Clinical trial NCT04983264
Conditions: Sickle Cell Disease
Sponsor: Pfizer
Start date: 2021-05-21; Completion date: 2022-12-06
Enrollment: 6 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the safety, tolerability, and pharmacokinetics (PK), and pharmacodynamics (i.e., how the body absorbs, distributes, breaks down, and excretes) of GBT021601, a hemoglobin S (HbS) polymerization inhibitor, in participants with SCD, following single and multiple ascending doses.

Detailed description:
This is an open-label intrapatient single dose followed by a multiple dose escalation study in at least six (6) participants with SCD.

Arms: arm 1: Refer to Study Description arm 2: Refer to Study Description
Interventions: intervention 1: GBT021601
Intervention descriptions: intervention 1: Tablets and capsules which contain GBT021601 drug substance

Protocol documents:
Prot_000.pdf: 


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1. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES .................2 
2. 
SYNOPSIS ...................................................................................................................7 
SCHEDULES OF ASSESSMENTS AND PROCEDURES .........................................................11 
LIST OF ABBREVIATIONS ........................................................................................................18 
3. 
INTRODUCTION AND BACKGROUND ...............................................................21 
3.1. 
Introduction .................................................................................................................21 
3.2. 
Study Drug Background .............................................................................................22 
3.3. 
Summary of Findings to Date .....................................................................................22 
3.3.1. 
Nonclinical Experience ...............................................................................................22 
3.3.2. 
Clinical Experience .....................................................................................................22 
3.3.3. 
Summary of Known and Potential Risks of GBT021601 ..........................................23 
3.4. 
Study Rationale ...........................................................................................................23 
3.4.1. 
Rationale for Study Design .........................................................................................23 
3.4.2. 
Rationale for Dose Selection ......................................................................................23 
3.4.2.1. 
Rationale for Single Dose Selection ...........................................................................23 
3.4.2.2. 
Rationale for Multiple Dose Selection .......................................................................25 
3.4.2.3. 
Rationale for Evaluation of Higher Dose of GBT021601 ..........................................25 
 
 
4. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................27 
4.1. 
Primary Objective .......................................................................................................27 
4.2. 
Secondary Objectives .................................................................................................27 
4.3. 
Overall Study Design ..................................................................................................27 
4.3.1. 
Single-dose Period (Part A) ........................................................................................28 
4.3.2. 
Multiple Ascending-dose Period (Part B) ...................................................................28 
4.3.3. 
Extended Treatment Period (Part C) ...........................................................................28 
4.4. 
Number of Participants ...............................................................................................29 
4.5. 
Duration of Study .......................................................................................................29 
4.6. 
Definition of Study Completion .................................................................................29 
4.7. 
End of Study ...............................................................................................................29 
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5. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS .....................................30 
5.1. 
Participant Inclusion Criteria ......................................................................................30 
5.2. 
Participant Exclusion Criteria .....................................................................................30 
5.2.1. 
Additional Exclusion Criteria (Part C): ......................................................................32 
5.3. 
Participant Re-Screening ............................................................................................33 
5.4. 
Participant Withdrawal ...............................................................................................33 
5.5. 
Early Termination of Study ........................................................................................33 
5.5.1. 
Stopping Rules ............................................................................................................34 
5.6. 
Safety Monitoring Committee ....................................................................................34 
5.7. 
Dose Escalation Criteria .............................................................................................35 
6. 
TREATMENT OF PARTICIPANTS .........................................................................36 
6.1. 
Description of Study Drug ..........................................................................................36 
6.2. 
Treatments Administered ............................................................................................36 
6.3. 
Method of Assigning Participants to Treatment Groups ............................................36 
6.4. 
Measurements of Treatment Compliance ...................................................................36 
6.5. 
Concomitant Medications, Procedures, Other Restrictions and Requirements ..........37 
6.5.1. 
Concomitant Medications and Procedures .................................................................37 
6.5.2. 
Other Restrictions .......................................................................................................37 
6.5.3. 
Fertility and Contraceptive Requirements ..................................................................37 
6.5.3.1. 
Female Participants of Childbearing Potential ...........................................................37 
6.5.3.2. 
Instructions for Male Participants Capable of Fathering a Child ...............................38 
6.5.3.3. 
Acceptable Forms of Contraception for Male Participants with Female 
Partners Capable of Reproduction ..............................................................................38 
7. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................39 
7.1. 
Study Drug ..................................................................................................................39 
7.2. 
Study Drug Packaging and Labeling ..........................................................................39 
7.3. 
Study Drug Storage .....................................................................................................39 
7.4. 
Blinding of Treatment Assignment ............................................................................39 
7.5. 
Administration ............................................................................................................39 
7.6. 
Study Drug Accountability and Disposal ...................................................................39 
8. 
PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENTS ............40 
8.1. 
Blood Sample Collection ............................................................................................40 
8.1.1. 
Single-dose Period ......................................................................................................40 


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8.1.2. 
Multiple Ascending-dose Period ................................................................................40 
8.2. 
Pharmacokinetic Analysis ..........................................................................................42 
8.3. 
Pharmacodynamic Analysis ........................................................................................42 
8.3.1. 
Other Pharmacodynamic Assessments .......................................................................42 
9. 
ASSESSMENT OF SAFETY .....................................................................................44 
9.1. 
Safety Parameters .......................................................................................................44 
9.1.1. 
Demographic/Medical History ...................................................................................44 
9.1.2. 
Vital Signs ..................................................................................................................44 
9.1.3. 
Weight and Height ......................................................................................................44 
9.1.4. 
Physical Examination .................................................................................................44 
9.1.5. 
Electrocardiogram .......................................................................................................44 
9.1.6. 
Laboratory Assessments .............................................................................................45 
9.1.6.1. 
Standard Clinical Laboratory Assessments ................................................................45 
9.1.6.2. 
Other Laboratory Assessments ...................................................................................45 
 
 
10. 
ASSESSMENT OF SAFETY — ADVERSE EVENTS ............................................48 
10.1. 
Adverse and Serious Adverse Events .........................................................................48 
10.1.1. 
Definition of Adverse Events .....................................................................................48 
10.1.2. 
Serious Adverse Event ................................................................................................48 
10.2. 
Severity .......................................................................................................................49 
10.3. 
Relationship to Study Drug ........................................................................................49 
10.4. 
Unexpected Adverse Reactions ..................................................................................50 
10.5. 
Recording Adverse Events .........................................................................................50 
10.5.1. 
General ........................................................................................................................50 
10.5.2. 
Diagnosis Versus Signs and Symptoms .....................................................................50 
10.5.3. 
Abnormal Laboratory Values .....................................................................................50 
10.6. 
Reporting Adverse Events ..........................................................................................51 
10.6.1. 
Serious Adverse Events ..............................................................................................51 
10.6.2. 
Reporting Suspected Unexpected Serious Adverse Reactions and Urgent 
Safety Issues ...............................................................................................................51 
10.7. 
Pregnancy ...................................................................................................................51 
10.8. 
Drug-induced Liver Injury ..........................................................................................52 
11. 
STATISTICS ..............................................................................................................53 
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11.1. 
Sample Size Calculation .............................................................................................53 
11.2. 
Analysis Populations ..................................................................................................53 
11.3. 
Interim Analysis ..........................................................................................................53 
11.4. 
Safety Analysis ...........................................................................................................53 
11.5. 
Pharmacokinetic Analysis ..........................................................................................53 
11.6. 
Pharmacodynamic Analysis ........................................................................................53 
11.7. 
Pharmacokinetic/Pharmacodynamic Relationships ....................................................53 
12. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................54 
12.1. 
Source Data .................................................................................................................54 
12.2. 
Data Collection ...........................................................................................................55 
13. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................56 
13.1. 
Monitoring ..................................................................................................................56 
13.2. 
Quality Control and Quality Assurance ......................................................................56 
13.3. 
Laboratory Accreditation ............................................................................................56 
14. 
ETHICS ......................................................................................................................57 
14.1. 
Ethical Conduct of the Study ......................................................................................57 
14.2. 
Good Clinical Practice ................................................................................................57 
14.3. 
Informed Consent .......................................................................................................57 
14.4. 
Institutional Review Board and Regulatory Approval ...............................................57 
14.5. 
Essential Documentation Requirements .....................................................................58 
14.6. 
Confidentiality ............................................................................................................58 
14.7. 
Regulatory, Ethical, and Legal Obligations ................................................................58 
14.8. 
Study Documentation and Data Storage .....................................................................58 
15. 
DATA HANDLING AND RECORDKEEPING .......................................................60 
15.1. 
Inspection of Records .................................................................................................60 
15.2. 
Retention of Records ..................................................................................................60 
15.3. 
Disclosure of Information ...........................................................................................61 
16. 
INSURANCE AND FINANCIAL DISCLOSURE ....................................................62 
17. 
PUBLICATION POLICY ..........................................................................................63 
18. 
REFERENCES ...........................................................................................................64 
 
 
 
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2. 
SYNOPSIS 
Study Number and Title: 
GBT021601-012: An Intrapatient Single Dose and Multiple Ascending Dose Study to Evaluate the 
Pharmacokinetics, Safety, Tolerability, and Pharmacodynamics of GBT021601, a Hemoglobin S 
Polymerization Inhibitor, in Participants with Sickle Cell Disease (SCD). 
Study Short Title: 
GBT021601-012 Single Dose and Multiple Ascending Dose in Participants with SCD. 
Estimated Number of Study Centers and Countries or Regions: 
Up to 3 sites in the United States of America. 
Study Rationale: 
This study will evaluate the pharmacokinetics (PK), safety, tolerability, and pharmacodynamics (PD) 
with a single dose followed by ascending, intrapatient doses of GBT021601, a hemoglobin S (HbS) 
polymerization inhibitor, in participants with SCD. 
Objectives: 
Primary 
 
To evaluate the safety and tolerability of a single dose and multiple ascending doses of 
GBT021601 in participants with SCD. 
Secondary 
 
To evaluate the PK of a single dose and multiple ascending doses of GBT021601 in 
participants with SCD. 
 
To evaluate the PD properties (effect on Hb oxygen equilibrium curves (OEC) as measured 
by % Hb modification and p50) of a single dose and multiple ascending doses of 
GBT021601 in participants with SCD. 
 
To confirm the relationship between time matched GBT021601 concentrations and the 
change from baseline or % change from baseline of clinical measures of anemia and 
hemolysis. 
 
 
 
 
 
 
 
Study Design: 
This is an open-label, intrapatient, single dose followed by a multiple dose escalation study in at least 
six (6) participants with SCD.  
Single-dose Period (Part A) 
After eligibility has been confirmed and the informed consent form signed, participants will be 
admitted into the clinical research unit (CRU) on the day prior to study drug administration (Day -1). 
On Day 1 a single oral dose of GBT021601 will be administered following an overnight fast of at least 
10 hours and no food will be allowed for at least 4 hours postdose. A dose of 100 mg is planned but the 
decision regarding the actual study dose will depend on the findings in the single ascending dose 
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Number of Participants: 
At least six (6) participants with SCD. Participants in Part A (single dose) will continue to Part B 
(multiple ascending-dose). As of Protocol Amendment 5, all eligible participants will proceed with the 
extended treatment period (Part C). 
Participant Selection Criteria: 
Participants with SCD ages 18 to 60 years, inclusive. 
Test Product, Dose, Route of Administration, and Duration of Treatment: 
Single-dose Period (Part A) 
 
GBT021601 will be provided as a single dose, orally administered, 100 mg tablet. 
Multiple Ascending-dose Period (Part B) and Extended Treatment Period (Part C) 
 
GBT021601 will be provided as orally administered multiple dose tablets and/or capsules for 
approximately 6 to 8 weeks (Part B) and for the approximately 6-week Extended Treatment 
Period (Part C).  
 
Loading and maintenance doses and frequency will be determined based on PK results from 
GBT021601-011 and on PK and /or hemoximetry results from Part A. Dose escalations will 
not exceed 2-fold the previous dose. For the Extended Treatment Period, the loading dose will 
be 300 mg, twice daily, for 4 days followed by a once daily maintenance dose of 150 mg. 
Criteria for Evaluation: 
Safety:  
Participant safety and tolerability will be monitored during the study using standard measures, 
including physical examination, vital signs, 12-lead electrocardiogram, safety laboratory assessments 
(hematology measurements, chemistry measurements [including measures of hemolysis]), urinalysis, 
concomitant medication usage and adverse event monitoring. 
Pharmacokinetics: 
Plasma and whole blood concentrations of GBT021601 will be determined using validated assay 
methods. Red blood cell (RBC) concentrations will be calculated. The following whole blood, plasma, 
and RBC PK parameters of GBT021601 will be calculated, if appropriate. See below for PK 
parameters to be collected during each phase. 
Single-dose Period (Part A): Maximum plasma/whole blood concentration (Cmax), time of maximum 
serum concentration (tmax), area under the concentration vs time curve from time zero to 24 hours 
(AUC0-24), area under the concentration vs time curve from zero to last quantifiable concentration 
(AUC0-t), area under the concentration vs time curve from time zero extrapolated to infinity (AUC0-∞), 
apparent clearance (CL/F), apparent volume of distribution during the terminal phase (Vz/F), half-life 
(t1/2) and % Hb occupancy. 
Multiple Dose (Part B and Part C): Plasma/whole blood Cmax, plasma/whole blood Cmin, plasma/whole 
blood AUC at steady-state, half-life (t½) and % Hb occupancy. 
Pharmacodynamics (Parts A, B, and C): 
Hemoximetry (the partial pressure of oxygen at which the hemoglobin protein is 20% and 50% 
saturated [p20 and p50, respectively]), RBC deformability, and serum erythropoietin will be measured. 
The relationship between time matched GBT021601 concentrations and the change from baseline or % 
change from baseline of clinical measures of anemia and hemolysis will be evaluated. 
 
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Planned Sample Size: 
Due to the exploratory nature of this study, no formal power or sample size calculations were used to 
determine cohort size. A sample size of at least 6 participants with SCD are expected to provide 
adequate characterization of PK and safety for both the Single-dose Period and the Multiple 
Ascending-dose Period. 
Statistical Analysis: 
Adverse events will be coded to system-organ class and preferred term using the Medical Dictionary 
for Regulatory Activities (MedDRA) and summarized. Vital signs and laboratory safety assessments 
will be presented with identification of clinically significant values and those outside of normal range. 
Electrocardiogram data 
will be presented with any clinically relevant abnormal findings or changes highlighted. The PK and 
PD parameters will be listed and summarized using appropriate descriptive statistics. 
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SCHEDULES OF ASSESSMENTS AND PROCEDURES 
Table 1: 
Schedule of Assessments for Single-dose Period (Part A) 
 
Screen 
Confinement 
Outpatient 
Study Day 
-30 to -2 
-1 
1 
2 
3 
4 
7 
14 
21 
28 
42 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility assessment 
X 
X 
 
 
 
 
 
 
 
 
 
Medical historya 
X 
 
 
 
 
 
 
 
 
 
 
Physical examinationb 
X 
X 
 
 
 
X 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Vital signsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG (triple tracing)d 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
Study drug administration  
 
 
X 
 
 
 
 
 
 
 
 
Serology (hepatitis A, B, C) HIV, SARS-CoV-2 
X 
 
 
 
 
 
 
 
 
 
 
Alcohol (breath or blood) and urine drugs of abuse 
screen 
X 
X 
 
 
 
 
 
 
 
 
 
Hematology, Serum chemistry, and Lipid Panele 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
aPTT, INR, PT 
X 
 
 
 
 
 
 
 
 
 
 
Serum erythropoietin 
 
X 
X 
 
 
X 
 
X 
 
X 
 
SCD documentation or Hemoglobin Electrophoresis 
X 
 
 
 
 
 
 
 
 
 
 
eGFRf 
X 
X 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
 
 
X 
 
 
 
 
 
Pregnancy test (women only)g 
X 
X 
 
 
 
 
 
X 
 
X 
 
FSH (postmenopausal women only) 
X 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic assessment (whole blood and 
plasma) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hemoximetry 
 
 
X 
X 
 
X 
X 
 
X 
 
X 
RBC deformability, dense cellsh 
 
 
X 
 
 
 
 
 
 
 
 


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Screen 
Confinement 
Outpatient 
Study Day 
-30 to -2 
-1 
1 
2 
3 
4 
7 
14 
21 
28 
42 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: aPTT, activated partial thromboplastin time; CoV, coronavirus; ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; 
EOS, end of study; ET, early termination; FSH, follicle-stimulating hormone; HIV, human immunodeficiency virus; INR, International Normalized Ratio; 
PCR, polymerase chain reaction; PT, prothrombin time; RBC, red blood cell; SARs, severe acute respiratory syndrome; SCD, sickle cell disease. 
a History update, if any, will be obtained. 
b A full physical examination should be conducted at Screening. All subsequent physical examinations should be signs and symptoms driven. 
c Vital Signs include blood pressure, heart rate, respiration rate, body temperature while the participant is in a supine position. See Table 2. 
d 12-Lead ECG on Day 1 should be performed within 30 minutes prior to dose, and 4 and 8 hours after dosing, then in the morning of each day of confinement 
and at any time at other clinic visits. See Table 2. 
e The Lipid Panel is done at the Screening Visit only. 
f The eGFR will be calculated at Screening and confirmed on Day -1 using the Cockcroft-Gault formula. 
g A serum pregnancy test will be conducted at Screening and ET and urine pregnancy test at all other visits. A serum pregnancy test will also be conducted when 
a positive urinary pregnancy test occurs for confirmation. 
h RBC deformability and dense cells will be tested on Day 1 predose and 12 hours postdose. 


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Table 2: 
Schedule of Select Study Procedures (First 48 hours) 
Procedure 
Sampling Timepoint 
Pre 
dose 
Postdose (hours) 
0.25 hr 
0.5 hr 
1 hr 
2 hr 
4 hr 
6 hr 
8 hr 
12 hr 
24 hr 
(Day 2) 
36 hr 
48 hr 
(Day 3) 
HR and BPa, b 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
RR and Body Temperaturea, b 
X 
 
 
 
 
 
 
 
 
X 
 
X 
12-lead safety ECGsb, c 
X 
 
 
X 
 
X 
 
x 
 
X 
 
X 
PK Samplingd 
X  
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: BP, blood pressure; ECG, electrocardiogram; HR, heart rate; PK, pharmacokinetic; RR, respiratory rate; SAD, single ascending dose. 
Note: For procedures scheduled to be performed at the same time, priority is to be given to collection of the PK samples at the designated time. 
ECGs, followed by vital signs, are to be taken before PK sampling, unless PK samples will be late as a result. If times are delayed due to technical difficulties, 
this will be noted, but not considered a protocol deviation. 
a HR, BP, RR, and body temperature will be measured after a participant has rested for at least 5 minutes in the supine position.  
b Window for collection: up to 3 hours predose, ± 15 minutes up to 12 hours post, ± 30 minutes if ≥ 24 hours postdose. 
c ECGs (12-lead) will be collected in triplicate within 5 minutes after a participant has rested at least 5 minutes in the supine position. Pre-dose ECGs and vital 
signs on Day 1 may be performed within 3 hours prior to dosing. 
d Predose blood PK sample to be collected within 60 minutes prior to dosing. Postdose collection windows are: 0.25, 0.5 and 1 hour ± 2 mins, 2 to 24 hours 
± 5 mins, 36 and 48 hours ± 10 mins. 
 


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Table 3: 
Schedule of Assessments for Multiple Ascending-dose Period (Part B)  
Study Week  
Week 8  
(Day 56  
+ 4 
weeks)a 
Week 9  
(Day 63  
± 3 days) 
Week 10  
(Day 70  
± 3 days) 
Week 11  
(Day 77  
+ 3 days  
Week 12  
(Day 84  
± 3 days) 
Week 13  
(Day 91  
±3 days) 
 
Week 14  
(Day 98)  
± 3 days) 
Week 15 
(Day 105) 
±3 days 
 
Week 16 
(Day 112) 
EOT 
 
Every 
4 weeks 
through 
EOB 
± 7 days 
Day 218  
(EOB/ET) 
Physical examination 
X 
 
 
 
 
X 
 
 
X 
 
X 
Height 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
 
 
 
 
 
 
 
 
Vital signsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
12-lead ECG 
(triple tracing)d 
X 
 
 
 
 
X 
 
 
X 
 
X 
Study drug 
administration 
Xe 
X 
X 
X 
X 
Xf 
X 
X 
X 
 
 
Dispense patient 
diaryg 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Collect patient 
diarygg 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Hematology and 
serum chemistry 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
Blood smearh 
X 
 
 
 
 
 
 
 
X 
 
X 
Serum erythropoietin 
X 
 
 
 
 
X 
X 
 
X 
 
 
eGFRi 
X 
 
 
 
 
X 
 
 
 
 
X 
Urinalysis 
X 
 
 
 
 
X 
 
 
 
 
X 
Pregnancy test 
(women only)j 
X 
 
 
 
 
X 
 
 
 
 
 
Pharmacokinetic 
assessment (whole 
blood and plasma)k 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Study Week  
Week 8  
(Day 56  
+ 4 
weeks)a 
Week 9  
(Day 63  
± 3 days) 
Week 10  
(Day 70  
± 3 days) 
Week 11  
(Day 77  
+ 3 days  
Week 12  
(Day 84  
± 3 days) 
Week 13  
(Day 91  
±3 days) 
 
Week 14  
(Day 98)  
± 3 days) 
Week 15 
(Day 105) 
±3 days 
 
Week 16 
(Day 112) 
EOT 
 
Every 
4 weeks 
through 
EOB 
± 7 days 
Day 218  
(EOB/ET) 
Hemoximetryk 
X 
X 
X 
 
 
X 
 
X 
X 
 
X 
RBC deformability, 
dense cells 
(if feasible)k 
X 
X 
X 
 
 
X 
 
X 
X 
 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Clinic visit 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Abbreviations: ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; EOB, end of Part B; ET, early termination; RBC, red blood cell. 
Note: For procedures scheduled to be performed at the same time, priority is to be given to collection of the PK samples at the designated time. 
ECGs, followed by vital signs, are to be taken before PK sampling unless PK samples will be late as a result 
a Week 8 (Day 56) is the first visit in the Multiple-Ascending-dose Period.  
b The Day 218 Visit will occur approximately 5 half-lives after the dose at Week 16. 
c HR, BP, RR, and body temperature will be measured after a participant has rested for at least 5 minutes in the supine position. Assessment of vital signs may be 
performed up to 3 hours predose. 
d 12-Lead ECG should be performed within 30 minutes prior to dose and will be collected in triplicate within 5 minutes after a participant has rested at least 
5 minutes in the supine position. 
e Study drug will be administered as a loading dose of TBD mg and a maintenance dose of TBD mg every TBD (Dose 1) beginning at the Week 8 (Day 56) 
Visit. Participants will receive maintenance Dose 1 through Week 10. At the Week 8 Visit, the participant will remain in the clinic for 4 hours postdose for 
vitals, 12-lead ECG and AE assessment. 
f Study drug will be administered as a loading dose of TBD mg and a maintenance dose of TBD mg every TBD (Dose 2) beginning at the Week 13 (Day 91) 
Visit. Participants will receive maintenance Dose 2 through Week 16. At the Week 13 Visit, the participant will remain in the clinic for 4 hours postdose for 
vitals, 12-lead ECG and AE assessment 
g Site to dispense a new diary and collect the previous diary from the patient, when applicable. Diary to be collected only during the maintenance dosing when 
the participant is self-administering study drug at home. Participants should be instructed to complete the diary each week and return it at the next visit for site 
review. 
h A blood smear is to be performed before the Multiple Ascending Dosing Period Day 56 and Day 112 visits. 
i The eGFR will be calculated using the Cockcroft-Gault formula. 
j A urine pregnancy test will be conducted. A serum pregnancy test will also be conducted when a positive urinary pregnancy test occurs for confirmation. 
k Samples for PK will be collected: predose, 0.25 to 1 hours postdose and 2 to 4 hours postdose. Sample collection times for hemoximetry and RBC 
deformability should be aligned with the predose PK sample and the 2 to 4 hour postdose PK sample. No 0.25 to 1 hour postdose sample shall be collected for 
hemoximetry or RBC deformability. The predose blood sample for PK and PD assessments should be collected within 30 minutes prior to dosing. 


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Table 4: 
Schedule of Assessments for Extended Treatment Period (Part C) 
Study Day/Week   
Part C 
Screening  
Visit  
(Day -28 to 
Day -1) 
 
Part C 
 Day 1 
Part C  
Week 2  
(Day 14  
± 3 days) 
Part C  
Week 4  
(Day 28   
± 3 days) 
         
Part C  
Week 6 
(Day 42)  
± 3 days)  
EOET 
Part C  
Week 10 
(Day 70 ± 3 
days) 
Part C  
Week 14 
(Day 98 ± 3 
days)  
Final Visit  
(EOS/
 
Informed Consent 
X 
 
 
 
 
 
 
 
Eligibility confirmationa 
X 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
X 
 
X 
X 
Weight 
X 
X 
 
 
X 
 
X 
X 
Vital signsb 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG (triple tracing)c 
X 
X 
X 
X 
X 
 
X 
X 
Study drug administrationd 
 
X 
X 
X 
X 
 
 
 
Dispense participant diarye 
 
X 
X 
X 
 
 
 
 
Collect participant diarye 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology and serum 
chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
Serum erythropoietin 
X 
X 
 
 
X 
 
X 
X 
eGFRf 
X 
X 
 
 
X 
 
X 
X 
Urinalysis 
X 
X 
 
 
X 
 
X 
X 
Pregnancy test 
(women only)g 
X 
X 
 
 
X 
 
X 
X 
Pharmacokinetic assessment 
(whole blood and plasma)h 
 
X 
X 
X 
X 
X 
X 
X 
Hemoximetryh 
 
X 
 
X 
X 
 
X 
X 
CCI
CCI




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LIST OF ABBREVIATIONS 
The following abbreviations and specialist terms are used in this study protocol. 
Abbreviation or 
Specialist Term 
Explanation 
ADLs 
Activities of daily living 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC0-24 
Area under the concentration vs time curve from time zero to 24 hours 
AUC0-t 
Area under the concentration vs time curve from zero to last quantifiable 
concentration 
AUC0-∞ 
Area under the concentration vs time curve from time zero extrapolated to infinity 
BP 
Blood pressure 
BPM 
Beats per minute 
 
 
CL/F 
Apparent clearance 
Cmax 
Maximum plasma/whole blood concentration 
Cmin 
Minimum plasma/whole blood concentration 
 
 
CoV 
Coronavirus 
COVID-19 
Coronavirus disease 2019 
CRO 
Contract research organization 
CRU 
Clinical research unit 
CYP 
Cytochrome P450 
°C 
Degrees Celsius 
 
 
DILI 
Drug-induced liver injury 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EOS 
End of Study 
EOT 
End of Treatment 
EPO 
Erythropoietin 
ET 
Early Termination 
FDA 
(United States) Food and Drug Administration 
 
 
CCI
CCI
CCI
CCI


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Abbreviation or 
Specialist Term 
Explanation 
FIH 
First-in-human 
FSH 
Follicle-stimulating hormone 
GBT 
Global Blood Therapeutics, Inc. 
GCP 
Good Clinical Practice 
Hb 
Hemoglobin 
Hb-O2 
Hemoglobin-oxygen 
HbS 
Sickle hemoglobin 
HbSB 
Double heterozygote for HbS and b-0 thalassemia 
HbSS 
Homozygous for sickle cell allele 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
HU 
Hydroxyurea 
IgM 
Immunoglobulin M 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NOAEL 
No-observed-adverse-effect level 
 
 
 
 
OxyHb 
Oxy-hemoglobin 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PT 
Prothrombin time 
p20 
Hemoglobin protein is 20% saturated 
p50 
Hemoglobin protein is 50% saturated 
RBC 
Red blood cell 
RR 
Respiratory rate 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SARS 
Severe acute respiratory syndrome 
SCD 
Sickle cell disease 
SMC 
Safety Monitoring Committee 
CCI
CCI


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Abbreviation or 
Specialist Term 
Explanation 
tmax 
Time of maximum serum concentration 
t½ 
Half-life 
ULN 
Upper limit of normal 
US 
United States 
Vz/F 
Apparent volume of distribution during the terminal phase 


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3. 
INTRODUCTION AND BACKGROUND 
3.1. 
Introduction 
Global Blood Therapeutics, Inc. (GBT; the Sponsor) intends to develop GBT021601, a sickle 
hemoglobin (HbS) polymerization inhibitor for the treatment of sickle cell disease (SCD). 
Sickle cell disease is an inherited disorder caused by a point mutation in the β-globin gene 
leading to formation of HbS. A primary and obligatory event in the molecular pathogenesis of 
SCD is the polymerization of intracellular HbS following deoxygenation in the microvasculature. 
HbS polymerization leads to decreased red blood cells (RBC) deformability, morphologic 
sickling of RBCs, decreased RBC survival, and microvascular obstruction (Bunn, 1997). 
Clinically, SCD is a devastating and debilitating disease marked by the pathophysiologic features 
of hemolytic anemia, vaso-occlusion, and progressive end-organ damage. Despite current 
standards of care, including hydroxyurea (HU), blood transfusion, and supportive care with 
analgesia, patients with SCD continue to suffer serious morbidity and premature mortality. 
A drug that inhibits HbS polymerization in all RBCs has the potential to provide superior 
efficacy to available treatments. GBT021601 is an HbS polymerization inhibitor being developed 
by GBT for the treatment of SCD. GBT021601 increases hemoglobin-oxygen (Hb-O2) affinity 
and stabilizes hemoglobin (Hb) in the oxy-hemoglobin (oxyHb) state thereby inhibiting 
polymerization of HbS in RBCs. By addressing this underlying mechanism of SCD, GBT021601 
has the potential to be a disease-modifying therapy, leading to improved anemia, reduced 
hemolysis and the potential to reduce the end-organ damage resulting from chronic hemolytic 
anemia. Proof of concept for this Hb modification approach has been provided with voxelotor, 
an orally administered small molecule inhibitor of HbS polymerization. 
Voxelotor is an allosteric modifier of Hb-O2 affinity and following binding to Hb, stabilizes the 
oxyhemoglobin state (Metcalf, 2017; Oksenberg 2016), thereby inhibiting polymerization of 
HbS in RBCs and in patients with SCD.  
Data from the Phase 3 study of voxelotor in patients with SCD showed a dose-dependent 
improvement in hemolytic anemia, with an increase in Hb and concomitant decrease in clinical 
measures of hemolysis (including indirect bilirubin, reticulocytes, and lactate dehydrogenase) 
(Vichinsky, 2019).  
The % Hb occupancy approximates the percentage of high-affinity anti-polymerizing oxyHb 
molecules per RBC and is calculated as a percentage of the molar ratio of drug concentration in 
RBCs to the estimated Hb concentration (5000 μM) in RBCs (Howard, 2019; 
Hutchaleelaha, 2019). 
Clinical studies with voxelotor in patients with SCD showed that daily doses of 1500 mg 
(the FDA-approved dose), which achieved a mean Hb occupancy of ~27%, was well tolerated 
and resulted in a clinically meaningful increase in Hb by > 1 g/dL in > 50% patients with 
concurrent reductions in clinical measures of hemolysis (Vichinsky, 2019). Additionally, the 
highest Hb occupancy achieved in that study with 1500 mg was 45%. In SCD mice treated with 
GBT021601, a Hb occupancy of ~6% resulted in a > 1 g/dL increase in Hb concentration in all 
animals. Moreover, at a GBT021601 Hb occupancy of ~29% (similar to the mean achieved by 
the 1500 mg dose of voxelotor in SCD patients), GBT021601 caused a sustained and almost 
complete elimination of circulating sickled RBCs, reduced reticulocyte counts by > 50%, 


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increased RBC half-life by 6.1 days, and normalized Hb with a 6.7 g/dL increase from baseline 
in SCD mice. These data indicate that at similar Hb occupancies, GBT021601 is expected to be 
more potent than voxelotor in patients with SCD. 
Voxelotor was recently approved by the United States (US) Food and Drug Administration 
(FDA), under the tradename OXBRYTA®, for the treatment of SCD in adults and pediatric 
patients 12 years of age and older. 
As stated above, GBT021601 shares the same mechanism of action as voxelotor and thus is 
designed to optimize the potential for clinical benefit derived from stabilizing oxyHb.  
Erythropoiesis increases in response to tissue hypoxia, and this increase is mediated by tissue 
sensing of hypoxia resulting in an increase in erythropoietin production, which in turn causes an 
increase in reticulocyte production. Because increased erythropoiesis is the compensatory 
response for decreased tissue oxygen extraction, treatment effects on these markers were 
assessed in the Phase 3 voxelotor study. No evidence of a compensatory erythropoietic response 
was seen with voxelotor at 900 mg and 1500 mg: erythropoietin did not increase and 
reticulocytes decreased. 
The safety related to pharmacology of GBT021601 is also supported by the safety findings for 
voxelotor, which was found to be well tolerated without demonstrated safety concerns in studies 
on both healthy participants and patients with SCD (Hutchaleelaha, 2019; Vichinsky, 2019). 
3.2. 
Study Drug Background 
GBT021601 increases Hb-O2 affinity and stabilizes Hb in the oxyHb state thereby inhibiting 
polymerization of HbS in RBCs. In preclinical animal studies, GBT021601 partitioned 
preferentially to the RBC compartment with a mean blood/plasma ratio of 48–122:1. 
Thus, similar to voxelotor, GBT021601 is expected to partition preferentially into RBCs, 
where it specifically binds to Hb, and therefore minimizes plasma exposures. 
3.3. 
Summary of Findings to Date 
3.3.1. 
Nonclinical Experience 
Nonclinical studies have been conducted to characterize GBT021601, including primary and 
secondary pharmacodynamics (PD), safety, pharmacology, pharmacokinetics (PK), and 
toxicology. The results from these studies support planned clinical studies with GBT021601 and 
are described in detail in the GBT021601 Investigator's Brochure. 
3.3.2. 
Clinical Experience 
A first-in-human (FIH) single ascending and multiple ascending dose (SAD/MAD) study in 
healthy participants (Study GBT021601-011) is ongoing. Safety and PK data on single doses 
from 50 mg to 2200 mg in healthy participants has demonstrated that GBT021601 is well 
tolerated with a linear dose-dependent increase in percent Hb occupancy. Safety and PK 
assessments for multi-day loading doses and daily maintenance doses of 15, 25, and 50 mg for 
14 days has been completed in three cohorts of the MAD. 
For the current Study GBT021601-012, in Part A, six adults with SCD have received a single 
100 mg dose of GBT021601, and the dose has been well tolerated. After an 8-week washout, 




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GBT021601 and correlated with reversible microscopic changes of increased hematopoiesis in 
the bone marrow (rats and monkeys) and spleen (rats). The no-observed-adverse-effect level 
(NOAEL) was 30 mg/kg/day in cynomolgus monkeys and 50 mg/kg/day in rats following oral 
administration of GBT021601 for 13 weeks (Table 5). 
 
Table 5: 
Thirteen-Week Oral Toxicity Studies in Rats and Cynomolgus Monkeys: 
Whole Blood and Plasma Exposures and Hemoglobin Occupancies Achieved 
at the No-Observed-Adverse-Effect Levels 
Species 
Day 91: Mean Exposures to GBT021601a 
GBT021601 
NOAEL 
(mg/kg/day) 
% Hb 
Occupancyb 
Cmax (µg/mL) 
AUC0-t (µg•h/mL) 
Whole 
Blood 
Plasma 
Whole Blood 
Plasma 
Rat 
832 
33.2 
15,750 
482 
50 
60 
Cynomolgus 
monkey 
902 
23.3 
18,600 
290 
30 
83 
Abbreviations: AUC0-t, area under the concentration-time curve from the start of dose administration to the time at 
which the last quantifiable concentration was observed; Cmax, maximum blood or plasma concentration; 
NOAEL, no-observed-adverse-effect level. 
a Mean of males and females. 
b Estimated by comparing the molar ratio of GBT021601 to hemoglobin in erythrocytes. 
 
In rats, while pharmacologically mediated increased erythropoiesis was observed at this 60% Hb 
occupancy (and in turn, led to the designation of 50 mg/kg/day as the NOAEL), these effects are 
monitorable, reversible, and were not associated with adverse findings. Additionally, in a post-
hoc analysis of the pivotal HOPE study, 8 of 81 participants (9.9%) taking 1500 mg of voxelotor 
daily exceeded 50% Hb occupancy during treatment (GBT data on file). Therefore, for these 
reasons, attaining 60% occupancy in a clinical study does not raise specific safety concerns.  
A dose of 100 mg GBT021601 was estimated using: 
1. A human equivalent dose of 8 mg/kg/day, derived using the 28-day rat NOAEL of 
50 mg/kg/day and a body surface area conversion factor of 6.2 (Table 5); 
2. A human body weight of 60 kg; 
3. A safety factor of 5. 
This estimation method is consistent with that described in the United States Food and Drug 
Administration Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial 
Clinical Trials for Therapeutics in Adult Healthy Volunteers (FDA, 2005). 
For the initial clinical evaluation in participants with SCD, the recommended starting dose of 
100 mg GBT021601 will be administered as a single dose. This 2-fold higher starting dose, 
derived using a safety factor of 5 for participants relative to that (50 mg using a safety factor of 
10) for healthy participants, is based on risk-benefit considerations. Furthermore, key 
GBT021601-related effects in the 28-day oral studies in rats and monkeys were consistent with 
exaggerated pharmacological effects at high Hb occupancies and were generally reversible, 
indicating a low risk to participants at a dose of 100 mg. 


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3.4.2.2. 
Rationale for Multiple Dose Selection 
The starting multiple ascending dose is predicted to achieve a Cmax at steady-state no higher than 
2-fold the Cmax already achieved and well tolerated following a single ascending dose or multiple 
ascending dose in healthy participants (Study GBT021601-011). The starting multiple ascending 
dose is also predicted to achieve ~ 20% to 30% Hb occupancy, a level of Hb 
occupancy/modification which has been well tolerated with voxelotor (Hutchaleelaha, 2019 and 
Vichinsky, 2019). If needed, dose escalation will proceed at up to 2-fold until > 30% 
occupancy/modification (40% Hb occupancy has been well tolerated without tissue hypoxia in 
healthy participants with voxelotor [Hutchaleelaha, 2019]) has been reached and by less than 
1.3-fold, thereafter.  
The doses and frequency for the multiple ascending dose period of this study will be determined 
based on the results from the FIH Study GBT021601-011 in healthy participants and the single-
dose, Day 42 PK and hemoximetry analysis in participants with SCD in this study. At the time of 
the first administration of GBT021601 to participants with SCD, safety data from the first 5 
cohorts (50, 100, 200, 400, and 800 mg) and PK data from the first 3 cohorts from the SAD FIH 
Study GBT021601 will be available. A Safety Monitoring Committee (SMC, Section 7.6) will 
convene to review the safety, tolerability, and PK data when a minimum of 4 participants with 
SCD who have received a single dose of GBT021601 have reached Week 6 (Day 42). If the 
SMC agrees to initiate the intrapatient multiple-dose portion of the study, participants will 
receive a maintenance dose (possibly preceded by a loading dose) at Week 8 (+ 4 weeks).  
The maintenance dose will be administered for the following 9 weeks (Week 8 to Week 16). 
After the first multiple dose period (Week 8 through Week 10), if the % Hb occupancy is higher 
than 30%, the participant may remain on the same maintenance dose or have a dose increase that 
maintains the % Hb occupancy/modification at > 30%.  
If the % Hb occupancy is less than 30%, the participant will dose escalate at Week 13. 
At Week 13, eligible participants will be dose escalated to receive a maintenance dose 
(possibly preceded by a loading dose) based on a predicted target of > 30% Hb occupancy as 
determined by the PK results of GBT021601-011 and Day 42 PK and/or hemoximetry from the 
Single-dose Period.  
At the proposed starting dose of 100 mg in SCD participants and subsequent, intrapatient 
multiple dose escalation, there may be sufficient Hb occupancies (after multiple dosing) to 
provide potentially beneficial pharmacological effects.  
3.4.2.3. 
Rationale for Evaluation of Higher Dose of GBT021601 
As of Protocol Amendment 5, after a total of 8 weeks of treatment, all participants in this study 
demonstrated improvements in hematologic parameters, including reticulocytes and absolute 
reticulocytes, lactate dehydrogenase, and indirect bilirubin (Brown, 2021). Preliminary findings 
indicate a dose-related mean increase from about 15% to 32% in Hb occupancy after dosing with 
50 mg daily and 100 mg daily respectively. Preliminary clinical safety data show that 
GBT021601 has been well tolerated with no significant treatment-related safety findings 
reported. An extended treatment period evaluating a dose escalation to 150 mg once daily for at 
least 6 weeks preceded by a loading dose of 300 mg, given twice daily over 4 days (the loading 
dose is being administered twice daily to minimize the potential for any gastrointestinal effect 








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4.4. 
Number of Participants 
At least 6 participants will participate in both the Single-dose Period and the intrapatient 
Multiple Ascending-dose Period. As of Protocol Amendment 5, all eligible participants will 
proceed with the extended treatment period. 
4.5. 
Duration of Study 
The maximum duration of the study is dependent on the half-life of GBT021601. At a minimum, 
study duration will include a 28-day Screening period, an 8-week Single-dose Period, and a 
6-week Multiple Ascending-dose Period for a total of 18 weeks. This will be followed by an 
EOS Visit 5 half-lives after the final dose of GBT021601. It is anticipated that the EOS will not 
exceed 120 days after the final dose. As of Protocol Amendment 5, the maximum duration of the 
study will be approximately 53 weeks, which includes the approximately 6-week Extended 
Treatment Period, and an 8-week follow up. 
4.6. 
Definition of Study Completion 
The EOB Visit will occur after completion of the Multiple Ascending-dose Periods as presented 
in Table 3 and the EOS Visit will occur after completion of the Extended Treatment Period as 
presented in Table 4. 
Participants who terminate from the study early will have Early Termination (ET) 
Visit procedures performed at the time of discontinuation. Participants with ongoing clinically 
significant clinical or laboratory findings will be followed until the finding is resolved or 
medically stable; reasonable attempts will be made to follow-up with participants. All serious 
and nonserious adverse events (AEs) must be followed until they are resolved or stabilized, 
or until reasonable attempts to determine resolution of the event are exhausted. The Investigator 
should use his/her discretion in ordering additional tests as necessary to monitor the resolution of 
such events. Participation in the study will end once all study assessments and visits have been 
completed. 
4.7. 
End of Study 
The EOS is defined as the date when the last participant has completed all study procedures up to 
and including EOS or ET visits, as specified in Table 4.  


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5. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS 
5.1. 
Participant Inclusion Criteria 
Participants must meet all inclusion criteria to be eligible for study participation. 
1. Male or female with SCD. 
2. Documentation of SCD genotype homozygous for sickle cell allele (HbSS) or double 
heterozygote for HbS and β-0 thalassemia (HbSB). 
3. Age 18 to ≤ 60 years, inclusive. 
4. Hb ≥ 5.5 and ≤ 10.5 g/dL during Screening and considered stable and close to Baseline 
by the Investigator. 
5. For participants taking HU, the dose in mg/kg must be stable for at least 90 days prior to 
signing the informed consent form (ICF) and with no anticipated need for dose 
adjustments during the study in the opinion of the Investigator. 
6. Female participants of child-bearing potential, must agree to use highly effective methods 
of contraception or practice abstinence from study start to 165 days after the last dose of 
study drug. Males who are not surgically sterile with partners of childbearing potential 
must agree to use a highly effective method of birth control during the study and for 
165 days after the last dose of study drug. A highly effective method of contraception is 
defined as one that results in a low documented failure rate when used consistently and 
correctly such as: condom plus use of an intrauterine device; intrauterine system or 
hormonal method of contraception (oral, injected, implanted, or transdermal) for their 
female partner; or sexual abstinence. In addition, males who are not surgically sterile with 
a partner who is pregnant must agree to condom use or maintain sexual abstinence during 
the study and for 165 days after the last dose of study drug.  
7. Males must agree to not donate sperm from study start through 165 days after the final dose. 
8. Participant has provided documented informed consent. 
5.2. 
Participant Exclusion Criteria 
Participants meeting any of the following exclusion criteria will not be eligible for study 
enrollment: 
1. More than 10 vaso-occlusive crises within 12 months of Screening that required a 
telemedicine, hospital, emergency room, or clinic visit. 
2. Female participant who is breastfeeding or pregnant. 
3. Receiving regularly scheduled RBC transfusion therapy (also termed chronic, 
prophylactic, or preventive transfusion) or have received an RBC transfusion for any 
reason within 60 days of signing the ICF or at any time during the Screening period. 
4. Hospitalized for sickle cell crisis or other vaso-occlusive event within 14 days of signing 
the ICF or within 28 days prior to the start of study treatment (ie, participants with a 
vaso-occlusive event must wait at least 14 days before signing an ICF and Screening 
period must be at least 14 days before the start of study treatment). 


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5. Screening laboratory test of alanine aminotransferase (ALT) > 4 × upper limit of normal 
(ULN). 
6. Acute illness or clinically significant bacterial, fungal, parasitic, or viral infection which 
requires therapy, including acute bacterial infection requiring antibiotics within 14 days 
prior to the start of study drug administration. 
7. Participants with positive Screening tests for hepatitis (A, B, or C) or human 
immunodeficiency virus (HIV) or who are known to have active hepatitis infection or to 
be HIV positive or hepatitis C antibody positive. 
8. Participants with symptomatic coronavirus disease 2019 (COVID-19) infection, 
temporary exclusion. 
9. Estimated glomerular filtration rate (eGFR) < 50 mL/min/1.73 m2 at the Screening Visit, 
calculated by the central laboratory, or is on chronic dialysis. 
10. 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). 
11. History of unstable or deteriorating cardiac or pulmonary disease within 6 months prior to 
consent including but not limited to the following:  
a. 
Unstable angina pectoris or myocardial infarction or elective coronary intervention 
b. Congestive heart failure requiring hospitalization 
c. 
Uncontrolled clinically significant arrhythmias, high grade atrioventricular block 
(ie, Mobitz II or 3rd degree), pacemaker, or implantable cardioverter-defibrillator. 
d. Pulmonary hypertension 
12. Abnormal and clinically significant 12-lead ECG, including QT interval corrected for 
heart rate according to Fridericia’s formula (QTcF) > 450 ms, QRS interval ≥ 120 ms, 
PR interval > 220 ms, based on the average of triplicated ECG, assessed at Screening and 
the day prior to start of study treatment. If any of these test results are out of range the test 
can be repeated once (in triplicate). 
13. Any condition affecting drug absorption, such as major surgery involving the stomach or 
small intestine (prior cholecystectomy is acceptable). 
14. Has received an investigational drug (including vaccines, except COVID-19 vaccine) 
within 5 times the elimination half-life (if known) or within 30 days (if the elimination 
half-life is unknown) prior to study drug administration or is concurrently enrolled in any 
research judged not to be scientifically or medically compatible with this study.  
15. Difficulty with venous access or unsuitable or unwilling to undergo intravenous catheter 
insertion. 
16. Medical, psychological, or behavioral conditions, which, in the opinion of the 
Investigator, may preclude safe participation, confound study interpretation, interfere 
with compliance, or preclude informed consent. 


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17. Received erythropoietin or other hematopoietic growth factor treatment within 28 days of 
signing ICF or is anticipated to require such agents during the study. 
18. Ongoing or recent (within 2 years) substance abuse or positive alcohol/drugs of abuse 
results at Screening or the day prior to the start of GBT021601 treatment. 
19. Known allergy to GBT021601 or other Hb polymerization inhibitors. 
20. Current or recent use of voxelotor, crizanlizumab or L-glutamine. Recent use is defined 
as within the past 3 months prior to the start of GBT021601 treatment. 
21. Ongoing or recent use of strong inducers of CYP (cytochrome P450) 3A4/CYP3A5. 
Recent is defined as within 5 half-lives or 30 days, whichever is longer prior to the start 
of GBT021601 treatment. 
22. Ongoing or recent use of strong inhibitors of CYP3A4/CYP3A5. Recent is defined as 
within 5 half-lives prior to the start of GBT021601 treatment. 
23. Ongoing or recent use of the P-glycoprotein substrates digoxin and dabigatran. Recent is 
defined as within 5 half-lives prior to the start of GBT021601 treatment. 
24. Use of a prohibited prescription or nonprescription drugs and dietary supplements 
(including herbal and alternative medications), as specified in Section 6.5.2. 
25. Consumption of grapefruit and/or grapefruit juice within 14 days prior to Day -1 and is 
unwilling to abstain from consumption of grapefruit and/or grapefruit juice until the 
EOS/ET. 
26. Any other condition or prior therapy that, in the Investigator’s opinion, would confound 
or interfere with the evaluation of or PK, safety, tolerability, and PD of the study drug, 
interfere with study compliance, or preclude informed consent. 
27. History of severe allergic reaction (including anaphylaxis) to any substance, or previous 
status asthmaticus. 
5.2.1. 
Additional Exclusion Criteria (Part C): 
28. More than 10 VOCs within 10 months of Screening. 
29. For Part C of the study recent use of voxelotor is defined as within 10 days prior to the 
start of GBT021601 treatment. 
30. Ongoing or recent use of strong or moderate inducers of CYP3A4/CYP3A5. Recent is 
defined as withing 5 elimination half-lives or 14 days, whichever is longer prior to the 
start of GBT021601 treatment. 
31. Ongoing or recent use of strong or moderate inhibitors of CYP3A4/CYP3A5. Recent is 
defined as within 5 elimination half-lives prior to the start of GBT021601 treatment. 
32. Consumption of Seville oranges within 14 days prior to the start of GBT021601 
treatment and is unwilling to abstain from consumption of Seville oranges until the 
EOS/ET Visit. 


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33. History of overt stroke including hemorrhagic stroke or transient ischemic attack (TIA) or 
spinal cord injury, magnetic resonance angiography (MRA)-defined vasculopathy, or 
magnetic resonance imaging (MRI)/transcranial doppler (TCD)-documented silent 
cerebral infarcts within 2 years of screening. 
34. Ongoing or recent (within 2 years) substance abuse (alcohol). 
35. Has received COVID-19 vaccine (first dose, second dose, or booster dose), authorized by 
regional regulatory authority, within 7 days prior to start of GBT021601 treatment. 
36. Has received an exchange transfusion for any reason within 90 days prior to the start of 
GBT021601 treatment. 
5.3. 
Participant Re-Screening 
Participants who screen fail may be rescreened as long as the participant was not a screen fail 
due to noncompliance with the protocol (ie, positive urine drugs of abuse screen, etc). If the 
participant is re-screened, the participant must again consent to participate in the study and a new 
Screening number must be used. All Screening assessments will be repeated.  
5.4. 
Participant Withdrawal 
Participants are free to discontinue the study at any time, for any reason, and without prejudice to 
further treatment. The Investigator may remove a participant if, in the Investigator’s judgment, 
continued participation would pose unacceptable risk to the participant or to the integrity of the 
study data. All procedures for the ET Visit must be completed. Reasons for removal or 
withdrawal may include: 
 Withdrawal of consent 
 Discretion of the Investigator/Sponsor 
 Participant noncompliance 
 Safety concern by the Investigator or the Sponsor 
Once dosed, participants who discontinue the study due to an AE will not be replaced. 
Participants who discontinue the study due to reasons other than an AE or who have 
non-evaluable PK samples may be replaced at the discretion of the Sponsor. 
In the event of a participant’s withdrawal, the Investigator will promptly notify the Medical 
Monitor and Study Director and will make every effort to complete the Early Termination (ET) 
assessments. All withdrawn participants with ongoing clinically significant AEs/serious adverse 
events (SAEs) or laboratory findings will be followed until the finding is resolved or medically 
stable; reasonable attempts will be made to follow-up with participants. 
5.5. 
Early Termination of Study 
The Sponsor has the right to terminate this study at any time. Reasons for terminating the study 
may include, but are not limited to, (1) the incidence or severity of AEs in this or other studies 
indicating a potential health hazard to participants, and (2) in the Sponsor’s judgment, there are 
no further benefits to be achieved from the study.  


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If the study is terminated early, the Sponsor shall inform all Investigators/institutions, regulatory 
authorities, and the Institutional Review Board (IRB). 
5.5.1. 
Stopping Rules 
All participants will be closely monitored for any AEs by the site Investigator and the Sponsor’s 
Medical Monitor. The SMC will meet to review the Day 42 PK data as well as safety and 
tolerability data prior to the first and second dose escalations in the multiple ascending dose 
period of the study. Additionally, the SMC will meet on an ad hoc basis under any condition(s) 
where decisions about ongoing participant dosing in the study is in question and participant 
safety may be at risk. Criteria that may warrant an ad hoc SMC meeting include, but are not 
limited to the following:  
1. A participant experiences any AE Grade ≥ 2 or SAE. 
2. A participant experiences worsening of an ongoing AE by ≥ 1 grade. 
3. A participant experiences any other finding (symptoms, physical examination, 
laboratory) whose severity may preclude dosing new participants in the study. 
AEs will be graded based on National Cancer Institute’s Common Toxicity Criteria Scale 
(NCI CTCAE v5). The individual participant’s tolerability to the study drug will be determined 
based on the criteria provided below. Individual Dose Stopping Rules 
Dosing for any individual participant will be stopped if the participant experiences a SAE or a 
clinically significant nonserious AE, which in the opinion of the Principal Investigator or 
Sponsor’s Medical Monitor, warrants discontinuation of the study for that participant’s well-being. 
5.6. 
Safety Monitoring Committee 
The sites’ Principal Investigators and the Sponsor’s Medical Monitor will closely monitor the 
safety of the study participants throughout the duration of study. The SMC will review the 
totality of safety, tolerability, and available PK and PD data to monitor safety. 
The SMC will be composed of the Principal Investigators from each site, or designee, and 
Sponsor representatives, including the Medical Monitor, Clinical Pharmacologist, Biostatistician, 
and Product Safety Officer and/or Product Safety Medical Scientist. The SMC will have overall 
responsibility for any safety and tolerability decisions and for proceeding with dose escalation. 
Details of the scope including decision, responsibilities, action taken, and frequency of the SMC 
will be provided in the SMC charter. 
In the Multiple Ascending-dose Period of the study, the SMC will review safety, tolerability, PK, 
and PD data through Day 42 after the single dose from at least 4 participants. The Sponsor will 
inform the SMC in writing regarding the GBT021601 half-life, and dosing interval of 
steady-state multiple dosing for the participants of this study.  
For the Extended treatment period (Part C), the SMC will meet on an ad hoc basis under any 
condition(s) where decisions about ongoing participant dosing in the study is in question and 
participant safety may be at risk. 
This is an open label study, so the data reviewed to make dose escalation decisions will not be 
blinded.  


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5.7. 
Dose Escalation Criteria 
The % Hb occupancy by GBT021601 will be calculated from the PK as the ratio of GBT021601 
concentration to the Hb (estimated at 5mM) in RBCs. The Hb% modification will be based on 
hemoximetry data. The Hb% occupancy/modification will be utilized as a PD marker because it 
is a measure of target engagement that has been employed in prior clinical studies of hemoglobin 
modifying agents.  
Dose escalation will be pharmacologically guided (based on PK and PD target levels, Table 6). 
Dose escalation will proceed after review of safety, tolerability, PK, and PD data through 
Day 42. Dose escalation will stop according to the stopping rules (Section 5.5.1). Dose escalation 
will proceed (no more than 2-fold increments) beginning with the Dose 1 with a predicted target 
of ~20% to 30% Hb occupancy/modification and Dose 2 with a predicted target of > 30% Hb 
occupancy/modification.  
Concerns over potential acute mechanism-related toxicities (tissue hypoxia) are related to the 
peak achieved % Hb occupancy and therefore to the maximum plasma concentration (Cmax). 
For this reason, prior to initiating multiple doses, safety, tolerability, PK, and PD data will be 
reviewed by the SMC. Prior to dose escalation, dose levels may be revised if indicated, based on 
PK/PD data.  
Progression to the next higher dose will only occur if the previous dose level was deemed by the 
SMC to be safe and well tolerated. 
When it is not appropriate to escalate the dose, then the same dose or a titrated dose may also be 
investigated depending upon the results of the safety data from the previous dose levels. 
 
Table 6: 
Target % Hb Occupancy/Modification for Multiple Ascending-dose Period, 
Intrapatient Dose Escalation  
Dose Escalation 
Level 
Predicted % Hb 
Occupancy/Modification 
Anticipated Loading 
Dose (mg)a 
Anticipated Maintenance  
Dose (mg)a 
Dose 1 
~20% to 30% 
TBD 
TBD every TBD 
Dose 2 
> 30% 
TBD 
TBD every TBD 
a The GBT021601 dose levels and frequency to be evaluated will be determined based on PK/PD evaluation of 
single doses in healthy volunteers and Day 42 PK in adults with SCD. 
 
Based on the findings from Dose Levels 1 and 2, there were no significant safety concerns 
related to GBT021601 and based on PPK modeling, the planned doses are expected to result in 
Hb occupancy of approximately 54%.   
 
Table 7: 
Model-Predicted Dose Planned for Extended Treatment Period 
Loading Dose 
Maintenance Dose 
Mean Targeted % Hb 
Occupancy 
300 mg BID x 4 days 
 
150 mg QD 
~54% 
 


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6. 
TREATMENT OF PARTICIPANTS 
6.1. 
Description of Study Drug 
Study drug details are presented in Table 8.  
 
Table 8: 
Identity of Study Drugs 
Study Drug 
Dosage Form 
Strength 
GBT021601 
Tablet 
100 mg 
GBT021601 
Capsule 
5 mg, 25 mg 
 
As of Protocol Amendment 5, study drug will be provided as a tablet or capsule as per Table 9. 
 
Table 9: 
Study Drug for Extended Treatment Period 
Study Drug 
Dosage Form 
Dose Strength 
GBT021601 
Tablet 
100 mg 
GBT021601 
Capsule 
25 mg 
 
GBT021601 tablets and capsules will be provided by the Sponsor. 
6.2. 
Treatments Administered 
Study drug will be administered orally with approximately 240 mL non-carbonated room 
temperature water. 
6.3. 
Method of Assigning Participants to Treatment Groups 
This is an open-label, single-arm, intrapatient, single dose and multiple dose escalation study. 
Participants will be assigned a study identification number during Screening and a separate 
number assigned at enrollment. 
6.4. 
Measurements of Treatment Compliance 
The first dose of the study drug will be administered by delegated and trained staff at the clinical 
research unit (CRU). Details regarding dosing, including the dose administered and the date and 
time of dosing, will be recorded in a dosing diary during the maintenance doses. Additionally, 
a hand and mouth check will be performed to verify that the administered dose was swallowed. 
For the Multiple Ascending-dose Period of this trial, at Week 8 and Week 13 Visits, the loading 
dose (as applicable) will be administered by delegated and trained staff at the CRU. Details 
regarding dosing, including the dose administered and the date and time of dosing, will be 
recorded. Maintenance doses will be administered either by the CRU staff during visits or by the 
participant based on the to be determined frequency of dosing. Recording of dosing to monitor 
compliance will also be based on the dosing frequency. 


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6.5. 
Concomitant Medications, Procedures, Other Restrictions and 
Requirements 
6.5.1. 
Concomitant Medications and Procedures 
Study participants will be allowed to take other medications as needed with the exception of 
those described listed in Section 6.5.2. All concomitant medications will be documented. 
In the interests of participant safety and acceptable standards of medical care the Investigator 
will be permitted to prescribe treatment(s) at his/her discretion. All treatments must be recorded 
in the participants’ electronic case report form (eCRF) (medication, dose, treatment duration and 
indication). 
6.5.2. 
Other Restrictions 
Participants will be instructed to adhere to the following restrictions: 
 Participants are not permitted to use drugs of abuse from Screening through EOS/ET 
Visit. 
 Participants are not permitted to use herbal preparations or dietary supplements, 
or any drugs that induce or inhibit study drug-specific CYP(s) within 14 days or 
5 half-lives, whichever is longer, prior to Day -1. 
 Participants are not permitted to use voxelotor, crizanlizumab, or L-glutamine while 
participating in this clinical study. 
 Participants are not permitted to consume grapefruit and/or grapefruit juice from 
14 days prior to Day -1 through the EOS/ET Visit. 
 During the Single-dose Period, participants are not permitted to consume any food 
and drink from outside of the CRU while residing at the CRU. 
 Participants are not permitted to participate in any other interventional clinical study 
or donate blood or plasma while participating in this clinical study. 
6.5.3. 
Fertility and Contraceptive Requirements 
6.5.3.1. 
Female Participants of Childbearing Potential 
Refer to Inclusion Criterion 6. 
Female participants who are of child-bearing potential are required to use highly effective 
methods of contraception. 
Highly effective contraception methods are defined as the following: 
a. Estrogen and progestogen containing hormonal contraception associated with 
inhibition of ovulation OR progestogen only hormonal contraception associated with 
inhibition of ovulation by oral, implantable, or injectable route of administration 
b. An intrauterine device (IUD) 
c. An intrauterine hormone-releasing system (IUS) 


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d. Females with bilateral tubal occlusion 
e. Surgically sterile male partner (eg, vasectomy) 
f. True sexual abstinence, defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments. Periodic abstinence 
(eg, calendar, ovulation, symptom-thermal, post-ovulation methods), and withdrawal 
are not acceptable methods of contraception. 
6.5.3.2. 
Instructions for Male Participants Capable of Fathering a Child 
There is no information about effects that GBT021601 could have on male sperm and on the 
development of the fetus in humans. Therefore, it is important that the female partners of male 
participants do not become pregnant during the study and for a total period of 165 days after the 
male participant has taken the last dose of GBT021601. 
As a precaution, all male participants who are sexually active and not surgically sterile should 
avoid fathering a child by either true abstinence or the use of barrier methods of contraception 
plus highly effective contraception for their female partner if of childbearing potential.  
6.5.3.3. 
Acceptable Forms of Contraception for Male Participants with Female Partners 
Capable of Reproduction 
Refer to Inclusion Criterion 6. 
Male participants who are not surgically sterile with partners of childbearing potential must 
agree to use a highly effective method of birth control during the study and for 165 days after the 
last dose of study drug. A highly effective method of contraception is defined as one that results 
in a low documented failure rate when used consistently and correctly such as: condom plus use 
of an intrauterine device; intrauterine system or hormonal method of contraception 
(oral, injected, implanted, or transdermal) for their female partner; or sexual abstinence. 
Male participants who are not surgically sterile with a partner who is pregnant must agree to 
condom use or maintain sexual abstinence during the study and for 165 days after the last dose of 
study drug. 


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7. 
STUDY DRUG MATERIALS AND MANAGEMENT 
7.1. 
Study Drug 
GBT021601 will be provided as a tablet formulation in the strength of 100 mg and a capsule 
formulation in strengths of 5 mg and 25 mg. All excipients used are compendial grade and are 
listed in the FDA’s Inactive Ingredients Database. As of Protocol Amendment 5, GBT021601 
will be provided as a 100 mg tablet or a 25 mg capsule. 
7.2. 
Study Drug Packaging and Labeling 
GBT021601 will be provided in high density polyethylene (HDPE) bottles of 30 tablets and in 
separate HDPE bottles of 30 capsules with child resistant caps with induction seal and labeled 
according to local regulations.  
7.3. 
Study Drug Storage 
Study drug will be stored at controlled room temperature between 15°C to 25°C in the storage 
area of the investigational site pharmacy, which is a secure, temperature controlled, locked 
environment with restricted access. 
No special considerations for safe handling of GBT021601 are required. 
7.4. 
Blinding of Treatment Assignment 
Not applicable since this is an open-label study. 
7.5. 
Administration 
GBT021601 will be administered orally. For the single-dose period, participants will fast at least 
10 hours before and for at least 4 hours after study drug administration. Water will be allowed as 
desired except for 1 hour before and 1 hour after study drug administration.  
For the multiple ascending-dose period of the study, GBT021601 can be taken with or without 
food.  
Each dose will be administered orally with approximately 240 mL of water (additional water to 
complete dosing is allowed). Participants will be instructed to swallow the tablets or capsules 
within 5 minutes. If the participant vomits, the dose should not be repeated. 
7.6. 
Study Drug Accountability and Disposal 
The Investigator must ensure that all study drug supplies are kept in a secure locked area with 
access limited to those authorized by the Investigator. The Investigator must maintain accurate 
records of the receipt of all study drug shipped by the Sponsor or their representative, including 
but not limited to the date received, lot number, amount received, and the disposition of all study 
drug. Current dispensing records will also be maintained including the date and amount of study 
drug dispensed and the participant receiving the study drug. All remaining study drug not 
required by regulations to be held by the CRU must be reconciled prior to destruction. Drug may 
be returned to the Sponsor’s representative immediately after the study is completed or destroyed 
on-site with Sponsor approval. 


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8. 
PHARMACOKINETIC AND PHARMACODYNAMIC 
ASSESSMENTS 
8.1. 
Blood Sample Collection 
The PK/PD samples for GBT021601 will be collected at time points specified in the PK/PD 
sampling schedules (Table 1, Table 2, Table 3, and Table 4). Sample collection, processing, and 
shipping details will be outlined in a separate study reference manual. 
For procedures scheduled to be performed at the same time, priority is to be given to collection 
of the PK samples at the designated time. ECGs, followed by vital signs, are to be performed 
before PK sampling unless PK samples will be delayed as a result.  
8.1.1. 
Single-dose Period 
During the Single-dose Period, plasma and whole blood PK samples will be collected at the 
following times: 
Pre-dose (within 60 minutes of dosing) and postdose at 0.25, 0.5, 1, 2, 4, 6, 8, 12 hours; 24 hours 
(Day 2), 36 hours, 48 hours (Day 3), and 72 hours (Day 4); Days 7, 14, 21, 28, and 42. 
The windows for sample collection are provided in Table 10. 
 
Table 10: 
Windows for PK Sample Collection – Single-dose Period 
Sample Collection Time 
Allowed Deviation 
0.0 – 1.0 hour 
± 2 minutes 
> 1.0 – 24.0 hours 
± 5 minutes 
> 24.0 – 72.0 hours 
± 10 minutes 
> 72.0 – 144.0 hours 
± 15 minutes 
> 144.0 hours 
± 24 hours 
 
Blood samples for hemoximetry and RBC deformability, dense cells will be collected at the 
same time as the PK samples at pre-dose and 12 hours postdose on Day 1. In addition, 
hemoximetry samples will be collected on Days 2, 4, 7, 21, and 42. 
8.1.2. 
Multiple Ascending-dose Period 
Plasma and whole blood pre-dose and postdose PK samples will be collected in the Multiple 
Ascending-dose period as listed in Table 11. Whole blood samples for hemoximetry and RBC 
deformability, dense cells will be collected at the same time as the PK samples. 
 


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Table 11: 
PK and PD Sample Collection Times – Multiple Ascending-dose Period 
Week 
Pre-dosea 
Postdose 
8 
1 PK/PD sample Pre-dose 
1 PK sample between 0.25 hour to 1 hour 
1 PK/PD sample between 2 to 4 hours 
9 
1 PK/PD sample Pre-dose 
1 PK sample between 0.25 hour to 1 hour 
1 PK/PD sample between 2 to 4 hours 
10 
1 PK/PD sample Pre-dose 
1 PK sample between 0.25 hour to 1 hour 
1 PK/PD sample between 2 to 4 hours 
11 
1 PK sample Pre-dose 
1 PK sample between 0.25 hour to 1 hour,  
1 PK/ sample between 2 to 4 hours 
12 
1 PK sample Pre-dose 
1 PK sample between 0.25 hour to 1 hour 
1 PK sample between 2 to 4 hours 
13 
1 PK/PD sample Pre-dose 
1 PK sample between 0.25 hour to 1 hour 
1 PK/PD sample between 2 to 4 hours 
14 
1 PK sample Pre-dose 
1 PK sample between 0.25 hour to 1 hour 
1 PK sample between 2 to 4 hours 
15 
1 PK sample Pre-dose 
1 PK sample between 0.25 hour to 1 hour 
1 PK sample between 2 to 4 hours 
16 EOT 
1 PK/PD sample Pre-dose 
1 PK sample between 0.25 hour to 1 hour 
1 PK/PD sample between 2 to 4 hours 
EOS/ET  
Anytime during visit 
 
Abbreviations: PD, pharmacodynamics; PK, pharmacokinetics. 
a The pre-dose blood sample for PK and PD assessments should be collected within 30 minutes prior to dosing. 
 
Table 12: 
PK and PD Sample Collection Times –Extended Treatment Period 
 
Extended Treatment Period 
Pre-dosea 
Postdose 
Week 
Day  
1 
1 
1 PK/PD sample  
1 PK sample between 0.25 hour to 1 hour 
1 PK/PD sample between 2 to 4 hours 
2 
15 
1 PK/PD sample  
1 PK sample between 0.25 hour to 1 hour 
1 PK/PD sample between 2 to 4 hours 
4 
29 
1 PK sample  
1 PK sample between 0.25 hour to 1 hour 
1 PK sample between 2 to 4 hours 
6 
43 
1 PK sample  
1 PK sample between 0.25 hour to 1 hour 
1 PK sample between 2 to 4 hours 
10 
71 
1 PK sample  
 
14  
98 
1 PK sample  
 
Final Visit 
Anytime during visit 
 
Abbreviations: PD, pharmacodynamics; PK, pharmacokinetics.  
a The pre-dose blood sample for PK and PD assessments should be collected within 30 minutes prior to dosing. 
 
CCI




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CCI


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9. 
ASSESSMENT OF SAFETY 
9.1. 
Safety Parameters 
9.1.1. 
Demographic/Medical History 
The Investigator or designee will collect a complete medical and surgical history at Screening 
and again at CRU admission to determine if any changes have occurred since Screening. 
9.1.2. 
Vital Signs 
Vital signs assessments will include respiratory rate (breaths per minute), systolic and diastolic 
BP (mmHg), and heart rate (HR) (beats per minute [bpm]) and body temperature, which will be 
measured after a participant has rested for at least 5 minutes in the supine position as per Table 1, 
Table 2, Table 3, and Table 4.   
Any clinically significant abnormal vital sign assessment requires at least 1 repeat measurement. 
Vital signs abnormalities that are (1) considered clinically significant initially and on 
confirmation, (2) require a participant to be discontinued from the study, (3) require a participant 
to receive treatment, or (4) require a change or discontinuation from the study drug 
(if applicable) will be recorded as AEs. 
9.1.3. 
Weight and Height 
Height will be completed at Screening only and weight as per Table 1,Table 3, and Table 4. 
9.1.4. 
Physical Examination 
A full physical examination will be conducted at Screening. All subsequent physical 
examinations should be signs and symptoms driven. Full physical examination will include 
examination of the following: general appearance, head, ears, eyes, nose, throat, neck, skin, 
cardiovascular system, respiratory system, gastrointestinal system, musculoskeletal system, 
lymph nodes, and nervous system (Table 1,Table 3, and Table 4). 
An abnormal physical examination finding during the on-study period (ie, following dose 
administration) that is considered clinically significant and (1) requires the participant to be 
discontinued from the study, or (2) requires the participant to receive treatment will be recorded 
as an AE. 
9.1.5. 
Electrocardiogram 
Electrocardiograms (ECG) (12-lead) will be collected in triplicate within 5 minutes as per 
Table 1, Table 2, Table 3, and Table 4. 
ECGs will be recorded after a participant has rested at least 5 minutes in the supine position. 
The following ECG parameters will be recorded: HR, PR, QRS, QT, and QTcF intervals.  
ECG assessment will include interpretation of the tracings (eg, rhythm, presence of arrhythmia 
or conduction defects, any evidence of myocardial ischemia/infarction, or ST segment, T-wave, 
and U-wave abnormalities). The Investigator or designee is responsible for reviewing and over-
reading the ECG interpretation, for assessing whether the ECG machine interpretation findings 


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are accurate, appropriate, normal, or abnormal, and for providing corrected interpretations as 
appropriate. In addition, any abnormal ECGs will be assessed for clinical significance. 
Additional ECGs may be obtained if clinically indicated and must be obtained if abnormal and 
clinically significant or thought to be an error (eg, lead placement error, movement artifact, etc.). 
Any additional relevant data obtained by the Investigator during the course of this study will be 
supplied to the Sponsor. 
For any ECG that the Investigator considers clinically significant, the Investigator will: 
 Repeat the ECG. 
 Follow-up ECG(s) will be obtained if any significant abnormalities are detected after 
dose administration to document resolution and as clinically indicated. 
 Record as an AE any ECG that is 1) confirmed by the Investigator as clinically 
significant, 2) requires a participant to be discontinued from the study, or 3) requires a 
participant to receive treatment. 
9.1.6. 
Laboratory Assessments 
9.1.6.1. 
Standard Clinical Laboratory Assessments 
Clinical laboratories described in Table 13 will be collected as outlined in Table 1 and Table 3, 
and Table 4. A certified laboratory will be utilized to process and provide results for the clinical 
laboratory tests. The Baseline laboratory test results for clinical assessment for a particular test 
will be defined as the last measurement prior to the first dose of study drug. 
During Screening, if a participant has an out-of-range value for a clinical laboratory parameter 
that the Investigator believes is not clinically significant or that the Investigator does not believe 
is correct (eg, laboratory or specimen processing error), but the Investigator wants to confirm 
with a repeat laboratory test, a single repeat is allowed to confirm the initial result. 
All out of-range values will be assessed by the Investigator as clinically significant or not 
clinically significant. For any laboratory test value outside the reference range that the 
Investigator considers clinically significant during the on-study period (ie, following dose 
administration), the Investigator will repeat the test to verify the out-of-range value and clinical 
significance. 
Additional safety laboratory tests may be conducted as needed by the Investigator to evaluate 
participant safety. 
9.1.6.2. 
Other Laboratory Assessments 
Assessments of p50 and p20 will be conducted by hemoximetry as indicated in Table 1, Table 3, 
and Table 4 . Assessments of RBC deformability and dense cells will be conducted as indicated 
in Table 1, Table 3, and Table 4.  
Assessments of serum erythropoietin (EPO) will be conducted as indicated in Table 1 and 
Table 3, and Table 4. 






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10. 
ASSESSMENT OF SAFETY — ADVERSE EVENTS 
10.1. 
Adverse and Serious Adverse Events 
10.1.1. 
Definition of Adverse Events 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered related to the study drug. An AE can therefore be any 
unfavorable and unintended sign, symptom, or disease temporally associated with the use of a 
study drug. An AE may also constitute complications occurring as a result of protocol-mandated 
interventions (eg, invasive procedures such as biopsies), including the period prior to receiving 
the first dose of the study drug (eg, medication washout). In addition to new events, any increase 
in the severity or frequency of a pre-existing condition occurring after the participant signs the 
ICF is considered to be an AE. This includes any side effect, injury, toxicity, or sensitivity 
reaction. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the drug 
caused the AE. For the purposes of expedited safety reporting, “reasonable possibility” means 
there is evidence to suggest a causal relationship between the drug and the AE. Suspected 
adverse reaction implies a lesser degree of certainty about causality than adverse reaction, 
which means any AE caused by a drug. 
A life-threatening AE or life-threatening suspected adverse reaction is an AE or suspected 
adverse reaction that, in the view of either the Investigator or Sponsor, places the study 
participant at immediate risk of death. It does not include an AE or suspected adverse reaction 
that, had it occurred in a more severe form, might have caused death. 
An AE or suspected adverse reaction is considered to be “unexpected” if it is not listed in the 
Reference Safety Information section of the current IB or is not listed at the specificity or 
severity that has been observed. 
10.1.2. 
Serious Adverse Event 
A SAE or serious suspected adverse reaction is an AE or suspected adverse reaction that, at any 
dose, in the view of either the Investigator or Sponsor, results in any of the following outcomes: 
 Death; 
 A life-threatening AE; 
 Inpatient hospitalization or prolongation of existing hospitalization; 
 Persistent or significant incapacity or disability (substantial disruption of the ability to 
conduct normal life functions); 
 A congenital anomaly/birth defect; or 
 Important medical events that may not result in death, be immediately 
life-threatening, or require hospitalization may be considered serious when, based 
upon medical judgment, they may jeopardize the study participant and may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
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Note: Hospitalization planned prior to study enrollment (eg, for elective surgeries) is not 
considered to be an SAE. Hospitalizations that occur for pre-existing conditions that are 
scheduled after study enrollment are considered SAEs. 
10.2. 
Severity 
Whenever possible, the severity of all AEs will be graded using the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0. 
For AEs not adequately addressed in the NCI CTCAE, Version 5.0, the following criteria should 
be used. 
 Grade 1 – Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
 Grade 2 – Moderate: Minimal, local or noninvasive intervention indicated; 
limited age-appropriate instrumental activities of daily living (ADLs). 
 Grade 3 – Severe: Medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADLs. 
 Grade 4 – Life-threatening: Life-threatening consequences; urgent intervention 
indicated. 
 Grade 5 – Fatal: Death. 
To make sure that there is no confusion or misunderstanding between the terms “serious” and 
“severe”, which are not synonymous, the following note of clarification is provided. The term 
“severe” is often used to describe the intensity (severity) of a specific event (ie, mild, moderate, 
or severe); the event itself, however, may be of relatively minor medical significance (eg, severe 
headache). This is not the same as “serious”, which is based on the study participant/event 
outcome or action criteria associated with events that pose a threat to a participant’s life or 
functioning. Seriousness (not severity) serves as a guide for defining regulatory reporting 
obligations. 
10.3. 
Relationship to Study Drug 
The relationship of an AE to the study drug should be determined by the Investigator according 
to the following definitions: 
 Not Related: Evidence exists that the AE has an etiology other than the study drug 
and/or the temporal relationship of the AE/SAE to the study drug administration 
makes the relationship unlikely. If an SAE is not considered to be related to study 
drug, then an alternative explanation should be provided. 
 Related: A temporal relationship exists between the event onset and the 
administration of the study drug and makes a causal relationship possible or probable. 
It cannot be readily explained by the participant’s clinical state or concomitant 
therapies and may appear, with some degree of certainty, to be related based on the 
known therapeutic and pharmacologic actions of the drug. Good clinical judgment 
should be used for determining causal assessment. 


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10.4. 
Unexpected Adverse Reactions 
An AE is “unexpected” if its nature and severity are not consistent with the information about the 
study drug provided in the Reference Safety Information in the IB. 
10.5. 
Recording Adverse Events 
10.5.1. 
General 
All AEs will be recorded from the time the study participant signs the ICF form until the EOS 
Visit or ET Visit, whichever comes first. All AEs must be reported on the AE electronic case 
report form (eCRF) via the electronic data capture system. The Investigator is responsible for 
evaluating all AEs, obtaining supporting documents, and ensuring that documentation of the 
event is complete. Details of each reported AE must include at a minimum severity, relationship 
to study treatment, duration, and outcome. All serious and nonserious AEs must be followed 
until they are resolved or stabilized, or until reasonable attempts to determine resolution of the 
event are exhausted. 
Any participant who experiences an AE may be discontinued from study treatment at any time at 
the discretion of the Investigator. The Sponsor/Medical Monitor(s) must be notified of the study 
participant discontinuation. 
10.5.2. 
Diagnosis Versus Signs and Symptoms 
If known, a diagnosis should be recorded in the eCRF rather than individual signs and symptoms 
(eg, record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be medically 
characterized as a single diagnosis or syndrome at the time of reporting, each individual event 
should be recorded separately in the eCRF. If a diagnosis is subsequently established, it should 
be reported as follow-up information. 
10.5.3. 
Abnormal Laboratory Values 
Clinically significant laboratory abnormalities will be recorded in the AE eCRF 
(eg, abnormalities that have clinical sequelae, more frequent follow-up assessments, or further 
diagnostic investigation). If the clinically significant laboratory abnormality is a sign of a disease 
or syndrome (eg, alkaline phosphatase and bilirubin 5 × ULN associated with cholecystitis), 
only the diagnosis (eg, cholecystitis) should be recorded in the eCRF. 
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the eCRF. If the laboratory abnormality can be 
characterized by a precise clinical term, the clinical term should be recorded. For example, 
a serum potassium level of 7.0 mEq/L should be recorded as “hyperkalemia”. 
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded on the AE eCRF, unless their severity, seriousness, or etiology 
changes. 


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10.6. 
Reporting Adverse Events 
10.6.1. 
Serious Adverse Events 
All SAEs, regardless of causal attribution, must be reported by the Investigator or designee or 
site personnel within 24 hours of awareness by completing the paper SAE report forms and 
submit via fax or email to Sponsor’s Pharmacovigilance or designated CRO. 
The Sponsor or designee may request additional source documentation pertaining to the SAE 
from the investigational site. Follow-up reports must be submitted within 24 hours of awareness, 
and participant identifier information (eg, name, medical record number) must be redacted in the 
hospital discharge summaries, autopsy reports, and/or death certificates. 
Follow-up SAE information must be submitted within 24 hours of awareness as additional 
information becomes available. All SAEs regardless of causal attribution must be followed to 
resolution or stabilization, or until reasonable attempts to determine resolution of the SAE are 
performed. 
Investigators are not obligated to actively seek SAE information from participants that complete 
the study, but investigators are encouraged to notify the Sponsor, or designee, of any SAEs of 
which they become aware occurring at any time after a participant has discontinued or completed 
the study that they judge may be reasonably related to treatment with study drug or study 
participation. 
10.6.2. 
Reporting Suspected Unexpected Serious Adverse Reactions and Urgent Safety 
Issues 
The Sponsor or designee is responsible for reporting suspected unexpected serious adverse 
reactions (SUSARs) to regulatory agencies, competent authorities, IRB, and Investigators as per 
local laws and regulations. Fatal and life-threatening SUSARs will be submitted no later than 
7 calendar days of the Sponsor’s or designee’s first knowledge of the event and follow-up 
information submitted within an additional 8 calendar days, or as otherwise required per local 
laws and regulations. All other SUSARs will be submitted within 15 calendar days of the 
Sponsor’s or designee’s first knowledge of the event. The Investigator is responsible for 
notifying the local IRB of all SAEs that occur at his or her site as required by local regulations or 
IRB policies, if this responsibility resides with the site. 
Investigators are required to report any urgent safety matters to the Sponsor or designee within 
24 hours of awareness. The Sponsor or designee will inform regulatory authorities, IRBs, and 
Investigators, as applicable, of any events (eg, change to the safety profile of GBT021601, major 
safety findings that may place study participants at risk) that may occur during the clinical study 
that do not fall within the definition of a SUSAR but may adversely affect the safety of study 
participants. 
10.7. 
Pregnancy 
If a participant becomes pregnant while on study, the pregnancy must be reported to the Sponsor 
or designee within 24 hours of awareness. The Investigator will discuss the risks and concerns of 
study drug exposure to a developing fetus and counsel the participant and/or pregnant partner 
(or ensure such counseling is provided). 


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Reported pregnancy of a participant while participating in this study will be monitored for the 
full duration of the pregnancy, and/or followed through a definitive outcome (ie, birth or 
spontaneous or elective abortion). Pregnancies in partners of male study participants will 
similarly be monitored for the full duration of the pregnancy and/or followed through a definitive 
outcome (ie, birth or spontaneous or elective abortion). 
An uncomplicated pregnancy will not be considered an AE or SAE. Pregnancy complications 
such as spontaneous abortion/miscarriage and congenital anomalies are considered SAEs and 
must be reported as described in Section 10.6.1. Note that an elective abortion is not considered 
an SAE. Pregnancy and pregnancy outcomes must be reported on a Pregnancy Notification 
Form or Pregnancy Outcome Form, respectively, and sent to the Sponsor or designee within 
24 hours of the Investigator site personnel learning of the pregnancy or pregnancy outcome.  
The child born to a female participant or partner of a male participant exposed to study drug will 
be followed for 3 months after delivery. The outcome of any pregnancy and the presence or 
absence of any congenital abnormality will be recorded in the Pregnancy Outcome Form and 
reported to the Sponsor or designee. Any congenital abnormalities in the offspring will be 
reported as an SAE and must be reported as described in Section 10.6.1. 
Information regarding pregnancy testing (including definition of females of childbearing 
potential) is provided in Section 6.5.3. Highly effective means of contraception are 
listed in Section 6.5.3.3. 
10.8. 
Drug-induced Liver Injury 
Participants will be monitored for signs of drug-induced liver injury (DILI).  
Potential events of DILI will be defined as meeting all the following criteria (as specified in the 
FDA Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation. 
[FDA, 2009]):  
 ALT > 4 × ULN or aspartate aminotransferase > 3 × ULN 
 No other reason can be found to explain the combination of laboratory value 
increases (eg, acute viral hepatitis; alcoholic and autoimmune hepatitis; hepatobiliary 
disorders; nonalcoholic steatohepatitis; cardiovascular causes; concomitant 
treatments) 
Potential events of DILI will be reported as SAEs (Section 10.6.1). All participants with 
potential DILI will be closely followed until abnormalities return to normal or baseline or until 
all attempts to determine resolution of the event are exhausted. 


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11. 
STATISTICS 
Study data will be reported using summary tables, figures, and listings. Study analyses will be 
descriptive in nature and no formal statistical tests are planned. 
11.1. 
Sample Size Calculation 
Due to the exploratory nature of this study, no formal power or sample size calculations were 
used to determine cohort size. A sample size of up to 6 participants with SCD are expected to 
provide adequate characterization of PK and safety. 
11.2. 
Analysis Populations 
Safety Population: All participants who received study drug. 
Pharmacokinetic Full Population: All participants who received study drug and have at least 
1 concentration data point (plasma or whole blood). 
Pharmacokinetic Evaluable Population: All participants who received study drug and have a 
sufficient PK profile to derive at least 1 PK parameter. 
11.3. 
Interim Analysis 
There is no formal planned interim analysis.  
11.4. 
Safety Analysis 
AEs will be coded to system organ class and preferred term using the Medical Dictionary for 
Regulatory Activities (MedDRA) and summarized. Vital signs and laboratory safety assessments 
will be presented with identification of values outside of normal range. Electrocardiogram data 
will be presented, with any clinically relevant abnormal findings or changes highlighted. 
11.5. 
Pharmacokinetic Analysis 
Noncompartmental PK analysis or population PK analysis using nonlinear mixed-effect 
modeling will be performed to characterize GBT021601 PK in plasma, and whole blood 
following single and multiple doses.  
11.6. 
Pharmacodynamic Analysis 
Pharmacodynamic markers and computed PD parameters will be listed. Individual and mean PD 
marker data will be presented graphically.  
  
11.7. 
Pharmacokinetic/Pharmacodynamic Relationships 
The relationships between PK and PD may be explored by PK/PD modeling, if appropriate. 
Results of these analyses will be presented in a separate report. 
CCI


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12. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The Investigator will permit study-related monitoring, audits, IRB review, and regulatory 
inspection, as appropriate, by providing direct access to source data/documents. 
12.1. 
Source Data 
Original documents, data, records (eg, clinic records, laboratory notes, memoranda, participant 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
participant files, and records kept at the pharmacy, laboratories, and medico-technical 
departments involved in the clinical study), and all relevant sections of the participant’s medical 
records and all other data collection made specific to this study constitute source documents. 
Before an investigational site can enter a participant into the study, a representative of Sponsor 
and/or designee will visit the CRU to: 
 Determine the adequacy of the facilities; and 
 Discuss with the Investigator and other personnel their responsibilities with respect to 
protocol adherence, and the responsibilities of the Sponsor or its representatives. 
This will be documented in a Clinical Study Agreement between the Sponsor and the 
Investigator. 
During the study, a monitor from the Sponsor or representative will have regular contact with the 
investigational site, for the following: 
 Provide information and support to the Investigator(s). 
 Confirm that facilities remain acceptable. 
 Confirm that the investigational team is adhering to the protocol that data are being 
accurately recorded in the eCRF, and that study drug accountability checks are being 
performed and dosing diaries reviewed. 
 Perform source data verification. This includes a comparison of the data in the eCRF 
with the participant’s medical records at the hospital or practice, and other records 
relevant to the study. This will require direct access to all original records for each 
participant (eg, clinic charts). 
 Record and report any protocol deviations not previously sent to the Sponsor. 
 Confirm AEs and SAEs have been properly documented on eCRFs and confirm any 
SAEs have been forwarded to the Sponsor or safety designee and those SAEs that met 
criteria for reporting have been forwarded to the IRB. 
The monitor will be available between visits if the Investigator or other staff needs information. 


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12.2. 
Data Collection 
The Investigator will be responsible for maintaining accurate and adequate source documents. 
All relevant observations and data related to the study will be recorded. This will include medical 
and medication history, physical examinations, a review of inclusion and exclusion criteria, 
investigational treatment administration and record of sample collection, clinical assessments, 
AEs, and final evaluation(s).  
Data for each participant will be recorded on the eCRF. An eCRF must be completed for every 
participant enrolled in the study. When data are complete, the Investigator or medically qualified 
sub-Investigator listed on FDA Form 1572 will apply his/her signature on the eCRF indicating 
he/she has reviewed and approves of the data collected on the eCRF. The monitor will review all 
eCRFs and compare data to those contained in clinic notes and participants’ source 
documents/medical records. 


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13. 
QUALITY CONTROL AND QUALITY ASSURANCE 
13.1. 
Monitoring 
Site personnel will be provided with training on how to collect quality data for the study, and a 
Sponsor monitor or designee will be contacting the site periodically to review study conduct and 
data recorded at the site. At the Sponsor’s discretion, on-site monitoring visits may be conducted 
prestudy, during the study, and following study completion. These visits are to provide the 
Sponsor with the opportunity to evaluate study progress; verify the accuracy and completeness of 
source data and eCRFs; and ensure that all protocol and Good Clinical Practice (GCP) 
requirements, applicable country-specific regulations, and Investigator obligations are being 
fulfilled. The Sponsor may terminate study participation if study-site personnel do not follow the 
protocol or GCP. Additionally, individual participants may be excluded if a medical record 
review indicates protocol deviations or if other factors appear to jeopardize the validity of the 
study. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected 
during the monitoring visits are resolved. 
13.2. 
Quality Control and Quality Assurance 
The Sponsor may conduct quality assurance audits of this study. If such an audit occurs, the 
Investigator agrees to allow the auditor direct access to all relevant documents (eg, all participant 
records, medical records, and eCRFs) and access to all corresponding portions of the office, 
clinic, laboratory, or pharmacy that may have been involved with the study. The Investigator will 
allocate his or her time and that of the study-site personnel to the auditor to discuss findings and 
any relevant issues. 
In addition, regulatory agencies may conduct a regulatory inspection of this study. If such an 
inspection occurs, the Investigator agrees to notify the Sponsor upon notification by the 
regulatory agency. The Investigator agrees to allow the inspector direct access to all relevant 
documents and to allocate his or her time and that of the study-site personnel to the inspector to 
discuss findings and any relevant issues. The Investigator will allow Sponsor personnel to be 
present as an observer during a regulatory inspection, if requested. 
13.3. 
Laboratory Accreditation 
The laboratory facility used for analysis of clinical laboratory samples must provide evidence of 
adequate licensure or accreditation. Copies of laboratory certification, licensure, and reference 
ranges (as appropriate) will be supplied to the Sponsor prior to study initiation. The Sponsor or 
designee should be notified of any changes in reference range values or certification/license 
renewal during the study. 


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14. 
ETHICS 
14.1. 
Ethical Conduct of the Study 
The Investigator will ensure that this study is conducted in full conformity with the current 
revision of the 1964 Declaration of Helsinki. 
The Investigator is generally not to deviate from the protocol. In medical emergencies, the 
Investigator will use medical judgment and will remove the participant from immediate hazard. 
The Investigator will immediately notify the Sponsor and IRB regarding the nature of the 
emergency and the course of action taken. The Investigator is to notify the Sponsor of any 
inadvertent protocol deviations upon discovery and is to document the deviations appropriately 
in the study files or on the eCRFs. The Sponsor assumes no responsibility or liability for any 
deviations. Major changes in the protocol initiated by the Sponsor will be provided as an 
amendment and must be approved by the IRB prior to implementation (refer to Section 14.4). 
14.2. 
Good Clinical Practice 
The study will be conducted according to the protocol, guidelines established by the International 
Council for Harmonisation (ICH) for GCP in clinical studies and country-specific requirements 
as applicable. 
14.3. 
Informed Consent 
Each individual will be provided with oral and written information describing the nature, purpose 
and duration of the study, participation/termination conditions, and risks and benefits. Prior to 
initiation of any study-related procedures, participants (and/or their parent or legal guardian for 
participants under 18 years of age) will sign and date the ICF to participate in the study. 
Participants under 18 years of age (and their parent or legal guardian) will review the ICF and 
sign a Child Assent Form, according to local institution/IRB guidelines. The parent or legal 
guardian for participants under 18 years of age will also sign and date an authorization form 
required under the Health Insurance Portability and Accountability Act (HIPAA), if applicable, 
that authorizes the use and disclosure of the participant’s protected health information. In the 
event of a pregnancy in the female partner of a male participant, a pregnancy consent form will 
be provided to allow the follow-up of the pregnancy. 
Participants unable to sign the ICF may participate in the study if a legal representative or 
witness provides the consent (in accordance with the procedures of ICH-GCP and local 
regulations) and the participant confirms his/her interest in study participation. The participant, 
parent, or legal guardian will be informed that he/she can freely withdraw consent and stop 
participation in the study at any time with no prejudice to further treatment. It is the parent or 
legal guardian’s responsibility to communicate this decision to the Investigator. 
14.4. 
Institutional Review Board and Regulatory Approval 
The Investigator must inform and obtain approval from the IRB for the conduct of the study at 
named sites and for the protocol, the participant ICF, and any other written information that will 
be provided to the participants and any advertisements that will be used. Written approval must 
be obtained prior to enrollment of participants into the study and shipment of study drug. 


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Proposed amendments to the protocol and documents must be discussed with the Sponsor and 
CRO, and then submitted to the IRB for approval, as well as submitted to regulatory authorities 
for approval prior to implementation. Amendments may be implemented only after a copy of the 
local IRB approval letter has been transmitted to the Sponsor. Amendments that are intended to 
eliminate an apparent immediate hazard to participants may be implemented prior to receiving 
Sponsor or IRB approval. However, in this case, approval must be obtained as soon as possible 
after implementation. 
The Investigator will be responsible for ensuring that an annual update is sent to the IRB to 
facilitate their continuing review of the study (if needed) and that the IRB is informed about the 
end of the study. Copies of the update, subsequent approvals, and final letter must be sent to the 
Sponsor. The Investigator will inform the IRB of any reportable AEs. 
14.5. 
Essential Documentation Requirements 
The Sponsor or Sponsor’s representative will collect from the investigational site the required 
essential regulatory documents per ICH guidance prior to study drug shipment to the site. 
14.6. 
Confidentiality 
The Investigator must ensure that the participant’s privacy is maintained. In the eCRF and other 
documents submitted to the Sponsor, participants will be identified by a participant study number 
only. Documents that are not submitted to the Sponsor (eg, signed ICF) should be kept in a 
strictly confidential file by the Investigator. 
The Investigator shall permit authorized representatives of the Sponsor, regulatory agencies, and 
IRBs to review the portion of the participant’s medical record that is directly related to the study. 
As part of the required content of informed consent, the participant must be informed that his/her 
records will be reviewed in this manner. 
14.7. 
Regulatory, Ethical, and Legal Obligations 
The study will comply with the applicable local data protection regulations. Data collected will 
be pseudonymized. 
The processing of the personal data of participants will be minimized by making use of a unique 
participant study number only on study documents and electronic database(s). 
All study documents will be stored securely and only accessible by study staff and authorized 
personnel. The study staff will safeguard the privacy of participants’ personal data. 
The participant information sheet/informed consent for the study will inform participant of their 
rights. 
14.8. 
Study Documentation and Data Storage 
The Investigator must retain a comprehensive and centralized filing system of all study-related 
documentation that is suitable for inspection by the Sponsor and representatives of regulatory 
authorities. 


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The Investigator must retain essential documents as detailed in Section 15.2. Participant files and 
other source data (including copies of protocols, original reports of test results, investigational 
agent dispensing logs, correspondence, records of informed consent, and other documents 
pertaining to the conduct of the study) must be kept for the maximum period of time permitted 
by the institution. Documents should be stored in such a way that they can be accessed/data 
retrieved at a later date. Consideration should be given to security and environmental risks. 
No study document will be destroyed without prior written agreement between the Sponsor and 
the Investigator. Should the Investigator wish to assign the study records to another party or 
move them to another location, written agreement must be obtained from the Sponsor. 


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15. 
DATA HANDLING AND RECORDKEEPING 
15.1. 
Inspection of Records 
The Sponsor or Sponsor’s representatives will be allowed to conduct site visits to the 
investigation facilities for the purpose of monitoring any aspect of the study. The Investigator 
agrees to allow the monitor to inspect the drug storage area, study drug stocks, drug 
accountability records, participant charts and study source documents, and other records relative 
to study conduct. 
The Investigator agrees to maintain a regulatory binder, paper or electronic, in a current, 
organized fashion; this binder will contain documentation supportive of the protocol- and 
GCP-compliance of the study. The contents of the binder will be organized according to the 
standards of ICH E6, Section 8 (Essential Documents). The Investigator agrees to make this 
binder accessible to the monitor, auditor, and representatives of regulatory agencies and the IRB. 
15.2. 
Retention of Records 
The Investigator will maintain adequate records, including participants’ medical records, 
laboratory reports, signed consent forms, drug accountability records, safety reports, information 
regarding participants who discontinued the protocol, and any other pertinent data. All study 
records must be retained for at least 2 years after the last approval of a marketing application in 
the US or an ICH region and until (1) there are no pending or contemplated marketing 
applications in the US or an ICH region, or (2) at least 2 years have elapsed since the formal 
discontinuation of clinical development of the study drug under study. The 
Investigator/institution should retain participant identifiers for at least 15 years after the 
completion or discontinuation of study. Study participant files and other resource data must be 
kept for the maximum period of time permitted by the hospital or institution but not less than 
15 years. These documents should be retained for a longer period, if required by the applicable 
regulatory requirements or by the Sponsor. The Sponsor must be notified should the 
Investigator/institution be unable to continue with the maintenance of study participant files for 
the full 15 years. All study records must be stored in a secure and safe facility. 
The Investigator must retain protocols, amendments, IRB approvals, copies of the Form 
FDA 1572, signed and dated consent forms, medical records, eCRFs, drug accountability 
records, all correspondence, and any other documents pertaining to the conduct of the study. 
If the Investigator moves, withdraws from an investigation, or retires, the responsibility for 
maintaining the records may be transferred to another person who will accept responsibility. 
Notice of transfer must be made to and agreed by the Sponsor. The Investigator must notify the 
Sponsor immediately in the event of accidental loss or destruction of any protocol records. 


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15.3. 
Disclosure of Information 
Participants’ medical information obtained as a result of this study is considered confidential, 
and disclosure to third parties other than those noted in this protocol is prohibited. Subject to any 
applicable authorization(s), all reports and communications relating to participants in this study 
will identify participants only by initials and number.  
Medical information resulting from a participant’s participation in this study may be given to the 
participant’s personal physician, other authorized parties, or appropriate medical personnel 
responsible for the participant’s participation in this clinical study. Data generated in this study 
will be available for inspection on request by government regulatory agency auditors; the 
Sponsor, the Sponsor’s Medical Monitor, and their designated representatives; the IRB; and 
other authorized parties. All information concerning the study drug and the Sponsor’s operations 
(such as patent applications, formulas, manufacturing processes, basic scientific data, or other 
information supplied by the Sponsor and not previously published) is considered to be 
confidential and shall remain the sole property of the Sponsor. 
The Investigator agrees to use this information only in conducting this study and not to use it for 
other purposes without the Sponsor’s prior written consent. The information developed in this 
clinical study will be used by the Sponsor in the clinical development of GBT021601 and, 
therefore, may be disclosed by the Sponsor as required to authorized parties (including its 
corporate partners for the study drug, if any, and their designated representatives), other clinical 
Investigators, pharmaceutical companies, the US FDA, and other government agencies. 
Any information, inventions, discoveries (whether patentable or not), innovations, suggestions, 
ideas, and reports made or developed by the Investigator(s) as a result of conducting this study 
shall be promptly disclosed to the Sponsor and shall be the sole property of the Sponsor. 
The Investigator agrees, upon the Sponsor’s request and at the Sponsor’s expense, to execute 
such documents and to take such other actions as the Sponsor deems necessary or appropriate to 
obtain patents in the Sponsor’s name covering any of the foregoing. 






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18. 
REFERENCES 
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.  
Bunn HF. Pathogenesis and treatment of sickle cell disease. N Engl J Med. 1997;337(11):762-769. 
Chonat S, Fields E, Baratz H, Watt A, Pochron M, Dixon S, et al. Improvement in Red Blood 
Cell Physiology in Children with Sickle Cell Anemia Receiving Voxelotor. Blood. Nov 13, 2019 
(Supp 1); 2281 
FDA Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation. 2009. 
Available at: https://www.fda.gov/downloads/guidances/UCM174090.pdf. Accessed 
08 January 2019. 
FDA Guidance for Industry: Estimating the Maximum Safe Starting Dose in Clinical Trials for 
Therapeutics in Adult Healthy Volunteers. 2005. 
Global Blood Therapeutics, Inc. GBT021601 Investigator’s Brochure. Version 1.0, 2020. 
Howard J, Hemmaway CJ, Telfer P, Layton DM, Porter J, Awogbade M, et al. A phase 1/2 
ascending dose study and open-label extension study of voxelotor in patients with sickle cell 
disease. Blood. 2019;133:1865–1875. 
Hutchaleelaha A, Patel M, Washington C, Siu V, Allen A, Oksenberg D, et al. Pharmacokinetics 
and Pharmacodynamics of Voxelotor (GBT440) in Healthy Adults and Patients with Sickle Cell 
Disease, Br J Clin Pharmacol. 2019;1–13. 
Metcalf B, Chuang C, Dufu K, Patel M, Silva-Garcia A, Johnson C, et al. Discovery of GBT440, 
an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin. ACS Med Chem Lett. 2017 
Jan 23;8(3):321-326. 
Oksenberg D, Dufu K, Patel MP, Chuang C, Li Z, Xu Q, et al. GBT440 increases haemoglobin 
oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell 
disease. Brit J Haematol. 2016;175(1):141–53. 
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.  
Oxbryta®, United States Full Prescribing Information, 2021 
http://www.oxbryta.com/pdf/prescribing-information.pdf 
United States Food and Drug Administration Guidance for the Industry: Estimating the Maximum 
Safe Starting Dose in Clinical Trials for Therapeutics in Adult Healthy Volunteers. July 2005. 
Vichinsky E, Hoppe CC, Ataga KI, Ware RE, Nduba V, El-Beshlawy A, et al. A phase 3 
randomized trial of voxelotor in sickle cell disease. N Engl J Med. 2019;381:509-519. 
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.  



SAP_001.pdf: 
Global Blood Therapeutics, Inc. 
Protocol No. GBT021601-012 
ICON Project No. 3507/0052 
Statistical Analysis Plan Final v3.0 
24 MAR 2023 
CONFIDENTIAL 
Pa ge 1 of 44 
 
 
PPD 
PPD 
STATISTICAL ANALYSIS PLAN 
 
 
 
AN INTRAPATIENT SINGLE DOSE AND MULTIPLE ASCENDING 
DOSE STUDY TO EVALUATE THE PHARMACOKINETICS, SAFETY, 
TOLERABILITY, AND PHARMACODYNAMICS OF GBT021601, A 
HEMOGLOBIN S POLYMERIZATION INHIBITOR, IN PARTICIPANTS 
WITH SICKLE CELL DISEASE (SCD) 
 
 
SAP Version 3.0 
FINAL 
Date: 24 MAR 2023 
 
for 
 
Protocol No. GBT021601-012 
 
 
Submitted to: 
GBT Inc., a wholly owned subsidiary of Pfizer 
 
 
 
 
 
 
 
 
Prepared by: 
 
 
 
 
PPD 
 
 
PPD 


Global Blood Therapeutics, Inc. 
Protocol No. GBT021601-012 
ICON Project No. 3507/0052 
Statistical Analysis Plan Final v3.0 
24 MAR 2023 
CONFIDENTIAL 
Pa ge 2 of 44 
 
 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
a PTT 
 Activated Partial Thromboplastin Time 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC0-24 
Area under the concentration vs time curve from time zero to 24 hours 
AUC0-t 
Area under the concentration vs time curve from zero to last quantifiable concentration 
AUC0-∞ 
Area under the concentration vs time curve from time zero extrapolated to infinity 
BLQ 
Below Quantifiable Limit 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BPM 
Beats Per Minute 
CCI  
CI 
Confidence Interval 
CL/F 
Apparent Clearance 
Cmax 
Maximum Blood Concentration 
Cmin 
Minimum Blood Concentration 
CCI 
 
CoV 
Coronavirus 
CRA 
Clinical Research Associate 
CSR 
Clinical Study Report 
CV 
Coefficient of Variation 
CYP 
Cytochrome P450 
DMP 
Data Management Plan 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
EOS 
End Of Study 
EOT 
End Of Treatment 
EPO 
Erythropoietin 
FIH 
First In Human 
FSH 
Follicle Stimulating Hormone 
Hb 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
HR 
Heart Rate 
ICH 
International Conference on Harmonisation 
IgM 
Immunoglobulin M 
MAD 
Multiple Ascending Dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
N 
Number 
CCI  
CCI  


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p20 
Hemoglobin protein is 20% saturated 
p50 
Hemoglobin protein is 50% saturated 
PCR 
Polymerase Chain Reaction 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PT 
Preferred Term 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAD 
Single Ascending Dose 
SCD 
Sickle Cell Disease 
SD 
Standard Deviation 
SMC 
Safety Monitoring Committee 
SOC 
System Organ Class 
SSP 
Study-Specific Procedure 
t1/2 
Half-life 
TEAE 
Treatment-Emergent Adverse Event 
tmax 
Time of maximum serum concentration 
Vz/F 
Apparent volume of distribution during the terminal phase 
VOC 
Vaso-Occlusive Crisis 
WHO 
World Health Organization 


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REVISION HISTORY 
 
 
Version 
Number 
Effective Date 
Changes since previous version 
Final 1.0 
28 APR 2022 
Original version, Not Applicable 
CCI 
 
2) Addition of MAD PK TLFs presentation 
3) Typo errors 
Final 3.0 
24 MAR 2023 
1) TEAE definition updated 
2) Section 7.17.2: criteria for character values for quantitative laboratory 
parameters added. 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ......................................................................................................... 2 
REVISION HISTORY .................................................................................................................... 4 
TABLE OF CONTENTS ................................................................................................................. 5 
1. 
INTRODUCTION ................................................................................................................... 8 
2. 
STUDY OBJECTIVES ........................................................................................................... 9 
2.1 
Objective ........................................................................................................................... 9 
2.1.1 Primary Objective .............................................................................................................. 9 
2.1.2 Secondary Objectives ....................................................................................................... 9 
CCI 
 
3. 
STUDY DESIGN ................................................................................................................... 10 
3.1 
General ............................................................................................................................ 10 
3.2 
Study Population ............................................................................................................. 20 
3.3 
Evaluations at Screening and Check-in ........................................................................... 20 
3.4 
Randomization and Treatment Assignments ................................................................... 20 
3.5 
Determination of Sample Size ......................................................................................... 20 
3.6 
Study Drug Administration ............................................................................................. 20 
3.7 
Concomitant Medications and Procedures ...................................................................... 20 
3.8 
Drug Administration and Compliance ............................................................................ 21 
3.9 
Evaluation of Efficacy ..................................................................................................... 21 
3.10 Evaluation of Pharmacokinetic Sampling Schedule ........................................................ 21 
3.11 Evaluation of Pharmacodynamics Sampling Schedule ................................................... 23 
3.12 Evaluation of Treatment Safety ....................................................................................... 23 
3.12.1 Adverse Events ................................................................................................................ 23 
3.12.1.1 
Drug-induced Liver Injury ....................................................................................... 24 
3.12.2 Clinical Laboratory Assessments .................................................................................... 24 
3.12.3 Vital Signs ....................................................................................................................... 25 
3.12.4 Electrocardiogram ............................................................................................................ 26 
3.12.5 Physical Examinations .................................................................................................... 26 
3.12.6 Medical and Surgical History .......................................................................................... 26 
3.13 Protocol Deviation Reporting .......................................................................................... 26 
4. 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSIS ............... 27 


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5. 
QUALITY CONTROL AND QUALITY ASSURANCE METHODS FOR DATA 
ANALYSIS ................................................................................................................................... 28 
6.1 
Pharmacokinetic Analysis .............................................................................................. 29 
6.2 
Treatment of Outliers ..................................................................................................... 30 
6.3 
Non-Quantifiable Concentrations ................................................................................... 31 
6.4 
Pharmacodynamic Analysis ........................................................................................... 31 
7. 
STATISTICAL METHODS .................................................................................................. 32 
7.1 
General ........................................................................................................................... 32 
7.2 
Handling of Dropouts or Missing Data .......................................................................... 32 
7.3 
Handling of missing/ incomplete dates for Adverse Event ............................................ 33 
7.4 
Handling of missing or partial Prior/Concomitant Medication Dates ............................ 33 
7.4 
Multiple Comparisons and Multiplicity ......................................................................... 33 
7.5 
Adjustments for covariates ............................................................................................. 34 
7.6 
Multicenter Studies ........................................................................................................ 34 
7.7 
Examination of Subgroups ............................................................................................. 34 
7.8 
Coding dictionaries ......................................................................................................... 34 
7.8 
Analysis Sets .................................................................................................................. 34 
7.8.1 Safety Population ........................................................................................................... 34 
7.8.2 Pharmacokinetic Population ........................................................................................... 34 
7.9 
Participant Accountability .............................................................................................. 34 
7.10 Protocol Deviations ........................................................................................................ 34 
7.11 Participant Demographics and Baseline Characteristics ................................................ 35 
7.12 Baseline Sickle Cell Disease .......................................................................................... 35 
7.13 Hemoglobin Response ................................................................................................... 35 
7.14 Medical and Surgical History ......................................................................................... 35 
7.15 Measurements of Treatment Compliance ....................................................................... 35 
7.16 Pharmacokinetic Analysis .............................................................................................. 35 
7.17 Safety Analyses .............................................................................................................. 36 
7.17.1 Adverse Events ............................................................................................................... 36 
7.17.2 Clinical Laboratory Assessments ................................................................................... 37 
7.17.3 Vital Signs ...................................................................................................................... 37 
7.17.4 Electrocardiograms ......................................................................................................... 37 
7.17.5 Prior and Concomitant Medications ............................................................................... 37 


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CCI 
 
7.18 Planned Interim Analysis ............................................................................................... 38 
7.19 General Conventions for Tables, Listings and Figures .................................................. 38 
8. 
LIST OF TABLES, FIGURES, AND LISTINGS ................................................................. 41 


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1. INTRODUCTION 
This statistical analysis plan (SAP) is consistent with the statistical methods section of the final 
study protocol (Version 6.0, Amendment 5 dated 08 March 2022) and includes additional detail 
of pharmacokinetics (PK), pharmacodynamics (PD) and safety summaries to be included in the 
clinical study report (CSR). 


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2. 
STUDY OBJECTIVES 
 
2.1 
Objective 
The following are the study objectives: 
2.1.1 
Primary Objective 
• To evaluate the safety and tolerability of a single dose and multiple ascending doses of 
GBT021601 in participants with SCD. 
2.1.2 
Secondary Objectives 
• To evaluate the PK of a single dose and multiple ascending doses of GBT021601 in 
participants with SCD. 
• 
 
• To confirm the relationship between time-matched GBT021601 concentrations and the 
change from baseline or % change from baseline of clinical measures of anemia and 
hemolysis. 
CCI  
 
 
CCI 


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3. 
STUDY DESIGN 
 
3.1 General 
 
This is an open-label intra-patient single dose and multiple ascending dose study in at least 6 
participants with SCD. The study schematic is presented in Figure 3-1. 
 
Single-dose Period (Part A) 
After eligibility has been confirmed and the informed consent form signed, particip ants will be 
admitted into the clinical research unit (CRU) on the day prior to study drug administration 
(Day -1). A single oral dose of 100 mg of GBT021601 will be administered following an 
overnight fast of at least 10 hours and no food will be allowed for at least 4 hours postdose. The 
dose will be no higher than a dose that has been well tolerated by the healthy participants in the 
FIH study. Participants will remain confined to the CRU until 72 hours after dosing (Day 4) and 
return for brief visits on Days 7, 14, 21, 28, and 42. 
 
Multiple Ascending-dose Period (Part B) 
After a sufficient washout period (minimum of 56 days) and completion of a minimum of 
4 participants in the Single-dose Period, the SMC will convene to review the safety, tolerability, 
and PK data from Day 42. If the SMC agrees to initiate the intra-patient multiple ascending dose 
portion of the study, participants will receive a maintenance dose regimen which may or may not 
be preceded by a loading dose at Week 8 (± 4 weeks). The initial loading dose and maintenance 
dose and frequency will be based on a predicted target of ~20% to 30% Hb occupancy as 
determined by the PK results from the SAD part of study GBT021601 -011 in healthy 
participants and PK and hemoximetry results (occupancy/modif ication) from Part A. The 
maintenance dose will be administered through Week 10. After the first multiple dose period, if 
the % Hb occupancy is higher than 30%, the participant will remain on a maintenance dose that 
maintains the % Hb occupancy at >30% and will not dose escalate, based on SMC 
recommendation. If the % Hb occupancy is less than 30%, the participant will dose escalate at 
Week 13. 
 
At the Week 13 Visit, participants may be dose escalated to receive a loading dose and 
subsequent maintenance dose based on a predicted target of >30% occupancy/modification as 
determined by the PK results of GBT021601-011 and Part A of this study. Week 16 will be the 
end of treatment (EOT) Visit and participants will return to the clinical site for the end of Part B 
Safety Follow-up Visit approximately 5 half-lives after the final dose at Week 16. The 
elimination half-life will be determined from the PK results from the GBT021601-011 study and 
Day 42 following a single dose of 100 mg. It is anticipated that 5 half-lives will not exceed 120 
days after the final dose. 
Participants will not be confined at the CRU during the Multiple Dose Period. 
 
 
 
CCI 
 


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Based on the findings from Dose Levels 1 and 2, there were no significant safety con cerns 
related to GBT021601 and based on PK modeling, the planned doses for Part C are expected to 
result in Hb occupancy of approximately 54%. 
 
Eligible participants may proceed with an Extended Treatment Period of at least 6 weeks, with a 
300 mg loading dose twice daily over 4 days and subsequent maintenance dose of 150 mg once 
daily starting from Part C Day 1 and continuing through Part C Week 6. 
 
 
 
 
 
The EOB Visit will occur after completion of the Multiple Ascending-dose Period as presented 
in Table 3-3. The EOS Visit will occur after completion of the Extended Treatment Period as 
presented in Table 3-4. 
CCI 
CCI 


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Protocol No. GBT021601-012 
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Figure 3-1: 
Study Schematic for GBT021601-012: 
 


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Table3-1: Schedule of Assessments for Single-dose Period (Part A) 
Scree 
n 
Confinement 
Outpatient 
Study Day 
-30 
to -2 
-1 
1 
2 
3 
4 
7 
14 
21 
28 
42 
Informed consent 
X 
Eligibility assessment 
X 
X 
Medical historya 
X 
Physical examinationb 
X 
X 
X 
Height 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG (triple tracing)d 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug administration 
X 
Serology (hepatitis A, B, C) HIV, 
SARS-CoV-2 
X 
Alcohol (breath or blood) and urine 
drugs of abuse screen 
X 
X 
Hematology, Serum chemistry, and 
Lipid Panele 
X 
X 
X 
X 
X 
X 
a PTT, INR, PT 
X 
Serum erythropoietin 
X 
X 
X 
X 
X 
SCD documentation or Hemoglobin 
Electrophoresis 
X 
eGFRf 
X 
X 
Urinalysis 
X 
X 
X 
Pregnancy test (women only)g 
X 
X 
X 
X 
FSH (postmenopausal women only) 
X 
Pharmacokinetic assessment (whole 
blood and plasma) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hemoximetry 
X 
X 
X 
X 
X 
X 
RBC deformability, dense cellsh 
X 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbrevia tions: a PTT, activated partial thromboplastin time; CoV, coronavirus; ECG, electrocardiogram; eGFR, 
estimated glomerular filtration rate; EOS, end of study; ET, early termination; FSH, follicle-stimulating hormone; 
HIV, human immunodeficiency virus; INR, International Normalized Ratio; PCR, polymerase chain reaction; PT, 
prothrombin time; RBC, red blood cell; SARs, severe acute respiratory syndrome; SCD, sickle cell disease. 
 
a History update, if any, will be obtained. 
b A full physical examination should be conducted at Screening. All subsequent physical examinations should be 
signs and symptoms driven. 
c Vital Signs include blood pressure, heart rate, respiration rate, body temperature while the participant is in a supine 
position. 
d 12-Lead ECG on Day 1 should be performed within 30 minutes prior to dose, and 4 and 8 hours after dosing, then 
in the morning of each day of confinement and at any time at other clinic visits. 


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e The Lipid Panel is done at the Screening Visit only. 
f The eGFR will be calculated at Screening and confirmed on Day -1 using the Cockcroft-Gault formula. 
g A serum pregnancy test will be conducted a t Screening and ET and urine pregnancy test at all other visits. A serum 
pregnancy test will also be conducted when a positive urinary pregnancy test occurs for confirmation. 
h RBC deformability and dense cells will be tested on Day 1 predose and 12 hours postdose. 


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Table 3-2: Schedule of Select Study Procedures (First 48 hours) 
Sampling Timepoint (hours postdose) 
Procedure 
Predose 
Postdose 
0.25 
hr 
0.5 hr 1 hr 2 hr 4 hr 6 hr 8 hr 12 hr 24 hr 
(Day 2) 
36 hr 48 hr 
(Day 3) 
HR and BPa, b 
X 
X 
X 
X 
X 
X 
X 
X 
RR and Body 
Temperaturea, b 
X 
X 
X 
12-lead safety 
ECGsb, c 
X 
X 
X 
X 
X 
X 
PK Samplingd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbrevia tions: BP, blood pressure; ECG, electrocardiogram; HR, heart rate; PK, pharmacokinetic; RR, respiratory 
rate; SAD, single ascending dose. 
Note: For procedures scheduled to be performed at the same time, priority is to be given to collection of the PK 
samples at the designated time. ECGs, followed by vital signs, are to be taken before PK sampling, unless PK 
samples will be late as a result. If times are delayed due to technical difficulties, this will be noted, but not 
considered a protocol violation. 
 
a HR, BP, RR, and body temperature will be measured after a participant has rested for at least 5 minutes in the 
supine position. 
b Window for collection: up to 3 hours predose, ± 15 minutes up to 12 hours post, ± 30 minutes if ≥ 24 hours 
postdose. 
c ECGs (12-lead) will be collected in triplicate within 5 minutes after a participant has rested at least 5 minutes in 
the supine position. Predose ECGs and vital signs on Day 1 may be performed within 3 hours prior to dosing. 
d Predose blood PK sample to be collected within 60 minutes prior to dosing. Postdose collection windows are: 0.25, 
0.5 and 1 hour ± 2 mins, 2 to 24 hours ± 5 mins, 36 and 48 hours ± 10 mins. 


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Table 3-3: Schedule of Assessments for Multiple Ascending-dose Period (Part B) 
Study Week 
Week 8 
(Day 
56 
+ 4 
weeks)a 
Week 
9 
(Day 
63 
±3 
days) 
Week 
10 
(Day 
70 
± 3 
days) 
Week 
11 
(Day 
77 
+ 3 
days) 
Week 
12 
(Day 
84 
± 3 
days) 
Week 
13 
(Day 
91 
±3 
days) 
Week 
14 
(Day 98) 
± 3 days 
Week 15 
(Day 105) 
± 3 days 
Week 16 
(Day 112) 
EOT 
Every 
4 weeks 
through 
EOB 
± 7 days 
Day 
218 
(EOB)/ 
ET 
Physical 
examination 
X 
X 
X 
X 
Height 
Weight 
X 
X 
Vital signsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
(triple tracing)d 
X 
X 
X 
X 
Study drug 
administration 
Xe 
X 
X 
Xf 
X 
Xf 
X 
X 
X 
Dispense patient 
diaryg 
X 
X 
X 
X 
X 
X 
X 
X 
Collect patient 
diaryg 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology and 
serum chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood smearh 
X 
X 
X 
Serum 
erythropoietin 
X 
X 
X 
X 
eGFRi 
X 
X 
X 
Urinalysis 
X 
X 
X 
Pregnancy test 
(women only)j 
X 
X 
Pharmacokinetic 
assessment 
(whole blood 
and plasma)k 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hemoximetryk 
X 
X 
X 
X 
X 
X 
RBC 
deformability, 
dense cells (if 
feasible)k 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinic visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; EOB, end of Part B; ET, early 
termination; RBC, red blood cell. 


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Note: For procedures scheduled to be performed at the same time, priority is to be given to collection of the PK 
samples at the designated time. 
ECGs, followed by vital signs, are to be taken before PK sampling unless PK samples will be late as a result 
a Week 8 (Day 56) is the first visit in the Multiple-Ascending-dose Period. 
b The Day 218 Visit will occur approximately 5 half-lives after the dose at Week 16. 
c HR, BP, RR, and body temperature will be measured after a participant has rested for at least 5 minutes in the 
supine position. Assessment of vital signs may be performed up to 3 hours predose. 
d 12-Lead ECG should be performed within 30 minutes prior to dose and will be collected in triplicate within 5 
minutes after a participant has rested at least 5 minutes in the supine position. 
e Study drug will be administered as a loading dose of TBD mg and a maintenance dose of TBD mg every TBD 
(Dose 1) beginning at the Week 8 (Day 56) Visit. Participants will receive maintenance Dose 1 through Week 12. At 
the Week 8 Visit, the participant will remain in the clinic for 4 hours postdose for vitals, 12-lead ECG and AE 
assessment. 
f Study drug will be administered as a loading dose of TBD mg and a maintenance dose of TBD mg every TBD 
(Dose 2) beginning at the Week 13 (Day 91) Visit. Participants will receive maintenance Dose 2 through Week 16. 
At the Week 13 Visit, the participant will remain in the clinic for 4 hours postdose for vitals, 12-lead ECG and AE 
assessment 
g Site to dispense a new diary and collect the previous diary from the patient, when applicable. Diary to be collected 
only during the maintenance dosing when the participant is self -administering study drug at home. Participants 
should be instructed to complete the diary each week and return it at the next visit for site review. 
h A blood smear is to be performed before the Multiple Ascending Dosing Period Day 56 and Day 112 visits. 
i The eGFR will be calculated using the Cockcroft-Gault formula. 
j A urine pregnancy test will be conducted. A serum pregnancy test will also be conducted when a positive urinary 
pregnancy test occurs for confirmation. 
k Samples for PK will be collected: predose, 0.25 to 21 hours postdose and 2 to 4 hours postdose. Sample collection 
times for hemoximetry and RBC deformability should be aligned with the predose PK sample and the 2 to 4 hour 
postdose PK sample. No 0.25 to 1 hour postdosesample shall be collected for hemoximetry or RBC deformability. 
The predose blood sample for PK and PD assessments should be collected within 30 minutes prior to dosing. 


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Table 3-4: Schedule of Assessments for Extended Treatment Period (Part C) 
 
Study 
Day/Week 
Part C 
Screening 
Visit 
(Day -28 to 
Day -1) 
Part C 
Day 1 
Part C 
Week 2 
(Day 14 
± 3 days) 
Part C 
Week 4 
(Day 28 
± 3 days) 
Part C 
Week 6 
(Day 42) 
± 3 days) 
EOET 
Part C 
Week 10 
(Day 70 ± 3 
days) 
Part C 
Week 14 
(Day 98 ± 3 
days) 
Final 
Visit 
(EOS/ 
OLE) 
Informed Consent 
X 
Eligibility 
confirma tiona 
X 
Physica l 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
Vital signsb 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
(triple tracing)c 
X 
X 
X 
X 
X 
X 
X 
Study drug 
administrationd 
X 
X 
X 
X 
Dispense 
participant diarye 
X 
X 
X 
Collect participant
X 
X 
X 
CCI 
 
 
 
 
 
 
 
 
 
 
 
 
y 
X 
X 
X 
X 
X 
X 
X 
X 
and serum 
chemistry 
Serum 
X 
X 
X 
X 
X 
eGFRf 
X 
X 
X 
X 
X 
Urina lysis 
X 
X 
X 
X 
X 
Pregna ncy test 
(women only)g 
X 
X 
X 
X 
X 
Pha rmacokinetic 
assessment 
X 
X 
X 
X 
X 
X 
X 
Hemoximetryh 
X 
X 
X 
X 
X 
RBC 
deformability, 
dense cells (if 
feasible)h 
X 
X 
X 
X 
X 
Blood smear 
X 
X 
X 
X 
 
CCI 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 


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Abbrevia tions: CCI 
 ECG, electrocardiogra m; eGFR, estimated glomerula r 
filtration rate; EOET, End of Extended Treatment; EOS, end of study; ET, early termination; CCI 
 
Note: For procedures scheduled to be performed at the same time, priority is to be given to collection of the PK 
sa mples at the designated time. ECGs, followed by vital signs, are to be taken before PK sampling unless PK 
sa mples will be late as a result. 
a For newly enrolled participants, the Screening Visit will be the same as that in Table 3-1. 
b HR, BP, RR, and body temperature will be measured after a participant has rested for at least 5 minutes in the 
supine position. Assessment of vital signs may be performed up to 3 hours predose. 
c 12-Lead ECG should be performed within 30 minutes prior to dose at Part C Day 1, Part C Week 2, and 4 hours 
post dose at Part C Weeks 4 and 6. All ECGs will be collected in triplicate within 5 minutes after a participant has 
rested at least 5 minutes in the supine position. 
d Study drug will be administered beginning at the Day 1 Visit as a loading dose of 300 mg twice daily for four 
days followed by a maintenance dose of 150 mg once daily through at least Pa rt C Week 6 (if treatment will be 
extended beyond 6-weeks, a dditional study drug administration and Visits will be added). At the Part C Week 4 
and CCI   Week 6 Visits, the participant will rema in in the clinic for 4 hours postdose for vitals, 12-lead ECG 
and AE assessment. 
e Site to dispense a new diary and collect the previous diary from the participant, per a bove. Dia ry to be completed 
throughout the study, except for the first loading dose a nd any maintenance doses administered in the clinic. The 
actual time of every dose administration should be recorded in the diary or at the clinic to enable PK calculations. 
Participants should be instructed to complete the diary as wellas the Bristol stool chart.CCI 
 
 
f The eGFR will be calculated using the Cockcroft-Ga ult formula. 
g A urine pregna ncy test will be conducted. A serum pregnancy test will also be conducted when a positive urinary 
pregnancy test occurs for confirmation. 
h Samples for PK will be collected: prior to the first dose at Part C Day 1, Part C Week 2, Part C Week 4, Part C 
Week 6 as well as at 0.25 to 1 hour post-dose and 2 to 4 hours post dose on the Week 4 and Week 6 visits. Sa mple 
collection times for hemoximetry and RBC deformability should be aligned with the pre- dose PK sample and the 
2 to 4-hour post-dose PK sample (for Week 4 and Week 6 visits). Refer to Table 3-9 for specifics. No 0.25 to 1- 
hour post-dose samples shall be collectedfor hemoximetry or RBC deformability. The predose blood sample for 
PK and PD assessments should be collected within 30 minutes prior to dosing. 


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3.2 
Study Population 
At least 6 participants with SCD ages 18 to 60 years, inclusive will be enrolled (dosed) in this 
study. Participants in Part A (single dose) will be continued to Part B (multiple ascending-dose) 
based on SMC review of data. All eligible participants will proceed with the extended treatment 
period (Part C). 
3.3 
Evaluations at Screening and Check-in 
Screening procedures will be conducted within 30 days prior to Day 1 dosing (Day -30 to 
Day -2). Screening and check-in evaluations for the single dose period each period are presented 
in Table 3-1 and screening activities for Part C are found in Table 3-4. 
3.4 
Randomization and Treatment Assignments 
Participants will be enrolled sequentially into this open-label, fixed-sequence study. 
Randomization will not be performed in the study. 
3.5 
Determination of Sample Size 
No sample size estimation was performed to determine the cohort size. The sample size is based 
on practical considerations, and not on a formal statistical power calculation. Six participants 
with SCD are expected to provide adequate characterization of PK and safety. 
3.6 
Study Drug Administration 
GBT021601 will be administered orally. For the single-dose period, participants will fast at least 
10 hours before and for at least 4 hours after study drug administration. Water will be allowed as 
desired except for 1 hour before and 1 hour after study drug administration. 
 
Part A: Single oral dose of GBT021601 100 mg on Day 1. 
 
Part B: The starting multiple ascending doses will be chosen to achieve ~20% to 30% Hb 
occupancy with once daily treatment (Dose 1) proceeded by loading doses. In addition, this dose 
level is predicted to achieve a Cmax at steady-state no higher than 2-fold the Cmax observed and 
well tolerated following single dose or multiple doses in study GBT021601-011. For the second 
dose level (Dose 2), the target of >30% Hb occupancy will be used as determined by the PK 
results found in GBT021601-011 and results from Part A of this study given at Weeks 8 -13. 
 
Part C: 300 mg loading dose twice daily over 4 days subsequent maintenance dose of 150 mg 
once daily starting from Day 5 and continuing through Week 6. 
3.7 
Concomitant Medications and Procedures 
Study participants will be allowed to take other medications as needed as described in protocol. 
All concomitant medications will be documented. 
 
In the interests of participant safety and acceptable standards of medical care the Investigator 
will be permitted to prescribe treatment(s) at his/her discretion. All treatments must be recorded 
in the participants’ electronic case report form (eCRF) (medication, dose, treatment duration and 
indication) procedures along with start and stop date, type and reason for procedures will be 
captured on eCRF. 


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3.8 
Drug Administration and Compliance 
Study drug will be administered orally with approximately 240 mL non-carbonated room 
temperature water. Both tablets and capsules will be provided by sponsor. 
 
Table 3-5: Identity of Study Drugs 
Study Drug 
Dosage Form 
Dose 
GBT021601 
Tablet 
100 mg 
GBT021601 
Capsule 
5 mg, 25 mg 
 
Study drug will be provided as a tablet or capsule as per below table: 
 
Table 3-6: Study Drug for Extended Treatment Period 
Study Drug 
Dosage Form 
Dose 
GBT021601 
Tablet 
100 mg 
GBT021601 
Capsule 
25 mg 
 
The first dose of the study drug will be administered by delegated and trained staff at the CRU. 
A hand and mouth check will be performed to verify that the administered dose was swallowed. 
 
For the Multiple Ascending-dose Period of this trial, at Week 8 and Week 13 Visits, the initial 
loading dose (as applicable) will be administered by delegated and trained staff at the CRU. 
Details regarding dosing, including the dose administered and the date and time of dosing, will 
be recorded. 
For Extended Treatment Period of at least 6 weeks, loading dose will be 300 mg twice daily over 
4 days and subsequent maintenance dose of 150 mg once daily starting from Part C Day 1 and 
continuing through Part C Week 6. 
3.9 
Evaluation of Efficacy 
This section is not applicable for this study. 
3.10 Evaluation of Pharmacokinetic Sampling Schedule 
The PK samples for GBT021601 will be collected at time points specified in the PK/PD 
sampling schedules (Table 3-1, Table 3-2, Table 3-3 and Table 3-4). 
 
Single-dose Period: During the Single-dose Period, plasma and whole blood PK samples will be 
collected at the following times: Predose (within 60 minutes of dosing) and postdose at 0.25, 0.5, 
1, 2, 4, 6, 8, 12 hours; 24 hours (Day 2), 36 hours, 48 hours (Day 3), and 72 hours (Day 4); 
Days 7, 14, 21, 28, and 42. The windows for sample collection are provided in table below: 
Table 3-7: Windows for PK Sample Collection – Single-dose Period 
 
Sample Collection Time 
Allowed Deviation 
0.0 – 1.0 hour 
± 2 minutes 


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Sample Collection Time 
Allowed Deviation 
> 1.0 – 24.0 hours 
± 5 minutes 
> 24.0 – 72.0 hours 
± 10 minutes 
> 72.0 – 144.0 hours 
± 15 minutes 
> 144.0 hours 
± 24 hours 
 
Multiple Ascending-dose Period: Plasma and whole blood predose and postdose PK samples will 
be collected in the Multiple Ascending-dose period as listed in below table: 
Table 3-8: PK and PD Sample Collection Times – Multiple Ascending-dose Period 
 
Week 
Predosea 
Postdose 
8 
1 PK/PD sample Predose 
1 PK/PD sample between 0.25 hour to 1 hour 
1 PK/PD sample between 2 to 4 hours 
9 
1 PK/PD sample Predose 
1 PK/PD sample between 0.25 hour to 1 hour 
1 PK/PD sample between 2 to 4 hours 
10 
1 PK/PD sample Predose 
1 PK/PD sample between 0.25 hour to 1 hour 
1 PK/PD sample between 2 to 4 hours 
11 
1 PK/PD sample Predose 
1 PK/PD sample between 0.25 hour to 1 hour, 
1 PK/PD sample between 2 to 4 hours 
12 
1 PK/PD sample Predose 
1 PK/PD sample between 0.25 hour to 1 hour 
1 PK/PD sample between 2 to 4 hours 
13 
1 PK/PD sample Predose 
1 PK/PD sample between 0.25 hour to 1 hour 
1 PK/PD sample between 2 to 4 hours 
14 
1 PK/PD sample Predose 
1 PK/PD sample between 0.25 hour to 1 hour 
1 PK/PD sample between 2 to 4 hours 
15 
1 PK/PD sample Predose 
1 PK/PD sample between 0.25 hour to 1 hour 
1 PK/PD sample between 2 to 4 hours 
16 EOT 
1 PK/PD sample Predose 
1 PK/PD sample between 0.25 hour to 1 hour 
1 PK/PD sample between 2 to 4 hours 
EOB/ET 
Anytime during visit 
a The pre-dose blood sample for PK and PD assessments should be collected within 30 minutes prior to dosing. 
 
Table 3-9: PK and PD Sample Collection Times –Extended Treatment Period (Part C) 
 
Extended Treatment Period 
Pre-dosea 
Postdose 
Week 
Day 
1 
1 
1 PK/PD sample 
1 PK sa mple between 0.25 hour to 1 hour 
1 PK/PD sa mple between 2 to 4 hours 
2 
15 
1 PK/PD sample 
1 PK sa mple between 0.25 hour to 1 hour 
1 PK/PD sa mple between 2 to 4 hours 


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CCI 
 
4 
29 
1 PK sa mple 
1 PK sa mple at 4 hours 
6 
43 
1 PK sa mple 
1 PK sa mple between 0.25 hour to 1 hour 
1 PK sa mple at 2 hours 
10 
71 
1 PK sa mple 
14 
98 
1 PK sa mple 
Final Visit 
Anytime during visit 
a 
The pre-dose blood sample for PK and PD assessments should be collected within 30 minutes prior to dosing. 
 
3.11 
Evaluation of Pharmacodynamics Sampling Schedule 
Single dose-period: Blood samples for hemoximetry, RBC deformability and dense cells will be 
collected at the same time as the PK samples (refer Table 3-7) at predose and 12 hours postdose 
on Day 1. In addition, hemoximetry samples will be collected on Days 2, 4, 7, 21, and 42. 
Multiple ascending dose-period: Whole blood samples for hemoximetry, RBC deformability and 
dense cells will be collected at the same time as the PK samples (refer Table 3-8). 
Extended Treatment Period: Whole blood samples for hemoximetry, RBC deformability and 
dense cells will be collected on Day 1 and Day 15 (refer Table 3-9). 
 
 
 
 
 
3.12 
Evaluation of Treatment Safety 
 
3.12.1 Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence associated with the use of 
a drug in humans, whether or not considered related to the study drug. An AE can therefore be 
any unfavorable and unintended sign, symptom, or disease temporally associated with the use of 
a study drug. A suspected adverse reaction is any AE for which there is a reasonable possibility 
that the drug caused the AE. 
 
A treatment-emergent AE (TEAE) is an AE that occurs or worsens during the on-treatment 
period defined as the time from the first dose of study drug through minimum of 56 days + last 
dose of study treatment, date of study completion/discontinuation. 
 
A Serious Adverse Event (SAE) is defined as any event that results in death, is immediately life 
threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results 
in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect or 
important medical events. 


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All AEs will be recorded from the time the study participant signs the Informed Consent Form 
(ICF) until the EOS Visit or ET Visit, whichever comes first. All AEs must be reported on the 
AE electronic case report form (eCRF) via the electronic data capture system. All serious and 
non-serious AEs must be followed until they are resolved or stabilized, or until reasonable 
attempts to determine resolution of the event are exhausted. Any participant who experiences an 
AE may be discontinued from study treatment at any time at the discretion of the Investigator. 
The Sponsor/Medical Monitor(s) must be notif ied of the study participant discontinuation. 
The following details will be collected: description of the AE, onset date/time, action taken with 
study drug, outcome, severity (grade 1, grade 2, grade 3, grade 4 or grade 5), seriousness (yes, 
no) and relationship to study drug administration (not related or related). 
3.12.1.1 
Drug-induced Liver Injury 
Participants will be monitored for signs of drug-induced liver injury (DILI). 
 
Potential events of DILI will be defined as meeting all the following criteria (as specified in the 
FDA Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation. 
[FDA, 2009]): 
• ALT > 4 × ULN or aspartate aminotransferase > 3 × ULN 
• No other reason can be found to explain the combination of laboratory value increases 
(e.g., acute viral hepatitis; alcoholic and autoimmune hepatitis; hepatobiliary disorders; 
nonalcoholic steatohepatitis; cardiovascular causes; concomitant treatments) 
 
Potential events of DILI will be reported as SAEs. All participants with potential DILI will be 
closely followed until abnormalities return to normal or baseline or until all attempts to 
determine resolution of the event are exhausted. 
 
3.12.2 Clinical Laboratory Assessments 
Laboratory evaluations will be collected for hematology, coagulation, chemistry, urinalysis and 
other parameters. Refer to Table 3-10. 
 
Additional safety laboratory tests may be conducted as needed by the Investigator to evaluate 
participant safety. 


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Table 3-10: Clinical Laboratory Tests 
 
Hematology 
Coagulation 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Hb 
International 
normalized ratio 
ALT 
Albumin 
Alkaline phosphatase 
AST 
Bicarbonate 
Blood urea nitrogen 
Calcium 
Chloride 
Creatine 
phosphokinase 
Creatinine 
Fasting glucose 
Lactate dehydrogenase 
Magnesium 
Phosphorous 
Potassium 
Sodium 
Total bilirubin (direct 
and indirect) 
Total protein 
Uric acid 
eGFRa 
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocytes 
Microscopic 
analysis of sediment 
if clinically 
indicated 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
Urine Drug screen 
Cannabinoids 
Amphetamines 
Methamphetamines 
Opiates 
Methadone 
Cocaine 
Benzodiazepines 
Phencyclidine 
Barbiturates 
Alcohol breath test 
EPO 
FSH (post-menopausal 
females only) 
Pregnancy - serum and 
urine (females only)b 
Lipid Panel 
Amylase 
Lipase 
Hemoximetry 
RBC deformability 
and dense cells 
Serology Panel: 
HIV 1/2 antibody 
Hepatitis A virus IgM 
antibody 
Hepatitis B virus 
surface antigen 
Hepatitis C virus 
antibody 
SARS CoV-2 
RBC count 
Prothrombin time 
Mean corpuscular 
a PTT 
volume 
Mean corpuscular 
Hb 
Mean corpuscular 
Hb concentration 
Reticulocyte count 
(absolute and %) 
Platelet count 
(estimate not 
acceptable) 
White blood cell 
count including 
differential count 
(percent and 
absolute): 
• Neutrophils 
• Lymphocytes 
• Monocytes 
• Basophils 
• Eosinophils 
a Using the using the Cockcroft-Gault formula. 
b Tests will be conducted at the clinic. 
 
3.12.3 Vital Signs 
Vital signs assessments will include respiratory rate (breaths per minute), systolic and diastolic 
blood pressure (BP) (mmHg), and heart rate (HR) (beats per minute [bpm]) and body 
temperature, which will be measured after a participant has rested for at least 5 minutes in the 
supine position. Any clinically significant abnormal vital sign assessment requires at least 1 
repeat measurement. 
 
Vital signs abnormalities that are (1) considered clinically significant initially and on 
confirmation, (2) require a participant to be discontinued from the study, (3) require a participant 
to receive treatment, or (4) require a change or discontinuation from the study drug (if 
applicable) will be recorded as AEs. 


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3.12.4 Electrocardiogram 
Electrocardiogram (ECG) (12-lead) will be collected in triplicate within 5 minutes. The 
following ECG parameters will be recorded: HR, PR, QRS, QT, and QTcF intervals. ECGs will 
be collected at the time points in the schedules of assessments/procedures in Table 3-1 to Table 
3-4. 
For any ECG that the Investigator considers clinically significant, the Investigator will: 
• Repeat the ECG. 
 
• Follow-up ECG(s) will be obtained if any significant abnormalities are detected after 
dose administration to document resolution and as clinically indicated. 
 
• Record as an AE any ECG that is 1) confirmed by the Investigator as clinically 
significant, 2) requires a participant to be discontinued from the study, or 3) requires a 
participant to receive treatment 
 
3.12.5 Physical Examinations 
A full physical examination will be conducted at Screening. All subsequent physical 
examinations should be signs and symptoms driven. Full physical examination will include 
examination of the following: general appearance, head, ears, eyes, nose, throat, neck, skin, 
cardiovascular system, respiratory system, gastrointestinal system, musculoskeletal system, 
lymph nodes, and nervous system (Table 3-1 to Table 3-4). 
 
An abnormal physical examination finding during the on-study period (i.e., following dose 
administration) that is considered clinically significant and (1) requires the participant to be 
discontinued from the study, or (2) requires the participant to receive treatment will be recorded 
as an AE. 
 
3.12.6 Medical and Surgical History 
Medical and surgical history will be collected at Screening and again at CRU admission to 
determine if any changes have occurred since screening. 
3.13 Protocol Deviation Reporting 
Procedural deviations found by the Clinical Research Associate (CRA) during monitoring visits 
and data deviations captured on the case report form (CRF) and found through programming and 
examining the database will be listed by participant. 


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4. 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSIS 
 
All analyses specified in this SAP are consistent with the final study protocol (Version 6.0, 
Amendment 5 dated 08 March 2022). Any changes in this analysis provided or any additional 
analysis performed will be documented in CSR. 


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5. 
QUALITY CONTROL AND QUALITY ASSURANCE METHODS FOR DATA 
ANALYSIS 
 
Case report forms will be monitored and processed according to the ICON Study Specific 
Procedure (SSP) DM-35070052.01 Data Management Plan (DMP). The DMP describes CRF data 
processing, edit checks, data query management, medical dictionary coding, SAE reconciliation, 
data transfers, and data quality review through database lock or any necessary reopening of the 
database. After database lock, the data will be retrieved from the database using SAS GRID 
Linux/SAS Studio - SAS® 9.4 version (or higher). 


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6. 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSIS 
 
6.1 Pharmacokinetic Analysis 
Pharmacokinetic variables will be calculated from the RBC, plasma and whole blood 
concentration data for GBT021601 using non-compartmental methodsCCI 
 
and actual sampling times for 
single dose part only. 
 
The following PK parameters will be determined for RBC, plasma and whole blood 
concentrations of GBT021601: 
Single-dose parameter: 
Term 
Parameter 
Description 
Cmax 
Maximum observed concentration 
Observed peak concentration obtained directly 
from the experimental data without 
interpolation. 
tmax 
Time to maximum observed 
concentration 
Time corresponding to Cmax. 
AUC0-24 
AUC from time 0 to 24 hr 
Calculated by linear/log trapezoid rule. At 24 hr 
the last quantifiable concentration 
AUC0-t 
Area under the concentration-time 
curve (AUC) from time 0 to the time 
of the last quantifiable concentration 
Calculated by linear/log trapezoid rule. 
AUC0-∞ 
AUC from time 0 to infinity 
AUC0-t + the area extrapolated from the last 
quantifiable concentration to infinity (i.e., 
Clast/λz). 
CL/F Apparent 
Oral Clearance 
Dose/AUC0-∞ 
Dose/AUC0-∞ 
Vz/F 
Apparent volume of distribution 
Dose/(AUC0-∞ * λz) 
t1/2 
Terminal phase (apparent 
elimination) half-life 
ln(2)/λz 
 
The concentrations of GBT021601 in RBC will be derived using the following equation: 
 
 
The RBC concentration will be determined using individual hematocrit data collected on the day 
of PK sample collection. If hematocrit data are not available, the RBC value will be set to 
missing. 


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Only data points that describe the terminal elimination log-linear decline will be used in the 
regression equation for calculation of λz; Cmax and any data point in the distribution phase are not 
included in the calculation. A minimum of 3 points will be used for determination of λz. A 
general rule of adjusted R2 ≥ 0.80 will be considered as acceptable for calculation of λz. If 
adjusted R2 falls below 0.80, then λz will be reported as Not Determined (ND) and that 
participant’s values for λz, t1/2, CL/F, Vz/F and AUC0-∞ will reported in the appropriate listings 
but will be flagged and excluded from descriptive summaries and statistical analysis. If the 
extrapolated AUCinf is more than 20%, then AUCinf, CL/F and Vz/F will be listed but flagged and 
excluded from descriptive summaries and statistical analysis. 
 
Blood to plasma ratios and RBC to plasma ratios for Cmax and AUC will also be determined. 
Multiple Dosing Period 
 
Concentrations of GBT021601 in whole blood, plasma, and RBC will be listed for apparent Cmin 
(minimum concentration from predose to 4 hours postdose) and Cmax (maximum concentration 
from predose to 4 hours postdose) for each subject by visit and dose level. Descriptive statistics [n, 
arithmetic mean, SD, coefficient of variation (CV) %, geometric mean, and geometric mean 
CV%] will be summarized. For Part C, concentration data till Week 2 will not be summarized. 
 
%Hb Occupancy 
 
For both the SAD and MAD portions of the study the Cmax (SAD) and apparent Cmin and Cmax 
(MAD) values will be used to calculate Hb occupancy with the following equation. 
 
% 𝐻𝐻𝐻𝐻 𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜 = [𝐺𝐺𝐺𝐺𝐺𝐺021601]𝑅𝑅𝑅𝑅𝑅𝑅 
𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀 
 
MCHC = mean corpuscular hemoglobin concentration; the MCHC value on the day of PK 
sample collection will be used. If MCHC value is not available, the % Hb occupancy value will 
be set to missing. 
 
The % Hb occupancy of GBT021601 will be listed and summarized for each visit by treatment 
group, including n, arithmetic mean, SD, CV %, and in graphical format (linear scale [MAD 
only]). 
6.2 Treatment of Outliers 
Individual concentration-time points, if considered anomalous, may be excluded from the 
analysis at the discretion of the pharmacokineticist following a review of the available 
documentation. Any such exclusion will be discussed with the sponsor and clearly outlined in the 
study report. 
 
Entire individual treatment profiles for a participant may be excluded following review of the 
available documentation and discussion with the sponsor. However, results of analysis with and 
without the excluded profiles may be presented in the study report. Any such exclusion will be 
clearly listed in the study report along with justification for exclusion. 


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CCI 
Any anomalous concentration values observed at predose will be identified and discussed in the 
CSR. Participants who experience emesis during the course of the study will be excluded from 
the PK summaries and statistical analysis if vomiting occurs at or before 2 times median Tmax. 
6.3 Non-Quantifiable Concentrations 
All concentration values reported as no results (not collected or ND) will be treated as missing. 
For the calculation of concentration summaries, plotting mean and individual concentration time 
profiles, all concentrations below quantifiable limit (BLQ) will be treated as zero. For the 
purpose of calculating PK parameters, BLQ values will be treated as zero prior to the first 
measurable concentration. After the first measurable concentration, subsequent BLQ values will 
be treated as missing. 
6.4 Pharmacodynamic Analysis 
 
 
 
A separate report will be prepared for rest of the PD parameters analysis (hemoximetry and RBC 
deformability). 


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7. 
STATISTICAL METHODS 
 
7.1 General 
The statistical analysis will be conducted following the principles specified in the International 
Conference on Harmonisation (ICH) Topic E9 Statistical Principles for Clinical Trials 
(CPMP/ICH/363/96). 
 
All statistical tabulations and analyses will be done using SAS GRID Linux/SAS Studio - SAS® 
9.4 version (or higher) and any exceptions will be detailed in the CSR. 
 
All continuous data will be listed with the same precision as presented in the database. Both 
observed values and change-from-baseline values for each participant will be given where 
applicable. Unless otherwise noted, continuous variables will be summarized using number of 
non-missing observations (n), mean, standard deviation (SD), median, quartile (Q1 and Q3), 
minimum, and maximum; categorical variables will be summarized using the frequency count 
and the percentage of participants in each category. 
 
In the data listings, study day relative to first dose of study drug may be presented. Study day 
relative to first dose will be calculated as: event date – first dose date (+ 1 if event date ≥ first 
dose date). 
 
For Part A (SAD), baseline will be the average of screening and day -1 values prior to the first 
study drug administration in the study. 
 
For Part B (MAD) and Part C (Extended treatment period), baseline will be the last measurement 
prior to the 2nd drug administration, i.e. the value on Day 56 should be the baseline. 
 
The change from baseline and percent change from baseline to any subsequent post-baseline visit 
will be calculated as the absolute difference between that post-baseline visit’s value and the 
baseline visit value, as below: 
Change from baseline = Post-baseline value – Baseline value. 
Percent Change from baseline = [(Post baseline value – Baseline value) /Baseline value]*100. 
 
For safety summaries, the unscheduled and repeat assessments will not be summarized; however, 
will be included in the data listing. PK, PD, and safety data will be summarized by loading and 
maintenance doses or overall, as applicable. 
 
Statistical analysis will be performed separately for Part A (SAD), Part B (MAD) and Part C 
(Extended treatment period) for PK, PD, and safety analysis. 
 
7.2 Handling of Dropouts or Missing Data 
Missing data will not be imputed except for the way described to handle concentration in Section 
6.1.2. 


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7.3 Handling of missing/ incomplete dates for Adverse Event 
Imputation rules for missing or partial AE start date are defined below: 
 
If only Day of AE start date is missing: 
If the start date has month and year but day is missing, the first day of the month will be imputed 
• If this date is earlier than the first dose date, then the first dose date will be used instead. 
• If this date is later than the stop date (possibly imputed), then the stop date will be used 
instead. 
If Day and Month of AE start date are missing: 
If the start date has year, but day and month are missing, the 1st of January will be imputed 
• If this date is earlier than the first dose date, then the first dose date will be used instead. 
• If this date is later than the stop date (possibly imputed), then the stop date will be used 
instead. 
If Year of AE start date is missing: 
If the year of AE start is missing or AE start date is completely missing, then imputation will not 
be done. 
 
If the AE end date (full or partial) is before the first dose date then the AE should be considered 
as a pre-treatment AE. Otherwise, the AE will be considered as TEAE. 
7.4 
Handling of missing or partial Prior/Concomitant Medication Dates 
Missing or partial medication start date: 
a. If only Day is missing, the first day of the month will be assumed. 
b. If Day and Month are both missing, the first day of the year will be assumed. 
c. If Day, Month and Year are all missing, the day before the first dose date will be 
assumed. 
Missing or partial medication stop date: 
a. If only Day is missing, the last day of the month will be assumed. 
b. If Day and Month are both missing, the last day of the year will be assumed. 
c. If Day, Month and year are all missing, ‘ongoing status to stop date will be 
assigned. 
 
7.4 Multiple Comparisons and Multiplicity 
No multiple comparison or multiplicity adjustment will be done based on the objective of the 
study. 


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Protocol No. GBT021601-012 
ICON Project No. 3507/0052 
Statistical Analysis Plan Final v3.0 
24 MAR 2023 
CONFIDENTIAL 
Page 34 of 44 
 
 
7.5 Adjustments for covariates 
Not applicable 
7.6 Multicenter Studies 
This study will be conducted in up to 3 sites in United States of America. 
7.7 Examination of Subgroups 
No subgroup analyses are planned. 
7.8 Coding dictionaries 
Medical history, concomitant procedures and AEs will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA) Version 24.0 or higher. Medications will be coded using 
the World Health Organization Drug Dictionary (WHO Global B3 format - March 2021 or 
higher). 
7.8 
Analysis Sets 
 
7.8.1 
Safety Population 
All participants who received any amount of study drug (GBT021601). 
7.8.2 
Pharmacokinetic Population 
All participants who received at least 1 dose of GBT021601and have at least 1 plasma or whole 
blood concentration data point. 
7.9 
Participant Accountability 
Summaries of analysis populations and subject disposition will be presented by overall and will 
contain the following information: 
• Number and percent of subjects received any dose (Safety Population) 
• Number of subjects who completed Single dose period 
• Number of subjects who completed Multiple ascending-dose period 
• Number and percent of subjects who completed the treatment 
• Number and percent of subjects who discontinued the treatment and reason for early 
discontinuation of the treatment 
• Number and percent of subjects who completed the study 
• Number and percent of subjects who discontinued early and reason for early 
discontinuation 
• Number and percent of participants in the PK full and PK evaluable population. 
Percentage will be based on the number of safety population. Participant disposition will be 
presented in listing for all safety subjects. 
7.10 
Protocol Deviations 
Major protocol deviations will be identified prior to database lock for any intentional or 
unintentional change, or noncompliance with the approved protocol procedures or requirements. 
All protocol deviations will be listed using safety population. 


Global Blood Therapeutics, Inc. 
Protocol No. GBT021601-012 
ICON Project No. 3507/0052 
Statistical Analysis Plan Final v3.0 
24 MAR 2023 
CONFIDENTIAL 
Page 35 of 44 
 
 
7.11 
Participant Demographics and Baseline Characteristics 
Participant demographics and baseline characteristics will be listed and summarized 
descriptively for all participants by overall. The summary will include the participants’ age at 
informed consent (in years), gender, race, ethnicity, weight (in kg), height (in cm), and Body 
Mass Index (in kg/m2) using safety population. 
7.12 
Baseline Sickle Cell Disease 
Number of Vaso-Occlusive Crisis (VOC) including the number of VOCs requiring 
hospitalization and the number of blood transf usion during the previous 12 months will be 
summarized categorically. 
 
Additional summaries including the number and percentage of subjects who currently use 
hydroxyurea, who have each genotype (HbSS or HbS β0 Thalassemia) and who experienced a 
sickle cell complication prior to study enrolment will be presented. Baseline lab values including 
Hb and reticulocyte count will be summarized using descriptive statistics. 
 
7.13 
Hemoglobin Response 
Hemoglobin response, defined as an increase in Hb > 1 g/dL, will be listed and summarized 
descriptively at each postdose visit. Subjects who discontinue early or do not have a postdose 
visit, are not included in the analysis for Hb response. No missing data imputation or adjustment 
for transfusion will be performed for this endpoint. 
 
7.14 
Medical and Surgical History 
The medical and surgical history data will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA, Version 24.0 or higher) and will be listed using safety population. 
7.15 
Measurements of Treatment Compliance 
Individual participant listing will be provided for eCRF collected exposure data using safety 
population. 
7.16 
Pharmacokinetic Analysis 
The PK population will be used for all concentration listings and individual figures. Plasma, 
RBC (if applicable) and whole blood GBT021601 concentrations will be listed and summarized 
for each visit/ time point for single dose including n, nBLQ, mean, SD, geometric mean, 
coefficient of variation (CV), median, minimum and maximum. 
 
The drug concentrations will be presented in graphical formats (linear and semi-log scales) as 
mean and individual profiles. Overlay of individual RBC, plasma and whole blood GBT021601 
concentration profiles over time will be provided. 
All plasma, RBC (if applicable) and whole blood GBT021601 PK parameters for single dose 
will be listed for PK population. Summary statistics (n, mean, SD, geometric mean, median, 
minimum, maximum, and CV) will be calculated for the plasma, RBC and whole blood 
GBT021601 PK parameters. For tmax, only n, minimum, median and maximum will be reported. 


Global Blood Therapeutics, Inc. 
Protocol No. GBT021601-012 
ICON Project No. 3507/0052 
Statistical Analysis Plan Final v3.0 
24 MAR 2023 
CONFIDENTIAL 
Page 36 of 44 
 
 
7.17 
Safety Analyses 
All Safety analysis will be presented using the Safety population. 
 
All safety data will be summarized by Part A (SAD), Part B (MAD) and Part C (extended 
treatment period) or overall (as applicable), and visit/ time point. No statistical tests will be 
performed. 
7.17.1 Adverse Events 
All AE summaries will include treatment emergent AEs and will be presented for SCD related 
and SCD non-related separately. 
 
SCD related AEs include: 
 
SCD-related AEs comprise the following PTs: sickle cell anemia with crisis, ACS, pneumonia 
grouped terms (includes all PTs of pneumonia reported in this study), priapism, and 
osteonecrosis. 
 
All AEs will be coded by primary system organ class (SOC) and preferred term (PT) according 
to the MedDRA Version 24.0 or higher and presented by participant in data listings. 
 
The overall incidence of TEAEs (number of events, number and percentage of participants) will 
be summarized parts and overall. It includes: AEs, TEAEs, TEAEs by severity, SAEs, causally 
related TEAEs and SAEs, TEAEs leading to study or treatment discontinuation, life-threatening 
SAEs, and SAEs resulting in death. 
 
The TEAEs will be summarized and tabulated at both the participant (n [%] of participants) and 
event (number of events) level: 
• TEAEs by SOC and PT 
• TEAEs by SOC, PT and maximum reported severity 
• TEAEs by SOC, PT and closest relationship to study drug 
• TEAEs by SOC, PT 
 
For the incidence at the participant level by SOC and PT, if a participant experiences more than 1 
event within the same SOC and PT, only 1 occurrence will be included in the incidence. 
 
For the incidence at the participant level by SOC, PT, and severity, if a participant experiences 
more than 1 event within the same SOC and PT, only the most severe occurrence will be 
included in the incidence. 
For the incidence at the participant level by SOC, PT, and relationship, if a participant 
experiences more than 1 event within the same SOC and PT, only the closest relationship will be 
included in the incidence. 
 
Any SAEs, AEs with outcome of death, or AEs resulting in discontinuation of study or study 
drug will be listed separately. 


Global Blood Therapeutics, Inc. 
Protocol No. GBT021601-012 
ICON Project No. 3507/0052 
Statistical Analysis Plan Final v3.0 
24 MAR 2023 
CONFIDENTIAL 
Page 37 of 44 
 
 
7.17.2 Clinical Laboratory Assessments 
Observed values, change from baseline and percent change from baseline for each parameter of 
continuous clinical laboratory values (hematology, coagulation, chemistry and urinalysis) will be 
summarized by visit/time points using descriptive statistics. 
 
A listing of all clinical laboratory data for each participant at each visit will be presented. 
Laboratory values that are abnormal clinically significant values will be presented. 
If the character result is reported for quantitative laboratory parameter, then for summary and 
analysis it will be changed as follows into numerical value – 
 
a) 
If less than ‘<’ sign is used then the value will be reduced by 1 point from the last 
precision digit 
 
b) 
If greater than ‘>’ sign is used then 1 point will be added to the last precision digit. 
Eg: if the lab parameter is reported to 2 decimal precision, <40.01 then for summary and analysis 
it will be treated as 40.00, if the parameter is reported with 1 decimal precision <40.1 then it will 
be considered as 40.0 and if lab parameter is reported as whole number >40 then it will be 
considered as 41. 
7.17.3 Vital Signs 
Observed and change from baseline vital signs values will be summarized at each time point 
using safety population. Vital signs data will be listed by participant at each visit/ time point. 
7.17.4 Electrocardiograms 
Observed values and change from baseline of 12-lead ECG parameters (heart rate, PR, QRS, QT, 
and QTcF intervals) will be summarized descriptively at each scheduled visit/ time point 
collected using safety population. For the timepoints where triplicate ECGs were collected, in 
listing all the three values and average will be presented and for summary statistics only average 
value will be used. 
 
Individual ECG data including outlier will be listed. ECG interpretation will be summarized as 
counts and percentages and the same will be listed. 
7.17.5 Prior and Concomitant Medications 
Concomitant medication is defined as any medication with a start date prior to the date of the 
first dose of study drug and continuing after the first dose of study drug or with a start date on or 
after the date of the first dose of study drug. 
Prior medication is defined as any medication with a stop date prior to the date of the first dose 
of study drug. 
 
Prior and Concomitant medications will be coded using the WHO Drug Dictionary (WHO 
Global B3 format - March 2021 or higher) and classified according to anatomical therapeutic 
chemical code (ATC) levels 4 and Preferred Name. All prior and concomitant medications will 
be listed. 


Global Blood Therapeutics, Inc. 
Protocol No. GBT021601-012 
ICON Project No. 3507/0052 
Statistical Analysis Plan Final v3.0 
24 MAR 2023 
CONFIDENTIAL 
Page 38 of 44 
 
 
CCI 
 
 
7.18 
Planned Interim Analysis 
There is no planned interim analysis. 
 
The site’s Principal Investigator and the Sponsor’s Medical Monitor will closely monitor the 
safety of the study participants throughout the duration of study. The SMC will review the 
totality of safety, tolerability, and available PK and PD data to monitor safety. 
 
The SMC will be composed of the Principal Investigators from each site, or designee, and 
Sponsor representatives, including the Medical Monitor, Clinical Pharmacologist, Biostatistician, 
and Safety Scientist. The SMC will have overall responsibility f or any safety and tolerability 
decisions and for proceeding with dose escalation. Details of the scope including decision, 
responsibilities, action taken, and frequency of the SMC will be provided in the SMC charter. 
Format of tables and listings for SMC meeting is provided in mocks document. 
 
In the MAD Period of the study, the SMC will review safety, tolerability, PK, and PD data 
through Day 42 after the single dose from at least 4 participants. The Sponsor will inform the 
SMC in writing regarding the GBT021601 t1/2, and dosing interval of steady state multiple 
dosing for the participants of this study. 
 
For the Extended treatment period (Part C), the SMC will meet on an ad hoc basis under any 
condition(s) where decisions about ongoing participant dosing in the study is in question and 
participant safety may be at risk. 
 
This is an open label study, so the data reviewed to make dose escalation decisions will not be 
blinded. 
7.19 
General Conventions for Tables, Listings and Figures 
Tables and listings will be presented in landscape mode with minimum of 3/4” bound edge 
margin and 3/8” other margins on 8.5” x 11” paper. 
 
Times new roman font size of no less than 8 point will be used for tables and listings. 
 
A source line will be included on the bottom of each page of all tables and listings. It will contain 
the SAS code program name and the run date and time. 
 
Each variable is recorded to a specific number of decimal places. If the raw data is presented 
with varying precision, then the least precise value will be considered as the data precision. 


Global Blood Therapeutics, Inc. 
Protocol No. GBT021601-012 
ICON Project No. 3507/0052 
Statistical Analysis Plan Final v3.0 
24 MAR 2023 
CONFIDENTIAL 
Page 39 of 44 
 
 
For all summary tables, unless otherwise specified, the number of decimal places provided in the 
tables and listings will be based on the accuracy of the least accurate value in the raw data as 
follows: 
 
N 
integer 
Arithmetic mean 
1 decimal place more than the least accurate number in the raw data 
SD 
2 decimal place more than the least accurate number in the raw data 
CV(%) 
2 decimal places 
Geometric mean 
1 decimal place more than the least accurate number in the raw data 
Median 
1 decimal place more than the least accurate number in the raw data 
Minimum 
same number of decimal places as raw data 
Maximum 
same number of decimal places as raw data 
Confidence interval 
same number of decimals as the associated statistic 
Percentage 
1 decimal place 
 
 
Following is the mock presentation for tables and listings 
 
1.  Tables 
 
Table 14.1.1 Summary of Participant Disposition (Safety Population) 
Overall 
(N=XX) 
Disposition 
n (%) 
 
 
Subjects who were 
Dosed 
xxxxxx 
…… 
 
 
 
Safety tables will be presented by part and Overall. 


Global Blood Therapeutics, Inc. 
Protocol No. GBT021601-012 
ICON Project No. 3507/0052 
Statistical Analysis Plan Final v3.0 
24 MAR 2023 
CONFIDENTIAL 
Page 40 of 44 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 ….. 
 
CCI 


Global Blood Therapeutics, Inc. 
Protocol No. GBT021601-012 
ICON Project No. 3507/0052 
Statistical Analysis Plan Final v3.0 
24 MAR 2023 
CONFIDENTIAL 
Page 41 of 44 
 
 
CCI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI 


Global Blood Therapeutics, Inc. 
Protocol No. GBT021601-012 
ICON Project No. 3507/0052 
Statistical Analysis Plan Final v3.0 
24 MAR 2023 
CCI 
CONFIDENTIAL 
Page 42 of 44 
 
 
CCI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Global Blood Therapeutics, Inc. 
Protocol No. GBT021601-012 
ICON Project No. 3507/0052 
Statistical Analysis Plan Final v3.0 
24 MAR 2023 
CCI 
CONFIDENTIAL 
Page 43 of 44 
 
 
CCI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Global Blood Therapeutics, Inc. 
Protocol No. GBT021601-012 
ICON Project No. 3507/0052 
Statistical Analysis Plan Final v3.0 
24 MAR 2023 
CONFIDENTIAL 
Page 44 of 44