Clinical trial NCT02462967
Conditions: Hypertension, Portal
Keywords: Liver Cirrhosis
Sponsor: Galectin Therapeutics Inc.
Start date: 2015-06-01; Completion date: 2017-10-01
Enrollment: 162 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Study GT 026 is a Phase 2, multicenter, parallel group, North American, randomized, placebo controlled, double blind study. This study will enroll subjects with portal hypertension (HVPG greater than or equal to 6 mm Hg) who also have a liver biopsy with cirrhosis (Ishak stage 5 or 6), presumably due to NASH, excluding subjects with medium and large varices and those with decompensated cirrhosis.

Subjects with portal hypertension and cirrhosis will be randomly assigned (1:1:1 ratio) to receive 1 of 3 treatment assignments including placebo, GR MD 02 in a dose of 2 mg/kg lean body mass, or GR MD 02 in a dose of 8 mg/kg lean body mass administered every other week over a 52 week period for a total of 26 intravenous infusions. The primary endpoint analysis is the baseline adjusted change in HVPG at 1 year (53 55 weeks) in subjects treated with placebo as compared to subjects treated with GR MD 02 (2 mg/kg/week or 8 mg/kg/week).

An esophagogastroduodenoscopy (EGD) with evaluation for varices, HVPG, and liver biopsy will be performed before the first infusion and after the final 26th dose of the investigational medicinal product (IMP). Additionally, subjects will undergo a FibroScan (if available) prior to the first infusion, at Infusion Visit 13, and 14 to 28 days following final 26th infusion, an methacetin breath test (MBT), will be performed if available at screening, at Infusion Visit 13, and 14 to 28 days after the final infusion, and blood will be collected for assessment of biomarkers.

All subjects are to attend 2 postdose visits: the first will occur 14 to 28 days after the final dose administration and a second will occur 14 days following the first postdose visit.

Subjects will be offered enrollment into a subsequent separate study, an open label extension study, if there is adequate tolerability and no safety issues or signs of clinical progression that would recommend discontinuation.

Subjects who do not enroll in the open label extension study will be contacted via telephone every 6 months for 2 years and annually thereafter for a total of 4 years.

Detailed description:

Arms: arm 1: GR MD 02 in a dose of 2 mg/kg lean body mass administered every other week over a 52 week period for a total of 26 infusions arm 2: GR MD 02 in a dose of 8 mg/kg lean body mass administered every other week over a 52 week period for a total of 26 infusions arm 3: Phosphate buffered saline solution administered every other week over a 52 week period for a total of 26 infusions
Interventions: intervention 1: GR-MD-02 intervention 2: Placebo
Intervention descriptions: intervention 1: GR MD 02 (galactoarabino rhamnogalacturonate), a complex carbohydrate drug that binds to galectin 3 intervention 2: Placebo for GR-MD-02

Protocol documents:
Prot_000.pdf: 
 
CLINICAL STUDY PROTOCOL 
IND Number 115459 
 
A Multicenter, Randomized, Placebo-Controlled, Double-Blind, 
Parallel-Group, Phase 2 Clinical Trial to Evaluate the Safety and Efficacy 
of GR-MD-02 for the Treatment of Liver Fibrosis and Resultant Portal 
Hypertension in Patients with NASH Cirrhosis 
The NASH-CX Trial 
 
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GT-026 
Sponsor: 
Galectin Therapeutics Inc 
4960 Peachtree Industrial Blvd, Suite 240 
Norcross, GA 30071 
Sponsor Contact: 
Peter G. Traber, MD 
President, CEO, CMO 
Telephone: 713-540-9776 
PPD Project Manager: 
Vivian Sadler 
Associate Director, Global Project Management 
General Medicine 
929 N Front St 
Wilmington, NC 28401 
PPD Medical Monitor: 
Michael Barri, MD  
929 N Front St 
Wilmington, NC 28401 
SAE Hotline: 1-800-201-8725 
Version of Protocol: 
GT-026 Original 
Date of Protocol:  
20 February 2015 
 
 
 
CONFIDENTIAL 
All financial and nonfinancial support for this study will be provided by Galectin 
Therapeutics Inc. The concepts and information contained in this document or generated 
during the study are considered proprietary and may not be disclosed in whole or in part 
without the expressed, written consent of Galectin Therapeutics Inc. 
The study will be conducted according to the International Conference on Harmonisation 
harmonised tripartite guideline E6(R1): Good Clinical Practice. 
 
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Galectin Therapeutics Inc. 
GR-MD-02 (galactoarabino-rhamnogalacturnate) 
Protocol: GT-026 Original 
20 February 2015 
 
Page 6 
Table of Contents 
Table of Contents ....................................................................................................................... 6 
List of Tables ............................................................................................................................ 10 
List of Figures .......................................................................................................................... 11 
Protocol Synopsis..................................................................................................................... 12 
List of Abbreviations................................................................................................................ 21 
1 
Introduction ...................................................................................................................... 23 
2 
Study Objectives ............................................................................................................... 25 
2.1 
Primary Objective ................................................................................................... 25 
2.2 
Secondary Objectives.............................................................................................. 25 
2.3 
Exploratory Objectives ........................................................................................... 27 
2.4 
Safety Objectives .................................................................................................... 27 
2.5 
Pharmacokinetic Objective ..................................................................................... 27 
3 
Investigational Plan .......................................................................................................... 28 
3.1 
Study Design ........................................................................................................... 28 
3.1.1 
Rationale of Study Design ....................................................................... 32 
4 
Subject Selection and Withdrawal Criteria ...................................................................... 34 
4.1 
Selection of Study Population ................................................................................. 34 
4.1.1 
Inclusion Criteria ..................................................................................... 34 
4.1.2 
Exclusion Criteria .................................................................................... 35 
4.2 
Withdrawal of Subjects from the Study .................................................................. 39 
4.2.1 
Reasons for Withdrawal/Discontinuation ................................................ 39 
4.2.2 
Handling of Withdrawals ......................................................................... 40 
4.2.3 
Replacements ........................................................................................... 40 
5 
Study Treatments .............................................................................................................. 41 
5.1 
Method of Assigning Subjects to Treatment Groups .............................................. 41 
5.2 
Treatments Administered ........................................................................................ 41 
5.3 
Identity of Investigational Medicinal Product ........................................................ 42 
5.4 
Management of Clinical Supplies ........................................................................... 43 
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Galectin Therapeutics Inc. 
GR-MD-02 (galactoarabino-rhamnogalacturnate) 
Protocol: GT-026 Original 
20 February 2015 
 
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5.4.1 
Investigational Medicinal Product Packaging and Storage ..................... 43 
5.4.2 
Test Article Accountability ...................................................................... 43 
5.4.3 
Other Supplies ......................................................................................... 44 
5.5 
Overdose Management ........................................................................................... 44 
5.5.1 
Treatment of Overdose ............................................................................ 44 
5.5.2 
Medication Errors .................................................................................... 44 
5.5.3 
Treatment of Medication Errors ............................................................... 45 
5.6 
Misuse for Illegal Purposes ..................................................................................... 45 
5.7 
Blinding .................................................................................................................. 45 
5.7.1 
Breaking the Blind ................................................................................... 45 
5.8 
Treatment Compliance ............................................................................................ 46 
5.9 
Prior and Concomitant Therapy .............................................................................. 46 
5.10 Prohibited Medications or Therapies ...................................................................... 46 
6 
Study Assessments and Procedures .................................................................................. 48 
6.1 
Study Visits ............................................................................................................. 48 
6.1.1 
Prescreening Visit (Week –9) ................................................................... 48 
6.1.2 
Screening Visit (Week -8 to Day 0) ......................................................... 49 
6.1.3 
Treatment Phase ....................................................................................... 51 
6.1.3.1 
Randomization ......................................................................................... 51 
6.1.3.2 
Two Weeks Prior to Infusion Visit 1 ........................................................ 51 
6.1.3.3 
Infusion Visit 1 (Week 1) ......................................................................... 51 
6.1.3.4 
Infusion Visits 2, 3, 4, 5, and 6 (Weeks 3, 5, 7, 9, and 11 ± 3 Days, 
respectively) ............................................................................................. 52 
6.1.3.5 
Infusion Visit 7 (Week 13 ± 3 Days) ....................................................... 53 
6.1.3.6 
Infusion Visits 8, 9, 10, 11, and 12 (Weeks 15, 17, 19, 21, and 23 
± 3 Days) .................................................................................................. 54 
6.1.3.7 
Infusion Visit 13 (Week 25 ± 3 Days) ..................................................... 54 
6.1.3.8 
Infusion Visits 14, 15, 16, 17, 18, and 19 (Weeks 27, 29, 31, 33, 35, and 
37 ± 3 Days) ............................................................................................. 56 
6.1.3.9 
Infusion Visit 20 (Week 39 ± 3 Days) ..................................................... 56 
6.1.3.10 Infusion Visit 21 (Week 41 ± 3 Days) ..................................................... 57 
6.1.3.11 Infusion Visits 22, 23, 24, and 25 (Weeks 43, 45, 47, and 49 ± 3 Days) . 58 
6.1.3.12 Infusion Visit 26 (Week 51 ± 3 Days) ..................................................... 58 
6.1.4 
Follow-up (14-28 Days After Final Dose; Weeks 53-55 ± 3 Days) ........ 59 
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Galectin Therapeutics Inc. 
GR-MD-02 (galactoarabino-rhamnogalacturnate) 
Protocol: GT-026 Original 
20 February 2015 
 
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6.1.5 
Follow-up/Early Termination (Week 57 ± 3 Days) ................................. 60 
6.1.5.1 
Open-Label Safety Extension Study ........................................................ 61 
6.1.6 
End-of-Study Telephone Contact ............................................................. 61 
6.2 
Efficacy Assessments .............................................................................................. 61 
6.2.1 
HVPG Measurement ................................................................................ 61 
6.2.2 
Liver Biopsy ............................................................................................ 62 
6.2.3 
FibroScan ................................................................................................. 62 
6.2.4 
13C-methacetin Breath Test ...................................................................... 62 
6.2.5 
Child-Turcotte-Pugh Score ...................................................................... 64 
6.2.6 
MELD Score ............................................................................................ 65 
6.2.7 
EGD Evaluation ....................................................................................... 65 
6.3 
Exploratory Assessments ........................................................................................ 66 
6.3.1 
Chronic Liver Disease Questionnaire ...................................................... 66 
6.3.2 
Biomarkers ............................................................................................... 66 
6.3.2.1 
Enhanced Liver Fibrosis Test ................................................................... 66 
6.3.2.2 
FibroTest/FibroSure ................................................................................. 66 
6.3.2.3 
Galectin-3 ................................................................................................ 67 
6.3.3 
Plasma and Serum Samples ..................................................................... 67 
6.4 
Safety Assessments ................................................................................................. 67 
6.4.1 
Vital Sign Measurements ......................................................................... 67 
6.4.2 
Physical Examination .............................................................................. 67 
6.4.3 
Electrocardiogram .................................................................................... 68 
6.4.4 
Chest Radiograph ..................................................................................... 68 
6.4.5 
Adverse Events ........................................................................................ 68 
6.4.5.1 
Definitions of Adverse Events ................................................................. 68 
6.4.5.2 
Eliciting and Documenting Adverse Events ............................................ 69 
6.4.5.3 
Reporting Adverse Events ....................................................................... 69 
6.4.5.4 
Assessment of Severity ............................................................................ 70 
6.4.5.5 
Assessment of Causality .......................................................................... 70 
6.4.5.6 
Exceptions ................................................................................................ 71 
6.4.5.7 
Follow-Up of Subjects Reporting Adverse Events .................................. 71 
6.4.6 
Pregnancy ................................................................................................ 72 
6.4.7 
Laboratory Analyses ................................................................................ 72 
6.4.8 
Hematology .............................................................................................. 73 
6.4.9 
Blood Chemistry ...................................................................................... 73 
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Galectin Therapeutics Inc. 
GR-MD-02 (galactoarabino-rhamnogalacturnate) 
Protocol: GT-026 Original 
20 February 2015 
 
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6.4.10 
Urinalysis ................................................................................................. 73 
6.4.11 
Alcohol TLFB .......................................................................................... 73 
6.5 
Pharmacokinetic Assessments ................................................................................ 74 
6.6 
Sample Collections ................................................................................................. 74 
7 
Statistical and Analytical Plan .......................................................................................... 75 
7.1 
Primary Efficacy Endpoint ..................................................................................... 75 
7.2 
Secondary Efficacy Endpoints ................................................................................ 75 
7.3 
Exploratory Endpoints ............................................................................................ 76 
7.4 
Safety Endpoints ..................................................................................................... 76 
7.5 
Pharmacokinetic Endpoint ...................................................................................... 77 
7.6 
Sample Size Calculations ........................................................................................ 77 
7.7 
Analysis Sets ........................................................................................................... 79 
7.8 
Description of Subgroups to Be Analyzed .............................................................. 80 
7.9 
Statistical Analysis Methodology ........................................................................... 80 
7.9.1 
Analysis of Primary Efficacy Endpoint ................................................... 81 
7.9.2 
Analysis of Key Secondary Efficacy Endpoints ...................................... 81 
7.9.3 
Analysis of the Exploratory Efficacy Endpoint ....................................... 82 
7.9.4 
Safety Analyses ........................................................................................ 82 
7.9.5 
Pharmacokinetic Analyses ....................................................................... 83 
7.9.6 
Other Analyses ......................................................................................... 84 
7.9.7 
Interim Analyses ...................................................................................... 85 
7.10 Data Quality Assurance........................................................................................... 86 
7.10.1 
Data Management .................................................................................... 86 
8 
Ethics ................................................................................................................................ 88 
8.1 
Independent Ethics Committee or Institutional Review Board .............................. 88 
8.2 
Ethical Conduct of the Study .................................................................................. 88 
8.3 
Subject Information and Consent ........................................................................... 88 
9 
Investigator’s Obligations ................................................................................................ 90 
9.1 
Confidentiality ........................................................................................................ 90 
9.2 
Financial Disclosure and Obligations ..................................................................... 90 
9.3 
Investigator Documentation .................................................................................... 91 
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Galectin Therapeutics Inc. 
GR-MD-02 (galactoarabino-rhamnogalacturnate) 
Protocol: GT-026 Original 
20 February 2015 
 
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9.4 
Study Conduct ......................................................................................................... 91 
9.5 
Adherence to Protocol ............................................................................................ 91 
9.6 
Adverse Events and Study Report Requirements ................................................... 92 
9.7 
Investigator’s Final Report ..................................................................................... 92 
9.8 
Records Retention ................................................................................................... 92 
9.9 
Publications ............................................................................................................. 92 
10 Study Management ........................................................................................................... 93 
10.1 Monitoring .............................................................................................................. 93 
10.1.1 
Independent Data Safety Monitoring Board ............................................ 93 
10.1.2 
Monitoring of the Study ........................................................................... 94 
10.1.3 
Inspection of Records .............................................................................. 94 
10.2 Management of Protocol Amendments and Deviations.......................................... 94 
10.2.1 
Modification of the Protocol .................................................................... 94 
10.2.2 
Protocol Deviations ................................................................................. 95 
10.3 Study Termination ................................................................................................... 95 
10.4 Final Report ............................................................................................................ 95 
11 Reference List................................................................................................................... 97 
12 Appendices ..................................................................................................................... 100 
12.1 Appendix: Schedule of Events .............................................................................. 100 
12.2 Appendix: The AUDIT Questionnaire .................................................................. 108 
12.3 Appendix: The Chronic Liver Disease Questionnaire .......................................... 109 
12.4 Alcohol TLFB ....................................................................................................... 110 
12.4.1 
Alcohol TLFB Calendar 2015 ............................................................... 110 
12.4.2 
Alcohol TLFB Calendar 2016 ................................................................ 111 
12.4.3 
Alcohol TLFB Calendar 2017 ............................................................... 112 
12.4.4 
Instructions for Completing the Alcohol TLFB ..................................... 113 
 
List of Tables 
Table 5-1 
Composition of GR-MD-02 Concentrate ........................................................ 41 
Table 6-1 
Child-Turcotte-Pugh Scoring System ............................................................. 64 
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Galectin Therapeutics Inc. 
GR-MD-02 (galactoarabino-rhamnogalacturnate) 
Protocol: GT-026 Original 
20 February 2015 
 
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Table 6-2 
Child-Turcotte-Pugh Classification ................................................................ 64 
Table 7-1 
HVPG (mm Hg) at Baseline and 12 Months for Subjects in the Placebo Group 
in the Timolol Clinical Study .......................................................................... 79 
Table 7-2 
Absolute Change in HVPG (mm Hg) at 12 Months for Subjects in the Placebo 
Group in the Timolol Clinical Study ............................................................... 79 
Table 12-1 
Schedule of Events - Prescreening and Screening ........................................ 101 
Table 12-2 
Schedule of Events - Randomization, Treatment Phase, and Follow-up/Early 
Termination ................................................................................................... 104 
Table 12-3 
Schedule of Events - End-of-Study Telephone Contacta .............................. 107 
 
List of Figures 
Figure 3-1 
Study Design GT-026 ...................................................................................... 29 
Figure 3-2 
Prescreening and Screening Flow Chart GT-026 ............................................ 30 
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Galectin Therapeutics Inc. 
GR-MD-02 (galactoarabino-rhamnogalacturnate) 
Protocol: GT-026 Original 
20 February 2015 
 
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Protocol Synopsis 
Protocol Number: 
GT-026 
Title: 
A Multicenter, Randomized, Placebo-Controlled, 
Double-Blind, Parallel-Group, Phase 2 Clinical Trial to 
Evaluate the Safety and Efficacy of GR-MD-02 for the 
Treatment of Liver Fibrosis and Resultant Portal 
Hypertension in Patients with NASH Cirrhosis. The 
NASH-CX Trial 
Sponsor: 
Galectin Therapeutics Inc 
4960 Peachtree Industrial Blvd, Suite 240 
Norcross, GA 30071 
Study Phase: 
Phase 2 
Study Centers: 
Approximately 45 to 60 study centers in the United States 
and Canada 
Indication: 
Portal hypertension with cirrhosis or advanced bridging 
fibrosis due to nonalcoholic steatohepatitis (NASH) 
Rationale: 
Nonalcoholic steatohepatitis is a chronic inflammatory 
disease of the liver characterized by progressive fibrosis that 
eventually leads to cirrhosis in a subset of subjects; the 
complications of portal hypertension due to liver fibrosis can 
result in death or liver transplantation. There are currently no 
medical therapies approved for NASH or for portal 
hypertension due to liver fibrosis, and this therapeutic area 
represents an area of significant unmet medical need. 
Galectin-3, a protein that binds to galactose-containing 
oligosaccharides, has been shown to be critical in the 
pathophysiology of NASH and liver fibrosis. GR-MD-02 
galactoarabino-rhamnogalacturnate, a complex carbohydrate 
drug that binds to galectin-3, has shown robust efficacy in 
preclinical models of NASH and liver fibrosis and was safe 
and well tolerated in Phase 1 studies. Therefore, the overall 
objective of this clinical study is to establish the safety and 
efficacy of GR-MD-02 as compared to placebo in the 
reduction of portal pressure as a surrogate for a reduction in 
fibrosis in subjects with compensated cirrhosis due to NASH. 
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Galectin Therapeutics Inc. 
GR-MD-02 (galactoarabino-rhamnogalacturnate) 
Protocol: GT-026 Original 
20 February 2015 
 
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Objectives: 
The primary objective is to evaluate the efficacy of 
GR-MD-02 on reducing hepatic venous pressure gradient 
(HVPG) as a measure of portal pressure compared to placebo 
at 1 year of treatment.  
Secondary objectives are to evaluate differences in relevant 
assessments of fibrosis and cirrhosis between 
GR-MD-02-treated and placebo-treated subjects. The 
secondary objectives are to evaluate:  
• 
The effect of GR-MD-02 on change in the collagen 
proportional area at 1 year compared to placebo as 
determined by digital morphometric analysis of liver 
biopsies  
• 
The effect of GR-MD-02 on liver stiffness as determined 
by FibroScan® score prior to the first infusion, at 
Infusion Visit 13, and 14-28 days after final infusion as 
compared to placebo 
• 
The effect of GR-MD-02 on the metabolic capacity of 
the liver as determined by cPDR30 (percentage dose 
recovery) value of the 13C-methacetin breath test (MBT) 
(for those study centers where the MBT is available) at 
screening, at Infusion Visit 13, and 14-28 days after final 
infusion as compared to placebo 
• 
The effect of GR-MD-02 on progression of cirrhosis at 
1 year as compared to placebo, defined as the 
development of any of the following:  
o 
esophageal variceal hemorrhage or portal 
hypertensive gastropathy hemorrhage (confirmed by 
endoscopy or interventional radiology) 
o 
clinically apparent ascites  
o 
spontaneous bacterial peritonitis 
o 
overt hepatic encephalopathy (defined by the 
clinical judgment of the principal investigator, but 
should include the presence of lethargy, 
disorientation, inappropriate behavior, and the 
presence of asterixis) 
o 
an increase in Child-Turcotte-Pugh score ≥2  
o 
newly diagnosed varices in a subject without prior 
varices  
o 
progression from small to medium or large varices  
 
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Galectin Therapeutics Inc. 
GR-MD-02 (galactoarabino-rhamnogalacturnate) 
Protocol: GT-026 Original 
20 February 2015 
 
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o reaching model for end-stage liver disease score ≥15 
as measured on 2 consecutive occasions  
o listing for a liver transplant or the performance of a 
liver transplant 
o liver-related mortality 
 
Exploratory objectives are to evaluate: 
• 
Differences in health-related quality of life using the 
subject-completed chronic liver disease questionnaire 
following administration of GR-MD-02 or placebo at 
1 year.  
• 
Baseline-adjusted change in FibroTest® (FibroSure®) and 
enhanced liver fibrosis score at Infusion Visits 7, 13, 20, 
and 14-28 days after final infusion 
• 
Changes in liver biopsy staining for alpha smooth muscle 
actin and galectin-3 in subjects treated with GR-MD-02 
or placebo at 1 year 
Safety objectives are to assess the safety and tolerability of 
GR-MD-02 versus placebo at 1 year. 
Pharmacokinetic Objectives are to: 
• 
Evaluate systemic exposure following multiple doses of 
GR-MD-02 in subjects with portal hypertension due to 
NASH cirrhosis. 
• 
Explore the population pharmacokinetics of GR-MD-02 
in subjects with NASH with portal hypertension and 
cirrhosis or advanced bridging fibrosis. 
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Galectin Therapeutics Inc. 
GR-MD-02 (galactoarabino-rhamnogalacturnate) 
Protocol: GT-026 Original 
20 February 2015 
 
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Subject Population: 
Subjects will be entered into the study and randomly assigned 
if they have both an HVPG measurement greater than or 
equal to 6 mm Hg and a liver biopsy with advanced bridging 
fibrosis (Ishak stage 4) or cirrhosis (Ishak stage 5 or 6), 
presumably due to NASH. A liver biopsy diagnosis of 
cirrhosis or advanced bridging fibrosis, presumably due to 
NASH will include the following 2 categories: 1) cirrhosis or 
advanced bridging fibrosis with a definitive pathological 
diagnosis of NASH (presence of fat, ballooning degeneration, 
and inflammation) or 2) cirrhosis or advanced bridging 
fibrosis wherein the subject has greater than 5 years of 
obesity and/or diabetes with negative viral hepatitis markers 
and a biopsy showing cirrhosis with any amount of fat. 
Additional inclusion criteria will include age at least 18 years 
and less than or equal to 75 years old at the time of screening, 
ability to provide written informed consent, and subjects of 
nonchildbearing potential or willing to use acceptable 
contraception throughout the duration of the treatment period 
and for 90 days after their last dose of study treatment. 
 
Exclusion criteria will include current or past history of 
significant alcohol consumption defined as more than 
20 grams per day in females and more than 30 grams per day 
in males for a period of more than 3 consecutive months 
within 1 year prior to screening, history of recent weight 
reduction surgery, presence of a transjugular intrahepatic 
porto-systemic shunt, history of hepatic decompensation, 
evidence of other forms of liver disease, laboratory values 
indicative of advanced cirrhosis (Child-Turcotte-Pugh 
Class B or C or model for end-stage liver disease greater than 
or equal to 15), various concomitant illnesses (human 
immunodeficiency virus-positive subjects, recent major 
surgery [within 8 weeks of randomization], uncontrolled 
heart disease, concurrent infection or fever of unknown 
origin, illicit drug use, history of malignancy), participation 
in an investigational new drug study within 30 days prior to 
randomization (including follow-up visits) or at any time 
during the current study, clinically significant medical or 
psychiatric condition considered a high risk for participation 
in a study, failure to give informed consent, and known 
allergies to the investigational medicinal product (IMP) or 
any of its excipients. 
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Galectin Therapeutics Inc. 
GR-MD-02 (galactoarabino-rhamnogalacturnate) 
Protocol: GT-026 Original 
20 February 2015 
 
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Study Design: 
Study GT-026 is a Phase 2, multicenter, parallel-group, North 
American, randomized, placebo-controlled, double-blind 
study. This study will enroll subjects with portal hypertension 
(HVPG greater than or equal to 6 mm Hg) who also have a 
liver biopsy showing advanced fibrosis (Ishak stage 4) or 
cirrhosis (Ishak stage 5 or 6), presumably due to NASH, 
excluding subjects with medium and large varices and those 
with decompensated cirrhosis. All subjects are required to 
have signed institutional review board- or independent ethics 
committee-approved informed consent form prior to 
undergoing any study specific procedures.  
 
Subjects with portal hypertension and advanced bridging 
fibrosis or cirrhosis will be randomly assigned (1:1:1) to 
receive 1 of 3 treatment assignments including placebo, 
GR-MD-02 in a dose of 2 mg/kg lean body mass, or 
GR-MD-02 in a dose of 8 mg/kg lean body mass 
administered every other week over a 52-week period for a 
total of 26 intravenous infusions. The primary endpoint 
analysis is the baseline-adjusted change in HVPG at 1 year 
(53-55 weeks) in subjects treated with placebo as compared 
to subjects treated with GR-MD-02 (2 mg/kg/week or 
8 mg/kg/week). 
 
An esophagogastroduodenoscopy (EGD) with evaluation for 
varices, HVPG, and liver biopsy will be performed before the 
first infusion and after the final 26th dose of IMP. 
Additionally, prior to the first infusion, at Infusion Visit 13, 
and 14 to 28 days following final 26th infusion, subjects will 
undergo a FibroScan, an MBT (if available), and blood will 
be collected for assessment of biomarkers. 
All subjects are to attend 2 postdose visits: the first will occur 
14 to 28 days after the final dose administration and a second 
will occur 14 days following the first postdose visit. 
Subjects will be offered enrollment into a subsequent 
separate study, an open-label extension study, if there is 
adequate tolerability and no safety issues or signs of clinical 
progression that would recommend discontinuation. 
Subjects who do not enroll in the open-label extension study 
will be contacted via telephone every 6 months for 2 years 
and annually thereafter for a total of 4 years. 
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Galectin Therapeutics Inc. 
GR-MD-02 (galactoarabino-rhamnogalacturnate) 
Protocol: GT-026 Original 
20 February 2015 
 
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Estimated Study 
Duration: 
Subjects will remain on study therapy for a total of 52 weeks 
unless intolerable side effects develop or the subject is 
withdrawn from study participation. In addition, subjects will 
have a 1-week prescreening period, up to an 8-week 
screening period, and up to a 6-week postdosing period 
(2 postdose visits) for a total duration of up to 67 weeks. 
Efficacy Assessments: 
Efficacy assessments will include HVPG measurement, liver 
biopsy, EGD evaluation, FibroScan, a MBT (if available), 
progression of cirrhosis, chronic liver disease questionnaire, 
and serum biomarker tests. 
Pharmacokinetic or 
Pharmacodynamic 
Assessments: 
Plasma levels of GR-MD-02 will be assessed in all subjects. 
Systemic drug exposure will be assessed at Infusion Visits 1, 
2, 3, 4, 7, 10, 13, and 26 during the study. Population 
pharmacokinetics of GR-MD-02 in subjects with NASH with 
portal hypertension and cirrhosis or advanced bridging 
fibrosis will be evaluated. 
Safety Assessments: 
Safety assessments will include incidence of adverse events 
(AEs) during study treatment, emergent physical examination 
abnormalities, emergent vital sign measurements and 
electrocardiogram abnormalities, and laboratory parameter 
abnormalities. 
A data safety monitoring board (DSMB) will be established 
that includes a panel of at least 3 independent medical 
experts and an unblinded biostatistician. An official charter 
will be established. The primary role of the DSMB will be to 
periodically monitor the safety of the clinical study. The 
DSMB will meet at several predetermined times during the 
study and at any other times when it is determined by the 
study monitors or principal investigators that such a review is 
warranted. An unblinded monitoring team will also be added 
to the study. 
All subjects receiving any part of at least 1 infusion of study 
treatment will be evaluated for safety. The safety analyses 
will include evaluation of the incidence of 
treatment-emergent AEs (TEAEs), grade 3 or greater AEs, 
serious AEs (SAEs), and TEAEs leading to discontinuation 
of study treatment using the Common Terminology Criteria 
for Adverse Events Version 4.0 or higher. 
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Galectin Therapeutics Inc. 
GR-MD-02 (galactoarabino-rhamnogalacturnate) 
Protocol: GT-026 Original 
20 February 2015 
 
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Study Drug, Dosage, 
and Route of 
Administration: 
Subjects in the GR-MD-02 treatment groups will be 
randomly assigned to receive either 2 mg/kg lean body 
weight (up to a maximum of 200 mg total) or 8 mg/kg lean 
body weight (up to a maximum of 800 mg total). The IMP 
will be diluted in 100 mL of normal saline and infused 
intravenously via a peripheral vein over a period of 
approximately 60 minutes. The IMP will be administered 
every other week for 52 weeks for a total of 26 doses. No 
dose modification for GR-MD-02 is allowed. Subjects in the 
placebo arm will receive placebo diluted in normal saline 
administered in the same fashion. Active drug and placebo 
will be blinded (by an unblinded pharmacist) by using 
amber-colored intravenous bag covers and amber-colored 
tubing and sealed with tamper-evident tape. 
Sample Size: 
A total of 52 subjects will be randomly assigned into each of 
3 parallel treatment groups in a 1:1:1 ratio for a total of 
156 subjects in the study. 
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Statistical Methods: 
All efficacy and safety parameters, subject demographics as 
well as medical and social history, and other baseline subject 
characteristics (including prior NASH treatments and 
associated response/side effects) will be summarized by 
treatment group for the 3 individual treatment groups, for 
both GR-MD-02 treatment groups combined versus the 
placebo group, for the full-analysis (intent-to-treat), modified 
intent-to-treat, and per-protocol sets. 
Baseline is defined as the last assessment prior to infusion 
with IMP (ie, the predosing assessment present in the 
database that is most proximate to the time of IMP 
administration). Measurements that are obtained after the 
first dose of study treatment will be considered postbaseline 
values. Change from baseline is defined as the postbaseline 
value minus the baseline value. 
The primary efficacy endpoint analysis will be carried out 
using an analysis of covariance model, with the HVPG 
change from baseline at Weeks 53 to 55 as the dependent 
variable. The model will include treatment group at 
randomization and the baseline HVPG as a covariate.  
Methods for dealing with missing data including dates, 
efficacy and safety results will be specified in the statistical 
analysis plan. 
Adverse events will be classified using the Medical 
Dictionary for Regulatory Activities (MedDRA) 
(Version 17.1), and summarized by MedDRA system organ 
class and preferred term. Events from the time of the subject 
signing informed consent must be reported. Adverse events 
prior to exposure to IMP are considered pretreatment AEs 
and will be provided in a listing separate from the listing for 
TEAEs.  
 
Only TEAEs, and not pretreatment AEs, will be used for 
tabular summaries and be graded according to the protocol 
guidelines. Each AE will be assessed for relatedness to the 
IMP agent per se and for the rest of the infusion procedure. 
The duration of all TEAEs in days, from start to end, will be 
summarized as a numeric variable.  
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All prior treatments for liver cirrhosis and NASH will be 
recorded in the electronic case report form. All other 
concomitant medications taken from 30 days prior to 
screening and throughout the entire duration of the subject’s 
participation in the study will be collected in the electronic 
case report form. Concomitant medications are defined as 
medications taken any time after the start of exposure to IMP. 
Prior medications are defined as nonstudy medications 
discontinued prior to the start of exposure to IMP. All other 
concomitant medications taken from 30 days prior to 
Screening and throughout the entire duration of the subject’s 
time on study will be collected in the electronic case report 
form. Concomitant medications are defined as medications 
taken any time after the start of exposure to IMP. Prior 
medications are defined as medications discontinued prior to 
the start of exposure to IMP. The prior and concomitant 
medications taken during the study will be summarized using 
number of subjects (n) and percentage (%) by individual 
treatment group, for both GR-MD-02 groups combined, for 
the placebo group, and overall (all subjects). All prior and 
concomitant medications will be coded using the WHO Drug 
Dictionary (Version 1 Sep 2014) and further coded against 
Anatomic Therapeutic Chemical classification.  
Laboratory and vital sign measurement will be evaluated 
over time using descriptive statistics. Shift analyses of 
relevant clinical laboratory parameters will be produced 
showing shifts from baseline across low, normal, and high 
categories presented by time point. 
Date of Protocol: 
20 February 2015 
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Galectin Therapeutics Inc. 
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Protocol: GT-026 Original 
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List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
AUDIT 
Alcohol Use Disorders Identification Test 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
CLDQ 
chronic liver disease questionnaire 
Cmax 
observed maximum plasma or serum concentration after administration 
CPA 
collagen proportional area 
cPDR30 
percentage dose recovery 
CYP3A4 
cytochrome P450 3A4 
DOB 
delta over baseline 
DSMB 
data safety monitoring board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EGD 
esophagogastroduodenoscopy 
ELF 
enhanced liver fibrosis 
FAS 
full-analysis set 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
GR-MD-02 
galactoarabino-rhamnogalacturnate 
HIV 
human immunodeficiency virus 
HVPG 
hepatic venous pressure gradient 
ICF 
informed consent form 
ICH E6(R1) 
International Conference on Harmonisation harmonised tripartite 
guideline 
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
INR 
international normalized ratio 
IRB 
institutional review board 
IV 
intravenous 
IWRS 
interactive web response system 
kPa 
kiloPascals 
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Protocol: GT-026 Original 
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Abbreviation 
Definition 
LBM 
lean body mass 
MBT 
13C-methacetin breath test 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
model for end-stage liver disease 
NAFLD 
nonalcoholic fatty liver disease 
NASH 
nonalcoholic steatohepatitis 
OLES 
open-label extension study 
PK 
pharmacokinetic 
PDR 
percentage dose recovery rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
TBW 
total body weight 
TEAE 
treatment-emergent adverse event 
TLFB 
timeline followback 
Tn 
time point 
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Galectin Therapeutics Inc. 
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Protocol: GT-026 Original 
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1 
Introduction 
Nonalcoholic fatty liver disease (NAFLD), or fatty liver, and nonalcoholic steatohepatitis 
(NASH) are common liver disorders in the United States. The major feature in NAFLD is fat 
accumulation in hepatocytes with minimal inflammation. It is estimated that the worldwide 
prevalence of NAFLD ranges from 6.3% to 33% with a median of 20% in the general 
population (Chalasani 2012), but a recent study in asymptomatic middle-aged adults in the 
US suggests that it may be as high as 46% (Williams 2011). A subset of individuals with 
NAFLD are found to have NASH, which is characterized by excessive fat accumulation in 
hepatocytes (steatosis) with the addition of inflammatory cell infiltrates, evidence of damage 
to hepatocytes (ballooning degeneration), and the deposition of fibrous tissue. It is estimated 
that 3% to 5% of Americans are affected by NASH (Chalasani 2005), with as many as 12.2% 
in asymptomatic adults (Williams 2011). While the prevalence of cirrhosis in NASH is not 
clearly defined, as many as one-third of NASH subjects progress to advanced fibrosis 
(Caldwell 2010). The only therapy available to these advanced subjects is liver 
transplantation. Currently the percentage of liver transplantations performed in the US for 
NASH is between 10% and 15%, but the numbers are increasing and it has been suggested 
that it may become the leading cause for liver transplantation over the next 20 years 
(Rinella 2011).  
The galectin-3 protein has recently been implicated in the pathogenesis of NASH. Galectins 
are a family of proteins, containing 15 members (11 identified in humans), which have the 
property of binding avidly to galactose containing oligosaccharides associated with 
glycoproteins (Di 2011). GR-MD-02 (galactoarabino- rhamnogalacturnate) represents a new 
type of agent for the therapy of subjects with NASH and advanced fibrosis. GR-MD-02 is a 
complex carbohydrate molecule derived from a natural plant compound which contains 
oligosaccharide chains containing galactose residues and binds to galectin-3, and to a lesser 
extent, galectin-1. Cellular experiments demonstrate that GR-MD-02 is not toxic to cells but 
is capable of inhibiting the expression of inflammatory cytokines in a monocyte/macrophage 
model of inflammation and reduces cell surface galectin-3 from fibrogenic liver stellate cells. 
GR-MD-02 has been tested in 2 models of liver fibrosis, a mouse model that reliably 
produced a pathological picture of NASH with a fibrosis and a toxin-induced model of liver 
fibrosis in rats. Multiple studies were completed in the mouse NASH model that showed that 
GR-MD-02 consistently reduced the activity of NASH, reduced or eliminated fibrosis as 
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Galectin Therapeutics Inc. 
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Protocol: GT-026 Original 
20 February 2015 
 
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measured by liver collagen, and reduced the expression of galectin-3 in liver macrophages 
(Traber 2013a). Much more robust fibrosis and cirrhosis were induced in rats treated with 
thioacetamide in which animals developed fibrosis that replaced 25% of the liver with 
collagen and had all of the pathological characteristics of cirrhosis. Treatment of cirrhotic rats 
with 4 weekly doses GR-MD-02 resulted in reduction of collagen to below 10%, reversal of 
cirrhosis, and reduced portal hypertension (Traber 2013b). 
The results from a Phase 1 study (Galectin 2014) indicated GR-MD-02 was safe and well 
tolerated at single and multiple doses of 2, 4, and 8 mg/kg. Pharmacokinetics revealed drug 
exposure in humans at the 8-mg/kg dose that was equivalent to the upper range of the 
targeted therapeutic dose determined from effective doses in NASH animal models, thus 
providing support for the proposed Phase 2 dosing regimen. There was evidence of an effect 
on a relevant disease marker, with a dose-dependent reduction in FibroTest® (FibroSure®) 
scores due to a reduction in alpha-2 macroglobulin levels. Additionally, there was a signal of 
reduced liver stiffness as assessed by FibroScan® in subjects treated with an 8-mg/kg dose of 
GR-MD-02. 
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Galectin Therapeutics Inc. 
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2 
Study Objectives 
2.1 Primary Objective 
The primary objective is to evaluate the efficacy of GR-MD-02 on reducing hepatic venous 
pressure gradient (HVPG) as a measure of portal pressure compared to placebo at 1 year of 
treatment. 
2.2 Secondary Objectives 
The secondary objectives of this study are to evaluate differences in relevant assessments of 
fibrosis and cirrhosis between GR-MD-02-treated and placebo-treated subjects.  
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The secondary objectives are to evaluate: 
• 
The effect of GR-MD-02 on change in the collagen proportional area (CPA) at 
1 year compared to placebo as determined by digital morphometric analysis of 
liver biopsies 
• 
The effect of GR-MD-02 on liver stiffness as determined by the FibroScan score 
prior to the first infusion, at Infusion Visit 13, and 14-28 days after final 
infusion as compared to placebo 
• 
The effect of GR-MD-02 on the metabolic capacity of the liver as determined 
by cPDR30 (percentage dose recovery) value of the 13C-methacetin breath test 
(MBT) (if available) at screening, at Infusion Visit 13, and 14-28 days after final 
infusion as compared to placebo 
• 
The effect of GR-MD-02 on progression of cirrhosis at 1 year as compared to 
placebo, defined as the development of any of the following:  
o esophageal variceal hemorrhage or portal hypertensive gastropathy 
hemorrhage (confirmed by endoscopy or interventional radiology) 
o clinically apparent ascites  
o spontaneous bacterial peritonitis 
o overt hepatic encephalopathy (defined by the clinical judgment of the 
principal investigator, but should include the presence of lethargy, 
disorientation, inappropriate behavior, and the presence of asterixis) 
o an increase in Child-Turcotte-Pugh score ≥2  
o newly diagnosed varices in a subject without prior varices  
o progression from small to medium or large varices  
o reaching a model for end-stage liver disease (MELD) score ≥15 as 
measured on 2 consecutive occasions 
o listing for a liver transplant or the performance of a liver transplant 
o liver-related mortality 
 
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2.3 Exploratory Objectives 
The exploratory objectives are to evaluate: 
• Difference in health-related quality of life using the subject-completed chronic 
liver disease questionnaire (CLDQ) following administration of GR-MD-02 or 
placebo at 1 year 
• Baseline-adjusted change in FibroTest (FibroSure) and the enhanced liver 
fibrosis (ELF) score at Infusion Visits  7, 13, 20, and 14-28 days after final 
infusion 
• Changes in liver biopsy staining for alpha smooth muscle actin and galectin-3 in 
subjects treated with GR-MD-02 or placebo at 1 year 
2.4 Safety Objectives 
The safety objectives are to assess the safety and tolerability of GR-MD-02 versus placebo at 
1 year. 
2.5 Pharmacokinetic Objective 
The pharmacokinetic (PK) objectives are to evaluate systemic exposure following multiple 
doses of GR-MD-02 in subjects with portal hypertension due to NASH cirrhosis and to 
explore the population pharmacokinetics of GR-MD-02 in subjects with NASH with portal 
hypertension and cirrhosis or advanced bridging fibrosis.  
Note: Formal population PK analysis will not be performed in this study. However, 
GR-MD-02 plasma levels will be used to evaluate systemic exposure following multiple 
doses. In the Phase 1 clinical study (Galectin 2014), the observed maximum plasma or serum 
concentration after administration (Cmax) drug levels for all doses were well correlated with 
the area under the concentration-time curve (h*µg/mL) (p<0.001, r squared = 0.91). 
Therefore, Cmax plasma levels at 2 hours following the dose of GR-MD-02 will be used to 
estimate the systemic exposure of the drug. Plasma levels of GR-MD-02 will be evaluated at 
the initiation of the study in all subjects, 2 hours after investigational medicinal product 
(IMP) infusion at Infusion Visits 1, 2, 3, 4, 7, 10, 13, and 26. Trough levels of drug will not 
be informative, since there were only measurable levels of drug detected through 72 hours 
following a dose and were thereafter undetectable (assay limit of detection of 1.2 µg/mL).  
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3 
Investigational Plan 
3.1 Study Design 
Study GT-026 is a Phase 2, multicenter, parallel-group, North American, randomized, 
placebo-controlled, double-blind study of subjects with portal hypertension due to advanced 
bridging fibrosis or cirrhosis. The study will be conducted in 45 to 60 study centers in the 
United States and Canada.  
This study will enroll subjects with portal hypertension (HVPG greater than or equal to 
6 mm Hg) who also have a liver biopsy showing cirrhosis (Ishak stage 5 or 6), or advanced 
bridging fibrosis (Ishak stage 4) presumably due to NASH, excluding subjects with medium 
and large varices and those with decompensated cirrhosis (as defined by the presence of 
clinically detectable ascites, any episode of variceal bleeding, and overt hepatic 
encephalopathy). Subjects with portal hypertension and the appropriate biopsy findings will 
be randomly assigned (1:1:1) to receive 1 of 3 treatment assignments: placebo, GR-MD-02 in 
a dose of 2 mg/kg lean body mass, or GR-MD-02 in a dose of 8 mg/kg lean body mass 
administered every other week over a 52-week period for a total of 26 infusions (Figure 3-1). 
The primary endpoint analysis is the baseline-adjusted change in HVPG at 1 year 
(53 - 55 weeks) in subjects treated with placebo as compared to subjects treated with 
GR-MD-02 (2 mg/kg/week or 8 mg/kg/week). The model will include treatment group at 
randomization and the baseline HVPG as a covariate. 
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Figure 3-1 
Study Design GT-026 
Prescreening  (Week  -9) 
& 
Screening Evaluation 
(up to 8 weeks)
Medium &
Large
Varices
Placebo
GR-MD-02 (2 mg/kg)
GR-MD-02 (8 mg/kg)
EGD
HVPG
LB
EGD
HVPG
LB
26 
every 
other week 
infusions
Week 
53-55
Week 1
EOS 
Week 
57
 
Abbreviations: EGD, esophagogastroduodenoscopy; HVPG, hepatic venous pressure gradient; LB, liver biopsy 
(percutaneous or transjugular) 
The study will include prescreening, screening, randomization, treatment, and follow-up 
periods. No dose modification for GR-MD-02 will be allowed. 
A flow chart depicting the prescreening and screening procedures is provided in Figure 3-2. 
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Protocol: GT-026 Original 
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Figure 3-2 
Prescreening and Screening Flow Chart GT-026 
Previous liver biopsy 
with NASH with 
cirrhosis  (Ishak stage 5 
or 6) or advanced 
bridging fibrosis (Ishak 
stage 4)
EGD*
Clinical diagnosis of 
NASH with FibroScan® 
score ≥ 12 kPa
Medium or large 
varices or varices 
with red signs
No varices or 
small varices
Does not 
qualify 
for study 
inclusion
Does not 
qualify 
for study 
inclusion
HVPG measurement 
and liver biopsy*
•
HVPG ≥ 6 mmHg
•
Liver biopsy with 
Ishak stage 4, 5, or 6 
fibrosis consistent 
with NASH
RANDOMIZATION
Yes
No
Yes
No
Yes
Nonlaboratory and 
laboratory inclusion 
and exclusion 
criteria met
 
Abbreviations: EGD, esophagogastroduodenoscopy; HVPG, hepatic venous pressure gradient; NASH, 
nonalcoholic steatohepatitis 
Note: 13C-methacetin breath test (if available) to be performed before either EGD, liver biopsy, or HVPG at 
investigator’s discretion. 
 
Prescreening: Prescreening may begin at Week –9. Prior to beginning prescreening 
procedures, the subject must sign the informed consent form (ICF). Criteria have been 
established to avoid unnecessary medical procedures (HVPG, esophagogastroduodenoscopy 
[EGD] and biopsy) in subjects who have a high likelihood of not meeting key study 
requirements. Subjects who have had a previous liver biopsy with a diagnosis of NASH with 
either advanced bridging fibrosis (Ishak stage 4) or cirrhosis (Ishak stage 5 or 6) are eligible 
to move forward to screening. Subjects with a presumptive clinical diagnosis of NASH 
(based on the assessment of the principal investigator) will have a FibroScan to assess the 
potential for fibrosis. Subjects who have a FibroScan score of at least 12.0 kiloPascals (kPa) 
will be considered to have advanced fibrosis and will proceed to screening. Likewise, 
subjects with a documented qualifying FibroScan score within the previous 12 months of 
screening may proceed to screening. 
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Screening: The screening window is up to 8 weeks.  
Subjects will undergo the following required procedures to assess eligibility during the 
screening period: HVPG measurement, liver biopsy, and EGD. Additionally, at the time of 
1 of these 3 procedures (at the discretion of the investigator), subjects will have a MBT 
performed (if available) prior to the procedure. Eligible subjects will have both an HVPG 
screening measurement of at least 6 mm Hg and a liver biopsy with advanced bridging 
fibrosis (Ishak stage 4) or cirrhosis (Ishak stage 5 or 6), presumably due to NASH. Central 
reading groups will be used to assess the appropriateness of biopsy and HVPG 
measurements. A liver biopsy diagnosis of advanced bridging fibrosis or cirrhosis, 
presumably due to NASH, will include the following 2 categories:  
1. Cirrhosis or advanced bridging fibrosis with a definitive pathological diagnosis of 
NASH (presence of fat, ballooning degeneration, and inflammation) or; 
2. Cirrhosis or advanced bridging fibrosis wherein the subject has greater than 5 years of 
obesity (body mass index [BMI] >30) and/or diabetes with negative viral hepatitis 
markers and a biopsy showing cirrhosis or advanced bridging fibrosis with any 
amount of fat 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will proceed 
to randomization and the treatment phase. Subjects who fail to meet eligibility criteria due to 
an abnormal laboratory result may undergo retesting of the abnormal laboratory parameter 
during the screening window and at the discretion of the investigator and with prior approval 
of the medical monitor. 
Treatment Phase: Subjects with portal hypertension who meet all of the other criteria for 
study inclusion will be randomly assigned (1:1:1) to receive 1 of 3 treatment assignments 
including placebo, GR-MD-02 in a dose of 2 mg/kg lean body mass, or GR-MD-02 in a dose 
of 8 mg/kg lean body mass administered every other week over a 52-week period for a total 
of 26 infusions. During the treatment phase of the study, all subjects randomly assigned to 
IMP will attend study visits according to the schedule of visits for study administration and 
monitoring (Table 12-2). Safety (12-lead electrocardiogram [ECG], physical examinations, 
vital sign measurements, adverse event [AE] monitoring, and safety laboratory assessments), 
and efficacy (FibroScan, MBT (if available), biomarkers, assessment of cirrhosis 
complications [esophageal variceal hemorrhage or portal hypertensive gastropathy 
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hemorrhage, clinically apparent ascites, spontaneous bacterial peritonitis, overt hepatic 
encephalopathy, listing for a liver transplant or the performance of a liver transplant], and 
quality of life) will be monitored throughout the treatment phase. 
Postdose Final Visit (14-28 days): All subjects will attend a visit (or visits) 14 to 28 days 
after final dose. During this visit, safety (AE monitoring and safety laboratory assessments) 
and efficacy (FibroScan, MBT [if available], biomarkers, EGD, HVPG, and a liver biopsy) 
assessments will be collected/performed (Table 12-2).  
Follow-up/Early Termination Visit: All subjects are to attend a follow-up/early termination 
visit 14 days after the postdose final visit to evaluate safety. During this visit, a 12-lead ECG, 
a physical examination, vital sign measurements, and AE monitoring will be 
collected/performed (Table 12-2). 
Open-Label Extension Study: Following study completion, subjects will be offered 
enrollment into a subsequent separate study, an open-label extension study (OLES), if there 
is adequate tolerability and no safety issues or signs of clinical progression that would require 
discontinuation.  
End-of-Study Telephone Contact: Subjects who do not enroll into the OLES will be 
contacted via telephone every 6 months for 2 years, and annually thereafter for a total of 
4 years, for a brief update and are to be assessed for survival, listing for a liver transplant or 
the performance of a liver transplant, or complications of chronic liver disease (ascites, 
spontaneous bacterial peritonitis, variceal bleeding, and encephalopathy; Table 12-3). 
3.1.1 
Rationale of Study Design  
Nonalcoholic steatohepatitis is a chronic inflammatory disease of the liver characterized by 
progressive fibrosis that eventually leads to cirrhosis in a subset of subjects. Cirrhosis results 
in portal hypertension, the complications of which (variceal hemorrhage, ascites with 
bacterial peritonitis, hepatic encephalopathy) can result in death or the need for liver 
transplantation. There are currently no medical therapies approved for NASH or for portal 
hypertension by reducing liver fibrosis, and this therapeutic area represents an area of 
significant unmet medical need. Galectin-3, a protein that binds to galactose-containing 
oligosaccharides, has been shown to be critical in the pathophysiology of NASH and liver 
fibrosis. GR-MD-02, a complex carbohydrate drug that binds to galectin-3, has shown robust 
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efficacy in preclinical models of NASH and liver fibrosis and was safe and well tolerated in 
Phase 1 studies. Therefore, the overall objective of this clinical study is to establish the safety 
and efficacy of GR-MD-02 as compared to placebo in the reduction of portal pressure as a 
surrogate for a reduction in fibrosis in subjects with compensated cirrhosis due to NASH. 
Two doses of GR-MD-02 will be evaluated in this clinical study, 2 mg/kg and 8 mg/kg lean 
body weight. The doses are calculated on lean body weight because the drug is distributed 
primarily in the blood compartment. These 2 doses were chosen because the drug exposure in 
humans based on area under the concentration-time curve spans the predicted therapeutic 
range determined in preclinical studies. The dose of 2 mg/kg is lower than the lowest 
effective dose evaluated in the preclinical NASH model and 8 mg/kg is in the upper range of 
the therapeutic window. 
GR-MD-02 will be administered every other week over 52 weeks for a total of 26 doses. 
Liver fibrosis is a chronic condition and, even with an effective therapy, it is likely to require 
a relatively prolonged therapy to have a clinically relevant effect. Most authorities in the field 
believe and the US Food and Drug Administration (FDA) advised that 12 months of therapy 
is likely a minimum required to demonstrate a significant antifibrotic effect.  
GR-MD-02 will be compared to a placebo infusion consisting of vials of placebo 
(phosphate-buffered saline) diluted in 100 mL of normal saline in this study. No therapies 
have been shown to be effective for the treatment of liver fibrosis in humans and, therefore, 
placebo is an appropriate comparator. 
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4 
Subject Selection and Withdrawal Criteria 
4.1 Selection of Study Population 
Approximately 156 subjects will be enrolled at 45 to 60 study centers in the United States 
and Canada. Subjects will be assigned to study treatment only if they meet all of the 
inclusion criteria and none of the exclusion criteria. 
Deviations from the inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability, or subject 
safety. Therefore, adherence to the criteria as specified in the protocol is essential. 
4.1.1 
Inclusion Criteria 
Each subject must meet all of the following criteria to be enrolled in this study: 
1. Has a HVPG measurement ≥6 mm Hg. 
2. Has a liver biopsy with advanced bridging fibrosis (Ishak stage 4) or cirrhosis (Ishak 
stage 5 or 6), presumably due to NASH. A liver biopsy diagnosis of advanced bridging 
fibrosis or cirrhosis, presumably due to NASH will include the following 2 categories:  
a. Advanced bridging fibrosis or cirrhosis with a definitive pathological diagnosis of 
NASH (presence of fat, ballooning degeneration, and inflammation) or;  
b. Advanced bridging fibrosis or cirrhosis wherein the subject has greater than 
5 years of obesity (BMI >30) and/or diabetes with negative viral hepatitis markers 
(hepatitis B and hepatitis C) and a biopsy showing any amount of fat. 
3. Is ≥18 years of age and ≤75 years of age at the time of screening. 
4. Is willing and able to provide written informed consent prior to the initiation of any 
study-specific procedures. 
5. Is not pregnant and must have a negative serum pregnancy test result prior to 
randomization. 
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6. If a fertile man or woman participating in heterosexual relations, agrees to use 
effective means of contraception (ie, 2 effective methods of contraception, one of 
which must be a physical barrier method). 
• 
Effective forms of contraception include condom, hormonal methods (birth 
control pills, injections or implants), diaphragm, cervical cap, or intrauterine 
device throughout his/her participation in this study and for 90 days after 
discontinuation of study treatment. Surgically sterile males and females are 
not required to use contraception provided they have been considered 
surgically sterile for at least 6 months. Surgical sterility includes history of 
vasectomy, hysterectomy, bilateral salpingo-oophorectomy, or bilateral tubal 
ligation. Postmenopausal women who have been amenorrheic for at least 
2 years at the time of screening will be considered sterile. 
7. If a lactating woman, agrees to discontinue nursing before the start of study treatment 
and refrain from nursing until 90 days after the last dose of study treatment. 
8. If a man, agrees to refrain from sperm donation throughout the study period and for a 
period of 90 days following the last dose of IMP. Female subjects may not begin a 
cycle of ova donation or harvest throughout the study period and for a period of 
90 days following the last dose of IMP.  
9. Prior to randomization, any subject on statins, angiotensin converting enzyme 
inhibitors, angiotensin II receptor blockers, or β-1 selective adrenergic receptor 
inhibitors should have been on a stable dose for at least 2 months and all attempts 
should be made to continue the subject on the same dose of the medication for the 
duration of study participation. 
4.1.2 
Exclusion Criteria 
Subjects meeting any of the following criteria will be excluded from the study: 
1. Has a history of hepatic decompensation including any episode of variceal bleeding, 
clinically detectable ascites, or overt hepatic encephalopathy (defined by the clinical 
judgment of the principal investigator but should include the presence of lethargy, 
disorientation, inappropriate behavior, and the presence of asterixis). 
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2. Has a presence of medium or large varices or varices with red signs regardless of size 
based on endoscopy. 
• Small varices are defined by veins that occupy >25% of the distal one third of 
the esophageal lumen when insufflated. Veins that completely flatten upon 
insufflation of the esophagus are not conserved varices. Any varices larger than 
that are medium (up to 50%) or large (>50%).  
• Red signs include red wale markings (dilated venules oriented longitudinally on 
the variceal surface), cherry red spots (small, red, spotty dilated venules usually 
approximately 2 mm in diameter on the variceal surface) or hematocystic spots 
(large, round, crimson red projection >3 mm that look like a blood blister on the 
variceal surface). 
3. Has had a prior transjugular porto-systemic shunt procedure. 
4. Has evidence of other forms of chronic liver disease including viral hepatitis B or C, 
primary biliary cirrhosis, primary sclerosing cholangitis, Wilson’s disease, alpha-1 
antitrypsin deficiency, alcoholic hepatitis, hemochromatosis, liver cancer, history of 
biliary diversion, or autoimmune hepatitis. 
5. Has any of the following laboratory values: 
a. Serum alanine aminotransferase levels >10 × the upper limits of normal 
b. Serum aspartate aminotransferase levels >10 × the upper limits of normal 
c. Serum creatinine ≥2.0 mg/dL  
d. Platelet count <60 000/mm3  
e. Serum albumin ≤2.8 g/dL 
f. International normalized ratio (INR) ≥1.7 
g.  
Direct bilirubin ≥2.0 mg/dL 
6. A MELD score ≥15 or Child-Turcotte-Pugh Class B or C. 
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7. Is unwilling or unable to safely undergo HVPG or liver biopsy. 
8. Has known positivity for human immunodeficiency virus (HIV) infection or a positive 
HIV test result at screening. 
9. Has had major surgery within 8 weeks of randomization, significant traumatic injury 
within 6 months, or anticipation of need for major surgical procedure during the 
course of the study. 
10. Has a history of a solid organ transplant requiring current immunosuppression therapy. 
11. Has used nonselective β-adrenergic inhibitors within 6 weeks prior to randomization 
or at any time during the study. 
12. Has planned or anticipated variceal ligation therapy during the study. 
13. Has had weight reduction surgery within the past 3 years or plans to undergo weight 
reduction surgery during the study. 
14. Has current, significant alcohol consumption or a history of significant alcohol 
consumption for a period of more than 3 consecutive months any time within 1 year 
prior to screening. 
• 
Significant alcohol consumption is defined as more than 20 grams per day in 
females and more than 30 grams per day in males. On average, a standard 
drink in the United States is considered to be 14 g of alcohol equivalent to 
12  fluid oz of regular beer (5% alcohol), 5 fluid oz of table wine (12% 
alcohol), or 1.5 fluid oz of 80 proof spirits (40% alcohol).  
A score of ≥8 on the Alcohol Use Disorders Identification Test (AUDIT) 
(Babor 2000) will result in exclusion. (The AUDIT is provided in 
Section 12.2.)  
15. Has a positive urine screen result for amphetamines, cocaine, or nonprescription 
opiates (heroin, morphine) at screening. 
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16. Has clinically significant and uncontrolled cardiovascular disease (eg, uncontrolled 
hypertension, myocardial infarction within 6 months prior to randomization, unstable 
angina), New York Heart Association Grade II or greater congestive heart failure, 
serious cardiac arrhythmia requiring devise/ablation or Grade II or greater peripheral 
vascular disease within 12 months prior to randomization. 
17. Has a history of clinically significant hematologic, renal, hepatic, pulmonary, 
neurological, psychiatric, gastrointestinal, systemic inflammatory, metabolic or 
endocrine disorder or any other condition that, in the opinion of the investigator, 
renders the subject a poor candidate for inclusion into the study. 
18. Has concurrent infection including diagnoses of fever of unknown origin at the time of 
randomization (subjects must be afebrile at the start of therapy). 
19. Has a history of malignancy, except for the following adequately treated nonmetastatic 
basal cell skin cancer; any other type of skin cancer, except melanoma, that has been 
adequately treated and has not recurred for at least 1 year prior to enrollment; and 
adequately treated in situ cervical cancer that has not recurred for at least 1 year prior 
to screening. 
20. Participates in an investigational new drug study within 30 days prior to 
randomization (including follow-up visits) or at any time during the current study. 
21. Has a clinically significant medical or psychiatric condition considered high risk for 
participation in an investigational study. 
22. Fails to give informed consent. 
23. Has known allergies to the IMP or any of its excipients. 
24. Is an employee or family member of the investigator or study center personnel. 
25. Needs concomitant use of drugs with a narrow therapeutic window metabolized by 
cytochrome P450 3A4 (CYP3A4) isozyme including specifically the fast-acting 
opioids alfentanil and fentanyl; the immunosuppressive drugs cyclosporine, sirolimus, 
and tacrolimus; the cardiovascular agents ergotamine, quinidine, and 
dihydroergotamine; and the psychotropic agent pimozide. 
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4.2 Withdrawal of Subjects from the Study 
The duration of the study is defined for each subject as the date a signed written informed 
consent is provided through the last follow-up visit, up to 42 days following the last IMP 
infusion. 
4.2.1 
Reasons for Withdrawal/Discontinuation 
Subjects may withdraw from the study at any time and for any reason without prejudice to 
their future medical care by the investigator or at the study center. Every effort should be 
made to keep subjects in the study. The reasons for subjects not completing the study will be 
recorded. A subject may be withdrawn from the study for any of the following reasons: 
1. Significant noncompliance with the protocol 
2. A serious or intolerable AE(s) that, in the investigator’s opinion, requires withdrawal 
from the study 
3. Laboratory safety assessments that reveal clinically significant hematological or 
biochemical changes from the baseline values 
4. Symptoms or an intercurrent illness not consistent with the protocol requirements for 
study participation or that justifies withdrawal 
5. Lost to follow-up 
6. Pregnancy 
7. The subject withdraws consent or the investigator or sponsor decides to discontinue 
the subject’s participation in the study. 
The investigator will also withdraw subjects if Galectin Therapeutics Inc terminates the 
study. Upon occurrence of a serious or intolerable AE, the investigator will confer with the 
sponsor. If a subject is discontinued because of an AE, the event will be followed until it is 
resolved. Any subject may withdraw his or her consent at any time. 
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4.2.2 
Handling of Withdrawals 
Subjects are free to withdraw from the study or study treatment at any time upon request. 
Subject participation in the study may be stopped at any time at the discretion of the 
investigator or at the request of the sponsor. 
Subjects who discontinue study treatment or active participation in the study will no longer 
receive IMP. When a subject withdraws from the study, the reason(s) for withdrawal shall be 
recorded by the investigator on the relevant page of the electronic case report form (eCRF). 
Whenever possible, all subjects who discontinue study treatment or withdraw from the study 
prematurely will undergo all end-of-study assessments. Subjects who fail to return for final 
assessments will be contacted by the study center (2 documented telephone calls followed by 
1 registered letter) in an attempt to have them comply with the protocol. 
It is vital to obtain follow-up data on any subject withdrawn because of an AE or serious AE 
(SAE). In every case, efforts must be made to undertake protocol-specified, safety, follow-up 
procedures. 
4.2.3 
Replacements 
Subjects who are randomly assigned to IMP and prematurely discontinued from the study 
will not be replaced. 
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5 
Study Treatments 
5.1 Method of Assigning Subjects to Treatment Groups 
Subjects will be randomly assigned to receive 2 mg/kg lean body weight of GR-MD-02, 
8 mg/kg lean body weight of GR-MD-02, or placebo using a 1:1:1 allocation ratio. An 
interactive web response system (IWRS) will be used to administer the randomization 
schedule. Unblinded biostatistics personnel not participating in the conduct of the study will 
generate the randomization schedule using SAS software Version 9.2 or later (SAS Institute 
Inc, Cary, North Carolina) for IWRS, which will link sequential subject randomization 
numbers to treatment codes.  
The IWRS will send visit notifications to the study center personnel confirming the subject 
data that were entered. All study visits will have a visit window of ± 3 days. The IWRS 
notifications should be filed in source.  
5.2 Treatments Administered 
The GR-MD-02 for injection is supplied in a sterile aqueous solution of phosphate-buffered 
saline at a concentration of 30 mg/mL GR-MD-02 and should be diluted to the target dose in 
normal saline and administered intravenously over a period of approximately 60 minutes. 
The product is expected to be stable at pH 4.0 to 7.5.  
GR-MD-02 solution will be supplied in 10-mL vials with the following composition to the 
study center (Table 5-1). 
Table 5-1 
Composition of GR-MD-02 Concentrate 
Ingredient 
Concentration 
GR-MD-02 
300 mg 
USP sodium chloride 
82 mg 
USP disodium phosphate heptahydrate 
14.4 mg 
USP monosodium phosphate monohydrate 
2.4 mg 
USP sterile water for injection 
to 10 mL 
Instructions on dosing preparation are provided in the Pharmacy Manual. 
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Once the infusion solutions are prepared, they may be stored at a room temperature 
(20°C-25°C [68°F-77°F]) and should be administered within 24 hours of preparation. 
Infusions should be administered intravenously over a period of approximately 60 minutes. 
Frequency of administration should be once every 2 weeks (Table 12-2). 
5.3 Identity of Investigational Medicinal Product 
GR-MD-02 (galactoarabino-rhamnogalacturnate) is a soluble polysaccharide composed of an 
alternating α-(1,2)-L-rhamnosyl-α-(1,4)-D-galacturonosyl backbone with side branches 
composed of mainly galactose and arabinose oligosaccharides.  
GR-MD-02 for injection is a clear, light yellow-tan solution and is supplied in 10-mL sterile 
vials at a concentration of 30 mg/mL of GR-MD-02 in phosphate-buffered saline.  
Detailed instructions for the preparation and administration of the GR-MD-02 by slow 
intravenous (IV) drip over a period of approximately 60 minutes will be provided in the 
Pharmacy Manual.  
Lean body mass (LBM) will be used for dosing because it is anticipated that many subjects 
will be obese and GR-MD-02 is distributed primarily in the blood compartment. Lean body 
mass will be estimated from height and weight measurements using formulas that have been 
well-validated in obese individuals (Janmahasatian 2005): 
• 
Males: LBM = 9270 × TBW (total body weight)/(6680 + 216 × BMI) 
• 
Females: LBM = 9270 × TBW/(8780 + 244 × BMI) 
Total body weight is in kilograms and BMI is in mass (weight in kilograms)/(height in 
meters2). Tables of LBM values for a range of heights and weights will be provided to the 
pharmacies participating in the study as a check for the calculations. 
The study pharmacist at each study center will be unblinded in the preparation of IMP for 
infusion. Infusion solutions will be prepared as specified in the Pharmacy Manual in IV bags 
and placed in amber-colored IV bag covers with amber-colored tubing and infusion sets. The 
amber-colored bags will be sealed with tamper-evident tapes. Once prepared by the 
unblinded pharmacist, the placebo and drug solutions in the IV infusion set-up will be 
indistinguishable. Thus, the study subjects, primary investigators, and medical personnel will 
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be blinded throughout the study as to whether the subject is receiving active drug or placebo. 
Upon completion of IMP infusion, documentation of the discarded infusion set must be 
recorded to indicate no unblinding occurred. 
5.4 Management of Clinical Supplies 
5.4.1 
Investigational Medicinal Product Packaging and Storage 
Galectin Therapeutics Inc will provide IMP to the study centers. The following drug supplies 
will be used in the study: 
• 
GR-MD-02, supplied as 10-mL sterile vials 
• 
Placebo (phosphate-buffered saline solution), supplied as 10-mL sterile vials 
GR-MD-02 for injection (30 mg/mL) and placebo to be used for the study 
(phosphate-buffered saline) in 10-mL vials are manufactured by Catalent Pharma Solutions, 
Woodstock, Illinois, and packaged and labeled for the study center by Catalent Pharma 
Solutions, Philadelphia, Pennsylvania. 
The GR-MD-02 for injection (30 mg/mL) vials and placebo vials are to be stored under 
refrigerated conditions at 2°C to 8°C (36°F-46°F) until preparation of the drug infusion 
solution. To prepare the final infusion solution for administration, the GR-MD-02 will be 
diluted in sterile normal saline as required to achieve the target dose. Instructions on dosing 
preparation are provided in the Pharmacy Manual.  
5.4.2 
Test Article Accountability 
The investigator will maintain accurate records of receipt of all test articles, including dates 
of receipt. In addition, accurate records will be kept regarding when and how much test 
article is dispensed and used by each subject in the study. Reasons for departure from the 
expected dispensing regimen must also be recorded. Upon completion of IMP infusion, 
documentation of the discarded infusion set must be recorded to indicate no unblinding 
occurred. At the completion of the study, to satisfy regulatory requirements regarding drug 
accountability, IMP will be reconciled and retained or destroyed according to applicable 
regulations. 
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5.4.3 
Other Supplies 
In addition to drug and placebo for the study, each study center will also be provided sterile 
syringe filters, amber-colored bag covers (with tamper-evident tape) and amber-colored 
infusion tubing sets. See the Pharmacy Manual for the specifications and details regarding 
these ancillary supplies. 
5.5 Overdose Management 
An overdose is any dose of study treatment given to a subject or taken by a subject that 
exceeds the dose described in the protocol. Any overdose, with or without associated AEs, 
must be promptly reported to PPD Pharmacovigilance:   
• SAE Hotline: 
1-800-201-8725 
• SAE Fax line: 1-888-488-9697 
Overdoses without signs or symptoms do not need to be recorded as AEs; in case of any AEs 
associated with the overdose, these should be reported in relevant AE/SAE sections in the 
eCRF. 
5.5.1 
Treatment of Overdose 
There are no known or anticipated adverse effects of GR-MD-02 overdose. The subject 
should be observed, but there are no specific therapies to be instituted. 
5.5.2 
Medication Errors 
A medication error is any unintentional error in prescribing, dispensing, or administration of 
the IMP. The IMP will be prepared and administered at the study center by trained personnel, 
thereby reducing the risk of medication errors. 
Acceptable treatment windows for infusions will be ± 3 days. Infusions given outside of 
accepted windows will be considered “out-of-window” doses. If a dose is out of window, the 
subject should be brought back into compliance with his or her visit dosing schedule. The 
subject should not dose within 7 days of the previous or next dose unless the medical monitor 
is consulted and agrees. 
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Any AEs resulting from medication errors will be recorded as AEs in the eCRF. 
5.5.3 
Treatment of Medication Errors 
Should a medication error occur, the subject should be observed; however, there are no 
specific therapies to be instituted. 
5.6 Misuse for Illegal Purposes 
GR-MD-02 does not have known effects that may be addictive and there are no other known 
reasons for misuse. 
5.7 Blinding 
The aqueous solution  of GR-MD-02 is light yellow-tan. It has not been possible to match the 
color with a placebo formulation. Therefore, the study pharmacist at each study center will be 
unblinded in the preparation of IMP for infusion. The formulated 10-mL solutions will be 
prepared for infusion as specified in the Pharmacy Manual in IV bags and placed in 
amber-colored IV bag covers with amber-colored tubing and infusion sets. The 
amber-colored bags will be sealed with tamper-evident tape. Placebo and drug solutions to be 
administered in the IV infusion set up are indistinguishable. Thus, the study subjects, primary 
investigators, and medical personnel will be blinded to the identity of the administration. 
Infusion of the IMP causes no local reaction in animal studies or in humans participating in 
the Phase 1 clinical study and, therefore, should not affect blinding. 
5.7.1 
Breaking the Blind 
A subject’s treatment assignment will not be broken until the end of the study unless medical 
treatment of the subject depends on knowing the study treatment the subject received. In the 
event that the blind needs to be broken because of a medical emergency, the investigator may 
unblind an individual subject’s treatment allocation. As soon as possible, the investigator 
should first contact the medical monitor to discuss the medical emergency and the reason for 
revealing the actual treatment received by that subject. The treatment assignment will be 
unblinded by the investigator through IWRS. Reasons for treatment unblinding must be 
clearly explained and justified in the eCRF. The date on which the code was broken together 
with the identity of the person responsible must also be documented. 
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5.8 Treatment Compliance 
Subject compliance will be determined by infusion records.  
Acceptable windows for IMP dosing are ± 3 days. Infusions given outside of accepted 
windows will be considered “out-of-window” doses. If a dose is out of window, the subject 
should be brought back into compliance with his or her visit dosing schedule. The subject 
should not dose within 7 days of the previous or next dose unless the medical monitor is 
consulted and agrees. 
5.9 Prior and Concomitant Therapy  
Use of all concomitant medications will be recorded in the subject’s eCRF. The minimum 
requirement is that drug name, reason for use, dose, and the dates of administration will be 
recorded. This will include all prescription drugs, herbal products, vitamins, minerals, and 
over-the-counter medications. Any changes in concomitant medications will also be recorded 
in the subject’s eCRF. 
All prior treatments for liver cirrhosis and NASH will be recorded in the eCRF. All other 
concomitant medications taken from 30 days prior to screening and throughout the entire 
duration of the subject’s participation in the study will be documented in the eCRF. 
Concomitant medications are defined as medications taken any time after the start of 
exposure to IMP. Prior medications are defined as nonstudy medications discontinued prior 
to the start of exposure to IMP. 
Any concomitant medication deemed necessary for the welfare of the subject during the 
study may be given at the discretion of the investigator. If prohibited medications are needed 
for the welfare of the subject, the subject should be discontinued from the study. It is the 
responsibility of the investigator to ensure that details regarding the medication are recorded 
in full in the eCRF. 
5.10 Prohibited Medications or Therapies 
Excluded from use are drugs with a narrow therapeutic window metabolized by CYP3A4, 
including specifically the fast-acting opioids alfentanil and fentanyl; the immunosuppressive 
drugs cyclosporine, sirolimus, and tacrolimus; the cardiovascular agents ergotamine, 
quinidine, and dihydroergotamine; and the psychotropic agent pimozide. In vitro experiments 
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have shown some inhibition of CYP3A4 enzyme expression and activity at levels of drug 
exposure much higher than obtained in this study. A human drug-drug interaction study is 
being conducted to evaluate whether there are any changes in in the pharmacokinetics of a 
model CYP3A4-metabolized drug. Once the results of this study are available, this exclusion 
criterion may be modified. 
Nonselective β-adrenergic inhibitors for the purpose of treatment of portal hypertension are 
prohibited during the study as well as any off-label drugs. 
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6 
Study Assessments and Procedures 
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Manual/Investigator Site File Notebook which will 
provide the study center personnel with administrative and detailed technical information that 
does not impact subject safety. 
Before any study procedures are performed, all potential subjects will sign an ICF. Subjects 
will have the opportunity to have any questions answered before signing the ICF. The 
investigator must address all questions raised by the subject. The investigator will also sign 
the ICF. 
The schedule of events for prescreening and screening is provided in Table 12-1, for 
randomization, treatment phase, and follow-up in Table 12-2, and for the end-of-study 
telephone contact in Table 12-3. 
6.1 Study Visits 
6.1.1 
Prescreening Visit (Week –9) 
After the subject has provided informed consent, the following information will be collected 
(Table 12-1): 
• 
Enter the IWRS and register subject visit data. 
• 
NASH diagnosis: Subjects who have had a previous liver biopsy with a 
diagnosis of NASH with either advanced bridging fibrosis (Ishak stage 4) or 
cirrhosis (Ishak stage 5 or 6) are eligible to move forward to screening. 
• 
Conduct a FibroScan: Subjects with a presumptive clinical diagnosis of NASH 
(based on the assessment of the principal investigator) will have a FibroScan to 
assess the potential of fibrosis. Subjects who have a FibroScan score of 
≥12.0 kPa will be considered to have advanced fibrosis and will proceed to 
screening. Likewise, subjects with a documented qualifying FibroScan score 
within the previous 12 months of screening may proceed to screening. 
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6.1.2 
Screening Visit (Week -8 to Day 0) 
The screening visit window is up to 8 weeks after the prescreening visit. Subjects who fail to 
meet eligibility criteria within this 8-week period due to an abnormal laboratory result may 
undergo retesting of the abnormal laboratory parameter during the screening window and at 
the discretion of the investigator and with prior approval of the medical monitor. During the 
screening visit, the following information will be collected (Figure 3-2 and Table 12-1): 
• 
Enter the IWRS and register subject visit data. 
• 
Inclusion/exclusion criteria include AUDIT alcohol consumption questionnaire. 
The AUDIT is a screening tool to identify the early signs of hazardous and 
harmful drinking and identify mild dependence. This questionnaire 
(10 questions total) will be given to the subject at the beginning of the screening 
visit and will be considered source documentation. The subject will sign and 
date the questionnaire upon completion. 
• 
Collect demographic information. 
• 
Collect medical, surgical, and medication history (concomitant medications 
taken from 30 days prior to screening). 
• 
Perform a 12-lead ECG assessment. 
• 
Perform hematology testing. 
• 
Perform blood chemistry testing. 
• 
Perform coagulation profile. 
• 
Obtain MELD score. 
• 
Perform viral hepatitis B and C serology. 
• 
Perform HIV serology. 
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• 
Perform urine drug screen for amphetamines, cocaine, and nonprescription 
opiates. 
• 
Perform urinalysis testing. 
• 
Perform serum pregnancy test (females of childbearing potential only). 
• 
Perform chest radiograph (posterior-anterior and lateral views). 
• 
Obtain Child-Turcotte-Pugh score and class (A, B, or C). 
• 
Perform a complete physical examination (including height [in centimeters] and 
weight [in kilograms]) with particular attention to examination for stigmata of 
liver disease/cirrhosis. 
• 
Collect vital sign measurements (including heart and respiratory rate, blood 
pressure, and body temperature). 
• 
Perform MBT (if available) prior to EGD, HVPG, or liver biopsy (at the 
discretion of the investigator). 
• 
EGD  
Subjects will have had an EGD within 2 months prior to randomization. 
Subjects with medium or large varices or varices with red signs (red wale marks 
or red spots), regardless of size, will be excluded from study participation. 
Subjects without varices or with small varices will continue to HVPG 
measurement and liver biopsy.  
• 
Obtain demographic information. 
• 
HVPG  
Subjects must have both an HVPG measurement ≥6 mm Hg and a liver biopsy 
with advanced bridging fibrosis (Ishak stage 4) or cirrhosis (Ishak stage 5 or 6), 
presumably due to NASH. Subjects without varices or with small varices will 
have hepatic venous catheterization with measurement of both wedged and free 
hepatic venous pressures and standardized calculation of the HVPG prior to 
randomization and first IMP infusion. 
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• 
Obtain liver biopsy  
Liver biopsy may be obtained via a percutaneous approach or a transjugular 
approach during the HVPG procedure, at the preference of the investigator.  
• 
AE monitoring. 
6.1.3 
Treatment Phase 
6.1.3.1 
Randomization 
Randomization must occur between 3 and 8 weeks after screening has begun. The IWRS will 
be used to administer the randomization schedule. 
Prior to Infusion Visit 1, subjects with portal hypertension and the appropriate biopsy will be 
randomly assigned (1:1:1) to receive 1 of 3 treatment assignments: placebo, GR-MD-02 in 
dose of 2 mg/kg lean body mass, or GR-MD-02 in a dose of 8 mg/kg lean body mass. 
Subjects will be entered into the study and randomly assigned if they have both an HVPG 
screening measurement greater than or equal to 6 mm Hg and a liver biopsy with advanced 
bridging fibrosis (Ishak stage 4) or cirrhosis (Ishak stage 5 or 6), presumably due to NASH 
and meet all inclusion criteria and no exclusion criteria. 
6.1.3.2 
Two Weeks Prior to Infusion Visit 1 
Within 2 weeks prior to the first infusion, a FibroScan will be conducted. 
6.1.3.3 
Infusion Visit 1 (Week 1) 
During the Infusion 1 Visit, the following procedures and assessments will be performed 
after randomization and prior to administration of IMP (Table 12-2): 
• 
Enter the IWRS and register subject visit data. 
• 
CLDQ (This questionnaire will be given to the subject at the beginning of the 
visit and will be considered source documentation.) 
• 
Alcohol timeline followback (TLFB) (This will be given to the subject at the 
beginning of the visit and will be considered source documentation.) 
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• 
Perform a limited physical examination (including weight and examination of 
the heart, lung, and abdomen). 
• 
Collect vital sign measurements (including heart and respiratory rate, blood 
pressure, and body temperature). 
• 
Perform hematology testing. 
• 
Perform blood chemistry testing. 
• 
Collect biomarkers blood sample (will include the ELF test and FibroTest 
[FibroSure], and galectin-3). 
• 
Collect plasma and serum sample for storage at –20°C. 
The following information will be collected after IMP administration: 
• 
AE monitoring. 
• 
Record concomitant medications. 
The following will be performed 2 hours after the end of the IMP infusion: 
• 
Collect PK sample. 
6.1.3.4 
Infusion Visits 2, 3, 4, 5, and 6 (Weeks 3, 5, 7, 9, and 11 ± 3 Days, 
respectively) 
The following procedures and assessments will be performed prior to administration of IMP: 
• 
Enter the IWRS and register subject visit data. 
• 
Alcohol TLFB (This will be given to the subject at the beginning of the visit 
and will be considered source documentation.) (Infusion Visit 5) 
• 
Assessment of cirrhosis complications (Infusion Visits 3 and 5). 
• 
Perform a limited physical examination (including weight and examination of 
the heart, lung, and abdomen). 
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• 
Collect vital sign measurements (including heart and respiratory rate, blood 
pressure, and body temperature). 
• 
Perform urine pregnancy test (females of childbearing potential only) (Infusion 
Visits 3 and 5). 
The following information will be collected after IMP administration: 
• 
AE monitoring. 
• 
Record concomitant medications. 
The following will be performed 2 hours after the end of the IMP infusion 
• 
Collect PK sample (Infusion Visits 2, 3, and 4) 
6.1.3.5 
Infusion Visit 7 (Week 13 ± 3 Days) 
The following procedures and assessments will be performed prior to administration of IMP: 
• 
Enter the IWRS and register subject visit data 
• 
Assessment of cirrhosis complications 
• 
Perform a limited physical examination (including weight and examination of 
the heart, lung, and abdomen)  
• 
Collect vital sign measurements (including heart and respiratory rate, blood 
pressure, and body temperature) 
• 
Perform urine pregnancy test (females of childbearing potential only) 
• 
Perform hematology testing 
• 
Perform blood chemistry testing 
The following information will be collected after IMP administration: 
• 
AE monitoring 
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• 
Record concomitant medications 
The following will be performed 2 hours after the end of the IMP infusion 
• 
Collect PK sample 
6.1.3.6 
Infusion Visits 8, 9, 10, 11, and 12 (Weeks 15, 17, 19, 21, and 23 
± 3 Days) 
The following procedures and assessments will be performed prior to administration of IMP: 
• 
Enter the IWRS and register subject visit data. 
• 
Assessment of cirrhosis complications (Infusion Visits 9 and 11). 
• 
Alcohol TLFB (This will be given to the subject at the beginning of the visit 
and will be considered source documentation.) (Infusion Visit 9) 
• 
Perform a limited physical examination including weight and examination of 
the heart, lung, and abdomen). 
• 
Collect vital sign measurements (including heart and respiratory rate, blood 
pressure, and body temperature). 
• 
Perform urine pregnancy test (females of childbearing potential only) (Infusion 
Visits 9 and 11). 
The following information will be collected after IMP administration: 
• 
AE monitoring. 
• 
Record concomitant medications. 
The following will be collected 2 hours after IMP infusion 
• 
Collect PK sample (Infusion Visit 10). 
6.1.3.7 
Infusion Visit 13 (Week 25 ± 3 Days) 
The following procedures and assessments will be performed prior to administration of IMP: 
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• 
Enter the IWRS and register subject visit data. 
• 
Alcohol TLFB (This questionnaire will be given to the subject at the beginning 
of the visit and will be considered source documentation.) 
• 
Assessment of cirrhosis complications. 
• 
Perform a limited physical examination (including weight and examination of 
the heart, lung, and abdomen). 
• 
Collect vital sign measurements (including heart and respiratory rate, blood 
pressure, and body temperature). 
• 
Perform urine pregnancy test (females of childbearing potential only).  
• 
Perform hematology testing. 
• 
Perform blood chemistry testing. 
• 
Obtain MELD score. 
• 
Conduct a FibroScan. 
• 
Perform MBT (if available). 
• 
Collect biomarkers blood sample (will include the ELF test, FibroTest 
[FibroSure], and galectin-3). 
• 
Collect plasma and serum sample for storage at –20°C. 
The following information will be collected after IMP administration: 
• 
Perform a 12-lead ECG assessment. 
• 
Obtain Child-Turcotte-Pugh score and class (A, B, or C). 
• 
AE monitoring. 
• 
Record concomitant medications. 
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The following will be collected 2 hours after the end of the IMP infusion 
• 
Collect PK sample  
6.1.3.8 
Infusion Visits 14, 15, 16, 17, 18, and 19 (Weeks 27, 29, 31, 33, 35, 
and 37 ± 3 Days) 
The following procedures and assessments will be performed prior to administration of IMP: 
• 
Enter the IWRS and register subject visit data. 
• 
Alcohol TLFB (This questionnaire will be given to the subject at the beginning 
of the visit and will be considered source documentation.) (Infusion Visit 17) 
• 
Assessment of cirrhosis complications (Infusion Visits 15, 17, and 19). 
• 
Perform a limited physical examination (including weight and examination of 
the heart, lung, and abdomen). 
• 
Collect vital sign measurements (including heart and respiratory rate, blood 
pressure, and body temperature). 
• 
Perform urine pregnancy test (females of childbearing potential only) (Infusion 
Visits 15, 17, and 19). 
The following information will be collected after IMP administration: 
• 
AE monitoring. 
• 
Record concomitant medications. 
6.1.3.9 
Infusion Visit 20 (Week 39 ± 3 Days) 
The following procedures and assessments will be performed prior to administration of IMP: 
• 
Enter the IWRS and register subject visit data 
• 
Perform a limited physical examination (including weight and examination of 
the heart, lung, and abdomen) 
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• 
Collect vital sign measurements (including heart and respiratory rate, blood 
pressure, and body temperature) 
• 
Perform hematology testing 
• 
Perform blood chemistry testing 
The following information will be collected after IMP administration: 
• 
AE monitoring 
• 
Record concomitant medications 
6.1.3.10 
Infusion Visit 21 (Week 41 ± 3 Days) 
The following procedures and assessments will be performed prior to administration of IMP: 
• 
Enter the IWRS and register subject visit data. 
• 
Alcohol TLFB (This questionnaire will be given to the subject at the beginning 
of the visit and will be considered source documentation.) 
• 
Assessment of cirrhosis complications. 
• 
Perform a limited physical examination (including weight and examination of 
the heart, lung, and abdomen). 
• 
Collect vital sign measurements (including heart and respiratory rate, blood 
pressure, and body temperature). 
• 
Perform urine pregnancy test (females of childbearing potential only). 
The following information will be collected after IMP administration: 
• 
AE monitoring. 
• 
Record concomitant medications. 
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6.1.3.11 
Infusion Visits 22, 23, 24, and 25 (Weeks 43, 45, 47, and 49 
± 3 Days) 
The following procedures and assessments will be performed prior to administration of IMP: 
• 
Enter the IWRS and register subject visit data. 
• 
Alcohol TLFB (This questionnaire will be given to the subject at the beginning 
of the visit and will be considered source documentation.) (Infusion Visit 25) 
• 
Assessment of cirrhosis complications (Infusion Visits 23 and 25). 
• 
Perform a limited physical examination including weight and examination of 
the heart, lung, and abdomen). 
• 
Collect vital sign measurements (including heart and respiratory rate, blood 
pressure, and body temperature). 
• 
Perform urine pregnancy test (females of childbearing potential only) (Infusion 
Visits 23 and 25). 
The following information will be collected after IMP administration: 
• 
AE monitoring. 
• 
Record concomitant medications. 
6.1.3.12 
Infusion Visit 26 (Week 51 ± 3 Days) 
The following procedures and assessments will be performed prior to administration of IMP: 
• 
Enter the IWRS and register subject visit data. 
• 
CLDQ (This questionnaire will be given to the subject at the beginning of the 
visit and will be considered source documentation.) 
• 
Assessment of cirrhosis complications. 
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• 
Perform a limited physical examination (including weight and examination of 
the heart, lung, and abdomen). 
• 
Collect vital sign measurements (including heart and respiratory rate, blood 
pressure, and body temperature). 
• 
Perform hematology testing. 
• 
Perform blood chemistry testing. 
• 
Obtain MELD score. 
• 
Collect plasma and serum sample for freezing at –20°C. 
The following information will be collected after IMP administration: 
• 
Obtain Child-Turcotte-Pugh score and class (A, B, or C). 
• 
AE monitoring. 
• 
Record concomitant medications. 
The following will be collected 2 hours after the end of the IMP infusion: 
• 
Collect PK sample  
6.1.4 
Follow-up (14-28 Days After Final Dose; Weeks 53-55 ± 3 Days) 
Within 14 to 28 days after the final 26th dose of IMP or, where feasible, following study 
termination, the following information will be collected (Table 12-2): 
• 
Enter the IWRS and register subject visit data 
• 
Perform a limited physical examination including weight and examination of 
the heart, lung, and abdomen) 
• 
Collect vital sign measurements (including heart and respiratory rate, blood 
pressure, and body temperature) 
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• 
Conduct a FibroScan 
• 
Perform MBT (if available) 
• 
Collect biomarkers blood sample (will include the ELF test, FibroTest 
[FibroSure], and galectin-3) 
• 
Perform EGD (must be performed on a different day within the 14 to 28-day 
follow-up period than when the HVPG assessment is performed) 
• 
Perform HVPG 
• 
Obtain a liver biopsy 
• 
Perform hematology testing 
• 
Perform blood chemistry testing 
• 
AE monitoring 
• 
Record concomitant medications 
6.1.5 
Follow-up/Early Termination (Week 57 ± 3 Days) 
Fourteen days after the previous visit (Section 6.1.4), the following information will be 
collected (Table 12-2): 
• 
Enter the IWRS and register subject visit data 
• 
Perform a 12-lead ECG assessment 
• 
Perform a limited physical examination (including weight and examination of 
the heart, lung, and abdomen) 
• 
Collect vital sign measurements (including heart and respiratory rate, blood 
pressure, and body temperature) 
• 
AE monitoring 
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• 
Record concomitant medications 
6.1.5.1 
Open-Label Safety Extension Study 
Following study completion, subjects will be offered enrollment into a subsequent separate 
study, an OLES if there is adequate tolerability and no safety issues or signs of clinical 
progression that would recommend discontinuation.  
6.1.6 
End-of-Study Telephone Contact 
Subjects who do not enroll in the OLES will be  contacted via telephone every 6 months for 
2 years, and annually thereafter for a total of 4 years, for a brief upda te. Subjects are to be 
assessed for survival, listing for a liv er transplant or the performance of a liver transplant, or 
complications of chronic liver disease (ascites, spontaneous b acterial peritonitis, variceal 
bleeding, and encephalopathy; Table 12-3).  
6.2 Efficacy Assessments 
Refer to the Study Manual for specific procedures to be followed for the various efficacy 
assessments. Timing of the efficacy assessments is provided in the schedule of events in 
Table 12-2, and Table 12-3. 
6.2.1 
HVPG Measurement 
Evaluation of portal hypertension will be done using HVPG measurement. Subjects without 
varices or with small varices will have hepatic venous catheterization with measurement of 
both wedged and free hepatic venous pressures and standardized calculation of the HVPG 
prior to randomization and first IMP dose. All HVPG pressure tracings will be performed 
according to the study guidelines provided in the Study Manual. All HVPG tracings will be 
evaluated at a central reading facility by a single experienced investigator (Dr Guadalupe 
Garcia-Tsao, Yale University) to confirm that the subjects meet criteria for inclusion prior to 
randomization. 
Blinded paired HVPG tracings from prior to randomization and at the end of the study will 
be evaluated at the same central facility by the experienced investigator.  
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6.2.2 
Liver Biopsy 
Liver biopsies will be evaluated to determine the general pathological diagnosis and to 
quantitatively evaluate the degree of liver fibrosis. In a central pathology laboratory, paired 
biopsies from baseline and the end of treatment for each individual will be stained with Sirius 
red, which stains specifically type I collagen, and digital morphometry used to quantitate the 
percentage of the liver biopsy that stains with Sirius red, as previously described 
(McHutchison 2010). The change in liver collagen (a surrogate for fibrosis) will be measured 
by the change in the CPA at 1 year on paired liver biopsies from prior to randomization and 
at the end of study. All liver biopsies will be performed according to the study guidelines 
provided in the Study Manual. Liver biopsies will be evaluated at a central pathology 
laboratory by a single, experienced pathologist (Dr. Zack Goodman, INNOVA Medical 
Center).  
In addition, as exploratory endpoints, liver biopsies will be stained with antibodies to alpha 
smooth muscle and galectin-3 and similarly quantified (McHutchison 2010). The change in 
staining of these 2 proteins will be compared for each subject at baseline and the end of 
treatment. 
6.2.3 
FibroScan 
FibroScan is an FDA approved, noninvasive diagnostic instrument that uses an 
electromechanical vibrator and pulse-echo ultrasound to evaluate the elastic shear wave in 
liver tissue which is a measure of liver stiffness. The stiffness of the liver is recorded as the 
pressure measurement of kPa. The stiffness of the liver correlates with the degree of liver 
fibrosis as assessed by liver biopsy, including subjects with NASH (Wong 2010). One 
advantage of this method is that the volume of liver tissue assessed is approximately 
100 times greater than volume assessed by liver biopsy. As such, FibroScan represents a 
promising noninvasive, outpatient method for measuring changes in liver fibrosis over time. 
FibroScan evaluations will be performed after an 8-hour fast according to the study 
guidelines provided in the Study Manual and as per the manufacturer’s instructions. 
6.2.4 
13C-methacetin Breath Test 
The MBT is a noninvasive tool to assess microsomal capacity to metabolize the 
nonradioactive 13C-labeled methacetin. For those study centers where the MBT is approved, 
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the test will be performed after an 8-hour fast according to the study guidelines provided in 
the Study Manual and as per the manufacturer’s instructions. The study center will make a 
follow-up telephone call to the subject to capture any AEs that may have occurred within 
48 hours after the breath test. 
The Breath Test System consists of the BreathID® MCS device and a test kit containing a 
breath collection cannula and a nonradioactive isotope 13C-methacetin solution. The 
BreathID device measures and computes the 13CO2/12CO2 ratio in the subject’s exhaled 
breath in real time. 
The device is based on an FDA-approved device (510k#: K130524) for assessment of 
Helicobacter pylori infection in the stomach utilizing 13C-urea as a substrate. Performance 
and safety of the device utilizing the 13C-methacetin substrate for assessment of liver 
function have been studied in thousands of subjects worldwide, including in a large US 
pivotal study (G080107) enrolling over 400 subjects with chronic liver disease from 
11 participating sites (including 141 subjects with biopsy proven cirrhosis). This study 
demonstrated an excellent safety profile of the MBT. Furthermore, there are currently 
2 ongoing studies (G140190, G140254) for detection of clinically significant portal 
hypertension in subjects with advanced liver disease and for assessment of correlation to 
severity of liver disease in subjects with NAFLD. 
The MBT parameter to be used in the current study is the cPDR 30, which is th e cumulative 
percentage dose recovery of the metabolized 13C-methacetin 30 minutes after ingestion of the 
test substrate. It is obtained by using the following steps: 
1. All delta over baseline (DOB) m easures with corresponding tim e point (Tn) will be 
noted on the eCRF. Ea ch DOB wi ll be pl otted by the BreathID device using the 
following formula:  
DOB = 13CO2/12CO2 @Tn - 13CO2/12CO2 @T0 
where T0 is the baseline sample time (0) and Tn is the time point of the post-ingestion 
sample in minutes. 
2. The DOBs will be tran sformed into percentag e dose reco very rates (PDRs) at a 
specific time point (n) by using the following formula: 
PDRn =1.817853*DOBn × w0.5378 × h0.3963 
While: w = weight (in kg), h = height (in cm) 
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3. The following formula will be used to obtain cPDR30: 
 
6.2.5 
Child-Turcotte-Pugh Score 
The Child-Turcotte-Pugh score provides an assessment of the prognosis of chronic liver 
disease. In this classification system, various laboratory and clinical parameters are scored as 
shown in Table 6-1. 
Table 6-1 
Child-Turcotte-Pugh Scoring System 
Categories 
Scoring System 
Bilirubin 
+1: <2 mg/dL 
+2: 2-3 mg/dL 
+3: >3 mg/dL 
Albumin 
+1: >3.5 g/dL 
+2: 2.8-3.5 g/dL 
+3: <2.8 g/dL 
International normalized ratio 
+1: <1.7 
+2: 1.7-2.2 
+3: >2.2 
Ascites 
+1: No ascites 
+2: Ascites, medically controlled 
+3: Ascites, poorly controlled 
Encephalopathy 
+1: No encephalopathy 
+2: Encephalopathy, medically controlled 
+3: Encephalopathy, poorly controlled 
 
The total score determines the classification as show in Table 6-2. 
Table 6-2 
Child-Turcotte-Pugh Classification 
Points 
Class 
One-Year Survival 
Two-Year Survival 
5-6 
A 
100% 
85% 
7-9 
B 
81% 
57% 
10-15 
C 
45% 
35% 
 
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The subjects enrolled in this study will have Class A, well-compensated cirrhosis with a 
nearly 100% one-year survival. Additionally, a 2-point increase in the actual score will be 
used as an indication of progression of disease. 
6.2.6 
MELD Score 
The MELD score assesses the severity of chronic liver disease and is used for prioritizing 
allocation of liver transplants. The MELD score will be calculated from laboratory tests 
(serum bilirubin, serum creatinine, and prothrombin time INR).  
MELD score = (0.957 × ln(serum creatinine) + 0.378 × ln(serum bilirubin) + 1.120 × ln(INR) 
+ 0.643) × 10 (if hemodialysis, value for creatinine is automatically set to 4.0) 
Note: If any score is less than 1, the MELD assumes the score is equal to 1.  
6.2.7 
EGD Evaluation  
Subjects will undergo an EGD within 2 months prior to randomization and within 14 to 28 
days after the final 26th dose of IMP or where feasible following study termination and the 
following information will be collected.  
Esophageal varices, if present, will be classified as follows:  
1. 
Large varices >50% impingement on the lumen;  
2. 
Small varices <25% impingement on lumen;  
3. 
Medium varices are intermediate between small and large varices.  
Subjects with medium or large varices or varices with red signs, regardless of size, will be 
excluded from study participation. Red signs include red wale markings (dilated venules 
oriented longitudinally on the variceal surface), cherry red spots (small, red, spotty dilated 
venules usually about 2 mm in diameter on the variceal surface) or hematocystic spots (large, 
round, crimson red projection greater than 3 mm that looks like a blood blister on the variceal 
surface). Subjects without varices or with small varices will advance to HVPG measurement 
and liver biopsy. Consistent with the American Association for the Study of Liver Disease 
practice guidelines (Garcia-Tsao 2007), subjects with small varices will not receive treatment 
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with nonselective β-adrenergic inhibitors or variceal ligation therapy during the clinical study 
since long-term benefit has not been established for small varices. At the discretion of the 
principal investigator, subjects who have no varices or small varices and are currently on 
β-adrenergic inhibitors may be withdrawn from therapy at least 4 weeks prior to 
randomization. 
6.3 Exploratory Assessments 
6.3.1 
Chronic Liver Disease Questionnaire 
The CLDQ is a tool used to measure health-related quality of life in subjects with liver 
disease and has demonstrated good reliability and validity in subjects with chronic liver 
disease (Younossi 1999). The instrument includes 29 questions with 6 domains: abdominal 
symptoms, systemic symptoms, fatigue, activity, emotional function, and worry. The CLDQ 
will be given to the subject at the beginning of the visit (Table 12-2), and will be considered 
source documentation. The CLDQ is provided in Section 12.3. 
6.3.2 
Biomarkers 
Blood will be collected for assessment of biomarkers (Table 12-2). Tests will include the ELF 
test, FibroTest (FibroSure), and galectin-3. At each of these times, a blood sample will be 
frozen (–20°C; –4°F) and held before treatment and at the end of treatment for other possible 
poststudy biomarker testing. 
6.3.2.1 
Enhanced Liver Fibrosis Test 
The ELF is a method to predict the severity and clinical outcome in chronic liver diseases. 
The ELF test uses a routine blood sample to measure procollagen-III 
aminoterminal-propeptide, tissue inhibitor of matrix metalloproteinase-1, and hyaluronic 
acid. 
6.3.2.2 
FibroTest/FibroSure 
The FibroTest score (FibroSure in the United States), is a composite score that has been 
correlated with the extent of liver fibrosis. This score is calculated from the subject’s age, 
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sex, alpha-2-macroglobulin, haptoglobin, apolipoprotein A1, γ-glutamyl transpeptidase, and 
total bilirubin. 
6.3.2.3 
Galectin-3 
Blood will be collected for assessment of galectin-3 (Table 12-2). 
6.3.3 
Plasma and Serum Samples  
Plasma and serum samples will be collected at Visits 1, 13, and 26 (Table 12-2). These 
samples will be stored at at –20°C. 
6.4 Safety Assessments 
All subjects receiving any part of at least 1 infusion of study treatment will be evaluated for 
safety. Safety assessments will include incidence of AEs during study treatment, emergent 
physical examination abnormalities, emergent vital sign and ECG abnormalities, and 
laboratory parameter abnormalities.  
6.4.1 
Vital Sign Measurements 
Vital sign measurements (including heart and respiratory rate, blood pressure, and body 
temperature) will be collected before administration of IMP (Table 12-1 and Table 12-2).  
Blood pressure will be obtained with the subject in the supine position and measured twice 
consecutively with a 1-minute interval between measurements. The average of the 
2 measurements will be recorded. 
6.4.2 
Physical Examination 
A complete physical examination, including height and weight, will be performed at 
screening, with particular attention to examination for stigmata of liver disease/cirrhosis 
(Table 12-1). A limited physical examination will only include weight and examination of the 
heart, lung, and abdomen during the treatment phase (Table 12-2).  
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6.4.3 
Electrocardiogram 
A standard 12-lead ECG will be performed during screening and the treatment phase (Table 
12-1 and Table 12-2).  
Twelve-lead ECGs will be systematically digitally recorded after the subject has been in the 
supine position for at least 10 minutes. The electrodes will be positioned in the same location 
on the subject for each ECG recording. Electrocardiograms will be recorded before blood 
sampling. 
6.4.4 
Chest Radiograph 
Chest radiographs (posterior-anterior and lateral views) will be performed at screening (Table 
12-1). 
6.4.5 
Adverse Events 
6.4.5.1 
Definitions of Adverse Events 
The investigator is responsible for reporting all treatment-emergent AEs (TEAEs) that are 
observed or reported during the study, regardless of their relationship to IMP or their clinical 
significance. 
An AE is defined as any untoward medical occurrence in a subject enrolled into this study, 
regardless of its causal relationship to IMP. Subjects will be instructed to contact the 
investigator at any time after randomization if any symptoms develop. 
A TEAE is defined as any event not present before exposure to IMP or any event already 
present that worsens in either intensity or frequency after exposure to IMP. 
An SAE is defined as any event that results in death, is immediately life threatening, requires 
inpatient hospitalization or prolongation of existing hospitalization, results in persistent or 
significant disability/incapacity, or is a congenital anomaly/birth defect. Important medical 
events that may not result in death, be life threatening, or require hospitalization may be 
considered SAEs when, based upon appropriate medical judgment, they may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the outcomes listed 
in this definition. Examples of such medical events include allergic bronchospasm requiring 
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intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that 
do not result in inpatient hospitalization, or the development of drug dependency or drug 
abuse. 
6.4.5.2 
Eliciting and Documenting Adverse Events 
All AEs (serious and nonserious) will be assessed beginning at screening and up to 42 days 
after the last dose of IMP. 
Serious AEs that occur more than 42 days after the last dose of IMP need not be reported 
unless the investigator considers them related to IMP. 
At every study visit, subjects will be asked a standard nonleading question to elicit any 
medically related changes in their well-being. They will also be asked if they have been 
hospitalized, had any accidents, used any new medications, or changed concomitant 
medication regimens (both prescription and over-the-counter medications). 
In addition to subject observations, AEs identified from any study data (eg, laboratory values, 
physical examination findings, ECG changes) or identified from review of other documents 
that are relevant to subject safety will be documented on the AE page in the eCRF. 
6.4.5.3 
Reporting Adverse Events 
All AEs reported or observed during the study will be recorded on the AE page in the eCRF. 
Information to be collected includes drug treatment, dose, event term, time of onset, 
investigator-specified assessment of severity and relationship to IMP, time of resolution of 
the event, seriousness, any required treatment or evaluations, and outcome. Adverse events 
resulting from concurrent illnesses, reactions to concurrent illnesses, reactions to concurrent 
medications, or progression of disease states must also be reported. All AEs will be followed 
to adequate resolution. The Medical Dictionary for Regulatory Activities (MedDRA, 
Version 17.1) will be used to code all AEs.  
Any medical condition that is present at the time that the subject is screened but does not 
deteriorate should not be reported as an AE. However, if the subject’s condition deteriorates 
at any time during the study, it should be recorded as an AE. 
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Any AE that meets SAE criteria (Section 6.4.5.1) must be reported to the sponsor (designee) 
immediately (ie, within 24 hours) after the time study center personnel first learn about the 
event.  
Study center personnel should complete the AE eCRF using electronic data capture, 
designating the event as serious. If electronic data capture is unavailable, complete an SAE 
form using the following contact information: 
 
Pharmacovigilance 
 
929 N Front St 
 
Wilmington, NC 28401 
 
SAE Hotline: 1-800-201-8725 
 
SAE Fax line: 1-888-488-9697 
6.4.5.4 
Assessment of Severity 
The severity, or intensity, of an AE refers to the extent to which an AE affects the subject’s 
daily activities. The intensity of the AE will be rated as mild, moderate, or severe using the 
following criteria: 
Mild: 
These events require minimal or no treatment and do not interfere with the 
subject’s daily activities. 
Moderate: 
These events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with 
normal functioning. 
Severe: 
These events interrupt a subject’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually incapacitating. 
 
Changes in the severity of an AE should be documented to allow an assessment of the 
duration of the event at each level of intensity to be performed. Adverse events characterized 
as intermittent do not require documentation of onset and duration of each episode. 
6.4.5.5 
Assessment of Causality 
The investigator’s assessment of an AE’s relationship to IMP will be part of the 
documentation process, but it is not a factor in determining what is or is not reported in the 
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study. If there is any doubt as to whether a clinical observation is an AE, the event should be 
reported. 
The relationship or association of the test article in causing or contributing to the AE will be 
characterized using the following classification and criteria: 
Unrelated: 
This relationship suggests that there is no association between the IMP and the 
reported event. 
Possible: 
This relationship suggests that treatment with the IMP caused or contributed to 
the AE, ie, the event follows a reasonable temporal sequence from the time of 
IMP administration or follows a known response pattern to the IMP, but could 
also have been produced by other factors. 
Probable: 
This relationship suggests that a reasonable temporal sequence of the event 
with IMP administration exists and, based upon the known pharmacological 
action of the drug, known or previously reported adverse reactions to the drug 
or class of drugs, or judgment based on the investigator’s clinical experience, 
the association of the event with the IMP seems likely. The event disappears or 
decreases on cessation or reduction of the dose of IMP. 
Definite: 
This relationship suggests that a definite causal relationship exists between IMP 
administration and the AE, and other conditions (concurrent illness, 
progression/expression of disease state, or concurrent medication reaction) do 
not appear to explain the event. The event reappears or worsens if the IMP is 
re-administered. 
6.4.5.6 
Exceptions 
While the following events may fulfill the serious criteria, they do not need to be reported as 
SAEs: hospitalizations/emergency room stays lasting less than 24 hours not meeting other 
serious criteria, hospitalizations for baseline conditions that do not worsen after starting study 
participation, hospitalizations for elective procedures anticipated or scheduled prior to study 
participation, and events expected as part of progression of disease under study.  
6.4.5.7 
Follow-Up of Subjects Reporting Adverse Events 
All AEs must be reported in detail on the appropriate page in the eCRF and followed to 
satisfactory resolution, until the investigator deems the event to be chronic or not clinically 
significant, or until the subject is considered to be stable. 
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6.4.6 
Pregnancy 
Pregnancy is not regarded as an AE unless there is a suspicion that an IMP may have 
interfered with the effectiveness of a contraceptive medication. Any pregnancy that occurs 
during study participation must be reported using a clinical study pregnancy form. The 
pregnancy must be followed up to determine outcome (including spontaneous miscarriage, 
elective termination, normal birth, or congenital abnormality) and status of mother and child, 
even if the subject was discontinued from the study. Pregnancy complications and elective 
terminations for medical reasons must be reported as an AE or SAE. Spontaneous 
miscarriages must be reported as an SAE. 
Pregnancy must be reported in the same manner as an SAE to PPD Pharmacovigilance by the 
study center within 24 hours of being informed of the event. If a pregnancy occurs during the 
study, study treatment must be discontinued immediately (or per sponsor directive), and the 
pregnancy report form submitted to PPD Pharmacovigilance via the SAE fax line. The study 
center should submit the pregnancy follow-up form to document the outcome of the 
pregnancy (health of the neonate). In the event of a miscarriage, therapeutic abortion, death 
in utero, or the pregnancy outcome leads to an SAE for the mother, follow the Procedure for 
Reporting an SAE (Section 6.4.5.3). In the event of a congenital anomaly, an SAE form for 
the baby must be completed. 
Any SAE occurring in association with a pregnancy that is brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the study treatment must be promptly reported to Galectin Therapeutics 
Inc. 
6.4.7 
Laboratory Analyses 
Any abnormal laboratory test (hematology, clinical chemistry, or urinalysis) or other safety 
assessment results (eg, ECGs, radiological scans, vital sign measurements), including those 
that worsen from baseline, believed to be clinically significant in the medical and scientific 
judgment of the investigator are to be recorded as AEs or SAEs. 
However, any clinically significant laboratory assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for the 
subject’s condition, are not to be reported as AEs or SAEs. 
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6.4.8 
Hematology 
Tests will include the following: 
Hemoglobin  
Differential: 
Hematocrit  
 
Neutrophils 
Red blood cells  
 
Lymphocytes 
White blood cells 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
 
 
Prothrombin time 
 
 
Partial thromboplastin time 
 
 
Haptoglobin 
6.4.9 
Blood Chemistry 
Tests will include the following:  
Alanine aminotransferase  
Chloride 
Phosphorus 
Albumin 
Creatinine 
Potassium 
Alkaline phosphatase 
Fasting insulin level 
Sodium 
Aspartate aminotransferase  
γ-glutamyl transferase  
Total and direct bilirubin 
Bicarbonate 
Glucose 
Total protein 
Blood urea nitrogen  
Lactate dehydrogenase  
Uric acid 
Calcium 
Magnesium 
 
6.4.10 
Urinalysis 
Refer to the Study Manual for collecting urinalysis samples. Tests will include the following: 
Color 
Glucose 
Red blood cells 
Clarity 
Blood 
Hyaline and other casts 
pH 
Bilirubin 
Bacteria 
Specific gravity 
Leukocyte esterase 
Epithelial cells 
Ketones 
Nitrite 
Crystals 
Protein 
White blood cells 
Yeast 
6.4.11 
Alcohol TLFB 
Current alcohol consumption will be assessed during the treatment phase (Table 12-2) using 
the Alcohol TLFB. The Alcohol TLFB is a drinking assessment method that obtains estimates 
of daily drinking and has been evaluated with clinical and nonclinical populations. Using a 
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calendar, subjects will provide retrospective estimates of their daily drinking over a specified 
time period. The Alcohol TLFB will be given to the subject at the beginning of the visit 
(Table 12-2), and will be considered source documentation. 
Subjects should be instructed to refrain from regular alcohol use during the study. If subjects 
are found on the calendar to be drinking greater than or equal to 7 standard alcoholic drinks 
per week, they will be asked to stop drinking or reduce their intake. The Alcohol TLBF 
Calendars for the years 2015, 2016, and 2017 along with instructions are provided in 
Section 12.4.  
6.5 Pharmacokinetic Assessments 
Plasma levels of GR-MD-02 will be assessed in all subjects (Table 12-2). Plasma levels of 
GR-MD-02 will be assessed 2 hours following the infusion of IMP in all subjects after 
Infusion Visits 1, 2, 3, 4, 7 10, 13, and 26. At the first data safety monitoring board (DSMB) 
meeting, the panel will evaluate GR-MD-02 Cmax plasma levels after Infusion Visits 1, 2, 3, 
and 4 for the first 30 subjects. 
Blood samples for bioanalytical assay will be handled as described in the Study Manual. The 
date of PK blood collection must be recorded in the subject’s eCRF. Each label will state the 
study number, subject number, matrix (plasma), and study day of the sample. 
6.6 Sample Collections 
All safety laboratory tests will be collected after the subject has been fasting for at least 
8 hours. Each subject with have blood drawn for hematology and chemistry (including 
fasting insulin level). Refer to the Study Manual for instructions for sample handling and 
shipping. 
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7 
Statistical and Analytical Plan 
A summary of statistical methods is presented in the following sections and will be described 
in more detail in the statistical analysis plan (SAP). 
7.1 Primary Efficacy Endpoint 
The primary efficacy endpoint analysis is the baseline-adjusted change in HVPG at 1 year 
(53-55 weeks) in subjects treated with placebo as compared to subjects treated with 
GR-MD-02 (2 mg/kg/week or 8 mg/kg/week). 
7.2 Secondary Efficacy Endpoints 
The secondary endpoints are: 
• The baseline-adjusted absolute change in the CPA at 1 year as determined by 
digital morphometric analysis of liver biopsies 
• The baseline-adjusted change in liver stiffness as determined by FibroScan score 
prior to the first infusion, at Infusion Visit 13, and 14-28 days after final infusion 
• The baseline-adjusted change in the metabolic capacity of the liver as 
determined by cPDR30 of the MBT (if available) at screening, Infusion Visit 13, 
and 14-28 days after final infusion 
• The difference between GR-MD-02-treated and placebo-treated subjects in the 
progression of cirrhosis at 1 year, defined as the development of any of the 
following:  
o esophageal variceal hemorrhage or portal hypertensive gastropathy 
hemorrhage (confirmed by endoscopy or interventional radiology) 
o clinically apparent ascites 
o spontaneous bacterial peritonitis 
o overt hepatic encephalopathy 
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o an increase in Child-Turcotte-Pugh score ≥2 
o newly diagnosed varices in a subject without prior varices 
o progression from small to medium or large varices 
o qualification for liver transplant defined as a MELD score ≥15 
o listing for a liver transplant or the performance of a liver transplant 
o liver-related mortality 
7.3 Exploratory Endpoints 
Exploratory endpoints are to evaluate: 
• Difference in health-related quality of life (using the subject-completed CLDQ) 
following administration of GR-MD-02 or placebo at 1 year  
• Baseline-adjusted change in FibroTest (FibroSure) and ELF score at Infusion 
Visits 7, 13, 20, and 14-28 days after final infusion 
• Changes in liver biopsy staining for alpha smooth muscle and galectin-3 in 
subjects treated with GR-MD-02 or placebo at 1 year 
o HVPG ≥10 and <15 mm Hg (elevated portal pressure, with potential 
development of varices, classified as clinically significant portal hypertension)  
o HVPG ≥15 (increased incidence of complications from varices) 
7.4 Safety Endpoints 
The safety endpoints include the incidence of AEs during study treatment, emergent physical 
examination abnormalities, emergent vital sign and ECG abnormalities, and laboratory 
parameter abnormalities.  
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7.5 Pharmacokinetic Endpoint 
The PK endpoints include plasma concentrations and population PK parameters of 
GR-MD-02.  
7.6 Sample Size Calculations 
A total of approximately 156 subjects will be enrolled in the study. Sample size calculations 
are based on the comparison of the primary efficacy variable, change in HVPG from 
baseline, with the following assumptions (key assumptions discussed as follows):  
1. True mean change in HVPG from baseline at 52 weeks in the placebo group, 
Δp= 0 
2. True mean change in HVPG from baseline at 52 weeks in either GR-MD-02 dose 
group, ΔG = -2 mm Hg 
3. Common SD for difference in HVPG, σ = 3 mm Hg 
4. Null hypothesis, H0: θ = G - Δp= 0 
5. Type I error, α = 0.05 (2-sided significance test) 
6. Power = 80% 
7. Statistical test = 2-sample t -test for mean difference 
8. Randomization ratio = 1:1:1 
9. Drop-out rate of 25% 
For a mean difference of 2 mm Hg and accounting for a 25% dropout rate, the total sample 
size of 156 subjects (n = 52 subjects per group) will be required to achieve power of 80% 
with a 2-sided type I error rate of 0.05. 
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Discussion of assumptions: 
1. True mean change in HVPG from baseline at 52 weeks in the placebo group was 
set at 0 mm Hg. While one might assume that the fibrosis would progress over a 
1-year period and there might be a resultant increase in HVPG, the conservative 
assumption was made that there would be no change. 
2. True mean change in HVPG from baseline at 52 weeks in either GR-MD-02 dose 
group was set at 2 mm Hg. A reduction of 2 mm Hg in HVPG was chosen because 
a change of this degree is likely to be of clinical significance. The results of 
pharmacological therapies, such as nonselective β-blockers have been remarkably 
consistent across therapeutic studies. If the HVPG is reduced by at least 20% from 
baseline, the risk of variceal bleeding, rebleeding, and other complications of 
portal hypertension such as ascites, spontaneous bacterial peritonitis and 
hepatorenal syndrome markedly decreases and survival improves 
(VillanuevaVillanueva 2009; Escorsell 2000; Abraldes 2003). In addition, a 10% 
reduction in HVPG has been shown to prevent the development of varices 
(Groszmann 2005). Therefore, it appears that a reduction in HVPG between 10% 
to 20% confers clinical benefit of reduced variceal bleeding. It is anticipated that 
the mean HVPG for the experimental groups will be between 10 mm Hg and 
15 mm Hg, as in other similarly designed studies (Groszmann 2005). Therefore, a 
2 mm Hg change in HVPG between placebo and treated groups would be between 
15% and 20%, which is likely to be of clinical significance.  
3. The common SD for difference in HVPG over 1 year for subjects in the placebo 
group was set at σ = 3 mm Hg. This assumption was determined from primary 
data, obtained from the investigator (Dr Guadalupe Garcia-Tsao), from a 
longitudinal clinical study (Groszmann 2005). Table 7-1 and Table 7-2 show data 
for subjects in the placebo group who had baseline and 12-month HVPG 
measurements (n = 82), of which 32 subjects had a baseline HVPG <10 mm Hg 
and 50 subjects had a baseline HVPG ≥10 mm Hg. From these data, the SD of the 
absolute change at 12 months in the placebo group was 2.85 mm Hg. Therefore, 
the assumption of 3 mm Hg for the sample size calculation appears valid.  
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Table 7-1 
HVPG (mm Hg) at Baseline and 12 Months for Subjects in the 
Placebo Group in the Timolol Clinical Study 
Treatment 
Variable 
N 
Mean 
SD 
Median 
Lower 
Quartile 
Upper 
Quartile 
Min 
Max 
Placebo 
HVPG 
Baseline 
82 
11.29 
3.97 
10.75 
8 
14 
6 
23.5 
Placebo 
HVPG 
12 mo 
82 
10.98 
3.82 
10.9 
8 
14 
4 
22.0 
Abbreviations: Max, maximum; min, minimum; SD, standard deviation 
Source: Groszmann 2005  
Table 7-2 
Absolute Change in HVPG (mm Hg) at 12 Months for Subjects in 
the Placebo Group in the Timolol Clinical Study 
Treatment 
N 
Mean 
SD 
Median 
Lower 
Quartile 
Upper 
Quartile 
Placebo 
82 
0.31 
2.85 
0.5 
-1 
2 
Abbreviation: SD, standard deviation 
Source: Groszmann 2005  
 
7.7 Analysis Sets 
The following analysis sets will be used in the statistical analyses. 
Full-Analysis set (FAS): The FAS, or intent-to-treat group, will consist of all subjects who 
were randomly assigned to IMP. All analyses using the FAS will group subjects according to 
randomized treatment. The FAS will be used as the primary efficacy analysis set. 
Modified-Intent-to-Treat analysis set: The modified intent-to-treat set will consist of all 
subjects who were randomly assigned, received at least 1 infusion, and had at least 
1 postbaseline efficacy assessment (from Section 6.2). All analyses using the modified 
intent-to-treat set will group subjects according to randomized treatment. 
Per-protocol set: The per-protocol set will consist of all FAS subjects who have at least 80% 
compliance with study treatment, have not taken any prohibited medication, have no 
significant protocol deviations, and restricted to each subject’s time on IMP plus 30 days 
thereafter for the analysis of progression of efficacy events. All analyses using the 
per-protocol set will group subjects according to treatment actually received. 
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Safety set: The safety set will consist of all subjects who received any IMP. All analyses 
using the safety set will group subjects according to treatment actually received. 
Pharmacokinetic set: The PK analysis set will consist of subjects who provide at least 1 Cmax 
PK sample. 
7.8 Description of Subgroups to Be Analyzed 
No subgroup analyses are planned. 
7.9 Statistical Analysis Methodology 
Statistical analysis will be performed using SAS software Version 9.1.3 or later. Continuous 
variables will be summarized by randomized treatment group using the mean, the SD, 
median, 25th and 75th percentiles, minimum value, and maximum value. Point estimates and 
the associated 95% confidence interval for the difference in baseline-adjusted efficacy 
parameters will be summarized in a similar manner. Categorical variables will be 
summarized by randomization treatment group using frequency counts and percentages. All 
baseline and postbaseline data used for safety and efficacy evaluations will be listed in data 
listings. 
Baseline is defined as the last assessment prior to infusion with IMP (ie, the predosing 
assessment present in the database that is most proximate to the time of IMP administration). 
Measurements that are obtained after the first dose of study treatment will be considered 
postbaseline values. Change from baseline is defined as the postbaseline value minus the 
baseline value. 
All statistical tests will be 2-sided and will be at the 5% level of significance. Due to the 
small number of subjects expected to be enrolled at each study center, all summaries and 
analyses will be performed using data pooled across study centers. Any imbalances in subject 
enrollment at study centers will be reviewed and methods for accommodating/eliminating the 
potential effect on efficacy analyses will be addressed in the SAP. 
For analysis variables that are not normally distributed, alternative methods will be applied 
including the use of the Poisson-regression model (or the negative binomial) for counts data. 
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For others, a nonparametric method based on Hodge-Lehmann estimate (or similar) and 
associated 95% confidence interval on median difference will be applied (Hodges 1963). 
Methods for dealing with missing data including dates, efficacy and safety results will be 
specified in the SAP.  
Details of the statistical analyses, methods, adjustments for multiplicity, and data conventions 
will be described in the SAP. 
7.9.1 
Analysis of Primary Efficacy Endpoint 
The primary efficacy endpoint analysis is the baseline-adjusted change in HVPG at 1 year 
(53 to 55 weeks) in subjects treated with placebo as compared to subjects treated with 
GR-MD-02 (2 mg/kg/week or 8 mg/kg/week). Change in HVPG from baseline will be 
compared between treatments groups using analysis of covariance adjusted for baseline 
HVPG. Treatment group will be included in the model as indicator variables where T1 = 1 if 
subject is randomly assigned to 2 mg/kg/week and 0 otherwise and T2 = 1 if subject is 
randomly assigned to 8 mg/kg/week and 0 otherwise. The following hypotheses will be 
tested based on the parameter estimates (and standard errors) from the fit of the analysis of 
covariance model: 
H01: ΔT1 - Δp= 0 vs HA1: ΔT1 - Δp ≠ 0 
H02: ΔT2 - Δp= 0 vs HA2: ΔT2 - Δp ≠ 0 
The closed testing procedure of Bonferroni-Holm (1988) will be used to adjust for multiple 
comparisons of each GR-MD-02 dose (T1 and T2) with placebo so that overall type I error 
rate is preserved at 0.050 (2-sided). If at least 1 of 2 doses is found to be significantly better 
than placebo, the 2 doses will be compared with each other at the 0.05 level to address dose 
response. 
7.9.2 
Analysis of Key Secondary Efficacy Endpoints 
Key secondary endpoints will be examined using a gatekeeper statistical approach. If the 
primary endpoint is significant (α <0.05), analysis will proceed to the secondary endpoints. 
Since the evaluation of secondary endpoints will proceed using a prespecified hierarchy 
without statistical correction for multiplicity, if a secondary endpoint does not meet statistical 
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significance, all subsequent analysis will be treated as exploratory only. The key secondary 
endpoints will be evaluated in the following sequence:  
• 
Baseline-adjusted mean change in CPA will be compared between treatment 
groups using robust regression (M estimation method, Huber 1973) to account 
for skewedness of the data with adjustment for baseline CPA.  
• 
The baseline-adjusted mean change in FibroScan at 1 year will be analyzed 
using similar methods previously defined for the primary efficacy endpoint  
• 
The baseline-adjusted mean change in MBT (if available) at 1 year will be 
analyzed using similar methods previously defined for the primary efficacy 
endpoint  
• 
The incidence of complications of cirrhosis with portal hypertension at 1 year 
will be compared between groups using chi-square analysis. 
7.9.3 
Analysis of the Exploratory Efficacy Endpoint 
All exploratory endpoints will be analyzed in the same fashion as the primary endpoint. 
7.9.4 
Safety Analyses 
All subjects receiving any part of at least 1 infusion of study treatment will be evaluated for 
safety. The safety analyses will include evaluation of the incidence of treatment-emergent 
adverse events (TEAEs), grade 3 or greater AEs, SAEs and AEs leading to discontinuation of 
study treatment using the Common Terminology Criteria for Adverse Events Version 4.0 or 
higher. Laboratory and vital sign measurement will be evaluated over time on study using 
descriptive statistics. Shift analyses of relevant clinical laboratory parameters will be 
produced showing shifts across low, normal, and high categories. 
All heart rate (beats per minute), 12-lead ECG parameters, PR interval (milliseconds), QRS 
interval (milliseconds), QT interval (milliseconds), and QTc interval (milliseconds) will be 
measured, and overall interpretation will be summarized for all subjects by study visit 
including the last visit of the study.  
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Electrocardiogram parameters will be summarized using descriptive statistics. Mean and 
mean change from baseline values will be presented for every scheduled assessment. Change 
from baseline will be calculated as the postbaseline measurement minus the baseline 
measurement. If either the baseline or postbaseline value is missing, the observation will not 
be included in the change from baseline summary. In addition, counts and percentages for 
ECG overall interpretation (normal, abnormal, clinically significant, and not clinically 
significant) will be presented for each scheduled assessment. 
For physical examinations, the results (normal, abnormal, or not done) by body system of the 
full physical examination at the randomization visit and follow-up visits will be summarized 
with descriptive statistics by treatment group and visit. For physical examinations performed 
at postrandomization time points, the number and percentage of subjects with no change or 
any significant changes since the previous examination will be presented by treatment 
received. In addition, a shift table will be included to summarize the number and percentage 
of subjects with changes from baseline to each postrandomization visit by body system for 
each treatment group. The number and percentage of subjects with normal and abnormal 
results (clinically significant versus not clinically significant) for each body system will be 
presented by treatment group. 
Vital sign measurements (respiration, heart rate, temperature, systolic and diastolic blood 
pressure), height (at screening only), and BMI will be summarized descriptively at each 
scheduled visit. Mean and mean change from baseline values will be presented. Change from 
baseline will be calculated as postbaseline measurement minus baseline measurement. If 
either the baseline or postbaseline value is missing, the observation will not be included in 
the change from baseline summary. 
All safety data will be listed by subject, parameter, and time point. 
7.9.5 
Pharmacokinetic Analyses 
Pharmacokinetic data will be summarized descriptively. Descriptive statistics for GR-MD-02 
concentrations by dose group and visit will include arithmetic mean, SD, coefficient of 
variation, minimum, median, maximum, geometric mean and coefficient of variation 
geometric mean as appropriate. If appropriate, data will be further stratified by age, gender, 
and/or other demographic variables. Standard graphics, including plots of arithmetic mean 
(+SD) concentration by dose group and visit (both linear and semi-logarithmic), overlay plots 
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of mean concentration and individual concentrations (both linear and semi-logarithmic) will 
be provided. 
All concentrations below the limit of quantification or missing data will be labelled as such 
in concentration data listings. Concentrations below the lower limit of quantitation will be 
treated as zero in summary statistics of concentration data. All PK concentration data will be 
listed by subject and visit. 
No statistical analyses o f the pharmacokinetic data are planned. GR-MD-02 plasma levels 
will be used to evaluate system ic exposure following multiple dosing. Based on  the high  
correlation between area under the concentration-time curve and C max of GR-MD-02 in the 
Phase 1 clinical study ( Galectin 2014), the plasm a levels at 2 hours (approximate Cmax) 
following the dose of GR-MD-02 will b e used to  estimate the system ic exposure and to  
assess the attainment of the steady state of GR-MD-02.  
Exploratory population PK analysis will be performed. The nonlinear mixed-effect modeling 
approach will be used to evaluate the population pharmacokinetics of GR-MD-02. The 
population pharmacokinetic modeling will be performed using the NONMEM software (Icon 
Development Solutions, Hanover, MD). 
The structural PK model will contain PK parameters such as clearance and volume of 
distribution as fixed-effect parameters. The intersubject variability in the parameter estimates 
and the random residual error in the data will be estimated with an appropriate error model. 
The best-fit model will be selected based on the standard criteria, such as objective function 
values and diagnostic plots. Covariates affecting the intersubject variability will be explored 
and, if possible, quantified. Pharmacokinetic data from the previous Phase 1 clinical study 
will be pooled with data from this study, if appropriate. The population pharmacokinetic 
analysis plan will be provided in an analysis plan.  
7.9.6 
Other Analyses 
Summary statistical analyses will be provided for baseline assessments such as demographics 
and medical history. 
The numbers and percentages of subjects in each treatment group taking concomitant 
medications, defined as nonstudy medications with a stop date on or after the date of the first 
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infusion of study treatment, will be summarized by dictionary coded terms (WHO Drug 
Dictionary (Version 1 Sep 2014). Medications that started prior to the first infusion of study 
treatment but continued during treatment will also be defined as concomitant. Ongoing 
medications without stop dates are considered concomitant. Prior medications, defined as 
nonstudy medications with a stop date before the first infusion of study treatment, will also 
be summarized by treatment group. Medications with partial onset/stop dates that indicate 
that the medication could be concomitant in relation to the start date of study treatment will 
be classified as concomitant. Otherwise, they will be classified as prior medications.  
Investigational medicinal product exposure and overall percent compliance will be calculated 
per subject in the FAS population and summarized by treatment group using descriptive 
statistics. 
Additional exploratory analyses for the MBT (if available): A model/algorithm will be 
developed to increase correlation with HVPG measurements and biopsy results. 
All available breath test parameters (DOB at the respective times) will be collected from the 
completed eCRFs. The DOBs will be transformed to PDR by normalizing the DOB using 
subject weight and height (see Section 6.2.4). The area under the DOB and under the PDR 
curve will be calculated for a 5-minute time interval resulting in cDOB and cPDR at 5, 10, 
15, 20, 25, 30, 35, 40, 45, 50, 55, and 60 minutes, respectively. The algorithm will be 
developed using either logistic regression or neural network or any other known 
methodology including all available breath test parameters, as well as subject demographic 
and laboratory data. Using a cut-point on the score, a binary diagnosis of (yes/no) will be 
obtained for several HVPG cut-offs, as well as histological scores. Cross-validation methods 
will be used to test algorithm stability. 
7.9.7 
Interim Analyses 
An interim analysis of PK data will be conducted for the DSMB meeting as outlined in 
Section 10.1.1: Independent Data Safety Monitoring Board. 
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7.10 Data Quality Assurance 
The sponsor’s (or an authorized representative’s) Quality Assurance Department may 
conduct on-site audits of all aspects of the clinical study either during the study or after the 
study has been completed. 
The clinical study may also be subject to inspection by regulatory authorities (national or 
foreign), as well as the institutional review board/independent ethics committee (IRB/IEC) to 
ascertain that the study is being or has been conducted in accordance with protocol 
requirements, Good Clinical Practice (GCP), as well as the applicable regulatory 
requirements. 
7.10.1 
Data Management 
As part of the responsibilities assumed by participating in the study, the investigator agrees to 
maintain adequate case histories for the subjects treated as part of the research under this 
protocol. The investigator agrees to maintain accurate eCRFs and source documentation as 
part of the case histories. These source documents may include hospital records, clinical and 
office charts, chest x-ray and interpretation, questionnaires, pharmacy dispensing, and other 
records. 
The eCRF will be supplied by PPD. All eCRF information is to be filled in. If an item is not 
available or is not applicable, this fact should be indicated. Blank spaces should not be 
present unless otherwise directed. Corrections to the eCRF will be entered in the eCRF by the 
investigator or an authorized designee. All changes, including date and person performing 
corrections, will be available via the audit trail, which is part of the electronic system. For 
corrections made via data queries, a reason for any alteration must be provided. 
The CRF data for this study will be collected with an electronic data capture tool, Medidata 
RAVE. Each completed eCRF must be reviewed, signed, and dated by the investigator in a 
timely manner. The completed eCRF will be collected by clinical monitors as soon as 
practical after completion. 
Clinical data management will be performed in accordance with applicable Galectin 
Therapeutics Inc standards and data cleaning procedures to ensure the integrity of the data, 
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eg, removing errors and inconsistencies in the data. Adverse events and concomitant 
medication terms will be coded using MedDRA, an internal validated medication dictionary. 
After database lock, each study center will receive a CDROM containing all of their study 
center-specific eCRF data as entered into Medidata RAVE for the study, including full 
discrepancy and audit history. Additionally, a CDROM copy of all of the study center’s data 
will be created and sent to the sponsor for storage. A duplicate CDROM copy will be 
maintained by PPD for their records. In all cases, subject initials will not be collected or 
transmitted to the sponsor. 
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8 
Ethics 
8.1 Independent Ethics Committee or Institutional Review Board 
Federal regulations and the International Conference on Harmonisation (ICH) harmonised 
tripartite guideline E6(R1): Good Clinical Practice require that approval be obtained from an 
IRB/IEC before participation of human subjects in research studies. Before study onset, the 
protocol, informed consent, advertisements to be used for the recruitment of study subjects, 
and any other written information regarding this study to be provided to the subject or the 
subject’s legal guardian must be approved by the IRB/IEC. Documentation of all IRB/IEC 
approvals and of the IRB/IEC compliance with ICH E6(R1): GCP will be maintained by the 
study center and will be available for review by the sponsor or its designee. 
All IRB/IEC approvals should be signed by the IRB/IEC chairman or designee and must 
identify the IRB/IEC name and address, the clinical protocol by title or protocol number or 
both, and the date approval or a favorable opinion was granted. 
The investigator is responsible for providing written summaries of the progress and status of 
the study at intervals not exceeding 1 year or otherwise specified by the IRB/IEC. The 
investigator must promptly supply the sponsor or its designee, the IRB/IEC, and, where 
applicable, the institution, with written reports on any changes significantly affecting the 
conduct of the study or increasing the risk to subjects. 
8.2 Ethical Conduct of the Study 
The study will be performed in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki, ICH E6(R1) GCP, and all applicable regulations. 
8.3 Subject Information and Consent 
A written informed consent in compliance with US Title 21 Code of Federal Regulations 
(CFR) Part 50 shall be obtained from each subject before entering the study or performing 
any unusual or nonroutine procedure that involves risk to the subject. An informed consent 
template may be provided by the sponsor to investigative study centers. If any 
institution-specific modifications to study-related procedures are proposed or made by the 
study center, the consent should be reviewed by the sponsor or its designee or both before 
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IRB/IEC submission. Once reviewed, the consent will be submitted by the investigator to his 
or her IRB/IEC for review and approval before the start of the study. If the ICF is revised 
during the course of the study, all active participating subjects must sign the revised form. 
Before recruitment and enrollment, each prospective subject or his or her legal guardian will 
be given a full explanation of the study and be allowed to read the approved ICF. Once the 
investigator is assured that the subject/legal guardian understands the implications of 
participating in the study, the subject/legal guardian will be asked to give consent to 
participate in the study by signing the ICF. 
The investigator shall retain the signed original ICF(s) and give a copy of the signed and 
dated ICF to the subject or legal guardian. 
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9 
Investigator’s Obligations 
The following administrative items are meant to guide the investigator in the conduct of the 
study but may be subject to change based on industry and governmental standard operating 
procedures, working practice documents, or guidelines. Changes will be reported to the 
IRB/IEC but will not result in protocol amendments. 
9.1 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain subject confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the written 
permission of the subject (or the subject’s legal guardian), except as necessary for monitoring 
and auditing by the sponsor, its designee, the US FDA, or the IRB/IEC. 
The investigator and all employees and coworkers involved with this study may not disclose 
or use for any purpose other than performance of the study any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
study. Prior written agreement from the sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties. 
9.2 Financial Disclosure and Obligations 
Investigators are required to provide financial disclosure information to allow the sponsor to 
submit the complete and accurate certification or disclosure statements required under 
21 CFR 54. In addition, the investigator must provide to the sponsor a commitment to 
promptly update this information if any relevant changes occur during the course of the 
investigation and for 1 year following the completion of the study. 
Neither the sponsor nor PPD is financially responsible for further testing or treatment of any 
medical condition that may be detected during the screening process. In addition, in the 
absence of specific arrangements, neither the sponsor nor PPD is financially responsible for 
further treatment of the subject’s disease. 
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9.3 Investigator Documentation 
Prior to beginning the study, the investigator will be asked to comply with ICH E6(R1) 8.2 
and 21 CFR 50 by providing the following essential documents, including but not limited to: 
• 
IRB/IEC approval 
• 
Original investigator-signed investigator agreement page of the protocol 
• 
Form FDA 1572, fully executed, and all updates on a new fully executed Form 
FDA 1572 
• 
Curriculum vitae for the investigator and each subinvestigator listed on Form 
FDA 1572 
• 
Financial disclosure information to allow the sponsor to submit complete and 
accurate certification or disclosure statements required under 21 CFR 54. In 
addition, the investigators must provide to the sponsor a commitment to 
promptly update this information if any relevant changes occur during the 
course of the investigation and for 1 year after the completion of the study. 
• 
IRB/IEC-approved informed consent, samples of study center advertisements 
for recruitment for this study, and any other written information regarding this 
study that is to be provided to the subject or legal guardian 
9.4 Study Conduct 
The investigator agrees that the study will be conducted according to the principles of ICH 
E6(R1). The investigator will conduct all aspects of this study in accordance with all 
national, state, and local laws or regulations. Study information from this protocol will be 
posted on publicly available clinicaltrials.gov before enrollment of subjects begins. 
9.5 Adherence to Protocol 
The investigator agrees to conduct the study as outlined in this protocol and in accordance 
with ICH E6(R1) and all applicable guidelines and regulations. 
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9.6 Adverse Events and Study Report Requirements 
By participating in this study, the investigator agrees to submit reports of SAEs according to 
the timeline and method outlined in this protocol. In addition, the investigator agrees to 
submit annual reports to the study center IRB/IEC, as appropriate. 
9.7 Investigator’s Final Report 
Upon completion of the study, the investigator, where applicable, should inform the 
institution; the investigator/institution should provide the IRB/IEC with a summary of the 
study’s outcome and the sponsor and regulatory authority(ies) with any reports required. 
9.8 Records Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH E6(R1) region and until there are no pending or 
contemplated marketing applications in an ICH E6(R1) region or at least 2 years have 
elapsed since the formal discontinuation of clinical development of the IMP. These 
documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or by an agreement with the sponsor. It is the responsibility of the 
sponsor to inform the investigator/institution as to when these documents no longer need to 
be retained. 
9.9 Publications 
After completion of the study, the data may be considered for reporting at a scientific 
meeting or for publication in a scientific journal. In these cases, the sponsor will be 
responsible for these activities and will work with the investigators to determine how the 
manuscript is written and edited, the number and order of authors, the publication to which it 
will be submitted, and other related issues. The sponsor has final approval authority over all 
such issues. 
Data are the property of the sponsor and cannot be published without prior authorization 
from the sponsor, but data and publication thereof will not be unduly withheld. 
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10 Study Management 
10.1 Monitoring 
10.1.1 
Independent Data Safety Monitoring Board 
A DSMB will be established that includes a panel of at least 3 independent members to 
include medical experts and an unblinded biostatistician. An official charter will be 
established and approved by all members and Galectin Therapeutics Inc. The primary role of 
the DSMB will be to periodically monitor the safety of the clinical study. The DSMB will 
meet at several predetermined times during the study and at any other time when it is 
determined by the DSMB or Galectin Therapeutics Inc that such a review is warranted. An 
organizational meeting will be held prior to the first subject randomly assigned to IMP to 
review and approve the DSMB Charter and to review the output to be provided to the DSMB 
for scheduled reviews. In addition, an unblinded monitoring team will be established. 
The first scheduled DSMB review meeting will be after the first 30 subjects in the study have 
received 7 doses of IMP. The purpose of this early look at safety is to ensure that there are no 
unexpected AEs in the population being evaluated in this study. The second scheduled 
DSMB review meeting will occur after approximately 50% of the total number of subjects to 
be enrolled has received 13 doses of IMP. The DSMB will then meet again after 50% of 
subjects have received 26 doses of IMP. 
At the first DSMB meeting, the panel will also evaluate GR-MD-02 Cmax plasma levels after 
Infusion Visits 1, 2, 3, and 4 for the first 30 subjects. There should be approximately 
10 subjects who received 2 mg/kg and 10 subjects who received 8 mg/kg in this group of 
subjects. With the aid of a clinical pharmacologist on the panel, the DSMB will assess Cmax 
levels as a surrogate for systemic exposure, with increasing number of doses in the groups 
receiving IMP and compare the levels to the safety margins indicated by long-term animal 
toxicology studies. 
The investigative study center staff, subjects, the sponsor and its representatives, and 
representatives of the CRO, except those responsible for providing unblinded data to the 
DSMB, will remain blinded throughout the full duration of the study until after the database 
is locked at the conclusion of the blinded treatment period. 
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10.1.2 
Monitoring of the Study 
The clinical monitor, as a representative of the sponsor, has the obligation to closely follow 
the study. In doing so, the monitor will visit the investigator and study center at periodic 
intervals, in addition to maintaining necessary telephone and letter contact. The monitor will 
maintain current personal knowledge of the study through observation, review of study 
records and source documentation, and discussion of the conduct of the study with the 
investigator and personnel. 
All aspects of the study will be carefully monitored, by the sponsor or its designee, for 
compliance with applicable governmental regulation with respect to current GCP and current 
standard operating procedures. 
For the purposes of this study, a blinded and unblinded monitoring team will be used. 
10.1.3 
Inspection of Records 
Investigators and institutions involved in the study will permit study-related monitoring, 
audits, IRB/IEC review, and regulatory inspections by providing direct access to all study 
records. In the event of an audit, the investigator agrees to allow the sponsor, representatives 
of the sponsor, or a regulatory agency (eg, FDA or other regulatory agency) access to all 
study records. 
The investigator should promptly notify the sponsor and PPD of any audits scheduled by any 
regulatory authorities and promptly forward copies of any audit reports received to the 
sponsor. 
10.2 Management of Protocol Amendments and Deviations 
10.2.1 
Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent, 
immediate hazard to the subject, must be reviewed and approved by the sponsor or its 
designee. Amendments to the protocol must be submitted in writing to the investigator’s 
IRB/IEC for approval before subjects can be enrolled into an amended protocol. 
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10.2.2 
Protocol Deviations 
The investigator or designee must document and explain in the subject’s source 
documentation any deviation from the approved protocol. The investigator may implement a 
deviation from, or a change of, the protocol to eliminate an immediate hazard to study 
subjects without prior IRB/IEC approval. As soon as possible after such an occurrence, the 
implemented deviation or change, the reasons for it, and any proposed protocol amendments 
should be submitted to the IRB/IEC for review and approval, to the sponsor for agreement, 
and to the regulatory authorities, if required. 
A deviation from the protocol is an unintended or unanticipated departure from the 
procedures or processes approved by the sponsor and the IRB/IEC and agreed to by the 
investigator. A significant deviation occurs when there is nonadherence to the protocol by the 
subject or investigator that results in a significant, additional risk to the subject. Significant 
deviations can include nonadherence to inclusion or exclusion criteria, enrollment of the 
subject without prior sponsor approval, or nonadherence to FDA regulations or ICH E6(R1) 
GCP guidelines, and will lead to the subject being withdrawn from the study (Section 4.2). 
Protocol deviations will be documented by the clinical monitor throughout the course of 
monitoring visits. Principal investigators will be notified in writing by the monitor of 
deviations. The IRB/IEC should be notified of all protocol deviations in a timely manner. 
10.3 Study Termination 
Although Galectin Therapeutics Inc has every intention of completing the study, Galectin 
Therapeutics Inc reserves the right to discontinue the study at any time for clinical or 
administrative reasons. 
The end of the study is defined as the date on which the last subject completes the last visit 
(includes follow-up visit). 
10.4 Final Report 
Whether the study is completed or prematurely terminated, the sponsor will ensure that the 
clinical study reports are prepared and provided to the regulatory agency(ies), as required by 
the applicable regulatory requirement(s). The sponsor will also ensure that the clinical study 
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reports in marketing applications meet the standards of the ICH E6(R1): Structure and 
content of clinical study reports. 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results. 
Upon completion of the clinical study report, the sponsor will provide the investigator with 
the full summary of the study results. The investigator is encouraged to share the summary 
results with the study subjects, as appropriate. The study results will be posted on publicly 
available clinical trial registers. 
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11 Reference List 
Abraldes JG, Tarantino I, Turnes J, et al. Hemodynamic response to pharmacological 
treatment of portal hypertension and long-term prognosis of cirrhosis. Hepatology. 
2003;37(4):902-8. 
Babor TF, Higgins-Biddle JC, Saunders JB, et al. AUDIT; The alcohol use disorders 
identification test: guidelines for use in primary care, 2nd ed. [Internet].  Geneva: World 
Health Organization; 2000 [cited 2013 Apr 30]. p. 17. Available from: 
http://www.who.int/substance_abuse/activities/sbi/en/. 
Caldwell S, Argo C. The natural history of non-alcoholic fatty liver disease. Dig Dis. 
2010;28(1):162-8. 
Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic 
fatty liver disease: practice Guideline by the American Association for the Study of Liver 
Diseases, American College of Gastroenterology, and the American Gastroenterological 
Association. Hepatology. 2012;55(6):2005-23. 
Di LS, Sundblad V, Cerliani JP, et al. When galectins recognize glycans: from biochemistry 
to physiology and back again. Biochemistry. 2011;50(37):7842-57. 
Escorsell A, Bordas JM, Castañeda B, et al. Predictive value of the variceal pressure response 
to continued pharmacological therapy in patients with cirrhosis and portal hypertension. 
Hepatology. 2000;31(5):1061-7. 
Exalenz Bioscience Ltd. Clinical study of the BreathID® system to train the algorithm for the 
¹³C-octanoate breath test with or without the ¹³C-methacetin breath test (OBT and MBT, 
respectively) for correlation with histological findings of non-alcoholic fatty liver disease 
(NAFLD). January 2015. IDE Approval G140254. 
Exalenz Bioscience Ltd. Clinical study of the BreathID® LF system to train the algorithm for 
the ¹³C-methacetin breath test (MBT) in assessment of portal hypertension in patients with 
compensated liver cirrhosis. November 2014. IDE Approval G140190. 
Exalenz Bioscience Ltd. Pivotal study to evaluate the efficacy and safety of the BreathID® 
system for detection of cirrhosis using the¹³C-methacetin breath test (MBT). July 2008. IDE 
Approval G080107. 
Galectin Pharmaceuticals Inc (Norcross, Georgia). A multi-center, partially blinded, 
maximum tolerated multiple dose escalation, Phase 1 clinical trial to evaluate the safety of 
GR-MD-02 in subjects with non-alcoholic steatohepatitis (NASH) with advanced hepatic 
fibrosis. 17 Jun 2014. Protocol No.: GT-020. Version 4. 96 p. 
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Garcia-Tsao G, Sanyal AJ, Grace ND. Prevention and management of gastroesophageal 
varices and variceal hemorrhage in cirrhosis. Hepatology. 2007;46(3):922-38. 
Garcia-Tsao G, Bosch J. Management of varices and variceal hemorrhage in cirrhosis. N 
Engl J Med. 2010;362(9):823-32. 
Groszmann RJ, Garcia-Tsao G, Bosch J, et al. Beta-blockers to prevent gastroesophageal 
varices in patients with cirrhosis. N Engl J Med. 2005;353(21):2254-61. 
Hodges, JL and Lehmann EL. Estimates of location based on rank test. The Annals of 
Mathematical Statistics. 1963;34(2):598-611. 
Huber, PJ. Robust Regression: Asymptotics, Conjectures and Monte Carlo. Annals of 
Statistics. 1973;1:799-821. 
Janmahasatian S, Duffull SB, Ash S, et al. Quantification of lean bodyweight. Clin 
Pharmacokinet. 2005;44(10):1051-65. 
McHutchison J, Goodman Z, Patel K, et al. Farglitazar lacks antifibrotic activity in patients 
with chronic hepatitis C infection. Gastroenterology. 2010;138(4):1365-73. 
Rinella ME. Will the increased prevalence of nonalcoholic steatohepatitis (NASH) in the age 
of better hepatitis C virus therapy make NASH the deadlier disease? Hepatology. 
2011;54(4):1118-20. 
Sobell LC, Maisto SA, Sobell MB, et al. Reliability of alcohol abusers’ self-reports of 
drinking behavior. Behav Res Ther. 1979;17(2):157-60. 
Sobell LC, Sobell MB. Timeline Follow-back: A technique for assessing self-reported 
alcohol consumption. In: Litten RZ, Allen JP (editors). Measuring alcohol consumption: 
Psychosocial and biochemical methods. Humana; -Totowa, NJ: 1992. P. 41-72. 
Sobell LC and Sobell MB. Alcohol Timeline Followback (TLFB) Users’ Manual. Toronto: 
Addiction Research Foundation, 1995. 
Traber PG, Zomer E. Therapy of experimental NASH and fibrosis with galectin inhibitors. 
PLoS One. 2013a;8(12):e83481. 
Traber PG, Chou H, Zomer E, et al. Regression of fibrosis and reversal of cirrhosis in rats by 
galectin inhibitors in thioacetamide-induced liver disease. PLoS One. 2013b;8(10):e75361. 
Villanueva C, Aracil C, Colomo A, et al. Acute hemodynamic response to beta-blockers and 
prediction of long-term outcome in primary prophylaxis of variceal bleeding. 
Gastroenterology. 2009;137(1):119-28. 
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Younossi Z, Guyatt G, Kiwi M, et al. Development of a disease specific questionnaire to 
measure health related quality of life in patients with chronic liver disease. Gut. 
1999;45(2):295-300. 
Williams CD, Stengel J, Asike MI, et al. Prevalence of nonalcoholic fatty liver disease and 
nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and 
liver biopsy: a prospective study. Gastroenterology. 2011;140(1):124-31. 
Wong VW, Vergniol J, Wong GL,  et al. Diagnosis of fibrosis and cirrhosis using liver 
stiffness measurement in nonalcoholic fatty liver disease. Hepatology. 2010;51(2):454-62. 
 
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12 Appendices 
12.1 Appendix: Schedule of Events  
 
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Table 12-1 
Schedule of Events - Prescreening and Screening 
Procedure 
Prescreening 
Screening  
Week 
Week –9 
Week -8 to Day 0a 
IWRS 
X 
X 
Informed consent 
X 
 
NASH Diagnosis 
Xb 
 
FibroScan 
Xb 
 
Inclusion/exclusion criteria 
 
X 
AUDIT 
 
X 
Demographic information 
 
X 
Medical, surgical, medication history 
 
X 
12-lead ECG 
 
X 
Hematology 
 
Xc 
Blood chemistry 
 
Xd 
Coagulation profile 
 
X 
MELD score 
 
X 
Viral hepatitis B and C serology 
 
X 
HIV serology 
 
X 
Urine drug screen (amphetamines, cocaine, and nonprescription opiates) 
 
X 
Urinalysis 
 
Xe 
Serum pregnancy test (females of childbearing potential only) 
 
Xf 
Chest radiographs (posterior-anterior and lateral views) 
 
X 
Child-Turcotte-Pugh score 
 
X 
Complete physical examination 
 
Xg 
 
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Table 12-1 
Schedule of Events - Prescreening and Screening, Continued 
Procedure 
Prescreening 
Screening  
Week 
Week –9 
Week -8 to Day 0a 
Vital sign measurements 
 
Xh 
MBT (if available) 
 
Xi 
EGD 
 
Xj 
HVPG 
 
Xk 
Liver biopsy 
 
X 
AE monitoring 
 
X 
Abbreviations: AE, adverse event; AUDIT, Alcohol Use Disorders Identification Test; ECG, electrocardiogram; EGD, esophagogastroduodenoscopy; HIV, human 
immunodeficiency virus; HVPG, hepatic venous pressure gradient; IWRS, interactive web response system; MBT, 13C-methacetin breath test; MELD, model for end-stage 
liver disease; NASH, nonalcoholic steatohepatitis. 
a 
The screening visit window is up to 8 weeks. Subjects who fail to meet eligibility criteria during the screening period due to an abnormal laboratory result may undergo 
retesting of the abnormal laboratory parameter during the screening window and at the discretion of the investigator and with prior approval of the medical monitor. 
b 
Subjects who have had a previous liver biopsy with either advanced bridging fibrosis (Ishak stage 4) or cirrhosis (Ishak stage 5 or 6) are eligible to move forward to screening. 
Subjects with a presumptive clinical diagnosis of NASH (based on the assessment of the principal investigator) will have a FibroScan to assess the potential for fibrosis. 
Subjects who have a FibroScan score of ≥12.0 kPa will be considered to have advanced fibrosis and will proceed to screening. Likewise, subjects with a documented 
qualifying FibroScan score within the previous 12 months of screening may proceed to screening. 
c 
Hematology will include complete blood cell count with differential (red blood cells, white blood cells, red cell indices, platelets, hemoglobin, and hematocrit). 
d 
Blood chemistry will include alanine aminotransferase, aspartate aminotransferase, albumin, alkaline phosphatase, bicarbonate, blood urea nitrogen, calcium, chloride, 
creatinine, glucose, lactate dehydrogenase, magnesium, phosphorus, potassium, sodium, total and direct bilirubin, total protein, uric acid, γ-glutamyl transferase, and fasting 
insulin level. Subjects must be in a fasted state prior to blood collection. 
e 
Urinalysis will include bacteria, bilirubin, blood, crystals, color, clarity, epithelial cells, glucose, hyaline and other casts, leukocyte esterase, nitrite,  pH, specific gravity, 
ketones, protein, red blood cells, white blood cells, and yeast. 
f 
Serum pregnancy test for females of childbearing potential only. (A urine pregnancy test will be given every 4 weeks during the treatment phase.) 
g 
Including height (in cm) and weight (in kg) with particular attention to examination for stigmata of liver disease/cirrhosis). 
h 
Vital sign measurements include heart and respiratory rate, blood pressure, and body temperature. Blood pressure will be obtained with the subject in the supine position and 
measured twice consecutively with a 1-minute interval between measurements. The average of the 2 measurements will be recorded. 
i 
The MBT (if available) will be performed prior to EGD, HVPG, or liver biopsy (at the discretion of the investigator). The study center will make a follow-up telephone call 
to the subject to capture any AEs that may have occurred within 48 hours after the breath test. 
j 
Subjects will have had an EGD within 2 months prior to randomization. Subjects with medium or large varices or varices with red signs (red wale marks or red spots), 
regardless of size, will be excluded from study participation. Subjects without varices or with small varices will continue to HVPG measurement and liver biopsy. 
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k 
Subjects must have both an HVPG measurement ≥6 mm Hg and a liver biopsy with advanced bridging fibrosis (Ishak stage 4) or cirrhosis (Ishak stage 5 or 6), presumably 
due to NASH. Subjects without varices or with small varices will have hepatic venous catheterization with measurement of both wedged and free hepatic venous pressures 
and standardized calculation of the HVPG prior to randomization and first IMP infusion.  
 
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Table 12-2 
Schedule of Events - Randomization, Treatment Phase, and Follow-up/Early Termination 
Infusion Visit 
0 
1 
2, 3, 4, 5, 
6 
7 
8, 9, 10, 
11, 12 
13 
14, 15, 16, 17, 
18, 19 
20  
21 
22, 23, 24, 
25 
26 
14-28 Days 
After Final 
Dose 
14 Days After 
Previous Visit/ET 
Week ± 3 days 
 
1 
3, 5, 7, 9, 
11 
13 
15, 17, 19, 
21, 23 
25 
27, 29, 31, 33, 
35, 37 
39 
41 
43, 45, 47, 
49 
51 
53-55 
57 
IWRS 
R
A
N
D
O
M
I 
Z
A
T 
I 
O
N 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FibroScan 
Xa 
 
 
 
X 
 
 
 
 
 
X 
 
MBT (if available) 
 
 
 
 
X 
 
 
 
 
 
X 
 
CLDQb 
X 
 
 
 
 
 
 
 
 
X 
 
 
Alcohol TLFB b 
X 
X - Inf 
Visit 5 
 
X - Inf 
Visit 9 
X 
X - Inf Visit 
17 
 
X 
X - Inf Visit 
25 
 
 
 
Limited physical 
examinationc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine pregnancy testd 
 
X - 
Inf Visits 
3, 5 
X 
X -  
Inf Visits 
9, 11 
X 
X - 
Inf Visits  
15, 17, 19 
 
X 
X -  
Inf Visits  
23, 25 
 
 
 
Vital sign measurementse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematologyf  
X 
 
X 
 
X 
 
X 
 
 
X 
X 
 
Blood chemistryg 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
 
MELD score 
 
 
 
 
X 
 
 
 
 
X 
 
 
Biomarkers blood sampleh 
X 
 
 
 
X 
 
 
 
 
 
X 
 
Plasma and serum sample 
for storage 
X 
 
 
 
X 
 
 
 
 
X 
 
 
IMP administrationi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
12-lead ECG 
 
 
 
 
X 
 
 
 
 
 
 
X 
Child-Turcotte-Pugh score 
 
 
 
 
X 
 
 
 
 
X 
 
 
EGDj 
 
 
 
 
 
 
 
 
 
 
 
X 
 
HVPGj 
 
 
 
 
 
 
 
 
 
 
X 
 
 
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Table 12-2 
Schedule of Events - Randomization, Treatment Phase, and Follow-up/Early Termination, Continued  
Infusion Visit 
0 
1 
2, 3, 4, 5, 
6 
7 
8, 9, 10, 
11, 12 
13 
14, 15, 16, 17, 
18, 19 
20  
21 
22, 23, 24, 
25 
26 
14-28 Days 
After Final 
Dose 
14 Days After 
Previous Visit/ET 
Week ± 3 days 
 
1 
3, 5, 7, 9, 
11 
13 
15, 17, 19, 
21, 23 
25 
27, 29, 31, 33, 
35, 37 
39 
41 
43, 45, 47, 
49 
51 
53-55 
57 
Liver biopsyj 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Assessment of cirrhosis 
complications 
 
X - Inf 
Visits  
3, 5 
X 
X - Inf 
Visits  
9, 11 
X 
X - Inf Visits 
15, 17, 19 
 
X 
X - Inf 
Visits  
23, 25 
X 
 
 
AE monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK samplek 
X 
X -  
Inf Visits 
2, 3, 4 
X 
X - Inf 
Visit 10 
X 
 
 
 
 
X 
 
 
Abbreviations: AE, adverse event; TLFB, Timeline Followback; EGD, esophagogastroduodenoscopy; CLDQ, chronic liver disease questionnaire; 
ECG, electrocardiogram; ET, early termination; HVPG, hepatic venous pressure gradient; IMP, investigational medicinal product; Inf, infusion; IWRS, 
interactive web response system; MBT, 13C-methacetin breath test; MELD, model for end-stage liver disease; PK, pharmacokinetic. 
Note: Subjects will be entered into the study and randomly assigned to IMP if they have both an HVPG screening measurement ≥6 mm Hg and a liver biopsy 
with advanced bridging fibrosis (Ishak stage 4) or cirrhosis (Ishak stage 5 or 6) presumably due to NASH.  
Note: Acceptable treatment windows for infusions will be ± 3 days. Infusions given outside of accepted windows will be considered “out-of-window” doses. If a 
dose is out of window, the subject should be brought back into compliance with their visit dosing schedule. The subject should not dose within 7 days of the 
previous or next dose unless the medical monitor is consulted. 
Note: Randomization must occur prior to Infusion Visit 1. 
a 
Within 2 weeks prior to the first infusion.  
b 
To be administered at the beginning of the visit. 
c 
Limited physical examination includes weight and examination of the heart, lung, and abdomen. 
d 
Urine pregnancy test will be given to females of childbearing potential every 4 weeks during the treatment phase 
e 
Vital sign measurements include heart and respiratory rate, blood pressure and body temperature prior to IMP administration. Blood pressure will be 
obtained with the subject in the supine position and measured twice consecutively with a 1-minute interval between measurements. The average of the 
2 measurements will be recorded. 
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GR-MD-02 (galactoarabino-rhamnogalacturnate) 
Protocol: GT-026 Original 
20 February 2015 
 
Page 106 
f 
Hematology will include complete blood cell count with differential (red blood cells, white blood cells, , red cell indices, platelets, hemoglobin, and 
hematocrit). 
g 
Blood chemistry will include alanine aminotransferase, aspartate aminotransferase, albumin, alkaline phosphatase, bicarbonate, blood urea nitrogen, calcium, 
chloride, creatinine, glucose, lactate dehydrogenase, magnesium, phosphorus, potassium, sodium, total and direct bilirubin, total protein, uric acid, 
γ-glutamyl transferase, and fasting insulin level. Subjects must be in a fasted state prior to blood collection. 
h 
Biomarker blood tests will include the enhanced liver fibrosis test, FibroTest (FibroSure), and galectin-3 and will occur prior to first infusion and at Infusion 
Visits 13 and 14 to 28 days following final 26th infusion. 
i 
IMP administration will occur after the following procedures: limited physical examination, vital sign measurements, hematology, blood chemistry, and 
biomarker blood samples. 
j 
Within 14 to 28 days after the final 26th dose of IMP or where feasible following study termination due to the occurrence of a clinical event or withdrawal of 
consent. EGD must be performed on a different day within the 14- to 28-day follow-up period than when the HVPG assessment is performed. 
k 
The PK sample will be collected 2 hours after the end of the IMP infusion. 
 
107


Galectin Therapeutics Inc. 
GR-MD-02 (galactoarabino-rhamnogalacturnate) 
Protocol: GT-026 Original                                                                                                                                                                                          20 February 2015 
 
Page 107 
 
Table 12-3 
Schedule of Events - End-of-Study Telephone Contacta 
Assessment 
Year 1 
Months 6, 12 
Year 2 
Months 18, 24 
Year 3 
Month 36 
Year 4 
Month 48 
Survival 
X 
X X X 
Listing for a liver transplant 
X 
X 
X 
X 
Performance of a liver transplanta 
X 
X X X 
Complications of chronic liver diseaseb 
X 
X X X 
a 
For those subjects who do not enroll in the open-label extension study. 
b 
Telephone contact will discontinue if a subject undergoes a liver transplant. 
c 
Complications of chronic liver disease include ascites, spontaneous bacterial peritonitis, variceal bleeding, and encephalopathy. 
 
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Galectin Therapeutics Inc. 
GR-MD-02 (galactoarabino-rhamnogalacturnate) 
Protocol: GT-026 Original 
20 February 2015 
 
Page 108 
12.2 Appendix: The AUDIT Questionnaire 
The full AUDIT manual will be provided in the Study Manual. 
Babor TF, Higgins-Biddle JC, Saunders JB, et al. AUDIT; The alcohol use disorders 
identification test: guidelines for use in primary care, 2nd ed. [Internet].  Geneva: World 
Health Organization; 2000 [cited 2013 Apr 30]. p. 31. Available from: 
http://www.who.int/substance_abuse/activities/sbi/en/. 
109


APPENDI X B I 31 
Box 10 
The Alcohol Use Disorders Identification Test: Self-Report Version 
PATIENT: Because alcohol use can affect your health and can interfere with certain medications and 
treatments, it is important that we ask some questions about your use of alcohol. Your answers 
will remain confidential so please be honest. 
Place an X in one box that best describes your answer to each question. 
Questions 
0 
1 
2 
3 
4 
1. How often do you have 
Never 
Monthly 
2-4 times 
2-3 times 
4 or more 
a drink containing alcohol? 
or less 
a month 
a week 
times a week 
2. How many drinks containing 
1or2 
3or4 
5or6 
7 to 9 
10 or more 
alcohol do you have on a typical 
day when you are drinking? 
3. How often do you have six or 
Never 
Less than 
Monthly 
Weekly 
Daily or 
more drinks on one 
monthly 
almost 
occasion? 
daily 
4. How often during the last 
Never 
Less than 
Monthly 
Weekly 
Daily or 
year have you found that you 
monthly 
almost 
were not able to stop drinking 
daily 
once you had started? 
5. How often during the last 
Never 
Less than 
Monthly 
Weekly 
Daily or 
year have you failed to do 
monthly 
almost 
what was normally expected of 
daily 
you because of drinking? 
6. How often during the last year 
Never 
Less than 
Monthly 
Weekly 
Daily or 
have you needed a first drink 
monthly 
almost 
in the morning to get yourself 
daily 
going after a heavy drinking 
session? 
7. How often during the last year 
Never 
Less than 
Monthly 
Weekly 
Daily or 
have you had a feeling of guilt 
monthly 
almost 
or remorse after drinking? 
daily 
8. How often during the last year 
Never 
Less than 
Monthly 
Weekly 
Daily or 
have you been unable to remem-
monthly 
almost 
ber what happened the night 
daily 
before because of your drinking? 
9. Have you or someone else 
No 
Yes, but 
Yes, 
been injured because of 
not in the 
during the 
your drinking? 
last year 
last year 
10. Has a relative, friend, doctor, or 
No 
Yes, but 
Yes, 
other health care worker been 
not in the 
during the 
concerned about your drinking 
last year 
last year 
or suggested you cut down? 
Total 
110


Galectin Therapeutics Inc. 
GR-MD-02 (galactoarabino-rhamnogalacturnate) 
Protocol: GT-026 Original 
20 February 2015 
 
Page 109 
 
12.3 Appendix: The Chronic Liver Disease Questionnaire 
 
111


 Younossi 1997 
Revised December 28, 1998 
The Chronic Liver Disease Questionnaire (CLDQ) 
 
This questionnaire is designed to find out how you have been feeling during the last two weeks.  You will 
be asked about your symptoms related to your liver disease, how you have been affected in doing 
activities, and how your mood has been.  Please complete all of the questions and select only one 
response for each question.  
 
1. 
How much of the time during the last two weeks have you been troubled by a feeling of 
abdominal bloating? 
 
1 
All of the time 
2 
Most of the time 
3 
A good bit of the time 
4 
Some of the time 
5 
A little of the time 
6 
Hardly any of the time 
7 
None of the time 
 
2. 
How much of the time have you been tired or fatigued during the last two weeks? 
 
1 
All of the time 
2 
Most of the time 
3 
A good bit of the time 
4 
Some of the time 
5 
A little of the time 
6 
Hardly any of the time 
7 
None of the time 
 
3. 
How much of the time during the last 2 weeks have you experienced bodily pain? 
 
1 
All of the time 
2 
Most of the time 
3 
A good bit of the time 
4 
Some of the time 
5 
A little of the time 
6 
Hardly any of the time 
7 
None of the time 
 
4. 
How often during the last two weeks have you felt sleepy during the day? 
 
1 
All of the time 
2 
Most of the time 
3 
A good bit of the time 
4 
Some of the time 
5 
A little of the time 
6 
Hardly any of the time 
7 
None of the time 
 
 
 
 
 
 
112


 Younossi 1997 
Revised December 28, 1998 
5. 
How much of the time during the last two weeks have you experienced abdominal pain? 
 
1 
All of the time 
2 
Most of the time 
3 
A good bit of the time 
4 
Some of the time 
5 
A little of the time 
6 
Hardly any of the time 
7 
None of the time 
 
6. 
How much of the time during the last two weeks has shortness of breath been a problem for 
you in your daily activities? 
 
1 
All of the time 
2 
Most of the time 
3 
A good bit of the time 
4 
Some of the time 
5 
A little of the time 
6 
Hardly any of the time 
7 
None of the time 
 
7. 
How much of the time during the last two weeks have you not been able to eat as much as 
you would like? 
 
1 
All of the time 
2 
Most of the time 
3 
A good bit of the time 
4 
Some of the time 
5 
A little of the time 
6 
Hardly any of the time 
7 
None of the time 
 
8. 
How much of the time in the last two weeks have you been bothered by having decreased 
strength? 
 
1 
All of the time 
2 
Most of the time 
3 
A good bit of the time 
4 
Some of the time 
5 
A little of the time 
6 
Hardly any of the time 
7 
None of the time 
 
9. 
How often during last 2 weeks have you had trouble lifting or carrying heavy objects? 
 
1 
All of the time 
2 
Most of the time 
3 
A good bit of the time 
4 
Some of the time 
5 
A little of the time 
6 
Hardly any of the time 
7 
None of the time 
 
 
113


 Younossi 1997 
Revised December 28, 1998 
 
10. 
How often during the last two weeks have you felt anxious? 
 
1 
All of the time 
2 
Most of the time 
3 
A good bit of the time 
4 
Some of the time 
5 
A little of the time 
6 
Hardly any of the time 
7 
None of the time 
 
11. 
How often during the last 2 weeks have you felt a decreased level of  energy? 
 
1 
All of the time 
2 
Most of the time 
3 
A good bit of the time 
4 
Some of the time 
5 
A little of the time 
6 
Hardly any of the time 
7 
None of the time 
 
12. 
How much of the time during the last two weeks have you felt unhappy? 
 
1 
All of the time 
2 
Most of the time 
3 
A good bit of the time 
4 
Some of the time 
5 
A little of the time 
6 
Hardly any of the time 
7 
None of the time 
 
13. 
How often during the last two weeks have you felt drowsy? 
 
1 
All of the time 
2 
Most of the time 
3 
A good bit of the time 
4 
Some of the time 
5 
A little of the time 
6 
Hardly any of the time 
7 
None of the time 
 
14. 
How much of the time during the last two weeks have you been bothered by a limitation of 
your diet? 
 
1 
All of the time 
2 
Most of the time 
3 
A good bit of the time 
4 
Some of the time 
5 
A little of the time 
6 
Hardly any of the time 
7 
None of the time 
 
 
 
114


 Younossi 1997 
Revised December 28, 1998 
 
 
15. 
How often during the last two weeks have you been irritable? 
 
1 
All of the time 
2 
Most of the time 
3 
A good bit of the time 
4 
Some of the time 
5 
A little of the time 
6 
Hardly any of the time 
7 
None of the time 
 
16. 
How much of the time during the last two weeks have you had difficulty sleeping at night? 
 
1 
All of the time 
2 
Most of the time 
3 
A good bit of the time 
4 
Some of the time 
5 
A little of the time 
6 
Hardly any of the time 
7 
None of the time 
 
17. 
 How much of the time during the last two weeks have you been troubled by a feeling of 
abdominal discomfort? 
 
1 
All of the time 
2 
Most of the time 
3 
A good bit of the time 
4 
Some of the time 
5 
A little of the time 
6 
Hardly any of the time 
7 
None of the time 
 
18. 
How much of the time during the last two weeks have you been worried about the impact 
your liver disease has on your family? 
 
1 
All of the time 
2 
Most of the time 
3 
A good bit of the time 
4 
Some of the time 
5 
A little of the time 
6 
Hardly any of the time 
7 
None of the time 
 
19. 
How much of the time during the last two weeks have you had mood swings? 
 
1 
All of the time 
2 
Most of the time 
3 
A good bit of the time 
4 
Some of the time 
5 
A little of the time 
6 
Hardly any of the time 
7 
None of the time 
 
115


 Younossi 1997 
Revised December 28, 1998 
 
 
20. 
How much of the time during the last two weeks have you been unable to fall asleep at 
night? 
 
1 
All of the time 
2 
Most of the time 
3 
A good bit of the time 
4 
Some of the time 
5 
A little of the time 
6 
Hardly any of the time 
7 
None of the time 
 
21. 
How often during the last two weeks have you had muscle cramps? 
 
1 
All of the time 
2 
Most of the time 
3 
A good bit of the time 
4 
Some of the time 
5 
A little of the time 
6 
Hardly any of the time 
7 
None of the time 
 
22. 
 How much of the time during the last two weeks have you been worried that your 
symptoms will develop into major problems? 
 
1 
All of the time 
2 
Most of the time 
3 
A good bit of the time 
4 
Some of the time 
5 
A little of the time 
6 
Hardly any of the time 
7 
None of the time 
 
23. 
How much of the time during the last two weeks have you had a dry mouth? 
 
1 
All of the time 
2 
Most of the time 
3 
A good bit of the time 
4 
Some of the time 
5 
A little of the time 
6 
Hardly any of the time 
7 
None of the time 
 
24. 
How much of the time during the last two weeks have you felt depressed? 
 
1 
All of the time 
2 
Most of the time 
3 
A good bit of the time 
4 
Some of the time 
5 
A little of the time 
6 
Hardly any of the time 
7 
None of the time 
 
116


 Younossi 1997 
Revised December 28, 1998 
 
 
25. 
How much of the time during the last two weeks have you been worried about your 
condition getting worse? 
 
1 
All of the time 
2 
Most of the time 
3 
A good bit of the time 
4 
Some of the time 
5 
A little of the time 
6 
Hardly any of the time 
7 
None of the time 
 
26. 
How much of the time during the last two weeks have you had problems concentrating? 
 
1 
All of the time 
2 
Most of the time 
3 
A good bit of the time 
4 
Some of the time 
5 
A little of the time 
6 
Hardly any of the time 
7 
None of the time 
 
27. 
How much of the time have you been troubled by itching during the last two weeks? 
 
1 
All of the time 
2 
Most of the time 
3 
A good bit of the time 
4 
Some of the time 
5 
A little of the time 
6 
Hardly any of the time 
7 
None of the time 
 
28. 
How much of the time during the last two weeks have you been worried about never feeling 
any better? 
 
1 
All of the time 
2 
Most of the time 
3 
A good bit of the time 
4 
Some of the time 
5 
A little of the time 
6 
Hardly any of the time 
7 
None of the time 
 
29. 
How much of the time during the last two weeks have you been concerned about the 
availability of a liver if you need a liver transplant? 
 
1 
All of the time 
2 
Most of the time 
3 
A good bit of the time 
4 
Some of the time 
5 
A little of the time 
6 
Hardly any of the time 
7 
None of the time 
117


 Younossi 1997 
Révisée 28 décembre 1998  
Questionnaire sur la maladie chronique du foie  
(Chronic Liver Disease Questionnaire, CLDQ) 
 
 Ce questionnaire est conçu pour comprendre comment vous vous êtes senti au cours des deux 
dernières semaines.  On vous posera des questions concernant des symptômes associés à votre maladie 
du foie, concernant comment vous avez été affecté dans vos activités, et comment votre humeur s'en est 
vue changer.  Veuillez compléter toutes les questions et ne sélectionner qu'une seule réponse pour 
chaque question.  
 
1. 
Au cours des deux dernières semaines, pendant combien de temps vous êtes-vous senti 
affecté par un ventre gonflé? 
 
1 
Tout le temps 
2 
La plupart du temps 
3 
Une bonne partie du temps 
4 
Une partie du temps 
5 
Quelque peu pendant cette période 
6 
À peine 
7 
En aucun temps 
 
2. 
Pendant combien de temps vous êtes-vous senti fatigué au cours des deux dernières 
semaines? 
 
1 
Tout le temps 
2 
La plupart du temps 
3 
Une bonne partie du temps 
4 
Une partie du temps 
5 
Quelque peu pendant cette période 
6 
À peine 
7 
En aucun temps 
 
3. 
Au cours des 2 dernières semaines, pendant combien de temps avez-vous ressenti une 
douleur physique? 
 
1 
Tout le temps 
2 
La plupart du temps 
3 
Une bonne partie du temps 
4 
Une partie du temps 
5 
Quelque peu pendant cette période 
6 
À peine 
7 
En aucun temps 
 
4. 
Au cours des deux dernières semaines, pendant combien de temps vous êtes-vous senti 
fatigué pendant la journée? 
 
1 
Tout le temps 
2 
La plupart du temps 
3 
Une bonne partie du temps 
4 
Une partie du temps 
5 
Quelque peu pendant cette période 
6 
À peine 
7 
En aucun temps 
118


 Younossi 1997 
Révisée 28 décembre 1998  
5. 
Au cours des deux dernières semaines, pendant combien de temps avez-vous ressenti une 
douleur abdominale? 
 
1 
Tout le temps 
2 
La plupart du temps 
3 
Une bonne partie du temps 
4 
Une partie du temps 
5 
Quelque peu pendant cette période 
6 
À peine 
7 
En aucun temps 
 
6. 
Au cours des deux dernières semaines, avez-vous eu le souffle court pendant vos activités 
quotidiennes? 
 
1 
Tout le temps 
2 
La plupart du temps 
3 
Une bonne partie du temps 
4 
Une partie du temps 
5 
Quelque peu pendant cette période 
6 
À peine 
7 
En aucun temps 
 
7. 
Au cours des deux dernières semaines, n'avez-vous pas été en mesure de manger autant 
que vous l'auriez souhaité? 
 
1 
Tout le temps 
2 
La plupart du temps 
3 
Une bonne partie du temps 
4 
Une partie du temps 
5 
Quelque peu pendant cette période 
6 
À peine 
7 
En aucun temps 
 
8. 
Au cours des deux premières semaines, pendant combien de temps avez-vous été affecté 
par un manque de puissance physique? 
 
1 
Tout le temps 
2 
La plupart du temps 
3 
Une bonne partie du temps 
4 
Une partie du temps 
5 
Quelque peu pendant cette période 
6 
À peine 
7 
En aucun temps 
 
9. 
Au cours des 2 dernières semaines, à quelle fréquence avez-vous rencontré des difficultés 
pour transporter des objets lourds? 
 
1 
Tout le temps 
2 
La plupart du temps 
3 
Une bonne partie du temps 
4 
Une partie du temps 
5 
Quelque peu pendant cette période 
6 
À peine 
7 
En aucun temps 
119


 Younossi 1997 
Révisée 28 décembre 1998  
10. 
Au cours des deux dernières semaines, pendant combien de temps vous êtes-vous senti 
anxieux pendant la journée? 
 
1 
Tout le temps 
2 
La plupart du temps 
3 
Une bonne partie du temps 
4 
Une partie du temps 
5 
Quelque peu pendant cette période 
6 
À peine 
7 
En aucun temps 
 
11. 
Au cours des 2 dernières semaines, à quelle fréquence vous êtes-vous senti comme étant 
affecté par une diminution du niveau d'énergie? 
 
1 
Tout le temps 
2 
La plupart du temps 
3 
Une bonne partie du temps 
4 
Une partie du temps 
5 
Quelque peu pendant cette période 
6 
À peine 
7 
En aucun temps 
 
12. 
Pendant combien de temps vous êtes-vous senti malheureux au cours des deux dernières 
semaines? 
 
1 
Tout le temps 
2 
La plupart du temps 
3 
Une bonne partie du temps 
4 
Une partie du temps 
5 
Quelque peu pendant cette période 
6 
À peine 
7 
En aucun temps 
 
13. 
Au cours des deux dernières semaines, pendant combien de temps vous êtes-vous senti 
somnolent au cours de la journée? 
 
1 
Tout le temps 
2 
La plupart du temps 
3 
Une bonne partie du temps 
4 
Une partie du temps 
5 
Quelque peu pendant cette période 
6 
À peine 
7 
En aucun temps 
 
14. 
Au cours des deux dernières semaines, à quelle fréquence avez-vous été empêché par une 
limite de votre diète? 
 
1 
Tout le temps 
2 
La plupart du temps 
3 
Une bonne partie du temps 
4 
Une partie du temps 
5 
Quelque peu pendant cette période 
6 
À peine 
7 
En aucun temps 
120


 Younossi 1997 
Révisée 28 décembre 1998  
 
15. 
Au cours des deux dernières semaines, pendant combien de temps vous êtes-vous senti 
irritable au cours de la journée? 
 
1 
Tout le temps 
2 
La plupart du temps 
3 
Une bonne partie du temps 
4 
Une partie du temps 
5 
Quelque peu pendant cette période 
6 
À peine 
7 
En aucun temps 
 
16. 
Au cours des deux dernières semaines, pendant combien de temps avez-vous eu de la 
difficulté à dormir pendant la nuit? 
 
1 
Tout le temps 
2 
La plupart du temps 
3 
Une bonne partie du temps 
4 
Une partie du temps 
5 
Quelque peu pendant cette période 
6 
À peine 
7 
En aucun temps 
 
17. 
 Au cours des deux dernières semaines, pendant combien de temps vous êtes-vous senti 
affligé d'un inconfort abdominal? 
 
1 
Tout le temps 
2 
La plupart du temps 
3 
Une bonne partie du temps 
4 
Une partie du temps 
5 
Quelque peu pendant cette période 
6 
À peine 
7 
En aucun temps 
 
18. 
Au cours des deux dernières semaines, à quel point avez-vous été inquiet de l'impact de la 
maladie sur votre famille? 
 
1 
Tout le temps 
2 
La plupart du temps 
3 
Une bonne partie du temps 
4 
Une partie du temps 
5 
Quelque peu pendant cette période 
6 
À peine 
7 
En aucun temps 
 
121


 Younossi 1997 
Révisée 28 décembre 1998  
19. 
Pendant combien de temps vous êtes-vous senti malheureux au cours des deux dernières 
semaines? Avez-vous réussi à amener un marbre qui donne du charme à cet endroit vide de 
la maison. 
 
1 
Tout le temps 
2 
La plupart du temps 
3 
Une bonne partie du temps 
4 
Une partie du temps 
5 
Quelque peu pendant cette période 
6 
À peine 
7 
En aucun temps 
 
20. 
Au cours des deux dernières semaines, pendant combien de temps avez-vous été incapable 
de dormir pendant la nuit? 
 
1 
Tout le temps 
2 
La plupart du temps 
3 
Une bonne partie du temps 
4 
Une partie du temps 
5 
Quelque peu pendant cette période 
6 
À peine 
7 
En aucun temps 
 
21. 
Au cours des deux dernières semaines, à quelle fréquence avez-vous eu des crampes 
musculaires? 
 
1 
Tout le temps 
2 
La plupart du temps 
3 
Une bonne partie du temps 
4 
Une partie du temps 
5 
Quelque peu pendant cette période 
6 
À peine 
7 
En aucun temps 
 
22. 
 Au cours des deux dernières semaines, combien de temps avez-vous été inquiété de voir 
vos symptômes se développer en problèmes majeurs? 
 
1 
Tout le temps 
2 
La plupart du temps 
3 
Une bonne partie du temps 
4 
Une partie du temps 
5 
Quelque peu pendant cette période 
6 
À peine 
7 
En aucun temps 
 
23. 
Pendant combien de temps avez-vous senti que votre gorge était sèche? 
 
1 
Tout le temps 
2 
La plupart du temps 
3 
Une bonne partie du temps 
4 
Une partie du temps 
5 
Quelque peu pendant cette période 
6 
À peine 
7 
En aucun temps 
122


 Younossi 1997 
Révisée 28 décembre 1998  
24. 
Au cours des deux dernières semaines, pendant combien de temps vous êtes-vous senti 
déprimé? 
 
1 
Tout le temps 
2 
La plupart du temps 
3 
Une bonne partie du temps 
4 
Une partie du temps 
5 
Quelque peu pendant cette période 
6 
À peine 
7 
En aucun temps 
 
25. 
Au cours des deux dernières semaines, à quel intervalle vous êtes-vous inquiété de voir 
votre situation empirer? 
 
1 
Tout le temps 
2 
La plupart du temps 
3 
Une bonne partie du temps 
4 
Une partie du temps 
5 
Quelque peu pendant cette période 
6 
À peine 
7 
En aucun temps 
 
26. 
Pendant combien de temps avez-vous senti que vous aviez des problèmes de 
concentration? 
 
1 
Tout le temps 
2 
La plupart du temps 
3 
Une bonne partie du temps 
4 
Une partie du temps 
5 
Quelque peu pendant cette période 
6 
À peine 
7 
En aucun temps 
 
27. 
Au cours des deux dernières semaines, pendant combien de temps vous êtes-vous senti 
importuné par des démangeaisons? 
 
1 
Tout le temps 
2 
La plupart du temps 
3 
Une bonne partie du temps 
4 
Une partie du temps 
5 
Quelque peu pendant cette période 
6 
À peine 
7 
En aucun temps 
 
28. 
Au cours des deux dernières semaines, vous êtes-vous inquiété de ne jamais vous sentir 
mieux qu'à ce moment? 
 
1 
Tout le temps 
2 
La plupart du temps 
3 
Une bonne partie du temps 
4 
Une partie du temps 
5 
Quelque peu pendant cette période 
6 
À peine 
7 
En aucun temps 
123


 Younossi 1997 
Révisée 28 décembre 1998  
 
29. 
Au cours des deux dernières semaines, pendant combien de temps vous êtes-vous inquiété 
de recevoir une transplantation dont vous aviez besoin? 
 
1 
Tout le temps 
2 
La plupart du temps 
3 
Une bonne partie du temps 
4 
Une partie du temps 
5 
Quelque peu pendant cette période 
6 
À peine 
7 
En aucun temps 
124


 Younossi 1997 
Revisado el 28 de diciembre de 1998 
Cuestionario sobre la enfermedad hepática crónica (CLDQ, por su sigla en 
inglés) 
 
 Este cuestionario está diseñado para averiguar cómo se ha sentido durante las últimas dos semanas. Se 
le harán preguntas sobre los síntomas que ha sufrido a causa de su enfermedad hepática, sobre cómo se 
han visto afectadas sus actividades cotidianas y sobre su estado de ánimo. Complete todas las preguntas
 
 
y seleccione sólo una respuesta para cada pregunta. 
1. 
Durante las últimas dos semanas ¿con qué frecuencia ha sufrido molestias a causa de una 
sensación de distensión abdominal? 
 
1 
Siempre 
2 
La mayor parte del tiempo 
3 
Una buena parte del tiempo 
4 
Algunas veces 
5 
Muy pocas veces 
6 
Casi nunca 
7 
Nunca 
 
2. 
Durante las últimas dos semanas ¿con qué frecuencia se ha sentido cansado o fatigado? 
 
1 
Siempre 
2 
La mayor parte del tiempo 
3 
Una buena parte del tiempo 
4 
Algunas veces 
5 
Muy pocas veces 
6 
Casi nunca 
7 
Nunca 
 
3. 
Durante las últimas dos semanas ¿con qué frecuencia ha sentido dolor corporal? 
 
1 
Siempre 
2 
La mayor parte del tiempo 
3 
Una buena parte del tiempo 
4 
Algunas veces 
5 
Muy pocas veces 
6 
Casi nunca 
7 
Nunca 
 
4. 
Durante las últimas dos semanas ¿con qué frecuencia se ha sentido somnoliento durante el 
día? 
 
1 
Siempre 
2 
La mayor parte del tiempo 
3 
Una buena parte del tiempo 
4 
Algunas veces 
5 
Muy pocas veces 
6 
Casi nunca 
7 
Nunca 
 
 
 
125


 Younossi 1997 
Revisado el 28 de diciembre de 1998 
 
 
 
5. 
Durante las últimas dos semanas ¿con qué frecuencia ha sentido dolor abdominal? 
 
1 
Siempre 
2 
La mayor parte del tiempo 
3 
Una buena parte del tiempo 
4 
Algunas veces 
5 
Muy pocas veces 
6 
Casi nunca 
7 
Nunca 
 
6. 
Durante las últimas dos semanas ¿con qué frecuencia la falta de aliento le ha dificultado la 
realización de sus actividades cotidianas? 
 
1 
Siempre 
2 
La mayor parte del tiempo 
3 
Una buena parte del tiempo 
4 
Algunas veces 
5 
Muy pocas veces 
6 
Casi nunca 
7 
Nunca 
 
7. 
Durante las últimas dos semanas ¿con qué frecuencia no ha podido comer todo lo que 
hubiera querido? 
 
1 
Siempre 
2 
La mayor parte del tiempo 
3 
Una buena parte del tiempo 
4 
Algunas veces 
5 
Muy pocas veces 
6 
Casi nunca 
7 
Nunca 
 
8. 
Durante las últimas dos semanas ¿con qué frecuencia ha sufrido molestias a causa de una 
sensación de debilidad? 
 
1 
Siempre 
2 
La mayor parte del tiempo 
3 
Una buena parte del tiempo 
4 
Algunas veces 
5 
Muy pocas veces 
6 
Casi nunca 
7 
Nunca 
 
9. 
Durante las últimas dos semanas ¿con qué frecuencia ha tenido inconvenientes al levantar 
o transportar objetos pesados? 
 
1 
Siempre 
2 
La mayor parte del tiempo 
3 
Una buena parte del tiempo 
4 
Algunas veces 
5 
Muy pocas veces 
126


 Younossi 1997 
Revisado el 28 de diciembre de 1998 
6 
Casi nunca 
7 
Nunca 
 
 
 
10. 
Durante las últimas dos semanas ¿con qué frecuencia se ha sentido ansioso? 
 
1 
Siempre 
2 
La mayor parte del tiempo 
3 
Una buena parte del tiempo 
4 
Algunas veces 
5 
Muy pocas veces 
6 
Casi nunca 
7 
Nunca 
 
11. 
Durante las últimas dos semanas ¿con qué frecuencia se ha sentido débil? 
 
1 
Siempre 
2 
La mayor parte del tiempo 
3 
Una buena parte del tiempo 
4 
Algunas veces 
5 
Muy pocas veces 
6 
Casi nunca 
7 
Nunca 
 
12. 
Durante las últimas dos semanas ¿con qué frecuencia se ha sentido triste? 
 
1 
Siempre 
2 
La mayor parte del tiempo 
3 
Una buena parte del tiempo 
4 
Algunas veces 
5 
Muy pocas veces 
6 
Casi nunca 
7 
Nunca 
 
13. 
Durante las últimas dos semanas ¿con qué frecuencia se ha sentido somnoliento? 
 
1 
Siempre 
2 
La mayor parte del tiempo 
3 
Una buena parte del tiempo 
4 
Algunas veces 
5 
Muy pocas veces 
6 
Casi nunca 
7 
Nunca 
 
14. 
Durante las últimas dos semanas ¿con qué frecuencia se ha sentido molesto a causa de una 
limitación en su dieta? 
 
1 
Siempre 
2 
La mayor parte del tiempo 
3 
Una buena parte del tiempo 
4 
Algunas veces 
5 
Muy pocas veces 
6 
Casi nunca 
127


 Younossi 1997 
Revisado el 28 de diciembre de 1998 
7 
Nunca 
 
 
 
 
 
15. 
Durante las últimas dos semanas ¿con qué frecuencia ha estado irritable? 
 
1 
Siempre 
2 
La mayor parte del tiempo 
3 
Una buena parte del tiempo 
4 
Algunas veces 
5 
Muy pocas veces 
6 
Casi nunca 
7 
Nunca 
 
16. 
Durante las últimas dos semanas ¿con qué frecuencia ha tenido dificultad para dormir por 
la noche? 
 
1 
Siempre 
2 
La mayor parte del tiempo 
3 
Una buena parte del tiempo 
4 
Algunas veces 
5 
Muy pocas veces 
6 
Casi nunca 
7 
Nunca 
 
17. 
 Durante las últimas dos semanas ¿con qué frecuencia ha sufrido molestias a causa de una 
sensación de malestar abdominal? 
 
1 
Siempre 
2 
La mayor parte del tiempo 
3 
Una buena parte del tiempo 
4 
Algunas veces 
5 
Muy pocas veces 
6 
Casi nunca 
7 
Nunca 
 
18. 
Durante las últimas dos semanas ¿con qué frecuencia ha estado preocupado por la 
repercusión que tiene su enfermedad hepática en su familia? 
 
1 
Siempre 
2 
La mayor parte del tiempo 
3 
Una buena parte del tiempo 
4 
Algunas veces 
5 
Muy pocas veces 
6 
Casi nunca 
7 
Nunca 
 
19. 
Durante las últimas dos semanas ¿con qué frecuencia ha sufrido cambios bruscos de 
ánimo? 
 
1 
Siempre 
2 
La mayor parte del tiempo 
128


 Younossi 1997 
Revisado el 28 de diciembre de 1998 
3 
Una buena parte del tiempo 
4 
Algunas veces 
5 
Muy pocas veces 
6 
Casi nunca 
7 
Nunca 
 
 
 
20. 
Durante las últimas dos semanas ¿con qué frecuencia no ha podido quedarse dormido por 
la noche? 
 
1 
Siempre 
2 
La mayor parte del tiempo 
3 
Una buena parte del tiempo 
4 
Algunas veces 
5 
Muy pocas veces 
6 
Casi nunca 
7 
Nunca 
 
21. 
Durante las últimas dos semanas ¿con qué frecuencia ha sufrido calambres musculares? 
 
1 
Siempre 
2 
La mayor parte del tiempo 
3 
Una buena parte del tiempo 
4 
Algunas veces 
5 
Muy pocas veces 
6 
Casi nunca 
7 
Nunca 
 
22. 
 Durante las últimas dos semanas ¿con qué frecuencia ha estado preocupado por la 
posibilidad de que sus síntomas se conviertan en problemas más graves? 
 
1 
Siempre 
2 
La mayor parte del tiempo 
3 
Una buena parte del tiempo 
4 
Algunas veces 
5 
Muy pocas veces 
6 
Casi nunca 
7 
Nunca 
 
23. 
Durante las últimas dos semanas ¿con qué frecuencia ha tenido la boca reseca? 
 
1 
Siempre 
2 
La mayor parte del tiempo 
3 
Una buena parte del tiempo 
4 
Algunas veces 
5 
Muy pocas veces 
6 
Casi nunca 
7 
Nunca 
 
24. 
Durante las últimas dos semanas ¿con qué frecuencia se ha sentido deprimido? 
 
1 
Siempre 
2 
La mayor parte del tiempo 
129


 Younossi 1997 
Revisado el 28 de diciembre de 1998 
3 
Una buena parte del tiempo 
4 
Algunas veces 
5 
Muy pocas veces 
6 
Casi nunca 
7 
Nunca 
 
 
 
25. 
Durante las últimas dos semanas ¿con qué frecuencia ha estado preocupado por la 
posibilidad de que su enfermedad empeore? 
 
1 
Siempre 
2 
La mayor parte del tiempo 
3 
Una buena parte del tiempo 
4 
Algunas veces 
5 
Muy pocas veces 
6 
Casi nunca 
7 
Nunca 
 
26. 
Durante las últimas dos semanas ¿con qué frecuencia ha tenido dificultad para 
concentrarse? 
 
1 
Siempre 
2 
La mayor parte del tiempo 
3 
Una buena parte del tiempo 
4 
Algunas veces 
5 
Muy pocas veces 
6 
Casi nunca 
7 
Nunca 
 
27. 
Durante las últimas dos semanas ¿con qué frecuencia ha sufrido molestias a causa de 
picazón? 
 
1 
Siempre 
2 
La mayor parte del tiempo 
3 
Una buena parte del tiempo 
4 
Algunas veces 
5 
Muy pocas veces 
6 
Casi nunca 
7 
Nunca 
 
28. 
Durante las últimas dos semanas ¿con qué frecuencia ha estado preocupado por la 
posibilidad de que usted nunca se sienta mejor? 
 
1 
Siempre 
2 
La mayor parte del tiempo 
3 
Una buena parte del tiempo 
4 
Algunas veces 
5 
Muy pocas veces 
6 
Casi nunca 
7 
Nunca 
 
29. 
Durante las últimas dos semanas ¿con qué frecuencia ha estado preocupado por la 
disponibilidad de un hígado si usted llegara a necesitar un trasplante? 
130


 Younossi 1997 
Revisado el 28 de diciembre de 1998 
 
1 
Siempre 
2 
La mayor parte del tiempo 
3 
Una buena parte del tiempo 
4 
Algunas veces 
5 
Muy pocas veces 
6 
Casi nunca 
7 
Nunca 
131


Galectin Therapeutics Inc. 
GR-MD-02 (galactoarabino-rhamnogalacturnate) 
Protocol: GT-026 Original 
20 February 2015 
 
Page 110 
12.4 Alcohol TLFB  
Sobell LC, Maisto SA, Sobell MB, et al. Reliability of alcohol abusers’ self-reports of 
drinking behavior. Behav Res Ther. 1979;17(2):157-60. 
Sobell LC, Sobell MB. Timeline Follow-back: A technique for assessing self-reported 
alcohol consumption. In: Litten RZ, Allen JP (editors). Measuring alcohol consumption: 
Psychosocial and biochemical methods. Humana; -Totowa, NJ: 1992. P. 41-72. 
Sobell LC and Sobell MB. Alcohol Timeline Followback (TLFB) Users’ Manual. Toronto: 
Addiction Research Foundation, 1995. 
12.4.1 
Alcohol TLFB Calendar 2015 
132


Name/ID#:  
 
 
Date:  
 
 
TIMELINE FOLLOWBACK CALENDAR: 2015 
 
 
 
 
 
 
 
 
 
 
 
 
 
2015 
SUN 
MON 
TUES 
WED 
THURS 
FRI 
SAT 
 
 
 
 
 
1
 New Year’s Day 
2 
3 
J 
4 
5 
6 
7 
8 
9 
10 
A 
11 
12 
13 
14 
15 
16 
17 
N 
18 
19 
M. Luther King  20 
21 
22 
23 
24 
 
25 
26 
27 
28 
29 
30 
31 
F 
1 
2 
3 
4 
5 
6 
7 
E 
8 
9 
10 
11 
12 
13 
14
 Valentine’s Day 
B 
15 
16 
Pres. Day  
17 
18 
19
 Chinese New Yr
20 
21 
 
22 
23 
24 
25
  
26 
27 
28 
M 
1 
2 
3 
4 
5 
6 
7 
A 
8 
9 
10 
11 
12 
13 
14  
R 
15 
16 
17
 St. Patrick’s Day 18 
19 
20 
21 
 
22 
23 
24 
25 
26 
27 
28 
 
29 
30 
31 
1 
2 
3
 Passover 
4
 Good Friday 
A 
5
 Easter 
6 
7 
8 
9
  
10  
11
  
P 
12
  
13
  
14 
15 
16 
17 
18 
R 
19 
20
  
21 
22 
23 
24 
25 
 
26 
27 
28 
29 
30 
1 
2 
M 
3 
4 
5 
6 
7 
8 
9 
A 
10
 Mother’s Day 
11 
12 
13 
14 
15 
16 
Y 
17 
18 
19 
20 
21 
22 
23 
 
24 
25
 Memorial Day  
26 
27 
28 
29 
30 
 
31 
 
 
 
 
 
 
 
One 5 oz glass of 
regular (12%) 
wine 
1 ½ oz of hard liquor 
(e.g. rum, vodka, 
whiskey) 
1 mixed or straight 
drink with 1 ½ oz 
hard liquor  
1 Standard Drink is Equal to 
One 12 oz 
can/bottle of 
beer 
Complete the Following 
Start Date (Day 1):   
 
 
 
   End Date (yesterday): 
   
MO  
DY 
       YR   
 
 
MO 
 
DY 
       YR  
133


TLFB 2015 
 
 
2 
 
TLFB 2004 
2 
 
2015 
SUN 
MON 
TUES 
WED 
THURS 
FRI 
SAT 
 
 
1 
2 
3 
4 
5 
6 
J 
7 
8 
9 
10 
11 
12 
13 
U 
14 
15 
16 
17 
18 
19 
20 
N 
21
 Father’s Day 
22 
23 
24 
25 
26 
27 
 
28 
29 
30 
1  
2 
3 
4 
Independence Day  
J 
5 
6 
7 
8 
9 
10 
11 
U 
12 
13 
14 
15 
16 
17 
18 
L 
19 
20
  
21 
22 
23 
24 
25 
 
26 
27 
28 
29 
30 
31 
1 
A 
2 
3  
4 
5 
6 
7 
8 
U 
9 
10 
11 
12 
13 
14 
15 
G 
16 
17 
18 
19 
20 
21 
22 
 
23 
24 
25 
26 
27 
28 
29 
 
30 
31 
1 
2 
3 
4 
5 
S 
6 
7
 Labor Day 
8 
9 
10 
11 
12 
E 
13
 Rosh Hashanah 
14 
15 
16 
17 
18 
19
 Rosh Hashanah 
P 
20 
21
  
22
 Yom Kippur 
23 
24 
25 
26 
 
27 
28
  
29 
30
  
1 
2 
3 
O 
4 
5 
6 
7 
8 
9 
10 
C 
11 
12
 Columbus Day 
13 
14 
15 
16 
17 
T 
18 
19 
20 
21 
22 
23 
24 
 
25 
26 
27 
28 
29 
30 
31
 Halloween 
N 
1 
2 
3
 Election Day  
4 
5 
6 
7 
O 
8 
9 
10
  
11 
Veterans Day 
12 
13 
14 
V 
15 
16 
17 
18 
19 
20 
21 
 
22 
23 
24 
25 
26
 Thanksgiving  
27 
28 
 
29 
30 
1 
2 
3 
4 
5 
D 
6
 Hanukkah 
7 
8 
9 
10 
11 
12
  
E 
13 
14
  
15 
16 
17 
18 
19 
C 
20 
21 
22 
23 
24 
25
 Christmas  
26  
 
27 
28 
29 
30 
31
 New Year’s Eve 
 
 
 
134


Galectin Therapeutics Inc. 
GR-MD-02 (galactoarabino-rhamnogalacturnate) 
Protocol: GT-026 Original 
20 February 2015 
 
Page 111 
12.4.2 
Alcohol TLFB Calendar 2016 
135


Name/ID#:  
 
 
Date:  
 
 
TIMELINE FOLLOWBACK CALENDAR: 2016 
 
 
 
 
 
 
 
 
 
 
 
 
2016 
SUN 
MON 
TUES 
WED 
THURS 
FRI 
SAT 
 
 
 
 
 
 
1
 New Year’s  
2 
J 
3 
4 
5 
6 
7 
8
 Chinese New Yr 
9 
A 
10 
11 
12 
13 
14 
15 
16 
N 
17 
18 
M. Luther King  
19 
20 
21 
22 
23 
 
24 
25 
26 
27 
28 
29 
30 
 
31 
1 
2 
3 
4 
5 
6 
F 
7 
8 
9 
10 
11 
12 
13 
E 
14
 Valentine’s Day 
15 
President’s Day  16 
17 
18 
19 
20 
B 
21 
22 
23 
24 
25 
26 
27 
 
28 
29
 Leap Year 
1 
2 
3 
4 
5 
M 
6 
7 
8 
9 
10 
11 
12 
A 
13 
14 
15 
16
  
17
 St.Patrick’s Day 
18 
19 
R 
20 
21 
22 
23 
24 
25
 Good Friday 
26 
 
27
 Easter Sunday 
28 
29 
39 
31 
1 
2 
A 
3 
4 
5 
6 
7 
8 
9 
P 
10 
11 
12 
13 
14 
15 
15 
R 
17 
18 
19 
20 
21 
22
 Passover 
23 
 
24 
25 
26 
27 
28 
29 
30 
M 
1 
2 
3 
4 
5 
6 
7 
A 
8
 Mother’s Day 
9 
10 
11 
12 
13 
14 
Y 
15 
16 
17 
18 
19 
20 
21 
 
22 
23
  
24 
25 
26 
27 
28 
 
29 
30
 Memorial Day 
31 
 
 
 
 
 
One 5 oz glass of 
regular (12%) 
wine 
1 ½ oz of hard liquor 
(e.g. rum, vodka, 
whiskey) 
1 mixed or straight 
drink with 1 ½ oz 
hard liquor  
1 Standard Drink is Equal to 
One 12 oz 
can/bottle of 
beer 
Complete the Following 
Start Date (Day 1):   
 
 
 
   End Date (yesterday): 
   
MO  
DY 
       YR   
 
 
MO 
 
DY 
       YR  
136


TLFB 2016 
 
2 
 
 
 
 
  
 
2 
 
2016 
SUN 
MON 
TUES 
WED 
THURS 
FRI 
SAT 
 
 
 
 
1 
2 
3 
4 
J 
5 
6 
7 
8 
9 
10 
11 
U 
12 
13 
14 
15 
16 
17 
18 
N 
19
Father’s Day 
20 
21 
22 
23 
24 
25 
26 
26 
27 
28 
29 
30 
1 
2 
J 
3  
4
 Independence Day 
5 
6 
7 
8 
19 
U 
10 
11 
12 
13 
14 
15 
16 
L 
17 
18 
19 
20 
21 
22 
23 
 
24 
25 
26 
27 
28 
29 
30 
A 
31 
1 
2 
3 
4 
5 
6 
U 
7 
8 
9 
10 
11 
12 
13 
G 
14 
15 
16 
17 
18 
19 
20 
 
21 
22 
23 
24 
25 
26 
27 
 
28 
29 
30 
31 
1 
2 
3 
S 
4 
5 
6 
7 
8 
9 
10 
E 
11 
12 
13 
14 
15 
16 
17 
P 
18 
19 
20 
21 
22 
23 
24 
 
25 
26 
27 
28 
29 
30 
1 
O 
2
 Rosh Hashanah 
3 
4 
5 
6 
7 
8 
C 
9 
10 
11 
12
 Yom Kippur 
13 
14 
15 
T 
16 
17 
18 
19 
20 
21 
22 
 
23 
24 
25 
26 
27 
28 
29 
 
30 
31
 Halloween 
1 
2 
3 
4 
5 
N 
6 
7 
8 
Election Day 
9 
10
  
11
 Veterans’ Day 
12 
O 
13 
14
 Columbus Day 
15 
16 
17 
18 
19 
V 
20 
21 
22 
23 
24
 Thanksgiving 
25 
26 
 
27 
28 
29 
30 
1 
2 
3 
D 
4 
5 
6 
7 
8 
9 
10 
E 
11 
12 
13 
14 
15 
16 
17 
C 
18 
19 
20 
21 
22 
23
  
24
 Hanukkah 
 
25
 Christmas 
26 
27 
28 
29 
30 
31
 New Year’s Eve 
  
137


Galectin Therapeutics Inc. 
GR-MD-02 (galactoarabino-rhamnogalacturnate) 
Protocol: GT-026 Original 
20 February 2015 
 
Page 112 
12.4.3 
Alcohol TLFB Calendar 2017 
138


Name/ID#:  
 
 
Date:  
 
 
TIMELINE FOLLOWBACK CALENDAR: 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2017 
SUN 
MON 
TUES 
WED 
THURS 
FRI 
SAT 
 
1
 New Year’s 
2 
3 4 5 6 7 
J 
8 
9 
10 
11 
12 
13 
14 
A 
15 
16 
M. L. King  
17 
18 
19 
20 
21 
N 
22 
23 
24 
25 
26 
27 
28
Chinese New Yr 
 
29 
30 
31 
1 
2 
3 
4 
F 
5 
6 7 8 9 1
0 
11 
E 
12 
13 
14
 Valentine’s Day  15 
16 
17 
18 
B 
19 
20
 Presidents’ Day 
21 
22 
23 
24 
25 
 
26 
27 
28 
1
  
2 
3 4 
M 
5 
6 7 8 9 1
0 
11 
A 
12 
13 
14 
15 
16 
17 
St. Patrick’s Day 
18
  
R 
19 
20 
21 
22 
23 
24 
25 
 
26 
27 
28 
29 
30 
31 
1 
A 
2 
3 4
  
5 
6 7
   
8 
P 
9  
10 
11
 Passover 
12 
13
  
14
 Good Friday 
15 
R 
16 
 Easter 
17 
18 
19 
20 
21 
22 
 
23 
24 
25 
26 
27 
28 
29 
 
30 
1 
2 3 4 5 6 
M 
7 
8 
9 
10 
11 
12 
13 
A 
14
 Mother’s Day 
15 
16 
17 
18 
19 
20 
Y 
21 
22 
23 
24 
25 
26 
27 
 
28 
29 
Memorial Day 
30 
31 
 
 
 
 
 
 
 
One 5 oz glass of 
regular (12%) 
wine 
1 ½ oz of hard liquor 
(e.g. rum, vodka, 
whiskey) 
1 mixed or straight 
drink with 1 ½ oz 
hard liquor  
1 Standard Drink is Equal to 
One 12 oz 
can/bottle 
of beer 
Complete the Following 
Start Date (Day 1):   
 
 
 
   End Date (yesterday): 
   
MO  
DY 
       YR   
 
 
MO 
DY 
YR  
139


TLFB 2017 
  
2 
 
 
 
2017 
SUN 
MON 
TUES 
WED 
THURS 
FRI 
SAT 
 
 
 
 
 
1 
2 3 
J 
4 
5 6 7 8 9 1
0 
U 
11 
12 
13 
14 
15 
16 
17 
N 
18 
Father’s Day 
19 
20 
21 
22 
23 
24 
 
25 
26 
27 
28 
29 
30 
1 
J 
2 
3 4
 
July 4th 
5 
6 7 8 
U 
9 
10 
11 
12 
13 
14 
15 
L 
16 
17 
18 
19 
20 
21 
22 
 
23 
24 
25 
26 
27 
28 
29 
 
30 
31 
1 
2 3 4 5 
A 
6 
7 8 9 1
0 
11 
12 
U 
13 
14 
15 
16 
17 
18 
19 
G 
20 
21 
22 
23 
24 
25 
26 
 
27 
28 
29 
30 
31 
1 
2 
S 
3 
4
 Labor Day 
5 
6 7 8 9 
E 
10 
11 
12 
13 
14 
15 
16 
P 
17 
18 
19 
20 
21 
22 
23  
 
24 
25 
26 
27 
28 
29 
30
 Rosh Hashanah 
O 
1 
2
  
3 
4 5 6 7 
C 
8 
9
 Columbus Day 
10 
11 
12 
13 
14 
T 
15 
16 
17 
18 
19 
20 
21 
 
22 
23 
24 
25 
26 
27 
28 
 
29 
30
 Yom Kippur 
31 
Halloween 
1  
2 
3 4 
N 
5 
6 7 8 9 1
0
  
11
 Veterans Day 
O 
12
  
13 
14 
15 
16 
17 
18 
V 
19 
20 
21 
22 
23
Thanksgiving 
24 
25 
 
26 
27 
28 
29 
30 
1 
2 
D 
3 
4 5 6
  
7 
8 9 
E 
10 
11 
12
 Hanukkah 
13 
14 
15 
16
  
C 
17 
18 
19 
20 
21 
22 
23 
 
24 
25
 Christmas 
26  
27 
28 
29 
30 
 
31
 New Years Eve 
 
 
 
 
 
 
 
140


Galectin Therapeutics Inc. 
GR-MD-02 (galactoarabino-rhamnogalacturnate) 
Protocol: GT-026 Original 
20 February 2015 
 
Page 113 
12.4.4 
Instructions for Completing the Alcohol TLFB 
141


Sobell, L. C. & Sobell, M. B., 2000 
 Instructions for Filling Out the Timeline Alcohol Use Calendar 
To help us evaluate your drinking, we need to get an idea of what your alcohol use was like in the past 
____ days. To do this, we would like you to fill out the attached calendar.  
 Filling out the calendar is not hard! 
 Try to be as accurate as possible. 
 We recognize you won’t have perfect recall. That’s OKAY. 
 
 WHAT TO FILL IN 
• The idea is to put a number in for each day on the calendar. 
• On days when you did not drink, you should write a ”0”. 
• On days when you did drink, you should write in the total number of drinks you had.  
• We want you to record your drinking on the calendar using Standard Drinks. For example, if you had 6 
beers, write the number 6 for that day. If you drank two or more different kinds of alcoholic beverages in a 
day such as 2 beers and 3 glasses of wine, you would write the number 5 for that day. 
It’s important that something is written for every day, even if it is a “0”. 
 
 YOUR BEST ESTIMATE  
• We realize it isn’t easy to recall things with 100% accuracy.  
• If you are not sure whether you drank 7 or 11 drinks or whether you drank on a Thursday or a Friday, give it 
your best guess! What is important is that 7 or 11 drinks is very different from 1 or 2 drinks or 25 drinks. The 
goal is to get a sense of how frequently you drank, how much you drank, and your patterns of drinking. 
 
 HELPFUL HINTS 
• If you have an appointment book you can use it to help you recall your drinking. 
• Holidays such as Thanksgiving and Christmas are marked on the calendar to help you better recall your 
drinking. Also, think about how much you drank on personal holidays & events such as birthdays, 
vacations, or parties. 
• If you have regular drinking patterns you can use these to help you recall your drinking. For example, you 
may have a daily or weekend/weekday pattern, or drink more in the summer or on trips, or you may drink 
on Wednesdays after playing sports. 
 
 COMPLETING THE CALENDAR  
• A blank calendar is attached.  Write in the number of Standard Drinks that you had each day.  
• The time period we are talking about on the calendar is  
from ________________________ to _______________________. 
• In estimating your drinking, be as accurate as possible. 
• DOUBLE CHECK THAT ALL DAYS ARE FILLED IN BEFORE RETURNING THE CALENDAR.  
• Before you start look at the SAMPLE CALENDAR AND STANDARD DRINK CHART on the next page.
142


 
 
2 
 
Sobell, L. C. & Sobell, M. B., 2000 
 
 Instructions for Filling Out the Timeline Alcohol Use Calendar 
 
 SAMPLE CALENDAR 
 
 
2000 
SUN 
MON 
TUES 
WED 
THURS 
FRI 
SAT 
 
 
 
 
 
 
1 
8 
2 
0 
S 
3 
7 
4 Labor Day 
0 
5 
3 
6 
8 
7 
1 
8 
0 
9 
11 
E 
10 
2 
11 
2 
12 
0 
13 
3 
14 
5 
15 
14 
16 
4 
P 
17 
2 
18 
0 
19 
0 
20 
0 
21 
0 
22 
2 
23 
13 
T 
24 
0 
25 
0 
26 
6 
27 
0 
28 
0 
29 
0 
30 
2 
 
U. S. STANDARD DRINK CONVERSION CHART 
One Standard Drink Is Equal To 
 
 12 oz of BEER (5%) 
 
 
 
 5 oz of WINE  (10% – 12%) 
 
 
 
 3 oz of FORTIFIED WINE (16% – 18%) 
 
 1.5 oz of HARD LIQUOR (86 proof – 100 proof; 43% – 50%) 
 
 
 WINE: 1 Bottle 
 
25 oz/750 ml 
= 
5 standard drinks 
 
40 oz/1.5 liter 
= 
8 standard drinks 
 
25 oz fortified 
= 
8 1/3 standard drinks 
 
 HARD LIQUOR: 1 Bottle 
 
12 oz (mickey) 
= 
8 standard drinks 
 
26 oz 
= 
17 1/3 standard drinks 
 
40 oz 
= 
26 2/3 standard drinks 
 
143

SAP_001.pdf: 
Galectin Therapeutics Inc 
 
GR-MD-02 
Protocol: GT-026 
 
Clinical study report 
16.1.9 
Documentation of Statistical Methods 
This section contains the following documents: 
Statistical analysis plan version 3.0 dated 01 June 2017 
Statistical analysis plan addendum version 2.0 dated 26 January 2018 
 




Galectin Therapeutics Inc 
 
Statistical Analysis Plan, Version 3.0 
GT-026 
 
Date Issued: JUNE2017 
 
  
 
 
 
II
 
Version 
Date 
Brief description of changes 
By whom 
1.0 
30MAR2015 
Original 
Yu Feng 
2.0  
02JUN2015 
Updated based on protocol amendment 
Yu Feng 
3.0 
JUNE2017 
Updated based on new request on topline 
analysis 
Shelley Liu 
 
 


Galectin Therapeutics Inc 
 
Statistical Analysis Plan, Version 3.0 
GT-026 
 
Date Issued: JUNE2017 
 
  
 
 
 
III 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ...................................................................................................... V 
1. 
INTRODUCTION ............................................................................................................ 7 
2. 
OBJECTIVES ................................................................................................................... 7 
2.1. PRIMARY OBJECTIVE .......................................................................................................... 7 
2.2. SECONDARY OBJECTIVES ................................................................................................... 7 
2.3. EXPLORATORY OBJECTIVES ............................................................................................... 8 
2.4. SAFETY OBJECTIVES ........................................................................................................... 8 
2.5. PHARMACOKINETIC OBJECTIVE .......................................................................................... 9 
3. 
INVESTIGATIONAL PLAN .......................................................................................... 9 
3.1. OVERALL STUDY DESIGN AND PLAN .................................................................................. 9 
3.2. STUDY ENDPOINTS ........................................................................................................... 11 
3.2.1. 
Primary Endpoint...................................................................................................... 11 
3.2.2. 
Secondary Endpoints ................................................................................................ 11 
3.2.3. 
Exploratory Endpoints .............................................................................................. 12 
3.2.4. 
Safety Endpoints........................................................................................................ 12 
3.2.5. 
PK Endpoint .............................................................................................................. 12 
4. 
GENERAL STATISTICAL CONSIDERATIONS ..................................................... 12 
4.1. SAMPLE SIZE .................................................................................................................... 13 
4.2. RANDOMIZATION, STRATIFICATION, AND BLINDING ........................................................ 14 
4.3. ANALYSIS SET .................................................................................................................. 14 
4.3.1. 
Full-Analysis Set ....................................................................................................... 14 
4.3.2. 
Modified-Intent-to-Treat Set ..................................................................................... 14 
4.3.3. 
Per Protocol Set ........................................................................................................ 14 
4.3.4. 
Safety Set ................................................................................................................... 15 
4.3.5. 
Pharmacokinetic Set ................................................................................................. 15 
5. 
SUBJECT DISPOSITION ............................................................................................. 15 
5.1. DISPOSITION ..................................................................................................................... 15 
5.2. PROTOCOL DEVIATIONS ................................................................................................... 15 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................. 15 
6.1. DEMOGRAPHICS ................................................................................................................ 15 
6.2. BASELINE DISEASE CHARACTERISTICS ............................................................................. 16 
6.3. ALCOHOL USAGE.............................................................................................................. 16 
6.4. MEDICAL AND SURGICAL HISTORY .................................................................................. 16 
6.5. INCLUSION AND EXCLUSION CRITERIA ............................................................................. 16 
7. 
TREATMENTS AND MEDICATIONS ....................................................................... 16 
7.1. PRIOR AND CONCOMITANT MEDICATIONS ........................................................................ 17 
7.2. STUDY TREATMENTS ........................................................................................................ 18 
7.2.1. 
Extent of Exposure .................................................................................................... 18 
7.2.2. 
Treatment Compliance and Modifications................................................................ 18 


Galectin Therapeutics Inc 
 
Statistical Analysis Plan, Version 3.0 
GT-026 
 
Date Issued: JUNE2017 
 
  
 
 
 
IV 
8. 
EFFICACY ANALYSIS................................................................................................. 18 
8.1. PRIMARY EFFICACY ENDPOINT ......................................................................................... 19 
8.1.1. 
Primary Analysis ....................................................................................................... 19 
8.2. KEY SECONDARY EFFICACY ENDPOINTS .......................................................................... 20 
8.2.1. 
Key Secondary Efficacy Analysis .............................................................................. 21 
8.3. EXPLORATORY ENDPOINTS ............................................................................................... 24 
9. 
SAFETY ANALYSIS ..................................................................................................... 25 
9.1. ADVERSE EVENTS ............................................................................................................. 25 
9.1.1. 
Relationship of Adverse Events to Study Drug ......................................................... 27 
9.1.2. 
Severity of Adverse Events ........................................................................................ 27 
9.2. CLINICAL LABORATORY EVALUATIONS ........................................................................... 27 
9.3. BIOMARKER MEASUREMENTS .......................................................................................... 27 
9.4. VITAL SIGN MEASUREMENTS ........................................................................................... 27 
9.5. PHYSICAL EXAMINATION ................................................................................................. 28 
9.6. ELECTROCARDIOGRAM (ECG) ......................................................................................... 28 
10. 
PHARMACOKINETICS ............................................................................................... 28 
10.1. 
PLASMA CONCENTRATIONS........................................................................................... 28 
10.2. 
PLASMA PHARMACOKINETIC PARAMETERS .................................................................. 29 
11. 
INTERIM ANALYSIS ................................................................................................... 29 
12. 
DATA SAFETY MONITORING BOARD .................................................................. 29 
13. 
REFERENCES ................................................................................................................ 31 


Galectin Therapeutics Inc 
 
Statistical Analysis Plan, Version 3.0 
GT-026 
 
Date Issued: JUNE2017 
 
  
 
 
 
V 
List of Abbreviations 
 
Abbreviation 
Definition 
α-SMA 
Alpha smooth muscle actin 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUDIT 
Alcohol Use Disorders Identification Test 
BLQ 
Below the limit of quantitation 
BMI 
Body mass index 
CI 
Confidence interval 
CLDQ 
chronic liver disease questionnaire 
Cmax 
Observed maximum plasma or serum concentration after administration 
CPA 
Collagen proportional area 
CV 
Coefficient of variation 
cPDR  
Percentage dose recovery 
DOB 
Delta over baseline 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EGD 
Esophagogastroduodenoscopy 
ELF 
Enhanced Liver Fibrosis 
FAS 
Full-analysis set 
FHVP 
Free hepatic venous pressure 
GEE 
Generalized estimating equation 
GR-MD-02 
Galactoarabino-rhamnogalaturonate 
HRQOL 
Health-related quality of life  
HVPG 
Hepatic venous pressure gradient 
IMP 
Investigational medicinal product 
IWRS 
Interactive web response system 
LBM 
Lean body mass 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 


Galectin Therapeutics Inc 
 
Statistical Analysis Plan, Version 3.0 
GT-026 
 
Date Issued: JUNE2017 
 
  
 
 
 
VI 
Abbreviation 
Definition 
MELD 
Model for End-stage Liver Disease 
MITT 
Modified-intent-to-treat 
MMRM 
Mixed Model Repeated Measures 
NASH 
Nonalcoholic steatohepatitis 
OLES 
Open-label extension study 
PK 
Pharmacokinetic(s) 
PP 
Per-protocol set 
PPD 
Pharmaceutical Product Development 
Q1 
First quartile 
Q3 
Third quartile 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal value 
WHO 
World Health Organization 
WHVP 
Wedged hepatic venous pressure 
 


Galectin Therapeutics Inc 
 
Statistical Analysis Plan, Version 3.0 
GT-026 
 
Date Issued: JUNE2017 
 
  
 
 
 
7 
 
1. Introduction 
Nonalcoholic steatohepatitis (NASH) is liver inflammation and damage caused by a 
buildup of fat in the liver which is becoming common in the United States. It develops 
most often in patients with at least one of the following risk factors: obesity, dyslipidemia, 
and glucose intolerance. Cirrhosis with portal hypertension due to NASH will eventually 
lead to liver transplantation or death.  
Galectin-3 protein has recently been implicated in the pathogenesis of NASH. 
Galactoarabino-rhamnogalacturonate (GR-MD-02) has been shown to be safe and well 
tolerated at single and multiple doses of 2, 4, and 8 mg/kg in a Phase 1 study (Galectin 
2014). Pharmacokinetics revealed drug exposure in humans at the 8-mg/kg dose that was 
equivalent to the upper range of the targeted therapeutic dose determined from effective 
doses in NASH animal models, thus providing support for the Phase 2 dosing regimen. 
The purpose of the Statistical Analysis Plan (SAP) is to describe the analyses and data 
presentations for Galectin’s protocol GT-026. This SAP outlines the types of analyses that 
will address the study objectives, and explains in detail how the data will be handled and 
analyzed. It contains the definitions of analysis populations and statistical methods for the 
analysis of efficacy, safety and PK. 
2. Objectives 
2.1. Primary Objective 
The primary objective of this study is to evaluate the efficacy of GR-MD-02 on reducing 
hepatic venous pressure gradient (HVPG) as a measure of portal pressure compared to 
placebo at 1 year of treatment. 
2.2. Secondary Objectives 
The secondary objectives of this study are to evaluate: 
 The effect of GR-MD-02 on change in the collagen proportional area (CPA) at 
1 year compared to placebo as determined by digital morphometric analysis of liver 
biopsies 
 The effect of GR-MD-02 on change in Ishak histopathological staging at 1 year 
compared to placebo as assessed on liver biopsy 
 The effect of GR-MD-02 on liver stiffness as determined by the FibroScan® score  
(for those study centers where the FibroScan® is available) prior to the first 
infusion, at Infusion Visit 13, and 14 to 28 days after final infusion as compared to 
placebo 
 The effect of GR-MD-02 on the metabolic capacity of the liver as determined by 
percentage dose recovery (cPDR30 ) value of the 13C-methacetin breath test (MBT) 


Galectin Therapeutics Inc 
 
Statistical Analysis Plan, Version 3.0 
GT-026 
 
Date Issued: JUNE2017 
 
  
 
 
 
8 
(for those study centers where the MBT is available)at screening, at Infusion 
Visit 13, and 14 to 28 days after final infusion as compared to placebo 
 The effect of GR-MD-02 on change in Brunt-Kleiner histopathological staging at 1 
year compared to placebo as assessed on liver biopsy  
 The effect of GR-MD-02 on progression of cirrhosis at 1 year as compared to 
placebo, defined as the development of any of the following:  
o esophageal variceal hemorrhage or portal hypertensive gastropathy 
hemorrhage (confirmed by endoscopy or interventional radiology) 
o clinically apparent ascites  
o spontaneous bacterial peritonitis 
o overt hepatic encephalopathy (defined by the clinical judgment of the 
principal investigator, but shall include the presence of lethargy, 
disorientation, inappropriate behavior, and the presence of asterixis) 
o an increase from baseline in Child-Turcotte-Pugh Score ≥2 points 
o newly diagnosed varices in a subject without prior varices  
o progression from small to medium or large varices  
o reaching a model for end-stage liver disease (MELD) score ≥15 as measured 
on 2 consecutive occasions  
o listing for a liver transplant or the performance of a liver transplant 
o liver-related mortality 
2.3. Exploratory Objectives 
The exploratory objectives of this study are to evaluate: 
 Difference in health-related quality of life (HRQOL) using the subject-completed 
chronic liver disease questionnaire (CLDQ) following administration of 
GR-MD-02 or placebo at 1 year 
 Baseline-adjusted change in FibroTest (FibroSure) and the enhanced liver fibrosis 
(ELF) score at Infusion Visits 7, 13, 20, and 14 to 28 days after final infusion 
 Changes in liver biopsy staining for alpha smooth muscle actin (α-SMA) and 
galectin-3 in subjects treated with GR-MD-02 or placebo at 1 year  
2.4. Safety Objectives 
The safety objectives of this study are to assess the safety and tolerability of GR-MD-02 
versus placebo at 1 year. 


Galectin Therapeutics Inc 
 
Statistical Analysis Plan, Version 3.0 
GT-026 
 
Date Issued: JUNE2017 
 
  
 
 
 
9 
2.5. Pharmacokinetic Objective 
The PK objectives are to evaluate systemic exposure following multiple doses of 
GR-MD-02 and to explore the population pharmacokinetics of GR-MD-02 in subjects with 
NASH with portal hypertension and cirrhosis. 
3. Investigational Plan 
3.1. Overall Study Design and Plan 
This is a Phase 2, multi-center, parallel group, North American, randomized, 
placebo-controlled, double-blind study of subjects with portal hypertension due to 
cirrhosis.  
Approximately 156 subjects with portal hypertension (HVPG ≥6 mm Hg) will be enrolled 
in the study at 45 to 60 study centers in the US and Canada. The subject must have a liver 
biopsy showing cirrhosis (Ishak stage 5 or 6) presumably due to NASH, excluding subjects 
with medium and large varices and those with decompensated cirrhosis (as defined by the 
presence of clinically detectable ascites, any episode of variceal bleeding, and overt hepatic 
encephalopathy).  
Subjects with portal hypertension and the appropriate biopsy findings will be randomized 
in a 1:1:1 ratio according to the randomization schedule to receive 1 of 3 treatment 
assignments: placebo, GR-MD-02 in dose of 2 mg/kg lean body mass (LBM), or 
GR-MD-02 in a dose of 8 mg/kg LBM administered every other week over a 52 week 
period for a total of 26 infusions. (Figure 3-1) 
The study includes Prescreening, Screening, Treatment, Follow-up phases. 
Prescreening: Prescreening may begin at Week -9 to evaluate the eligibility for diagnosis 
of NASH and FibroScan® (at sites where it is available). Subjects with qualifying 
diagnosis and FibroScan® score may proceed to screening. 
Screening: The screening window is up to 8 weeks after prescreening visit. Subjects will 
undergo the following required procedures to assess eligibility during the screening period: 
EGD, HVPG measurement, liver biopsy, MBT (if available) and serum transaminases. 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will 
proceed to randomization and the treatment phase.  
Treatment Phase: Subjects will be randomly assigned (1:1:1) to receive 1 of 3 treatment 
assignments before the first infusion and will be administered every other week over a 
52 week period for a total of 26 infusions. Safety and efficacy assessment will be 
monitored during the treatment phase. 


Galectin Therapeutics Inc 
 
Statistical Analysis Plan, Version 3.0 
GT-026 
 
Date Issued: JUNE2017 
 
  
 
 
 
10 
Medical Care of Cirrhosis During the Study: General care of subjects with cirrhosis will 
be maintained during the study, including screening for hepatocellular carcinoma, at the 
discretion of the investigator. 
Post Final Visit (14-28 Days): All subjects will attend a visit (or visits) 14 to 28 days after 
final dose. During this visit, selected safety and efficacy assessments will be 
collected/performed. 
Follow-up/Early Termination Visit: All subjects are to attend a follow-up/early 
termination visit 14 days after the postdose final visit to evaluate safety. During this visit, 
safety assessments will be collected/performed. Whenever possible, all subjects who are 
terminated from the study early should have a FibroScan® and an MBT performed at a 
follow-up visit. Whenever possible, subjects who are terminated from the study following 
at least 13 infusions should also have all the post-study evaluations including EGD, HVPG, 
and liver biopsy performed in addition to the FibroScan® and MBT. 
Open-Label Extension Study: Following study completion, subjects will be offered 
enrollment into a subsequent separate study, an open-label extension study (OLES), if there 
is adequate tolerability and no safety issues or signs of clinical progression that would 
require discontinuation.  
End-of-Study Telephone Contact: Subjects who do not enroll into the OLES, will be 
contacted via phone every 6 months for 2 years, and annually thereafter for a total of 
4 years, for a brief update and are to be assessed for survival, listing for liver 
transplantation, liver transplantation, or complications of chronic liver disease (ascites, 
spontaneous bacterial peritonitis, variceal bleeding, and encephalopathy). 


Galectin Therapeutics Inc 
 
Statistical Analysis Plan, Version 3.0 
GT-026 
 
Date Issued: JUNE2017 
 
  
 
 
 
11 
Figure 3-1 
Study Design GT-026 
 
3.2. Study Endpoints 
3.2.1. Primary Endpoint 
The baseline-adjusted change in HVPG at 1 year (53-55 weeks) in subjects treated with 
placebo as compared to subjects treated with GR-MD-02 (2 mg/kg or 8 mg/kg). 
3.2.2. Secondary Endpoints 
 The baseline-adjusted mean change in the CPA at 1 year as determined by 
digital morphometric analysis of liver biopsies 
 Proportion of subjects who have at least one stage change in Ishak 
histopathological staging of fibrosis at 1 year as assessed on liver biopsy  
 The baseline-adjusted mean change in liver stiffness as determined by 
FibroScan® (if available) score prior to the first infusion, at Infusion Visit 
13, and 14 to 28 days after final infusion 
 The baseline-adjusted mean change in the metabolic capacity of the liver as 
determined by cPDR30 of the MBT (if available) at screening, Infusion Visit 
13, and 14 to 28 days after final infusion 
 Proportion of subjects who have at least one stage change in Brunt-Kleiner 
histopathological staging of fibrosis at 1 year as assessed on liver biopsy  


Galectin Therapeutics Inc 
 
Statistical Analysis Plan, Version 3.0 
GT-026 
 
Date Issued: JUNE2017 
 
  
 
 
 
12 
 The difference between GR-MD-02-treated and placebo-treated subjects in 
the progression of cirrhosis at 1 year, defined as the development of any of 
the following: 
o esophageal variceal hemorrhage or portal hypertensive gastropathy 
hemorrhage (confirmed by endoscopy or interventional radiology) 
o clinically apparent ascites  
o spontaneous bacterial peritonitis 
o overt hepatic encephalopathy 
o an increase from baseline in Child-Turcotte-Pugh Score ≥2 points 
o newly diagnosed varices in a subject without prior varices  
o progression from small to medium or large varices  
o qualification for liver transplant defined as a MELD score ≥15 
o listing for a liver transplant or the performance of a liver transplant 
o liver-related mortality 
3.2.3. Exploratory Endpoints 
 Difference in health-related quality of life (using the subject-completed 
CLDQ) following administration of GR-MD-02 or placebo at 1 year 
 Baseline-adjusted change in FibroTest (FibroSure) and ELF score at 
Infusion Visits 7, 13, 20, and 14 to 28 days after final infusion 
 Changes in liver biopsy staining for α-SMA and galectin-3 in subjects 
treated with GR-MD-02 or placebo at 1 year  
3.2.4. Safety Endpoints 
The safety endpoints include the incidence of AEs during study treatment, emergent 
physical examination abnormalities, emergent vital sign and ECG abnormalities, and 
laboratory parameter abnormalities. 
3.2.5. PK Endpoint 
The PK endpoints include plasma concentrations and population PK parameters of 
GR-MD-02. 
The population PK analysis will be described in a separate modeling analysis plan. 
4. General Statistical Considerations 
Study day for events on or after the date of the first infusion will be defined as the number 
of days from the date of the first infusion of IMP, plus 1 day, so that the date of the first 


Galectin Therapeutics Inc 
 
Statistical Analysis Plan, Version 3.0 
GT-026 
 
Date Issued: JUNE2017 
 
  
 
 
 
13 
infusion will be defined as Day 1. For events before the date of the first infusion, study day 
will be calculated as the difference in days between the date of the first infusion and the 
date of interest. Thus, the day before the date of the first infusion will be defined as Day -1. 
This means there will be no study day zero (0). 
Baseline is defined as the last assessment prior to the first infusion of IMP. All baseline 
measurements must have been collected prior to administration of first infusion of IMP. 
Measurements that are obtained after the first infusion of IMP will be considered as post-
baseline values. If the measurement of a variable is not made on a given subject prior to the 
first infusion of IMP, then that subject will be considered not to have a baseline value for 
that variable. Change from baseline is defined as post-baseline assessment minus baseline 
assessment. 
Continuous data will be described using the following descriptive statistics: the number of 
subjects (n), mean, standard deviation (SD), median, the first quartile (Q1), the third 
quartile (Q3), minimum and maximum, where appropriate. Categorical data will be 
summarized using the frequency count (n) and percentage (%) of subjects for each 
category, where appropriate.  
Unless otherwise specified, all statistical tests and confident intervals (CIs) will be two-
sided and conducted at the 0.05 significance level. If analysis variables are not normally 
distributed, Poisson-regression model (or the negative binomial) will be applied for counts 
data.  
No imputation will be applied for missing data unless otherwise specified. 
All collected data used for safety and efficacy evaluations will be presented in listings. 
Data will be displayed in all listings sorted by treatment group and subject identifier unless 
specified otherwise. 
All analyses will be conducted using SAS® Version 9.1.3 or higher. The Medical 
Dictionary for Regulatory Activities (MedDRA) will be used for coding adverse events.  
Prior or concomitant medication data will be coded using the World Health Organization 
(WHO) Drug Dictionary. 
4.1. Sample Size 
The sample size of 52 subjects per treatment arm assumes a mean difference in the change 
of HVPG from baseline at 52 weeks between an active treatment arm and placebo of 2 mm 
Hg with a SD of 3 mm Hg, and allows for a 25% dropout rate and 80% power to detect a 
statistically significant difference at an α level of 0.05. A difference of 2 mm Hg in the 
change of HVPG is considered to be of “clinical significance” (Villanueva 2009; 
Escorsell 2000; Abraldes 2003). The SD of 3 mm Hg at a mean change of HVPG of 2 mm 
Hg from baseline is based on primary data, obtained from an investigator (Dr Guadalupe 
Garcia-Tsao), as reported in a published longitudinal clinical study (Groszmann 2005).  


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4.2. Randomization, Stratification, and Blinding 
Approximately 156 eligible subjects will be randomly assigned to one of the following 
3 treatment groups in a 1:1:1 ratio: 
 Approximately 52 subjects are assigned to GR-MD-02 in dose of 2 mg/kg LBM 
 Approximately 52 subjects are assigned to GR-MD-02 in dose of 8 mg/kg LBM 
 Approximately 52 subjects are assigned to placebo 
The randomization mechanism for the study will be deployed within an interactive web 
response system (IWRS). Unblinded biostatisticians will generate the randomization 
schedule using SAS software Version 9.2 or later for IWRS which will link sequential 
subject randomization numbers to treatment codes allocated at random with a 1:1:1 
randomization ratio.  
Except in an emergency, investigators, Galectin, or other persons involved in study 
conduct will not know the randomization schedule and study drug allocation before study 
completion. The IWRS system will be used if emergency unblinding is required. This 
would generally only be used in an emergency, when knowledge of the actual treatment 
becomes medically necessary.  
4.3. Analysis Set 
4.3.1. Full-Analysis Set 
The full-analysis set (FAS), or intent-to-treat group, will consist of all subjects who were 
randomly assigned to IMP. The FAS will be used as the primary efficacy analysis set. 
All subjects in the FAS set will be analyzed according to the treatment they were 
randomized to receive. 
4.3.2. Modified-Intent-to-Treat Set 
The Modified-Intent-to-Treat (MITT) set will consist of all subjects who were randomly 
assigned, received at least 1 infusion, and had at least 1 post-baseline efficacy assessment. 
All subjects in the MITT set will be analyzed according to the treatment they were 
randomized to receive. 
4.3.3. Per Protocol Set 
The per protocol (PP) set will consist of all FAS subjects who have at least 80% 
compliance with study treatment, have not taken any prohibited medication, have no 
significant protocol deviations, and restricted to each subject’s time on IMP plus 30 days 
thereafter for the analysis of progression of efficacy events.  
All subjects in the PP set will be analyzed according to the treatment they actually 
received. 


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4.3.4. Safety Set 
The safety set will consist of all subjects who received any IMP. All subjects in the safety 
set will be analyzed according to the treatment they actually received. 
4.3.5. Pharmacokinetic Set  
The PK analysis set will consist of subjects who provide at least 1 Cmax PK sample. 
5. Subject Disposition 
5.1. Disposition 
A disposition of subjects includes the number and percentage of subjects for the following 
categories: subjects who were randomized, subjects who completed the study, subjects 
who discontinued from the study. All percentages will be based on the number of subjects 
randomized using the FAS population. 
The reasons for discontinuation of study participation will also be summarized in the 
tables.  
Subject disposition data will be presented in a listing. 
5.2. Protocol Deviations 
Protocol deviations/violations will be identified and assessed by the investigator in 
accordance with the procedures or processes approved by the sponsor. The protocol 
deviations/violations will be defined prior to unblinding of the database. The significant 
protocol deviations/violations will be summarized by treatment group using the FAS 
population. A listing of subjects with all protocol deviations/violations will also be 
provided. 
6. Demographics and Baseline Characteristics 
This summarization will be based on the FAS population set and presented by treatment 
group and overall. Descriptive statistics will be calculated for continuous variables and 
frequency counts and percentages will be applied to categorical variables. No inferential 
statistics will be presented. All subject demographic and baseline characteristic data will be 
presented in listings. 
6.1. Demographics 
The demographics and baseline characteristics summary will be presented in a table by 
treatment group and overall. The following variables will be included:  
 Age (years) 
 Sex (male, female) 
 Race 


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 Ethnicity 
 Baseline height (cm) 
 Baseline weight (kg) 
 Baseline body mass index (BMI) (kg/m2) 
 Baseline lean body mass (LBM) (kg) 
 Baseline Alcohol Use Disorders Identification Test (AUDIT) 
Age in years will be calculated by using the date of birth from the informed consent date 
and will be rounded down to an integer. BMI is calculated as follows: 
BMI = weight (kg) / (height (m))2 
Alcohol consumption will be evaluated by AUDIT which contains 10 questions scaling 
from 0 to 4, the total score based on the sum of 10 individual scores will be summarized.  
6.2. Baseline Disease Characteristics 
Summaries of baseline disease characteristics will be presented by treatment group and 
overall, and include, but are not limit to the baseline HVPG, diagnosis of NASH, CPA, 
FibroScan® (if available) score, Ishak histopathological stage and Brunt-Kleiner 
histopathological stage.  
6.3. Alcohol Usage 
Alcohol timeline followback (TLFB) will be used to assess subjects’ alcohol consumption 
for the years 2015, 2016 and 2017. Subjects’ daily drinking will be recorded as amount of 
standard drink on the calendar. The estimate daily drinking over the time will be 
summarized by treatment group and overall for the FAS population. 
6.4. Medical and Surgical History 
The number and percentage of subjects with any medical and surgical history will be 
summarized overall and for each body system. Body systems will be included as recorded 
on the eCRF. Percentages will be calculated based on number of subjects for the safety 
population.  
Subject medical history data including specific details will be presented in a listing.  
6.5. Inclusion and Exclusion Criteria 
Subjects who do not meet all inclusion and exclusion criteria, as presented in Section 4.1.1 
and 4.1.2 of the protocol, will be presented in a listing.  
7. Treatments and Medications 
This summarization of treatments and medications will be based on the safety population 
set and presented by treatment group and overall. Descriptive statistics will be calculated 


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for continuous variables and frequency counts and percentages will be applied to 
categorical variables. No inferential statistics will be presented.  
7.1. Prior and Concomitant Medications 
All prior medications for liver cirrhosis and NASH will be recorded in the eCRF and all 
other medications taken from 30 days prior to screening and throughout the entire duration 
of the subject’s participation in the study will be documented in the eCRF. A concomitant 
medication is defined as medications taken any time after the first infusion of IMP. A prior 
medication is defined as nonstudy medications discontinued prior to the first infusion of 
IMP. 
Missing start dates for concomitant medications data will be handled as follows (where 
UK, UKN and UKNW indicate unknown or missing Day, Month and Year respectively):  
 UK-MMM-YYYY: impute 01-MMM-YYYY. If the month and year are the same 
as the first dose month and year, then impute the date of the first dose; 
 UK-UKN-YYYY: If the year is prior to the year of the first dose, impute 01-JAN-
YYYY of the collected year. If the year is the same as the first dose year, then 
impute the date of the first dose. If the year is after the year of the first dose, impute 
01-JAN-YYYY; 
 UK-UKN-UKNW: impute date of the first dose. 
Missing stop dates for concomitant medications data will be handled as follows (where 
UK, UKN and UKNW indicate unknown or missing Day, Month and Year respectively): 
 UK-MMM-YYYY: impute the last day of the month; 
 UK-UKN-YYYY: impute 31-DEC-YYYY; 
 UK-UKN-UKNW: leave as missing. 
If imputed start date is after the end date of concomitant medication, the start date will be 
set same as end date. 
Prior and concomitant medications will be coded using the World Health Organization 
Drug dictionary (WHO Drug) Version 1 March 2015. The dictionary will be updated 
throughout the life of the project to allow for the most recent version of the dictionary to be 
used. The medication names will be coded according to the Anatomical Therapeutic 
Chemical (ATC) class and preferred terms provided in the dictionary. 
Prior and concomitant medications will be summarized in separate tables. The tables will 
present the number and percentage of subjects by ATC class and preferred term for each 
treatment group and overall. ATC classes will be sorted in decreasing order of frequency 
based on the total number of subjects who take each medication in the total column, while 
preferred terms within each drug class will be presented alphabetically. In addition, the 
total number of medications and the number and percentage of subjects receiving at least 1 


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medication will also be presented. If a subject has multiple medications for a given 
preferred term the subject will only be counted once.  
All prior and concomitant medications will be presented in a listing. 
7.2. Study Treatments 
GR-MD-02 and matching placebo will be available in 10-mL sterile vials at a 
concentration of 30 mg/mL. The treatment regimen consists of 26 injection visits biweekly 
from week 1. The dosing will be determined by LBM, since it is anticipated that many 
subjects will be obese and GR-MD-02 is distributed primarily in the blood compartment. 
7.2.1. Extent of Exposure 
Duration of exposure is defined as the total number of days a subject is exposed to study 
medication and will be presented as the total number of days from the first infusion date to 
the last infusion date (date of last infusion minus the date of first infusion + 1).  
The exposure to study drug is defined as the cumulative number of injections taken by 
subjects, since dose is based on subjects’ LBM.  
The extent of exposure and study drug exposure will be summarized descriptively in a 
table. 
A listing will present subject data for first dose date, last dose date, extent of exposure, and 
study drug exposure.  
7.2.2. Treatment Compliance and Modifications 
Treatment compliance is defined as 
Compliance (%) =  


study
the
during
received
be
to
planned
injections
of
Number
received
injections
of
Number
100

 
The overall study drug compliance rate will be summarized by treatment group using the 
descriptive statistics. The number and percentage of subjects in each of the following 
compliance rate categories (<80, >=80 to 100) will also be reported. 
Percentages will be calculated out of the number of subjects who were dosed at that dosing 
period. The number and percentage of subjects in each compliance rate category will be 
presented. 
8. Efficacy Analysis 
All efficacy analyses will be performed using the FAS population.  Specific analyses, 
detailed below, will be performed on the MITT and the PP populations.   


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8.1. Primary Efficacy Endpoint 
HVPG will be collected at screening and 14 to 28 days after final dose (53-55 weeks), and 
used as a measure of portal hypertension. Both wedged hepatic venous pressure (WHVP) 
and free hepatic venous pressure (FHVP) will be measured for subjects without varices or 
with small varices. HVPG is defined as the difference between the WHVP and the FHVP. 
A single experienced investigator, Dr Guadalupe Garcia-Tsao (Yale University), will 
evaluate all HVPG tracings at a central reading facility.  
The HVPG will be summarized for the FAS population by visit and treatment group, for 
all scheduled visits, along with the change from baseline descriptively in a summary table 
and graphically. In addition, the number and percentage of subjects will be summarized by 
the following HVPG categories (mild portal hypertension (MPH) ie  ≥6 mmHg to <10 
mmHg and clinically significant portal hypertension (CSPH) ie ≥10 mmHg).  
8.1.1. Primary Analysis 
 
The primary efficacy endpoint, change from baseline in HVPG at 1 year (53 to 55 weeks), 
will be analyzed using analysis of covariance (ANCOVA) with baseline values taken as a 
covariate using the FAS population at a significant level of 0.05 (2-sided). Treatment effect 
will be evaluated as a contrast of each active treatment versus placebo and described using 
continuous summary. To control the type I error rate due to multiple comparisons, the 
Bonferoni-Holm (1988) procedure for the comparison between treatment group and control 
will be implemented. Estimate of mean difference along with 95% CI will also be 
presented. 
Missing HVPG at 1 year will be imputed using the last observation carried forward 
(LOCF) method. The sensitivity analysis will be performed on the change from baseline in 
HVPG based on the LOCF values in the FAS population using the same statistical 
methodology described above. 
Additional sensitivity analyses for HVPG will include: 
 Change from baseline in HVPG at 1 year in the MITT population. 
 Change from baseline in HVPG at 1 year in the PP population. 
The following subgroup analysis will also be conducted in the MITT population:  
 Change from baseline in HVPG at 1 year by baseline HVPG category of MPH and 
CSPH  
 Change from baseline in HVPG at 1 year by gender. 
 Percentage of subjects who have ≥ 10% and ≥ 20%  decrease at 1 Year in HVPG  
by baseline HVPG category of MPH and CSPH  
 Percentage of subjects with HVPG at CSPH level at Baseline and at MPH level at 1 
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8.2. Key Secondary Efficacy Endpoints 
There are six key secondary efficacy endpoints: CPA, Ishak histopathological stage, 
FibroScan®, MBT, Brunt-Kleiner histopathological stage and complications of cirrhosis. 
CPA 
CPA will be used to measure liver collagen (a surrogate for fibrosis) by evaluation of liver 
biopsy at screening and 14 to 28 days after final dose (53 to 55 weeks). A single 
experienced pathologist, Dr Zack Goodman (INNOVA Medical Center), will evaluate all 
liver biopsies at a central pathology laboratory.  
The CPA will be summarized for the FAS population by visit and treatment group, for all 
scheduled visits, along with the change from baseline descriptively in a summary table and 
graphically.  
Ishak histopathological stage 
Fibrosis will be evaluated by liver biopsy and be staged according to the Ishak 
histopathological stage (0-6) at screening and 14 to 28 days after final dose (53 to 55 
weeks).The number and percentage of subjects by Ishak histopathological stage will be 
summarized using the FAS population by treatment group. The number and percentage of 
subjects changing in Ishak histopathological stages will also be presented. 
FibroScan® 
FibroScan® will be only performed at the study centers where it is available and used to 
evaluate liver stiffness which is recorded as the pressure measurement of kPa at the 
scheduled visits.  
The FibroScan® (if available) will be summarized for the FAS population by visit and 
treatment group, for all scheduled visits, along with the change from baseline descriptively 
in a summary table and graphically.  
MBT 
The MBT will only be performed at the study centers where it is approved. The cumulative 
percentage dose recovery of the metabolized 13C-methacetin 30 minutes after ingestion of 
the test substrate will be used as the MBT parameter for this study. Delta over baseline 
(DOB) with corresponding time point (
n
T ) will be collected on the eCRF. 
The cPDR30 is defined as: 






	


	


n
i
i
i
i
i
PDR
PDR
T
T
PDR
T
cPDR
2
1
1
1
1
30
2
60
2
60
 
where 
3963
.
0
5378
.
0
817853
.
1
h
w
DOB
PDR
i
i




, 
weight
w 
 (kg),  
height
h 
 (cm).  
Brunt-Kleiner histopathological stage 


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Fibrosis will be evaluated by liver biopsy and be staged according to the Brunt-Kleiner 
histopathological stage (0-4) at screening and 14 to 28 days after final dose (53 to 55 
weeks). 
The number and percentage of subjects by Brunt-Kleiner histopathological stage will be 
summarized using the FAS population by treatment group. The number and percentage of 
subjects changing in Brunt-Kleiner histopathological stages will also be presented. 
Complications of cirrhosis  
Complications of cirrhosis with portal hypertension is defined as the development of any 
of the following: 
 esophageal variceal hemorrhage or portal hypertensive gastropathy 
hemorrhage (confirmed by endoscopy or interventional radiology) 
 clinically apparent ascites  
 spontaneous bacterial peritonitis 
 overt hepatic encephalopathy 
 an increase in Child-Turcotte-Pugh Score ≥2 points 
 newly diagnosed varices in a subject without prior varices  
 progression from small to medium or large varices  
 qualification for liver transplant defined as a MELD score ≥15 
 listing for a liver transplant or the performance of a liver transplant 
 liver-related mortality 
The incidence of complications will be summarized in a table with count and percentage of 
subjects by each complication event using the FAS population by treatment group. 
Subjects with any complication event will also be presented. 
In addition, Child-Turcotte-Pugh score and MELD score will be summarized descriptively 
at the scheduled visits. Child-Turcotte-Pugh class and MELD score (<15, ≥15) will also be 
summarized. 
8.2.1. Key Secondary Efficacy Analysis 
The 6 key secondary efficacy endpoints will be examined using a gatekeeper statistical 
approach and will be tested sequentially in the order of 1) CPA, 2) FibroScan®, 3) Ishak 
histopathological stage, 4) MBT, 5) Brunt-Kleiner histopathological stage, 
6) complications of cirrhosis. Analysis of the secondary endpoints will be conducted if the 
primary endpoint is significant (α<0.05). If a secondary endpoint does not meet statistical 
significance, then all the subsequent secondary endpoints will be treated as exploratory. 
CPA 


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The change from baseline in CPA at 1 year (53 to 55 weeks), will be analyzed using robust 
regression (M estimation method, Huber 1973) using the FAS population at a significant 
level of 0.05 (2-sided). Treatment effect will be evaluated as a contrast of each active 
treatment versus placebo and described using continuous summary.  
Sensitivity analyses for CPA will include: 
 Change from baseline in CPA at 1 year will be analyzed based on the LOCF values 
using the FAS population. 
 Change from baseline in CPA at 1 year will be analyzed using the MITT 
population. 
 Change from baseline in CPA at 1 year will be analyzed using the PP population. 
Ishak histopathological stage 
The proportion of subjects who have at least one stage change in Ishak histopathological 
staging of fibrosis at 1 year will be analyzed using the FAS population. Fisher Exact Test 
will be used to compare the difference between treatment groups. 
Sensitivity analyses for Ishak histopathological stage will include: 
 The proportion of subjects who have at least one stage change in Ishak 
histopathological staging of fibrosis at 1 year will be analyzed using the MITT 
population. 
 The proportion of subjects who have at least one stage change in Ishak 
histopathological staging of fibrosis at 1 year will be analyzed using the PP 
population. 
FibroScan® 
The change from baseline in FibroScan® (if available) at 1 year will be analogous to the 
primary efficacy endpoint, using the ANCOVA model for the FAS population. The 
baseline value of FibroScan® (if available) will be used as a continuous covariate in the 
ANCOVA model. 
Sensitivity analyses for FibroScan® (if available) will include: 
 Change from baseline in FibroScan® (if available) at 1 year will be analyzed based 
on the LOCF values using the FAS population. 
 Change from baseline in FibroScan® (if available) at 1 year will be analyzed using 
the MITT population. 
 Change from baseline in FibroScan® (if available) at 1 year will be analyzed using 
the PP population. 
 Treatment effect for FibroScan® (if available) overtime will be estimated using a 
mixed model repeated measures (MMRM) analysis with the FAS population.  


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MBT 
The change from baseline in MBT (if available) at 1 year will be analogous to the primary 
efficacy endpoint, using the ANCOVA model using the FAS population. The baseline 
MBT will be used as a continuous covariate in the ANCOVA model. 
Sensitivity analyses for MBT (if available) will include: 
 Change from baseline in MBT (if available) at 1 year will be analyzed based on the 
LOCF values using the FAS population. 
 Change from baseline in MBT (if available) at 1 year will be analyzed using the 
MITT population. 
 Change from baseline in MBT (if available) at 1 year will be analyzed using the PP 
population. 
 Treatment effect for MBT (if available) overtime will be estimated using MMRM 
analysis with the FAS population.  
Brunt-Kleiner histopathological stage 
The proportion of subjects who have at least one stage change in Brunt-Kleiner 
histopathological staging of fibrosis at 1 year will be analyzed using the FAS population. 
Fisher Exact Test will be used to compare the difference between treatment groups. 
Sensitivity analyses for Brunt-Kleiner histopathological stage will include: 
 The proportion of subjects who have at least one stage change in Brunt-Kleiner 
histopathological staging of fibrosis at 1 year will be analyzed using the MITT 
population. 
 The proportion of subjects who have at least one stage change in Brunt-Kleiner 
histopathological staging of fibrosis at 1 year will be analyzed using the PP 
population. 
Complications of cirrhosis  
The incidence of complications of cirrhosis with portal hypertension at 1 year will be 
analyzed using the FAS population. A standard chi-square test will be used to compare the 
incidence of complications of cirrhosis between treatment groups.  
Sensitivity analyses for complications of cirrhosis will include: 
 The incidence of complications of cirrhosis with portal hypertension at 1 year will 
be analyzed using the MITT population. 
 The incidence of complications of cirrhosis with portal hypertension at 1 year will 
be analyzed using the PP population. 
 Time to complications of cirrhosis will be analyzed using Kaplan-Meier curves and 
compared between treatment groups using a log-rank test. Median time to 


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complications of cirrhosis, Q1 and Q3 will be presented, along with 95% CI. Time 
to complications of cirrhosis is defined as the time from the date of randomization 
to the first documentation of any complication of cirrhosis described in section 8.2. 
Subjects without development of complications of cirrhosis will be censored at the 
date of last assessment of cirrhosis complications.  
8.3. Exploratory Endpoints  
Each of the following exploratory efficacy endpoints will be analyzed analogous to the 
primary efficacy endpoint, using the ANCOVA model unless otherwise specified. For each 
endpoint, the baseline value of the endpoint will be used as a continuous covariate in the 
ANCOVA model.  
 Difference in health-related quality of life (using the subject-completed CLDQ) 
following administration of GR-MD-02 or placebo at 1 year 
 Baseline-adjusted change in FibroTest (FibroSure) and ELF score at Infusion Visits 
7, 13, 20, and 14-28 days after final infusion 
 Changes in liver biopsy staining for α-SMA and galectin-3 in subjects treated with 
GR-MD-02 or placebo at 1 year will be evaluated using robust regression (M 
estimation method) 
CLDQ 
CLDQ is a self-administered questionnaire that consists 29 items on a seven-point scale, 
ranging from the worst (1) to the best (7) possible function. The questionnaire includes 
following 6 domains:  
 
Domains 
Items 
Abdominal symptoms (AS) 
1, 5, 17 
Fatigue (FA) 
2, 4, 8, 11, 13 
Systemic symptoms (SS) 
3, 6, 21, 23, 27 
Activity (AC) 
7, 9, 14 
Emotional function (EF) 
10, 12, 15, 16, 19, 20, 24, 26 
Worry (WO) 
18, 22, 25, 28, 29 
 
Average score of each domain will be computed. The average score across six domain 
average scores will also be derived as the overall average score. The derived domain 
average and overall average score will be summarized at scheduled visits. If the score is 
missing for some individual items, the domain average score should be calculated as an 
average of available items if more than 50% of items in that domain are available. If 50% 
or less of the items are available for a domain, the domain average score is set as missing 
too. 


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FibroTest (FibroSure) and ELF Score 
Missing values will be imputed using the LOCF method for the post-baseline visits for 
FibroTest score and ELF score. Also, the ANCOVA model will be conducted for both 
observed values and LOCF values. 
Treatment effects for FibroTest score and ELF score overtime will be estimated using 
MMRM analysis with the FAS population respectively.  
Each exploratory test will also be summarized for the FAS population at all scheduled 
visits, along with the change from baseline descriptively in summary tables. 
 
9. Safety Analysis 
All analysis of safety will be conducted using the Safety set.  
9.1. Adverse Events 
An adverse event (AE), including serious AE (SAE), is defined as any untoward medical 
occurrence in a subject enrolled into this study, regardless of its causal relationship to IMP.  
A treatment-emergent adverse event (TEAE) is defined as any event which occurs on or 
after the first double-blind dose date and up to 30 days after the last dose date of the 
double-blind study drug. 
In order to determine a TEAE when the start date of an AE is missing or incomplete, it will 
be assumed to have occurred after the first infusion of IMP except if an incomplete date 
indicates that the event started prior to the first infusion. 
In the event that only a partial end date (month/year) is available, and the month/year 
occurs before Day 1 of the study, the AE will not be considered treatment-emergent. 
However, the partial onset date (month/year) of AE will be handled as follows (where UK, 
UKN and UKNW indicate unknown or missing Day, Month and Year respectively):  
 UK-MMM-YYYY:  
o impute the last day of the month, if the year is less than the first dose year 
or the year is the same as the first dose year and the month is less than or 
equal to the first dose month; 
o impute 01-MMM-YYYY, if the year is greater than the first dose year or 
the year is the same as the first dose year and the month is greater than the 
first dose month; 
o impute the date of the first dose, if the month and year are the same as the 
first dose month and year. 
 UK-UKN-YYYY: 
o impute 31-DEC-YYYY, if the year is less than the first dose year; 


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o impute 01-JAN-YYYY, if the year is greater than the first dose year;  
o impute the date of the first dose, if the year are the same as the first dose 
year.  
 UK-UKN-UKNW: impute date of the first dose. 
If the AE end date is complete and the partial AE start date imputed by the rules above is 
after the AE end date, then the start date will be imputed by the AE end date. 
All AEs will be coded according to the most recent version of the Medical Dictionary for 
Regulatory Activities (MedDRA), version 18.0. Severity of AE will also be reported 
according to the NCI Common Terminology Criteria for Adverse Events version 4.03. 
The incidence of AEs will be summarized in tables with count and percentage of subjects 
with AEs by system organ class (SOC) and preferred term. Unless otherwise specified, at 
each level of SOC or preferred term, a subject with multiple events will only be counted 
once per SOC or preferred term. Percentages of subjects with AEs will be calculated out of 
the number of subjects in the safety population. Tables will be sorted by SOC and 
preferred term based on total frequency in overall group. 
The following categories of AE will be summarized: 
 TEAEs 
 Severity (1, 2, 3, 4 and 5) of AEs 
 Relationship of AEs to study drug  
 Grade 3 or greater AEs 
 AEs leading to discontinuation of study treatment 
 AEs leading to death 
 Relationship of TEAEs to study drug  
 Grade 3 or greater TEAEs 
 TEAEs leading to discontinuation of study treatment 
 TEAEs leading to death 
 SAEs 
 Serious TEAEs 
 Serious and grade 3 or greater TEAEs 
 Serious TEAEs leading to discontinuation of study treatment 
 Serious TEAEs leading to death 
All AEs will be presented in data listings. TEAEs will be flagged in the listings. 


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9.1.1. Relationship of Adverse Events to Study Drug 
The relationship of AEs to study drug (Unrelated, Possible, Probable, Definite) will be 
summarized. Possible, probable, definite will be considered as related to study drug. If 
relationship to treatment is missing, it will be assumed to be related. 
9.1.2. Severity of Adverse Events 
All AEs will be summarized by maximum severity (1, 2, 3, 4 and 5). If a subject reports 
multiple occurrences of a specific event within a specific analysis period, the subject will 
be counted only once by the maximum severity. No imputation will be done for missing 
severity. 
9.2. Clinical Laboratory Evaluations 
Laboratory assessments, including hematology, coagulation and chemistry, will be 
evaluated over time on the study. All summaries will be based on the units provided by the 
central laboratory, no conversion will be done and missing values will not be imputed.  
Urinalysis assessments will only be collected at screening visit. 
Summary statistics of the observed values and change from baseline will be provided at the 
scheduled visits for hematology, coagulation and chemistry laboratory parameters. The 
number and percentage of subjects with shift in normal/abnormal from baseline will be 
presented in a shift table at the post-baseline scheduled visits for hematology, coagulation 
and chemistry laboratory parameters.  
Clinically significant laboratory values will be summarized for subjects meeting at least 
one of the criteria and change from baseline will be presented in a shift table. 
 Alanine aminotransferase (ALT) ≥3 × Upper Limit of Normal Value (ULN) and 
total bilirubin  ≥2 × ULN 
 Aspartate aminotransferase (AST) ≥3 × ULN and total bilirubin  ≥2 × ULN 
 Albumin <2.8 g/dL 
All laboratory data will also be presented in listings. 
9.3. Biomarker Measurements 
A blood sample will be collected for assessment of galectin-3 at Infusion Visits 1, 7, 13, 
20, and 14 to 28 days after final infusion. Summary statistics of the observed values and 
change from baseline will be provided at the scheduled visits for the safety population. 
9.4. Vital Sign Measurements 
Vital sign measurements including respiratory rate (bpm), heart rate (beats per minute), 
temperature (C), systolic blood pressure (mmHg), diastolic blood pressure (mmHg), 
weight (kg) and BMI (kg/m2) will be summarized descriptively using the safety population 


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at the scheduled visits. Change from baseline values will also be summarized descriptively 
at the scheduled visits. All vital signs will be presented in a listing. 
9.5. Physical Examination 
A complete physical examination will be performed at screening, with particular attention 
to examination for stigmata of liver disease/cirrhosis. A limited physical examination will 
only include weight and examination of the heart, lung, and abdomen during the treatment 
phase.  
The number and percentage of subjects with each physical examination outcome (normal, 
abnormal, or not done) will be summarized using the safety population by body system at 
scheduled visits. Also the number and percentage of subjects with change from baseline 
will be presented in a shift table by body system at the post-baseline scheduled visits. 
All physical examination results will be presented in a listing. 
9.6. Electrocardiogram (ECG) 
12-lead ECG assessments including PR interval (milliseconds), QRS interval 
(milliseconds), QT interval (milliseconds), and QTc interval (milliseconds) will be 
summarized descriptively using the safety population at the scheduled visits. Change from 
baseline values will also be summarized descriptively at the scheduled visits, 
The number and percentage for ECG overall interpretation (normal or abnormal and not 
clinically significant vs. clinically significant,) will be summarized at scheduled visits. 
Also the number and percentage of subjects with change from baseline will be presented in 
a shift table at the post-baseline scheduled visits. 
All ECG assessments will be presented in a listing. 
10. Pharmacokinetics 
All PK analysis will be conducted using the PK population.  
10.1. Plasma Concentrations 
PK blood samples will be collected at the following times: 
 Infusion Visit 1: Approximately 2 hours following the end of the infusion, on the 
day following the infusion (Nondosing Visit 1 [ie, Day 2]), and on Nondosing 
Visit 2 (ie, Day 3) following the infusion. The blood sample collections on 
Nondosing Visits 1 and 2 (ie, Days 2 and 3) can occur at any time during those 
days.  
 Infusion Visit 2: Approximately 2 hours following the end of the infusion 
 Infusion Visit 3: Approximately 2 hours following the end of the infusion 
 Infusion Visit 4: Approximately 2 hours following the end of the infusion and on 
Nondosing Visit 3 (which can be either Day 2 or 3 following the infusion). The 


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blood sample collection on Nondosing Visit 3 (ie, Day 2 or 3) can occur at any time 
during those days. 
 Infusion Visit 7: Any time after the end of infusion on the day of the infusion.  
The individual plasma concentrations of GR-MD-02 will be listed for each subject. The 
listing will include subject number, dose group, scheduled visit, date and time of 
collection, actual relative time to dose, and plasma concentrations. All concentrations 
below the limit of quantification (BLQ) or missing data will be labelled as such in 
concentration data listings. 
GR-MD-02 concentrations will be summarized using descriptive statistics by dose group, 
visit, and scheduled time point. Descriptive statistics will include arithmetic mean, SD, 
coefficient of variation (CV), minimum, median, maximum, geometric mean and 
geometric mean CV. Concentrations that are BLQ will be treated as zero in the summary 
statistics of concentration data. All missing concentrations will be treated as missing in the 
summary statistics of concentration data. 
Plots of arithmetic mean (±SD) concentration versus visit and time (both linear and semi-
logarithmic) by dose group and individual concentrations versus visit and time (both linear 
and semi-logarithmic) will be provided. For ease of presentation, nominal sampling times 
will be used to present results in figures.  
10.2. Plasma Pharmacokinetic Parameters 
GR-MD-02 plasma concentrations will be used to evaluate systemic exposure following 
multiple dosing. Based on the high correlation between the area under the concentration-
time curve and Cmax of GR-MD-02 in the Phase 1 clinical study (Galectin 2014) (p<0.001, 
r squared = 0.91), the plasma levels at 2 hours (approximate Cmax) following the dose of 
GR-MD-02 will be used to estimate the systemic exposure and to assess the attainment of 
the steady state of GR-MD-02. 
All PK analyses will be conducted by the Department of Clinical Pharmacology, PPD, 
Inc., Richmond, VA, USA. 
11. Interim Analysis 
An interim analysis of PK data is planned for the first Data Safety Monitoring Board 
(DSMB) meeting. It is expected that PK analysis will be performed on the GR-MD-02 
plasma concentrations for the first 30 subjects after Infusion Visits 1, 2, 3, 4 and 7. There 
should be approximately 10 subjects who received 2 mg/kg and 10 subjects who received 
8 mg/kg in this group of subjects.  
12. Data Safety Monitoring Board 
An independent Data Safety Monitoring Board (DSMB) will be composed of medical 
experts and an unblinded biostatistician who will not participate in the study. The DSMB 
will be responsible for periodically monitoring the safety of the clinical study and 


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providing recommendations for the study by reviewing the safety data at several 
predetermined times during the study and at any other time when it is determined by the 
DSMB or Galectin Therapeutics Inc that such a review is warranted. 
The DSMB review will occur as follows: 
 after the first 30 subjects in the study have received 7 doses of IMP; 
 after the approximately 50% of subjects to be enrolled has received 13 doses of 
IMP;  
 after 50% of subjects have received 26 doses of IMP. 
In addition to review of the safety data, the first DSMB meeting will also assess 
GR-MD-02 Cmax plasma levels after Infusion Visits 1, 2, 3, 4 and 7 for the first 30 subjects. 
 
 


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13. References 
Galectin Pharmaceuticals, Inc. A Multi-Center, Partially Blinded, Maximum Tolerated 
Multiple Dose Escalation, Phase 1 Clinical Trial to Evaluate the Safety of GR-MD-02 in 
Subjects with Non-Alcoholic Steatohepatitis (NASH) with Advanced Hepatic Fibrosis. 
17 Jun 2014. Protocol No. GT-020. Version 4. 96p. 
Garcia-Tsao G, Sanyal AJ, Grace ND. Prevention and Management of Gastroesophageal 
Varices and Variceal Hemorrhage in Cirrhosis. Hepatology. 2007;46:922-938. 
Garcia-Tsao G, Bosch J. Management of varices and variceal hemorrhage in cirrhosis. N 
Engl J Med 2010 Mar 4;362(9):823-832. 
Groszmann RJ, Garcia-Tsao G, Bosch J, Grace ND, Burroughs AK, Planas R, et al. Beta-
blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med 2005 
Nov 24;353(21):2254-2261. 
Huber, PJ. Robust Regression: Asymptotics, Conjectures and Monte Carlo. Annals of 
Statistics. 1973;1, 799–821. 
  


 
Galectin Therapeutics Inc 
 
GT-026 
 
A Multicenter, Randomized, Placebo-Controlled, Double-Blind, 
Parallel-Group, Phase 2 Clinical Trial to Evaluate the Safety and Efficacy 
of GR-MD-02 for the Treatment of Liver Fibrosis and Resultant Portal 
Hypertension in Patients with NASH Cirrhosis 
 
The NASH-CX Trial 
 
26 Jan 2018 
 
Statistical Analysis Plan Addendum 
 
Version 2.0 
 
Prepared by: 
 
PPD 
3575 Quakerbridge Road, Suite 201 
Hamilton, NJ 08619 
 
 
 
 
 


The additional data analysis as listed below will be performed as post-hoc analysis. The main 
objective is to repeat primary and secondary analysis on the following subgroups: 
a. Patients with baseline (BL) varices, and patients without BL varices.  
b. Patients with MPH (baseline HVPG 6 to <10 mmHg) and patients with CSPH 
(baseline HVPG (≥ 10 mmHg) 
For definition of analysis set and other terminology or abbreviation, please refer to final SAP. 
However, the subject who was randomized but have not received any treatment will be removed 
from all analysis sets used in post-hoc. In addition, the missing value at scheduled visit will be 
imputed by result from subsequent unscheduled visit. For example, if a subject’s HVPG at Week 
53-55 visit was not collected, but there’s a subsequent unscheduled visit with valid result, this 
unscheduled result will be used as subject’s HVPG result at Week 53-55. 
For LOCF analysis, include all patients that had an early termination visit, and carry forward 
their last observation result. 
 
Analyses on Primary Endpoint HVPG 
1. Perform ANCOVA to determine effect of varices on HVPG on FAS LOCF dataset: 
a. Week 53/55 HVPG is used as dependent with BL HVPG as covariate, and with 
dose, varices and dose varices interaction as fixed factors. 
2. Run ANCOVA for FAS LOCF, mITT LOCF, and PP LOCF for HVPG with Least square 
difference (LSD) mean comparison (no Bonferroni correction) on subset of patients with 
/ without baseline varices: 
a. BL Change in HVPG vs dose with BL HVPG as a covariate (i.e. adjust for 
baseline HVPG)  
b. Percent Change from BL HVPG vs dose with no covariate/no baseline adjustment  
3. Perform similar ANCOVA/ANOVA analyses of MPH and CSPH for each subset, this 
would result in the following: 
a. Analyses of patients without varices and with MPH – using FAS LOCF,  mITT 
LOCF and PP LOCF for HVPG with LSD mean comparison (no Bonferroni 
correction) on: 
i. ANCOVA for BL Change in HVPG vs dose with BL HVPG as a covariate 
(i.e. adjust for baseline HVPG)  
ii. ANOVA for Percent Change from BL HVPG vs dose with no covariate/no 
baseline adjustment  
b. Analyses of patients without varices and with CSPH - using ITT LOCF, mITT 
LOCF,  and PP LOCF for HVPG with LSD mean comparison (no Bonferroni 
correction) on: 
i. ANCOVA for BL Change in HVPG vs dose with BL HVPG as a covariate 
(i.e. adjust for baseline HVPG)  
ii. ANOVA for Percent Change from BL HVPG vs dose with no covariate/no 
baseline adjustment  


c. Analyses of patients with varices and with MPH (6 to <10 mmHg) -- using ITT 
LOCF LOCF,  mITT LOCF and PP LOCF for HVPG with LSD mean comparison 
(no Bonferroni correction) on: 
i. ANCOVA for BL Change in HVPG vs dose with BL HVPG as a covariate 
(i.e. adjust for baseline HVPG) 
ii. ANOVA for Percent Change from BL HVPG vs dose with no covariate/no 
baseline adjustment 
d. Analyses of patients with varices and CSPH (≥ 10 mmHg) -- using ITT LOCF, 
mITT LOCF, and PP LOCF for HVPG with LSD mean comparison (no 
Bonferroni correction) on: 
i. ANCOVA for BL Change in HVPG vs dose with BL HVPG as a covariate 
(i.e. adjust for baseline HVPG) 
ii. ANOVA for Percent Change from BL HVPG vs dose with no covariate/no 
baseline adjustment 
 
Analyses on Secondary Endpoint Collagen Proportional Area (CPA) 
All post-hoc analysis performed on HVPG parameter will be repeated for Collagen 
Proportional Area (CPA). 
 
Analyses on Secondary Endpoints using FAS set 
 
1. Perform BL Change vs. Dose using MMRM model for continuous data and Ordinal 
Logistic Regression (OLR) Analysis for categorical data for the following datasets: all 
data, With Varices, Without Varices, Without Varices and MPH, Without Varices and 
CSPH, With Varices and MPH, and With Varices and CSPH.  
2. The change from baseline at Week 53/55 of categorical variable will be the response and 
treatment will be explanatory variable in OLR model. If Week 53/55 is missing, LOCF 
rule will be applied for imputation. The change from baseline will be classified to 
Decrease, No Change and Increase. The result of odds ratio and its 95%CI as well as p-
value from Wald Chi Square test will be presented in the table. The lowest level ie 
Decrease is the event level in response. 
3. The change from baseline at each visit of continuous variable will be the dependent 
variable in MMRM analysis. Baseline is the covariate and treatment, visit and interaction 
of treatment and visit are factors. If scheduled assessment is missing and a subsequent 
unscheduled assessment is available, the scheduled assessment will be imputed by 
unscheduled assessment. 
4. The following parameters will be analyzed: 
a. Change in NAFLD Activity Score (OLR) (LVBNAS) 
b. Change in each Component of the NAFLD Activity Score: 
i. Change in hepatocyte ballooning score (OLR) 
ii. Change in inflammation (OLR) 
iii. Change in steatosis/fat (OLR) 
c. Change in Fibrosis Staging Score (OLR) 


i. Ishak staging score (OLR) 
ii. Brunt staging score (OLR) 
d. Change in FibroTest Score (MMRM)  
e. Change in each Component of the FibroTest Score: 
i. Change in Alpha2 Macroglobulin (MMRM) 
ii. Change in Haptoglobin (MMRM) 
iii. Change in Apolipoprotein A1 (MMRM)  
iv. Change in Gamma-glutamyl transpeptidase, GGT (MMRM) 
v. Change in Total Bilirubin (MMRM) 
vi. Change in Alanine Transaminase, ALT (MMRM)  
f. Change in ELF Score (MMRM) 
g. Change in each Component of the ELF Score: 
i. Change in tissue inhibitor of metalloproteinases 1, TIMP-1 (MMRM) 
ii. Change in amino-terminal propeptide of type III procollagen, PIIINP 
(MMRM) 
iii. Change in hyaluronic acid, HA (MMRM) 
h. Change in AST/ALT Ratio (MMRM) 
i. Change in Platelet Count (MMRM) 
j. Change in ACTITEST Score (MMRM) 
k. Change in GAL-3 (biomarker, MMRM) 
 
5. Perform Chi Square Test without correction on overall data as well as the subset Without 
Varices for the following: 
a. All Complications (for patients with at least one complication) 
b. Each separate complication 
c. Perform all analyses in a through e above also for combined active groups (GR2 + 
GR8) vs. placebo