The Effect of Voxelotor on Exercise Capacity of Youths With Sickle Cell Anemia
Phase: PHASE4
Conditions: Sickle Cell Anemia
Sponsor: Elizabeth Yang, MD, PhD

The Effect of Voxelotor on Exercise Capacity of Youths 
with Sickle Cell Anemia 
Short Title: Voxelotor SCA Exercise Study 
Protocol Number: ESR-C006 
National Clinical Trial (NCT) Identified Number:  <Number, if available> 
Principal Investigator: Elizabeth Yang 
Funded by: Global Blood Therapeutics (GBT) 
Version Number:  v.1.0 
5 June 2020 
 
 
Summary of Changes from Previous Version: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
 
 
 
 
 
 

  
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Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................ 1 
1 
PROTOCOL SUMMARY .............................................................................................................................. 2 
1.1 
Synopsis .............................................................................................................................................. 2 
1.2 
Schema ................................................................................................................................................ 4 
1.3 
Schedule of Activities (SoA) .............................................................................................................. 5 
2 
INTRODUCTION ........................................................................................................................................... 5 
2.1 
Study Rationale ................................................................................................................................... 5 
2.2 
Background ......................................................................................................................................... 5 
2.3 
Risk/Benefit Assessment ................................................................................................................... 7 
2.3.1 
Known Potential Risks .................................................................................................... 7 
2.3.2 
Known Potential Benefits ............................................................................................... 8 
2.3.3 
Assessment of Potential Risks and Benefits ............................................................... 8 
3 
OBJECTIVES AND ENDPOINTS ............................................................................................................... 8 
4 
STUDY DESIGN ............................................................................................................................................ 9 
4.1 
Overall Design ..................................................................................................................................... 9 
4.2 
Scientific Rationale for Study Design .............................................................................................. 9 
4.3 
Justification for Dose ........................................................................................................................ 10 
4.4 
End of Study Definition .................................................................................................................... 10 
5 
STUDY POPULATION ............................................................................................................................... 10 
5.1 
Inclusion Criteria ............................................................................................................................... 10 
5.2 
Exclusion Criteria .............................................................................................................................. 11 
5.3 
Lifestyle Considerations ................................................................................................................... 11 
5.4 
Screen Failures ................................................................................................................................. 11 
5.5 
Strategies for Recruitment and Retention ..................................................................................... 11 
6 
STUDY INTERVENTION ........................................................................................................................... 12 
6.1 
Study Intervention(s) Administration .............................................................................................. 12 
6.1.1 
Study Intervention Description .................................................................................... 12 
6.1.2 
Dosing and Administration ........................................................................................... 12 
6.2 
Preparation/Handling/Storage/Accountability ............................................................................... 12 
6.2.1 
Acquisition and accountability ..................................................................................... 13 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ............................................... 13 
6.2.3 
Product Storage and Stability ...................................................................................... 13 
6.2.4 
Preparation .................................................................................................................... 13 
6.3 
Measures to Minimize Bias: Randomization and Blinding .......................................................... 13 
6.4 
Study Intervention Compliance ....................................................................................................... 13 
6.5 
Concomitant Therapy ....................................................................................................................... 13 
6.5.1 
Rescue Medicine ........................................................................................................... 13 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ................................................................................................................... 14 
7.1 
Discontinuation of Study Intervention ............................................................................................ 14 
7.2 
Participant Discontinuation/Withdrawal from the Study .............................................................. 14 
7.3 
Lost to Follow-Up .............................................................................................................................. 14 
8 
STUDY ASSESSMENTS AND PROCEDURES .................................................................................... 15 
8.1 
Efficacy Assessments ...................................................................................................................... 16 
8.2 
Safety and Other Assessments ...................................................................................................... 16 

  
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Adverse Events and Serious Adverse Events .............................................................................. 16 
8.3.1 
Definition of Adverse Events (AE) .............................................................................. 16 
8.3.2 
Definition of Serious Adverse Events (SAE) ............................................................. 16 
8.3.3 
Classification of an Adverse Event ............................................................................. 16 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ...................... 18 
8.3.5 
Adverse Event Reporting ............................................................................................. 18 
8.3.6 
Serious Adverse Event Reporting .............................................................................. 19 
8.3.7 
Reporting Events to Participants ................................................................................ 19 
8.3.8 
Events of Special Interest ............................................................................................ 19 
8.3.9 
Reporting of Pregnancy ............................................................................................... 19 
8.4 
Unanticipated Problems ................................................................................................................... 20 
19 
8.4.3 
Reporting Unanticipated Problems to Participants .................................................. 20 
9 
STATISTICAL CONSIDERATIONS ......................................................................................................... 20 
9.1 
Statistical Hypotheses ...................................................................................................................... 20 
9.2 
Sample Size Determination ............................................................................................................. 20 
9.3 
Populations for Analyses ................................................................................................................. 21 
9.4 
Statistical Analyses .......................................................................................................................... 21 
9.4.1 
General Approach ......................................................................................................... 21 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................ 21 
9.4.3 
Analysis of the Secondary Endpoint(s) ...................................................................... 21 
9.4.4 
Safety Analyses ............................................................................................................. 21 
9.4.5 
Baseline Descriptive Statistics .................................................................................... 22 
9.4.6 
Planned Interim Analyses ............................................................................................ 22 
9.4.7 
Sub-Group Analyses .................................................................................................... 21 
9.4.8 
Tabulation of Individual participant Data ................................................................... 22 
9.4.9 
Exploratory Analyses .................................................................................................... 22 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................. 22 
10.1 
Regulatory, Ethical, and Study Oversight Considerations .......................................................... 22 
10.1.1 
Informed Consent Process .......................................................................................... 22 
10.1.2 
Study Discontinuation and Closure ............................................................................ 23 
10.1.3 
Confidentiality and Privacy .......................................................................................... 23 
10.1.4 
Future Use of Stored Specimens and Data .............................................................. 25 
10.1.5 
Key Roles and Study Governance ............................................................................. 25 
10.1.6 
Safety Oversight ............................................................................................................ 26 
10.1.7 
Clinical Monitoring ......................................................................................................... 26 
10.1.8 
Quality Assurance and Quality Control ...................................................................... 26 
10.1.9 
Data Handling and Record Keeping ........................................................................... 26 
10.1.10 
Protocol Deviations ....................................................................................................... 27 
10.1.11 
Publication and Data Sharing Policy .......................................................................... 27 
10.1.12 
Conflict of Interest Policy ............................................................................................. 27 
10.2 
Additional Considerations ................................................................................................................ 28 
10.3 
Abbreviations ..................................................................................................................................... 29 
10.4 
Protocol Amendment History .......................................................................................................... 31 
11 
REFERENCES ............................................................................................................................................ 32 

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STATEMENT OF COMPLIANCE 
This pilot study will be conducted in accordance with International Conference on Harmonisation 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 sponsor Global Blood Therapeutics, 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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1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
The Effect of Voxelotor on Exercise Capacity of Youths with Sickle Cell 
Anemia 
Study Description: 
This study is a pilot, open-label, single-arm study to evaluate the effect of 
voxelotor on exercise capacity, as measured by cardiopulmonary exercise 
testing (CPET) in patients 12 years of age and older with sickle cell anemia 
(SCA). Voxelotor was recently approved for the treatment of SCA in patients 
12 years and older. We hypothesize that exercise capacity will be 
improved by voxelotor treatment in sickle cell patients whether they are 
on Hydroxyurea or not. This study will assess exercise capacity by 
cardiopulmonary exercise testing (CPET) before and after 8 weeks of 
voxelotor therapy. 
 
Objectives: 
 
Primary Objective: To evaluate the effect of voxelotor on peak oxygen 
consumption (VO2) in adolescents with SCA as assessed by change in CPET 
from baseline.  
 
 
Secondary Objective: To correlate peak VO2 with biochemical markers, 
including hemoglobin, reticulocyte count, bilirubin, lactate dehydrogenase, 
haptoglobin, % Hgb F expressing cells, P50 oxygen dissociation, point of 
sickling (POS), and dense cells.  
 
Exploratory Objective: To evaluate the effect of voxelotor on HRQOL as 
assessed by patient-reported outcome (PGIC) and clinician-reported 
outcome (CGIC) at end of treatment study visit 
Endpoints: 
Primary endpoint: Change in Peak VO2 from baseline  
 
Secondary endpoint: Hemoglobin and biochemical markers of sickling and 
hemolysis 
 
Exploratory endpoint: Clinician and Patient Global Impression of Change 
assessment (CGIC and PGIC) 
 
 
Study Population: 
1.1.1.1.1.1 Patients seen in the Pediatric Sickle Cell Program in Northern 
Virginia (Fairfax, VA) who have a genetically severe forms of 
sickle cell disease (including Hgb SS, Hgb Sbeta0thalassemia, 
or Hgb SCHarlem) and are age 12 or older.  
 
 

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Phase: 
This is a single-center, open-label, single-arm longitudinal interventional 
pilot study.  
 
Description of 
Sites/Facilities Enrolling 
Participants: 
 
The outpatient sickle cell clinic of Pediatric Specialists of Virginia located in 
the Schar Cancer Institute on Inova Hospital Campus in Fairfax, VA. This 
pilot study aims to enroll 10 patients.   
  
Description of Study 
Intervention: 
During the open-label treatment period, all participants will receive 
voxelotor at a fixed dose of 1500mg (administered as three 500mg tablets) 
orally once daily for 8 weeks  
 
 
Study Duration: 
12 months 
 
 
Participant Duration: 
 6 months 
 
 

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1.2 
SCHEMA 
  
 
Enrollment  
Visit 
 
 
 
Visit 1 
1 month 
 
 
 
Visit 2 
1-2 months 
 
 
Visit 3 
2 months 
 
 
 
Visit 4 
3 months 
 
 
 
Visit 5 
4 months 
 
 
 
Visit 6 
4-5 months 
 
 
 
 
Visit 7 
6 months 
 
 
 
 Subjects will be recruited during routine clinic visits and undergo screening assessments 
after signed informed consent has been obtained.  All eligibility criteria must be met prior 
to enrollment. Screening labs: CBC, retic, CMP, lactate dehydrogenase, haptoglobin, 
Hemoglobin F.  
This visit should be at least 1 month from enrollment visit. Obtain blood sample for 
baseline assessments. CBC, retic, CMP, lactate dehydrogenase, haptoglobin, Hemoglobin 
electrophoresis, % F cells, P50 oxygen dissociation, ektacytometry, point of sickling (POS), 
dense cells. Schedule first CPET if CBC and % Hgb F stable.   
1st follow-up visit, 1 month after initiation of study drug voxelotor. Obtain routine labs: 
CBC, retic, CMP, lactate dehydrogenase, haptoglobin, Hgb F 
This visit should be as soon as can be scheduled after 1st CPET. Obtain routine labs: CBC, 
retic, CMP, lactate dehydrogenase, haptoglobin, Hgb F. Initiate treatment with voxelotor  
Final Assessments 
Obtain routine labs: CBC, retic, CMP, 
lactate dehydrogenase, haptoglobin, 
Hemoglobin electrophoresis. Fill out 
CGIC and PGIC questionnaire 
Perform 1st CPET, as soon as can be scheduled after Visit 1 
2nd follow-up visit on study drug Voxelotor, 1 month after Visit 4. Obtain study labs: CBC, 
retic, CMP, lactate dehydrogenase, haptoglobin, Hemoglobin electrophoresis, % F cells, 
P50 oxygen dissociation ektacytometry, point of sickling (POS), dense cells.  Schedule 2nd 
CPET. Continue voxelotor treatment until 2nd CPET. 
Perform 2nd CPET, as soon as can be scheduled after Visit 5 

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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
Procedures 
Screening/ 
Enrollment 
Day -60 
Study Visit 1 
 Day -30 
 +/- 7 days 
Study Visit 2 
Day  
– 29 to -1 
Study Visit 3 
Day 1 
 +/- 14 days 
Study Visit 4 
Day 30 
+/- 7 days 
Study Visit 5 
Day 60 
+/- 7 days 
Study Visit 6 
Day 60-89 
 
Final Study 
Visit 7 
Day 90 
+/- 14 days 
Informed consent 
x 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
Dispense voxelotord 
 
 
 
x 
x 
xd 
 
Concomitant 
Medication review 
x 
x 
 
x 
x 
x 
 
x 
Physical exam 
x 
x 
 
x 
x 
x 
 
x 
Vital signs, Ht, Wt 
x 
x 
x 
x 
x 
x 
x 
x 
Performance status 
x 
 
 
 
 
x 
 
x 
Routine labs  a 
x 
x 
 
x 
x 
x 
 
x 
Study labs b 
 
x 
 
 
 
x 
 
 
Pregnancy test c 
x 
 
 
x 
x 
x 
 
 
Adverse event review 
and evaluation 
x 
 
 
x 
x 
x 
 
x 
Schedule CPET 
 
x 
 
 
 
x 
 
 
CPET 
 
 
x 
 
 
 
x 
 
CGI, PGI assessments 
 
 
 
 
 
 
 
x 
Data collection and 
entry 
x 
x 
 
x 
x 
x 
 
x 
a Routine labs: CBC diff, retic, CMP, LDH, haptoglobin, Hemoglobin F or hemoglobin electrophoresis  
b Study labs: Send to UCSF Dr. Frans Kuypers lab: % F cells, P50 oxygen dissociation, ektacytometry, point of sickling (POS), dense cells. 
c  Pregnancy test: All menstruating female participants 
d Participants will be treated with voxelotor for at least 8 weeks before the 2nd CPET, which will be scheduled as close to the date following 8 weeks of 
treatment with voxelotor.  Participants will continue voxelotor until the 2nd CPET is completed.  
 
 
 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
The beta globin mutation in sickle cell disease leads to production of sickle hemoglobin (HbS) that in the 
deoxygenated state polymerizes and results in sickling and hemolysis of red blood cells. Studies have 
shown that children and adults with sickle cell anemia (SCA) exhibit decreased cardiopulmonary fitness. 
While multiple factors influence exercise capacity, anemia is directly related to oxygen-carrying capacity 
and is one factor that affects cardiopulmonary fitness. Low exercise capacity in SCA is partly due to low 
hemoglobin. Voxelotor is a recently approved therapy for SCA, shown to decrease hemolysis and 
increase hemoglobin in untreated as well as Hydroxyurea-treated SCA patients. Increasing hemoglobin is 
expected to increase oxygen carrying capacity, therefore, treatment with voxelotor is expected to 
improve exercise capacity. 
2.2 
BACKGROUND  

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Why do we need to know about exercise tolerance in SCA? 
 
Physical activity has been significantly limiting for patients with sickle cell anemia. Whereas 
people with sickle cell trait (SCT) engage in high intensity athletics and military training, individuals with 
sickle cell anemia (SCA) have not participated, either due to patients’ own inability to tolerate exercise 
or restrictions placed upon them by others, or a combination of factors1,2.  In the era of hydroxyurea, 
lifestyles for many SCA patients have improved. In our own pediatric sickle cell program, which has a 
high hydroxyurea usage rate, many children are described by their parents as being as active as other 
children, and some teenagers participate in team sports and even try out for varsity sports, including 
football. As sickle cell providers, we are often asked by school athletic departments to sign sports 
clearance forms and list specific restrictions for the student with sickle cell disease. While organizations 
such as NCAA provide general guidelines for SCT, no published specific guidelines exist for SCA3,4.  What 
is known about SCT, i.e., increased risk of exertional rhabdomyolysis, is not directly applicable to SCA, 
which presents distinct challenges, not the least of which appears to be limited physical ability. Yet, 
regular exercise has been shown to improve health in chronic illnesses, including sickle cell disease1, 5-9.  
Increasingly, demonstration that exercise is beneficial in SCA is prompting SCA healthcare providers to 
encourage their patients to be physically active. Given SCA youths’ desire to be athletic and the 
advocacy for physical exercise in SCA, understanding the exercise capacity in SCA is increasingly 
necessary. 
How is exercise capacity measured? 
 
Cardiopulmonary exercise testing, or CPET, is the commonly accepted benchmark of aerobic 
capacity10, 11.  While a subject is performing a standardized exercise protocol with incremental ramping, 
either on a bicycle or a treadmill, and breathing through a non-rebreathing mouthpiece, expired air is 
analyzed via breath-by-breath sampling. Fractions of oxygen, carbon dioxide, air volume and flow are 
measured to calculate oxygen uptake (VO2), carbon dioxide output (VCO2) and minute ventilation, all in 
real-time. The peak VO2 (VO2 max) is the maximal ability of the subject to take in and utilize oxygen, 
which is the functional aerobic exercise capacity. Peak VO2 is determined by the cardiovascular, 
pulmonary, musculoskeletal, as well as the hematologic system. CPET is most commonly done in adults, 
but is also utilized in children, particularly in those with cystic fibrosis and congenital heart disease, as 
well as in adolescents with sickle cell disease12.  
What is known about exercise testing in SCA? 
 
Although reports are limited, exercise in SCA has been investigated, and the field is growing. 
Experience in these investigations, including GBT’s phase 1/2 voxelotor study, has reassured that 
maximal exercise testing is safe in SCA and does not induce pain or other sickle cell crisis1, 8, 13, 14, 24. 
Studies have shown that children and adults with SCA exhibit decreased cardiopulmonary fitness, most 
informatively demonstrated through cardiopulmonary exercise testing (CPET) and peak oxygen 
consumption. Peak VO2 in adolescents and adults with SCA in ergometric bicycle CPET was as much as 
30% lower than controls, even after adjusting for BMI and hemoglobin15, 16, 17.  A study of more than 200 
adults with SCA using a standard Balke treadmill exercise test found lower exercise capacity among 
participants than the general African American population, with lower exercise capacity associating with 
lower hemoglobin14,18.  SCA is a systemic disease affecting all organs, and decreased peak VO2 is likely 
multi-factorial. Anemia directly affects oxygen-carrying capacity, and low hemoglobin would be 
expected to compromise aerobic activity. Indeed, CPET before and after transfusion both in patients 
with chronic anemia conditions and in pre-surgical patients with anemia showed ~10% difference in 

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peak VO219, 20.  Thus, low hemoglobin in SCA is likely one factor contributing to decreased exercise 
capacity, and increasing hemoglobin in SCA might improve VO2 max.  
Can medical therapy improve exercise capacity of sickle cell patients? 
 
Our clinical experience suggests that physical ability is improved in young patients treated with 
Hydroxyurea, but this has not been documented. Voxelotor can further raise hemoglobin in untreated 
patients as well as patients already on Hydroxyurea21. Our patient population includes a cohort of 
teenagers eligible for treatment with voxelotor, and although most are on Hydroxyurea, not all respond 
with significant increases in hemoglobin. While an exercise study in 1997 found Hydroxyurea treatment 
correlated with better exercise performance22, more recently published exercise studies in SCA have not 
compared patients treated with and without Hydroxyurea.  Regardless, one would expect that peak VO2 
would improve with voxelotor due to its positive effect on hemoglobin, as well as indirect effects of 
decreased sickling and hemolysis. In GBT’s phase 1/2 voxelotor study, CPET was done in 12 adult sickle 
cell patients to address the concern that the higher O2 affinity of drug-modified hemoglobin could 
negatively impact oxygen consumption. No significant change, either positive or negative, was observed 
in VO2 max and ventilatory threshold, but the voxelotor doses used in that study were below GBT’s 
currently recommended dose 24. Thus, the question of whether voxelotor treatment, at the currently 
recommended dose, could improve exercise capacity is unanswered. 
 
This study aims to determine whether changes in peak VO2 can be detected in youths with SCA 
after treatment with voxelotor.  
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
 
Physical risk 
Voxelotor: The most common adverse reactions reported with incidence > 10% are headache, diarrhea, 
abdominal pain, nausea, fatigue, rash, and pyrexia. No significant toxicities requiring medical intervention 
have been reported. If a subject complains of intolerable side effects, voxelotor will be stopped and the 
subject will come off study. Voxelotor binds to hemoglobin. When the drug is stopped, voxelotor-modified 
hemoglobin will degrade, and no long-term risk is expected.  
CPET: Aggravation of SCA symptoms during exercise testing is unlikely, because exercise testing is stopped 
when participants complain of fatigue or discomfort. Studies of exercise testing in patients with sickle cell 
disease have been published, including GBT’s phase 1/2 voxelotor study, and no adverse events, such as 
pain crisis, have been reported. , 8, 13, 14-17, 24 
Venipuncture: The risks of drawing blood from a vein include fainting, local pain, bruising, swelling, or rarely 
an infection at the needle site. Patients routinely have blood draws as part of regular sickle cell care, and 
this study will take blood from the same venipuncture as routine care blood draws, no extra venipunctures 
are required. In the event of adverse effects to the subjects, necessary medical or professional intervention 
will be instituted immediately. Approximately 5 cc (1 teaspoon) of blood will be drawn for study labs on 2 
occasions in the study. 
Psychological risk 

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Voxelotor treatment: Most patients are already taking the medication for sickle cell disease. Adding another 
oral medication to be taken at the same time as the existing medication is unlikely to induce an adverse 
psychological effect. 
 
CPET: Patients may experience potential anxiety, stress, and uncomfortable emotions if CPET results are not 
as they expected. As we do not know what the expected peak VO2 will be for our patient population, we 
have no expected results for peak VO2 and will not be communicating any expectations to our patients that 
might be anxiety-provoking. CPET will be explained to patients and patients will be prepared for CPET by the 
exercise physiologist to reduce apprehension and anxiety. A pediatric psychologist is part of the sickle cell 
care team and is available to provide counseling, if needed.  
 
Venipuncture: Blood draw is part of routine sickle cell care. This study will obtain blood from the same 
venipuncture used for routine blood work, therefor will post no additional psychological effect. 
 
Economic risk 
Patients and/or their parents will be compensated for participation and their travel costs to the exercise lab 
will be covered by the study, therefore there is no economic risk. 
 
Legal risk 
There is no legal risk. 
 
Social risk 
Privacy will be maintained. There is no foreseeable social risk.  
  
2.3.2 KNOWN POTENTIAL BENEFITS  
 
Immediate direct benefits of study participation to the patients include free access to the newly FDA 
approved medication voxelotor, rise in hemoglobin and improved oxygen carrying capacity, as well as 
free exercise testing that can provide information for personal physical activity guidelines.  
 
Long-range benefits include fewer complications of sickle cell disease and potentially improved lifestyle.  
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
Voxelotor has proven benefit in sickle cell disease without toxicity. CPET has been shown to be safe for 
sickle cell patients. The risk of minor adverse reactions to voxelotor is significantly outweighed by the 
benefit of higher hemoglobin, decreased sickling, and fewer sickle cell complications. The information 
gained from this study about exercise capacity, which is a functional outcome of the new medication 
(rather than just a blood test result), greatly outweighs the inconvenience of trips to the exercise lab.  
 
 
 
 
 
 
  
 

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3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
Compare peak VO2 from sequential 
CPETs performed on SCA patients 
before and during voxelotor 
therapy  
 
Change in Peak VO2 from baseline to 
Week 8 (voxelotor) 
The gold standard for 
exercise capacity is 
peak VO2.  
Secondary 
 
 
Correlate peak VO2 with 
biochemical markers, including 
hemoglobin, reticulocyte count, 
bilirubin, lactate dehydrogenase, 
haptoglobin, hemoglobin F, % F 
cells, P50 oxygen dissociation, 
point of sickling. 
Correlation 
of 
peak 
VO2 
with 
biochemical markers of sickling and 
hemolysis 
These are established 
measurements of the 
biochemical effects of 
sickling and hemolysis. 
They will show 
whether improved 
exercise capacity is a 
direct or indirect effect 
of voxelotor’s 
biochemical activity.   
Tertiary/Exploratory  
 
 
HRQOL assessment 
Clinician Global Impression of Change 
and Patient Global Impression of 
Change assessments (CGIC and PGIC) 
The small number of 
patients on this pilot 
study may limit CPET 
quantitative results 
from reaching 
statistical significance. 
Whether or not peak 
VO2 changes 
significantly on 
voxelotor, whether 
voxelotor has the 
potential to offer 
overall clinical 
improvement and 
better quality of life 
can be assessed.  
 
 
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
 
Hypothesis: Voxelotor improves exercise capacity in SCA patients. 
 

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Study type: single-center, open-label, single-arm longitudinal interventional pilot study 
 
Methods: Patients with genetically severe forms of sickle cell disease age 12 or older will be enrolled 
from the PSV sickle cell clinic in Northern Virginia. A baseline CPET will be performed. Voxelotor will be 
initiated, and a second CPET will be performed. The CPET after the study intervention (voxelotor) will be 
compared to the baseline CPET. Each patient will be his/her own control.  
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
The phenotype of sickle cell anemia is variable, depending on genetic modifiers, such as baseline fetal 
hemoglobin level, and response to the existing sickle cell therapy Hydroxyurea. The baseline hemoglobin 
in sickle cell anemia patients vary; individuals’ physical activity also vary, whether they have sickle cell 
disease or not, and CPET results would likely show significant inter-subject variability across the sickle 
cell population. To answer the question whether voxelotor increases exercise capacity for individual 
patients taking the drug, inter-subject variability can be eliminated by comparing each subject to 
him/herself. In addition, fewer subjects will be needed in a longitudinal design than if subjects were 
divided into a study group and a control group. Therefore, we chose a longitudinal design, in which each 
participant’s CPET after voxelotor is compared to the same participant’s CPET before initiation of 
voxelotor.  
 
4.3 
JUSTIFICATION FOR DOSE 
 
The dose of 1500 mg daily for voxelotor is the standard approved dose, as a result of dose comparison 
studies completed and published by GBT. 
 
 
4.4 
END OF STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed all phases of the 
study including 2 CPETs and the last visit shown in the Schedule of Activities (SoA), Section 1.3. 
 
 
5 
STUDY POPULATION 
 
 
5.1 
INCLUSION CRITERIA 
 
Subjects will be recruited from the Pediatric Specialists of Virginia Sickle Cell Program. 
 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. Provision of signed and dated informed consent form 
2. Stated willingness to comply with all study procedures and availability for the duration of the 
study  
3. Male or female, age > 12 years 
4. In good general health as evidenced by medical history and diagnosed with a genetically severe 
form of sickle cell anemia (Hgb SS, Hgb S beta 0 thalassemia, Hgb SCHarlem, and others) 

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5. Patients who are on Hydroxyurea need to be on a stable dose for at least 3 months without 
anticipated change in dosing until the study is completed. 
6. Ability to take oral medication and willingness to adhere to daily voxelotor and 2 CPETs at 
scheduled intervals. 
7. For females of reproductive potential who are sexually active: use of highly effective 
contraception for at least 1 month prior to screening and agreement to use such a method 
during study participation and for an additional 30 days after the end of study.  
8. For males of reproductive potential: use of condoms or other methods to ensure effective 
contraception with partner 
 
5.2 
EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
 
1. Patients on chronic transfusions or who received a transfusion within last 8 weeks 
2. Patients who had hospitalization for vaso-occlusive crisis or acute chest syndrome within 30 
days prior to informed consent/assent. 
3. Patients who have screening alanine aminotransferase (ALT) > 4X upper limit of normal 
4. Patients who suffer from physical inactivity attributable to clinically significant musculoskeletal, 
cardiovascular, or respiratory comorbidities 
5. Patients already taking commercially available voxelotor 
6. Prior hypersensitivity to voxelotor or excipients. 
7. Pregnant patients 
 
5.3 
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. 
 
 
5.4 
SCREEN FAILURES 
 
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). 
 
Individuals who do not meet the criteria for participation in this trial (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. 
 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 

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• 
Target study sample size is 10 patients with any mix of male or female gender 
• 
Anticipated accrual rate is 2-3 a month 
• 
Participants will be recruited when they come to the PSV sickle cell clinic in Northern Virginia 
• 
Potential participants will be identified by preview of patients scheduled for upcoming clinics. 
Potential participants will be pre-screened through electronic medical record. They will be 
approached during their clinic visit 
• 
Recruitment flyer will be emailed and mailed to potential participants. It will also be handed to 
patients and families when they come to clinic.  
• 
The study requires 5-6 months of participation, CRA will keep in constant contact with 
participants by telephone. $150 plus the cost of a meal will be offered as compensation for 
completion of each CPET, to be paid to the participant, with parental consent if the participant is 
< age 18.  
• 
Transportation to and from the exercise lab will be covered by the study 
• 
A full CPET report that can be used for personal exercise and sports guidelines will be provided 
to each participant. 
• 
This study population are patients with sickle cell anemia, who are all in minority groups 
historically under-represented. Our patient population includes African-Americans, Africans, 
Hispanics, and Middle Easterners.  
• 
This is a pediatric study, therefore, the vulnerable population of minors are included by 
definition.  
 
 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
No text is to be entered in this section; rather it should be included under the relevant subheadings 
below.   
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
The study intervention is voxelotor, taken orally. It will be used for the approved indication of sickle cell 
anemia. This is a single-arm study. There is no control intervention.  
6.1.2 DOSING AND ADMINISTRATION 
 
Participants will be instructed to take voxelotor 1500mg consisting of three 500mg-tablets once daily for 
at least 8 weeks. It can be taken with Hydroxyurea. 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). Voxelotor will be dispensed from the sickle cell clinic in bottles with 90 tablets 
each for a 30-day supply.  
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
No text is to be entered in this section; rather it should be included under the relevant subheadings 
below.   
 

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6.2.1 ACQUISITION AND ACCOUNTABILITY 
 
Voxelotor tablets will be supplied in high-density polyethylene bottles with induction-sealed 
polypropylene child-resistant caps. Packaged and labeled drug product (voxelotor) will be supplied by 
GBT and shipped to the clinical site. Study drug will be dispensed at Visit 3 in bottles of 90 tablets. The 
PSV pharmacist will receive the bottles, which will be stored in a temperature controlled locked med 
room. The PI will dispense the drug. The study coordinator or PI will pick up/sign pharmacy log and 
dispense study drug to participant with instructions during the study visit.  
 
The participants will bring the medicine bottle back to clinic each month. Unused pills will be counted 
and recorded. Dates of receipt, dispense, return, lot numbers, and pill counts will all be recorded in a 
log.  
  
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Voxelotor comes in 500mg tablets that are film-coated, light yellow to yellow, oval shaped, biconvex, 
debossed with “GBT 500” on one side. It is packaged in bottles of 90 tablets with child-resistant closure.  
 
6.2.3 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 storage area of the investigational site’s clinic medication room which is 
a secure, locked environment with restricted access. No special procedures for the safe handling of 
voxelotor are required. 
 
 
6.2.4 PREPARATION 
 
Voxelotor is a tablet ready to be swallowed. There is no drug preparation.  
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
Not applicable. There is no randomization. 
 
 
6.4 
STUDY INTERVENTION COMPLIANCE 
 
Each bottle of voxelotor contains 90 tablets. The dose is 3 tablets a day. Each bottle lasts 30 days. 
Participants will be scheduled for clinic visits no longer than 30 days apart. Participants will be given a 
bottle of voxelotor at a clinic visit and will be asked to bring back the bottle with left over pills in it. 
Compliance will be determined by pill counting. The number of pills remaining will be counted and 
subtracted from 90 to get the number of pills taken, which can be divided by 3 to get the number of 
days the drug was taken. The difference between the number of days drug was taken and the number of 
days between the clinic visits is the number of days drug was missed.  
 

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6.5 
CONCOMITANT THERAPY 
 
All concomitant medications will be recorded each time a subject comes to clinic. Hydroxyurea is 
permitted as a concomitant medication but hydroxyurea dose change during the study is not permitted. 
 
Participants will be asked always to check with the PI or clinical study staff before taking a new 
medication. Medications that are Inducers or inhibitors of cytochrome CYP3A4 may affect voxelotor 
metabolism, and participants will be told to avoid these medications.  
 
 
6.5.1 RESCUE MEDICINE 
 
Not-applicable 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
 
If a participant discontinues voxelotor before completing the 2nd CPET but is willing to resume treatment 
on study, then the participant must take voxelotor continuously for at least 1 month before performing 
the 2nd CPET. If the participant discontinues voxelotor and is unwilling to resume treatment per the 
study protocol, then the participant will be discontinued from the study.  Only routine clinical laboratory 
monitoring blood work results will be collected at the time of treatment discontinuation, not study labs.   
 
7.2 
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: 
 
• 
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 
• 
Participant unable to perform CPET 
• 
Participant unexpectedly moves to another location not within travel distance of the exercise 
lab and is unable to complete the 2nd CPET before moving 
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 be replaced. 

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7.3 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to return for both of the study visits 
before study drug initiation and both of the study visits after initiation of study drug, or if he or she fails 
to show for scheduled CPETs 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, including at least 3 telephone calls using all 
available phone numbers for the patient and the emergency contact, 3 emails, letters to the 
participant and to the participant’s pediatrician or PCP. These contact attempts will 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. 
 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
 
Efficacy of study drug will be assessed as follows: 
• 
CPET (cardiopulmonary exercise test) is non-invasive and will be performed using a motorized 
treadmill (Trackmaster Model TMX428, Full Vision, Inc.). Participants will have their nose clipped 
and breathe through a mouthpiece with a nonbreathing valve. Breath by breath gas exchange 
data will be collected and analyzed using a VMax Encore 29C metabolic cart (CareFusion Corp, 
San Diego, CA). The participants will have EKG leads and pulse oximetry monitoring while 
running on a treadmill that increases in incline incrementally to induce peak physical effort 
according to a modified Bruce protocol based on patient age, size, and exercise ability. A peak 
exercise response will be defined as a respiratory exchange ratio of greater than 1.1 or to 
patient’s volitional fatigue. The patient exercises for 8-12 minutes. Approximately 1.5 hour will 
be allotted for the entire CPET visit, which will include checking in, explanation of the procedure, 
preparation and setup for the test, the exercise test itself, and post-test debriefing. This exercise 
test will be done twice by each participant: once before and once after starting the study drug. 
The CPET report will be provided to the participant.  
• 
During exercise the following will be measured and recorded: 
• 
· 12-Lead ECG 
• 
· Pulse oximetry 
• 
· Blood Pressure 
• 
· Peak HR 
• 
· Peak VO2 (ml/kg/min) 

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• 
· Peak VO2 (L/min) 
• 
· Respiratory Exchange Ratio (RER) 
• 
· O2 Pulse 
• 
· VE/VO2 
• 
· VE/VCO2 
• 
· VO2/HR 
• 
· VAT (ventilatory anaerobic threshold) 
• 
· Percent VO2 at VAT 
• 
Blood will be drawn for study labs once before the study drug and once after. Study labs will be 
performed by the research laboratory of Dr. Frans Kuypers at UCSF. Blood samples will be sent 
by FEDEX overnight. 
 
• 
Blood work as part of regular standard of care will continue to be done during the study. 
 
• 
The “Patient Global Impression of Change” and the “Clinician Global Impression of Change” 
single-question surveys will be completed by the participant and the clinician, respectively, at 
the final study visit.  
 
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
 
Screening and enrollment can occur in the same visit. Screening consists of physical exam and vital signs 
to ensure general good health of the patient, as well as reviewing labs and medication dose to ensure 
that the hemoglobin and Hydroxyurea dose have been stable for 3 months. The study procedure CPET 
will be explained to potential participants in detail at the screening/enrollment visit. 
 
All visits will include physical examination, vital sign, standard of care labs, and assessment of adverse 
events, which will be entered into CRFs.  
 
 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
Adverse event means any untoward medical occurrence associated with the use of voxelotor or 
performance of exercise testing, whether or not considered intervention-related (21 CFR 312.32 (a)). 
 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
An AE or suspected AE is considered “serious” if it results in any of the following outcomes: death, a life-
threatening adverse event, inpatient hospitalization, a persistent or significant incapacity or substantial 
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participant or require medical or surgical intervention. An AE for this study may be a hypersensitivity 
reaction in the form of bronchospasm requiring intensive treatment in the emergency room or clinic or 
result in hospitalization.  
 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT. 
8.3.3.1 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.  
• 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 
All adverse events (AEs) will be assessed for relationship to study intervention as the following: 
Related – The AE is known to occur with voxelotor, such as diarrhea, nausea, abdominal pain, and 
there is a reasonable possibility that voxelotor caused the AE, or there is a temporal relationship 
between voxelotor and the event.  
Not Related – There is not a reasonable possibility that voxelotor caused the event, there is no 
temporal relationship between voxelotor and event onset, or an alternate etiology has been 
established. 
 
OR 
 
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 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. 

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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. 
 
 
8.3.3.3 EXPECTEDNESS  
 
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 voxelotor in Section 2.3.1. 
 
Expected AEs include: headache, diarrhea, abdominal pain, nausea, fatigue, rash, pyrexia 
 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
Example text provided as a guide, customize as needed: 
 
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. 
 
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 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. 
 

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8.3.5 ADVERSE EVENT REPORTING  
AEs will be reported to the GBT Medical Affairs Research Program at regular intervals as required by 
GBT. SAEs will be reported to GBT Pharmacovigilance or Designee and to the IRB within 24 hours after 
the investigator learns of the event. GBT or 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 GBT’s initial receipt of the information.  
 
Expected AEs will be recorded in CRFs.  
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
The study principal investigator will immediately report to GBT Pharmacovigilance or Designee 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 GBT Pharmacovigilance or Designee. 
 
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 GBT and should be provided as soon as possible. 
 
GBT Pharmacovigilance or Designee 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.  In addition, GBT Pharmacovigilance or Designee must notify FDA and all participating 
investigators in an Investigational New Drug (IND) safety report of potential serious risks, from clinical 
trials or any other source, as soon as possible, but in no case later than 15 calendar days after GBT 
Pharmacovigilance or Designee determines that the information qualifies for reporting. 
 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
 
Not applicable 
 
8.3.8 EVENTS OF SPECIAL INTEREST  
 
Not applicable 
8.3.9 REPORTING OF PREGNANCY  
 

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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. 
 
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
Since the study intervention is a FDA-approved commercially available medication and CPET is a 
standardized orderable test, unanticipated problems would not involve risks but rather might be: 
 
• 
Inability to enroll the expected number of patients, in which case, the possibility of extending 
the study until 10 patients are enrolled will be discussed with GBT.  
• 
Subject unexpectedly moves away to a location such that travel to the exercise lab is not 
feasible and can no longer complete the study, in which case, the option of enrolling another 
subject to maintain the total number of evaluable subjects at 10 will be discussed with the 
sponsor 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
 
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.] 
 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 

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Not applicable 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
 
• 
Primary Efficacy Endpoint(s): Peak VO2 in the CPET on voxelotor is higher than peak VO2 in 
baseline CPET.  
 
• 
Secondary Efficacy Endpoint(s): Higher peak VO2 is correlated with improved biochemical 
markers of sickling and hemolysis. 
 
Paired t-test will be used to evaluate results, as patients are their own controls.  
 
9.2 
SAMPLE SIZE DETERMINATION 
 
This is a pilot study of 10 patients to define the magnitude of change. Power cannot be calculated at this 
time.  
 
9.3 
POPULATIONS FOR ANALYSES 
 
There will be one dataset for this pilot study of 10 patients.  
 
9.4 
STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
 
Peak VO2 is measured as ml/kg/min or L/min and statistics will be presented as percent change 
between the peak VO2 on voxelotor and baseline peak VO2. 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 first be analyzed descriptively.   
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
The primary endpoint is peak VO2, which is a quantitative measurement from the CPET instrument.  
There will be a single measurement as a baseline and another single measurement after the study drug 
for each participant. Paired t-test will be used to compare the 2 peak VO2s.  
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
The secondary endpoint is a group of biochemical tests, each with a different scale and different unit of 
measure. For each biochemical test, there will be a baseline measurement and a measurement after the 
study drug for each participant. Appropriate statistical comparison will be used for each biochemical 
measurement.  
 

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9.4.4 SAFETY ANALYSES 
 
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.  
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
 
Not applicable. There will only be one group. 
 
9.4.6 PLANNED INTERIM ANALYSES  
 
Not applicable 
 
9.4.7 SUB-GROUP ANALYSES 
 
Not applicable 
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
Individual participant data will be listed by measure and time point.  
 
9.4.9 EXPLORATORY ANALYSES 
 
There are no exploratory analyses. 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
 
 
 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention. The following consent materials are submitted with this 
protocol: sample consent and assent form, voxelotor information sheet.  
 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 

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Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be Institutional 
Review Board (IRB)-approved and the participant will be asked to read and review the document. The 
investigator will explain the research study to the participant and answer any questions that may arise. 
A verbal explanation will be provided in terms suited to the participant’s comprehension of the 
purposes, procedures, and potential risks of the study and of their rights as research participants.  
Participants will have the opportunity to carefully review the written consent form and ask questions 
prior to signing. The participants should have the opportunity to discuss the study with their family or 
surrogates or think about it prior to agreeing to participate. The participant will sign the informed 
consent document prior to any procedures being done specifically for the study. Participants must be 
informed that participation is voluntary and that they may withdraw from the study at any time, without 
prejudice. A copy of the informed consent document will be given to the participants for their records. 
The informed consent process will be conducted and documented in the source document (including the 
date), and the form signed, before the participant undergoes any study-specific procedures. The rights 
and welfare of the participants will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study.  
 
For subjects age < 18, the parent or legal guardian will sign the consent and the subject will sign the 
assent.  
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to study participants, investigator, and GBT Medical 
Affairs Research Program and the IRB. If the study is prematurely terminated or suspended, the Principal 
Investigator (PI) will promptly inform study participants, the Institutional Review Board (IRB), and GBT 
Medical Affairs Research Program and will provide the reason(s) for the termination or suspension.  
Study participants will be contacted, as applicable, and be informed of changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the IRB and/or Food and Drug Administration (FDA). 
 
 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators and the 
study team. This confidentiality covers the clinical information relating to participants. Therefore, the 

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study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized third 
party without prior written approval of the Principal Investigator.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the Principal Investigator, representatives of the 
Institutional Review Board (IRB), regulatory agencies or pharmaceutical company supplying study 
product may inspect all documents and records required to be maintained by the investigator, including 
but not limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants 
in this study. The clinical study site will permit access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies and requirements. 
 
Study participant research data, which are for purposes of statistical analysis and scientific reporting, 
will be stored in a local secure database. This will not include the participant’s contact or identifying 
information. Rather, individual participants and their research data will be identified by a unique study 
identification number. The study data entry and study management system used will be secured and 
password protected. At the end of the study, all study data will be de-identified and archived. 
 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study will be analyzed and stored in a password-protected file on the site server. 
After the study is completed, the de-identified, archived data will be held by the sponsor investigator. 
Permission for GBT to access data will be included in the informed consent.  
 
No biological specimens will be retained and no genetic material will be collected in this study. 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
Provide the name and contact information of the Principal Investigator and the Medical Monitor. 
Principal Investigator 
Elizabeth Yang, MD, PhD 
Pediatric Specialists of Virginia  
8081 Innovation Park Dr. Fairfax, 
VA 22031 
571-472-1717 
eyang@psvcare.org 
 
The Medical Monitor will be the PI and the IRB, if necessary 
 
The study team will consist of: 
Principal Investigator – Elizabeth Yang, MD, PhD 

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Co-Investigators – Jared Hershenson, MD, Laura Caldarera, MA, RCEP, Ana Cortez, DO, Frans Kuypers, 
PhD 
Clinical Research Assistants 
Pharmacist 
 
 
10.1.6 SAFETY OVERSIGHT 
 
The study intervention is taking an oral, commercially available, FDA-approved drug and the study 
measurement is doing exercise studies, which is minimal risk. No DSMB is required.  
 
10.1.7 CLINICAL MONITORING 
 
This study is minimal risk, monitoring by PI and IRB is sufficient. No CMP is necessary.  
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
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 exercise 
lab is a certified exercise lab and will conduct its own quality control. The research lab conducts quality 
control on all its instrumentation and lab protocols.  
 
Summarized data will be provided to GBT in study progress reports.  
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 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 when necessary as source document 
worksheets for recording data for each participant enrolled in the study.  Data will be recorded in 
password-protected database accessible only by PI and the study personnel. Any source document on 
paper will be stored in locked cabinet in the Clinical Research Associate’s office.  
 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered a database designed for this study. The data system 
includes password protection. Clinical data will be entered directly from the source documents. 
 
 
 
10.1.9.2 STUDY RECORDS RETENTION  

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Study documents will be retained for 3 years or as required by the IRB after completion of the study. No 
records will be destroyed without the written consent of the Sponsor-Investigator, if applicable. It is the 
responsibility of the investigator to determine when these documents no longer need to be retained. 
 
 
10.1.10 
PROTOCOL DEVIATIONS  
 
Examples of protocol deviations in this study include: 
• 
Noncompliance with voxelotor 
• 
Starting the study drug before baseline CPET 
• 
Failure to send study labs 
Protocol deviations will be reported to the Sponsor-Investigator and a decision will be made whether to 
discontinue the subject from study, if the data from the subject will become uninterpretable.  
 
 
10.1.11 
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.  Data from this study may be requested from other researchers x years after the 
completion of the primary endpoint by contacting the study Principal Investigator. 
 
 
 
10.1.12 
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.  
 
10.2 ADDITIONAL CONSIDERATIONS 
 
 
 

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10.3 ABBREVIATIONS 
The list below includes abbreviations utilized in this template.  However, this list should be customized for 
each protocol (i.e., abbreviations not used should be removed and new abbreviations used should be 
added to this list). 
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
CFR 
Code of Federal Regulations 
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 
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 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
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 
ITT 
Intention-To-Treat 
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 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 

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SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
 
 
 

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10.4 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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