................30
17.2
Statistical Analyses..................................................................................................30
17.3
Data Management, Quality Assurance and Quality Control...................................31
17.4
Study Record Retention..........................................................................................32
17.5
Protocol Deviations.................................................................................................32
18.
Provisions to Monitor the Data to Ensure the Safety of Participants................................32
19.
Provisions to Protect the Privacy Interests of Participants................................................33
19.1
Publication and Data Sharing Policy .......................................................................33
19.2
Conflict of Interest Policy........................................................................................36
20.
Economic Burden to Participants ......................................................................................36
21.
Consent Process.................................................................................................................36
22.
Setting................................................................................................................................38
23.
Resources Available...........................................................................................................38
24.
References.........................................................................................................................39
25.
Appendix............................................................................................................................42

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STATEMENT OF COMPLIANCE
This pilot study will be conducted in accordance with International Conference on Harmonization 
Good Clinical Practice (ICH GCP), applicable US Code of Federal Regulations (CFR).  As the 
Sponsor-Investigator, the PI will assure that no deviation from, or changes to the protocol, will 
take place without prior agreement from the investigational drug supplier Global Blood 
Therapeutics, a subsidiary of Pfizer as of October 5th 2022, and documented approval from the 
IRB, except where necessary to eliminate an immediate hazard(s) to the study participants. All 
personnel involved in the conduct of this study have completed Human Subjects Protection and 
ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB for review and approval.  Approval of both the protocol and the consent 
form will be obtained before any participant is enrolled.  Any amendment to the protocol will be 
reviewed and approved by the IRB before the changes are implemented to the study.  All changes 
to the consent form will be IRB approved.

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PROTOCOL SIGNATURE PAGE
Protocol Title:
The Effect of Voxelotor on Cerebral Hemodynamic Response in Children with Sickle Cell Anemia 
(VoxSCAN)
Version/Date: 2.2 dated December 05, 2023
SPONSOR APPROVAL
I, the Sponsor-Investigator, have read this protocol and agree it contains all necessary 
information required to conduct the study. 
The protocol is being conducted in accordance with International Council on Harmonization (ICH) 
Good Clinical Practice (GCP) and all applicable federal, state and local regulations governing the 
conduct of this research, including the Department of Health and Human Services 45 Code of 
Federal Regulations (CFR) Part 46, FDA 21 CFR Parts 50, 54, 56, 312 and 812. 
Sponsor - Investigator (Print):
Signature:
Date: 

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1. Study Summary
Study Title
ESR-C007: The Effect of Voxelotor on Cerebral Hemodynamic 
Response in Children with Sickle Cell Anemia
Phase
Single-center, open label pilot study.
Study Design
This study is a pilot, open-label, single-arm study to evaluate 
the effect of voxelotor on cerebral hemodynamics, as 
measured by diffuse correlation spectroscopy and frequency 
domain near-infrared spectroscopy (DCS/FDNIRS) in patients 4 
-30 years of age with sickle cell anemia (SCA).   We hypothesize 
that as hemoglobin increases due to voxelotor, cerebral blood 
flow (CBF) and oxygen extraction fraction (OEF) will decrease. 
To test this hypothesis, CBF, OEF, and oxygen metabolism 
(CMRO2) will be assessed by DCS/NIRS in participants prior to, 
periodically throughout, and after 12 weeks of treatment with 
voxelotor.  The results of this study will be used to inform a 
larger study. 
Primary Objective
The primary objective of this research is to evaluate the effect 
of voxelotor on CBF, OEF and CMRO2 in children with SCA as 
assessed by change from baseline in DCS/NIRS at 4 and 12 
weeks.  
Secondary Objective
The secondary objective of this research is to evaluate the 
correlation between changes in CBF, OEF and CMRO2 and 
change in markers of anemia, hemolysis and RBC health at 4 
and 12 weeks.
Research 
Intervention(s)/Interactions
The study intervention is voxelotor, administered orally. It will 
be used for the approved indication of sickle cell disease. This 
is a single-arm study. There is no control intervention. 
Drug Intervention: Voxelotor

Voxelotor tablets: 300 or 500 mg, administered orally

Voxelotor dispersible tablets: 100 and/or 300 mg, 
administered orally
All participants will receive voxelotor. Participants 12 years or 
older will take 1500 mg/day. Participants younger than 12 
years of age will receive a dose based on their body weight to 
provide exposure corresponding to the adult dose of 1500 
mg/day. 
Study Population
We plan to recruit male and female children ages 4-30 years 
with sickle cell anemia (HbSS, HbS/β0thal) who are followed in 
the Pediatric Sickle Cell Program at Children’s Healthcare of 
Atlanta 

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Sample Size
This is a pilot study involving 50 participants to define the 
magnitude of change. Power cannot be calculated at this time. 
Study Duration for 
Individual Participants
Up to 16 weeks
Total Study Duration
30 months
Funding Source (if any)
Global Blood Therapeutics (GBT)
Study Specific 
Abbreviations/ Definitions
ACS
Acute chest syndrome
ALT
Alanine aminotransferase
AE
Adverse Event
ANCOVA
Analysis of Covariance
Bil
Bilirubin
β0thal
Homozygous sickle cell disease
CBF
Cerebral blood flow
CFR
Code of Federal Regulations
CHOA
Children’s Healthcare of Atlanta
CLIA
Clinical Laboratory Improvement Amendments
CMP
Clinical Monitoring Plan
COC
Certificate of Confidentiality
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case Report Form
DCC
Data Coordinating Center
DCS
Diffuse Correlation Spectroscopy
DHHS
Department of Health and Human Services
DSMB
Data Safety Monitoring Board
DRE
Disease-Related Event
EC
Ethics Committee
eCRF
Electronic Case Report Forms
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act of 
2007
FDNIRS
Frequency domain near-infrared spectroscopy
FFR
Federal Financial Report
GBT
Global Blood Therapeutics
GCP
Good Clinical Practice
GLP
Good Laboratory Practices
GMP
Good Manufacturing Practices
GWAS
Genome-Wide Association Studies
HbS
Hemoglobin  sickle
HbSS
Classic sickle cell disease
HIPAA
Health Insurance Portability and Accountability Act 
IB
Investigator’s Brochure
ICH
International Conference on Harmonization 
ICMJE
International Committee of Medical Journal Editors
IDE
Investigational Device Exemption
IND
Investigational New Drug Application
IRB
Institutional Review Board
ISM
Independent Safety Monitor
ISO
International Organization for Standardization

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ITT
Intention-To-Treat
LDH
Lactate Dehydrogenase
LSMEANS
Least-squares Means
MedDRA
Medical Dictionary for Regulatory Activities
MOP
Manual of Procedures
MSDS
Material Safety Data Sheet
NCT
National Clinical Trial
NIH 
National Institutes of Health
NIH IC
NIH Institute or Center
NIRS
Near infrared spectroscopy
ODC
Oxygen Dissociation Curve
OEF
Oxygen extraction fraction
OHRP
Office for Human Research Protections
PI
Principal Investigator
QA
Quality Assurance
QC
Quality Control
Retic
Reticulocytes
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SCD
Sickle Cell Disease
SMC
Safety Monitoring Committee
SOA
Schedule of Activities
SOC
System Organ Class
SOP
Standard Operating Procedure
TCD
Transcranial Doppler
ULN
Upper limit of normal
UP
Unanticipated Problem
US
United States
VOC
Vaso-occlusive crisis

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2. Objectives and Endpoints
OBJECTIVES
ENDPOINTS
JUSTIFICATION FOR 
ENDPOINTS
Primary
Evaluate the cerebral 
hemodynamic effects of 
voxelotor
Change in CBF, OEF and 
CMRO2 from baseline at 
Week 4 and 12 
Voxelotor is a promising 
new drug that improves 
hemoglobin levels and 
reduces the incidence of 
worsening anemia in SCD. 
However, it is unclear 
whether this increase in 
hemoglobin is associated 
with reductions in blood 
flow and oxygen extraction 
in the brain
Secondary
Evaluate the relationship 
between CBF, OEF, CMRO2 and 
change in total Hb levels 
Correlation of CBF, OEF, 
CMRO2 and change in total 
Hb levels from baseline  
By increasing hemoglobin 
levels, voxelotor may show 
improvement in CBF, OEF, 
CMRO2 akin to the effects 
of blood transfusion but 
without the detrimental 
side effects.
Evaluate the relationship 
between CBF, OEF, CMRO2 and 
voxelotor-modified Hb levels 
Correlation of CBF, OEF, 
CMRO2 and level of RBC 
content of voxelotor-
modified Hb
Voxelotor modification of 
Hb correlate to 
improvement of anemia. 
Quantified level of Hb 
modification (via HPLC or 
PK) may correlate with 
improvement in CBF, OEF, 
CMRO2
Exploratory
Evaluate the relationship 
between CBF, OEF, CMRO2 and 
measures of RBC health 
Correlation of CBF, OEF, 
CMRO2 and change in 
markers of RBC hemolysis 
(LDH, indirect Bil) and 
morphology (blood smear, 
RBC indices, retic, dense 
cells, and adhesion) from 
baseline  
Restored RBC health is 
measured by reduction in 
hemolysis (measured by 
blood chemistry labs) and 
improvement in RBC 
morphology. Measured 
improvements in RBC 
health may correlate with 

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OBJECTIVES
ENDPOINTS
JUSTIFICATION FOR 
ENDPOINTS
improvement in CBF, OEF, 
CMRO2

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3. Background
Sickle cell disease (SCD) is a genetic blood disorder that has profound effects on the brain. In the 
presence of chronic anemia, the brain microvasculature 
dilates in order to maintain adequate oxygen delivery to 
the tissue1–6. As cerebral blood flow increases and the 
vasculature 
becomes 
maximally 
dilated, 
oxygen 
extraction fraction (OEF, defined as the difference 
between arterial and venous oxygen content) increases 
to keep up with metabolic demand 2,7–10. Unfortunately, 
this state of maximized response leaves the brain 
vulnerable and ill-equipped to adapt to increased 
metabolic 
demand; 
consequently, 
the 
tissue 
is 
susceptible to infarction when blood flow/volume are 
insufficient to maintain sufficient oxygen metabolism11 
(see Figure 1). 
Chronic transfusion is used in patients with sickle cell 
disease to increase arterial hemoglobin concentration, 
which improves oxygen carrying capacity to the tissue. 
Recent work with MRI has confirmed that improved 
oxygen carrying capacity in turn reduces elevated 
cerebral blood flow (CBF) and oxygen extraction1,7,9,12. 
Although cerebral oxygen metabolism appears to remain 
unchanged after transfusion, the return of oxygen 
extraction and blood flow to “normal” levels is thought to alleviate metabolic stress and improve 
the brain’s ability to respond to increased metabolic demand1. Indeed, chronic transfusion 
therapy has been proven to reduce the incidence of both silent and overt infarcts in pediatric 
SCD patients13,14. Despite the beneficial effects of transfusion, the therapy is not without 
significant risks, i.e., infection, iron overload, alloimmunization, and comes with a substantial 
burden to patients and their families15,16. Moreover, the Silent Cerebral Infarct Multi-Center 
Clinical Trial (SIT) revealed that new silent infarct is prevented in only 1 out of every 13 children 
treated with transfusion therapy13. Thus, alternative therapeutic strategies that improve oxygen 
delivery to the brain without the risks associated with transfusion are needed to alleviate 
metabolic stress and reduce the risk of stroke. 
Voxelotor (Oxbryta) is a new drug for patients with sickle cell disease that improves hemoglobin 
levels and reduces the incidence of worsening anemia17. However, it is unclear whether this 
increase in hemoglobin is associated with a reduction in cerebral metabolic stress. In this work, 
we will determine the effects of voxelotor on cerebral hemodynamics. We hypothesize that as 
hemoglobin increases due to voxelotor, cerebral blood flow and oxygen extraction fraction will 
decrease, similar to the effects of blood transfusion. To test this hypothesis, measurements of 
brain blood flow, oxygen extraction, and oxygen metabolism will be made using the Buckley Lab’s 
customized diffuse correlation spectroscopy and frequency domain near-infrared spectroscopy 
system (DCS/FDNIRS). These well-validated, non-invasive optical techniques utilize near-infrared 
Figure 1, Hypothesized mechanism of ischemic 
injury in pediatric sickle cell disease (Adapted from 
Juttukonda et al., JMRI 2019). As anemia worsens, 
arterial oxygen delivery is reduced. To compensate 
for this reduction, the cerebrovascular dilates to 
increase cerebral blood flow (red). As vascular 
reserve is exhausted and CBF plateaus, oxygen 
extraction fraction (blue) increases to preserve 
oxygen metabolism (green). Eventually there is a 
mismatch between tissue metabolic demand 
(dotted black) and oxygen metabolism, and 
infarction ensues. Transfusion acts to increase 
oxygen delivery and is thought to relieve metabolic 
stress by reducing oxygen extraction and cerebral 
blood flow and improving vascular reserve. We 
hypothesize that the increase in hemoglobin 
caused by voxelotor will act in a similar fashion to 
reduce oxygen extraction fraction and blood flow.

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light to penetrate deep into tissue (~1-2 cm) in order to estimate an average oxygen saturation 
of the microvasculature, i.e., capillaries, arterioles, and venules18–21. Our preliminary results with 
DCS/FDNIRS applied to children with sickle cell disease suggest that the techniques are sensitive 
to alterations in blood flow and oxygen extraction in these patients associated with changes in 
hemoglobin.
In a recently ancillary analysis of data from a Phase 2 Open Label Multicenter Trial (HOPE-
KIDS 1; NCT02850406) voxelotor therapy in children with SCD was associated with improvements 
in RBC health as early as 12 weeks of treatment25. Compared with pretreatment measures, RBC 
deformability performed at fixed shear stress and at varying osmolality showed sustained 
improvement. Upon gradual deoxygenation, RBC deformability under shear stress continued to 
improve with voxelotor. Furthermore, RBC sickling began at a much lower partial pressure of 
oxygen (pO2) compared with pretreatment values, which confirmed that voxelotor prevents ex 
vivo sickling in humans. In addition, the leftward shifts in oxygen dissociation curves (partial 
pressure p20 and p50) confirmed increased Hb-oxygen affinity with voxelotor treatment25. In this 
work, we will explore how measurements of RBC health are associated with cerebral 
hemodynamics. We hypothesize that voxelotor modification of hemoglobin and improvements 
of RBC health will correlate with change in cerebral blood flow and oxygen extraction fraction. 
To test this hypothesis, measurements of RBC morphology, hemolysis, Hb modification, RBC 
deformability and adhesion will be made prior and during treatment period. 
4. Study Intervention/Investigational Agent
Voxelotor is a promising new drug for patients with sickle cell disease that improves hemoglobin 
levels and reduces the incidence of worsening anemia. However, it is unclear whether this 
increase in hemoglobin is associated with a reduction in cerebral metabolic stress. In this work, 
we will determine the effects of voxelotor on cerebral hemodynamics.
4.1
Dosing and Administration
We plan to treat 50 patients in this study. All participants will receive voxelotor, administered 
orally once daily as tablets or dispersible tablets at a dose based on their body weight, for the 
duration of their enrollment in the study.  Participants ≥ 12 years will be instructed to take a 
1500mg dose of voxelotor consisting of three 500mg tablets once daily.  Participants age 4-12 
years will be instructed to take dispersible tablets once daily at a dose based on their body weight 
for the duration of treatment.  The participant’s weight at enrollment will be used to determine 
the starting voxelotor dose in this study.  Voxelotor, in all formulations, may be taken with or 
without food. Voxelotor dispersible tablets should be dispersed in clear liquid (e.g., water, clear 
soda, apple juice, electrolyte drinks, flavored drinks, or sports drinks). Detailed instructions for 
study drug administration will be provided to participants and their caregivers/legal guardians, 
as needed.
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). 

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For AEs that affect safety and tolerability, a trial of reducing or holding (temporarily stopping) the 
dose may be used. All instances of voxelotor dose modification (dose reduction, interruption, or 
discontinuation) should be documented in the participant’s medical record. 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. 
4.2
Dose Justification
The recommended dosage of Voxelotor is 1500 mg taken orally daily, with or without food. The 
dose of voxelotor to be used in this study (weight-based 1500 mg equivalent) is based on clinical 
efficacy and safety results from voxelotor clinical studies in adult and adolescent participants 
combined with Pop PK modeling, physiologically based PK (PBPK) modeling, and allometric 
scaling. Dosing for participants <12 years of age will be weight based, as presented in 
Table 1, and is anticipated to provide exposures similar to adolescent participants receiving 
voxelotor 1500 mg.  These doses are based on Pop PK and, PBPK modeling and allometric scaling 
and are expected to provide exposures of voxelotor equivalent to exposures observed in adults 
(Study GBT440-031) and adolescents (Studies GBT440-007 and GBT440-031)26,27
Table 1:
Voxelotor Weight-based Doses for Participants Less than 12 Years of Age
Population
Voxelotor Doses (1500 mg Equivalent)
10 to <20 kg
600 mg
20 to <40 kg
900 mg
≥40 kg
1500 mg
Participants will receive voxelotor administered orally daily as tablets (300 or 500mg) or 
dispersible tablets (100 mg and 300 mg each). All participants younger than 12 years of age will 
receive a dose based on their body weight to provide exposure corresponding to the adult dose 
of 1500 mg/day. Participants 12 years or older will take 1500 mg/day.
4.3
Acquisition and Accountability
All study drug packaging must be returned at each visit, regardless of whether they are empty or 
contain unused study drug (voxelotor). Unused tablets will be counted and recorded. Dates of 
receipt, dispense, return, lot numbers, and tablet counts will all be recorded in a log. 
In accordance with GCP, the investigational site will account for all supplies of voxelotor drug 
product. Details of receipt, storage, assembly, and return will be recorded. The Investigator must 
ensure that all drug product supplies are kept in a secure locked area with access limited to those 
authorized by the Investigator.
The Sponsor Investigator (or designee) will maintain an accurate record of the receipt of 
voxelotor drug product as shipped by GBT, including, but not limited to, the date received, 
storage conditions/location, lot number, amount received, and the disposition of all voxelotor 
drug product.

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Current dispensing records will also be maintained including the date and amount of voxelotor 
drug product dispensed and the participant receiving the drug product. This drug accountability 
record will be available for inspection at any time.
All unused supplies of voxelotor drug product will either be destroyed by the site or returned to 
the shipping depot at the end of the study.
4.4
Formulation, Appearance, Packaging, and Labeling
Voxelotor will be supplied as 300 or 500 mg tablets or as 100 mg and 300 mg dispersible tablets. 
Voxelotor dispersible tablets will be supplied in HDPE bottles with induction sealed 
polypropylene child-resistant caps.
Voxelotor tablets will be supplied in high-density polyethylene (HDPE) bottles with induction-
sealed polypropylene child-resistant caps. Bottles and/or cartons will be labeled according to 
applicable regulations. 
4.5
Product Storage and Stability
Voxelotor will be stored at controlled room temperature between 15 °C and 25°C (59°F to 77°F) 
in a secure, temperature-controlled and locked environment with restricted access at the 
Sponsor-Investigator’s site. No special procedures for the safe handling of voxelotor are required.
4.6
Preparation
Voxelotor is a tablet ready to be swallowed. Voxelotor dispersible tablets should be dispersed in 
clear liquid (e.g., water, clear soda, apple juice, electrolyte drinks, flavored drinks, or sports 
drinks). Detailed instructions for study drug administration will be provided to participants and 
their caregivers/legal guardians, as needed.
4.7
Study Intervention Compliance
Study drug compliance will be assessed by counting of unused tablets or stick packs. In addition, 
medication compliance will be reported by the participant and caregiver. 
4.8
Concomitant Therapy
A concomitant medication is defined as any prescription or over-the-counter preparation, 
including vitamins and supplements.  All concomitant medications will be recorded in the 
participants medical record and the study case report form at study visits.   Participants will be 
asked always to check with the PI or clinical study staff before taking a new medication.  
Prohibited medications include sensitive CYP3A4 substrates with a narrow therapeutic index and 
strong CYP3A4 inhibitors.  

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5. Procedures Involved
5.1
Study Schema
Screening
        Wk 12
Study Entry
Open Label Treatment Period
EOS
(up to 8wks after last 
treatment)
DCS/NIRS 
Day 1
EOT
Study Population, N=50
•
Age 4-30 years
•
HbSS, S/β0 thalassemia 
•
Stable HU permitted 
•
No transfusion in prior 8 wks
Study Outcomes 
•
10: Change in CBF, OEF, CMRO2 
from baseline at 12 Weeks
•
20: Correlation between CBF, 
OEF and change in total Hb and 
Hb modification
•
Exploratory: Correlation between 
CBF, OEF, CMRO2 and change 
in measures of RBC health 
Wk 4          Wk 8
DCS/NIRS 
DCS/NIRS 

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5.2
Schedule of Assessments (SoA)
FDNIRS/DCS and TCD measurements will be made on D1, or within the screening period 
depending on researcher availability.  For the 4w, 8w, and 12w and end of study visits, the 
time point given spans a window of +/- 7 days. For patients continuing commercial 
voxelotor after 12w, the end of treatment (12w) visit will also serve as the end of study visit.  
Patients who will not continue commercial voxelotor after 12w will complete an end of 
study visit up to 8 weeks after last study dose.
Treatment
Screening 
(up to 28 days)
D1
(+/- 7d)
4w
(+/- 7d)
8w
(+/- 7d)
12w
(+/- 7d)
End of Study
(up to 8 wks post-treatment)
Consent/Assent 
X
Inclusion/Exclusion Criteria
X
Medical History & PE
X
X
X
Height, weight
X
X
X
Vital signs, pulse oximetry
X
X
X
X
X
X
CBC diff, retic
X
X
X
X
X
X
CMP & LDH
X
X
X
Hb Electrophoresis 
X
X
Hb morphology 
X
X
X
X
X
X
RBC Health 
X
X
FDNIRS/DCS (performed by 
Buckley Lab staff)
X
X
X
Transcranial Doppler 
ultrasound (TCD)
(X)
X
X
Pregnancy testing (for 
females of child bearing 
potential)
X
Adverse event reporting
X
X
X
X
X
X
Drug dispensing
X
X
X
X
5.3
Efficacy, Safety, and Other Assessments
Screening will occur up to 28 days prior to the start of the study. The subject’s medical chart will 
be used for screening and for part of collection of trial data, per Health Insurance Portability and 
Accountability Act (HIPAA) rules, other relevant federal or state laws, and local institutional 
requirements, as applicable.  Information obtained from the medical chart will include: 
a) List of current medications and their doses
b) Vital signs

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c) Transfusion history
d) Stroke history
e) Previous MRI and/or MRA’s
f)
Previous sleep studies
g) Previous transcranial Doppler ultrasound 
results.
The study procedures and evaluations to be done as part 
of the study to support the determination of efficacy, as 
per the primary and secondary objectives outlined in this 
protocol, will include:

DCS/FDNIRS assessments. Measurements of 
cerebral blood flow, oxygen extraction, and 
oxygen metabolism will be made by a trained 
study staff personnel using a customized diffuse 
correlation 
spectroscopy 
combined 
with 
frequency domain near 
infrared 
spectroscopy 
oximeter (Figure 2). A 
DCS/FDNIRS 
optical 
sensor will be manually 
held over the right and 
left forehead to obtain a 
brief (<1min) resting 
state measure of brain 
hemodynamics.  
Measurements will be repeated up to 3 times per hemisphere (Figure 3). Total time of 
exam is typically 15-30 minutes. Measurements will be made before, and at 4 and 12 
weeks after the start of voxelotor. Measurements will be obtained in quiet area of Aflac 
outpatient clinics using PPE and hand hygiene practices according to hospital policy. 

A research blood specimen will be obtained when a clinical sample is unavailable. Up to 
sixteen mLs of venous blood will be collected at each visit.  Laboratory assessments 
relevant to measures predictive of voxelotor response and to measures of RBC Health will 
be performed at local (central CHOA lab) clinical labs.  Local laboratory assessments will 
include complete blood count, reticulocyte count, hemoglobin electrophoresis, RBC 
dense cells and measures of RBC hemolysis (LDH, indirect bilirubin). RBC health laboratory 
assessments will include but are not limited to RBC adhesion. 

Procedures that will be completed during the study as part of regular standard of clinical 
care: These include physical examination, vital sign assessment (heart rate, blood 
pressure, pulse oximetry, etc.), medical history.

Transcranial Doppler ultrasound assessment of blood flow velocity in the main feeding 
arteries.  Measurements will follow standard clinical protocols that are outlined routine 
screening in children with sickle cell disease. Baseline TCD assessment may occur at 
screening or at D+1 visit prior to study medication.
Figure 3, (a) Non-invasive FDNIRS/DCS sensor comprised of fiber optics embedded in a 
3D printed holder. The top row of fibers are for FDNIRS and the bottom row are for DCS 
(b) Depth sensitivity of FDNIRS/DCS measurements in a representative 10 year old child. 
(c) Patient measurement with a  similar hand-held FDNIRS/DCS sensor. 
Figure 
2, 
Picture 
of 
portable 
NIRS/DCS 
instrumentation.  The cart takes up a footprint of 
approximately 1.5ft x 3ft.

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5.4
Adverse Events and Serious Adverse Events
Definition of Adverse Events (AE)
Adverse event means any untoward medical occurrence associated with the use of Voxelotor or 
NIRS/DCS measurements of cerebral hemodynamics, whether or not considered intervention-
related (21 CFR 312.32 (a)).
Definition of Serious Adverse Events (SAE)
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of 
either the investigator or sponsor, it results in any of the following outcomes: death, a life-
threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions, or a congenital anomaly/birth defect. Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered serious when, based 
upon appropriate medical judgment, they may jeopardize the participant and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples 
of such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse.
Classification of an AE (Severity of Event)
For adverse events (AEs), guidelines will be used to describe severity. 
•
Mild – Events require minimal or no treatment and do not interfere with the 
participant’s daily activities. 
•
Moderate – Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with functioning.
•
Severe – Events interrupt a participant’s usual daily activity and may require systemic 
drug therapy or other treatment.  Severe events are usually potentially life-threatening 
or incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”.
Classification of an AE (Relationship to Study Intervention)
All adverse events (AEs) will be assessed for relationship to study intervention as the following:
Definitely Related – There is clear evidence to suggest a causal relationship, and 
other possible contributing factors can be ruled out. The clinical event, including 
an abnormal laboratory test result, occurs in a plausible time relationship to taking 
voxelotor and cannot be explained by concurrent disease or other drugs or 
chemicals. The response to withdrawal of the study intervention (dechallenge) 
should be clinically plausible. The event must be pharmacologically or 
phenomenologically definitive, with use of a satisfactory rechallenge procedure if 
necessary.
Probably Related – There is evidence to suggest a causal relationship, and the 
influence of other factors is unlikely. The clinical event, including an abnormal 

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laboratory test result, occurs within a reasonable time after taking voxelotor, is 
unlikely to be attributed to concurrent disease or other drugs or chemicals, and 
follows a clinically reasonable response on withdrawal (dechallenge). Rechallenge 
information is not required to fulfill this definition.
Potentially Related – There is some evidence to suggest a causal relationship (e.g., 
the event occurred within a reasonable time after taking voxelotor). However, 
other factors may have contributed to the event (e.g., the participant’s clinical 
condition, other concomitant events). Although an AE may rate only as “possibly 
related” soon after discovery, it can be flagged as requiring more information and 
later be upgraded to “probably related” or “definitely related”, as appropriate.
Unlikely to be related – A clinical event, including an abnormal laboratory test 
result, whose temporal relationship to voxelotor makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after taking 
voxelotor) and in which other drugs or chemicals or underlying disease provides 
plausible explanations (e.g., the participant’s clinical condition, other concomitant 
treatments).
Not Related – The AE is completely independent of voxelotor, and/or evidence 
exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician.
Classification of an AE (Expectedness) *additional information can be found in Attachment A at 
the end of this document
The PI will be responsible for determining whether an adverse event (AE) is expected or 
unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the 
event is not consistent with the risk information previously described for the study intervention. 
Expected AEs include the following: headache, diarrhea, abdominal pain, nausea, fatigue, rash, 
and pyrexia.
5.5
Time Period and Frequency for Event Assessment and Follow-up
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the 
attention of study personnel during study visits and interviews of a study participant presenting 
for medical care, or upon review by the study PI. 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured 
on the appropriate study database form. Information to be collected includes event description, 
time of onset, clinician’s assessment of severity, relationship to study product (assessed only by 
those with the training and authority to make a diagnosis), and time of resolution/stabilization 
of the event. All AEs occurring while on study must be documented appropriately regardless of 
relationship. All AEs will be followed to adequate resolution.

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Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE. 
Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode.
The PI or study coordinator will record all reportable events with start dates occurring any time 
after informed consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the 
last day of study participation.  At each study visit, the investigator will inquire about the 
occurrence of AE/SAEs since the last visit.  Events will be followed for outcome information until 
resolution or stabilization.
5.6
Adverse Event Reporting
AEs will be reported to Pfizer at regular intervals as required by Pfizer. SAEs will be reported to 
Pfizer within 24 hours after the investigator learns of the event and to the IRB according to IRB 
Policies & Procedures.  The Sponsor-Investigator will be responsible for notifying the FDA of any 
unexpected fatal or life-threatening suspected SAE as soon as possible, but in no case later than 
7 calendar days after Sponsor-Investigator's initial receipt of the information. 
Expected AEs will be recorded in CRFs. 
5.7
Serious Adverse Event Reporting
The study principal investigator will immediately report to Emory IRB according to their Policies 
& Procedures as well as to Pfizer any serious adverse event, whether or not considered study 
intervention related, including those listed in the protocol or investigator brochure and must 
include an assessment of whether there is a reasonable possibility that the study intervention 
caused the event within 24 hours of finding out about the event. Study endpoints that are serious 
adverse events (e.g., all-cause mortality) must be reported in accordance with the protocol unless 
there is evidence suggesting a causal relationship between the study intervention and the event 
(e.g., death from anaphylaxis). In that case, the investigator must immediately report the event 
to the IRB and Pfizer.
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the PI 
deems the event to be chronic or the participant is stable. Other supporting documentation of 
the event may be requested by Pfizer and should be provided as soon as possible.
The Sponsor-Investigator will be responsible for notifying the Food and Drug Administration 
(FDA) of any unexpected fatal or life-threatening suspected adverse reaction as soon as possible, 
but in no case later than 7 calendar days after the initial receipt of the information from the study 
principal investigator. The Sponsor-Investigator or Designee must notify the FDA and all 
participating investigators in an Investigational New Drug (IND) safety report of potential serious 

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risks, from clinical trials or any other source, as soon as possible, but in no case later than 15 
calendar days after the Sponsor-Investigator determines that the information qualifies for 
reporting. In addition, the Sponsor-Investigator is responsible for notifying Pfizer of the FDA 
reported safety event and provide all documentation submitted to the FDA, including the safety 
event narrative.
5.8
Reporting of Pregnancy
In the event of pregnancy that occurs during study, the pregnancy will be reported to GBT 
Pharmacovigilance or Designee and the decision for the participant to continue on study or not 
will depend on the specific situation and will be discussed with GBT Pharmacovigilance or 
Designee. Pregnancies should be monitored for the full duration of pregnancy and/or followed 
through to a definitive outcome. The outcome of a pregnancy event will be reported to GBT 
Pharmacovigilance or Designee. 
5.9
Unanticipated Problems
Definition of Unanticipated Problems (UP)
The Office for Human Research Protections (OHRP) considers unanticipated problems involving 
risks to participants or others to include, in general, any incident, experience, or outcome that 
meets all of the following criteria:
o
Unexpected in terms of nature, severity, or frequency given (a) the 
research procedures that are described in the protocol-related documents, 
such as the Institutional Review Board (IRB)-approved research protocol 
and informed consent document; and (b) the characteristics of the 
participant population being studied;
o
Related or possibly related to participation in the research (“possibly 
related” means there is a reasonable possibility that the incident, 
experience, or outcome may have been caused by the procedures involved 
in the research); and
o
Suggests that the research places participants or others at a greater risk of 
harm (including physical, psychological, economic, or social harm) than 
was previously known or recognized.
This definition could include an unanticipated adverse device effect, any serious adverse effect 
on health or safety or any life-threatening problem or death caused by, or associated with, a 
device, if that effect, problem, or death was not previously identified in nature, severity, or 
degree of incidence in the investigational plan or application (including a supplementary plan or 
application), or any other unanticipated serious problem associated with a device that relates to 
the rights, safety, or welfare of subjects (21 CFR 812.3(s)).
Unanticipated Problems Reporting

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The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review 
Board (IRB) and to the principal investigator (PI). The UP report will include the following 
information:
•
Protocol identifying information: protocol title and number, PI’s name, and the IRB 
project number;
•
A detailed description of the event, incident, experience, or outcome; 
•
An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP; 
•
A description of any changes to the protocol or other corrective actions that have 
been taken or are proposed in response to the UP.
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:  
•
UPs that are serious adverse events (SAEs) will be reported to the IRB and to GBT 
Pharmacovigilance or Designee within 24 hours of the investigator becoming aware 
of the event. 
•
Any other UP will be reported to the IRB and to GBT Pharmacovigilance or Designee 
within 10 days of the investigator becoming aware of the problem. 
•
All UPs should be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures), the supporting agency head (or designee), 
and the Office for Human Research Protections (OHRP) within 10 days of the IRB’s 
receipt of the report of the problem from the investigator.
5.10
End of Study
A participant is considered to have completed the study if he or she has completed all phases of 
the study including the last visit or the last scheduled procedure shown in the Schedule of 
Activities (SoA). For patients continuing commercial Voxelotor after 12w, the end of treatment 
(12w) visit will also serve as the end of study visit.  Patients who will not continue commercial 
Voxelotor after 12w will complete an end of study visit up to 8 weeks after last study dose.
6. Data and Specimen Banking 
Data obtained during this research may be stored for future use. Data will be stored indefinitely 
on password protected computers on servers managed by Children’s Healthcare of 
Atlanta/Emory University and only accessible be authorized personnel. Paper data is stored in a 
locked cabinet in a locked office. Only study personnel have access to input data into electronic 
database. Data collected and stored will include, but not limited to:

demographic data

data collected from surveys

medical treatment data

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Data will be maintained for the duration of the study and thereafter as required by funding 
sources.
Deidentified data from this study may be requested from other researchers after the completion 
of the primary endpoint by contacting the Principal Investigator and presenting appropriate 
regulatory approvals.
No biological specimens will be retained, and no genetic material will be collected in this study.
7. Sharing of Results with Participants
In the event that medically significant and clinically actionable results are found, this information 
will be shared with providers. Results would be provided to the subject's physician who will 
discuss with the patient or legal guardian and appropriate treatment, repeat testing, genetic 
counseling or follow-up testing would be discussed and decided locally on a case by-case basis.
8. Study Timelines
The duration of an individual participant’s participation in the study is approximately 16 weeks. 
We anticipated enrolling about 5-8 subjects per month, with 9 month expected duration to enroll 
all study participants. The estimated date for the investigators to complete this study is 28 
months. 
9. Inclusion and Exclusion Criteria
9.1
Inclusion Criteria
Subjects will be recruited from the CHOA Aflac Sickle Cell Comprehensive Clinics located at the 
Scottish Rite campus and the Egleston campus.
In order to be eligible to participate in this study, an individual must meet all of the following 
criteria:
1. Written informed parental/guardian consent and participant assent for patients < 18y or 
written informed consent for patients > 18y has been obtained per institutional review 
board (IRB)/Ethics Committee (EC) policy and requirements, consistent with ICH 
guidelines.
2. Stated willingness to comply with all study procedures and availability for the duration of 
the study 
3. Male or female participants, ages 4 to 30 years, inclusive 
4. Homozygous hemoglobin SS (HbSS) or hemoglobin S/beta0 thalassemia (HbS/β0 thal
5. Hemoglobin (Hb): Hb ≤10.5 g/dL at baseline
6. Concomitant hydroxyurea (HU) therapy is allowed if the dose has been stable for at least 
3 months with no anticipated need for dose adjustments during the study and no sign of 
hematological toxicity.
7. Ability to take oral medication and willingness to adhere to daily voxelotor and scheduled 
DCS/NIRS assessments. 

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8. If sexually active and female, must agree to abstain from sexual intercourse or to use a 
highly effective method of contraception throughout the study period and for 30 days 
after discontinuation of study drug. If sexually active and male, must agree to abstain 
from sexual intercourse or willing to use barrier methods of contraception throughout 
the study period and for 30 days after discontinuation of study drug.
9. Females of child-bearing potential, i.e., who have begun menstruation and are sexually 
active, are required to have a negative pregnancy test at screening before the initial 
administration of study drug.
9.2
Exclusion Criteria
An individual who meets any of the following criteria will be ineligible for participation in this 
study:
1. Any one of the following requiring medical attention within 14 days prior to signing the 
informed consent form (ICF):

Vaso-occlusive crisis (VOC)

Acute chest syndrome (ACS)

Splenic sequestration crisis

Dactylitis
2. Requires chronic transfusion therapy
3. RBC transfusion within 60 days of signing the ICF  
4. Renal dysfunction requiring chronic dialysis or creatinine ≥1.5 mg/dL.
5. Hepatic dysfunction characterized by alanine aminotransferase (ALT) >4× upper limit of 
normal (ULN) for age.
6. Clinically relevant cardiac abnormality, in the opinion of the Investigator, such as:

Hemodynamically significant heart disease, e.g., congenital heart defect, 
uncompensated heart failure, or any unstable cardiac condition

An arrhythmic heart condition requiring medical therapy
7. QTcF >450 msec, congenital long QT syndrome, second- or third-degree heart block at 
rest (with the exception of asymptomatic Mobitz type I second degree heart block).
8. Received an investigational drug within 30 days or 5 half-lives, whichever is longer, of 
signing the ICF.
9. Heavy smoker (defined as smoking more than 10 cigarettes/day or its nicotine equivalent 
including e-cigarettes).
10. Unlikely to comply with the study procedures.
11. Other medical, psychological, or addictive condition that, in the opinion of the 
Investigator, would confound or interfere with evaluation of safety and/or PK of the 
investigational drug, prevent compliance with the study protocol, or preclude informed 
consent.
12. Any condition affecting drug absorption, such as major surgery involving the stomach or 
small intestine (prior cholecystectomy is acceptable).

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13. History of malignancy within the past 2 years prior to treatment Day 1 requiring 
chemotherapy and/or radiation (with the exception of local therapy for non-melanoma 
skin malignancy).
14. Clinically significant bacterial, fungal, parasitic, or viral infection currently receiving or that 
will require therapy.
Participants with acute bacterial infection requiring antibiotic use should delay 
screening until the course of antibiotic therapy has been completed and the 
infection has resolved, in the opinion of the investigator.
Known active hepatitis A, B, or C infection or human immunodeficiency virus (HIV)-
positive; known active 
Known active malaria.
15. Pregnant patients
16. Evidence of abnormal high blood flow velocities on TCD of 200 cm/sec or more
9.3
Lifestyle Considerations
During this study, participants are asked to:

Refrain from using herbal medications (e.g., St. John’s Wort), or medications that are 
sensitive cytochrome CYP3A4 substrates or CYP3A4 modulators, such as fluconazole.
10. Vulnerable Populations
There are no restrictions in the inclusion or exclusion criteria in regard to race, ethnicity, or 
gender. However, SCD is more common in certain ethnic groups including individuals of African 
descent such as African Americans and Hispanic-Americans from Central and South America and 
individuals of Middle Eastern, Asian, Indian, and Mediterranean descent. Thus, we anticipate that 
our cohort will be reflective of this. 
This research includes individuals who are not yet adults. Safeguards are in place to protect their 
rights and welfare. This study research is consistent with the Declaration of Helsinki in that the 
research is necessary to promote the health of children with sickle cell disease. 
Children will not be enrolled without the informed consent of parents and the assent (or consent) 
of the child per IRB/REB/local ethics committee policies and guidelines. 
Declining to participate in the research will not affect their care.
11. Local Number of Participants
Approximately 50 subjects are expected to be accrued in this research. The anticipated accrual 
rate is 5-8 subjects per month.
12. Recruitment Methods
12.1
Subject Identification
Potential participants will be recruited from outpatient sickle cell clinic at Children’s Healthcare 
of Atlanta. Providers, including physicians, advanced practice providers (APPs-nurse practitioners 

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or physician assistants), or genetic counselors will identify potential participants based on their 
diagnoses at the time of their scheduled clinical visits.
Patients under the care of providers at Children’s Healthcare of Atlanta (CHOA) sites who have 
sickle cell disease may be approached for enrollment at any time after being diagnosed.
We plan to enroll children with sickle cell disease with any mix of male or female gender, ranging 
in age from 4 to 30 years.  
IRB approved study team members will identify potential candidates through medical record 
review. Patients and families of the Children’s Healthcare of Atlanta inpatient and outpatient 
sickle cell disease clinics will be contacted by a study team member prior to their scheduled 
appointment.  Patients and families may be approached in the clinic or via a phone call. 
12.2
Screen Failures
Individuals who do not meet the criteria for participation in this trial (screen failure) because 
recent vaso-occlusive crisis (VOC), acute chest syndrome (ACS), splenic sequestration crisis, or 
dactylitis may be rescreened. Rescreened participants should be assigned the same participant 
number as for the initial screening.
Individuals who do not meet the criteria for participation in this study (screen failure) because 
hydroxyurea dose or hemoglobin had not been stable for 3 months may be rescreened. 
Rescreened participants should be assigned the same participant number as for the initial 
screening.
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not entered in the study. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any serious adverse event (SAE).
13. Withdrawal of Participants
13.1
Discontinuation of Study Intervention
At any point in the study, the child or parents can withdraw from the study. Discontinuation from 
voxelotor treatment will end participation in the study.
13.2
Participant Discontinuation/Withdrawal from the Study
Participants are free to withdraw from participation in the study at any time upon request.
An investigator may discontinue or withdraw a participant from the study for the following 
reasons:

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
Pregnancy

Significant study intervention non-compliance 

If any clinical adverse event (AE), such as hypersensitivity to the study drug, laboratory 
abnormality, or other medical condition or situation occurs such that continued 
participation in the study would not be in the best interest of the participant

If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation

Disease progression which requires discontinuation of the study intervention
The reason for participant discontinuation or withdrawal from the study will be recorded on the 
Case Report Form (CRF). Subjects who sign the informed consent form and subsequently 
withdraw, or are withdrawn or discontinued from the study, will not be replaced.
Once dosed, participants who discontinue/withdraw the study will not be replaced. We 
estimate 40 subjects will be sufficient to achieve the primary, secondary, and exploratory 
endpoints. Our target sample size of 50 allows for approximately 20% drop out rate. This 
dropout rate far exceeds the actual dropout rate in the large multicenter Phase 2a study of 
voxelotor use in pediatrics (GBT440-007). 
13.3
Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she fails to return for scheduled visits 
and is unable to be contacted by the study site staff. 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit:

The site will attempt to contact the participant and reschedule the missed visit within 1-
2 weeks and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain if the participant wishes to and/or should continue in the study.

Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 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 or study file. 

Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.
14. Risks to Participants
Treatment with this study drug may also involve risks that we currently don’t know about. 
As of  November 2019, commercial Oxbryta (voxelotor) was approved for treatment of sickle 
cell disease in adults and pediatrics 12 years and older. In December 2021, the indication was 
modified to include pediatrics 4 years and older. 

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The most common adverse reactions (incidence >10%) are headache, diarrhea, abdominal pain, 
nausea, fatigue, rash, and pyrexia. Other reported side effects include symptoms like a common 
cold (upper respiratory tract infection), pain (including pain in joints, stomach, chest, and back) 
and vomiting.
All of these side effects were also reported by people who took placebo (a sugar pill, containing 
no voxelotor). Adults and children had sickle cell pain crises during previous and current studies 
with voxelotor, but they occurred as often as in people who received placebo (sugar pill, 
containing no voxelotor); most of these events were thought to be related to SCD. Acute chest 
syndrome and priapism also occurred on other studies with voxelotor – these events were less 
common and are known to be related to SCD. Overall, the sides effects observed in adults and 
children were similar. 
Uncommon side effects (occurring in 0.1 % to 1% of people; between 1 and 10 in a thousand 
people): Allergic reactions that the study doctors thought were caused by voxelotor were also 
reported in one person with SCD. Symptoms of this allergic reaction included face swelling and 
fever. Symptoms went away after the study drug was stopped.
Unknown risks: It is possible that your SCD symptoms will not improve during the study or may 
even worsen. Treatment with this study drug may also involve risks to your future health that 
we currently don’t know about. 
Interaction with other medications: The effects of the study drug may change when taken with 
other drugs.  Among these are carbamazepine, phenytoin, rifampin and St. John’s Wort
Blood draw: The risks of drawing blood from a vein include fainting and pain, bruising, swelling, 
or rarely infection at the needle site. These discomforts are brief and transient.
DCS/NIRS test: The light used in the DCS/NIRS sensor delivers less power than the energy your 
child would receive from the sun on an outdoor walk on a sunny day. This energy is also below 
the American National Standards Institute (ANSI) light levels and is in compliance with the United 
States Food and Drug Administration (FDA).  See Appendix for more information. Children with 
sensitive skin might have minor temporary skin irritation from contact with the optical sensor on 
the forehead.
15. Potential Benefits to Participants
Voxelotor is being offered as a treatment for your SCD for the reasons previously indicated. If it 
is effective, symptoms of SCD may improve, however participants may or may not receive any 
benefit from being in this Study. It is possible that your symptoms may get better, stay the same 
or get worse. This study is designed to learn more about the effects of a novel treatment for sickle 
cell disease (voxelotor) on the brain. We hope that the study results will be used to help others 
in the future.

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16. Compensation to Participants
Subjects will be compensated for their time. A $50.00 gift card will be given to the subject after 
completion of each measurement session, for a total up to $250.00 for the completion of all 
study measures. 
17. Statistical Considerations, Data Management and Confidentiality
17.1
Statistical Considerations
Statistical Hypothesis

Primary Endpoint: CBF and OEF are significantly lower at 4 and 12 weeks of 
treatment with voxelotor compared to pre-treatment levels. Paired t-test or 
Wilcoxon signed-rank test will be used to evaluate results, as patients are their 
own controls.

Secondary Endpoints: The change in OEF and CBF from pre-treatment levels are 
significantly correlated with the change in hemoglobin. The change in OEF and CBF 
from pre-treatment levels are correlated with markers of hemolysis.
Sample Size Determination
This is a pilot study involving 50 participants to define the magnitude of change. Power 
cannot be calculated at this time. 
Populations for Analyses
There will be one dataset for this pilot study of 50 participants. 
17.2
Statistical Analyses
General Approach
As the primary objective of this study is to obtain clinical and laboratory information 
to justify a larger clinical efficacy trial of voxelotor in SCA patients, the results of this 
study will be descriptive.  
Analysis of the Primary Efficacy Endpoint
To test our hypothesis that voxelotor reduces oxygen extraction and blood flow, we 
will compare changes in the DCS/FDNIRS-measured outcome variables (CBF, OEF, 
CMRO2) from baseline levels using one-sample paired t-test or Wilcoxon signed-rank 
test, as appropriate. Measures will be adjusted for the increase in hemoglobin 
observed (i.e., relative change in OEF per g/dL change in hemoglobin).
Analysis of the Secondary/Exploratory Endpoints
Linear mixed-effects regression models with random-intercept at the patient level will 
be used to examine the association of each outcome measure (OEF, CBF, and CMRO2) 
with demographical (sex and age) and laboratory data (Hb, reticulocyte count, 
bilirubin, LDH, Hb occupancy, oxygen dissociation curves, RBC deformability and 

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mitochondrial content). These models will be two-level and will account for repeated 
measures (0, 4, and 12 week measurements) nested within the same patient. 
Safety Analysis 
AEs will be coded by MedDRA terminology. Each AE will be counted once for a given 
participant. Severity, relationship to study drug, expectedness, dates, outcome, and 
duration of AEs will be reported. 
Baseline Descriptive Statistics 
Due to the anticipated small number of participants descriptive statistics will be 
used primarily to present the chart-extracted data. Summary of patient 
characteristics such as age, prior sickle cell complications, disease-modifying 
therapy, laboratory and radiology findings and outcomes will be presented. 
Descriptive analyses will involve calculation of proportions (frequencies) for 
categorical data. For continuous variables, mean and standard deviation (normally 
distributed data) or median and interquartile ranges (not normally distributed data) 
will be presented. Chi Square (or Fisher’s Exact test as applicable) will be used to 
compare categorical variables presented as proportions of total. Student’s t-test or 
one-way ANOVA will be used to compare continuous parametric variables and non-
parametric variables, respectively. Aid in statistical analysis, if indicated, will be 
sought via the Emory Biostatistics Core.
Tabulation of Individual Participant Data
Individual participant data will be listed by measure and time point.
17.3
Data Management, Quality Assurance and Quality Control 
Data Collection and Management Responsibilities
Data collection is the responsibility of the study team under the supervision of the 
principal investigator. The investigator is responsible for ensuring the accuracy, 
completeness, legibility, and timeliness of the data reported.
All source documents will be completed in a neat, legible manner to ensure accurate 
interpretation of data.  
Hardcopies of the study visit worksheets will be provided for use as source document 
worksheets for recording data for each participant enrolled in the study.  Data 
recorded in the electronic case report form (eCRF) derived from source documents 
should be consistent with the data recorded on the source documents. Data will be 
recorded in password-protected database accessible only by PI and the study 
personnel. Any paper source documents will be stored in a locked cabinet in the 
Investigator’s office. 

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Quality Assurance and Quality Control
Study staff are trained extensively on the operation of the DCS/FDNIRS device prior 
to performing measurements. Documentation regarding device settings, sensor 
settings, and sensor positioning is completed at each measurement session. Periodic 
performance testing of the DCS/FDNIRS device is completed routinely with calibration 
standards.  
The clinical site will perform internal quality management of study conduct, data 
collection, documentation and completion. The PI will check the quality and accuracy 
of data entry. The research lab conducts quality control on all its instrumentation and 
lab protocols. 
Summarized data will be provided to GBT in study progress reports. 
17.4
Study Record Retention
There is no set time for destroying information collected for this study.  As this is an 
investigational, pilot study, we may use the data for future studies, and we also may need to 
access additional clinical information of the patient in the future as we delve deeper into the data 
and discover new aspects of the relationship between cerebral hemodynamics and clinical 
condition to explore.
17.5
Protocol Deviations
It is the responsibility of the Principal Investigator to use continuous vigilance to identify and 
report deviations to Emory IRB within 10 working days of identification of the protocol deviation, 
or within 10 working days of the scheduled protocol-required activity.  All deviations must be 
addressed in study source documents, reported to the Emory University IRB and included in the 
study progress reports submitted to GBT.  Protocol deviations must be sent to the reviewing 
Institutional Review Board (IRB) per their policies. The site investigator is responsible for knowing 
and adhering to the reviewing IRB requirements.
18. Provisions to Monitor the Data to Ensure the Safety of Participants
Internal monitoring of the trial for protocol compliance and data accuracy will be the 
responsibility of the Research Administration QA/QI Analyst. The trial will be monitored for 
completion of the informed consent forms, clinical data capture forms, IP dispense logs and 
treatment-related adverse events not related to SCD. In addition, the credentials, delegation of 
authority and training logs will be monitored for study member. The monitoring will occur 
according to the following schedule:

At least every six months while participants are receiving intervention and

Annually while participants are in follow-up

Close-Out Study Visit
 

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Additional monitoring may be performed in the event of Serious Adverse Events if deemed 
necessary by the monitoring committee or if requested by the Principal Investigator.
 
This study will be conducted in compliance with the Aflac Cancer & Blood Disorders Center Data 
Safety Monitoring Board (DSMB) for Phase 1 and 2 pediatric studies. In brief, the role of the Data 
Safety Monitoring Board (DSMB) is to protect the interests of subjects and the scientific integrity 
for all Phase 1 and 2 studies. The DSMB consists of 7 members including a chair, a statistician, a 
pharmacist, and at least one external member.
 
The DSMB meets on a quarterly basis to review current study results, as well as data available to 
the DSMB from other related studies. The DSMB will provide recommendations for each study 
reviewed to change the study or to continue the study unchanged and will determine the 
frequency of future meetings.
 
Data and Safety Board reports for Institutional Review Boards will be prepared. The Principal 
Investigator assumes responsibility for assuring that the study is carried out in accordance with 
the DSMP.
 
DSMP Requirement
How this Requirement is Met
Frequency
Responsible Party(ies)
Site Monitoring at pre-
determined intervals: The 
Principal Investigator has a 
responsibility to ensure that 
the study is following all 
aspects of the protocol.
There should be a standard operating 
procedure to review data (whether a 
sample or 100%) at pre-determined 
intervals to ensure that there is 
adequate documentation of critical 
elements such as eligibility criteria. 
Monitoring is required at the following 
timepoints (but may be done more 
frequently):

study initiation 

at least every six months while 
participants are receiving 
intervention and

annually while participants 
are in follow-up
At a minimum, a review 
is required annually 
when no one has been 
enrolled or the study is 
in long term follow up. 
Additional interim 
monitoring at least 
once every 12-24 weeks 
based on the site 
activity, and more as 
needed, to include the 
possibility of remote 
monitoring.
Delegate a responsible 
party for each requirement 
below*. Self-assessment is 
NOT acceptable. An 
experienced, 
knowledgeable person who 
is independent of the study 
team should serve as 
monitor. A Contract 
Research Organization 
(CRO) may be used. 
Consult the IRB Office 
regarding acceptable 
qualifications for the 
independent monitor, if not 
using an outside expert 
such as a CRO.
 
Real-time review of 
participant data during 
initial data collection.
Inclusion/Exclusion Checklist is 
completed by the CRC and 
reviewed by the PI for approval 
and signoff. The CRC will also 
signoff
This is completed 
when study 
subjects enroll
Study team and PI
100% review of 
regulatory files
Regulatory binder will be 
created to house all Regulatory 
documents for review. 
Regulatory files will be reviewed 
by monitor at monitoring visits.
Start of study, close 
out and as 
necessary in 
between
Team coordinators, 
QA/QI Analyst

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100% review of consent 
forms
Per Aflac policy, all consents are 
reviewed in real time by 2 
separate coordinators.  The first 
review is within 5 days of the 
consent. The next review is 
within 5 days of the first review 
but within 10 days of the 
consent date. Consents will be 
reviewed by monitor at 
monitoring visits.
As consents are 
signed
Team coordinators
QA/QI Analyst
Review of credentials, 
training records, the 
delegation of 
responsibility logs (if 
applicable)
Study training logs are kept in 
the Regulatory Binder for review 
with the upkeep of the 
coordinators. This information 
will be reviewed by monitor at 
monitoring visits.
Reviewed every 
time there are 
study team 
changes as well as 
study amendments
Team coordinators
QA/QI Analyst
Comparison of case 
report forms (CRF) to 
source documentation 
for accuracy and 
completion
Data will be stored on Erin 
Buckley’s lab’s server. The 
assigned monitor will compare 
data in the study database to 
the source data on the CRFs. 
Discrepant data and queries will 
be sent to the study team who 
will be required to respond to 
each item. CRF documentation 
will be reviewed by monitor at 
monitoring visits.
Yearly Review
Buckley Lab, CHOA  
QA/QI Analyst 
Review of 
documentation of all 
adverse events
The PI will have oversight on the 
documentation of AE’s which 
will be logged and tracked by 
the study Coordinator and kept 
in the subject’s study chart. AE 
documentation will be reviewed 
by monitor at monitoring visits.
Every time an AE 
occurs the Study 
Coordinator will log 
it. Monitor will 
review at specified 
monitoring 
intervals.
PI, Team Coordinators, 
QA/QI Analyst 
Monitoring of critical 
data points (eligibility, 
study endpoints, etc.)
Data Collection of critical data 
points is the responsibility of the 
study coordinators under the 
supervision of the principal 
investigator. The coordinators 
are responsible for ensuring 
accuracy, completeness, 
legibility, and timeliness of the 
data reported. The monitor will 
Eligibility will be 
confirmed at time 
of patient 
enrollment. Study 
endpoints will be 
reviewed at end of 
each treatment 
period. 
 
Principal Investigator, 
Team Coordinators, 
and QA/QI Analyst

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review critical data points at 
monitoring visits. The PI will 
have oversight over all data 
collected for the study and will 
review all monitoring reports 
upon the completion of a 
monitoring visit. 
Laboratory review of 
processing and storage 
of specimens
Coordinators will process labs. 
Labs are typically shipped same 
day of collection but can be 
stored on site as well. 
If samples are 
stored, they are 
reviewed at the 
visits and close-out 
visit
Buckley Lab, Team 
Coordinators, QA/QI 
Analyst
Assessment of laboratory 
specimens stored locally
The specimens will be stored in 
Buckley lab (HSRB E169)
Yearly
Buckley Lab
Test article 
accountability review
Buckley lab is responsible for 
device maintenance and 
calibration. Calibration records 
will be reviewed by monitor at 
monitoring visits.
Calibration will be 
done prior to each 
measurement
Buckley Lab,  QA/QI 
Analyst
Accountability logs, 
dispensing records, and 
other participant records
All IP and IP logs are monitored 
and housed with the Research 
Pharmacist within NCoup. IP 
logs will be reviewed by monitor 
at monitoring visits.
 
Will be monitored 
at least once 
monthly, more 
frequently if an 
active patient is on 
the study
Research Pharmacist, 
QA/QI Analyst
For FDA regulated 
studies, the following 
requirements apply:
How this Requirement is Met
Timing, frequency, 
and intensity of 
monitoring
Responsible Party(ies)
Monitoring methods 
(may include centralized, 
on-site, and self-
monitoring)
Previously, CTAC did a review 
after the first 10 subjects and 
the results of that were 
provided in the comments of 
the CR already. The QA/QI 
Analyst will be monitoring this 
study going forward.
As per protocol
QA/QI Analyst 
*For international studies, you are required to engage a CRO that is working in the site country and/or to consult with Emory’s 
legal counsel regarding compliance with the country’s clinical research regulations.
 
19. Provisions to Protect the Privacy Interests of Participants
Eligible subjects will be identified by treating physicians, APPs, and/or genetic counselors with 
whom they already have a treating relationship. A description of the study will be provided to 
potential subjects by the provider or a study staff designee. The provider will be able to answer 

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any questions about participation and data to be collected and to ensure that participants’ 
privacy interests are protected. Study interactions will be kept strictly confidential. 
Data will be stored on a secure server maintained by CHOA/Emory University. All data will be de-
identified and aggregated prior to being analyzed and published. 
No personnel will be authorized to use study data or specimen for any other purpose other than 
what falls within the scope of the study. Only authorized personnel will have access to any 
identifying information. The only other groups that will have access to data and specimens are 
members of supervisory organizations, such as IRB, and then only as part of routine review or 
audit.
Any electronic records will be maintained in a de-identified manner in a locked, password-
protected data file/database, and access to this will be limited to the research team, requiring 
both login ID and password. Study data will only be accessed from School of Medicine/ CHOA 
computers that are compliant with all SOM Data security policies and are both backed up and 
encrypted. Any email correspondence between study investigators and staff will be completed 
using emory.edu or choa.org accounts. If study materials need to be transmitted electronically, 
senders will send the email in an encrypted fashion. All research staff have received extensive 
training on storing and transmitting secure data. 
19.1
Publication and Data Sharing Policy
This study will be conducted in accordance with the following publication and data sharing 
policies and regulations:
Any final peer-reviewed journal manuscripts that arise from this study will be submitted to the 
digital archive PubMed Central upon acceptance for publication.
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-
Funded Clinical Trial Information and the Clinical Trials Registration and Results Information 
Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and results information 
from this trial will be submitted to ClinicalTrials.gov. In addition, every attempt will be made to 
publish results in peer-reviewed journals. 
19.2
Conflict of Interest Policy
All study team members will disclose conflicts of interest, which will be managed in ways that 
prevents interference with proper conduct of the study. 
20. Economic Burden to Participants
Participants and/or their families will be responsible for costs associated with fuel, parking, 
childcare, or any procedures considered standard of care. Data and samples for this study will be 
collected at scheduled research visits and/or provided electronically via the internet at their 

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convenience. While participants are responsible for their regular clinical care, they are not 
responsible for any costs associated with this study.
21. Consent Process
Informed Consent
1. Informed consent/assent will be obtained prior to the collection of research data. 
Assent and consent forms will be Institutional Review Board (IRB) approved, and 
assent and consent will be obtained per IRB policies and guidelines. The participant or 
parent/legal guardian may withdraw consent at any time throughout the course of 
the study. A signed copy of the informed consent document will be given to the 
participants' parent/legal guardian. By signing the informed consent form, the 
participant's parent/legal guardian agrees that the participant will be enrolled in the 
study until the participant is withdrawn voluntarily or for any reason.
2. For children under the age of majority or capacity (as locally defined} at the time of 
parental consent, once the child reaches the age of majority or capacity, informed 
consent must be obtained from that subject to allow 1) his/her name, other 
identifying information, data and specimens, to continue to be available to study 
investigators; 2) ongoing collection of research data; and 3) for future contact.
3. Informed consent will include:
o Permission to access and provide clinical data centrally for study-related research
o Permission to contact for future research
o Permission to contact for return of medically significant and actionable research 
results (optional)
o Permission to store de-identified data in a manner such that it can be efficiently 
shared with collaborators and other investigators.
Setting of Consent Discussion
Potential subjects identified by providers will be approached about the study by an 
authorized member of the study staff (e.g. Clinical Research Associate, Research 
Coordinator) at the time of a regularly scheduled clinic visit. The study will be described 
in detail to the Potential Subject/family through a conversation expected to take 15-30 
minutes. To minimize the possibility of coercion, the voluntary nature of participation will 
be emphasized and no compensation for participation will be offered. The Potential 
Subjects/family will be given ample opportunity to ask questions for clarification and will 
be asked to describe their understanding of the study to ensure their understanding. If 
desired by the Potential Subject, they will be allowed to consider and discuss participation 
with other family and sign consent forms to be returned via mail or electronically.
Documentation of Informed Consent

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Paper Assent and Consent forms will be IRB approved and serve as the primary 
documentation of informed consent/assent for the subjects.
Enrollment
The Primary Subject (a child with SCD) will be assigned a Unique Subject Identifier upon 
entry to study.
Non-English-Speaking Participants  
The language(s), other than English, that are understood by prospective participants or 
representatives are unknown. If the patient and/or family is not able to clearly understand 
English, they will have access to this program if they meet eligibility criteria. A CHOA certified 
interpreter will participate in the consent process. CHOA interpreters are available 24 hours/day, 
7 days/week. Consent/authorization will be obtained using the IRB-approved English consent, 
along with a short form in the appropriate language. The interpreter orally translates the English 
consent. Consent is obtained only if consenting staff and the interpreter are convinced that the 
patient/family understands the translation, and all questions have been addressed. It will be 
stressed that treatment is available whether or not the patient/family agrees to participate in the 
study. 
Participants who are not yet adults (children, teenagers)  
This study will enroll children and teenagers who have not attained the legal age/capacity for 
consent for research, as locally defined. Therefore, parents or another Legally Authorized 
Representative will provide informed consent prior to Subject enrollment. 
Assent will be obtained from appropriately aged Subjects who are not yet adults. Local IRB 
guidelines may vary, but generally, assent is not required from children younger than 6 years old, 
verbal assent will be obtained from children 6 to 10 years old, and signed assent will be obtained 
from children aged 10 to <17 years old, subject to Institutional regulations. 
Cognitively Impaired Adults  
All consenting staff will adhere to consenting guidelines and explain all alternatives to 
participation. All questions and concerns are addressed during the consenting process. Subjects 
are encouraged to take home the consent and forms before deciding to participate in this 
research. The consenting process involves asking questions to ensure the subjects understand 
the process and the study.
Adults Unable to Consent  
Consent will be obtained from a LAR for adults who are unable to consent per institutional policy. 
We will utilize institutional research SOPs to document consent in writing.
Waiver or Alteration of Consent Process (consent will not be obtained, required 
information will not be disclosed, or the research involves deception)

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We are requesting a waiver of HIPAA authorization to initially identify participants eligible for this 
research.  
22. Setting
Children’s Healthcare of Atlanta (CHOA) is the main healthcare entity caring for children across 
the state of Georgia, and training site for Emory University pediatric residents and fellows. Faculty 
are employed by Emory University and clinical service occurs at CHOA. Emory University is the 
academic affiliate of CHOA. Our Sickle Cell Disease Program is the largest pediatric program in 
the country, caring for more than 2,000 children and young adults. Combining the latest proven 
technology and research with a caring, child-friendly approach makes the Aflac Cancer and Blood 
Disorders Center of Children's Healthcare of Atlanta—the county’s largest pediatric hematology 
program—a top choice for the treatment of sickle cell disease. The Aflac Cancer & Blood 
Disorders Center’s Clinical Research Office (CRO) houses clinical research coordinators and data 
analysts at Egleston and Scottish Rite for faculty within Aflac.
23. Resources Available
The Principal Investigators will have effort designated for the design, oversight, and management 
of the study.  The Principal Investigator and other site personnel will be credentialed and trained 
to perform research specific activities. Documentation of their training will be maintained in 
study regulatory files.
All Co-Investigators and Study Staff will be trained in the proper conduct of the protocol, the 
research procedures and their duties and functions. Training will be conducted by the Principal 
Investigator or designee via in person or web-based video conferencing. 

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24. References
1. Liem RI. Balancing exercise risk and benefits: lessons learned from sickle cell trait and 
sickle cell anemia. Hematology Am Soc Hematol Educ Program. 2018 Nov 30;2018(1):418-
425. doi: 10.1182/asheducation-2018.1.418. Review. PMID:3050434
2. Omwanghe OA, Muntz DS, Kwon S, Montgomery S, Kemiki O, Hsu LL, Thompson AA, Liem 
RI. Self-Reported physical activity and exercise patterns in children with sickle cell disease. 
Pediatr Exerc Sci. 2017 Aug;29(3):388-395. doi: 10.1123/pes.2016-0276. Epub 2017 May 
22. PMID:28530510
3. Al-Rimawi H, Jallad S. Sport participation in adolescents with sickle cell disease. Pediatr 
Endocrinol Rev. 2008 Oct;6 Suppl 1:214-6. Review. PMID:19337181
4. Connes P, Machado R, Hue O, Reid H. Exercise limitation, exercise testing and exercise 
recommendations in sickle cell anemia. Clin Hemorheol Microcirc. 2011;49(1-4):151-63. 
doi: 10.3233/CH-2011-1465. Review. PMID:22214686
5. Cooper DM, Liem RI. Translating exercise benefits in sickle cell disease. Blood. 2019 Dec 
19;134(25):2227-2229. 
doi: 
10.1182/blood.2019003651. 
No 
abstract 
available. 
PMID:31856272
6. Merlet AN, Chatel B, Hourdé C, Ravelojaona M, Bendahan D, Féasson L, Messonnier LA. 
How sickle cell disease impairs skeletal muscle function: implications in daily life. Med Sci 
Sports Exerc. 2019 Jan;51(1):4-11. doi: 10.1249/MSS.0000000000001757. Review. 
PMID:30095751
7. Merlet AN, Messonnier LA, Coudy-Gandilhon C, Béchet D, Gellen B, Rupp T, Galactéros F, 
Bartolucci P, Féasson L. Beneficial effects of endurance exercise training on skeletal 
muscle microvasculature in sickle cell disease patients. Blood. 2019 Dec 19;134(25):2233-
2241. doi: 10.1182/blood.2019001055. PMID:31742587
8. Gellen B, Messonnier LA, Galactéros F, Audureau E, Merlet AN, Rupp T, Peyrot S, Martin 
C, Féasson L, Bartolucci P; EXDRE collaborative study group. Moderate-intensity 
endurance-exercise training in patients with sickle-cell disease without severe chronic 
complications (EXDRE): an open-label randomised controlled trial. Lancet Haematol. 2018 
Nov;5(11):e554-e562. doi: 10.1016/S2352-3026(18)30163-7. PMID:30389037
9. Grau M, Nader E, Jerke M, Schenk A, Renoux C, Dietz T, Collins B, Bizjak DA, Joly P, Bloch 
W, Prokop A, Connes P. Impact of a six week training program on ventilatory efficiency, 
red blood cell rheological parameters and red blood cell nitric oxide signaling in young 
sickle cell anemia patients: a pilot study. J Clin Med. 2019 Dec 5;8(12). pii: E2155. doi: 
10.3390/jcm8122155. PMID: 31817545
10. Mezzani A. Cardiopulmonary exercise testing: Basics of methodology and measurements. 
Ann Am Thorac Soc. 2017 Jul;14(Supplement_1):S3-S11. doi:10.1513/AnnalsATS.201612-
997FR. Review.PMID: 28510504
11. Milani RV, Lavie CJ, Mehra MR, Ventura HO. Understanding the basics of cardiopulmonary 
exercise testing. Mayo Clin Proc. 2006 Dec;81(12):1603-11. Review. PMID:17165639
12. Pianosi PT, Liem RI, McMurray RG, Cerny FJ, Falk B, Kemper HC. Pediatric exercise testing: 
value and implications of peak oxygen uptake. MID:30389037.  Children (Basel). 2017 Jan 
24;4(1). pii: E6. doi: 10.3390/children4010006. Review. PMID:28125022
13. van Beers EJI, van der Plas MN Nur, E, Bogaard HJ, van Steenwijk RP, Biemond BJ, Bresser 
Pl. Exercise tolerance, lung function abnormalities, anemia, and cardiothoracic ratio in 

Voxelotor SCA NIRS Study (VoxSCAN)
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sickle cell patients. Am J Hematol. 2014 Aug;89(8):819-24. doi: 10.1002/ajh.23752. Epub 
2014 May 16.
14. Hutchaleelaha A, Patel M, Washington C, Siu V, Allen E, Oksenberg D, Gretler DD, Mant T, 
Lehrer-Graiwer J. Pharmacokinetics and pharmacodynamics of voxelotor (GBT440) in 
healthy adults and patients with sickle cell disease. Br J Clin Pharmacol. 2019 
Jun;85(6):1290-1302. doi: 10.1111/bcp.13896. Epub 2019 Mar 31. PMID:30743314
15. Liem RI, Reddy M, Pelligra SA, Savant AP, Fernhall B, Rodeghier M, Thompson AA. Reduced 
fitness and abnormal cardiopulmonary responses to maximal exercise testing in children 
and young adults with sickle cell anemia. Physiol Rep. 2015 Apr;3(4). pii: e12338. doi: 
10.14814/phy2.12338. Erratum in: Physiol Rep. 2016 Jan;4(1). pii: e12680. doi: 
10.14814/phy2.12680 
16. Watson AM, Liem RI, Lu Z, Saville B, Acra S, Shankar S, Buchowski M. Longitudinal 
differences in aerobic capacity between children with sickle cell anemia and matched 
controls. Pediatr Blood Cancer 2015 Apr;62(4):648-53. doi: 10.1002/pbc.25383. Epub 
2014 Dec 31.
17. Powell AW, Alsaied T, Niss O, Fleck RJ, Malik P, Quinn CT, Mays WA, Taylor MD, Chin C. 
Abnormal submaximal cardiopulmonary exercise parameters predict impaired peak 
exercise performance in sickle cell anemia patients. Pediatr Blood Cancer. 2019 
Jun;66(6):e27703. doi: 10.1002/pbc.27703. Epub 2019 Mar 7. PMID:30848046
18. Badawy SM, Payne AB, Rodeghier MJ, Liem RI. Exercise Capacity and Clinical Outcomes in 
Adults Followed in the Cooperative Study for Sickle Cell Disease (CSSCD) Eur J Haematol. 
2018 October; 101(4): 532–541. doi:10.1111/ejh.13140. 
19.  Wright SE, Pearce B, Snowden CP, Anderson H, Wallis JP. Cardiopulmonary exercise 
testing before and after blood transfusion: a prospective clinical study. Br J Anaesth. 2014 
Jul;113(1):91-6. doi: 10.1093/bja/aeu050. Epub 2014 Mar 28
20.  Otto JM, O'Doherty AF, Hennis PJ, Cooper JA, Grocott MP, Snowdon C, Carlisle JB, Swart 
M, Richards T, Montgomery HE.  Association between preoperative haemoglobin 
concentration and cardiopulmonary exercise variables: a multicenter study. Perioper Med 
(Lond). 2013 Sep 13;2(1):18. doi: 10.1186/2047-0525-2-18. PMID:24472426
21. Vichinsky E, Hoppe CC, Ataga KI, Ware RE, Nduba V, El-Beshlawy A, Hassab H, Achebe 
MM, Alkindi S, Brown RC, Diuguid DL, Telfer P, Tsitsikas DA, Elghandour A, Gordeuk 
VR, Kanter J, Abboud MR, Lehrer-Graiwer J, Tonda M, Intondi A, Tong B, Howard J; HOPE 
Trial Investigators. A phase 3 randomized trial of Voxelotor in sickle cell disease. N Engl J 
Med. 2019 Aug 8;381(6):509-519. doi: 10.1056/NEJMoa1903212. Epub 2019 Jun 14. 
PMID:31199090
22.  Hackney AC, Hezier W, Gulledge TP, Jones S, Strayhorn D, Busby M, Hoffman E, Orringer 
EP. Effects of hydroxyurea administration on the body weight, body composition and 
exercise performance of patients with sickle-cell anaemia, Clin Sci (Lond) 92 (1997), 481–
486. PMID:9176021
23. Dufu K, Lehrer-Graiwer J, Ramos E, Oksenberg D. GBT440 inhibits sickling of sickle cell trait 
blood under in vitro conditions mimicking strenuous exercise. Hematol Rep. 2016 Sep 
28;8(3):6637. eCollection 2016 Sep 28. PMID:27757216
24. Howard J, Hemmaway CJ, Telfer P, Layton DM, Porter J, Awogbade M, Mant T, Gretler DD, 
Dufu K, Hutchaleelaha A, Patel M, Siu V, Dixon S, Landsman N, Tonda M, Lehrer-Graiwer 

Voxelotor SCA NIRS Study (VoxSCAN)
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J. A phase 1/2 ascending dose study and open-label extension study of voxelotor in 
patients with sickle cell disease. Blood. 2019 Apr 25;133(17):1865-1875. doi: 
10.1182/blood-2018-08-868893. Epub 2019 Jan 17.PMID: 30655275 
25. Chonat S, Fields E, Baratz H, Watt A, Patel M, Dixon S, Tonda M, Brown C, Archer D. 
Improvement in Red Blood Cell Physiology in Children With Sickle Cell Anemia Receiving 
Voxelotor: An Ancillary Single-Center Pilot Study From the HOPE-KIDS Trial. Manuscript in 
preparation.
26. Green ML, Savic RM, Tonda M, Jorga K, Washington CB. Model-informed drug 
development of voxelotor in sickle cell disease: Exposure-response analysis to support 
dosing and confirm mechanism of action. CPT Pharmacometrics Syst Pharmacol. 2022 
Jun;11(6):698-710. doi: 10.1002/psp4.12780. Epub 2022 Apr 21. PMID: 35447017
27. Estepp JH, Kalpatthi R, Woods G, Trompeter S, Liem RI, Sims K, Inati A, Inusa BPD, 
Campbell A, Piccone C, Abboud MR, Smith-Whitley K, Dixon S, Tonda M, 
Washington C, Griffin NM, Brown C. Safety and efficacy of voxelotor in pediatric 
patients with sickle cell disease aged 4 to 11 years. Pediatr Blood Cancer. 2022 
Aug;69(8):e29716. doi: 10.1002/pbc.29716. Epub 2022 Apr 21. PMID: 35451176.

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25. Appendix 
Diffuse Optical Spectroscopy Device and Laser Safety
The Diffuse Optical Spectroscopy device employed herein is a research device constructed in house.  It 
employs two Diffuse Optical Spectroscopy systems, one called Diffuse Correlation Spectroscopy (DCS) and 
one called frequency domain near-infrared spectroscopy (fdNIRS). The DCS system uses an 852 nm long-
coherence length laser, two 4-channel photon-counting avalanche photodiodes, and a hardware or 
software autocorrelator board. The fdNIRS system is a customized commercial frequency-domain 
oximeter with 8 near-infrared laser sources ranging from 650 to 830nm and 4 photomultiplier tube (PMT) 
detectors.  Both DCS and fdNIRS components fit on a portable cart that can be wheeled to the subject’s 
bedside.  The light from/to these devices is delivered to/from the tissue of the subject through fiber optic 
cables arranged within a custom-designed optical sensors. The optical fibers are arranged on a rectangular 
flexible sensor of a size no larger than 3 in2. The fibers are flexible and are modified to emit and collect 
light with a 90-degree angle so that the sensor can lay flat against the skin. 
The American National Standards Institute provides recommendations for the safe use of lasers and laser 
systems that operate between at wavelengths of 0.18 m - 1 mm 103.  According to the ANSI standards, 
the lasers used in both the FDNIRS and DCS devices fall under Class 3b, meaning that they may be 
hazardous for direct eye exposure, but there is a low probability of tissue injury for diffuse reflectance. A 
summary of the ANSI laser classifications can be found here. 
The Maximum Permissible Exposure (MPE)
According to ANSI standards, the single most useful number for laser safety calculations is the Maximum 
Permissible Exposure (MPE, with units of power per area). The 
MPE is the maximum irradiance or radiant exposure that may be 
incident upon the eye or the skin without causing biological 
damage.

Skin:
𝑀𝑃𝐸=
0.2 
0.2 ∙𝐶𝑎
,𝜆< 0.7𝜇𝑚
,𝜆> 0.7𝜇𝑚 

Eyes:
𝑀𝑃𝐸=
0.001 
0.001 ∙𝐶𝑎
,𝜆< 0.7𝜇𝑚
,𝜆> 0.7𝜇𝑚 
where 𝐶𝑎= 102(𝜆―.7) and  is the operating wavelength of the 
laser. Note that in these calculations,  is measured in μm not 
nm (i.e. 700 nm = 0.7μm).  Table 1 shows the MPE values for 
wavelengths in the near-infrared that are routinely used in our 
FDNIRS/DCS device.  
MPE is dependent upon the specifications of the optical 
system. Here we list laser specifications, along with the 
specifications for the fiber optic-based sensors that we have 
custom designed for our FDNIRS and DCS devices.  
FDNIRS: up to 16 low power laser diodes. The diodes are 
multiplexed so that only one diode is “on” at a time.  
These diodes are commonly used lasers on a wide range 
of applications and contain the same semiconductor 
active media as LEDs. They are operated in continuous 
wave (CW) mode.
Wavelength 
(nm)
MPE, skin 
(W/cm2)
MPE, eye 
(W/cm2)
660
0.20
0.0010
670
0.20
0.0010
680
0.20
0.0010
690
0.20
0.0010
700
0.20
0.0010
710
0.21
0.0010
720
0.22
0.0011
730
0.23
0.0011
740
0.24
0.0012
750
0.25
0.0013
760
0.26
0.0013
770
0.28
0.0014
780
0.29
0.0014
790
0.30
0.0015
800
0.32
0.0016
810
0.33
0.0017
820
0.35
0.0017
830
0.36
0.0018
840
0.38
0.0019
850
0.40
0.0020
860
0.42
0.0021
Table 1

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λ = Wavelengths range from 660 to 830 nm (0.66-0.83 um)
ΦL = Power at the laser <20 mW (0.02 W)
Φ = Power at the probe <10 mW (0.01 W)
a = Beam diameter at the probe ~ 0.30 cm
NA = Fiber’s numerical aperture ~ 0.37  
φ = Beam divergence = 2arcsin 𝑁𝐴~ 0.76 rad
DCS: A single solid-state, long coherence-length (>5 m) laser, which is essentially a laser diode 
with a longer cavity. Because the detection fibers required for DCS measurements are single mode 
fibers, a higher power laser (compared to FDNIRS) is required.  The laser is operated in continuous 
wave mode.
λ = wavelength = 852 nm
ΦL = Power at the laser = 100 mW (0.1 W)
Φ = Power out of the sensor = 25 mW (0.025 W)
a = Beam diameter at the sensor > 0.30 cm
NA = Fiber’s numerical aperture ~ 0.37
φ = beam divergence = 1.57 rad (because we add a diffuser to the sensor surface)
Calculation of Irradiance of FDNIRS/DCS Lasers
The following formula is used to calculate what is the irradiance (E) of our lasers:
E=power (W)/spot area (cm2)
All of our FDNIRS/DCS custom sensors are designed such that the irradiance is less than the stated 
wavelength-dependent ANSI MPE for skin exposure.  For example, for the DCS laser, we use a 0.3cm beam 
diameter (radius, r = 0.15cm) at the sensor and the laser power (Φ) out of the sensor is 25mW, thus the 
irradiance to the skin from our laser is:
𝐸= Φ
𝜋𝑟2
2 =0.35 W/cm2
As Table 1 shows, this irradiance of 0.35 W/cm2 is less than the MPE at 852nm of 0.40 W/cm2.  We have 
performed similar calculations for all of our FDNIRS lasers to confirm that they also yield irradiance levels 
that fall well below MPE limits.
Nominal Hazard Zone (NHZ)
In addition to the MPE, the other major specification used in laser safety calculations is the Nominal 
Hazard Zone (NHZ). The NHZ is the distance within which the irradiance of the laser beam is greater than 
the MPE. This distance depends not only on the wavelength of light and time of light exposure, but also 
on the beam’s path to your eye, e.g., direct viewing, specular reflectance, or diffuse reflectance.  Due to 
divergence, as the distance from the source or focus of the beam (or its reflection) increases, the 
irradiance (E) decreases. That boundary defines the NHZ.
The Nominal Ocular Hazard Distance (NOHD) for any particular laser represents the distance (rNOHD) 
within which it is possible to exceed the MPE:
 𝑟𝑁𝑂𝐻𝐷=
1
𝜑
4Φ
𝜋𝑀𝑃𝐸― 𝑎2,
where a is the diameter of the beam coming from 
the light source (cm), and Φ is the laser power (W). 𝜑 is the beam divergence (rad) is equal to 2arcsin 𝑁𝐴, 
where NA is the numerical aperture of the light source (rad).

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Calculation of Nominal Ocular Hazard Distance (NOHD) of Our Lasers
For the FDNIRS lasers, using the following parameters:
Φ = 0.020 W
r = 0.3 cm
φ = beam divergence = 0.76 rad = 43
MPEe at 785 nm = 0.0014 W/cm2
We find that the rNOHD = 5.65 cm  (6.32 cm for Φ= 0.025 W).  For the DCS laser, which has a wider divergence 
angle (φ = 1.57 rad = 90), rNOHD = 2.73 cm.  For comparison, using typical parameters of a laser pointer, 
we see that these ocular hazard distances are quite small:
Φ = 0.005 W
r = 0.3 cm
φ = 1mrad = 0.001 rad
MPEe=0.001
rNOHD=2,505 cm (25 m)
Calculation of Minimum Optical Density Eyeglasses Needed for the Irradiance of our Lasers:
OD=log(E/MPEe)=2.3 at 785nm for 20mW power. However, since the NOHD of our lasers is less than 10 
cm, our lasers can be considered as class IIIA and therefore safety eyeglasses are not needed 104.  See the 
excerpts below for more information (page 46):
Under IEC requirements, the assessment of levels of irradiance or radiant exposure for 
the purposes of determining the magnitude of exposure in relation to the MPE within the 
wavelength range from 302.S nm (in the ultraviolet region) to 4000 nm (in the infrared) 
are made at a distance of 100 mm from the laser source. This is to take account of the 
likely closest distance of approach and, for the eye, the minimum distance (the near point) 
at which objects can be clearly focused on the retina. For this reason, when the NOHD for 
a given laser system has been determined to be less than 100 mm (which can often arise 
in the case of laser diodes at the lower levels of class 38), protective measures beyond 
the controlled use of viewing aids may not be necessary, provided that the personnel 
concerned are fully aware of the nature of the potential hazards and the conditions under 
which a hazardous exposure could arise.
 The NOHD is the distance from the source at which the exposure drops to the level of the 
MPE. Beyond this distance intra-beam viewing would be safe for the unaided eye but 
could remain hazardous if magnifying optical instruments were to be used. This is often 
the case in optical-fiber technology, when microscopes and magnifying lenses may be 
used for examining the end of optical fibers or for critical work with small components. 
The extended NOHD is the distance from the source at which the exposure drops to the 
equivalent of the class I AEL contained within a 50-mm diameter centered on the optical 
axis. Beyond this distance the exposure can be considered safe for intra-beam viewing 
even with the use of viewing aids. (Provided, of course, that these do not have a collection 
aperture greater than 50 mm.) The equations for fiber divergence given earlier can be 
used to determine these distances using the procedures described in Chapter 6.
We can thus define three zones (illustrated in Figure 1.17). Within the NOHD there is a 
potential hazard to the eye and eye protection would be needed. Between the NOHD and 
the extended NOHD unaided viewing is safe but the use of viewing aids needs to be 

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controlled. Beyond the extended NOHD there is essentially no hazard and no controls are 
therefore needed.
This concept is particularly useful for dealing with divergent class 3B systems. Class 3B has 
the potential for causing injury to the unaided eye and would thus normally be restricted 
to operation within enclosed laser areas in a similar manner to class 4. It can be found 
with divergent emission, however, particularly at the lower levels of class 3B, that the 
NOHD is considerably less than 100 mm, and that therefore intra-beam viewing would 
not normally present a hazard to the unaided eye. The wearing of eye protection could 
therefore be unnecessary. In fact, when work of a similar nature is being regularly 
undertaken with divergent class 3B systems, it is possible to set up controlled laser 
working areas based on the degree of hazard rather than simply on the laser class.
Class 3B with NOHD Less than 100 mm
The work could be done alongside class 3A systems and similar conditions would apply. 
Personal eye protection need not be worn, but the use of any magnifying optics must be 
restricted and only those viewing aids incorporating suitable eye protection should be 
permitted.
Class 3B with NOHD Greater than 100 mm But Less than 1m
The 1-m limit here is somewhat arbitrary but is intended to indicate a hazard localized to 
the area immediately surrounding the laser source. The wearing of personal eye 
protection is necessary and the area should be enclosed to prevent line-of-sight viewing 
from outside the area but, provided that appropriate warning signs are clearly displayed 
that the area is within premises to which access is normally restricted and that equipment 
is never allowed to be left running while unattended, fully interlocked access should not 
be necessary.
Attachment A
REPORTING SERIOUS ADVERSE EVENTS
Definitions
“Adverse Event” or “AE” means an untoward medical occurrence in a Study subject receiving 
the Pfizer Product, or an individual otherwise exposed to the Pfizer Product, without regard to 
whether there is a causal relationship between the Pfizer Product and the medical occurrence.
“Serious Adverse Event” or “SAE” means any Adverse Event, without regard to causality, that is 
life-threatening (i.e., causes an immediate risk of death) or that results in any of the following 
outcomes: death; inpatient hospitalization or prolongation of existing hospitalization; persistent 
or significant disability or incapacity (i.e., substantial disruption of the ability to conduct normal 
life functions); or a congenital anomaly or birth defect. Any other medical event that, in the 
medical judgment of Principal Investigator, may jeopardize the health of the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above, also is 
considered an SAE. A planned medical or surgical procedure is not, in itself, an SAE. 

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“Device Incident” is any malfunction or deterioration in the characteristics and/or performance 
of a medical device made available on the market, including use error due to ergonomic 
features, as well as any inadequacy in the information supplied by the manufacturer and any 
undesirable side effect. 
“Serious Device Incident” means any incident that directly or indirectly led, might have led or 
might lead to any of the following: death of a patient, user or other person, temporary or 
permanent serious deterioration of the patient's, user's or other person's state of health, 
serious public health threat. A serious deterioration in health would include: a life-threatening 
illness or injury, a permanent impairment of a body function or permanent damage to a body 
structure or necessitates medical or surgical intervention to preclude permanent impairment of 
a body function or permanent damage to a body structure. Permanent means irreversible 
impairment or damage to a body structure or function, excluding trivial impairment or damage. 
“Reportable Event” means any SAE, Device Incident or Serious Device Incident, whether 
individually or collectively.
If the Pfizer Product is, or contains, a medical device, all references to SAEs herein should be 
read to include the term “Reportable Event.”
Reporting Requirements. Additional information about the requirements herein and detailed 
information about reporting SAEs to Pfizer (including applicable reporting forms and 
completion guide) has been provided to the Principal Investigator and is available on Pfizer’s 
online grant system. Institution will ensure that this additional, detailed, information is 
provided to all Study Staff engaged in the reporting of SAEs.
1. Timing and Scope. Within 24 hours of Institution’s first awareness of an SAE, or immediately 
if the SAE is fatal or life-threatening, Institution will notify Pfizer by fax, email or E2B (as 
concurred with Pfizer) of any SAE for which reporting hereunder is required. SAEs that are 
subject to these reporting requirements are those that occur in: (i) Study subjects who are 
assigned or, in the case of a blinded Study, possibly assigned to receive the Pfizer Product; 
or (ii) individuals otherwise exposed to the Pfizer Product. 
Institution will notify Pfizer of any such SAE within the timeframes set forth herein even if 
complete information is not yet available. Institution will ensure that all Study Staff notify 
Institution of any SAE immediately upon becoming aware. 
2. Reporting Format. Each Study site will report SAEs using one of the following: (i) a reporting 
form approved by the local regulatory authority, (ii) a CIOMS form, (iii) a Pfizer provided 
Investigator Sponsored Research or Clinical Research Collaboration Interventional Serious 
Adverse Event Report Form or (iv) any other form prospectively approved by Pfizer. The 
Reportable Event Fax Cover Sheet provided by Pfizer also must be included with each SAE 
submitted. 
3. Specific SAEs. Exposure to the Pfizer Product during pregnancy or lactation, drug overdose, 
medication error, occupational/environmental exposure to the Pfizer Product and lack of 
efficacy of the Pfizer Product are reportable to Pfizer.
3.1. Exposure during pregnancy and lactation are reported independently from any 
associated SAE. Medication errors and overdoses are reportable only if associated with 

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an SAE. Occupational/environmental exposure is reported independently from any 
associated AE/SAE. 
3.2. Lack of Efficacy is reportable only if associated with an SAE (except for certain 
scenarios which are outlined in the Pfizer provided training materials: vaccines, 
contraceptive and anti-infectives products). 
4. Hy’s Law: If the Pfizer Product is not approved in the US for the indication being studied, 
(irrespective of being authorized/approved elsewhere), cases of potential drug-induced liver 
injury as assessed by laboratory test values (“Hy’s Law Cases”) are SAEs reportable to Pfizer. 
If a Study subject develops abnormal values in aspartate transaminase (“AST”) or alanine 
transaminase (“ALT”) or both, concurrent with abnormal elevations in total bilirubin and 
there is no other known cause of liver injury, that event would be classified as a Hy’s Law 
Case.
5. Crizotinib: If Study subjects will receive crizotinib, any AE of potential sight threatening 
event (“PSTE”) or severe visual loss (“SVL”) must be reported as an SAE in subjects treated 
with crizotinib, even if the study drug is not (or is not otherwise related to) crizotinib. 
5.1. SVL is defined as Grade 3 or Grade 4 eye disorders based on Common Terminology 
Criteria for Adverse Events (“CTCAE”) published by the National Cancer Institute. 
According to CTCAE, Grade 3 eye disorders include symptomatic retinopathy with 
marked decrease in visual acuity (worse than 20/40) or disabling (limited self-care 
activities of daily living). Grade 4 eye disorders include blindness (20/200 or worse) in 
the affected eye. 
5.2. PSTE includes all identified Grade 2 eye disorders listed above (except visual field 
defect) and the following Grade 2 eye disorders: retinal detachment, retinal edema, 
maculopathy, iritis, uveitis, and abnormal visual field tests. 
6. Exclusions. Specifically excluded from the reporting requirements for SAEs is: (i) any SAE 
identified in the Protocol as anticipated to occur in the Study population at some frequency 
independent of drug exposure, unless a Principal Investigator suspects a causal relationship 
between the SAE and the Pfizer Product; and (ii) if the Pfizer Product is an oncology drug, 
any SAE judged by a Principal Investigator to represent progression of the malignancy under 
study, unless it results in death within the SAE reporting period. 
7. Reporting Period. SAEs that are subject to these reporting requirements are those that: 
(i) occur from the first dose of the Pfizer Product or the Study subject’s enrollment in the 
Study (whichever is later) through 28 calendar days after the last administration of the 
Pfizer Product or the subject’s last Study visit (whichever is earlier), or longer if so specified 
in the Protocol; or (ii) occur any time after the 28-day period (i.e., any time after the 
completion of the active study collection/reporting period), if Institution or Principal 
Investigator suspects a causal relationship between the Pfizer Product and the SAE.
8. Follow-Up Information. Institution will assist Pfizer in investigating any SAE and will provide 
any follow-up information reasonably requested by Pfizer.
9. Regulatory Reporting. Reporting an SAE to Pfizer does not relieve Institution of 
responsibility for reporting such SAE to appropriate regulatory authorities, if required.  
10. IMP and SRSD. Principal Investigator will identify the Pfizer Investigational Medicinal 
Product(s) and respective Single Reference Safety Documents to be used for expectedness 

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assessment for the Study and will provide this information via Pfizer’s online grants system 
prior to Study start. 
11. Pfizer-Provided Safety Information. Pfizer distributes ISR line listings to Institutions bi-
annually, or more frequently based on the risk assessment of the ongoing interventional 
clinical studies.