Clinical trial NCT03041909
Conditions: Sickle Cell Disease
Sponsor: Global Blood Therapeutics
Start date: 2016-08-01; Completion date: 2017-08-01
Enrollment: 5 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open label, single arm study which enrolled 5 subjects with SCD who previously participated in the GBT440-001 study (NCT02285088).

Detailed description:
This is an open label, single arm study which enrolled 5 subjects with SCD who previously participated in the GBT440-001 study (NCT02285088).

Dosing of study drug was 2 to 6 months, depending on subject's dose assignment in the last administration of study drug in GBT440-001 (NCT02285088).

The primary objective of the study was to evaluate the safety and tolerability of up to a total of 6 months dosing of subjects with SCD who participated in the GBT440-001 study (NCT02285088).

Arms: arm 1: Single Arm / open label
Interventions: intervention 1: GBT440
Intervention descriptions: intervention 1: Oral drug

Protocol documents:
Prot_SAP_000.pdf: 
 
Clinical Study Protocol (Version 2) 
 
 
Page 1 of 67 
 
 
 
 
 
Form No:  PI_TP_RW001 Revision 5 
Reference:  PI_OP_MW0203 
Effective Date: 01Sep2010 
 
Copyright © 2008, 2009, 2010 Quintiles Transnational Corp. All rights reserved.  The contents of this document are 
confidential and proprietary to Quintiles Transnational Corp. Unauthorized use, disclosure or reproduction is strictly 
prohibited. 
 
 
An open label single arm extension study to further evaluate the safety, 
tolerability and treatment response of GBT440 in patients with Sickle Cell 
Disease who participated in the Phase 1 Study GBT440-001 
 
 
 
 
 
Protocol Number: 
 
GBT440-024 
Quintiles Study Number: 
 
BYA73740 
EudraCT Number: 
 
2016-002123-28  
Product: 
 
GBT440 
Indication: 
 
Sickle Cell Disease 
Clinical Phase: 
 
IIa 
Principal Investigator: 
 
Professor Timothy Mant, FRCP, FFPM 
Sponsor: 
 
Global Blood Therapeutics, Inc. 
Version: 
 
Version 2 
Date: 
 
28 September 2016 
 
 
 
 
This protocol is the confidential property of Global Blood Therapeutics, Inc, 
and is intended solely for the guidance of this clinical investigation. This 
protocol may not be disclosed to parties not associated with the clinical 
investigation or used for any other purpose without the prior written consent of 
Global Blood Therapeutics, Inc. 
 
 


 
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Clinical Study Protocol  
Version 2 
Date 28 September 2016 
Quintiles Study Number: BYA73740 
Protocol Number:GBT440-024 
EudraCT Number:2016-002123-28 
 
 
 
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Summary of protocol amendments 
Revisions 
 
Inclusion criteria has been changed from  
o Subjects with SCD who are currently enrolled in the GBT440-001 study, 
Cohort 15 or 17 
 
to: 
 
o Subjects with SCD who have participated in the GBT440-001 study. 
 
 Dose titration section has been added allowing increase in dose by 300 mg 
increments every 2 weeks up to maximum of 1500 mg, if in the opinion of the 
investigator the subject is tolerating the current dose level and might derive further 
benefit from an increase in dose (e.g. the hemolysis measures have improved but 
not yet normalized). 
 Placebo subjects in Cohort 15 will initiate treatment with GBT440 at 900 mg. 
 Removed concomitant medication restrictions for CYP2D6 substrates 
 Removed the collection of the SCD severity questionnaire 
 Updated clinical experience with GBT440 in Study GBT440-001 
Rationale for revisions 
 Because of delays in initiating the GBT440-024 study, several subjects from 
Cohort 17 of GBT440-001 had already completed dosing and were unable to 
participate. In addition, many subjects from earlier cohorts expressed interest in 
longer term, open label dosing with GBT440 in GBT440-024. For this reason the 
inclusion criteria have been expanded to allow enrolment of subjects with SCD 
who have completed the GBT440-001 study. These individuals will follow the 
same schedule indicated in the relevant schedule of assessments (SOA) in 
Section17.0. 
 Dose titration has been added because data from the GBT440-001 study has 
shown a linear and highly significant relationship between GBT440 blood level 
and improvement in hemolysis and no plateau effect has been reached. This 
suggests that subjects may derive greater benefit at higher doses achieving higher 
haemoglobin occupancy. Furthermore the target for optimal efficacy based on 
individuals with HbS/Hereditary persistence of fetal haemoglobin is 20-30% 
haemoglobin occupancy (Ngo 2011) and the preliminary PK data from Cohort 17 
showed that the majority of subjects did not maintain haemoglobin occupancy 


 
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Clinical Study Protocol  
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Protocol Number:GBT440-024 
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>20% at 900 mg daily dosing.  In addition, no dose limiting toxicities or 
concerning dose-or exposure related toxicities pose a safety concern with higher 
doses. At 1500 mg, the predicted Cmax is 167 µg/mL, which is less than the Cmax 
already observed and found to be well-tolerated in healthy volunteers in 
GBT440-001 294 µg/mL, 900 mg [Cohort 10]). Provided the principal 
investigator determines that the 600 mg or the 900 mg dose is well tolerated (after 
at least 28 days of prior dosing), and that the subject may receive further benefit 
from higher dosing (further improvement in haemoglobin, reticulocyte count or 
unconjugated bilirubin) the dose may be increase by one capsule (300 mg) every 
two weeks up to a maximum of 1500 mg.  
 Placebo subjects in Cohort 15 will initiate treatment with GBT440 at 900 mg to 
increase the likelihood of achieving haemoglobin occupancy ≥ 20%. 
 
The concomitant medication restrictions for CYP2D6 has been removed because 
preliminary data from the clinical drug-drug interaction study, GBT440-017, 
suggest that GBT440 does not inhibit metoprolol, a CYP2D6 substrate.   
 The version of the SCD severity questionnaire used in this study is an older 
version, the updated, current version will be added to the upcoming Phase 3 study. 


 
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Clinical Study Protocol  
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Date 28 September 2016 
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Protocol Number:GBT440-024 
EudraCT Number:2016-002123-28 
 
 
 
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1.0 STUDY CONTACTS 
PRINCIPAL INVESTIGATOR: 
Professor Timothy Mant, FRCP, FFPM 
The BRC Clinical Research Facility  
Floor 15  
The Tower Wing,  
Guy’s and St Thomas’s NHS Foundation Trust  (GSTT) 
Great Maze Pond  
London SE1 9RT 
Tel: +44 (0)7796930350 
Email: tim.mant@kcl.ac.uk 
 
 
INVESTIGATIONAL SITE: 
 
The BRC Clinical Research Facility  
Floor 15 The Tower Wing,  
Guy’s Hospital 
Guy’s and St Thomas’s NHS Foundation 
Trust  (GSTT)  
Great Maze Pond  
London SE1 9RT 
Quintiles Drug Research Unit at Guy's 
Hospital, Quintiles Ltd., 
6 Newcomen Street,  
London  
SE1 1YR,  
United Kingdom 
Tel:  +44 (0) 0207 188 1103 
Tel:  +44 (0) 0207 910 7700 
Email Stephen.Barnett@gstt.nhs.uk 
Fax:  +44 (0) 0207 910 7800 
 
 
SPONSOR MEDICAL MONITOR/24 HOUR MEDICAL CONTACT: 
Josh Lehrer-Graiwer, MPhil, MD, FACC  
Senior Director, Clinical Sciences  
Global Blood Therapeutics, Inc. 
Tel: 
+1 650 741 7744 
Fax: 
+1 650 741 7701 
Mob: 
+1 415 317 2608 
E-mail: jlehrer@globalbloodtx.com 
 
SPONSOR REPRESENTATIVE: 
Josh Lehrer-Graiwer, MPhil, MD, FACC  
Senior Director, Clinical Sciences 
Global Blood Therapeutics 
 
SPONSOR: 
Global Blood Therapeutics, Inc. 
400 East Jamie Court, Suite 101, 
South San Francisco,  
CA 94080 
United States of America 
Tel: 
+1 650 741 7700 
Fax: 
+1 650 741 7701 


 
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Clinical Study Protocol  
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Date 28 September 2016 
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Protocol Number:GBT440-024 
EudraCT Number:2016-002123-28 
 
 
 
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LABORATORY ANALYSIS: 
Viapath 
John Roberts 
Guy’s Hospital 
Guy’s and St Thomas’s NHS Foundation Trust  (GSTT)  
Great Maze Pond  
London SE1 9RT  
Tel: +44(0)207 188 9684 
Email: John.Roberts@viapath.co.uk 
 
 
BIOANALYTICAL ANALYSIS: 
Worldwide Clinical Trials 
8609 Cross Park Drive 
Austin, TX 78754 
United States of America 
Tel: 
+1 512 834 7766 
 
 


 
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Clinical Study Protocol  
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Date 28 September 2016 
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Protocol Number:GBT440-024 
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2.0 TABLE OF CONTENTS 
1.0 
STUDY CONTACTS .................................................................................. 4 
2.0 
TABLE OF CONTENTS ............................................................................ 6 
3.0 
TABULATED PROTOCOL SUMMARY ................................................ 10 
4.0 
LIST OF ABBREVIATIONS .................................................................... 13 
5.0 
INTRODUCTION ..................................................................................... 14 
5.1 
Nonclinical Experience .............................................................................. 16 
5.1.1 
Safety Pharmacology ................................................................................. 16 
5.1.2 
Pharmacokinetics ....................................................................................... 16 
5.1.3 
Nonclinical Pharmacology ......................................................................... 16 
5.1.4 
Metabolism ................................................................................................ 17 
5.1.5 
Toxicology ................................................................................................. 18 
5.1.6 
Toxicokinetics ............................................................................................ 18 
5.2 
Clinical Experience .................................................................................... 18 
5.2.1 
Overview of Clinical Studies to Date ........................................................ 18 
5.2.2 
Additional Phase 1 Data ............................................................................ 23 
5.3 
Rationale .................................................................................................... 23 
5.3.1 
Rationale for Dose Titration ...................................................................... 24 
5.4 
Risk Assessment ........................................................................................ 24 
5.5 
Urgent safety measures .............................................................................. 25 
6.0 
STUDY OBJECTIVES ............................................................................. 26 
6.1 
Primary Objective ...................................................................................... 26 
6.2 
Secondary Objectives ................................................................................ 26 
6.3 
Exploratory Objectives .............................................................................. 26 
7.0 
INVESTIGATIONAL PLAN .................................................................... 27 
7.1 
Overall Study Design ................................................................................. 27 
7.1.1 
Stopping Rules ........................................................................................... 28 
7.2 
Study Population ........................................................................................ 29 
7.2.1 
Subject Inclusion Criteria .......................................................................... 29 
7.2.2 
Subject Exclusion Criteria ......................................................................... 29 
7.2.3 
Restrictions ................................................................................................ 31 
7.2.3.1 
Avoidance of Pregnancy ............................................................................ 32 
7.2.3.2 
Acceptable Forms of Contraception .......................................................... 32 
7.2.3.3 
Time Period for the Collection of Pregnancy Information ........................ 33 
7.2.3.4 
Follow-up in the Event of a Pregnancy ..................................................... 34 
7.2.4 
Subject Withdrawals .................................................................................. 34 
7.2.5 
Study Termination ..................................................................................... 34 
8.0 
STUDY TREATMENT ............................................................................. 35 


 
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8.1 
Investigational Product(s) .......................................................................... 35 
8.1.1 
Supply, Packaging and Labelling .............................................................. 35 
8.1.2 
Storage and Handling Procedures .............................................................. 35 
8.1.3 
Accountability ............................................................................................ 35 
8.2 
Dosage and Administration ....................................................................... 35 
8.2.1 
Dose Titration ............................................................................................ 36 
8.3 
Dose Modification ..................................................................................... 36 
8.4 
Warnings and Precautions ......................................................................... 37 
8.5 
Prior and Concomitant Medication ............................................................ 37 
8.6 
Method of Assigning Subjects to Treatment Groups ................................ 37 
8.7 
Randomisation Procedures ........................................................................ 38 
9.0 
STUDY PROCEDURES ........................................................................... 38 
9.1 
Pharmacokinetic Assessments ................................................................... 39 
9.2 
Pharmacodynamic/Treatment Response Assessments .............................. 39 
9.2.1 
Haemolysis markers: ................................................................................. 39 
9.2.2 
Disease Related Assessments: ................................................................... 39 
9.3 
Safety Assessments .................................................................................... 40 
9.3.1 
Adverse Events .......................................................................................... 40 
9.3.2 
Reporting of Adverse Events ..................................................................... 40 
9.3.3 
Categorisation of Adverse Events ............................................................. 43 
9.3.4 
Causal Relationship Assessment ............................................................... 44 
9.3.5 
Action Taken ............................................................................................. 44 
9.3.6 
Outcome ..................................................................................................... 45 
9.3.7 
Coding of Adverse Events ......................................................................... 45 
9.4 
Clinical Laboratory Safety Tests ............................................................... 45 
9.5 
Clinical Laboratory Safety Tests ............................................................... 45 
9.6 
Clinical Safety Assessments ...................................................................... 47 
10.0 
DATA COLLECTION .............................................................................. 48 
11.0 
EVALUATION OF STUDY DATA ......................................................... 49 
11.1 
Evaluation of Pharmacokinetic Parameters ............................................... 49 
11.2 
Evaluation of Pharmacodynamic Measures ............................................... 49 
11.2.1 
Haemolysis markers: ................................................................................. 49 
11.2.2 
Disease Related Assessments: ................................................................... 49 
11.3 
Evaluation of Safety .................................................................................. 49 
12.0 
STATISTICAL METHODS ...................................................................... 50 
12.1 
Sample Size Determination ....................................................................... 50 
12.2 
Subject Population for Analyses ................................................................ 50 
12.3 
Pharmacokinetic Analysis ......................................................................... 50 
12.4 
Pharmacodynamic/Efficacy Analysis ........................................................ 51 
12.5 
Safety Data Analysis .................................................................................. 51 
13.0 
STUDY REPORT ...................................................................................... 52 


 
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14.0 
REGULATORY AND ETHICAL ISSUES .............................................. 52 
14.1 
Regulatory and Ethics Review and Approval ............................................ 52 
14.2 
Informed Consent ...................................................................................... 52 
14.3 
Indemnity and Compensation .................................................................... 52 
15.0 
STUDY MANAGEMENT ........................................................................ 54 
15.1 
Quality Assurance and Quality Control ..................................................... 54 
15.2 
Protocol Adherence ................................................................................... 54 
15.3 
Documents Necessary for Initiation of Study ............................................ 54 
15.4 
Study Monitoring ....................................................................................... 55 
15.5 
Study Closure ............................................................................................. 55 
15.6 
Study Record Retention ............................................................................. 55 
15.7 
Publication Policy ...................................................................................... 56 
16.0 
REFERENCES .......................................................................................... 57 
17.0 
STUDY SCHEDULE ................................................................................ 60 
18.0 
PROTOCOL SIGNATURES .................................................................... 66 
 
 
 


 
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LIST OF TABLES 
 
Table 1 
CYP substrates with Narrow Therapeutic Range.......................................... 31 
Table 2 
Estimated Blood Volumes: ........................................................................... 38 
Table 3 
Laboratory Parameters .................................................................................. 46 
Table 4 
Schedule of Assessments Group 1 ................................................................ 60 
Table 5 
Schedule of Assessments for Groups 2, 4 and 5 ........................................... 62 
Table 6 
Schedule of Assessments Group 3 ................................................................ 64 
 
 
LIST OF FIGURES 
Figure 1 
Hemoglobin (g/dL):  Relative Change from Baseline, Median and 25th 
and 75th Percentiles ...................................................................................... 21 
Figure 2 
Changes in Lactate Dehydrogenase Levels ................................................... 22 
Figure 3 
Changes in Erythropoietin Levels ................................................................. 22 
 


 
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Protocol Number:GBT440-024 
EudraCT Number:2016-002123-28 
 
 
 
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3.0 TABULATED PROTOCOL SUMMARY 
 
Name of Sponsor/Company: 
 
Global Blood Therapeutics, Inc. 
Name of Finished 
Product(s): 
GBT440 300 mg capsules  
 
Name of Active 
Ingredient(s): 
GBT440  
Title of Study:  
An open label single arm extension study to further evaluate the safety, tolerability and treatment 
response of GBT440 in patients with Sickle Cell Disease who participated in the Phase 1 Study 
GBT440-001. 
Principal Investigator: 
Professor Timothy Mant, FRCP, FFPM 
Investigational Site: 
The BRC Clinical Research Facility, Floor 15, The Tower Wing , Guy’s Hospital, Guy’s and St 
Thomas’s NHS Foundation Trust Great Maze Pond, London SE1 9RT, UK  
Clinical Phase: 
Phase IIa 
Objectives: 
Primary objective  
To evaluate the safety and tolerability of up to a total of 6 months dosing in subjects with sickle cell 
disease (SCD) who participated in the GBT440-001 study. 
Secondary objectives  
To observe the pharmacokinetics (PK) of GBT440 in plasma and whole blood in subjects with SCD. 
To characterize the effect on biomarkers of hemolysis in subjects with SCD. 
Exploratory objectives 
To obtain data on exploratory markers of sickle cell disease activity. 
To obtain data on sickle cell disease symptoms. 
Methodology: 
This is an open label, single arm study.   
Up to 16 subjects with SCD who are 1) enrolled in the GBT440-001 study (Cohorts 15 and 17 only) and 
are in the treatment period or have completed the treatment period within the prior 7 days or 2) have 
previously completed the GBT440-001 study will be eligible to initiate daily dosing in this study.  
Subjects continuing directly from the GBT440-001 study will continue to receive the treatment and dose 
assigned or a lower dose if the dose was reduced in the GBT440-001 study.  Placebo subjects will 
receive active treatment. Subjects who previously completed the GBT440-001 study will receive 900 mg 
daily.  Prior to enrolment into this study the individual subject treatment allocations for eligible subjects 
from the GBT440-001 will be unblinded and subjects will be assigned to the following treatment groups:  
 


 
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Group 1 
Subjects from Cohort 17 in the GBT440-001 study who have received GBT440 900 mg per day for 
4 months will continue receiving GBT440 900 mg per day for a further 2 months in this study. 
Group 2 
Subjects from Cohort 17 in the GBT440-001 study who have received placebo for 4 months will receive 
GBT440 900 mg per day for 6 months in this study. 
Group 3 
Subjects from Cohort 15 in the GBT440-001 study who have received GBT440 600 mg per day for two 
months will continue receiving GBT440 600 mg for a further 4 months in this study or the dose may be 
increased if the subject has tolerated 600 mg in GBT440-001. 
Group 4 
Subjects from Cohort 15 in the GBT440-001 study who have received placebo for 2 months will receive 
GBT440 900 mg per day for 6 months in this study. 
Group 5 
Subjects from Cohort 7, 11, 12, 14 16 or 17 who received either GBT440 or placebo who are enrolled 
into this study will receive GBT440 at a dose of 900 mg per day for 6 months. 
All Subjects will receive a total of 6 months treatment with GBT440 which will include treatment with 
GBT440 in the GBT440-001 study for subjects in Cohort 15 or 17.  Subjects from Cohort 7, 11, 12, 14, 
16 or 17 who received either GBT440 or placebo and are currently off study in GBT440-001 will receive 
a total of 6 months of treatment with GBT440 in this study.. 
The dose may be increased by 300 mg increments (1 capsule) every 2 weeks up to maximum of 
1500 mg, if in the opinion of the investigator the subject is tolerating the current dose level and might 
derive further benefit from an increase in dose (e.g. hemolysis measures have improved but not 
normalized). 
A Safety Monitoring Committee (SMC) consisting of the Principal Investigator, Sponsor Medical 
Monitor, and Independent Safety Physician will have overall responsibility for assessing safety and 
tolerability. The SMC will review cumulative data at least monthly to determine whether continued 
dosing may proceed. The responsibilities of the SMC will be described in a separate charter. 
Number of Subjects: 
Up to 8 SCD subjects from GBT440-001 cohort 17 (900 mg per day), up to 8 SCD subjects from 
GBT440-001 cohort 15 (600 mg per day), and additional SCD subjects who previously  completed 
GBT440-001 may be enrolled up to a total sample size not exceeding 16 subjects. 
Main Criteria for Inclusion: 
Subjects with SCD who are currently enrolled in the GBT440-001 study, Cohort 15 or 17.  
Subjects with SCD from Cohort 7, 11, 12, 14, 16 or 17 from the GBT440-001 study. 
Eligibility may be determined from assessments obtained as part of the GBT440-001 study within 7 days 
of dosing in this study for subjects in Cohort 15 or 17. 
Eligibility must be determined from assessments obtained during baseline visit for subjects who were 
previously enrolled in Cohorts 7, 11, 12, 14, 16 or 17. 
Subjects who if female and of child bearing potential, are using highly effective methods of 
contraception from study start to 3 months after the last dose of investigational medicinal product (IMP). 
Female subjects must continue to have a negative pregnancy test result. 


 
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Subjects whose clinical laboratory test results are not clinically relevant and continue to be acceptable to 
the Investigator. 
Subjects who if male are willing to continue to use barrier methods of contraception, from study start to 
3 months after the last dose of investigational product. 
Test Product, Dose and Route of Administration: 
GBT440 300 mg oral capsules for oral administration. 
Duration of Treatment: 
Subjects will continue dosing until they have received a total of 6 months treatment with GBT440 which 
includes prior dosing with GBT440 in the GBT440-001 study for subjects enrolled in Cohorts 15 or 17. 
Subjects from Cohort 7, 11, 12, 14, 16 or 17 who received either GBT440 or placebo will receive a total 
of 6 months of treatment with GBT440 in this study. 
Criteria for Evaluation 
Pharmacokinetics: 
Whole blood and plasma levels of GBT440 as indicated in the schedule of assessments (SOA). 
Pharmacodynamics: 
Haemolysis markers: 
Haemoglobin, unconjugated bilirubin, LDH, absolute and % reticulocyte counts and % dense cells will 
be measured as indicated in the SOA. 
Disease Related Assessments: 
Inflammatory markers and exploratory biomarkers related to SCD disease severity will be assessed as 
indicated in the SOA. 
Safety: 
The safety evaluation will include blood pressure, pulse rate, body temperature, respiratory rate, ECG 
parameters, clinical laboratory tests (haematology, serum biochemistry (including erythropoietin), 
coagulation, urinalysis and urine microscopy) and adverse events. 
Statistical Methods 
Pharmacokinetic Parameters: 
Whole blood and plasma levels of GBT440 will be listed and summarised using appropriate descriptive 
statistics by dose and study day. 
Where appropriate an estimate of t1/2 will be computed and presented in tabular form with appropriate 
descriptive statistics. 
Pharmacodynamic Parameters: 
Haemolysis and Disease related assessments will be listed and summarised using appropriate descriptive 
statistics. 
Safety Parameters: 
Individual and summary blood pressures, heart rate, body temperature, respiratory rate, ECG parameters 
and clinical laboratory data (haematology, serum biochemistry and coagulation) will be presented in 
tabular form with appropriate descriptive statistics. Adverse events will be tabulated and summarized. 


 
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4.0 LIST OF ABBREVIATIONS  
 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALK 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration time curve 
CI 
Confidence interval 
CK 
Creatine kinase 
CPMP 
Committee for Proprietary Medicinal Products 
CRF 
Case report form 
CRP 
C reactive protein 
CV 
Coefficient of variation 
Cmax 
Maximum plasma concentration 
ECG 
Electrocardiogram 
EEG 
Electroencephalogram 
EU GMP 
European Union – Good Manufacturing Practice 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transpeptidase 
HBsAg 
Hepatitis B surface antigen 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s brochure 
ICH 
International Conference on Harmonization 
IMP 
Investigational medicinal product 
IMPD 
Investigational medicinal product dossier 
LS mean 
Least squares mean 
LDH 
Lactate dehydrogenase 
Max 
Maximum 
MHRA 
Medicines and Healthcare products Regulatory Agency 
Min 
Minimum 
NOAEL 
No observed adverse effect level 
PT 
Prothrombin time 
QP 
Qualified person 
SAE 
Serious adverse event 
t½ 
Apparent terminal half life 
 
 
 


 
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5.0 INTRODUCTION   
Sickle cell disease (SCD) is an inherited disorder caused by a point mutation in the  
β-globin gene leading to formation of haemoglobin S (HbS).  Sickle cell disease 
predominantly occurs in individuals whose ancestors originated from sub-Saharan Africa, 
Spanish speaking regions of the Western Hemisphere (South America, Caribbean, Central 
America); Saudi Arabia; India; and Mediterranean countries including Turkey, Greece, 
and Italy.  It is the most common single gene disorder in African Americans.  A primary 
and obligatory event in the molecular pathogenesis of SCD is the polymerisation of 
deoxygenated HbS and the resultant sickling of red blood cells (RBC).  Sickle cell disease 
is characterised by haemolytic anemia and vaso-occlusion leading to progressive end-
organ damage with a clinical course of life-long pain, disability and early death.   
Management strategies for SCD have evolved very slowly, and treatment of SCD remains 
a serious unmet medical need.  Hydroxyurea (HU) is the only approved therapy for SCD 
but is limited by its side effect profile, poor patient adherence, variable patient responses, 
and concerns of long-term toxicity (Brandow et al, 2010).  In addition to HU treatment, 
transfusions with normal blood are widely used in this patient population to alleviate 
symptomatic anaemia and reduce sickling.  Attaining anti-sickling activity by blood 
transfusions has its own limitations: the treatments are expensive, not uniformly 
accessible and accompanied by risks (Wahl et al, 2009).  The only curative treatment is 
bone marrow transplantation from a histocompatible donor, an option that has been 
available since the 1990s (Platt and Guinana, 2014), but bone marrow transplantation 
carries significant risks and is associated with a ~5% mortality rate (Nathan, 2013).  
Despite the current standard of care, including HU, blood transfusion, and palliative 
therapy for acute attacks, patients with SCD continue to suffer serious morbidity and 
premature mortality (Steinberg et al, 2003). 
To date, no drugs have been approved that specifically target the underlying mechanism 
of sickle cell disease.  The mechanism of action of HU involves a highly variable increase 
in the level of foetal haemoglobin (HbF) in a limited subset of RBCs (F-cells), resulting 
in limited protection from sickling. Foetal haemoglobin is the predominant haemoglobin 
during foetal development and begins to decline in production shortly after birth. 
Synthesis of adult haemoglobin, HbA begins shortly before birth and nears its adult 
proportion approximately 6 to 9 months postpartum. HbF powerfully inhibits the 
polymerization of deoxyHbS due to its high oxygen affinity as well as intrinsic structural 
characteristics that block polymer formation. Individuals who are homozygous for the βS 
gene show no disease manifestations until late in the first year of life when the declining 
level of HbF no longer protects against deoxyHbS polymerization. The protective effect 
of HbF has been further validated by the observation that rare individuals who are 


 
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compound heterozygotes for the βS gene and a gene deletion resulting in persistent HbF 
expression (HbS-HPFH) do not have manifestations of sickle cell disease. HbS-HPFH is 
typically associated with 20-30% HbF levels distributed equally among erythrocytes 
(pancellular). In addition, a form of deletional HbS-HPFH has been described with 
pancellular HbF levels of 10% and few, if any, sickle-cell related events [Akinsheye et al, 
2011].  Taken together, the data from subjects with HbS-HPFH suggests that pancellular 
HbF of 20-30% prevents sickle cell disease and that levels as lows as 10% may be 
sufficient for protection. 
Because oxyhaemoglobin is a potent inhibitor of HbS polymerization, allosteric 
modification of haemoglobin to increase the proportion of oxyhaemoglobin is a 
promising strategy to achieve inhibition of HbS polymerization in all RBCs [Noguchi et 
al, 1988].  Prior experimental haemoglobin modifying agents (BW12C and tucaresol) 
have provided proof of concept for the haemoglobin modification approach by 
demonstrating an increase in oxyhaemoglobin and a decrease in clinical biomarkers of 
haemolysis [Keidan et al, 1986; Arya et al, 1996].  Despite the increase in haemoglobin 
oxygen affinity, these drugs were well tolerated by healthy volunteers and they remained 
well-compensated both at near maximal exercise and at rest with little change in basal 
oxygen consumption or resting heart rate [Nicholls et al, 1989]. 
GBT440 
Global Blood Therapeutics (GBT) has developed GBT440, a small molecule allosteric 
modulator of haemoglobin oxygen affinity, for the treatment of SCD.  GBT440 is 
administered orally in capsules. 
The mechanism of action of GBT440 involves inhibition of HbS polymerisation by 
increasing the affinity of haemoglobin for oxygen.  Haemoglobin exists in both a relaxed 
(R) and a tense (T) state with high and low affinity for oxygen, respectively (Eaton et al, 
1999).  Upon binding to HbS, GBT440 effectively maintains a targeted fraction of HbS in 
the R state. Haemoglobin S molecules that are in the R (oxygenated) state are potent 
inhibitors of HbS polymerisation and, conversely, only deoxygenated HbS is capable of 
polymerising to create sickling of red blood cells.  Because GBT440 binds to the 
haemoglobin α chain, its effects on the oxygen equilibrium curves (OEC) are expected to 
be similar in normal and sickle blood.  Nonclinical data and data from prior experimental 
haemoglobin modifying agents demonstrate that only a fraction of haemoglobin (20 to 
30%) must be maintained in the R state in order to inhibit sickling.  Based on data from 
prior experimental compounds and genetic data from high affinity haemoglobin mutations 
in humans, 20 to 30% haemoglobin modification by GBT440 should be safely achievable 
in humans. 


 
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GBT440 was rationally designed, based on a knowledge of the chemical structure and 
mode of haemoglobin binding of prior haemoglobin modifying agents in order to improve 
potency and specificity for haemoglobin (Abdulmalik et al, 2011).  A medicinal 
chemistry program was used to optimise activity in in vitro haemoximetry and 
polymerisation assays and to achieve a 1:1 stoichiometry of binding per haemoglobin 
tetramer compared to the 2:1 stoichiometry of prior compounds.  Subsequently, GBT440 
was found to be considerably more potent than all reported predecessor compounds in in 
vitro assays and to have sustained exposure following oral dosing in multiple animal 
species.  
5.1 
Nonclinical Experience 
5.1.1 
Safety Pharmacology 
Safety assessments of GBT440 in three in vivo studies did not identify any biologically 
significant effects in the central nervous system (CNS) and respiratory system. There 
were minor effects in the cardiovascular (CV) safety pharmacology studies, with a mild 
increase in systolic BP at higher doses (1000 mg/kg) and a small decrease (15.3%) in 
hERG channel current at 10µM. Based on these results, there appears to be a low risk to 
humans for adverse effects on CNS, respiratory, or CV function. 
5.1.2 
Pharmacokinetics 
Pharmacokinetic evaluation showed that GBT440 had low blood clearance (CL), low 
blood Vss, a long terminal t½ and was well absorbed in all animal species tested.  
GBT440 whole blood concentrations were much higher than plasma concentrations 
(calculated RBC: plasma ratio ~150:1), consistent with a high affinity and specificity of 
GBT440 for Hb. The pharmacokinetic (PK) properties of GBT440 in animals suggest that 
it will preferentially bind to Hb and be slowly but completely eliminated from the body.  
With increasing doses in rats and dogs, the exposure of GBT440 is increased less than 
dose-proportional.  
5.1.3 
Nonclinical Pharmacology 
An overview of the key nonclinical data is provided below.  For a more detailed 
discussion of the nonclinical pharmacology, pharmacokinetic and toxicology studies 
conducted to date, please refer to the Investigator’s Brochure for GBT440 for the 
treatment of SCD. 
Primary PD studies of GBT440 consisted of in vitro and in vivo studies to characterize 
(a) GBT440 binding and affinity for Hb, (b) the effect of GBT440 on HbS modification 
using purified Hb, washed RBCs, and whole blood, and (c) the efficacy of GBT440 in 
vivo in a mouse model of SCD.  The in vitro assays of increasing complexity included 
measuring Hb-O2 affinity via haemoximetry, quantifying stabilization of the 


 
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oxyhaemoglobin state conformation, delaying HbS polymerization at low oxygen tension, 
preventing in vitro sickling induced by a low oxygen environment, and decreasing 
viscosity and improving deformability of RBCs in blood from patients with SCD. In 
addition, these studies show that GBT440-modified Hb retains the Bohr Effect, which is 
the ability to augment oxygen delivery in metabolically active (low pH) tissues. 
Collectively, these studies demonstrate that GBT440 potently increases Hb-O2 affinity 
with high specificity of binding to Hb; stabilizes the oxy or R-state conformation of Hb; 
prevents HbS polymerization and RBC sickling in vitro; improves sickle blood viscosity, 
and deformability in vitro; and increases HbS-oxygen affinity and RBC half-life, while 
decreasing ex vivo sickling and reticulocyte count in a SCD mouse model. 
5.1.4 
Metabolism 
Studies in rat and dog indicate that metabolism was the major route of elimination 
involving both Phase I and Phase II metabolism pathways. Renal excretion of GBT440 
was a minor elimination pathway. GBT440 metabolites were excreted in both urine and 
feces.  
Evaluation of enzymes involved in the metabolism of GBT440 was conducted with 
13 recombinant human CYP450 enzymes and recombinant human aldehyde oxidase and 
aldehyde dehydrogenase 1A1. The data suggests that GBT440 could be metabolized by 
CYP1A1, 1B1, 2B6, 2C9, 2C19, 3A4, and 3A5.  The clinical relevance for potential drug 
interactions when GBT440 is co-administered with CYP inducers or inhibitors is 
unknown at this time. 
GBT440 inhibited CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 
enzymes in vitro with Ki values from 0.8 to 112 µM.  However, based on preliminary data 
from the GBT440-003 drug-drug interaction (DDI) study, GBT440 does not appear to 
inhibit CYP1A2, CYP2C9 or 2C19 but may be a weak inhibitor of CYP3A4.  Clinical 
DDI studies to assess whether GBT440 inhibits CYP2C8 or CYP2D6 are planned. 
A CYP450 induction study was assessed for CYP1A2, CYP2B6, and CYP3A4 using 
human cryopreserved hepatocytes.  GBT440 at ≥ 10 μM may cause increases in CYP2B6 
expression and may be acting through the constitutive androstane receptor.  The clinical 
implications are not known. 
GBT440 was evaluated as a potential inhibitor of human OAT1, OAT3, OCT1, OCT2, 
OATP1B1, OATP1B3, MATE1, MATE2K, BCRP, P-gp, and BSEP-mediated 
transporters. GBT440 has potential to inhibit OAT3 transporter which may result in a 
higher concentration of co-administered drug(s) that is a substrate for this transporter.  
However, since GBT440 does not appear to be excreted unchanged in urine the likelihood 
of an interaction is low.  GBT440 was also tested as a potential substrate for human Pgp, 


 
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BCRP, OATP1B1-, OATP1B3-, OATP1A2-, and BSEP-mediated transporters.  The data 
indicates that GBT440 was not a substrate for any of these transporters tested.  
5.1.5 
Toxicology 
Nonclinical toxicology studies have defined no observed adverse effect levels (NOAEL) 
for GBT440 in rats and monkeys for up to 13 weeks and for dogs following 28 days of 
dosing, assessed toxicokinetics in 4 species (rat, dog, monkey, and rabbit), and 
determined the reversibility of any effects.  The majority of effects in rats were 
considered related to the mechanism of action or adaptive, reversible effects.  In dogs and 
monkeys, gastrointestinal (GI) effects appeared to be dose-limiting.  A genotoxicity 
battery indicated a low risk of genotoxic effects and dose range-finding embryo-fetal 
studies in rats and rabbits did not reveal notable effects on embryo-fetal development. 
A six month toxicology study in rats and a 9-month toxicology study in monkeys are 
currently ongoing with projected data availability in Q3 2016 (rat) and Q1 2017 (monkey) 
respectively. 
More details on the completed studies are contained in the GBT440 Investigator 
Brochure.  
5.1.6 
Toxicokinetics 
The steady state PK parameters (whole blood) on Day 28 in rats dosed with 
250 mg/kg/day (NOAEL) was 1055 µg/mL (3,127 µM) Cmax and 17950 µg*hr/mL 
AUC0-24.  The adverse effects in the dog study occurred at much lower exposures than 
observed in the rat study (285 µg/mL [845 µM] Cmax and 5840 µg*hr/mL AUC0-24, 
1000 mg/kg dose group), and were possibly secondary to changes caused by chronic 
vomiting and faecal changes (soft stool, liquid, diarrhoea). 
5.2 
Clinical Experience  
5.2.1 
Overview of Clinical Studies to Date 
As of 01 August 2016, 251 subjects, including 204 healthy subjects and 47 subjects with 
SCD, have been treated with single or multiple doses (up to 15 days in healthy subjects, 
and up to 90 days in subjects with SCD) of GBT440 across 9 clinical studies.  
A Phase 1/2 study (Protocol GBT440-001) evaluating the safety, tolerability, 
pharmacokinetics (PK), and PD effects of single and multiple doses of orally 
administered GBT440 in healthy subjects and subjects with SCD is ongoing.  A total of 
95 subjects (48 healthy subjects and 47 subjects with SCD) have received GBT440.  
Healthy subjects have received single doses of GBT440 ranging from 100 to 2800 mg, 
and have received multiple-doses of 300, 600, or 900 mg/day for up to 15 days.  In 
subjects with SCD, GBT440 has also been evaluated in multiple doses of 500, 700, and 


 
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1000 mg/day for up to 28 days, and multiple doses of 700 and 900 mg/day for up to 
90 days.  An additional cohort is subjects with sickle cell–hemoglobin C (HbSC) or 
HbS/β+thalassemia is currently ongoing at a dose of 600 mg for 28 days. 
In addition to the studies noted above, there are 8 clinical pharmacology studies 
(GBT440-002, GBT440-003, GBT440-004, GBT440-005, GBT440-008, GBT440-017, 
GBT440-018 and GBT440-019) in which a total of 156 healthy subjects received 
GBT440.  
Study GBT440-001  
GBT440-001 is an ongoing, Phase 1, randomized, placebo-controlled, double-blind, 
single and multiple ascending dose study of the tolerability and PK of GBT440 in healthy 
subjects and in subjects with SCD that is being conducted at a single study site in the 
United Kingdom. The study was initiated in December 2014. The study is being 
conducted under the supervision of a Study Monitoring Committee (SMC), consisting of 
the Principal Investigator from the study site, the Sponsor’s medical monitor, and an 
independent safety physician. The investigator and study subjects are blinded to treatment 
assignment. The SMC has conducted regular reviews of the safety data collected in this 
study through 9 June 2016.  
The study includes 3 parts (Parts A, B, and C):  
 Part A consists of a single ascending dose evaluation in healthy subjects and in 
subjects with SCD  
 Part B consists of a 15-day multiple ascending dose evaluation in healthy subjects 
and a 28-day multiple ascending dose evaluation in subjects with SCD  
 Part C consists of a 90-day multiple dose evaluation in subjects with SCD. An 
amendment has been submitted to extend the dosing period by a further 30 days.  
In addition to the above, within Part A, the effect of food (low-fat meal) on the PK profile 
of GBT440 was evaluated in 1 of the healthy subject cohorts in a crossover design. 
Subjects in this cohort received 2 doses of GBT440 or placebo; the first dose followed an 
8- to 10-hour fast and, following a washout period, the second dose followed a meal. 
Part A 
Forty-eight (48) subjects have been dosed in 6 single dose cohorts  comprised of 40 
healthy volunteer subjects (30 received single doses of GBT440 ranging from 100 to 
2800 mg and 10 received placebo- Cohorts 1 to 5) and 8 subjects ( cohort 7) with SCD 
(6 received GBT440 1000 mg and 2 received placebo) in this study. 
Note: Cohort 6 was not required.  


 
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Part B 
Sixty two subjects have been dosed in 6 multiple dose cohorts comprised of 24 healthy 
volunteer subjects (cohorts 8, 9 and10) dosed for up to 15 days (18 received GBT440 at 
doses of 300, 600 or 900 mg/day and 6 received placebo), 16 subjects (cohort 11) with 
SCD dosed for 28 days (12 receiving GBT440 700 mg/day and 4 receiving 
placebo),14 subjects (Cohort 12) with SCD dosed for 28 days (GBT440 500 mg/day 
/placebo), 8 subjects (Cohort 14) with SCD dosed for 28 days (6 receiving GBT440 
500 mg twice a day/2 receiving placebo). One subject (cohort 15) with SCD (HbSC and 
HbS/β+thalassemia) has been dosed GBT440 600mg/day/placebo for 28 days. A further 
7 subjects (Cohort 15) with SCD (HbSC and HbS/β+thalassemia) are to commence dosing 
with GBT440 600mg/day/placebo for 60 days.  
Note: Cohorts 6 and 13 were not required. 
Part C  
Eight subjects (Cohort 16) with SCD have commenced dosing for 90 days (6 receiving 
GBT440 700 mg/day and 2 receiving placebo). All eight subjects have completed.  
In Cohort 17, 8 subjects with SCD have commenced dosing for up to 118days receiving 
GBT440 900 mg/day /placebo). Two of these subjects have completed 90 days of dosing, 
four of these subjects have completed 118 days of dosing, and two are ongoing.  As of 03 
August 2016  two subjects from Cohort 17 have enrolled into this study (GBT440-024). 
Results  
Safety data are now available and have been reviewed by the SMC through end of the 
dosing period for subjects in Part A, for 24 healthy subjects who received doses of 
GBT440 300, 600, or 900 mg/day for up to 15 days in Part B, and 38 SCD subjects in 
Cohorts 11, 12 and 14 who received GBT440 700 mg/day, GBT440 500 mg/day for 28 
days and GBT440 500 mg/twice a day respectively.  All serious and severe AE data are 
reviewed by the sponsor and principal investigator as events emerge on an ongoing basis.  
To date no drug related serious or severe adverse events have occurred. 
In Parts A and B the most frequently reported events were primarily gastrointestinal 
events (stomach ache, stomach pain, abdominal pain, diarrhea and loose stools), headache 
and rash.  Adverse events in healthy subjects and SCD subjects were generally similar 
except for sickle cell related pain and nausea which were reported in SCD but not healthy 
volunteer subjects.  
The majority of adverse events were mild (Grade 1).  In Part A (Cohort 1), one Grade 2 
event of upper respiratory tract infection was considered by the investigator to be possibly 
related to study drug and in Part B (Cohorts 8, 10 and 11) three Grade 2 events of 


 
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headache were considered possibly related to study drug.  As described above, there have 
been no drug-related severe or serious adverse events. 
Safety Monitoring Committee data review has not identified any abnormal or clinically 
significant trends in vital signs, ECG or safety laboratory data across cohorts.  No adverse 
events or protocol-defined dose limiting toxicity criteria associated with tissue hypoxia or 
hyperviscosity have been observed and there have been no cases of moderate or severe 
suspected drug hypersensitivity.  Furthermore, the SMC has also provided approval to 
proceed with 2 cohorts of SCD subjects who will receive 90-day dosing of study drug. In 
Part C, which includes fourteen subjects who have completed dosing with 
GBT440/Placebo there have been no severe or serious drug-related adverse events. 
Treatment with GBT440 resulted in a large and sustained reduction in clinical markers of 
hemolysis (as evidenced by declining unconjugated bilirubin and reticulocyte counts and 
an improvement in anemia). The increase in Hb after 90 days of dosing is shown in 
Figure 1.  No significant changes from Baseline were observed for subjects receiving 
placebo.  These results are consistent with inhibition of HbS polymerization leading to 
decreased RBC damage, improved RBC lifespan, and improvement in tissue oxygen 
delivery.  Additional treatment response data, including data from 28-day cohorts, is 
provided in the GBT440 IB.   
Figure 1 
Hemoglobin (g/dL):  Relative Change from Baseline, Median and 25th and 
75th Percentiles 
Change in Haemoglobin - (g/dL)
-1.0
-0.5
0.0
0.5
1.0
1.5
2.0
2.5
Days
-
1
1
5
2
8
4
3
6
0
9
0
Group:
700 mg x 90 days
Placebo
2.5
2.0
1.5
1.0
0.5
0
-0.5
-1.0
---- Placebo (pooled) 
---- GBT440 700 mg x 90 days
0                  15           28             43                  60                                  90
Days
Change from Baseline
 


 
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Figure 2 
Changes in Lactate Dehydrogenase Levels 
 
Figure 3 
Changes in Erythropoietin Levels 
 
 


 
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5.2.2 
Additional Phase 1 Data 
A total of 156 healthy subjects have been enrolled in the 8 Phase 1 clinical pharmacology 
studies (GBT440-002, GBT440-003, GBT440-004, GBT440-005, GBT440-008, 
GBT440-017, GBT440-018, and GBT440-019).  Results are available for GBT440-003 
(cocktail drug interaction) and GBT440-004 (relative bioavailability), and preliminary 
results are available for GBT440-005 (food effect) and GBT440-008 (CYP2C8 
interaction study) and GBT440-019 (PPI interaction study).  Studies GBT440-017 
(CYP2D6 interaction study) and GBT440-018 (bioavailability study [tablet compared to 
capsule formulation]) are ongoing. 
5.3 
Rationale 
To date GBT440 has been generally well tolerated in patients with SCD for up to 90 days. 
There have not been any drug related SAEs and no unexpected AEs.  
In addition preliminary pharmacodynamic data from patients with SCD treated with 
GBT440 for 28 days  indicate  a significant reduction in the number of the sickled RBCs, 
improvement in haemolysis markers as evidenced by declines in reticulocyte counts, 
unconjugated bilirubin and lactate dehydrogenase (LDH) levels and an improvement in 
anemia are encouraging. The initial impression of blinded data reviewed by the SMC 
suggests emerging data from GBT440-001 suggest that these improvements are sustained 
over 90 days of treatment. 
Given the significant unmet need in SCD, there is an interest in determining the potential 
for further development of GBT440 by generating safety and efficacy data with longer 
term dosing (greater than 90 days) as quickly as possible while still safeguarding the 
safety of subjects.  To do this safely and efficiently subjects in ongoing cohorts 17 and 15 
in the GBT440-001 study will be enrolled in this proposed extension study.  Additionally, 
SCD subjects from earlier Cohorts (i.e. Cohorts 7, 11, 12, 14 or 16) from GBT440-001 
will be approached for enrollment into this study.  Because of delays in initiating the 
GBT440-024 study, several subjects from Cohort 17 of GBT440-001 completed dosing 
and were unable to participate in this study. Many subjects from earlier cohorts expressed 
interest in longer term dosing with GBT440. The inclusion criteria have been expanded to 
allow enrolment of subjects with SCD who have completed the GBT440-001 study 
however total enrollment into this study will be limited to a total of 16 subjects. To 
continue to ensure the safety of subjects, regular safety monitoring and additional 
periodic SMC review during the total 6 month treatment period will be implemented.  In 
particular, haemoglobin levels, reticulocyte count and erythropoietin levels will be 
monitored for evidence of tissue hypoxia/hyperviscosity.  GBT440 treatment will be 
discontinued for excessive Hb increase or dose reduced for evidence of hyperviscosity 
based on increasing Hb, erythropoietin and reticulocyte levels. 


 
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5.3.1 
Rationale for Dose Titration 
Dose titration has been added because data from the GBT440-001 study has shown a 
linear and highly significant relationship between GBT440 blood level and improvement 
in hemolysis and no plateau effect has been reached. This suggests that subjects may 
derive greater benefit at higher doses achieving higher haemoglobin occupancy. 
Furthermore the target for optimal efficacy based on individuals with HbS/Hereditary 
persistence of fetal haemoglobin is 20-30% haemoglobin occupancy (Ngo 2011) and the 
preliminary PK data from Cohort 17 showed that the majority of subjects did not maintain 
haemoglobin occupancy >20% at 900 mg daily dosing.  In addition, no dose limiting 
toxicities or concerning dose-or exposure related toxicities pose a safety concern with 
higher doses. Doses of 1000 mg for 28 days and 900 mg for 90 days have been well 
tolerated, with the majority of AEs were Grade 1 or 2 in severity.  At 1500 mg, the 
predicted Cmax is 167 µg/mL, which is less than the Cmax already observed and found to be 
well-tolerated in healthy volunteerrs in GBT440-001 (294 µg/mL at 900 mg [Cohort 10]).  
To assess the higher dose of 1500 mg, subjects will be dose escalated by 300 mg over 
2-week intervals.  The principal investigator will determine if the 600 mg or the 900 mg 
dose is well tolerated (after at least 28 days of prior dosing), and that the subject may 
receive further benefit from higher dosing (further improvement in haemoglobin, 
reticulocyte count or unconjugated bilirubin) the dose may be increase by one capsule 
(300 mg) every two weeks up to a maximum of 1500 mg.  
This study will be performed in compliance with the protocol, ICH GCP and applicable 
regulatory requirements.  Aspects of the study concerned with the investigational 
medicinal product(s) (IMPs) will meet the requirements of EU GMP. 
5.4 
Risk Assessment 
Based on the mechanism of action of GBT440 and findings in the nonclinical safety 
toxicology studies, GBT440 could cause tissue hypoxia.  In GLP toxicology studies, rats 
dosed for 28 days with ≥250 mg/kg/day demonstrated increased erythropoietin and red 
cell mass (Hct, RBC, or Hb) with extramedullary hematopoiesis and bone marrow 
hypercellularity.  These findings are consistent with expected physiologic compensation 
to hypoxia, were not considered adverse, and were reversible. 
In prior clinical experience with other agents, no adverse reactions related to tissue 
hypoxia were reported at the highest tested doses of tucaresol administered in either 
healthy subjects (maximum 40% Hb-modification) or subjects with SCD (maximum 24% 
Hb modification), or BW12C infusions in either healthy subjects (maximum 40% Hb-
modification) or subjects with SCD (23% Hb modification) (Arya 1996, Keidan 1986, 
Nicholls 1989, Rolan 1995).  Appropriate acute and chronic compensatory physiologic 
responses to tissue hypoxia were observed, including an increase in heart rate during 


 
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moderate exercise and a slight increase in reticulocyte counts at high doses (Nicholls 
1989, Rolan 1995, Rolan 1993).  Importantly, healthy subjects were well compensated- 
both at rest and at near maximal exercise with little change in resting heart rate (Nicholls 
1989).  Potential tissue hypoxia can be monitored by hematology laboratory studies, 
erythropoietin levels, and cardiovascular parameters.  
Gastrointestinal effects (primarily emesis, and soft or liquid feces) were observed in all 
species and were dose-limiting in dogs and monkeys.  Gastrointestinal erosions, ulcers, or 
epithelial hyperplasia were observed at high doses in rats. 
Preliminary results from Study GBT440-001 evaluating GBT440 in adult subjects suggest 
that GBT440 is well tolerated in healthy subjects at single doses from 100 to 2800 mg and 
in subjects with SCD at a single dose of 1000 mg.  The results also suggest that GBT440 
is well tolerated in healthy subjects following repeat administration at dosages up to 
900 mg once daily for 15 days, and in subjects with SCD following administration at 
dosages up to 1000 mg once daily for 28 days.  The Safety Monitoring Committee (SMC) 
review of ongoing dosing in a 90 day treatment cohort at 700 mg and 900 mg per day has 
found GBT440 to be generally safe and well tolerated (as of 06 June 2016).  The most 
commonly reported AEs across all subjects principally included diarrhea and headache; 
these events were often considered by the Investigator to be treatment-related.  In 
addition, the decline in erythropoietin levels suggest an improvement in oxygen delivery 
either by increase in hemoglobin or improvement in microvascular blood flow, or both. 
5.5 
Urgent safety measures 
In accordance with UK Law [Medicines for Human Use (Clinical Trials) as amended:  SI 
1031 Part 4 Section 30] the Sponsor and Investigator may take appropriate urgent safety 
measures in order to protect the subjects of a clinical trial against any immediate hazard 
to their health or safety.  If such measures are taken the Sponsor shall immediately (no 
later than 3 days from the date the measures are taken) give written notice to the licensing 
authority and the relevant ethics committee of the measures taken and the circumstances 
giving rise to those measures. 


 
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6.0 STUDY OBJECTIVES 
6.1 
Primary Objective 
 To evaluate the safety and tolerability of up to a total of 6 months dosing in 
subjects with sickle cell disease (SCD) who participated in the GBT440-001 
study. 
6.2 
Secondary Objectives 
 To observe the pharmacokinetics (PK) of GBT440 in plasma and whole blood in 
subjects with SCD. 
 To characterize the effect on biomarkers of hemolysis in subjects with SCD. 
6.3 
Exploratory Objectives 
 To obtain data on exploratory markers of sickle cell disease activity. 
 To obtain data on sickle cell disease symptoms. 


 
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7.0 INVESTIGATIONAL PLAN 
7.1 
Overall Study Design 
This is an open label, single arm study.   
Up to 16 subjects with SCD who were enrolled in the GBT440-001 study (Cohorts 7, 11, 
12, 14, 15, 16 or 17 will be eligible to participate.. On attendance to the clinic, subjects in 
Cohorts 15 or 17 will be asked whether they want to be considered for study GBT440-
024. If the subject is interested in study GBT440-024 all consent activities will be 
completed before the samples/procedures for GBT440-024 are collected/performed. For 
subjects who were enrolled in Cohorts 7, 11, 12, 14, 16 or 17 who are interested in 
participating in study GBT440-024, all consent activities will be completed before the 
samples/procedures for GBT440-024 are collected/performed. Prior to enrolment into this 
study the individual subject treatment allocations for eligible subjects from the GBT440-
001 (Cohorts 15 or 17) will be unblinded and subjects will be assigned to the following 
treatment groups:  
 Group 1 
Subjects from Cohort 17 in the GBT440-001 study who have received GBT440 900 mg 
per day for 4 months will continue receiving GBT440 900 mg per day for a further 
2 months in this study. 
Group 2 
Subjects from Cohort 17 in the GBT440-001 study who have received placebo for 
2 months will receive GBT440 900 mg per day for 6 months in this study. 
Group 3 
Subjects from Cohort 15 in the GBT440-001 study who have received GBT440 600 mg 
per day for 2 months will continue receiving GBT440 600 mg for a further 4 months in 
this study or the dose may be increased if the subject has tolerated 600 mg in 
GBT440-001. 
Group 4 
Subjects from Cohort 15 in the GBT440-001 study who have received placebo for 
2 months will receive GBT440 900 mg per day for 6 months in this study. 
Group 5 
Subjects from Cohort 7, 11, 12, 14, 16 or 17 who received either GBT440 or placebo will 
receive a total of continuous 6 months of treatment with GBT440 in this study 
(GBT440 024) at a dose of 900 mg per day. 


 
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Subjects enrolled on this study will be numbered based on the subject number that were 
assigned in Study GBT440-001 with the addition of 24 to the beginning of the subject 
number. eg, Subject 17001 in study GBT440-001 will be assigned number 2417-1001 in 
study this study. 
Subject numbering in this study will be as follows:  
GBT440-001 
Cohort 
GBT440-001 Subject 
Number 
GBT440-
024 Group 
GBT440-024 Subject 
Number 
17 
17001-17008 
1 and 2 
2417-1001 to 2417-1008 
15 
15001-15008 
3 and 4 
2415-1001 to 2415-1008 
7 
07001-07008 
5 
2407-1001 to 2407-1008 
11 
11001-11016 
2411-1001 to 2411-1016 
12 
12001-12014 
2412-1001to 2412-1014 
14 
14001-14008 
2414-1001 to2414-1008 
16 
16001-16008 
2416-1001 to 2416-1008 
 
If a subject from GBT440-001 elects not to participate in this protocol, their 
corresponding identification number would remain unused.  
All Subjects will receive a total of 6 months treatment with GBT440 which will include treatment 
with GBT440 in the GBT440-001 study for subjects in Cohort 15 or 17.  Subjects from Cohort 7, 
11, 12, 14, 16 or 17 who received either GBT440 or placebo will receive a total of 6 months of 
treatment with GBT440 in this study. 
A Safety Monitoring Committee (SMC) consisting of the Principal Investigator, Sponsor 
Medical Monitor, and Independent Safety Physician will have overall responsibility for 
assessing safety and tolerability. The SMC will review cumulative data at least monthly 
to determine whether continued dosing may proceed. The responsibilities of the SMC will 
be described in a separate charter. 
7.1.1 
Stopping Rules 
Individual subject stopping rule 
 Dosing for any individual subject will be stopped if the subject experiences a 
serious adverse event (SAE) or a clinically significant non serious AE, which in 


 
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the opinion of the Principal Investigator or Sponsor’s Medical Monitor, warrants 
discontinuation of the study for that subject’s wellbeing. 
7.2 
Study Population 
Male/female patients with sickle cell disease will be entered into this study provided that 
they satisfy the following inclusion/exclusion criteria. 
7.2.1 
Subject Inclusion Criteria 
1. Male or female subjects with HbSS, HbS/β0thalassemia, HbS/β+thalassemia, or 
HbSC aged 18 to 60 years inclusive and  >50 kg who have enrolled in cohorts 15 
or 17 of the GBT440-001 study and will not experience interruption in dosing for 
greater than 7 days prior to commencing continuation of dosing in this extension 
study protocol. 
2. Male or female subjects who were enrolled in Cohorts 7, 11, 12, 14, 16 or 17 in 
the GBT440-001 study (and are currently off-study) are eligible to enroll into this 
study. 
3. Subjects who if female and of child bearing potential, agree to continue to use 
highly effective methods of contraception prior to enrolment in this study and for 
3 months after the last dose of IMP. 
4. Subjects whose clinical laboratory test results are not clinically relevant and 
continue to be acceptable to the Investigator at the final visit of the GBT440-001 
study for subjects enrolled in Cohort 15 or 17. 
5. Subjects who if male are willing to continue to use barrier methods of 
contraception, prior to enrolment in this study to 3 months after the last dose of 
IMP. 
7.2.2 
Subject Exclusion Criteria 
1. Subjects requiring chronic transfusion therapy. 
2. Subjects receiving a blood transfusion within 30 days of enrolment in this study. 
3. Subjects with alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) >5x upper limit of normal reference range (ULN)  
4. Subjects with moderate or severe renal dysfunction (calculated modification of 
diet in renal disease estimated glomerular filtration rate (MDRD eGFR) 
<60mL/min/1.73 m2 appropriately corrected for race and gender). 


 
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5. Subjects with any history of congestive heart failure requiring hospitalisation or 
whose 12 lead ECG prior to enrolment has a confirmed QTcF interval of >450 
msec for male subjects or >470 msec for female subjects. 
6. Subjects who do not conform to the above inclusion criteria. 
7. Female subjects who are pregnant, trying to become pregnant or lactating. 
8. Subjects who have a clinically relevant history or presence of respiratory, 
gastrointestinal, renal, hepatic, haematological, lymphatic, neurological, 
cardiovascular, psychiatric, musculoskeletal, genitourinary, immunological, 
dermatological, connective tissue diseases or disorders, or additional risk factors 
for torsades de pointe (e.g., heart failure, hypokalemia, personal or family history 
of long QTc interval). 
9. Subjects who have a history of relevant atopy. 
10. Subjects who have a history of relevant drug hypersensitivity. 
11. Subjects who have a history of alcoholism. 
12. Subjects who have a history of drug abuse (N.B. occasional recreational cannabis 
use is not an exclusion). 
13. Subjects who consume more than 14 (female subjects) or 21 (male subjects) units 
of alcohol a week.  
14. Subjects who have a significant infection or known inflammatory process on 
admission to this study. 
15. Subjects who have acute gastrointestinal symptoms at the time of admission (e.g. 
nausea, vomiting, diarrhoea, heartburn). 
16. Subjects who have an acute infection such as influenza at the time of admission. 
17. Subjects (females of child-bearing potential and males) who do not agree to use 
contraception (as defined in Section 7.2.3.2). 
18. Subjects who are vegans. 
19. Subjects who cannot communicate reliably with the Investigator. 
20. Subjects who are unlikely to co-operate with the requirements of the study. 


 
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7.2.3 
Restrictions 
 Since GBT440 is a weak inhibitor of cytochrome P450 (CYP3A4), GBT440 
should be used with caution with CYP3A4 substrates with a narrow therapeutic 
index (refer to Table 1). 
 In vitro data suggest that GBT440 could be metabolized by CYP1A1, 1B1, 2B6, 
2C9, 2C19, 3A4, and 3A5.  Thus strong inducers of CYP2B6, CYP2C9, 
CYP2C19, and CYP3A4/CYP3A5 should be prohibited (Table 2).  The use of 
herbal medications (e.g., St. John’s Wort) are not allowed. 
 Table 1 
CYP substrates with Narrow Therapeutic Range  
CYP Enzymes 
Substrates with narrow therapeutic range* 
CYP3A4 
alfentanil, astemizole, cisapride, cyclosporine, dihdroergotamine, 
ergotamine, fentanyl, pimozide, quindine, sirolimus, tacrolimus, 
terfenadine 
CYP2C8 
None 
*Substrates with narrow therapeutic range refers to drugs whose exposure-response relationship 
indicates that small increases in their exposure levels by the concomitant use of CYP-inhibitors may 
lead to serious safety concerns.   
Adapted from: FDA DRAFT Guidance for Industry: Drug Interactions Studies-Study 
Design, Data Analysis, Implications for Dosing, and Labeling Recommendations. 
February 2012. 
Table 2:  Strong CYP Inducers  
CYP 
Strong Inducers 
CYP3A4/3A5 
Aavasimibe, carbamazepine, phenytoin, rifampin, St. John’s wort 
CYP2B6, CYP2C9, CYP2C19 
currently no known inducers 
Please note the following:  This is not an exhaustive list.  For an updated list, refer to the following 
link:  
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsL
abeling/ucm080499.htm. 
 During the study, male subjects should continue to avoid consuming more than 
3 units of alcohol per day and female subjects should continue to avoid consuming 
more than 2 units of alcohol per day. 
 Subjects will be required to abstain from blood or plasma donation until 3 months 
after the final medical examination at the study clinic follow up. 
If a subject does not comply with these restrictions or tests positive to any laboratory tests 
(e.g. drug, alcohol) they may be excluded or withdrawn from the study. 


 
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7.2.3.1 
Avoidance of Pregnancy 
Women of Child Bearing Potential 
Pregnancy should be avoided by either true abstinence or the use of highly effective 
means of contraception (see Section 7.2.3.2) for the duration of the study and a total 
period of 3 months after the subject has taken the last dose of GBT440. 
In order to include women of child bearing potential in any clinical trial, certain 
precautions pertaining to pregnancy must be taken.  These will include serum pregnancy 
testing at enrollment and urine pregnancy test at the times indicated in Table 4, Table 5 
and Table 6.  
Female subjects who become pregnant during a study will be withdrawn. 
Women of Non-Child Bearing Potential 
Female subjects of non-child bearing potential are defined as; bilateral oopherectomy / 
hysterectomy/ post-menopausal females being amenorrhoeic for greater than 2 years with 
an appropriate clinical profile, e.g. age appropriate, history of vasomotor symptoms.  
Instructions for Male Subjects 
There is no information about effects that GBT440 could have on the development of the 
foetus in humans.  Therefore, it is important that the partners of male subjects do not 
become pregnant during the study and for a total period of 3 months after the male subject 
has taken the last dose of GBT440.   
As a precaution, all male subjects should avoid fathering a child by either true abstinence 
or the use of barrier methods of contraception (see Section 7.2.3.2).  
As there is no information for GBT440 being secreted in the ejaculate, male subjects 
(including men who have had vasectomies) whose partners are currently pregnant should 
use barrier methods for the duration of the study and for 3 months afterwards.  This is to 
ensure that the foetus is not exposed to the IMP in the ejaculate. 
7.2.3.2 
Acceptable Forms of Contraception 
Highly effective methods of birth control are defined as those which result in a low 
failure rate (i.e. less than 1% per year) when used consistently and correctly.  
 Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation: 
o Oral 
o Intravaginal 


 
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o Transdermal 
Hormonal contraception must be supplemented with a barrier method (preferably 
male condom). 
 Progestogen-only hormonal contraception associated with inhibition of ovulation: 
o Oral 
o Injectable 
o Implantable 
Hormonal contraception must be supplemented with a barrier method (preferably 
male condom). 
 Intrauterine device (IUD) 
 Intrauterine hormone-releasing system (IUS) 
 Bilateral tubal occlusion 
 Vasectomised partner. Note that vasectomised partner is a highly effective birth 
control method provided that partner is the sole sexual partner of the woman of 
child bearing potential trial participant and that the vasectomised partner has 
received medical assessment of the surgical success. 
 Sexual abstinence. Sexual abstinence is considered a highly effective method only 
if the subject is refraining from heterosexual intercourse during the entire period 
of risk associated with the study treatments. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the subject. 
For male subjects: 
 Barrier methods of contraception:  condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.  The use 
of barrier contraceptives should always be supplemented with the use of a 
spermicide. The following should be noted: 
7.2.3.3 
Time Period for the Collection of Pregnancy Information 
All pregnancies in female subjects and the female partners of male subjects receiving at 
least one dose of IMP will be recorded from first dose to 3 months after the final dose. 


 
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7.2.3.4 
Follow-up in the Event of a Pregnancy 
If a female subject, or the female partner of a male subject, who has received IMP 
becomes pregnant, the pregnancy will be recorded.  The ethics committee and the 
Sponsor will be informed.  The subject will be asked to provide information on the 
outcome of the pregnancy, including premature termination should the case arise.  
Spontaneous miscarriage and congenital abnormalities will be reported as SAEs. 
The follow-up period will be deemed to have ended when the health status of the child 
has been determined at birth. 
7.2.4 
Subject Withdrawals 
The Principal Investigator will make every reasonable attempt to complete the study.  A 
subject may withdraw for any reason.  The Principal Investigator will advise the Sponsor 
of the withdrawal of any subject. 
A subject may be withdrawn in any of the following circumstances: 
 AEs; 
 Protocol violation; 
 Withdrawal of consent; 
 Termination of the study by the Principal Investigator or Sponsor. 
Subjects who voluntarily withdraw are termed dropouts.  Dropouts and subjects 
withdrawn due to protocol violations may be replaced following discussion with the 
Principal Investigator and Sponsor. 
Subjects withdrawn due to an adverse event will not be replaced. 
Should a subject request or decide to withdraw from the study, all efforts must be made to 
complete and report the observations as thoroughly as possible up to the date of 
withdrawal.  Subjects withdrawing due to an AE should be followed up according to 
follow-up visit. 
7.2.5 
Study Termination 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating the 
study may include, but are not limited to, the incidence or severity of adverse events in 
this or other studies indicating a potential health hazard to subjects. 


 
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8.0 STUDY TREATMENT 
8.1 
Investigational Product(s) 
GBT440 oral capsules 300 mg capsules.   
8.1.1 
Supply, Packaging and Labelling 
GBT440 oral capsules will be supplied to the Investigational Site by GBT or their 
representative. 
Individual subject treatments will be dispensed by the Investigational Site Pharmacist.  
A release document signed by Investigational Site Pharmacist or designee at the 
Investigational Site will be placed in the appropriate section of the Trial Master File to 
document labelling and dispensing of the study drug to the subject.  A Pharmacy Manual 
(detailing IMP handling instructions) will be in place to cover all pharmacy related 
activities, and IMP accountability. . 
8.1.2 
Storage and Handling Procedures 
All study medication will be stored at 25°C protected from light in the storage area of the 
Investigational Site Pharmacy, which is a secure, temperature controlled, locked 
environment with restricted access. 
No special procedures for the safe handling of GBT440 are required.  The Sponsor will be 
permitted upon request to audit the supplies, storage, dispensing procedures and records 
provided that the blind of the study is not compromised. 
8.1.3 
Accountability 
In accordance with GCP, the Investigational Site will account for all supplies of GBT440.  
Details of receipt, storage, assembly and return will be recorded.  
All unused supplies of GBT440 will either be destroyed by the Investigational Site or 
returned to the study Sponsor at the end of the study in accordance with instruction by the 
Sponsor.  
8.2 
Dosage and Administration 
GBT440 will be administered as oral capsule formulations with water as follows. 
During the outpatient dosing period and in between study visits, subjects will not be 
required to fast and should take their study drug in the morning.  
On study visits during the dosing period when PK samples are collected, subjects should 
have an overnight fast prior to taking study drug in clinic.   


 
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Additionally, during the outpatient dosing period in between study visits, subjects may  
be contacted weekly phone by clinic staff to confirm study drug administration. 
Dosing will be stopped if the Hb is >12.8 g/dL but may restart at a reduced dose once the 
Hb is <12 g/dl following consultation and agreement of the referring SCD NHS 
haematologist. 
8.2.1 
Dose Titration 
Provided the Principal Investigator determines that the 600mg dose (in Cohort 15), 
900 mg dose (in Cohort 17), and 900 mg dose in the Cohorts  7, 11, 12, 14, 16 or 17 is 
well tolerated (after at least 28 days of dosing), and that the subject may receive further 
benefit from higher dosing (further improvement in haemoglobin, reticulocyte count or 
unconjugated bilirubin) the dose may be increase by one capsule (300 mg) every two 
weeks up to a maximum of 1500 mg dose.  
When increasing the dose, the subject should return to clinical every 2 weeks for 
Laboratory and AE assessments 
8.3 
Dose Modification  
Dose modification may be considered if warranted and as outlined below.  All instances 
of study drug modification (change in dosing frequency, dose reduction or 
discontinuation) are to be captured in the subject research record and on the CRF and will 
require prompt notification of the medical monitor (i.e., typically within 48 hours).  If the 
conditions/event leading to the dose modification have resolved, the original dose level 
and once a day dosing frequency should be resumed, unless in the judgement of the 
investigator, this cannot be done safely. Dose reductions will be made in 300 mg 
increments. 
Dose level may be reduced for: 
 Mild or moderate (Grade ≤2) adverse events that persist for ≥72. 
 Moderate (Grade ≥2) adverse events that require intervention (excluding over the 
counter symptomatic treatment such as acetaminophen, NSAIDs, antacids, 
antihistamines), that in the Investigator’s judgement are deemed study drug 
related.   
 Severe (Grade ≥3) adverse events that are not serious and that in the Investigator’s 
judgement are deemed study drug related.  
Study drug may be suspended for: 
 Any AE that, in the opinion of the Investigator is drug related and warrants 
suspension of dosing. 


 
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 Re-initiation of dosing will be based on the Investigator’s clinical assessment in 
consultation with the sponsor. 
 If the conditions/event leading to the dose suspension have improved or resolved, 
dosing should be resumed at the original dose level and once a day dosing 
frequency, unless in the judgement of the investigator, this cannot be done safely.  
Study drug may be discontinued for: 
 Grade ≥ 3 drug-related SAE 
 Any AE that, at the discretion of the Investigator, warrants discontinuation of 
study drug.  
8.4 
Warnings and Precautions 
The preclinical data suggest an acceptable safety margin. The clinical data to date 
suggests that GBT440 is well tolerated. However GBT440 is in early clinical 
development. Facilities and staff for resuscitation and the treatment of other medical 
emergencies will be provided during clinic visits. During outpatient dosing periods, 
subjects will be provided with emergency numbers and contacted on a regular basis 
(weekly) by clinic staff to monitor their wellbeing.  
8.5 
Prior and Concomitant Medication 
The SCD subjects will be allowed to take the medications as needed with the exception of 
those described listed in Section 7.2.3. All concomitant medication will be documented. 
In the interests of subject 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 subjects’ case report form (CRF) (medication, dose, treatment duration 
and indication). 
Subjects will be provided with a diary card for completion during outpatient periods and 
will be instructed to document in the diary all details of AEs, and details of any 
medication taken 
8.6 
Method of Assigning Subjects to Treatment Groups 
Following confirmation of continued eligibility subjects will be assigned to the following 
treatment groups: 
Group 1  
Subjects from Cohort 17 in the GBT440-001 study who have received GBT440 900 mg 
per day for 4 months will continue receiving GBT440 900 mg per day for a further 
2 months in this study. 


 
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Group 2  
Subjects from Cohort 17 in the GBT440-001 study who have received placebo for 
4 months will receive GBT440 900 mg per day for 6 months in this study. 
Group 3  
Subjects from Cohort 15 in the GBT440-001 study who have received GBT440 600 mg 
per day for 2 months will continue receiving GBT440 600 mg for a further 4 months in 
this study or the dose may be increased if the subject has tolerated 600 mg in 
GBT440-001. 
Group 4  
Subjects from Cohort 15 in the GBT440-001 study who have received placebo for 
2 months will receive GBT440 900mg per day for 6 months in this study. 
Group 5 
Subjects from Cohort 7, 11, 12, 14, 16 or 17 who received either GBT440 or placebo who 
are enrolled into this study will receive GBT440 at a dose of 900 mg per day for a total of 
6 months in this study. 
All Subjects will receive a total of 6 months treatment with GBT440 which will include 
treatment with GBT440 in the GBT440-001 study for subjects in Cohort 15 or 17.  
Subjects from Cohort 7, 11, 12, 14, 16 or 17 who received either GBT440 or placebo will 
receive a total of 6 months of treatment with GBT440 in this study. 
8.7 
Randomisation Procedures 
Not Applicable – this is an open label single arm study in which all subjects will receive 
GBT440.  
9.0 STUDY PROCEDURES  
Table 2 
Estimated Blood Volumes:   
Assessment 
Sample Volume 
(mL) 
No. of 
Samples 
Total Volume 
(mL) 
Sickle Cell Disease Subjects:  Multiple Dose  
Safety 
 
 
 
 
Serum Biochemistry 
3.5 
  Up to 10 
35.0 
 
Coagulation 
1.8 
  Up to 8 
14.4 
 
Haematology  
2.0 
  Up to 10 
20.0 
 
Pregnancy 
3.5 
8 
28.0 
 
Hba1c 
3.5 
7 
24.5 
Pharmacokinetic 
 
 
 
 
GBT440 
2.0 
11 
22.0 
 
 
 
 
 
Pharmacodynamic 
 
 
 
 
 
 
 
 
 
Serum erythropoietin (EPO) 
3.5 
Up to 8 
28.0 


 
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Assessment 
Sample Volume 
(mL) 
No. of 
Samples 
Total Volume 
(mL) 
 
Frozen 
Plasma 
Reserved 
for 
immunology/inflammation 
ELISAs 
and exploratory markers 
5.0 
Up to 8 
40.0 
 
Haemoglobin electrophoresis 
2.0 
Up to 4 
8.0 
 
Carboxyhaemoglobin 
2.0 
Up to 7 
14.0 
Disease Related 
 
 
 
 
Dense Cells 
2.0 
Up to 8 
16.0 
 
NT pro-BNP 
2.0 
Up to 8 
16.0 
Total [b] 
 
 
335.9 
Sample volumes are based on direct venipuncture. 
9.1 
Pharmacokinetic Assessments  
Serial whole blood samples will be obtained from all and SCD subjects at the times 
shown in the schedule of events (see Section 17.0) for the determination of GBT440 
concentrations in whole blood and plasma.   
Blood and plasma samples will be analyzed for GBT440 using a validated liquid 
chromatography-tandem mass spectrometry (LC-MS/MS) method. 
9.2 
Pharmacodynamic/Treatment Response Assessments  
Sample collection and assessment times are included in the schedule of events (see  
Section 17.0). 
9.2.1 
Haemolysis markers: 
Haemoglobin, unconjugated bilirubin, LDH, absolute and % reticulocyte counts and % 
dense cells will be measured. 
9.2.2 
Disease Related Assessments: 
Inflammatory markers and exploratory biomarkers related to SCD disease severity will be 
assessed and may include, but are not limited to: 
 Serum erythropoietin  
 Urine microalbumin  
 Plasma cytokines or other exploratory markers of SCD  
 Haemoglobin F levels  
 Immune and Inflammatory plasma biomarkers (e.g. inflammatory cytokines) 
 


 
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9.3 
Safety Assessments  
9.3.1 
Adverse Events 
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. 
An AE can therefore be any clinically significant sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
Adverse Drug Reaction (ADR) 
Any untoward and unintended response in a subject to an IMP which is related to any 
dose administered to that subject. 
Serious Adverse Event (SAE) 
An adverse reaction is ‘serious’ if it: 
 Results in death; 
 Is life-threatening; 
 Requires hospitalization or prolongation of existing hospitalization; 
 Results in persistent or significant disability or incapacity; 
 Consists of a congenital anomaly or birth defect; 
 Is a medically important event. 
Unexpected Adverse Reactions 
An adverse reaction is ‘unexpected’ if its nature and severity are not consistent with the 
information about the medicinal product in question set out: 
 In the case of a product with a marketing authorization, in the summary of product 
characteristics for that product; 
 In the case of any other IMP, in the Investigator’s Brochure relating to the trial in 
question (Investigator's Brochure Version 3, 2016). 
9.3.2 
Reporting of Adverse Events 
All AEs must be fully recorded in the AE book throughout the entire study period and 
will be transcribed into the subjects’ CRF, whether or not they are considered to be drug-
related.  Signs and symptoms of each AE should be described in detail: onset time and 


 
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date, offset time and date, description of event, severity and relationship to IMP, action 
taken and outcome. 
Adverse events ongoing from study GBT440-001 will be recorded and identified in the 
CRF as being ongoing from study GBT440-001 for Cohorts 15 or 17. 
Adverse events will be recorded beginning with administration of study drug in 
GBT440-024.  
All adverse events should be followed until recovery to the normal state has been 
achieved. In the event of a subject not returning to the clinical unit, the outcome of this 
event will be recorded as lost at follow up. 
Diagnosis versus Signs and Symptoms 
If known, a diagnosis should be recorded on the CRF rather than individual signs and 
symptoms (e.g. 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 as an AE or SAE on the CRF.  If a diagnosis is 
subsequently established, it should be reported as follow-up information. 
Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (e.g. cascade events or clinical 
sequelae) should be identified by their primary cause.  For example, if severe diarrhea is 
known to have resulted in dehydration, it is sufficient to record only diarrhea as an AE or 
SAE on the CRF.  
However, medically significant AEs occurring secondary to an initiating event that are 
separated in time should be recorded as independent events on the CRF.  For example, if 
a severe gastrointestinal haemorrhage leads to renal failure, both events should be 
recorded separately on the CRF. 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution between patient 
evaluation time points.  Such events should only be recorded once in the CRF unless their 
severity increases.  If a persistent AE becomes more severe, it should be recorded again 
on the CRF.   
A recurrent AE is one that occurs and resolves between patient evaluation time points and 
subsequently recurs.  All recurrent AEs should be recorded on the CRF. 


 
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Abnormal Laboratory Values 
Only clinically significant laboratory abnormalities that require active management will 
be recorded as AEs or SAEs on the CRF (e.g. abnormalities that require study drug dose 
modification, discontinuation of study treatment, more frequent follow-up assessments, 
further diagnostic investigation, etc.). 
If the clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g. 
alkaline phosphatase and bilirubin 5× the ULN associated with cholecystitis), only the 
diagnosis (e.g. cholecystitis) needs to be recorded on the CRF. 
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded as an AE or SAE on the CRF.  If the laboratory 
abnormality can be characterised by a precise clinical term, the clinical term should be 
recorded as the AE or SAE.  For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as “hyperkalemia.” 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded as AEs or SAEs on the Adverse Event CRF, unless 
their severity, seriousness, or etiology changes.  
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study.  Such 
conditions should be recorded on the CRF. 
A preexisting medical condition should be recorded as an AE or SAE only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the CRF, it is important to convey the concept that the 
preexisting condition has changed by including applicable descriptors (e.g. “more 
frequent headaches”). 
Worsening of Sickle Cell Disease 
Complications related to SCD should be recorded as an AE or SAE only if judged by the 
investigator to have unexpectedly worsened in severity and/or frequency or changed in 
nature any time during the study.  When recording an unanticipated worsening of SCD on 
the CRF, it is important to convey the concept that the condition has changed by 
including applicable descriptors (e.g. “expansion of nonhealing leg ulcer”). Specific 
SCD- related AEs will be tabulated and reported (see assessment of safety section). 
Protocol-Defined Events of Special Interest 
The following events are events of special interest and will need to be reported to the 
Sponsor’s medical representative Josh Lehrer-Graiwer, MPhil, MD, FACC within 
24 hours, irrespective of regulatory seriousness criteria: any suspected drug 


 
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hypersensitivity reactions. Suspected drug hypersensitivity includes but is not limited to 
any occurrence of two or more of the following: fever, rash or lymphadenopathy. 
Reporting of SAEs and SUSARs 
SAEs occurring on this study will be reported to the Sponsor’s medical representative 
Josh Lehrer-Graiwer, MPhil, MD, FACC within 24 hours.  The Principal Investigator will 
be requested to complete a separate SAE reporting form in addition to the information on 
the CRF and in the AE book. 
The Medicines for Human Use (Clinical Trials) Regulations 2004 (Statutory Instrument 
1031) and subsequent amendments define the following terms: 
A suspected unexpected serious adverse reaction (SUSAR) which is fatal or 
life-threatening must be reported to the competent authority and ethics committee 
immediately (within 7 days) after the Sponsor became aware of the event.  Any additional 
information must be reported within 8 days of sending the first report.  
A SUSAR which is not fatal or life-threatening must be reported to the competent 
authority and ethics committee as soon as possible (within 15 days) after the Sponsor 
becomes aware of the event. 
If a clinical trial is being conducted at a trial site in a third country in addition to sites in 
the United Kingdom, the Sponsor of that trial shall ensure that all SUSARs occurring at 
that site are entered into the European database established in accordance with Article 11 
of the EU Clinical Trials Directive. 
As soon as practicable after the end of the reporting year, a Sponsor shall, in relation to 
each IMP tested in clinical trials in the United Kingdom for which he is the Sponsor 
provide the licensing authority and the relevant ethics committees with -  
 A list of all the suspected serious adverse reactions which have occurred during 
that year in relation to: 
 those trials, whether at trial sites in the United Kingdom or elsewhere;  
 or any other trials relating to that product which are conducted outside the 
United Kingdom and for which he is the Sponsor;  
 including those reactions relating to any investigational medicinal product used as 
a placebo or as a reference in those trials; and 
 A report on the safety of the subjects of those trials. 
9.3.3 
Categorisation of Adverse Events 
General AE grading scale: 


 
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 Grade 1:  Transient or mild discomfort (<48 hours); no interference with daily 
activities; no medical intervention required.  
 Grade 2:  Mild to moderate interference with daily activity; no or minimal medical 
intervention required.  
 Grade 3:  Considerable interference with daily activity; medical intervention 
required; hospitalization possible. 
9.3.4 
Causal Relationship Assessment 
Causal relationship assessment to drug treatments is required for purposes of reporting 
AEs.  To promote consistency, the following guidelines should be taken into 
considerations along with good clinical and scientific judgment when determining the 
relationship of drug treatments to an AE: 
Definitely Related: 
A clinical event, including laboratory test abnormality, occurring in 
a plausible time relationship to the medication administration, and 
which cannot be explained by concurrent disease or other drugs or 
chemicals.  The response to withdrawal of the drug should be 
clinically plausible. 
Possibly Related: 
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to the medication administration, but 
which could also be explained by concurrent disease or other drugs 
or chemicals.  Information on the drug withdrawal may be lacking 
or unclear. 
Unlikely Related: 
A clinical event, including laboratory test abnormality, with little or 
no temporal relationship to medication administration, and which 
other drugs, chemicals or underlying disease provide plausible 
explanations. 
Not Related: 
A clinical event, including laboratory test abnormality that has no 
temporal relationship to the medication or has more likely 
alternative etiology. 
9.3.5 
Action Taken 
Action taken will be defined as: 
 None; 
 Dose reduced; 
 Dosing interrupted; 


 
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 Dosing stopped. 
9.3.6 
Outcome 
Outcome will be defined as: 
 Resolved; 
 Ongoing; 
 Lost to follow up. 
9.3.7 
Coding of Adverse Events 
All AEs will be coded using the current version of Medical Dictionary for Regulatory 
Activities (MedDRA). 
9.4 
Clinical Laboratory Safety Tests 
Sample collection times are included in the schedule of events (see Section 17.0). 
9.5 
Clinical Laboratory Safety Tests 
Sample collection times are included in the schedule of events (see Section 17.0). 


 
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Table 3 
Laboratory Parameters 
Panel 
Parameters 
Haematology 
 
Red blood cell count 
Haemoglobin 
Haematocrit 
Platelet count 
Mean cell volume 
White blood cell count (total 
leucocytes) 
Red cell distribution width-SD 
Red cell distribution width-CV 
Neutrophils (absolute and %) 
Lymphocytes (absolute and %) 
Monocytes (absolute and %) 
Eosinophils (absolute and %) 
Basophils (absolute and %) 
Mean corpuscular haemoglobin 
Mean corpuscular haemoglobin 
concentration 
Reticulocyte count 
 
Coagulation 
 
 
Prothrombin time 
Activated partial thrombin time 
International normalised ratio 
 
Serum biochemistry  
 
Aspartate transaminase 
Alanine transaminase 
Alkaline phosphatase 
Total bilirubin [direct and 
indirect] 
Lactate dehydrogenase (LDH) 
Creatine kinase [a] 
C-reactive protein 
 
Sodium 
Potassium 
Chloride 
Urea 
Creatinine 
Albumin  
Calcium 
Phosphate 
Glucose 
Bicarbonate 
Iron studies (serum ferritin, iron 
and transferrin calculated  
[% transferrin saturation])  
Urinalysis 
Leucocytes 
Protein 
Bilirubin 
Urobilinogen 
Glucose 
Ketones 
Blood 
pH 
Nitrite 
Specific gravity 
microalbumin 
creatinine 
Urine microscopy 
To be performed where clinically indicated 
 
 
 
 
 
 
Serum/urine pregnancy test [b] 
 [a] Creatine kinase MB fraction will be performed if clinically indicated.  
[b] The pregnancy test will be conducted in urine for subjects enrolling from Cohort 17 and 15. The 
pregnancy test will be conducted on a serum sample at baseline visit for subjects from Cohort 7, 11, 12, 
14 or 16 and in urine at the other times. 
[c] At the physicians discretion when clinically indicated.  
 
Additional and repeat testing may be performed at the discretion of the Investigator. 


 
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Unless otherwise specified all clinical laboratory tests will be performed by Viapath. 
Details of all methodology and reference ranges are provided in the Trial Master File.   
9.6 
Clinical Safety Assessments 
Assessment times are included in the schedule of events (see Section 17.0). 
Vital Signs 
Blood pressure, heart rate, respiration rate and oral temperature will be measured using an 
automated instrument after the subject has rested comfortably for 2 minutes in the supine 
position.  Additional vital signs may be added for safety of the subjects at the discretion 
of the Investigator. 
12 Lead ECG 
Computerised 12-lead ECG recordings will be obtained as  a single measurement.  Each 
lead shall be recorded for at least 3 beats at a speed of 25 mm/sec.  Subjects should be 
lying quietly in a fully supine position for at least 5 minutes prior to each 12-lead ECG. 
The following parameters will be recorded: rhythm, ventricular rate, PR interval, QRS 
duration, QT and QTcF. 
Medical History 
A complete medical history will include evaluation (past or present) of the following:  
general, head and neck, eyes, ears, nose throat, chest/respiratory, heart/cardiovascular, 
gastrointestinal/liver, gynecological/urogenital, musculoskeletal/extremities, skin, 
neurological/psychiatric, endocrine/metabolic, haematologic/lymphatic, allergies/drug 
sensitivities, past surgeries, substance abuse or any other diseases or disorders.  
Physical Examination 
Physical examinations will be performed by a physician and will include the examination 
of the following: general appearance, eyes, ears, nose, throat, chest/respiratory, 
heart/cardiovascular, gastrointestinal/liver, musculoskeletal/extremities, 
dermatological/skin, thyroid/neck, lymph nodes, neurological/psychiatric. The physical 
examinations will include specific surveillance for skin rashes and lymphadenopathy. 
In addition a directed physical examination may be conducted if there are any previously 
identified or new signs or symptoms including any adverse events or diagnoses the 
subject has experienced since the last visit.  Changes from baseline abnormalities should 
be recorded at each subsequent physical examination.  New or worsened abnormalities 
should be recorded as adverse events if appropriate. 


 
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Height and Body Weight 
Height will only be measured at baseline visit  The subjects will be required to remove 
footwear and will wear normal indoor clothing during the measurement of height and 
weight. 
10.0 DATA COLLECTION 
 Paper CRFs will be produced by Quintiles.  Study data including laboratory safety data 
will be recorded in the CRF by the Investigational Site Staff.  Laboratory safety data will 
be recorded in the CRF only if the lab cannot provide an electronic transfer. 
Study data will be recorded on source documents provided by Quintiles when direct data 
entry into CRFs is inappropriate or impractical.  Data from source documents will be 
transcribed, where necessary, into CRFs by the Investigational Site staff. All source 
documents will be retained by the investigational site.  Photocopies of completed source 
documents will be provided only if essential (i.e. for regulatory purposes) at the request of 
the Sponsor. 
The CRFs must be kept in order and up-to-date so that they always reflect the latest 
observations on the enrolled subjects. 
 Safety laboratory data may be integrated with the consolidated clinical data by Quintiles 
before database lock. 
All records should be kept in conformance to applicable national laws and regulations. 
Adverse events will be coded using the current MedDRA thesaurus; concomitant 
medication will be coded using WHO DD (if required). 
CRFs must be completed legibly for each subject enrolled in the study and signed-off by 
the Investigator.  


 
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11.0 EVALUATION OF STUDY DATA 
11.1 Evaluation of Pharmacokinetic Parameters 
Whole blood and plasma levels of GBT440 as indicated in the schedule of assessments in 
section 17.  
11.2 Evaluation of Pharmacodynamic Measures 
11.2.1 Haemolysis markers: 
Haemoglobin, unconjugated bilirubin, LDH, absolute and % reticulocyte counts and % 
dense cells will be measured as indicated in the SOA. 
11.2.2 Disease Related Assessments: 
 
Inflammatory markers and exploratory biomarkers related to SCD disease severity will be 
assessed as indicated in the SOA.   
11.3 Evaluation of Safety 
The safety evaluation will include blood pressure, pulse rate, body temperature, 
respiratory rate, ECG parameters, clinical laboratory tests (haematology, serum 
biochemistry (including erythropoietin), coagulation, urinalysis and urine microscopy) 
and adverse events. 


 
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12.0 STATISTICAL METHODS 
Statistical programming and analyses will be performed using established statistical 
methods.  Details of all planned analyses will be specified in a separate statistical analysis 
plan. 
The study data will be reported using summary tables, figures, and data listings.  
Continuous variables will be summarized using mean, standard deviation (SD), 
coefficient of variation (CV%, as appropriate), median, minimum, maximum, and, as 
appropriate, geometric mean.  Categorical variables will be summarized by presenting the 
number (frequency) and percentage in each category. 
12.1 Sample Size Determination 
This is an extension study following on from GBT440-001. The sample size has therefore 
not been subject to any statistical considerations.  
12.2 Subject Population for Analyses 
The PK population will consist of all subjects who receive active study drug and have at 
least 1 measured concentration at a scheduled PK time point after start of dosing for at 
least 1 PK analyte.  If any subjects are found to be noncompliant with respect to dosing or 
have incomplete data, protocol violations, or clinical events that affect PK, a decision will 
be made on a case-by-case basis as to their inclusion in the analysis.  Subjects in this 
population will be used for all PK summaries. 
The PD population will consist of all subjects who receive active study drug, and have at 
least 1 measured value at a scheduled PD time point after start of dosing for at least 1 PD 
analyte.  If any subjects are found to be noncompliant with respect to dosing or have 
incomplete data, or protocol violations, a decision will be made on a case-by-case basis as 
to their inclusion in the analysis.  Subjects in this population will be used for all PD 
summaries. 
The safety population will include all subjects who receive at least 1 dose of the study 
drug.  Subjects in this population will be used for all demographic and safety summaries. 
12.3 Pharmacokinetic Analysis 
A listing of PK sample collection times will be provided.  Whole blood and plasma levels 
of GBT440 will be listed and summarised using appropriate descriptive statistics by dose 
and study day. Where appropriate an estimate of apparent elimination half -life (t ½ ) will 
be computed and presented in tabular form with appropriate descriptive statistics  


 
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12.4 Pharmacodynamic/Efficacy Analysis 
Haemolysis and Disease related assessments will be listed and summarised at each time 
point using appropriate descriptive statistics. 
12.5 Safety Data Analysis 
Individual and summary blood pressures, heart rate, body temperature, respiratory rate, 
ECG parameters and clinical laboratory data (haematology, serum biochemistry and 
coagulation) will be presented in tabular form with appropriate descriptive statistics. 
Adverse events will be tabulated and summarized. 


 
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13.0 STUDY REPORT  
A clinical study report, compliant with the requirements of ICH E3, will be prepared by 
Quintiles.   
14.0 REGULATORY AND ETHICAL ISSUES 
14.1 Regulatory and Ethics Review and Approval 
The study will be submitted for to the Medicines and Healthcare products Regulatory 
Agency (MHRA-UK) for review and approval and to an Ethics Committee for ethical 
review and approval. 
14.2 Informed Consent 
Informed consent will be given freely after the subject has been informed of the nature, 
significance, implications and risks of the trial; and consent is evidenced in writing, dated 
and signed, or otherwise marked, by that person so as to indicate his/her consent, prior to 
the start of the study.  The nature of the informed consent will comply with the current 
version of the Declaration of Helsinki, the current requirements of GCP (Committee for 
Proprietary Medicinal Products/ICH/135/95 and local regulation (The requirements are 
set out in Schedule 1 of Statutory Instrument 1031 and amendments) which ever provides 
the greater subject protection. 
14.3 Indemnity and Compensation 
In accordance with Statutory Instrument 1031 and amendments section 15 (5i, j) and the 
EU Clinical Trials Directive 2000/20/EC Article 3 (2f), provision is to be made for: 
 The indemnity or compensation in the event of injury or death attributable to the 
clinical trial; and  
 Insurance or indemnity to cover the liability of the Investigator or Sponsor. 
Therefore the Sponsor Global Blood Therapeutics Inc will indemnify the Investigators, 
The BRC Clinical Research facility (KCL and GSTT) from all and any claims arising out 
of this study except for their negligence or malpractice and providing that the study is 
conducted according to the standards established by the protocol. 
In the event that it can be demonstrated that a subject suffers any significant deterioration 
in health or well-being or any harmful susceptibility or toxicity as a direct result of their 
participation in this study then Global Blood Therapeutics, Inc will agree to abide by the 
current ABPI and FDA with regard to compensation payable to the subject.  The amount 
of compensation will be calculated by reference to the level of damages commonly 
awarded in law for UK for similar injuries at the time when such injury occurred. 


 
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The Investigators, The BRC Clinical Research facility (KCL and GSTT) declare to 
having insurance cover for the malpractice and/or negligence of their employees and 
agents. 


 
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15.0 STUDY MANAGEMENT  
15.1 Quality Assurance and Quality Control 
In accordance with the guideline for ICH GCP, the Sponsor has responsibility for 
implementing and maintaining quality assurance and quality control systems, and the 
ultimate responsibility for the quality integrity of the trial data resides with the Sponsor. 
15.2 Protocol Adherence 
The protocol must be read thoroughly and the instructions followed exactly.  Any 
deviations should be agreed by both the Sponsor and the Investigator, with the 
appropriate written and approved protocol amendments made to reflect the changes 
agreed upon.  Where the deviation occurs for the well-being of the subject, the Sponsor 
must be informed of the action agreed upon. 
15.3 Documents Necessary for Initiation of Study 
The following documents will be available prior to the first administration of the drug to 
the first subject: 
 Regulatory authorisation; 
 Copy of current Investigator’s Brochure; 
 Risk assessment report; 
 Completed and signed investigator agreement/contract; 
 Signed original of the final protocol; 
 Ethics Committee approval; 
 Copy of the constitution of the Research Ethics Committee;   
 A list of members of the Ethics Committee; 
 A copy of the consent form and subject information to be used; 
 The curriculum vitae of all Investigators; 
 The Qualified Person’s certification for the release of each batch of IMP; 
 A technical agreement between the Sponsor and The Investigational Site defining 
the responsibilities of the Sponsor, The Investigational Site and  Quintiles Ltd. and 
any third parties significantly involved in the supply chain of the IMP, where 
applicable; 


 
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 The product specification file, where applicable; and  
A list of laboratory reference range values for parameters measured in the study. 
15.4 Study Monitoring  
The Investigator will allow trial-related monitoring audits, ethics committee review, and 
regulatory inspection allowing direct access to the source data/documents. 
15.5 Study Closure 
Premature termination of the study by either Principal Investigator or Sponsor will be 
governed under the terms of the contract between both parties. 
15.6 Study Record Retention 
In accordance with SI 1928, the Sponsor and the Principal Investigator shall ensure that 
the documents contained, or which have been contained, in the trial master file are 
retained for at least 5 years after the conclusion of the trial and that during that period are: 
 Readily available to the licensing authority on request; and 
 Complete and legible. 
All data derived from the study will remain the property of the Sponsor, Global Blood 
Therapeutics.  The study will be the subject of a final clinical study report compiled by, or 
by order of the Sponsor. 
All correspondence (e.g. with the Sponsor, ethics committee) relating to this study should 
be kept in the appropriate file folders. 
Records of subjects source documents, CRF’s, IMP inventory, pertaining to the study 
must be kept on file.  Records must be retained according to the current ICH Guidelines 
on GCP. 
The Sponsor and Principal Investigator shall ensure that the medical files of trial subjects 
are retained for at least 5 years after the conclusion of the trial.  The Sponsor shall appoint 
named individuals within his organization to be responsible for archiving the documents 
which are, or have been, contained in the trial master file.  Access to those documents 
shall be restricted to those appointed individuals.  If there is transfer of ownership of data 
or documents connected with the clinical trial: 
 The Sponsor shall record the transfer; and 
 The new owner shall be responsible for data retention and archiving in accordance 
Statutory Instrument 1031 and amendments. 


 
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If the Principal 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. 
15.7 Publication Policy 
After completion of the study, the Sponsor may prepare a joint publication with the 
Principal Investigator.  The Investigator must undertake not to submit any part of the 
individual data from this protocol for publication without prior consent of the Sponsor at 
a mutually agreed time. 


 
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16.0 REFERENCES 
(Investigator's Brochure Version 3, 2016) 
Investigator’s Brochure, GBT440, Anti-sickling hemoglobin modifier for sickle cell 
disease.  Global Blood Therapeutics.  Version 1.1, 2014. 
(Abdulmalik et al, 2011) 
Osheiza Abdulmalik, Mohini S. Ghatge, Faik N. Musayev, Apurvasena Parikh, Qiukan 
Chen, Jisheng Yang, Ijeoma Nnamani, Richmond Danso-Danquah, Dorothy N. Eseonu, 
Toshio Asakura, Donald J. Abraham, Jurgen Venitzc and Martin K. Safob:   
Crystallographic analysis of human hemoglobin elucidates the structural basis of the 
potent and dual antisickling activity of pyridyl derivatives of vanillin. Acta Cryst. 2011. 
D67, 920–928 
(Akinsheye I et al. 2011) 
Akinsheye I, Alsultan A, Solovieff N, Ngo D, Baldwin CT, Sebastiani P, et al. Fetal 
hemoglobin in sickle cell anemia. Blood. 2011; 118(1):19-27. 
(Arya et al, 1996) 
Arya R, Rolan P. E, Wootton R, Posner J and Bellingham A.J:  Tucaresol increases 
oxygen affinity and reduces haemolysis in subjects with sickle cell anaemia. Brit Jorn 
Haem 1996, 93, 817-821, 
(Brandow et al, 2010) 
Amanda M. Brandow and Julie A. Panepinto:  Hydroxyurea Use in Sickle Cell Disease: 
The Battle with Low Rates of Prescription, Poor Patient Compliance, and Fears of 
Toxicities and Side Effects. Expert Rev Hematol. 2010 June; 3(3): 255–260 
(Eaton et al, 1999) 
William A. Eaton, Eric. R. Henry, James Hofrichter and Andrea Mozzarelli:  Is 
cooperative oxygen binding by hemoglobinreally understood? Nature Structural Biology, 
1999, vol 6 no 4, April  
(Keidan et al, 1986) 
Keidan A. J, White R. D, Huehns E. R, Franklin I. M, Joy M and Stuart J:   Effect Of 
Bw12c On Oxygen Affinity Of Haemoglobin In Sickle-Cell Disease.  The Lancet, April 
12, 1986. 
(Lehrer-Graiwer, et al 2015) 
Lehrer-Graiwer J, Howard J, Hemmaway CJ, Awogbade M, Telfer P, Layton M, et al. 
GBT440, a potent anti-sickling hemoglobin modifier reduces hemolysis, improves anemia 


 
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and nearly eliminates sickle cells in peripheral blood of patients with sickle cell disease. Oral 
presentation: American Society of Hematology Annual Meeting; Orlando, FL. 2015. 
(Nathan, 2013) 
David G. Nathan:  Hemoglobin disorders: a look to the future.  Blood 2013 122: 859-860 
(Ngo 2011) 
Ngo D, A:  British Journal of Haematology, 156, 259–264, 2011 
(Nicholls et al, 1989) 
Nicholls A. J, Parker J. E and Posner J:  Increased Hb-02 affinity induced by BW12C in 
healthy volunteers: effect on heart rate.  Proceedings of the BPS, 5-7 April 1989 
(Noguchi et al, 1988) 
Noguchi C.T, Rodgers G.P, Serjent G and Schechter A.N:  Levels of fetal hemoglobin 
necessary for treatment of sickle cell disease.  New England Medical Journal of 
Medicine, Jan 14, 1988 
(Platt and Guinana, 2014) 
Platt O.S and Guinana E.C:  Bone Marrow transplantaion in sickle cell anaemia - The 
dilema of choice. New England Journal of Medicine 2014 Vol 335 No6 
(Rolan et al, 1993)  
Rolan P. E, Parker J. E, Gray S. J, Weatherley B. C, Ingram J, Leavens W, Wootton R 
and Posner J:  The pharmacokinetics, tolerability and pharmacodynamics of tucaresol 
(589C80; 4[2-formyl-3-hydroxyphenoxymethyl] benzoic acid), a potential anti-sickling 
agent, following oral administration to healthy subjects.  Br. J. clin. Pharmac. 1993, 35, 
419-425 
(Rolan et al, 1995) 
Rolan P. E, Mercer A. J, Wootton R.  and Posner J:  Pharmacokinetics and 
pharmacodynamics of tucaresol, an antisickling agent, in healthy volunteers. Br J clin 
Pharmac 1995; 39: 375-380 
(Safo et al, 2004) 
Martin K. Safo, Osheiza Abdulmalik, Richmond Danso-Danquah, James C. Burnett, 
Samuel Nokuri, Gajanan S. Joshi, Faik N. Musayev, Toshio Asakura, and Donald J. 
Abraham:  Structural Basis for the Potent Antisickling Effect of a Novel Class of Five-
Membered Heterocyclic Aldehydic Compounds. J. Med. Chem. 2004, 47, 4665-4676 
(Steinberg et al, 2003) 


 
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Steinberg et al:  Effect of hydroxyurea on Mortality and morbidity in adult sickle cell 
anemia.  Risk and benifits up to 9 years of treatment. JAMA, April 2, 2003 vol 289, No 
13. 
(Wahl et al, 2009) 
Shannon Wahl and Keith C. Quirolo:  Current issues in blood transfusion for sickle cell 
disease, Current Opinion in Pediatrics 2009, 21:15–21 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Version 2 
Date 28 September 2016 
Quintiles Study Number: BYA73740 
Protocol Number:GBT440-024 
EudraCT Number:2016-002123-28 
 
 
 
Page 60 of 67 
 
17.0 STUDY SCHEDULE 
Table 4 
Schedule of Assessments Group 1 
Group 1: Subjects from Cohort 17 in the GBT440-001 study who have received GBT440 
900mg per day for 4 months will continue receiving GBT440 900 mg per day for a 
further 2 months.   
Assessments  
Enrolment  
Outpatient  Treatment Period 
Day number  
Last treatment 
day GBT440-001 
(+6 days) a  
1 a 
15 
+/-3 
days g 
30 
+/-3 
days 
45 
+/-3 
days g 
60 
+/-3 
days 
67 
+/-3 
days 
74 
+/-5 
days 
88 
end  
Visit number  
0 
1 
 
2 
 
3 
4 
5 
6 
Informed consent  
X 
X 
 
 
 
 
 
 
 
Eligibility assessment  
X 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
Physical examination b 
X 
 
X 
X 
X 
X 
 
 
X 
Weight 
X 
 
X 
X 
X 
X 
 
 
X 
Vital signs  
X 
X 
X 
X 
X 
X 
 
 
X 
12 Lead ECG (single) c 
 
 
 
X 
 
X 
 
 
X 
Drug administration d 
 
X 
-----------------------------------------X 
 
Adverse events 
X-------------------------------------------------------------------------------------------X 
Urinalysis e 
X 
 
X 
 
X 
 
 
 
X 
Urine 
microalbumin/creatinine 
X 
 
 
 
 
 
 
 
X 
Haematology e 
X 
 
X 
X 
X 
X 
 
 
X 
Serum biochemistry e 
X 
 
X 
X 
X 
X 
 
 
X 
Coagulation e 
X 
 
X 
 
X 
 
 
 
X 
Pregnancy test (females 
only) 
X 
 
 
X 
 
X 
 
 
X 
Haemoglobin 
electrophoresis  
 
 
 
 
 
 
 
 
X 
PK samples (plasma 
and whole blood) f 
X 
 
 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Serum erythropoietin  
Xh 
 
 
X 
 
X 
 
 
X 
Exploratory plasma 
biomarkers  
Xh 
 
 
X 
 
X 
 
 
X 
Dense cells  
Xh 
 
 
X 
 
X 
 
 
X 
Carboxyhaemoglobin  
Xh 
 
 
 
 
 
 
 
X 
HbA1c 
Xh 
 
 
 
 
 
 
 
X 
NT-proBNP 
Xh 
 
 
 
 
 
 
 
X 
Concomitant 
medication diary  
X-------------------------------------------------------------------------------------------------------X 
Key 
a:  
Enrolment and visit 1 may be combined.  On admission to the clinic the subjects will be asked 
whether they want to be considered for study GBT440-024.  If the subject is interested in being 
enrolled on study GBT440-024 all consent activities will be completed before the 
samples/procedures for GBT440-001 or GBT440-024 are collected/performed.  Visit 0 (enrolment 
visit) is the last day of treatment in GBT440-001, which can be 6 days before Visit 1. If the last day 
of treatment in GBT440-001 (Day 118 or Day 60 for Cohort 17 and Cohort 15) – the enrolment visit 
is not being repeated as standalone visit. 
b:  
Complete physical examination on enrolment, a limited physical examination on all other days. 
Directed physical examinations will be performed as required. 
c:  
12 lead ECG (single) will be performed within 30 minutes prior to dose  
d:  
GBT440 900 mg(three capsules) will be administered daily in the morning. On days when PK 
samples are drawn GBT 440 should be administered after an overnight fast.  


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Version 2 
Date 28 September 2016 
Quintiles Study Number: BYA73740 
Protocol Number:GBT440-024 
EudraCT Number:2016-002123-28 
 
 
 
Page 61 of 67 
 
During the dosing period subjects will be contacted every week in between out-patient visits to 
confirm GBT440 administration and subject well -being.  
e:  
Additional samples will be collected if clinically indicated 
f:   
PK samples will be drawn pre dose. If the dose is increased to 1500 mg, please collect the following 
timepoints: pre dose, then 1-4 hours, 6-8 hours and 24 hours post dose on study visit days of 
Day 15 (±3 days) , Day 60 (±3 days)  and Days 90 (±3 days) of receiving 1500 mg.g: 
Days 15 
and 45 are only to be conducted if the dose is increased to 1500 mg. 
h: 
Can be omitted if measurements were collected in the past 7 days as part of the GBT440-001 
study. 
 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Version 2 
Date 28 September 2016 
Quintiles Study Number: BYA73740 
Protocol Number:GBT440-024 
EudraCT Number:2016-002123-28 
 
 
 
Page 62 of 67 
 
Table 5 
Schedule of Assessments for Groups 2, 4 and 5 
Groups 2: Subjects from Cohort 17 in the GBT440-001 study who have received placebo for 4 months will receive GBT440 900mg per day for 6 months 
Group 4: Subjects from Cohort 15 in the GBT440-001 study who have received placebo for 2 months will receive GBT440 900 mg per day for 6 months 
Group 5: Subjects with SCD from Cohorts 7, 11, 12, 14, 16 or 17 in the GBT440-001 study will receive GBT440 900 mg per day for 6 months 
Assessments  
Enrolment a 
 
Outpatient  Treatment Period  
Day number  
Last 
treatment 
day 
GBT440-
001 
(+6 
days) 
Cohorts 15 
and 17  
Baseline 
for 
Cohort 
7,11,12,14, 
16 or 17 
(within 7 
days of 
Day`1) 
1 
+/-3 
days 
a 
15 
+/-3 
days 
30 
+/-3 
days 
45 
+/-3 
days 
60 
+/-3 
days 
90 
+/-3 
days 
120+/-3 
days 
150+/-3 
days 
180 
+/-3 
days  
187+/-3 
days  
194 
+/-5 
days 
208 
End  
Visit number  
0 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Informed consent  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility assessment  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination b 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
 
 
X 
Weight 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Vital signs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
12 Lead ECG (single) c 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
Drug administration d 
 
 
X------------------------------------------------------------------------------------------------------X           
 
 
Adverse events 
 
 
X-------------------------------------------------------------------------------------------------------------------------------------------------X 
Urinalysis e 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
 
 
X 
Urine microalbumin/creatinine 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
Haematology e 
X 
X 
 
X 
X 
X 
- 
X 
X 
X 
X 
 
 
X 
Serum biochemistry e 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Coagulation e 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
X 
Pregnancy test (females only) 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
Haemoglobin electrophoresis  
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
PK samples (plasma and whole 
blood) f 
X 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Serum erythropoietin  
Xh 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
Exploratory plasma biomarkers  
Xh 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Version 2 
Date 28 September 2016 
Quintiles Study Number: BYA73740 
Protocol Number:GBT440-024 
EudraCT Number:2016-002123-28 
 
 
 
Page 63 of 67 
 
Assessments  
Enrolment a 
 
Outpatient  Treatment Period  
Day number  
Last 
treatment 
day 
GBT440-
001 
(+6 
days) 
Cohorts 15 
and 17  
Baseline 
for 
Cohort 
7,11,12,14, 
16 or 17 
(within 7 
days of 
Day`1) 
1 
+/-3 
days 
a 
15 
+/-3 
days 
30 
+/-3 
days 
45 
+/-3 
days 
60 
+/-3 
days 
90 
+/-3 
days 
120+/-3 
days 
150+/-3 
days 
180 
+/-3 
days  
187+/-3 
days  
194 
+/-5 
days 
208 
End  
Dense cells  
Xh 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
Carboxyhaemoglobin  
Xh 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
HbA1c 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
NT-proBNP 
Xh 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Concomitant medication diary  
 
X 
X---------------------------------------------------------------------------------------------------------------------------------------------X 
Key 
Note:  Visit 0 is the last treatment day for subjects in GBT-440-001 (Day 118 for Cohort 17 and Day 60 for Cohort 15) 
a:  
Enrolment and visit 1 may be combined. On admission to the clinic the subjects will be asked whether they want to be considered for study GBT440-024.  If the 
subject is interested in being enrolled on study GBT440-024 all consent activities will be completed before the samples/procedures for GBT440-001 or GBT440-024 
are collected/performed. Visit 0 (enrolment visit) is the last day of treatment in GBT440-001, which can be 6 days before Visit 1. If the last day of treatment in 
GBT440-001 (Day 118 or Day 60 for Cohort 17 and Cohort 15) – the enrolment visit is not being repeated as standalone visit. 
b:  
Complete physical examination on enrolment, a limited physical examination on all other days. Directed physical examinations will be performed as required. 
c:  
12 lead ECG (single) will be performed within 30 minutes prior to dose  
d:  
GBT440 900mg(three capsules) for Group 2 and GBT 440 600mg (2 capsules) for Group 4  and GBT440 900 mg (3 capsules) for Group 5 will be administered daily in 
the morning. On days when PK samples are drawn GBT 440 should be administered after an overnight fast.  
During the dosing period, subjects will be contacted every week in between outpatient visits to confirm GBT440 administration and subject well being. 
e:  
Additional samples will be collected if clinically indicated 
f:   
PK samples will be drawn pre dose.  If the dose is increased to 1500 mg, please collect the following timepoints: pre dose, then 1-4 hours, 6-8 hours and 24 hours 
post dose on study visit days of Day 15 (±3 days) , Day 60 (±3 days)  and Days 90 (±3 days) of receiving 1500 mg.  
h: 
Can be omitted if measurements were collected in the past 7 days as part of the GBT440-001 study. 


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Version 2 
Date 28 September 2016 
Quintiles Study Number: BYA73740 
Protocol Number:GBT440-024 
EudraCT Number:2016-002123-28 
 
 
 
Page 64 of 67 
 
 
Table 6 
Schedule of Assessments Group 3 
Group 3: Subjects from Cohort 15 in the GBT440-001 study who have received GBT440 600 mg per day 
for 2 months will continue receiving GBT440 600 mg per day for a further 4 months (the dose may be 
increased if the subject tolerated 600 mg in GBT440-001).  
Assessments  
Enrolment  Outpatient  Treatment Period 
Day number  
Last treatment 
day GBT440-
001 (+6 days) a  
1 
+/-3 
days 
a 
30 
+/-3 
days 
45 
+/-3 
daysg  
60 
+/-3 
days 
90 
+/-3 
days 
120+/-
3 
days 
127 
+/-3 
days  
134+/-
5 
days  
148 
End  
  
Visit number  
0 
1 
2 
 
3 
4 
5 
6 
7 
8 
Informed consent  
X 
X 
 
 
 
 
 
 
 
 
Eligibility assessment  
X 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Physical examination b 
X 
 
X 
X 
X 
X 
X 
 
 
X 
Weight 
X 
 
X 
X 
X 
X 
X 
 
 
X 
Vital signs  
X 
X 
X 
X 
X 
X 
X 
 
 
X 
12 Lead ECG (single) c 
X 
 
X 
 
X 
X 
X 
 
 
X 
Drug administration d 
X-----------------------------------------------------------------------X 
 
Adverse events 
X------------------------------------------------------------------------------------------------------X 
Urinalysis e 
X 
 
 
X 
 
X 
X 
 
 
X 
Urine 
microalbumin/creatinine 
X 
 
 
 
 
 
X 
 
 
X 
Haematology e 
X 
 
X 
X 
X 
X 
X 
 
 
X 
Serum biochemistry e 
X 
 
X 
X 
X 
X 
X 
 
 
X 
Coagulation e 
X 
 
 
X 
 
X 
X 
 
 
X 
Pregnancy test (females 
only) 
X 
 
X 
 
X 
X 
X 
 
 
X 
Haemoglobin 
electrophoresis  
 
 
 
 
X 
X 
 
 
 
X 
PK samples (plasma 
and whole blood) f 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Serum erythropoietin  
Xg 
 
X 
 
X 
X 
X 
X 
 
X 
Exploratory plasma 
biomarkers  
Xg 
 
X 
 
X 
X 
X 
 
 
X 
Dense cells  
Xg 
 
X 
 
X 
X 
X 
 
 
X 
Carboxyhaemoglobin  
Xg 
 
 
 
X 
 
 
 
 
X 
HbA1c 
Xg 
 
 
 
 
X 
 
 
 
X 
NT-proBNP 
Xg 
 
 
 
 
X 
 
 
 
X 
Modified  SCD severity 
questionnaire  
X 
 
X 
 
X 
X 
X 
X 
 
X 
Concomitant 
medication diary  
X-------------------------------------------------------------------------------------------------------X 
Key 
a:  
Enrolment and visit 1 may be combined. On admission to the clinic the subjects will be asked 
whether they want to be considered for study GBT440-024.  If the subject is interested in being 
enrolled on study GBT440-024 all consent activities will be completed before the 
samples/procedures for GBT440-001 or GBT440-024 are collected/performed. Visit 0 (enrolment 
visit) is the last day of treatment in GBT440-001, which can be 6 days before Visit 1. If the last day 
of treatment in GBT440-001 (Day 118 or Day 60 for Cohort 17 and Cohort 15) – the enrolment visit 
is not being repeated as standalone visit. 
b:  
Complete physical examination on enrolment, a limited physical examination on all other days. 
Directed physical examinations will be performed as required. 
c:  
12 lead ECG (single) will be performed within 30 minutes prior to dose  
d:  
GBT440 600mg (two capsules) will be administered daily in the morning. On days when PK 
samples are drawn GBT 440 should be administered after an overnight fast.  


 
CONFIDENTIAL 
 
Clinical Study Protocol  
Version 2 
Date 28 September 2016 
Quintiles Study Number: BYA73740 
Protocol Number:GBT440-024 
EudraCT Number:2016-002123-28 
 
 
 
Page 65 of 67 
 
During the dosing period, subjects will be contacted every week in between outpatient visits to 
confirm GBT440 administration and subject well-being.  
e:  
PK samples will be drawn pre dose.  . If the dose is increased to 1500 mg, please collect the 
following timepoints: pre dose, then 1-4 hours, 6-8 hours and 24 hours post dose on study visit days 
of Day 15 (±3 days) , Day 60 (±3 days)  and Days 90 (±3 days) of receiving 1500 mg. 
f. 
Days 45 are only to be conducted if the dose is increased to 1500 mg. 
g: 
Can be omitted if measurements were collected in the past 7 days as part of the GBT440-001 
study.