Conditions: Safety and Tolerability
Keywords: GB1211 Phase 1 First Time in Human Safety Tolerability Pharmacokinetics Single Ascending Dose (SAD) Multiple Ascending Dose (MAD) Healthy Volunteers Nonalcoholic Steatohepatitis (NASH) Liver Fibrosis
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 78
Healthy volunteers: yes

Brief summary:
This was a Phase 1, randomized, double-blind, placebo-controlled, first-in-human study in which the safety, tolerability, and pharmacokinetics of orally administered GB1211 will be evaluated in healthy adult subjects and adult subjects with indication of suspected Nonalcoholic steatohepatitis (NASH) and liver fibrosis.

Detailed description:
The study consisted of 2 parts: a SAD phase (Part A) which enrolled a total of 5 cohorts of healthy subjects and a MAD phase (Part B) which enrolled 2 cohorts of healthy subjects. Two additional cohorts A6 and A7, were added following dose escalation analysis.

The planned optional Part C was to include a multiple-dose cohort of 25 subjects with suspected NASH and liver fibrosis (Cohort C1). However, Part C of the study was not performed as per Sponsor's decision.

Arms:
arm 1: 6 healthy subjects are administered 5 mg of GB1211 capsules orally as a single dose in the fasted state. 2 subjects receive placebo. 2 subjects (1 active and 1 placebo) will be dosed at least 24 hours before the remaining subjects, where continuation to dose the remaining subjects will be at the Investigator's discretion. arm 2: 6 healthy subjects are administered 20 mg of GB1211 capsules orally as a single dose in the fasted state. 2 subjects receive placebo. 2 subjects (1 active and 1 placebo) will be dosed at least 24 hours before the remaining subjects, where continuation to dose the remaining subjects will be at the Investigator's discretion. arm 3: 6 healthy subjects are administered 50 mg of GB1211 capsules orally as a single dose. 2 subjects receive placebo. 2 subjects (1 active and 1 placebo) will be dosed at least 24 hours before the remaining subjects, where continuation to dose the remaining subjects will be at the Investigator's discretion. Each subject will participate in 2 treatment periods separated by a minimum of 7 days. In Treatment Period 1 doses will be administered in the fasted state, in Treatment Period 2 doses will be administered 30 minutes after the start of a high fat breakfast. Subjects will receive the same treatment in both periods. arm 4: 6 healthy subjects are administered 100 mg of GB1211 capsules orally as a single dose in the fasted state. 2 subjects receive placebo. 2 subjects (1 active and 1 placebo) will be dosed at least 24 hours before the remaining subjects, where continuation to dose the remaining subjects will be at the Investigator's discretion. arm 5: 6 healthy subjects are administered 200 mg of GB1211 capsules orally as a single dose in the fasted state. 2 subjects receive placebo. 2 subjects (1 active and 1 placebo) will be dosed at least 24 hours before the remaining subjects, where continuation to dose the remaining subjects will be at the Investigator's discretion. arm 6: GB1211 administered orally twice daily over 10 days. 8 healthy subjects received GB1211 and 3 subjects will receive placebo. Following review of data in Part A (Cohorts A1 to A6), subjects received twice daily (BID) doses under fasted conditions on Days 1 to 9, inclusive, and a final single dose administration on the morning of Day 10 in accordance with the randomisation schedule. arm 7: GB1211 administered orally twice daily over 10 days. 8 healthy subjects received GB1211 and 3 subjects will receive placebo. Following review of data in Part A (Cohorts A1 to A6), subjects received twice daily (BID) doses under fasted conditions on Days 1 to 9, inclusive, and a final single dose administration on the morning of Day 10 in accordance with the randomisation schedule.. arm 8: 8 healthy subjects are administered 50 mg (10 x 5mg capsules) or placebo without sentinel dosing. Optional cohort, as was added following dose-escalation analysis. arm 9: 8 healthy subjects are administered 400 mg (8 x 50mg capsules) or placebo without sentinel dosing. Optional cohort, as was added following dose-escalation analysis. arm 10: In Part A - 2 subjects from each arm (A1-A5) will receive placebo. arm 11: Part B - 3 subjects from each arm B1 and B2 will receive placebo.

Interventions: intervention 1: GB1211 intervention 2: Placebo
Intervention descriptions: intervention 1: Hard capsules for oral use intervention 2: Hard capsules for oral use

Protocol document:
Prot_001.pdf: 
TITLE PAGE 
Protocol 
GB1211 - A Randomised, Double-Blind, Placebo-Controlled, 
First-In-Human, Study of Orally Administered GB1211 to Evaluate the 
Safety, Tolerability, and Pharmacokinetics of Single Ascending Doses 
(SAD) and Multiple Ascending Doses (MAD) in Healthy Subjects and in 
Subjects with Suspected Nonalcoholic Steatohepatitis (NASH) and Liver 
Fibrosis 
Protocol Status: Final Version 2.0 
Original Protocol Date: 11 October 2018 
Protocol Version 2.0 Date: 05 November 2018 
Investigational Product: GB1211 
Protocol Reference Number: GB1211-001 
Covance Study Number: 8392356 
Sponsor: 
Galecto Biotech 
Cobis Science Park 
Ole Maaloes Vej 3 
DK-2200 Copenhagen 
Denmark 
Sponsor Signatory: 
Principal Investigator: 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the Sponsor. 




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INVESTIGATOR AGREEMENT 
I have read the protocol and agree to conduct the study as described herein. 
Date 
Principal Investigator 
Protocol Version 2.0, 05 November 2018 
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SUMMARY OF AMENDED PROTOCOL CHANGES 
PROTOCOL VERSION 2.0 (AMENDMENT 1) 
This amendment to the Final Study Protocol, dated 11 October 2018, has been issued to add a 
study restriction to minimise exposure to ultraviolet (UV) light as recommended by the 
Medicines and Healthcare products Regulatory Agency (MHRA). 
Details of the changes incorporated in this amendment are provided in the table below. 
Protocol Section 
Description of Changes from Final Protocol, dated 11 October 2018 
1.5 
New text added in bold: 
In albino and pigmented mice, [14C]-GB1211-related radioactivity was 
well absorbed and rapidly distributed into tissues, [14C]-GB1211-related 
radioactivity was rapidly eliminated from tissues, and the mean overall 
recovery of the radioactivity administered was 103%. GB1211 showed a 
trend for distribution to the uveal tract and skin of pigmented mice. 
This was reversible and below the limit of quantification at 168 
hours. 
4.4 
Addition of exclusion criterion 20: 
Subject is not willing to minimise or avoid exposure to natural or 
artificial sunlight (tanning beds or UVA/B treatment) following 
administration of study drug until 24 hours after the last dose. 
4.5 
Addition of exclusion criterion 20: 
Subject is not willing to minimise or avoid exposure to natural or 
artificial sunlight (tanning beds or UVA/B treatment) following 
administration of study drug until 24 hours after the last dose. 
4.6 
Addition of exclusion criterion 26: 
Subject is not willing to minimise or avoid exposure to natural or 
artificial sunlight (tanning beds or UVA/B treatment) following 
administration of study drug until 24 hours after the last dose. 
6.6 
An additional section was added to Section 6: 


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6.6. Exposure to Ultraviolet Light 
Subjects should minimise or avoid exposure to natural or artificial 
sunlight (tanning beds or UVA/B treatment) following 
administration of study drug until 24 hours after the last dose. If 
subjects need to be outdoors during this period, they should wear 
loose fitting clothes that protect skin from sun exposure and discuss 
other sun protection measures with the Investigator. 
 


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STUDY IDENTIFICATION 
Sponsor
Galecto Biotech
Cobis Science Park 
Ole Maaloes Vej 3 
DK-2200 Copenhagen 
Denmark 
Sponsor’s Study Contact 
Chief Medical Officer 
Galecto Biotech 
Cobis Science Park 
Ole Maaloes Vej 3 
DK-2200 Copenhagen 
Denmark 
Medical Monitor 
Covance  
Maidenhead Office Park 
Westacott Way 
Littlewick Green 
Maidenhead, SL6 3QH 
UK 
Study Site (Parts A and B) 
Covance Clinical Research Unit Ltd. 
Springfield House 
Hyde Street 
Leeds, LS2 9LH 
UK 
Part C Study Site(s) and 
Investigator(s)  
Study site(s) and Investigator(s) in the EU 
Principal Investigator (Parts A and 
B) 
Covance Clinical Research Unit 
Ltd. Springfield House 
Hyde Street 
Leeds, LS2 9LH 
UK  
 
Clinical Laboratory (Parts A and 
B) 
Covance Clinical Pathology Services 
Otley Road 
Harrogate, HG3 1PY 
UK 
Bioanalytical Laboratory 
Covance Laboratories Ltd 


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Otley Road 
Harrogate, HG3 1PY 
UK 
Statistician
Covance Biometrics 


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SYNOPSIS 
Title of study: GB1211 – A Randomised, Double-Blind, Placebo-Controlled, First-In-Human, 
Study of Orally Administered GB1211 to Evaluate the Safety, Tolerability, and Pharmacokinetics 
of Single Ascending Doses (SAD) and Multiple Ascending Doses (MAD) in Healthy Subjects and 
in Subjects with Suspected Nonalcoholic Steatohepatitis (NASH) and Liver Fibrosis 
Objectives:  
The primary objectives of the study are: 
• 
to evaluate the safety and tolerability of single and multiple doses of GB1211 administered 
to healthy subjects. 
• 
to evaluate the safety and tolerability of multiple doses of GB1211 administered to subjects 
with suspected NASH and liver fibrosis. 
The secondary objectives of the study are: 
• 
to evaluate the pharmacokinetics (PK) of single doses of GB1211 in plasma and urine in 
healthy subjects, and the PK of multiple doses of GB1211 in plasma of healthy subjects and 
subjects with suspected NASH and liver fibrosis 
• 
to determine the effect of food on the single oral dose PK of GB1211. 
The exploratory objectives of the study are: 
• 
to investigate biomarkers related to GB1211 activity at single and/or multiple doses in 
comparison to placebo in healthy subjects and subjects with suspected NASH and liver 
fibrosis. 
• 
to investigate biomarkers of metabolism, inflammation, and fibrosis following multiple 
doses of GB1211 in healthy subjects and/or subjects with suspected NASH and liver 
fibrosis.  
• 
to identify metabolites of GB1211 in plasma and urine. 
Study design: 
This is a Phase 1, randomised, double-blind, placebo-controlled, first-in-human study in which the 
safety, tolerability, and PK of orally administered GB1211 will be assessed in healthy adult subjects 
and adult subjects with suspected NASH and liver fibrosis. 
Suspected NASH is defined as the presence or history of fatty liver, together with elevated alanine 
aminotransferase (ALT), plus either confirmed type 2 diabetes mellitus (T2DM) or metabolic 
syndrome, in the absence of any other liver disease. Additional criteria aim to enrich for individuals 
with liver fibrosis (as per inclusion criteria). 
The study will consist of 3 parts: a SAD phase (Part A) enrolling a total of 5 cohorts of healthy 
subjects; a MAD phase (Part B) enrolling 2 cohorts of healthy subjects; and an optional Part C 
MAD phase enrolling 1 cohort of subjects with suspected NASH and liver fibrosis. One cohort of 
Part A will receive GB1211 under both fasted and fed conditions to investigate the effect of food. 
Number of subjects: 
Part A: 40 subjects will be studied in 5 cohorts (Cohorts A1 to A5) 
Part B: 22 subjects will be studied in 2 cohorts (Cohorts B1 to B2) 
Part C: 25 subjects will be studied in 1 cohort (Cohort C1) 


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Diagnosis and main criteria for inclusion: 
Parts A and B: 
Male or female subjects aged between 18 and 55 years (inclusive) for Part A, and between 18 and 
60 years (inclusive) for Part B; with a body mass index (BMI) ≥ 18.0 kg/m2 and ≤ 32.0 kg/m2, who 
must be healthy, as determined by no clinically significant findings from medical history, physical 
examination, 12-lead electrocardiogram (ECG), vital signs measurements, and clinical laboratory 
evaluations (congenital nonhaemolytic hyperbilirubinemia [eg, suspicion of Gilbert’s syndrome 
based on total and direct bilirubin] is not acceptable) at Screening and Check-in as assessed by the 
Investigator (or designee), as applicable. 
Part C:  
Male or female subjects aged between 18 and 60 years (inclusive) with a BMI ≥ 25.0 kg/m2 and 
≤ 38.0 kg/m2 and a documented history of fatty liver within the last 24 weeks by one of the 
following: magnetic resonance imaging (MRI) suggesting liver fat ≥ 8%, ultrasound (US) indicating 
fatty liver, or Fibroscan Controlled Attenuation Parameter (CAP) > 270 dB/m. In subjects without a 
documented history of fatty liver, a Fibroscan CAP or US can be performed at Screening. Subjects 
with a Fibroscan CAP > 270 dB/m or US indicating fatty liver are eligible. In addition, subjects 
should have metabolic syndrome (Adult Treatment Panel III definition) or T2DM (defined as stable 
diabetes with glycosylated haemoglobin (HbA1c) ≤ 9.5%); have ALT ≥ 20 U/L for females and 
≥ 30 U/L for males at Screening; and have Fibroscan ≥ 7 KPa and < 13 KPa, or Fibrosis-4 (FIB-4) 
index ≥ 1.1 and < 3.25. 
Investigational products, dose, and mode of administration: 
Test products: 5 and 50 mg GB1211 capsules 
Proposed dose levels for Part A: 5, 20, 50, 100, and 200 mg 
Proposed dose levels for Part B: to be determined based on data from Part A.  
Proposed dose level for Part C: to be determined based on data from Part A, and data from at least 
1 Part B cohort. 
The dosing frequency/interval and dosing duration for Part B will be fully decided, in consultation 
with the Sponsor, on the basis of data from Part A; and for Part C, will be fully decided on the basis 
of data from Part A and at least 1 Part B cohort. The daily dose administered will not exceed the 
highest dose administered in Part A. 
Administration route: oral 
Reference product and mode of administration: 
Reference product: placebo capsules 
Administration route: oral 
Duration of subject participation in the study: 
Planned Screening duration: approximately 4 weeks. 
Planned study duration (Screening to Follow-up):  
   Part A, Cohorts A1 to A5 (excluding food-effect cohort, planned to be Cohort A3: approximately   
5 weeks.  
   Part A, Food-effect cohort (planned to be Cohort A3): approximately 6 to 7 weeks. 
   Part B: approximately 6 to 7 weeks. 
   Part C: approximately 11 weeks. 


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Endpoints: 
Primary endpoints: 
Incidence and severity of adverse events, incidence of laboratory abnormalities (haematology, 
clinical chemistry, urinalysis), 12-lead ECG parameters, vital signs measurements, and physical 
examinations. 
Secondary endpoints: 
Blood samples for the analysis of plasma concentrations of GB1211 following single and multiple 
oral doses of GB1211. In addition, urine samples for the analysis of urinary concentrations of 
GB1211 following single oral doses of GB1211 (Part A). 
The PK parameter endpoints for Part A will include area under the plasma concentration-time curve 
(AUC) from time zero to infinity (AUC0-∞), AUC from time zero to the time of the last quantifiable 
concentration (AUC0-tlast), maximum observed plasma concentration (Cmax), time of the maximum 
observed plasma concentration (Tmax), apparent plasma terminal elimination half-life (t1/2), apparent 
total plasma clearance (CL/F), apparent volume of distribution (Vz/F), amount of drug excreted in 
urine (Ae), percentage of dose excreted unchanged (fe) in urine, and renal clearance (CLR). In 
Parts B and C, the PK parameters will include AUC over a dosing interval (AUC0-τ), AUC0-∞, Cmax, 
Tmax, t1/2, minimum observed plasma concentration (Cmin), observed accumulation ratio based on 
AUC0-τ (RAAUC0-τ), and observed accumulation ratio based on Cmax (RACmax). Other PK parameters 
may also be reported. 
Exploratory endpoints: 
For all SAD and MAD cohorts (Parts A, B, and C), exploratory biomarker endpoints include serum 
galectin-3, chemokine (C-C motif) ligand (CCL)-4 (CCL4), and other biomarkers may also be 
measured in an exploratory fashion. For all MAD cohorts (Parts B and C), changes from baseline at 
Day 10 (healthy subjects) and Day 42 (subjects with suspected NASH and liver fibrosis) will be 
assessed in fasting plasma glucose and insulin; in lipid profile; in heat shock C-reactive protein 
(hsCRP), interleukin (IL)-12, monocyte chemotactic protein (MCP)-1, tumor necrosis factor (TNF)-
alpha, CCL2, CCL3, CCL4 and the chemokine (C-C motif) receptors (CCR)-1 and CCR2; and 
other biomarkers of inflammation as required. For the MAD cohort in subjects with suspected 
NASH and liver fibrosis (Part C), changes from baseline at Day 42 in biomarkers of fibrosis, 
including but not limited to extracellular matrix proteins (tissue inhibitor of matrix 
metalloproteinase-1 [TIMP-1], hyaluronic acid [HA], and aminoterminal peptide of pro-collagen III 
[P3NP]), A9, E74-like transcription factor (ELF) panel, cytokeratin (CK)-18, plasminogen activator 
inhibitor (PAI)-1, chitinase-3-like protein-1 (CH3L1), IL6, and pro-collagen 3. In addition, 
identification of GB1211 metabolites in plasma and urine. 
Statistical methods: 
Pharmacokinetics: 
Individual plasma and urine concentrations of GB1211 (Part A only for urine concentrations) will 
be listed and summarised using descriptive statistics. Individual and mean GB1211 
concentration-time profiles will be presented graphically.  
Where data are available, GB1211 dose proportionality will be examined across the dose cohorts. 
The PK parameters will be analysed for dose proportionality using a power model approach or 
analysis of variance (ANOVA) model as appropriate. Where data are available, the effect of food at 
1 dose level in Part A will be investigated using an ANOVA model. 
Exploratory biomarker data: 
Exploratory biomarker data will be listed and summarised using descriptive statistics. No formal 
statistical analysis of exploratory biomarker data is planned. 
Safety: 
Safety parameters will be listed and summarised using descriptive statistics. No formal statistical 
analysis of safety data is planned. 


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TABLE OF CONTENTS 
TITLE PAGE .............................................................................................................................1 
SPONSOR APPROVAL ...........................................................................................................2 
INVESTIGATOR AGREEMENT.............................................................................................3 
SUMMARY OF AMENDED PROTOCOL CHANGES ..........................................................4 
STUDY IDENTIFICATION .....................................................................................................6 
SYNOPSIS .................................................................................................................................8 
TABLE OF CONTENTS .........................................................................................................11 
LIST OF TABLES AND FIGURES........................................................................................13 
LIST OF ABBREVIATIONS ..................................................................................................14 
1. 
INTRODUCTION ...........................................................................................................17 
1.1. 
Overview ................................................................................................................17 
1.2. 
Summary of Nonclinical Pharmacology ................................................................17 
1.3. 
Summary of Safety Pharmacology ........................................................................18 
1.4. 
Summary of Toxicology ........................................................................................18 
1.5. 
Summary of Nonclinical Pharmacokinetics ...........................................................19 
1.6. 
Summary of Clinical Experience ...........................................................................21 
1.7. 
Study Rationale ......................................................................................................21 
1.8. 
Benefit-risk Assessment .........................................................................................21 
2. 
OBJECTIVES AND ENDPOINTS .................................................................................22 
2.1. 
Objectives ..............................................................................................................22 
2.2. 
Endpoints ...............................................................................................................22 
2.2.1. 
Primary Endpoints .......................................................................................22 
2.2.2. 
Secondary Endpoints ...................................................................................23 
2.2.3. 
Exploratory Endpoints .................................................................................23 
3. 
INVESTIGATIONAL PLAN ..........................................................................................24 
3.1. 
Overall Study Design and Plan ..............................................................................24 
3.1.1. 
Part A ...........................................................................................................24 
3.1.2. 
Part B ...........................................................................................................26 
3.1.3. 
Part C (Optional) ..........................................................................................28 
3.2. 
Study Start and End of Study Definitions ..............................................................29 
3.3. 
Additional Groups ..................................................................................................29 
3.4. 
Discussion of Study Design, Including the Choice of Control Groups .................29 
3.4.1. 
Dose Interval ................................................................................................30 
3.5. 
Selection of Doses in the Study .............................................................................31 
3.6. 
Dose Escalation ......................................................................................................32 
3.7. 
Dose Escalation Stopping Criteria .........................................................................32 
4. 
SELECTION OF STUDY POPULATION .....................................................................33 


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4.1. 
Inclusion Criteria for Parts A: Healthy Subjects ....................................................33 
4.2. 
Inclusion Criteria for Part B: Healthy Subjects .....................................................34 
4.3. 
Inclusion Criteria for Part C: Subjects with Suspected NASH and Liver 
Fibrosis ...................................................................................................................34 
4.4. 
Exclusion Criteria for Part A: Healthy Subjects ....................................................35 
4.5. 
Exclusion Criteria for Part B: Healthy Subjects ....................................................36 
4.6. 
Exclusion Criteria for Part C: Subjects with Suspected NASH and Liver 
Fibrosis ...................................................................................................................38 
4.7. 
Subject Number and Identification ........................................................................40 
4.8. 
Subject Withdrawal and Replacement ...................................................................40 
4.9. 
Study Termination .................................................................................................41 
5. 
STUDY TREATMENTS .................................................................................................41 
5.1. 
Description, Storage, Packaging, and Labelling ....................................................41 
5.2. 
Study Treatment Administration ............................................................................42 
5.3. 
Randomisation .......................................................................................................42 
5.4. 
Blinding..................................................................................................................43 
5.5. 
Treatment Compliance ...........................................................................................43 
5.6. 
Drug Accountability...............................................................................................43 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ................................44 
6.1. 
Concomitant Therapies ..........................................................................................44 
6.1.1. 
Concomitant Therapies for Parts A and B ...................................................44 
6.1.2. 
Concomitant Therapies for Part C ...............................................................44 
6.2. 
Diet .........................................................................................................................44 
6.2.1. 
Parts A and B ...............................................................................................44 
6.2.2. 
Part C ...........................................................................................................45 
6.3. 
Smoking .................................................................................................................46 
6.4. 
Exercise ..................................................................................................................46 
6.5. 
Blood Donation ......................................................................................................46 
6.6. 
Exposure to Ultraviolet Light ................................................................................46 
7. 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................47 
7.1. 
Pharmacokinetic Assessments ...............................................................................47 
7.1.1. 
Sample Collection and Processing ...............................................................47 
7.1.2. 
Analytical Methodology ..............................................................................47 
7.2. 
Exploratory Biomarker Assessments .....................................................................48 
7.3. 
Safety and Tolerability Assessments .....................................................................48 
7.3.1. 
Adverse Events ............................................................................................48 
7.3.2. 
Clinical Laboratory Evaluations ..................................................................49 
7.3.3. 
Vital Signs ....................................................................................................49 
7.3.4. 
Electrocardiogram ........................................................................................50 


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7.3.5. 
Physical Examination...................................................................................51 
7.3.6. 
Body Weight ................................................................................................51 
8. 
SAMPLE SIZE AND DATA ANALYSIS ......................................................................51 
8.1. 
Determination of Sample Size ...............................................................................51 
8.2. 
Analysis Populations ..............................................................................................51 
8.2.1. 
Safety Population .........................................................................................51 
8.2.2. 
Pharmacokinetic Population ........................................................................51 
8.2.3. 
Biomarker Population ..................................................................................51 
8.3. 
Pharmacokinetic Analyses .....................................................................................51 
8.4. 
Exploratory Biomarker Analyses ...........................................................................52 
8.5. 
Safety Analysis ......................................................................................................52 
8.6. 
Interim Analysis .....................................................................................................52 
9. 
REFERENCES ................................................................................................................52 
10. APPENDICES .................................................................................................................54 
Appendix 1: Adverse Event Reporting ..............................................................................55 
Appendix 2: Clinical Laboratory Evaluations ...................................................................59 
Appendix 3: Total Blood Volume ......................................................................................60 
Appendix 4: Contraception Guidance ................................................................................63 
Appendix 5: Regulatory, Ethical, and Study Oversight Considerations ............................66 
Appendix 6: Schedule of Assessments ..............................................................................70 
 
LIST OF TABLES AND FIGURES 
Table 1: Pharmacokinetics Parameters of GB1211 in Mice ..............................................20 
Table 2: Pharmacokinetics Parameters of GB1211 in Beagle Dogs ..................................20 
Table 3: Proposed Investigational Medicinal Product Dose Levels ..................................31 
Table 4: Capsule Assembly for Part A ..............................................................................42 
Table 5: High-fat Breakfast Content ..................................................................................45 
 
Figure 1: Study Schematic - Part A Cohorts (Except the Food-Effect Cohort) .................25 
Figure 2: Study Schematic - Part A Food-Effect Cohort (Planned to be Cohort A3) .......26 
Figure 3: Planned Dose Levels (Part A) ............................................................................26 
Figure 4: Study Schematic (Part B) ...................................................................................27 
Figure 5: Planned Dose Levels (Part B) ............................................................................28 
Figure 6: Study Schematic (Part C) ...................................................................................29 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
Ae 
amount of drug excreted in urine 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUC0-24 
area under the plasma concentration-time curve from time zero 
to 24 hours postdose 
AUC0-∞ 
area under the plasma concentration-time curve from time zero 
to infinity 
AUC0-tlast 
area under the plasma concentration-time curve from time zero 
to the time of the last quantifiable concentration 
AUC0-τ 
area under the plasma concentration-time curve over a dosing 
interval 
BCRP 
breast cancer resistance protein 
BID 
twice daily 
BMI 
body mass index 
CAP 
Controlled Attenuation Parameter 
CCL 
chemokine (C-C motif) ligand 
CCR 
chemokine (C-C motif) receptor 
CFR 
Code of Federal Regulations 
CH3L1 
chitinase-3 like protein-1 
CK18 
cytokeratin 18 
CL/F 
apparent total plasma clearance 
CLR 
renal clearance 
Cmax 
maximum observed plasma concentration 
Cmin 
minimum observed plasma concentration 
CRO 
Contract Research Organisation 
CRU 
Clinical Research Unit 
CSA 
clinical study agreement 
CYP 
cytochrome P450 
DSS 
Drug Safety Services 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ELF 
E74-like transcription factors  
eCRF 
electronic Case Report Form 


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EDC 
electronic data capture 
ELF 
E74-like transcription factors 
fe 
percentage of drug excreted unchanged 
FIB-4 
Fibrosis-4 
FL 
fatty liver 
FSH 
follicle-stimulating hormone 
GLP 
Good Laboratory Practice 
HA 
hyaluronic acid 
HbA1c 
glycosylated haemoglobin 
HDL 
high density lipoprotein 
HED 
human equivalent dose 
hERG 
human ether-à-go-go-related gene 
hsCRP 
heat shock C-reactive protein 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
IC50 
half maximal inhibitory concentration 
ICF 
Informed Consent Form 
ICH 
International Council for/Conference on Harmonisation 
IL 
interleukin 
IMP 
investigational medicinal product 
LBBB 
left bundle branch block 
LDL 
low density lipoprotein 
MAD 
multiple ascending dose(s) 
MCP-1 
monocyte chemotactic protein-1 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MRSD 
maximum recommended starting dose 
NAFLD 
nonalcoholic fatty liver disease 
NASH 
nonalcoholic steatohepatitis 
NOAEL 
no observed adverse effect level 
P3NP 
aminoterminal peptide of pro-collagen III 
PAI-1 
plasminogen activator inhibitor-1 
PD 
Pharmacodynamic(s) 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
QD 
once daily 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate using Fridericia’s method 
RAAUC0-τ 
observed accumulation ratio based on AUC0-τ 
RACmax 
observed accumulation ratio based on Cmax 


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SAD 
single ascending dose(s) 
SAE 
serious adverse event 
t1/2 
apparent plasma terminal elimination half-life 
T2DM 
type 2 diabetes mellitus 
TBD 
to be determined 
TIMP-1 
tissue inhibitor of matrix metalloproteinase-1 
Tmax 
time of the maximum observed plasma concentration 
TMF 
Trial Master File 
TNF-α 
tumor necrosis factor-α 
ULN 
upper limit of normal 
US 
ultrasound 
UV 
ultraviolet 
Vz/F 
apparent volume of distribution 
WBC 
White blood  
 
 


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1. INTRODUCTION 
1.1. 
Overview 
Galectin-3, a beta-galactoside binding lectin, is a key regulator of fibrosis and inflammation 
in lung, liver, and kidney. Mice deficient in galectin-3 are protected from fibrosis and exhibit 
reduced scarring in response to injury. Galectin-3 regulates myofibroblast differentiation (the 
major source of collagens during tissue fibrosis) and also has profound effects on 
macrophage polarisation. In addition, secretion of galectin-3 by macrophages results in 
activation of myofibroblasts, further amplifying a pro-fibrotic loop.1,2 Galectin-3 inhibitors, 
when delivered locally in the lung, have also been shown to reduce fibrosis in mice.3,4  
Nonalcoholic fatty liver disease (NAFLD) affects about a third of the adult population in 
Western nations, and may manifest histologically as a fatty liver or steatohepatitis. Fatty liver 
is generally non-progressive or progresses slowly compared to nonalcoholic steatohepatitis 
(NASH), which is more likely to lead to progressive fibrotic remodelling of the liver 
culminating in cirrhosis. Prevalence of NASH cirrhosis is growing and it is at present, the 
second leading cause for liver transplantation. There is no approved therapy for NASH or 
NASH fibrosis.  
The gold standard methodology for the diagnosis on NASH is liver biopsy. Nonalcoholic 
steatohepatitis is characterised by a pattern of injury composed of steatosis, lobular 
inflammation, and ballooning degeneration. Liver biopsy is an invasive methodology and 
subject to a certain degree of sampling variability; however, there are no noninvasive tools to 
diagnose definite NASH with enough accuracy to serve as a stand-alone entry criteria for 
advanced phase trials and to avoid using histology-based endpoints. However, in early proof 
of concept trials, noninvasive models are generally used to identify those who may have 
definite NASH with some degree of fibrosis (“suspected NASH with liver fibrosis”).5 
Galecto Biotech is developing a systemically active galectin-3 inhibitor for the treatment of 
fibrotic disorders such as NASH, renal fibrosis, and cardiac fibrosis. This is the first time 
GB1211 will be administered to humans. Additional details on GB1211 can be found in the 
Investigator’s Brochure (IB).6  
1.2. 
Summary of Nonclinical Pharmacology 
In 2 primary pharmacodynamic (PD) studies, the effect of GB1211 on carbon 
tetrachloride-induced liver fibrosis in mice was evaluated. The percentage area of Picrosirius 
Red positive staining in liver sections was significantly reduced in animals given 10 mg/kg 
GB1211 twice daily (BID; p = 0.009), indicating decreased fibrotic collagen deposition in the 
hepatic parenchyma; and significantly reduced (p ≤ 0.05) in once daily and BID groups in a 
second study. The collagen content, measured by hydroxyproline, was also found to be 
significantly reduced in the BID group of one study. There were no clear significant changes 
in liver function, liver fibrosis biomarkers, or indicators of the collagen life cycle, with the 
exception of increased serum ALT with 10 mg/kg GB1211 BID in 1 study. In a secondary 
PD study, GB1211 showed no cross-reactivity against an industry standard panel of 87 
enzyme and radioligand binding assays. 


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1.3. 
Summary of Safety Pharmacology 
In a Good Laboratory Practice (GLP) study in male CD-1 mice, no effects were observed on 
the central nervous system or body temperature or respiratory parameters when given a single 
oral dose of up to 500 mg/kg. In another GLP study in male telemeterized Beagle dogs, no 
effects were observed on hemodynamic or electrocardiography parameters, or body 
temperature, when given a single oral dose of up to 50 mg/kg. In 6-week repeat-dose toxicity 
studies, there was also no evidence of gastrointestinal toxicity or renal toxicity in mice or 
dogs; and GB1211 was negative in all genotoxicity studies.  
In addition, 2 human ether-à-go-go-related gene (hERG) studies were conducted. In the 
non-GLP study, GB1211 significantly (p ≤ 0.05) inhibited the hERG tail current density at 1 
and 10 μM by 16.8% and 35.9%, respectively. There was no evidence of reversal based on 
measures taken after a 5-minute washout period in cells exposed to 10 μM. In the GLP study, 
GB1211 significantly (p < 0.05) inhibited the hERG tail current amplitude at all 
concentrations (6.83%, 28.51%, 57.60%, and 93.33% for 0.3, 1, 10, and 100 μM, 
respectively). The half maximal inhibitory concentration (IC50) was 5.06 μM (2700 ng/mL). 
1.4. 
Summary of Toxicology 
As detailed in Section 4.3 of the IB6, repeat-dose toxicity studies were conducted in 2 species, 
the CD-1 mouse and Beagle dog: 
• In 2 mice repeat-dose toxicity studies, there were no GB1211-related deaths.  
o In a non-GLP study, there were no significant findings in mice given single 
escalating oral doses up to 500 mg/kg, or daily oral doses at 500 mg/kg/day 
for 14 days.  No effects on body weights, food consumption, clinical 
pathology, organ weights, or macroscopic or microscopic findings were 
observed. Systemic saturation was observed at doses > 50 mg/kg/day. 
o In the 6-week GLP study (doses of 50, 150, and 500 mg/kg/day), there were 
no GB1211-related deaths. However, there were 10 deaths in total, with 
4 animals sacrificed in moribund condition with eye-related changes, 3 were 
due to gavage errors (2 were sacrificed moribund, 1 was found dead), and the 
cause of 3 deaths was not determined (1 was sacrificed moribund due to 
clinical observations and 2 were found dead). Additional details for these 
deaths can be found in the IB6 (Section 4.3.2.1.2). No GB1211-related, adverse 
effects were observed (no effects on clinical signs, ophthalmic observations, 
body weights, food consumption, clinical pathology parameters, organ weight, 
or macroscopic or microscopic pathology were observed in the dosing or 
recovery periods). The no observed adverse effect level (NOAEL) was 
500 mg/kg/day, which corresponded to maximum observed plasma 
concentration (Cmax) values of 17005.0 and 22506.6 ng/mL, and area under the 
plasma concentration-time curve (AUC) from zero to the time of the last 
quantifiable concentration (AUC0-tlast) values of 46617.4 and 
58355.9 ng·h/mL, for males and females, respectively, on Day 42 (Table 1). 


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• In 2 dog repeat-dose toxicity studies, systemic saturation was observed at doses 
> 50 mg/kg. No GB1211-related adverse effects were observed. Increases in QT and 
QT interval corrected for heart rate (QTc) intervals noted in males at 15 or 
50 mg/kg/day and females at 50 mg/kg/day were not considered adverse because the 
range of individual QT values were within what would be considered the normal 
range for the dog. The left bundle branch block (LBBB) noted in one female at 
50 mg/kg/day (1 hour postdose in Week 6) is not a normal variation in dogs, however, 
as it was present during the predose phase collection for this animal, it was not 
considered to be GB1211 related (Covance study 8377741 – to be published). In 
addition, no electrocardiogram (ECG) findings were observed in telemeterized dogs 
given up to 50 mg/kg in the cardiovascular safety pharmacology study. The NOAEL 
was 50 mg/kg/day, which corresponded to Cmax values of 27047.0 and 
17789.9 ng/mL, and AUC0-tlast values of 117585.2 and 63452.2 ng·h/mL, for males 
and females, respectively, on Day 42 (Table 2). 
In addition, there was no genotoxic potential for GB1211 in appropriately conducted assays 
in bacteria (reverse mutation test), human lymphocytes (in vitro micronucleus test), and in 
mouse bone marrow (in vivo micronucleus test).  
No developmental and reproductive toxicology studies have been conducted so far. 
1.5. 
Summary of Nonclinical Pharmacokinetics 
In the 6-week GLP study6 in CD-1 mice (doses of 50, 150, and 500 mg/kg/day; Table 1) Cmax 
values were reached between 15 minutes and 2 hours. Apparent plasma terminal half-life 
(t1/2) values ranged between 1.93 and 3.63 hours. In general, increases in AUC0-tlast on Day 1 
and Day 42 were less than dose-proportional between 50 and 500 mg/kg, with AUC0-tlast 
being higher at 150 mg/kg/day than at 500 mg/kg/day on Day 42 for both male and females.   
The Cmax and AUC0-tlast values on Day 42 decreased after daily administration. No sex 
differences were observed.    


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Table 1: Pharmacokinetics Parameters of GB1211 in Mice 
Day 
Dose 
(mg/kg/day) 
Sex 
AUC0-tlast (ng.h/mL) 
Cmax 
(ng/mL) 
Tmax  
(h) 
1 
50 
male 
85188.1 
25548.7 
0.50 
 
 
female 
58347.7 
14780.3 
0.50 
 
150 
male 
86490.1 
38013.2 
0.25 
 
 
female 
90348.9 
38686.2 
0.25 
 
500 
male 
95727.5 
41296.0 
0.25 
 
 
female 
71134.5 
40542.6 
0.25 
42 
50 
male 
41631.3 
12156.1 
1.00 
 
 
female 
46117.4 
9952.2 
2.00 
 
150 
male 
52541.3 
17555.2 
1.00 
 
 
female 
61185.3 
21443.2 
1.00 
 
500a 
male 
46617.4 
17005.0 
0.25 
 
 
female 
58355.9 
22506.6 
0.25 
Abbreviations: AUC0-tlast = area under the plasma concentration-time curve from time zero to the time of the last quantifiable 
concentration; Cmax = maximum concentration; Tmax = time to maximum concentration. 
a The no observed adverse effect level 
In the 6-week study in Beagle dogs6 (doses of 5, 15, and 50 mg/kg/day; Table 2) Cmax values 
were reached between 0.5 and 1.02 hours. Values for t1/2 ranged between 4.47 and 8.23 hours. 
In general, increases in AUC0-tlast values on Day 1 and Day 42 were approximately 
dose-proportional between 5 and 15 mg/kg and were less than dose-proportional between 15 
and 50 mg/kg. Mean Cmax and AUC0-tlast values were similar between Day 1 and Day 42, 
suggesting no accumulation. Concentrations were generally higher for males when compared 
to females. 
Table 2: Pharmacokinetics Parameters of GB1211 in Beagle Dogs 
Day 
Dose 
(mg/kg/day) 
Sex 
AUC0-tlast (ng.h/mL) 
Cmax 
(ng/mL) 
Tmax  
(h) 
1 
5 
male 
14776.3 
6299.9 
1.00 
 
 
female 
8597.9 
4237.6 
1.00 
 
15 
male 
39752.7 
13333.4 
0.84 
 
 
female 
43431.2 
16870.1 
1.00 
 
50 
male 
102302.0 
45911.1 
0.70 
 
 
female 
79036.9 
35203.0 
1.00 
42 
5 
male 
11995.6 
3831.0 
1.00 
 
 
female 
13579.7 
4737.1 
1.33 
 
15 
male 
26322.4 
7847.7 
0.83 
 
 
female 
34587.6 
14161.3 
1.00 
 
50a 
male 
117585.2 
102302.0 
1.00 
 
 
female 
63452.2 
79036.9 
0.95 
Abbreviations: AUC0-tlast = area under the plasma concentration-time curve from time zero to the time of the last quantifiable 
concentration; Cmax = maximum concentration; Tmax = time to maximum concentration. 
a The no observed adverse effect level 
In 5 pharmacokinetic (PK) studies, effects of GB1211 on human ATP binding cassette 
transporters, single-dose absorption, tissue distribution, and elimination, protein binding, in 
vitro metabolism, and enzyme inhibition were evaluated. Results indicated that GB1211 is a 


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substrate of P-glycoprotein (P-gp), but not of breast cancer resistance protein (BCRP); and an 
inhibitor of BCRP, but not of P-gp. The mean free fractions of GB1211 in plasma were 
14.1% (rabbit), 7.66% (mouse), 5.34% (human), 3.87% (dog), 1.22% (rat); and protein 
binding was not concentration dependent. Mean elimination half-lives from plasma were 1.46 
(intravenous) and 3.04 hours (oral), with total plasma exposure (AUC0-tlast) to 
[14C]-GB1211-related radioactivity at 1170 (intravenous) and 13100 h.ng eq./g (oral). Oral 
bioavailability was 109%. In albino and pigmented mice, [14C]-GB1211-related radioactivity 
was well absorbed and rapidly distributed into tissues, [14C]-GB1211-related radioactivity 
was rapidly eliminated from tissues, and the mean overall recovery of the radioactivity 
administered was 103%. GB1211 showed a trend for distribution to the uveal tract and skin 
of pigmented mice. This was reversible and below the limit of quantification at 168 hours. 
(refer to Sections 4.2.3 and 4.2.5 of IB6 for further information). The mean free fractions of 
GB1211 in human liver microsomes across GB1211 concentrations were similar at protein 
concentrations of 0.1 mg/mL (97.8%) and 1 mg/mL (67.6%), but at 5 mg/mL the free fraction 
was higher at 1 µM (61.5%) than at 10 μM (26.4%) and 100 μM (36.4%). The metabolic 
turnover (percent of parent remaining) of [14C]-GB1211 was most extensive in dog, mouse, 
and rat hepatocytes; was lower in rabbit; and was negligible in human hepatocytes. No 
unique human in vitro metabolites were formed and the proportions of metabolites present in 
the human profiles were not greater than those observed in the other species. Enzyme 
activities mediated by cytochrome P450 (CYP)-1A2, CYP2C8, CYP2D6 and CYP3A4 were 
weakly inhibited by GB1211, and the inhibition was not considered to be metabolism 
dependent.  
Further details from the nonclinical PK programme can be found in the IB.6  
1.6. 
Summary of Clinical Experience 
This study is a first-in-human study. No clinical studies have been performed with GB1211 to 
date. 
1.7. 
Study Rationale 
The principal aim of this study is to obtain safety and tolerability data when GB1211 is 
administered orally as single doses and as multiple doses to healthy subjects. In addition, an 
optional part has been included to obtain safety and tolerability data when GB1211 is 
administered orally as multiple doses to subjects with suspected NASH and liver fibrosis 
(refer to Section 3.1). This information, together with the PK data, will help establish the 
doses and dosing regimen suitable for future studies in subjects with the targeted indication. 
The effect of GB1211 on exploratory biomarkers will also be investigated, along with the 
effects of food on the PK of GB1211. 
1.8. 
Benefit-risk Assessment 
Healthy subjects and subjects with suspected NASH and liver fibrosis in the current study 
will not receive any health benefit (beyond that of an assessment of their medical status) from 
participating in the study. The risks of participation are primarily those associated with 
adverse reactions to the investigational medicinal product (IMP), although there may also be 
some discomfort from collection of blood samples and other study procedures. More 


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information about the known and expected benefits, risks, and reasonably anticipated adverse 
effects associated with GB1211 may be found in the IB.6  
2. OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
The primary objectives of the study are: 
• to evaluate the safety and tolerability of single and multiple doses of GB1211 
administered to healthy subjects. 
• to evaluate the safety and tolerability of multiple doses of GB1211 administered to 
subjects with suspected NASH and liver fibrosis. 
The secondary objectives of the study are: 
• to evaluate the PK of single doses of GB1211 in plasma and urine in healthy 
subjects and the PK of multiple doses of GB1211 in plasma of healthy subjects 
and subjects with suspected NASH and liver fibrosis. 
• to determine the effect of food on the single oral dose PK of GB1211. 
The exploratory objectives of the study are:  
• to investigate biomarkers related to GB1211 activity at single and/or multiple 
doses in comparison to placebo in healthy subjects and subjects with suspected 
NASH and liver fibrosis. 
• to investigate biomarkers of metabolism, inflammation, and fibrosis following 
multiple doses of GB1211 in healthy subjects and/or subjects with suspected 
NASH and liver fibrosis. 
• to identify metabolites of GB1211 in plasma and urine.  
2.2. 
Endpoints  
2.2.1. 
Primary Endpoints 
The primary safety endpoints for the study are as follows:  
• incidence and severity of adverse events (AEs) 
• incidence of laboratory abnormalities, based on haematology, clinical chemistry, 
and urinalysis test results 
• 12-lead ECG parameters 
• vital signs measurements 
• physical examinations 


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2.2.2. 
Secondary Endpoints 
For Part A, the single ascending dose (SAD) in healthy subjects, PK outcome endpoints of 
GB1211 are as follows: 
• AUC from time zero to infinity (AUC0-∞) 
• AUC0-tlast 
• Cmax 
• time of the maximum observed plasma concentration (Tmax) 
• t1/2 
• apparent total plasma clearance (CL/F) 
•  apparent volume of distribution (Vz/F) 
•  amount of drug excreted in urine (Ae) 
•  percentage of dose excreted unchanged (fe) in urine 
• renal clearance (CLR)  
For Parts B and C, the multiple ascending doses (MAD) in healthy subjects and subjects with 
suspected NASH and liver fibrosis, PK outcome endpoints of GB1211 are as follows: 
• AUC over a dosing interval (AUC0-τ) 
• AUC0-∞ 
• Cmax 
• Tmax 
• t1/2 
• minimum observed plasma concentration (Cmin) 
• observed accumulation ratio based on AUC0-τ (RAAUC0-τ) 
• observed accumulation ratio based on Cmax (RACmax) 
Other PK parameters may also be reported if necessary. 
2.2.3. 
Exploratory Endpoints 
• The following biomarkers related to the GB1211 activity and biomarkers of 
metabolism, inflammation, and fibrosis will be assessed as follows: 
• For all SAD and MAD cohorts (Parts A, B, and C): 
o Serum galectin-3 
o Chemokine (C-C motif) ligand (CCL)-4 
o Other biomarkers may also be measured in an exploratory fashion. 


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• For MAD cohorts only (Parts B and C): 
o Changes from baseline at Day 10 (healthy subjects) and Day 42 (subjects with 
suspected NASH and liver fibrosis) in fasting plasma glucose and insulin. 
o Changes from baseline at Day 10 (healthy subjects) and Day 42 (subjects with 
suspected NASH and liver fibrosis) in lipid profile. 
o Changes from baseline at Day 10 (healthy subjects) and Day 42 (subjects with 
suspected NASH and liver fibrosis) in heat shock C-reactive protein (hsCRP), 
interleukin (IL)-12, monocyte chemotactic protein (MCP)-1, and tumor 
necrosis factor (TNF)-α, as well as the proinflammatory chemokines, CCL2, 
CCL3, CCL4, and the chemokine receptors chemokine (C-C motif) receptor 
(CCR)-1 and CCR2; and other biomarkers of inflammation as required. 
• For subjects with suspected NASH and liver fibrosis only (Part C, MAD cohort):   
o Changes from baseline at Day 42 in biomarkers of fibrosis, including but not 
limited to extracellular matrix proteins (tissue inhibitor of matrix 
metalloproteinase-1 [TIMP-1], hyaluronic acid [HA], and aminoterminal 
peptide of pro-collagen III [P3NP]), A9, E74-like transcription factor (ELF) 
panel, cytokeratin (CK)-18, plasminogen activator inhibitor (PAI)-1, 
chitinase-3 like protein-1 (CH3L1), IL6, and pro-collagen 3. 
• Identification of GB1211 metabolites in plasma and urine.  
3. INVESTIGATIONAL PLAN 
This is a Phase 1, randomised, double-blind, placebo-controlled, first-in-human study in 
which the safety, tolerability, and PK of orally administered GB1211 will be assessed in 
healthy adult subjects and adult subjects with suspected NASH and liver fibrosis.  
Suspected NASH is defined as the presence or history of fatty liver, together with elevated 
alanine aminotransferase (ALT; defined as ALT values ≥ 30 U/L in males or ≥ 20 U/L in 
females), plus either confirmed type 2 diabetes mellitus (T2DM) or metabolic syndrome 
(Adult Treatment Panel III definition), in the absence of any other liver disease. Additional 
criteria aim to enrich for individuals with liver fibrosis (as per inclusion criteria; Section 4.3). 
The study will consist of 3 parts: a SAD phase (Part A) enrolling a total of 5 cohorts of 
healthy subjects; a MAD phase (Part B) enrolling 2 cohorts of healthy subjects; and an 
optional Part C MAD phase, enrolling 1 cohort of subjects with suspected NASH and liver 
fibrosis. One cohort of Part A will receive GB1211 under both fasted and fed conditions to 
investigate the effect of food.  
3.1. 
Overall Study Design and Plan 
3.1.1. 
Part A 
Part A will comprise a single-dose, sequential-cohort study incorporating a single-cohort, 
randomised, 2-part arm to investigate the effect of food. Overall, 40 subjects will be studied 
in 5 cohorts (Cohort A1 to A5), with each cohort consisting of 8 subjects. 


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Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Each subject will participate in 1 treatment period only, 
residing at the Clinical Research Unit (CRU) from Day -1 (the day before dosing) to Day 3 
(48 hours postdose), except for the food-effect cohort (planned to be Cohort A3), where each 
subject will participate in 2 treatment periods separated by a minimum of 7 days.  
All subjects will return for a Follow-up visit 5 to 7 days after their final dose.  
Dose Regimen: 
In each of Cohorts A1 to A5, 6 subjects will receive GB1211 and 2 will receive placebo. In 
all cohorts, except the food-effect cohort, all doses will be administered in the fasted state in 
accordance with a randomisation schedule on the morning of Day 1. For the food-effect 
cohort, which is planned to be Cohort A3, Treatment Period 1, Day 1 doses will be 
administered in the fasted state in accordance with the randomisation schedule and in 
Treatment Period 2, Day 1 doses will be given 30 minutes after the start of a high fat 
breakfast. Each subject in Cohorts A1 to A5 (except the food-effect cohort) will receive only 
a single dose of GB1211 or placebo during the study. In the food-effect cohort, subjects will 
receive the same treatment in both periods and will receive 2 single doses of GB1211 or 
placebo during the study. 
In Cohorts A1 to A5 (except the fed period of the food-effect cohort), dosing will occur such 
that 2 subjects (1 active and 1 placebo) will be dosed at least 24 hours before the remaining 
subjects, where continuation to dose the remaining subjects will be at the Investigator’s 
discretion. 
Based on the ongoing review of the safety, tolerability, and PK results, additional 
nonresidential visits may be required. The number of additional visits per subject will not 
exceed 3 and will not extend beyond 28 days after each final dosing occasion. 
An overview of the study design is shown in Figure 1 and Figure 2 and the planned dose 
levels in Figure 3. 
Figure 1: Study Schematic - Part A Cohorts (Except the Food-Effect Cohort) 
 
Abbreviation: CRU = Clinical Research Unit 


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Figure 2: Study Schematic - Part A Food-Effect Cohort (Planned to be Cohort A3) 
 
Abbreviation: CRU = Clinical Research Unit 
 
Figure 3: Planned Dose Levels (Part A) 
 
The total duration of study participation for each subject (from Screening through Follow-up 
visit) for all Part A cohorts except the food-effect cohort is anticipated to be approximately 
5 weeks. For each subject in the food-effect cohort (planned to be Cohort A3), the total 
duration is anticipated to be approximately 6 to 7 weeks. 
3.1.2. 
Part B 
Part B will comprise a multiple-dose, sequential-cohort study. Overall, 22 subjects will be 
studied in 2 cohorts (Cohorts B1 to B2), with each cohort consisting of 11 subjects. Dosing in 


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Part B will start following review of safety, tolerability, and PK data from a single dose with 
exposure higher than the predicted steady-state exposure. 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Each subject will participate in 1 treatment period only 
and reside at the CRU from Day -1 (the day before dosing) until the morning of Day 11 
(24 hours after the final dose on Day 10). 
All subjects will return for a Follow-up visit 5 to 7 days after their final dose.  
Dose Regimen: 
In each of Cohorts B1 to B2, 8 subjects will receive GB1211 and 3 subjects will receive 
placebo. The dietary state for dosing in Part B will be fasted unless data from the food-effect 
cohort is available and supports dosing in the fed state. For all subjects, the planned dosing 
will be BID on Days 1 to 9, inclusive, and a final single dose administration will occur in the 
morning of Day 10. The dosing interval/frequency and dosing duration in Part B may be 
changed following review of data from cohorts in Part A (Section 3.4). The predicted total 
daily exposure will not exceed the highest exposure observed in Part A. There will be a 
minimum of 10 days between dose escalations for each cohort. 
An overview of the study design is shown in Figure 4 and the planned dose levels in Figure 5. 
Figure 4: Study Schematic (Part B) 
 
Abbreviations: BID = twice-daily; CRU = Clinical Research Unit 


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Figure 5: Planned Dose Levels (Part B) 
 
Abbreviations: BID = twice-daily; TBD = to be determined 
The total duration of study participation for each subject (from Screening through Follow-up 
visit) is anticipated to be approximately 6 to 7 weeks. 
3.1.3. 
Part C (Optional) 
Part C will comprise a multiple-dose cohort of 25 subjects with suspected NASH and liver 
fibrosis (Cohort C1). Part C may start following review of data from Part A and at least 
1 Part B cohort. 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Each subject will participate in 1 treatment period only 
and reside at the CRU from Day -1 (the day before dosing) until the morning of Day 2, 
returning for nonresidential visits on Days 7, 14, 21, 28, and 35. Subjects will then check 
back into the CRU on Day 41 until the morning of Day 43 (24 hours after the final dose on 
Day 42). 
All subjects will return for a Follow-up visit 5 to 7 days after their final dose. 
Dose Regimen: 
For Part C, Cohort C1, 15 subjects will receive GB1211 and 10 subjects will receive placebo. 
The dietary state for dosing in Part C will be fasted unless data from the food-effect cohort is 
available and supports dosing in the fed state. For all subjects, the planned dosing will be BID 
on Days 1 to 41 inclusive, and a final single dose administration will occur in the morning of 
Day 42. The total daily dose administered, dose interval/frequency, and dosing duration will 
be based on review of data from Parts A and B. 
An overview of the study design is shown in Figure 6. 


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Figure 6: Study Schematic (Part C) 
 
Abbreviations: BID = twice-daily; CRU = Clinical Research Unit 
The dose level of Part C is to be determined following completion of Part A and at least 
1 cohort of Part B. 
The total duration of study participation for each subject (from Screening through Follow-up 
visit) for Cohort C1 is anticipated to be approximately 11 weeks.  
A Schedule of Assessments is presented in Appendix 6. 
3.2. 
 Study Start and End of Study Definitions 
The start of the study is defined as the date the first subject, who is subsequently enrolled, 
signs an Informed Consent Form (ICF). The point of enrolment occurs at the time of subject 
number allocation. The end of the study is defined as the date of the last subject’s last 
assessment (scheduled or unscheduled). 
3.3. 
Additional Groups 
Following review of the safety, tolerability, and PK data, additional dose cohorts (where 
systemic exposure is not expected to exceed that stated in the dose escalation stopping criteria 
[Section 3.7]) may be added to the study. Up to 3 further cohorts may be included in each of 
Parts A, B, and C. The requirement for additional cohorts will be agreed with the Sponsor 
and documented in the Trial Master File (TMF). 
3.4. 
Discussion of Study Design, Including the Choice of Control Groups 
For Parts A and B of the study, a sequential-cohort, ascending-dose design has been chosen 
for safety reasons as GB1211 is in the early stages of clinical development, with Part A of the 
study being the first time it will be administered to humans. Oral doses have been chosen for 
all parts of the study, as this is the intended clinical route of administration. A 2-part design 
has been chosen for the food-effect arm, as this gives a within-subject assessment of the 
influence of food on the PK of GB1211 and so increases the power of the study for the given 
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It is the intent of Part B to dose subjects such that steady-state plasma levels of GB1211 are 
achieved and maintained for several days. Based on the available nonclinical data, it is 
expected that this will be achieved following 9 days of BID dosing; however, a full review of 
all the safety, tolerability, and PK data from Part A will be performed to confirm the dose 
regimen for Part B. The dose regimen will comprise no less than once every day and will not 
exceed 4-times-daily dosing. The dosing duration will comprise no fewer than 7 consecutive 
days and will not exceed 14 consecutive days of dosing.  
Conducting the initial single- and MAD in healthy subjects mitigates the potential 
confounding effects of the disease state and concomitant medications.  
For Part C, it is the intent to dose subjects with suspected NASH and liver fibrosis to 
investigate safety, tolerability, PK, and the effect on specified exploratory biomarkers 
following multiple oral doses of GB1211 in subjects of the targeted indication. Preclinical 
toxicology data provides evidence for dosing over 42 days for Part C, and a study by 
Mudaliar et al., indicates that decreases in serum markers of fibrosis were observed following 
6 weeks administration of obeticholic acid in NAFLD patients7; however, a full review of all 
the safety, tolerability, PK, and emerging exploratory biomarker data from Parts A and B will 
be performed to confirm the dose regimen for Part C. 
Details of the dosing regimen and duration used for Parts B and C of the study will be 
documented in the TMF. 
Based upon the nonclinical data, the duration of each treatment period is considered adequate 
to achieve the study objectives. Where applicable, an interval of at least 7 days between 
treatment periods in the food-effect arm is considered adequate to prevent carryover of 
GB1211; however, may be adjusted based on emerging PK data. 
This study will be double-blind and placebo-controlled in order to avoid bias in the collection 
and evaluation of data during its conduct. Placebo has been chosen as the control treatment to 
assess whether any observed effects are treatment-related or simply reflect the study 
conditions. 
Continuous 12-lead ECG monitoring will be included in this study in order to explore 
potential GB1211 effects on the QT interval, with a view of supporting a potential thorough 
QT study waiver. 
3.4.1. 
Dose Interval 
Following thorough review of all available nonclinical data (pharmacological and 
toxicological), dosing at each dose level in Part A will be such that 2 subjects (1 GB1211 and 
1 placebo) will be dosed 24 hours before the remaining 6 subjects. After dosing the first 
2 subjects on a separate day, a minimum of a 5-minute dosing interval for the remaining 
6 subjects in each dose-ascending cohort is considered acceptable. Continuation to dose the 
remaining 6 subjects will be at the Investigator’s discretion.  
For Part B, sentinel dosing is not planned as the total daily dose administered will not exceed 
a dose shown to be safe and well tolerated in Part A. In addition, accumulation is not 
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in Part B will not exceed a well-tolerated exposure in Part A. However, following review of 
data in Part A, sentinel dosing may be introduced for Part B cohorts, if exposure is predicted 
to exceed the maximum exposure in Part A. 
3.5. 
Selection of Doses in the Study 
In the 42-day repeat oral dose toxicology studies, NOAELs in the mouse and the dog were 
500 mg/kg/day and 50 mg/kg, respectively, corresponding to human equivalent doses (HEDs) 
of 40 and 27 mg/kg, respectively. Therefore applying a 10-fold safety margin the maximum 
recommended starting dose (MRSD) is 2.7 mg/kg, approximately 162 mg for a 60 kg subject. 
In vitro data in human cells suggests an IC50 of GB1211 of 0.1 µM (0.5 µg/mL) supporting 
the chosen MRSD. 
In the PD study6 evaluating the effect of GB1211 in carbon tetrachloride-induced liver 
fibrosis in mice there was no pharmacological activity observed at 2 mg/kg but there was 
activity at 10 mg/kg. Therefore the MRSD that is not considered to be pharmacologically 
active, based on the 2 mg/kg dose level, is 0.16 mg/kg, equivalent to approximately 9.6 mg in 
a 60 kg subject. The lowest pharmacologically active dose has been defined as 10 mg/kg, 
representing a HED of 48 mg for a 60 kg subject. 
The proposed starting dose of 5 mg is 1.9-fold lower than the MRSD of 9.6 mg (based on the 
PD study6) and therefore is not expected to have any pharmacological activity.  
The proposed IMP dose levels for the study are shown in Table 3. As described in Section 3.6 
each dose following the starting dose may be subject to change based on review of data from 
previous cohorts.  
Table 3: Proposed Investigational Medicinal Product Dose Levels  
Study 
Part 
Cohort 
Subject 
Numbers 
Treatment Period 1 
Treatment Period 2 
Part A 
A1 
101 – 108 
5 mg or placebo (fasted) 
 
 
A2 
109 – 116 
20 mg or placebo (fasted) 
 
 
A3 
117 – 124 
50 mg or placebo (fasted) 
50 mg or placebo (fed) 
 
A4 
125 – 132 
100 mg or placebo (fasted) 
 
 
A5 
133 – 140 
200 mg or placebo (fasted) 
 
Part B 
B1 
201 – 211 
TBD 
 
 
B2 
212 – 222 
TBD 
 
Part C 
C1 
301 - 325 
TBD 
 
Abbreviation: TBD = to be determined 
For Part B of the study, dose levels, dosing frequency/interval, and dosing duration will be 
fully decided, in consultation with the Sponsor, on the basis of data from Part A of the study. 
For Part C of the study, dose levels, dosing frequency/interval, and dosing duration will be 
fully decided, in consultation with the Sponsor, on the basis of data from Part A, and at least 
1 Part B cohort. The total daily dose of GB1211 administered during this part of the study 
will not exceed the maximum well-tolerated dose level studied in Part A. 


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Dose levels should not increase by more than 5-fold for predicted nonpharmacologically 
active dose levels and by 3-fold for predicted pharmacologically active dose levels.  
The highest dose level may exceed the top dose shown in the above table, providing systemic 
exposure does not exceed that stated in the dose escalation stopping criteria (Section 3.7). 
Details of all doses administered in Parts A, B, and C of the study will be documented in the 
TMF. 
3.6. 
Dose Escalation 
Doses will be administered in an escalating manner following satisfactory review by the 
Sponsor and Investigator of the safety and tolerability data (up to 48 hours post-final dose) 
and PK data (up to 24 hours post-final dose) from the lower dose levels. Doses may be 
reduced and may be lower than the starting dose. There will be a minimum of 10 days 
between dose escalations to allow sufficient time for an adequate safety review. 
Dose escalation in both Parts A and B will only occur if data from a minimum of 6 and 
7 subjects, respectively, have been reviewed from the previous lower dose cohort, such that 
data from a minimum of 4 subjects who have received GB1211 will be used to make the dose 
escalation decision. 
The justification for this is as follows: 
• Based upon nonclinical data, no clinically important off-target effects are 
expected within the proposed dose range. 
• A minimum of 4 subjects receiving the active drug is considered sufficient to 
characterise the safety profile and PK response to GB1211. 
Between each dose escalation, the Investigator will review all available blinded data to ensure 
it is safe to proceed with the planned dose escalation. An interim safety report, summarising 
results from all available safety assessments, will be sent to the Sponsor prior to the start of 
each successive cohort. Any clinically significant results will be discussed with the Sponsor 
before dose escalation continues. Interim PK data will also be reviewed in terms of dose 
escalation and to confirm that the study design remains appropriate. In the event of a 
disagreement between Sponsor and Investigator on the dose escalation decision, the decision 
of the Investigator will be upheld. 
3.7. 
Dose Escalation Stopping Criteria 
The study will be halted if 1 or more subjects experience an serious adverse event (SAE) that 
is considered to be related to IMP or 2 or more subjects experience severe AEs that are 
considered to be related to IMP. If, following an internal safety review, the Sponsor deems it 
appropriate to restart the study; this can be done following approval of a substantial protocol 
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In Parts A and B, following consultation with the Sponsor, dose escalation will stop if: 
• One or more subjects in a cohort experience an SAE that is considered to be 
related to IMP or 2 or more subjects in a cohort experience severe AEs that are 
considered to be related to IMP. 
• Clinically relevant signs or symptoms of similar nature occur in 2 or more 
subjects in a cohort that, in the opinion of the Investigator, warrant stopping of 
dose escalation. 
• There is evidence of clinically significant increases in liver function tests 
(aspartate aminotransferase [AST], ALT, alkaline phosphatase, bilirubin, and/or 
gamma-glutamyl transferase), defined as 3 times the upper limit of normal (ULN) 
in 2 or more subjects in a cohort (confirmed with repeat testing), which are 
considered related to the IMP in the opinion of the Investigator. 
• QT interval corrected for heart rate using Fridericia’s method (QTcF) 
increases > 60 msec compared to baseline (predose) and/or absolute QTcF 
values > 500 msec (confirmed by repeat measurement) in 2 or more subjects in a 
cohort. 
• The systemic exposure for any individual subject is predicted to exceed a Cmax of 
19755 ng/mL and/or an AUC from time zero to 24 hours postdose (AUC0-24) of 
52486 ng.h/mL; ie, systemic exposure will be no greater than the lowest exposure 
at the NOAEL (Criterion is based on preclinical toxicology data from both male 
and female mice, where no gender differences were observed in terms of safety 
findings). 
4. SELECTION OF STUDY POPULATION 
4.1. 
Inclusion Criteria for Parts A: Healthy Subjects 
Subjects for Part A must satisfy all of the following criteria at the Screening visit unless 
otherwise stated: 
1. Males or females, of any race, between 18 and 55 years of age, inclusive.  
2. Body mass index (BMI) of 18.0 to 32.0 kg/m2 (inclusive) with a minimum body 
weight of 50 kg. 
3. In good health, determined by no clinically significant findings from medical history, 
physical examination, 12-lead ECG, vital signs measurements, and clinical laboratory 
evaluations (congenital nonhaemolytic hyperbilirubinemia [eg, suspicion of Gilbert’s 
syndrome based on total and direct bilirubin] is not acceptable) at Screening and 
Check-in as assessed by the Investigator (or designee), as applicable. 
4. Resting heart rate ≥ 45 bpm and ≤ 90 bpm with a single 12-lead ECG at Screening. 
5. Females will not be pregnant or lactating, and females of childbearing potential and 
males will agree to use contraception as detailed in Appendix 4.  


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6. Male subjects must agree to refrain from sperm donation and females should refrain 
from ova donation from the date of Check-in (Day -1) until 90 days after the 
Follow-up visit. 
7. Able to comprehend and willing to sign an ICF and to abide by the study restrictions. 
4.2. 
Inclusion Criteria for Part B: Healthy Subjects 
Subjects for Part B must satisfy all of the following criteria at the Screening visit unless 
otherwise stated: 
1. Males or females, of any race, between 18 and 60 years of age, inclusive.  
2. Body mass index (BMI) of 18.0 to 32.0 kg/m2 (inclusive) with a minimum body 
weight of 50 kg. 
3. In good health, determined by no clinically significant findings from medical history, 
physical examination, 12-lead ECG, vital signs measurements, and clinical laboratory 
evaluations (congenital nonhaemolytic hyperbilirubinemia [eg, suspicion of Gilbert’s 
syndrome based on total and direct bilirubin] is not acceptable) at Screening and 
Check-in as assessed by the Investigator (or designee), as applicable. 
4. Females will not be pregnant or lactating, and females of childbearing potential and 
males will agree to use contraception as detailed in Appendix 4.  
5. Male subjects must agree to refrain from sperm donation and females should refrain 
from ova donation from the date of Check-in (Day -1) until 90 days after the 
Follow-up visit. 
6. Able to comprehend and willing to sign an ICF and to abide by the study restrictions. 
4.3. 
Inclusion Criteria for Part C: Subjects with Suspected NASH and Liver Fibrosis 
Subjects for Parts C must satisfy all of the following criteria at the Screening visit unless 
otherwise stated: 
1. Males or females, of any race, between 18 and 60 years of age, inclusive.  
2. Body mass index (BMI) of ≥ 25.0 and ≤ 38.0 kg/m2.  
3. Documented history of fatty liver within the last 24 weeks by one of the following: 
magnetic resonance imaging (MRI) suggesting liver fat ≥ 8%, ultrasound (US) 
indicating fatty liver, or Fibroscan Controlled Attenuation Parameter (CAP) 
> 270 dB/m. In subjects without a documented history of fatty liver, a Fibroscan CAP 
or US can be performed at Screening. Subjects with Fibroscan CAP > 270 dB/m or 
US indicating fatty liver are eligible. 
4. Metabolic syndrome (Adult Treatment Panel III definition) or T2DM (defined as 
stable diabetes with glycosylated haemoglobin [HbA1c] ≤ 9.5%). 
5. Alanine aminotransferase (ALT) ≥ 20 U/L for females and ≥ 30 U/L for males at 
Screening. 
6. Fibroscan ≥ 7 KPa and < 13 KPa, or Fibrosis-4 (FIB-4) index ≥ 1.1 and < 3.25. 


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7. Females of nonchildbearing potential defined as permanently sterile (ie, due to 
hysterectomy, bilateral salpingectomy, and/or bilateral oophorectomy) or 
postmenopausal (defined as at least 12 months postcessation of menses without an 
alternative medical cause and follicle-stimulating hormone [FSH] level 
≥ 40 mIU/mL). Males will agree to use contraception as detailed in Appendix 4.  
8. Male subjects must agree to refrain from sperm donation and females should refrain 
from ova donation from the date of Check-in (Day -1) until 90 days after the 
Follow-up visit. 
9. Able to comprehend and willing to sign an ICF and to abide by the study restrictions. 
4.4. 
Exclusion Criteria for Part A: Healthy Subjects 
Subjects from Part A will be excluded from the study if they satisfy any of the following 
criteria at the Screening visit unless otherwise stated: 
1. Significant history or clinical manifestation of any metabolic, allergic, dermatological, 
hepatic, renal, haematological, pulmonary, cardiovascular, gastrointestinal, 
neurological, respiratory, endocrine, or psychiatric disorder, as determined by the 
Investigator (or designee). 
2. History of febrile illness within 7 days prior to the first dose of study drug or subjects 
with evidence of active infection. 
3. History of significant hypersensitivity, intolerance, or allergy to any drug compound, 
food, or other substance, unless approved by the Investigator (or designee). 
4. History of stomach or intestinal surgery or resection that would potentially alter 
absorption and/or excretion of orally administered drugs (uncomplicated 
appendectomy and hernia repair will be allowed, but not cholecystectomy).  
5. Any of the following: 
a. QTcF > 450 msec confirmed by repeat measurement.  
b. QRS duration > 110 msec confirmed by repeat measurement.  
c. PR interval > 220 msec confirmed by repeat measurement.  
d. findings which would make QTc measurements difficult or QTc data 
uninterpretable. 
e. history of additional risk factors for torsades de pointes (eg, heart failure, 
hypokalaemia, family history of long QT syndrome). 
6. History of alcoholism or drug/chemical abuse within 1 year prior to Check-in. 
7. Alcohol consumption of > 21 units per week for males and > 14 units per week for 
females. One unit of alcohol equals ½ pint (285 mL) of beer or lager, 1 glass 
(125 mL) of wine, or 1/6 gill (25 mL) of spirits.  
8. Positive alcohol breath test result or positive urine drug screen (confirmed by repeat) 
at Screening or Check-in. 


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9. Positive hepatitis panel and/or positive human immunodeficiency virus (HIV) test 
(Appendix 2).  
10. Participation in a clinical study involving administration of an investigational agent or 
vaccine (new chemical entity) or having received a biological product in the past 
90 days prior to dosing.  
11. Use or intend to use any medications/products known to alter drug absorption, 
metabolism, or elimination processes, including St. John’s wort, within 30 days prior 
to dosing, unless deemed acceptable by the Investigator (or designee).  
12. Use or intend to use any prescription medications/products other than hormone 
replacement therapy, oral, implantable, transdermal, injectable, or intrauterine 
contraceptives within 14 days prior to dosing, unless deemed acceptable by the 
Investigator (or designee).  
13. Use or intend to use slow-release medications/products considered to still be active 
within 14 days prior to Check-in, unless deemed acceptable by the Investigator (or 
designee). 
14. Use or intend to use any nonprescription medications/products including vitamins, 
minerals, and phytotherapeutic/herbal/plant-derived preparations within 7 days prior 
to Check-in, unless deemed acceptable by the Investigator (or designee). 
15. Use of tobacco- or nicotine-containing products within 3 months prior to Check-in, or 
positive cotinine at Screening or Check-in.  
16. Receipt of blood products within 2 months prior to Check-in and donation of blood 
from 3 months prior to Screening, plasma from 2 weeks prior to Screening, or 
platelets from 6 weeks prior to Screening.  
17. Poor peripheral venous access. 
18. Have previously completed or withdrawn from this study investigating GB1211, and 
have previously received the investigational product.  
19. Subject who, in the opinion of the Investigator (or designee), should not participate in 
this study. 
20. Subject is not willing to minimise or avoid exposure to natural or artificial sunlight 
(tanning beds or UVA/B treatment) following administration of study drug until 
24 hours after the last dose. 
4.5. 
Exclusion Criteria for Part B: Healthy Subjects 
Subjects from Part B will be excluded from the study if they satisfy any of the following 
criteria at the Screening visit unless otherwise stated: 
1. Significant history or clinical manifestation of any metabolic, allergic, dermatological, 
hepatic, renal, haematological, pulmonary, cardiovascular, gastrointestinal, 
neurological, respiratory, endocrine, or psychiatric disorder, as determined by the 
Investigator (or designee). 


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2. History of febrile illness within 7 days prior to the first dose of study drug or subjects 
with evidence of active infection. 
3. History of significant hypersensitivity, intolerance, or allergy to any drug compound, 
food, or other substance, unless approved by the Investigator (or designee). 
4. History of stomach or intestinal surgery or resection that would potentially alter 
absorption and/or excretion of orally administered drugs (uncomplicated 
appendectomy and hernia repair will be allowed, but not cholecystectomy).  
5. Clinically significant ECG abnormalities or QTcF greater than 450 msec for males 
and 470 msec for females at either Screening or Day 1 predose, or any prior history of 
QT abnormality. 
6. History of alcoholism or drug/chemical abuse within 1 year prior to Check-in. 
7. Alcohol consumption of > 21 units per week for males and > 14 units per week for 
females. One unit of alcohol equals ½ pint (285 mL) of beer or lager, 1 glass 
(125 mL) of wine, or 1/6 gill (25 mL) of spirits.  
8. Positive alcohol breath test result or positive urine drug screen (confirmed by repeat) 
at Screening or Check-in. 
9. Positive hepatitis panel and/or positive HIV test (Appendix 2).  
10. Participation in a clinical study involving administration of an investigational agent or 
vaccine (new chemical entity) or having received a biological product in the past 
90 days prior to dosing.  
11. Use or intend to use any medications/products known to alter drug absorption, 
metabolism, or elimination processes, including St. John’s wort, within 30 days prior 
to dosing, unless deemed acceptable by the Investigator (or designee).  
12. Use or intend to use any prescription medications/products other than hormone 
replacement therapy, oral, implantable, transdermal, injectable, or intrauterine 
contraceptives within 14 days prior to dosing, unless deemed acceptable by the 
Investigator (or designee).  
13. Use or intend to use slow-release medications/products considered to still be active 
within 14 days prior to Check-in, unless deemed acceptable by the Investigator (or 
designee). 
14. Use or intend to use any nonprescription medications/products including vitamins, 
minerals, and phytotherapeutic/herbal/plant-derived preparations within 7 days prior 
to Check-in, unless deemed acceptable by the Investigator (or designee). 
15. Use of tobacco- or nicotine-containing products within 3 months prior to Check-in, or 
positive cotinine at Screening or Check-in.  
16. Receipt of blood products within 2 months prior to Check-in and donation of blood 
from 3 months prior to Screening, plasma from 2 weeks prior to Screening, or 
platelets from 6 weeks prior to Screening.  
17. Poor peripheral venous access. 


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18. Have previously completed or withdrawn from this study investigating GB1211 and 
have previously received the investigational product 
19. Subject who, in the opinion of the Investigator (or designee), should not participate in 
this study. 
20. Subject is not willing to minimise or avoid exposure to natural or artificial sunlight 
(tanning beds or UVA/B treatment) following administration of study drug until 
24 hours after the last dose. 
4.6. 
Exclusion Criteria for Part C: Subjects with Suspected NASH and Liver Fibrosis 
Subjects from Part C will be excluded from the study if they satisfy any of the following 
criteria at the Screening visit unless otherwise stated: 
1. If diabetic and diabetes is other than T2DM. 
2. Subjects, who have had bariatric surgery of any kind or, in the opinion of the 
Investigator, have experienced a clinically significant change in body weight within 
the 3 months prior to Screening. 
3. History of any known serious disease (such as cancer, except skin basocellular 
carcinomas, major infection, clinically significant gastrointestinal disorder, major 
autoimmune disease) or other disease which in the Investigator’s opinion would 
exclude the patient from the study. 
4. The following clinical laboratory results at Screening:  
• Total Bilirubin > 2 × ULN 
• ALT > 155 U/L for females and > 185 U/L for males 
• AST > 155 U/L for females and > 200 U/L for males 
5. Other abnormal clinical laboratory values that are considered clinically significant for 
this population. 
6. History of febrile illness within 7 days prior to the first dose of study drug or subjects 
with evidence of active infection. 
7. History of significant hypersensitivity, intolerance, or allergy to any drug compound, 
food, or other substance, unless approved by the Investigator (or designee). 
8. History of stomach or intestinal surgery or resection that would potentially alter 
absorption and/or excretion of orally administered drugs (uncomplicated 
appendectomy, cholecystectomy, and hernia repair will be allowed).  
9. Clinically significant ECG abnormalities or QTcF greater than 450 msec for males 
and 470 msec for females at either Screening or Day 1 predose, or any prior history of 
QT abnormality. 
10. History of alcoholism or drug/chemical abuse within 1 year prior to Check-in. 
11. Alcohol consumption of > 14 units per week for males and for females. One unit of 
alcohol equals ½ pint (285 mL) of beer or lager, 1 glass (125 mL) of wine, or 1/6 gill 
(25 mL) of spirits.  


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12. Positive alcohol breath test result or positive urine drug screen (confirmed by repeat) 
at Screening or Check-in. 
13. Positive hepatitis panel and/or positive HIV test (Appendix 2).  
14. Clinically significant laboratory abnormalities, as determined by the Investigator.  
15. A creatinine clearance of less than 50 mL/min (as calculated by Cockcroft-Gault 
equation) or estimated glomerular filtration rate (eGFR) < 60 mL/[min*1.73 m²] at 
Screening. 
16. Participation in a clinical study involving administration of an investigational agent or 
vaccine (new chemical entity) or having received a biological product in the past 
90 days prior to dosing. 
17. Use or intend to use any medications/products known to alter drug absorption, 
metabolism, or elimination processes, including St. John’s wort, within 30 days prior 
to dosing, unless deemed acceptable by the Investigator (or designee).  
18. Use or intend to use slow-release medications/products considered to still be active 
within 14 days prior to Check-in, unless deemed acceptable by the Investigator (or 
designee). 
19. Subject taking any antidiabetic medications, with the exception of metformin, 
sulfonylureas, gliptins, and sodium/glucose co-transporter 2 inhibitors, within 
3 months prior to Screening. 
20. Use of any of the following non-permitted medication within 6 months prior to 
Screening: amiodarone, bile salt chelators, methotrexate, pharmacological doses of 
systemic corticosteroids for at least 2 consecutive weeks, or any other medications 
known to affect liver function. 
21. Use or intend to use any nonprescription medications/products including vitamins 
(Vitamin E at dose <400 U is permitted, Vitamin E at dose 400 U is allowed if on a 
stable dose for 2 months prior), minerals, and phytotherapeutic/herbal/plant-derived 
preparations within 7 days prior to Check-in, unless deemed acceptable by the 
Investigator (or designee). 
22. Receipt of blood products within 2 months prior to Check-in and donation of blood 
from 3 months prior to Screening, plasma from 2 weeks prior to Screening, or 
platelets from 6 weeks prior to Screening.  
23. Poor peripheral venous access. 
24. Have previously completed or withdrawn from this study investigating GB1211, and 
have previously received the investigational product.  
25. Subject who, in the opinion of the Investigator (or designee), should not participate in 
this study.  
26. Subject is not willing to minimise or avoid exposure to natural or artificial sunlight 
(tanning beds or UVA/B treatment) following administration of study drug until 
24 hours after the last dose. 


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For Parts A and B, subjects may previously have been screened on a generic basis to 
determine their eligibility for inclusion in Phase I clinical studies conducted at the CRU. If 
generic screening was performed within the specified study screening window, selected 
study-specific procedures will be repeated either at an additional Screening visit or on 
admission to the CRU on Day -1.  
4.7. 
Subject Number and Identification 
Subjects will have a unique identification number used at Screening. Subjects will be 
assigned a subject number at the time of first dose/dosing. Assignment of subject numbers 
will be in ascending order and no numbers will be omitted (eg, in Part A Subjects 0101, 0102, 
etc, in Part B Subjects 0201, 0202, etc, in Part C Subjects 0301, 0302, etc). Replacement 
subjects (Section 4.8) will be assigned a subject number corresponding to the number of the 
subject he/she is replacing plus 1000 (eg, Subject 1101 replaces Subject 101). 
Subjects will be identified by subject number only on all study documentation. A list 
identifying the subjects by subject number will be kept in the Site Master File. 
4.8. 
Subject Withdrawal and Replacement 
A subject is free to withdraw from the study at any time. In addition, a subject will be 
withdrawn if any of the following criteria are met: 
• change in compliance with any inclusion/exclusion criterion that is clinically 
relevant and affects subject safety as determined by the Investigator (or designee). 
• noncompliance with the study restrictions that might affect subject safety or study 
assessments/objectives, as considered applicable by the Investigator (or designee). 
• any clinically relevant sign or symptom that, in the opinion of the Investigator (or 
designee), warrants subject withdrawal. 
In the event of confirmed results for any of the following criteria, dosing of a subject with the 
IMP will be stopped permanently: 
• 
QTcF increases > 60 msec compared to baseline (predose) and/or absolute 
QTcF values > 500 msec (confirmed by repeat measurement). 
• 
Systemic exposure for any individual subject is predicted to exceed a Cmax of 
19755 ng/mL and/or an AUC0-24 of 52486 ng.h/mL; ie, systemic exposure will 
be no greater than the lowest exposure at the NOAEL.  
• 
Liver chemistry results: 
1. ALT or AST > 5 x ULN, which is confirmed by repeat 
2. ALT or AST >  3 x ULN, which is confirmed and total bilirubin > 2 x 
ULN or international normalised ratio >1.5 
3. ALT or AST > 3 x ULN, which is confirmed and the new appearance 
(ie, onset coincides with the changes in hepatic enzymes) of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, 


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or eosinophilia (> ULN) felt by the Investigator to be potentially 
related to hepatic inflammation/injury. 
If a subject is withdrawn, the Sponsor will be notified and the date and reason(s) for the 
withdrawal will be documented in the subject’s electronic Case Report Form (eCRF). If a 
subject is withdrawn, efforts will be made to perform all follow-up assessments, if possible 
(Appendix 6). Other procedures may be performed at the Investigator’s (or designee’s) and/or 
Sponsor’s discretion. If the subject is in-house, these procedures should be performed before 
the subject is discharged from the clinic. The Investigator (or designee) may also request that 
the subject return for an additional Follow-up visit. All withdrawn subjects will be followed 
until resolution of all their AEs or until the unresolved AEs are judged by the Investigator (or 
designee) to have stabilised. 
Subjects who are withdrawn for reasons not related to study drug may be replaced following 
discussion between the Investigator and the Sponsor. Subjects withdrawn as a result of AEs 
thought to be related to the study drug will generally not be replaced. 
4.9. 
Study Termination 
The study may be discontinued at the discretion of the Investigator (or designee), Sponsor, or 
Sponsor’s Medical Monitor if any of the following criteria are met: 
• adverse events unknown to date (ie, not previously reported in any similar 
investigational study drug trial with respect to their nature, severity, and/or 
duration). 
• increased frequency, severity, and/or duration of known, anticipated, or previously 
reported AEs (this may also apply to AEs defined at Check-in as baseline signs 
and symptoms). 
• medical or ethical reasons affecting the continued performance of the study. 
• difficulties in the recruitment of subjects. 
• cancellation of drug development. 
5. STUDY TREATMENTS 
5.1. 
Description, Storage, Packaging, and Labelling 
The IMPs (5 and 50 mg GB1211 and placebo capsules) will be supplied by the Sponsor (or 
designee), along with the batch/lot numbers and Certificates of Analysis. A Certificate of 
Release authorised by a Qualified Person in the EU will also be issued for the IMP. 
The IMP will be provided in high-density polyethylene bottles and stored according to the 
instructions on the label. The IMPs will be stored at the study site in a location that is locked 
with restricted access. 
The bulk drug container and unit dose containers will be labelled in accordance with national 
laws and regulations. The IMPs will be transferred from bulk supplies into the subject’s dose 
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Capsules for the planned dose levels in Part A of the study will be assembled as shown in 
Table 4. 
Table 4: Capsule Assembly for Part A 
 
Dose Level 
(mg) 
Number of Capsules to be Assembled 
Cohort 
Dose of GB1211 
Placebo 
A1 
5 
1 x 5 mg 
1 x capsules 
A2 
20 
4 x 5 mg 
4 x capsules 
A3 
50 
1 x 50 mg 
1 x capsules 
A4 
100 
2 x 50 mg 
2 x capsules 
A5 
200 
4 x 50 mg 
4 x capsules 
5.2. 
Study Treatment Administration 
Each dose of GB1211 and placebo will be administered orally with approximately 240 mL of 
room temperature water. In Part A, all doses will be administered after an overnight fast of at 
least 10 hours, with the exception of the food-effect cohort (planned to be Cohort A3), where 
the dose given in Treatment Period 2 will be administered 30 minutes after starting a high-fat 
breakfast. The dietary status for dosing in Parts B and C will be fasted unless data from the 
food-effect cohort is available and supports dosing in the fed state. 
Subjects in Part A and B will be administered the IMP in numerical order while standing and 
will not be permitted to lie supine for 2 hours after dosing, except as necessitated by the 
occurrence of an AE(s) and/or study procedures.  
In Part C, the doses of GB1211 (taken at the site) on Days 1/2 and Days 41/42 will be 
administered to subjects at the study site while standing and will not be permitted to lie 
supine for 2 hours after dosing, except as necessitated by occurrence of an AE(s) and/or study 
procedures; but all other doses will be administered by the subject at home. 
5.3. 
Randomisation 
For Parts A and B, the randomisation code will be produced by the statistics department at 
Covance using a computer-generated pseudo-random permutation procedure. Randomisation 
for Part C is to be confirmed. 
In Part A, 2 subjects per cohort will be randomly assigned to receive placebo. For all cohorts 
in Part A (except the fed treatment period of the food-effect cohort), sentinel dosing will 
occur whereby 2 subjects (1 active and 1 placebo) will be dosed on 1 day and, providing no 
safety concerns arise, the remaining 6 subjects will be dosed after 24 hours.  
Subjects in the food-effect cohort (planned to be Cohort A3) will be randomised to receive 
the same treatment in Treatment Periods 1 and 2.  
In Part B, 3 subjects per cohort will be randomly assigned to receive placebo, and in Part C, 
10 subjects in Cohort C1 will be randomly assigned to receive placebo. 


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Prior to the start of the study, live randomisation code will be distributed according to the 
randomisation specification form and will include the Covance CRU pharmacy staff.  
5.4. 
Blinding 
The following controls will be employed to maintain the double-blind status of the study: 
• The placebo capsules will be identical in appearance to the GB1211. 
• The Investigator and other members of staff involved with the study will remain 
blinded to the treatment randomisation code during the assembly procedure. 
• Interim bioanalytical data will be provided to Covance in a blinded manner. 
• Where possible, exploratory biomarker data will be provided to Covance in a 
blinded manner. 
To maintain the blind, the Investigator will be provided with a sealed randomisation code for 
each subject, containing details of their treatment. These individual sealed envelopes will be 
kept in a limited access area that is accessible 24 hours a day. In order to manage subject 
safety or to support dose escalation decisions (in the event of possibly treatment-related SAEs 
or severe AEs), the decision to unblind resides solely with the Investigator. Whenever 
possible, and providing it does not interfere with or delay any decision in the best interest of 
the subject, the Investigator will discuss the intended code-break with the Sponsor. If it 
becomes necessary to break the code during the study, the date, time, and reason will be 
recorded in the subject’s source data and on the individual envelope and will be witnessed by 
a second person. 
5.5. 
Treatment Compliance 
The following measures will be employed to ensure treatment compliance for Parts A and B: 
• All doses will be administered under the supervision of suitably qualified study 
site staff. 
• Immediately after dose administration, visual inspection of the mouth and hands 
will be performed for each subject. 
• At each dosing occasion, a predose and postdose inventory of IMP will be 
performed on the dose containers. 
For Part C, treatment compliance will be assessed based on the number of capsules provided 
on Day 1 compared to the number of capsules returned on Day 42. 
5.6. 
Drug Accountability 
The Investigator (or designee) will maintain an accurate record of the receipt of the study 
supplies received. In addition, an accurate drug disposition record will be kept, specifying the 
amount dispensed to each subject and the date of dispensing. This drug accountability record 
will be available for inspection at any time. At the completion of the study, the original drug 
accountability record will be available for review by the Sponsor upon request. 


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For each batch of unit doses, the empty used unit dose containers will be discarded upon 
satisfactory completion of the compliance and accountability procedures. Any unused 
assembled unit doses will be retained until completion of the study. 
At the completion of the study, all unused supplies will be returned to the Sponsor or 
disposed of by the study site, per the Sponsor’s written instructions. 
6. CONCOMITANT THERAPIES AND OTHER RESTRICTIONS 
6.1. 
Concomitant Therapies  
6.1.1. 
Concomitant Therapies for Parts A and B 
Subjects of Part A and B will refrain from use of any prescription or nonprescription 
medications/products during the study until the Follow-up visit, unless the Investigator (or 
designee) and/or Sponsor have given their prior consent.  
Paracetamol/acetaminophen (2 g/day for up to 3 consecutive days), hormone replacement 
therapy, oral, implantable, transdermal, injectable, or intrauterine contraceptives are 
acceptable concomitant medications.  
The administration of any other concomitant medications during the study is prohibited 
without prior approval of the Investigator (or designee), unless its use is deemed necessary 
for treatment of an AE. Any medication taken by a subject during the course of the study and 
the reason for its use will be documented in the source data. 
6.1.2. 
Concomitant Therapies for Part C 
Subjects of Part C will refrain from use of any prescription or nonprescription 
medications/products during the study with exceptions, as stated in Section 4.6, until the 
Follow-up visit, unless the Investigator (or designee) and/or Sponsor have given their prior 
consent.  
Paracetamol/acetaminophen (2 g/day for up to 3 consecutive days) and hormone replacement 
therapy are acceptable concomitant medications.  
The administration of any other concomitant medications during the study is prohibited 
without prior approval of the Investigator (or designee), unless its use is deemed necessary 
for treatment of an AE. Any medication taken by a subject during the course of the study and 
the reason for its use will be documented in the source data. 
6.2. 
Diet 
6.2.1. 
Parts A and B 
While confined at the study site for Parts A and B, subjects will receive a standardised diet at 
scheduled times that do not conflict with other study-related activities. Subjects will be fasted 
overnight (at least 8 hours) before collection of blood samples for clinical laboratory 
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On the days with intensive PK assessments (Day 1 for Part A and Days 1 and 10 for Part B), 
meals will be identical for each cohort, with the exception of the high-fat breakfast for the 
food-effect cohort (planned to be Cohort A3). 
On Day 1 in Part A, subjects will be fasted for at least 10 hours prior to study drug 
administration until 4 hours postdose, when a meal will be provided (lunch times on Day 1 
will be staggered between subjects to ensure this). With the exception of water given with the 
dose, subjects will not be allowed fluids from 1 hour prior to until 2 hours after dosing. Meals 
will be provided as appropriate at other times. Other than the fluid restrictions on dosing 
days, water will be freely available at all times. 
For the food-effect cohort (planned to be Cohort A3), subjects receiving the GB1211 or 
placebo under fed conditions will consume the following high-fat breakfast (Table 5) before 
dosing. Subjects should start the meal 30 minutes prior to administration of the IMP. Study 
subjects should eat this meal in 30 minutes or less. The drug product should be administered 
30 minutes after start of the meal. 
Table 5: High-fat Breakfast Content 
High-fat Breakfast 
120 g fried eggs (2 eggs) in vegetable oil 
50 g bacon (2 rashers) 
72 g toasted white bread (2 slices) 
13 g butter (2 pats) 
108 g hash brown (3 each) 
240 g whole milk 
Total calories: 973 kcal 
This high-fat meal contains the equivalent of approximately 150 protein calories, 
250 carbohydrate calories, and 500 to 600 fat calories. 
In Part B, the time interval between meals and dosing will be determined by the PK data from 
Part A and will be documented in the TMF. Meals will be provided as appropriate at other 
times. With the exception of water given with the dose, subjects will not be allowed fluids 
from 1 hour prior to dosing until 2 hours after dosing. Other than these fluid restrictions, 
water will be freely available at all times. 
For Parts A and B, foods and beverages containing poppy seeds, grapefruit, or Seville 
oranges will not be allowed from 7 days prior to Check-in until the Follow-up visit. 
Caffeine-containing foods and beverages will not be allowed from 36 hours before Check-in 
until Discharge.  
Consumption of alcohol will not be permitted from 36 hours prior to Check-in until the 
Follow-up visit.  
6.2.2. 
Part C 
While confined at the study site for Part C (Days -1 to 2 and Days 41 to 43), subjects will 
receive a standardised diet at scheduled times that do not conflict with other study-related 


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activities. Subjects will be fasted overnight (at least 8 hours) before collection of blood 
samples for safety laboratory tests.  
On the days with intensive PK assessments (Days 1 and 42), every effort will be made to 
ensure within a subject that they have the same meal on these PK assessment days. 
The time interval between meals and dosing will be determined by the PK data from Part A 
and will be documented in the TMF. During the residential or nonresidential visits, meals will 
be provided as appropriate at other times. With the exception of water given with the dose, 
subjects will not be allowed fluids from 1 hour prior to dosing until 2 hours after dosing. 
Other than these fluid restrictions, water will be freely available at all times. 
From 7 days prior to Check-in until the Follow-up visit, foods and beverages containing 
poppy seeds, grapefruit, or Seville oranges will not be allowed. Caffeine-containing foods 
and beverages will not be allowed from 36 hours before each site visit.  
Consumption of alcohol will not be permitted from 36 hours prior to each site visit. During 
the rest of study, the patient should limit alcohol consumption to 2 units per day. 
6.3. 
Smoking 
For Parts A and B, subjects will not be permitted to use tobacco- or nicotine-containing 
products within 3 months prior to Check-in until the Follow-up visit. 
6.4. 
Exercise 
Subjects are required to refrain from strenuous exercise from 7 days before Check-in until the 
Follow-up visit and will otherwise maintain their normal level of physical activity during this 
time (ie, will not begin a new exercise program nor participate in any unusually strenuous 
physical exertion). 
6.5. 
Blood Donation 
Subjects are required to refrain from donation of blood from 3 months prior to Screening, 
plasma from 2 weeks prior to Screening, and platelets from 6 weeks prior to Screening until 
3 months after the Follow-up visit.  
6.6. 
Exposure to Ultraviolet Light 
Subjects should minimise or avoid exposure to natural or artificial sunlight (tanning beds or 
UVA/B treatment) following administration of study drug until 24 hours after the last dose. If 
subjects need to be outdoors during this period, they should wear loose fitting clothes that 
protect skin from sun exposure and discuss other sun protection measures with the 
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7. STUDY ASSESSMENTS AND PROCEDURES 
Every effort will be made to schedule and perform the procedures as closely as possible to the 
nominal time, giving considerations to appropriate posture conditions, practical restrictions, 
and the other procedures to be performed at the same timepoint. 
The highest priority procedures will be performed closest to the nominal time. The order of 
priority for scheduling procedures around a timepoint is (in descending order of priority): 
• dosing 
• blood samples 
• urine samples (Part A only) (for GB1211 assay) 
• any other procedures (ECGs will be scheduled before vital signs measurements). 
Where activities at a given timepoint coincide, consideration must be given to ensure that the 
following order of activities is maintained: ECGs, vital signs, blood draws. 
7.1. 
Pharmacokinetic Assessments 
7.1.1. 
Sample Collection and Processing 
Blood samples (approximately 1 × 4 mL) will be collected by venipuncture or cannulation at 
the times indicated in the Schedule of Assessments in Appendix 6. Furthermore, up to 
3 additional blood samples may be taken from each subject per treatment period, with the 
maximum volume of blood withdrawn per subject not exceeding the limit detailed in 
Appendix 3. Any changes to the scheduled times of PK assessments will be agreed with the 
Sponsor and documented in the TMF. Samples taken from subjects who received placebo 
will not be analysed. 
Procedures for collection, processing, and shipping of PK blood samples will be detailed in a 
separate document.  
Urine samples for Part A will be collected into preweighed polyethylene containers over the 
time intervals indicated in the Schedule of Assessments in Appendix 6. Procedures for 
collection, processing, and shipping of PK urine samples will be detailed in a separate 
document. 
7.1.2. 
Analytical Methodology 
Plasma and urine concentrations of GB1211 will be determined using validated analytical 
procedures. Specifics of the analytical methods will be provided in separate documents. 
An exploratory analysis of GB1211 metabolites in plasma and urine may be performed 
utilising the blood and urine samples collected for PK evaluation. If performed, the results of 
this analysis will be reported separately to the clinical study report. 


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7.2. 
Exploratory Biomarker Assessments 
Biomarkers (as listed in Section 2.2.3) in which to assess the exploratory objectives include: 
• Serum galectin-3 
• CCL4 
• Fasting plasma glucose and insulin 
• Lipid profile (eg, low density lipoprotein [LDL], high density lipoprotein [HDL], 
total cholesterol, triglycerides) 
• hsCRP, IL-12, MCP1, and TNF-α, as well as the proinflammatory chemokines, 
CCL2, CCL3, CCL4, and the chemokine receptors CCR1 and CCR2; and other 
biomarkers of inflammation as required 
• Exploratory biomarkers related to fibrosis will include but are not limited to 
extracellular matrix proteins (TIMP-1, HA, and P3NP), A9, ELF panel, CK18, 
PAI-1, CH3L1, IL6, and pro-collagen 3  
The list of biomarkers for the exploratory endpoints may be subject to change based on 
ongoing review of the data. 
The timings of all exploratory biomarker assessments to be performed (as described in 
Section 2.2.3) during the study are indicated in the Schedule of Assessments in Appendix 6 
and may be subject to change based on the ongoing review of the data.  
Blood samples for these assessments will be collected by venipuncture or cannulation, with 
blood volumes including 3 additional blood samples if required (each subject per treatment 
period) detailed in Appendix 3. To avoid potential issues with repeat freeze thawing, samples 
of serum will be aliquoted into a minimum of 2 but ideally 3 aliquots. Samples for biomarker 
analysis will be shipped to an alternate site (to be determined) for analysis, and may be kept 
for future analysis of other exploratory biomarkers. 
Any changes to the scheduled times of biomarker assessments will be agreed with the 
Sponsor and documented in the TMF. 
7.3. 
Safety and Tolerability Assessments 
Additional safety and tolerability assessments as described below will be performed at other 
times if judged to be clinically appropriate or if the ongoing review of the data suggests a 
more detailed assessment of clinical laboratory safety evaluations is required. 
7.3.1. 
Adverse Events 
Adverse event definitions, assignment of severity and causality, and procedures for reporting 
SAEs are detailed in Appendix 1. 
The condition of each subject will be monitored from the time of signing the ICF to final 
Discharge from the study. Subjects will be observed for any signs or symptoms and asked 
about their condition by open questioning, such as “How have you been feeling since you 


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were last asked?”, at least once each day while resident at the study site and at each study 
visit. Subjects will also be encouraged to spontaneously report AEs occurring at any other 
time during the study. 
Any AEs and remedial action required will be recorded in the subject’s source data. The 
nature, time of onset, duration, and severity will be documented, together with an 
Investigator’s (or designee’s) opinion of the relationship to study drug. 
Adverse events recorded during the course of the study will be followed up, where possible, 
until resolution or until the unresolved AEs are judged by the Investigator (or designee) to 
have stabilised. This will be completed at the Investigator’s (or designee’s) discretion. 
7.3.2. 
Clinical Laboratory Evaluations 
Blood and urine samples will be collected for clinical laboratory evaluations (including 
clinical chemistry, haematology, urinalysis, serology [including coagulation parameters for 
Part C]) at the times indicated in the Schedule of Assessments in Appendix 6. Clinical 
laboratory evaluations are listed in Appendix 2. Additional clinical laboratory evaluations 
will be performed at other times if judged to be clinically appropriate or if the ongoing review 
of the data suggests a more detailed assessment of clinical laboratory safety evaluations is 
required. 
Subjects will be asked to provide urine samples for drugs of abuse screen and will undergo an 
alcohol breath test at the times indicated in the Schedule of Assessments in Appendix 6. For 
all female subjects, a pregnancy test will be performed at the times indicated in the Schedule 
of Assessments in Appendix 6.  
An Investigator (or designee) will perform a clinical assessment of all clinical laboratory 
data. 
7.3.3. 
Vital Signs 
Supine blood pressure, supine pulse rate, and oral body temperature will be assessed at the 
times indicated in the Schedule of Assessments in Appendix 6. Vital signs may also be 
performed at other times if judged to be clinically appropriate or if the ongoing review of the 
data suggests a more detailed assessment of vital signs is required. 
Day 1 predose blood pressure and pulse rate will be measured in triplicate at approximately 
2-minute intervals. The median value will be used as the baseline value in the data analysis. 
All subsequent measurements will be performed singly and repeated once if outside the 
relevant clinical reference ranges. Oral body temperature will be measured singly. 
Subjects must be supine for at least 5 minutes before blood pressure and pulse rate 
measurements. 


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7.3.4. 
Electrocardiogram 
7.3.4.1. 
12-Lead Electrocardiogram 
Resting 12-lead ECGs will be recorded after the subject has been supine and at rest for at 
least 5 minutes at the times indicated in the Schedule of Assessments in Appendix 6. Single 
12-lead ECGs will be repeated once if either of the following criteria apply: 
• QTcF value > 500 msec 
• QTcF change from the baseline (predose) is > 60 msec. 
Additional 12-lead ECGs may be performed at other times if judged to be clinically 
appropriate or if the ongoing review of the data suggests a more detailed assessment of ECGs 
is required. The Investigator (or designee) will perform a clinical assessment of each 12-lead 
ECG.  
Day 1 predose 12-lead ECGs will be measured in triplicate at approximately 2-minute 
intervals. The mean value will be used as the baseline value in the data analysis. All 
subsequent measurements will be performed singly and repeated once if outside the relevant 
clinical reference ranges. 
7.3.4.2. 
Telemetry 
Cardiac rhythm will be monitored by telemetry at the times indicated in the Schedule of 
Assessments in Appendix 6. 
Telemetry is not planned for Parts B and C of the study but may be implemented if any 
clinically significant findings are identified in the data from Part A. 
7.3.4.3. 
Continuous 12-lead Electrocardiogram Monitoring for Part A 
Continuous 12-lead ECG monitoring using a digital recorder will take place at the times 
indicated in the Schedule of Assessments in Appendix 6. Continuous 12-lead ECG 
monitoring will not be performed in the fed treatment period in Part A. 
All continuous ECG data collected on study will be archived without extraction or analysis 
and will not be reported in the scope of this study. 
Subjects will be supine for at least 10 minutes before the extraction timepoint and for 
5 minutes from the start of each extraction timepoint (each extraction will last for 5 minutes). 
Environmental distractions (eg, television, radio, conversation) should be avoided during the 
pre-ECG resting period and during ECG recording.  
When coinciding, vital signs assessments and PK sampling should always be performed after 
the ECG extraction time window. If a separate ECG machine is being used for safety 
assessments described in Section 7.3.4.1, that machine should be in place prior to the 
extraction window to permit safety ECGs to be recorded irrespective of the extraction 
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recorded after the extraction window. If an integral system is used, safety ECGs may be 
recorded irrespective of the extraction window. 
7.3.5. 
Physical Examination 
A full physical examination or symptom-directed physical examination will be performed at 
the timepoints specified in the Schedule of Assessments in Appendix 6. Full physical 
examination will usually only be performed at Screening. 
7.3.6. 
Body Weight 
Body weight (in underclothes) will be recorded at the times indicated in the Schedule of 
Assessments in Appendix 6. 
8. SAMPLE SIZE AND DATA ANALYSIS 
8.1. 
Determination of Sample Size 
No formal statistical assessment, in terms of sample size, has been conducted as this is the 
first time GB1211 is being administered to humans. However, the number of subjects in each 
part of the present study is common in early clinical pharmacology studies and is considered 
sufficient to achieve the objectives of the study. 
8.2. 
Analysis Populations 
8.2.1. 
Safety Population 
The safety population will include all subjects who received at least 1 dose of study treatment 
(GB1211 or placebo). 
8.2.2. 
Pharmacokinetic Population 
The PK population will include all subjects who received at least 1 dose of GB1211 and have 
evaluable PK data. A subject will be excluded from the PK summary statistics and statistical 
analysis if the subject has an AE of vomiting that occurs at or before 2-times median time to 
maximum concentration.  
8.2.3. 
Biomarker Population 
The biomarker population will include all subjects who received at least 1 dose of study 
treatment (GB1211 or placebo) and have at least 1 postdose biomarker assessment. 
8.3. 
Pharmacokinetic Analyses 
Noncompartmental PK analysis will be performed on individual plasma and urine (Part A 
only for urine) concentration data, using commercial software such as Phoenix® WinNonlin®.  
Plasma and urine concentrations (Part A only for urine) of GB1211 and PK parameters will 
be listed and summarised using descriptive statistics. Individual and mean GB1211 
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In Part A, where data are available, GB1211 dose proportionality will be examined across 
dose cohorts. The PK parameters will be analysed for dose proportionality using a power 
model approach or analysis of variance (ANOVA) model as appropriate. Where data are 
available, the effect of food at 1 dose level in Part A will be investigated using ANOVA. 
In Part B, the PK parameters on Day 10 will be analysed for dose proportionality using a 
power model approach or ANOVA model as appropriate. 
8.4. 
Exploratory Biomarker Analyses 
Exploratory biomarker data will be listed and summarised using descriptive statistics. No 
formal statistical analysis of exploratory biomarker data is planned. 
8.5. 
Safety Analysis 
Safety parameters will be listed and summarised using descriptive statistics. No formal 
statistical analysis of safety data is planned. Each AE will be coded using the Medical 
Dictionary for Regulatory Activities. 
8.6. 
Interim Analysis 
No formal interim analyses are planned for this study. 
9. REFERENCES 
1.  MacKinnon AC, Farnworth SL, Hodkinson PS, Henderson NC, Atkinson KM, Leffler H, 
et al. Regulation of alternative macrophage activation by galectin-3. J Immunol. 2008 
Feb 15;180(4):2650–8.  
2.  Henderson NC, Mackinnon AC, Farnworth SL, Kipari T, Haslett C, Iredale JP, et al. 
Galectin-3 expression and secretion links macrophages to the promotion of renal fibrosis. 
Am J Pathol. 2008 Feb;172(2):288–98.  
3.  Mackinnon AC, Gibbons MA, Farnworth SL, Leffler H, Nilsson UJ, Delaine T, et al. 
Regulation of transforming growth factor-β1-driven lung fibrosis by galectin-3. Am J 
Respir Crit Care Med. 2012 Mar 1;185(5):537–46.  
4.  Delaine T, Collins P, MacKinnon A, Sharma G, Stegmayr J, Rajput VK, et al. Galectin-
3-Binding Glycomimetics that Strongly Reduce Bleomycin-Induced Lung Fibrosis and 
Modulate Intracellular Glycan Recognition. Chembiochem Eur J Chem Biol. 2016 
15;17(18):1759–70.  
5.  Filozof C, Chow S-C, Dimick‐Santos L, Chen Y-F, Williams RN, Goldstein BJ, et al. 
Clinical endpoints and adaptive clinical trials in precirrhotic nonalcoholic steatohepatitis: 
Facilitating development approaches for an emerging epidemic. Hepatol Commun. 2017 
Sep 1;1(7):577–85.  
6.  Galecto Biotech. GB1211 - Investigator’s Brochure - Version 2.0. 2018.  


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7.  Mudaliar S, Henry RR, Sanyal AJ, Morrow L, Marschall H-U, Kipnes M, et al. Efficacy 
and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 
diabetes and nonalcoholic fatty liver disease. Gastroenterology. 2013 Sep;145(3):574–
582.e1.  
 
 
 


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10. APPENDICES 


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Appendix 1: Adverse Event Reporting 
Definitions 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product, which does not necessarily have 
a causal relationship with this treatment. An AE can therefore be any unfavourable and/or 
unintended sign (including a clinically significant abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a study drug, whether or not related to the study 
drug. 
Assessment of Severity 
The Investigator will be asked to provide an assessment of the severity of the AE using the 
following categories:  
• Mild: Usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of daily 
living. 
• Moderate: Usually alleviated with additional specific therapeutic intervention. 
The event interferes with usual activities of daily living, causing discomfort but 
poses no significant or permanent risk of harm to the subject. 
• Severe: Interrupts usual activities of daily living, or significantly affects clinical 
status, or may require intensive therapeutic intervention. 
Relationship to Study Treatment 
The Investigator (or designee) will make a determination of the relationship of the AE to the 
study drug using a 4-category system according to the following guidelines: 
• Not Related: The AE is definitely caused by the subject’s clinical state or the 
study procedure/conditions. 
• Unlikely Related: The temporal association between the AE and the drug is such 
that the drug is not likely to have any reasonable association with the AE. 
• Possibly Related: The AE follows a reasonable temporal sequence from the time 
of drug administration but could have been produced by the subject’s clinical state 
or the study procedures/conditions. 
• Related: The AE follows a reasonable temporal sequence from administration of 
the drug, abates upon discontinuation of the drug, follows a known or 
hypothesised cause-effect relationship, and (if appropriate) reappears when the 
drug is reintroduced.  
Follow-up of Adverse Events 
Every reasonable effort will be made to follow up with subjects who have AEs. Any subject 
who has an ongoing AE that is possibly related or related to the investigational medicinal 


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product (IMP) or study procedures at the Follow-up visit will be followed up, where possible, 
until resolution or until the unresolved AE is judged by the Investigator (or designee) to have 
stabilised. This will be completed at the Investigator’s (or designee’s) discretion. Any subject 
who has an ongoing AE that is not related or unlikely related to the IMP or study procedures 
at the Follow-up visit can be closed out as ongoing at the Investigator’s discretion.  
Adverse Drug Reactions 
All noxious and unintended responses to an IMP (ie, where a causal relationship between an 
IMP and an AE is at least a reasonable possibility) related to any dose should be considered 
adverse drug reactions. 
For marketed medicinal products, a response to a drug which is noxious and unintended and 
which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of diseases 
or for modification of physiological function is to be considered an adverse drug reaction. 
An unexpected adverse drug reaction is defined as an adverse reaction, the nature or severity 
of which is not consistent with the applicable product information (eg, Investigator’s 
Brochure for an unapproved IMP). 
Serious Adverse Events 
A serious AE (SAE) is defined as any untoward medical occurrence that at any dose either: 
• results in death 
• is life-threatening 
• requires inpatient hospitalisation or prolongation of existing hospitalisation 
• results in persistent or significant disability/incapacity (disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions) 
• results in a congenital anomaly/birth defect 
• results in an important medical event (see below). 
Important medical events that may not result in death, be life-threatening, or require 
hospitalisation may be considered SAEs when, based upon appropriate medical judgment, 
they may jeopardise the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. 
Instances of death or congenital abnormality, if brought to the attention of the Investigator at 
any time after cessation of the study treatment and considered by the Investigator to be 
possibly related to the study treatment, will be reported to the Sponsor. 
Definition of Life-threatening 
An AE is life-threatening if the subject was at immediate risk of death from the event as it 
occurred (ie, does not include a reaction that might have caused death if it had occurred in a 
more serious form). For instance, drug-induced hepatitis that resolved without evidence of 


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hepatic failure would not be considered life-threatening even though drug-induced hepatitis 
can be fatal. 
Definition of Hospitalisation 
Adverse events requiring hospitalisation should be considered serious. In general, 
hospitalisation signifies that the subject has been detained (usually involving an overnight 
stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate at the Clinical Research Unit (CRU). When in doubt as to whether 
hospitalisation occurred or was necessary, the AE should be considered as serious. 
Hospitalisation for elective surgery or routine clinical procedures, which are not the result of 
an AE, need not be considered AEs and should be recorded on a Clinical Assessment Form 
and added to the electronic Case Report Form. If anything untoward is reported during the 
procedure, this must be reported as an AE and either ‘serious’ or ‘nonserious’ attributed 
according to the usual criteria. 
Serious Adverse Event Reporting 
Covance Drug Safety Solutions (DSS) are responsible for coordinating the reporting of SAEs 
in accordance with the European Directive 2001/20/EC. 
The Investigator will complete an SAE report form and forward it by facsimile or email to 
DSS and the Sponsor immediately (within 24 hours) upon becoming aware of an SAE. 
The responsibilities of Covance DSS include the following: 
• Prepare an AE reporting plan prior to the start of the study. Where this plan differs 
from the applicable CRU standard operating procedure on SAE reporting, the 
Safety Management Plan will always take precedence. 
• Receive and review SAE report forms from the CRU and inform the Sponsor of 
the SAE within 2 working days of the initial notification to DSS. Drug Safety 
Services will delete any information from the SAE report forms that may identify 
the subject. 
• Write case narratives and enter the case into Covance’s safety database as defined 
in the AE reporting plan. 
• Produce appropriate reports of all Suspected Unexpected Serious Adverse 
Reactions and forward to the Ethics Committee, Medicines and Healthcare 
Products Regulatory Agency, Principal Investigator, and the Sponsor within the 
timeframes stipulated in the Clinical Trials Directive Guideline (ENTR/CT 3).  
The responsibility for reporting SAEs will be transferred to the Sponsor 28 days after the end 
of the study. 


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Pregnancy 
Pregnancy (maternal or paternal exposure to study drug) does not meet the definition of an 
AE. However, to fulfil regulatory requirements any pregnancy should be reported following 
the SAE process to collect data on the outcome for both mother and foetus. 
 
 


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Appendix 2: Clinical Laboratory Evaluations 
Clinical chemistry: 
Haematology: 
Urinalysis: 
Alanine aminotransferase  
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Calcium 
Chloride 
Total Cholesterol 
High density lipoprotein 
Cholesterol 
Low density lipoprotein 
Cholesterol 
Creatininea 
Direct bilirubin  
Gamma-glutamyl transferase 
Glucose 
Inorganic phosphate  
Potassium  
Sodium  
Total bilirubin 
Total protein 
Triglycerides 
Urea 
Haematocrit  
Haemoglobin 
Mean cell haemoglobin 
Mean cell haemoglobin 
concentration 
Mean cell volume 
Platelet count 
Red blood cell (RBC) count 
White blood cell (WBC) count 
WBC differential: 
   Basophils 
   Eosinophils 
   Lymphocytes 
   Monocytes 
   Neutrophils 
 
 
Blood 
Glucose 
Ketones 
pH 
Protein 
Specific gravity 
Urobilinogen 
Microscopic examination  
 
Coagulation profilef: 
Activated partial thromboplastin 
time 
International normalised ratio 
Prothrombin time 
 
Serologyb: 
Drug screenc: 
Hormone panel - females 
only: 
Hepatitis B surface antigen 
Hepatitis C antibody 
Human immunodeficiency 
(HIV-1 and HIV-2) antibodies 
and p24 antigen 
 
Including but not limited to:  
Amphetamines/methamphetamines 
Barbiturates 
Benzodiazepines 
Cocaine (metabolite) 
Methadone 
Phencyclidine 
Opiates 
Tetrahydrocannabinol/ 
cannabinoids 
Tricyclic antidepressants  
Cotinine testg 
 
Alcohol breath testc  
Follicle-stimulating hormoned  
Serum pregnancy test (human 
chorionic gonadotropin)d 
Urine pregnancy teste 
Other: 
Glycosylated haemoglobin 
(HbA1c)f 
a Creatinine clearance only to be analysed for Part C and at Screening. 
b Only analysed at Screening. 
c Only analysed at Screening and Check-in.  
d Performed at Screening for all females.  
e Performed for all females at Check-in and post-dosing. A positive urine pregnancy test will be confirmed with a serum 
pregnancy test.  
f Part C only. 
g Parts A and B only. 


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Appendix 3: Total Blood Volume 
The following blood volumes will be withdrawn for each subject in Part A (except the 
food-effect cohort [planned to be Cohort A3]). 
 
Volume per blood 
sample (mL) 
Planned number of blood 
samples  
Total amount 
of blood (mL) 
Clinical laboratory 
evaluations 
7.5 
4 
30 
Serology 
3.5 
1 
3.5 
GB1211 
pharmacokinetics 
4 
14 
56 
Exploratory biomarker 
assessments (eg, serum 
galectin-3 and 
chemokine C-C motif 
ligand-4 [CCL4]) 
4 
2 
8 
Total: 
97.5 
If extra blood samples are required (as per Sections 7.1, 7.2, and 7.3), the maximum blood 
volume to be withdrawn per subject will not exceed the volume of a standard blood donation. 
The following blood volumes will be withdrawn for each subject in the food-effect cohort of 
Part A (planned to be Cohort A3). 
 
Volume per blood 
sample (mL) 
Planned number of blood 
samples  
Total amount 
of blood (mL) 
Clinical laboratory 
evaluations 
7.5 
6 
45 
Serology 
3.5 
1 
3.5 
GB1211 
pharmacokinetics 
4 
28 
112 
Exploratory biomarker 
assessments (eg, serum 
galectin-3 and CCL4) 
4 
4 
16 
Total: 
176.5 
If extra blood samples are required (as per Sections 7.1, 7.2, and 7.3), the maximum blood 
volume to be withdrawn per subject will not exceed the volume of a standard blood donation. 


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The following blood volumes will be withdrawn for each subject in Part B. 
 
Volume per blood 
sample (mL) 
Planned number of blood 
samples  
Total 
amount of 
blood (mL) 
Clinical laboratory 
evaluations (including 
exploratory biomarker 
assessment of lipid 
profile and glucose) 
7.5 
8 
60 
Serology 
3.5 
1 
3.5 
GB1211 
pharmacokinetics 
4 
27 
108 
Exploratory biomarker 
assessment - serum 
galectin-3 
4 
2 
8 
Exploratory biomarker 
assessment - insulin 
4 
2 
8 
Exploratory biomarker 
assessments - 
inflammation (eg, 
proinflammatory 
chemokines [including 
CCL4] and heat shock 
C-reactive protein 
[hsCRP], interleukin-12 
[IL-12], and tumor 
necrosis factor [TNF]-α; 
and other biomarkers of 
inflammation as 
required) 
10 
2 
20 
Total: 
207.5 
If extra blood samples are required (as per Sections 7.1, 7.2, and 7.3), the maximum blood 
volume to be withdrawn per subject will not exceed the volume of a standard blood donation. 


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The following blood volumes will be withdrawn for each subject in Part C. 
 
Volume per blood 
sample (mL) 
Planned number of blood 
samples 
Total 
amount of 
blood (mL) 
Clinical laboratory 
evaluations (including 
exploratory biomarker 
assessment of lipid 
profile and glucose) 
7.5 
8 
60 
Serology 
3.5 
1 
3.5 
Coagulation 
1.8 
6 
10.8 
GB1211 
pharmacokinetics 
4 
22 
88 
Exploratory biomarker 
assessment - serum 
galectin-3 
4 
4 
16 
Exploratory biomarker 
assessment - insulin 
4 
4 
16 
Exploratory biomarker 
assessments - 
inflammation (eg, 
proinflammatory 
chemokines [including 
CCL4] and hsCRP, 
IL-12 and TNF-α; other 
biomarkers of 
inflammation as 
required) and 
exploratory biomarkers 
of fibrosis 
10 
2 
20 
                                                                 Total: 
214.3 
If extra blood samples are required (as per Sections 7.1, 7.2, and 7.3), the maximum blood 
volume to be withdrawn per subject will not exceed the volume of a standard blood donation. 
 


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Appendix 4: Contraception Guidance 
Definitions 
Women of Childbearing Potential: premenopausal females who are anatomically and 
physiologically capable of becoming pregnant following menarche. 
Women of Nonchildbearing Potential:  
1. Surgically sterile: females who are permanently sterile via hysterectomy, 
bilateral salpingectomy, and/or bilateral oophorectomy by reported medical 
history and/or medical records. Surgical sterilisation to have occurred a minimum 
of 6 weeks, or at the Investigator’s discretion, prior to Screening. 
2. Postmenopausal: Females at least 45 years of age with amenorrhea for 12 months 
without an alternative medical reason with confirmatory follicle-stimulating 
hormone (FSH) levels of ≥ 40 mIU/mL. The amenorrhea should not be induced by 
a medical condition such as anorexia nervosa, hypothyroid disease or polycystic 
ovarian disease, or by extreme exercise. It should not be due to concomitant 
medications that may have induced the amenorrhea such as oral contraceptives, 
hormones, gonadotropin-releasing hormones, anti-oestrogens, or selective 
oestrogen receptor modulators.  
Fertile male: a male that is considered fertile after puberty. 
Infertile male: permanently sterile male via bilateral orchiectomy. 
Contraception Guidance 
Female Subjects 
Female subjects who are of nonchildbearing potential will not be required to use 
contraception.  
Female subjects of childbearing potential must be willing to use 2 methods (1 primary and 
1 secondary method) of birth control from the time of signing the Informed Consent Form 
until 90 days after the Follow-up visit. Primary (non-barrier) methods of contraception 
include: 
• hormonal injection (as prescribed) 
• combined oral contraceptive pill or progestin/progestogen-only pill (as prescribed) 
• combined hormonal patch (as prescribed) 
• combined hormonal vaginal ring (as prescribed) 
• surgical method performed at least 3 months prior to the Screening visit: 
o 
bilateral tubal ligation 
o 
Essure® (hysteroscopic bilateral tubal occlusion) with confirmation of 
occlusion of the fallopian tubes 


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• hormonal implant 
• hormonal or non-hormonal intrauterine device 
• vasectomised male partner (sterilisation performed at least 90 days prior to the 
Screening visit, with verbal confirmation of surgical success, and the sole partner 
for the female subject)  
Secondary (barrier) methods of contraception include: 
• male condom with spermicide 
• female condom with spermicide 
• over-the-counter sponge with spermicide 
• cervical cap with spermicide (as prescribed) 
• diaphragm with spermicide (as prescribed). 
Female subjects of childbearing potential should refrain from donation of ova from Check-in 
(Day -1) until 90 days after the Follow-up visit. 
Male Subjects 
Male subjects (even with a history of vasectomy) with partners of childbearing potential must 
use a male barrier method of contraception (ie, male condom with spermicide) in addition to 
a second method of acceptable contraception from Check-in until 90 days after the Follow-up 
visit. Acceptable methods of contraception for female partners include: 
• hormonal injection 
• combined oral contraceptive pill or progestin/progestogen-only pill 
• combined hormonal patch 
• combined hormonal vaginal ring 
• surgical method (bilateral tubal ligation or Essure® [hysteroscopic bilateral tubal 
occlusion])  
• hormonal implant 
• hormonal or non-hormonal intrauterine device 
• over-the-counter sponge with spermicide 
• cervical cap with spermicide 
• diaphragm with spermicide 
An acceptable second method of contraception for male subjects is vasectomy that has been 
performed at least 90 days prior to the Screening visit, with verbal confirmation of surgical 
success. 


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For male subjects (even with a history of vasectomy), sexual intercourse with female partners 
who are pregnant or breastfeeding should be avoided unless condoms are used from the time 
of the first dose until 90 days after the Follow-up visit. Male subjects are required to refrain 
from donation of sperm from Check-in until 90 days after the Follow-up visit. 
Sexual Abstinence and Same-sex Relationships 
For subjects who practice true abstinence, subjects must be abstinent for at least 6 months 
prior to Screening and must agree to remain abstinent from the time of signing the ICF until 
90 days after the Follow-up visit. 
A subject in a same-sex relationship at the time of signing the ICF must agree to refrain from 
engaging in a heterosexual relationship from the time of signing the ICF until 90 days after 
the Follow-up visit. 
 


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Appendix 5: Regulatory, Ethical, and Study Oversight Considerations 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines. 
• Applicable International Conference on Harmonisation (ICH) Good Clinical 
Practice (GCP) Guidelines. 
• Applicable laws and regulations. 
The protocol, protocol amendments, Informed Consent Form (ICF), Investigator Brochure, 
and other relevant documents must be submitted to an Ethics Committee (EC) by the 
Investigator and reviewed and approved by the EC before the study is initiated.  
Any substantial protocol amendments, likely to affect the safety of the subjects or the conduct 
of the study, will require EC and regulatory authority (as locally required) approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study subjects or any nonsubstantial changes, as defined by 
regulatory requirements.  
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the EC annually or more 
frequently in accordance with the requirements, policies, and procedures 
established by the EC. 
• Notifying the EC of serious adverse events or other significant safety findings as 
required by EC procedures. 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the EC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations. 
Finances and Insurance 
Financing and insurance will be addressed in a separate agreement. 
Informed Consent 
Prior to starting participation in the study, each subject will be provided with a study-specific 
ICF giving details of the study drugs, procedures, and potential risks of the study. Subjects 
will be instructed that they are free to obtain further information from the Investigator (or 
designee) and that their participation is voluntary and they are free to withdraw from the 
study at any time. Subjects will be given an opportunity to ask questions about the study prior 
to providing consent for participation. 


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Following discussion of the study with Clinical Research Unit personnel, subjects will sign 
2 copies of the ICF in the presence of a suitably trained member of staff to indicate that they 
are freely giving their informed consent. One copy will be given to the subject, and the other 
will be maintained in the subject’s records. 
Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
Subject Data Protection 
Subjects will be assigned a unique identifier and will not be identified by name in electronic 
Case Report Forms (eCRFs), study-related forms, study reports, or any related publications. 
Subject and Investigator personal data will be treated in compliance with all applicable laws 
and regulations. In the event the study protocol, study report, or study data are included in a 
public registry, all identifiable information from individual subjects or Investigators will be 
redacted according to applicable laws and regulations.  
The subject must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the subject. The subject must also be informed that his/her study-related data 
may be examined by Sponsor or Contract Research Organisation (CRO) auditors or other 
authorised personnel appointed by the Sponsor, by appropriate EC members, and by 
inspectors from regulatory authorities. 
Disclosure 
All information provided regarding the study, as well as all information collected and/or 
documented during the course of the study, will be regarded as confidential. The Investigator 
(or designee) agrees not to disclose such information in any way without prior written 
permission from the Sponsor. 
Data Quality Assurance 
The following data quality steps will be implemented: 
• All relevant subject data relating to the study will be recorded on eCRFs unless 
directly transmitted to the Sponsor or designee electronically (eg, laboratory data). 
The Investigator is responsible for verifying that data entries are accurate and 
correct by electronically signing the eCRF.  
• The Investigator must maintain accurate documentation (source data) that 
supports the information entered in the eCRF.  
• The Investigator must permit study-related monitoring, audits, EC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• Covance is responsible for the data management of this study including quality 
checking of the data. Predefined agreed risks, monitoring thresholds, quality 
tolerance thresholds, controls, and mitigation plans will be documented in a risk 


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management register. Additional details of quality checking to be performed on 
the data may be included in a Data Management Plan.  
• A Study Monitor will perform ongoing source data verification to confirm that 
data entered into the eCRF by authorised site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of subjects are 
being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the Investigator in the study site archive for at least 
5 years after the end of the study unless local regulations or institutional policies 
require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.  
Investigator Documentation Responsibilities 
All individual, subject-specific study data will also be entered into a 21 CFR 
Part 11-compliant electronic data capture (EDC) system on an eCRF in a timely fashion. 
All data generated from external sources (eg, laboratory and bioanalytical data), and 
transmitted to Covance electronically, will be integrated with the subject’s eCRF data in 
accordance with the Data Management Plan.  
An eCRF must be completed for each enrolled subject who undergoes any screening 
procedures, according to the eCRF completion instructions. The Sponsor, or CRO, will 
review the supporting source documentation against the data entered into the eCRFs to verify 
the accuracy of the electronic data. The Investigator will ensure that corrections are made to 
the eCRFs and that data queries are resolved in a timely fashion by the study staff. 
The Investigator will sign and date the eCRF via the EDC system’s electronic signature 
procedure. These signatures will indicate that the Investigator reviewed and approved the 
data on the eCRF, data queries, and site notifications. 
Publications 
If on completion of the study the data warrant publication, the Investigator may publish the 
results in recognised (refereed) scientific journals subject to the provisions of the clinical 
study agreement (CSA). Unless otherwise specified in the CSA, the following process will 
occur: 
If the Investigator expects to participate in the publication of data generated from this site, the 
institution and Investigator will submit reports, abstracts, manuscripts, and/or other 
presentation materials to the Sponsor for review before submission for publication or 
presentation. The Sponsor will have 60 days to respond with any requested revisions 
including, without limitation, the deletion of confidential information. The Investigator will 
act in good faith upon requested revisions, except the Investigator will delete any confidential 


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information from such proposed publications. The Investigator will delay submission of such 
publication or presentation materials for up to an additional 90 days in order to have a patent 
application(s) filed. 


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Appendix 6: Schedule of Assessments 


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Table 1: Schedule of Assessments – Part A (Single Dose) 
Study Procedures 
Screening 
Treatment Period 1 (and 2 for Food-Effect Cohort)  
Follow-up  
(5-7 days Postdose) 
Day -1 
Days 1 to 3 
Informed consent 
X 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
Demographic data 
X 
 
 
 
Medical history 
X 
Xa
 
 
Urinary drug screen 
X
X 
 
 
Alcohol breath test 
X 
X 
 
 
Serology 
X 
 
 
 
Pregnancy testb 
X 
X 
 
X 
Follicle-stimulating hormone 
Xe
 
 
 
Height and body weight 
X 
 
 
 
Study residency: 
 
 
 
 
Check-in 
 
X 
 
 
Check-out 
 
 
Day 3 (48 hours postdose)  
 
Nonresidential visit 
X 
 
 
X 
Study drug administration: 
 
 
 
 
GB1211 or placebo 
 
 
Day 1 (0 hours) (30 minutes after starting a high-fat 
breakfast in Treatment Period 2 for food-effect cohort 
[planned to be Cohort A3]) 
 
Pharmacokinetics: 
 
 
 
 
Blood sampling 
 
 
Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 
48 hours postdose  
 
Urine sampling 
 
 
Predose (spot collection) and 0 to 6, 6 to 12, 12 to 24, and 
24 to 48 hours postdose 
 
Exploratory biomarker assessments:
 
 
 
 


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Table 1: Schedule of Assessments – Part A (Single Dose) 
Study Procedures 
Screening 
Treatment Period 1 (and 2 for Food-Effect Cohort)  
Follow-up  
(5-7 days Postdose) 
Day -1 
Days 1 to 3 
Blood sample for biomarker assessments 
(eg, serum galectin-3 and CCL4)  
 
 
Predose and 24 hours postdose 
 
Safety and tolerability: 
 
 
 
 
Adverse event recording 
X 
X 
Ongoing 
X 
Prior/concomitant medication monitoring 
X 
X 
Ongoing 
X 
Clinical laboratory evaluations 
X 
X 
48 hours postdose 
X 
Vital sign measurements (blood pressure, 
pulse rate, and oral body temperature) 
X 
 
Predose, 1, 2, 4, 8, 24, and 48 hours postdose 
X 
12-lead ECG 
X 
 
Predose, 1, 4, 24, and 48 hours postdose 
X 
Telemetry 
 
 
From at least -1 hour predose to 4 hours postdose 
 
Continuous 12-lead ECG 
 
 
Xc 
 
Physical examination 
X  
Xd 
Prior to discharged 
Xd 
Abbreviations: CCL4 = chemokine (C-C) motif ligand 4; ECG = electrocardiogram.  
a Interim medical history. 
b In all females. Performed in serum at Screening and in urine at all other times. A positive urine pregnancy test will be confirmed with a serum pregnancy test.  
c Monitor for 12-lead ECG recording will be worn from 2 hours predose to 25 hours postdose on Day 1. Extraction timepoints will be 60, 45, and 30 minutes predose (averaged for baseline) and 
at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 postdose. Continuous 12-lead ECG recording will only be performed in the fasted treatment periods. 
d Symptom-directed physical examination. 
e In all females. 


Protocol Version 2.0 
CONFIDENTIAL 
Covance Study: 8392356 
Protocol Reference: GB1211-001 
Protocol Version 2.0, 05 November 2018 
Page 73 of 78 
Table 2: Schedule of Assessments – Part B (Multiple Dose) 
Study Procedures 
Screening 
Day -1 
Days 1 to 11 
Follow-up  
(5-7 days 
Post-Final Dose) 
Informed consent 
X 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
Demographic data 
X 
 
 
 
Medical history 
X 
Xa
 
 
Urinary drug screen 
X 
X 
 
 
Alcohol breath test 
X 
X 
 
 
Serology 
X 
 
 
 
Pregnancy testc
X 
X 
 
X 
Follicle-stimulating hormone 
Xf 
 
 
 
Height and body weight 
X 
Xe 
 
Xe
Study residency: 
 
 
 
 
Check-in 
 
X 
 
 
Check-out 
 
 
Day 11 (24 hours postdose) 
 
Nonresidential visit 
X 
 
 
X 
Study drug administration: 
 
 
 
 
GB1211 or placebo 
 
 
Day 1 to 9 (0 and 12 hour) and Day 10 (0 hour)b
 
Pharmacokinetics: 
 
 
 
 
Blood sampling  
 
 
Day 1: pre-am dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-am 
dose 
Days 4 to 9: pre-am dose 
Day 10: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-final dose 
Day 11: 24 hours post-final dose 
 
Exploratory biomarker 
assessments: 
 
 
 
 


Protocol Version 2.0 
CONFIDENTIAL 
Covance Study: 8392356 
Protocol Reference: GB1211-001 
Protocol Version 2.0, 05 November 2018 
Page 74 of 78 
Table 2: Schedule of Assessments – Part B (Multiple Dose) 
Study Procedures 
Screening 
Day -1 
Days 1 to 11 
Follow-up  
(5-7 days 
Post-Final Dose) 
Serum galectin-3  
 
 
Day 1: pre-am dose 
Day 10: predose  
 
Fasting glucose and insulin  
 
 
Day 1: pre-am dose 
Day 10: predose 
 
Lipid profile (eg, LDL, HDL, total 
cholesterol, and triglycerides) 
 
 
Day 1: pre-am dose 
Day 10: predose 
 
hsCRP, IL-12, TNF-α, MCP-1 and 
proinflammatory chemokines (CCL2, 
CCL3, CCL4, and the chemokine 
receptors CCR1 and CCR2); and 
other biomarkers of inflammation as 
required 
 
 
Day 1: pre-am dose 
Day 10: predose   
 
Safety and tolerability: 
 
 
 
 
Adverse event recording 
X 
X 
Ongoing 
X 
Prior/concomitant medication 
monitoring 
X 
X 
Ongoing 
X 
Clinical laboratory evaluations 
X 
X 
Days 4 and 6: pre-am dose  
Day 11: 24 hours post-final dose 
X 
Vital sign measurements (blood 
pressure, pulse rate, and oral body 
temperature) 
X 
 
Day 1: pre-am dose, 2, 4, and 8 hours post-am dose 
Days 2 to 9: pre-am dose 
Day 10: predose, 2, 4, and 8 hours post-final dose 
X 
12-lead ECG 
X 
 
Day 1: pre-am dose and 4 hours post-am dose 
Day 5: pre-am dose and 4 hours post-am dose 
Day 10: predose and 4 hours post-final dose 
X 
Physical examination 
X  
Xd 
Prior to Discharge on Day 11d 
Xd 


Protocol Version 2.0 
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Covance Study: 8392356 
Protocol Reference: GB1211-001 
Protocol Version 2.0, 05 November 2018 
Page 75 of 78 
Abbreviations: CCL = chemokine (C-C motif) ligand; CCR = chemokine (C-C motif) ligand receptor; ECG = electrocardiogram; HDL = high density lipoprotein; hsCRP = heat shock 
C-reactive protein; IL = interleukin; LDL = low density lipoprotein; MCP1 = monocyte chemotactic protein-1; TNF-α = tumor necrosis factor-alpha.  
a Interim medical history. 
b Timings relative to dose administration on Day 1. 
c In all females. Performed in serum at Screening and in urine at all other times. A positive urine pregnancy test will be confirmed with a serum pregnancy test.  
d Symptom-directed physical examination. 
e Body weight only. 
f In all females. 
 


Protocol Version 2.0 
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Covance Study: 8392356 
Protocol Reference: GB1211-001 
Protocol Version 2.0, 05 November 2018 
Page 76 of 78 
Table 3: Schedule of Assessments – Part C (Multiple Dose in Subjects with Suspected NASH and Liver Fibrosis) 
Study Procedures 
Screening 
Day -1 
Days 1 to 43 
Follow-up  
(5-7 days 
Post-Final Dose) 
Informed consent 
X 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
Demographic data 
X 
 
 
 
Medical history 
X 
Xa
 
 
Urinary drug screen 
X 
X 
 
 
Alcohol breath test 
X 
X 
 
 
Serology 
X 
 
 
 
Pregnancy testc
X 
X 
 
X 
Follicle-stimulating hormone 
Xi 
 
 
 
Height and body weight 
X 
Xg 
 
Xg 
Fibroscan CAP or Ultrasounde 
X 
 
 
 
Site staff to query alcohol 
consumption prior to site visitsf 
 
 
At each site visit 
X 
Study residency: 
 
 
 
 
Check-in 
 
X 
Day 41 
 
Check-out 
 
 
Day 2 and Day 43 (24 hours post-final dose) 
 
Nonresidential visit 
X 
 
Days 7, 14, 21, 28, and 35 
X 
Study drug administration: 
 
 
 
 
GB1211 or placebo 
 
 
Days 1 to 41 (0 and 12 hour) and Day 42 (0 hour)b
 
Pharmacokinetics: 
 
 
 
 
Blood sampling  
 
 
Day 1: pre-am dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-am dose
Day 2: pre-am dose (24 hours post Day 1 am dose) 
Day 42: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-final dose 
Day 43: 24 hours post-final dose 
 


Protocol Version 2.0 
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Covance Study: 8392356 
Protocol Reference: GB1211-001 
Protocol Version 2.0, 05 November 2018 
Page 77 of 78 
Table 3: Schedule of Assessments – Part C (Multiple Dose in Subjects with Suspected NASH and Liver Fibrosis) 
Study Procedures 
Screening 
Day -1 
Days 1 to 43 
Follow-up  
(5-7 days 
Post-Final Dose) 
Exploratory biomarker 
assessments: 
 
 
 
 
Serum galectin-3 
 
 
Day 1: pre-am dose 
Day 14, 28, and 42h 
 
Fasting glucose and insulin  
 
 
Day 1: pre-am dose 
Days 14, 28, and 42h  
 
Lipid profile (eg, LDL, HDL, total 
cholesterol, and triglycerides) 
 
 
Day 1: pre-am dose 
Days 14, 28, and 42h 
 
hsCRP, IL-12, TNF-α, MCP-1, and 
proinflammatory chemokines 
(CCL2, CCL3, CCL4, and the 
chemokine receptors CCR1 and 
CCR2); and other biomarkers of 
inflammation as required 
 
 
Day 1: pre-am dose  
Day 42h  
 
Exploratory biomarkers of fibrosis 
(including but not limited to 
extracellular matrix proteins 
[TIMP-1, HA, and P3NP], A9, ELF 
panel, CK18, PAI-1, CH3L1, IL6, 
pro-collagen 3)  
 
 
Day 1: pre-am dose 
Day 42h 
 
Safety and tolerability: 
 
 
 
 
Adverse event recording 
X 
X 
Ongoing 
X 
Prior/concomitant medication 
monitoring 
X 
X 
Ongoing 
X 


Protocol Version 2.0 
CONFIDENTIAL 
Covance Study: 8392356 
Protocol Reference: GB1211-001 
Protocol Version 2.0, 05 November 2018 
Page 78 of 78 
Table 3: Schedule of Assessments – Part C (Multiple Dose in Subjects with Suspected NASH and Liver Fibrosis) 
Study Procedures 
Screening 
Day -1 
Days 1 to 43 
Follow-up  
(5-7 days 
Post-Final Dose) 
Clinical laboratory evaluations 
(including HbA1c and coagulation 
profile) 
X 
X 
Day 14 and Day 28: pre-am dose 
Day 43: 24 hours post-final dose 
X 
Vital sign measurements (blood 
pressure, pulse rate, and oral body 
temperature) 
X 
 
Day 1: pre-am dose, 4, and 8 hours post-am dose 
Day 2: pre-am dose 
Days 7, 14, 21, 28, and 35 
Day 42: predose, 4, 8 hours post-final dose 
Day 43: 24 hours post-final dose 
X 
12-lead ECG 
X 
 
Day 1: pre-am dose and 4 hours post-am dose 
Days 14 and 28  
Day 42: predose, 4 hours post-final dose 
Day 43: 24 hours post-final dose 
X 
Physical examination 
X  
Xd
Day 1d 
Xd 
Abbreviations: CAP = Controlled Attenuation Parameter; CCL = chemokine (C-C motif) ligand; CCR = chemokine (C-C motif) ligand receptor; CH3L1 = chitinase-3 like protein-1; CK18 = 
cytokeratin 18; ECG = electrocardiogram; ELF = E74-like transcription factors; HA = hyaluronic acid; HbA1c  = glycosylated haemoglobin; HDL = high density lipoprotein; hsCRP = heat 
shock C-reactive protein; IL = interleukin; LDL = low density lipoprotein; MCP1 = monocyte chemotactic protein-1; P3NP = aminoterminal peptide of pro-collagen III; PAI-1 = plasminogen 
activator inhibitor-1; NASH = nonalcoholic steatohepatitis; TIMP-1 = tissue inhibitor of matrix metalloproteinase-1; TNF-α = tumor necrosis factor-alpha.  
a Interim medical history. 
b Timings relative to dose administration on Day 1. 
c In all females. Performed in serum at Screening and in urine at all other times. A positive urine pregnancy test will be confirmed with a serum pregnancy test.  
d Symptom-directed physical examination. 
e Fibroscan only to be performed in subjects who do not have documented history of fatty liver. 
f Site to query whether subject has consumed alcohol within 36 hours of the site visit; and whether alcohol consumption has been limited to 2 units per day on all other days of study. Protocol 
deviations to be recorded if subject has not. 
g Body weight only. 
h Post dosing samples for biomarkers should be collected at approximately the same time each visit. 
i In all females.   
 

SAP_000.pdf: 
Final V1: 25 July 2019 
 
Page 1 of 25 
 
STATISTICAL ANALYSIS PLAN 
GB1211 - A Randomised, Double-Blind, Placebo-Controlled, First-In-Human, Study of 
Orally Administered GB1211 to Evaluate the Safety, Tolerability, and Pharmacokinetics of 
Single Ascending Doses (SAD) and Multiple Ascending Doses (MAD) in Healthy Subjects 
and in Subjects with Suspected Nonalcoholic Steatohepatitis (NASH) and Liver Fibrosis 
Statistical Analysis Plan Status: Final V1 
Statistical Analysis Plan Date: 25 July 2019 
Study Drug: GB1211 
Sponsor Reference Number: GB1211-001 (Parts A and B) 
Covance Study Number: 8392356 
Clinical Phase 1 
 
 
Sponsor: 
 
Galecto Biotech 
Cobis Science Park 
Ole Maaloes Vej 3 
DK-2200 Copenhagen 
Denmark 
 
Study Site for Parts A and B: 
Covance Clinical Research Unit Ltd. 
Springfield House, Hyde Street 
Leeds, LS2 9LH 
UK 
 
 
Sponsor Signatory: 
Dr Richard Marshall 
Telephone:  (+44) (0) 7717800184 
Principal Investigator: 
Dr Ashley Brooks, MBChB 
Telephone:  (+44) (0) 1133013521 
 
 
 


Statistical Analysis Plan  
 
CONFIDENTIAL 
Covance Study: 8392356 
 
Sponsor Reference: GB1211-001 
 
Final V1: 25 July 2019 
 
Page 2 of 25 
 
1  STATISTICAL ANALYSIS PLAN APPROVAL SIGNATURES 
By signing this page when the Statistical Analysis Plan (SAP) is considered final, the signatories 
agree to the statistical, pharmacokinetic (PK), and biomarker analyses to be performed for this 
study, and to the basic format of the tables, figures, and listings (TFLs). Once the SAP has been 
signed, programming of the TFLs based upon this document can proceed. Any modifications to 
the SAP and TFLs made after signing may result in a work-scope change. 
 
 


Statistical Analysis Plan  
 
CONFIDENTIAL 
Covance Study: 8392356 
 
Sponsor Reference: GB1211-001 
 
Final V1: 25 July 2019 
 
Page 3 of 25 
 
2  TABLE OF CONTENTS 
1 
STATISTICAL ANALYSIS PLAN APPROVAL SIGNATURES ................................. 2 
2 
TABLE OF CONTENTS ............................................................................................... 3 
3 
ABBREVIATIONS........................................................................................................ 5 
4 
INTRODUCTION ......................................................................................................... 7 
5 
STUDY OBJECTIVES .................................................................................................. 7 
6 
STUDY DESIGN ........................................................................................................... 8 
6.1 
Part A ...................................................................................................................... 8 
6.2 
Part B .................................................................................................................... 10 
6.3 
Part C (Optional) ................................................................................................... 12 
7 
TREATMENTS ........................................................................................................... 13 
8 
SAMPLE SIZE JUSTIFICATION ............................................................................... 13 
9 
DEFINITION OF ANALYSIS POPULATIONS .......................................................... 14 
10 STATISTICAL METHODOLOGY ............................................................................. 14 
10.1 General .................................................................................................................. 14 
10.1.1 Definition of Baseline and Change from Baseline ......................................... 15 
10.1.2 Repeat and Unscheduled Readings ............................................................... 15 
10.2 Demographics and Subject Disposition .................................................................. 15 
10.3 Pharmacokinetic Assessment ................................................................................. 15 
10.3.1 Criteria for Handling Concentrations Below the Limit of Quantification in 
Pharmacokinetic Analysis ............................................................................. 17 
10.3.2 Criteria for the Calculation of an Apparent Terminal Elimination Half-Life .. 18 
10.4 Presentation of Pharmacokinetic Data .................................................................... 19 
10.4.1 Presentation Pharmacokinetic Concentration Data ........................................ 19 
10.4.2 Pharmacokinetic Statistical Methodology ..................................................... 19 
10.5 Biomarker Assessment .......................................................................................... 22 
10.6 Safety and Tolerability Assessments ...................................................................... 22 
10.6.1 Adverse Events ............................................................................................. 22 
10.6.2 Clinical Laboratory Parameters ..................................................................... 23 
10.6.3 Vital Signs .................................................................................................... 23 
10.6.4 Electrocardiogram ........................................................................................ 23 
10.6.5 Other Assessments ....................................................................................... 24 
10.6.6 Safety and Tolerability Statistical Methodology ............................................ 24 


Statistical Analysis Plan  
 
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Covance Study: 8392356 
 
Sponsor Reference: GB1211-001 
 
Final V1: 25 July 2019 
 
Page 4 of 25 
 
11 INTERIM ANALYSES ............................................................................................... 24 
12 CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ...... 24 
13 DATA PRESENTATION ............................................................................................ 24 
13.1 Insufficient Data for Presentation............................................................................ 24 
14 REFERENCES ............................................................................................................ 24 


Statistical Analysis Plan  
 
CONFIDENTIAL 
Covance Study: 8392356 
 
Sponsor Reference: GB1211-001 
 
Final V1: 25 July 2019 
 
Page 5 of 25 
 
 
3  ABBREVIATIONS 
Abbreviations pertain to the SAP only (not the TFLs). 
ADaM 
analysis data model 
Ae 
Amount of drug excreted unchanged in urine  
AE 
adverse event 
AUC0- 
Area under the plasma concentration-time curve over a dosing 
interval (τ = 12 hours) 
AUC0-tlast 
Area under the plasma concentration-time curve from time zero to 
the time of the last quantifiable concentration 
AUC0-∞ 
Area under the plasma concentration-time curve from time zero to 
infinity 
%AUCextrap 
Area under the plasma concentration-time curve extrapolated from 
last quantifiable concentration to infinity as a percentage of total 
AUC 
BID 
twice daily 
BLQ 
below the level of quantification 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence interval 
CL/F 
Apparent total plasma clearance 
CLR 
Renal clearance 
Cmax 
Maximum observed plasma concentration  
Cmin 
Minimum observed plasma concentration  
CRF 
Case Report Form 
CRU 
Clinical Research Unit 
CSR 
Clinical Study Report 
CV% 
coefficient of variation 
EC 
Early Clinical 
ECG 
electrocardiogram 
fe 
Percentage of dose excreted unchanged in urine  
ICH 
International Conference on Harmonisation 
LLOQ 
lower limit of quantification 


Statistical Analysis Plan  
 
CONFIDENTIAL 
Covance Study: 8392356 
 
Sponsor Reference: GB1211-001 
 
Final V1: 25 July 2019 
 
Page 6 of 25 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
NASH 
Nonalcoholic Steatohepatitis  
NC 
Not calculated 
NR 
No result 
PK 
pharmacokinetic 
QTc 
QT correction; QT interval corrected for heart rate 
QTcB 
QTc calculated using the Bazett correction 
QTcF 
QTc calculated using the Fridericia correction  
RAAUC0-τ 
Observed accumulation ratio based on AUC0-τ   
RACmax 
Observed accumulation ratio based on C max 
SAP 
Statistical Analysis Plan 
TBD 
To be determined 
TEAE 
treatment-emergent adverse event 
TFLs 
tables, figures, and listings 
t1/2 
Apparent plasma terminal elimination half-life 
Tmax 
Time of the maximum observed plasma concentration 
Vz/F 
Apparent volume of distribution during the terminal elimination 
phase 
 
 


Statistical Analysis Plan  
 
CONFIDENTIAL 
Covance Study: 8392356 
 
Sponsor Reference: GB1211-001 
 
Final V1: 25 July 2019 
 
Page 7 of 25 
 
 
4  INTRODUCTION 
This SAP has been developed after review of the clinical study protocol (Final Version 2.0 dated 
05 November 2018). 
This SAP describes the planned analysis of the safety, tolerability, PK, and biomarker data from 
this study. A detailed description of the planned TFLs to be presented in the Clinical Study 
Report (CSR) is provided in the accompanying TFL shell document. 
The intent of this document is to provide guidance for the statistical analyses of PK and 
Biomarker data. In general, the analyses are based on information from the protocol, unless they 
have been modified by agreement between Galecto Biotech and Covance Early Clinical (EC) 
Biometrics. A limited amount of information concerning this study (eg, objectives, study design) 
is given to help the reader’s interpretation. This SAP must be finalised prior to the lock of the 
clinical database for this study. When the SAP and TFL shells are agreed upon and finalised, 
they will serve as the template for this study’s CSR. 
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon 
between Galecto Biotech and Covance EC Biometrics and identified in the CSR. 
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 guideline entitled, “Guidance for Industry: Statistical 
Principles for Clinical Trials” and the ICH E3 guideline entitled, “Guidance for Industry: 
Structure and Content of Clinical Study Reports.”1,2 
5  STUDY OBJECTIVES 
The primary objectives of the study are: 
 to evaluate the safety and tolerability of single and multiple doses of GB1211 
administered to healthy subjects. 
 to evaluate the safety and tolerability of multiple doses of GB1211 administered to 
subjects with suspected NASH and liver fibrosis. 
The secondary objectives of the study are: 
 to evaluate the PK of single doses of GB1211 in plasma and urine in healthy subjects 
and the PK of multiple doses of GB1211 in plasma of healthy subjects and subjects 
with suspected NASH and liver fibrosis. 
 to determine the effect of food on the single oral dose PK of GB1211. 


Statistical Analysis Plan  
 
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Covance Study: 8392356 
 
Sponsor Reference: GB1211-001 
 
Final V1: 25 July 2019 
 
Page 8 of 25 
 
The exploratory objectives of the study are:  
 to investigate biomarkers related to GB1211 activity at single and/or multiple doses in 
comparison to placebo in healthy subjects and subjects with suspected NASH and 
liver fibrosis. 
 to investigate biomarkers of metabolism, inflammation, and fibrosis following multiple 
doses of GB1211 in healthy subjects and/or subjects with suspected NASH and liver 
fibrosis. 
 to identify metabolites of GB1211 in plasma and urine.  
6  STUDY DESIGN 
6.1 
Part A 
Part A will comprise a single-dose, sequential-cohort study incorporating a single-cohort, 
randomised, 2-part arm to investigate the effect of food. Overall, 40 subjects will be studied in 5 
cohorts (Cohorts A1 to A5), with each cohort consisting of 8 subjects. 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Each subject will participate in 1 treatment period only, 
residing at the Clinical Research Unit (CRU) from Day -1 (the day before dosing) to Day 3 (48 
hours postdose), except for the food-effect cohort (planned to be Cohort A3), where each subject 
will participate in 2 treatment periods separated by a minimum of 7 days.  
All subjects will return for a Follow-up visit 5 to 7 days after their final dose.  
Dose Regimen: 
In each of Cohorts A1 to A5, 6 subjects will receive GB1211 and 2 will receive placebo. In all 
cohorts, except the food-effect cohort, all doses will be administered in the fasted state in 
accordance with a randomisation schedule on the morning of Day 1. For the food-effect cohort, 
which is planned to be Cohort A3, Treatment Period 1, Day 1 doses will be administered in the 
fasted state in accordance with the randomisation schedule and in Treatment Period 2, Day 1 
doses will be given 30 minutes after the start of a high fat breakfast. Each subject in Cohorts A1 
to A5 (except the food-effect cohort) will receive only a single dose of GB1211 or placebo 
during the study. In the food-effect cohort, subjects will receive the same treatment in both 
periods and will receive 2 single doses of GB1211 or placebo during the study. 
In Cohorts A1 to A5 (except the fed period of the food-effect cohort), dosing will occur such that 
2 subjects (1 active and 1 placebo) will be dosed at least 24 hours before the remaining subjects, 
where continuation to dose the remaining subjects will be at the Investigator’s discretion. 
Based on the ongoing review of the safety, tolerability, and PK results, additional nonresidential 
visits may be required. The number of additional visits per subject will not exceed 3 and will not 
extend beyond 28 days after each final dosing occasion. 


Statistical Analysis Plan  
 
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Covance Study: 8392356 
 
Sponsor Reference: GB1211-001 
 
Final V1: 25 July 2019 
 
Page 9 of 25 
 
An overview of the study design is shown in Figure 1 and Figure 2 and the planned dose levels 
in Figure 3. 
Figure 1: Study Schematic - Part A Cohorts (Except the Food-Effect Cohort) 
 
Abbreviation: CRU = Clinical Research Unit 
Figure 2: Study Schematic - Part A Food-Effect Cohort (Planned to be Cohort A3) 
 
Abbreviation: CRU = Clinical Research Unit 
 


Statistical Analysis Plan  
 
CONFIDENTIAL 
Covance Study: 8392356 
 
Sponsor Reference: GB1211-001 
 
Final V1: 25 July 2019 
 
Page 10 of 25 
 
Figure 3: Planned Dose Levels (Part A) 
 
The total duration of study participation for each subject (from Screening through Follow-up 
visit) for all Part A cohorts except the food-effect cohort is anticipated to be approximately 
5 weeks. For each subject in the food-effect cohort (planned to be Cohort A3), the total duration 
is anticipated to be approximately 6 to 7 weeks. 
6.2 
Part B 
Part B will comprise a multiple-dose, sequential-cohort study. Overall, 22 subjects will be 
studied in 2 cohorts (Cohorts B1 to B2), with each cohort consisting of 11 subjects. Dosing in 
Part B will start following review of safety, tolerability, and PK data from a single dose with 
exposure higher than the predicted steady-state exposure. 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Each subject will participate in 1 treatment period only and 
reside at the CRU from Day -1 (the day before dosing) until the morning of Day 11 (24 hours 
after the final dose on Day 10). 
All subjects will return for a Follow-up visit 5 to 7 days after their final dose.  
Dose Regimen: 
In each of Cohorts B1 to B2, 8 subjects will receive GB1211 and 3 subjects will receive placebo. 
The dietary state for dosing in Part B will be fasted unless data from the food-effect cohort is 


Statistical Analysis Plan  
 
CONFIDENTIAL 
Covance Study: 8392356 
 
Sponsor Reference: GB1211-001 
 
Final V1: 25 July 2019 
 
Page 11 of 25 
 
available and supports dosing in the fed state. For all subjects, the planned dosing will be BID on 
Days 1 to 9, inclusive, and a final single dose administration will occur in the morning of 
Day 10. The dosing interval/frequency and dosing duration in Part B may be changed following 
review of data from cohorts in Part A. The predicted total daily exposure will not exceed the 
highest exposure observed in Part A. There will be a minimum of 10 days between dose 
escalations for each cohort. 
An overview of the study design is shown in Figure 4 and the planned dose levels in Figure 5. 
Figure 4: Study Schematic (Part B) 
 
Abbreviations: BID = twice-daily; CRU = Clinical Research Unit 
Figure 5: Planned Dose Levels (Part B) 
 
Abbreviations: BID = twice-daily; TBD = to be determined 
The total duration of study participation for each subject (from Screening through Follow-up 
visit) is anticipated to be approximately 6 to 7 weeks. 


Statistical Analysis Plan  
 
CONFIDENTIAL 
Covance Study: 8392356 
 
Sponsor Reference: GB1211-001 
 
Final V1: 25 July 2019 
 
Page 12 of 25 
 
6.3 
Part C (Optional) 
Part C will comprise a multiple-dose cohort of 25 subjects with suspected NASH and liver 
fibrosis (Cohort C1). Part C may start following review of data from Part A and at least 1 Part B 
cohort. 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Each subject will participate in 1 treatment period only and 
reside at the CRU from Day -1 (the day before dosing) until the morning of Day 2, returning for 
nonresidential visits on Days 7, 14, 21, 28, and 35. Subjects will then check back into the CRU 
on Day 41 until the morning of Day 43 (24 hours after the final dose on Day 42). 
All subjects will return for a Follow-up visit 5 to 7 days after their final dose. 
Dose Regimen: 
For Part C, Cohort C1, 15 subjects will receive GB1211 and 10 subjects will receive placebo. 
The dietary state for dosing in Part C will be fasted unless data from the food-effect cohort is 
available and supports dosing in the fed state. For all subjects, the planned dosing will be BID on 
Days 1 to 41 inclusive, and a final single dose administration will occur in the morning of Day 
42. The total daily dose administered, dose interval/frequency, and dosing duration will be based 
on review of data from Parts A and B. 
An overview of the study design is shown in Figure 6. 
Figure 6: Study Schematic (Part C) 
 
Abbreviations: BID = twice-daily; CRU = Clinical Research Unit 
The dose level of Part C is to be determined following completion of Part A and at least 1 cohort 
of Part B. 


Statistical Analysis Plan  
 
CONFIDENTIAL 
Covance Study: 8392356 
 
Sponsor Reference: GB1211-001 
 
Final V1: 25 July 2019 
 
Page 13 of 25 
 
The total duration of study participation for each subject (from Screening through Follow-up 
visit) for Cohort C1 is anticipated to be approximately 11 weeks.  
This SAP and the accompanying shells are related to the analysis of Parts A and B only. 
7  TREATMENTS 
The following is a list of the study treatment abbreviations and ordering that will be used in the 
TFLs. 
Part 
Study Treatment Name 
Treatment Order on TFLs 
A 
 
Placebo (fasted) 
1 
Placebo (fed) 
2 
5 mg GB1211 (fasted) 
3 
20 mg GB1211 (fasted) 
4 
50 mg (10 x 5 mg) GB1211 (fasted) 
5 
50 mg (1 x 50 mg) GB1211 (fasted) 
6 
50 mg (1 x 50 mg) GB1211 (fed) 
7 
100 mg GB1211 (fasted) 
8 
200 mg GB1211 (fasted) 
9 
400 mg GB1211 (fasted) 
10 
B 
Placebo bid  
11 
50 mg GB1211 bid 
12 
100 mg GB1211 bid 
13 
8  SAMPLE SIZE JUSTIFICATION 
No formal statistical assessment, in terms of sample size, has been conducted as this is the first 
time GB1211 is being administered to humans. However, the number of subjects in each part of 
the present study is common in early clinical pharmacology studies and is considered sufficient 
to achieve the objectives of the study. 


Statistical Analysis Plan  
 
CONFIDENTIAL 
Covance Study: 8392356 
 
Sponsor Reference: GB1211-001 
 
Final V1: 25 July 2019 
 
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9  DEFINITION OF ANALYSIS POPULATIONS 
The Safety Population will consist of all subjects who received at least 1 dose of study drug 
(GB1211 or placebo). 
The PK population will include all subjects who received at least 1 dose of GB1211 and have 
evaluable PK data. A subject may be excluded from the PK summary statistics and statistical 
analysis if the subject has an AE of vomiting that occurs at or before 2-times median time to 
maximum concentration.  
The Biomarker Population will include all subjects who received at least 1 dose of study 
treatment (GB1211 or placebo) and have at least 1 postdose biomarker assessment. 
All protocol deviations that occur during the study will be considered prior to database lock for 
their severity/impact and will be taken into consideration when subjects are assigned to analysis 
populations. Details of subject assignment to the analysis populations will be listed. 
The All Subjects Population will consist of any subjects who signed informed consent and had 
study assessments recorded on the database as per the protocol. 
10  
STATISTICAL METHODOLOGY 
10.1 General 
Data listings will be provided for the All Subjects Population. Summary statistics and statistical 
analyses will be performed for subjects included in the relevant analysis populations 
(Safety/PK/Biomarker).  
For continuous data, summary statistics will include the arithmetic mean, arithmetic standard 
deviation, median, minimum, maximum, and number. For log-normal data (eg, the PK 
parameters: areas under the concentration-time curve [AUCs] and maximum observed 
concentration [Cmax]), the geometric mean and geometric coefficient of variation (CV%) will 
also be presented. For categorical data, frequency counts and percentages will be presented. Data 
listings will be provided for all subjects up to the point of withdrawal, with any subjects 
excluded from the relevant population highlighted. For the calculation of summary statistics and 
statistical analysis, unrounded data will be used. 
Missing values will not be imputed. 
Data analysis will be performed using SAS® Version 9.4 or later. 
Analysis Data Model (ADaM) datasets will be prepared using Clinical Data Interchange 
Standards Consortium (CDISC) ADaM Version 2.1, and CDISC ADaM Implementation Guide 
Version 1.1. Pinnacle 21 Community Validator Version 2.2.0 will be utilised to ensure 
compliance with CDISC standards. 


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10.1.1 Definition of Baseline and Change from Baseline 
Baseline for each parameter is defined as the last value measured prior to dosing, including 
repeat (vital signs and electrocardiograms [ECGs]) and unscheduled (clinical laboratory 
parameters) readings (see Section 10.1.2 for definitions of repeat and unscheduled readings). For 
vital signs taken in triplicate, baseline will be the median of the last 3 values taken prior to 
dosing (pre-am dosing for multiple dose parts). For ECGs taken in triplicate, baseline will be the 
mean of the last 3 values taken prior to dosing (pre-am dosing for multiple dose parts). 
Mean change from baseline is the mean of all individual subjects’ change from baseline values. 
Each individual change from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoint. The individual subject’s change from baseline 
values will be used to calculate the mean change from baseline using a SAS procedure such as 
Proc Univariate. 
10.1.2 Repeat and Unscheduled Readings 
Repeat readings occur when the original vital signs or ECG result requires confirmation. Repeat 
readings are labelled as ‘Repeat’ in the listings and replace the original readings in all summaries 
and changes from baseline presentations and calculations. Prior to dosing, all readings taken in 
addition to the original reading are defined as predose repeats. Postdose repeat readings are 
defined as readings collected within 15 minutes of the actual time of the original reading. Where 
results are taken in triplicate and repeated, the last 3 readings are used in all subsequent 
calculations. 
With the exception of predose results described above, unscheduled readings for vital signs or 
ECGs are defined as readings collected >15 minutes from the actual time of the original reading. 
Where results are taken in triplicate, the original reading is defined as the first reading of the 
triplicate. All results not taken at a scheduled timepoint for other data types (eg, clinical 
laboratory parameters) are unscheduled. Unscheduled readings are labelled as ‘Unscheduled’ in 
the listings. Because unscheduled readings are not associated with any scheduled timepoint, they 
are excluded from all summaries (with the exception that they may be used as baseline, as stated 
in Section 10.1.1). 
10.2 Demographics and Subject Disposition 
The demographic variables age, sex, race, ethnicity, body weight, height, and body mass index 
will be summarised and listed. Subject disposition will be summarised and listed. 
10.3 Pharmacokinetic Assessment 
The following pharmacokinetic parameters will be determined where possible from the 
concentrations of GB1211 using non-compartmental methods performed using Phoenix 
WinNonlin (Certara, Inc., Version 8.1 or higher): 


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Part A (Single Dose) 
Plasma 
Parameter 
Definition 
AUC0-tlast 
Area under the plasma concentration-time curve from time zero to the time of the last 
quantifiable concentration 
AUC0-∞ 
Area under the plasma concentration-time curve from time zero to infinity 
%AUCextrap 
Area under the plasma concentration-time curve extrapolated from last quantifiable 
concentration to infinity as a percentage of total AUC 
Cmax 
Maximum observed plasma concentration  
Tmax 
Time of the maximum observed plasma concentration 
t1/2 
Apparent plasma terminal elimination half-life 
CL/F 
Apparent total plasma clearance 
Vz/F 
Apparent volume of distribution during the terminal elimination phase  
Urine 
Parameter 
Definition 
Ae 
Amount of drug excreted unchanged in urine (and cumulative Ae) 
fe 
Percentage of dose excreted unchanged in urine (and cumulative fe) 
CLR 
Renal clearance  
 
Parts B and C (Multiple Dose) 
Plasma 
Parameter 
Definition 
AUC0- 
Area under the plasma concentration-time curve over a dosing interval (τ = 12 hours) 
AUC0-∞ 
Area under the plasma concentration-time curve from time zero to infinity (Day 1 only) 
%AUCextrap 
Area under the plasma concentration-time curve extrapolated from last quantifiable 
concentration to infinity as a percentage of total AUC (Day 1 only) 
Cmax 
Maximum observed plasma concentration  
Cmin 
Minimum observed plasma concentration  
Tmax 
Time of the maximum observed plasma concentration 
t1/2 
Apparent plasma terminal elimination half-life 
CL/F 
Apparent total plasma clearance 
Vz/F 
Apparent volume of distribution during the terminal elimination phase  
RAAUC0-τ 
Observed accumulation ratio based on AUC0-τ   
RACmax 
Observed accumulation ratio based on C max 
In addition, dose and body weight normalised values (norm) for AUC0-tlast, AUC0-τ, AUC0-∞ and 
Cmax will be determined by dividing the original PK parameter by mg/kg.  


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Additional pharmacokinetic parameters may be determined where appropriate. 
Pharmacokinetic analysis will, where possible, be carried out using actual postdose times 
recorded in the raw data. If actual sampling times are missing, nominal times may be used.  
Concentrations are used as supplied by the analytical laboratory for PK analysis. The units of 
concentration and resulting PK parameters, with amount or concentration in the unit, will be 
presented as they are received from the analytical laboratory.  
Cmax, Cmin and Tmax will be obtained directly from the plasma concentration-time profiles.   
For multiple peaks, the highest postdose concentration will be reported as Cmax. In the case that 
multiple peaks are of equal magnitude, the earliest Tmax will be reported.  
AUC will be calculated using the linear trapezoidal method when concentrations are increasing and 
the logarithmic trapezoidal method when concentrations are decreasing (linear up/log down rule). 
The parameters based on observed Clast will be reported. 
The amount excreted in urine (Ae) for each urine collection interval will be calculated as the product 
of urine concentration and urine volume; Cumulative Ae will be calculated by summing the Ae 
values for each collection interval over the 0-48 h period. 
The percent of the dose excreted (fe) will be calculated for each urine collection interval (i) and 
cumulatively over 0-48 h according to the following formula: 
100
dose
)i(
Ae
)i(
fe


 
CLR will be calculated according to the following formula: 
h
x
h
x
h
x
R
AUC
Ae
CL




0
0
0
 
where 0-x h represents a common cumulative time interval (eg, 0 to 48 hours after dosing). 
10.3.1 Criteria for Handling Concentrations Below the Limit of Quantification in 
Pharmacokinetic Analysis 
 Concentration values that are below the level of quantification (BLQ) will be set to zero, 
with defined exceptions as follows; 
o Any embedded BLQ value (between 2 quantifiable concentrations) and BLQ 
values following the last quantifiable concentration in a profile will be set to 
missing for the purposes of PK analysis. 


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o If there are late positive concentration values following 2 BLQ concentration 
values in the apparent terminal phase, these values will be evaluated. If these 
values are considered to be anomalous, they will be set to missing. 
o If an entire concentration-time profile is BLQ, the profile will be excluded from 
the PK analysis. 
10.3.2 Criteria for the Calculation of an Apparent Terminal Elimination Half-Life 
Number of Data Points 
 At least three data points will be included in the regression analysis and preferably 
should not include Cmax. 
10.3.2.1 Goodness of Fit 
 When assessing terminal elimination phases, the R2 adjusted value will be used as a 
measure of the goodness of fit of the data points to the determined line.  
 An elimination half-life will only be calculated if the R2 adjusted value of the regression 
line is greater than or equal to 0.7. 
10.3.2.2 Period of Estimation 
 Time period used for the estimation of apparent plasma terminal elimination half-lives, 
where possible, will be over at least two half-lives.  
 Where an apparent plasma terminal elimination half-life is estimated over a time period 
of less than twice their resultant half-lifethe robustness of the value should be discussed in 
the study report. 
10.3.2.3 Calculation of AUC 
 The minimum requirement for the calculation of AUC will be the inclusion of at least 
three consecutive plasma concentrations above the lower limit of quantification 
(LLOQ), with at least one of these concentrations following Cmax. 
 For any partial AUC determination (i.e. AUC over a dosing interval), nominal time will 
generally be used for the end of the interval. Actual times for partial AUC intervals may 
be used at the discretion of the Pharmacokineticist.  
 AUC0-∞ values where the percentage extrapolation is less than 20% will be reported. 
AUC0-∞ values where the percentage extrapolation is greater than 20% may be excluded 
from descriptive statistics as discretion of pharmacokineticist 
10.3.2.4 Anomalous Values 
 If a value is considered to be anomalous due to being inconsistent with the expected 
pharmacokinetic profile, it may be appropriate to exclude this point from the 


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pharmacokinetic analysis. However, the exclusion of data must have strong justification 
and will be documented in the raw data and study report. 
10.4 Presentation of Pharmacokinetic Data 
10.4.1 Presentation Pharmacokinetic Concentration Data 
 
 The following rules will be applied if there are values that are BLQ or if there are 
missing values (e.g., no result [NR]) in a concentration data series to be summarised. 
o For the calculation of summary statistics, BLQ values will be set to zero. 
o If an embedded BLQ value is considered anomalous within the 
concentration-time profile, this value will be excluded from the summary 
statistics. 
o Where there is NR, these will be set to missing. 
o If there are less than three values in the data series, only the min, max and N will 
be presented. The other summary statistics will be denoted as not calculated (NC). 
BLQ is considered a value. 
o If all the values are BLQ, then the arithmetic mean, arithmetic SD, median, min 
and max will be presented as zero, and the geometric mean and geometric CV% 
will be denoted as NC. 
o If the value of the arithmetic mean or median is below the lower limit of 
quantification, these values will be presented as zero and the geometric mean and 
geometric CV% will be denoted as NC. 
 
10.4.2 Pharmacokinetic Statistical Methodology 
All investigational product plasma concentration data and derived PK parameters will be listed 
and summarised.  
Dose proportionality for Part A 
AUC0-∞, AUC0-tlast and Cmax will be assessed for dose proportionality on Day 1 for Part A (fasted 
doses only). Data will be analysed over 2 dose ranges: 50 mg to 400 mg (50 mg capsule 
formulation) and 5 to 50 mg (5 mg capsule formulation). Data will be presented graphically to 
display the PK of the treatments.  
To investigate dose proportionality3 a statistical analysis using the power model3 will be 
conducted. The power model will have the form: 


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Y = a*(dose)b 
where Y is the PK parameter, and a and b are the coefficient and exponent, respectively, of the 
power equation. 
By taking logarithms, the power model can be analysed using linear regression and has the form: 
ln(Y) = b*ln(dose) + error  
For dose proportionality the slope of the regression line (b) = 1 and for dose independence 
b = 0. 
An additional classification term for treatment will be added to the above model to assess 
departure from linearity. Linearity, and hence the power model, will be assumed appropriate if 
the treatment term is not significant at the 5% significance level and the diagnostic plots seem 
reasonable. The assessment of linearity may also be determined visually from plots by the 
pharmacokineticist. This assessment may over-ride the statistical assessment, where this occurs it 
will be detailed in the CSR. 
If the assumption of linearity is considered acceptable and the 95% confidence interval 
(CI) for b is close to unity, the relationship between dose and the PK parameter will be 
concluded to be dose proportional for the dose range studied. Caution should be used when 
interpreting results since this study is not based on power calculations.  
If the assumption of linearity is considered unacceptable then log-transformed4, dose-normalised 
PK parameters will be analysed using an analysis of variance5 (ANOVA) model. The model will 
include treatment as a fixed effect. 
Least squares (LS) mean for each dose level will be calculated. P-values for overall and pairwise 
treatment comparisons will be presented. 
Residual plots will be produced to assess the adequacy of the model. 
An example of the SAS code that will be used is as follows: 
/* Lack of fit test */ 
proc mixed data=<indata>; 
  class trtmnt; 
  model l_pk = logdose trtmnt / htype=1; 
  ods output tests1=tests; 
  run;  
 
 
 
 
 


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/* Exponent parameters */ 
proc mixed data=<indata>; 
  model l_pk = logdose / solution cl alpha=0.1; 
  ods output solutionf=estimate; 
 run; 
 
/* Dose normalised parameters */ 
proc mixed data=<indata>; 
  class trtmnt; 
  model l_pk = trtmnt; 
  lsmeans trtmnt / pdiff alpha=.05 cl; 
run; 
  
where l_pk is the log-transformed (base e) PK parameter. 
Statistical analysis will be used to determine pooled estimates (across the dose levels analysed) 
of the between-subject variability in the PK parameters. 
Dose proportionality for Part B 
AUC0- and Cmax will be assessed for dose proportionality on Day 10 for Part B. Data will be 
presented graphically to display the PK of the treatments.  
Log-transformed, dose-normalised PK parameters will be analysed using an ANOVA model. 
The model will include treatment as a fixed effect. 
Least squares (LS) mean for each dose level will be calculated. P-values for overall and pairwise 
treatment comparisons will be presented. 
Residual plots will be produced to assess the adequacy of the model. 
Statistical analysis will be used to determine pooled estimates (across the dose levels analysed) 
of the between-subject variability in the PK parameters. 
Food effect 
The PK parameters AUC0-∞, AUC0-tlast and Cmax will be log-transformed (base e) prior to analysis 
and will be analysed using a mixed model6.  The model will include treatment as a fixed effect 
and subject as a random effect. An example of the SAS code that will be used (assuming 
TRTMNT coding is 1= fed state, 2= fasted state) is as follows: 


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proc mixed data=xxx; 
 
class subject trtmnt; 
 
model l_pk = trtmnt / ddfm=kr; 
 
random intercept / subject=subject; 
 
estimate ‘Test - Ref’ trtmnt 1 -1 / cl alpha=0.1; 
 
lsmeans trtmnt; 
 
run; 
where l_pk is the log-transformed (base e) PK parameter.  
Least squares means will be calculated for the fed and fasted treatments. Mean differences 
between the fed and fasted treatments will be calculated.  The residual variance from the mixed 
model will be used to calculate 90 and 95% CIs for the difference between the fed and fasted 
treatments. These values will be back-transformed to give geometric least squares means, a point 
estimate and 90 and 95% CIs for the ratio of the fed treatment relative to the fasted treatment.  
Within-subject coefficients of variation (CVW) will be calculated for based on the log-normal 
distribution using the following formula: 
CVW(%) = [exp(mse) – 1]½ x 100 
where mse is the residual error from the mixed model. 
Residual plots will be produced to assess the adequacy of the model. 
10.5 Biomarker Assessment 
Exploratory biomarker data will be listed and summarised using descriptive statistics. No formal 
statistical analysis of exploratory biomarker data is planned. Changes from baseline will be listed 
and summarised. Boxplots of changes from baseline will also be presented by treatment. 
10.6 Safety and Tolerability Assessments 
10.6.1 Adverse Events 
A baseline sign and symptom is defined as an adverse event (AE) that starts after the subject has 
provided written informed consent and that resolves prior to the first dosing occasion, or an AE 
that starts prior to the first dosing occasion and does not increase in severity after dosing. A 
treatment-emergent AE (TEAE) is defined as an AE that occurs postdose or that is present 
predose and becomes more severe postdose.  
All AEs will be listed. The TEAEs will be summarised by treatment, severity, and relationship to 
the study drug. The frequency (the number of TEAEs, the number of subjects experiencing a 
TEAE, and the percentage of subjects experiencing a TEAE) of TEAEs will be summarised by 
treatment, and by Medical Dictionary for Regulatory Activities system organ class and preferred 
term. A frequency summary will be presented by day of onset across the multiple-dosing period.  
The summary and frequency TEAE tables will be presented for all causalities and for those 
TEAEs considered related to the study drug (those that have a relationship of possibly related or 


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related). Any severe or serious AEs will be tabulated. For any AEs that change severity ratings 
the AE will be included only once under the maximum severity rating in the summaries.    
For multiple dose parts onset times postdose are calculated from the last dose administered. 
10.6.2 Clinical Laboratory Parameters 
Serum biochemistry and haematology data will be summarised by treatment. Changes from 
baseline will be calculated. In addition, all serum biochemistry, haematology, and urinalysis data 
outside the clinical reference ranges will be listed by parameter and treatment. 
Values for any serum biochemistry, haematology, and urinalysis values outside the clinical 
reference ranges will be flagged on the individual subject data listings. 
10.6.3 Vital Signs 
Where vital signs are measured in triplicate (at approximately 2-minute intervals), the median 
value will be used in all subsequent calculations. Changes from baseline will be calculated.  
Vital signs values outside the clinical reference ranges will be flagged on the individual subject 
data listings. 
The vital signs data will be summarised by treatment, together with changes from baseline.  
Figures of mean vital signs and mean change from baseline profiles will be presented by 
treatment.  
10.6.4 Electrocardiogram 
The ECG data will be obtained directly from the 12-lead ECG traces. These data include the QT 
interval calculated using the Bazett correction (QTcB), the QT interval calculated using the 
Fridericia correction (QTcF), the PR and QT intervals, the QRS duration, and heart rate.  
Where ECGs are measured in triplicate (at approximately 2-minute intervals), the mean value 
will be used in all subsequent calculations. Changes from baseline will be calculated.    
Values for ECG parameters outside the clinical reference ranges will be flagged on the individual 
subject data listings. 
The ECG data will be summarised by treatment, together with changes from baseline. Figures of 
mean ECG data and mean change from baseline profiles will be presented by treatment.  
An outlier analysis will be performed including all individual postdose measurements (not the 
mean data), including all repeat and unscheduled readings. The frequency of subjects with a 
maximum increase from baseline in QTcB and QTcF intervals will be summarised for each 
treatment according to the following categories: >30, >60, and ≤30 ms. All incidences of >30 
and >60 ms will be flagged on the listing. In addition, the frequency of subjects with QTcB and 
QTcF postdose values will be summarised for each treatment, according to the following 


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categories: >450, >480, >500, and ≤450 ms. All incidences of >450, >480, and >500 ms will be 
flagged on the listing.  
10.6.5 Other Assessments 
All other safety assessments not detailed in this section will be listed but not summarised or 
statistically analysed. 
Medical history data will not be presented. 
10.6.6 Safety and Tolerability Statistical Methodology 
No inferential statistical analyses are planned. 
11  
INTERIM ANALYSES 
No interim statistical analyses are planned. 
12  
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES 
There were no changes from the protocol-specified statistical analyses. 
13  
DATA PRESENTATION 
13.1 Insufficient Data for Presentation 
Some of the TFLs may not have sufficient numbers of subjects or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the center of the table, 
such as, “No serious adverse events occurred for this study.” 
14  
REFERENCES 
1. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998. 
2. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995. 
3. Gough K, Hutchinson M, Keene O, Byrom B, Ellis S, Lacey L et al.  Assessment of dose 
proportionality:  Report from the Statisticians in the Pharmaceutical 
Industry/Pharmacokinetics UK joint working party.  Drug Information Journal 1995; 29: 
1039-1048. 
4. Keene ON.  The log transformation is special.  Statistics in Medicine 1995; 14: 811-819. 


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5. Snedecor GW, Cochran WG.  Statistical Methods (8th edition).  Iowa: Iowa State Univ Press, 
1989: 217-253. 
6. Brown H, Prescott R.  Applied Mixed Models in Medicine.  Wiley, 1999; Ch 7.