Conditions: NASH - Nonalcoholic Steatohepatitis
Keywords: Nonalcoholic steatohepatitis (NASH) FXR agonist Nonalcoholic Fatty Liver Disease (NAFLD) THR-β agonist
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 162
Healthy volunteers: no

Brief summary:
This is a Phase 2a Multicenter, Randomized, Double-Blind, Placebo-Controlled Clinical Study to Evaluate the Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of Orally Administered TERN-501 as Monotherapy as well as in Combination with TERN-101 in Noncirrhotic Adults with Presumed Non-Alcoholic Steatohepatitis (NASH)

Detailed description:

Arms:
arm 1: Orally administered. arm 2: Orally administered. arm 3: Orally administered. arm 4: Orally administered. arm 5: Orally administered. arm 6: Orally administered. arm 7: Orally administered.

Interventions: intervention 1: TERN-501 intervention 2: TERN-101 intervention 3: Placebo
Intervention descriptions: intervention 1: Investigational drug intervention 2: Investigational drug intervention 3: Matching placebo

Protocol document:
Prot_000.pdf: 
Protocol TERNCB-2002
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Version: Amendment 2
Version Date: 18 July 2022
CONFIDENTIAL
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CLINICAL STUDY PROTOCOL
Protocol Title:
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
Phase 2a Clinical Study to Evaluate the Safety, Efficacy, 
Pharmacokinetics, and Pharmacodynamics of Orally Administered 
TERN-501 as Monotherapy as well as in Combination with TERN-
101 in Noncirrhotic Adults with Presumed Non-Alcoholic 
Steatohepatitis (NASH)
Protocol Number: 
TERNCB-2002
Protocol Version: 
Amendment 2
Version Date:
Supersedes:
18 July 2022
Amendment 1; 02 May 2022
Compounds: 
TERN-501, TERN-101
Study Phase: 
2a
Sponsor Name: 
Terns, Inc. 
Legal Registered 
Address: 
1065 E. Hillsdale Blvd. Suite 100
Foster City, California 94404
Regulatory Agency 
Identifier Number(s)
FDA IND: 
CONFIDENTIAL
This document contains confidential information, which should not be copied, referred to, 
released or published without written approval from Terns, Inc.




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Table of Contents 
1. 
Protocol Summary ..........................................................................................................7 
1.1. 
Synopsis ............................................................................................................................7 
1.2. 
Schema ............................................................................................................................11 
1.3. 
Schedule of Activities (SoA) ..........................................................................................12 
2. 
Introduction ...................................................................................................................20 
2.1. 
Overview of Non-alcoholic Steatohepatitis (NASH) and Unmet 
Need ................................................................................................................................20 
2.2. 
Background .....................................................................................................................20 
2.2.1. 
THR-  Agonism and TERN-501 for Treatment of NASH .............................................20 
2.2.2. 
Combination of TERN-501+TERN-101 for Treatment of NASH .................................26 
2.3. 
Benefit/Risk Assessment ................................................................................................34 
3. 
Objectives and Endpoints ............................................................................................38 
4. 
Study Design ..................................................................................................................40 
4.1. 
Overall Design ................................................................................................................40 
4.2. 
Scientific Rationale for Study Design ............................................................................40 
4.3. 
Justification for Dose ......................................................................................................40 
5. 
Study Population ...........................................................................................................43 
5.1. 
Inclusion Criteria ............................................................................................................43 
5.2. 
Exclusion Criteria ...........................................................................................................44 
5.3. 
Lifestyle Considerations .................................................................................................48 
5.3.1. 
Lifestyle Counseling .......................................................................................................48 
5.3.2. 
Meals and Dietary Restrictions .......................................................................................48 
5.3.3. 
Alcohol, Cannabis, and Illicit Drug Use .........................................................................49 
5.4. 
Screen Failures ................................................................................................................49 
6. 
Study Drug.....................................................................................................................50 
6.1. 
Study Drug(s) ..................................................................................................................50 
6.2. 
Study Drug Administration .............................................................................................51 
6.3. 
Preparation/Handling/Storage/Dispensing/Accountability .............................................51 
6.4. 
Measures to Minimize Bias: Randomization and Blinding ............................................52 
6.4.1. 
Unblinding ......................................................................................................................52 
6.4.2. 
Patient Enrollment and Study Drug Assignment ............................................................52 
6.5. 
Study Drug Compliance..................................................................................................53 
6.6. 
Concomitant Therapy .....................................................................................................53 
6.7. 
Dose Modifications .........................................................................................................55 
6.8. 
Dose Interruptions...........................................................................................................55 
6.8.1. 
Dose Interruptions due to COVID-19 .............................................................................55 
6.9. 
Intervention after the End of the Study ...........................................................................56 
7. 
Discontinuation of Study, Study Drug and Patient 
Discontinuation or Withdrawal ...................................................................................57 
g 


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7.1. 
Study and Study Drug Stopping Criteria ........................................................................57 
7.1.1. 
Study Stopping Criteria...................................................................................................57 
7.1.2. 
Discontinuation of Study Drug .......................................................................................57 
7.2. 
Patient Discontinuation/Withdrawal from the Study ......................................................58 
7.3. 
Lost to Follow up ............................................................................................................59 
8. 
Study Assessments and Procedures.............................................................................60 
8.1. 
Study Assessments ..........................................................................................................60 
8.1.1. 
Demographics .................................................................................................................60 
8.1.2. 
Height and Weight ..........................................................................................................60 
8.1.3. 
Medical History ..............................................................................................................60 
8.1.4. 
Physical Examinations ....................................................................................................60 
8.1.5. 
Vital Signs .......................................................................................................................61 
8.1.6. 
Electrocardiograms .........................................................................................................61 
8.1.7. 
Cardiovascular Safety Monitoring ..................................................................................61 
8.1.8. 
Thyroid Axis Safety Monitoring .....................................................................................62 
8.1.9. 
Clinical Laboratory Assessments ....................................................................................63 
8.1.10. Transient Elastography and Controlled Attenuation Parameter by 
FibroScan® ......................................................................................................................65 
8.1.11. FibroScan-AST (FAST) Score ........................................................................................66 
8.1.12. Magnetic Resonance Imaging: Proton Density Fat Fraction 
(MRI-PDFF) and Corrected T1 (cT1).............................................................................66 
8.2. 
Pharmacokinetics ............................................................................................................67 
8.3. 
Pharmacodynamics .........................................................................................................67 
8.4. 
Biomarkers ......................................................................................................................68 
8.5. 
Adverse Events and Serious Adverse Events .................................................................68 
8.5.1. 
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................69 
8.5.2. 
Method of Detecting AEs and SAEs ..............................................................................69 
8.5.3. 
Follow-up of AEs and SAEs ...........................................................................................69 
8.5.4. 
Regulatory Reporting Requirements for SAEs ...............................................................70 
8.5.5. 
Pregnancy ........................................................................................................................70 
8.5.6. 
Assessment of Pruritus ....................................................................................................70 
8.6. 
Treatment of Overdose ...................................................................................................71 
8.7. 
Medical Resource Utilization and Health Economics ....................................................71 
9. 
Statistical Considerations .............................................................................................72 
9.1. 
Statistical Hypotheses .....................................................................................................72 
9.2. 
Sample Size Determination ............................................................................................72 
9.3. 
Analysis Sets ...................................................................................................................73 
9.4. 
Statistical Analyses .........................................................................................................73 
9.4.1. 
General Considerations ...................................................................................................73 
9.4.2. 
Primary Endpoint ............................................................................................................74 
9.4.3. 
Secondary Endpoints ......................................................................................................74 
9.4.4. 
Exploratory Endpoints ....................................................................................................75 
9.4.5. 
Safety Endpoints .............................................................................................................76 


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9.5. 
Interim Analyses .............................................................................................................76 
10. 
Regulatory, Ethical, and Study Oversight Considerations .......................................77 
10.1. 
Regulatory and Ethical Considerations...........................................................................77 
10.1.1. Financial Disclosure........................................................................................................77 
10.1.2. Informed Consent Process ..............................................................................................77 
10.1.3. Data Protection................................................................................................................78 
10.1.4. Dissemination of Clinical Study Data.............................................................................78 
10.1.5. Data Quality Assurance ..................................................................................................79 
10.1.6. Protocol Deviations .........................................................................................................79 
10.1.7. Source Documents ..........................................................................................................80 
10.1.8. Study and Site Start and Closure ....................................................................................80 
Appendix 1: Clinical Laboratory Tests ..........................................................................................82 
Appendix 2: Sample Collection for Pharmacokinetics and 
Pharmacodynamics .........................................................................................................85 
Appendix 3: Liver Chemistry Increased Monitoring Criteria ........................................................87 
 ..................................................................................................88 
Appendix 5: Chronic Kidney Disease Epidemiology Collaboration (CKD-
EPI) Formula to Estimate Glomerular Filtration Rate ....................................................89 
Appendix 6: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ............................................................................90 
Appendix 7: Contraceptive Guidance and Collection of Pregnancy 
Information .....................................................................................................................95 
Appendix 8: Pruritus Numerical Rating Scale ...............................................................................98 
Appendix 9: COVID-19 Assessments ...........................................................................................99 
Appendix 10: Abbreviations ........................................................................................................100 
Appendix 11: Investigator Signature Page ..................................................................................104 
Appendix 12: Protocol Amendment History ...............................................................................105 
Appendix 13: References .............................................................................................................106 
List of Tables 
Table 1 
Activity and Selectivity of TERN-501 in Coactivator Recruitment Assay 
22 
Table 2 
Estimated Safety Margins for Human Doses of TERN-501 Based on 13-week 
TERN-501 Repeat-dose Toxicity Studies (AUC) 
23 
Table 3 
Pharmacodynamic effects of multiple dose administration of TERN-501 at 
Day 15 
25 
Table 4 
Estimated Safety Margins for Human Doses of TERN-101 Based on 13-week 
TERN-101 Repeat-dose Toxicity Studies (AUC) 
28 
Table 5 
Estimated Safety Margins for Human Doses of TERN-501 and TERN-101 in 
Combination Based on Definitive 13-week Repeat-dose Toxicity Studies (AUC)
 
33 
Table 6 
Study Drug by Dose Group 
51 
Table 7 
Protocol-Required Clinical Laboratory Assessments 
82 
  
 
 


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Table 8 
PK/PD Sampling Timepoints 
85 
Table 9 
PD Laboratory Assessments 
86 
Table 10 
Liver Chemistry Increased Monitoring Criterion and Follow-Up 
87 
Table 11 
Contraceptive Methods 
96 
List of Figures 
Figure 1 
Effects of 12 Weeks of TERN-501, TERN-101, or TERN-501+TERN-101 
Combination on NALFD Activity Score and Steatosis, in a DIO-GAN Mouse 
Model of NASH 
31 








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Intervention Groups and Duration: 
The total study duration will be approximately 22 weeks, consisting of up to a 6-week Screening 
period (42 days), a 12-week Treatment period, and a 4-week Follow-up period.  
Screening Period 
The  6-week Screening period initiates upon signing an Informed Consent, at which point 
eligibility criteria will be reviewed. Each eligible patient will be scheduled for Week 0/Day 1.  
Treatment Period 
The 12-week double-blind, randomized treatment period will initiate at Week 0/Day 1 after 
confirming eligibility. The blinded study drugs (TERN-501, TERN-101, TERN-501+TERN-101, 
or matching placebo) will be orally administered once daily.  
Patients will return to the site at Weeks 2, 4, 6, 8, and 12 for safety and laboratory assessments. 
Study drug will be dispensed at Week 0/Day 1, Week 4, and Week 8. Week 12 is the last day of 
treatment.  
Intensive PK/PD sampling will be performed in approximately 42 patients participating in the 
PK/PD sub-study on the day of first dose (Week 0/Day 1) and on the day of last dose of study 
drug (Week 12).  
Transient elastography (TE) and controlled attenuation parameter (CAP) by FibroScan® will be 
completed at Screening or Day 1, and Week 12. MRI-PDFF, and cT1 will be completed at 
Screening, Week 6, and Week 12. FibroScan® and MRI-PDFF will be performed at early 
termination (ET) only if not done within the prior 4 weeks, and the patient has had at least 4 
weeks of dosing.   
All visits through Week 12 will have a ± 3 days visit window from the specific study day.  
Follow-up Period 
All patients will return to site for follow up safety assessments at Week 16. Week 16 will have a 
7 days /+2 days visit window.  
If study drug is permanently discontinued for any reason outlined in Section 7, the patient will be 
encouraged to remain in the study to be evaluated at the remaining visits through the Follow-Up 
visit. See the Schedule of Activities for data to be collected at the time of discontinuation of 
study drug and follow-up, and for any further evaluations that need to be completed. 
 


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1.2. 
Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
     
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
















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f If a patient requires home quarantine due to SARS-CoV-2 infection or exposure, or due to COVID-19 symptoms or other associated concern with attending an in-
person study visit, in accordance with Section 6.8.1 
feasible, and/or remote visits via telephone, telemedicine, or other appropriate virtual communication may be substituted for a visit to the site.  
g In the event of symptoms suggestive of COVID-19, ad hoc testing (including molecular test such as PCR or viral antigen serology, and/or antibody testing) may be 
c
 
h If a patient is required to be quarantined due to active infection of COVID-19 or exposure to COVID-19 or is otherwise unable to visit the site due COVID-19, study 
drug may be mailed to the patient or made available via another appropriate mechanism (ie, curbside pickup, etc.). 
i If TE and CAP were collected at Screening, these assessments will not be required on Day 1. See Section 5.1, inclusion criteria #4b for additional details. 
j For patients participating in the PK/PD sub-study, drug must be self-administered in the morning approximately 24 hours before their Week 12 visit. If not, the 
Week 12 PK/PD sub-study visit should be re-scheduled for the following day.  
Abbreviations: 7 C4 = 7 -hydroxy-4-cholesten-3-one;  AE = adverse event; ALT = alanine transaminase; AST = aspartate transaminase; BMI = body mass index; CAP = 
controlled attenuation parameter; CK18 = cytokeratin-18; COVID-19 = coronavirus disease 2019; CTCAE = common terminology criteria for adverse events; sCTX = 
serum terminal telopeptide of type 1 collagen; ECG = electrocardiogram; ELF = enhanced liver fibrosis;  ET = early termination; eGFR = estimated glomerular filtration 
rate; FSH = follicle stimulating hormone; HA = hyaluronic acid; FGF19 = fibroblast growth factor-19; HbA1c = hemoglobin A1c; HBsAG = hepatitis B surface antigen; 
HCV = hepatitis C virus; HIV = human immunodeficiency virus; hsCRP = high sensitivity C-reactive protein; INR = international normalized ratio; IWRS = interactive 
web response system; MRI-cT1 =  magnetic resonance imaging corrected T1; MRI-PDFF = magnetic resonance imaging proton density fact fraction; NCI =  National 
Cancer Institute; PCR = polymerase chain reaction; PD = pharmacodynamics; PIIINP = procollagen III N-terminal propeptide; sPINP = serum procollagen type I N-
propeptide; PK = pharmacokinetics; PRO-C3 = released N-terminal pro-peptide of type III collagen; rT3 = reverse T3; SAE = serious adverse event; TBG = thyroid binding 
globulin; TE = transient elastography; TIMP-1 = tissue inhibitor of metalloproteinases-1; ULN = upper limit of normal; WOCBP = women of childbearing potential. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


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2. 
Introduction 
2.1. 
Overview of Non-alcoholic Steatohepatitis (NASH) and Unmet Need  
This study is a randomized, double-blind, placebo-controlled, parallel-group treatment, phase 2a 
study to evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics of orally 
administered TERN-501 as monotherapy and in combination with TERN-101 in noncirrhotic 
adult patients with presumed NASH. 
NAFLD is characterized by an excessive accumulation of fat deposits in liver tissue, commonly 
associated with co-morbidities such as obesity, diabetes mellitus, and dyslipidemia, in the 
absence of secondary causes of liver fat accumulation. NASH, an advanced form of NAFLD, is 
defined by the presence of hepatic inflammation and hepatocellular ballooning, with or without 
fibrosis, in the setting of underlying hepatic steatosis. Progression from NAFLD to NASH can be 
rapid and, with progression, NASH can lead to cirrhosis, decompensated liver disease, and 
increased risk for hepatic carcinoma and liver-related mortality (Ekstedt 2015). Complications 
from end-stage liver disease (e.g., jaundice, edema, ascites, portal hypertension, coagulopathy, 
hepatic encephalopathy) are challenging to manage and may require liver transplantation. NASH 
was recently identified as the second leading etiologic indication for liver transplantation in the 
United States (US), and it is projected to become the leading cause of liver transplantation in the 
coming years (Wong 2015). Patients with NAFLD have a 7-fold increased risk of mortality from 
hepatocellular carcinoma compared with a matched reference population (Ekstedt 2015). 
NAFLD is the most common cause of chronic liver disease in North America (Chalasani 2018), 
and its prevalence of NAFLD is steadily increasing with the aging population and cardiovascular 
and endocrine comorbidities associated with obesity, (e.g., atherosclerosis, insulin 
resistance/diabetes mellitus) (Dietrich 2014, Lonardo 2018, Andronescu 2018). Approximately 
30% of patients with NAFLD may progress to NASH. Currently, there are no approved therapies 
for NASH. Therapeutic options are limited to management of comorbidities such as 
hyperlipidemia, insulin resistance/diabetes, and obesity, with weight loss through diet and 
exercise as a key treatment for NASH (Chalasani 2018). However, many patients are unable to 
comply long-term with the required dietary and lifestyle changes. For advanced fibrosis, 
cirrhosis, and hepatocellular carcinoma, liver transplantation may be the only treatment option. A 
therapeutic agent that addresses NASH would offer a significant advancement for this unmet 
medical need. 
2.2. 
Background 
2.2.1. 
THR-  Agonism and TERN-501 for Treatment of NASH 
THR-
role in energy metabolism, with stimulation of THR-
s 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 


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reduction (Taub 2013; Harrison 2019). Thyroid hormone regulates metabolism by modulating 
gene expression directly and through crosstalk with other nuclear hormone receptors (Liu 2010).  
Thyroid hormone agonism was initially explored for treatment of dyslipidemia using first 
generation agents such as eprotirome and sobetirome (Zucchi 2020). Eprotirome, a modestly 
selective THR-
but led to increased liver enzymes in a phase 3 trial (Sjouke 2014). Other earlier agonists with 
modest THR-
of bone loss (Ladenson 2010) and cardiac toxicity 
(Coronary Drug Project 1972). Currently, two synthetic THR-
linical 
development for NASH, resmetirom (MGL-3196, Madrigal Pharmaceuticals) a liver-directed, 
orally active agonist of THR-
P450-activated prodrug. Resmetirom improved lipid parameters, reduced liver fat, and improved 
histologic measures of NASH on liver biopsy over 36 weeks, with an overall reassuring safety 
profile (Harrison 2019). VK2809 reduced cholesterol and both serum and hepatic triglycerides at 
doses that were sparing of cardiac toxicity and did not affect body or heart weight, glycemia, or 
the thyroid hormone axis in animal models (Erion 2007). Preliminary clinical study data 
indicates that VK2809 reduced liver fat content and improved lipid profiles over 12 weeks of 
treatment with no noted safety concerns (Loomba 2019); however, increases in mean ALT in a 
dose-dependent fashion over 14 days of dosing in healthy volunteers have been reported (Lian 
2016).  
TERN-501, a novel thyroid hormone analogue, is being developed for NASH. TERN-501 has a 
23-fold selectivity for THR-
-  in vitro and shows enhanced liver distribution. In a rat 
distribution study, TERN-501 concentrations in the liver were 2.5-fold higher than in plasma and 
kidney, and 16-fold higher than in the heart. With high selectivity for THR-
-
enhanced liver distribution, TERN-501 may offer NASH patients an important treatment option. 
In the FIH study (Study TERN501-1009), single doses up to 60 mg and once daily doses up to 
10 mg for 14 days were assessed in healthy subjects with mildly elevated LDL cholesterol. 
TERN-501 was overall safe and well-tolerated with a favorable PK profile and demonstrated 
significant increases in SHBG, a key marker of hepatic THR-
 and significant 
reductions in LDL cholesterol and other lipid parameters, supporting further investigation of 
TERN-501 in patients with NASH (See Section 2.2.1.2). Detailed background on thyroid 
hormone and the potential role of THR-
and TERN-501 in NASH are 
provided in the 
 
2.2.1.1. 
Nonclinical Studies of TERN-501 
Key findings from nonclinical studies including pharmacology, pharmacokinetics, and 
toxicology for TERN-501, are summarized below. Additional details are available in the 
 
2.2.1.1.1. Pharmacology of TERN-501 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 






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described below. Additional details of the study design and results are available in the 
.  
Study TERN501-1009 had four parts: Parts A and B were double-blinded, randomized, and 
placebo-controlled and included single- and multiple-ascending dose (SAD and MAD) cohorts, 
respectively. Single doses of 3 mg, 10 mg, 30 mg, and 60 mg TERN-501 were evaluated in 
Part A (SAD) and once daily dosing of 1 mg, 3 mg, 6 mg, and 10 mg TERN-501 for 14 days 
were evaluated in Part B (MAD), with 8 subjects in each dose cohort randomized 3:1 
(TERN-501:placebo); Part C consisted of 2 open-label, drug-drug interaction (DDI) cohorts  
one cohort evaluated the effect of 10 mg TERN-501 at steady-state on the PK of a single 10-mg 
dose of rosuvastatin, a probe OATP (organic anion transporting polypeptide)/BCRP (breast 
cancer resistance protein) substrate. The other DDI cohort in Part C evaluated the effect of 15 mg 
TERN-101 at steady-state on the PK of a single 3 mg dose of TERN-501, and the results are 
summarized in Section 2.2.2.4.1; Part D of the study was an open-label, food effect cohort which 
evaluated the effect of a high-fat meal on the PK of a single 10-mg dose of TERN-501 compared 
to fasted administration.  
Treatments in all cohorts were overall safe and well-tolerated. No deaths, serious AEs, or 
withdrawals due to AEs were reported in the study. In Part A (SAD) and Part B (MAD), no 
predefined study or study drug stopping criteria or dose escalation stopping criteria were met. 
Frequent vital signs and 12-lead ECG collection in the SAD and MAD cohorts revealed no 
remarkable findings. In Part A (SAD cohorts), all AEs were mild or moderate in severity, and no 
clinically meaningful changes or trends were seen in clinical laboratory parameters after single-
dose administration of TERN-501 up to 60 mg. In Part B (MAD cohorts), all AEs were mild in 
severity. Thyroid axis test findings appeared consistent with peripheral thyroid hormone 
modulation with lowering of free T4 without changes in free T3 or TSH, which were highly 
variable. ALT and AST values were also highly variable, but overall similar across the treatment 
groups; no subject who received TERN-501 had ALT  2x ULN and no subject with elevated 
 2x baseline) had an associated increase in bilirubin levels. GGT mean values over 
time were generally similar to placebo for 1 mg, 3 mg, and 6 mg TERN-501 groups, and changes 
were not significantly different from placebo at Day 15 for these dosing groups. GGT increases 
for 10 mg TERN-501 were significantly higher than placebo throughout the treatment period, 
although values remained below the ULN. No apparent changes or trends were seen in ALP or 
total bilirubin levels over time. 
 3 mg TERN-501 
appear to be dose-dependent and can be explained by increases seen in SHBG, reflecting THR-
agonist target engagement. Free testosterone and other sex hormones including estradiol, FSH, 
and LH remained largely unchanged. No clinically meaningful changes were observed in other 
clinical laboratory and safety assessments including cardiac biomarkers.  
TERN-501 PK had low variability and was approximately dose-proportional from 3 mg to 60 mg 
following single doses and from 1 mg to 10 mg following multiple doses. Single-dose PK was 
predictive of multiple-dose PK with modest (< 2-fold) accumulation at steady state upon once 
daily dosing, consistent with the median half-life of approximately 14 to 21 hours following 
single or multiple doses. Urinary clearance appears to be a minor pathway of elimination of 
TERN-501, with a mean of < 3% of the dose excreted as unchanged TERN-501 in the urine.  
 
 
 
 
  
 
 
 
  
  


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In Part B (MAD cohorts), SHBG increases were significant and dose-dependent (Table 3), with 
least squares mean (LSM) percent changes from baseline of 17%, 57%, 136%, and 165% on 
Day 15 in the 1 mg, 3 mg, 6 mg, and 10 mg groups, respectively (-6% in placebo). In general, 
SHBG levels continued to increase during the 2-week treatment period and were significantly 
different from placebo at most time points in the 3 mg, 6 mg, and 10 mg cohorts. Significant 
reductions in LDL cholesterol were observed at most timepoints during the treatment period in 
the 6 mg and 10 mg cohorts. Although reductions in LDL cholesterol were similar between 
TERN-501 dose groups at Day 15, the rate of LDL cholesterol decline appeared slower in the 
1 mg group during the 14-day treatment period. Dose-dependent reductions in Apo B were 
observed on Day 15 and were significant in the 3 mg, 6 mg, and 10 mg groups. Total cholesterol 
was reduced in all TERN-501 groups with statistically significant percent reductions at Day 15 in 
the 3 mg and 10 mg dose groups compared to placebo. Triglycerides were numerically lower in 
TERN-501 groups, which reached statistical significance at Day 15 in the TERN-501 10 mg 
group compared to placebo. Percent change in HDL cholesterol at Day 15 was not significantly 
different for any TERN-501 group vs placebo. Together these data indicate that administration of 
TERN-501 led to robust THR-
 and significant decreases in circulating 
lipid levels including LDL cholesterol, Apo B, total cholesterol, and triglycerides. 
Table 3 
Pharmacodynamic effects of multiple dose administration of TERN-501 at 
Day 15 
 
Placebo 
1 mg 
3 mg 
6 mg 
10 mg 
SHBG 
-5.8%  
(19.6) 
17.4% 
(20.6) 
57.4% 
(20.8)* 
135.5% 
(20.5)* 
165.0% 
(20.6)* 
LDL cholesterol 
-3.9% 
(5.0) 
-16.4% 
(5.2) 
-16.7% 
(5.1) 
-18.8% 
 (5.2) 
-20.2% 
(5.1)* 
Apo B 
-4.8% 
(3.9) 
-14.4% 
(4.1) 
-17.9% 
(4.0)* 
-22.8% 
 (4.0)* 
-27.0% 
(4.0)* 
Total cholesterol 
-5.5% 
(3.7) 
-14.3% 
(3.8) 
-16.2% 
(3.8)* 
-14.9% 
(3.8) 
-19.7% 
(3.8)* 
Triglycerides 
-13.0%  
(7.1) 
-18.3% 
(7.7) 
-21.4% 
(7.7) 
-20.2%  
(7.7) 
-35.8% 
(7.7)* 
Abbreviations: SHBG = sex hormone binding globulin; LDL = low density lipoprotein; Apo B = apolipoprotein B.  
Effect of multiple dose administration of TERN-501 on pharmacodynamic (PD) parameters at Day 15. Change in PD parameters 
expressed as least squares mean (LSM) percent change from baseline (standard error) based on Analysis of Covariance 
(ANCOVA) model.  
*Statistically significant (p-value <0.05) LSM percent change from baseline relative to placebo. 
In the TERN-501 10 mg + rosuvastatin 10 mg DDI cohort of Part C where the potential for 
TERN-501 to affect the exposure of OATP1B1/1B3 and/or BCRP substrates was evaluated, all 
AEs were mild and determined either not related or unlikely related to TERN-501; an AE of 
somnolence was considered possibly related to rosuvastatin by the Investigator. The thyroid axis 
and liver enzyme data were generally consistent with what was observed in the TERN-501 
10 mg MAD cohort. In the presence of TERN-501, rosuvastatin AUCinf and Cmax increased 27% 
and 41%, respectively, which was not considered clinically significant. As such, TERN-501 is 
not considered an inhibitor of OATP or BCRP at clinically relevant doses/exposures and OATP 
 
  
 
 


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and/or BCRP substrates, including statins, may be co-administered with TERN-501 without dose 
modification.  
The effect of TERN-101 on TERN-501 PK was also evaluated in Part C of the study and the 
results are reported in Section 2.2.2.4.1.  
In Part D (food effect cohort), no AEs were reported and no remarkable findings in safety 
assessments including vital signs, ECG parameters, and clinical laboratory tests were observed. 
TERN-501 AUCinf and Cmax were decreased approximately 38% and 53%, respectively, when 
administered with a high-fat meal versus fasted administration. The current phase 2a study will 
require dosing on an empty stomach (no food or drink besides clear liquids for approximately 2 
hours before and 1 hour after study drug administration) to minimize PK variability and overlap 
in exposures between doses. 
2.2.2. 
Combination of TERN-501+TERN-101 for Treatment of NASH 
Although the pathogenesis of NASH is not yet fully understood, the mechanisms leading to 
NASH appear to be multifactorial, involving effects of metabolic dysregulation on hepatocytes 
with contribution from nonparenchymal liver cells, driving oxidative stress, hepatic cell injury 
and inflammation, and the onset of fibrosis (Magee 2016). Many therapeutic targets are being 
pursued for NASH, reflecting the heterogeneous pathways of disease pathogenesis 
(Romero 2020). Due to the multifactorial pathophysiology of NASH, combination approaches to 
NASH treatment utilizing agents with complementary mechanisms of action against the multiple 
pathogenic processes that contribute to the disease may offer the most benefit. 
Farnesoid X receptor (FXR), which modulates metabolic pathways including bile acid synthesis, 
de novo lipogenesis, and glucose metabolism, is the most advanced target currently being 
pursued for NASH. FXR activation has been shown to improve histological features associated 
with NASH including hepatic steatosis, inflammation, hepatocyte ballooning, and fibrosis. The 
anti-fibrotic and pleotropic metabolic benefits of FXR activation may be complementary to the 
beneficial effects of THR- agonism. In addition, LDL cholesterol reductions with THR-
agonists such as TERN-501 may provide an advantage in patients when coadministered with an 
FXR agonist, which can be associated with LDL cholesterol increases. 
TERN-101, a highly selective, potent agonist of FXR, was overall safe and well-tolerated at all 
dose levels evaluated in a 12-week phase 2a, proof-of-concept study in patients with presumed 
NASH and demonstrated reductions in ALT and liver fat content assessed by MRI-PDFF 
(Study TERN101-2001; Section 2.2.2.2). In that study, TERN-101 significantly reduced cT1, 
suggesting a beneficial effect on liver fibroinflammation in NASH. Thus, combining TERN-501, 
with its anticipated antisteatotic effect in the liver and favorable effects on systemic lipids, and 
TERN-101, with its potential pleotropic beneficial effects including improvement in 
fibroinflammation, may provide greater benefit over either agent as monotherapy and warrants 
further investigation.  
Key findings from nonclinical and clinical studies of TERN-101 to-date are summarized below 
(see Section 2.2.2.1 and Section 2.2.2.2). In addition, nonclinical studies evaluating safety and 
efficacy of TERN-501+TERN-101 in NASH pharmacology models (see Section 2.2.2.3) and 
assessments for DDI of TERN-501+TERN-101 (see Section 2.2.2.4.1) are summarized below. 
 
 
 
 
 
 
 
 
 


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2.2.2.1. 
Nonclinical Studies of TERN-101 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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were Grade 1 or Grade 2, and there were no treatment related SAEs. No patient discontinued 
TERN-101 or placebo due to an AE. Pruritus, which was predominantly mild and transient, 
occurred in 15% of TERN-101 treated patients overall without an apparent dose response, and 
11.5% of patients who received the TERN-101 10 mg dose; there were no patients with pruritus 
events in the placebo group. No patient discontinued or had dose adjustments of TERN-101 due 
to pruritus. No TERN-101 treated patient had evidence of drug-induced liver injury or a 
treatment-emergent increase in ALT to > 2x upper limit of normal. TERN-101 doses lower than 
15 mg did not result in a clinically meaningful or sustained change from baseline in adverse lipid 
findings through 12 weeks of treatment. Increases in LDL and decreases in HDL that were 
significantly different from placebo from Week 4 through Week12 were observed in the 
TERN-101 15 mg group. Statin therapy was not initiated or changed for any patients during the 
treatment period. 
Efficacy results provide initial evidence of TERN-101 treatment effects in NASH. In the 
secondary endpoint of percent change from baseline in ALT at Week 12, there were numerical 
declines in the TERN-101 10 mg and 15 mg groups, of overall similar magnitude, without 
statistically significant changes relative to placebo. Significant ALT declines relative to placebo 
were seen at earlier time points (beginning at Week 2) for these dose groups. Significant 
reduction in GGT with all doses of TERN-101 were seen throughout the dosing period, with 
overall similar magnitude for the 10 mg and 15 mg groups. Statistically significant decreases in 
MRI-PDFF were observed at Week 6 in TERN-101-treated patients, indicating early effects of 
TERN-101 on liver fat content reduction, with numerical reductions at Week 12. Statistically 
significant reductions were observed in all TERN-101 dose groups relative to placebo in cT1, an 
imaging biomarker for liver fibroinflammation. The declines were observed at the first 
assessment time point (Week 6) and were sustained through Week 12. The observation of early 
and sustained cT1 decreases suggest TERN-101 may primarily act to decrease fibroinflammation 
in NASH.  
TERN-101 exposures in NASH patients were approximately dose proportional and generally as 
expected based on earlier studies in healthy participants; PD evaluations 
confirmed FXR target engagement in the liver and intestines, respectively. Statistically 
in the TERN-101 10 mg and 15 mg groups indicating sustained hepatic FXR target engagement 
at these doses, while changes in the 5 mg dose level were not significantly different from 
placebo. 
were not statistically different between the TERN-101 10 mg 
and 15 mg groups at any timepoint. In patients who participated in a PD sub-study (N = 26), 
maximum induction of FGF19 was observed at 6 hours post-dose, and levels generally returned 
to baseline levels at 24 hours post-dose, suggestive of transient FXR target engagement in the 
intestines.  
Overall, FXR agonist TERN-101 was generally safe and well-tolerated at all doses studied in 
NASH patients in Study TERN101-2001. Treatment with TERN-101 resulted in decreases in 
ALT, cT1, and MRI-PDFF. Significant declines in cT1 as early as Week 6 and through Week 12 
suggest TERN-101 may primarily act to decrease fibroinflammation in NASH. Efficacy 
appeared overall similar for the 10 mg and 15 mg groups.  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


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2.2.2.3. 
Nonclinical Studies of TERN-501+TERN-101 
2.2.2.3.1. Evaluation of TERN-501+TERN-101 Combination Efficacy in Pharmacology 
Models of NASH 
To assess the potential therapeutic benefit of combining agonists of THR-  and FXR, the 
efficacy of TERN-501 and TERN-101 as single agents and in combination was tested in 
2 different pharmacology models of NASH. In the first study, DIO mice were administered 
TERN-501 and TERN-101 for 28 days concomitantly with the hepatoxic agent CCl4 to induce 
inflammation and fibrosis. In this model, treatment with TERN-501 and TERN-101 as single 
agents significantly lowered liver steatosis and serum triglycerides. TERN-501 and the 
combination of TERN-501+TERN-101 showed significantly greater reductions in steatosis 
compared to TERN-101 treatment alone. However, since TERN-501 treatment alone reduced 
steatosis to healthy control levels, potential additive effects of TERN-101 treatment on steatosis 
were difficult to discern in the combination treatment group. The combination of 
TERN-501+TERN-101 showed greater reductions in serum total cholesterol compared with 
either single agent treatment alone. Liver fibrosis in this model was significantly improved by 
treatment with the combination of TERN-501+TERN-101, but not by treatment with either 
single agent alone. Gene expression analysis in the liver showed that genes associated with 
fibrosis and inflammation were significantly reduced by the combination of 
TERN-501+TERN-101 relative to vehicle control, and the magnitude of change was greater for 
the combination treatment group compared to treatment with single agents alone.  
In a second study, the efficacy of TERN-501 and TERN-101 as single agents and in combination 
was assessed in a strictly DIO model of NASH developed by Gubra (Hansen 2020). In this 
model, termed DIO-Gubra Amylin NASH (DIO-GAN), mice were fed a diet high in fat, 
cholesterol, and fructose for > 35 weeks to induce the histopathological features of NASH and 
fibrosis. TERN-501 was administered once-daily for 12-weeks as a single agent at doses of 
0.3 mg/kg (TERN-501-low), 2 mg/kg (TERN-501-med), 10 mg/kg (TERN-501-high) or at these 
same dose levels in combination with 10 mg/kg TERN-101 (Combo-low, Combo-med, or 
Combo-high). 12-week treatment with TERN-501 alone or in combination with TERN-101 
significantly reduced hepatomegaly relative to vehicle control, with the greatest effects on liver 
weight observed in the combination treatment groups. Although all treatment groups reduced 
plasma and liver total cholesterol, greatest reductions were observed in mice treated with the 
combination of TERN-501+TERN-101. NAS was used for histological assessment of NASH and 
determined for each animal at baseline and after 12 weeks of treatment. After a 12-week 
treatment, NAS was significantly lower in mice treated with the combination of 
TERN-501+TERN-101 compared with vehicle control (Figure 1A). Moreover, a greater 
percentage of mice treated with the combination of TERN-101+TERN-101 showed NAS 
improvement relative to baseline compared to single agent treatments. In the TERN-101 
 1 point NAS improvement, compared to 31%, 
27%, and 62% in the TERN-501-low, TERN-501-med, and TERN-501-high single agent 
treatment groups, respectively. Combination treatment was even more effective, with 69%, 81%, 
 1-point NAS improvement in the Combo-low, Combo-med, and 
Combo-high groups, respectively. In addition, the magnitude of NAS improvement from 
baseline was greater for the combination treatment groups (Figure 1B). 
 
 
 
 
 
 
 
 
 
 
 
 
 




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significance. Body weight loss has been associated with beneficial effects on NASH parameters 
in both rodent models of NASH and in human studies. However, TERN-101 and the 
combination of TERN-501+TERN-101 (Combo-low and Combo-med) showed comparable 
effects on weight loss in this study, suggesting that the greater overall efficacy of the 
combination treatment was not solely due to reductions in body weight.  
Together these data suggest that the combination of TERN-501+TERN-101 resulted in greater 
overall efficacy compared to treatment with single agents.  
2.2.2.3.2. Nonclinical Safety Studies of TERN-501+TERN-101   
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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expected. As such, TERN-101 and TERN-501 can be administered in combination without dose 
modification of either agent. 
2.3. 
Benefit/Risk Assessment 
This study will provide information on the safety and potential efficacy of TERN-501 
monotherapy and TERN-501+TERN-101 combination therapy in noncirrhotic NASH patients 
and support development of TERN-501 monotherapy and/or TERN-501+TERN-101 
combination therapy for the treatment of NASH. While the safety and efficacy of TERN-501 
monotherapy and TERN-501+TERN-101 combination therapy have not been evaluated in a 
NASH population, nonclinical and clinical experience with TERN-501 and TERN-101 as 
individual agents, as well as nonclinical data for the combination of TERN-501+TERN-101 
(summarized in Section 2.2), indicate the potential for efficacy and an acceptable safety profile 
of TERN-501 monotherapy and TERN-501+TERN-101 combination therapy.  
Potential anticipated risks for the patients participating in the study are assessed based on 
understanding of the individual agents (i.e., TERN-501, TERN-101) and their mechanisms of 
action, including known class effects and theoretical risks of THR-
as available nonclinical and clinical study data. Anticipated risks for each agent and for the 
combination are discussed separately below. In addition, patients participating in this study may 
also have study procedure-related risks, including pain and bruising from blood draws. 
Risks Relevant to TERN-501 or THR-
onism 
Based on nonclinical and clinical experience to date, there are no identified adverse drug 
reactions associated with TERN-501. Data from the TERN-501 FIH study (TERN501-1009) 
indicate single doses up to 60 mg and once daily doses up to 10 mg for 14 days in healthy 
subjects were overall safe and well-tolerated.  
For any THR-
which could include effects on the cardiovascular and skeletal systems such as increased heart 
rate, cardiac hypertrophy, muscle wasting, and reduced bone density, in addition to the other 
clinical signs or symptoms that are possible with hyper/hypothyroidism. THR-
predominant THR expressed in the heart and bone, and responsible for most of the unwanted 
cardiovascular and skeletal effects associated with thyroid hormone stimulation (Johansson 
1998; Gloss 2001; Sinha 2019; Gorka 2013). As described previously, THR-
liver has been implicated in lowering free T4 (prohormone) without changes in T3 (active 
hormone) or TSH, which may be attributed to peripheral thyroid hormone modulation (Taub 
2013; Berry 1990).  
Toxicology studies for TERN-501 suggest the possibility of peripheral and central thyroid 
hormone modulation with TERN-501 based on dose-dependent reduction of TSH in rodents, 
which was considered a non-adverse finding. In FIH Study TERN501-1009, however, thyroid 
axis test findings appeared consistent with peripheral thyroid hormone modulation, showing 
dose-dependent lowering of free T4 without changes in free T3 or TSH. No clinical signs or 
symptoms of hyper/hypothyroidism were reported as AEs at any dose level evaluated in the 
study. Extensive cardiovascular monitoring including frequent vital signs, 12-lead 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 


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electrocardiograms (ECGs), and cardiac biomarkers showed no clinically significant changes in 
those parameters. Overall, there was no evidence for central thyroid axis suppression or cardiac 
toxicity with TERN-501 administered at single doses up to 60 mg and repeat doses of up to 
10 mg once daily for up to 14 days in the FIH study. Nonclinical studies for TERN-501 support 
lack of anticipated adverse cardiovascular effects at clinically relevant doses. Refer to the TERN-
501 
 for additional details.   
Increased liver enzymes have been observed with THR-  agonism (Lian 2016; Sjouke 2014). In 
Study TERN501-1009, there was no evidence of drug-induced liver injury and no subject who 
received TERN-501 in the SAD or MAD cohorts had ALT  2x ULN. GGT increases for 10 mg 
TERN-501 were significantly higher than placebo throughout the 14-day treatment period, 
although values remained below the ULN. GGT changes were not significantly different from 
placebo at Day 15 for 1 mg, 3 mg, or 6 mg TERN-501 dosing groups. Alkaline phosphatase and 
total bilirubin values were largely unchanged across all TERN-501 groups over 14 days of 
dosing in the study.  
While bone loss may occur in the setting of thyroid hormone excess, this is mediated largely 
through THR-
Sinha 2019; Gorka 2013). There was no evidence in Study TERN501-1009 to 
indicate a possible adverse effect on bone with TERN-501 over 14 days of dosing, and no 
nonclinical data for TERN-501 available to date suggest such an effect. Notably, there were no 
significant effects on bone mineral density observed in the phase 2 study of resmetirom over 36-
weeks of dosing (Harrison 2019).  
Reflecting hepatic THR-  target engagement with TERN-501, significant and dose-dependent 
increases in SHBG were observed in the MAD cohorts of Study TERN501-1009. Increases in 
total testosterone, which were seen at TERN-501 
, are likely explained by the 
increases in SHBG. Free testosterone (active hormone) and other sex hormones including 
estradiol, FSH, and LH remained largely unchanged. Of note, SHBG increases on their own are 
not considered a safety risk and may in fact reflect potential for NASH benefit; the subgroup of 
patients with larger SHBG increases with resmetirom had greater benefit in terms of liver fat 
content reduction and NASH histologic improvement (Harrison 2019).  
Potential adverse effects may be anticipated based on results reported with other THR-
For example, the most commonly reported AEs with resmetirom, currently being evaluated in 
phase 3, include diarrhea and nausea (Harrison 2019).  
Currently, there are no warnings, precautions, or contraindications with the use of TERN-501. 
Embryofetal development studies have not yet been conducted, and TERN-501 has not been 
administered to pregnant or breastfeeding women. The risks of TERN-501 to the fetus or neonate 
are unknown, and TERN-501 should not be administered to pregnant or lactating women or 
women of childbearing potential who are not using protocol defined methods of contraception. 
Risks Relevant to TERN-101 or FXR Agonism 
Based on available nonclinical and clinical data to-date, there are no identified adverse drug 
reactions associated with TERN-101. TERN-101 has been evaluated in four phase 1 studies in 
healthy volunteers, and a phase 2a study in NASH patients with 12 weeks of dosing and has been 
overall safe and well-tolerated.  
 
 
 
 
 
   
 
 


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Liver enzyme elevations, lipid abnormalities (elevation in LDL and reduction in HDL), and 
pruritus have been reported with FXR agonists (e.g., OCA, cilofexor, tropifexor) (Harrison 2021; 
Patel 2020; Badman 2019; Younossi 2019; Neuschwander-Tetri 2015; Mudaliar 2013). For 
TERN-101, in the first study of multiple doses of capsule formulation, 2 subjects receiving 
400-mg capsules experienced transient, asymptomatic transaminase elevation without 
hyperbilirubinemia or increases in ALP; a similar finding was seen in one placebo subject. No 
similar transaminase changes were observed with repeat doses up to 150 mg of TERN-101 
capsules or with single TERN-101 tablet doses up to 25 mg in healthy volunteers.  
In a phase 2a, 12-week study of TERN-101 5 mg, 10 mg, 15 mg (tablet formulation), or placebo 
in NASH patients (Study TERN101-2001), no TERN-101 treated patient had evidence of drug-
induced livery injury or a treatment-emergent increase in ALT to >2× the ULN. LDL cholesterol 
increases and HDL cholesterol decreases were statistically different from placebo for the TERN-
101 15 mg group, but not for the 5 mg and 10 mg groups at Week 12, and changes were overall 
moderate in nature. Pruritus, which was predominantly mild and transient, occurred in 15% of 
TERN-101 treated patients overall and no placebo patients, with no TERN-101 dose-dependent 
effect. No patient discontinued or had dose adjustments of TERN-101 due to pruritus.  
Currently, there are no warnings, precautions, or contraindications with the use of TERN-101. 
Embryofetal development studies have not been conducted, and TERN-101 has not been 
administered to pregnant or breastfeeding women. The risks of TERN-101 to the fetus or neonate 
are unknown, and TERN-101 should not be administered to pregnant or lactating patients or 
patients of childbearing potential who are not following protocol-specified contraception 
requirements. 
Risks Relevant to TERN-501+TERN-101 Combination 
An overview of clinical risks potentially anticipated for TERN-501 and TERN-101 individually 
is presented above. Data from the TERN-501+TERN-101 DDI cohort of the FIH Study 
TERN501-1009 indicate that exposures of TERN-501 and TERN-101 when administered in 
combination are expected to be comparable to exposures of the individual agent when 
administered alone. Nonclinical safety studies overall support that dosing of TERN-501 and 
TERN-101 in combination is unlikely to produce unique risks beyond those of the individual 
agents.  
The combination of TERN-501+TERN-101 is not anticipated to change any potential for central 
thyroid axis modulation relative to TERN-501 alone or increase the theoretical risks for effects 
on cardiovascular or skeletal systems due to systemic thyroid hormone stimulation. The 
combination of TERN-501+TERN-101 is also not anticipated to change any potential for 
TERN-101 effects on sex hormone levels. 
There is the possibility that combining TERN-501 and TERN-101 could potentially offset 
adverse effects from each individual agent. For example, the anticipated LDL cholesterol 
lowering effect from THR-  agonism may mitigate risk of LDL cholesterol increase associated 
with FXR agonism. However, TERN-501 is not expected to change the risk of HDL cholesterol 
reduction by TERN-101.  
Although elevation of liver enzymes has been reported with FXR and THR-
 (Mudaliar 
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TERN-501 or TERN-101 and there is no expectation for liver enzymes to worsen with the 
combination of TERN-501+TERN-101 compared to either agent administered alone based on 
available data.   
Finally, the administration of TERN-501+TERN-101 is not anticipated to change the potential 
for pruritus associated with TERN-101.  
Taking the anticipated or potential risks described above into consideration, the protocol has 
been designed to minimize the risk to patients. Safety monitoring outlined for the proposed study 
TERNCB-2002 is intended to detect potential safety signals. Patients will be monitored for AEs 
during the study and followed appropriately for AE resolution. Detailed guidance on potential 
signs and symptoms of thyroid dysfunction are provided in Section 8.1.8. Clinical signs or 
symptoms of hyper/hypothyroidism should be documented as AEs with appropriate follow-up 
until resolution. Vital signs and 12-lead ECGs will be collected for cardiovascular monitoring to 
ensure patient safety, along with clinical assessment for any AEs that are cardiovascular in 
nature (Section 8.1.7). Laboratory tests including thyroid axis tests, liver function tests, lipid 
panel, hematology, and clinical chemistry will be monitored, with assessment of sex hormones 
and bone turnover markers for characterization of any changes in these parameters, as well.  
There are currently no approved therapies for NASH. Overall, based on clinical experience of 
TERN-501 in healthy volunteers and TERN-101 in healthy volunteers and in NASH patients, the 
benefit/risk assessment is considered to be acceptable for patients participating in this study. 
More detailed information about the nonclinical and clinical data on TERN-501 and TERN-101 
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fibrosis-4; GGT = gamma-glutamyl transferase; HA = hyaluronic acid; MRI = magnetic resonance imaging; MRI-
PDFF = magnetic resonance imaging proton density fact fraction; PIIINP = procollagen III N-terminal propeptide; 
PD = pharmacodynamics; PK = pharmacokinetics; PRO-C3 = released N-terminal pro-peptide of type III collagen; 
rT3 = reverse T3; SHBG = sex hormone binding globulin; TIMP-1 = tissue inhibitor of metalloproteinases-1; TE = 
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4. 
Study Design 
4.1. 
Overall Design 
This study is a multicenter, randomized, double-blind, placebo-controlled, parallel-group 
treatment, phase 2a study. 
Approximately 140 noncirrhotic NASH patients with fibrosis identified based on prior liver 
biopsy and/or imaging and clinical criteria who meet study eligibility criteria will be enrolled and 
randomized equally into 7 groups: once daily orally administered TERN-501 1 mg (n=20), 
TERN-501 3 mg (n=20), TERN-501 6 mg (n=20), TERN-501 3 mg+TERN-101 10 mg (n=20), 
TERN-501 6 mg+TERN-101 10 mg (n=20), TERN-101 10 mg (n=20), or matching placebo 
(n=20).  
Of the 140 patients randomized, approximately 42 patients (approximately 6 per group) will take 
part in an intensive PK and pharmacodynamic (PD) collection after the first dose and after the 
last dose of study drug. Patients who are not participating in the PK/PD sub-study will have 
sparse PK and trough PD sampling only.  
The total study duration will be approximately 22 weeks, consisting of a 6-week Screening 
Period, a 12-week Treatment Period, and a 4-week Follow-up Period.  
4.2. 
Scientific Rationale for Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.3. 
Justification for Dose 
TERN-501 Dose Rationale as Monotherapy:  
Dose levels of 1 mg, 3 mg, and 6 mg TERN-501 administered once daily as monotherapy were 
chosen based on collective assessments of safety, PK, and PD data from the TERN-501 FIH 
study (Study TERN501-1009). TERN-501 will be dosed on an empty stomach to minimize 
variability and overlap in exposures between dose groups. Single doses of TERN-501 up to 
60 mg and once daily administration of 1 mg, 3 mg, 6 mg, and 10 mg doses for 14 days were 
overall safe and well-tolerated in healthy volunteers (Section 2.2.1.2). In the multiple dose 


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cohorts, all AEs were mild (Grade 1), and most were considered unrelated to study drug. Dose-
dependent declines in free T4 were observed without clear changes in TSH or T3, consistent with 
peripheral thyroid hormone modulation; there were no clinical signs or symptoms of 
hyper/hypothyroidism reported. GGT changes for 1 mg, 3 mg, and 6 mg TERN-501 were similar 
to placebo on Day 15. Total testosterone increases seen at dose
 3 mg TERN-501 appeared to 
be dose-dependent and can be explained by the increases in SHBG observed in the study.  
Dose-dependent increases from baseline in SHBG, a highly sensitive PD marker of hepatic 
THR-  agonism, were seen throughout the TERN-501 treatment period, with mean increases at 
Day 15 ranging from 17% to 165% in the 1 mg through 10 mg dose cohorts, which were 
significant in the 3 mg, 6 mg, and 10 mg groups. The mean SHBG increases at 3 mg (57%) and 6 
mg (136%) were comparable to or greater than the mean SHBG increases seen after 14-day 
treatment with 80 mg and 100 mg of resmetirom (Taub 2013), the most advanced THR-  agonist 
in development for NASH, with both doses currently being evaluated in a registrational phase 3 
trial (Harrison 2019). 
level from baseline at Week 12) was correlated with the greatest reductions in the MRI-PDFF at 
Week 12 and histological improvement of NASH at Week 36 (Harrison 2019). The less than 
dose-proportional increase in SHBG between 6 mg and 10 mg and partially overlapping PK, 
indicate a potential plateau in effect of TERN-501 at doses higher than 6 mg. LDL cholesterol, 
another important PD marker of THR-  agonism, was significantly reduced at most timepoints 
during the treatment period in the 6 mg TERN-501 group, with similar magnitude of decline for 
the 1 mg, 3 mg, and 6 mg groups at Day 15 (-16.4%, -16.7%, and -18.8% for 1, 3, and 6 mg, 
respectively). The significant increases in SHBG together with LDL cholesterol decreases seen 
in the 3 mg and 6 mg TERN-501 groups indicate robust THR-  target engagement and the 
potential for efficacy, including reductions in liver fat content, in NASH patients. Additionally, 
the TERN-501 PK exposures observed in the 3 mg and 6 mg groups were at or above the TERN-
501 efficacious exposures seen in a NASH mouse model (Kirschberg 2020). While the SHBG 
increase on Day 15 in the 1 mg group was not statistically significant compared to placebo, the 
LDL cholesterol decrease in the 1 mg group was comparable to decreases observed in the 3 mg 
and 6 mg groups, indicating THR-  target engagement and the potential for efficacy, and 
warranting further investigation of 1 mg as the lower end of the TERN-501 monotherapy dose 
range in NASH patients.   
With the linear, dose-proportional PK demonstrated in the FIH study, dose levels of 1 mg, 3 mg, 
and 6 mg are expected to provide 2- to 3-fold differences in exposures with minimal overlap. 
Based on the available safety data from the FIH study and a  6-fold margin relative to the 
NOAEL in dogs, the more sensitive toxicology species, all doses selected are expected to have 
an acceptable safety margin in NASH patients in this 12-week study (see Section 2.2.2.1.2.1). As 
such, the safety, PK, and PD data support the selection of 1 mg, 3 mg, and 6 mg doses of TERN-
501 for the monotherapy arms of this study. 
TERN-101 Dose Rationale: 
A dose level of 10 mg TERN-101 once daily was selected to be administered in combination 
with TERN-501, and as a monotherapy control, based on efficacy, safety, PK, and PD data. 
TERN-101 has been evaluated at doses of 5 mg, 10 mg, and 15 mg once daily in NASH patients 
for 12 weeks in a phase 2a study (Study TERN101-2001). Overall, TERN-101 was generally 
 
 
 
 
 
   
 
 
 
 
 


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safe and well-tolerated at all dose levels studied. Pruritus was observed in 11.5% of patients who 
received 10 mg TERN-101 in the study; all pruritus AEs were mild or moderate and did not 
result in study or treatment discontinuation. LDL cholesterol changes with 10 mg TERN-101 
were not statistically different from placebo during the 12 weeks of treatment. Transient 
reductions in HDL cholesterol were seen in the 10 mg group at Week 4 through Week 8, but 
percent change from baseline for 10 mg TERN-101 was not statistically different from placebo at 
Week 12. TERN-101 10 mg reduced ALT, GGT, MRI-PDFF, and cT1. The effects of 
TERN-101 on 7 C4, a marker of FXR target engagement, appeared to plateau at the 10 mg dose, 
suggesting maximal or near maximal target engagement was achieved at 10 mg. Additionally, 
safety, pharmacology, and toxicology studies support the continued study of TERN-101 at 10 mg 
(see Section 2.2.2.1.2.1). Thus, balancing the potential for efficacy with the overall safety 
profile, 10 mg TERN-101 was selected as the optimal dose to combine with TERN-501 and as a 
monotherapy comparator arm. 
TERN-501 Dose Rationale in Combination with TERN-101 10 mg: 
This study will assess 2 dose levels of TERN-501, 3 mg and 6 mg, in combination with a single 
dose level of TERN-101 (10 mg), administered once daily. Doses of 3 mg and 6 mg TERN-501 
were selected to be evaluated in combination with 10 mg TERN-101 based on a collective 
consideration of preclinical and clinical safety, PK, and PD data, with the aim to assess dose 
levels expected to be efficacious as monotherapy. Evaluating the two highest doses of 
TERN-501 selected for monotherapy dose-ranging to be administered in combination with 
TERN-101 allows for safety characterization of the combination at the upper end of TERN-501 
dose levels and exploration of additive efficacy when the two drugs are combined in comparison 
to monotherapy doses expected to be efficacious.  
Based on the mechanisms of action and available data, TERN-501 and TERN-101 in 
combination is not expected to worsen the safety profile seen with either agent in monotherapy, 
with the potential for beneficial effect on certain aspects of safety when administered in 
combination. TERN-501 is not expected to cause pruritus or increase the incidence or severity of 
pruritus that may occur with TERN-101 treatment. Additionally, TERN-501 may have a 
beneficial effect on the safety profile of TERN-101 with respect to LDL cholesterol, as 
TERN-501 is expected to decrease LDL cholesterol, as seen in Study TERN501-1009. Based on 
this and the lack of PK interaction between the compounds, evaluation of the monotherapy dose 
levels of each agent in combination is considered appropriate to maximize potential therapeutic 
benefit while minimizing risks.  
No clinically meaningful difference in PK was observed in Study TERN501-1009 when 
TERN-501 and TERN-101 were coadministered in healthy subjects that would warrant dose 
modification. The lowest safety margin for each agent when dosed in combination in nonclinical 
studies is approximately 16-fold for TERN-501 and approximately 2-fold for TERN-101 relative 
to anticipated exposures from human doses of 6 mg TERN-501 and 10 mg TERN-101, 
respectively (see Section 2.2.2.3.2). The lack of a clinically significant PK interaction between 
TERN-501 and TERN-101 and the preclinical and clinical safety, PK, and PD data available to 
date provide appropriate evidence for selecting 3 mg and 6 mg doses of TERN-501 to be 
administered in combination with 10 mg TERN-101 in this study. 
 


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5. 
Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Patients are eligible to be included in the study only if all of the following criteria are met: 
1. Must be 18 to 75 years of age inclusive, at the time of signing the informed consent 
2. Male or female, willing to follow contraception requirements defined by study protocol 
(Appendix 7); female patients of childbearing potential must also have negative serum 
pregnancy test at screening, not be breastfeeding, and not plan to become pregnant during 
the study or within 30 days after dosing of study drug 
3. 
2 
4. NASH diagnosed by prior biopsy and/or imaging criteria as follows:  
a. For diagnosis based on prior biopsy:  
i. Step 1: Noncirrhotic NASH with fibrosis (F1, F2, or F3 based on NASH 
Clinical Research Network scoring system) diagnosed by historical biopsy 
within 1 year prior to randomization, with no subsequent treatment for 
NASH and stable weight (< 5% weight loss) since the time of the biopsy. 
Results from a previous study biopsy are permissible if drug was deemed 
non-therapeutic or patient received placebo. 
ii. Step 2: Patients meeting these and all other eligibility criteria will undergo 
 800 msec 
for randomization. 
b. For diagnosis based on imaging:  
i. Step 1: Liver stiffness measured by TE of 7.6 - 21 kPa and 
CAP > 300 dB/m by FibroScan® within 3 months prior to Screening. (If 
results are available within this timeframe, assessment does not need to be 
performed at Screening but will be collected on Day 1. If TE and CAP 
were performed at Screening, these do not need to be repeated on Day 1.) 
ii. Step 2: Patients meeting these and all other eligibility criteria will undergo 
MRI and must have liver fat content by PDFF 
 800 msec 
for randomization.  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5. All patients must have MRI-
 800 msec 
6. Capable of giving signed informed consent as described in Section 10.1.2, which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol, including ability to consistently take study drug once daily on 
an empty stomach 
5.2. 
Exclusion Criteria  
Patients are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. History or clinical evidence of chronic liver diseases other than NAFLD including but not 
limited to: 
a. Active hepatitis B defined as positive Hep B surface antigen at screening  
b. Active hepatitis C defined as positive Hep C virus (HCV) antibody (anti-HCV) 
and HCV ribonucleic acid (RNA). Patients with anti-HCV but negative HCV 
RNA will be eligible for participation if HCV RNA has been negative for at least 
1 year.  
c. Autoimmune liver disease 
d. Primary biliary cirrhosis 
e. Primary sclerosing cholangitis 
f. 
 
g. 
hemolysis  
h. Hemochromatosis or other iron overload  
i. Alpha-1-antitrypsin deficiency 
j. Alcoholic liver disease 
k. Prior known drug-induced hepatotoxicity 
l. Known bile duct obstruction 
m. Suspected or proven liver cancer  
2. History or known clinical evidence of cirrhosis, esophageal varices, hepatic 
decompensation or other severe liver impairment, including ascites, hepatic 
encephalopathy, and variceal bleeding 
3. History of liver transplant, or current placement on a liver transplant list 
4. Current or prior thyroid cancer, thyrotoxicosis, or pituitary disorders, or with known 
multiple endocrine neoplasia (MEN) type 2 syndrome 
5. Abnormal thyroid examination including but not limited to enlarged thyroid gland 
(i.e., goiter) or thyroid nodules  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 


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6. Current diagnosis or history of thyroid disease, except for patients with primary 
hypothyroidism who have been on stable dose of thyroid hormone replacement therapy 
with levothyroxine for at least 6 months prior to Screening through randomization; 
patients must have normal TSH and free T4, per exclusion criteria #7 and be clinically 
euthyroid at Screening. 
7. Clinical evidence of thyroid disease indicated by TSH or free T4 levels outside the 
normal range at Screening.  
Note: In patients in whom there is no known history of thyroid disease and who are not 
on thyroid hormone replacement medication, if TSH is up to 1.5 x ULN at Screening 
with normal free T4, 1 repeat test is allowed to confirm the elevation in TSH. If TSH 
and free T4 are normal upon repeat testing and there is no clinical suspicion of thyroid 
disease or history of elevated TSH, the patient may be included. All thyroid axis testing 
should be performed in the morning, approximately at the same time. 
8. Total bilirubin > 1.2 mg/dL  
9. Albumin < 3.5 g/dL  
10. INR > 1.2 in patients who are not on anticoagulant therapy 
11. ALT or AST > 5 × ULN 
12. Unstable elevated ALT or AST: Patients with ALT or AST > 60 IU/L must have 
evidence of a stable value over at least a 2-week time period prior to randomization as 
evidenced by one of the following:   
a. 
Comparison to a historical value, if available, obtained within 2 to 12 weeks prior 
 
OR 
b. 
Repeat value at least 2 weeks after the Screening value: Repeat value should be 
 30% higher than the value from the Screening visit, and the repeat value must be 
 60 IU/L at Screening) 
Note: If the Investigator has clinical suspicion for acute liver injury in a patient for 
other reasons, the patient should be excluded after discussion with the Medical 
Monitor. 
Note: The MRI-PDFF and cT1 may proceed on the basis of the initial ALT value at 
Screening, given all other eligibility criteria are met, but randomization should not 
occur prior to confirmation of ALT and/or AST stability as specified above.  
13. ALP > 1.5 x ULN 
14. Platelet count < 150,000 /mm3 
15. eGFR < 60 mL/min/1.73m2 (Refer to Appendix 5 for the eGFR formula) 
16. Weight loss of > 5% total body weight within 3 months prior to Screening 
17. History of a malignancy within 2 years of screening, with the following exceptions:  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
    
 
 
   
 
 
 
 
 
 
 
 


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a. 
Adequately treated carcinoma in situ of the cervix 
b. Adequately treated basal or squamous cell cancer or other localized non-melanoma 
skin cancer  
18. Prior or planned (during the study period) bariatric surgery (e.g., gastroplasty, roux-en-Y 
gastric bypass) 
19. Type 1 diabetes  
20. Uncontrolled diabetes with HbA1c > 9.5%. Note: Patients with or without Type 2 
diabetes may be enrolled provided all eligibility criteria are met 
21. Unstable cardiovascular (CV) disease defined as myocardial infarction, unstable angina, 
percutaneous intervention, coronary artery bypass graft, or stroke within 6 months prior 
to randomization 
22. Uncontrolled hyperlipidemia defined as 
treatment or triglycerides > 500 mg/dL  
23. LDL cholesterol < 40 mg/dL in patients who are not taking LDL cholesterol lowering 
therapy 
24. Clinically significant abnormalities in 12-lead ECG at Screening, or known history of 
such abnormalities including but not limited to: 
a. 
II/III-degree atrioventricular block or bundle branch block (right and left) 
b. 
Arrhythmia (except occasional supraventricular premature beat) 
c. 
QT-
method (QTc) > 450 msec 
for males or > 470 msec for females 
d. 
Personal or family history of prolonged QT syndrome 
Note: An ECG can be repeated in instances of lead placement error, incomplete or 
uninterpretable tracings, or suspicion of machine error at Screening 
25. Known hypersensitivities to the study drugs (TERN-501 or TERN-101) or to any 
formulation excipients 
26. Clinically significant multiple or severe drug allergies, intolerance to topical 
corticosteroids, or severe post-treatment hypersensitivity reactions  
27. Known allergy, intolerance, or contraindication to beta blockers 
28. Alcohol consumption of > 2 standard drinks per day for males and > one standard drink 
per day for females over a period of more than 3 consecutive months in the year prior to 
Screening. Remote history of alcoholism with abstinence > 12 months prior to Screening 
and no history of alcoholic liver disease is permissible 
Note: A standard drink is defined as 12 oz (360 ml) beer (5% alcohol), 1.5 oz (45 ml) 
80 proof liquor (40% alcohol), or 5 oz (150 ml) wine (12% alcohol) 
29. Illicit substance/chemical abuse in the 12 months prior to Screening 
 
 
 
 
 
 
 
 
 
 
 
 
  


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30. Cannabis use (tetrahydrocannabinol [THC] and cannabidiol [CBD]) within 14 days of 
randomization 
31. Unwilling to abstain from excessive alcohol use (defined in exclusion criterion #28 
above), cannabis use, and illicit substance use during study participation 
32. Contraindications or inability to complete MRI scanning (ie, weight restrictions, presence 
of permanent pacemaker, implanted cardiac devices, etc.) 
33. Positive for human immunodeficiency virus (HIV) infection 
34. Laboratory or clinical evidence of current infection with Severe Acute Respiratory 
Syndrome Coronavirus 2 (SARS-CoV-2), i.e., COVID-19 
35. Presence of any condition that could, in the opinion of the Investigator, compromise the 
 
Prior Therapy  
36. Historical or current use of drugs or therapies that may interfere with thyroid function 
(except for thyroid hormone replacement therapy with levothyroxine per exclusion 
criteria #6 and #37), including but not limited to methimazole, propylthiouracil, tyrosine 
kinase inhibitors, lithium, iodide, and propranolol; these therapies are also prohibited 
through end of study follow-up per Section 6.6 
37. Initiation, discontinuation, or dose adjustment of thyroid hormone replacement therapy 
within 6 months prior to Screening through Randomization (Note: patients must be 
clinically euthyroid per exclusion criteria #6, with normal TSH and T4 per exclusion 
criteria #7) 
38. Use of medications specifically for weight loss within 12 months prior to Randomization; 
these therapies are also prohibited through end of study follow-up per Section 6.6 
39. Use within 3 months prior to Screening through Randomization: resmetirom or other 
investigational THR-
OCA or other investigational FXR agonists, pioglitazone 
high-dose vitamin E (> 400 IU/day); these therapies are also 
prohibited through end of study follow-up per Section 6.6  
40. Initiation, discontinuation, or dose adjustment within 3 months prior to Screening 
(i.e., must be on stable dose for 3 months prior to Screening) through Randomization; or 
dose adjustment expected during study participation: 
a. 
GLP-1 analogues, DPP-4 inhibitors, and SGLT2 inhibitors 
b. 
Insulin with > 30% dose adjustment (Note:  30% dose adjustment is allowed) 
c. 
Statins, PCSK9 inhibitors or other lipid modifying medications 
d. 
V
 
e. 
Hormonal contraceptives 
41. Use within 3 months prior to Randomization: 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 


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a. 
Medications potentially impacting steatohepatitis, including but not limited to 
systemic corticosteroids (prednisone equivalent of > 10 mg/day for > 2 weeks), 
amiodarone, tamoxifen and methotrexate; these therapies are also prohibited from 
randomization through end of study follow-up per Section 6.6. Note: use of 
systemic corticosteroids for  2 weeks within 3 months prior to Randomization 
and through the end of the study is allowed 
42. Initiation, discontinuation, or dose titration within 2 months prior to Randomization (i.e. 
must be on stable dose for 2 months prior to Randomization); or dose adjustment 
expected during study participation:  
a. 
Metformin and other antidiabetic drugs not described above 
43. Use within 2 weeks prior to Randomization: 
a. 
Vaccination for influenza, COVID-19, or other routine vaccinations 
b. 
Strong cytochrome P450 3A (CYP3A), P-glycoprotein (P-gp), or breast cancer 
resistant protein (BCRP) inducers or inhibitors, or anticipated to require treatment 
with strong CYP3A, P-gp, or BCRP inducers or inhibitors during study 
participation (See Section 6.6 for details.) 
Prior Clinical Study Experience 
44. Participation in another clinical study within 3 months or 5 half-lives of the other 
investigational agent (whichever is longer) prior to randomization. Patients who can 
demonstrate they did not receive active drug or who received an investigational treatment 
that was deemed non-therapeutic during clinical study participation are eligible for 
enrollment 
5.3. 
Lifestyle Considerations 
Contraceptives or other means of birth control are required during study participation (see 
Appendix 7).  
5.3.1. 
Lifestyle Counseling 
Guidance should be provided on key elements of a healthy lifestyle at each visit including diet, 
exercise, weight loss, and avoidance of alcohol per standard of care management for this patient 
population.  
5.3.2. 
Meals and Dietary Restrictions 
Patients should arrive at the clinic fasting for assessments and dosing as defined in the Schedule 
of Activities (Section 1.1). This includes at least an 8-hour fast prior to the visit, during which 
food and drink is restricted. Water is allowed ad libitum.  
Patients participating in the PK/PD sub-study at (Week 0/Day 1) and Week 12 should arrive at 
the clinic fasting (an 8-hour fast prior to the visit) and restrict food and drink until 2 hours post-
 


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dose. Food and drink may resume after this timepoint. Patients participating in the PK/PD sub-
study do not need to be fasting for blood collection at Week 12: 48- or 72-hours post-dose. 
Patients should refrain from consumption of grapefruit or grapefruit juice 2 weeks before 
Randomization and through the end of treatment (Section 6.6).  
5.3.3. 
Alcohol, Cannabis, and Illicit Drug Use 
Patients must agree to not consume > 14 standard drinks per week for males and > 7 standard 
drinks per week for females. A standard drink is defined as 12 oz (360 ml) beer, 1.5 oz (45 ml) 
liquor, or 5 oz (150 ml) wine.  
Patients must abstain from THC (cannabis) and illicit drug use during study participation.  
Patients must abstain from CBD use during study participation. Short term topical CBD use 
(< 14 days) is acceptable.   
5.4. 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical study but are not 
subsequently randomized. A minimal set of screen failure information is required and will be 
documented to ensure transparent reporting of screen failure patients to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any serious adverse event (SAE). 
Any patient who screen fails due to SARS-CoV-2 testing or clinical status may re-screen at the 
discretion of the Investigator once SARS-CoV-2 infection has resolved. Any other requests for 
re-screening must be discussed with the Sponsor.  


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6. 
Study Drug 
Study drug is defined as any investigational intervention(s), marketed product(s), or placebo 
intended to be administered to a study patient according to the study protocol. 
6.1. 
Study Drug(s)  
Intervention 
Name 
TERN-501 
capsules 
TERN-501 
Placebo to match 
(identical in 
shape, size, 
appearance, and 
color to TERN-
501 capsules) 
TERN-101 
tablets 
TERN-101 
Placebo to match 
(identical in 
shape, size, 
appearance, and 
color to TERN-
101 tablets) 
Type  
Drug 
Drug 
Drug 
Drug 
Dose 
Formulation 
Capsule 
Capsule 
Tablet 
Tablet 
Unit Dose 
Strength(s) 
1 mg or 3 mg per 
capsule 
N/A 
5 mg per tablet 
N/A 
Route of 
Administration
Oral 
Oral 
Oral 
Oral 
Use 
Experimental 
Placebo  
Experimental 
Placebo  
IMP and 
NIMP 
IMP  
IMP  
IMP  
IMP  
Sourcing 
Provided 
centrally by the 
Sponsor 
Provided 
centrally by the 
Sponsor 
Provided 
centrally by the 
Sponsor 
Provided 
centrally by the 
Sponsor 
Packaging and 
Labeling 
Study drug will 
be provided in a 
labelled carton 
containing 
one/two bottles 
of capsules for 4-
week use. Each 
bottle and carton 
will be labeled as 
required per 
country 
requirements.  
Study drug will 
be provided in a 
labelled carton 
containing 
one/two bottles 
of capsules for 4-
week use. Each 
bottle and carton 
will be labeled as 
required per 
country 
requirements. 
Study drug will 
be provided in a 
labelled carton 
containing 
one/two bottles 
of tablets for 4-
week use. Each 
bottle and carton 
will be labeled as 
required per 
country 
requirements.  
Study drug will 
be provided in a 
labelled carton 
containing 
one/two bottles 
of tablets for 4-
week use. Each 
bottle and carton 
will be labeled as 
required per 
country 
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6.2. 
Study Drug Administration  
Patients will be instructed to take one capsule/tablet from each bottle by mouth daily, at 
approximately the same time each day, on an empty stomach (no food or drink besides clear 
liquids for approximately 2 hours before and 1 hour after study drug administration), for a total 
of 2 capsules and 2 tablets each day as shown in Table 6.  
For subjects participating in the PK/PD sub-study, study drug should be administered 
approximately 24 hours prior to their Week 12 visit. 
Table 6 
Study Drug by Dose Group 
Dose Group 
TERN-501 
Capsules 
TERN-501 Placebo 
to Match 
TERN-101 
Tablets 
TERN-101 Placebo 
to Match 
Placebo QD 
Not applicable 
Two placebo capsules 
Not applicable 
Two placebo tablets 
TERN-501 1 mg QD 
One 1 mg 
capsule 
One placebo capsule 
Not applicable 
Two placebo tablets 
TERN-501 3 mg QD 
One 3 mg 
capsule 
One placebo capsule 
Not applicable 
Two placebo tablets 
TERN-501 6 mg QD 
Two 3 mg 
capsules 
Not applicable 
Not applicable 
Two placebo tablets 
TERN-501 3 mg QD + 
TERN-101 10 mg QD 
One 3 mg 
capsule 
One placebo capsule 
Two 5 mg 
tablets 
Not applicable 
TERN-501 6 mg QD + 
TERN-101 10 mg QD 
Two 3 mg 
capsules 
Not applicable 
Two 5 mg 
tablets 
Not applicable 
TERN-101 10 mg QD 
Not applicable 
Two placebo capsules 
Two 5 mg 
tablets 
Not applicable 
Abbreviations: QD = once a day 
6.3. 
Preparation/Handling/Storage/Dispensing/Accountability 
The Investigator or designee must provide acknowledgement of receipt of each shipment of 
study drug including appropriate temperature conditions have been maintained during transit for 
all study drug received and any discrepancies are reported and resolved before use of the study 
drug. 
Only patients enrolled in the study may receive study drug and only authorized site staff may 
supply or administer study drug. All study drugs must be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the Investigator and authorized site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study drug accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study drugs are provided in 
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6.4. 
Measures to Minimize Bias: Randomization and Blinding 
Patients will be randomized to 1 of 3 dose levels TERN-501 monotherapy, 1 of 2 dose levels 
TERN-501+TERN-101, 10mg TERN-101 monotherapy, or placebo using an Interactive Web 
Response System (IWRS). Before the study is initiated, the log-in information and directions for 
the IWRS will be provided to each site.  
Approximately 140 patients will be randomized equally into one of the 7 treatment groups to 
receive once daily orally administered TERN-501 1 mg (n=20), TERN-501 3 mg (n=20), 
TERN-501 6 mg (n=20), TERN-501 3 mg+TERN-101 10 mg (n=20), TERN-501 6 mg+TERN-
101 10 mg (n=20), TERN-101 10 mg (n=20), or matching placebo (n=20).   
All personnel directly involved in the conduct of the study (i.e., Investigators, patients, all study 
personnel, Medical Monitor, and the Sponsor) 
dose group throughout the course of the study. Individuals in IP packaging and labeling who 
have Unblinded Inventory Manager role in the IXRS system for study drug inventory 
management will remain unblinded. Individuals at the PK bioanalytical laboratory will remain 
unblinded to facilitate sample processing, as placebo samples will not be analyzed for PK. Study 
drug will be dispensed at the study visits as summarized in Schedule of Activities. Returned 
study drug should not be re-dispensed to patients.  
6.4.1. 
Unblinding  
affect immediate medical management of the patient. The IWRS will be programmed with blind-
breaking instructions. In case of an emergency, the Investigator has the sole responsibility for 
determining if unblinding of a 
 intervention assignment is warranted. Patient safety must 
always be the first consideration in making such a determination. If the Investigator decides that 
unblinding is warranted, the Investigator should make every effort to contact the Medical 
Monitor/Sponsor prior to unblinding a patient
emergency treatment of the patient. If a patient
Sponsor must be notified within 24 hours after breaking the blind. The date and reason that the 
blind was broken must be recorded in the source documentation and case report form (CRF), as 
applicable. 
Any unblinding of Sponsor personnel for expedited reporting of suspected unexpected serious 
adverse reactions (SUSARs) or other reasons will be addressed in a separate plan.  
6.4.2. 
Patient Enrollment and Study Drug Assignment 
It is the responsibility of the Investigator to ensure that patient eligibility is confirmed prior to 
randomization. Documentation of the personally signed and dated informed consent of each 
patient, using the study specific ICF, is required before initiating the Screening Period.  
obtained from the IWRS. Once eligibility to participate has been established, the randomized 
treatment assignment will be obtained from the IWRS. 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.5. 
Study Drug Compliance 
Patients will be dispensed study during their study visits and will self-administer study drug at 
home. Compliance will be assessed by direct questioning and counting returned capsules/tablets 
during the study visits and documented in the source documents and/or electronic case report 
form (eCRF). Deviation(s) from the prescribed dosage regimen should be recorded in the eCRF.   
If a patient is required to be quarantined due to active infection of Coronavirus Disease 2019 
(COVID-19) or exposure to COVID-19 or is otherwise unable to visit the site due to COVID-19, 
study drug may be mailed to the patient or made available via another appropriate mechanism 
(ie, curbside pickup, etc.). 
Patients will be asked to maintain records of self-administered drug on non-study visit days. A 
record of the number of study drug capsules/tablets dispensed to and taken by each patient must 
be maintained and reconciled with study drug and compliance records at the site. Study drug start 
and stop dates, including dates for delays will also be recorded in the eCRF. 
6.6. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the patient is receiving at the time of randomization or receives 
during the study must be recorded at each study visit along with: 
 Reason for use 
 Dates of administration including start and end dates 
 Dosage information including dose and frequency 
Thyroid hormone replacement therapy during the study treatment: 
 If determined necessary by Investigator, in consultation with the Medical Monitor, dose 
adjustment (dose increase or decrease, or discontinuation) of thyroid hormone 
replacement therapy with levothyroxine is allowed once after at least 6 weeks of study 
drug administration. See Section 8.1.8 for more information on thyroid axis safety 
monitoring   
Medications prohibited for use through the end of study:  
 Medications or therapies that may interfere with thyroid function (except in patients who 
were on a stable dose of thyroid hormone replacement therapy with levothyroxine for 
primary hypothyroidism prior to study entry), including but not limited to initiation of 
thyroid hormone replacement therapy, methimazole, propylthiouracil, tyrosine kinase 
inhibitors, lithium, iodide, and propranolol; patients who require such medications or 
therapies must discontinue study drug (See Section 7.1.2.) 
 Medications specifically used for weight loss 
 Medications with potential impact on NASH outcome, including resmetirom or other 
investigational THR-
obeticholic acid or other investigational FXR agonists, 
-dose vitamin E (> 400 IU/day) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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 Medications potentially impacting steatohepatitis, including but not limited to systemic 
corticosteroids (prednisone equivalent of > 10 mg/day for > 2 weeks), amiodarone, 
tamoxifen and methotrexate. Use of systemic corticosteroids for  2 weeks within 
3 months prior to randomization and through the end of the study is allowed  
Medications discouraged for initiation, discontinuation, or dose adjustment through the end of 
study, but allowed if deemed necessary for clinical management 
tion:  
 V
 
 Metformin, GLP-1 analogues, DPP-4 inhibitors, SGLT2 inhibitors, and other diabetic 
drugs  
 Insulin with > 30% dose adjustment 
 
 Statins, PCSK9 inhibitors, or other lipid modifying medications 
 Hormonal contraceptives 
Medications prohibited for use through the last dose of treatment:  
There is potential for TERN-501 absorption to be increased or decreased by co-administered 
drugs that are intestinal P-gp and BCRP inhibitors or inducers, respectively, based on in vitro 
data. As such, strong P-gp and/or BCRP inhibitors or inducers are prohibited from this study. 
There is potential for CYP3A4 inhibitors or inducers to increase or decrease the exposure of 
TERN-101, respectively. As such, strong CYP3A4 inhibitors or inducers are prohibited from this 
study. 
A noncomprehensive list of known strong CYP3A inducers and inhibitors, P-gp inhibitors and 
inducers, and BCRP inhibitors is provided below: 
 Potent CYP3A inhibitors prohibited on study include but are not limited to: boceprevir, 
cobicistat, ritonavir, grapefruit juice, itraconazole, ketoconazole, osaconazole, telaprevir, 
telithromycin, troleandomycin, voriconazole, clarithromycin, idelalisib, nefazodone, and 
nelfinavir 
 P-gp inhibitors prohibited on study include but are not limited to: amiodarone, carvedilol, 
clarithromycin, cyclosporine, dronedarone, itraconazole, lapatinib, propafenone, 
quinidine, ranolazine, ritonavir, and verapamil 
 BCRP inhibitors prohibited on study include but are not limited to: curcumin, 
cyclosporine, eltrombopag  
 Potent CYP3A and/or P-gp inducers prohibited on study include but are not limited to: 
apalutamide, carbamazepine, enzalutamide, fosphenytoin, mitotane, phenytoin, rifampin, 
 
Patients who require initiation of strong CYP3A and/or P-gp inducers or strong CYP3A, P-gp, 
and/or BCRP inhibitors during the study should discontinue study drug (Section 7.1.2.). For 
patients who subsequently discontinue prohibited medications, study drug administration may 
not be resumed unless agreed by the Medical Monitor. Patients who do not resume study drug 
will continue in the study to be evaluated at the remaining visits through the Follow-Up visit. 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 


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Medications discouraged for use through the last dose of treatment:  
Moderate CYP3A inhibitor use is discouraged during study participation. Management of 
patients who initiate moderate CYP3A4 inhibitors during the course of study treatment should be 
discussed with the Medical Monitor.  
A noncomprehensive list for known moderate CYP3A4 inhibitors is provided below: 
 Moderate CYP3A4 inhibitors discouraged on study include but are not limited to: 
aprepitant, ciprofloxacin, conivaptan, crizotinib, cyclosporine, diltiazem, dronedarone, 
erythromycin, fluconazole, fluvoxamine, imatinib, and verapamil 
The Medical Monitor should be contacted if there are any questions regarding concomitant 
therapy. Any dose adjustments that may be required during study participation should be 
discussed with the Medical Monitor. 
6.7. 
Dose Modifications 
Dose modifications of study drug are not permitted.  
6.8. 
Dose Interruptions 
On all non-study visit days, patients will self-administer the study drug orally once daily. If a 
patient forgets to self-administer study drug at their usual time on a given day, the dose can be 
taken on the same day when the patient remembers, with the exception below:  
 For patients participating in the PK/PD sub-study, drug must be self-administered in the 
morning approximately 24 hours before their Week 12 visit. If not, the Week 12 PK/PD 
sub-study visit should be re-scheduled for the following day.  
If a patient forgets to self-administer study drug on a given day, it will be designated a missed 
dose. Dosing may continue orally once daily according to the protocol schedule after a missed 
dose.  
If study drug is discontinued or suspended for safety reasons considered related to study drug, 
dosing should not be resumed without consultation with the Medical Monitor. Information on 
stopping study drug for patients due to safety/other reasons is detailed in Section 7.  
6.8.1. 
Dose Interruptions due to COVID-19 
If a patient requires home quarantine due to SARS-CoV-2 infection or exposure, or due to 
COVID-19 symptoms, the patient may continue study drug provided that appropriate safety 
follow-up is possible and that hospitalization is not required. Home health care visits may be 
made available to continue study assessments 
remote visits via telephone, telemedicine, or other appropriate virtual communication may be 
substituted for a visit to the site. Sites should discuss the mechanism for safety follow-up with 
the Medical Monitor. For additional details for study drug dispensation, please see Section 6.5.  
If a patient has symptoms of COVID-19 requiring hospitalization, study drug must be 
discontinued during hospitalization. A case-by-case assessment of whether to resume study drug 
can be done upon discharge. Dosing should not be resumed without consultation with the 
 
 
 
 
 
 
 
 
 


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Medical Monitor. The patient should be encouraged to remain in the study to be evaluated at the 
remaining visits through the Follow-Up visit.  
6.9. 
Intervention after the End of the Study 
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7. 
Discontinuation of Study, Study Drug and Patient Discontinuation or 
Withdrawal 
7.1. 
Study and Study Drug Stopping Criteria 
7.1.1. 
Study Stopping Criteria 
Blinded safety review including, but not limited to, laboratory values, vital signs, ECGs, and 
AEs will be conducted regularly throughout the study and will assess whether any of the 
following criteria are met: 
 One patient experiences a Grade V CTCAE considered related to study medication by the 
Investigator, or 
 Two patients experience the same Grade IV CTCAE considered related to study 
medication by the Investigator, or 
 Three patients experience the same Grade III CTCAE considered related to study 
medication by the Investigator 
Note: Causality of AEs will be determined by the Investigator based on the 4-category system 
specified in Appendix 6.   
In the event that study enrollment and/or dosing is stopped due to one or more of the criteria 
specified above, the causality of these adverse events will be further investigated by an 
Independent Medical Monitor (IMM); if adverse events are deemed to be unrelated to study drug 
(i.e., TERN-501, TERN-101, or TERN-501+TERN-101) by the IMM, then enrollment and/or 
dosing may resume. 
The Sponsor may temporarily or permanently stop the study at any time for safety concerns. 
7.1.2. 
 Discontinuation of Study Drug 
Study drug must be discontinued for an individual patient in the following instances:  
 If an AE of Grade 3 or above based on National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) 5.0 occurs and is considered related 
to study drug as judged by the Investigator per the guidance in Appendix 6.  
 Development of TSH level outside the normal range (confirmed by repeat testing) that is 
determined to be clinically significant or warrants initiation of new medications or 
therapies to treat thyroid dysfunction of signs of hyper/hypothyroidism. (Note: Dose 
adjustment of thyroid hormone replacement therapy with levothyroxine without 
discontinuing study drug may be allowed once after at least 6 weeks of study drug 
administration 
upon consultation with Medical Monitor as 
referenced in Section 6.6). 
 Necessary use of nonpermitted concomitant drug (ie. CYP3A4/P-gp/BCRP strong 
inhibitor/inducer) as referenced in Section 6.6. 
 
 
 
 
 
 
 
 
 


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 Symptoms of COVID-19 requiring hospitalization. 
 Change in status that, in the judgement of the Investigator compromises 
ability to continue treatment 
.  
 Patient request to discontinue study drug for any reason. 
 Pregnancy during the study (refer to Appendix 7). 
 Sponsor discretion.  
 Discontinuation of the study at the request of the Sponsor, a regulatory agency, or 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC). 
Study drug may be discontinued upon confirmation by repeat testing for an individual patient in 
the following instances at the discretion of the Investigator, and the Medical Monitor should be 
informed if any of the following occurs:  
 If one of the following laboratory abnormalities is confirmed by repeat testing, 
considered related to the study drug and does not have alternative etiology (repeat test 
should be performed within 48-72 hours once initial abnormality is detected): 
o 
ALT or AST > 8 × ULN  
o 
ALT or AST > 5 × ULN for more than 1 week during study drug administration 
o 
ALT or AST > 2× Baseline with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%) 
o 
ALT or AST > 2 × Baseline and total bilirubin > 2 × ULN or INR > 1.5 for more 
than 1 week, confirmed with a repeat assessment 
o 
ALP > 5 x ULN 
o 
ALP > 3 x ULN and total bilirubin > 2x ULN 
Study drug administration may not be resumed unless discussed and agreed with the Medical 
Monitor. 
In addition, Investigators may permanently discontinue study drug at their discretion, for 
example, due to patient non-compliance with study drug or study assessments. 
If study drug is permanently discontinued, the patient should remain in the study to be evaluated 
at the remaining visits through the Follow-Up visit; scheduled assessments may be performed at 
 in consultation with Medical Monitor/Sponsor; PK samples will not be 
collected at subsequent visits after study drug discontinuation. See the Schedule of Activities for 
data to be collected at the time of discontinuation of study drug and follow-up and for any further 
evaluations that need to be completed. 
7.2. 
Patient Discontinuation/Withdrawal from the Study 
A patient may withdraw from the study at any time at his/her own request or may be withdrawn 
at any time at the discretion of the Investigator for safety, behavioral, compliance, or 
administrative reasons.  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 


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Patients discontinuing the study at any time for any reason (Early Termination [ET]) should 
complete the ET visit as soon as feasible and return for a Follow-Up approximately 4 weeks after 
the last dose of study drug. See the Schedule of Activities for data to be collected at the time of 
study discontinuation and follow-up and for any further evaluations that need to be completed. 
If the patient withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use any data collected before such a withdrawal of consent. 
If a patient withdraws from the study, he/she may request destruction of any samples taken and 
not tested, and the Investigator must document this in the site study records. 
7.3. 
Lost to Follow up 
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit: 
 The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible, counsel the patient on the importance of maintaining the assigned visit schedule 
and ascertain whether or not the patient wishes to and/or should continue in the study. 
 Before a patient is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the patient (where possible, 3 telephone calls and, if 
necessary, a certified letter to the patient
methods). These contact attempts should be documented in the patient
. 
 
Should the patient continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
Discontinuation of specific sites or of the study as a whole are addressed in Section 10.1.8 and 
Section 7.1.1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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8. 
Study Assessments and Procedures 
Study procedures and their timing are summarized in the Schedule of Activities. Protocol 
waivers or exemptions are not allowed. 
Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of all 
patients screened and to confirm eligibility or record reasons for screening failure, as applicable. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. 
If a patient requires home quarantine due to SARS-CoV-2 infection or exposure, or due to 
COVID-19 symptoms or other associated concern with attending an in-person study visit, in 
accordance with Section 6.8.1, home health care visits may be made available to continue study 
telemedicine, or other appropriate virtual communication may be substituted for a visit to the 
site. 
8.1. 
Study Assessments 
Planned time points for all safety assessments are provided in the Schedule of Activities 
(Section 1.3).  
8.1.1. 
Demographics 
Demographic data includes age (year of birth), sex, race, and ethnicity.  
8.1.2. 
Height and Weight 
Height and weight are collected at Screening and will be used to calculate BMI for eligibility. 
Only weight is collected at Weeks 0, 6, 12, 16, and ET.   
8.1.3. 
Medical History 
Medical history including details of illnesses, allergies, or procedures including liver biopsy, 
date(s) of onset, whether condition(s) is currently ongoing, medication history, including alcohol 
use, will be collected for all patients at Screening and prior to Randomization.  
8.1.4. 
Physical Examinations 
A complete physical examination be performed at Screening, Week 16, and ET and will include 
assessments of general appearance, cardiovascular, respiratory, abdomen, head and neck 
(including ears, eyes, nose and throat), lymph nodes, thyroid, and musculoskeletal systems.  
A targeted physical examination will be conducted at all other study visits as needed, based on 
clinical judgement of the Investigator, to evaluate reported current or prior AEs, symptoms 
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Investigators should pay special attention to clinical signs related to previous serious illnesses. 
8.1.5. 
Vital Signs 
Temperature, pulse rate, respiratory rate, and blood pressure will be assessed at all study visits as 
outlined in the Schedule of Activities (Section 1.3) and maintained in source documentation.  
Blood pressure and pulse measurements will be assessed with a completely automated device. 
Manual techniques will be used only if an automated device is not available. 
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for the 
patient in a quiet setting without distractions (eg, television, cell phones). 
8.1.6. 
Electrocardiograms 
Single 12-lead ECGs will be obtained at all study visits as outlined in the Schedule of Activities 
(Section 1.3) using an ECG machine that automatically calculates the heart rate and measures 
PR, QRS, and QT intervals. QTc will be calculated using the formula outlined in Appendix 4. 
In the instance of patient-reported symptoms considered potentially cardiac in nature such as 
chest pain/pressure, palpitations, dizziness, shortness of breath, or report of patient recently 
seeking medical care for such symptoms (e.g., emergency room visit), perform an an-hoc ECG, 
and, per the clinical judgement of the Investigator, obtain cardiology consult as needed.  
Participants will be instructed to lie supine for at least 10 minutes prior to 12-lead ECG 
collection. During ECG collection, participants should be in a quiet setting, without distractions, 
and refrain from talking or moving their arms or legs. 
The Investigator will review the ECGs for any clinically significant abnormalities.  
8.1.7. 
Cardiovascular Safety Monitoring 
Cardiovascular safety will be monitored via vital signs (see Section 8.1.5) and 12-lead ECGs (see 
Section 8.1.6) along with clinical assessment of adverse events that may represent signs or 
symptoms of cardiac toxicity.  
Signs and symptoms that may reflect cardiovascular toxicity include the following, with clinical 
significance to be determined by the Investigator:  
 Vital signs changes including hypertension, hypotension, tachycardia, or bradycardia  
 12-lead ECG findings including tachycardia, bradycardia, atrial fibrillation or flutter, 
ventricular arrythmia, or QTc prolongation 
 Clinical symptoms suggestive of cardiac ischemia or other cardiac dysfunction such as 
chest pain/pressure, palpitations, shortness of breath, or edema 
Potential signs or symptoms consistent with cardiovascular toxicity should be carefully 
evaluated, with repeat of assessments (e.g., vital signs, ECG, laboratory values) to confirm 
findings and follow-up until resolution. 
Signs or symptoms should be designated as AEs with CTCAE v5.0 severity determined per 
Appendix 6. Participant discontinuation of study drug criteria are outlined in Section 7.1.2. 
 
 
 


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8.1.8. 
Thyroid Axis Safety Monitoring 
Clinical signs and symptoms of hyper/hypothyroidism are variable and should be considered 
when assessing participants for AEs throughout the course of the study.  
Major signs and symptoms of hyperthyroidism are: 
 Overt hyperthyroidism is characterized by a constellation of symptoms including anxiety, 
emotional lability, restlessness, irritability, psychosis, agitation, depression, insomnia, 
weakness, tremor, palpitations, heat intolerance, increased perspiration, or weight loss 
(although weight gain may also be seen due to appetite stimulation). Signs may include 
hyperactivity, rapid speech, eye lid lag, warm and moist skin, tachycardia, systolic 
hypertension, proximal muscle weakness, or hyperreflexia 
 Other symptoms may include hyperdefecation, urinary frequency, atrial fibrillation, heart 
failure, premature atrial contractions, shortness of breath, myopathy, hypercalcemia, or 
osteoporosis (with prolonged thyroid hormone excess) 
Major signs and symptoms of hypothyroidism are: 
 Effects of slowing of metabolic processes such as slow movement and speech, delayed 
relaxation of tendon reflexes, bradycardia, fatigue and weakness, cold intolerance, 
dyspnea on exertion, weight gain, cognitive dysfunction, or constipation 
 Effects of accumulation of matrix substances such as coarse skin, puffy facies and loss of 
eyebrows, periorbital edema, tongue enlargement, dry skin, hoarseness, or edema 
 Others such as diastolic hypertension, decreased hearing, myalgia and paresthesia, 
depression, or arthralgia 
Liver function test monitoring criteria include guidance on increased monitoring in the event of 
alkaline phosphatase elevation (Appendix 3), as hyperthyroidism-associated liver injury may be 
cholestatic in nature and present with high alkaline phosphatase levels. Study drug 
discontinuation guidelines for ALP elevations are included in Section 7.1.2. 
Thyroid axis testing will be performed as outlined in the Schedule of Activities and Appendix 1. 
Peripheral thyroid hormone modulation with THR-
nism may lead to lowering free T4 
(prohormone) without changes in T3 (active hormone) or TSH (Section 7.1.2). In the FIH study 
(Study TERN501-1009), dose-dependent decreases in free T4 were observed without clear 
changes in T3 or TSH over 14 days of treatment with TERN-501, which appeared consistent 
with peripheral thyroid hormone modulation with THR-
While minor fluctuations in 
thyroid hormone (e.g., ~20%) within the normal range are not considered clinically relevant in 
euthyroid patients (Dong 2000), overt alterations of TSH could reflect unwanted effects on the 
central thyroid axis. In the event of systemic thyroid hormone effects of TERN-501, clear TSH 
decline to below the normal range would be an indicator of likely central thyroid axis 
suppression. However, clinical manifestations should be considered in determining clinical 
thyroid status. Similarly, changes in T3 (and/or T4, if unblinded) should be interpreted in the 
setting of the TSH changes and clinical factors.   
TSH or other thyroid axis tests outside the normal range should be confirmed by repeat testing. 
Repeat testing should be performed within 7 days of the test result.  All thyroid axis testing 
including repeat testing should be performed in the morning, approximately at the same time. 
 
 
 
 
 
 
 


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Study drug should be discontinued in a patient with TSH level outside the normal range 
(confirmed by repeat testing) that is determined to be clinically significant or that warrants 
initiation of new medications or therapies to treat apparent thyroid dysfunction or 
hyper/hypothyroidism (Section 7.1.2). T4 will be blinded during the study to avoid potential 
unblinding of treatment assignment (Section 8.1.9.1). Free T4 and/or total T4 results may be 
made available at the I
necessary for clinical management for patients. 
Ongoing assessment of AEs considered possibly related to thyroid dysfunction should be 
conducted until symptoms resolve or stabilize. In the event of abnormal thyroid laboratory 
assessments, repeat assessment should be conducted approximately every 3 to 7 days, at the 
discretion of the Investigator, until levels normalize. Patients who have thyroid axis tests outside 
of the normal range at Follow-Up visit that are determined to be clinically significant by the 
Investigator should be monitored until laboratory values normalize and/or any symptoms are 
resolved. 
For guidance on dose adjustment of thyroid hormone replacement therapy with levothyroxine 
during the study, see Section 6.6, Concomitant Therapy. 
8.1.9. 
Clinical Laboratory Assessments 
See Appendix 1 for the list of clinical laboratory tests to be performed and refer to the Schedule 
of Activities (Section 1.3) for the timing and frequency. 
The Investigator must review the laboratory report, document this review, and record any AEs 
per the guidance in Appendix 6. The laboratory reports must be filed with the source documents.  
Shifts of clinically significant Grade 3 or Grade 4 laboratory abnormalities or any clinically 
significant laboratory abnormalities considered possibly related to study drug in the opinion of 
the Investigator should be repeated within 48-72 hours and followed to resolution or until stable. 
All protocol-required laboratory assessments, as defined in Appendix 1, must be conducted in 
accordance with the laboratory manual and the Schedule of Activities. 
8.1.9.1. 
Blinded Laboratory Assessments 
Laboratory results that could potentially unblind the study will not be reported to investigative 
sites or other blinded personnel until the study has been unblinded unless deemed necessary for 
patient safety or clinical decision-making during the study. This includes all PD analyses listed 
in Appendix 2. All clinical safety laboratory assessments listed in Appendix 1 will be available 
to investigative sites for safety monitoring, except for the analytes noted below.  
 
 
 
 
 
 
  




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8.1.9.2. 
Liver Function Tests 
ALT and/or AST stability should be evaluated prior to randomization, if applicable, per 
Section 5.  
During the course of the study, LFTs will be monitored per the Schedule of Activities (see 
Section 1.3). Refer to Appendix 1 for a list of tests to be performed, and to Appendix 3 for 
additional information on criteria for increased liver chemistry monitoring. 
8.1.9.3. 
Bone Turnover Markers 
While bone loss may occur in the event of thyroid hormone excess, this is mediated largely 
through THR-  (Sinha 2019; Gorka 2013). Although no significant effects on bone mineral 
density was observed at Week 36 in the phase 2 resmetirom study (Harrison 2019) and no 
TERN-501 data available to date suggest an adverse thyromimetic effect on bone, samples to 
measure serum bone turnover markers will be collected in this study. Specifically, serum 
procollagen type I N propeptide (sPINP) as a marker of bone formation and serum C-terminal 
cross-linking telopeptide of type I collagen (sCTX) as a marker of bone resorption will be 
assessed at visits specified in the Schedule of Activities (Section 1.3).  
8.1.10. 
Transient Elastography and Controlled Attenuation Parameter by FibroScan® 
Liver stiffness by TE and CAP may be assessed at Screening to determine study eligibility 
(Section 5.1). If TE and CAP were performed at Screening, these parameters do not need to be 
repeated on Day 1. TE and CAP will also be conducted at Week 12, and at ET only if not done 
within the prior 4 weeks, and the patient has had at least 4 weeks of dosing (see Section 1.1).  
The transient elastography requirement is intended to select for patients likely to have at least F1 
fibrosis. The protocol excludes patients with cirrhosis based on medical history or clinical signs 
or symptoms (Exclusion criteria #2). Prior studies indicate variability in the ranges of liver 
stiffness measured by transient elastography in NASH patients with fibrosis or cirrhosis. In 
STELLAR-3, which enrolled patients with bridging fibrosis, median liver stiffness at baseline 
was approximately 13 kPa, with an interquartile range between 10 and 17 kPa (Harrison 2020). 
In STELLAR-4, which enrolled patients with cirrhosis, median liver stiffness at baseline was 
approximately 20-21 kPa, with an interquartile range between 14 and 30 kPa (Harrison 2020). 
The utility of transient elastography to diagnose cirrhosis in the setting of NASH also appears 
limited based on the low positive predictive value (PPV) of even relatively high kPa thresholds. 
For a threshold of 21 kPa, the upper limit for this study, the PPV for F4 fibrosis (i.e., cirrhosis) in 
the setting of NASH is 0.37 (which may be even lower in a population with low prevalence of 
cirrhosis, such as one in which cirrhosis is excluded on clinical grounds), with a negative 
predictive value of 0.96 (Eddowes 2019). This threshold has a sensitivity of 0.59 and a 
specificity of 0.90 for a diagnosis of cirrhosis in the setting of NASH (Eddowes 2019). 
CAP is an assessment of liver steatosis and is generally used to complement the assessment of 
liver stiffness by transient elastography for evidence of NASH (Eddowes 2019). CAP estimates 
the total ultrasonic attenuation (go-and-return path), expressed in dB/m, based on the postulate 
that fat affects ultrasound propagation. A CAP threshold of 274 dB/m has sensitivity of 0.9 and 
 


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specificity of 0.6 for ide
Eddowes 2019). The threshold of 
300 dB/m was chosen to identify patients who are likely to have elevated liver steatosis, in 
conjunction with the other imaging assessments at screening, including MRI-PDFF and cT1. 
8.1.11. 
FibroScan-AST (FAST) Score 
The FAST score, a number between 0 and 1, uses the liver stiffness by TE and CAP 
measurements from FibroScan® combined with levels of AST 
NASH. A score  0.67 has been reported to indicate a high risk for NASH (Newsome 2020).  
The FAST score will be derived based on TE and CAP by FibroScan® combined with AST 
value. 
8.1.12. 
Magnetic Resonance Imaging: Proton Density Fat Fraction (MRI-PDFF) and 
Corrected T1 (cT1)   
MRI-PDFF quantifies the relative amount of water vs. fat in a tissue, while cT1 is a novel MRI-
based quantitative metric for assessing a composite of liver inflammation and fibrosis.  
MRI-PDFF quantifies the relative amount of water vs. fat in a tissue based on signals from 
proton groups that vary depending on tissue cell type (Caussy 2018). PDFF is expressed as a 
percentage (range from 0-100%) representing the ratio of density of mobile protons from 
triglycerides relative to total triglyceride and water mobile proton density (although there are 
also triglyceride elements that are not visible by magnetic resonance and do not contribute to 
PDFF determination). In the liver, PDFF correlates with histological assessment of hepatic 
steatosis, and PDFF has been advanced as a measure of liver fat content to assess treatment 
response in NASH studies (Caussy 2018). PDFF values correlate with NAS score on liver 
histology, with a strong correlation with steatosis (rs = 0.68, p < 0.001) (Dennis 2021). A PDFF 
 (Szczepaniak 2005; 
Tang 2013). PDFF and cT1 values have been shown to be strongly correlated with each other in 
NASH patients (rs = 0.66, p < 0.001) (Dennis 2021). The threshold of MRI-PDFF for study entry 
 was chosen to identify patients who are likely to have elevated liver steatosis, in 
conjunction with the other imaging assessments at screening, including cT1. 
Corrected T1 is based on multiparametric MRI data, measuring relaxation time that varies based 
on extracellular tissue fluid attributed to inflammation and fibrosis, with a longer relaxation time 
occurring with more extracellular fluid; the measurement is corrected for elevated iron content, 
which has an opposing effect on relaxation time (Banerjee 2014). Values for cT1 have been 
shown to correlate with the NAFLD Activity Score (NAS) and its components, as well as with 
degree of fibrosis by liver histology (Banerjee 2014; Dennis 2021). A population at low risk for 
NAFLD was found to have values ranging from 573 to 852 msec with a median of 666 msec and 
interquartile range from 643 to 694 msec, with high cT1 values (e.g. > 875 msec) having been 
shown to strongly predict liver-related clinical outcomes (e.g., hepatic encephalopathy, variceal 
bleeding, ascites, death) (Mojtahed 2019). In conjunction with other screening assessments, a 
threshold of 800 msec for study entry will enrich for a NASH population with fibrosis; this 
fibrosis (Banerjee 2014). 
MRI-PDFF and cT1 assessments will be performed at Screening. An MRI-PDFF and cT1 scan 
may proceed based on the initial screening ALT and AST values, given all other eligibility 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 


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criteria are met, but randomization should not occur prior to confirmation of ALT and/or AST 
stability as necessary, per Section 5. The images will be analyzed by a central reader. MRI-PDFF 
and cT1 will also be conducted at Week 6 and Week 12, or at ET only if not done within the 
prior 4 weeks, and the patient has had at least 4 weeks of dosing (Section 1.3).   
8.2. 
Pharmacokinetics 
Blood samples will be collected for measurement of plasma concentrations of TERN-501, 
TERN-101, and TERN-101 metabolite TRN-000971 at timepoints specified in Appendix 2 and 
as specified in the Schedule of Activities (Section 1.3).  
Patients in the PK/PD sub-study will undergo intensive and sparse PK sample collection as 
specified in the Schedule of Activities (Section 1.3) and Appendix 2.  
Patients who are not participating in the PK/PD sub-study will undergo sparse PK sampling 
collection only, as specified in the Schedule of Activities (Section 1.3) and Appendix 2.  
Instructions for the collection and handling of biological samples will be provided by the 
Sponsor. The actual date and time (24-hour clock time) of each sample will be recorded as well 
as actual dosing date and time (24-hours clock time) of the last dose prior to PK sample 
collection. 
Samples will be used to evaluate the PK of study drug. Samples collected for analyses of study 
drug concentration may also be used to evaluate safety or efficacy aspects related to concerns 
arising during or after the study. 
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded. 
In addition, any remaining (leftover) samples may be stored and used for optional exploratory 
future research on biomarker variants thought to play a role in NASH or to develop methods or 
assays related to the disease process or mechanism of action of the study drug.  Patients must 
provide informed consent for optional exploratory future research as specified in Section 10.1.2. 
Samples collected for pharmacokinetic assessments will be destroyed no later than 15 years after 
the end of study. 
8.3. 
Pharmacodynamics 
Blood samples will be collected for measurement of PD markers of THR-
and FXR agonism at 
timepoints specified in Appendix 2 and as specified in the Schedule of Activities. 
Patients in the PK/PD sub-study will undergo intensive PD sample collection for FGF19, 
 
as well as trough PD sample collection for lipid panel, 
, SHBG, and bile acids as specified 
in the Schedule of Activities and Appendix 2.  
Patients who are not participating in the PK/PD sub-study will undergo trough PD sampling only 
for lipid panel, 
, SHBG, and bile acids as specified in the Schedule of Activities and 
Appendix 2.  
Bile acids will only be tested on Week 0, Week 12, and at ET. 
  
 
 


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Instructions for the collection and handling of biological samples will be provided by the 
Sponsor. The actual date and time (24-hour clock time) of each sample will be recorded. 
Samples will be used to evaluate the pharmacodynamics of study drug. Samples collected for 
analyses of study drug pharmacodynamics may also be used to evaluate safety or efficacy 
aspects related to concerns arising during or after the study. 
In addition, any remaining (leftover) samples may be stored and used for optional exploratory 
future research on biomarker variants thought to play a role in NASH or to develop methods or 
assays related to the disease process or mechanism of action of the study drug. Patients must 
provide informed consent for optional exploratory future research as specified in Section 10.1.2. 
Samples collected for pharmacodynamic assessments, and any remaining samples stored and 
used for optional exploratory future research will be destroyed no later than 15 years after the 
end of study. 
8.4. 
Biomarkers 
Collection of samples for biomarkers related to NASH is also part of this study. The following 
samples will be collected from all patients in this study as specified in the Schedule of Activities 
(Section 1.3):  
 Blood collection for the following biomarkers: CK-18 (M30 and M65), ELF (PIIINP, 
TIMP-1, HA), and PRO-C3 
 rT3 will be assessed as an exploratory biomarker of THR-
 and collected as part 
of the thyroid axis testing panel  
Leftover samples may also be used to assess additional NASH biomarkers based on the safety, 
efficacy, and PD biomarker results of this study. 
The following exploratory fibrosis scores may also be calculated: FIB-4, ELF, and FAST score 
and. Biomarkers inform exploratory objectives to further understand FXR and THR- agonism 
in NAFLD and NASH, and their association with the observed clinical responses to treatment 
with study drug. 
In addition, any remaining (leftover) samples may be stored and used for optional exploratory 
future research on biomarker variants thought to play a role in NASH or to develop methods or 
assays related to the disease process or mechanism of action of the study drug. Patients must 
provide informed consent for optional exploratory future research as specified in Section 10.1.2. 
The samples collected for biomarkers and any remaining samples stored and used for optional 
exploratory future research will be destroyed no later than 15 years after the end of study. 
8.5. 
Adverse Events and Serious Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical study patient, temporally 
associated with the use of study drug, whether or not considered related to the study drug.  
An SAE is defined as any untoward medical occurrence that, at any dose, results in the 
following: death; is life threatening; requires in-patient hospitalization; results in persistent 
disability or incapacity; is a congenital anomaly or birth defect; or is a medically important event 
or reaction that may not be immediately life-threatening or result in death or hospitalization but 
 
 
 
 


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may jeopardize the patient or may require medical or surgical intervention to prevent one of the 
other outcomes in the definition.  
Events meeting the definition of an AE or SAE are defined in Appendix 6, including details on 
recording, reporting, and follow-up of AEs and SAEs, assessment of intensity, and assessment of 
causality. AEs will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or 
the patient s legally authorized representative) at every study visit. 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study drug or study procedures, or that caused 
the patient to discontinue the study drug (see Section 7). 
8.5.1. 
Time Period and Frequency for Collecting AE and SAE Information 
After informed consent but prior to initiation of study drug, the following types of events should 
be reported: all AEs and SAEs related to protocol-mandated procedures.  
Medical occurrences (events considered not related to protocol-mandated procedures) that begin 
before the start of study drug but after obtaining informed consent will be recorded on the 
Medical History/Current Medical Conditions section of the eCRF not the AE section. 
All AEs and SAEs, regardless of cause or relationship, will be collected from the start of study 
drug through the Follow-Up visit, at every study visit, as specified in the Schedule of Activities 
(Section 1.1). 
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 6. The Investigator will 
submit any updated SAE data to the Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek reports of AEs or SAEs after conclusion of the 
study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a patient has been discharged from the study, and he/she considers the event to be 
reasonably related to the study drug or study participation, the Investigator must promptly notify 
the Sponsor. 
8.5.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 6. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences. 
8.5.3. 
Follow-up of AEs and SAEs 
After the initial AE and/or SAE report, the Investigator is required to proactively follow each 
patient at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the 
event is otherwise explained, or the patient is lost to follow-up (as defined in Section 7.3). 
Further information on follow-up procedures is provided in Appendix 6. 
 


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8.5.4. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of patients and the safety of a study 
drug under clinical investigation can be met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study drug under clinical investigation. The Sponsor 
will comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/IEC, and Investigators. 
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to Investigators as necessary. 
An Investigator who receives an investigator safety report describing a SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the sponsor will review and then file 
it along with the 
and will notify the IRB/IEC, if appropriate according to 
local requirements. 
8.5.5. 
Pregnancy 
Details of all pregnancies in female patients and female partners of male patients will be 
collected after the start of study drug until 30 days following the last dose of the study drug. 
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 6 and 
Appendix 7. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.5.6. 
Assessment of Pruritus 
For patients who report AEs consistent with pruritus, photographs of the affected area(s) will be 
taken at the discretion of the Investigator (eg, if there are visible skin lesions; photos that would 
identify the patient, ie, of the entire face, will be avoided). A qualified staff member will 
administer the Pruritus Numerical Rating Scale (Appendix 8) at each study visit when pruritus is 
reported or noted as ongoing. If pruritus is reported (either ongoing or at any time since the last 
visit), the clinical site will provide details on these events in the AE eCRF page.  
The Investigator will be asked to provide an assessment of the severity of the AE using the NCI 
CTCAE v5.0 categories for pruritus as follows:  
 Grade 1: Mild or localized; topical intervention indicated.  
 Grade 2: Widespread and intermittent; skin changes from scratching (eg, edema, 
papulation, excoriations, lichenification, oozing/crusts); oral intervention indicated; 
limiting instrumental activities of daily living (ADL).  
 Grade 3: Widespread and constant; limiting self-care, ADL, or sleep; systemic 
corticosteroid or immunosuppressive therapy indicated. 
 
 
 
 
 


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For Grade 3 cases, follow up by telephone contact or in person visit should occur within 3 days 
or at the discretion of the Investigator. Additional follow up may take place until symptoms 
improve. Refer to Section 7 for additional information on study drug discontinuation and study 
stopping rules.   
8.6. 
Treatment of Overdose 
Overdose with TERN-501 monotherapy, TERN-101 monotherapy, or TERN-501+TERN-101 
has not been reported. Neither the effect of overdose nor antidote are known. The maximum 
amount of TERN-101 that can be safely administered in a single dose has not been determined. 
The highest single dose of TERN-101 in clinical studies was 25 mg in the tablet formulation and 
600 mg in the capsule formulation (see Section 2.2.2.2) and the highest single dose of TERN-501 
in clinical studies was 60 mg. The highest single dose of TERN-501+TERN-101 was 3mg and 
15mg respectively. Patients who receive higher than the protocol-defined dose should be 
carefully monitored for AEs, and the quantity of the excess dose and duration of excess dose 
should be documented in the eCRF; the Medical Monitor should be notified immediately. Refer 
to Appendix 6 for additional information on AE reporting.  
In an instance in which a patient receives higher than the protocol-defined dose, decisions 
regarding any future dosing of study drug will be made by the Investigator in consultation with 
the Sponsor based on the clinical evaluation of the patient. 
8.7. 
Medical Resource Utilization and Health Economics 
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9. 
Statistical Considerations 
9.1. 
Statistical Hypotheses 
The primary statistical analysis will test whether the mean relative change from baseline in MRI-
PDFF is (H1) or is not (H0) different between placebo and TERN-501 monotherapy. Secondary 
statistical analyses will test whether the mean relative change from baseline in MRI-PDFF is 
(H1) or is not (H0) different between placebo and TERN-501+TERN-101. Similarly, statistical 
analyses of cT1 will test whether the mean change from baseline is (H1) or is not (H0) different 
between placebo and TERN-501 monotherapy and between placebo and TERN-501+TERN-101. 
In addition, exploratory analyses will evaluate all pairwise comparisons between the different 
TERN-501 doses and of TERN-101 compared to placebo and will be considered nominal and 
descriptive. 
9.2. 
Sample Size Determination 
Approximately 140 patients will be randomized into one of the 7 groups (n=20 each) to detect a 
clinically meaningful difference in the primary endpoint and secondary endpoints of MRI-PDFF 
relative reduction at Week 12 and secondary endpoints of cT1 reduction at Week 12 between 
placebo and TERN-501 monotherapy and separately between placebo and TERN-501+TERN-
101. 
Power was estimated based on published literature for THR-  agonist resmetirom (to estimate 
TERN-501 effect) and clinical data for TERN-101 (Study TERN101-2001). Assuming a pooled 
standard deviation of 22% (Study TERN101-2001 final analysis), with a two-sided alpha of 0.05, 
a mean relative reduction difference in MRI-PDFF at Week 12 of 
 23% between placebo (n=20) and TERN-501 monotherapy (n=20) will provide 
approximately 90% power (Harrison 2019). 
 36% between placebo (n=20) and TERN-501+TERN-101 (n=20) will provide >90% 
power, based on placebo treatment effect from resmetirom (Harrison 2019) and sum of 
treatment effects from resmetirom (to estimate TERN-501 effect) and minimum 
treatment effect for TERN-101 (Study TERN101-2001), assuming an additive effect of 
the two agents in combination.    
Assuming a pooled standard deviation of 82 msec (Study TERN101-2001 final analysis), with a 
two-sided alpha of 0.05, a mean reduction difference in cT1 at Week 12  
 of 77 msec between placebo (n=20) and TERN-501 monotherapy (n=20) will provide 
approximately 82% power (Harrison 2018). 
 134 msec between placebo (n=20) and TERN-501+TERN-101 (n=20) will provide >90% 
power, based on placebo treatment effect from resmetirom (Harrison 2019) and sum of 
treatment effects from resmetirom (to estimate TERN-501 effect) and minimum 
treatment effect for TERN-101 (Study TERN101-2001), assuming an additive effect of 
the two agents in combination.    
Patients who are randomized but do not receive study drug for any reason may be replaced. In 
addition, patients who discontinue treatment early for reasons other than safety (i.e., withdrawal 
 
 
 
 


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of consent, lost to follow-
discretion. Replacement patients will receive the same treatment assignment as the patient that 
discontinued treatment early. 
9.3. 
Analysis Sets 
The following analysis sets are defined: 
Analysis Sets 
Description 
Screened  
All patients who sign the ICF 
Randomized 
All patients who are randomized into any one of treatment 
groups. Treatment assignment will be based on the 
randomized treatment. 
Pharmacokinetic (PK) 
All randomized patients who received at least 1 dose of 
TERN-501 and/or TERN-101 and have evaluable PK data. 
Treatment assignment will be based on the treatment actually 
received. 
Pharmacodynamic (PD) 
All randomized patients who received at least 1 dose of study 
drug (TERN-501, TERN-101, or placebo) and for whom PD 
markers can be evaluated. Treatment assignment will be 
based on the treatment actually received. 
PK/PD sub-study 
All patients who consented to and participated in the PK/PD 
sub-study and received at least 1 dose of study drug (TERN-
501, TERN-101, or placebo). Treatment assignment will be 
based on the treatment actually received. 
Safety 
All patients who received at least 1 dose of study drug. 
Treatment assignment will be based on the treatment actually 
received. 
Efficacy  
All randomized patients who received at least 1 dose of study 
drug. Treatment assignment will be based on the randomized 
treatment. 
9.4. 
Statistical Analyses 
This section presents a summary of the planned statistical analyses. The statistical analysis plan 
(SAP) will provide the details and will be finalized prior to clinical database lock (DBL). 
9.4.1. 
General Considerations 
For continuous data, summary statistics will include the number of non-missing observations (n), 
arithmetic mean, arithmetic standard deviation, median, 25th percentile (Q1), 75th percentile 
(Q3), minimum, and maximum. For log-normal data (eg, the PK parameters: AUCs and 
maximum observed concentration [Cmax]), the geometric mean and geometric coefficient of 
 
 
 
 
 
 
 
 
 
 
 


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variation (CV%) will also be presented. For categorical data, frequency counts and percentages 
will be presented.  
The baseline value for statistical analyses of quantitative laboratory parameters is defined as the 
mean of all available evaluations, including any unscheduled or repeat assessments, prior to the 
first administration of study drug.  Otherwise, the baseline value is defined to be the latest 
assessment value prior to the first administration of study drug, unless specified in the SAP. 
Missing values will not be imputed for primary analyses. However, sensitivity analyses will be 
conducted to evaluate the effect of missing data. Further details will be specified in the SAP.  
No adjustments for multiplicity will be made. 
Data analysis will be performed using SAS® Version 9.4 or higher. Noncompartmental PK 
parameters will be estimated from individual plasma concentration data using Phoenix® 
WinNonlin®. 
9.4.2. 
Primary Endpoint 
Analyses of MRI-PDFF will be based on the Efficacy Analysis Set. Descriptive statistics of 
MRI-PDFF results, absolute change from baseline, and relative change from baseline will be 
summarized by treatment group and visit. Analyses of relative change from baseline will be 
carried out using an ANCOVA model at Week 12 with relative change from baseline as the 
dependent variable including treatment group as a fixed effect and baseline as a covariate.   
The estimates of least-square (LS) means, standard errors (SE), and 95% confidence intervals 
(Cis) will be presented by treatment group. Estimates of the LS mean difference between TERN-
501 monotherapy and placebo will be presented with the associated standard error of the 
difference, and 95% CI of the difference. 
9.4.3. 
Secondary Endpoints 
9.4.3.1. 
Change from Baseline in cT1 at Week 12 
Analyses of cT1 will be based on the Efficacy Analysis Set. Descriptive statistics of cT1 results, 
change from baseline, and percent change from baseline will be summarized by treatment group 
and visit.  Corrected T1 will be analyzed in the same manner as MRI-PDFF. Secondary endpoint 
comparisons will include TERN-501 monotherapy compared to placebo and 
TERN-501+TERN-101 compared to placebo.  
9.4.3.2. 
Change from Baseline in MRI-PDFF at Week 12 
In addition to the primary endpoint comparison, secondary endpoint comparisons include 
TERN-501+TERN-101 compared to placebo. 
9.4.3.3. 
Treatment-Emergent Adverse Events 
Reported AEs will be coded using the latest version of Medical Dictionary for Regulatory 
Activities. Patient incidence of treatment-emergent AEs (TEAEs) will be summarized by 
treatment group and MedDRA system organ class (SOC) and preferred term (PT) using the 
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9.4.4. 
Exploratory Endpoints 
9.4.4.1. 
Efficacy Endpoints 
All exploratory efficacy analyses will be performed on Efficacy Analysis Set. Exploratory 
analyses will evaluate all pairwise comparisons between the 7 treatment groups and will be 
considered nominal and descriptive. 
The primary and secondary endpoints evaluate Week 12 MRI-PDFF and cT1, while exploratory 
endpoints will summarize and analyze other applicable time points and additional treatment 
group comparisons of TERN-501+TERN-101 to TERN-501 monotherapy and TERN-101 
monotherapy in the same manner specified for the primary and secondary endpoints. Additional 
details will be specified in the SAP. 
Change (and separately percent change) from baseline in liver enzymes, NASH and fibrosis 
biomarkers, and liver stiffness will be summarized and analyzed at applicable time points using 
the same ANCOVA model specified for the primary endpoint. 
FAST score will be calculated based on liver stiffness and AST values (Newsome 2020). 
MRI-PDFF responders will be defined as any patient with a relative decrease of at least 30%. 
Non-responders will be defined as any patient who did not have at least a 30% relative decrease. 
The number and percentage, with associated two-sided exact (Clopper-Pearson) 95% CI, of 
patients in each category (response, nonresponse) will be presented by treatment group at 
applicable time points.  A Chi-square test will be used to compare treatment groups. 
cT1 responders will be defined any patient with a decrease of at least 80 msec. Non-responders 
will be defined any patient who did not have at least an 80 msec decrease.  cT1 response will be 
summarized and analyzed at applicable time points in the same manner as specified for MRI-
PDFF. 
9.4.4.2. 
Pharmacokinetic Endpoints 
Individual plasma concentrations of TERN-501, TERN-101, and TERN-101 metabolite 
TRN-000971 will be listed by timepoint and summarized by treatment group. PK of other 
metabolites may be explored. Individual and mean concentration-time profiles will be presented 
graphically in linear and semi-log scales.  
Derived PK parameters from the PK/PD sub-study will be listed individually and summarized 
with descriptive statistics, including arithmetic and geometric mean, median, standard deviation, 
coefficient of variation (CV), geometric CV, minimum and maximum.  
9.4.4.3. 
Pharmacodynamic Endpoints 
PD markers of THR- agonism include SHBG and lipids, while PD markers of FXR agonism 
include FGF19, 
. Descriptive statistics of PD marker results, change from 
baseline, and percent change from baseline will be summarized by treatment group and visit. 
Change (and separately percent change) from baseline will be analyzed at applicable time points 
using the same ANCOVA model specified for the primary endpoint.  
 
 
 
 


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Pharmacodynamic parameters may also be calculated, summarized, and described by plotting the 
concentration-time curve or time-effect curve.  
9.4.5. 
Safety Endpoints 
In addition to the secondary endpoint of patient incidence of TEAEs, patient incidence of TEAEs 
will also be summarized by maximum intensity and study drug causality. Summaries of 
treatment-emergent SAEs will be summarized in the same manner as the secondary endpoint. 
Vital signs and quantitative safety laboratory measurements will be summarized by treatment 
group and scheduled time points.  Laboratory abnormalities will be graded according to NCI 
CTCAE Version 5.0, where applicable. The number and percentage of subjects experiencing 
treatment-emergent graded lab toxicities will be summarized by treatment group and toxicity 
grade. 
9.5. 
Interim Analyses  
No formal interim analyses are planned.   


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10. 
Regulatory, Ethical, and Study Oversight Considerations 
10.1. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
 Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
 Applicable International Council on Harmonisation (ICH) Good Clinical Practice (GCP) 
Guidelines 
 Applicable laws and regulations 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(eg., advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study patients. 
The Investigator will be responsible for the following: 
 Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
 Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
 Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other applicable local 
regulations 
10.1.1. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.2. 
Informed Consent Process 
The Investigator or his/her representative will explain the nature of the study to the patient or 
his/her legally authorized representative and answer all questions regarding the study. 
Patients must be informed that their participation is voluntary. Patients or their legally authorized 
representative will be required to sign a statement of informed consent that meets the 
 
 
 
 
 
 


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requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study center. 
The medical record must include a statement that written informed consent was obtained before 
the patient was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
Patients must be re-consented to the most current version of the ICF(s) during their participation 
in the study. 
A copy of the ICF(s) must be provided to the patient or the patient
representative. 
The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional exploratory research for up to 15 years after the end of the study. The Investigator or 
authorized designee will explain to each patient the objectives of the exploratory research. 
Patients will be told that they are free to refuse to participate and may withdraw their consent at 
any time and for any reason during the storage period. A separate signature will be required to 
document a patient s agreement to allow any remaining specimens to be used for exploratory 
research. Patients who decline to participate in this optional research will not provide this 
separate signature. 
Written informed consent may be obtained via telephone with appropriate documentation of how 
the informed consent form was transmitted to the patient, (such as via email, fax, or mail) and 
how signature was obtained. Screening may be initiated via telephone to avoid a visit to the site 
if the patient is disqualified based on medical history. 
10.1.3. 
Data Protection 
Patients will be assigned a unique identifier by the sponsor. Any patient records or datasets that 
are transferred to the sponsor will contain the identifier only; patient names or any information 
which would make the patient identifiable will not be transferred. 
The patient must be informed that his/her personal study-related data will be used by the sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to 
the patient who will be required to give consent for their data to be used as described in the 
informed consent.  
The patient must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.4. 
Dissemination of Clinical Study Data 
A clinical study report (CSR) will be prepared and provided to the regulatory agency(ies) by 
Terns, Inc, as appropriate. Terns, Inc. will ensure that the report meets the standards set out in the 
ICH Guideline for Structure and Content of Clinical Study Reports (ICH E3). Note that an 
abbreviated report may be prepared in certain cases. Public disclosure of study results will be in 
accordance with all applicable laws and ICH guidelines. The posting of company-sponsored 
www.ClinTrials.gov and other publicly accessible sites. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10.1.5. 
Data Quality Assurance 
All patient data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or electronically 
signing the CRF. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality such as 
Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities and requirements, including handling of noncompliance issues and monitoring 
techniques (central, remote, or on-site monitoring) are available in the Monitoring Plan and site-
specific contracts.  
The sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
The sponsor assumes accountability for actions delegated to other individuals (eg, Contract 
Research Organizations). 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study agreements, 
ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator until at least 2 years after the last approval of a marketing application 
in an ICH region (ie, United States, Europe, or Japan) and until there are no pending or 
contemplated marketing applications in an ICH region (ie, United States, Europe, or Japan) or at 
least 2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product. These documents should be retained for a longer period however if 
required by the applicable regulatory requirement(s) or if needed by the sponsor. No records may 
be destroyed during the retention period without the written approval of the sponsor. No records 
may be transferred to another location or party without written notification to the sponsor. 
10.1.6. 
Protocol Deviations 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. In the event of a significant deviation related to 
gross non-compliance from the protocol, or events that impose significant risk to patient safety, 
the Investigator or designee must notify the Sponsor or designee immediately. Deviations must 
procedures or processes.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10.1.7. 
Source Documents 
Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected. Source documents are stored at the Investigator
 
Data reported on the eCRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records, depending on the 
study.  
The required source data should include notes containing at least the following information for 
each patient:  
 Patient identification (name, date of birth, gender) 
 Documentation that the patient meets eligibility criteria 
 Documentation of the reason(s) a consented patient is not enrolled 
 Participation in study (including study number) 
 Study discussed and date of informed consent 
 Dates of all visits 
 Documentation that protocol-specific procedures were performed 
 Start and end date (including dose regimen) of study drug administration, including dates 
of dispensation and return as applicable 
 Record of all AEs and other safety parameters (start and end date, and including causality 
and severity) 
 Concomitant medications (including start and end date, dose if relevant; dose changes) 
 Date of study completion and reason for early discontinuation, if applicable  
10.1.8. 
Study and Site Start and Closure 
The first patient screened is considered the first act of recruitment and will be the study start 
date. 
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or Investigator may include but are 
not limited to: 
 Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor s procedures, or GCP guidelines 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


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 Inadequate recruitment of patients by the Investigator 
 Discontinuation of further study drug development 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The Investigator shall promptly inform the subject and 
should assure appropriate follow-up care as warranted by the protocol or as medically necessary. 
 
 






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Investigators must document their review of each laboratory safety report. Shifts of clinically 
significant Grade 3 or Grade 4 laboratory abnormalities or any clinically significant laboratory 
abnormalities considered possibly related to study drug in the opinion of the Investigator should 
be repeated within 48-72 hours and followed to resolution or until stable. 
Laboratory/analyte results that could potentially unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded. See 
Section 8.1.9.1 for more details. 








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Appendix 4: Fri
 
A single 12-lead ECG will be obtained as outlined in the Schedule of Activities (see Section 1.1) 
using an ECG machine that automatically calculates the heart rate and measures PR, QRS, and 
QT intervals. QTc will be calculated using Fri
.  
The Investigator will review the ECGs for any clinically significant abnormalities.  
Fri
 
QTc = QT/(RR^0.33) 
http://www.thecalculator.co/health/QTc-Calculator-385.html 
 
 
 
  
 
 
 
 


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Appendix 5: Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
Formula to Estimate Glomerular Filtration Rate  
GFR = 141 × min(Scr
 × max(Scr
-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if black] 
 
Abbreviations / Units:  
SCr (standardized serum creatinine) = mg/dL 
 
-0.329 (females) or -0.411 (males) 
 
 
age = years 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
  
 
 
 
 
 
  












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Appendix 7: Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below).  
Women in the following categories are not considered WOCBP 
1. Premenopausal female with surgical sterility defined as 1 of the following: 
 Documented hysterectomy 
 Documented bilateral salpingectomy 
 Documented bilateral oophorectomy 
2. Postmenopausal female 
 A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
o A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception 
or hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with more than one FSH measurement is required.  
 Females on HRT and whose menopausal status is in doubt will be required to follow the 
protocol-mandated contraception guidance if they wish to continue their HRT during the 
study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal 
status before study enrollment. 
For individuals with permanent infertility due to an alternate medical cause not listed above, (eg, 
mullerian agenesis, androgen insensitivity), investigator discretion should be applied to 
determining study entry.  
records, medical examination, or medical history interview. 
Contraception Guidance: 
Male patients who are sexually active with a female partner of childbearing potential must be 
either surgically sterile (confirmed by azoospermia > 90 days after the procedure or vasectomy) 
or follow the guidance per Table 11 during the study and until 30 days following the last dose of 
study drug. Male patients must not donate sperm from the first dose of study drug until 30 days 
following the last dose of the study drug. 
Female patients of childbearing potential must have negative serum pregnancy test at screening 
and negative urine pregnancy test at randomization, not be breastfeeding, and not plan to become 
pregnant during study or within 30 days after dosing of study drug. Female patients of 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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Collection of Pregnancy Information:  
Male patients with partners who become pregnant 
The Investigator will attempt to collect pregnancy information on any male patient
partner who becomes pregnant while the male patient is in this study, or if they become pregnant 
within 30 days following the last dose of the study drug. This applies only to male patients who 
receive study drug. 
After obtaining the necessary signed informed consent from the pregnant female partner directly, 
the Investigator will record pregnancy information on the appropriate form and submit it to the 
sponsor within 24 hours of le
followed to determine the outcome of the pregnancy. Information on the status of the mother and 
child will be forwarded to the sponsor. Generally, the follow-up will be no longer than 6 to 8 
weeks following the estimated delivery date. Any termination of the pregnancy will be reported 
regardless of fetal status (presence or absence of anomalies) or indication for the procedure.  
Female Patients Who Become Pregnant 
Any female patient who becomes pregnant while participating in the study will discontinue study 
drug.  
The Investigator will collect pregnancy information on any female patient who becomes 
pregnant while participating in this study, or if they become pregnant 30 days following the last 
dose of study drug. The initial information will be recorded on the appropriate form and 
submitted to the sponsor within 24 hours of learning of a patient's pregnancy.  
The patient will be followed to determine the outcome of the pregnancy. The Investigator will 
collect follow-up information on the patient and the neonate and the information will be 
forwarded to the sponsor. Generally, follow-up will not be required for longer than 6 to 8 weeks 
beyond the estimated delivery date. Any termination of pregnancy will be reported, regardless of 
fetal status (presence or absence of anomalies) or indication for the procedure. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE.  
A spontaneous abortion (occurring at < 22 weeks gestational age) or still birth (occurring at 
> 22 weeks gestational age) is always considered to be an SAE and will be reported as such.  
Any post-study pregnancy related SAE considered reasonably related to the study drug by the 
Investigator will be reported to the sponsor as described in Section 8.5.5. While the Investigator 
is not obligated to actively seek this information in former study patients, he or she may learn of 
an SAE through spontaneous reporting. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 8: Pruritus Numerical Rating Scale  
This Numerical Rating Scale was adapted from IFSI SIG/EADV Task Force Pruritus 
assessments available at http://www.pruritussymposium.de/numericalratingscale.html 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


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Appendix 9: COVID-19 Assessments 
At Screening:  
 SARS-CoV-2 testing to assess for active infection (eg, molecular test such as polymerase 
chain reaction [PCR] or viral antigen serology) and past infection (Immunoglobulin G 
[IgG] antibody required; Immunoglobulin M [IgM] antibody recommended in addition).  
 Testing at Screening may be omitted for patients who have completed a COVID-19 
 
At Weeks 0, 6, and 12:  
 Testing for past infection via antibody testing (IgG and IgM) if prior IgG was negative  
 If Week 0 occurs within 2 weeks of Screening, site may omit repeat SARS-CoV-2 testing 
 
 If IgM antibody test is positive, may reflex to test for SARS-CoV-2 active infection at 
 discretion 
 Testing at these timepoints may be omitted for patients who have completed a COVID-19 
 
Ad-hoc:  
 In the event of symptoms suggestive of COVID-19, ad hoc testing (including molecular 
test such as PCR or viral antigen serology, and/or antibody testing, once available via the 
central laboratory)
 
Sites may use local laboratory testing for COVID-19 assessments instead of central laboratory, 
per site preference. If a local laboratory is used, the results must be entered into the eCRF. 
Results from previous testing may be used if completed within 2 weeks of a scheduled Screening 
or on-study visit. 
Any positive tests reflecting active or recent infection (eg, molecular test such as PCR or viral 
antigen serology, or IgM antibody) require management per local public health guidelines, at the 
direction of the Investigator. 
If technological changes result in changes to the assays implemented to assess for SARS-CoV-2, 
available central lab assays and testing mechanisms may change. 
The testing approach and schedule may be modified based on the evolving landscape of the 
pandemic or in response to local public health requirements. In that event, regulatory 
requirements, IRB requirements, and local institutional guidelines will be followed, as necessary. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


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Appendix 10: Abbreviations 
Abbreviation or 
Special Term 
Explanation 
 
-hydroxy-4-cholesten-3-one 
-hCG 
Human chorionic gonadotropin 
ADaM 
Analysis Data Model 
ADL 
Activities of Daily Living 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase  
ANCOVA 
Analysis of covariance 
apo A1
Apolipoprotein A1 
apo B
Apolipoprotein B 
aPTT 
activated partial thromboplastin clotting time 
AST 
Aspartate transaminase 
AUC 
Area under the concentration-time curve 
BCRP 
Breast cancer resistance protein 
BMI 
Body mass index 
BUN 
Biliary urea nitrogen 
CAP 
Controlled attenuation parameter 
CCl4 
Carbon tetrachloride 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CK-18 
Cytokeratin-18 
COVID-19 
Coronavirus disease 2019 
CPK 
Creatinine phosphokinase 
CONSORT 
Consolidated Standards of Reporting Trials 
Cmax 
Maximal concentration 
CRF 
Case report form 
CSR 
Clinical study report 
cT1 
Corrected T1 
Ctau 
concentration at the end of the dosing interval 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTX 
c-terminal cross-linking telopeptide of type I collagen 
CYP 
cytochrome P450 
CYP3A 
cytochrome P450 3A 
CV 
Coefficient of variation 
 
 


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Abbreviation or 
Special Term 
Explanation 
DBL 
Database lock 
DIO 
Diet-induced obesity 
eGFR 
Estimated glomerular filtration rate 
eCRF 
Electronic case report form 
ECG 
Electrocardiographic 
ELF 
Enhanced liver fibrosis 
ET 
Early Termination 
FAST 
FibroScan-AST score 
FDA 
Food and Drug Administration 
FGF 
Fibroblast growth factor 
FGF-19 
Fibroblast growth factor -19 
FIB-4 
Fibrosis 4 
FSH 
Follicle stimulating hormone 
FXR 
Farnesoid X receptor 
GCP 
Good clinical practice 
GGT 
Gamma-glutamyl transpeptidase 
HA 
Hyaluronic acid 
HBsAG 
Hepatitis B virus surface antigen 
HCV 
Hepatitis C virus 
HDL 
High-density lipoprotein 
HIV 
Human immunodeficiency virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HRT 
Hormone replacement therapy 
ICF 
Informed consent form 
ICH 
International Council on Harmonisation 
IEC 
IMM 
Independent Ethics Committee 
Independent Medical Monitor 
IND 
Investigational new drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
IWRS 
Interactive web response system 
LAM 
lactational amenorrhoea method 
LDL 
Low-density lipoprotein  
LDLR 
Low-density lipoprotein receptor  


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Abbreviation or 
Special Term 
Explanation 
LFC 
Liver fat content 
LH 
Luteinizing hormone 
LFT 
Liver function test 
LSM 
Least square mean 
MCH 
Mean corpuscular hemoglobin 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI-cT1 
Magnetic Resonance Imaging Corrected T1  
MRI-PDFF 
Magnetic Resonance Imaging Proton Density Fat Fraction  
mpk 
mg/kg 
NAFLD 
Non-alcoholic fatty liver disease 
NAS 
Non-alcoholic fatty liver disease activity score 
NASH 
Non-alcoholic Steatohepatitis 
NCI 
National Cancer Institute 
NHP 
Nonhuman primate 
NOAEL 
No observed adverse effect level 
OATP 
Organic anion transporting polypeptide 
OCA 
Obeticholic acid 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamics 
PIIINP 
Procollagen III n-terminal propeptide 
PINP 
Procollagen type I N propeptide 
PK 
Pharmacokinetics 
PO 
Per os (oral); by mouth 
PRO-C3 
Pro-peptide of type III collagen 
QD 
Once daily (quaque die) 
RBC 
Red blood cell 
RNA 
Ribonucleic acid 
rT3 
Reverse triiodothyronine 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SCr 
Standardized serum creatinine 
SD 
SHBG 
Standard Deviation 
Sex hormone binding globulin 
SoA 
Schedule of Activities 


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Abbreviation or 
Special Term 
Explanation 
SUSR 
Suspected unexpected serious adverse reactions 
T3 
Triiodothyronine 
T4 
Thyroxine 
TBG 
Thyroxine binding globulin 
TCHO 
Total cholesterol 
TDI 
Time dependent inhibition 
TE 
Transient elastography 
TEAE 
Treatment emergent adverse event 
TERN-101 
An investigational FXR agonist 
TERN-501 
An investigational THR-
 
TG 
Triglycerides  
THC 
Tetrahydrocannabinol 
THR 
Thyroid hormone receptor 
THR-  
 
THR-  
 
TIMP-1 
Tissue inhibitor of metalloproteinases-1 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
US 
United States 
USPI 
United States prescribing information/package insert 
VLDL 
Very low-density lipoprotein 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
 
 
 
 
 
 
  
 
 
  


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Appendix 11: Investigator Signature Page 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 2a Clinical Study to 
Evaluate the Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of Orally Administered 
TERN-501 as Monotherapy as well as in Combination with TERN-101 in Noncirrhotic Adults 
with Presumed Non-Alcoholic Steatohepatitis (NASH) 
Protocol Number:  
 
TERNCB-2002 
Protocol Version/Date:  
Amendment 2; 18 July 2022 
I confirm that I have read the above-mentioned protocol and its attachments. I agree to conduct 
the described trial in compliance with all stipulations of the protocol, regulations and ICH E6 
Guideline for Good Clinical Practice (GCP). I will provide all study personnel under my 
supervision copies of the protocol and access to all information provided by Terns, Inc. I will 
discuss this material with them to ensure that they are fully informed about the study drug and 
the study. 
____________________________________ 
Principal Investigator Name (Printed)  
 
____________________________________ 
Signature  
 
____________________________________ 
Date 
 
 


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Appendix 12: Protocol Amendment History 
This document (dated 18 July 2022) is the Amendment 2, and the document history is below. 
The Summary of Changes for each amendment listed below will be provided separately.  
DOCUMENT HISTORY 
Document 
Date 
Amendment 2 
18 July 2022 
Amendment 1 
02 May 2022 
Original 
16 March 2022 


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Tang A, Tan J, Sun M, Hamilton G, Bydder M, Wolfson T, Gamst AC, Middleton M, Brunt EM, 
Loomba R, Lavine JE, Schwimmer JB, Sirlin CB. Nonalcoholic fatty liver disease: MR imaging 
of liver proton density fat fraction to assess hepatic steatosis. Radiology. 2013 May;267(2):422-
31. doi: 10.1148/radiol.12120896. Epub 2013 Feb 4. PMID: 23382291; PMCID: PMC3632805. 
Taub R, Chiang E, Chabot-Blanchet M, Kelly MJ, Reeves RA, Guertin MC, et al. Lipid lowering 
in healthy volunteers treated with multiple doses of MGL-3196, a liver-targeted thyroid hormone 
receptor-
. Atherosclerosis. 2013; Oct; 230:373-80. doi: 
10.1016/j.atherosclerosis.2013.07.056. Epub 2013 Aug 21. PMID: 24075770. 
Wang Y et al. Safety, Pharmacokinetics, Pharmacodynamics, and Formulation of Liver-
Distributed Farnesoid X-Receptor Agonist TERN-101 in Healthy Volunteers. Clinical 
Pharmacology in Drug Development 2021, 00(0). 
Wong RJ, Aguilar M, Cheung R, Perumpail RB, Harrison SA, Younossi ZM, Ahmed A. 
Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults 
awaiting liver transplantation in the United States. Gastroenterol. 2015;148: 547-55. 
Younossi ZM, Raziu V, Loomba R, Rinella M, Anstee QM, Goodman Z et al. Obeticholic acid 
for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicenter, 
randomized, placebo-controlled phase 3 trial. Lancet. 2019;394:2184-96. 
Zhang Y and Edwards PA. FXR Signaling in Metabolic Disease. FEBS Lett. 2008;582:10-18. 
Zucchi R. Thyroid Hormone Analogues: An Update. THYROID 2020. 
 
 

SAP_001.pdf: 
 
Statistical Analysis Plan 
 
CONFIDENTIAL 
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Protocol Reference: TERNCB-2002 
 
 
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Statistical Analysis Plan 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 2a Clinical Study to 
Evaluate the Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of Orally 
Administered TERN-501 as Monotherapy as well as in Combination with TERN-101 in 
Noncirrhotic Adults with Presumed Non-Alcoholic Steatohepatitis (NASH) 
 
Statistical Analysis Plan Version: Final 2.0 
Statistical Analysis Plan Date: 26JULY2023 
Investigational Products: TERN-501, TERN-101 
Protocol Reference: TERNCB-2002 
Labcorp Drug Development Study ID: 000000231152 
Sponsor: Terns, Inc. 
 
 
Author: 
 
 
 
 
 
 
 


 
Statistical Analysis Plan 
 
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Information described herein is confidential and may be disclosed only with the express written 
permission of the sponsor. 
 
 
 
 
 
 


 
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Table of Contents 
1. Source Documents ................................................................................................................ 8 
2. Protocol Details ..................................................................................................................... 9 
2.1. Overall Study Design ......................................................................................................9 
2.1.1. Study Procedures ..................................................................................................... 9 
2.1.2. Study Population ..................................................................................................... 9 
2.1.3. Study Drug ............................................................................................................... 9 
2.1.4. Treatment Assignment, Blinding, and Randomization Methodology ................... 11 
2.2. Study Objectives ...........................................................................................................12 
2.2.1. Primary Objective .................................................................................................. 12 
2.2.2. Secondary Objectives ............................................................................................ 12 
2.2.3. Exploratory Objectives .......................................................................................... 13 
2.3. Sample Size and Power .................................................................................................13 
3. Statistical Methods .............................................................................................................. 15 
3.1. General Principles .........................................................................................................15 
3.2. Computing Environments .............................................................................................16 
3.3. Partial Dates ..................................................................................................................17 
3.4. Missing Data .................................................................................................................17 
3.5. Data Conventions ..........................................................................................................17 
3.6. Standard Calculations ....................................................................................................17 
3.7. Treatments .....................................................................................................................18 
3.8. Visits..............................................................................................................................18 
3.8.1. Windows ................................................................................................................ 18 
3.8.2. Definition of Baselines ........................................................................................... 20 
3.8.3. Definition of End of Treatment ............................................................................. 21 
4. Analysis Sets ....................................................................................................................... 22 
5. Examination of Subgroups .................................................................................................. 23 
6. Study Population ................................................................................................................. 24 
6.1. Patient Disposition ........................................................................................................24 


 
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6.2. Demographics and Baseline Characteristics .................................................................24 
6.3. Protocol Deviations .......................................................................................................28 
6.4. General Medical History ...............................................................................................29 
6.5. Prior and Concomitant Medications ..............................................................................29 
7. Efficacy Analyses ............................................................................................................... 30 
7.1. Adjustments for Covariates ...........................................................................................30 
7.2. Handling of Dropouts or Missing Data .........................................................................30 
7.3. Interim Analyses and Data Monitoring .........................................................................30 
7.4. Multicenter Studies .......................................................................................................30 
7.5. Use of an “Efficacy Subset” of Patients ........................................................................30 
7.6. Multiple Comparisons/Multiplicity ...............................................................................30 
7.7. Analysis and Reporting of Change and Relative Change from Baseline ......................31 
7.8. MRI-PDFF Analyses .....................................................................................................31 
7.8.1. cT1.......................................................................................................................... 32 
7.9. Liver Enzymes (ALT, AST, GGT) ...............................................................................32 
7.10. NASH and Fibrosis Biomarkers ..................................................................................33 
7.11. Reverse T3 (rT3) .........................................................................................................33 
Change in rT3 and FT3/rT3 will be analyzed according to Section 7.7 and pairwise 
comparisons in Section 7.6 using the efficacy analysis set. .................................................33 
7.12. Fibrosis-4 (FIB-4) Score .............................................................................................33 
7.13. Enhanced Liver Fibrosis (ELF) Score .........................................................................33 
7.14. Nonalcoholic Fatty Liver Disease (NAFLD) Fibrosis Score ......................................34 
7.15. FAST Score .................................................................................................................34 
7.16. TE and CAP ................................................................................................................35 
7.17. Pharmacokinetic Analyses ..........................................................................................35 
7.17.1. Criteria for the Calculation of Apparent Terminal Elimination Rate Constant and 
Half-life 38 
7.17.2. Criteria for Calculation and Reporting of Area Under the Concentration-time 
Curve 39 


 
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7.17.3. Criteria for Handling Concentrations Below the Limit of Quantification or 
Missing Concentrations for Pharmacokinetic Analysis (i.e., PK Parameter Generation) 39 
7.17.4. Presentation of Pharmacokinetic Data ............................................................... 40 
7.18. Pharmacodynamic Analyses .......................................................................................41 
7.18.1. PD Parameter Data Handling ............................................................................... 42 
7.18.2. Statistical Methods for PD Parameters ............................................................... 42 
7.18.3. PK/PD Analyses .................................................................................................... 43 
8. Safety Analyses ................................................................................................................... 44 
8.1. Extent of Exposure ........................................................................................................44 
8.2. Adverse Events ..............................................................................................................45 
8.2.1. Overall Summary of Adverse Events ..................................................................... 45 
8.2.2. Patient Incidence of Adverse Events ..................................................................... 46 
8.2.3. Pruritus .................................................................................................................. 47 
8.3. Clinical Safety Laboratory Evaluations ........................................................................48 
8.3.1. Treatment Emergent Abnormalities...................................................................... 48 
8.3.2. Thyroid Axis Testing ............................................................................................... 50 
8.3.3. Sex Hormones ........................................................................................................ 50 
8.3.4. Bone Turnover Markers ......................................................................................... 51 
8.3.5. Shifts in Normal Range .......................................................................................... 51 
8.4. Vital Signs .....................................................................................................................51 
8.5. Electrocardiograms........................................................................................................51 
9. Other Assessments .............................................................................................................. 53 
10. Changes to Protocol Planned Analyses............................................................................. 54 
11. Appendices ........................................................................................................................ 55 
 
 


 
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List of Tables 
 
Table 1 Study Drug ................................................................................................................. 10 
Table 2 Study Drug Administration by Dose Group .............................................................. 11 
Table 3 Treatment Group Labels and Ordering ...................................................................... 18 
Table 4 Treatment Period Visit Windows .............................................................................. 20 
Table 5 Analysis Sets .............................................................................................................. 22 
Table 6 Pairwise Comparison for Display .............................................................................. 30 
Table 7 Hierarchical Testing Strategy .................................................................................... 31 
Table 8 PK Profile Day 1* ...................................................................................................... 36 
Table 9 PK Profile Week 12* ................................................................................................. 37 
Table 10 Plasma PD Parameters ............................................................................................. 42 
Table 11 Liver Function Tests Potentially Reflecting Hepatoxicity Liver Function Tests .... 50 
 
 






 
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2. Protocol Details 
2.1. Overall Study Design 
This study is a multicenter, randomized, double-blind, placebo-controlled, parallel-group 
treatment, phase 2a study.  
Approximately 140 non-cirrhotic NASH patients with fibrosis identified based on prior liver 
biopsy and/or imaging and clinical criteria who meet study eligibility criteria will be enrolled 
and randomized equally into 7 groups: once daily orally administered TERN-501 1 mg 
(n=20), TERN-501 3 mg (n=20), TERN-501 6 mg (n=20), TERN-501 3 mg+TERN-101 10 
mg (n=20), TERN-501 6 mg+TERN-101 10 mg (n=20), TERN-101 10 mg (n=20), or 
matching placebo (n=20).  
Of the 140 patients randomized, approximately 42 patients (approximately 6 per group) will 
take part in an intensive PK and pharmacodynamic (PD) collection after the first dose and 
after the last dose of study drug. Patients who are not participating in the PK/PD sub-study 
will have sparse PK and trough PD sampling only.  
The total study duration will be approximately 22 weeks, consisting of a 6-week Screening 
Period, a 12-week Treatment Period, and a 4-week Follow-up Period. 
2.1.1. Study Procedures 
The overall schedule of activities is outlined in Section 1.3 of the study protocol. See study 
protocol for complete details. 
2.1.2. Study Population 
This study includes non-cirrhotic presumed NASH patients. Inclusion and exclusion criteria 
are provided in Sections 5.1 and 5.2, respectively, of the study protocol. 
2.1.3. Study Drug 
Study drug is defined as any investigational intervention(s), marketed product(s), or placebo 
intended to be administered to a study patient according to the study protocol. 
 
 


 
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Table 1 Study Drug 
Intervention 
Name  
TERN-501 
capsules  
TERN-501 
Placebo to 
match (identical 
in shape, size, 
appearance, and 
color to TERN-
501 capsules)  
TERN-101 
tablets  
TERN-101 
Placebo to 
match (identical 
in shape, size, 
appearance, and 
color to TERN-
101 tablets)  
Type  
Drug  
Drug  
Drug  
Drug  
Dose 
Formulation  
Capsule  
Capsule  
Tablet  
Tablet  
Unit Dose 
Strength(s)  
1 mg or 3 mg 
per capsule  
N/A  
5 mg per tablet  
N/A  
Route of 
Administration  
Oral  
Oral  
Oral  
Oral  
Use  
Experimental  
Placebo  
Experimental  
Placebo  
IMP and 
NIMP  
IMP  
IMP  
IMP  
IMP  
Sourcing  
Provided 
centrally by the 
Sponsor  
Provided 
centrally by the 
Sponsor  
Provided 
centrally by the 
Sponsor  
Provided 
centrally by the 
Sponsor  
Packaging and 
Labeling  
Study drug will 
be provided in a 
labelled carton 
containing 
one/two bottles 
of capsules for 
4-week use. 
Each bottle and 
carton will be 
labeled as 
required per 
country 
requirements.  
Study drug will 
be provided in a 
labelled carton 
containing 
one/two bottles 
of capsules for 
4-week use. 
Each bottle and 
carton will be 
labeled as 
required per 
country 
requirements.  
Study drug will 
be provided in a 
labelled carton 
containing 
one/two bottles 
of tablets for 4-
week use. Each 
bottle and 
carton will be 
labeled as 
required per 
country 
requirements.  
Study drug will 
be provided in a 
labelled carton 
containing 
one/two bottles 
of tablets for 4-
week use. Each 
bottle and 
carton will be 
labeled as 
required per 
country 
requirements.  
 
Patients will be instructed to take one capsule/tablet from each bottle by mouth daily, at 
approximately the same time each day, on an empty stomach (no food or drink besides clear 
liquids for approximately 2 hours before and 1 hour after study drug administration), for a 
total of 2 capsules and 2 tablets each day as shown in Table 6. 


 
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For subjects participating in the PK/PD sub-study, study drug should be administered 
approximately 24 hours prior to their Week 12 visit. 
Table 2 Study Drug Administration by Dose Group 
Dose Group  
TERN-501 
Capsules  
TERN-501 
Placebo to 
Match  
TERN-101 
Tablets  
TERN-101 
Placebo to 
Match  
Placebo QD  
Not applicable  
Two placebo 
capsules  
Not applicable  
Two placebo 
tablets  
TERN-101 10 
mg QD  
Not applicable  
Two placebo 
capsules  
Two 5 mg 
tablets  
Not applicable  
TERN-501 1 
mg QD  
One 1 mg 
capsule  
One placebo 
capsule  
Not applicable  
Two placebo 
tablets  
TERN-501 3 
mg QD  
One 3 mg 
capsule  
One placebo 
capsule  
Not applicable  
Two placebo 
tablets  
TERN-501 6 
mg QD  
Two 3 mg 
capsules  
Not applicable  
Not applicable  
Two placebo 
tablets  
TERN-501 3 
mg QD +  
TERN-101 10 
mg QD  
One 3 mg 
capsule  
One placebo 
capsule  
Two 5 mg 
tablets  
Not applicable  
TERN-501 6 
mg QD +  
TERN-101 10 
mg QD  
Two 3 mg 
capsules  
Not applicable  
Two 5 mg 
tablets  
Not applicable  
 
Patients who are randomized but do not receive study drug for any reason may be replaced. 
2.1.4. Treatment Assignment, Blinding, and Randomization Methodology 
Patients will be randomized to study drug or placebo using an Interactive Web Response 
System (IWRS). Approximately 140 patients will be randomized at an overall ratio of 
1:1:1:1:1:1:1 into the 7 groups treatment groups as described in Table 2.  
Investigators, patients, all study personnel, and the Sponsor will remain blinded to each 
patient’s assigned dose group throughout the course of the study. The randomization codes 
will be provided to bioanalytics to allow for the exclusion of placebo patients from the PK 
assay. 
Randomization codes will remain blinded until the trial is officially unblinded. 


 
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Emergency unblinding procedures are outlined in Section 6.4.1 of the study protocol and in 
the unblinding plan. Additional unblinding will be reviewed in the medical monitor plan 
(Maintaining Study Blind and Unblinding Plan). 
2.2. Study Objectives 
2.2.1. Primary Objective 
To evaluate the effect of TERN-501 monotherapy on liver fat content as assessed by MRI-
PDFF compared to placebo. 
2.2.1.1. Endpoint for the Primary Objective 
Relative change from baseline in MRI-PDFF at Week 12 for TERN-501 compared to 
placebo. 
 
2.2.2. Secondary Objectives 
• To evaluate the effect of TERN-501 monotherapy on cT1 relaxation time compared 
to placebo 
 
• To evaluate the effect of TERN-501+TERN-101 on liver fat content as assessed by  
MRI-PDFF and on cT1 relaxation time compared to placebo 
 
• To evaluate safety and tolerability of TERN-501 monotherapy and TERN-
501+TERN-101  
 
2.2.2.1. Endpoints for the Secondary Objectives 
• Change from baseline in cT1 relaxation time at Week 12 for TERN-501 compared to 
placebo  
• Relative change from baseline in MRI-PDFF at Week 12 for TERN-501+TERN-101 
compared to placebo  
• Change from baseline in cT1 relaxation time at Week 12 for TERN-501+TERN-101 
compared to placebo  
• Patient incidence of treatment emergent adverse events  
 


 
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2.2.3. Exploratory Objectives 
• To explore the effect of TERN-501 monotherapy on efficacy and markers of target 
engagement compared to placebo 
• To explore the effect of TERN-501+TERN-101 on efficacy and markers of target 
engagement, compared to placebo and/or each monotherapy 
• To evaluate the pharmacokinetics of TERN-501 and TERN-101 administered alone 
and in combination  
2.2.3.1. Endpoints for the Exploratory Objectives 
• Change from baseline in the following parameters, as applicable: 
o ALT, AST, and GGT 
o FIB-4, CK-18 (M30 and M65), ELF (PIIINP, TIMP-1, HA), PRO-C3, and 
FAST score 
o TE and CAP 
o MRI-PDFF (relative change) and cT1 
o SHBG 
o Lipid panel (for PD as well as safety evaluation) 
o rT3 
o FGF19, bile acids, and 7αC4 
 
• Proportion of responders on MRI-PDFF and/or cT1 with the following: 
o ≥ 30% relative reduction in MRI-PDFF 
o ≥ 80 msec reduction in cT1  
 
• PK parameters (e.g., AUC, Cmax, Ctau)  
2.3. Sample Size and Power 
Approximately 140 patients will be randomized into one of the 7 groups (n=20 each) to 
detect a clinically meaningful difference in the primary endpoint and secondary endpoints of 
MRI-PDFF relative reduction at Week 12 and secondary endpoints of cT1 reduction at Week 
12 between placebo and TERN-501 monotherapy and separately between placebo and 
TERN-501+TERN-101. 
Power was estimated based on published literature for THR-β agonist resmetirom (to 
estimate TERN-501 effect) and clinical data for TERN-101 (Study TERN101-2001). 
Assuming a pooled standard deviation of 22% (Study TERN101-2001 final analysis), with a 
two-sided alpha of 0.05, a mean relative reduction difference in MRI-PDFF at Week 12 of: 


 
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• 23% between placebo (n=20) and TERN-501 monotherapy (n=20) will provide 
approximately 90% power (Harrison 2019). 
• 36% between placebo (n=20) and TERN-501+TERN-101 (n=20) will provide >90% 
power, based on placebo treatment effect from resmetirom (Harrison 2019) and sum 
of treatment effects from resmetirom (to estimate TERN-501 effect) and minimum 
treatment effect for TERN-101 (Study TERN101-2001), assuming an additive effect 
of the two agents in combination. 
Assuming a pooled standard deviation of 82 msec (Study TERN101-2001 final analysis), 
with a two-sided alpha of 0.05, a mean reduction difference in cT1 at Week 12 of: 
• 77 msec between placebo (n=20) and TERN-501 monotherapy (n=20) will provide 
approximately 82% power (Harrison 2018). 
• 134 msec between placebo (n=20) and TERN-501+TERN-101 (n=20) will provide 
>90% power, based on placebo treatment effect from resmetirom (Harrison 2019) and 
sum of treatment effects from resmetirom (to estimate TERN-501 effect) and 
minimum treatment effect for TERN-101 (Study TERN101-2001), assuming an 
additive effect of the two agents in combination. 
Patients who are randomized but do not receive study drug for any reason may be replaced. 
In addition, patients who discontinue treatment early for reasons other than safety (i.e., 
withdrawal of consent, lost to follow-up, patient relocated, etc.) may also be replaced, at the 
Sponsor’s discretion. Replacement patients will receive the same treatment assignment as the 
patient that discontinued treatment early.  


 
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3. Statistical Methods 
3.1. General Principles 
All data processing, summarization and analyses will be performed using Labcorp Drug 
Development’s SAS Environment / Version 9.4 (or later) of the SAS statistical software 
package.   
Individual patient data obtained from electronic case report forms (eCRFs), central 
laboratories, external sources, and any derived data will be presented in data listings by patient. 
The primary data source will be used for all analyses. All data listings that contain an 
evaluation date will contain a relative study day. Pre-treatment and on-treatment study days 
are numbered relative to the day of the first dose of study drug which is designated as Day 1. 
The preceding day is Day -1, the day before that is Day -2, etc. 
All outputs will be incorporated into Microsoft Word rich text format (.rtf) files, sorted and 
labeled according to the International Council for Harmonization (ICH) E3 guideline, E3 
Structure and Content of Clinical Study Reports, and formatted to the appropriate page size(s), 
font type, and font size according to Food and Drug Administration (FDA) guidance of 
Portable Document Format Specifications. 
For categorical variables, summary tabulations of the number and percentage of patients within 
each category of the parameter will be presented. Percentage calculations will be based on non-
missing data, unless otherwise specified. For each parameter, the total number of patients with 
a response will be provided. Percentages are rounded to 1 decimal place, unless otherwise 
specified. 
For frequency counts of categorical variables, categories whose counts are zero will be 
displayed for the sake of completeness. For example, if none of the patients discontinue due to 
“Lost to Follow-up,” this reason will be included in the table with a count of 0. Percentages 
will be presented to 1 decimal place, with the exception of 0, which will be presented without 
percent, and 100, which will be presented without decimal places. Values less than 0.1% will 
be presented as “<0.1%.” Values less than 100% but greater than 99.9% will be presented as 
“>99.9%.” 
For continuous variables, the number of patients, mean, standard deviation (SD), median, 25th 
(Q1) and 75th (Q3) percentiles, minimum, and maximum values will be presented. The 
precision of summary statistics, unless otherwise specified will be as follows: mean, median, 
Q1, and Q3 to 1 more decimal place than the raw data, SD to 2 decimal places more than the 
raw data, and minimum and maximum to the same decimal places as the raw data. In general, 
the number of decimal places should not exceed 3 decimal places unless appropriate. 


 
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For log-normal data (e.g., the PK parameters of area under the concentration-time curve [AUC] 
and maximum observed concentration [Cmax]), the geometric mean and geometric coefficient 
of variation (CV%) will also be presented. The precision of descriptive statistics will be as 
follows: mean, median, Q1, and Q3 to 1 more decimal place than the raw data, SD to 2 decimal 
places more than the raw data, the minimum and maximum to the same number of decimal 
places as the raw data, geometric mean to 3 significant figures, and geometric CV% to 1 
decimal place. The PK parameters will be presented to 1 decimal place. 
Confidence intervals (CIs) will be provided and will be rounded to 1 decimal place, unless 
otherwise specified, in the table and listing shell. A full set of summary statistics will only be 
presented if there are 3 or more values available. If there are less than 3 values, only the min, 
max, and N will be presented. The other summary statistics will be denoted as not calculated 
(NC). 
For tables where rounding is required, rounding will be done to the nearest round-off unit. For 
example, when rounding to the nearest integer, values ≥XX.5 will be rounded up to XX+1 
(e.g., 97.5 will round up to 98), while values <XX.5 will be rounded down to XX (e.g., 97.4 
will round down to 97). 
All statistical tests comparing groups will be conducted at the 2-sided, 0.05 level of 
significance, unless otherwise specified. Summary statistics for each treatment group will be 
presented, as well as the two-sided 95% CIs for comparing groups. 
Specifications for table, figures, and data listing formats can be found in the TFL shells 
specifications for this study.  
All data recorded on the case report form will be included in data listings. 
3.2. Computing Environments 
All descriptive statistical analyses will be performed using SAS software Version 9.4 or higher, 
unless otherwise noted. 
Plasma PK and PD parameters for TERN-501 and TERN-101 will be estimated using non-
compartmental methods with Phoenix WinNonlin® Version 8.3 or higher. 
Medical history and AEs will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) version 23.0. Concomitant medications will be coded using World Health 
Organization Drug Dictionary (WHODD), B2 Enhanced March 2020. 
Study Data Tabulation Model (SDTM) and Analysis Data Model (ADaM) datasets will be 
prepared using Clinical Data Interchange Standards Consortium (CDISC) SDTM 
Implementation Guide (IG) Version 3.3, ADaM Version 2.1, and CDISC ADaM IG Version 
1.2 including most current occurrence and time to event IGs. 


 
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3.3. Partial Dates  
Imputation of partial adverse event and concomitant medication dates are specified in 
Appendix 2.  
All clinical data recorded on the case report form will be included in data listings. 
3.4. Missing Data 
Treatment end date will be the date of last dose from the End of Study Treatment page of the 
CRF. If this is missing, then the last date (dispensing or return) from the study drug 
accountability page will be used.  
3.5. Data Conventions 
The precision of original measurements will be maintained in summaries, when possible. 
Quantitative safety laboratory tests containing less than (<) and greater than (>) symbols are 
test results that are below and above quantifiable limits, respectively. In order to retain these 
values for analysis purpose, the following will be imputed and stored within the analysis 
datasets: 
• 
For values with <, the imputed value will be the numeric portion × 0.9. 
• 
For values with >, the imputed value will be the numeric portion × 1.1. 
PK and PD imputation of values below the limitation of quantitation (BLQ) are specified in 
Section 7.17.4 and Section 7.18, respectively. 
Variables with a non-normal distribution that impacts the interpretation or validity of the 
planned analysis may have a data transformation applied (e.g., ln, log10). 
3.6. Standard Calculations 
Variables requiring calculation will be derived using the following formulas: 
• 
Days – A duration expressed in days between one date (date1) and another later date 
(date2) will be calculated using the following formulas: 
duration in days = date2 – date1 + 1, where date1 ≥ first administration date 
duration in days = date2 – date1, where date1 < first administration date 
• 
Months – A duration expressed in months is calculated as the number of days divided 
by 30.4375 
• 
Years – A duration expressed in years between one date (date1) and another date 
(date2) is calculated using the following formulas: 


 
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duration in years = (date2 – date1 + 1)/365.25, where date1 ≥ first 
administration date 
duration in years = (date2 – date1)/365.25, where date1 < first administration 
date 
• 
Body Mass Index (BMI) – BMI is calculated using height (cm) and weight (kg) using 
the following formula: 
BMI (kg/m2) = body weight (kg) / ([height (cm)/100]2) 
• 
Change (CHG) will be calculated as: 
Change = later value – earlier baseline value 
• 
Relative change (PCHG or percent change) will be calculated as: 
Relative change = ([Change] / baseline value) × 100 
If a baseline value is 0, the relative change will be missing and not included in summary 
calculations. Within listings, this value will be displayed as NC (not calculable). 
3.7. Treatments 
Table 3 presents how the dose groups will be presented in TFLs as treatment groups, 
including the order. 
Table 3 Treatment Group Labels and Ordering 
Treatment Group Label  
Order on TFLs  
Placebo  
1  
101 10 mg  
2 
501 1 mg  
3 
501 3 mg  
4  
501 6 mg  
5  
501 3 mg + 101 10 mg  
6 
501 6 mg + 101 10 mg  
7  
Screen failures will be presented on by-patient listings where data is available. 
3.8.  Visits 
3.8.1.  Windows 
In data listings, the relative study day of all dates from first dose will be presented. 


 
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Scheduled visit assessments will be determined based on a two-step process using the 
parameters of exposure to study drug and scheduled visit assessment windows. 
Step 1: 
• 
The last dose date (maximum from dates of discontinuation form and exposure data) 
must be within 14 days, inclusive, of the last assessment of those within the treatment 
exposure period (12 weeks). If the last dose date is after or within 14 days inclusive of 
the Week 12 assessment there will be an assumption that all previous assessments were 
performed while under proper drug exposure. Any assessments performed greater than 
14 days of the last dose date will be considered unscheduled irrespective of Table 4 
mapping.  
Step 2: 
• 
Use Table 4 to initially map the appropriate assessment under consideration 
• 
For multiple assessments mapped to the same scheduled visit interval, select the 
assessment date that is closest to the target day of the visit window in terms of 
absolute difference, irrespective of scheduled or unscheduled visit type. Any 
assessment not selected in the window is considered unscheduled. 
In the event of a scheduled visit assessment tie AND the assessment was performed as an 
original scheduled assessment select this over an unscheduled; if both assessments are 
unscheduled or scheduled select the first assessment, then classify the other as unscheduled.  
 


 
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Table 4 Treatment Period Visit Windows 
Target Scheduled Visit  
Target Study 
Daya  
Analysis Window Study Daya  
 
 
Low 
High 
Targeted physical examination, vital signs, ECG, chemistry and hematology labs 
Baseline 
1  
See Section 3.6.2  
Week 2  
15  
2  
22  
Week 4  
29  
23  
36  
Week 6  
43  
37  
50  
Week 8  
57  
51  
70  
Week 12 
85  
71 
99 
Thyroid axis testing 
Baseline 
1  
See Section 3.6.2  
Week 2  
15  
2  
29  
Week 6  
43  
37  
50  
Week 12 
85  
71 
99 
Weight, MRI-PDFF, MRI-cT1, and fibrosis biomarkers 
Baseline 
1  
See Section 3.6.2  
Week 6  
43  
29  
57 
Week 12b 
85  
71 
99 
Week 16 
For all 
parameters, use 
nominal visit as 
recorded on 
CRF. 
 
 
a Study Day will be calculated from first dose of study drug. Visit windows defined by the low 
and high values are inclusive. 
 
3.8.2.  Definition of Baselines 
The baseline value for statistical analyses of quantitative laboratory parameters is defined as 
the last non-missing assessment, including any unscheduled or repeat assessments, collected 
prior to the first administration of study drug, unless otherwise specified.  
For glucose and lipid parameters, only assessments taken while fasting for 8 hours will be 
included in the baseline derivation. 
The baseline value for analyses of qualitative parameters (e.g., normal/abnormal) is defined as 
the last evaluation prior to the first administration of study drug. 


 
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The baseline value for analyses of weight, body mass index (BMI), and electrocardiogram 
parameters is defined as the last evaluation prior to the first administration of study drug. 
3.8.3. Definition of End of Treatment 
The End of Treatment value will be defined as the Week 12 value, either scheduled or 
windowed per Table 5. If a Week 12 value is not available, the last non-missing value on or 
before the last dose date will be used. 


 
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4.  Analysis Sets 
Table 5 defines the analysis sets to be used. 
Table 5 Analysis Sets 
Analysis Sets  
Description  
Screened  
All patients who sign the ICF  
Randomized  
All patients who are randomized into any one 
of treatment groups. Treatment assignment will 
be based on the randomized treatment.  
Pharmacokinetic (PK)  
All randomized patients who received at least 1 
dose of TERN-501 and/or TERN-101 and have 
evaluable PK data. Treatment assignment will 
be based on the treatment actually received.  
Pharmacodynamic (PD)  
All randomized patients who received at least 1 
dose of study drug (TERN-501, TERN-101, 
and/or placebo) and for whom PD markers can 
be evaluated. Treatment assignment will be 
based on the treatment actually received.  
PK/PD sub-study  
All randomized patients who consented to and 
participated in the PK/PD sub-study and 
received at least 1 dose of study drug (TERN-
501 and/or TERN-101). Treatment assignment 
will be based on the treatment actually 
received.  
Safety  
All randomized patients who received at least 1 
dose of study drug. Treatment assignment will 
be based on the treatment actually received.  
Efficacy  
All randomized patients who received at least 1 
dose of study drug. Treatment assignment will 
be based on the randomized treatment.  
Per Protocol (PP)  
 
All randomized patients who have completed 
the study without any major protocol deviations 
affecting the interpretation of the efficacy, PK, 
or PD results 
 


 
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5. Examination of Subgroups 
Subgroups will be assessed at Baseline and only if there are a sufficient number of patients in 
each group, i.e., at least 5 patients in each treatment group. Each efficacy analysis description 
in Section 7 includes the description of subgroup analyses. 
Baseline subgroups of interest are as follows: 
• 
Age categories: < 65, ≥ 65 years 
• 
Sex: Male, Female 
• 
Baseline BMI: < 30 kg/m2, ≥30 - < 35 kg/m2, ≥35 - < 40 kg/m2, ≥ 40 kg/m2 
• 
Baseline Comorbidity of diabetes (yes, no) will be based on Medical History case 
report form, Medical Dictionary of Regulatory Activities (MedDRA) preferred term 
Baseline use of Statins defined by the WHODD Standardized Drug Grouping (SDG) 
of ‘Statins’. This subgroup will only be used for the safety analysis of lipids 
(Section8.3.3). 
• 
cT1 classified as elevated (800 – 875 msec) and high (>875 msec) 


 
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6.  Study Population  
6.1. Patient Disposition  
Patient disposition will be summarized for the Screening Analysis Set by treatment group 
and overall total. The summary will include:  
  
• 
Number of patients screened.  
• 
Number of screen failures, i.e., screened but not randomized, with reasons for screen 
failure. The denominator for percentage of screen failures will be the number of 
patients screened. The denominator for percentages for reasons for screen failures 
will be the number of screen failures.  
• 
Number randomized. The denominator for percentage of randomized patients will be 
the number of patients screened.  
• 
Number randomized and not treated. The denominator for percentage of randomized 
and not treated patients will be the number of patients randomized.  
• 
Number in each analysis set. The denominator for percentage in each analysis set will 
be the number of randomized patients. In addition, the number of patients randomized 
to the PK/PD substudy will be presented.  
• 
Number who discontinued treatment early and reason(s) for discontinuation of 
treatment. The denominator for percentages will be the number of randomized and 
treated patients (Efficacy Analysis Set).  
• 
Number who discontinued from study prior to completing the study and reason(s) for 
discontinuation. The denominator for percentages will be the number of randomized 
and treated patients (Efficacy Analysis Set).  
A by-patient data listing of study disposition information including the reasons for treatment 
and/or study termination will be presented. Withdrawal of consent details will also be included, 
if applicable.  
A by-patient data listing including the reasons for exclusion from each analysis set will be 
presented. 
6.2. Demographics and Baseline Characteristics 
Demographic variables will include the following: 
• 
Age at informed consent including the subgroup of < 65 years vs ≥ 65 years 
• 
Sex 
• 
Race 
• 
Ethnicity 


 
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Other baseline characteristics will include the following: 
• 
Weight (kg) 
• 
Height (cm) 
• 
BMI (kg/m2) including the following subgroups: 
o  < 30, 
o  ≥ 30 - < 35 
o ≥ 35  - < 40 
o ≥ 40 kg/m2 
• 
Baseline liver stiffness measure (LSM) by transient elastography (kPa) 
• 
Baseline Controlled Attenuation Parameter (CAP; dB/m) 
• 
Baseline LFC (%) by MRI-PDFF 
• 
Baseline cTI (msec) by MRI including the following subgroups:  
o Elevated (800 – 875 msec),  
o and High (> 875 msec). 
• 
Liver Biopsy within 1 years of randomization 
• 
Baseline fibrosis stage (F1, F2, F3) 
• 
Baseline NAFLD Activity Score (NAS) 
• 
Baseline ELF including the following subgroups: 
• 
Low (< 7.7) 
• 
Intermediate (≥ 7.7 to < 9.8) 
• 
High (≥ 9.8) 
• 
Baseline PRO-C3 including the following subgroups: 
• 
< 17.5 


 
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• 
≥ 17.5 
• 
Baseline FAST Score including the following subgroups: 
• 
< 0.67 
• 
≥ 0.67 
• 
Baseline Comorbidities will be based on Medical History case report form, Medical 
Dictionary of Regulatory Activities (MedDRA) preferred term (PT)  
o Diabetes status (yes, no) will be defined as PT preferred term (PT) includes 
“diabetes mellitus” or “Diabetic neuropathy” will be assigned yes, otherwise 
no.  
o Hypertension (yes, no) will be defined as PT of “Hypertension” will be 
assigned yes, otherwise no.  
o Dyslipidemia (yes, no) will be defined as Standardized MedDRA query 
(SMQ) of “Dyslipidemia (SMQ)” will be assigned yes, otherwise no.  
o  Primary hypothyroidism (yes, no) will be defined as Standardized MedDRA 
Hypothyroidism (SMQ)  
• 
Baseline medication use, defined as starting prior to first administration of study drug, 
regardless of end date:  
o Statins defined by the WHODD Standardized Drug Grouping (SDG) of 
“Statins”  
o 
 PCSK9 inhibitors defined by the WHODD terms “Inclisiran”, “Alirocumab”, 
“Evolocumab”  
o Fish oil defined by the WHODD Standardized Drug Grouping (SDG) of 
“Omega-3 Fatty Acid” 
o Fibrates defined by the WHODD Standardized Drug Grouping (SDG) of 
“Fibrates”  
o Levothyroxine defined by the WHODD Standardized Drug Grouping (SDG) 
of Levothyroxine  
o Antihypertension medications defined by the WHODD SDG of 
“Antihypertensives”  


 
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o Antithrombotic medications defined by WHODD SDG of “Antithrombotic 
drugs”  
o Antidiabetic medications defined by the WHODD SDG of “Drugs used in 
diabetes”  
o 
Hormonal contraceptives defined by the WHODD SDG of “Drugs used in 
Hormonal contraception” 
o Vitamin E defined by the WHODD drug codes beginning in “001105” or if 
“VITAMIN E” is found in the preferred drug name  
o Pioglitazone or other PPARγ agonists defined by WHODD ATC level 4 
A10BD and A10BG  
o GLP-1 analogues defined by WHODD ATC level 4 code (term) A10BJ 
(Glucagon-like peptide-1 [GLP-1] analogues)  
o DPP-4 inhibitors defined by WHODD ATC level 4 code (term) A10BH 
(Dipeptidyl peptidase 4 [DPP-4] inhibitors)  
o SGLT2 inhibitors defined by WHODD ATC level 4 code (term) A10BK 
(Sodium-glucose co-transporter 2 [SGLT2] inhibitors)  
The following baseline laboratory tests will be summarized as continuous variables and as 
frequencies for categorizations described:  
• 
Baseline ALT level (U/L):  
o  ≤ 60 U/L versus > 60 U/L (overall and by sex)  
o < 2x ULN versus ≥ 2x ULN to < 5x ULN 
• 
Baseline AST level (U/L): The same subgroups as specified for ALT above will be 
used.  
• 
Baseline GGT level (U/L): ≤ ULN, > ULN  
• 
Baseline ALP level (U/L): ≤ ULN, > ULN  
• 
Baseline total bilirubin level (mg/dL) 
• 
Baseline fasting HDL cholesterol (mg/dL)  
• 
Baseline fasting LDL cholesterol (mg/dL)  


 
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• 
Baseline fasting total cholesterol (mg/dL)  
• 
Baseline fasting triglycerides (mg/dL)  
• 
Baseline fasting glucose level (mg/dL)  
• 
HbA1c (%): < 6.5%, ≥ 6.5%  
• 
Baseline platelet count (109/L): 
• 
Baseline free T3 (FT3) 
• 
Baseline total T3 
• 
Baseline free T4 
• 
Baseline total T4 
• 
Baseline TBG 
• 
Baseline rT3 
• 
Baseline FT3/rT3 
Demographics and baseline characteristics will be summarized by treatment group and overall, 
for the Safety, Efficacy, and Per Protocol Analysis Sets.  
All demographic and baseline characteristics data will be presented in by-patient data listings.  
No inferential statistical comparisons will be performed. 
6.3. Protocol Deviations 
Protocol deviations will be identified and documented in the clinical trial management system 
(CTMS). Major protocol deviations that could potentially affect the conclusions of the study 
will be identified prior to database lock and unblinding of individual patient treatment 
information. 
Major protocol deviations include, but are not limited to 
• 
Patients who entered the study even though they did not satisfy the entry criteria. 
• 
Patients who developed withdrawal criteria during the study but were not withdrawn. 
• 
Patients who received the wrong treatment or were dispensed an incorrect dose. 


 
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• 
Patients who received an excluded concomitant treatment. 
All protocol deviations and major protocol deviations will be summarized separately by 
treatment group and overall total for each deviation category using the Efficacy Analysis Set. 
All protocol deviations and separately only major protocol deviations will be presented in a 
by-patient data listing.  
6.4. General Medical History 
All medical history conditions will be coded using the Medical Dictionary of Regulatory 
Activities (MedDRA). Medical history will be summarized by treatment group and overall 
total by system organ class and preferred term, using the Safety Analysis Set. Summaries will 
be ordered by descending order of the overall incidence of system organ class and preferred 
term within each system organ class. 
6.5. Prior and Concomitant Medications 
Prior medications are defined as medications that started before first study drug administration 
and either stopped before or continued after first study drug administration. Concomitant 
medications are defined as medications that are being taken while on study drug through 30 
days after last dose or through the Follow-Up Period (Week 16). Medications that are ongoing 
on the date of the first administration of study drug will be classified as both prior and 
concomitant. Any medication that cannot be confirmed as stopping before the start of study 
drug will be classified as both a prior and a concomitant medication. Imputation of partial dates 
is defined in Appendix 2. 
Prior and concomitant medications will be summarized separately and the number and 
percentage of patients in each treatment group who took at least one prior (concomitant) 
medication as well as the number and percentage of patients who took each type of medication 
will be summarized by Anatomic Therapeutic Class (ATC) Level 2 and preferred name for the 
Safety Analysis Set. If a patient has more than one occurrence of the same preferred name, 
then the preferred name will be counted only once for that patient. Similarly, if a patient has 
more than one preferred name within ATC Level 2, then the patient will be counted only once 
in that ATC Level 2. 
Any medications with potential beneficial impact on NASH outcome and steatohepatitis will 
be presented in a separate by-patient listing.  
 


 
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7. Efficacy Analyses 
7.1. Adjustments for Covariates 
The Baseline value will be used as a covariate in each ANCOVA model. 
7.2. Handling of Dropouts or Missing Data 
Primary analyses will be based on observed data. For the primary endpoint, a sensitivity 
analysis will be conducted for patients who do not complete the Week 12 visit, where the last 
on-treatment value, including any values collected at unscheduled visits, will be carried 
forward (LOCF) and used for Week 12.  
7.3. Interim Analyses and Data Monitoring 
No interim analysis or data monitoring committees are planned for this study. 
7.4. Multicenter Studies 
The randomization is not stratified by site. Likewise, analyses of data will not be stratified by 
study site. 
7.5. Use of an “Efficacy Subset” of Patients 
Not Applicable. 
7.6. Multiple Comparisons/Multiplicity 
Table 6 depicts the pairwise comparisons which will be performed denoted by “X”. 
Table 6 Pairwise Comparison for Display 
 
101 
501 (1) 
501 (3) 
501 (6) 
101+501 (3) 
101+501 (6) 
Placebo 
X 
X 
X 
X 
X 
X 
501 (3) 
 
 
 
 
X 
 
501 (6) 
 
 
 
 
 
X 
 
Table 7 depicts the order or comparison for the hierarchical testing strategy. 
   


 
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Table 7 Hierarchical Testing Strategy 
MRI-PDFF 
 
101 
501 (1) 
501 (3) 
501 (6) 
101+501 (3) 
101+501 (6) 
Placebo 
 
3 
2 
1 
5 
4 
501 (3) 
 
 
 
 
7 
 
501 (6) 
 
 
 
 
 
6 
cT1 
 
101 
501 (1) 
501 (3) 
501 (6) 
101+501 (3) 
101+501 (6) 
Placebo 
4 
3 
2 
1 
6 
5 
501 (3) 
 
 
 
 
8 
 
501 (6) 
 
 
 
 
 
7 
 
7.7. Analysis and Reporting of Change and Relative Change from Baseline 
Analysis of change and relative change will be performed using a type III sum of squares 
ANCOVA model with treatment group as a fixed effect and baseline covariate, where 
applicable. Least squares (LS) means and standard errors (SE) as well as 95% confidence 
intervals (CIs) will be presented for each treatment group at each scheduled visit.  
LS estimates of the mean difference, SE, and 95% CI between each TERN active treatment 
group versus placebo comparison will be presented at scheduled visits. Analyses will include 
the pairwise comparisons in table 6 of Section 7.6 at week 12, unless otherwise specified. 
Relative change will include LS means, SE, and 95% CI but only MRI-PDFF relative change 
will include inferential statistics. 
Table displays:  
(1) Observed result descriptive statistics, as described in Section 3.1, will be displayed 
within the same table.  
(2) All scheduled visits should be reported. 
(3) Pooling of treatment group should not be performed or displayed unless noted 
otherwise. 
7.8. MRI-PDFF Analyses 
For all MRI-PDFF analyses, relative change from baseline and absolute change in MRI-
PDFF will be analyzed and reported according to Section 7.7 using the pairwise comparisons 
in Section 7.6 for the efficacy and per protocol analysis sets.  


 
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An additional sensitivity analysis of relative change in MRI-PDFF at Week 12 using a last 
observation carried forward (LOCF) approach will be performed according to Section 7.7 
using the pairwise comparisons in Section 7.6 for the efficacy analysis set. The LOCF endpoint 
will be labelled “End of Treatment”. For the LOCF analysis, patients who complete Week 12, 
the Week 12 value will be used. For patients who do not complete treatment, the last value on 
treatment will be used. Otherwise, the Week 12 response will be missing. 
An analysis of MRI-PDFF relative change responders using the pairwise comparisons in 
Section 7.6 will be performed using the efficacy analysis set. Responders will be defined as 
any patient with a relative decrease of at least: (1) 30% (i.e., ≤-30%), (2) 40%, (3) 50% at 
weeks 6 and 12. Non-responders will be defined as any patient who did not have at least a 
relative decrease for each specific analysis. The frequency and percentage of responders along 
with a two-sided exact (Clopper-Pearson) 95% CI for the percentage of responders will be 
presented. For each pairwise comparison, the difference in percentage of responders, 95% CI, 
and p-value using a chi-square test will be presented. 
7.8.1. cT1 
For all cT1 analyses, change from baseline in cT1 will be analyzed and reported according to 
Section 7.7 using the pairwise comparisons in Section 7.6 for the efficacy and per-protocol 
analysis sets.  
An analysis of cT1 change responders using the pairwise comparisons in Section 7.6 will be 
performed for the efficacy analysis set. Responders will be defined as any patient with a 
decrease of at least 80 msec at weeks 6 and 12. Non-responders will be defined as any patient 
who did not have at least a 80 msec decrease for each specific analysis. The frequency and 
percentage of responders along with a two-sided exact (Clopper-Pearson) 95% CI for the 
percentage of responders will be presented. For each pairwise comparison, the difference in 
percentage of responders, 95% CI, and p-values using a chi-square test will be presented. 
7.9. Liver Enzymes (ALT, AST, GGT) 
For ALT, AST, and GGT analyses, change from baseline will be analyzed according to 
Section 7.7 using the pairwise comparisons in Section 7.6 for the efficacy analysis set.  
An analysis of ALT change responders using the pairwise comparisons in Section 7.6 will be 
performed for the efficacy analysis set. Responders will be defined as any patient with a 
decrease of at least 17 U/L from baseline at weeks 6 and 12. Non-responders will be defined 
as any patient who did not have at least a decrease for each specific analysis. The frequency 


 
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and percentage of responders along with a two-sided exact (Clopper-Pearson) 95% CI for the 
percentage of responders will be presented. For each pairwise comparison, the difference in 
percentage of responders, 95% CI, and p-value using a chi-square test will be presented. 
7.10. NASH and Fibrosis Biomarkers 
Change from baseline in markers of hepatic fibrosis and apoptosis include CK-18 (M30 and 
M65), PIIINP, TIMP-1, HA, and PRO-C3, will be analyzed according to Section 7.7 and 
pairwise comparisons in Section 7.6 using the efficacy analysis set. 
7.11. Reverse T3 (rT3) 
Change in rT3 and FT3/rT3 will be analyzed according to Section 7.7 and pairwise 
comparisons in Section 7.6 using the efficacy analysis set.  
7.12. Fibrosis-4 (FIB-4) Score 
The Fibrosis-4 (FIB-4) score helps to estimate the amount of scarring in the liver. The FIB-4 
score is calculated as:  
[Age (years) × AST (U/L)] ÷ [Platelet Count (109/L) × ALT (U/L)0.5].   
Age at informed consent will be used.  Lab values at each visit, from the same visit, will be 
used.  The central lab calculation of FIB-4 will be used in analyses. The FIB-4 score will be 
calculated at baseline, Week 6, Week 12, and Week 16. 
The change from baseline in FIB-4 score will be analyzed in the same manner as specified in 
Section 7.7 and pairwise comparisons in Section 7.6 using the efficacy analysis set.  
7.13. Enhanced Liver Fibrosis (ELF) Score 
The enhanced liver fibrosis (ELF) score will be calculated as:  
2.278 + 0.851 ln (HA) + 0.751 ln (PIIINP) + 0.394 ln (TIMP-1).  
Lab values from the same visit will be used to calculate the ELF score. The central lab 
calculation of ELF will be used in analyses.  Programming will also calculate the score 
programmatically for validation. The ELF score will be calculated at baseline and post-baseline 
visits Week 6 and Week 12. 


 
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The change from baseline in ELF score will be analyzed in the same manner as specified in 
Section 7.7 and pairwise comparisons in Section 7.6 using the efficacy analysis set. 
7.14. Nonalcoholic Fatty Liver Disease (NAFLD) Fibrosis Score 
The Nonalcoholic Fatty Liver Disease (NAFLD) fibrosis score will be calculated as:  
-1.675 + [0.037 × Age (years)] + [0.094 × BMI (kg/m2)] + [1.13 × baseline diabetes 
status (yes = 1, no = 0)] + [0.99 × AST/ALT ratio] – [0.013 × Platelet Count (109/L)] 
– [0.66 × Albumin (g/dL)].  
Age at informed consent and baseline diabetes status will be used. BMI at Screening, Baseline, 
and Weeks 6, 12, and 16 will be calculated using the weight from that visit and height from 
screening. Programming will calculate the score at each to be used in analyses.  The NAFLD 
fibrosis score will be calculated at screening, baseline, Week 6, Week 12, and Week 16. 
The change from baseline in NAFLD fibrosis score will be analyzed in the same manner as 
specified in Section 7.7 and pairwise comparisons in Section 7.6 using the efficacy analysis 
set.   
7.14.1.1. AST to Platelet Ratio Index (APRI) 
The AST to Platelet Ratio Index (APRI) will be calculated as:  
(AST Level [IU/L] / AST Upper Limit of Normal IU/L]) × 100 / Platelet Count 
(109/L).  
Lab values at each visit, from the same visit, will be used.  The APRI will be calculated at 
baseline, Week 6, Week 12, and Week 16. 
The change from baseline in APRI will be analyzed in the same manner as specified in Section 
7.7 and pairwise comparisons in Section 7.6 using the efficacy analysis set.   
7.15. FAST Score  
The change from baseline in the FAST score will be analyzed as described in Section 7.7 and 
pairwise comparisons in Section 7.6 using the efficacy analysis set. 
The FAST score was calculated according to the following formula10:  
FAST = {exp (–1.65 + 1.07 × ln (LSM) + 2.66 × 10–8 × CAP3 – 63.3 × AST–1)}/{1 + exp (–
1.65 + 1.07 × ln (LSM) + 2.66 × 10–8 × CAP3 – 63.3 × AST–1)}. 


 
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7.16. TE and CAP 
The change from baseline in TE and CAP will be analyzed as described in Section 7.7 and pairwise 
comparisons in Section 7.6 using efficacy analysis set. 
7.17. Pharmacokinetic Analyses 
PK Parameter Generation: 
 The following PK parameters will be determined where possible from the plasma 
concentrations of TERN-501, TERN-101, and TERN-101 metabolite TRN-000971 using 
noncompartmental methods in validated software program Phoenix WinNonlin (Certara, 
Version 8.3.5 or higher) for all patients for the PK Sub-study Analysis Set: 
 


 
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Table 8 PK Profile Day 1* 
Parameter 
Unitsa 
Definition 
AUC0-last 
h*ng/mL 
area under the concentration-time curve from time 0 to the time 
of the last quantifiable concentration (tlast)c 
AUCtau 
h*ng/mL 
area under the concentration‑time curve over a dosing interval 
(τ) 
AUC0-∞ 
h*ng/mL 
area under the concentration-time curve from time 0 
extrapolated to infinityc 
%AUCextrap 
% 
percentage of area under the concentration-time curve due to 
extrapolation from the last quantifiable concentration to infinity 
Cmax 
ng/mL 
maximum observed concentration 
Ctau 
ng/mL 
concentration observed at the end of the dosing 
interval/immediately prior to dosing 
Tmax 
h 
time of the maximum observed concentration 
Tlast 
h 
time of the last quantifiable concentration 
t1/2 
h 
apparent terminal elimination half-life 
CL/F 
L/h 
apparent total clearance (parent analyte only) 
Vz/F 
L 
apparent volume of distribution during the terminal phase 
(parent analyte only) 
MR AUC0-τ 
 
metabolite:parent ratio based on AUC0-τ 
AUC0-tau/D 
h*ng/mL/mg AUC0-τ normalized by dose administeredd 
AUC0-last/D 
h*xg/mL/xg 
AUC0-tlast normalized by dose administeredd 
AUC0-∞/D 
h*ng/mL/mg AUC0-∞ normalized by dose administeredd. 
Cmax/D 
ng/mL/mg 
Cmax normalized by dose administeredd 
a Units are based on concentration units (provided by the bioanalytical lab or preferred units for presentation of PK 
parameters) and dose units used in the study. 
b The AUC will be calculated using the linear trapezoidal rule for increasing concentrations and the logarithmic rule for 
decreasing concentrations (linear up/log down rule).  
c Based on the last observed quantifiable concentration 
d Calculated by dividing the parameter by the dose (mg) 
* Concentration-time profile following dosing on Profile Day 1 
 
 
 


 
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Table 9 PK Profile Week 12* 
Parameter 
Unitsa 
Definition 
AUC0-last 
h*ng/mL 
area under the concentration-time curve from time 0 to the time of 
the last quantifiable concentration (tlast)b 
AUCtau 
h*ng/mL 
area under the concentration‑time curve over a dosing interval (τ) 
Cmax 
ng/mL 
maximum observed concentration 
Ctau 
ng/mL 
concentration observed at the end of the dosing 
interval/immediately prior to dosing 
Tmax 
h 
time of the maximum observed concentration 
Tlast 
 
 
t1/2 
h 
apparent terminal elimination half-life 
CL/F 
L/h 
apparent total clearance (parent analyte only) 
Vz/F 
L 
apparent volume of distribution during the terminal phase (parent 
analyte only) 
MRAUC0-tau 
 
metabolite: parent ratio based on AUC0-tau 
ARAUC 
 
accumulation ratio based on AUC0-tau 
ARCmax 
 
accumulation ratio based on Cmax during the dosing interval  
AUC0-tau/D 
h*ng/mL/mg AUC0-τ normalized by dose administeredd 
AUC0-last/D 
h*ng/mL/mg AUC0-tlast normalized by dose administeredd 
Cmax/D 
ng/mL/mg 
Cmax normalized by dose administered d 
LR 
 
Linearity ratio 
The dosing interval τ is 24 hours. 
a Units are based on concentration units (provided by the bioanalytical lab or preferred units for presentation of PK 
parameters) and dose units used in the study. 
b Area under the concentration-time curve will be calculated using the linear trapezoidal rule for increasing concentrations 
and the logarithmic rule for decreasing concentrations (linear up/log down rule). 
c Based on the last observed quantifiable concentration 
d Calculated by dividing the parameter by the dose (mg) 
* Concentration-time profile following multiple dosing on Profile Week 12  
Additional PK parameters may be determined where appropriate. 
Pharmacokinetic analysis will be carried out where possible using actual dose administered 
and actual postdose blood sampling times. If an actual time is missing, the sample 
concentration result will be treated as missing unless there is scientific justification to include 
the result using the nominal time. 


 
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The parameters Cmax, Ctau, tlast, and tmax will be obtained directly from the concentration-time 
profiles. If Cmax occurs at more than 1 timepoint, tmax will be assigned to the first occurrence 
of Cmax. 
The metabolite: parent ratio(s) (MRAUC) will be calculated as follows: 
MRAUC = (AUC TRN-000971 / MW TRN-000971) / (AUC TERN-101 / MW TERN-
101), where MW is the molecular weight of each analyte. 
The molecular weights of parent analyte and metabolite(s) to be used in the adjustment are as 
follows: 
TERN-101  = 540.44 g/mol 
TRN-000971 = 716.56 g/mol 
The parameter AUC0-tlast or other common partial area may be used to determine MRAUC if 
AUC0-∞ or AUC0-τ cannot be reliably calculated for the majority of subjects. 
The linearity ratio (LR) will be calculated as ratio of AUC0-τ following multiple dosing to 
AUC0-∞ following a single dose: 
LR = AUC0-τ Profile Week 12 / AUC0-∞ Profile Day 1 
7.17.1. Criteria for the Calculation of Apparent Terminal Elimination Rate Constant 
and Half-life 
The start of the terminal elimination phase for each subject will be defined by visual inspection 
and generally will be the first point at which there is no systematic deviation from the log-
linear decline in concentrations. 
The apparent terminal elimination rate constant (λz) will only be calculated when a reliable 
estimate can be obtained using at least 3 data points, preferably not including Cmax, and the 
adjusted coefficient for determination of exponential fit (R2-adj) of the regression line is ≥
0.7. Parameters requiring λz for their calculation (eg, AUC0-∞, t1/2, CL/F (Profile Day 1 only), 
Vz/F) will only be calculated if the R2-adj value of the regression line is ≥0.7. 
 
The following regression-related diagnostic PK parameters will be determined where 
possible: 


 
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Parameter 
Units 
Definition 
λz 
1/h 
apparent terminal elimination rate constant 
λz Upper 
h 
end of exponential fit 
λz Lower 
h 
start of exponential fit 
λz N 
 
number of data points included in the log-linear regression 
λz Span Ratio 
 
time period over which λz was determined as a ratio of t1/2 
R2-adj 
 
adjusted coefficient for determination of exponential fit 
Where possible, the span of time used in the determination of λz (i.e., the difference between λz Upper and λz Lower) should be ≥2 half-
lives. If the λz Span Ratio is <2, the robustness of the t1/2 values will be discussed in the clinical study report (CSR). 
7.17.2. Criteria for Calculation and Reporting of Area Under the Concentration-time 
Curve 
The minimum requirement for the calculation of AUC will be the inclusion of at least 3 
consecutive concentrations above the lower limit of quantification. If there are only 3 
consecutive concentrations, at least 1 should follow Cmax. An exception may be made for 
metabolite, where Cmax may be the last timepoint. 
If the extrapolated area is >20%, AUC0-∞ (and derived parameters) may be excluded from the 
summary statistics at the discretion of the sponsor or pharmacokineticist. 
If the τ PK blood sample is collected slightly early (i.e., the 24 hours sample), the actual 
sampling time of the τ sample may be used for the calculation of AUC0-τ. However, the AUC0-
τ parameter will be calculated if the τ sample is within 60 minutes of the nominal sampling 
time. 
7.17.3. Criteria for Handling Concentrations Below the Limit of Quantification or 
Missing Concentrations for Pharmacokinetic Analysis (i.e., PK Parameter Generation) 
For the purposes of PK parameter generation, plasma concentrations below the limit of 
quantification (BLQ) will be assigned a value of 0 before the first measurable concentration 
and thereafter BLQ concentrations will be treated as missing. The following rules apply to the 
specific situations defined below:  
• If an entire concentration-time profile is BLQ, it will be excluded from PK analysis. 
• Where there is NR, these will be set to missing. 
• Where 2 or more consecutive concentrations are BLQ at the end of a profile, the 
profile will be deemed to have terminated and any further quantifiable concentrations 
will be set to missing for the calculation of the PK parameters, unless they are 


 
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considered to be a true characteristic of the profile of the drug. If a predose plasma 
concentration is missing, it will be set to 0 by default within Phoenix WinNonlin for 
the first dosing day (Study Profile Day 1). 
• For multiple dose (Study Profile Week 12), if the analyte concentration at τ (i.e., 24 
hours postdose for once daily dosing) is missing, this may be substituted with the 
predose concentration. Similarly, if the predose concentration is missing then this 
may be substituted with the concentration at τ. 
7.17.3.1. Treatment of Outliers in Pharmacokinetic Analysis 
If a value is considered to be anomalous due to being inconsistent with the expected PK 
profile, it may be appropriate to exclude the value from the PK analysis. However, the 
exclusion of any data must have strong justification and will be documented in the CSR. 
Any quantifiable predose concentration value on the first dosing day (Study Profile Day 1) 
will be considered anomalous and set to missing for the PK analysis if determined as predose 
after investigation. This will be set to 0 by default in Phoenix WinNonlin. 
7.17.4. Presentation of Pharmacokinetic Data 
A listing of PK blood sample collection times as well as plasma concentrations will be 
presented for TERN-501, TERN-101, and TERN-101 metabolite TRN-000971 separately for 
all patients for the Pharmacokinetics Analysis Set.  
Pharmacokinetic concentrations will be summarized for the PK Analysis Set for each timepoint 
by treatment group using protocol scheduled times and appropriate summary statistics. 
Individual patient and geometric mean concentration-time profiles, for each TERN-101 dose, 
will be presented graphically on linear and logarithmic concentration scales for PK/PD 
substudy patients for Day 1 and Week 12. 
If the actual time of sample collection deviates from the nominal time by more than ±10%, the 
plasma concentration will be flagged and excluded from the summary statistics. Individual 
concentrations deemed to be anomalous will be flagged in the listings and excluded from the 
summary statistics. For plasma concentration data, the following rules will apply: 
• Values that are BLQ will be set to 0 for the calculation of summary statistics and 
the number of values that are BLQ will be presented. 
• Arithmetic mean or median values that are BLQ will be presented as 0.  
• Where there is NR, these will be set to missing 


 
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• If there are less than three values in the data series, only the minimum, maximum, 
and number of observations will be presented. The other summary statistics will 
be denoted as not calculated (NC). BLQ is considered a value for these purposes. 
• If all values are BLQ, then the arithmetic mean, arithmetic SD, median, 
minimum, and maximum will be presented as 0, and the geometric mean and 
geometric CV% will be denoted as NC. 
For PK parameters, the following rule will apply: 
Geometric mean and coefficient of variation will not be calculated for Tlast or Tmax. 
7.18. Pharmacodynamic Analyses 
The pharmacodynamic (PD) endpoints of SHBG, lipid panel, FGF19, 7αC4, and bile acids 
are collected at the timepoints shown in Table 8 of the protocol.  
The change from baseline in SHBG, LDL-c, will be analyzed in the same manner as 
specified in Section 7.7 and pairwise comparisons in Section 7.6 using the efficacy analysis 
set.  
Plasma concentrations for 7αC4, FGF19, and bile acids that are BLQ will be set to ½ × BLQ. 
Plasma PD parameters will be computed for PD patients only. Plasma PD parameters for 7αC4 
and FGF19 will be calculated from the individual plasma concentrations using a non-
compartmental approach for Day 1 and Week 12. Day 1 will include pre dose and all post dose 
assessments prior to dosing on Day 2. Week 12 will include pre dose and all post dose 
assessments. The actual PD sampling times will be used for the PD analysis. If actual PD 
sampling times are missing, nominal times will be used. Table 1 below presents the plasma PD 
parameters to be calculated. 


 
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Table 10 Plasma PD Parameters 
Abbreviation 
Parameter Definition 
AUEC0-24 
Area under the effect-time curve from time 0 to 24 hours postdose 
RAUEC 
Ratio of AUEC (Week 12) /AUEC (Day 1). 
Cmin 
For 7αC4 only, minimum observed plasma concentration, obtained directly 
from the plasma concentration-time profiles. In the case where multiple 
minimums are of equal magnitude, the earliest minimum concentration will be 
reported as Cmin. 
RCmin 
For 7αC4 only, ratio of Cmin (Week 12) /Cmin (Day 1). 
Cmax 
For FGF19 only, maximum observed plasma concentration, obtained directly 
from the plasma concentration-time profiles. In the case where multiple peaks 
are of equal magnitude, the earliest peak concentration will be reported as 
Cmax. 
RCmax 
For FGF19 only, the ratio of Cmax (Week 12) /Cmax (Day 1). 
tmin 
For 7αC4 only, time of the minimum observed plasma concentration, obtained 
directly from the plasma concentration-time profiles. In the case where 
multiple minimums are of equal magnitude, the time of the earliest minimum 
will be reported as the tmin. 
tmax 
For FGF19 only, time of the maximum observed plasma concentration, 
obtained directly from the plasma concentration-time profiles. In the case 
where multiple peaks are of equal magnitude, the time of the earliest peak will 
be reported as the tmax. 
 
7.18.1. PD Parameter Data Handling 
7.18.1.1. Calculation of AUC 
AUCs will be calculated using linear up / log down trapezoidal rule. For any partial AUC 
determination (i.e., AUC over a dosing interval), nominal time will generally be used for the 
end of the interval. The minimum requirement for the calculation of AUC will be the inclusion 
of at least three consecutive plasma concentrations above the LLOQ, with at least one of these 
concentrations following Cmax for FGF19 and Cmin for 7αC4. 
7.18.2. Statistical Methods for PD Parameters 
Plasma PD parameters will be summarized by treatment group using descriptive statistics 
(number of non-missing observations, arithmetic mean, SD, median, minimum, maximum, 


 
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geometric mean, and geometric CV%). For the calculation of summary statistics, all NR and 
not calculated (NC) values in a data series will be set to missing. 
Analyses of AUC for both 7αC4 and FGF19, Cmax for FGF19, and Cmin for 7αC4 at Day 1 and 
Week 12 will be carried out using an analysis of variance (ANOVA) model with the PD 
parameter as the dependent variable including treatment group as a fixed effect. The estimate 
of the LS means, SE, and 95% CIs will be presented by treatment group. Estimates of the LS 
mean difference for each pairwise comparison will be presented with associated the standard 
error of the difference, and 95% CI of the difference. 
7.18.3. PK/PD Analyses 
For patients in the PK/PD substudy, Day 1 and Week 12 PK and PD (7αC4 and FGF19) 
concentrations will be plotted together by treatment group over time. Similarly, AUCs, Cmin, 
and Cmax for PK and PD will also be plotted by treatment group.  


 
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8. Safety Analyses 
All safety analyses will be conducted using the safety analysis set unless otherwise noted. 
8.1. Extent of Exposure 
Total duration of exposure will be calculated in days as the last date study drug administration 
– the first date study drug administration + 1. In addition, duration of exposure accounting for 
days where a dose was missed (referred to as interruptions on CRFs) will be calculated as total 
duration – sum of (Week X date of resumption – Week X start date of interruption) where X 
is the week number, i.e., 2, 4, 6, 8, and 12. The dates of interruption are from the Study Drug 
Interruptions CRF. If dates of missed doses are not available, the number of missed doses will 
be used. Duration of exposure, total and accounting for missed dosing days, will be 
summarized with descriptive statistics by treatment group. 
The number and percentage of patients with any missed dose and the total duration of days 
where doses were missed will be summarized with descriptive statistics by treatment group. 
Compliance based on the Study Drug Administration and Study Drug Interruptions CRFs will 
be calculated as: 
• 
100 × [((last date study drug administration – the first date study drug administration + 1) 
– sum of durations interrupted) / (last date study drug administration – the first date study 
drug administration + 1)]. 
Compliance will be calculated based on the Study Drug Accountability CRF as: 
• 
100 × [(Sum of tablets or capsules taken during study) / (Expected Taken)] 
Tablets and/or Capsules will be summed across all bottles, whether monotherapy or 
combination, at each week. 
Expected taken is calculated as the study day of the last dose date × 4 (number of tablets or 
capsule taken per day). Treatment compliance will be summarized with descriptive statistics 
by treatment group. The number and percentage of patients in each of the following compliance 
categories will be summarized by treatment group and overall total: 


 
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• 
< 80% 
• 
80% to ≤ 100% 
• 
> 100%. 
Study drug administration including missed doses, delays, and overdoses, and study drug 
dispensing and accountability, calculated durations of exposure, and calculated compliance 
will be presented in by-patient data listings.  
8.2. Adverse Events 
Adverse event (AE) verbatim terms on eCRFs will be mapped to preferred terms (PT) and 
system organ classes (SOC) using MedDRA. AE severity will be categorized using the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE, 
Version 5). 
All AEs will be listed, but summaries will be restricted to treatment emergent AEs (TEAEs), 
defined as any AE with a start date on or after the date of first administration of study drug 
through 30 days after the last administration of study drug or through the Follow-Up Period 
(Week 16). Related SAEs after Week 16 will be considered TEAEs. If it cannot be determined 
whether an AE is treatment emergent due to a partial onset date, then it will be counted as such. 
Methodology for imputation of partial AE start and stop dates is described in Appendix 2. Each 
summary will be displayed by treatment group. 
8.2.1. Overall Summary of Adverse Events 
An overall summary of TEAEs will be presented by treatment group. The number and 
percentage of patients who experience at least one of the following: 
• 
Any TEAE, All CTCAE grades 
• 
Grade 3 or higher TEAE 
• 
Serious TEAE 
• 
TEAE leading to death 
• 
Treatment-related TEAE, All CTCAE grades 
• 
Treatment-related Grade 3 or higher TEAE 
• 
Treatment-related serious TEAE 
• 
TEAE leading to study drug interruption 
• 
TEAE leading to study drug discontinuation 
• 
TEAE leading to discontinuation from the study 


 
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8.2.2. Patient Incidence of Adverse Events 
Summaries will be displayed by SOC and PT and will be ordered by descending order of group 
7 incidence of system organ class and preferred term within each system organ class. 
Summaries of the following types will be presented: 
• 
Patient incidence of TEAEs by MedDRA SOC and PT.  
• 
Patient incidence of TEAEs leading to study drug discontinuation by MedDRA SOC 
and PT. This is a subset of the AEs where Action Taken with Study Drug is checked 
as “Drug Withdrawn.” 
• 
Patient incidence of TEAEs leading to study drug interruption by MedDRA SOC and 
PT. This is a subset of the AEs where Action Taken with Study Drug is checked as 
“Drug Interrupted.” 
• 
Patient incidence of TEAEs leading to study discontinuation by MedDRA SOC and PT 
(subset of the AEs where Reason for Discontinuation on the End of Study CRF is 
“Adverse Event”). 
• 
Patient incidence of TEAE leading to death by MedDRA SOC and PT. 
• 
Patient incidence of TEAEs by MedDRA SOC, PT, and highest severity (CTCAE 
grade). At each level of patient summarization, a patient is classified according to the 
highest severity if the patient reported 1 or more events. AEs with missing severity 
(CTCAE grade) will be considered Grade 3 (severe) for this summary. 
• 
Patient incidence of CTCAE Grade 3 or higher TEAEs by MedDRA SOC and PT. At 
each level of patient summarization, a patient is classified according to the highest 
severity if the patient reported 1 or more events. AEs with missing severity (CTCAE 
grade) will be considered Grade 3 (severe) for this summary. 
• 
Patient incidence of treatment-related TEAEs by MedDRA SOC and PT. Related AEs 
are those with relationships reported as “Related” or “Possibly Related”. At each level 
of patient summarization, a patient is classified according to the closest relationship to 
study drug if the patient reported 1 or more events. AEs with a missing relationship 
will be considered related for this summary. 
• 
Patient incidence of treatment-related CTCAE Grade 3 or higher TEAEs by MedDRA 
SOC and PT. At each level of patient summarization, a patient is classified according 


 
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to the highest severity if the patient reported 1 or more events. AEs with missing 
severity (CTCAE grade) will be considered Grade 3 (severe) for this summary. AEs 
with a missing relationship will be considered related for this summary. 
• 
Patient incidence of serious TEAEs by MedDRA SOC and PT. 
The following listings will be presented by treatment group and patient, include study day 
event started and the duration of event: 
• 
All adverse events. 
• 
Serious adverse events (subset of the AEs where serious is marked as “Yes”). 
• 
Adverse events leading to study drug interruption (subset of the AEs where Action 
Taken with Study Drug is checked as “Study drug interrupted”). 
• 
Adverse events leading to study drug discontinuation (subset of the AEs where Action 
Taken with Study Drug is checked as “Study drug discontinued”). 
• 
Adverse events leading to study discontinuation (subset of the AEs where Reason for 
Discontinuation on the End of Study CRF is “Adverse Event”). 
• 
CTCAE Grade 3 or higher adverse events (subset of AEs where severity is marked as 
CTCAE Grade 3, 4, or 5). 
• 
Related adverse events (subset of the AEs where relationship marked as “Definitely 
Related” or “Possibly Related”). 
• 
CTCAE Grade 3 or higher treatment-related adverse events (subset of AEs where 
severity is marked as CTCAE Grade 3, 4, or 5). 
8.2.3. Pruritus  
For patients who report AEs consistent with pruritus at the visit, a qualified staff member will 
administer the Pruritus Numerical Rating Scale (see Appendix 8 of the study protocol). The 
Pruritus Numerical Rating Scale assesses a patient’s severity of itching on average and at its 
worst point, in the past 24 hours, on a scale of 0 (no itching) to 10 (worst imaginable itch). 
Pruritus events will be identified in the ADAE. 
Treatment-emergent pruritus is defined as any preferred term including “Prur”.  


 
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A separate by-patient listing for pruritus events will be provided with associated Pruritus 
Numerical Rating Scale results, if applicable. 
8.3. Clinical Safety Laboratory Evaluations 
All laboratory assessments are specified in Appendix 1 of the study protocol. Laboratory 
parameters will be summarized in conventional units. Coagulation parameters, hemoglobin 
A1c, direct bilirubin, and indirect bilirubin will not be summarized. 
Quantitative clinical chemistry, hematology, and urinalysis results will be summarized by 
treatment group using descriptive statistics at baseline and at each post-baseline visit. The 
change and percent change from baseline will also be summarized. 
Additional summaries will be provided by scheduled visits for the number and percentage of 
patients with  
• Total CK > 5x ULN 
• Hg < 10 mg/dL 
• HCT < 30% 
• platelets < 100,000 /microL 
• WBC < LLN 
All clinical safety laboratory data will be presented in by-patient data listings. A separate listing 
for central laboratory normal ranges, by lab category, lab test, lab parameter, sex, and age, will 
be presented.  
8.3.1. Treatment Emergent Abnormalities 
Quantitative laboratory tests will be assigned grades based on National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5. For each 
applicable laboratory test, a treatment emergent abnormality will be defined as a post-baseline 
through Week 16 CTCAE grade increase of ≥2 grades. 
The number and percentage of patients overall and by laboratory test, with any treatment 
emergent laboratory abnormality, CTCAE increase of ≥2 grades, will be presented. Similarly, 
the number and percentage of patients overall and by laboratory test, with CTCAE increase of 
≥1 grade will be presented. 


 
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Estimated glomerular filtration rate (eGFR) is calculated by the central lab using the Chronic 
Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. eGFR does not have a 
normal range within the central lab data. A normal range will be defined as ≥90 
mL/min/1.73m2. 
LDL cannot be graded via NCI CTCAE version 5. For the purposes of treatment emergent 
abnormalities, LDL will be graded as follows: 
• 
Optimal: < 100 mg/dL 
• 
Near or Above Optimal: 100 – 129 mg/dL 
• 
Borderline High: 130 – 159 mg/dL 
• 
High: 160 – 189 mg/dL 
• 
Very High: > 189 mg/dL 
Listings will be presented for any patient with any treatment emergent laboratory abnormality 
(post-baseline through Week 16 CTCAE increase of ≥ 2 grades). Normal ranges provided by 
the central laboratory will be presented in a listing. 
The number and percentage of patients meeting each criterion detailed in Table 11 will be 
presented. A listing will be presented for any patient meeting any of the criteria in Table 11. 


 
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Table 11 Liver Function Tests Potentially Reflecting Hepatoxicity Liver Function Tests 
Liver Function Tests 
Range of Test Values  
ALT or AST  
≥ 3 to < 5 x ULN 
 
≥5 to < 10 x ULN 
 
≥ 10 to < 20 x ULN 
 
≥ 20 x ULN 
Total bilirubin  
> ULN 
 
≥ 1.5 x ULN 
 
≥ 2 × ULN  
(AST or ALT) plus total bilirubin  
≥3 x ULN (ALT or AST) plus ≥ 1.5 x ULN 
(total bilirubin) 
 
≥ 3 x ULN (ALT or AST) plus ≥ 2 x ULN (total 
bilirubin) 
ALP 
≥ 2 x ULN 
ALP and total bilirubin 
≥ 2 x ULN (ALP) and ≥ 2 x ULN (total 
bilirubin) 
 
< 2 x ULN (ALP) and ≥ 2 x ULN (total 
bilirubin) 
 
≥ 2 x ULN (ALP) and < 2 x ULN (total 
bilirubin) 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of 
normal; ALP = Alkaline phosphatase.  
8.3.2. Thyroid Axis Testing 
TSH, free T3, free T4, total T3, total T4, and TBG  will be collected at Baseline and Weeks 2, 
6, 12, and 16, and/or ET. Estimates of the LS mean difference for the pairwise comparisons 
detailed in Section 7.7 with the associated standard error of the difference, and 95% CI of the 
difference, the standard error of the difference, and 95% CI of the difference will be presented. 
Summary statistics will be provided for the levels at each visit and for change from baseline 
by treatment groups.  
8.3.3. Sex Hormones 
Free and total testosterone, estradiol, FSH, and LH will be collected at Baseline and Week 12. 
Estimates of the LS mean difference for the pairwise comparisons detailed in Section 7.7 with 
the associated standard error of the difference, and 95% CI of the difference, the standard error 
of the difference, and 95% CI of the difference will be presented for change from baseline by 
treatment group and by sex. 


 
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8.3.4. Bone Turnover Markers 
The bone turnover markers sCTX and sPINP will be collected at Baseline, Week12, and Week 
16. Summary statistics will be provided for each parameter at each visit and for change from 
baseline at each visit. 
8.3.5. Shifts in Normal Range 
Shift tables for each laboratory test (hematology, chemistry, and urinalysis) showing the shift 
from normal at baseline to abnormal at each post-baseline visit will be presented by visit. 
Summaries will present the number and percentage of patients with shifts by treatment group. 
Denominators for percentages will be the number of patients with non-missing data at the 
specific assessment and baseline. 
8.4. Vital Signs 
Vital signs will be collected at each visit. Summary statistics will be provided for systolic and 
diastolic blood pressure, and heart rate for each visit. Any clinically significant abnormalities 
will be reported as adverse events. 
8.5. Electrocardiograms 
Summary statistics will be provided for heart rate, PR interval, QRS interval, QT interval, and 
QTcF at each visit. The investigator interpretation is collected as normal, abnormal not 
clinically significant (NCS), or abnormal clinically significant (CS). Patients whose 
interpretation shifts from normal to abnormal (CS or NCS) will be listed separately including 
description of the abnormality and any associated comments. 
Categorical summaries will for baseline, worst post-baseline, and change from baseline for the 
following QTcF values will be presented: 
• > 450 msec 
• > 480 msec 
• > 500 msec 
• Change from baseline > 30 msec 
• Change from baseline > 60 msec 


 
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All ECG results will be presented in by-patient data listings. If applicable, cardiologist consult 
information will be presented in a separate by-patient data listing. 


 
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9. Other Assessments 
Other assessments will be provided in by-patient data listings only; no summary tables will be 
provided, including but not limited to the following: 
• 
Eligibility details including unmet eligibility criteria 
• 
Informed consent 
• 
Randomization schema 
• 
Physical examination collection information 
• 
Serology 
• 
Pregnancy testing 
• 
FSH test  
• 
Urine drug screen 
• 
Alcohol test 
• 
Urinalysis and Urine Microscopic Examination 
• 
Coagulation 
• 
Hemoglobin A1c 
• 
Direct bilirubin 
• 
Indirect bilirubin 
• 
Laboratory reference ranges 
• 
Cardiology consult 
• 
Overdose 
• 
Comments 


 
Statistical Analysis Plan 
 
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Protocol Reference: TERNCB-2002 
 
 
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10. Changes to Protocol Planned Analyses 
There were no changes from the protocol planned analyses. 
 




 
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APPENDIX 2: IMPUTATION RULES FOR MISSING OR PARTIAL DATES FOR 
ADVERSE EVENTS AND CONCOMITANT MEDICATIONS 
Date 
Situation 
Imputation Rule 
Start Date 
Only month and year are known and 
month and year are prior to first 
dose date 
Use the last day of the month 
 
Only month and year are known and 
month and year are the same as first 
dose date 
Use the first study drug administration 
date 
 
Only month and year are known and 
month and year are after first dose 
date 
Use the first day of the month 
 
Only year is known and year is 
before first dose date 
Use Dec 31 of that year 
 
Only year is known and year is same 
as first dose date 
Use the first study drug administration 
date 
 
Only year is known and year is after 
first dose date 
Use Jan 1 of that year 
 
Entire date is missing 
Use the first study drug administration 
date 
 
The estimated start date is after a 
complete or imputed AE stop date 
Use the first day of the month of the 
AE stop date 
Stop/End Date 
Only month and year are known and 
month and year are prior to last dose 
date  
Use the last day of the month  
 
Only month and year are known and 
month and year are the same as last 
dose date  
Use the last dose date  
 
Only month and year are known and 
month and year are after last dose date  
Use the last day of the month  
 
Only year is known and year is before 
last dose date  
Use Dec 31 of that year  
 
Only year is known and year is same 
as last dose date  
Use the last study drug administration 
date  
 
Only year is known and year is after 
last dose date  
Use Dec 31 of that year  
 
Entire date is missing  
Use the last study drug administration 
date  
 
The estimated stop date is before a 
complete or imputed AE start date  
Use the last day of the month of the AE 
start date  
AE = adverse event, Dec = December, Jan = January 
 


 
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APPENDIX 3: ABBREVIATIONS 
Abbreviation or Special Term  Explanation  
7αC4  
7α-hydroxy-4-cholesten-3-one  
ADaM  
Analysis Data Model  
AE  
adverse event  
ALP  
alkaline phosphatase  
ALT  
alanine transaminase  
ANCOVA  
analysis of covariance  
AST  
aspartate transaminase  
ATC  
Anatomical Therapeutic Class  
AUC  
area under the concentration-time curve  
BLQ  
below limit of quantification  
BMI  
body mass index  
CAP  
Controlled Attenuation Parameter  
CDISC  
Clinical Data Interchange Standards Consortium  
CHG  
change from baseline ADaM basic dataset structure defined variable  
CI  
confidence interval  
CK-18  
cytokeratin-18  
COVID-19  
Coronavirus disease 2019  
Cmax  
maximal concentration  
CRF  
case report form  
CSR  
clinical study report  
CTCAE  
Common Terminology Criteria for Adverse Events  
CTMS  
clinical trial management system  
CV  
coefficient of variation  
DPP-4  
Dipeptidyl peptidase 4  
eGFR  
estimated glomerular filtration rate  
eCRF  
electronic case report form  
ECG  
electrocardiogram  
ET  
early termination  
FDA  
Food and Drug Administration  
FGF  
fibroblast growth factor  
FIB-4  
Fibrosis-4 Score  
FSH  
follicle stimulating hormone  
FXR  
farnesoid X receptor  
GGT  
gamma-glutamyl transpeptidase  
GLP-1  
Glucagon-like peptide-1  
HA  
hyaluronic acid  
HDL  
high-density lipoprotein  
hs-CRP  
high sensitivity C-reactive protein  
ICF  
informed consent form  
ICH  
International Council for Harmonisation  
IG  
implementation guide  
IMP  
investigational medicinal product  
INR  
international normalized ratio  
IWRS  
interactive web response system  
LDL  
low-density lipoprotein  


 
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Abbreviation or Special Term  Explanation  
LFC  
liver fat content  
LFT  
liver function test  
LLN  
lower limit of normal  
ln  
natural log  
LOCF 
Last observation carried forward 
LS  
least squares  
MedDRA  
Medical Dictionary for Regulatory Activities  
MMRM  
mixed model for repeated measures  
MRI-PDFF  
Magnetic Resonance Imaging Proton Density Fat Fraction  
NAFLD  
non-alcoholic fatty liver disease  
NAS  
non-alcoholic fatty liver disease activity score  
NASH  
non-alcoholic steatohepatitis  
NC  
not calculated  
NCA  
noncompartmental analysis  
NCI  
National Cancer Institute  
PCHG  
percent change from baseline ADaM basic dataset structure defined 
variable  
PIIINP  
procollagen III n-terminal propeptide  
PD  
pharmacodynamics  
PK  
pharmacokinetics  
PRO-C3  
pro-peptide of type III collagen  
Q1  
25th percentile, first quartile  
Q3  
75th percentile, third quartile  
QTcF 
QT corrected for heart rate by Fridericia's cube root formula 
REML  
restricted maximum likelihood  
SAE  
serious adverse event  
SAP  
statistical analysis plan  
SARS-CoV-2  
severe acute respiratory syndrome coronavirus 2  
SD  
standard deviation  
SDG  
Standardized Drug Grouping  
SDTM  
Study Data Tabulation Model  
SE  
least squares mean standard error  
SGLT-2  
Sodium-glucose co-transporter 2  
TEAE  
treatment emergent adverse event  
TERN-101  
investigational agonist of Farnesoid X receptor  
TIMP-1  
tissue inhibitor of metalloproteinases-1  
ULN  
upper limit of normal  
WHODD  
World Health Organization Drug Dictionary