Clinical trial NCT04004325
Conditions: Nonalcoholic Steatohepatitis (NASH) Overweight or Obesity
Sponsor: Forma Therapeutics, Inc.
Start date: 2019-05-17; Completion date: 2020-01-20
Enrollment: 14 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This Phase 1/2 study will evaluate safety, efficacy, PK, and PD of FT-4101 as a single agent in overweight/obese subjects with NASH.

The study may be conducted in up to 2 dosing cohorts.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: FT-4101 intervention 2: FT-4101 placebo intervention 3: Deuterated Water
Intervention descriptions: intervention 1: FT-4101 will be supplied as active capsules and will be administered per the protocol defined frequency and dose level. intervention 2: FT-4101 placebo will be supplied as placebo capsule matching in size and color to all the active capsules and will be administered per the protocol defined frequency and dose level. intervention 3: Deuterated water will be provided as individual ready-to-use, single dose bottles each containing 50 mL of deuterated water (70%).

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
Sponsor name: 
FORMA Therapeutics, Inc. 
NCT number 
NCT04004325 
Sponsor trial ID: 
4101-MET-201 
Official title of study: 
A phase 1/2, randomized, double-blind, placebo controlled 
study evaluating the safety, tolerability and efficacy of 
FT-4101 in overweight/obese subjects with NASH
Document date: 
23 July 2019 


FORMA Therapeutics, Inc. 
Clinical Study Protocol 
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Protocol No. 4101-MET-201 
Version 2.0_23-Jul-2019 
Clinical Development FT-4101 
Clinical Study Protocol 4101-MET-201 
A PHASE 1/2, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED STUDY EVALUATING THE SAFETY, 
TOLERABILITY AND EFFICACY OF FT-4101 IN 
OVERWEIGHT/OBESE SUBJECTS WITH NASH 
Sponsor: 
FORMA Therapeutics, Inc. 
500 Arsenal Street, Suite 100 
Watertown, MA 02472 
Sponsor Contact: 
 
 Clinical Development 
Clinical Research 
Organization: 
Authors: 
 (FORMA Therapeutics, Inc.),
 
 
, 
 
Document type: 
Clinical Study Protocol 
IND number: 
133992 
Version number: 
V2.0 
Development phase: 
Phase 1/2 
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Redacted protocol 
Includes redaction of personal identifiable information only. 


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Protocol No. 4101-MET-201 
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1.0 
ADMINISTRATIVE INFORMATION 
1.1 
Contacts 
A separate contact information list will be provided. 
1.2 
Document History 
Version 
Revision Date 
Revision Description 
1.0 
05-APR-2019
Original Document 
2.0 
23-JUL-2019
1. Incorporation of Administrative Letter/
Amendment dated 01 May 2019
a) Change of Inclusion Criterion # 3a.
All subjects, including the subjects that meet the
diagnosis of NASH with a previous liver biopsy,
will undergo a FibroScan at screening. This is
necessary as FibroScan is considered an endpoint
and a pre-treatment (screening) result is necessary
to evaluate the change from baseline to C4/D22.
Section 2.0 Study Summary, section 7.1 Inclusion
Criteria
(Comment: This criterion is further amended
under # 3 in this amendment [protocol version
2.0])
b) Change of number for rescheduling options at
check-in from 2 to 1.
Section 9.1.12 Check-in Procedure
c) Clarification of Exclusion Criterion #26. The
timepoint “1 year” was accidentally omitted in the
protocol and was re-added again.
Section 2.0 Study Summary, section 7.2 Exclusion
Criteria
d) Adjustments of language in order to comply
with Clinical Data Interchange Standards
Consortium (CDISC) controlled terminology for
electronic datasets.
Section 10.3.3 Action Taken and Outcome
f) Adjustments of “X-marks” in the Schedule of
Events to be consistent with protocol language.
Section 16.1, Appendix A
g) Clarification of footnote l under the Schedule
of Events
Section 16.1, Appendix A
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h) Clarification of terms
Gastrointestinal was added in order to ensure that
gastrointestinal system for the baseline physical
examination is the same as the abdominal
assessed at the abbreviated PE.
Section 9.1.4 Physical Examination
2. Incorporation of Administrative Letter dated
29 May 2019
a) Capturing of SAEs was changed. From now
on, SAEs will be entered electronically via EDC
with an autogenerated email. The email will be
sent to 
 Pharmacovigilance (PV) after
completion and saving of an AE, with choosing
the options “serious=yes”. The paper SAE report
form is only to be utilized if the site is unable to
access EDC for any reason.
Section 10.2 Recording of Adverse Events and
Serious Adverse Events, section 10.4.2 Serious
Adverse Events and Suspected Unexpected
Serious Adverse Serious Reactions (SUSARs)
Changes for this Amendment: 
3. Change of Inclusion Criterion # 3a
LSM by FibroScan is deleted as an inclusion
criterion. A FibroScan CAP value of ≥ 300 dB/m
is still required as part of the eligibility criteria.
LSM as entry criterion is eliminated, as it is
specific for a progressive NASH. The FibroScan
can be performed at screening or within 30 days
prior to screening.
Section 2.0 Study Summary, section 7.1 Inclusion
Criteria, 9.1.2 Screening, 9.1.17.4 FibroScan,
section 16.1, Appendix A
4. Change of Inclusion Criterion # 6c
Fasting plasma glucose (FPG) at screening was
changed from < 180 mg/dL to < 240 mg/dL, in
order to align with protocol section 9.1.14 Wash-
Out Period
Section 2.0 Study Summary, section 7.1 Inclusion
Criteria
1. Change of Exclusion Criterion # 19
Adjustments to contraindications for MRI
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examination to adhere to specific guidance 
provided by local imaging centers on 
contraindications. 
Section 2.0 Study Summary, section 7.2 Exclusion 
Criteria 
2. Change of Specified Timepoint for Prohibited
Medications
Any medication that is a strong inducer or strong
inhibitor of CYP3A4, is prohibited from 15 days
prior to dosing unless half-life is greater than 72
hours, then it is prohibited for 5 half-lives prior to
dosing. The timepoint of 30 days prior to dosing
has been adjusted to the above statement to
accommodate for the various drugs and half-lives.
Section 7.3.1 Prohibited Medications
3. Allowing to Collect Additional Samples
Covering all Types of Tissues for Potential
Future Analysis
Additional samples (e.g., including blood
samples, urine samples and all types of tissue
samples) may be collected and stored for potential
future analysis.
Section 9.1.8 Procedures for Clinical Laboratory
Samples
4. Incorporation of Updated IB, version 5.0
Updated language from IB and reference to
updated version have been incorporated
throughout the protocol.
Section 4.1 Background, section 4.3 Summary of
Pre-Clinical/Clinical Studies
5. Adding Sebum Collection Using Sebutape® for
Fatty Acid Concentration at D-14.
This sample will be stored for potential future
analyses.
Section 6.1 Study Design, section 16.1, Appendix
A
6. Clarification around Central Reader and
Incidental Findings on MRI Scans
MRI readings for safety will not be performed by
a central reader, but by the specific MRI imaging
center. MRI incidental findings discovered at
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screening will not be entered as adverse events, 
but recorded as medical history, as these pre-
existing conditions are found as a result of the 
screening procedure. 
Section 9.1.17.6 MRI-PDFF 
7. Recording of Deuterated Water Intake
Missed doses of deuterated water will be entered
into the CRF to check compliance.
Section 8.5.1 Deuterated Water
8. Compliance of IP Intake
In order to achieve appropriate coverage of IP,
subjects are not allowed to miss more than a
specific number of doses during their dosing
cycles. If subjects are non-compliant, they may be
excluded from the study.
Section 8.5 Dose Regimen
9. Exclusion of Cannabidiol Oil as Concomitant
Drug
Cannabidiol is a CYP inhibitor and will be added
to the list of CYP3A4 inhibitors and inducers. It
is covered under “other food components” in the
Exclusion Criteria.
Section 16.3, Appendix C
10. Adjustment of Blood Volume
Blood sampling for PK assessments will need 2.0
mL per sample instead of the projected 3.0 mL
per sample. This leads to a reduction of the total
blood volume for the study.
Section 9.1.16 Pharmacokinetic Assessments and
Schedule
11. Adding Hyperglycemia to Blood Glucose
Measurement at Hyperglycemia
Subjects’ blood glucose might be measured by
fingerstick whenever there are signs or symptoms
of hypoglycemia or hyperglycemia.
Hyperglycemia was added to ensure that subjects
blood glucose is monitored across all ranges for
the safety of the subject.
Section 9.1.13 Blood Glucose Monitoring by
Fingerstick
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12. Addition of ECG as primary safety endpoint
Change from baseline in 12-lead ECG added as
parameter in the objectives and endpoint sections
in order to be consistent with the statistical
analysis section of the protocol. ECG is used
during the study as safety criterion but was not
stated as is in specific section.
Section 2.0 Study Summary, section 5.1 Primary
Objectives and Endpoints
13. Change of sponsor contact title
Title of sponsor contact was changed from
Translational Medicine to Clinical Development.
Section Title Page and Sponsor Protocol
Approval Page
14. Clarifications to the Protocol
a) Exclusion Criterion #6, the exclusion of liver
cirrhosis by FibroSure® > 0.75, will be assessed
by the “Fibrosis Score” test reported on the
laboratory report.
Section 2.0 Study Summary, section 7.2 Exclusion
Criteria
b) Inclusion Criterion #2, the exclusion of
subjects with acute proliferative retinopathy, will
be based on the history of the subject and not on
an additional examination.
Section 2.0 Study Summary, section 7.1 Inclusion
Criteria
c) Clarification around the Exclusion Criterion
#16
Subjects with dry eyes due to wearing contact
lenses can be included in the study.
Section 2.0 Study Summary, section 7.2 Exclusion
Criteria
d) Clarification around Check-in Criterion #5 and
Check-in Procedure #4
Adjustments of language in order to provide
consistency throughout the protocol in regards to
time and concomitant medications
Section 7.3.2 Check-in Criteria, section 9.1.12
Check-in Procedure
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e) Clarification of Urinalysis
Leucocyte esterase or equivalent may be used.
Section 9.1.8 Procedure for clinical laboratory
samples
f) Row added in Schedule of Events for the
assessment of TSH in order to be consistent with
the protocol.
Section 16.1, Appendix A
g) Adjustment of wording for consistency. The
word Patient will be exchanged to Subject
throughout the section for the study conduct.
h) Deletion of reference [Turner, et al. 2003] in
text, as reference was not stated in the references
section.
Section 4.2 Rationale for the Proposed Study
i) Correction of typographical errors throughout
the protocol.
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1.3 
Approval 
Representatives of Sponsor will sign the agreement on the protocol. 
Investigators agreement on the protocol will be provided in a separate protocol approval 
document. 
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TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION .......................................................... 2 
1.1 
Contacts ................................................................................................... 2 
1.2 
Document History .................................................................................... 2 
1.3 
Approval .................................................................................................. 8 
2.0 
STUDY SUMMARY ................................................................................... 14 
3.0 
LIST OF ABBREVIATIONS ...................................................................... 24 
4.0 
INTRODUCTION ....................................................................................... 26 
4.1 
Background ............................................................................................ 26 
4.2 
Rationale for the Proposed Study............................................................ 27 
4.3 
Summary of Pre-Clinical /Clinical Studies ............................................. 28 
4.4 
Rationale for Treatment and Dose .......................................................... 29 
5.0 
STUDY OBJECTIVES AND ENDPOINTS ................................................ 30 
5.1 
Primary Objectives and Endpoints .......................................................... 30 
5.2 
Secondary Objectives and Endpoints ...................................................... 30 
5.3 
Exploratory Objectives and Endpoints .................................................... 31 
6.0 
STUDY DESIGN AND DESCRIPTION ..................................................... 33 
6.1 
Study Design .......................................................................................... 33 
6.2 
Study Description ................................................................................... 34 
6.3 
Rationale for Study Design and Endpoints.............................................. 37 
6.4 
Dose Escalation ...................................................................................... 37 
6.5 
Study Discontinuation and Stopping Criteria .......................................... 38 
6.5.1 
Dose Escalation Stopping Criteria ............................................. 38 
6.5.2 
Study Advancement after Dose Escalation Stopping Criteria ..... 39 
6.5.3 
Criteria for Early Termination of the Study ................................ 39 
6.5.4 
Criteria for Early Termination of Individual Subjects................. 40 
6.6 
Treatment Interruption with Dose Modifications .................................... 40 
7.0 
STUDY POPULATION .............................................................................. 43 
7.1 
Inclusion Criteria .................................................................................... 43 
7.2 
Exclusion Criteria................................................................................... 44 
7.3 
Study Restrictions/Precautions ............................................................... 46 
7.3.1 
Prohibited Medications .............................................................. 46 
7.3.2 
Check-in Criteria ....................................................................... 47 
7.3.3 
Anticipated Risks ...................................................................... 47 
8.0 
STUDY MATERIALS ................................................................................. 49 
8.1 
Investigational Products ......................................................................... 49 
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8.1.1 
FT-4101 .................................................................................... 49 
8.1.2 
Placebo ...................................................................................... 49 
8.2 
Other Medicinal Products ....................................................................... 49 
8.2.1 
Deuterated Water ....................................................................... 49 
8.3 
Packaging, and Labeling of Products ...................................................... 49 
8.4 
Storage and Drug Accountability of Products ......................................... 49 
8.5 
Dose Regimen ........................................................................................ 50 
8.5.1 
Deuterated Water ....................................................................... 53 
8.6 
Overdose ................................................................................................ 54 
8.7 
Randomization and Blinding .................................................................. 54 
8.8 
Breaking of Blinded Code ...................................................................... 54 
9.0 
STUDY PLAN............................................................................................. 56 
9.1 
Study Procedures .................................................................................... 56 
9.1.1 
Informed Consent and HIPAA Release ...................................... 56 
9.1.2 
Screening................................................................................... 56 
9.1.3 
Demographics and Medical History ........................................... 57 
9.1.4 
Physical Examination ................................................................ 57 
9.1.5 
Height, Weight, and BMI........................................................... 57 
9.1.6 
Vital Signs ................................................................................. 58 
9.1.7 
Concomitant Illness and Therapy ............................................... 58 
9.1.8 
Procedures for Clinical Laboratory Samples .............................. 58 
9.1.9 
Contraception ............................................................................ 60 
9.1.10 
Pregnancy .................................................................................. 63 
9.1.11 
ECG Procedure .......................................................................... 63 
9.1.12 
Check-in Procedure ................................................................... 64 
9.1.13 
Blood Glucose Monitoring by Fingerstick ................................. 64 
9.1.14 
Wash-Out Period ....................................................................... 64 
9.1.15 
Standardized Meals and Dietary Counseling .............................. 65 
9.1.16 
Pharmacokinetic Assessments and Schedule .............................. 65 
9.1.17 
Pharmacodynamic Assessments and Schedule ........................... 65 
9.1.18 
Blood Volume ........................................................................... 69 
10.0 
ADVERSE EVENTS ................................................................................... 70 
10.1 
Definitions ............................................................................................. 70 
10.1.1 
Adverse Event (AE)................................................................... 70 
10.1.2 
Treatment emergent Adverse Event (TEAE) .............................. 70 
10.1.3 
Serious Adverse Event (SAE) .................................................... 71 
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10.1.4 
Clinical Laboratory Assessments as Adverse Events and Serious 
Adverse Events .......................................................................... 72 
10.2 
Recording of Adverse Events and Serious Adverse Events ..................... 72 
10.3 
Evaluation of Adverse Events and Serious Adverse Events .................... 72 
10.3.1 
Intensity of AEs ......................................................................... 72 
10.3.2 
Causal Relationship to Study Treatment .................................... 73 
10.3.3 
Action Taken and Outcome ....................................................... 74 
10.4 
Reporting Procedures ............................................................................. 74 
10.4.1 
Any Adverse Event .................................................................... 74 
10.4.2 
Serious Adverse Events and Suspected Unexpected Serious 
Adverse Serious Reactions (SUSARs) ....................................... 74 
10.4.3 
Pregnancy or Drug Exposure during Pregnancy ......................... 75 
11.0 
DATA HANDLING AND MANAGEMENT .............................................. 76 
11.1 
Data Management .................................................................................. 76 
11.2 
CRFs (Electronic)................................................................................... 76 
11.2.1 
Clinical Data Management Workflow ........................................ 76 
11.2.2 
Data Entry of eCRFs.................................................................. 77 
11.2.3 
Corrections to eCRFs ................................................................. 77 
11.2.4 
PI Approval of eCRF Data ......................................................... 77 
11.3 
Retention of Documents ......................................................................... 77 
12.0 
STATISTICAL METHODS ........................................................................ 78 
12.1 
Statistical and Analytical Plans ............................................................... 78 
12.2 
Analysis Sets .......................................................................................... 78 
12.2.1 
Safety Set .................................................................................. 78 
12.2.2 
Pharmacokinetic (PK) Set .......................................................... 78 
12.2.3 
Preliminary Efficacy Set ............................................................ 78 
12.2.1 
Pharmacodynamic (PD) Set ....................................................... 78 
12.3 
Analysis of Demographics and Other Baseline Characteristics ............... 78 
12.4 
Analysis of the Pharmacokinetic Endpoints ............................................ 79 
12.4.1 
Analysis of Secondary Pharmacokinetic Endpoints .................... 79 
12.5 
Analysis of Preliminary Efficacy and Pharmacodynamic Endpoints ....... 79 
12.5.1 
Analysis of Primary Preliminary Efficacy Endpoints ................. 79 
12.5.2 
Analysis of Secondary Preliminary Efficacy and 
Pharmacodynamic Endpoints ..................................................... 80 
12.5.3 
Analysis of Exploratory Pharmacodynamic Endpoints ............... 81 
12.6 
Analysis and Endpoints .......................................................................... 81 
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12.6.1 
Analysis of Primary Safety and Tolerability Endpoints .............. 81 
12.7 
Interim Analysis ..................................................................................... 82 
12.8 
Determination of Sample Size ................................................................ 82 
13.0 
QUALITY CONTROL AND QUALITY ASSURANCE ............................. 83 
13.1 
Monitoring ............................................................................................. 83 
13.2 
Protocol Deviations ................................................................................ 83 
14.0 
ETHICAL ASPECTS OF THE STUDY ...................................................... 84 
14.1 
Institutional Review Board and/or Independent Ethics Committee .......... 84 
14.2 
Regulatory Authorities ........................................................................... 84 
14.3 
Responsibilities of the Investigator ......................................................... 84 
14.4 
Informed Consent ................................................................................... 85 
14.5 
Subject Confidentiality ........................................................................... 85 
14.6 
Publication, Disclosure, and Clinical Study Registration Policy .............. 86 
15.0 
REFERENCES ............................................................................................ 87 
16.0 
APPENDICES ............................................................................................. 91 
16.1 
Appendix A - Schedule of Events ........................................................... 91 
16.2 
Appendix B – PK Sampling Schedule .................................................... 95 
16.3 
Appendix C - CYP3A Strong Inhibitors and Inducers ............................. 96 
16.4 
Appendix D - Norwood’s Classification of Hair Loss ............................. 98 
16.5 
Appendix E - Savin’s Pictorial Grading of Female Pattern Hair Loss.... 100 
LIST OF IN-TEXT TABLES 
Table 6-1 FT-4101 Recommended Treatment Interruptions and Dose Modifications 
for Adverse Events ........................................................................... 41 
Table 6-2 Dose Reduction ....................................................................................... 42 
Table 7-1 Prohibited Medications ............................................................................ 46 
Table 8-1 Dosing Schedule for Treatment Cycles .................................................... 52 
Table 8-2 Dosing Schedule for Deuterated Water .................................................... 53 
Table 9-1 Clinical Laboratory Assessments ............................................................. 58 
Table 9-2 Deuterated Water Administration and Blood/Sebum Sampling for the DNL 
Assessments ..................................................................................... 67 
LIST OF IN-TEXT FIGURES 
Figure 6-1 Study Design Schematic ......................................................................... 33 
Figure 6-2 Dose Escalation Schematic ..................................................................... 38 
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Protocol No. 4101-MET-201 
 
Version 2.0_23-Jul-2019 
2.0 
STUDY SUMMARY 
Name of 
Investigation
al Product 
FT-4101 
Protocol 
Number 
4101-MET-201 
Protocol Title  A Phase 1/2, Randomized, Double-Blind, Placebo-Controlled Study 
Evaluating the Safety, Tolerability and Efficacy of FT-4101 in 
Overweight/Obese Subjects with NASH 
Primary 
Objectives 
and 
Endpoints 
To assess safety and tolerability of FT-4101 after administration of 
multiple doses in overweight/obese subjects with NASH by: 
• Incidence of treatment-emergent adverse events (TEAEs) 
• Incidence of clinical lab abnormalities 
• Incidence and severity of clinical findings on physical 
examination 
• Change from baseline in vital signs (blood pressure [BP], 
heart rate [HR], respiratory rate, and temperature]) 
• Change from baseline in 12-lead electrocardiogram (ECG) 
parameters 
To assess the preliminary efficacy of FT-4101 on liver fat after 
administration of multiple doses in overweight/obese subjects with 
NASH by: 
• Reduction (absolute and relative) of % liver fat on magnetic 
resonance imaging-estimated proton density fat fraction 
(MRI-PDFF) at 12 weeks 
Secondary 
Objectives 
and 
Endpoints 
To assess the preliminary efficacy of FT-4101 on liver fat after 
administration of multiple doses in overweight/obese subjects with 
NASH by: 
• Reduction (absolute and relative) of % liver fat on MRI-PDFF 
at 6 weeks 
• Proportion of subjects experiencing a relative reduction of 
30% or greater of % liver fat at week 12 as assessed by MRI-
PDFF 
To assess the pharmacodynamic (PD) effect of FT-4101 on circulating 
biomarkers of liver inflammation after administration of multiple 
doses in overweight/obese subjects with NASH by: 
• Reduction of liver biochemistry marker: Alanine 
aminotransferase (ALT), Aspartate aminotransferase (AST), 
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Gamma-glutamyl transferase (γGT), Alkaline phosphatase, 
and Total bilirubin 
To assess the pharmacokinetic (PK) profile of FT-4101 after 
administration of a single dose and multiple doses in 
overweight/obese subjects with NASH including, but not limited to: 
•
Maximum concentration (Cmax) 
•
Time to maximum concentration (Tmax)
•
Area under the concentration-time curve for a dosing interval
(AUCtau)
•
Trough plasma concentrations (Ctrough) at steady state 
Exploratory 
Objectives 
and 
Endpoints 
To assess the PD effect of FT-4101 on the inhibition of fasting 
hepatic de novo lipogenesis (DNL) after administration of multiple 
doses in overweight/obese subjects with NASH by using a 2-week 
deuterated water labeling protocol. 
To assess the PD effect of FT-4101 on skin surface sebum level using 
a Sebumeter® after administration of multiple doses in 
overweight/obese subjects with NASH by measuring: 
•
Total sebum production  
To assess the PD effect of FT-4101 on sebum lipids using Sebutape® 
after administration of multiple doses in overweight/obese subjects 
with NASH by measuring: 
•
Sebum fatty acid concentrations 
•
Sebum DNL  
To assess the PD effect of FT-4101 after administration of multiple 
doses in overweight/obese subjects with NASH by assessment of 
circulating biomarkers of liver injury and fibrosis, such as but not 
limited to: 
•
Enhanced liver fibrosis (ELF) score:
Hyaluronic acid (HA), Procollagen III amino terminal peptide
(PIIINP), Tissue inhibitor of metalloproteinases 1 (TIMP-1)
•
Cytokeratin-18 (CK-18) fragments, e.g., CK-18 M30 and CK-
18 M65
•
FibroSure®
•
PRO-C3
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To assess the PD effect of FT-4101 after administration of multiple 
doses in overweight/obese subjects with NASH by assessment of 
circulating metabolic parameters, such as but not limited to: 
•
Fasting Lipids
o
Total cholesterol
o
Low-density Lipoprotein cholesterol (LDL-c) direct
o
High-density Lipoprotein cholesterol (HDL-c)
o
Non-HDL cholesterol (non-HDL-c)
o
Triglycerides (TG)
o
Free fatty acids (FFA)
•
Glycemic parameters
o
Fasting plasma glucose (FPG)
o
Fasting insulin
o
HOMA-IR
o
HbA1c
•
Adiponectin (total and high molecular weight)
•
FGF-21
•
Malonyl carnitine 
To assess the PD effect of FT-4101 after administration of multiple 
doses in overweight/obese subjects with NASH by assessing steatosis 
(CAP) and liver stiffness (LSM) determined by FibroScan® at 12 
weeks.  
To assess the effect of FT-4101 after administration of multiple doses 
in overweight/obese subjects with NASH on imaging parameters 
assessed by MRI-PDFF: 
•
Liver Volume (L)
•
Liver Fat Volume Index (L) 
Phase of 
Development 
Phase 1/2  
Number of 
Study Sites 
Up to 3 sites 
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Protocol No. 4101-MET-201 
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Study 
Population 
Overweight/Obese subjects with NASH 
Number of 
Subjects 
At least 30 subjects, divided in 2 cohorts with at least 15 subjects per 
cohort. Drop-outs may be replaced in order to enroll sufficient 
subjects into the study, only after discussion with Sponsor and 
Investigator. 
Summary of 
Study Design 
This is a Phase 1/2, randomized, double-blind, placebo-controlled 
study evaluating the safety, tolerability and preliminary efficacy of an 
intermittent treatment with 3.0 mg and 4.5 mg FT-4101 over 12 
weeks in overweight/obese subjects with NASH.  
The study may be conducted in up to 2 dosing cohorts, that will 
overlap. Cohorts will enroll 15 subjects each, randomized to FT-4101 
or placebo in a ratio of 2:1 (10 on active, 5 on placebo). Cohort A will 
assess the administration of a dose of 3.0 mg FT-4101 given for 2 
weeks, alternating with a 1 week of no investigational product (IP), 
continued for 12 weeks. This design leads to 4 dosing cycles (2-week 
daily IP followed by 1 week of no IP).  After Cohort A (3.0 mg FT-
4101) received 6 weeks of treatment (2 dosing cycles), a dose 
escalation meeting will be held and an advancement to Cohort B (4.5 
mg FT-4101) will only be approved after the safety and tolerability 
data from Cohort A (3.0 mg FT-4101) are determined to be 
acceptable. Cohort B will be administered up to 4.5 mg FT-4101 with 
the same dosing design as in Cohort A. All subjects will undergo a 
screening visit, a run-in period, followed by multiple outpatient visits, 
2 in-house treatment periods, and a follow-up visit. An optional wash-
out period prior to dosing may be performed for subjects with T2DM 
on oral antidiabetic combination therapy. Safety, tolerability, PK and 
PD assessments will be performed throughout the study. Hepatic 
steatosis will be performed by MRI-PDFF. Hepatic and sebum DNL 
will be assessed using a 2-week deuterated water labelling protocol. 
Sebum and blood samples for additional PD and PK assessments will 
be collected throughout the study. For detail on all assessments, 
please see the Schedule of Events (SOE) in section 16.1. 
Treatments 
Treatment Schedule: 
Intermittent: Daily treatment for 2 weeks, alternating by 1 week 
without  
treatment; continuing until the end of week 12. 
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Cohorts 
Number of 
Subjects 
Treatment Schedule 
Drug Given 
Cohort 
A 
N=10 
Intermittent 
FT-4101 3.0 mg 
N=5 
Intermittent 
Matching Placebo
Cohort 
B 
N=10 
Intermittent 
FT-4101 4.5 mg 
N=5 
Intermittent 
Matching Placebo
Route of 
Administratio
n 
Study drug will be administered orally with 240 mL of water. 
Subjects do not need to be in a fasting state. 
Duration of 
Participation 
The duration of participation in this study, including Screening, 
Treatment Period and Follow-up will be approximately 20 weeks. 
Inclusion 
Criteria  
Subjects who meet all applicable criteria at Screening will be 
included in the study:  
1. Willing and able to give informed consent before any study-
specific procedures being performed. 
2. Male or female subjects ≥ 18 to ≤ 75 years. 
3. Meets all of the following criteria: 
a) CAP ≥ 300 dB/m by FibroScan® collected at screening or
within 30 days prior to screening. 
OR 
Liver biopsy within 24 months, consistent with NASH
(defined as the presence of steatosis, inflammation, and
ballooning) with stage 2-3 fibrosis according to the NASH
Clinical Research Network (CRN) classification (or
equivalent). 
Note criterion 3a must be met before evaluating 3b. 
b) Screening MRI-PDFF with ≥ 10% steatosis. 
4. Body mass index (BMI) > 25.0 to < 45.0 kg/m2. 
5. Stable body weight, defined as no weight gain or weight loss
> 5% over the previous 3 months. 
6. Subjects with T2DM may also be included, if: 
a) Subject with T2DM is on stable doses of metformin
monotherapy (subjects on combination therapy of metformin
and sulfonylurea (SU) need to undergo washout period of 7
days of SU prior to dosing) with no changes in medication
within the previous 6 months. 
b) HbA1c < 9% (one retest is permitted with the result of the
last test being conclusive). 
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c) Fasting plasma glucose (FPG) < 240 mg/dL (< 13.3
mmol/L) (one retest is permitted with the result of the last test
being conclusive).
7. Waist circumference ≤ 57 inches.
8. Female subjects must be non-pregnant and non-lactating.
Females may be surgically sterile, postmenopausal or of child-
bearing potential. Females of childbearing potential must be
using a highly effective method of birth control as outlined in
section 9.1.9 Contraception. 
Males must be surgically sterile, abstinent or if engaged in
sexual relations of child-bearing potential, the subject and his
partner must be using highly effective contraceptive methods.
For details see section 9.1.9 Contraception.
9. Willing and able to comply with scheduled visits, drug
administration plan, laboratory tests, other study procedures
and study restrictions.
Exclusion 
Criteria 
Subjects who meet any of the following criteria at Screening will be 
excluded from the study:  
1. Type 1 diabetes and type 2 diabetic subjects on insulin
therapy. 
2. Diabetic complications, such as history of acute proliferative
retinopathy. 
3. Recurrent severe hypoglycemia (more than 1 event ≤ 6
months) or hypoglycemic unawareness or recent severe
ketoacidosis (hospitalization 
≤ 6 months), as judged by the Investigator. 
4. Subjects with a history of, or active, chronic liver disease due
to alcohol, auto-immune, primary biliary cholangitis, HIV,
HBV or active HCV-infection, Wilson's, α-1-antitrypsin
deficiency, hemochromatosis, etc., and not due to NASH
disease. 
5. Any history of clinically significant or decompensated chronic
liver disease including esophageal varices, ascites,
encephalopathy or any hospitalization for treatment of chronic
liver disease; or MELD score ≥ 10. 
6. History of significant cirrhosis of the liver or FibroSure® >
0.75 at Screening (as shown on the laboratory report under
Fibrosis Score). 
7. Alcohol consumption greater than 14 drinks per week for men
or greater than 7 drinks per week for women and/or positive
alcohol breath test. (One drink is defined as 12 fluid ounces of
regular beer (5% alcohol), 5 fluid ounces of wine (12%
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alcohol), or 1.5 fluid ounces of 80 proof (40% alcohol) 
distilled spirits.) 
8. Introduction of an anti-obesity drug in the past 6 months prior
to screening.
9. History of gastrointestinal malabsorptive bariatric surgery, any
other gastrointestinal surgery that may induce malabsorption,
history of bowel resection > 20 cm, any malabsorption
disorder, severe gastroparesis, any GI procedure for weight
loss (including LAP-BAND®), as well as clinically significant
gastrointestinal disorders (e.g. peptic ulcers, severe
gastrointestinal reflux disease [GERD]) within less than 5
years.
10. Ingestion of drugs known to produce hepatic steatosis
including corticosteroids, high-dose estrogens, methotrexate,
tetracycline or amiodarone in the previous 6 months.
11. Ingestion of drugs (as listed in the Table Prohibited
Medication) from time points specified until completion of the
study. 
12. History of, or current cardiac dysrhythmias and/or a history of
cardiovascular disease events, including congestive heart
failure (class C and D of the American Heart Association
[AHA]), unstable coronary artery disease, myocardial
infarction.
13. Significant systemic or major illnesses other than liver
disease, including cerebrovascular disease, pulmonary disease,
renal failure, organ transplantation, serious psychiatric
disease, malignancy that, in the opinion of the investigator,
would preclude treatment with FT-4101 and/or adequate
follow up. 
14. History of chronic skin conditions such as psoriasis, eczema
or any recurring rash/dermatitis requiring oral or topical
corticosteroids or other topical applications within 12 months.
15. Hair loss or unexplained alopecia within 12 months.
16. History of chronic eye conditions, Sjögren syndrome or any
history of dry eyes or allergic conjunctivitis requiring artificial
tears or medicated eye drops or previous refractive surgery
within 12 months (Subjects with dry eyes due to wearing
contact lenses are eligible). 
17. History of major depression, anxiety, suicidal behavior or
attempts, or other unstable psychiatric disorders (within 2
years of screening), requiring medical treatment. (Subjects on
stable antidepressants are allowed). 
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18. Uncontrolled hypertension, defined as systolic blood pressure
>150 mmHg and/or diastolic blood pressure ≥ 100 mmHg at
screening (reading may be repeated on a different day).
(Subjects with uncontrolled hypertension may be rescreened
after 3 months, following initiation or adjustment of
antihypertensive therapy).
19. Any device or other contraindication with the MRI
examination, as per local imaging centers.
20. Ingestion of deuterated water within the previous 6 months.
21. Positive test for hepatitis B surface antigen (HBsAg), hepatitis
C antibody (HCV Ab), or human immunodeficiency virus type
1 (HIV-1) or type 2 (HIV-2) antibody.
22. Abnormal laboratory results:
a) Alanine aminotransferase (ALT) > 5 x upper limit of the
normal range (ULN)
b) Total bilirubin > 1 x ULN, except with diagnosis of
Gilbert's syndrome
c) International normalized ratio (INR) > 1.2 unless on
anticoagulant therapy
d) Fasting Triglycerides > 300 mg/dL. 
e) Platelet count < 100,000 /mm3
f)
Abnormal kidney function test with glomerular filtration
rate [GFR] < 60 mL/min/1.73m2 as estimated using the
MDRD equation. 
23. Participation in any other clinical interventional study
receiving active treatment within the previous 30 days or 5
half-lives, whichever is longer. 
24. Have a known hypersensitivity to any of the ingredients or
excipients of the study products. 
25. Subject is unable to abstain from smoking during confinement
periods. 
26. History of illicit drug abuse as judged by the Investigator
within approximately 1 year and positive test at Screening. 
27. Clinically under the effect of marijuana at screening, as per
Investigator evaluation.
28. Unwillingness to abstain from grapefruit (grapefruit
containing food and beverages), star fruit (carambola),
pomegranate, Seville orange and other food components that
may interact with CYP3A4 from check-in throughout the
entire course of the study. 
29. Donation or loss of > 500 mL of blood or blood product
within 56 days of dosing. 
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30. Any other condition which, in the opinion of the investigator
would impede competence or compliance or possibly hinder
completion of the study.
Sample Size 
A sample size of 15 subjects per cohort is empirically determined to 
assess the safety of the dose and characterize the PK.   
The total number of subjects will be approximately 30; 20 treated 
with FT-4101 and 10 with placebo.  With 10 evaluable subjects in the 
treated group and 10 evaluable subjects in the control group, there is 
84% power to detect a difference of 20% between the high dose 
treated group (cohort B) and the pooled placebo subjects from cohorts 
A and B in MRI-PDFF, assuming a standard deviation of 14% using a 
one-sided Wilcoxon-Mann-Whitney test with an alpha of 0.05. 
Statistical 
Methods 
Data analyses will follow a statistical analysis plan (SAP). 
The overall safety profile of FT-4101 will be assessed as the 
percentage of participants experiencing TEAE, serious TEAEs, 
TEAEs leading to premature study drug discontinuation, and 
treatment-emergent clinically significant laboratory abnormalities. 
Safety analysis will involve examination of the descriptive statistics 
and individual subject listings for any effects of study treatment on 
clinical tolerability and safety. 
Efficacy, PK and PD assessments for all dose groups will be analysed 
using descriptive methods; figures (bar charts or line plots) may also 
be generated to visualize the data. 
The primary preliminary efficacy analysis of the reduction (absolute 
and relative) of % liver fat on magnetic resonance imaging-estimated 
proton density fat fraction (MRI-PDFF) at 12 weeks will be analyzed 
using a Wilcoxon rank-sum test. The test will be one-sided and use a 
significance level of 0.05.  Subjects in each dose group will be tested 
against the pooled placebo subjects from each cohort. 
If more than one dose of FT-4101 is evaluated, control of the alpha 
level will be accomplished using Holm’s Sequential Bonferroni 
procedure [Holm 1979] to test each FT-4101 dose against the pooled 
placebo subjects. 
The secondary preliminary efficacy analysis of the reduction 
(absolute and relative) of % liver fat on magnetic resonance imaging-
estimated proton density fat fraction (MRI-PDFF) at 6 weeks will be 
analyzed similarly. The secondary preliminary efficacy analysis of the 
proportion of subjects with ≥ 30% relative reduction in liver fat at 
week 12 assessed by MRI-PDFF will be analyzed using a Fisher’s 
exact test.  
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Secondary pharmacodynamic endpoints and exploratory endpoints of 
fasting hepatic DNL will be analyzed using MMRM with the change 
from baseline as the dependent variable, baseline as a covariate and 
the factors, treatment group, visit, and the interaction of treatment 
group and visit. The least squares (LS) mean and its corresponding 
95% confidence interval and p-value will be presented. The LS mean 
difference between treatment groups will be presented along with the 
95% confidence interval and the p-value. 
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3.0 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC
Area under the concentration-time curve 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
BW 
Body weight 
CAP 
Controlled attenuation parameter 
CDM 
Clinical data management 
Cmax
Maximum concentration 
CRF 
Case report form 
CRO 
Clinical Research Organization 
CV 
Coefficient of variation 
DMP 
Data management plan 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
eCRF 
Electronic CRF 
FDA 
Food and Drug Administration 
FPG 
Fasting plasma glucose 
FSFV 
First subject first visit 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
HbA1C 
Glycosylated hemoglobin 
HbsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s brochure 
ICH 
International Conference on Harmonization 
ICU 
Intensive care unit 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 
Kg 
Kilogram 
lb 
Pound 
LS mean 
Least square mean 
Mcg 
Microgram 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligram 
NDA 
New Drug Application 
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Nmol 
Nanomol 
Non-HDL-c 
Non-HDL cholesterol 
PD 
Pharmacodynamics 
PE 
Physical examination 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PP 
Per-Protocol 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SOE 
Schedule of events 
SRC 
Safety Review Committee 
SU 
Sulfonylurea 
SUSAR 
Suspected unexpected serious adverse reaction 
t½ 
Terminal insulin half-life 
TEAE 
Treatment emergent adverse event 
TG 
Triglycerides 
TSH 
Thyroid-stimulating hormone 
U 
Unit 
ULN 
Upper limit of normal 
US 
United States  
USP 
Unites States Pharmacopeia 
WHO 
World Health Organization 
 
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4.0 
INTRODUCTION 
4.1 
Background 
Nonalcoholic steatohepatitis (NASH) is a chronic liver disease characterized 
pathologically by steatosis, or lipid accumulation in the liver, with evidence of cellular 
damage, inflammation, and fibrosis [Musso et al. 2016]. Currently, there are no effective 
treatments approved for NASH, which can progress to cirrhosis, hepatitis and ultimately 
hepatocellular carcinoma [Musso et al. 2016]. There are at least 16 million patients in the 
United States (US) and Canada with NASH, which is the second leading cause of liver 
transplants in the US [Sayiner et al. 2016]. NASH presents a significant healthcare 
burden with a high, unmet medical need. Ideally, treatment approaches to NASH would 
target multiple pathogenic axes of the disease, such as steatosis, inflammation and 
fibrosis. 
Accumulating evidence points towards increased hepatic de novo lipogenesis (DNL) as a 
key mediator in NASH pathophysiology. Uncontrolled DNL is a key contributor for liver 
steatosis through excessive triglyceride (TG) synthesis and deposition [Postic et al. 
2008]. Chronic activation of hepatic DNL and increase in the traffic of free fatty acids 
within hepatocytes can lead to generation of toxic lipid metabolites.  These lipotoxic 
metabolites act as reactive oxygen species (ROS), triggering endoplasmic reticulum (ER) 
stress, apoptosis and necrosis in the liver resident cells, hepatocytes, Kupffer cells and 
hepatic stellate cells (HSC) [Peverill al. 2014]. 
An emerging target for a multi-modal mechanism to treat NASH is fatty acid synthase 
(FASN), a key enzyme in the DNL pathway. FASN catalyzes the final step of DNL, 
converting acetyl-CoA and malonyl-CoA to the fatty acid palmitate, which can then 
undergo further modifications to other fatty acids and TGs [Kusakabe et al. 2000]. FASN 
gene expression level is aberrantly elevated in NASH patients as compared to healthy 
volunteers [Dorn et al. 2010; Mitsuyoshi et al. 2009]. Therefore, elevated FASN activity 
may be a major contributor to NASH through lipotoxicity-mediated tissue injury and cell 
death. Liver-specific ablation of the gene encoding FASN in mice (FASNLKO mice) 
results in malonyl-CoA increases and palmitate decreases in liver [Dentin et al. 2006]. 
FASNLKO mice on a standard diet show normal liver TG content, suggesting DNL may 
be dispensable in healthy liver and FASN inhibition may evade negative impact on non-
diseased liver function [Chakravarthy et al. 2005]. 
In addition to FASN’s role in steatosis and lipotoxicity, it may contribute to inflammation 
and the processes of fibrosis [Dorn et al. 2010]. Palmitate, the end product of the fatty 
acid synthesis pathway, upregulates toll-like receptor 4 (TLR4), pro-inflammatory 
cytokines and tumor necrosis factor-α (TNF-α) production in primary hepatocytes and 
Kupffer cells [Sawada et al. 2014]. DNL also generates the fatty acids necessary for T-
Helper 17 (Th17) cell differentiation and function [Berod et al. 2014]. Recent studies 
strengthen the hypotheses regarding the role of Th17 cells and interleukin-17 (IL-17) in 
NASH progression since increased levels of Th17 cells in human liver are associated 
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with the progression from non-alcoholic fatty liver disease (NAFLD) to NASH [Nati et 
al. 2016; Rau et al. 2016; Tan et al. 2013; Tang et al. 2011]. IL-17 also promotes liver 
fibrosis in a mouse model of liver disease (carbon tetrachloride [CCl4]–induced liver 
injury model) through HSC activation and subsequent collagen production [Meng et al. 
2012; Tan et al. 2013]. Stimulation of HSC activation occurs both by elevation of IL-17 
and by palmitate in mice [Harley et al. 2014; Xu et al. 2013; Tan et al. 2013]. Therefore, 
modulation of FASN offers a promising approach to treating NASH. 
FT-4101 is a potent, selective, orally bioavailable, small-molecule inhibitor of FASN, 
able to potently inhibit DNL and thus influence steatosis, being developed by FORMA 
Therapeutics Inc. and is intended as a treatment for patients with NASH. The clinical 
hypothesis is that FASN inhibition will reduce the rate of DNL, thereby reducing lipid 
accumulation in the liver responsible for the cellular damage, inflammation, and fibrosis 
that characterizes the pathology of NASH. 
4.2 
Rationale for the Proposed Study 
Inhibition of fractional DNL can be measured through use of stable isotopically labeled 
tracers in studies of metabolic kinetics [Hellerstein et al.1991; Lemieux et al. 1999] 
Metabolic infusion studies with sodium acetate (1-13C1) have been utilized to describe a 
temporal pattern of DNL in the postprandial state of healthy subjects and NAFLD 
patients. [Timlin and Parks 2005; Donnelly et al. 2005] More recently, deuterated (heavy) 
water (2H2O) labeling studies have demonstrated that in the non-stimulated setting, 
hepatic DNL is elevated in NASH patients compared to healthy controls [Lawitz et al. 
2018]. 
GS-0976, an inhibitor of ACC1/2, (enzymes upstream of FASN in the DNL pathway), 
has demonstrated a significant (60-70%) inhibition of DNL in healthy obese adult 
volunteers after a single dose or when administered chronically. [Westlin et al. 2016; 
Kirby et al. 2017]. However, a reduced level of DNL inhibition (~30%) was observed 
when an equivalent dose of GS-0976 was administered chronically to NASH subjects 
[Lawitz et al. 2018]. The almost > 2-fold difference in DNL inhibition (67-70% 
inhibition in HV vs ~30% inhibition in NASH) would indicate that a higher and/or a 
more sustained rate of DNL inhibition may be required in the treatment of NASH.  
This study will provide an opportunity to evaluate a dose range of FT-4101 that inhibited 
DNL in an obese, otherwise healthy adult population in a defined NASH patient 
population (defined as metabolically and cardiovascular stable) with further developed 
translational biomarker strategy for monitoring FASN inhibition, and extended safety 
assessment in this population. Clinical development of FT-4101 in a larger population of 
patients with NASH can then occur once FT-4101 has demonstrated acceptable safety 
and clinical activity in this defined NASH population. 
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4.3 
Summary of Pre-Clinical /Clinical Studies 
The preclinical in vivo studies have shown adverse effects in the skin and eye, that were 
reversible upon dose de-escalation and interruption. The exposure of FT-4101, necessary 
to demonstrate FASN inhibition in experimental models is below the NOAEL exposure 
in rats, the more sensitive species evaluated. Additional preclinical information is found 
in the Investigator’s Brochure (IB) version 5.0. 
To date, three clinical studies have enrolled subjects and are completed/clinically 
completed. As 01-May-2019, a total of 123 healthy volunteers have received FT-4101 in 
these studies, including 59 subjects with single doses, 10 subjects with two doses, 19 
subjects with multiple doses for up to 14 days, and 35 subjects with multiple doses for up 
to 28 days. A brief summary of each study is provided below; additional information is 
found in the IB version 5.0. 
FT-4101 has been evaluated in humans in a First-in-Human clinical study (Protocol No. 
4101-HVS-101) entitled “A randomized, placebo-controlled, double-blind, single 
ascending and multiple ascending dose study to assess the safety, pharmacokinetics and 
pharmacodynamics of FT-4101 in healthy adult volunteers”. This initial Phase 1 clinical 
study was a single center, double-blind dose escalation study of FT-4101 in healthy adult 
volunteers. FT-4101 was first administered as a single dose in single ascending dose 
(SAD) cohorts, and then administered daily for 14-28 days in multiple ascending dose 
(MAD) cohorts. The preliminary safety profile from this study demonstrated that 9 mg 
daily for 14 days continuously was tolerable while a dose of 27 mg daily for 14 days was 
not tolerated (due to AE’s, including dry eye and skin and alopecia). The safety profile of 
3 mg of FT-4101 administered daily for up to 4 weeks continuously was tolerable and per 
protocol criteria were met for consideration of additional dose escalation in healthy 
volunteers. The pharmacokinetic (PK) and pharmacodynamic (PD) profile from a daily 
dose of 3 mg FT-4101 indicated an exposure that was sufficient for sustained FASN 
inhibition in healthy obese volunteers based on accumulation of plasma malonyl carnitine 
and a 50% reduction in sebum palmitate. 
Higher daily doses of 4.5 mg and 6.0 mg of FT-4101 for up to 4 weeks continuously were 
then evaluated in clinical study FT-4101-CP-001 entitled “A phase 1, double-blind, 
randomized, placebo-controlled, multiple-dose study to assess the safety, 
pharmacokinetics, and pharmacodynamics of FT-4101 in obese but otherwise healthy 
adult subjects”. The preliminary safety profile of both the 4.5 mg and 6.0 mg dose of FT-
4101 administered daily for up to 4 weeks continuously was considered tolerable per 
protocol. However, 44% (4 of 9) subjects receiving 6 mg FT-4101 daily for 4 weeks 
reported grade 1 adverse events of dry skin and alopecia by the end of the 4-week dosing 
interval (all recovered in follow-up), suggesting continuous dosing of 6 mg FT-4101 
beyond 4-weeks would not be tolerable. One subject (11%) in the 4.5 mg treatment group 
reported a grade 1 adverse event of dry skin after 2-weeks of dosing, treated topically, 
and did not worsen with continued dosing. No AE’s of alopecia were reported in the 4.5 
mg treatment group. 
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The Clinical Study 4101-HVS-102, entitled “A randomized, placebo-controlled, double-
blind, pharmacodynamic study of a single oral dose of FT-4101 in healthy adult subjects” 
was a Phase 1, single center, 3-cohort study designed to characterize the 
pharmacodynamic effect of FT-4101 on FASN by conducting metabolic infusion studies 
using sodium acetate (1-13C1) for the measurement of fractional de novo lipogenesis 
(DNL) inhibition in the liver. A single dose of 3 mg, 6 mg or 9 mg of FT-4101 
administered to 10 subjects resulted sustained inhibition of fractional hepatic DNL of 
24%, 43% and 80% respectively. Based on a 1.6 to 2-fold accumulation, a chronic daily 
dose of 3.0 mg to 4.5 mg of FT-4101 would be predicted to achieve a sustained hepatic 
DNL inhibition rate from > 24% to up 80% over the dosing interval. This predicted range 
of hepatic DNL inhibition is consistent with the initial PD effects of inhibiting hepatic 
DNL (based on malonyl carnitine accumulation) and inhibiting sebum DNL (reduction in 
sebum palmitate/triglycerides) observed to date in the clinical studies. 
4.4 
Rationale for Treatment and Dose 
Based on the safety, PK and PD studies of FT-4101 in healthy adult volunteers, a study to 
confirm the safety and evaluate the PK/PD effects of FT-4101 administered chronically 
over 12 weeks in NASH patients is proposed.  The initial starting dose of 3.0 mg of FT-
4101 administered as intermittent therapy is planned based on the safety profile of this 
dose administered daily for 28 days in healthy obese adult volunteers. To reduce the risk 
for ≥ Grade 2 adverse effects due to chronic non-hepatic DNL inhibition, an empiric 
treatment interruption schedule will be evaluated. Subjects (n=15), will be randomized 
2:1 to receive FT-4101 or placebo for 4 treatment cycles. The duration of each treatment 
cycle is 3 weeks: subjects will receive FT-4101or placebo for 2 weeks followed by 1 
week of no treatment (2-weeks on/1-week off). 
Based on the experience reported by GS-0976, it is possible that NASH patients may 
require a higher level of FASN inhibition to achieve meaningful clinical activity as 
measured by a reduction in liver enzymes, hepatic steatosis by MRI-PDFF and hepatic 
DNL inhibition by deuterated water incorporation. Therefore, if after 6 weeks a 3 mg 
dose of FT-4101 or placebo given for 2-weeks on/1-week off, is found to be tolerable, a 
4.5 mg dose of FT-4101 or placebo given for 2-weeks on/1-week off may be evaluated in 
a second cohort of NASH patients. 
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5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Primary Objectives and Endpoints 
To assess safety and tolerability of FT-4101 after administration of multiple doses in 
overweight/obese subjects with NASH by: 
•
Incidence of treatment-emergent adverse events (TEAEs)
•
Incidence of clinical lab abnormalities
•
Incidence and severity of clinical findings on physical examination 
•
Change from baseline in vital signs (blood pressure [BP], heart rate [HR],
respiratory rate, and temperature])
•
Change from baseline in 12-lead electrocardiogram (ECG) parameters 
To assess the preliminary efficacy of FT-4101 on liver fat after administration of multiple 
doses in overweight/obese subjects with NASH by: 
•
Reduction (absolute and relative) of % liver fat on MRI-PDFF at 12 weeks
5.2 
Secondary Objectives and Endpoints
To assess the preliminary efficacy of FT-4101 on liver fat after administration of multiple 
doses in overweight/obese subjects with NASH by: 
•
Reduction (absolute and relative) of % liver fat on MRI-PDFF at 6 weeks 
•
Proportion of subjects experiencing a relative reduction of 30% or greater of liver
fat at week 12 as assessed by MRI-PDFF  
To assess the PD effect of FT-4101 on circulating biomarkers of liver inflammation after 
administration of multiple doses in overweight/obese subjects with NASH by: 
•
Reduction of liver biochemistry marker: Alanine aminotransferase (ALT),
Aspartate aminotransferase (AST), Gamma-glutamyl transferase (γGT), Alkaline
phosphatase, and Total bilirubin 
To assess the PK profile of FT-4101 after administration of a single dose and multiple 
doses in overweight/obese subjects with NASH including, but not limited to: 
•
Maximum concentration (Cmax) 
•
Time to maximum concentration (Tmax) 
•
Area under the concentration-time curve for a dosing interval (AUCtau) 
•
Trough plasma concentrations (Ctrough) at steady state 
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5.3 
Exploratory Objectives and Endpoints 
To assess the PD effect of FT-4101 on the inhibition of fasting hepatic DNL after 
administration of multiple doses in overweight/obese subjects with NASH by using a 2-
week deuterated water labeling protocol. 
To assess the PD effect of FT-4101 on skin surface sebum level using Sebumeter® after 
administration of multiple doses in overweight/obese subjects with NASH by measuring: 
•
Total sebum production
To assess the PD effect of FT-4101 on sebum lipids using Sebutape® after administration 
of multiple doses in overweight/obese subjects with NASH by measuring: 
•
Sebum fatty acid concentrations
•
Sebum DNL
To assess the PD effect of FT-4101 after administration of multiple doses in 
overweight/obese subjects with NASH by assessment of circulating biomarkers of liver 
injury and fibrosis, such as but not limited to: 
•
Enhanced liver fibrosis (ELF) score: 
Hyaluronic acid (HA), Procollagen III amino terminal peptide (PIIINP), Tissue
inhibitor of metalloproteinases 1 (TIMP-1) 
•
Cytokeratin-18 (CK-18) fragments, e.g., CK-18 M30 and CK-18 M65 
•
FibroSure® 
•
PRO-C3  
To assess the PD effect of FT-4101 after administration of multiple doses in 
overweight/obese subjects with NASH by assessment of circulating metabolic 
parameters, such as but not limited to: 
•
Fasting Lipids 
o
Total cholesterol 
o
Low-density Lipoprotein cholesterol (LDL-c) direct 
o
High-density Lipoprotein cholesterol (HDL-c) 
o
Non-HDL cholesterol (non-HDL-c) 
o
Triglycerides (TG) 
o
Free fatty acids (FFA) 
•
Glycemic parameters 
o
Fasting plasma glucose (FPG) 
o
Fasting insulin 
o
HOMA-IR 
o
HbA1c 
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• Adiponectin (total and high molecular weight)  
• FGF-21 
• Malonyl carnitine 
 
To assess the PD effect of FT-4101 after administration of multiple doses in 
overweight/obese subjects with NASH by assessing steatosis (CAP) and liver stiffness 
(LSM) determined by FibroScan® at 12 weeks. 
 
To assess the effect of FT-4101 after administration of multiple doses in 
overweight/obese subjects with NASH on imaging parameters assessed by MRI-PDFF 
• Liver Volume (L) 
• 
Liver Fat Volume Index (L) 
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6.0 
STUDY DESIGN AND DESCRIPTION 
6.1 
Study Design 
This is a Phase 1/2, randomized, double-blind, placebo-controlled study evaluating the 
safety, tolerability and preliminary efficacy of an intermittent treatment with 3.0 mg and 
4.5 mg FT-4101 over 12 weeks in overweight/obese subjects with NASH.  
The study will be conducted in up to 2 dosing cohorts, that will overlap. Cohorts will 
enroll 15 subjects each, randomized to FT-4101 or placebo in a ratio of 2:1 (10 on FT-
4101, 5 on placebo) 
Cohort A will assess the administration of a dose of 3.0 mg FT-4101 given for 2 weeks, 
alternating with 1 week of no investigational product (IP), continued for 12 weeks. This 
design leads to 4 dosing cycles (2-week daily IP followed by 1 week of no IP). Each 
cycle (C) will include 21 days (D) (e.g., C1/D1 to C1/D21) 
After 6 weeks, a dose escalation meeting will be held and an advancement to a higher 
dosing cohort will only be approved after the safety data from the ongoing cohort is 
determined to be acceptable. 
If the IP is deemed to be safe after 6 weeks of treatment (2 dosing cycles), an additional 
Cohort B may be added. Cohort B will comprise of up to 4.5 mg FT-4101, administered 
as in Cohort A, which is given for 2 weeks, alternating with a 1 week of no IP for 12 
weeks. 
If dose escalation does not proceed; dose de-escalation may occur in subsequent cohorts 
to a dose of 1.5 mg FT-4101 to further refine the dose or additional cohort may be added 
to evaluate the 3.0 mg dose cohort. The IP will be administered as in cohort A, given for 
2 weeks, alternating with a 1 week of no IP, continued for 12 weeks. 
Safety, tolerability, PK and PD assessments will be performed throughout the study. 
Figure 6-1 Study Design Schematic  
This study schematic includes study days assuming no visit windows or study 
interruptions due to AEs are being utilized. 
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6.2 
Study Description 
Screening: 
A Screening Visit will be performed between Day -45 (C1/D-45) and Day-14 (C1/D-14) 
of Cycle 1 to identify subjects for the study. All screening evaluations except MRI-PDFF 
will be performed first. Only eligible subjects will then undergo an MRI-PDFF for the 
assessment of liver fat within 30 days of C1/D-14 (results to be available prior to C1/D-
14).  
Wash-out period: 
In this optional wash-out period, only subjects with T2DM treated with a combination of 
metformin and SU will be washed off their SU, for at least 7 days prior to the start 
(C1/D-14) of the first deuterated water administration period. 
Run-in Period: 
Outpatient Visit on C1/D-14 (Start of first deuterated water administration period): 
Subjects will check into the clinic in the morning of C1/D-14 in fasting conditions. 
Sebum and blood for PD assessments will be collected prior to the administration of 
deuterated water. Subjects will be provided with the first administration of 50 mL 
deuterated water under in-house surveillance for subjects’ safety. Subjects will be 
provided with a supply of deuterated water and will get instructions on how to continue 
the administration of the deuterated water at home. Subjects will be asked to record their 
deuterated water intake in a subject diary for compliance reason. Subjects will be 
contacted/called daily to ensure compliance during the water labeling period.  Subjects 
will be counseled to maintain their normal diet and exercise regimen. 
Outpatient Visits on C1/D-11 and C1/D-7: 
Subjects will return to the clinic in fasting conditions on C1/D-11 and on C1/D-7 in order 
to undergo fasting blood sampling for hepatic DNL assessment.  The first (morning) 
drink of deuterated water will be administered in the clinic (after fasting blood sampling 
is completed) on C1/D-11. Deuterated water accountability will be performed, and 
subjects will be provided with additional deuterated water supply as needed. 
In-house Period 1 on C1/D-1 and C1/D1: 
C1/D-1: Subjects will check into the clinic in the morning of C1/D-1 in fasting condition. 
Blood sampling for laboratory and safety parameters will be performed. Subjects will be 
randomized to FT-4101 or placebo. Standardized conditions and meals will be provided. 
Subjects will then fast overnight. 
C1/D1: Vital signs and clinical assessments will be performed. Blood samples for 
baseline PD parameters (in fasting conditions) and for PK (pre-dose and post-dose) will 
be drawn. Sebum will be collected using Sebutape® and Sebumeter® assessments will be 
performed under standardized conditions.  The investigational product (IP) or placebo 
will be administered by qualified study staff after PD assessments are completed. This 
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will be the start of the first 3-week intermittent dosing cycle. Subject will be instructed on 
how to administer the study drug over the next 2 weeks, will be supplied with the study 
drug and a diary to record IP administrations, and will be sent home to start the first 2-
week continuous daily dosing period. 
A telephone call will be performed after the first week of IP administration for 
compliance reason and to assess safety and need for treatment interruption (see section 
6.6 for Dose Interruption/Dose Modification). 
Outpatient Visit on C1/D15: 
Subjects will return to the clinic on C1/D15 in in fasting condition in order to undergo 
safety, PK and PD assessments and to undergo an abbreviated focused physical exam. 
Drug accountability will be performed. Subjects will not be supplied with any study drug 
and will be sent home to start the first week of no dosing. Subject diaries will be checked. 
Outpatient Visit on C2/D1: 
Subjects will return to the clinic in the morning of C2/D1 in fasting condition in order to 
undergo safety, PK (pre-dose) and PD assessments and to undergo an abbreviated 
focused physical exam. Subjects will receive the first dose of the second IP cycle by 
qualified staff. Subject will be instructed on how to administer the study drug over the 
next 2 weeks, will be supplied with the study drug and will be sent home to start the 
second 2-week continuous daily dosing period. A telephone call may be performed 
during the week of IP administration for compliance reason and to assess safety/need for 
treatment interruption. 
Outpatient Visit on C2/D15: 
Subjects will return to the clinic on C2/D15 in fasting condition in order to undergo 
safety, PK and PD assessments and to undergo an abbreviated focused physical exam. 
Drug accountability will be performed. Subjects will not be supplied with any study drug 
and will be sent home to start the corresponding week of no dosing. 
Outpatient Visit on C3/D1: 
Subjects will return to the clinic in the morning of C3/D1 in fasting condition in order to 
undergo safety and PD assessments, as well as an abbreviated focused physical exam. An 
MRI will be performed up to 4 days prior to C3/D1. Subjects will receive the first dose of 
the next IP cycle by qualified staff. Subject will be instructed on how to administer the 
study drug over the next 2 weeks, will be supplied with the study drug and will be sent 
home to start the third 2-week continuous daily dosing period. Subjects will be reminded 
to maintain their regular diet and exercise regimes. A telephone call may be performed 
during the week of IP administration for compliance reason and to assess safety and need 
for treatment interruption. 
Safety assessments will be evaluated, and a decision will be made if it is safe to start with 
Cohort B in parallel to cohort A. 
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Outpatient Visit on C3/D15: 
Subjects will return to the clinic on C3/D15 in fasting condition in order to undergo 
safety, PK and PD assessments and to undergo an abbreviated focused physical exam. 
Drug accountability will be performed. Subjects will not be supplied with any study drug 
and will be sent home to start the corresponding week of no dosing. 
Outpatient Visit on C4/D1 (start of second deuterated water administration period): 
Subjects will check into the clinic in the morning of C4/D1 in fasting condition to 
undergo safety and PD assessments prior to the administration of deuterated water.  
Subjects will drink the first dose of deuterated water (50 mL) under in-house surveillance 
for subjects’ safety. Subjects will be provided with a supply of deuterated water and will 
get instructions on how to continue the administration of the deuterated water at home. 
Subjects will be asked to record the administration in a subject diary for compliance 
reason. Subjects will be contacted/called daily to ensure compliance during the deuterated 
water labeling period. Subjects will be counseled to maintain their normal diet and 
exercise regimen. 
Additionally, subjects will receive the first dose of the next IP cycle in-house by qualified 
staff. Subject will be supplied with the study drug and will be sent home to start the 
fourth 2-week continuous daily dosing period. A telephone call may be performed during 
the period of IP administration for compliance reasons and to assess safety and need for 
treatment interruption. 
Outpatient Visits on C4/D4 and C4/D8: 
Subjects will return to the clinic in fasting condition on C4/D4 and on C4/D8 in order to 
undergo fasting blood sampling for DNL and PK (pre-dose) assessments.  The first 
(morning) drink of deuterated water will be administered in the clinic (after fasting blood 
sampling) on C4/D4. Deuterated water accountability will be performed, and subjects 
will be provided with additional supply of deuterated water as needed. 
In-house Period 2 on C4/D14 and C4/D15: 
Subjects will check into the clinic in the morning of C4/D14 in fasting condition for an 
overnight in-house stay. Standardized conditions and meals will be provided during the 
in-house stay. Laboratory, safety, PK (pre-dose and post-dose) and PD assessments, an 
abbreviated focused physical exam and drug accountability will be performed according 
to the SOE in section 16.1. Subjects will not be supplied with any study drug and will be 
sent home to start the corresponding week of no dosing.  
Outpatient Visits on C4/D22: 
Subjects will return to the clinic on C4/D22 in fasting condition to undergo safety and PD 
assessments and to undergo an abbreviated focused physical exam. Subjects will undergo 
an MRI-PDFF for the assessment of liver fat up to 4 days prior to C4/D22. 
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Follow-up Visit: 
A follow-up visit will take place on C4/D29 in order to collect final safety assessments. 
For details on all assessments please see the SOE in section 16.1. 
For details on deuterated water administration and blood and sebum sampling for DNL 
assessments, please see section 9.1.17.5 De Novo Lipogenesis (DNL) Assessment. 
6.3 
Rationale for Study Design and Endpoints 
This MAD study will assess the safety and tolerability, PK and preliminary PD of FT-
4101 in overweight/obese subjects with NASH compared to placebo.  
Two (2) cohorts will be assessed in ascending order, but may overlap, to determine the 
response to an intermittent dosing cycle (2 weeks of doing followed by 1 week off 
dosing). 
Randomization is used to avoid bias introduced through an association between study 
drug allocation order and subject characteristics. 
A double-blind design has been chosen to avoid bias and to maintain the blind between 
the administration of the study drug and placebo for subjects and clinical staff. 
The placebo control group will control for changes in percent liver fat that may be caused 
by subjects’ lifestyle and diet changes that may occur over the period of study 
participation. 
Subjects with NASH will participate in the study, as these subjects are an important 
target population for FT-4101. Enrollment criteria will favor the target population. 
Percent liver fat will be determined by MRI-PDFF. 
The proposed PK endpoints are well-established, commonly used parameters to 
characterize pharmacological profiles of drugs.  
This is an exploratory study designed for proof of concept. 
6.4 
Dose Escalation 
Data from at least 12 subjects of Cohort A who have completed 2 of the 4 cycles of 
treatment (2 week on /1 week off) is required for safety review before dose escalation to 
Cohort B, provided no more than one subject had an early discontinuation suspected of 
being related to FT-4101.  The safety and tolerability data will be reviewed and if deemed 
appropriate by the Safety Review Committee (SRC) consisting of the coordinating PI, the 
Sponsor medical monitor and at least 1 additional participating center PI, a dose 
escalation decision to proceed to Cohort B will be made that is based on the reviewed 
data. If there are no safety concerns, the next cohort may start and may partially overlap 
with the previous one. 
The blind of the study will be maintained throughout. 
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Figure 6-2 Dose Escalation Schematic 
6.5 
Study Discontinuation and Stopping Criteria 
6.5.1 Dose Escalation Stopping Criteria 
Dose escalation may be stopped if one of the following conditions applies: 
•
Death of a subject (AE grade 5 toxicity) in a cohort, at any time, that is considered
related to the IP FT-4101 by the Investigator;
•
Two (2) or more of the subjects in a cohort have experienced a serious adverse
event (SAE) or medically significant adverse events (e.g., common terminology
criteria for adverse events (CTCAE) ≥ grade 3 may be used as a grading scale at
the discretion of Investigator), that is judged by the Investigator to be possibly or
probably related to the IP FT-4101;
•
Two (2) or more subjects in a cohort develop an AE (CTCAE grade ≥ 2 may be
used as a grading scale at the discretion of the Investigator) that persists for more
than 7 days and is considered related to the IP FT-4101 by the Investigator;
•
Two (2) or more FT-4101-treated subjects in a cohort develop an AE (CTCAE
grade ≥ 2) of any duration associated with the skin (including hair) or eye that is
considered to be at least possibly related by the Investigator;
•
Two (2) or more subjects in a cohort develop similar clinically significant
laboratory, significant ECG or vital signs abnormalities, or severe AEs in the
same organ class, indicating dose-limiting intolerance. Dose escalation may
proceed if after review of the data by the coordinating Investigator/medical
monitor and discussion with Sponsor, it is concluded that the events are not
related to the IP FT-4101;
•
It is determined that the limit of safety and/or tolerability of FT-4101 has been
reached. Decision will be made between Sponsor and Medical
Monitor/coordinating Investigator.
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6.5.2 Study Advancement after Dose Escalation Stopping Criteria 
After stopping criteria are met, the following may occur: 
•
Dose escalation may be stopped.
•
Dose escalation may continue as originally planned. This is only permissible if
the AE(s) that met stopping criteria is judged, after unblinded review, as not being
related to FT-4101;
•
A lower dose (lower than the dose that met stopping criteria) cohort may be
added.
If the SRC decides on any action other than continuing dose escalation as planned, they 
will communicate to the Unblinded Statistician the subject numbers who they believe 
meet stopping criteria. The Unblinded Statistician will check the treatment assignment of 
that subject; if the subject received placebo then the stopping criteria are not triggered for 
that subject, otherwise the stopping criteria will be triggered. The Unblinded Statistician 
will communicate to the SRC their agreement that the stopping criteria are met after 
review of the treatment assignments, if applicable. If stopping criteria are not met due to 
events of concern occurring in placebo subjects, the Unblinded Statistician will 
communicate that the stopping criteria were not met, and communicate the subject 
numbers, who do not qualify based on receiving placebo. This unblinding will only occur 
in cases where the SRC has identified events potentially meeting stopping criteria, and 
will be limited only to subject numbers, experiencing the events in question. The whole 
cohort will not be unblinded to the SRC. 
6.5.3 Criteria for Early Termination of the Study 
The study will be completed as planned unless one or more of the following criteria are 
satisfied that require temporary suspension or early termination of the study. 
•
New information or other evaluation regarding the safety or efficacy of the study
medication that indicates a change in the known risk/benefit profile for the
compound, such that the risk/benefit is no longer acceptable for subjects participating
in the study.
•
Significant violation of Good Clinical Practice (GCP) that compromises the ability to
achieve the primary study objectives or compromises subject safety.
•
Administrative Reasons, (e.g., Sponsor, an institutional review board (IRB)/
independent ethics committee (IEC), or regulatory authority elects to terminate or
suspend the study or the participation of an investigational site)
If the Sponsor, IRB/IEC, or regulatory authority elects to terminate or suspend the study 
or the participation of an investigational site, a study-specific procedure for early 
termination or suspension will be provided by the Sponsor; the procedure will be 
followed by applicable investigational sites during the course of termination or study 
suspension. 
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6.5.4 Criteria for Early Termination of Individual Subjects 
Subjects may withdraw their consent to participate in the study at any time. 
If a subject withdraws consent, the date and reason for consent withdrawal should be 
documented. Subjects will be encouraged to remain in the clinic for safety assessments 
until the Investigator deems that it is safe for the subject to be discharged. Subject data 
will be included in the analysis up to the date of the consent withdrawal. 
Criteria: 
•
AE or SAE that requires discontinuation at the discretion of the Investigator
•
Protocol violation or concurrent illness: If protocol violation or concurrent illness
occurs, which, in the clinical judgment of the Investigator or after discussion with the
Sponsor, may invalidate the study by interfering pharmacokinetically or
pharmacodynamically with the investigational products, the subject will be
withdrawn by the Investigator (e.g., lack of compliance with study protocol, or lack
of compliance with IP ingestion, as determined per Investigator)
•
Lost to follow-up. The subject did not return to the clinic and attempts to contact the
subject were unsuccessful. Attempts to contact the subject must be documented.
•
Voluntary withdrawal of consent (mandatory removal from study)
•
Discretion of Investigator (document reason on CRF)
•
Subject becomes pregnant or begins breastfeeding (mandatory)
•
Study discontinuation by Sponsor
Wherever possible, the tests and evaluations, including those listed for the Follow-up 
Visit should be performed for all subjects who discontinue prior to the completion of the 
study. 
In the event the Investigator determines to terminate a subject participation in the Clinical 
Study, the Investigator must notify the Sponsor of such decision and rationale 
immediately in writing. In all cases, the appropriate IRB/IEC and other applicable 
regulatory authorities shall be informed. 
6.6 
Treatment Interruption with Dose Modifications 
If a subject has an adverse event that is judged by the Investigator as related to study drug 
(i.e., assessed as unrelated to the underlying disease, intercurrent illness, or concomitant 
medications), then a treatment interruption with dose modification can be made according 
to the guidelines in Table 6-1 below. Deviations from these guidelines (e.g., drug 
interruption for a Grade 1 AE of skin or eye) may occur if agreed upon by the Principal 
Investigator and Medical Monitor. There should be no attempt to make up doses omitted 
due to toxicity. 
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Table 6-1 FT-4101 Recommended Treatment Interruptions and Dose Modifications 
for Adverse Events 
Severity of 
Adverse 
Events (AE) 
Proposed Treatment Interruption and Dose Modification 
Non-skin or eye 
Skin or eye 
Grade 1 
Symptomatic treatment allowed: 
Continue FT-4101/placebo through 
treatment period.  No dose 
modifications required. 
Symptomatic treatment allowed: 
Continue FT-4101/placebo through 
treatment period. 
•
If AE resolves < 7 days:
continue FT-4101/placebo at
same dose at next treatment
cycle;
•
If resolves ≥ 7 days:
dose reduction recommended at
next treatment cycle;
•
If AE not resolved at start of
next treatment cycle, delay start
of next treatment cycle for up
to 7 days until resolution and
dose reduce (discontinue study
treatment if AE delay in next
treatment > 7days due to AE
resolution).
Grade 2 
Symptomatic treatment allowed: 
Continue FT-4101/placebo treatment 
through the treatment period.  
If dose interruption is clinically 
indicated; 
•
If resolved to baseline within 72
hours of treatment interruption,
resume dosing at same dose
level
•
If resolved to baseline or Grade
1 > 72 hours of treatment
interruption, dose reduce (or
discontinue if prior dose
reduction)
Symptomatic treatment allowed: 
Dose interruption for the rest of 
treatment period required. 
Resumption of a reduced dose of 
FT-4101/placebo at the start of the 
next treatment may be considered if 
the following are met: 
•
Complete resolution of AE ≥ 7
days before start of next
treatment cycle
•
No prior dose reduction
•
Discussed and approved by
Medical Monitor
Grade 3 or 
higher 
Permanently discontinue treatmenta 
Permanently discontinue treatment 
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aException: In the setting of grade 3 nausea, vomiting, or diarrhea, hold treatment and if the subject is 
responsive to treatment measures within 72 hours, restarting FT-4101/placebo (at same dose or a reduced 
dose) may be considered after discussion with Medical Monitor. 
Subjects are allowed one dose reduction in this study. Recommended dose reductions 
based on the subject’s FT-4101/placebo starting dose are outline in Table 6-2 below: 
Table 6-2 Dose Reduction 
Starting dose 
Reduction level -1 
3.0 mg FT-4101/placebo 
1.5 mg FT-4101/placebo 
4.5 mg FT-4101/placebo 
3.0 mg FT-4101/placebo 
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7.0 
STUDY POPULATION 
7.1 
Inclusion Criteria 
Subjects who meet all applicable criteria at Screening will be included in the study: 
1. Willing and able to give informed consent before any study-specific procedures
being performed.
2. Male or female subjects ≥ 18 to ≤ 75 years.
3. Meets all of the following criteria: 
a) CAP ≥ 300 dB/m by FibroScan® collected at screening or within 30 days prior
to screening. 
OR
Liver biopsy within 24 months, consistent with NASH (defined as the
presence of steatosis, inflammation, and ballooning) with stage 2-3 fibrosis
according to the NASH Clinical Research Network (CRN) classification (or
equivalent).
Note criterion 3a must be met before evaluating 3b. 
b) Screening MRI-PDFF with ≥ 10% steatosis. 
4. Body mass index (BMI) > 25.0 to < 45.0 kg/m2. 
5. Stable body weight, defined as no weight gain or weight loss > 5% over the
previous 3 months. 
6. Subjects with T2DM may also be included, if: 
a) Subject with T2DM on stable doses of metformin monotherapy (subjects on
combination therapy of metformin and sulfonylurea (SU) need to undergo
washout period of 7 days of SU prior to dosing) with no changes in
medication within the previous 6 months. 
b) HbA1c < 9% (one retest is permitted with the result of the last test being
conclusive)
c) Fasting plasma glucose (FPG) < 240 mg/dL (<13.3 mmol/L) (one retest is
permitted with the result of the last test being conclusive) 
7. Waist circumference ≤ 57 inches.
8. Female subjects must be non-pregnant and non-lactating. 
Females may be surgically sterile, postmenopausal or of child-bearing potential. 
Females of childbearing potential must be using a highly effective method of birth
control. See section 9.1.9 Contraception 
Males must be surgically sterile, abstinent or if engaged in sexual relations of
child-bearing potential, the subject and his partner must be using highly effective
contraceptive methods. For details see section 9.1.9 Contraception. 
9. Willing and able to comply with scheduled visits, drug administration plan,
laboratory tests, other study procedures and study restrictions. 
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7.2 
Exclusion Criteria 
Subjects who meet any of the following criteria at Screening will be excluded from the 
study:  
1. Type 1 diabetes and type 2 diabetic subjects on insulin therapy.
2. Diabetic complications, such as history of acute proliferative retinopathy. 
3. Recurrent severe hypoglycemia (more than 1 event ≤ 6 month) or hypoglycemic
unawareness or recent severe ketoacidosis (hospitalization
≤ 6 month), as judged by the Investigator.
4. Subjects with a history of, or active, chronic liver disease due to alcohol, auto-
immune, primary biliary cholangitis, HIV, HBV or active HCV-infection,
Wilson's, α-1-antitrypsin deficiency, hemochromatosis, etc., and not due to NASH
disease.
5. Any history of clinically significant or decompensated chronic liver disease
including esophageal varices, ascites, encephalopathy or any hospitalization for
treatment of chronic liver disease; or MELD score ≥ 10. 
6. History of significant cirrhosis of the liver or FibroSure® > 0.75 at Screening (as
shown on the laboratory report under Fibrosis Score).
7. Alcohol consumption greater than 14 drinks per week for men or greater than 7
drinks per week for women and/or positive alcohol breath test. (One drink is
defined as 12 fluid ounces of regular beer (5% alcohol), 5 fluid ounces of wine
(12% alcohol), or 1.5 fluid ounces of 80 proof (40% alcohol) distilled spirits.) 
8. Introduction of an anti-obesity drug in the past 6 months prior to screening. 
9. History of gastrointestinal malabsorptive bariatric surgery any other
gastrointestinal surgery that may induce malabsorption, history of bowel resection
> 20 cm, any malabsorption disorder, severe gastroparesis, any GI procedure for
weight loss (including LAP-BAND®), as well as clinically significant
gastrointestinal disorders (e.g. peptic ulcers, severe gastrointestinal reflux disease
[GERD]) within less than 5 years. 
10. Ingestion of drugs known to produce hepatic steatosis including corticosteroids,
high-dose estrogens, methotrexate, tetracycline or amiodarone in the previous 6
months. 
11. Ingestion of drugs (as listed in the Table Prohibited Medication) from time points
specified until completion of the study. 
12. History of, or current cardiac dysrhythmias and/or a history of cardiovascular
disease event, including congestive heart failure (class C and D of the American
Heart Association [AHA]), unstable coronary artery disease, myocardial
infarction.
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13. Significant systemic or major illnesses other than liver disease, including
cerebrovascular disease, pulmonary disease, renal failure, organ transplantation,
serious psychiatric disease, malignancy that, in the opinion of the investigator,
would preclude treatment with FT-4101 and/or adequate follow up.
14. History of chronic skin and hair conditions such as psoriasis, eczema or any
recurring rash/dermatitis requiring oral or topical corticosteroids or other topical
applications within 12 months.
15. Hair loss or unexplained alopecia within 12 months.
16. History of chronic eye conditions, Sjögren syndrome or any history of dry eyes or
allergic conjunctivitis requiring artificial tears or medicated eye drops or previous
refractive surgery within 12 months (Subjects with dry eyes due to wearing
contact lenses are eligible).
17. History of major depression, anxiety, suicidal behavior or attempts, or other
unstable psychiatric disorders (within 2 years of screening), requiring medical
treatment. (Subjects on stable antidepressants are allowed). 
18. Uncontrolled hypertension, defined as systolic blood pressure >150 mmHg and/or
diastolic blood pressure ≥ 100 mmHg at screening (reading may be repeated on a
different day). (Subjects with uncontrolled hypertension may be rescreened after 3
months, following initiation or adjustment of antihypertensive therapy).
19. Any device or other contraindication with the MRI examination, as per local
imaging centers. 
20. Ingestion of deuterated water within the previous 6 months.
21. Positive test for hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV
Ab), or human immunodeficiency virus type 1 (HIV-1) or type 2 (HIV-2)
antibody.
22. Abnormal laboratory results:
a) Alanine aminotransferase (ALT) > 5 x upper limit of the normal range (ULN) 
b) Total bilirubin > 1 x ULN, except with diagnosis of Gilbert's syndrome 
c) International normalized ratio (INR) > 1.2 unless on anticoagulant therapy 
d) Fasting Triglycerides > 300 mg/dL 
e) Platelet count < 100,000 /mm3 
f) Abnormal kidney function test with glomerular filtration rate [GFR] < 60
mL/min/1.73m2 as estimated using the MDRD equation.
23. Participation in any other clinical interventional study receiving active treatment
within the previous 30 days or 5 half-lives whichever is longer. 
24. Have a known hypersensitivity to any of the ingredients or excipients of the study
products. 
25. Subject is unable to abstain from smoking during confinement periods. 
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26. History of illicit drug abuse as judged by the Investigator within approximately 1
year and positive test at Screening.
27. Clinically under the effect of marijuana at screening, as per Investigator
evaluation.
28. Unwillingness to abstain from grapefruit (grapefruit containing food and
beverages), star fruit (carambola), pomegranate, Seville orange and other food
components that may interact with CYP3A4 from check-in throughout the entire
course of the study.
29. Donation or loss of > 500 mL of blood or blood product within 56 days of dosing.
30. Any other condition which, in the opinion of the investigator would impede
competence or compliance or possibly hinder completion of the study. 
7.3 
Study Restrictions/Precautions
7.3.1 Prohibited Medications 
Use of the agents listed below (prescription or nonprescription) is prohibited from the 
time points specified until completion of all study activities. 
Table 7-1 Prohibited Medications 
Medication or Class 
Indication/Reason 
From time point specified 
until the end of the study 
Antihypertensive medication 
Hypertension 
Excluded unless on stable 
dose for at least 3 months 
prior to screening 
Statins 
Hyperlipidemia 
Excluded unless on stable 
dose for at least 3 months 
prior to screening 
Oral or systemic long-acting 
corticosteroids 
E.g., chronic or acute non-
infectious inflammatory
conditions, auto-immune
diseases
Within 3 months prior to 
screening 
Antacids, anticholinergics, 
antispasmodics (e.g., modafinil, 
phenytoin), 5HT3 antagonists, 
dopamine antagonists, or opiates, 
antiemetics  
Reduction/modification of 
GI motility 
Within 2 weeks prior to 
screening 
Orlistat, lorcaserin, sibutramine, 
etc., including over-the-counter 
and herbal supplements, or any 
medication with a labelled 
indication for weight loss or gain 
Weight control treatment 
Within 3 months prior to 
screening. 
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Medication that is a strong 
inducer or strong inhibitor of 
CYP3A4 
Please see Appendix C in section 
16.3. 
Interaction with CYP3A4 
Within 15 days prior to 
dosing, unless half-life is 
greater than 72 hours, then it is 
prohibited for 5 half-lives 
prior to dosing. 
7.3.2 Check-in Criteria 
At check-in for any in-house period(s), a subject will not be allowed to check in if they 
meet any of the following criteria and the treatment period may be rescheduled one time. 
The Sponsor will be notified about the rescheduling in a timely manner. 
1. Positive alcohol breath test.
2. Positive urine drug screen test.
3. Positive urine pregnancy test in female subjects. If sample is positive, blood
sample will be sent to local lab for confirmation. A negative test result is
mandatory prior to dosing.
4. Any medical condition that could interfere with the study, as judged by the
Investigator.
5. Any use of disallowed concomitant medications within the last 24 hours.
6.
Consumption of grapefruit (grapefruit containing food and beverages), star fruit
(carambola), pomegranate, Seville orange and other food components that may
interact with CYP3A4, within 24 hours prior to check-in.
7.3.3 Anticipated Risks 
Normal precautions taken for a human study, including the provision of emergency 
equipment, will be taken during this study. Qualified and well-trained physicians and 
medical staff will instruct the subjects.  
Possible anticipated, risks from the study procedure are outlined below: 
7.3.3.1 IP related adverse events 
Dosing with the IP may have adverse effects on the skin (including alopecia) and eye. 
These effects were reversible upon dose interruption in previous studies. An assessment 
of hair loss at baseline and during the treatment cycles is recommended to adequately 
assess any potential AE of alopecia occurring during study participation. For further 
information, please see Norwood’s Classification of Hair Loss in section 16.4, Savin’s 
Pictorial Grading of Female Pattern Hair Loss in section 16.5 and the Investigator’s 
Brochure (IB). 
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7.3.3.2 Deuterated Water adverse events 
The adverse effect reported with the intake of deuterated water is transient dizziness if the 
deuterated intake is more rapid than planned in this study. Dizziness typically resolves 
within 2-3 hours. Deuterated water has been given to humans for more than 70 years 
without problems. Animals have been raised for many generations on deuterated water, 
without any problems. No risks have been observed in studies examining the effect of 
deuterated water on male or female reproduction tissues, including sperm function. 
7.3.3.3 Procedure related adverse events 
Study procedures involve the placement of a catheter which may lead to allergic reaction, 
redness, swelling, bruising, pain, bleeding or infection at catheter insertion site. The study 
procedures also involved the use of adhesive to secure the placement medical equipment. 
The adhesive may cause an allergic reaction, redness, swelling or itching when in contact 
with the skin. 
7.3.3.4 Risks related to repeated blood draws 
Subjects will participate in several blood draws throughout the course of the study which 
have the potential to cause a venous line-vasovagal response, bruising, tenderness, and 
rarely infection. 
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8.0 
STUDY MATERIALS 
8.1 
Investigational Products 
8.1.1 FT-4101 
FT-4101 is a potent, selective, orally bioavailable, small-molecule inhibitor of Fatty Acid 
Synthase (FASN). It is a non-hygroscopic, crystalline solid, obtained as polymorph Type 
B.  FT-4101 capsules contain only drug substance filled into capsules with no other 
excipients. FT-4101 capsules will be provided in 3 different unit strengths for oral 
administration. For this study, the following doses may be used: 1.5 mg active capsules: 
Size 3 White/White opaque, 3 mg active capsules: Size 3 White/White opaque and 4.5 
mg active capsules: Size 3 White/White opaque will be used. 
8.1.2 Placebo 
Placebo capsule is matching in size and color to all the active capsules. Placebo capsule 
contain Avicel PH102, an inert and stable compendial excipient, and will be provided by 
the Sponsor.  
8.2 
Other Medicinal Products 
8.2.1 Deuterated Water 
Deuterated Water (70%) will be manufactured under cGMP conditions. Commercially 
available deuterated water will be provided by 
 from a qualified vendor. 
Deuterated water will be provided as individual ready-to-use, single dose bottles each 
containing 50 mL of deuterated water (70 %). 
8.3 
Packaging, and Labeling of Products 
Each dose strength of FT-4101 and matching placebo are packaged in high-density 
polyethylene (HDPE) induction sealed bottles. For this study, 66 capsules are packaged 
per bottle. 
The Sponsor will provide the Investigator with the labeled IP in accordance with specific 
country regulatory requirements. 
The deuterated water will be packaged in individual ready-to-use single dosing bottle 
(e.g. the bottle can only be used once) each containing 50 mL of deuterated water and 
labeled with specific country regulatory requirements. 
8.4 
Storage and Drug Accountability of Products 
All clinical material must be kept in an appropriate, limited-access, secure location. 
The investigational products (IP) and its storage instructions will be provided by the 
Sponsor. The IP FT-4101 must be stored securely at 15℃ to 30℃.  
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The IP placebo must be stored at 15°C to 30°C. 
The shipment of the IPs is recommended at 15°C to 25°C, packaged in a qualified 
shipper. 
Individual bottles of deuterated water will be stored at room temperature (15℃ to 30℃) 
according to instructions by the specific laboratory. 
The IP will be shipped from the Sponsor to 
 drug depot. 
 will 
distribute the IP and deuterated water to each site.  
The study staff is required to document the receipt, dispensing, and return/destruction of 
Study Products and supplies provided by or on behalf of the Sponsor. 
Each study site may destroy IP or return deuterated water to drug depot per pharmacy 
manual’s instructions after the close out visit.  
The Investigator or Investigator’s authorized staff must ensure the availability of proper 
storage conditions. The temperature of all study drugs will be monitored over 24 hours a 
day, 7 days a week (24/7). In case of incorrect storage, the Sponsor and monitor must be 
contacted without delay. 
No study drugs may be dispensed to any person not enrolled in the study.  
For further details please see the Pharmacy Manual. 
8.5 
Dose Regimen 
The first dose of IP and deuterated water will be administered by qualified study staff 
while subjects are under observation in the clinical research unit. Accountability for 
deuterated water and IP will be performed to monitor compliance.  
IP will be administered at t=0, orally with approximately 240 mL of water in the 
morning. Subjects do not need to be in a fasting state. A compliance check for the in-
house dosing (hand and mouth check) will confirm that subjects have swallowed the 
complete dose. Actual time of dosing will be documented in the source documents and 
eCRFs. 
During outpatient periods, subjects will take the IP at home once a day (QD) as instructed 
by study staff during the in-house period. Dosing will be intermittent, with 2 weeks of IP 
treatment and 1 week without any IP. Aim is to dose at approximately the same clock 
time on every dosing day. 
Missed IP doses: Ideally, subjects should not miss more than 25% dosing days (>3 days) 
within 1 cycle. If more IP doses are missed than above, the PI will need to decide, with 
input from the Sponsor Medical Monitor, on whether the subject should be withdrawn 
from the study and replaced. 
Details will be provided in the Operations Manual. 
To maintain the double-blind aspect of the study, the investigational products will be 
prepared by unblinded staff that is not participating in investigational product 
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administration or interacting with study subjects in any other way. The study staff 
participating in other aspects of the study will be blinded to treatment. 
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Table 8-1 Dosing Schedule for Treatment Cycles 
Cohorts 
Number 
of 
Subjects 
Treatment 
Schedule 
Treatment-
IP 
No-IP 
Treatment-
IP 
No-IP 
Treatment-
IP 
No-IP 
Treatment-
IP 
No-IP 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cohort 
A 
N=10 
Intermittent 
FT-4101 
3.0 mg 
QD Day 1-14 
No IP 
Day 15-
21 
FT-4101 
3.0 mg 
QD Day 1-14 
No IP 
Day 15-
21 
FT-4101 
3.0 mg 
QD Day 1-14 
No IP 
Day 15-21 
FT-4101 
3.0 mg 
QD Day 1-14 
No IP 
Day 15-21 
N=5 
Intermittent 
Matching 
Placebo 
QD Day 1-14 
No IP 
Day 15-
21 
Matching 
Placebo 
QD Day 1-14 
No IP 
Day 15-
21 
Matching 
Placebo 
QD Day 1-14 
No IP 
Day 5-21 
Matching 
Placebo 
QD Day 1-14 
No IP 
Day 15-21 
Cohort 
B 
N=10 
Intermittent 
FT-4101 
4.5 mg 
QD Day 1-14 
No IP 
Day 15-
21 
FT-4101 
4.5 mg 
QD Day 1-14 
No IP 
Day 15-
21 
FT-4101 
4.5 mg 
QD Day 1-14 
No IP 
Day 15-21 
FT-4101 
4.5 mg 
QD Day 1-14 
No IP 
Day 15-21 
N=5 
Intermittent 
Matching 
Placebo 
QD Day 1-14 
No IP 
Day 15-
21 
Matching 
Placebo 
QD Day 1-14 
No IP 
Day 15-
21 
Matching 
Placebo 
QD Day -14 
No IP 
Day 15-21 
Matching 
Placebo 
QD Day 1-14 
No IP 
Day 15-21 
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8.5.1 Deuterated Water 
Subjects will be instructed to drink 3 bottles of 50 mL of deuterated water (70%) daily on 
C1/D-14 through C1/D-8 and C4/D1 through C4/D7. Subjects will also be instructed to 
take each bottle of 50 mL of deuterated water at least 3 hours apart. 
The first oral dose of deuterated water will be administered in-house in the morning of 
C1/D-14 and C4/D1 after Sebutape® and DNL blood sample collections. Subjects do not 
need to be in a fasting state. A compliance check for the in-house dosing will be 
performed. Actual time of dosing will be documented in the source documents and 
eCRFs. Subjects will then be instructed to continue the administration of deuterated water 
at home. The oral intake should occur at approximately the same time of day ± 3 hours on 
every dosing day. During the outpatient phase, subjects will fill in a log recording their 
daily deuterated water intake. If a dose is missed, it should be considered a “loss” and 
noted in the daily log and will be recorded in the CRF. Subjects must not double up on 
their intake (not take two doses at once). 
If a deuterated water dose is missed, the subject should inform the study team and the 
team should record this information. There is no defined number of missed doses that 
constitutes non-compliance. Missed doses will be reported to the Sponsor Medical 
Monitor. The decision to withdraw a subject from study participation based on missed 
doses of deuterated water may be based on decision of the PI and the Sponsor Medical 
Monitor. If a subject is withdrawn, the subject can be replaced. 
For more details please see the Operations Manual. 
Table 8-2 Dosing Schedule for Deuterated Water 
Cohorts 
Subjects 
Treatment 
Schedule 
Treatment 
(7 days) 
Treatment 
(7 days) 
Cohort A 
N=15 
Daily 
Deuterated Water 
TID 50 mL (at least 
three hours apart) 
C1/D-14 to C1/D-8 
Deuterated Water 
TID 50 mL (at least 3 
hours apart) 
C4/D1 to C4/D7 
Cohort B 
N=15 
Daily 
Deuterated Water 
TID 50 mL (at least 
three hours apart) 
C1/D-14 to C1/D-8 
Deuterated Water 
TID 50 mL (at least 
three hours apart) 
C4/D1 to C4/D7 
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8.6 
Overdose 
If a study medication error occurs, it should be documented as Protocol Deviation. A 
brief description should be provided in the deviation, including whether the subject was 
symptomatic (list symptoms) or asymptomatic, and the event accidental or intentional. 
Dosing details should be captured on the Dosing Case Report Form. If the subject takes a 
dose of Study Drug that exceeds protocol specifications and the subject is symptomatic, 
then the symptom(s) should be documented as an AE. 
Should an overdose occur, the Investigator or designee should contact the Sponsor or 
designee within 24 hours of the investigator or qualified designee first becoming aware of 
the overdose. 
8.7 
Randomization and Blinding 
Subjects will be randomized to the treatment according to an interactive web response 
system (IWRS). Randomization numbers will be generated from 
. The IWRS 
will assign the next available randomization number at the time the site randomizes the 
subject, maintaining the 2:1 ratio (2 subjects on FT-4101 to 1 subject on placebo). Only 
authorized unblinded personnel will be able to see which treatment arm is assigned to a 
randomization number. Any replacement subjects will be randomized by IWRS to the 
same treatment arm that was assigned to the subject being replaced. The randomization 
number of the replaced subject will be incremented by 100 (e.g., subject 
 replaced 
with 
 subject 
 replaced with 
). 
8.8 
Breaking of Blinded Code 
The only persons with access to the treatment assignments during clinical conduct will be 
the designated pharmacy personnel who are responsible for the dispensing of study drug, 
the unblinded CRO operations team for investigational product accountability and serious 
adverse event (SAE) reporting, the unblinded statisticians who generate the 
randomization lists, and the bioanalyst for PK/PD samples. In general, the Sponsor 
Medical Monitor will remain blinded to treatment assignment. However, during the 
cohort safety review, if the decision is made to halt dose escalation due to an observed 
adverse event that potentially meets stopping criteria, the Sponsor Medical Monitor may 
be unblinded to that subject’s data to ensure that the subject in question is indeed 
receiving FT-4101 and not placebo. This information will be conveyed via the unblinded 
statistician and will be limited to the subject with the safety issue of concern. 
The code for a subject may be broken in a medical emergency, if knowing the identity of 
the treatment allocation would influence the treatment decision of the subject or if 
demanded by the subject. Unblinding will be done through the Electronic Data Capture 
(EDC), however if this is not available, the unblinded pharmacist at the site will have the 
subject list with treatment assignments, and as such would be able to break the blind in 
case of emergency. Whenever a code is broken, the person breaking the code must record 
the time, date, and reason as well as his/her initials in the source documents. During un-
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blinding procedure in case of medical emergency, it should be ensured that no study 
personnel is unblinded to other subjects. Study site personnel and Sponsor personnel 
directly associated with the conduct of the study will not be unblinded. 
If the study site needs to unblind a subject, the sponsor will, if possible, be contacted 
prior to breaking the blind. In all cases, the Study Monitor must be notified within 24 
hours after emergency unblinding. 
All codes (whether broken or not) must be kept throughout the trial period. 
Accountability of all broken or unbroken codes (hard copy or electronic) will be 
performed at or after trial closure and codes will be maintained in the Trial Investigator’s 
File (TIF) at the site. 
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9.0 
STUDY PLAN 
9.1 
Study Procedures 
9.1.1 Informed Consent and HIPAA Release 
Written informed consent will be obtained from each subject prior to performing any 
study-specific evaluations. The HIPAA release is embedded in the informed consent 
document. The informed consent document is subject to review and approval by the 
Sponsor and will be approved by a qualified IRB. The IRB-approved document must 
contain, at minimum, the eight basic elements of informed consent set forth in applicable 
law. Only the most recently IRB-approved informed consent document must be used to 
consent prospective study subjects. The Investigator (according to applicable regulatory 
requirements), or a person designated by the Investigator and under the Investigator’s 
responsibility, will fully inform the potential study subject of all pertinent aspects of the 
Clinical Study, including written information given approval/favorable opinion by the 
IRB/IEC.  
Prior to the potential subject’s participation in the Clinical Study, the written informed 
consent form must be signed, name filled in and personally dated by the subject and by 
the person who conducted the informed consent discussion, and by the Investigator. One 
copy of the signed and dated informed consent document will be given to the subject and 
the original retained by the Investigator/site. 
9.1.2 Screening 
Investigators must account for all subjects who sign informed consent forms. The 
Investigator will keep a Subject Screening and Enrollment Log at the investigational site. 
Subjects who have screen failed may be allowed to re-screen once at the discretion of the 
Investigator. A new screening number will be assigned. 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for this study. If subjects are fasting (only water for ≥ 10 hours), all screening assessments 
may be done on the same day. If subjects are not fasting, they will be invited to return for 
a second screening visit to complete any missing screening procedures (e.g. laboratory 
assessments). 
Subjects will be instructed on influencing factors and restrictions such as grapefruit 
containing food and beverages, star fruit (carambola), pomegranate, Seville orange and 
other food components that may interact with CYP3A4, smoking or medication and 
illness/infection. 
If subjects don’t have a diagnosis of NASH stage 2/3 assessed by liver biopsy performed 
within 24 months, FibroScan® (CAP) will be evaluated instead to identify subjects who are 
likely to have a liver fat content of ≥ 10% at MRI-PDFF. Depending on the outcome/results 
of these values, the subjects will proceed to MRI-PDFF or not. For further details on 
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parameters and outcome for the determination to proceed to MRI-PDFF see the Operations 
Manual. 
Subjects MELD score will be calculated according to the following formula: 
MELD(i) = 0.957 × ln(Cr) + 0.378 × ln(bilirubin) + 1.120 × ln(INR) + 0.643 
Then, round to the tenth decimal place and multiply by 10. For further details see the 
Operations Manual. 
9.1.3 Demographics and Medical History 
Demographic information, medical history and prior medications will be obtained at 
Screening. 
9.1.4 Physical Examination 
The baseline physical examination (PE) will consist of the following body systems: (1) 
eyes; (2) ears, nose, throat, neck, thyroid; (3) cardiovascular system; (4) respiratory 
system; (5) gastrointestinal system, mouth; (6) dermatologic system, including hair; (7) 
extremities; (8) musculoskeletal system; (9) central and peripheral nervous system, (10) 
lymph nodes and (11) testicular examination in male subjects. 
An abbreviated PE will be performed by the Investigator (or a qualified physician at the 
investigational site) at time points indicated in the SOE in section 16.1 for each cohort.  
For abbreviated PEs, the following will be examined and/or measured by the Investigator 
or medically-qualified designee: skin (crust, erosion, ulcer, rash, inflammation, etc); eyes 
(dryness, conjunctivitis, etc); hair (assessment of male pattern baldness using the 
Norwood scale [see Appendix D in section 16.4] or assessment of female pattern hair loss 
using the Savin scale [see Appendix E in section 16.5]); lymph nodes; and respiratory, 
cardiovascular, abdominal (gastrointestinal), and musculoskeletal systems.  
In addition, male subjects will undergo a testicular examination on C1/D-1 and C4/D29. 
A complete physical examination may be performed in case the subjects have symptoms 
or at the discretion of the Investigator. 
9.1.5 Height, Weight, and BMI 
Height (without shoes) will be measured once, during the Screening visit 
Weight (without shoes) will be measured fasting in the morning, with light clothing and 
post void at time points indicated in the SOE in section 16.1. 
BMI (kg/m2) will be calculated from height and weight. 
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9.1.6 Vital Signs 
Vital signs will include body temperature (aural), supine blood pressure (after 5 minutes 
resting), respiration rate and pulse rate (after 5 minutes resting). Vital sign measurements 
will be performed at days indicated in the SOE in section 16.1. 
9.1.7 Concomitant Illness and Therapy 
Concomitant therapy is any medication given in addition to the investigational product 
(including over-the-counter medications, herbal medications, and vitamin supplements) 
administered between screening and follow-up.  
Concomitant illness is any significant medical condition or disease that is present at study 
start (signing of informed consent). This includes clinically significant laboratory, ECG, 
or physical examination abnormalities noted at Screening examination. 
Details of all concomitant illnesses and therapies must be recorded at study entry and 
must be recorded on the subject’s CRF. Any changes in concomitant medication must be 
recorded at each visit. If the change influences the subject’s eligibility to continue in the 
study, the Sponsor must be informed. The information collected for each concomitant 
medication includes, at a minimum, start date, stop date or continuing, and indication.  
AEs related to administration of these therapies or procedures must also be documented 
on the appropriate eCRF. 
For prohibited medications, please see Table 7-1 Prohibited Medication. 
9.1.8 Procedures for Clinical Laboratory Samples 
All samples will be collected in accordance with acceptable laboratory procedures. 
Laboratory samples will be taken as described in the SOE in section 16.1. 
Additional samples (e.g., including blood samples, urine samples and all types of tissue 
samples) may be collected and stored for potential future analysis. For details please see 
the Laboratory Manual. 
Table 9-1 Clinical Laboratory Assessments 
Hematology 
Serum Chemistry 
Urinalysis 
CBC with differential: 
Hematocrit 
Hemoglobin 
mean corpuscular volume 
(MCV) 
mean corpuscular hemoglobin 
(MCH) 
mean corpuscular hemoglobin 
concentration (MCHC) 
red cell distribution width 
(RDW) 
Hepatic function panel: 
Alanine aminotransferase 
(ALT/SGPT) 
albumin, serum 
alkaline phosphatase, serum 
aspartate aminotransferase 
(AST/SGOT) 
bilirubin, direct 
bilirubin, total 
Routine urinalysis with 
microscopic examination on 
positives(a): 
Color 
appearance, 
specific gravity 
pH 
protein 
glucose 
ketones 
occult blood 
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Hematology 
Serum Chemistry 
Urinalysis 
percentage and absolute 
differential counts 
platelet count (RBC) 
red cell count 
white blood cell count (WBC) 
 
protein, total, serum 
gamma-glutamyl transferase 
(γGT) 
Renal function panel: 
Albumin, serum 
BUN 
BUN: creatinine ratio 
calcium, serum 
carbon dioxide, total 
chloride, serum 
creatinine, serum 
glucose, serum 
phosphorus, serum 
potassium, serum 
sodium, serum 
Lipid panel: 
Cholesterol, total 
high-density lipoprotein (HDL) 
cholesterol 
low-density lipoprotein (LDL) 
cholesterol (direct) 
triglycerides 
non-HDL cholesterol 
(calculated) 
Free fatty acid (FFA) 
Additional parameters: 
Lactic acid dehydrogenase 
(LDH) 
Magnesium 
Uric Acid 
 
leukocyte esterase (or 
equivalent) 
nitrite 
bilirubin 
urobilinogen 
 
Other Assessments 
Serum/Plasma/Whole Blood 
Urine 
Breath 
HBsAg 
Anti-HCV 
Anti HIV 
 
TSH 
 
PTT 
INR 
Glucose Metabolism 
Parameter: 
FPG 
Fasting Insulin 
HbA1c 
Drug Screen Profile 
Urine drug screen via 
commercial kit at the 
investigational site. 
 
 
Female Subjects Only 
human chorionic gonadotropin 
(hCG) 
 
follicle-stimulating hormone 
(FSH) test for postmenopausal 
women (defined as amenorrheic 
Alcohol breath test at timepoints 
stated in the SOE at the 
investigational site 
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Malonyl carnitine 
Adiponectin, total and high 
molecular weight 
FGF21 
Biomarkers: 
Hyaluronic acid (HA) 
Procollagen III amino terminal 
peptide (PIIINP) 
Tissue inhibitor of 
metalloproteinases 1 (TIMP-1) 
Cytokeratin-18 (CK-18) 
fragments 
FibroSure (NASH) 
PRO-C3 
female subjects <55 years of age 
and not surgically sterile) at 
Screening. 
(a) Microscopic analysis should be performed only if urine evaluations are abnormal.
The central laboratory will perform all necessary safety laboratory tests listed above. The 
results of safety laboratory tests and test to determine subjects’ eligibility will be sent to 
the Investigator or designee, who is responsible for reviewing these results. All laboratory 
safety data will be faxed or transferred electronically. 
Laboratory reports must be signed and dated by the Investigator or designee indicating 
that the report has been reviewed and any abnormalities have been assessed for clinical 
significance. 
All clinically significant laboratory abnormalities must be recorded as an AE. A clinically 
significant laboratory abnormality may be verified by retesting and may be followed 
upon discretion of the Investigator. 
9.1.9 Contraception 
Female subjects of non-childbearing potential 
Female subjects of non-childbearing potential must meet the following criteria: 
a) are either surgically sterile (hysterectomy, bilateral tubal ligation, bilateral
salpingectomy, and/or bilateral oophorectomy) at least 6 months before the Screening
Visit. If females’ sterility is confirmed, no pregnancy testing is required during the study.
The site will make an effort to retrieve medical records to document the sterility,
however, the absence of records will not exclude the subject. In case that medical records
cannot be obtained, serum pregnancy testing will be conducted at Screening, and urine
pregnancy testing will be conducted throughout the study.
b) are post-menopausal, defined as spontaneous amenorrhea for > 12 months at the
Screening Visit. Postmenopausal status will be confirmed through testing of FSH levels
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outside the normal range (as specified by responsible lab) at screening for amenorrheic 
female subjects < 55 years of age. 
Female subjects who state they are postmenopausal at the screening visit but have an 
FSH value that does not correspond with a postmenopausal FSH level, may have a serum 
hCG pregnancy test performed on a separate day. If test is negative and the subject agrees 
to be on a highly effective contraceptive method, subject may be enrolled in the study at 
the discretion of the Investigator. 
c) a negative serum pregnancy test before starting study treatment. 
 
Female subjects of child-bearing potential 
Female subjects of child-bearing potential must meet the following criteria: 
a) a negative serum pregnancy test before starting study treatment 
b) must agree to refrain from egg donation or harvest for 90 days after last dose of study 
drugs. 
c) If engaged in heterosexual intercourse must agree to use highly effective methods of 
contraception during intercourse, throughout the study period and for 90 days after the 
last dose of study drugs. 
 
Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhoea method are not 
acceptable methods of contraception.  
 
Acceptable methods of contraception under this protocol are listed below. 
 
Female subjects who are considered of childbearing potential must agree to use a highly 
effective method of contraception, which may include:  
• IUD  
• Abstinence: abstinence can be used, when in line with the preferred and usual 
lifestyle of the subject.  
• If a female subject confirms that her male partner(s) has been confirmed to be 
clinically sterile, this method is acceptable as the only means of contraception.  
• Hormonal implants 
 
Note: Hormonal contraceptives alone are not considered an effective method of birth 
control for female subjects participating in this study. Oral contraceptives can be used in 
combination with a male barrier method.  Furthermore, female condoms in combination 
with male condoms is not an acceptable method.  
 
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Childbearing Potential  
For all subjects of childbearing potential, all methods of contraception, including 
abstinence, must be in use from the time of consent through the final study visit, and for 
90 days after the last dose of study drug. Subjects who are not sexually active during the 
Screening Period must agree to the contraceptive requirements if they become sexually 
active with a partner of the opposite sex during the study and for 90 days after the last 
dose of study drug. Unique situations that may not fall within these specifications may be 
discussed with the Medical Monitor on an individual basis.  Female subjects will be 
considered of childbearing potential after the onset of their first menstrual period.  
During the study, regular serum human chorionic gonadotropin (hCG) pregnancy tests 
will be performed for sterilized women, when medical records are not available. In 
addition to a negative serum hCG pregnancy test at Screening, subjects also must have a 
negative urine hCG pregnancy test at outpatient visits and check-in to in-house periods. 
 
Male subjects  
Male subjects must meet the following criteria: 
a) are required to use barrier contraception (condom plus spermicide) during intercourse 
from Screening through study completions and for 90 days after the last dose of study 
drugs. 
b) must refrain from sperm donation from Screening through at least 90 days after the last 
dose of study drugs. 
Male subjects who can father a child must agree to use one highly effective method of 
contraception, which includes:  
• Abstinence: abstinence can be used, when in line with the preferred and usual 
lifestyle of the subject.  
• If a male subject confirms that his female partner(s) is not of childbearing 
potential (i.e., postmenopausal or post-surgical sterilization, as defined under 
child bearing potential) or is using a highly effective method of contraception, this 
is acceptable as the only means of contraception.   
Examples of highly effective methods of contraception for male subjects’ female 
partner(s) include:  
o Hormonal contraceptives in combination with male barrier contraception 
o Hormonal implants 
o Intrauterine device (IUD)  
Male subjects with documented infertility or surgical sterilization (performed at least six 
months before the first dose of study drug) are exempt from the contraception 
requirement. 
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9.1.10 Pregnancy 
In the event a subject becomes pregnant during the study, she should be withdrawn, and 
the study drug should be immediately discontinued. However, the subject will be 
encouraged to complete the post-treatment follow-up portion of the study to the extent 
that study procedures do not interfere with the pregnancy. 
In addition, any pregnancies in the partner of a male subject during the study or for 90 
days after the last dose should also be recorded.  
If the pregnancy occurs at any time during the study and the 90 days of last dose of active 
study medication, the pregnancy should be reported immediately to the Sponsor, using a 
pregnancy notification form. 
Study subjects will give consent on enrollment that the Investigator will report any 
pregnancy during the study to the Sponsor and that they will be asked to provide 
information about her pregnancy, delivery, and the health of her infant until age one 
month. Payment for all aspects of obstetrical care, child, or related care will be the 
subject’s responsibility.  
All reported pregnancies will be followed up to final outcome, using the pregnancy and 
pregnancy follow-up forms. The outcome, including any premature termination, will be 
reported to the Sponsor. An evaluation after the birth of the child may also be conducted. 
Pregnancy complications must be recorded as adverse event(s). If the infant has a 
congenital anomaly/birth defect this must be reported and followed up as a serious 
adverse event. 
9.1.11 ECG Procedure  
A standard 12-lead ECG will be recorded after 5 minutes in a supine position. 
The Investigator (or designee) will interpret the ECGs by use of an electronic 
measurement using the following categories: within normal limits, abnormal but not 
clinically significant, or abnormal with clinical significance. ECGs are performed 
according to the SOE in section 16.1. The following parameters will be recorded from the 
subject’s ECG trace as calculated by the machine algorithm: heart rate, QT interval, PR 
interval, QRS interval, RR interval, and QTc (corrected) using the Fridericia correction 
(QTcF = QT ÷ cube root of the R-R interval [where R-R is the duration of the entire 
cardiac cycle]). 
When ECGs are to be collected at the same time point as a blood collection, ECGs should 
be collected first to avoid any artificially increased heart rates due to the blood collection. 
In some cases, it may be appropriate to repeat abnormal ECGs. If a machine-read QTc 
value is prolonged, repeat measurements may not be necessary if the Investigator’s 
interpretation determines that the QTc value is in the acceptable range. 
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9.1.12 Check-in Procedure 
All subjects will check in to the clinic in the morning for the In-house Periods. The 
following will be assessed: 
1. Alcohol breath test.
2. Urine drug screen.
3. Urine pregnancy tests. (The negative result of the urine pregnancy test will allow to
check-in, while the negative test result of the serum pregnancy test must be available
prior to dosing on C1/D1).
4. Any use of disallowed prescription or non-prescription concomitant medications
within the last 24 hours.
5. Any medical condition that could interfere with glucose metabolism, as judged by the
Investigator.
6. Consumption of grapefruit (grapefruit containing food and beverages), star fruit
(carambola), pomegranate, Seville orange and other food components that may
interact with CYP3A4, within 24 hours prior to check-in.
Subjects who fulfill one or more of the stated criteria at check–in, will not be able to 
continue onto the treatment period. The treatment period will be rescheduled. Each 
treatment period may be rescheduled one time. After that, the subject will be excluded 
from the study. Replacement of subjects for all dosing periods may be permitted in order 
to enroll sufficient subjects into the study, only after discussion with Sponsor and 
Investigator. 
9.1.13 Blood Glucose Monitoring by Fingerstick 
Blood glucose might be measured by fingerstick whenever there are signs or symptoms 
of hypoglycemia or hyperglycemia. A confirmation measurement of the blood glucose 
value may be performed by YSI. 
9.1.14 Wash-Out Period 
The wash-out period is optional and only subjects with T2DM on combination therapy 
with metformin and sulfonylurea will have to undergo a wash-out period to discontinue 
the oral drug sulfonylurea (SU) until the end of the study. Medication with metformin 
monotherapy will be continued throughout the entire study on the same stable dose. 
Discontinuation of the SU must start at least 7 days prior to C1/D-14, the start of the 
deuterated water labeling period (starting wash-out at least on C1/D-21). All subjects will 
be instructed to monitor and document their fasting plasma glucose levels daily, using a 
glucometer. The subjects will be instructed on how to use the glucometer. A diary will be 
supplied by the study site. For further details on capturing data and documentation in the 
diary, please see the Operational Manual. They will be frequently (at least twice weekly) 
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contacted by qualified study site staff in the washout period to review their fasting plasma 
glucose values. If a subject has a confirmed morning fasting plasma glucose level (after 8 
hours of fasting) that is ≥ 240 mg/dL (13.3 mmol/L) and cannot be lowered to < 180 
mg/dL (10.0 mmol/L) in 7 days, verified by a standard laboratory analysis (ie, YSI 
glucose analyzer at the site), this subject will be excluded from further participation in the 
study.  
All subjects with T2DM will be provided with a blood glucose meter with sufficient 
supplies and test strips to monitor blood glucose at home during wash-out, run-in and/or 
outpatient periods. For further details on data capturing and documentation, please see the 
Operational Manual. 
9.1.15 Standardized Meals and Dietary Counseling 
Subjects will be counseled to maintain their normal diet and exercise regimen. They will 
be instructed not to start any new diets, supplements, or exercise programs during the 
study. 
During in-house period(s), subjects will receive standardized meals. The same 
standardized meals will be served on C1/D-1 and C4/D14 to standardize conditions prior 
to the C1/D1 and C4/D15 assessments. These meals will be provided up to 12 hours prior 
to start of scheduled fasting DNL samples on C1/D1 and C4/D15. 
The standardized weight maintaining meals will be provided using estimated BMR× 
activity factor of 1.5 to determine daily caloric intake. Daily calories are individualized to 
within 200 calories of estimated BMR x 1.5.  
9.1.16 Pharmacokinetic Assessments and Schedule 
Blood for PK analysis of the IP will be collected at the time points indicated in the SOE 
in section 16.1 and the PK sampling schedule in section 16.2. One 2.0 mL sample per 
scheduled time point will be collected and split equally to provide plasma for primary PK 
measurements and plasma as a secondary back-up sample. Instructions for sample 
processing and shipment will be provided in the Laboratory Manual. Pre-dose sampling 
will be taken within 15 minutes before dosing. PK blood sampling should be performed 
at the nominal time(s) specified in this clinical protocol. All actual PK sample collection 
times will be recorded in the source documents and CRF. Explanation should be provided 
in the source documents and CRF for missed or mishandled samples. 
Concentrations of FT-4101 in plasma will be measured using a validated liquid 
chromatography tandem mass spectrometry (LC-MS/MS) assay. 
9.1.17 Pharmacodynamic Assessments and Schedule 
9.1.17.1 Laboratory Parameter 
Blood for analyses of PD assessments will be collected at the time points indicated in the 
SOE in section 16.1. Sampling for fasting metabolic parameter (Lipids, FPG, fasting 
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insulin, HOMA-IR, HbA1c, Adiponectin (total and high molecular weight), FGF-21, and 
Malonyl carnitine), liver biochemistry (AST, ALT, γGT, AP, total bilirubin), liver injury 
and fibrosis biomarkers (CK-18 fragment, ELF score [HA, PIIINP, TIMP-1] [Guha et al. 
2008], PRO-C3, FibroSure® [Ratziu et al. 2006]), will be collected. 
Instructions for sample processing and shipment will be provided in the laboratory 
manual. 
9.1.17.2 Sebumeter® 
Sebumeter® is a measuring device to assess skin surface sebum levels. 
The measurement is performed via application of a specialized probe composed of a 
sebum sensitive film on its surface. Results are expressed in µg/cm² and correspond to 
the total amount of sebum collected on the film. 
For detailed instructions on use please see the Operations Manual. 
9.1.17.3 Collection of Sebum using Sebutape® 
The collection of sebum for the analysis of sebum fatty acid concentrations and sebum 
DNL will be performed with the Sebutape® technique. The Sebutape® (CuDerm Corp., 
Dallas TX) is comprised of an open-celled, microporous, hydrophobic polymeric film 
that is coated with an adhesive layer that will permit the passage of lipids as the 
Sebutape® tightly adheres to the skin surface. The surface area of one Sebutape® is ~5 
cm2. Further details of the procedure are described within the accompanying Operations 
Manual. 
9.1.17.4 FibroScan® (vibration controlled transient elastography) 
One-dimensional vibration controlled transient elastography (VCTE) assessed by 
FibroScan (EchoSens™, Paris, France) will be used in this study. 
At Screening or within 30 days prior to screening, subjects will be examined with the 
FibroScan to assess the controlled attenuation parameter (CAP) and liver elasticity/liver 
stiffness measurements (LSM). Subjects with FibroScan results obtained within 30 days 
prior to screening don’t need to undergo this procedure at screening. 
Only CAP will be used in order to qualify for the inclusion in the study. An additional 
FibroScan measurement will be performed at week 12.  
For the LSM, the device generates a low-frequency shear wave from a probe applied to 
the subject’s skin between the ribs. The speed of the wave spread is then measured 
between two points within the liver to allow the livers stiffness to be quantified. The 
wave will travel more rapidly through stiff tissue. An examination using the FibroScan 
consists of ten signal acquisitions at a single point; the whole process lasts around 15 
minutes. The results (LSM and CAP) are instantly displayed on a screen. 
For details please see the Operations Manual. 
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9.1.17.5 De Novo Lipogenesis (DNL) Assessment 
Steady state contribution of fractional DNL to plasma triglyceride (TG) palmitate 
(representing hepatic DNL) and sebum fatty acids (e.g. palmitate and/or sapienic acid) 
will be determined using mass isotopomer distribution analysis (MIDA). For the 
assessment of fractional hepatic DNL during the study, subjects need to be in fasting 
conditions (no food or drink, except for water for 10 hours prior). Fasting is not required 
for the assessment of sebum DNL. A 2-week deuterated water labeling approach will be 
used to allow fully labeling of newly synthesized fatty acids (DNL) in liver triglycerides 
and sebum. Multiple blood and sebum samples will be collected throughout the 
assessment period for the measurement of deuterium enrichment in fatty acids and body 
water.  
Sampling time points on different days should be at approximately the same clock time. 
For details please see the Operations Manual. 
Table 9-2 Deuterated Water Administration and Blood/Sebum Sampling for the 
DNL Assessments 
RUN-IN 
PERIOD 
Cycle / 
Days 
Deuterated 
Water Intake 
(3 x 50 
mL/day) 
Blood 
Collection for 
hepatic DNLa 
Sebum 
Collection for 
sebum DNL 
C1/D-14 
X 
Xb 
Xb 
C1/D-13 
X 
-- 
-- 
C1/D-12 
X 
-- 
-- 
C1/D -11 
X 
X 
-- 
C1/D -10 
X 
-- 
-- 
C1/D -9 
X 
-- 
-- 
C1/D-8 
X 
-- 
-- 
C1/D-7 
-- 
X 
-- 
C1/D-6 
-- 
-- 
-- 
C1/D-5 
-- 
-- 
-- 
C1/D-4 
-- 
-- 
-- 
C1/D-3 
-- 
-- 
-- 
C1/D-2 
-- 
-- 
-- 
C1/D-1 
-- 
-- 
-- 
C1/D1 
-- 
Xc 
X 
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TREATMENT 
PERIOD 
Days 
Deuterated 
Water Intake 
(3 x 50 
mL/day) 
Blood 
Collection for 
hepatic DNLa 
Sebum 
Collection for 
sebum DNL 
C3/D1 
-- 
X 
-- 
C3/D15 
-- 
X 
-- 
C4/D1 
X 
Xb,c 
Xb 
C4/D2 
X 
-- 
-- 
C4/D3 
X 
-- 
-- 
C4/D4 
X 
Xc  
-- 
C4/D5 
X 
-- 
-- 
C4/D6 
X 
-- 
-- 
C4/D7 
X 
-- 
-- 
C4/D8 
-- 
Xc 
-- 
C4/D9 
-- 
-- 
-- 
C4/D10 
-- 
-- 
-- 
C4/D11 
-- 
-- 
-- 
C4/D12 
-- 
-- 
-- 
C4/D13 
-- 
-- 
-- 
C4/D14 
-- 
-- 
-- 
C4/D15 
-- 
X 
X 
C4/D22 
-- 
X 
X 
aBlood samples for DNL taken after an overnight fast 
bBlood and sebum samples for DNL taken prior to administration of deuterated water 
cBlood samples taken prior to IP dosing 
9.1.17.6 MRI-PDFF 
Magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) deems as a 
noninvasive, quantitative, and accurate measure of percent liver fat or hepatic steatosis 
grade in this study to identify the study population and assess the treatment response. 
MRI-PDFF will be performed using a standardized imaging acquisition calibration 
protocol and the results will be determined by a central reader during the screening period 
(as baseline value), during week 6 (within a window of 4 days prior to C3/D1) and week 
12 (within a window of 4 days prior to C4/D22). 
For details please see the Operations Manual. 
Incidental MRI results will be reviewed by the PI. Those found at screening should not be 
recorded as AEs, but as medical history on the CRF. Results found after first dose will be 
recorded as AEs. For details see section 10.1.1 Adverse Events. 
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9.1.18 Blood Volume 
The estimated blood sampling volume for subjects is not expected to exceed 500 mL.  
Even in case of further unexpected blood sampling, extension of blood sampling period 
or necessary retesting, sampling volume will not exceed 50 mL. Actual blood volumes 
will be listed in the lab manual. 
 
 
 
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10.0 
ADVERSE EVENTS 
The investigator or designee and research site staff are responsible for the detection, 
documentation, classification, reporting, and follow-up of events meeting the definition 
of an AE or serious AE (SAE). Procedures for managing AEs and SAEs are detailed in 
the research site’s SOPs.  
Spontaneously reported or observed AEs will be recorded throughout the study beginning 
at the time the subject gives informed consent. AEs will be elicited using a non-leading 
question at designated time points. Regardless of seriousness, intensity, or presumed 
relationship to study drug, all AEs will be recorded in the source documentation from the 
time of first contact with the subject (e.g. Screening) until the end of the follow-up period 
of the study. All measures required for management of AEs will be recorded in the source 
documentation. 
10.1 
Definitions 
10.1.1 Adverse Event (AE) 
An AE is any undesirable and unintended medical event occurring to a subject in a 
clinical study, whether or not related to the study products. This includes events from the 
first study related activity after the subject has signed the informed consent and until post 
treatment follow-up period as defined in the protocol. The following should not be 
recorded as AEs, if recorded as medical history/concomitant illness on the CRF at 
screening: 
•
Pre-planned procedure, unless the condition for which the procedure was planned
has worsened from the first study related activity after the subject has signed the
informed consent
•
Pre-existing conditions found as a result of screening procedures
•
Pre-existing events that has not worsened in intensity or frequency from baseline.
10.1.2 Treatment emergent Adverse Event (TEAE) 
•
A TEAE is defined as any untoward medical occurrence in a subject administered a
medicinal product that does not necessarily have a causal relationship with this
treatment.
•
A TEAE can, therefore, be any unfavorable and unintended sign (including an
abnormal laboratory finding), symptom, or disease temporally associated with the use
of an investigational product, whether or not related to the investigational medicinal
product.
•
This includes an exacerbation of pre-existing conditions or events, intercurrent
illnesses, drug interaction, or the significant worsening of the indication under
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investigation that is not recorded elsewhere on the eCRF under specific efficacy 
assessments.   
Anticipated fluctuations of pre-existing conditions that do not represent a clinically 
significant exacerbation or worsening are not considered AEs. 
If progression of the underlying disease (i.e., the condition being treated with study drug) 
might be reasonably anticipated given the nature and severity of the underlying disease, 
then progression of the underlying disease per se will not constitute an AE. However, if 
the progression of the underlying disease meets the criterion for “serious” categorization 
of AEs (e.g., the underlying disease results in death or hospitalization, etc.), then the 
progression of underlying disease should be reported as an SAE. 
10.1.3 Serious Adverse Event (SAE) 
An SAE is any untoward medical occurrence that occurs at any dose (or, occurs after 
informed consent is given and prior to dosing) that: 
•
Results in death.  Any event resulting in death during the reporting period [from
signing of ICF through 28 days after last dose of study drug(s)] must be treated as an
SAE and reported as such.
•
Is life-threatening (subject is at immediate risk of death from the event as it occurred)
NOTE: this is different than Life-threatening severity criteria.
•
Requires in-subject hospitalization (formal admission to a hospital for medical
reasons) or prolongation of existing hospitalization
•
Results in persistent or significant disability/incapacity
•
Results in a congenital anomaly/birth defect
Important medical events that may not result in death, are not life-threatening, or do not 
require hospitalization may be considered SAEs when, based on appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples of such 
events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home or the development of drug dependency or drug abuse. 
The following are not considered SAEs and therefore do not need to be reported as such: 
•
Pre-planned or elective hospitalization including social and/or convenience situations
(e.g., hospitalization due to weather or travel issues)
•
Overdose of either study drug or concomitant medication unless the event meets SAE
criteria (e.g., hospitalization).  However, the event should still be captured as a non-
serious AE on the appropriate eCRF page
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10.1.4 Clinical Laboratory Assessments as Adverse Events and Serious Adverse 
Events 
It is the responsibility of the investigator to assess the clinical significance of all 
abnormal values as defined by the list of reference ranges from the local laboratory. In 
some cases, significant changes in lab values within the normal range will require similar 
judgment. 
An abnormal laboratory value that is not already associated with an AE is to be recorded 
as an AE only if any one of the following criteria is met: 
•
an action on the study drug is made as a result of the abnormality
•
intervention for management of the abnormality is required
•
at the discretion of the investigator should the abnormality be deemed clinically
significant
10.2 
Recording of Adverse Events and Serious Adverse Events 
•
Any AE that occurs after signing of ICF through 28 days after last dose of study
drug(s) should be recorded on the AE eCRF.
•
In order to avoid vague, ambiguous, or colloquial expressions, the AE should be
recorded in standard medical terminology rather than the subject’s own words.
•
Whenever possible, the investigator should combine signs and symptoms that
constitute a single disease entity or syndrome into a final diagnosis, if appropriate.
For example, fever, cough, and shortness of breath may be reported as pneumonia, if
that is the final diagnosis.
•
Each AE is to be evaluated for duration, severity, seriousness, and causal relationship
to the investigational drug.  The action taken and the outcome must also be recorded.
•
SAEs that occur during the study or within 28 days after last dose of study drug(s),
whether related to study drug, must be immediately reported to the Sponsor/SAE
designee. Clinical trial sites will enter SAE information directly into the EDC clinical
database within 24 hours of knowledge of the event.  After the 28-day reporting
window, only SAEs assessed as related to study drug need to be reported.
10.3 
Evaluation of Adverse Events and Serious Adverse Events 
The investigator or designee is responsible for making an assessment as to the seriousness, 
intensity, causality, action taken, and outcome of an AE. 
10.3.1 Intensity of AEs 
Intensity refers to the severity of the AE. The Investigator must categorize the severity of 
each AE according to the NCI CTCAE version 5.0. CTCAE guidelines can be referenced 
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at the following website: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm 
For any term that is not specifically listed in the CTCAE scale, intensity will be assigned 
a grade of one through five using the following CTCAE guidelines: 
Grade 1: Mild; asymptomatic or mild symptoms, clinical or diagnostic observations 
only; intervention not indicated 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living 
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
activities of daily living 
Grade 4: Life-threatening consequences; urgent intervention indicated 
Grade 5: Death related to AE 
10.3.2 Causal Relationship to Study Treatment 
Medical judgment should be used to determine the cause of the AE considering all 
relevant factors such as, but not limited to, the underlying study indication, coexisting 
disease, concomitant medication, relevant history, pattern of the AE, temporal 
relationship to the study medication, dechallenge or rechallenge. 
Not Related or Unlikely to be related 
•
An AE that is clearly due to extraneous causes (e.g., concurrent disease, concomitant
medications, disease under study, etc.)
•
It does not follow a reasonable temporal sequence from administration of study drug
•
It does not follow a known pattern of response to study drug
•
It does not reappear or worsen when study drug is restarted
•
An alternative explanation is likely even if not clearly identifiable
Related, Possibly related, or Probably related 
•
An AE that is difficult to assign to alternative causes
•
It follows a strong or reasonable temporal sequence from administration of study drug
•
It could not be reasonably explained by the subject’s clinical state, concurrent disease,
or other concomitant therapy administered to the subject
•
It follows a known response pattern to study drug
•
It is confirmed with a positive rechallenge or supporting laboratory data
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10.3.3 Action Taken and Outcome 
The investigator will record the action taken and outcome for each AE according to the 
following criteria: 
Action Taken with Study Drug 
•
None; Dose not changed
•
Dose reduced
•
Study drug temporarily interrupted
•
Study drug permanently discontinued
•
Other (specify); i.e., unknown or not applicable
Outcome 
•
Recovered
•
Recovered with sequelae
•
Ongoing; Not recovered
•
Death; Fatal
•
Lost to follow-up; Unknown
10.4 
Reporting Procedures 
10.4.1 Any Adverse Event 
Regardless of seriousness, intensity, or presumed relationship to study drug, all AEs will 
be recorded in the source documentation. Whenever possible, diagnoses will be recorded, 
when signs and symptoms are due to a common etiology. In addition, the investigator must 
record his or her opinion as to the intensity of the AE and whether the AE is related to study 
drug. All measures required for management of the AE will be recorded in the source 
documentation. 
10.4.2 Serious Adverse Events and Suspected Unexpected Serious Adverse Serious 
Reactions (SUSARs) 
All SAEs, regardless of relationship to study drug, must be reported to the Sponsor/SAE 
designee within 24 hours of knowledge of the event, according to the procedures below.  
It is important that the investigator provide an assessment of relationship of the SAE to 
study treatment at the time of the initial report. Clinical trial sites will enter SAE 
information directly into the EDC clinical database within 24 hours of knowledge of the 
event. 
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The Sponsor or its designee is responsible for submitting reports of AEs associated with 
the use of the drug that are both serious and unexpected to the U.S. Food and Drug 
Administration (FDA), according to 21 Code of Federal Regulations (CFR) 312.32; and 
to other applicable regulatory authorities, according to national law and/or local 
regulations. 
All investigators participating in ongoing clinical studies with the study medication will 
receive copies of these reports for prompt submission to their Institutional Review Board 
(IRB) or Independent Ethics Committee (IEC).  In accordance with the European 
Commission Clinical Trials Directive (2001/20/EC), the Sponsor or its designee will 
notify the relevant ethics committees in concerned member states of applicable suspected 
unexpected serious adverse reactions as individual notifications or through periodic line 
listings. 
The Sponsor or its designee will submit all safety updates and periodic reports to the 
regulatory authorities as required by applicable regulatory requirements (i.e., within 7 
days for treatment related unexpected fatal or life-threatening events; within 15 days for 
all other treatment related unexpected serious events).   
10.4.3 Pregnancy or Drug Exposure during Pregnancy 
• If a subject becomes pregnant during the study the investigator is to stop dosing with 
study drug(s) immediately. 
• A pregnancy is not considered to be an AE or SAE; however, it must be reported to 
the Sponsor using the Pregnancy Report Form within the same timelines as an SAE. 
This applies to a female subject or the female partner of a male subject (note: 
additional consent may be required to obtain information from the female partner). 
• The pregnancy should be followed through to outcome, whenever possible.  Once the 
outcome of the pregnancy is known, the Pregnancy Outcome Reporting Form should 
be completed and reported to the Sponsor. 
• AEs or SAEs that occur during pregnancy will be assessed and processed according 
to the AE or SAE processes using the appropriate AE or SAE forms.   
 
 
 
 
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11.0 
DATA HANDLING AND MANAGEMENT 
Clinical Data Management (CDM) is the responsibility of 
 Chula Vista, USA. 
11.1 
Data Management 
The full details of procedures for data handling will be documented in the Data 
Management Plan (DMP). 
AEs and medical history will be coded using the current version of the Medical 
Dictionary for Regulatory Activities (MedDRA). Concomitant medications will be coded 
using the World Health Organization (WHO) WHO Drug Global dictionary. The 
MedDRA version used will be recorded in the Study Master File documentation. 
Unique numbers will identify the subject and the biological material obtained from the 
subject. Appropriate measures such as encryption or deletion will be enforced to protect 
the identity of human subjects in all presentations and publications as required by 
local/regional/national requirements. 
Data from screening failures will be entered into the database. The data for screen 
failures will be limited to ICF date, demographics, and eligibility assessment including 
reason(s) for screen fail.  
Laboratory data from the central laboratory will be electronically transferred to 
 for database reconciliation purposes and loading into EDC for data review 
purposes. In cases where sensitive non-PK laboratory data is transferred via non-secure 
electronic networks, data will be encrypted during transfer. 
The laboratory will provide one copy of the laboratory reports to the site staff. The site 
staff will receive all laboratory data electronically or based on FAX reports directly from 
the laboratory. An Investigator must review, evaluate, sign and date the laboratory print-
outs upon receipt. The signed print-out of the laboratory reports are source data. 
All other results, including PK, PD data, and laboratory tests will be transferred 
electronically to the responsible Data Management Unit. 
11.2 
CRFs (Electronic) 
11.2.1 Clinical Data Management Workflow 
Electronic CRFs will be developed by the CDM, in collaboration with the clinical study 
team and statistician. CDM will document the process workflow in the DMP. After data 
entry, monitor(s) will source data verify (SDV) the eCRFs against the source documents. 
Queries may be issued to clarify the data entered. The PI will electronically sign the 
eCRFs after all data have been entered, source data verified, and all queries have been 
resolved. If corrections and/or resolution of queries are required after PI approvals, those 
eCRFs affected by changes will be re-signed by the PI. The database may be locked after 
the PI approvals are completed and the Sponsor has reviewed the data and authorized 
lock. 
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After database lock, CDM study design documentation and locked eCRFs (PDF) will be 
created and will be provided to the Sponsor. 
11.2.2 Data Entry of eCRFs 
Data required for analyses and subject safety assessments will be entered from source 
documentation into eCRFs. Instructions for data entry will be provided in the eCRF 
Completion Guidelines, developed by 
 CDM department. All site staff 
involved with entering data into the eCRFs will be trained prior to gaining access to the 
study database. 
11.2.3 Corrections to eCRFs 
Queries may be generated by the eCRF system during data entry, and queries may be 
generated by CDM staff, monitors, PIs, the Sponsor, and other data reviewers during the 
course of the study. Only specific site personnel will be authorized to make corrections to 
the eCRFs; CDM will train personnel prior to granting access in the eCRF system. 
Corrections will be made directly in the eCRF – by modifying existing data, adding new 
data, or deleting data, as appropriate. All data corrections will be logged in the electronic 
audit trail. 
11.2.4 PI Approval of eCRF Data 
The Investigator or Investigator’s authorized staff must ensure that all information 
derived from source documentation is consistent with the source information and 
accurately reflected in the eCRFs. By electronically signing the eCRFs, the Investigator 
confirms that the information is complete and correct. 
11.3 
Retention of Documents 
At the completion of the study, all records created by and under the supervision of the 
Investigator should be maintained in accordance with the requirements of the regulatory 
authority guideline and the GCP Guideline. These will be available for inspection at any 
time by the Sponsor or the FDA. 
Clinical study documents are archived upon completion of the study and maintained for 
at least 15 years from the study closure or longer in accordance with local regulation and 
applicable regulatory authority guidelines, and the study sponsor will be notified prior to 
destruction of study records. 
Current FDA guidelines require records to be retained for a period of 2 years following 
the date a marketing application is approved for the drug, for the indication for which it is 
being investigated. If no application is filed or if the application for the investigated 
indication is not approved, documents will be kept until 2 years after the investigation is 
discontinued and the FDA is notified. It is the sponsor’s responsibility to inform 
 as to when essential documents are no longer needed to be retained 
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12.0 
STATISTICAL METHODS 
12.1 
Statistical and Analytical Plans 
 will be responsible for the statistical services, including statistical analysis, 
statistical reports and the statistical analysis plan (SAP) to be developed prospectively 
prior to database final lock. With permission of the Sponsor, statistical services may be 
delegated under an agreement of transfer of responsibilities to a qualified vendor of 
 
The SAP will provide further details regarding the definition of analysis variables and 
analysis methodology to address all study objectives. It will also provide any changes or 
additions to the analyses that are not apparent in the protocol. 
12.2 
Analysis Sets 
12.2.1 Safety Set 
The Safety set will include all subjects who received IP (FT-4101 or Placebo) or 
deuterated water. The Safety set will be used for demographic, baseline characteristics 
and safety summaries. 
12.2.2 Pharmacokinetic (PK) Set 
The PK set will include all subjects who received FT-4101 or placebo with sufficient 
evaluable PK concentration data appropriate for the evaluation of interest (without major 
protocol deviations or violations that would have an impact on the absorption, 
distribution, metabolism, or excretion). The PK set will be used for analysis of PK 
endpoints. 
12.2.3 Preliminary Efficacy Set 
The Preliminary Efficacy set will include all subjects who received FT-4101 or placebo 
with at least one quantifiable baseline and one post baseline MRI-PDFF (without major 
protocol deviations or violations that would have an impact on the PD). The Preliminary 
Efficacy set will be used for analysis of MRI-PDFF endpoints. 
12.2.1 Pharmacodynamic (PD) Set 
The PD set will include all subjects who received FT-4101 or placebo without major 
protocol deviations or violations that would have an impact on PD.  The PD set will be 
used for analysis of PD endpoints. 
12.3 
Analysis of Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics will be summarized for all subjects overall and 
by cohort and treatment. Summary statistics (e.g., number of subjects, mean, median, 
standard deviation, and range) will be generated for continuous variables (e.g., age and 
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weight) and the number and percentage of subjects within each category will be 
presented for categorical variables. 
12.4 
Analysis of the Pharmacokinetic Endpoints 
Pharmacokinetic analysis will be performed for the PK set by treatment group if data is 
available. 
12.4.1 Analysis of Secondary Pharmacokinetic Endpoints 
12.4.1.1 Plasma Concentration of FT-4101 
PK concentrations will be summarized descriptively by dose and by timepoint. Line plots 
of individual concentration profiles with treatment group mean (± standard deviation) 
may be generated. 
12.4.1.2 Pharmacokinetic Parameters of FT-4101 
The following parameters will be derived from individual serum profiles: 
•
Maximum concentration (Cmax)
•
Time to maximum concentration (Tmax)
•
Area under the concentration-time curve for a dosing interval (AUCtau)
•
Trough plasma concentrations (Ctrough) at steady state
PK parameters will be descriptively summarized. 
12.5 
Analysis of Preliminary Efficacy and Pharmacodynamic Endpoints 
Preliminary Efficacy and pharmacodynamic analysis will be performed for the 
Preliminary Efficacy set using planned treatment assignment. 
Figures (bar charts or line plots) may be generated to visualize the data. 
12.5.1 Analysis of Primary Preliminary Efficacy Endpoints 
Placebo subjects will be pooled for pharmacodynamic analyses. 
The following is the primary preliminary efficacy endpoint: 
•
Reduction (absolute and relative) of % liver fat on magnetic resonance imaging-
estimated proton density fat fraction (MRI-PDFF) at 12 weeks
12.5.1.1 Liver Fat Assessed by MRI-PDFF at 12 weeks 
The observed values and the change (absolute) from baseline and the percent change 
from baseline of liver fat estimated from MRI-PDFF will be analyzed descriptively by 
treatment group and visit. 
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Change at Week 12 (absolute and relative) in percentage of liver fat as assessed by MRI-
PDFF will be analyzed by a Wilcoxon rank-sum test.  The test will be one-sided and use 
a significance level of 0.05.  Subjects in each dose group will be tested against the pooled 
placebo subjects from each cohort. 
If more than one dose of FT-4101 is evaluated, control of the alpha level will be 
accomplished using Holm’s Sequential Bonferroni procedure [Holm 1979] to test each 
FT-4101 dose against the pooled placebo subjects. 
12.5.2 Analysis of Secondary Preliminary Efficacy and Pharmacodynamic 
Endpoints 
The following are secondary preliminary efficacy endpoints: 
•
Reduction (absolute and relative) of % liver fat on magnetic resonance imaging-
estimated proton density fat fraction (MRI-PDFF) at 6 weeks
12.5.2.1 Liver Fat Assessed by MRI-PDFF 
Reduction of % liver fat on MRI-PDFF at 6 weeks will be analyzed similarly as the 
primary preliminary efficacy endpoint. 
In addition, a mixed effects model with repeated measures (MMRM) will be used to 
analyze the change from baseline, both absolute change and percent change (absolute and 
relative), to week 6 and week 12; the model will include baseline as a covariate and the 
factors, treatment group, visit, and the interaction of treatment group and visit. The least 
squares (LS) mean and its corresponding 95% confidence interval and p-value will be 
presented. The LS mean difference between treatment groups will be presented along 
with the 95% confidence interval and the p-value. 
12.5.2.2 Proportion of Subjects with ≥ 30% Relative Reduction in Liver Fat at Week 12 
Assessed by MRI-PDFF 
The proportion of subjects experiencing a relative reduction of 30% or greater of liver fat 
at week 12 as assessed by MRI-PDFF will be summarized descriptively and analyzed 
using a Fisher’s exact test. Subjects in each dose group will be tested against the pooled 
placebo subjects from each cohort. 
12.5.2.3 Liver Biochemistry Markers 
The following are secondary pharmacodynamic liver biochemistry marker endpoints: 
•
Alanine aminotransferase (ALT)
•
Aspartate aminotransferase (AST)
•
Gamma-glutamyl transferase (γGT)
•
Alkaline phosphatase
•
Total bilirubin
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The observed values and the change from baseline of the liver biochemistry markers 
above be analyzed descriptively by treatment group and visit. 
A MMRM will be used to analyze the change from baseline to C3/D1, C4/D15, and 
C4/D22; the model will include baseline as a covariate and the factors, treatment group, 
visit and the interaction between treatment group and visit. The least squares (LS) mean 
and its corresponding 95% confidence interval and p-value will be presented for each 
postbaseline visit. The LS mean difference between treatments will be presented along 
with the 95% confidence interval and the p-value for each postbaseline visit. 
12.5.3 Analysis of Exploratory Pharmacodynamic Endpoints 
In general, exploratory analysis will be descriptive, unless specified otherwise in the 
SAP. 
The observed value and the change from baseline of the exploratory endpoint parameters 
will be analysed descriptively by treatment group and visit. 
Fasting Hepatic DNL may be analysed using a statistical model. 
12.5.3.1 Fasting Hepatic De Novo Lipogenesis 
The following is the exploratory pharmacodynamic endpoint related to fasting hepatic de 
novo lipogenesis: 
• Inhibition of fasting hepatic de novo lipogenesis (DNL) after administration of 
multiple doses in overweight/obese subjects with NASH by using a 2-week 
deuterated water labeling protocol 
The derivation of the fasting hepatic DNL and the inhibition of hepatic DNL will be 
discussed in detail in the SAP.  
The observed values and the change from baseline of fasting hepatic DNL and hepatic 
DNL inhibition (%) will be analyzed descriptively by treatment group and visit. 
Inhibition of hepatic DNL over time will be analyzed graphically. 
A MMRM, similar to the MMRM described previously, may be used to analyze the 
change from baseline of fasting hepatic DNL and hepatic DNL inhibition. 
12.6 
Analysis and Endpoints 
12.6.1 Analysis of Primary Safety and Tolerability Endpoints 
To assess safety and tolerability of FT-4101 after administration of multiple doses in 
overweight/obese subjects with NASH by: 
• Incidence of treatment-emergent adverse events (TEAEs) 
• Incidence of clinical lab abnormalities 
• Incidence and severity of clinical findings on physical examination 
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•
Change from baseline in vital signs (blood pressure [BP], heart rate [HR],
respiratory rate, and temperature])
•
Change from baseline in 12-lead electrocardiogram (ECG) parameters
Safety and tolerability of the study drugs will be assessed by collection and review of 
adverse events, tolerability, laboratory parameters, physical examination, vital signs, and 
ECG parameters throughout the duration of the study. Safety analysis will involve 
examination of the descriptive statistics and individual subject listings for any effects of 
study treatment on clinical tolerability and safety. 
AEs will be summarized using the safety set. 
All AEs will be coded using MedDRA. Data will be summarized using preferred term 
and primary system organ class. 
Adverse event summaries will include the overall incidence (by system organ class and 
preferred term), events by maximum intensity, event by relationship to study treatment, 
events leading to discontinuation of study drug, and serious adverse events. Physical 
exam, vital signs, ECG, and laboratory parameters (hematology, chemistry, and 
urinalysis) will be summarized descriptively by treatment group. 
12.7 
Interim Analysis 
No interim analysis is planned. 
12.8 
Determination of Sample Size 
With 10 evaluable subjects in the treated group and 10 evaluable subjects in the control 
group, there is 84% power to detect a difference of 20% between the high dose treated 
group and the pooled placebo subjects in cohorts A and B in MRI-PDFF, assuming a 
standard deviation of 14% using a one-sided Wilcoxon-Mann-Whitney test with an alpha 
of 0.05. 
The total sample size will be 30 subjects, 15 subjects per cohort randomized 2:1 to 
receive FT-4101 or placebo. 
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13.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
13.1 
Monitoring 
A representative of 
 will monitor the study on a periodic basis. The 
determination of the extent and nature of monitoring will be based on considerations such 
as the objective, purpose, design, complexity, blinding, size, and endpoints of the study. 
Authorized representatives of 
 Sponsor or Regulatory authority will conduct 
on-site visits to review, audit, copy study-related documents. These representatives will 
meet with the Investigator(s) and appropriate staff at mutually convenient times to 
discuss study-related data and questions. 
Monitoring will follow a Monitoring Plan. 
13.2 
Protocol Deviations 
The Investigator should not deviate from the protocol, except where necessary to 
eliminate an immediate hazard to study subjects. Should other circumstances arise that 
will require deviation from protocol-specified procedures, unless there is an emergency 
or immediate need, the Investigator should contact the medical monitor and Sponsor to 
review and discuss the implications of the deviation and determine the appropriate course 
of action. Any deviation must be documented, stating the reason and date, the action 
taken, and the impact for the subject and/or the study. The documentation must be kept in 
the Investigator’s Study File and the Sponsor’s Study Master File. The Investigator 
should report the deviation to their IRB/EC per their reporting requirements. 
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14.0 
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted in accordance with the Protocol, the International 
Conference on Harmonization (ICH), current Guideline for Good Clinical Practice: 
Consolidated Guidance E6(R2) and applicable regulatory requirements including clinical 
research guidelines established by the Basic Principles defined in the U.S. 21 CFR Parts 
50, 56, and 312 and the principles enunciated in the Declaration of Helsinki (revised 
version Fortaleza 2013). 
14.1 
Institutional Review Board and/or Independent Ethics Committee 
Prior to commencement of the study, the protocol, any amendments, subject 
information/informed consent form, any other written information to be provided to the 
subject, subject recruitment procedures, information about payments and compensation 
available to subjects if not mentioned in the subject information, the Investigator’s 
current CV and/or other documentation evidencing qualifications, and other documents 
as required by the local Independent Ethics Committee (IEC)/Institutional Review Board 
(IRB) should be submitted. Written approval/favorable opinion must be obtained from 
IEC/IRB prior to commencement of the clinical study start. 
The Investigator shall provide to Sponsor or its designee a copy of the written and dated 
approval/favorable opinion by the applicable IRB/IEC.  
During the study, the Investigator must promptly report the following to the IEC/IRB: 
Updates to IB, unexpected SAEs where a causal relationship cannot be ruled out, 
substantial amendments to the protocol, non-substantial amendments, applicable 
deviations to the protocol, new information that may affect adversely the safety of the 
subjects or the conduct of the study (including new risk/benefit analysis in case it will 
have an impact on the planned follow-up of the subjects), annually written summaries of 
the study status and other documents as required by the local IEC/IRB. 
Substantial amendments must not be implemented before approval/favorable opinion, 
unless necessary to eliminate hazards to the subjects. 
The Investigator must maintain an accurate and complete record of all submissions made 
to the IEC/IRB. The records should be filed in the Investigator’s Study File and copies 
must be provided to the Sponsor.  
14.2 
Regulatory Authorities 
Regulatory Authorities will receive the Clinical Study Application, Protocol, 
Amendments to the Protocol, reports on SAEs and the Integrated Clinical Study Report 
according to national regulations. 
14.3 
Responsibilities of the Investigator 
The Investigator will conduct this clinical study in compliance with all applicable 
national, state, local or regional laws and regulatory requirements of the countries in 
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which the clinical study is performed. The Investigator will align his or her conduct in 
accordance with the “Responsibilities of the Investigator”. The Investigator should ensure 
that all persons involved in the conduct of the study are informed about the protocol, 
protocol amendments, study procedures, and study-related duties. 
Clinical research studies sponsored by the Sponsor are subject to ICH GCP and all the 
applicable local laws and regulations. The responsibilities imposed on Investigators by 
the FDA are summarized in the “Statement of Investigators” (Form FDA 1572), which 
must be completed and signed before the Investigator may participate in this study.  
14.4 
Informed Consent 
Once signed, the original informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) will be stored in the 
Investigator’s site file. The Investigator must document the date the subject signs the 
informed consent in the subject’s medical record. Copies of the signed informed consent 
form, the signed subject authorization form (if applicable), and subject information sheet 
(if applicable) shall be given to the subject. 
All revised informed consent forms must be reviewed and signed by relevant subjects or 
the relevant subject’s legally acceptable representative in the same manner as the original 
informed consent. The date the revised consent was obtained should be recorded in the 
subject’s medical record, and the subject should receive a copy of the revised informed 
consent form. 
14.5 
Subject Confidentiality 
The Sponsor and designees affirm and uphold the principle of the subject’s right to 
protection against invasion of privacy. Subject records will be kept private except when 
ordered by law. The following individuals will have access to study subject records: 
Principal Investigator and designees, study Sponsor, monitors and auditors, the FDA, 
other government offices and the IRB. 
Throughout this study, a subject’s source data will only be linked to the Sponsor’s 
clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, 
age, or date of birth, and subject initials may be used to verify the subject and accuracy of 
the subject’s unique identification number. 
The Investigator must agree to permit the Sponsor’s monitor or designee’s monitor, 
representatives from any regulatory authority, the Sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s source data or documents, including, 
but not limited to, laboratory test result reports, ECG reports, admission and discharge 
summaries for hospital admissions occurring during a subject’s study participation, and 
autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process. The confidentiality 
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of the verified data and the protection of the subjects must be respected during these 
inspections. 
Copies of any subject source documents that are provided to the Sponsor must have 
certain personally identifiable information removed. 
14.6 
Publication, Disclosure, and Clinical Study Registration Policy 
The Investigator will provide the Sponsor with truthful, accurate and complete test results 
and all data derived from the study. During the study, only the Sponsor may make study 
information available to other study Investigators or to regulatory agencies, except as 
required by law or regulation. Except as otherwise allowable in the clinical study site 
agreement, any public disclosure (including publicly accessible websites) related to the 
protocol or study results, other than study recruitment materials and/or advertisements, is 
the sole responsibility of the Sponsor. 
 or its designee will be responsible for preparing the Clinical Study Report. 
When all data has been fully analyzed, 
 or Sponsor will communicate the 
results of the Clinical Study to the Investigator(s).  
All information obtained as a result of this study or during the conduct of this study will 
be regarded as confidential.  The conditions regulating dissemination of the information 
derived from this clinical trial are described in the Clinical Trial Agreement. 
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15.0 
REFERENCES 
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Donnelly et al. 2005 
Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurum J, Boldt MD, Parks EJ. Sources of 
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Dorn et al. 2010 
Dorn C, Riener MO, Kirovski G, Saugspier M, Steib K, Weiss TS, et al. Expression of 
fatty acid synthase in nonalcoholic fatty liver disease. Int J Clin Exp Pathol. 2010; 3:505–
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Guha et al. 2008 
Guha IN, Parkes J, Roderick P, Chattopadhay D, Cross R, Harris S et al. Noninvasive 
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Hachad et al. 2010 
Hachad H, Ragueneau-Majlessi I, Levy RH. A useful tool for drug interaction evaluation: 
The University of Washington Metabolism and Transport Drug Interaction Database. 
Hum Genomics. 2010;5(1):61-72. 
Harley et al. 2014 
Harley ITW, Stankiewicz TE, Giles DA, Softic S, Flick LM, Cappelletti M, et al. IL-17 
signaling accelerates the progression of nonalcoholic fatty liver disease in mice. 
Hepatology. 2014 May; 59(5):1830–39. 
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lipogenesis in humans using stable isotopes. J Clin Invest. 1991;87(5):1841-1852.  
doi: 10.1172/JCI115206 
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Journal of Statistics 6:65-70 
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synthase is expressed mainly in adult hormone-sensitive cells or cells with high lipid 
metabolism and in proliferating fetal cells. J Histochem Cytochem, Off J Histochem Soc. 
2000; 48:613–22. 
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Safety, Pharmacokinetics, and Pharmacodynamic Effects on de Novo Lipogenesis of the 
Acetyl-CoA Carboxylase Inhibitor GS-0976 in Healthy Volunteers. AASLD: The Liver 
Meeting 2017, October 20-24, 2017. 
Lawitz et al. 2018 
Lawitz EJ, Coste A, Poordad F, Alkhouri N, Loo N, McColgan BJ et al. Acetyl-CoA 
Carboxylase Inhibitor GS-0976 for 12 Weeks Reduces Hepatic De Novo Lipogenesis and 
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Peverill W, Powell LW, Skoien R. Evolving concepts in the pathogenesis of NASH: 
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Rau M, Schilling AK, Meertens J, Hering I, Weiss J, Jurowich C, et al. Progression from 
Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis Is Marked by a Higher 
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16.0 
APPENDICES 
16.1 
Appendix A - Schedule of Events 
ASSESSMENT 
SCREEN  
RUN-IN PERIOD 
IN-HOUSE 
PERIOD 
OUTPATIENT VISITS 
IN-HOUSE 
PERIOD 
OUTPATIENT 
FOLLOW-UP 
StudyVisita 
Cycle (C) / Day (D) 
(Visit Window)a 
C1 
D-45 to
D-15
C1 
D-
14 
(+1) 
C1 
D-11 
(±1) 
C1 
D-7 
(±1) 
C1b 
D-1 
C1b 
D1 
C1 
D15 
(±1) 
C2c 
D1 
(±1) 
C2 
D15 
(±1) 
C3c 
D1 
(±1) 
C3 
D15 
(±1) 
C4c 
D1 
(±1) 
C4 
D4 
(±1) 
C4 
D8 
(±1) 
C4b 
D14 
C4b 
D15 
C4d 
D22 
(±1) 
C4e 
D29 
(±2) 
DOSINGf 
X 
X 
X 
X 
X 
X 
X 
Informed consent 
X 
Assess eligibility 
criteria 
X 
X 
Demography 
X 
Medical history 
X 
Xg 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BMI 
X 
X 
X 
X 
Height 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
(PE) 
X 
X 
Abbreviated PE 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
X 
X 
X 
X 
Hematology, serum 
chemistry & 
urinalysis  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
X 
X 
X 
X 
Fasting plasma 
glucose 
X 
Fasting lipid profile 
X 
X 
X 
X 
X 
X 
X 
TSH 
X 
HbA1c 
X 
X 
X 
X 
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ASSESSMENT 
SCREEN  
RUN-IN PERIOD 
IN-HOUSE 
PERIOD 
OUTPATIENT VISITS 
IN-HOUSE 
PERIOD 
OUTPATIENT 
FOLLOW-UP 
StudyVisita 
Cycle (C) / Day (D) 
(Visit Window)a 
C1 
D-45 to
D-15
C1 
D-
14 
(+1) 
C1 
D-11 
(±1) 
C1 
D-7 
(±1) 
C1b 
D-1 
C1b 
D1 
C1 
D15 
(±1) 
C2c 
D1 
(±1) 
C2 
D15 
(±1) 
C3c 
D1 
(±1) 
C3 
D15 
(±1) 
C4c 
D1 
(±1) 
C4 
D4 
(±1) 
C4 
D8 
(±1) 
C4b 
D14 
C4b 
D15 
C4d 
D22 
(±1) 
C4e 
D29 
(±2) 
Hep B, Hep C, HIV 
X 
Pregnancy test 
(serum) 
X 
Pregnancy test 
(urine) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FSH for 
postmenopausal 
X 
Urine drug screen 
X 
X 
X 
X 
Alcohol breath test 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Deuterated Water 
Labeling Period 
(3 x 50 mL/day)h 
C1/D-14 to 
C1/D-8 
C4/D1 to 
C4/D7 
Blood collection for 
fasting hepatic DNL 
assessmentsi,j
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood collection for 
PK assessmentsk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sebum collection 
using Sebutape® for 
fatty acid 
concentration 
Xn 
X 
X 
X 
X 
Sebum collection 
using Sebutape® for 
DNL 
X 
X 
X 
X 
X 
Sebumeter® for 
sebum production 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood collection for 
circulating 
biomarkersl 
X 
X 
X 
X 
FibroScan® (LSM 
and CAP) 
Xo 
X 
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ASSESSMENT 
SCREEN  
RUN-IN PERIOD 
IN-HOUSE 
PERIOD 
OUTPATIENT VISITS 
IN-HOUSE 
PERIOD 
OUTPATIENT 
FOLLOW-UP 
StudyVisita 
Cycle (C) / Day (D) 
(Visit Window)a 
C1 
D-45 to
D-15
C1 
D-
14 
(+1) 
C1 
D-11 
(±1) 
C1 
D-7 
(±1) 
C1b 
D-1 
C1b 
D1 
C1 
D15 
(±1) 
C2c 
D1 
(±1) 
C2 
D15 
(±1) 
C3c 
D1 
(±1) 
C3 
D15 
(±1) 
C4c 
D1 
(±1) 
C4 
D4 
(±1) 
C4 
D8 
(±1) 
C4b 
D14 
C4b 
D15 
C4d 
D22 
(±1) 
C4e 
D29 
(±2) 
MRI-PDFF 
X 
Xm 
Xm 
FibroSure® 
X 
X 
X 
Randomization 
X 
Record concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record adverse 
events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Deuterated water 
supply and 
accountability 
X 
X 
X 
X 
X 
X 
IP supply  
and IP accountability 
X 
X 
X 
X 
X 
X 
X 
X 
Subject Diary for 
-deuterated water
intake
- IP intake
- if T2DM glycemic
control
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Standardized 
controlled conditions 
and meals  
X 
X 
X 
X 
aCycle (C) 1 Day (D) 1 (C1/D1) is the start of the four 21-day treatment cycles.  Study visits occurring before C1/D1 are based on a countdown to this date. 
Subsequent study visits are defined by the days from the start of the most recent treatment cycle.  
bStudy windows are not provided on these study dates. C1/D1 is the start of study treatment. C1/D-1 must occur on the day prior to C1/D1.  C4/D14 and 
C4/D15 visits are required to occur starting on the last day of study treatment in cycle 4 (C4/D14), in order to obtain time and treatment day-dependent PK/PD 
samples. 
cDay 1 of treatment cycles 2-4 expected to start 22 days (±1) from start of previous treatment cycle (except when dose delays required for AE’s-see protocol). 
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dIn subjects who discontinue study participation before completion of the study treatment period in Cycle 4, the end of treatment (EOT) visit (C4/D22) should 
occur approximately ≥6 days from last dose of FT-4202/placebo. 
eIn subjects who discontinue study participation before completion of the study treatment period in Cycle 4, a follow-up visit occurring approximately 28 days 
from the start of the last treatment cycle (Day1) is requested. 
fDrug is administered QD on days 1-14 and held days 15-21 of each treatment cycle. Hold dose of IP in the morning of visits occurring during the active 
treatment period until all fasting visit procedures have been completed and as instructed per visit.
gInterim medical history 
hEach bottle of deuterated water should be consumed at least 3 hours apart 
iSubjects will be instructed to fast (no food or drink, except water) on the evening prior to the visit to ensure an approximate 10-hour fast prior to the fasted 
blood sample collection the next morning. Blood for DNL needs to be taken prior to consumption of deuterated water on C1/D-14, C1/D-11, C4/D1, and 
C4/D4. Blood samples for DNL are taken pre-dose on days IP is administered also. 
jIncludes blood for deuterium enrichment in palmitate and body water.  Samples should be collected same time of day. 
kPK sampling will follow Appendix B (PK sampling schedule) in section 16.2. 
lSampling for fasting circulating biomarker include metabolic parameter (FPG, fasting insulin, HOMA-IR, HbA1c, Adiponectin (total and high molecular 
weight), FGF-21, and Malonyl carnitine), liver injury and fibrosis biomarkers (CK-18 fragment, ELF score [HA, PIIINP, TIMP-1], PRO-C3). 
mTo be performed within a window of 4 days prior to C3/D1 and C4/D22 
nThese Sebutape samples collected at D-14 will be stored for potential future fatty acid analysis. 
oThis FibroScan can be performed at screening or within 30 days prior to screening. Both LSM and CAP values are captured and recorded. Both LSM and CAP 
are PD endpoints but only CAP (≥300dB/m) is part of the eligibility criteria.
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16.2 
Appendix B – PK Sampling Schedule 
Study Visit 
Cycle (C)/ 
Day (D) 
PK Sample 
Collection Time Points 
C1/D1 
Pre-dose 
- 15 min
C1/D1 
1 hour post-dose 
± 15 min 
C1/D1 
2 hours post-dose 
± 15 min 
C1/D1 
4 hours post-dose 
± 15 min 
C1/D1 
6 hours post-dose 
± 15 min 
C1/D15 
24 hours post-dose 
± 4 hours 
C2/D1 
Pre-dose 
± 15 min 
C2/D15 
24 hours post-dose 
± 4 hours 
C3/D15 
24 hours post-dose 
± 4 hours 
C4/D4 
Pre-dose 
± 15 min 
C4/D8 
Pre-dose 
± 15 min 
C4/D14 
Pre-dose 
± 15 min 
1 hour post-dose 
± 15 min 
2 hours post-dose 
± 15 min 
4 hours post-dose 
± 15 min 
6 hours post-dose 
± 15 min 
8 hours post-dose 
± 30 min 
12 hours post-dose 
± 60 min 
16 hours post-dose 
± 60 min 
C4/D15 
24 hours post-dose 
± 4 hours 
30 hours post-dose 
± 4 hours 
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16.3 
Appendix C - CYP3A Strong Inhibitors and Inducers 
Examples of strong clinical inhibitors for P450-mediated metabolism 
Strong inhibitors 
CYP3A 
boceprevir, cobicistat(a), conivaptan(a), danoprevir and ritonavir(b), 
elvitegravir and ritonavir(b), grapefruit juice(c,e), indinavir and 
ritonavir(b), itraconazole(a), ketoconazole, lopinavir and ritonavir(a,b), 
paritaprevir and ritonavir and (ombitasvir and/or dasabuvir)(b), 
posaconazole, ritonavir(a,b), saquinavir and ritonavir(a,b), telaprevir(c), 
tipranavir and ritonavir(c,d), troleandomycin, voriconazole 
clarithromycin(c), diltiazem(c), idelalisib, nefazodone, nelfinavir(c), 
cannabidiol (CBD) oil(f) 
Note: Strong, moderate, and weak inhibitors are drugs that increase the AUC of sensitive index substrates 
of a given metabolic pathway ≥5-fold, ≥2 to <5-fold, and ≥1.25 to <2-fold, respectively. Strong inhibitors 
of CYP3A causing ≥10-fold increase in AUC of sensitive index substrate(s) are shown above the dashed 
line. 
(a) Strong inhibitor of CYP1A2 and CYP2C19, and moderate inhibitor of CYP2D6 and CYP3A.
(b) Strong inhibitor of CYP2C19 and moderate inhibitor of CYP2C9 and CYP3A.
(c) Inhibitor of P-gp (defined as those increasing AUC of digoxin to ≥1.25-fold).
(d) Ritonavir is usually given in combination with other anti-HIV or anti-HCV drugs in clinical practice.
Caution should be used when extrapolating the observed effect of ritonavir alone to the effect of
combination regimens on CYP3A activities.
(e) The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-
dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain
preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another
preparation was used (e.g., low dose, single strength).
(f) TY Kong et al. 2018. Archives of Pharmaceutical Research; 41:691-710
Examples of strong clinical inducers for P450-mediated metabolism 
Strong inducers 
CYP3A 
carbamazepine(c), enzalutamide(d), mitotane, phenytoin(b), rifampin(a), St. 
John’s wort(e) 
Note: Strong, moderate, and weak inducers are drugs that decreases the AUC of sensitive index substrates 
of a given metabolic pathway by ≥80%, ≥50% to <80%, and ≥20% to <50%, respectively. 
(a) Strong inducer of CYP3A and moderate inducer of CYP1A2, CYP2C19.
(b) Strong inducer of CYP2C19, CYP3A, and moderate inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9.
(c) Strong inducer of CYP2B6, CYP3A, and moderate inducer of CYP2C9.
(d) Strong inducer of CYP3A and moderate inducer of CYP2C9, CYP2C19, CYP3A.
(e) The effect of St. John’s wort varies widely and is preparation-dependent.
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All tables are prepared to provide examples and are not intended to be an exhaustive list. 
DDI data were collected based on a search of the University of Washington Metabolism 
and Transport Drug Interaction Database [Hachad et al. 2010]. 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugI
nteractionsLabeling/ucm093664.htm 
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16.4 
Appendix D - Norwood’s Classification of Hair Loss 
Type I: 
There is minimal or no recession of the hairline. 
Type II: 
There are triangular, usually symmetrical, areas of recession at the frontotemporal 
hairline. 
Variant IIA: 
The hairline is anterior to the coronal plane 2 cm anterior to the external auditory 
meatus. 
Type III: 
This represents the minimal extent of hair loss, sufficient to be considered as baldness 
according to Norwood. There are deep symmetrical recessions at the temples that are 
bare or only sparsely covered by hair. In Type III vertex, the hair loss is primarily from 
the vertex with limited recession of the frontotemporal hairline that does not exceed the 
degree of recession seen in Type III. 
Variant IIIA: 
The hairline has receded back to a point between the limit of Type IIA and the level of 
the external auditory meatus. 
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Type IV: 
The frontotemporal recession is more severe than in Type III and there is sparse hair or 
no hair on the vertex. The two areas of hair loss are separated by a band of moderately 
dense hair that extends across the top. This band connects with the fully haired fringe on 
the sides of the scalp. 
Variant IVA: 
The hairline has receded beyond the external auditory meatus but has not reached the 
vertex. 
Type V: 
The vertex hair loss region is still separated from the frontotemporal region, but it is less 
distinct. The band of hair across the crown is narrower and sparser and the vertex and 
frontotemporal regions of hair loss are bigger. 
Variant VA: 
The area of denudation includes the vertex. Hair loss more severe than Type VA cannot 
be distinguished from Types VI or VII. 
Type VI: 
The bridge of hair that crosses the crown is gone with only sparse hair remaining. The 
frontotemporal and vertex regions are joined together, and the extent of hair loss is 
greater. 
Type VII: 
The most severe form of hair loss and only a narrow band of hair in a horseshoe shape 
remains on the sides and back of the scalp. This hair is usually not dense and may be 
quite fine. 
Source: [Norwood 1975] 
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16.5 
Appendix E - Savin’s Pictorial Grading of Female Pattern Hair Loss 
Source: [Savin 1992] 
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SAP_001.pdf: 
Cover Page for Statistical Analysis Plan 
Sponsor name: 
FORMA Therapeutics, Inc. 
NCT number 
NCT04004325 
Sponsor trial ID: 
4101-MET-201 
Official title of study: 
A phase 1/2, randomized, double-blind, placebo controlled 
study evaluating the safety, tolerability and efficacy of 
FT-4101 in overweight/obese subjects with NASH 
Document date: 
14 October 2019 


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Redacted statistical analysis plan 
Includes redaction of personal identifiable information only. 
. 


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FORMA 
Therapeutics, Inc. 
4101-MET-201 Statistical Analysis Plan 
Page 3 of 26 
TABLE OF CONTENTS 
1.
INTRODUCTION .......................................................................................................... 8
2.
STUDY OBJECTIVES AND ENDPOINTS ................................................................ 8 
2.1. 
Primary Objectives and Endpoint ................................................................................ 8 
2.2. 
Secondary Objectives and Endpoints ........................................................................... 8 
2.3. 
Exploratory Objectives and Endpoints ........................................................................ 9 
3.
STUDY OVERVIEW ................................................................................................... 10 
3.1. 
Study Design ................................................................................................................. 10 
3.2. 
Dose Reductions and Discontinuations ...................................................................... 11 
3.3. 
Study Procedures.......................................................................................................... 11 
3.4. 
Sample Size Consideration .......................................................................................... 11 
4.
ANALYSIS SETS ......................................................................................................... 11 
4.1. 
Randomized Analysis Set ............................................................................................ 11 
4.2. 
Safety Analysis Set ....................................................................................................... 12 
4.3. 
Pharmacokinetic Analysis Set ..................................................................................... 12 
4.4. 
Preliminary Efficacy Analysis Set .............................................................................. 12 
4.5. 
Pharmacodynamic Analysis Set .................................................................................. 12 
5.
INTERIM ANALYSIS ................................................................................................. 12 
6.
STATISTICAL METHODS OF DATA ANALYSIS ............................................... 12 
6.1. 
General Considerations ............................................................................................... 12 
6.1.1. 
Statistical Notation and Presentation ......................................................................... 12 
6.1.2. 
Hypothesis Testing and Multiplicity Adjustment ..................................................... 13 
6.1.3. 
Study Baseline ............................................................................................................... 13 
6.1.4. 
Handling of Multiple Observations ............................................................................ 13 
6.1.5. 
Handling of Missing or Partial Dates ......................................................................... 13 
6.1.5.1. Adverse Event Date Imputations ................................................................................ 13 
6.1.5.2. Medication Date Imputations ...................................................................................... 14 
6.1.6. 
Handling of Missing Efficacy Data ............................................................................. 14 
6.2. 
Subject Disposition ....................................................................................................... 14 
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6.3. 
Demographics and Baseline Characteristics ............................................................. 15 
6.4. 
Medical History ............................................................................................................ 15 
6.5. 
Subject Eligibility ......................................................................................................... 15 
6.6. 
Study Drug Administration ......................................................................................... 15 
6.7. 
Prior and Concomitant Medication ............................................................................ 15 
6.8. 
Protocol Deviations ...................................................................................................... 16 
6.9. 
Analysis of Pharmacokinetics Endpoints ................................................................... 16 
6.9.1. 
Plasma Concentration of FT-4101 .............................................................................. 16 
6.9.2. 
Pharmacokinetic Parameters of FT-4101 .................................................................. 16 
6.10. 
Analysis of Preliminary Efficacy and Pharmacodynamic Endpoints ..................... 17 
6.10.1. Analysis of Primary Preliminary Efficacy Endpoint ................................................ 17 
6.10.1.1. Reduction of Liver Fat Assessed by MRI-PDFF at 12 Weeks ................................. 17 
6.10.2. Analysis of Secondary Preliminary Efficacy and Pharmacodynamic Endpoints .. 17 
6.10.2.1. Reduction of Liver Fat Assessed by MRI-PDFF at 6 Weeks ................................... 18 
6.10.2.2. Proportion of Subjects with ≥ 30% Relative Reduction in Liver Fat at Week 12 
Assessed by MRI-PDFF .............................................................................................................. 18 
6.10.2.3. Reduction of Liver Biochemistry Markers ................................................................ 19 
6.10.3. Analysis of Exploratory Pharmacodynamic Endpoints ........................................... 19 
6.10.3.1. Change from Baseline in Fasting Hepatic De Novo Lipogenesis ............................. 20 
6.10.3.2. Skin Surface Sebum Level Using Sebumeter® .......................................................... 21 
6.10.3.3. Sebum FFA and Sebum DNL Using Sebutape® ....................................................... 21 
6.10.3.4. Circulating Biomarkers of Liver Injury and Fibrosis .............................................. 21 
6.10.3.5. Circulating Metabolic Parameters ............................................................................. 21 
6.10.3.6. Steatosis (CAP) and Liver Stiffness (LSM) Determined by FibroScan® ............... 21 
6.10.3.7. Imaging Parameters Assessed by MRI-PDFF ........................................................... 21 
6.11. 
Analysis of Safety Endpoints ....................................................................................... 21 
6.11.1. Analysis of Primary Safety and Tolerability Endpoints ........................................... 22 
6.11.1.1. Adverse Events ............................................................................................................. 22 
6.11.1.2. Clinical Laboratory Abnormalities ............................................................................ 22 
6.11.1.3. Physical Examination Findings ................................................................................... 23 
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6.11.1.4. Vital Signs ..................................................................................................................... 23 
6.11.1.5. 12-Lead Electrocardiogram Assessments .................................................................. 23 
6.12. 
Other Laboratory Assessments ................................................................................... 23 
7.
CHANGES TO THE PLANNED ANALYSIS IN THE PROTOCOL ................... 23 
8.
STATISTICAL SOFTWARE ..................................................................................... 23 
9.
APPENDIX ................................................................................................................... 24 
9.1. 
APPENDIX A – Schedule of Events (SOE) ............................................................... 24 
9.2. 
APPENDIX B – PK Sampling Schedule .................................................................... 26 
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Abbreviations 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomic Therapeutic Chemistry 
AUC0-inf 
Area under the concentration-time curve in the sampled matrix from zero 
(predose) extrapolated to infinite time 
AUC0-last 
Area under the concentration-time curve in the sampled matrix from zero 
(predose) to time of last quantifiable concentration 
AUCtau 
Area under the concentration-time curve for a dosing interval 
BLQ 
Below the Limit of Quantitation 
BP 
Blood Pressure 
CAP 
Controlled Attenuation Parameter 
CK-18 
Cytokeratin-18 
CL/F 
Apparent systemic clearance after extravascular dosing 
Cmax 
Maximum concentration 
Cmax/D 
Dose-normalized Maximum Concentration 
CO2 
Carbon Dioxide 
CTCAE 
Common Toxicity Criteria for Adverse Events 
Ctrough 
Trough plasma concentrations at steady state. 
DNL 
De Novo Lipogenesis 
ELF 
Enhanced Liver Fibrosis 
FFA 
Free Fatty Acids 
FPG 
Fasting Plasma Glucose 
FSH 
Follicle Stimulating Hormone 
γGT 
Gamma-glutamyl transferase 
HA 
Hyaluronic Acid 
hCG 
Human Chondroitin Beta 
HDL-c 
High-Density Lipoprotein Cholesterol 
Hep B 
Hepatitis B 
Hep C 
Hepatitis C 
HIV 
Human Immunodeficiency Virus 
HR 
Heart Rate 
IP 
Investigational Product 
LDL-c 
Low-Density Lipoprotein Cholesterol 
LS 
Least Squares 
LSM 
Liver Stiffness Measurement 
MedDRA 
Medical Dictionary For Regulatory Activities 
MMRM 
Mixed Effects Model with Repeated Measures 
MRI-PDFF 
Magnetic Resonance Imaging- Proton Density Fat Fraction 
NASH 
Nonalcoholic Steatohepatitis 
non-HDL-c 
Non-High-Density Lipoprotein Cholesterol 
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PD 
Pharmacodynamic 
PIIINP 
Procollagen III Amino Terminal Peptide 
PK 
Pharmacokinetic 
QTcF 
QT Corrected Using the Fridericia Correction 
REML 
Restricted Maximum Likelihood method 
SAP 
Statistical Analysis Plan 
SOE 
Schedule of Events 
t1/2 
Apparent terminal half-life 
T2DM 
Type 2 Diabetes Mellitus 
TEAE 
Treatment-Emergent Adverse Event 
TG 
Triglycerides 
TIMP-1 
Tissue Inhibitor of Metalloproteinases 1 
Tmax 
Time to maximum concentration 
Vz/F 
Apparent volume of distribution following extravascular dosing 
WHO 
World Health Organization 
 
 
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1. INTRODUCTION 
This document describes the statistical methods and procedures to be implemented in the 
analysis of treatment effect of FT-4101 in overweight/obese subjects with nonalcoholic 
steatohepatitis (NASH) compared to placebo. This statistical analysis plan (SAP) is based on the 
study protocol 4101-MET-201 (Version 2.0, 23-JUL-2019). If the data suggest and warrant it, 
deviations from this plan will be considered. Any deviations from this SAP must be substantiated 
by sound statistical rationale and documented in the final clinical study report; an amendment 
will be generated to document the revisions to the SAP. 
2. STUDY OBJECTIVES AND ENDPOINTS 
2.1. Primary Objectives and Endpoint 
The primary objectives of this study are: 
To assess safety and tolerability of FT-4101 after administration of multiple doses in 
overweight/obese subjects with NASH by: 
 Incidence of treatment-emergent adverse events (TEAEs) 
 Incidence of clinical lab abnormalities 
 Incidence and severity of clinical findings on physical examination 
 Change from baseline in vital signs (blood pressure [BP], heart rate [HR], respiratory 
rate, and temperature) 
 Change from baseline in 12-lead electrocardiogram parameters (heart rate, QT interval, 
PR interval, QRS interval, RR interval, and QTc [corrected] using the Fridericia 
correction [QTcF = QT/cubic root of the R-R interval, where R-R interval is the duration 
of the entire cardiac cycle]) 
To assess the preliminary efficacy of FT-4101 on liver fat after administration of multiple doses 
in overweight/obese subjects with NASH by: 
 Reduction (absolute and relative) of % liver fat on Magnetic Resonance Imaging- Proton 
Density Fat Fraction (MRI-PDFF) at 12 weeks 
2.2. Secondary Objectives and Endpoints 
The secondary objectives and endpoints of this study are: 
To assess the preliminary efficacy of FT-4101 on liver fat after administration of multiple doses 
in overweight/obese subjects with NASH by: 
 Reduction (absolute and relative) of % liver fat on MRI-PDFF at 6 weeks 
 Proportion of subjects experiencing a relative reduction of 30% or greater of liver fat at 
week 12 as assessed by MRI-PDFF 
To assess the pharmacodynamic (PD) effect of FT-4101 on circulating biomarkers of liver 
inflammation after administration of multiple doses in overweight/obsess subjects with NASH 
by: 
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 Reduction of liver biochemistry marker: Alanine aminotransferase (ALT), Aspartate 
aminotransferase (AST), Gamma-glutamyl transferase (γGT), Alkaline phosphatase, and 
Total bilirubin. 
To assess the PK profile of FT-4101 after administration of a single dose (C1/D1) and multiple 
doses (C4/D14-15) in overweight/obese subjects with NASH including, but not limited to: 
 Maximum concentration (Cmax) 
 Time to maximum concentration (Tmax) 
 Area under the concentration-time curve for a dosing interval (AUCtau) 
 Trough plasma concentrations (Ctrough) at steady state. 
2.3. Exploratory Objectives and Endpoints 
To assess the PD effect of FT-4101 on fasting hepatic de novo lipogenesis (DNL) after 
administration of multiple doses in overweight/obese subjects with NASH by using a 2-week 
deuterated water labeling protocol. 
 Change in fasting hepatic DNL (%) 
To assess the PD effect of FT-4101 on skin surface sebum level using Sebumeter® after 
administration of multiple doses in overweight/obese subjects with NASH by measuring: 
 Total sebum production 
To assess the PD effect of FT-4101 on sebum lipids using Sebutape® after administration of 
multiple doses in overweight/obese subjects with NASH by measuring: 
 Sebum fatty acid concentrations 
 Sebum DNL 
To assess the PD effect of FT-4101 after administration of multiple doses in overweight/obese 
subjects with NASH by assessment of circulating biomarkers of liver injury and fibrosis, such as 
but not limited to: 
 Enhanced liver fibrosis (ELF) score: 
Hyaluronic acid (HA), Procollagen III amino terminal peptide (PIIINP), Tissue inhibitor 
of metalloproteinases 1 (TIMP-1) 
 Cytokeratin-18 (CK-18) fragments, e.g., CK-18 M30 and CK-18 M65 
 FibroSure® 
 PRO-C3 
To assess the PD effect of FT-4101 after administration of multiple doses in overweight/obese 
subjects with NASH by assessment of circulating metabolic parameters, such as but not limited 
to: 
 Fasting Lipids 
o Total cholesterol 
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o Low-density Lipoprotein cholesterol (LDL-c) direct 
o High-density Lipoprotein cholesterol (HDL-c) 
o Non-HDL cholesterol (non-HDL-c) 
o Triglycerides (TG) 
o Free fatty acids (FFA) 
 Glycemic parameters 
o Fasting plasma glucose (FPG) 
o Fasting insulin 
o HOMA-IR 
o HbA1c 
 Adiponectin (total and high molecular weight) 
 FGF-21 
 Malonyl carnitine 
To assess the PD effect of FT-4101 after administration of multiple doses in overweight/obese 
subjects with NASH by assessing steatosis and liver stiffness determined by FibroScan® at 12 
weeks. 
 Controlled Attenuation Parameter (CAP) 
 Liver stiffness measurement (LSM) 
To assess the effect of FT-4101 after administration of multiple doses in overweight/obese 
subjects with NASH on imaging parameters assessed by MRI-PDFF: 
 Liver Volume (L) 
 Liver Fat Volume Index (L) 
3. STUDY OVERVIEW 
3.1. Study Design 
This is a Phase 1/2, randomized, double-blind, placebo-controlled study evaluating the safety, 
tolerability and preliminary efficacy of an intermittent treatment with 3.0 mg and 4.5 mg FT-
4101 over 12 weeks in overweight/obese subjects with NASH. 
Cohorts 
Number of Subjects Treatment Schedule 
Drug Given 
Cohort A 
N=10 
Intermittent 
FT-4101 3.0 mg 
N=5 
Intermittent 
Matching Placebo 
Cohort B 
N=10 
Intermittent 
FT-4101 4.5 mg 
N=5 
Intermittent 
Matching Placebo 
 
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The study may be conducted in up to 2 dosing cohorts, that will overlap. Cohorts will enroll 15 
subjects each, randomized to FT-4101 or placebo in a ratio of 2:1 (10 on active, 5 on placebo). 
Cohort A (3.0 mg FT-4101) will assess the administration of a dose of 3.0 mg FT-4101 given for 
2 weeks, alternating with a 1 week of no investigational product (IP), continued for 12 weeks. 
This design leads to 4 dosing cycles (2-week daily IP followed by 1 week of no IP). After Cohort 
A received 6 weeks of treatment (2 dosing cycles), a dose escalation meeting will be held and an 
advancement to Cohort B (4.5 mg FT-4101) will only be approved after the safety and 
tolerability data from Cohort A are determined to be acceptable. Cohort B will be administered 
up to 4.5 mg FT-4101 with the same dosing design as in Cohort A. All subjects will undergo a 
screening visit, a run-in period, followed by multiple outpatient visits, 2 in-house treatment 
periods, and a follow-up visit. An optional washout period prior to dosing may be performed for 
subjects with T2DM on oral antidiabetic combination therapy. Safety, tolerability, PK and PD 
assessments will be performed throughout the study. Hepatic steatosis assessments will be 
performed by MRI-PDFF. Hepatic and sebum DNL will be assessed using a 2-week deuterated 
water labelling protocol. Sebum and blood samples for additional PD and PK assessments will 
be collected throughout the study. 
3.2. Dose Reductions and Discontinuations 
Subjects are allowed one dose reduction in the study, based on TEAE severity grade (Grade 1 or 
2), system organ class (non-skin or non-eye vs skin or eye) and duration of TEAE resolution (< 7 
days or ≥ 7 days). Subjects who experience TEAE with severity Grade 3 or higher will result in 
permanent treatment discontinuation. Please see protocol section 6.6 for more details. 
3.3. Study Procedures 
For detail on all the assessments, please see the Schedule of Events (SOE) in the Appendix A. 
3.4. Sample Size Consideration 
With 10 evaluable subjects in the treated group and 10 evaluable subjects in the control group, 
there is 84% power to detect a difference of 20% in MRI-PDFF between any dose of FT-4101 
treated group and the pooled placebo subjects in cohorts A and B, assuming a standard deviation 
of 14% using a one-sided Wilcoxon-Mann-Whitney test with an alpha of 0.05. 
The total sample size will be 30 subjects, 15 subjects per cohort randomized 2:1 to receive FT-
4101 or placebo. 
4. ANALYSIS SETS 
The number of subjects and percentage of subjects in each analysis set will be summarized. A 
memo will be finalized prior to database lock to adjudicate each subject’s membership in each 
analysis set based on the following pre-specified definitions. 
4.1. Randomized Analysis Set 
The Randomized analysis set will include all randomized subjects. The Randomized analysis set 
will be used for summary of subject disposition, demographic, and baseline characteristics. 
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4.2. Safety Analysis Set 
The Safety analysis set will include all randomized subjects who received IP (FT-4101 or 
Placebo) or deuterated water. Subjects who took deuterated water and were not randomized will 
be excluded. The Safety analysis set will be used for safety summaries. 
4.3. Pharmacokinetic Analysis Set 
The PK analysis set will include all subjects who received FT-4101 with sufficient evaluable PK 
concentration data appropriate for the evaluation of interest without major protocol deviations or 
violations that would have an impact on the absorption, distribution, metabolism, or excretion. 
The PK analysis set will be used for analysis of PK endpoints. 
4.4. Preliminary Efficacy Analysis Set 
The Preliminary Efficacy analysis set will include all subjects who received FT-4101 or placebo 
with baseline and at least one quantifiable post baseline MRI-PDFF without major protocol 
deviations or violations that would have an impact on PD (Specifically MRI-PDFF). The 
Preliminary Efficacy analysis set will be used for analysis of MRI-PDFF endpoints. 
4.5. Pharmacodynamic Analysis Set 
The PD analysis set will include all subjects who received FT-4101 or placebo without major 
protocol deviations or violations that would have an impact on PD. The PD analysis set will be 
used for analysis of PD endpoints. 
5. INTERIM ANALYSIS 
No interim analysis is planned. 
6. STATISTICAL METHODS OF DATA ANALYSIS 
6.1. General Considerations 
Unless otherwise specified, all data will be provided in subject level listings in addition to 
summary tables or figures. 
6.1.1. Statistical Notation and Presentation 
Continuous data will be summarized in tables using the number of subjects (n), mean, median, 
standard deviation (SD), minimum and maximum. For PK concentration and parameter data, the 
geometric mean, and its standard error and coefficient of variation (CV%) of geometric mean 
will be provided as well. Categorical data will be summarized by count and percentage. The 
denominator will be the number of subjects or the number of records, whichever is more 
appropriate. 
Minimum and maximum values will use the precision of the original value in the database. 
Means, least squares (LS) means, and medians will be rounded to one decimal place greater than 
the precision of the original value. Estimates of SE, SD and the 90% confidence intervals will be 
rounded to two decimal places greater than the precision of the original value. Percentages will 
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be rounded to the nearest tenth digit. P-values will be presented with four decimal places, and p-
values less than 0.0001 will be presented as <.0001. 
6.1.2. Hypothesis Testing and Multiplicity Adjustment 
The primary preliminary efficacy endpoint will be tested using a one-sided test at an alpha level 
of 0.05. The null hypothesis and alternative hypothesis are presented below. 
H0: Diff ≥ 0 
Ha: Diff < 0 
Where Diff is the mean difference: FT-4101 minus Placebo. 
If more than one dose of FT-4101 is evaluated, control of the alpha level will be accomplished 
using Holm’s Sequential Bonferroni procedure to test each FT-4101 dose against the pooled 
placebo subjects. There will be two comparisons. 
The p-values of the multiple comparisons will be ordered from smallest to largest. The corrected 
p-value from each comparison, starting from the smallest original p-value, will be calculated 
based on the following formula: 
𝑝𝐵𝑜𝑛𝑓𝑒𝑟𝑟𝑜𝑛𝑖,𝑖|𝐶= (𝐶−𝑖+ 1) ∗𝑝 
where the number of comparisons is C, index i, ranges from 1 to C, and the original p-value that 
is to be corrected, p. Corrected p-values less than 0.05 will be considered statistically significant. 
6.1.3. Study Baseline 
Unless otherwise specified, baseline will be defined as the last non-missing pre-dose 
measurement. 
6.1.4. Handling of Multiple Observations 
Priority will be given to scheduled visits. Unscheduled assessments will be used if there are no 
scheduled visit assessments in the visit window per SOE; visit window in general is ±1 day, 
unless specified otherwise; follow-up visit is ±2 days. 
6.1.5. Handling of Missing or Partial Dates 
Date imputation will only be used for computational purposes; e.g., treatment-emergent status or 
identifying concomitant medications. Actual data values as they appear in the clinical database 
will be shown in the subject data listings. 
6.1.5.1. 
Adverse Event Date Imputations 
In cases of incomplete dates for adverse events (AEs), the missing component(s) will be assumed 
as the most conservative value(s) to conservatively capture AEs with missing start dates as 
treatment-emergent AEs (TEAEs) unless TEAE status was disqualified based on a pre-treatment 
stop date/time. The imputation rules are as follows: 
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 If “day” is the only missing field, impute the “day” as the first randomized dose date if 
the month and year of randomization are equal to the AE start month and year; otherwise, 
impute the “day” as the first day of the AE start month. 
 If “day” and “month” are missing, impute the “day” and “month” as the day and month 
of the first randomized dose date if “year” is the same as the year of randomization; 
otherwise, impute January 1 of the non-missing year. 
 Missing time will not be imputed. If “time” is missing and the start date is the same as the 
first dose date, then the time is assumed to be after the first dose time so that the event 
will be classified as treatment emergent. 
 If the start date is completely missing: 
o and from the end date (either complete or partial date) it cannot be deduced to be 
prior to the first dose date, then the AE will be assigned as a TEAE. 
o and from the end date (either complete or partial date) it can be deduced to be 
prior to the first dose date, then the AE will not be assigned as a TEAE. 
6.1.5.2. 
Medication Date Imputations 
Imputation of partial medication end dates is done for the purpose of classifying concomitant 
status of medications. The imputation rules are as follows: 
For medications with partial end dates: 
 If “day” is the only missing field, impute the “day” as the last day of the month. 
 If “day” and “month” are the missing fields, impute the “month” and “day” to Dec 31. 
 If end date is completely missing, then medication will be classified as a concomitant 
medication. 
6.1.6. Handling of Missing Efficacy Data  
Missing efficacy data will not be imputed. 
6.2. Subject Disposition 
Subject disposition will be presented for all subjects in the randomized analysis set. The count 
and percentage of subjects who are randomized, who are treated, who completed or discontinued 
from the study will be summarized by treatment group and overall. Furthermore, subjects who 
discontinued from the study will be summarized by reason for early discontinuation such as: 
 Adverse event (or serious adverse event) 
 Protocol Violation 
 Lost to follow-up 
 Voluntary withdrawal of consent 
 Discretion of Investigator 
 Pregnant or breast feeding 
 Study discontinuation by Sponsor 
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 Other 
6.3. Demographics and Baseline Characteristics 
Demographic and baseline characteristics such as, but not limited to, age, sex, race, ethnicity, 
height, weight, body mass index, waist circumference, MRI-PDFF, HbA1c and FPG will be 
summarized descriptively for all subjects overall and by treatment in the randomized analysis set. 
If composition of the Safety analysis set is different from that of the randomized population, 
demographics and baseline characteristics will be also summarized in the safety analysis set. 
6.4. Medical History 
Medical history will be summarized descriptively, with count and percentage, by coded term 
(using MedDRA version 22.0) and treatment group for the Safety analysis set. 
6.5. Subject Eligibility 
Subject eligibility data will only be listed. 
6.6. Study Drug Administration 
Subjects will receive their assigned dose orally with 240 mL of water. The total drug exposure 
(mg), the duration of exposure (days), drug dose modification, and the drug compliance will be 
summarized by treatment.  
The duration of exposure is defined as (date of last dose – date of first dose + 1 + 7). The drug 
compliance is defined as number of capsules taken/{(date of last dose – date of first dose + 1 + 
7)*2/3}*100. For each treatment group, drug compliance will be summarized by compliance 
category (<80%, 80-120%, and >120%).  
6.7. Prior and Concomitant Medication 
Concomitant medication is defined as any medication give in addition to the investigational 
product (including over-the counter medications, herbal medications, and vitamin supplements) 
administered between screening and follow-up.  
The latest version of the World Health Organization (WHO) Drug Global dictionary (Global B3 
Mar 2019) will be used to categorize verbatim descriptions of non-study medications into the 
Anatomic Therapeutic Chemistry (ATC) classification system. Each verbatim name will be 
classified by anatomical main group (ATC level 1), therapeutic subgroup (ATC level 2), 
pharmacological subgroup (ATC level 3), chemical subgroup (ATC level 4), and trade name. 
The number and percentage of subjects receiving any concomitant medications will be 
summarized by treatment group and ATC classification (ATC level 2 and level 4) for the Safety 
analysis set.  
 
 
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6.8. Protocol Deviations 
Protocol deviations will be summarized by the category of important or non-important by 
treatment group for the Safety analysis set. Important protocol deviations are thought to have 
possible impacts on the analysis. 
6.9. Analysis of Pharmacokinetics Endpoints 
6.9.1. Plasma Concentration of FT-4101 
PK concentrations will be summarized descriptively by treatment group, visit and nominal time 
point in the PK analysis set, including the arithmetic CV%. Concentrations that are below the 
limit of quantitation (BLQ) will be treated as zero for the computation of descriptive statistics. 
Individual subject concentration-time data will be graphically presented on linear and semi-
logarithmic scales with a separate graph for each dose level. Figures of arithmetic mean 
concentration-time data (±SD, as appropriate) will be presented for each treatment on linear and 
semi-logarithmic scales. Plots will be presented for PK samples collected during the first and last 
cycle and for all trough samples collected cumulatively across all cycles. 
A subject’s data listing of PK concentration will be provided. Subject’s PK concentrations which 
are not included in PK parameter derivation will be flagged.  Time difference between nominal 
time point and actual sampling time point will be presented. 
6.9.2. Pharmacokinetic Parameters of FT-4101 
For PK parameter calculations, BLQ concentrations will be assigned a value of zero if they 
precede quantifiable samples in the initial portion of the profile and will otherwise be treated as 
missing. Missing PK concentration data will not be imputed.  
PK parameters will be estimated separately from single dose profiles (C1D1) and multiple dose 
profiles (C4D14/15). The following are the PK parameters that will be estimated for FT-4101 in 
plasma by non-compartmental methods using actual elapsed time from dosing: 
 Maximum concentration (Cmax [ng/mL]) 
 Dose-normalized Cmax  (Cmax/D [mL-1])  
 Time to maximum concentration (Tmax [h]) 
 Area under the concentration-time curve for a dosing interval, calculated by linear up/log 
down trapezoidal summation (AUCtau [h*ng/mL]) 
 Area under the concentration-time curve in the sampled matrix from zero (predose) to 
time of last quantifiable concentration, calculated by linear up/log down trapezoidal 
summation (AUC0-last [h*ng/mL]) 
 Area under the concentration-time curve in the sampled matrix from zero (predose) 
extrapolated to infinite time, calculated by linear up/log down trapezoidal summation 
(AUC0-inf [h*ng/mL])  
 Dose-normalized AUC0-last [h/mL] 
 Dose-normalized AUCtau  [h/mL] 
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 Trough plasma concentrations (Ctrough [ng/mL]) at steady state (C1D15 and all 24h post-
dose time points thereafter) 
 Apparent terminal half-life (t1/2 [h]) 
 Apparent systemic clearance after extravascular dosing (CL/F [L/h]) 
 Apparent volume of distribution following extravascular dosing (Vz/F [L]) 
Half-life dependent parameters (AUC0-inf, CL/F, Vz/F) will only be presented if the data indicate 
that the sample collection period is adequate to determine t½. 
PK parameters will be summarized descriptively by visit and treatment group in the PK analysis 
set. 
6.10. Analysis of Preliminary Efficacy and Pharmacodynamic Endpoints 
Analysis of preliminary efficacy and PD endpoints will use the planned treatment assignment. 
Placebo subjects will be pooled for analysis. The percent change will be considered primary over 
absolute change. 
6.10.1. Analysis of Primary Preliminary Efficacy Endpoint 
The primary preliminary efficacy endpoint is: 
 Reduction (absolute and relative) of % liver fat on MRI-PDFF at 12 weeks 
6.10.1.1. 
Reduction of Liver Fat Assessed by MRI-PDFF at 12 Weeks 
The observed values and the change from baseline and the percent change from baseline of liver 
fat estimated from MRI-PDFF will be summarized descriptively by visit and treatment group. 
The change and percent change at Week 12 in liver fat (%) as assessed by MRI-PDFF will be 
analyzed by a Wilcoxon-Mann-Whitney test. The test will be one-sided and use a significance 
level of 0.05. Subjects in each dose group will be tested against the pooled placebo subjects from 
each cohort. 
Multiplicity adjustment to control the alpha level will be accomplished using Holm’s Sequential 
Bonferroni procedure as previously described. 
If change or percent change of MRI-PDFF is not obvious deviated from symmetric distribution, 
a two-sample independent t-test will be carried out to compare liver fat (%) between FT-4101 
treatment and the pooled placebo as supportive analysis, based on one-sided significance level of 
0.05. P value will be corrected using Holm’s Sequential Bonferroni procedure as previously 
described. 
6.10.2. Analysis of Secondary Preliminary Efficacy and Pharmacodynamic Endpoints 
The secondary preliminary efficacy endpoints are: 
 Reduction (absolute and relative) of % liver fat on MRI-PDFF at 6 weeks 
 Proportion of subjects experiencing a relative reduction of 30% or greater of liver fat at 
week 12 as assessed by MRI-PDFF 
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The secondary PD endpoints are: 
 Reduction of liver biochemistry markers: Alanine aminotransferase (ALT), Aspartate 
aminotransferase (AST), Gamma-glutamyl transferase (γGT), Alkaline phosphatase, and 
Total bilirubin 
6.10.2.1. 
Reduction of Liver Fat Assessed by MRI-PDFF at 6 Weeks 
The reduction of liver fat assessed by MRI-PDFF at 6 Weeks will be analyzed similar to the 
primary preliminary efficacy endpoint. 
A supportive analysis using a mixed effects model with repeated measures (MMRM) will be 
used to analyze the change from baseline, both absolute change and percent change (absolute and 
relative), to week 6 and week 12; the model will include change in liver fat (%) on MRI-PDFF 
(absolute and relative) as dependent variable, treatment group as independent variable, covariates 
including baseline liver fat (%), visit, interaction term of treatment and visit, and a random slope 
and intercept per subject. Model parameters will be estimated using the restricted maximum 
likelihood method (REML). An unstructured covariance matrix will be used to estimate the 
intercept-slope covariance. In case of convergence problem, other covariance structure will be 
used in the order of compound symmetry and variance component. The least squares (LS) means 
and their corresponding 90% confidence intervals and p-values at one sided test will be 
presented. The LS mean difference between treatment groups will be presented along with the 
90% confidence interval and p-value. 
The following SAS code will be used for the MMRM analysis: 
Proc mixed method=reml; 
    Class usubjid visit treat; 
    Model change [or percentchange] = baseline visit treat 
treat*visit /ddfm=kr solution alpha=0.05; 
    repeated visit /subject=usubjid type=un; 
Run; 
Where treat=treatment group (pooled placebo, FT4101 3.0 mg, FT 4101 4.5 mg), baseline = 
baseline liver fat (%), change = absolute change in liver fat (%) from baseline, percentchange = 
relative percent change in liver fat (%) from baseline, visit=study visit (Week 6, Week 12), 
usubjid = subject ID. 
 
6.10.2.2. 
Proportion of Subjects with ≥ 30% Relative Reduction in Liver Fat at Week 
12 Assessed by MRI-PDFF 
The proportion of subjects experiencing a relative reduction of 30% or greater of liver fat at 
week 12 as assessed by MRI-PDFF will be summarized descriptively and analyzed using a 
Fisher’s exact test. Subjects in each dose group will be compared to the pooled placebo subjects 
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from each cohort. P-values will be corrected using Holm’s Sequential Bonferroni procedure as 
previously described. 
6.10.2.3. 
Reduction of Liver Biochemistry Markers 
Liver biochemistry markers and the change from baseline will be summarized descriptively by 
visit and cohort and treatment group. A MMRM will be used to analyze the change from 
baseline to Week 6, Week 11, and Week 12; the model will include change from baseline as 
dependent variable, treatment group as independent variable, baseline and visit and interaction 
term of treatment and visit as covariates, and a random slope and intercept per subject. Model 
parameters will be estimated using REML. An unstructured covariance matrix will be used to 
estimate the intercept-slope covariance. In case of convergence problem, other covariance 
structure will be used in the order of compound symmetry and variance component. The LS 
mean and standard error and its corresponding 90% confidence intervals and p-values will be 
presented for each post-baseline visit. The LS mean difference between treatment and placebo 
will be presented along with its 90% confidence interval and the p-value for each post-baseline 
visit. Similar SAS code as described in Section 7.3.2.1 will be used. 
Each liver biochemistry marker (mean ± SD) will be also plotted over time by treatment group 
using line plot.  
6.10.3. Analysis of Exploratory Pharmacodynamic Endpoints 
In general, analysis of exploratory PD endpoints will be descriptive. 
The exploratory PD endpoints are: 
 Change from baseline in fasting hepatic DNL 
 Sebumeter®: 
o Change from baseline in total sebum production 
 Sebutape®: 
o Change from baseline in sebum free fatty acid concentrations 
o Change from baseline in sebum DNL 
 Circulating Biomarkers of Liver Injury and Fibrosis: 
o Change from baseline in ELF score: Hyaluronic acid (HA), Procollagen III amino 
terminal peptide (PIIINP), Tissue inhibitor of metalloproteinases 1 (TIMP-1) 
o Change from baseline in Cytokeratin-18 (CK-18) fragments, e.g., CK-18 M30 and 
CK-18 M65 
o Change from baseline in FibroSure® 
o Change from baseline in PRO-C3 
 Circulating Metabolic Parameters: 
o Change from baseline in fasting lipids: 
 Total cholesterol 
 Low-density Lipoprotein cholesterol (LDL-c) direct 
 High-density Lipoprotein cholesterol (HDL-c) 
 Non-HDL cholesterol (non-HDL-c) 
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 Triglycerides (TG) 
 Free fatty acids (FFA) 
o Change from baseline in glycemic parameters: 
 Fasting plasma glucose (FPG) 
 Fasting insulin 
 HOMA-IR 
 HbA1c 
o Change from baseline adiponectin (total and high molecular weight)  
o Change from baseline in FGF-21 
o Change from baseline in malonyl carnitine 
 FibroScan®: 
o Change from baseline in CAP 
o Change from baseline in LSM 
 MRI-PDFF: 
o Change from baseline in liver volume 
o Change from baseline in liver fat volume index 
6.10.3.1. 
Change from Baseline in Fasting Hepatic De Novo Lipogenesis 
Multiple blood samples will be collected at C1D-11, C1D-7, and C1D1 and post-dose at C4D4, 
C4D8, C4D15, and C4D22 to measure deuterium enrichment in plasma body water and plasma 
triglyceride-palmitate. Fractional DNL will be determined by the quantification of newly 
synthesized palmitate through the DNL pathway in blood sampled in the fasting state after two 
weeks labeling period.  
Fractional hepatic DNL (%) and its absolute and percentage changes from baseline will be 
summarized by visit and treatment group. P value from one-sided Wilcoxon-Mann-Whitney test 
at significance level of 0.05 will be provided.  In addition, the change from C4D15 to C4D22 
will be presented to evaluate rebound of DNL. 
A MMRM model will be used to analyze the absolute change in fraction of fasting hepatic DNL 
from baseline; the model will include change in fraction of fasting hepatic DNL from baseline as 
dependent variable, treatment group as independent variable, baseline fraction of fasting hepatic 
DNL and visit and interaction term of treatment and visit as covariate, and a random slope and 
intercept per subject. Model parameters will be estimated using REML. An unstructured 
covariance matrix will be used to estimate the intercept-slope covariance. In case of convergence 
problem, other covariance structure will be used in the order of compound symmetry and 
variance component. The LS mean and standard error and its corresponding 90% confidence 
intervals and p-values will be presented for each post-baseline visit. The LS mean difference 
between treatment and placebo will be presented along with its 90% confidence interval and the 
p-value for each post-baseline visit. Similar SAS code as described in Section 6.10.2.1 will be 
used. 
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Line plots of the fraction of fasting hepatic DNL (mean ± SD) will be plotted over time by 
treatment group for both pre-dose (C1D-11, C1D-7, and C1D1) and post-dose (C4D4, C4D8, 
C4D15, and C4D22); they will be overlaid to allow visual comparison.  
6.10.3.2. 
Skin Surface Sebum Level Using Sebumeter® 
Observed values and the change from baseline of total sebum production will be summarized by 
visit and treatment group. 
6.10.3.3. 
Sebum FFA and Sebum DNL Using Sebutape® 
Observed values and the change from baseline in FFA collected using Sebutape® will be 
summarized by visit and treatment. 
Observed values and the change from baseline in the Sebum DNL collected using Sebutape® 
will be summarized by visit and treatment.  
6.10.3.4. 
Circulating Biomarkers of Liver Injury and Fibrosis 
Observed values and the change from baseline of circulating biomarkers of liver injury and 
fibrosis will be summarized by visit and treatment group. 
6.10.3.5. 
Circulating Metabolic Parameters 
Observed values and the change from baseline of circulating metabolic parameters will be 
summarized by visit and treatment group. 
6.10.3.6. 
Steatosis (CAP) and Liver Stiffness (LSM) Determined by FibroScan® 
Observed values and the change from baseline of CAP and LSM will be summarized by visit and 
treatment group. 
6.10.3.7. 
Imaging Parameters Assessed by MRI-PDFF 
Observed values and the change from baseline of liver volume and liver fat volume index will be 
summarized by visit and treatment group. 
Liver fat volume index is calculated as PDFF(%) multiplied by Liver Volume (L). 
6.11. Analysis of Safety Endpoints 
The primary safety endpoints are: 
 Incidence of treatment-emergent adverse events (TEAEs) 
 Incidence of clinical lab abnormalities 
 Incidence and severity of clinical findings on physical examination 
 Change from baseline in vital signs (blood pressure [BP], heart rate [HR], respiratory 
rate, and temperature) 
 Change from baseline in 12-lead electrocardiogram parameters (HR, QT interval, PR 
interval, QRS interval, RR interval, and QTc [corrected] using the Fridericia correction 
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[QTcF = QT/cubic root of the R-R interval, where R-R is the duration of the entire 
cardiac cycle]) 
6.11.1. Analysis of Primary Safety and Tolerability Endpoints 
6.11.1.1. 
Adverse Events 
The latest version of the Medical Dictionary for Regulatory Activities (MedDRA version 22.0) 
will be used to code adverse events (and medical history). TEAEs will be summarized by 
treatment group. TEAE is defined as an adverse event with an onset that occurs after receiving 
the first dose of the study drug (AE start date ≥ first dose date) and within 30 days after receiving 
the last dose of the study drug (AE start date – last dose date ≤ 30). TEAEs will be tabulated 
including the following categories:  
o TEAEs by System Organ Class and Preferred Term.  
o Drug-related TEAEs by System Organ Class and Preferred Term. Related includes: 
Definitely Related, Possibly Related, or Probably Related; Unrelated includes: Not 
Related or Unlikely to be related. If drug relationship is missing, event will be 
considered related to the study drug.  
o TEAEs Leading to Discontinuation of Study Drug by System Organ Class and Preferred 
Term. 
o Serious TEAEs by System Organ Class and Preferred Term. 
o Drug-related Serious TEAEs by System Organ Class and Preferred Term. 
o Serious TEAEs Leading to Discontinuation of Study Drug by System Organ Class and 
Preferred Term. 
o Severity of TEAEs by System Organ Class and Preferred Term. Severity of TEAEs will 
be presented using National Cancer Intuitional Common Toxicity Criteria for Adverse 
Events (CTCAE) grade. Subjects with same AE more than once will have the maximum 
CTCAE grade counted within system organ class and preferred term.  
In each AE summary table above, subjects with same AE more than once will be counted only 
once within the same system organ class and preferred term. 
An overall summary TEAE table will be also provided to present number and percentage of 
subjects who had any TEAE, drug-related TEAE, CTCAE grade 3 or higher AE, CTCAE grade 
3 or higher drug-related TEAE, serious TEAE, drug-related serious TEAE, TEAE leading to 
drug discontinuation, TEAE leading to on-study death. On-study death is defined as death as the 
death that occurs between the first date of study drug and within 30 days after the last date of 
study drug. 
6.11.1.2. 
Clinical Laboratory Abnormalities 
All laboratory test values will be converted to international standardized units. If a lab value is 
reported using a non-numeric qualifier (e.g., less than (<) a certain value, or greater than (>) a 
certain value), the given numeric value will be used in the summary statistics, ignoring the non-
numeric qualifier. Observed values and the change from baseline of clinical laboratory 
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assessments for hematology, chemistry, and urinalysis will be summarized by visit and cohort 
and treatment group. Shift table will be used to assess maximum increase and/or decrease in 
CTCAE grade during the study period in the following laboratory measurements: 
 Hematology: Absolute lymphocyte count, absolute neutrophil count, hemoglobin, 
platelets, and white blood cell count. 
 Clinical chemistry: creatinine, calcium, CO2, magnesium, potassium, and sodium. 
 Liver Biochemistry Biomarkers: Alanine aminotransferase (ALT), Aspartate 
aminotransferase (AST), Gamma-glutamyl transferase (γGT), Alkaline phosphatase, and 
Total bilirubin. 
6.11.1.3. 
Physical Examination Findings 
Physical examination findings will only be listed. 
6.11.1.4. 
Vital Signs 
Observed values and the change from baseline in vital signs will be summarized by visit and 
cohort and treatment group. 
6.11.1.5. 
12-Lead Electrocardiogram Assessments 
Observed values and the change from baseline in 12-lead ECG parameters will be summarized 
by visit and cohort and treatment group. In addition, a categorical analysis of QTcF interval will 
be performed for each time point. The number and percentage of subjects in each QTcF interval 
(≤450 msec, >450 - ≤480 msec, >480 - ≤500 msec, and >500 msec) will be summarized. 
Categories of changes in QTcF interval from baseline (≥30 msec and ≥60 msec) will be tabulated 
as well. 
 QTcF will be summarized using a shift from baseline table to worst post-baseline change based 
on the categories described above. ECG interpretation will be summarized using a shift from 
baseline table to worst post-baseline assessment based on the categories of normal, abnormal not 
clinically significant, abnormal clinically significant, and not done/missing. 
6.12. Other Laboratory Assessments 
Other laboratory assessments such as pregnancy tests (hCG and FSH) and serology (hepatitis B, 
hepatitis C, and HIV) will be summarized descriptively by visit and treatment group. 
7. CHANGES TO THE PLANNED ANALYSIS IN THE PROTOCOL 
Two-sample independent t-test will be carried out to compare liver fat (%) between FT-4101 
treatment and the pooled placebo at 6 and 12 weeks as a supportive analysis, based on one-sided 
significance level of 0.05. 
8. STATISTICAL SOFTWARE 
All statistical analyses will be performed using SAS® version 9.4.
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9. APPENDIX 
9.1. APPENDIX A – Schedule of Events (SOE) 
ASSESSMENT 
SCREEN 
RUN-IN PERIOD 
IN-
HOUSE 
PERIOD 
OUTPATIENT VISITS 
IN-
HOUSE 
PERIOD 
OUTPATIENT 
FOLLOW-UP 
Study Visit 
Cycle(C)/Day(D) 
(Visit Window)a 
C1 
D-45 to 
D-15 
C1 
D-
14 
(+1) 
C1 
D-
11 
(±1) 
C1 
D-7 
(±1) 
C1b 
D-1 
 
C1b 
D1 
 
C1 
D15 
(±1) 
C2c 
D1 
(±1) 
C2 
D15 
(±1) 
C3c 
D1 
(±1) 
C3 
D15 
(±1) 
C4c 
D1 
(±1) 
C4 
D4 
(±1) 
C4 
D8 
(±1) 
C4b 
D14 
 
C4b 
D15 
 
C4d 
D22 
(±1) 
C4e 
D29 
(±2) 
DOSINGf 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
BMI 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination (PE) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviated PE 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
 
12-lead ECG 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
Hematology, serum chemistry & urinalysis 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
Coagulation 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Fasting plasma glucose 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting lipid profile 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
X 
 
TSH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1c 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
Hep B, Hep C, HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (serum) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (urine) 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
FSH for postmenopausal 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screen 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Alcohol breath test 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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ASSESSMENT 
SCREEN 
RUN-IN PERIOD 
IN-
HOUSE 
PERIOD 
OUTPATIENT VISITS 
IN-
HOUSE 
PERIOD 
OUTPATIENT 
FOLLOW-UP 
Study Visit 
Cycle(C)/Day(D) 
(Visit Window)a 
C1 
D-45 to 
D-15 
C1 
D-
14 
(+1) 
C1 
D-
11 
(±1) 
C1 
D-7 
(±1) 
C1b 
D-1 
 
C1b 
D1 
 
C1 
D15 
(±1) 
C2c 
D1 
(±1) 
C2 
D15 
(±1) 
C3c 
D1 
(±1) 
C3 
D15 
(±1) 
C4c 
D1 
(±1) 
C4 
D4 
(±1) 
C4 
D8 
(±1) 
C4b 
D14 
 
C4b 
D15 
 
C4d 
D22 
(±1) 
C4e 
D29 
(±2) 
Deuterated Water Labeling Period (3 x 50 
mL/day)h 
 
C1D-14 to 
C1/D-8 
 
 
 
 
 
 
 
 
C4/D1 to 
C4/D7 
 
 
 
 
 
Blood collection for fasting hepatic DNL 
assessmentsi,j 
 
X 
X 
X 
 
X 
 
 
 
X 
X 
X 
X 
X 
 
X 
X 
 
Blood collection for PK assessmentsk 
 
 
 
 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
 
Sebum collection using Sebutape® for fatty acid 
concentration 
 
Xn 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
 
Sebum collection using Sebutape® for DNL 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
 
Sebumeter® for sebum production 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
Blood collection for circulating biomarkersl 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
X 
 
FibroScan®(LSM and CAP) 
Xo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
MRI-PDFF 
X 
 
 
 
 
 
 
 
 
Xm 
 
 
 
 
 
 
Xm 
 
FibroSure® 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Randomization 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Deuterated water supply and accountability 
 
X 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
IP supply and IP accountability 
 
 
 
 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
 
 
 
Subject Diary for 
-deuterated water intake 
-IP intake 
If T2DM glycemic control 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Standardized controlled conditions and meals 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
 
 
aCycle (C) 1 Day (D) 1 (C1/D1) is the start of the four 21-day treatment cycles. Study visits occurring before C1/D1 are based on a countdown to this date. Subsequent study visits are defined by the 
days from the start of the most recent treatment cycle. 
bStudy windows are not provided on these study dates. C1/D1 is the start of study treatment. C1/D-1 must occur on the day prior to C1/D1. C4/D14 and C4/D15 visits are required to occur starting on 
the last day of study treatment in cycle 4 (C4/D14), in order to obtain time and treatment day-dependent PK/PD samples. 
cDay 1 of treatment cycles 2-4 expected to start 22 days (±1) from start of previous treatment cycle (except when dose delays required for AE’s-see protocol). 
dIn subjects who discontinue study participation before completion of the study treatment period in Cycle 4, the end of treatment (EOT) visit (C4/D22) should occur approximately ≥6 days from last 
dose of FT-4101/placebo. 
eIn subjects who discontinue study participation before completion of the study treatment period in Cycle 4, a follow-up visit occurring approximately 28 days from the start of the last treatment cycle 
(Day1) is requested. 
fDrug is administered QD on days 1-14 and held days 15-21 of each treatment cycle. Hold dose of IP in the morning of visits occurring during the active treatment period until all fasting visit procedures 
have been completed and as instructed per visit. 
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gInterim medical history 
hEach bottle of deuterated water should be consumed at least 3 hours apart 
iSubjects will be instructed to fast (no food or drink, except water) on the evening prior to the visit to ensure an approximate 10-hour fast prior to the fasted blood sample collection the next morning. 
Blood for DNL needs to be taken prior to consumption of deuterated water on C1/D-14, C1/D-11, C4/D1, and C4/D4. Blood samples for DNL are taken pre-dose on days IP is administered also. 
jIncludes blood for deuterium enrichment in palmitate and body water. Samples should be collected same time of day. 
kPK sampling will follow Appendix B (PK sampling schedule). 
lSampling for fasting circulating biomarker include metabolic parameter (Lipids, FPG, fasting insulin, HOMA-IR, HbA1c, Adiponectin (total and high molecular weight), FGF-21, and Malonyl 
carnitine), liver injury and fibrosis biomarkers (CK-18 fragment, ELF score [HA, PIIINP, TIMP-1], PRO-C3). 
mTo be performed within a window of 4 days prior to C3/D1 and C4/D22 
nThese Sebutape samples collected at D-14 will be stored for potential future fatty acid analysis. 
oThis FibroScan can be performed at screening or within 30 days prior to screening. Both LSM and CAP values are captured and recorded. Both LSM and CAP are PD endpoints but only CAP 
(≥300dB/m) is part of the eligibility criteria. 
9.2. APPENDIX B – PK Sampling Schedule 
Study Visit 
Cycle(C)/ 
Day(D) 
PK Sample Collection Time Points 
C1/D1 
Pre-dose 
- 15 min 
C1/D1 
1 hour post-dose 
± 15 min 
C1/D1 
2 hour post-dose 
± 15 min 
C1/D1 
4 hour post-dose 
± 15 min 
C1/D1 
6 hour post-dose 
± 15 min 
C1/D15 
24 hour post-dose 
± 4 hours 
C2/D1 
Pre-dose 
± 15 min 
C2/D15 
24 hour post-dose 
± 4 hours 
C3/D15 
24 hour post-dose 
± 4 hours 
C4/D4 
Pre-dose 
± 15 min 
C4/D8 
Pre-dose 
± 15 min 
C4/D14 
Pre-dose 
± 15 min 
1 hour post-dose 
± 15 min 
2 hour post-dose 
± 15 min 
4 hour post-dose 
± 15 min 
6 hour post-dose 
± 15 min 
8 hour post-dose 
± 30 min 
12 hour post-dose 
± 60 min 
16 hour post-dose 
± 60 min 
C4/D15 
24 hour post-dose 
± 4 hours 
30 hour post-dose 
± 4 hours 
 
 
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