A Phase 2, Multi-Center, Double-Blind, Randomized, Placebo-controlled Study of MGL-3196 in Patients With Non-alcoholic Steatohepatitis
Phase: PHASE2
Conditions: Non-alcoholic Steatohepatitis
Sponsor: Madrigal Pharmaceuticals, Inc.

Study Protocol 
Official title: 
A Phase 2, Multi-Center, Double-Blind, Randomized, Placebo-Controlled 
Study of MGL-3196 in Patients With Non-Alcoholic Steatohepatitis 
NCT Number: 
NCT02912260 
Document Date: 
26 December 2017 
 

 
 
CLINICAL STUDY PROTOCOL 
 
A Phase 2, Multi-Center, Double-Blind, Randomized, 
Placebo-Controlled Study of MGL-3196 in Patients With 
Non-Alcoholic Steatohepatitis 
Investigational Product: MGL-3196 
Protocol Number: MGL-3196-05 
 
 
Sponsor: 
Madrigal Pharmaceuticals, Inc. 
Four Tower Bridge, 200 Barr Harbor Drive, Suite 400 
West Conshohocken, PA 19428 
Telephone: 610-220-7260 
 
 
 
Original Protocol: 14 July 2016 
Amendment 1:  07 Sep 2016 
Amendment 2: 16 Dec 2016 
Amendment 3: 11 May 2017 
Amendment 4: 10 August 2017 
Amendment 5: 06 November 2017 
Amendment 6: 26 December 2017 
 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of Madrigal Pharmaceuticals, Inc. except to the extent that disclosure would be required 
by law and for the purpose of evaluating and/or conducting a clinical study for Madrigal 
Pharmaceuticals, Inc. You are allowed to disclose the contents of this document only to your 
Institutional Review Board (IRB) and study personnel directly involved with conducting this 
protocol. Persons to whom the information is disclosed must be informed that the information is 
confidential and proprietary to Madrigal Pharmaceuticals, Inc. and that it may not be further 
disclosed to third parties. 

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Protocol Amendment 6, 26 December 2017 
2 
SIGNATURE PAGE 
STUDY TITLE: A Phase 2, Multi-Center, Double-Blind, Randomized, Placebo-Controlled 
Study of MGL-3196 in Patients With Non-Alcoholic Steatohepatitis 
 
I, the undersigned, have read this protocol and agree that it contains all necessary information 
required to conduct the study. 
Signature 
 
 
 
 
 
 
 
Date 
______________________________________________  
____________________ 
 
Chief Medical Officer, Executive Vice President R&D 
Madrigal Pharmaceuticals, Inc. 
 

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INVESTIGATOR AGREEMENT 
By signing below I agree that: 
I have read this protocol. I approve this document and I agree that it contains all necessary details 
for carrying out the study as described. I will conduct this study in accordance with the design and 
specific provision of this protocol and will make a reasonable effort to complete the study within 
the time designated. I will provide copies of this protocol and access to all information furnished 
by Madrigal Pharmaceuticals, Inc. to study personnel under my supervision. I will discuss this 
material with them to ensure they are fully informed about the study product and study procedures. 
I will let them know that this information is confidential and proprietary to Madrigal 
Pharmaceuticals, Inc. and that it may not be further disclosed to third parties. I understand that the 
study may be terminated or enrollment suspended at any time by Madrigal Pharmaceuticals, Inc., 
with or without cause, or by me if it becomes necessary to protect the best interests of the study 
patients. 
I agree to conduct this study in full accordance with Food and Drug Administration Regulations, 
IRB and International Conference on Harmonisation (ICH) Guidelines for Good Clinical Practices 
(GCP). 
 
 
 
 
 
______________________________________________  
____________________ 
Investigator’s Signature 
 
 
 
 
 
Date 
 
 
 
______________________________________________ 
Investigator’s Printed Name 
 
 

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Table 1. Results of Week 12 Primary Endpoint Analysis 
  
ALL MGL-
3196  
High MGL-
3196¹  
Low MGL-
3196 
Placebo  
Number of patients 
 
 
 
 
Primary Endpoint: 
Relative change in MRI-PDFF (% change from baseline, median) 
Significance relative to placebo 
  
 
 
 
  
 
 
 
 
 
 
  
 
Percentage of patients  attaining ≥30% liver fat reduction 
Significance relative to placebo 
 
  
 
 
 
  
 
 
 
 
 
  
1 Prespecified MGL-3196 exposure groups >=2700 ng*hr/ml and <2700 ng*hr/ml 
MGL-3196-05 Amendment 6 adds a minor dose adjustment (increase in dose of 20-25%) in a 
small percentage (~10) of patients still completing the 36 week Main study, who have low 
exposure on doses of 60-80 mg (low predose exposure, low SHBG response).
 
 
 Several parameters and visits were assesed to assure that the data were not 
impacted by compliance issues (e.g. not taking drug the day before visit, taking drug prior to 
visit).
 
 
SHBG levels (blinded to 
patient ID) were reviewed because SHBG has a long half-life, and may be a marker for 
average drug exposure. Any dose adjustments will be made by unblinded personnel. 
 
 
 

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In patients remaining in the Main study or randomized to MGL-3196 who meet criteria 
and consent to Extension study: 
 
Table 2. Doses in Main and Extension Study in Patients Assigned to MGL-3196 in 
the Main Study 
Current 
dose 
Main Study Week 
2 PK (AUC, 
combined MGL-
3196 plus M1 on 
80 mg dose) 
Main 
Study 
Predose  
at Week 2  
Main study 
Predose  
Week 8 
(post dose 
adjustment) 
Main Study 
SHBG 
<+75% 
CFB at 
Week 12 
(post dose 
adjustment) 
Action in 
Main 
and/or 
Extension 
Study 
40 mg 
 
 
<5 ng/ml 
Yes 
Increase to 
60 mg/day 
60 mg 
<5500ng*hr*ml1 
 
< 1 ng/ml 
Yes 
Increase to 
80 mg/day 
80 mg 
<4000 ng*hr/ml 
AND SHBG 
%CFB<90) 
 
OR2  
Yes 
Increase to 
100 
mg/day 
100 mg 
≤3000 ng*hr/ml 
<5 ng/ml 
 
Increase to 
120 mg 
120 mg 
 
 
 
 
No change 
1 Recalculated 80 mg AUC based on corrected elimination rate constant for MGL-3196 and M1in patients 
who demonstrated average predose levels <5 ng/ml at Week 2,4,8 and had initial calculated AUC<7000 
ng*hr/ml. Change from Baseline (CFB).  
2 Either exposure <4000ng*hr/ml with SHBG%CFB<+90 OR SHBG<+70%CFB qualifies for increase to 
100 mg. 
 
Table 3. Dose Adjustment During Extension Study 
Extension Study Week 2  
|MGL-3196 Concentration 
Extension Study 
Extension Study 
Predose 
4 h post dose 
Week 2 SHBG 
Week 4 Action 
>35 ng/ml 
>1350 ng/ml 
>200% CFB* 
Downtitrate to 40 mg 
Patients not meeting criteria for 40, 80, 100 or 120 mg  
Downtitrate to 60 mg 
<15 ng/ml 
<600 ng/ml 
OR <75% 
increase** 
Remain on 80 mg or 
increase (see next rows) 
<5 ng/ml 
≤ 350 ng/ml 
No rule 
Increase to 100 mg 
<2 ng/ml 
≤ 150 ng/ml 
No rule 
Increase to 120 mg 
*Change From Baseline, where baseline is Extension Study Day 1. 
**Either predose<15ng/ml plus 4h<600ng/ml OR SHBG<+75%CFB. 

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Based on the Week 12 results, which are blinded to individual patient ID, the proposed 
predose and 4h postdose and SHBG levels as shown in Table 3 provide the primary basis 
for dose adjustment in the extension study. The only modification to this table from 
Amendment 5 is use of the SHBG algorithm for the 80 mg dose. Since the extension 
study is open label, it affords an opportunity to review SHBG, lipids, liver enzymes, and 
predose/4 h drug levels on an ongoing basis. In addition to the exploratory endpoints of 
the Extension study, goals will be to obtain additional dosing and PD information to 
supplement the data from the Main study that will be used to support dose selection for 
later studies, including, potentially, a pivotal NASH study.  The algorithms provided in 
this table, which are based on current criteria, may undergo minor alterations during the 
extension study.  
Given the overall safety, improvements in MRI-PDFF and liver enzymes in MGL-3196-
treated patients at 12 weeks, a few additional patients with persistent elevations without 
improvement in liver enzymes >=1.5-2X (placebo or MGL-3196, Weeks 16-30, Table 4). 
will be eligible for the extension study. 
 
Table 4. Modified ALT (AST) Inclusion Criteria for Extension Study 
Baseline ALT 
Average of ALT at Weeks 16, 20, 24, and 30 
ALT normal (<1.5 ULN) 
≥1.5 x ULN (and 30% worse than baseline) 
ALT =1.5-2X 
Improvement from baseline <30% and ALT 
=1.5-2X ULN 
ALT any 
ALT ≥ 2X 
Note: 
Normal ALT male 30; female 25:  
1.5 x male =45 and female=38;  
Note: 
ALT or AST values for weeks 16, 20, 24 
and 30 that are > 2 X Std Dev from mean 
will be excluded from the calculation of the 
average value. 
Note: 
When ALT does not meet criteria for 
inclusion, AST will be evaluated similarly 
to determine if criteria for inclusion are met 
based on AST, given normal values in men 
and women of 27 and 22, respectively and 
1.5X of 40 and 33 respectively. 
 
Many of these patients will have been assigned to placebo or, possibly, to an inadequate 
dose of MGL-3196. The baseline ALT inclusion requirement for females was increased 
in this Amendment, defining elevated ALT at >25 U/L rather than >19 U/L and 2X 
elevation at 50U/L.  

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Administrative changes not affecting the content or conduct of the protocol: 
Removed reference to serum pregnancy testing in Table B footnote 10. 
 

SUMMARY OF PROTOCOL AMENDMENT 5 CHANGES 
Administrative changes that may affect the content or conduct of the protocol: 
Addition of an extension phase of the study (“Extension Study”), adding 36 weeks of treatment 
for patients meeting selected criteria. 
Rationale: The major change in this protocol amendment is the inclusion of an extended dose 
study beyond 36 weeks for up to 36 weeks in a subset of enrolled patients who have 
persistently elevated liver enzymes, specifically defined by at least ALT ≥1.5X ULN (women 
≥29; men ≥45), (Table 1) or have demonstrated worsening of liver enzymes during the first 
36 weeks of the study, based on average liver enzymes between weeks 16-30, excluding 
outlier values (for example a transient spike in liver enzymes at a single visit). Based on the 
current estimate, ~25% of the total 125 enrolled patients might be eligible for the extension 
study. Persistently elevated liver enzymes are a good measure of NASH activity in NASH 
patients whose liver enzymes are elevated at baseline (many NASH patients have normal or 
mildly elevated liver enzymes). Approximately 36% of enrolled patients had ALT<1.5X at 
baseline and few of these patients showed worsening; these patients would not be eligible for 
the extension. Patients eligible for the extension study could include either placebo or drug-
treated patients. 
Table 1. ALT (AST) Inclusion Criteria for Extension Study 
Baseline ALT 
Average of ALT at Weeks 16, 20, 24, and 30 
ALT normal (<1.5 ULN) 
≥1.5 x ULN (and 30% worse than baseline) 
ALT =1.5-2X 
Worsened from baseline ≥ 30% 
ALT any 
ALT ≥ 2X 
Note: Normal ALT male 30; female 19:  
1.5 x male =45 and female=29 
Note: ALT or AST values for weeks 16, 20, 24 and 30 that 
are > 2 X Std Dev from mean will be excluded from 
the calculation of the average value. 
Note: When ALT does not meet criteria for inclusion, AST 
will be evaluated similarly to determine if criteria 
for inclusion are met based on AST, given normal 
values in men and women of 27 and 22, respectively 
and 1.5X of 40 and 33 respectively. 
 
The major rationale for the extension study is that the overall safety of the clinical study has 
been very good, with improvement in liver enzymes in the overall study, including a 
normalization of liver enzymes from baseline in a significant fraction of patients (see DSMB 
output, Table 4, on pages 23-12). Subsequent to the September DSMB meeting, additional 
patients out to 24 weeks (now 48 patients) continue to show similar average improvements in 
liver enzymes. 

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Added additional exploratory/tertiary objectives for the extension study (Synopsis and Sections 
2.3 and 7). 
Added description of extension phase of the study (Synopsis and Section 3.1.3). 
Addition of Inclusion Criteria #9 for eligibility to participate in the extension phase of the study 
(Synopsis and Section 4.1). 
Added that for patients eligible to participate in the extension phase of the study, the Extension 
Study Informed Consent must be signed prior to any Extension Study related procedures 
(Sections 6.1 and 9.6). 
Added that Early Termination Visit procedures could be for either Main Study or the Extension 
Study as indicated (Section 6.6). 
Added Extension Study visits and procedures (Sections 6.7, 9.8, 9.9, 9.10, 9.11, 9.12, 9.13, 9.14, 
and 9.16, and Appendix B). 
Added possibility of 120 mg dose in the Main Study (Section 8.1). 
Added Extension Study PK assessments (Synopsis and Section 8.2). 
Added new Appendix B with Extension Study Procedures. 
 
Administrative changes not affecting the content or conduct of the protocol: 
Added heading 3.1.4 for DSMB. 
Added description of Extension Study treatment group (Section 5.1). 
Changed headings of Section 6.4 and Appendix A to clarify that the visits and procedures where 
for the “Main Study”. 
Added heading 8.1 for Main Study PK assessments. 
References to Clinical Laboratory Analytes, Appendix B changed to Appendix C (Sections 6.2, 
6.4, and 9.8, and Appendix A). 
 

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Clarification in inclusion criteria #4 – specified quantitative ultrasound with liver fat > 10% and 
magnetic resonance spectroscopy consistent with significant liver steatosis (>10%). 
Change in inclusion criteria #5 – added note that patients with a liver fat content >9% but < 10% 
on MRI-PDFF and who are highly likely to have NASH as determined by Medical Monitors on 
biopsy may be included in the study but the total may not exceed 10% of the total study 
population (Synopsis and Section 4.1). 
Change in Note 2 of inclusion criteria #6 – removed weight gain as a significant change in 
metabolic status (Synopsis and Section 4.1). 
Change in inclusion criteria #7 – clarification to use the mean of both the AST and ALT values 
in determining worsening liver enzymes. Patients with elevated liver enzymes at screening that 
improve during the screening period >50% or are improved relative to historic liver enzymes are 
no longer excluded, because patients are appropriately counseled on diet and exercise at the 
screening visit, at times, resulting in improvement in liver enzyme tests during the screening 
period. There is no safety risk to these patients. If there is uncertainty about the baseline, because 
of a marked improvement from historic to screening values, a third ALT/AST assessment will be 
done during the screening period to insure that liver chemistries are not >30% worse than the 
screening values and that the baseline is stable. (Synopsis and Section 4.1) 
Removed exclusion criteria # 4 – exclusion for historic weight gain and weight loss is removed, 
except that patients with an eligible historic liver biopsy and with weight loss ≥5% after the time 
of the eligible historic liver biopsy prior to screening are excluded. (Synopsis and Section 4.2). 
Renumbered exclusion criteria #5 to #29 – numbers decreased by one. (Synopsis and Section 
4.2). 
Exclusion Criteria #8 (was originally #9) – clarification that glucagon-like peptide analogue is 
permitted if stable dose ≥ 6 months prior to screening or at time of liver biopsy, and a complex 
oral anti-diabetic (OAD) regimen (3 or more OADs) is permitted if the OAD is stable for three 
months and HbA1c < 8% (Synopsis and Section 4.2).  
Exclusion Criteria #13 (was originally #14) (Synopsis and Section 4.2) to clarify the assessment 
of hepatic decompensation 
Original text:  
• Clinical evidence of hepatic decompensation as defined by the presence of any of the 
following abnormalities: 
• Serum albumin <3.5 g/dL, 
• International normalized ratio >1.3 (a single retest is permitted if laboratory error is 
suspected), 
• Total bilirubin >1.3 mg/dL, or 
• History of esophageal varices, ascites, or hepatic encephalopathy; 
Changed to:  
Clinical evidence of hepatic decompensation which may be:  

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• Demonstrated by abnormalities such as platelets <140,000, serum albumin <3.5 g/dL, 
international normalized ratio >1.3 and/or total bilirubin >1.3 mg/dL; or 
• Established by the presence or history of esophageal varices, ascites, or hepatic 
encephalopathy;  
Note to protocol: Platelets < 140,000 remains an independent exclusion criterion. 
Change in exclusion criteria #14 (was originally #15) – clarification that patients with Gilbert’s 
syndrome are excluded if direct bilirubin is elevated and total bilirubin ≥ 2 or elevated total 
bilirubin is due to hemolysis to be consistent with FDA recommendation (Synopsis and Section 
4.2). 
Change to description of study drug administration (Section 5.5.3) – noted that dose adjustments 
may occur based on the process outlined in section 3.1.2. 
Changes to excluded medications (Section 5.6.1): 
• glipizide and tolbutamide treatment are permitted and removed as excluded medications; 
they had been excluded in error, no drug interaction predicted 
• chronic use of oral corticosteroids is exclusionary unless discontinued 3 months before 
screening. Addition of oral corticosteroids during the study except short term low dose < 1 
week taper is not allowed;  
Note to protocol: inhaled, nasal corticosteroids, joint and muscle corticosteroid injections are 
allowed 
Change that randomization may (previously “will”) continue until approximately 36 patients 
have continued at Week 4 on the 80 mg dose (Synopsis and Section 10.2.5). 
Reference #20 added (Synopsis, Section 3.1.2, and Section 14). 
Sponsor Address updated (Section 13.2.1) 

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SUMMARY OF PROTOCOL AMENDMENT 2 CHANGES 
Changes that have the potential to affect either the efficacy or safety assessments: 
Clarification and revisions to inclusion criteria #4  - added “confirmed” NASH diagnosis and 
clarified that at least one of the listed assessments is required (Synopsis and Section 4.1). 
Biopsy-proven NASH inclusion criteria #5 moved to #6 and revision to Note 2 – added “change 
in” (Synopsis and Section 4.1). 
Exclusion Criteria #9 – HbA1c criteria changed from 9% to 9.5%  (Synopsis and Section 4.2). 
Exclusion Criteria #10 (Synopsis and Section 4.2): 
Original text:  
Use of the following lipid-modifying therapies: fibrates, niacin, proprotein convertase 
subtilisin/kexin type 9 inhibitors, bile acid sequestrants, and statins;  
Note: Patients who require initiation on any of excluded lipid-modifying therapies at 
baseline or during the study must be discontinued from the study; 
Changed to:  
Use of the following lipid-modifying therapies: fibrates, niacin, proprotein convertase 
subtilisin/kexin type 9 inhibitors, and bile acid sequestrants. Atorvastatin up to 20 mg 
and rosuvastatin up to 10 mg, on stable dose for at least six weeks prior to 
randomization (four weeks prior to MRI), are allowed. Other statins are 
excluded.  Stable doses for at least three months prior to randomization of 
fish oils (omega-3 fatty acids, eicosapentaenoic acid, and docosahexaenoic 
acid) and ezetimibe are allowed;  
Note: Patients who require initiation of any excluded lipid-modifying therapies at baseline 
or during the study must be discontinued from the study. Statin dose increases are 
not allowed during the study; statin doses may be decreased during the 
study for tolerability or safety issues. Statin doses should be taken in the 
evening for at least two weeks prior to randomization; 
Exclusion Criteria #11 (Synopsis and Section 4.2): 
Original text:  
Use of obeticholic acid, ursodeoxycholic acid (Ursodiol® and Urso®), high dose vitamin 
E (>400 IU/day), or pioglitazone within 90 days prior to enrollment or since screening 
biopsy, whichever is longer; 
Changed to:  
Use of obeticholic acid, ursodeoxycholic acid (Ursodiol® and Urso®), high dose vitamin 
E (>400 IU/day) unless on stable dose of vitamin E >400 IU/day for at least 6 
months at the time of liver biopsy, or pioglitazone within 90 days prior to enrollment 
or since screening biopsy, whichever is longer;  

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Added exclusion criteria #24 – uncontrolled cardiac arrhythmia (Synopsis and Section 4.2). 
#25 - Myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery 
bypass graft, or stroke within 3 months prior to randomization (Synopsis and Section 4.2). 
Clarification that the DSMB will also assess cardiovascular events (Synopsis and Sections 3.1.2, 
and 10.2.4). 
Removed the possibility for patients who completed the 36-week Treatment Period to be eligible 
for an extension study (Synopsis and Section 3.1.2). 
Added that cardiovascular events are possible withdrawal criteria (Section 4.3). 
Add to the list of excluded medications drugs historically associated with NAFLD and drugs with 
known liver toxicity (Section 5.6.1). 
Added to the list of excluded medications, any drugs that have the potential to affect thyroid 
hormone production and/or interfere with thyroid function (Section 5.6.1). 
Specified fasting of at least 10 hours prior to each study visit (Section 6.4). 
Addition of Cardiovascular monitoring criteria (Synopsis and 9.18). 
Added CK-MB and Troponin I (Sections 6.4.1 to 6.4.10, 6.5, 6.6, and 9.8). 
Added Bile Acid Levels (Sections 6.4.1, 6.4.2, 6.4.5, 6.4.10, 6.6, and 9.8). 
At the Week 2 Visit, specified arriving at the study site predose after overnight fasting and 
collection of PK samples at predose, 2, 4, 6, and 8 hours postdose. Low fat meals permitted at 1 
hr postdose and 4 hours postdose (after 4 h blood draw) (Section 6.4.2). 
At the Week 4 Visit, changed the post dose PK collection to predose (Section 6.4.3). 
Updates to Sample Size Estimate (Synopsis and 10.2.5). 
Update to Schedule of Procedures in Appendix A to reflect protocol amendment changes 
(Appendix A). 
Addition of CK-MB, Troponin I, and Bile Acids to Appendix B – Clinical Laboratory Analytes. 
Removed Non LDL-Cholesterol from the Lipid Panel and secondary objectives (Synopsis, 
Sections 2.2 and 9.8, and Appendix B). 
 
Administrative changes not affecting the content or conduct of the protocol: 
Change in title for 
 (Signature Page). 
Added CK-MB to the List of Abbreviations and Definition of Terms 
Addition of 
 (Section 13.2.4). 
Addition of 
 (Section 13.2.5). 

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SYNOPSIS 
TITLE:  A Phase 2, Multi-Center, Double-Blind, Randomized, Placebo-Controlled Study of 
MGL-3196 in Patients With Non-Alcoholic Steatohepatitis 
PROTOCOL NUMBER:  MGL-3196-05 
INVESTIGATIONAL PRODUCT:  MGL-3196 
PHASE:  2 
INDICATION:  The indication for this study is the treatment of non-alcoholic steatohepatitis 
(NASH). 
OBJECTIVES: 
The primary objective of this study is to determine the effect of once-daily oral MGL-3196 80 mg 
versus placebo (randomized 2:1) for 12 weeks on the percent change in hepatic fat fraction by 
proton density fat fraction magnetic resonance imaging (MRI-PDFF) from baseline in patients 
with biopsy-proven NASH.  
The secondary objectives of this study are the following: 
• To determine the effect of once-daily oral MGL-3196 80 mg versus placebo for 36 weeks in 
patients with biopsy-proven NASH on the histological improvement from baseline on: 
o Two-point reduction in non-alcoholic fatty liver disease (NAFLD) activity score (NAS); 
o Resolution of NASH (ballooning = 0; inflammation = 0 to 1); or 
o Any individual component of NASH (hepatocellular steatosis, ballooning, fibrosis, or 
lobular inflammation);  
• To evaluate the safety and tolerability, including any changes in thyroid axis hormones, of 
once-daily oral MGL-3196 80 mg versus placebo after 12 and 36 weeks in patients with 
biopsy-proven NASH;  
• To evaluate the effect of once-daily oral MGL-3196 80 mg versus placebo for 36 weeks on 
the percent change in hepatic fat fraction by MRI-PDFF from baseline in patients with 
biopsy-proven NASH;  
• To evaluate the effect of once-daily oral MGL-3196 80 mg versus placebo for 12 and 36 weeks 
on the change in hepatic fat fraction by MRI-PDFF from baseline in patients with biopsy-
proven NASH; and 
• To determine the effect of once-daily oral MGL-3196 80 mg versus placebo after 12 and 36 
weeks in patients with biopsy-proven NASH on: 
o High-sensitivity C-reactive protein (hsCRP); 
o Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST); 

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o Previous liver biopsy consistent with NASH  
Note: Assessment of the above, or other objective modalities suggested by PI, will occur.  The 
choice of additional procedures, performed during the screening period prior to the screening MRI 
and liver biopsy, may include calculation of FIB-4, APRI, NAFLD fibrosis scores, and/or 
performance of fibroscan and/or CAP. 
5. Must have confirmation of ≥10% liver fat content on MRI-PDFF; 
Note: Patients with a liver fat content >9% but <10% on MRI-PDFF and who are highly likely 
to have NASH as determined by Medical Monitors on biopsy may be included in the study 
but the total may not exceed 10% of the total study population; 
6. Biopsy-proven NASH: 
• Must have had prior liver biopsy within 180 days of randomization with fibrosis stage 1 to 3 
and a NAS of ≥4 with at least a score of 1 in each of the following NAS components: 
• Steatosis (scored 0 to 3),  
• Ballooning degeneration (scored 0 to 2), and 
• Lobular inflammation (scored 0 to 3) 
Note 1: Patients who have clear ballooning with fibrosis but no inflammation or patients who have 
clear inflammation with fibrosis but no ballooning or patients with clear NASH without fibrosis 
may be included in the study but the total may not exceed 10% of the total study population;  
Note 2: If a historical biopsy is to be used, patients must have had no significant change in 
metabolic status (diabetes control, lipid metabolism, and/or >5% weight loss), significant change 
in diabetes medication, or change in use of medications listed in Exclusion #10 since the biopsy 
Note 3: If a historical biopsy is not available, patients must have confirmation of ≥10% liver fat 
content on MRI-PDFF prior to undergoing liver biopsy. However, if, in the opinion of the patient’s 
physician, the patient would benefit from and be advised to obtain a liver biopsy, the patient may 
undergo liver biopsy prior to MRI-PDFF 
7. Must have documented historical (3 weeks to 6 months prior to the study entry) ALT and AST 
levels consistent with the screening ALT and AST values. This consistency is established 
based on the following:  
o If the historical and screening ALT and AST values are both ≤1.5 × the upper limit of 
normal (ULN), there is no limit to the difference between the values.  
o If the historic ALT/AST are >1.5 X elevated and screening ALT and AST are markedly 
improved (>50% decreased or normalized) relative to historic, then a third ALT/AST 
determination will be made during screening to assure a stable baseline, and that there is 
no worsening of >30% from the screening values. If the difference is >30% and the second 
value is greater than the first value, a third value should be determined during the screening 
period to confirm lack of worsening trend in ALT/AST 
o If at least 1 of the values is >1.5 × ULN and the second value is greater than the first value, 
the difference the mean of ALT and AST in values must be ≤30%. If the difference is 
>30% and the second value is greater than the first value, a third value should be 
determined to confirm lack of worsening trend in ALT/AST.  If worsening trend is 

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confirmed (3 consecutive worsening values with difference from first value and second 
value >30%), patient will be excluded.  
Note: Patients who do not have the historical ALT and AST evaluations available may have their 
ALT and AST repeated during the screening period (both assessments need to be 3 weeks apart); 
8. Normal or minimally abnormal renal function as defined by estimated glomerular filtration 
rate (eGFR) ≥ 60. 
9. Eligibility for extension study. Within 60 days of completion of the Week 36 Visit in the main 
study, patients who meet the following additional criteria will be eligible to participate in the 
extension phase of this study: 
o Had 36-week MRI-PDFF 
o Had 36-week liver biopsy 
o No new exclusions that would prevent the patient from participating in up to 36 weeks of 
additional treatment 
o Meets at least one of the following liver enzyme criteria in the table below: 
Baseline ALT 
Average of ALT at Weeks 16, 20, 24, and 30 
ALT normal (<1.5 ULN) 
≥ 1.5 x ULN (and 30% worse than baseline) 
ALT =1.5-2X 
Improvement from baseline <30% and ALT 
=1.5-2X ULN 
ALT any 
ALT ≥ 2X 
Note: Normal ALT male 30; female 25:  
1.5 x male =45 and female=38 
Note: ALT or AST values for weeks 16, 20, 24 and 30 that 
are > 2 X Std Dev from mean will be excluded from 
the calculation of the average value. 
Note: When ALT does not meet criteria for inclusion, AST 
will be evaluated similarly to determine if criteria 
for inclusion are met based on AST, given normal 
values in men and women of 27 and 22, respectively 
and 1.5X of 40 and 33 respectively. 
 
Exclusion Criteria 
Note: Unless otherwise specified, repeat testing may be performed in consultation with the 
Medical Monitor. 
Patients who meet any of the following criteria will be excluded from participation in the study: 
1. History of significant alcohol consumption for a period of more than 3 consecutive months 
within 1 year prior to screening; 
Note: Significant alcohol consumption is defined as average of >20 g/day in female patients 
and >30 g/day in male patients;  

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2. Inability to reliably quantify alcohol consumption based upon judgment of the Investigator;  
3. Use of drugs historically associated with NAFLD (amiodarone, methotrexate, systemic 
glucocorticoids, tetracyclines, tamoxifen, estrogens at doses greater than those used for 
hormone replacement, anabolic steroids, valproic acid, and other known hepatotoxins) for 
more than 2 weeks in the year prior to screening;  
4. Hyperthyroidism;  
5. Patients on thyroid replacement therapy or with untreated clinical or subclinical 
hypothyroidism; 
Note:  If TSH is up to 1.5 x ULN on screening with normal free T4, one repeat test is allowed 
to confirm the elevation in TSH. If TSH and free T4 are normal upon repeat testing, patient 
may be included. Patients with a history of thyroid hormone replacement therapy or patients 
who have discontinued thyroid hormone replacement therapy (including thyroxine) ≥2 months 
prior to randomization may be included in the study if this criterion is met; 
During the study, patients who have elevated levels of TSH >7 IU/ml on at least two separate 
consecutive visits and are symptomatic of hypothyroidism, or TSH >10 IU/ml, who are 
indicated to be on thyroxine for clinical hypothyroidism, may initiate treatment with low doses 
of thyroxine consistent with American Thyroid Association guidelines, with frequent 
monitoring of TSH levels at Study Visits (and within 2 weeks of initiation of thyroxine), safety 
labs, and monitoring of other symptoms related to hyper or hypothyroidism. Thyroxine may 
be administered at ¼ to ½ the anticipated dose (a starting dose of 25 ug per day) with careful 
monitoring of TSH levels and symptoms related to hyper or hypothyroidism, with increments 
in thyroxine dose after no less than 4-6 weeks. 
NOTE: It is anticipated that initiation of thyroxine therapy will occur very infrequently during 
the study and 50-75 ug thyroxine replacement will suffice for most patients requiring thyroxine 
treatment. 
6. Prior or planned (during the study period) bariatric surgery (eg, gastroplasty, roux-en-Y gastric 
bypass);  
7. Type 1 diabetes; 
8. Uncontrolled Type 2 diabetes defined as: 
• Hemoglobin A1c ≥9.5% at screening (patients with HbA1c ≥9.5% may be rescreened),  
• Insulin dose adjustment >10% within 60 days prior to enrollment,  
• Requirement for glucagon-like peptide analogue (unless on a stable dose ≥ 6 months prior to 
screening) or a complex oral anti-diabetic (OAD) regimen (3 or more OADs) (unless the OAD 
is stable and HbA1c < 8%), or 
• History of severe hypoglycemia (symptomatic hypoglycemia requiring outside assistance to 
regain normal neurologic status);  
Note: Individual diabetes regimens will be reviewed by Investigator and may be adjusted based 
on American Diabetes Association guidelines;  
9. Use of the following lipid-modifying therapies: fibrates except fenofibrate taken at night for 
at least 2 weeks prior to randomization and during the study, niacin, proprotein convertase 

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subtilisin/kexin type 9 inhibitors, and bile acid sequestrants. Atorvastatin up to 20 mg and 
rosuvastatin up to 10 mg and pravastatin up to 20 mg, on stable dose for at least six weeks 
prior to randomization (four weeks prior to MRI), are allowed. Other statins are excluded. 
Stable doses for at least three months prior to randomization of fish oils (omega-3 fatty acids, 
eicosapentaenoic acid, and docosahexaenoic acid), fenofibrate and ezetimibe are allowed;  
Note: Very infrequently, given that lipid levels are blinded to investigators and study 
personnel, where indicated statin and other allowed lipid therapies may be modified or initiated 
after enrollment in the study. Statin doses may be decreased during the study for tolerability 
or safety issues. Statin doses should be taken in the evening for at least two weeks prior to 
randomization and for the duration of the study. 
10. Use of obeticholic acid, ursodeoxycholic acid (Ursodiol® and Urso®), high dose vitamin E 
(>400 IU/day) unless on stable dose of vitamin E >400 IU/day for at least 6 months at the time 
of liver biopsy, or pioglitazone within 90 days prior to enrollment or since screening biopsy, 
whichever is longer; 
11. Presence of cirrhosis on liver biopsy (stage 4 fibrosis);  
12. Platelet count <140,000/mm3; 
13. Clinical evidence of hepatic decompensation which may be:  
• Demonstrated by abnormalities such as platelets < 140,000, serum albumin <3.5 g/dL, 
international normalized ratio >1.3 and/or total bilirubin >1.3 mg/dL; or 
• Established by the presence or history of esophageal varices, ascites, or hepatic 
encephalopathy;  
14. Evidence of other forms of chronic liver disease including the following:  
• Hepatitis B (HepB) as defined by presence of HepB surface antigen at screening, 
• Hepatitis C (HepC) as defined by presence of HepC virus (HCV) antibody (anti-HCV) and 
HCV ribonucleic acid (RNA). Patients with positive anti-HCV who test negative for HCV 
RNA at screening will be allowed to participate in the study,  
• Evidence of ongoing autoimmune liver disease, 
• Primary biliary cirrhosis, 
• Primary sclerosing cholangitis, 
• Gilbert’s syndrome patients if direct bilirubin is elevated (in addition to total bilirubin ≥ 2) or 
there is evidence of hemolysis contributing to elevated total bilirubin 
• Wilson’s disease,  
• Homozygous alpha-1-anti-trypsin deficiency, 
• History of hemochromatosis or iron overload, 
• Drug-induced liver disease,  
• Known bile duct obstruction, 
• Suspected or proven liver cancer, or 

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• Any other type of liver disease other than NASH; 
15. Serum ALT or AST >5 × ULN; 
Note: Normal male and female ranges are 6 U/L to 41 U/L for ALT and 9 U/L to 34 U/L for 
AST at 
; 
16. Inability to safely obtain a liver biopsy; 
17. History of biliary diversion;  
18. Positive for human immunodeficiency virus (HIV) infection; 
19. Active, serious medical disease with likely life expectancy <2 years; 
20. History of malignant hypertension; 
21. Uncontrolled hypertension (either treated or untreated) defined as systolic blood pressure ˃160 
mmHg or a diastolic blood pressure ˃100 mmHg at screening;  
Note:  Retest of blood pressure after establishing good blood pressure control within a 
reasonable period of time, up to baseline visit, is permissible at the discretion of the 
Investigator; 
22. New York Heart Association class III or IV heart failure, or known left ventricular ejection 
fraction <30%; 
23. Uncontrolled cardiac arrhythmia, including confirmed QT interval corrected using Fridericia’s 
formula (QTcF) >450 msec for males and >470 msec for females at the screening 
electrocardiogram (ECG) assessment; 
24. Myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery 
bypass graft, or stroke within 3 months prior to randomization; 
25. Active substance abuse, including inhaled or injected drugs, within 1 year prior to screening; 
26. Use of any excluded medications listed in Section 5.6.1;  
27. Participation in an investigational new drug trial in the 30 days prior to randomization; or 
28. Any other condition which, in the opinion of the Investigator, would impede compliance, 
hinder completion of the study, compromise the well-being of the patient, or interfere with the 
study outcomes.  
STUDY DESIGN AND DURATION: 
This is a multi-center, double-blind, randomized, placebo-controlled study to evaluate the safety 
and efficacy of MGL-3196 in patients with NASH. Patients who qualify for study inclusion will 
be randomized to receive one of two 36-week treatments: MGL-3196 80 mg or placebo given 
orally once-daily in the morning. Following 12 weeks of treatment, the primary endpoint, percent 
change from baseline in hepatic fat fraction measured by MRI-PDFF, will be evaluated. At 36 
weeks, all patients will undergo liver biopsy.   
Screening Period 
Patients must provide written informed consent prior to any study procedures being performed. 
Patients will undergo screening procedures within 42 days of randomization. To participate in the 

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study, patients are required to have had a qualifying liver biopsy within 180 days of randomization. 
Patients must meet all of the inclusion criteria and none of the exclusion criteria to participate in 
the study.  
Treatment Period 
Following randomization, patients will begin the initial 12-week Treatment Period. Patients will 
undergo liver MRI-PDFF prior to the start of treatment (pre-dose), at the end of the initial 12-week 
Treatment Period (12 weeks after the start of treatment), and after continuing blinded treatment 
(MGL-3196 or placebo) for an additional 24 weeks (36 weeks after the start of treatment). A liver 
biopsy will be obtained prior to start of treatment (pre-dose) if the patient has not had a qualifying 
liver biopsy within 180 days of randomization and at 36 weeks. During the study, patients will 
return to the study site periodically for assessment of vital signs (temperature, pulse, respiratory 
rate, and seated blood pressure), 12-lead electrocardiogram (ECG), and clinical laboratory testing 
(hematology, chemistry, and urinalysis). During the study, patients who need to be placed on any 
excluded lipid lowering therapeutics will be discontinued from the study. Blood samples will be 
collected at specified times for the assessment of lipid parameters, thyroid hormone parameters, 
and other biomarkers. Patients will be evaluated for adverse events and concomitant medication 
use throughout the study. Patients should be monitored throughout the study for clinical signs and 
symptoms of hyper- or hypothyroidism.  
A PK assessment will be made at Week 2 including a pre-dose fasting determination and 
assessments at 2, 4, 6, and 8 hours postdose. As described in PK section, patients who have a 
calculated AUCinf ≤ to 5500 ng*hr/ml (combined MGL-3196 and MGL-3196-M1) will continue 
on 80 mg. For patients (~10%) with an AUCinf ≤3000 ng*hr/ml as described in Section 8 who are 
predicted to have exposure at 100 mg that remains AUC ≤5550 based on a conservative 
calculation, the MGL-3196 dose will be increased from 80 mg to 100 mg at the Week 4 visit. For 
patients with combined AUC >5500 ng*hr/ml, the dose of MGL-3196 will be reduced to 60 mg 
per day at the Week 4 visit. Patients with AUCinf >11,000 (combined MGL-3196 and M1) 
plus SHBG>150% increase from baseline at Week 2 (indicative that average or steady-state 
exposure is >11,000 ng*hr/ml) will be downtitrated to 40 mg at Week 4. If SHBG ≤150%, then 
patient will be downtitrated to 60 mg at Week 4, and patient’s 4 Week SHBG and predose 
concentrations will be evaluated. If at Week 4 SHBG >150% increase from baseline and predose 
>40ng/ml for MGL-3196 and >40ng/ml for M1 then patient will be downtitrated to 40 mg at the 
Week 8 visit. 
A combined MGL-3196 and MGL-3196-M1 exposure ≤ 5500 ng*hr/ml has not demonstrated a 
drug-related decrease in FT4 to < LLN < 0.7 ng/dL) in Phase 1 studies. However, patients with 
NASH without symptoms of hypothyroidism may occasionally have low baseline levels of FT4, 
with normal FT3 and TSH, and are not clinically or subclinically hypothyroid. Low FT4 in the 
presence of normal FT3 (active hormone) and TSH is not consistent with hypothyroidism; low 
FT4 is observed in euthyroid (formerly hypothyroid) patients treated with T3 monotherapy 20  
In patients continuing on 80 mg MGL-3196 (AUCinf < 5500) who have FT4 LLN (>.55 to <.7 
ng/dL): 
At Week 4 or later: 
• If FT3 remains normal (not decreased to <LLN) and TSH remains normal, the patient does 
not have symptms of hypothyroidism, the patient may continue on the current dose. 

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• Down titration to 60 mg may be made at the next visit, Week 8 or later if FT4 <LLN (>.55 
to <.7 ng/dL), FT3 and TSH are normal, and there is evidence that the decrease in FT4 
<LLN (>.55 to <.7 ng/dL) is drug-related including a >30% decrease from baseline in FT4, 
an increase in SHBG >120% from baseline and predose exposure >40 ng/ml for MGL-
3196 and > 40 ng/ml for MGL-3196-M1 that is consistent with increased drug exposure 
relative to the Week 2 PK assessment. 
In patients downtitrated to 60 mg at Week 4 who have FT4 LLN (>.55 to <.7 ng/dL): 
• At Week 8 or later, if FT3 and TSH remain normal, the patient does not have symptoms 
of hypothyroidism, the patient may continue on the current dose.  
• Down titration to 60 or 40 mg may be made at the next visit, Week 12 or later if FT4 <LLN 
(>.55 to <.7 ng/dL), FT3 and TSH are normal, and there is evidence that the decrease in 
FT4 <LLN (>.55 to <.7 ng/dL) is drug-related including a >30% decrease from baseline 
in FT4, an increase in SHBG >120% from baseline and predose exposure >40 ng/ml for 
MGL-3196 and > 40 ng/ml for MGL-3196-M1 that is consistent with increased drug 
exposure relative to the Week 2 PK assessment.  
If these conditions are not met, the patient will continue on current dose and thyroid indices 
reassessed at subsequent visits. Any randomized patients previously downtitrated based on LLN 
FT4 per Protocol Amendment 2 who did not meet these criteria for downtitration (Amendment 3) 
will be returned to the previous dose in a blinded fashion at the next visit.  
If FT4 is ≤.55 ng/dL on 80 or 60 mg dose with normal FT3 and TSH (which are unblinded to 
study personnel for all patients), even if the decrease in FT4 is not felt to be primarily drug-related, 
a down titration to 60 or 40 mg, respectively, may be made at the next visit as determined by 
Sponsor and Medical Monitor after blinded review. If it is determined after blinded review by 
Sponsor and Medical Monitor that thyroid therapy should be initiated, because thyroxine cannot 
be initiated without breaking the blind, the patient will be discontinued from the study and Early 
Termination assessments will be performed.  
 
Extension Study 
Within 60 days of completion of the main study Week 36 Visit, patients who meet Inclusion 
Criteria #9 will be eligible to participate in an extension phase of the study for an additional 36 
weeks of treatment.  The extension study will initially be blinded to treatment group, but the 
extension study will become unblinded at the time of completion of the main study. At the 
extension study initiation which may be as early as the 38-week visit, (Extension study Day 1 
visit), patients on placebo in the main study will begin receiving 80 mg MGL-3196 and at the 
Week 2 visit, all patients will have a PK assessment, and at Week 4 any dose adjustments will be 
made. All patients on active drug in the main study will initially receive MGL-3196 at the dose 
they were assigned to at the completion of the main study, and at the Week 4 visit they may have 
their dose adjusted up or down based on the Week 2 PK. 
 

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Dose Adjustments in Main and Extension Study in Patients Assigned to MGL-3196 in Main 
Study 
Current 
dose 
Main Study 
Week 2 PK 
(AUC, 
combined 
MGL-3196 plus 
M1 on 80 mg 
dose) 
Main 
Study 
Predose  
at Week 2  
Main study 
Predose  
Week 8 
(post dose 
adjustment) 
Main Study 
SHBG 
<+75% 
CFB at 
Week 12 
(post dose 
adjustment) 
Action in  
Main 
and/or 
Extension 
Study 
40 mg 
 
 
< 5 ng/ml 
Yes 
Increase to 
60 mg/day 
60 mg 
<5500ng*hr*ml1 
 
< 1 ng/ml 
Yes 
Increase to 
80 mg/day 
80 mg 
<4000 ng*hr/ml 
AND SHBG 
%CFB<90) 
 
 
OR2  
Yes 
 
Increase to 
100 mg/day 
100 mg 
≤3000 ng*hr/ml 
<5 ng/ml 
 
 
Increase to 
120 mg 
120 mg 
 
 
 
 
No change 
1 Recalculated 80 mg AUC based on corrected elimination rate constant for MGL-3196 and M1in patients 
who demonstrated average predose levels <5 ng/ml at Week 2,4,8 and had initial calculated AUC<7000 
ng*hr/ml. Change from Baseline (CFB).  
2 Either exposure <4000ng*hr/ml with SHBG%CFB<+90 OR SHBG<+70%CFB qualifies for increase to 
100 mg. 
 
Dose Adjustments in the Extension Study in Patients Assigned to Placebo in the  
Main Study  
Extension Study Week 2  
MGL-3196 Concentration 
Extension Study 
Extension Study 
Predose 
4 h post dose 
Week 2 SHBG 
Week 4 Action 
>35 ng/ml 
>1350 ng/ml 
>200% CFB* 
Downtitrate to 40 mg 
Patients not meeting criteria for 40, 80, 100 or 120 mg 
Downtitrate to 60 mg 
<15 ng/ml 
<600 ng/ml 
OR <75% CFB 
increase** 
Remain on 80 mg or 
increase (see next rows) 
<5 ng/ml 
≤ 350 ng/ml 
No rule 
Increase to 100 mg 
<2 ng/ml 
≤ 150 ng/ml 
No rule 
Increase to 120 mg 
*Change From Baseline, where baseline is Extension Study Day 1. 
**Either predose<15ng/ml plus 4h<600ng/ml OR SHBG<+75%CFB. 
 

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No titrations will be made based on TSH which has not changed in the Main Study. TSH will be 
unblinded in the Extension Study. Downtitrations have not been needed for changes in FT4, but 
the same downtitration rules will apply in the Extension Study. 
At the Extension Study Week 12 Visit, patients will have an MRI-PDFF. Within 10 days prior to 
or at the Extension Study Week 36 visit while the patient is still on treatment another MRI-PDFF 
will be performed. If available, a fibroscan may be performed at the Extension Study Week 36 
visit. 
 
DSMB 
A Data Safety Monitoring Board (DSMB) will oversee the study to ensure patient safety and to 
advise if any dosing alterations are recommended. The DSMB will review safety including thyroid 
hormone effects, liver-related events (ie, clinically meaningful elevations in liver enzymes ALT, 
AST, and bilirubin), cardiovascular assessment (ie, changes in ECG, cardiac biomarkers, cardiac 
AEs, cardiac symptoms, arrhythmias, etc.), SAEs for trends in causality, and other efficacy (lipid 
parameters) and safety data as needed. The DSMB will perform regularly scheduled reviews the 
first scheduled for when 25 patients have received 6 weeks of treatment. Additional regularly 
timed meetings will be held and ad hoc meetings may also occur if determined by Madrigal and 
the DSMB. 
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
MGL-3196 and matching placebo are available as hard gelatin capsules for oral administration in 
40 mg and 60 mg strengths. Patients will be randomized to 1 of 2 treatments: MGL-3196 80 mg 
or placebo given orally once-daily in the morning for 36 weeks. Each patient will receive study 
drug bottles labeled as A and B. Patients will take 1 capsule from bottle A and 1 capsule from 
bottle B at each dosing. Each bottle will contain 32 capsules (64 capsules total), enough for 4 
weeks + 4 days of dosing. Based on PK assessments and/or thyroid hormone results, the dose may 
be adjusted between 40 and 100 mg in intervals of 20 mg. The patient, study personnel, and 
Sponsor will remain blinded throughout the study.  
EFFICACY VARIABLES:  
The primary efficacy variable is percent change in hepatic fat fraction by MRI-PDFF from 
baseline at 12 weeks for MGL-3196 80 mg versus placebo.  
The secondary efficacy variables include the following: 
• The number and percentage of patients achieving a 2-point reduction in NAS at 36 weeks for 
MGL-3196 80 mg versus placebo; 
• The number and percentage of patients achieving resolution of NASH (ballooning = 0; 
inflammation = 0 to 1) at 36 weeks for MGL-3196 80 mg versus placebo; 
• The number and percentage of patients achieving a reduction in any individual component of 
NASH (hepatocellular steatosis, ballooning, fibrosis, or lobular inflammation) at 36 weeks for 
MGL-3196 80 mg versus placebo;  

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and MGL-3196-M1 based on Week 2 AUC(0-8), exposure at 8 h and historic geometric mean 
elimination rate constant for MGL-3196 and MGL-3196-M1 at the 80 mg dose.  
For patients eligible to participate in the extension phase of the study, at the Extension Study 
Week 2 visit, PK assessments at predose and 4 hours post dose will be made. See the tables on 
page 35 for dose adjustments. 
SAFETY VARIABLES: 
Safety variables to be assessed include safety laboratory tests, vital signs and anthropometrics, 
12-lead ECG with rhythm strip, dual-energy x-ray absorptiometry, physical examinations, 
adverse events, and clinical assessments.  
DRUG INDUCED LIVER INJURY MONITORING: 
Close clinical monitoring must be applied to the following:  
• Any patient who had normal baseline ALT, AST, and total bilirubin values and then 
experienced a newly treatment-emergent ALT and/or AST value >3 × ULN OR total 
bilirubin value >2 × ULN; or 
• Any patient who had elevated ALT, AST, or total bilirubin values at baseline and then 
experienced a 2-fold increase above the baseline ALT and/or AST values AND/OR a 
1.5-fold increase above the baseline total bilirubin values.  
The patient must return to the study site within 48 to 72 hours for a confirmatory evaluation and 
central laboratory testing. Repeat laboratory analyses must include the following chemistries: 
ALP, ALT, AST, total and direct bilirubin, international normalized ratio, and lactate 
dehydrogenase. At the same time repeat samples are drawn, a PK sample must be taken.  
CARDIOVASCULAR MONITORING 
Patients will be closely monitored for signs of cardiac toxicity including assessment of CV AEs 
and symptoms.  If any of the following abnormalities are identified, an additional clinical 
investigation may be appropriate: 
• Onset of new (i.e. not present at baseline or documented in the medical history) and 
clinically significant arrhythmia which is persistent (i.e. confirmed on repeat 
assessment)  
• Systolic hypertension (defined for the study as a SBP >160 mmHg and at least a 20 
mmHg increase from baseline) 
• Increase in troponin I vs. baseline and above ULN.  

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STATISTICAL ANALYSES: 
Analysis Populations: 
The Intent-to-Treat (ITT) Population will include all patients who are randomized in the study 
and receive at least 1 dose of study drug. The ITT Population will be used for all efficacy 
analyses. The Per Protocol Population will include all ITT patients who finish the Week 12 visit 
with valid MRI-PDFF measurements and do not have any major protocol deviations. Patients 
who are <80% compliant over the course of the initial 12-week Treatment Period will not be 
included in the Per Protocol Population. The Safety Population will include all patients who are 
randomized in the study and receive at least 1 dose of study drug and will be used for all safety 
analyses. 
Demographics, disposition, and study populations will be summarized descriptively. 
Efficacy: 
The primary efficacy variable will be the percent change in MRI-PDFF from baseline to 
Week 12. Summary statistics (number of patients, mean, standard deviation, median, minimum, 
and maximum) at all visits and change from baseline will be provided. The primary efficacy 
analysis will be analyzed with an analysis of covariance (ANCOVA) model with treatment as a 
factor. For any patients in the ITT Population with a missing primary efficacy parameter, the 
control (placebo)-based pattern mixture model will be used. Based on PK obtained in healthy 
volunteers dosed for up to two weeks on doses of MGL-3196 from 20-200 mg per day, a 
significant fraction of patients randomized to an 80 mg dose may have their dose reduced to 60 
mg after PK assessment at Week 2. The multiplicity (MGL-3196 60 mg versus placebo and 
MGL-3196 80 mg versus placebo) will be controlled by Dunnett’s Test. The primary efficacy 
analysis will be performed based on the ITT Population and repeated based on the Per Protocol 
Population. 
For the continuous secondary efficacy variables, the same ANCOVA model will be used. 
Normality will be tested for the model residuals. For certain efficacy variables (such as hsCRP 
and triglycerides), logarithm transformation may be performed prior to fitting the ANCOVA 
model. For the categorical secondary efficacy variables, Fisher’s exact test will be used to 
compare the odds ratio between MGL-3196 doses versus placebo. 
The same efficacy analyses used for the secondary efficacy variables will be used for the 
tertiary/exploratory efficacy variables.  
Subgroup analysis of the primary efficacy variable and/or selected secondary/other efficacy 
variables may be performed, such as gender (male/female), BMI (≥30 kg/m2 or <30 kg/m2), and 
age group (≥median or <median). 
Safety: 
The safety endpoints for this study include: adverse events, safety laboratory assessments, vital 
signs, 12-lead ECGs, concomitant medications, and clinical assessments. 
The adverse events will be coded using the latest version of the Medical Dictionary for 
Regulatory Activities. Treatment-emergent adverse events (TEAEs) will be defined as adverse 
events that are new or worsening after the first dose of study drug. A general summary of patients 
with TEAEs and serious adverse events (SAEs) will be tabulated with numbers and percentages 

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of patients, and repeated for severity and relationship to study drug per treatment group. The 
number of adverse events leading to withdrawal and SAEs leading to death will also be 
summarized. The incidence of TEAEs will be summarized by body system and treatment group. 
The safety laboratory data will be summarized by visit and by treatment group, along with 
changes from the baseline. The values that are <LLN or >ULN of the reference range will be 
flagged. Those values or changes in values that are identified as being clinically significant will 
be flagged. Laboratory abnormalities of special interest will be summarized. 
Interim Analysis: 
Interim analysis is not designed for this study. However, an analysis will be performed once all 
patients reach Week 12 of the Treatment Period. The analysis will assess the efficacy of 
MGL-3196 on percent change in liver fat by MRI-PDFF.  
SAMPLE SIZE DETERMINATION: 
Approximately 117 patients in total will be randomized to 80 mg (2/3) or placebo (1/3) 
treatments. After PK assessment, a significant fraction of patients’ combined AUC (MGL-3196 
plus MGL-3196-M1) may exceed 5500 ng*hr/ml resulting in a dose reduction to 60 mg. In order 
to power the study appropriately for an efficacious dose (which may be ≥ 80 mg), randomization 
may continue until approximately 36 patients have continued at Week 4 on the 80 mg dose. It 
is estimated that the treatment difference of percent change in hepatic fat fraction from baseline 
to Week 12 between any dose of MGL-3196 and the placebo group is about -30%. With a 
common standard deviation for the percent change in hepatic fat fraction at 35%, 36 patients per 
group completing the Week 12 visit will provide 90% power with a 2-sample t-test. The 
significance level is set as 0.025 for the consideration of multiplicity in comparisons of 2 daily 
dosing regimens of MGL-3196 versus the placebo group. The enrollment size is designed to 
allow for 10% drop out before the Week 12 visit, and as such, patients who drop out of the study 
will not be replaced. 
With the sample size of 39 patients per treatment, the power for selected secondary efficacy 
endpoints was calculated. The baseline hepatic fat fraction is expected to be approximately 15% 
to 17%, thus the change from baseline to Week 12 in hepatic fat fraction is approximately -5.5% 
when comparing to placebo. With common standard deviation of change in hepatic fat fraction 
as 6%, 36 completed patients will provide 94% power for the study when evaluating the 
treatment effect in change of hepatic fat fraction. 
In addition, the sample size is expected to provide meaningful liver biopsy-related data.  
SITES: Approximately 30 sites in the United States 
SPONSOR: 
Madrigal Pharmaceuticals, Inc. 
Four Tower Bridge, 200 Barr Harbor Drive, Suite 400  
West Conshohocken, PA 19428 
Telephone: 610-220-7260 

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TABLE OF CONTENTS 
SIGNATURE PAGE ...................................................................................................................... 2 
INVESTIGATOR AGREEMENT.................................................................................................. 3 
SUMMARY OF PROTOCOL AMENDMENT 6 CHANGES ...................................................... 4 
SUMMARY OF PROTOCOL AMENDMENT 5 CHANGES .................................................... 17 
SUMMARY OF PROTOCOL AMENDMENT 4 CHANGES .................................................... 27 
SUMMARY OF PROTOCOL AMENDMENT 3 CHANGES .................................................... 29 
SUMMARY OF PROTOCOL AMENDMENT 2 CHANGES .................................................... 33 
SUMMARY OF PROTOCOL AMENDMENT 1 CHANGES .................................................... 35 
SYNOPSIS .................................................................................................................................... 37 
TABLE OF CONTENTS .............................................................................................................. 53 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................. 58 
1 
INTRODUCTION AND BACKGROUND INFORMATION ........................................ 60 
1.1 
Background ................................................................................................................. 60 
1.2 
Rationale ..................................................................................................................... 60 
2 
STUDY OBJECTIVES ..................................................................................................... 62 
2.1 
Primary Objective ....................................................................................................... 62 
2.2 
Secondary Objectives.................................................................................................. 62 
2.3 
Exploratory Objectives ............................................................................................... 63 
3 
STUDY DESCRIPTION .................................................................................................. 64 
3.1 
Summary of Study Design .......................................................................................... 64 
3.1.1 Screening Period ................................................................................................... 64 
3.1.2 Treatment Period ................................................................................................... 64 
3.1.3 Extension Study .................................................................................................... 66 
3.1.4 DSMB ................................................................................................................... 67 
3.2 
Study Indication .......................................................................................................... 67 
4 
SELECTION AND WITHDRAWAL OF PATIENTS .................................................... 68 
4.1 
Inclusion Criteria ........................................................................................................ 68 
4.2 
Exclusion Criteria ....................................................................................................... 70 
4.3 
Withdrawal Criteria .................................................................................................... 73 
5 
STUDY TREATMENTS .................................................................................................. 75 
5.1 
Treatment Groups ....................................................................................................... 75 
5.2 
Rationale for Dosing ................................................................................................... 75 

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5.3 
Randomization and Blinding ...................................................................................... 75 
5.4 
Breaking the Blind ...................................................................................................... 75 
5.5 
Drug Supplies.............................................................................................................. 75 
5.5.1 Formulation and Packaging .................................................................................. 75 
5.5.2 Study Drug Preparation and Dispensing ............................................................... 76 
5.5.3 Study Drug Administration ................................................................................... 76 
5.5.4 Treatment Compliance .......................................................................................... 76 
5.5.5 Storage and Accountability ................................................................................... 76 
5.6 
Prior and Concomitant Medications and/or Procedures ............................................. 77 
5.6.1 Excluded Medications ........................................................................................... 77 
5.6.2 Documentation of Prior and Concomitant Medication Use .................................. 77 
6 
STUDY PROCEDURES .................................................................................................. 78 
6.1 
Informed Consent........................................................................................................ 78 
6.2 
Screening Period (Week -6 to Week 0) ...................................................................... 78 
6.3 
Randomization ............................................................................................................ 79 
6.4 
Main Study Treatment Period – Day 1 to Week 38 .................................................... 79 
6.4.1 Baseline Visit (Day1) ............................................................................................ 79 
6.4.2 Week 2 (Day 14) ................................................................................................... 80 
6.4.3 Week 4 (Day 28) ................................................................................................... 81 
6.4.4 Week 8 (Day 56) ................................................................................................... 81 
6.4.5 Week 12 (Day 84) ................................................................................................. 82 
6.4.6 Week 16 (Day 112) ............................................................................................... 83 
6.4.7 Week 20 (Day 140) ............................................................................................... 83 
6.4.8 Week 24 (Day 168) ............................................................................................... 84 
6.4.9 Week 30 (Day 210) ............................................................................................... 84 
6.4.10 Week 36 (Day 252) ............................................................................................... 85 
6.5 
Follow-Up Visit (Week 38 [Day 266]) ....................................................................... 86 
6.6 
Early Termination Visit and Withdrawal Procedures ................................................. 86 
6.7 
Extension Study .......................................................................................................... 87 
6.7.1 Extension Study Day 1 (Extension Day1) ............................................................ 87 
6.7.2 Extension Study Week 2 (Extension Day 14)....................................................... 88 
6.7.3 Extension Study Weeks 4, 8, 16, 20, 28, and 32 ................................................... 89 
6.7.4 Extension Study Week 12 (Extension Day 84)..................................................... 89 
6.7.5 Extension Study Week 24 (Extension Day 168)................................................... 90 

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6.7.6 Extension Study Week 36 (Extension Day 252)................................................... 91 
6.7.7 Extension Study Week 38 Follow-up Visit (Extension Day 266) ........................ 92 
6.7.8 Extension Study Early Termination Visit ............................................................. 92 
7 
EFFICACY ASSESSMENTS .......................................................................................... 93 
8 
PHARMACOKINETIC ASSESSMENTS ....................................................................... 95 
8.1 
Main Study .................................................................................................................. 95 
8.2 
Extension Study .......................................................................................................... 95 
9 
SAFETY ASSESSMENTS ............................................................................................... 97 
9.1 
Adverse Events ........................................................................................................... 97 
9.1.1 Adverse (Drug) Reaction ...................................................................................... 97 
9.1.2 Unexpected Adverse Drug Reaction ..................................................................... 97 
9.1.3 Assessment of Adverse Events by the Investigator .............................................. 98 
9.1.3.1 
Assessment of severity: ................................................................................... 98 
9.1.3.2 
Causality assessment: ...................................................................................... 98 
9.2 
Serious Adverse Events .............................................................................................. 99 
9.3 
Serious Adverse Event Reporting − Procedures for Investigators.............................. 99 
9.3.1.1 
Initial reports.................................................................................................... 99 
9.3.1.2 
Follow-up reports .......................................................................................... 100 
9.4 
Pregnancy Reporting ................................................................................................. 100 
9.5 
Expedited Reporting ................................................................................................. 100 
9.6 
Informed Consent...................................................................................................... 101 
9.7 
Demographic Information ......................................................................................... 101 
9.8 
Clinical Laboratory Evaluations ............................................................................... 101 
9.9 
Vital Signs and Anthropometrics .............................................................................. 103 
9.10 
Electrocardiograms ................................................................................................... 104 
9.11 
Physical Examinations .............................................................................................. 104 
9.12 
Diet and Lifestyle Counseling .................................................................................. 104 
9.13 
Health-Related Assessment-Quality of Life ............................................................. 104 
9.14 
Proton Density Fat Fraction Magnetic Resonance Imaging ..................................... 105 
9.15 
Liver Biopsy.............................................................................................................. 105 
9.16 
Dual-Energy X-Ray Absorptiometry ........................................................................ 105 
9.17 
Drug Induced Liver Injury Monitoring ..................................................................... 105 
9.18 
Cardiovascular Monitoring ....................................................................................... 106 
10 
STATISTICS .................................................................................................................. 109 

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10.1 
Analysis Populations ................................................................................................. 109 
10.2 
Statistical Methods .................................................................................................... 109 
10.2.1 Analysis of Efficacy ............................................................................................ 109 
10.2.1.1 
Primary efficacy analysis ............................................................................... 109 
10.2.1.2 
Secondary efficacy analysis........................................................................... 109 
10.2.1.3 
Other efficacy analysis .................................................................................. 109 
10.2.1.4 
Subgroup analysis .......................................................................................... 109 
10.2.2 Analysis of Safety ............................................................................................... 110 
10.2.3 Interim Analysis .................................................................................................. 110 
10.2.4 Data Safety Monitoring Board ............................................................................ 110 
10.2.5 Sample Size Determination................................................................................. 110 
11 
DATA MANAGEMENT AND RECORD KEEPING................................................... 112 
11.1 
Data Management ..................................................................................................... 112 
11.1.1 Data Handling ..................................................................................................... 112 
11.1.2 Computer Systems .............................................................................................. 112 
11.1.3 Data Entry ........................................................................................................... 112 
11.1.4 Medical Information Coding............................................................................... 112 
11.1.5 Data Validation ................................................................................................... 112 
11.2 
Record Keeping ........................................................................................................ 112 
12 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL ........................... 113 
12.1 
Ethical Conduct of the Study .................................................................................... 113 
12.2 
Institutional Review Board ....................................................................................... 113 
12.3 
Informed Consent...................................................................................................... 113 
12.4 
Study Monitoring Requirements ............................................................................... 113 
12.5 
Disclosure of Data..................................................................................................... 114 
12.6 
Retention of Records................................................................................................. 114 
12.7 
Publication Policy ..................................................................................................... 114 
12.8 
Financial Disclosure.................................................................................................. 115 
13 
STUDY ADMINISTRATIVE INFORMATION ........................................................... 116 
13.1 
Protocol Amendments ............................................................................................... 116 
13.2 
Address List .............................................................................................................. 116 
13.2.1 Sponsor ............................................................................................................... 116 
13.2.2 Contract Research Organization ......................................................................... 116 
13.2.3 Drug Safety ......................................................................................................... 116 

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13.2.4 Biological Specimens.......................................................................................... 116 
13.2.5 Pharmacokinetic Samples ................................................................................... 117 
14 
REFERENCES ............................................................................................................... 118 
APPENDIX A:  SCHEDULE OF PROCEDURES - MAIN STUDY ....................................... 120 
APPENDIX B: SCHEDULE OF PROCEDURES - EXTENSION STUDY ............................. 123 
APPENDIX C:  CLINICAL LABORATORY ANALYTES ..................................................... 126 
 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
 
 
ALP 
Alkaline phosphatase  
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance  
ApoB 
Apolipoprotein B 
APTT 
Activated partial prothrombin time 
APRI 
AST to platelet ratio 
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
CAP 
Controlled attenuation parameter 
CK-18 
Cytokeratin-18 
CK-MB 
Creatine Kinase-MB 
CRA 
Clinical research associate 
CTA 
Clinical trial authorization 
CTX 
C-terminal telopeptide 
CYP2C8 
Cytochrome P450 2C8 
CYP2C9 
Cytochrome P450 2C9 
DSMB 
Data Safety Monitoring Board 
DXA 
Dual-energy x-ray absorptiometry 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
ELF 
Enhanced liver function 
FIB-4 
Fibrosis-4 
FT3 
Free triiodothyronine 
FT4 
Free thyroxine 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
 
 
 
HCV 
Hepatitis C virus 
HDL-C 
High-density lipoprotein cholesterol 
HepB 
Hepatitis B 
HepC 
Hepatitis C 
HIV 
Human immunodeficiency virus 
 

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Abbreviation 
Definition 
hsCRP 
High-sensitivity C-reactive protein 
HR-QoL SF-36 
Health-related quality of life short form 36 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IUD 
Intrauterine device 
kPa 
kiloPascals 
LDL-C 
Low-density lipoprotein cholesterol 
LH 
Luteinizing hormone 
LLN 
Lower limit of normal 
Lp(a) 
Lipoprotein(a) 
MedDRA 
Medical Dictionary for Regulatory Activities 
NAFLD 
Non-alcoholic fatty liver disease 
NAS 
NAFLD activity score 
NASH 
Non-alcoholic steatohepatitis 
 
OAD 
Oral anti-diabetic 
MRI-PDFF 
Proton density fat fraction magnetic resonance imaging 
PK 
Pharmacokinetic 
PT 
Prothrombin time 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SHBG 
Sex hormone binding globulin 
T3 
Triiodothyronine 
T4 
Thyroxine 
TBG 
thyroxine binding globulin 
TEAE 
Treatment-emergent adverse event 
THR 
Thyroid hormone receptor 
THR-α 
Thyroid hormone receptor alpha 
THR-β 
Thyroid hormone receptor beta 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
 

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1 
INTRODUCTION AND BACKGROUND INFORMATION 
1.1 
Background 
Despite advances in treatment, approximately 70% of high-risk cardiovascular patients do not 
achieve low-density lipoprotein cholesterol (LDL-C) goals, and as many as 10% of 
hypercholesterolemic patients do not tolerate statins.1,2 Elevated LDL-C levels are associated with 
cardiovascular disease, including myocardial infarctions and strokes, and drugs such as statins that 
lower LDL-C also reduce cardiovascular morbidity and mortality. Insulin resistant type 2 diabetics 
have a high incidence of atherosclerosis, and 65% to 80% of diabetics die of macrovascular 
cardiovascular disease.3 Diabetes is associated with a dyslipidemia characterized by non-alcoholic 
fatty liver disease (NAFLD), elevated triglycerides, atherogenic low-density lipoprotein particles 
and reduced high-density lipoprotein cholesterol (HDL-C) that is not well treated by existing 
therapies.4,5 
In large part because of the worldwide obesity and diabetes epidemic, the prevalence of NAFLD 
has increased dramatically with prevalence rates of approximately 25% of the US population.6 
Non-alcoholic fatty liver disease may lead to non-alcoholic steatohepatitis (NASH), a more serious 
liver disease that can lead to liver cirrhosis and increased cardiovascular disease. Non-alcoholic 
steatohepatitis was described more than 30 years ago and is characterized by findings on liver 
biopsy including fatty changes with lobular hepatitis (ballooning and inflammation) in the absence 
of history of alcoholism. The histologic components of steatosis, inflammation, and ballooning 
degeneration may be accompanied by various degrees of fibrosis. 
MGL-3196 is a liver-directed, orally active, partial agonist for the thyroid hormone receptor 
(THR), with approximately 28-fold selectivity for the beta receptor compared to the active thyroid 
hormone, triiodothyronine (T3). Selectivity for a thyroid agonist at thyroid hormone receptor beta 
(THR-β) isoform, the predominant liver thyroid hormone receptor, has the potential of providing 
metabolic benefits of thyroid hormone that are mediated in the liver, while avoiding unwanted 
systemic actions of thyroid hormone in heart and bone that are largely mediated through THR 
alpha (THR-α).7  
Thyroxine (T4) via its active derivative, T3, provides beneficial metabolic effects on cholesterol, 
triglyceride, and liver triglyceride levels, primarily through action at the THR-β, the predominant 
hepatocyte THR.7,8,9,10,11 However, excessive levels of thyroid hormone can lead to adverse effects 
mediated by the THR-α receptor which is the major systemic thyroid hormone receptor.12,13 
MGL-3196 is a selective THR-β agonist with actions in the liver that is designed to avoid those 
systemic actions mediated through the THR-α and the central thyroid action suppression observed 
with previous analogues.  
1.2 
Rationale 
The deficiency in THR-β activity in NASH livers cannot be corrected by treatment with thyroid 
hormone because 1) thyroid hormone may be rapidly metabolized in NASH livers due to the action 
of deiodinases, and 2) thyroid hormone has undesirable systemic actions, particularly effects on 
the heart and bone because of its potency at the THR-α receptor.  
Thyroid hormone receptor analogs demonstrating an improved therapeutic window between 
beneficial lipid effects and adverse systemic effects have been developed and tested in clinical 
trials and demonstrated validation of cholesterol and triglyceride lowering.14,15 However, 

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eprotirome and other analogs also demonstrated safety issues that resulted in discontinuation of 
clinical development. These include low margins relative to doses that suppress the central thyroid 
axis, elevated liver enzymes in Phase 1, 2, and 3 studies, and other safety issues such as formation 
of a nitrated mutagenic impurity at gastric pH and collagen damage in a preclinical toxicology 
study.16, 17 
The oral THR-β agonist MGL-3196 was selected for clinical development based on its enhanced 
THR-β selectivity in functional THR assays and its greatly improved safety in preclinical animal 
models relative to other THR analogues and T3.18 Unlike previous clinical analogues, MGL-3196 
is highly THR-β selective in a functional coactivator recruitment assay and has virtually no THR-α 
activity. Liver uptake is mediated by hepatic transporters. In preclinical animal studies, MGL-3196 
showed rapid and robust lowering of non-HDL cholesterol, triglycerides, and liver triglycerides, 
with reduction in NASH gene transcripts, differentiating MGL-3196 from statins and other 
lipid-lowering agents. In 14-day Phase 1 studies in healthy human volunteers, once-daily doses of 
MGL-3196 showed rapid, robust reduction of LDL-C and triglycerides. In these studies, there was 
apparent safety at all doses tested and no evidence of the liver enzyme changes or central thyroid 
axis suppression that were seen with T3, T4, or previous clinical thyroid analogues.19 

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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to determine the effect of once-daily oral MGL-3196 80 mg 
versus placebo (randomized 2:1) for 12 weeks on the percent change in hepatic fat fraction by 
proton density fat fraction magnetic resonance imaging (MRI-PDFF) from baseline in patients 
with biopsy-proven NASH.  
2.2 
Secondary Objectives 
The secondary objectives of this study are the following: 
• To determine the effect of once-daily oral MGL-3196 80 mg versus placebo for 36 weeks in 
patients with biopsy-proven NASH on the histological improvement from baseline on: 
o Two-point reduction in NAFLD activity score (NAS); 
o Resolution of NASH (ballooning = 0; inflammation = 0 to 1); or 
o Any individual component of NASH (hepatocellular steatosis, ballooning, fibrosis, or 
lobular inflammation);  
• To evaluate the safety and tolerability, including any changes in thyroid axis hormones, of 
once-daily oral MGL-3196 80 mg versus placebo after 12 and 36 weeks in patients with 
biopsy-proven NASH;  
• To evaluate the effect of once-daily oral MGL-3196 80 mg versus placebo for 36 weeks on the 
percent change in hepatic fat fraction by MRI-PDFF from baseline in patients with 
biopsy-proven NASH;  
• To evaluate the effect of once-daily oral MGL-3196 80 mg versus placebo for 12 and 36 weeks 
on the change in hepatic fat fraction by MRI-PDFF from baseline in patients with biopsy-
proven NASH; and 
• To determine the effect of once-daily oral MGL-3196 80 mg versus placebo after 12 and 36 
weeks in patients with biopsy-proven NASH on: 
o High-sensitivity C-reactive protein (hsCRP); 
o Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST); 
o Lipid parameters including LDL-C, HDL-C, non-HDL-C, total cholesterol, triglycerides, 
apolipoprotein B (ApoB), and lipoprotein(a) (Lp[a]) particles; and 
o NASH and fibrosis biomarkers including cytokeratin-18 (CK-18), fibrosis-4 (FIB-4), and 
enhanced liver function (ELF) test. 

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3 
STUDY DESCRIPTION 
3.1 
Summary of Study Design 
This is a multi-center, double-blind, randomized, placebo-controlled study to evaluate the safety 
and efficacy of MGL-3196 in patients with NASH. Patients who qualify for study inclusion will 
be randomized to receive one of two 36-week treatments: MGL-3196 80 mg or placebo given 
orally once-daily in the morning. Following 12 weeks of treatment, the primary endpoint, percent 
change from baseline in hepatic fat fraction measured by MRI-PDFF, will be evaluated. At 36 
weeks, all patients will undergo liver biopsy.  
3.1.1 
Screening Period 
Patients must provide written informed consent prior to any study procedures being performed. 
Patients will undergo screening procedures within 42 days of randomization. To participate in the 
study, patients are required to have had a qualifying liver biopsy within 180 days of randomization. 
Patients must meet all of the inclusion criteria and none of the exclusion criteria to participate in 
the study.  
3.1.2 
Treatment Period 
Following randomization, patients will begin the initial 12-week Treatment Period. Patients will 
undergo liver MRI-PDFF prior to the start of treatment (pre-dose), at the end of the initial 12-week 
Treatment Period (12 weeks after the start of treatment), and after continuing blinded treatment 
(MGL-3196 or placebo) for an additional 24 weeks (36 weeks after the start of treatment). A liver 
biopsy will be obtained prior to start of treatment (pre-dose) if the patient has not had a qualifying 
liver biopsy within 180 days of randomization and at 36 weeks. During the study, patients will 
return to the study site periodically for assessment of vital signs (temperature, pulse, respiratory 
rate, and seated blood pressure), 12-lead electrocardiogram (ECG), and clinical laboratory testing 
(hematology, chemistry, and urinalysis). During the study, patients who need to be placed on any 
excluded lipid lowering therapeutics will be discontinued from the study. Blood samples will be 
collected at specified times for the assessment of lipid parameters, thyroid hormone parameters, 
and other biomarkers. Patients will be evaluated for adverse events and concomitant medication 
use throughout the study. Patients should be monitored throughout the study for clinical signs and 
symptoms of hyper- or hypothyroidism. 
A PK assessment will be made at Week 2 including a pre-dose fasting determination and 
assessments at 2, 4, 6, and 8 hours postdose. As described in PK section, patients who have a 
calculated AUCinf ≤ to 5500 ng*hr/ml (combined MGL-3196 and MGL-3196-M1) will continue 
on 80 mg. For patients (~ 10%) with an AUCinf ≤3000 ng*hr/ml as described in Section 8 who are 
predicted to have exposure at 100 mg that remains AUC ≤5550 based on a conservative 
calculation, the MGL-3196 dose will be increased from 80 mg to 100 mg at the Week 4 visit. For 
patients with combined AUC >5500 ng*hr/ml, the dose of MGL-3196 will be reduced to 60 mg 
per day on the Week 4 visit.  Patients with AUCinf >11,000 (combined MGL-3196 and M1) 
plus SHBG>150% increase from baseline at Week 2 (indicative that average or steady-state 
exposure is >11,000 ng*hr/ml) will be downtitrated to 40 mg at Week 4. If SHBG ≤150%, then 
patient will be downtitrated to 60 mg at Week 4, and patient’s Week 4 SHBG and predose 
concentrations will be evaluated. If at Week 4 SHBG >150% increase from baseline and predose 

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>40ng/ml for MGL-3196 and >40ng/ml for M1 then patient will be downtitrated to 40 mg at the 
Week 8 visit. 
A combined MGL-3196 and MGL-3196-M1 exposure ≤ 5500 ng*hr/ml has not demonstrated a 
drug-related decrease in FT4 to < LLN < 0.7 ng/dL) in Phase 1 studies. However, patients with 
NASH without symptoms of hypothyroidism may occasionally have low baseline levels of FT4, 
with normal FT3 and TSH, and are not clinically or subclinically hypothyroid. Low FT4 in the 
presence of normal FT3 (active hormone) and TSH is not consistent with hypothyroidism; low 
FT4 is observed in euthyroid (formerly hypothyroid) patients treated with T3 monotherapy 20 
In patients continuing on 80 mg MGL-3196 (AUCinf < 5500) who have FT4 LLN (>.55 to <.7 
ng/dL): 
 
At Week 4 or later: 
• If FT3 remains normal (not decreased to <LLN) and TSH remains normal, the patient does 
not have symptoms of hypothyroidism, the patient may continue on the current dose. 
• Down titration to 60 mg may be made at the next visit, Week 8 or later if FT4 <LLN (>.55 
to <.7 ng/dL), FT3 and TSH are normal, and there is evidence that the decrease in FT4 
<LLN (>.55 to <.7 ng/dL) is drug-related including a >30% decrease from baseline in FT4, 
an increase in SHBG >120% from baseline and predose exposure >40 ng/ml for MGL-
3196 and > 40 ng/ml for MGL-3196-M1 that is consistent with increased drug exposure 
relative to the Week 2 PK assessment. 
In patients downtitrated to 60 mg at Week 4 who have FT4 LLN (>.55 to <.7 ng/dL): 
• At Week 8 or later, if FT3 and TSH remain normal, the patient does not have symptoms of 
hypothyroidism, the patient may continue on the current dose.  
• Down titration to 60 or 40 mg may be made at the next visit, Week 12 or later if FT4 <LLN 
(>.55 to <.7 ng/dL), FT3 and TSH are normal, and there is evidence that the decrease in 
FT4 <LLN (>.55 to <.7 ng/dL) is drug-related including a >30% decrease from baseline in 
FT4, an increase in SHBG >120% from baseline and predose exposure >40 ng/ml for 
MGL-3196 and > 40 ng/ml for MGL-3196-M1 that is consistent with increased drug 
exposure relative to the Week 2 PK assessment.  
 
If these conditions are not met, the patient will continue on current dose and thyroid indices 
reassessed at subsequent visits. Any randomized patients previously downtitrated based on LLN 
FT4 per Protocol Amendment 2 who did not meet these criteria for downtitration (Amendment 3) 
will be returned to the previous dose in a blinded fashion at the next visit.  
If FT4 is ≤.55 ng/dL on 80 or 60 mg dose with normal FT3 and TSH (which are unblinded to study 
personnel for all patients), even if the decrease in FT4 is not felt to be primarily drug-related, a 
down titration to 60 or 40 mg, respectively, may be made at the next visit as determined by Sponsor 
and Medical Monitor after blinded review. If it is determined after blinded review by Sponsor and 
Medical Monitor that thyroid therapy should be initiated, because thyroxine cannot be initiated 
without breaking the blind, the patient will be discontinued from the study and Early Termination 
assessments will be performed.  

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3.1.3 
Extension Study 
Within 60 days of completion of the main study Week 36 Visit, patients who meet Inclusion 
Criteria #9 will be eligible to participate in an extension phase of the study for an additional 36 
weeks of treatment.  The extension study will initially be blinded to treatment group, but the 
extension study will become unblinded at the time of completion of the main study. At the 
extension study initiation which may be as early as the 38-week visit, (Extension study Day 1 
visit), patients on placebo in the main study will begin receiving 80 mg MGL-3196 and at the 
Week 2 visit, all patients will have a PK assessment, and at Week 4 any dose adjustments will be 
made. All patients on active drug in the main study will initially receive MGL-3196 at the dose 
they were assigned to at the completion of the main study, and at the Week 4 visit they may have 
their dose adjusted up or down based on the Week 2 PK.  
Dose Adjustments in Main or Extension Study in Patients Assigned to MGL-3196 in Main 
Study 
Current 
dose 
Main Study 
Week 2 PK 
(AUC, combined 
MGL-3196 plus 
M1 on 80 mg 
dose) 
Main Study 
Predose  
at Week 2  
Main study 
Predose  
Week 8 
(post dose 
adjustment) 
Main Study 
SHBG 
<+75% 
CFB at 
Week 12 
(post dose 
adjustment) 
Action in 
Main and/or 
Extension 
Study 
40 mg 
 
 
< 5 ng/ml 
Yes 
Increase to 60 
mg/day 
60 mg 
<5500 ng*hr/ml1 
 
< 1 ng/ml 
Yes 
Increase to 80 
mg/day 
80 mg 
<4000 ng*hr/ml 
AND SHBG 
%CFB<90)  
 
OR2 Yes 
 
Increase to 
100 mg/day 
100 mg 
≤3000 ng*hr/ml 
<5 ng/ml 
 
 
Increase to 
120 mg 
120 mg 
 
 
 
 
No change 
1 Recalculated 80 mg AUC based on corrected elimination rate constant for MGL-3196 and M1in patients who 
demonstrated average predose levels <5 ng/ml at Week 2,4,8 and had initial calculated AUC<7000 ng*hr/ml. 
Change from Baseline (CFB).  
2 Either exposure <4000ng*hr/ml with SHBG%CFB<+90 OR SHBG<+70%CFB qualifies for increase to 
100 mg. 
 

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Dose Adjustments in the Extension Study in Patients Assigned to Placebo in the Main Study 
Extension Study Week 2  
MGL-3196 Concentration 
Extension Study 
Extension Study 
Predose 
4 h post dose 
Week 2 SHBG 
Week 4 Action 
>35 ng/ml 
>1350 ng/ml 
>200% CFB* 
Downtitrate to 40 mg 
Patients not meeting criteria for 40, 80, 100 or 120 mg  
Downtitrate to 60 mg 
<15 ng/ml 
<600 ng/ml 
OR <75% CFB 
increase** 
Remain on 80 mg or 
increase (see next rows) 
<5 ng/ml 
≤ 350 ng/ml 
No rule 
Increase to 100 mg 
<2 ng/ml 
≤ 150 ng/ml 
No rule 
Increase to 120 mg 
*Change From Baseline, where baseline is Extension Study Day 1. 
**Either predose<15ng/ml plus 4h<600ng/ml OR SHBG<+75%CFB. 
 
No titrations will be made based on TSH which has not changed in the Main Study. TSH will be 
unblinded in the Extension Study. Downtitrations have not been needed for changes in FT4, but 
the same downtitration rules will apply in the Extension Study. 
At the Extension Study Week 12 Visit, patients will have an MRI-PDFF. Within 10 days prior to 
or at the Extension Study Week 36 visit while the patient is still on treatment another MRI-PDFF 
will be performed. If available, a fibroscan may be performed at the Extension Study Week 36 
visit. 
3.1.4 
DSMB 
A Data Safety Monitoring Board (DSMB) will oversee the study to ensure patient safety and to 
advise if any dosing alterations are recommended. The DSMB will review safety including thyroid 
hormone effects, liver-related events (ie, clinically meaningful elevations in liver enzymes ALT, 
AST, and bilirubin), cardiovascular assessment (ie, changes in ECG, cardiac biomarkers, cardiac 
AEs, cardiac symptoms, arrhythmias, etc.), SAEs for trends in causality, and other efficacy (lipid 
parameters) and safety data as needed. The DSMB will perform regularly scheduled reviews the 
first scheduled for when 25 patients have received 6 weeks of treatment. Additional regularly timed 
meetings will be held and ad hoc meetings may also occur if determined by Madrigal and the 
DSMB. 
3.2 
Study Indication 
The indication for this study is the treatment of NASH.  

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4 
SELECTION AND WITHDRAWAL OF PATIENTS 
4.1 
Inclusion Criteria 
The population for this study is male and female patients ≥18 years of age with biopsy-proven 
NASH.  
Patients who meet all of the following criteria will be eligible to participate in the study: 
1. Must be willing to participate in the study and provide written informed consent;  
2. Male and female adults ≥18 years of age; 
3. Female patients of child bearing potential with negative serum pregnancy (beta human 
chorionic gonadotropin) tests who are not breastfeeding, do not plan to become pregnant 
during the study, and agree to use effective birth control (ie, condoms, diaphragm, 
non-hormonal intrauterine device [IUD], or sexual abstinence [only if this is in line with the 
patient’s current lifestyle]) throughout the study and for at least 1 month after study 
completion; hormonal contraception (estrogens stable ≥3 months) and hormonal IUDs are 
permitted if used with a secondary birth control measure (eg, condoms); OR female patients 
of non-child bearing potential (ie, surgically [bilateral oophorectomy, hysterectomy, or tubal 
ligation] or naturally sterile [>12 consecutive months without menses]); Male patients who 
have sexual intercourse with a female partner of child bearing potential from the first dose of 
study drug until 1 month after study completion must be either surgically sterile (confirmed by 
documented azoospermia >90 days after the procedure) OR agree to use a condom with 
spermicide.  All male patients must agree not to donate sperm from the first dose of study drug 
until 1 month after study completion; 
4. Suspected or confirmed diagnosis of NASH suggested by the historical data and at least one 
of the following assessments within current and/or historical data sets (and, therefore, likely to 
meet MRI-PDFF and liver biopsy criteria outlined in Inclusion #5 and #6): 
o Metabolic syndrome (obesity, dyslipidemia, elevated blood pressure, elevated fasting 
glucose) with two or more of the following: type 2 diabetes/insulin resistance, BMI ≥ 34, 
history of hypertension, elevated liver enzymes (ALT, AST) 
o Fibroscan, magnetic resonance elastography, or serum biomarkers (eg, AST to platelet 
ratio [APRI], NAFLD fibrosis score, FIB-4 or ELF) consistent with liver fibrosis; 
o Controlled attenuation parameter (CAP), quantitative ultrasound (liver fat >10%), MRI-
PDFF, or magnetic resonance spectroscopy consistent with significant liver steatosis 
(>10%); 
o Previous liver biopsy consistent with NASH. 
Note: Assessment of the above, or other objective modalities suggested by PI, will occur.  The 
choice of additional procedures, performed during the screening period prior to the screening MRI 
and liver biopsy, may include calculation of FIB-4, APRI, NAFLD fibrosis scores, and/or 
performance of fibroscan and/or CAP. 
 

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5. Must have confirmation of ≥10% liver fat content on MRI-PDFF; 
Note: Patients with a liver fat content >9% but < 10% on MRI-PDFF and who are highly likely 
to have NASH as determined by Medical Monitors on biopsy may be included in the study but 
the total may not exceed 10% of the total study population;  
6. Biopsy-proven NASH: 
• Must have had prior liver biopsy within 180 days of randomization with fibrosis stage 1 to 3 
and a NAS of ≥4 with at least a score of 1 in each of the following NAS components: 
o Steatosis (scored 0 to 3),  
o Ballooning degeneration (scored 0 to 2), and 
o Lobular inflammation (scored 0 to 3); and 
Note 1: Patients who have clear ballooning with fibrosis but no inflammation or patients who 
have clear inflammation with fibrosis but no ballooning or patients with clear NASH without 
fibrosis may be included in the study but the total may not exceed 10% of the total study 
population;  
Note 2: If a historical biopsy is to be used, patients must have had no significant change in 
metabolic status (diabetes control, lipid metabolism, and/or >5% weight loss), significant 
change in diabetes medication, or change in use of medications listed in Exclusion #11 since 
the biopsy; 
Note 3: If a historical biopsy is not available, patients must have confirmation of ≥10% liver 
fat content on MRI-PDFF prior to undergoing liver biopsy. However, if, in the opinion of the 
patient’s physician, the patient would benefit from and be advised to obtain a liver biopsy, the 
patient may undergo liver biopsy prior to MRI-PDFF;  
7. Must have documented historical (3 weeks to 6 months prior to the study entry) ALT and AST 
levels consistent with the screening ALT and AST values. This consistency is established 
based on the following:  
o If the historical and screening ALT and AST values are both ≤1.5 × the upper limit of 
normal (ULN), there is no limit to the difference between the values  
o If the historic ALT/AST are >1.5 X elevated and screening ALT and AST are markedly 
improved (>50% decreased or normalized) relative to historic, then a third ALT/AST 
determination will be made during screening to assure a stable baseline, and that there is 
no worsening of >30% form the screening values. If the difference is >30% and the second 
value is greater than the first value, a third value should be determined during the screening 
period to confirm lack of worsening trend in ALT/AST  
o If at least 1 of the values is >1.5 × ULN and the second value is greater than the first value, 
the difference in the mean of ALT and AST values must be ≤30%. If the difference is >30% 
and the second value is greater than the first value, a third value should be determined to 
confirm lack of worsening trend in ALT/AST.  If worsening trend is confirmed (3 
consecutive worsening values with difference from first value and second value >30%), 
patient will be excluded.  

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Note: Patients who do not have the historical ALT and AST evaluations available may have their 
ALT and AST repeated during the screening period (both assessments need to be 3 weeks apart). 
8. Normal or minimally abnormal renal function as defined by estimated glomerular filtration 
rate (eGFR) ≥ 60. 
9. Eligibility for extension study. Within 60 days of completion of the Week 36 Visit in the main 
study, patients who meet the following additional criteria will be eligible to participate in the 
extension phase of this study: 
o Had 36-week MRI-PDFF 
o Had 36-week liver biopsy 
o No new exclusions that would prevent the patient from participating in up to 36 weeks of 
additional treatment 
o Meets at least one of the following liver enzyme criteria in the table below: 
Baseline ALT 
Average of ALT at Weeks 16, 20, 24, and 30 
ALT normal (<1.5 ULN) 
≥ 1.5 x ULN (and 30% worse than baseline) 
ALT =1.5-2X 
Improvement from baseline <30% and ALT 
=1.5-2X ULN 
ALT any 
ALT ≥ 2X 
Note: Normal ALT male 30; female 25:  
1.5 x male =45 and female=38 
Note: ALT or AST values for weeks 16, 20, 24 and 30 that 
are > 2 X Std Dev from mean will be excluded from 
the calculation of the average value. 
Note: When ALT does not meet criteria for inclusion, AST 
will be evaluated similarly to determine if criteria 
for inclusion are met based on AST, given normal 
values in men and women of 27 and 22, respectively 
and 1.5X of 40 and 33 respectively. 
 
4.2 
Exclusion Criteria 
Note: Unless otherwise specified, repeat testing may be performed in consultation with the 
Medical Monitor. 
Patients who meet any of the following criteria will be excluded from participation in the study: 
1. History of significant alcohol consumption for a period of more than 3 consecutive months 
within 1 year prior to screening; 
Note: Significant alcohol consumption is defined as average of >20 g/day in female patients 
and >30 g/day in male patients;  
2. Inability to reliably quantify alcohol consumption based upon judgment of the Investigator;  

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3. Use of drugs historically associated with NAFLD (amiodarone, methotrexate, systemic 
glucocorticoids, tetracyclines, tamoxifen, estrogens at doses greater than those used for 
hormone replacement, anabolic steroids, valproic acid, and other known hepatotoxins) for 
more than 2 weeks in the year prior to screening;  
4. Hyperthyroidism;  
5. Patients on thyroid replacement therapy or with untreated clinical or subclinical 
hypothyroidism; 
Note: If TSH is up to 1.5 x ULN on screening with normal free T4, one repeat test is allowed 
to confirm the elevation in TSH. If TSH and free T4 are normal upon repeat testing, patient 
may be included. Patients with a history of thyroid hormone replacement therapy or patients 
who have discontinued thyroid hormone replacement therapy (including thyroxine) ≥2 months 
prior to randomization may be included in the study if this criterion is met; 
During the study, patients who have elevated levels of TSH > 7 IU/ml on at least two separate 
consecutive visits and are symptomatic of hypothyroidism, or TSH>10 IU/ml, who are 
indicated to be on thyroxine for clinical hypothyroidism, may initiate treatment with low doses 
of thyroxine consistent with American Thyroid Association guidelines, with frequent 
monitoring of TSH levels at Study Visits (and within 2 weeks of initiation of thyroxine), safety 
labs, and monitoring of other symptoms related to hyper or hypothyroidism. Thyroxine may 
be administered at ¼ to ½ the anticipated dose (a starting dose of 25 ug per day) with careful 
monitoring of TSH levels and symptoms related to hyper or hypothyroidism, with increments 
in thyroxine dose after no less than 4-6 weeks.   
NOTE: It is anticipated that initiation of thyroxine therapy will occur very infrequently during 
the study and 50-75 ug thyroxine replacement will suffice for most patients requiring thyroxine 
treatment. 
6. Prior or planned (during the study period) bariatric surgery (eg, gastroplasty, roux-en-Y gastric 
bypass);  
7. Type 1 diabetes; 
8. Uncontrolled Type 2 diabetes defined as: 
• Hemoglobin A1c ≥9.5% at screening (patients with HbA1c ≥9.5% may be rescreened),  
• Insulin dose adjustment >10% within 60 days prior to enrollment,  
• Requirement for glucagon-like peptide analogue (unless on a stable dose ≥ 6 months prior to 
screening) or a complex oral anti-diabetic (OAD) regimen (3 or more OADs) (unless the OAD 
is stable and HbA1c < 8%), or 
• History of severe hypoglycemia (symptomatic hypoglycemia requiring outside assistance to 
regain normal neurologic status);  
Note: Individual diabetes regimens will be reviewed by Investigator and may be adjusted based 
on American Diabetes Association guidelines;  
9. Use of the following lipid-modifying therapies: fibrates except fenofibrate taken at night for at 
least 2 weeks prior to randomization and during the study, niacin, proprotein convertase 
subtilisin/kexin type 9 inhibitors, and bile acid sequestrants. Atorvastatin up to 20 mg and 

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rosuvastatin up to 10 mg and pravastatin up to 20 mg, on stable dose for at least six weeks 
prior to randomization (four weeks prior to MRI), are allowed. Other statins are excluded.  
Stable doses for at least three months prior to randomization of fish oils (omega-3 fatty acids, 
eicosapentaenoic acid, and docosahexaenoic acid), fenofibrate and ezetimibe are allowed;  
Note: Very infrequently, given that lipid levels are blinded to investigators and study personnel, 
where indicated statin and other allowed lipid therapies may be modified or initiated after 
enrollment in the study. Statin doses may be decreased during the study for tolerability or safety 
issues. Statin doses should be taken in the evening for at least two weeks prior to randomization 
and for the duration of the study. 
10. Use of obeticholic acid, ursodeoxycholic acid (Ursodiol® and Urso®), high dose vitamin E 
(>400 IU/day) unless on stable dose of vitamin E >400 IU/day for at least 6 months at the time 
of liver biopsy, or pioglitazone within 90 days prior to enrollment or since screening biopsy, 
whichever is longer. 
11. Presence of cirrhosis on liver biopsy (stage 4 fibrosis);  
12. Platelet count <140,000/mm3; 
13. Clinical evidence of hepatic decompensation which may be:  
• Demonstrated by abnormalities such as platelets < 140,000, serum albumin <3.5 g/dL, 
international normalized ratio >1.3 and/or total bilirubin >1.3 mg/dL; or 
• Established by the presence or history of esophageal varices, ascites, or hepatic 
encephalopathy;  
14. Evidence of other forms of chronic liver disease including the following:  
• Hepatitis B (HepB) as defined by presence of HepB surface antigen at screening, 
• Hepatitis C (HepC) as defined by presence of HepC virus (HCV) antibody (anti-HCV) and 
HCV ribonucleic acid (RNA). Patients with positive anti-HCV who test negative for HCV 
RNA at screening will be allowed to participate in the study,  
• Evidence of ongoing autoimmune liver disease, 
• Primary biliary cirrhosis, 
• Primary sclerosing cholangitis, 
• Gilbert’s syndrome patients if direct bilirubin is elevated (in addition to total bilirubin ≥ 2) or 
there is evidence of hemolysis contributing to elevated total bilirubin, 
• Wilson’s disease,  
• Homozygous alpha-1-anti-trypsin deficiency, 
• History of hemochromatosis or iron overload, 
• Drug-induced liver disease,  
• Known bile duct obstruction, 
• Suspected or proven liver cancer, or 

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• Any other type of liver disease other than NASH; 
15. Serum ALT or AST >5 × ULN; 
Note: Normal male and female ranges are 6 U/L to 41 U/L for ALT and 9 U/L to 34 U/L for 
AST at 
; 
16. Inability to safely obtain a liver biopsy; 
17. History of biliary diversion;  
18. Positive for human immunodeficiency virus (HIV) infection; 
19. Active, serious medical disease with likely life expectancy <2 years; 
20. History of malignant hypertension; 
21. Uncontrolled hypertension (either treated or untreated) defined as systolic blood pressure ˃160 
mmHg or a diastolic blood pressure ˃100 mmHg at screening;  
Note:  Retest of blood pressure after establishing good blood pressure control within a 
reasonable period of time, up to baseline visit, is permissible at the discretion of the 
Investigator; 
22. New York Heart Association class III or IV heart failure, or known left ventricular ejection 
fraction <30%; 
23. Uncontrolled cardiac arrhythmia, including confirmed QT interval corrected using Fridericia’s 
formula (QTcF) >450 msec for males and >470 msec for females at the screening 
electrocardiogram (ECG) assessment; 
24. Myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery 
bypass graft, or stroke within 3 months prior to randomization; 
25. Active substance abuse, including inhaled or injected drugs, within 1 year prior to screening; 
26. Use of any excluded medications listed in Section 5.6.1;  
27. Participation in an investigational new drug trial in the 30 days prior to randomization; or 
28. Any other condition which, in the opinion of the Investigator, would impede compliance, 
hinder completion of the study, compromise the well-being of the patient, or interfere with the 
study outcomes.   
4.3 
Withdrawal Criteria 
Participation of a patient in this clinical study may be discontinued for any of the following 
reasons: 
• The patient withdraws consent or requests discontinuation from the study for any reason; 
• Occurrence of any medical condition or circumstance that exposes the patient to substantial 
risk and/or does not allow the patient to adhere to the requirements of the protocol; 
• Any serious adverse event (SAE), clinically significant adverse event, severe laboratory 
abnormality, intercurrent illness, cardiovascular events such as new onset CHF, new onset or 
unstable angina or myocardial infarction, or other medical condition which indicates to the 
Investigator that continued participation is not in the best interest of the patient including 

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recurrent elevation of liver enzymes upon rechallenge or diagnosis of liver pathology other 
than NASH as described in Section 9.17; 
• Pregnancy; 
• Requirement of prohibited concomitant medication; 
• Patient failure to comply with protocol requirements or study-related procedures; or  
• Termination of the study by the Sponsor or the regulatory authority. 
If a patient withdraws prematurely from the study due to the above criteria or any other reason, 
study staff should make every effort to complete the full panel of assessments scheduled for the 
End of Treatment Visit. The reason for patient withdrawal must be documented in the electronic 
Case Report Form (eCRF). In the case of patients lost to follow-up, attempts to contact the patient 
must be made and documented in the patient’s medical records Withdrawn patients will not be 
replaced. 

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5 
STUDY TREATMENTS 
5.1 
Treatment Groups 
Patients who qualify for study inclusion will be randomized in the Main Study to receive one of 
two 36-week treatments: MGL-3196 80 mg or placebo given orally once-daily in the morning.  
Patients who qualify for the Extension Study will receive MGL-3196. Patients previously on 
placebo in the Main Study will receive MGL-3196 80 mg at the start of the Extension Study. 
Patients previously on MGL-3196 will continue on the same MGL-3196 dose of MGL-3196 in the 
Extension Study that they were on at Week 36 of the main study, with a possible dose adjustment 
at Week 4 of the extension study as described in Section 8.2. 
5.2 
Rationale for Dosing 
In 2 completed Phase 1 studies, MGL-3196 appeared to be safe and well tolerated at doses up to 
200 mg daily for 14 days. No safety concerns were observed during either study. Lipid efficacy 
data suggested the therapeutic dose to be less than the highest dose of 200 mg, as this dose did not 
show an improved benefit over lower doses and showed more variability in pharmacokinetic (PK) 
levels.  
5.3 
Randomization and Blinding 
Patients will be randomized 2:1, 80 mg or placebo treatment groups, using a computer-generated 
randomization schedule prepared by Medpace, Inc. prior to the start of the study. The number 
received during randomization will identify the patient throughout the study and will be used in 
the eCRF.  
Patients, the Sponsor, Investigators, and all site personnel involved with dispensing study 
medication, carrying out study procedures, evaluating patients, entering study data, and/or 
evaluating study data will be blinded to treatment assignment until database lock. Blinding will be 
accomplished by the Sponsor providing visually indistinguishable MGL-3196 and placebo.  
Packaging for MGL-3196 and placebo product will be identical with the exception of a unique 
bottle identification number on the label.  
5.4 
Breaking the Blind 
Until formal conclusion of the study, patients, Investigators, and all site study personnel will 
remain blinded as to treatment allocation, except in the event of a medical emergency which 
necessitates unblinding. In the event of a medical emergency when knowledge of the patient’s 
treatment assignment would influence the patient’s clinical care, the Investigator should contact 
the Medical Monitor to describe the emergency.  
5.5 
Drug Supplies 
5.5.1 
Formulation and Packaging 
The MGL-3196 active drug substance, 2-[3,5-Dichloro-4-95-isopropyl-6-oxo-1,6-dihydro-
pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4]triazine-6-carbonitrile, is a white 
to tan crystalline powder stable for 60 months at 25°C/60% relative humidity and 6 months at 
40°C/75% relative humidity.  

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5.6 
Prior and Concomitant Medications and/or Procedures 
5.6.1 
Excluded Medications 
Excluded medications include:  
• Triiodothyronine (liothyronine [Cytomel®]); 
• Thyroxine (excluded at time of randomization), and very infrequently used during the study, 
in that thyroxine therapy may be initiated in patients who become clinically hypothyroid during 
the study as described in exclusion criteria #5;  
Note: Patients who discontinue thyroxine ≥2 months prior to randomization may be included 
in the study, as described, during the study thyroxine therapy may be initiated;  
• Obeticholic acid, ursodeoxycholic acid (Ursodiol® and Urso®), high dose vitamin E 
(>400 IU/day) except as permitted in exclusion criteria #10, or pioglitazone within 90 days 
prior to enrollment or since screening biopsy, whichever is longer;  
• Use of the following lipid-modifying therapies: fibrates except for fenofibrate taken at night 
for at least 2 weeks prior to randomization and during the study, niacin, proprotein convertase 
subtilisin/kexin type 9 inhibitors, bile acid sequestrants, and statins except as permitted in the 
exclusion criteria #9; 
• Major inhibitors of organic anion-transporting polypeptide transporters such as gemfibrozil, 
cyclosporine A, or protease inhibitors;  
• Use of drugs historically associated with NAFLD (amiodarone, methotrexate, systemic 
glucocorticoids, tetracyclines, tamoxifen, estrogens at doses greater than those used for 
hormone replacement, anabolic steroids, valproic acid, and other known hepatotoxins) Drugs 
with known liver toxicity;  
• Repaglinide or a glitazone such as rosiglitazone (substrates of cytochrome P450 2C8 [CYP2C8] 
or gemfibrozil [inhibitor of CYP2C8]);  
• Chronic use of oral corticosteroids unless discontinued 3 months before screening. Addition 
of oral corticosteroids during the study except short term low dose < 1 week taper is not 
allowed. This exclusion does not include topical corticosteroids, or corticosteroid injections in 
muscle or joint; 
• Warfarin treatment; and 
• Any medications with the potential to affect thyroid hormone production and/or that may 
interfere with thyroid function including but not limited to methimazole, PTU, tyrosine kinase 
inhibitors, iodide, and glucocorticoids. Unless, for example, in the case of lithium, the 
medication is stably dosed and thyroid hormone levels are normal.  
5.6.2 
Documentation of Prior and Concomitant Medication Use 
All concomitant medications must be recorded in the eCRF. Any prior medication received within 
30 days of the first dose of study drug will be recorded in the eCRF. Concomitant treatments that 
are required to manage a patient’s medical condition during the trial will also be recorded in the 
eCRF.  

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6 
STUDY PROCEDURES 
6.1 
Informed Consent 
Informed consent will be obtained at the Screening Visit (Week -6 to Week 0) of the Main Study. 
For patients eligible to participate in the Extension Study, obtain informed consent prior to any 
Extension Study Day 1 procedures. 
6.2 
Screening Period (Week -6 to Week 0) 
The following procedures will be performed at the Screening Visit (Week -6 to Week 0): 
• Determine eligibility, including assessment of ALT and AST consistency; 
• Review of medical history, including substance abuse; 
• Obtain informed consent; 
• Collect demographic information; 
• Perform 12-lead ECG; 
• Perform complete physical examination; 
• Collect blood sample for: 
o HepB, HepC, and HIV;  
o Hematology, fasting chemistry, fasting lipid parameters, and fasting metabolic profiles (see 
Appendix C for a full list of analytes to be measured); 
Note: Must have a documented historical (3 weeks to 6 months prior to the study entry) 
ALT and AST levels consistent with the screening ALT and AST values. Patients who do 
not have historical ALT and AST evaluations available may have their ALT and AST 
repeated during the screening period [both assessments need to be ≥3 weeks apart]);  
o Thyroid axis hormones; 
o Activated partial prothrombin time (APTT), prothrombin time (PT), and international 
normalized ratio (INR); and 
o Serum pregnancy test (for women of child bearing potential only);  
• Collect urine sample for urinalysis;  
• Collect vital signs and anthropometrics; 
• Provide diet and lifestyle counseling; 
• Perform MRI-PDFF; 
• Perform liver biopsy only in the event that the patient does not have an available liver biopsy 
within 180 days of randomization, passes pre-screening procedures, and has a passing MRI-
PDFF; and 
• Review alcohol consumption, concomitant medications, and adverse events. 

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6.3 
Randomization 
Patients will be randomized at the Baseline Visit (Day 1).  
6.4 
Main Study Treatment Period – Day 1 to Week 38 
Following randomization to study medication, patients will return for visits and procedures within 
±3 days of the scheduled time except where noted. 
Prior to each visit, patients should fast for at least 10 hours. 
If a patient requires close clinical monitoring, the patient may be asked to return to the study site 
for additional visits or laboratory assessments (see Section 9.17).  
6.4.1 
Baseline Visit (Day1) 
The following procedures will be performed at the Baseline Visit (Day 1): 
• Determine eligibility;  
• Randomize patients;  
• Perform 12-lead ECG; 
• Perform symptom-directed physical examination;  
• Dispense study drug; 
• Collect blood sample for: 
o Hematology, fasting chemistry, fasting metabolic profiles, and fasting lipid parameters (see 
Appendix C for a full list of analytes to be measured);  
o Thyroid axis hormones; 
o Total and free (calculated) testosterone, luteinizing hormone (LH), follicle stimulating 
hormone (FSH), and estradiol; 
o CK-MB, troponin I, Sex hormone binding globulin (SHBG); 
o Alkaline phosphatase (ALP) isoenzymes; 
o CK-18, FIB-4, and ELF;  
o PK sampling (pre-dose);  
o hsCRP; 
o Fibrinogen, haptoglobin, alpha-2 macroglobulin, proBNP, apolipoprotein C-III, and 
ferritin;  
o Type 1 procollagen N-terminal propeptide and C-terminal telopeptide (CTX);  
o APTT, PT, INR; and 
o Genomic sample;  
o Bile acid levels; 

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• Collect urine sample for pregnancy test (for women of child bearing potential only) and 
urinalysis;  
• Collet vital signs and anthropometrics;  
• Perform dual-energy x-ray absorptiometry (DXA) scan; 
• Provide diet and lifestyle counseling; 
• Complete HR-QoL SF-36 assessment; and 
• Review alcohol consumption, concomitant medications, and adverse events.  
6.4.2 
Week 2 (Day 14)  
The following procedures will be performed at Week 2: 
• Arrive at the study site, pre-dose after overnight fasting; 
• Perform 12-lead ECG pre-dose and at 5 hours post dose; 
• Collect vital signs and anthropometrics; 
• Collect pre-dose blood sample for: 
o Hematology, fasting chemistry profiles, and fasting lipid parameters (see Appendix C for 
a full list of analytes to be measured);  
o CK-MB, troponin I, SHBG;  
o Pre-dose PK sampling;  
o APTT, PT, INR; and 
o Thyroid axis hormones;  
o Bile acid levels; 
• Administer study drug dose; 
• Collect blood for PK samples at 2, 4, 6, 8 h post dose administered in clinic; 
• Collect urine sample for pregnancy test (for women of child bearing potential only) and 
urinalysis; 
• Consume a low-fat meal at 1 hour post dose and at 4 hours post dose after the 4 hour PK sample 
collection; 
• Perform symptom-directed physical examination; 
• Assess study drug accountability; 
• Provide diet and lifestyle counseling; and 
• Review alcohol consumption, concomitant medications, and adverse events.  

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6.4.3 
Week 4 (Day 28) 
The following procedures will be performed at Week 4: 
• Perform 12-lead ECG; 
• Perform symptom-directed physical examination; 
• Dispense study drug and assess study drug accountability; 
• Collect vital signs and anthropometrics; 
• Collect blood sample for: 
o Hematology profiles, fasting chemistry profiles, and fasting lipid parameters (see 
Appendix C for a full list of analytes to be measured);  
o CK-MB, troponin I, SHBG;  
o PK sample (pre-dose);  
o APTT, PT, INR;  
o hsCRP; and 
o Thyroid axis hormones;  
• Collect urine sample for pregnancy test (for women of child bearing potential only) and 
urinalysis; 
• Provide diet and lifestyle counseling; 
• Complete HR-QoL SF-36 assessment; and 
• Review alcohol consumption, concomitant medications, and adverse events.  
6.4.4 
Week 8 (Day 56)  
The following procedures will be performed at Week 8: 
• Perform 12-lead ECG; 
• Perform symptom-directed physical examination; 
• Dispense study drug and assess study drug accountability; 
• Collect vital signs and anthropometrics; 
• Collect blood sample for: 
o Hematology profiles, fasting chemistry profiles, and fasting lipid parameters (see 
Appendix C for a full list of analytes to be measured);  
o CK-MB, troponin I, SHBG; 
o PK sample (pre-dose);  
o APTT, PT, INR; and 
o Thyroid axis hormones;  

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• Collect urine sample for pregnancy test (for women of child bearing potential only) and 
urinalysis; 
• Provide diet and lifestyle counseling; and 
• Review alcohol consumption, concomitant medications, and adverse events.  
6.4.5 
Week 12 (Day 84) 
The following procedures will be performed at Week 12: 
• Perform 12-lead ECG; 
• Perform symptom-directed physical examination; 
• Dispense study drug and assess study drug accountability; 
• Collect vital signs and anthropometrics; 
• Collect blood sample for: 
o Hematology profiles, fasting chemistry profiles, fasting metabolic panel, and fasting lipid 
parameters (see Appendix C for a full list of analytes to be measured);  
o Total testosterone, LH, FSH, and estradiol; 
o CK-MB, troponin I, SHBG; 
o ALP isoenzymes; 
o CK-18, FIB-4, and ELF;  
o hsCRP;  
o Fibrinogen, haptoglobin, alpha-2 macroglobulin, proBNP, apolipoprotein C-III, and 
ferritin;  
o Type 1 procollagen N-terminal propeptide and C-terminal telopeptide;  
o APTT, PT, INR; and 
o Thyroid axis hormones;  
o Bile acid levels; 
• Collect urine sample for pregnancy test (for women of child bearing potential only) and 
urinalysis;  
• Provide diet and lifestyle counseling; 
• Complete HR-QoL SF-36 assessment;  
• Perform MRI-PDFF; and 
• Review alcohol consumption, concomitant medications, and adverse events. 

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6.4.6 
Week 16 (Day 112) 
The following procedures will be performed at Week 16: 
• Perform 12-lead ECG; 
• Perform symptom-directed physical examination; 
• Dispense study drug and assess study drug accountability; 
• Collect vital signs and anthropometrics; 
• Collect blood sample for: 
o Hematology profiles, fasting chemistry profiles, and fasting lipid parameters (see 
Appendix C for a full list of analytes to be measured);  
o CK-MB, troponin I, SHBG; 
o PK sampling (pre-dose);  
o APTT, PT, INR; and 
o Thyroid axis hormones;  
• Collect urine sample for pregnancy test (for women of child bearing potential only) and 
urinalysis; 
• Provide diet and lifestyle counseling; and 
• Review alcohol consumption, concomitant medications, and adverse events. 
6.4.7 
Week 20 (Day 140) 
The following procedures will be performed at Week 20: 
• Perform 12-lead ECG; 
• Perform symptom-directed physical examination; 
• Dispense study drug and assess study drug accountability; 
• Collect vital signs and anthropometrics; 
• Collect blood sample for: 
o Hematology profiles, fasting chemistry profiles, and fasting lipid parameters (see 
Appendix C for a full list of analytes to be measured);  
o CK-MB, troponin I, SHBG; 
o APTT, PT, INR; and 
o Thyroid axis hormones;  
• Collect urine sample for pregnancy test (for women of child bearing potential only) and 
urinalysis; 
• Provide diet and lifestyle counseling; and 
• Review alcohol consumption, concomitant medications, and adverse events. 

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6.4.8 
Week 24 (Day 168)  
The following procedures will be performed at Week 24: 
• Perform 12-lead ECG; 
• Perform symptom-directed physical examination; 
• Dispense study drug and assess study drug accountability; 
• Collect vital signs and anthropometrics; 
• Collect blood sample for: 
o Hematology profiles, fasting chemistry profiles, and fasting lipid parameters (see 
Appendix C for a full list of analytes to be measured); 
o CK-MB, troponin I, SHBG;  
o PK sampling (pre-dose);  
o APTT, PT, INR;  
o hsCRP; and 
o Thyroid axis hormones;  
• Collect urine sample for pregnancy test (for women of child bearing potential only) and 
urinalysis; 
• Provide diet and lifestyle counseling; 
• Complete HR-QoL SF-36 assessment; and 
• Review alcohol consumption, concomitant medications, and adverse events. 
6.4.9 
Week 30 (Day 210) 
The following procedures will be performed at Week 30: 
• Perform 12-lead ECG; 
• Perform symptom-directed physical examination; 
• Dispense study drug and assess study drug accountability; 
• Collect vital signs and anthropometrics; 
• Collect blood sample for: 
o Hematology profiles, fasting chemistry profiles, and fasting lipid parameters (see 
Appendix C for a full list of analytes to be measured);  
o CK-MB, troponin I, SHBG; 
o APTT, PT, INR; and 
o Thyroid axis hormones;  
• Collect urine sample for pregnancy test (for women of child bearing potential only) and 
urinalysis; 
• Provide diet and lifestyle counseling; and 

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• Review alcohol consumption, concomitant medications, and adverse events. 
6.4.10 
Week 36 (Day 252) 
The following procedures will be performed at Week 36: 
• Perform 12-lead ECG; 
• Perform symptom-directed physical examination; 
• Assess study drug accountability; 
• Collect vital signs and anthropometrics; 
• Collect blood sample for: 
o Hematology profiles, fasting chemistry profiles, fasting metabolic panel, and fasting lipid 
parameters (see Appendix C for a full list of analytes to be measured);  
o Total and free (calculated) testosterone, LH, FSH, and estradiol; 
o CK-MB, troponin I, SHBG; 
o PK sampling (pre-dose);  
o ALP isoenzymes; 
o CK-18, FIB-4, and ELF;  
o Type 1 procollagen N-terminal propeptide and CTX;  
o Fibrinogen, haptoglobin, alpha-2 macroglobulin, proBNP, apolipoprotein C-III, and 
ferritin;  
o APTT, PT, INR;  
o hsCRP; and 
o Thyroid axis hormones;  
o Bile acid levels; 
• Collect urine sample for pregnancy test (for women of child bearing potential only) and 
urinalysis; 
• Perform liver biopsy (-10 days to + 3 days of the visit date); 
• Perform DXA scan; 
• Provide diet and lifestyle counseling; 
• Complete HR-QoL SF-36 assessment;  
• Perform MRI-PDFF (within 10 days prior to the visit date while still on treatment); and 
• Review alcohol consumption, concomitant medications, and adverse events. 
 
 

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6.5 
Follow-Up Visit (Week 38 [Day 266]) 
The following procedures will be performed at the Follow-Up Visit (Week 38): 
• Collect blood sample for: 
o Hematology, fasting chemistry profiles, and fasting lipid parameters (see Appendix C for 
a full list of analytes to be measured); 
o CK-MB, troponin I, Total testosterone, LH, FSH, estradiol, and SHBG; 
o ALP isoenzymes;  
o APTT, PT, INR; and 
o Thyroid axis hormones; and 
• Review concomitant medications and adverse events. 
6.6 
Early Termination Visit and Withdrawal Procedures 
Patients who are withdrawn from either the Main Study or Extension Study prior to completion 
will return to the study site for the Early Termination Visit. The following Early Termination 
procedures will be completed: 
Note: Completion of some procedures may depend on the guidance and discretion of the 
Investigators, Medical Monitors, and Sponsor taking into account factors such as why and when 
the patient terminated early. 
• Perform 12-lead ECG; 
• Perform symptom-directed physical examination; 
• Assess study drug accountability; 
• Collect vital signs and anthropometrics; 
• Collect blood sample for: 
o Hematology profiles, fasting chemistry profiles, fasting metabolic panel, and fasting lipid 
parameters (see Appendix C for a full list of analytes to be measured);  
o Total and free (calculated) testosterone, LH, FSH, and estradiol; 
o CK-MB, troponin I, SHBG; 
o PK sampling (pre-dose);  
o ALP isoenzymes; 
o CK-18, FIB-4, and ELF;  
o Type 1 procollagen N-terminal propeptide and CTX;  
o Fibrinogen, haptoglobin, alpha-2 macroglobulin, proBNP, apolipoprotein C-III, and 
ferritin;  
o APTT, PT, INR;  
o hsCRP; and 
o Thyroid axis hormones;  
o Bile acid levels; 

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• Collect urine sample for pregnancy test (for women of child bearing potential only) and 
urinalysis;  
• Perform liver biopsy (Main Study only); 
• Perform DXA scan; 
• Perform Fibroscan (if available); 
• Complete HR-QoL SF-36 assessment;  
• Perform MRI-PDFF; and 
• Review alcohol consumption, concomitant medications, and adverse events. 
 
6.7 
Extension Study  
For patients that are eligible to participate in the extension phase of the study and sign the informed 
consent for the extension, the following visits and procedures will be within ±3 days of the 
scheduled time except where noted. 
Prior to each visit, patients should fast for at least 10 hours. 
If a patient requires close clinical monitoring, the patient may be asked to return to the study site 
for additional visits or laboratory assessments (see Section 9.17).  
 
6.7.1 
Extension Study Day 1 (Extension Day1) 
The Extension Study Day 1 visit should occur within 60 days inclusive of the Main Study Week 
36 Visit and may occur concurrently with the Main Study Week 38 Follow-up Visit. The Extension 
Study Informed Consent Form must be signed prior to any Extension Study-related procedures. 
The following procedures will be performed at the Extension Study Day 1 Visit: 
• Perform 12-lead ECG; 
• Perform symptom-directed physical examination;  
• Collect blood sample for: 
o Hematology, fasting chemistry, fasting metabolic profiles, and fasting lipid parameters (see 
Appendix C for a full list of analytes to be measured);  
o Thyroid axis hormones; 
o PK sampling (pre-dose);  
o APTT, PT, INR; 
o Total and free (calculated) testosterone, luteinizing hormone (LH), follicle stimulating 
hormone (FSH), and estradiol; 
o CK-MB, troponin I, Sex hormone binding globulin (SHBG); 
o Alkaline phosphatase (ALP) isoenzymes; 

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o CK-18, FIB-4, and ELF;  
o hsCRP; 
o Fibrinogen, haptoglobin, alpha-2 macroglobulin, proBNP, apolipoprotein C-III, and 
ferritin;  
o Type 1 procollagen N-terminal propeptide and C-terminal telopeptide (CTX);  
o Bile acid levels; 
• Collect urine sample for pregnancy test (for women of child bearing potential only) and 
urinalysis;  
• Collect vital signs and anthropometrics;  
• Dispense study drug; 
• Provide diet and lifestyle counseling; 
• Complete HR-QoL SF-36 assessment; and 
• Review alcohol consumption, concomitant medications, and adverse events.  
6.7.2 
Extension Study Week 2 (Extension Day 14)  
The following procedures will be performed at Week 2 of the Extension Study: 
• Arrive at the study site, pre-dose after overnight fasting; 
• Perform 12-lead ECG pre-dose; 
• Collect vital signs and anthropometrics; 
• Collect pre-dose blood sample for: 
o Hematology, fasting chemistry, and fasting lipid parameters (see Appendix C for a full list 
of analytes to be measured);  
o CK-MB, troponin I, SHBG;  
o PK;  
o APTT, PT, INR; 
o Thyroid axis hormones;  
o Bile acid levels; 
• Administer study drug dose; 
• Consume a low-fat meal at 1 hour post dose; 
• Collect blood for a PK sample at 4 h post dose; 
• Collect urine sample for pregnancy test (for women of child bearing potential only) and 
urinalysis; 
• Perform symptom-directed physical examination; 
• Assess study drug accountability; 

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• Provide diet and lifestyle counseling; and 
• Review alcohol consumption, concomitant medications, and adverse events.  
6.7.3 
Extension Study Weeks 4, 8, 16, 20, 28, and 32 
The following procedures will be performed at Week 4, 8, 16, 20, 28, and 32 of the 
Extension Study: 
• Perform 12-lead ECG; 
• Perform symptom-directed physical examination; 
• Dispense study drug and assess study drug accountability; 
• Collect vital signs and anthropometrics; 
• Collect pre-dose blood sample for: 
o Hematology, fasting chemistry, and fasting lipid parameters (see Appendix C for a full list 
of analytes to be measured);  
o CK-MB, troponin I, SHBG;  
o PK (Weeks 4, 8, and 16);  
o APTT, PT, INR;  
o hsCRP (Week 4 only);  
o Thyroid axis hormones;  
• Collect urine sample for pregnancy test (for women of child bearing potential only) and 
urinalysis; 
• Provide diet and lifestyle counseling;  
• Complete HR-QoL SF-36 assessment (Week 4); and 
• Review alcohol consumption, concomitant medications, and adverse events.  
6.7.4 
Extension Study Week 12 (Extension Day 84) 
The following procedures will be performed at Week 12 of the Extension Study: 
• MRI-PDFF; 
• Perform 12-lead ECG; 
• Perform symptom-directed physical examination;  
• Collect vital signs and anthropometrics;  
• Collect pre-dose blood sample for: 
o Hematology, fasting chemistry, fasting metabolic profiles, and fasting lipid parameters (see 
Appendix C for a full list of analytes to be measured);  
o CK-MB, troponin I, SHBG; 

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o Bile Acids; 
o ALP isoenzymes; 
o APTT, PT, INR;  
o hsCRP; 
o Thyroid axis hormones; 
o Total and free (calculated) testosterone, luteinizing hormone (LH), follicle stimulating 
hormone (FSH), and estradiol; 
o CK-18, FIB-4, and ELF;  
o Fibrinogen, haptoglobin, alpha-2 macroglobulin, proBNP, apolipoprotein C-III, and 
ferritin;  
o Type 1 procollagen N-terminal propeptide and C-terminal telopeptide (CTX);  
• Collect urine sample for pregnancy test (for women of child bearing potential only) and 
urinalysis;  
• Dispense study drug and assess study drug accountability; 
• Administer study drug dose; 
• Provide diet and lifestyle counseling;  
• Complete HR-QoL SF-36 assessment; and 
• Review alcohol consumption, concomitant medications, and adverse events.  
6.7.5 
Extension Study Week 24 (Extension Day 168) 
The following procedures will be performed at Week 24 of the Extension Study: 
• Perform 12-lead ECG; 
• Perform symptom-directed physical examination;  
• Collect blood sample for: 
o Hematology, fasting chemistry, and fasting lipid parameters (see Appendix C for a full list 
of analytes to be measured);  
o CK-MB, troponin I, SHBG;  
o Thyroid axis hormones; 
o PK;  
o APTT, PT, INR;  
o hsCRP 
• Collect urine sample for pregnancy test (for women of child bearing potential only) and 
urinalysis;  
• Collect vital signs and anthropometrics;  

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• Dispense study drug and assess study drug accountability; 
• Administer study drug dose; 
• Provide diet and lifestyle counseling; 
• Complete HR-QoL SF-36 assessment; and 
• Review alcohol consumption, concomitant medications, and adverse events.  
6.7.6 
Extension Study Week 36 (Extension Day 252) 
The following procedures will be performed at Week 36 of the Extension Study: 
• Perform 12-lead ECG; 
• Perform symptom-directed physical examination; 
• Assess study drug accountability; 
• Collect vital signs and anthropometrics; 
• Collect blood sample for: 
o Hematology profiles, fasting chemistry profiles, fasting metabolic panel, and fasting lipid 
parameters (see Appendix C for a full list of analytes to be measured);  
o Total and free (calculated) testosterone, LH, FSH, and estradiol; 
o CK-MB, troponin I, SHBG; 
o PK sampling (pre-dose);  
o ALP isoenzymes; 
o CK-18, FIB-4, and ELF;  
o Type 1 procollagen N-terminal propeptide and CTX;  
o Fibrinogen, haptoglobin, alpha-2 macroglobulin, proBNP, apolipoprotein C-III, and 
ferritin;  
o APTT, PT, INR;  
o hsCRP; 
o Thyroid axis hormones;  
o Bile acid levels; 
• Collect urine sample for pregnancy test (for women of child bearing potential only) and 
urinalysis; 
• Perform DXA scan; 
• Provide diet and lifestyle counseling; 
• Complete HR-QoL SF-36 assessment; 
• Perform Fibroscan (if available); 

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• Perform MRI-PDFF (within 10 days prior to the visit date while still on treatment); and 
• Review alcohol consumption, concomitant medications, and adverse events. 
6.7.7 
Extension Study Week 38 Follow-up Visit (Extension Day 266) 
The following procedures will be performed at the Extension Study Follow-Up Visit (Week 38): 
• Collect blood sample for: 
o Hematology, fasting chemistry profiles, and fasting lipid parameters (see Appendix C for 
a full list of analytes to be measured); 
o CK-MB, troponin I, Total and free (calculated) testosterone, LH, FSH, estradiol, and 
SHBG; 
o ALP isoenzymes;  
o APTT, PT, INR; 
o Thyroid axis hormones; and 
• Review concomitant medications and adverse events. 
6.7.8 
Extension Study Early Termination Visit 
See Section 6.6. 
 

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8 
PHARMACOKINETIC ASSESSMENTS 
8.1 
Main Study 
Blood samples for PK assessments will be obtained pre-dose from patients at the Baseline Visit 
(Day 1), Weeks 2, 4, 8, 16, 24, and 36, and the Early Termination Visit. Patients will be instructed 
not to take study drug prior to PK sampling at these respective study weeks.  
At Week 2 visit, PK assessments will be made in the clinic after over-night fast at pre-dose. An 80 
mg dose of MGL-3196 or placebo will be administered and PK assessments will be made at 2, 4, 
6, and 8 hours post dose. Total AUCinf will be calculated for MGL-3196 and MGL-3196-M1 based 
on Week 2 AUC(0-8), exposure at 8 h and historic geometric mean elimination rate constant for 
MGL-3196 and MGL-3196-M1 at the 80 mg dose. Modeling based on historic data obtained for 
the 80 and 100 mg doses indicate that, using this approach, AUCactual (AUC(0-24)) is estimated within 
1.8%, SD 5.4% for MGL-3196 given at a dose of 80 mg and is slightly over estimated for MGL-
3196-M1 AUC by 5.7% SD 8.5% at a dose of 80 mg. Similar results were obtained for a 100 mg 
dose. Dose adjustment will be made to 60 mg once per day for any patients whose combined 
estimated MGL-3196 and MGL-3196-M1 (AUC(0-24)) at 2 weeks on the 80 mg dose exceeds 5500 
ng*hr/ml. All subjects previously dosed at 50 mg MGL-3196 had combined MGL-3196 plus 
MGL-3196-M1 less than 5500 ng*hr/ml, geo mean= 3400 ng*hr/ml. Notably, the trough pre-dose 
drug levels obtained at 50 -100 mg in the MAD study are also predictive of subjects’ relative AUCs 
at a given dose. For patients whose combined estimated AUC(0-24) at 2 weeks at the 80 mg dose is 
>11,000 ng*hr/ml plus SHBG>150% increased from baseline, the dose will be decreased to 40 mg 
at the 4 Week visit (or later per Synopsis), because, even given the greater than dose proportionate 
increase in exposure between a 60 and 80 mg dose, the exposure at 60 mg may be ≥5500 ng*hr/ml. 
For patients whose combined estimated AUC(0-24) at 2 weeks at the 80 mg dose is ≤ 3000 ng*hr/ml 
the dose will be increased to 100 mg at the 4 Week visit, as based on a conservative estimates, the 
predicted exposure at 100 mg will be significantly ≤ 5500 ng*hr/ml. This prediction is based on 
data obtained in healthy volunteers in which there is greater than dose proportionate increase in 
MGL-3196 between 80 and 100 mg daily doses, and less than dose proportionate increases in 
MGL-3196-M1 between 80 and 100 mg doses. Pharmacokinetic data (blinded to patient ID) 
obtained from the first 21 patients randomized to MGL-3196 suggest that there are no clear 
differences in MGL-3196 or MGL-3196-M1 exposure at the 80-mg dose between healthy 
volunteers and NASH patients enrolled in this study. 
For the patients who are relatively early in the Main Study (at week 24 or earlier), if their current 
dose is 100 mg, their Main Study Week 2 predose MGL-3196 PK value < 5 ng/mL and their Main 
Study Week 2 AUC ≤ 2500 ng*hr/mL, then their dose will be increased to 120 mg during the Main 
study and continued on 120 mg if they meet eligibility criteria for the extension study. 
8.2 
Extension Study 
For patients participating in the extension phase of the study, PK assessments will be made at 
Extension Study Day 1 predose and at the Extension Study Week 2 visit at predose and 4 hours 
post dose.  
All former placebo patients in the Main Study will be randomized to receive 80 mg dose of 
MGL-3196 for 4 weeks. All patients will have a PK assessment predose and 4 hours postdose at 
Extension Study Week 2. 

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Extension Study Dosing Action for Former Main Study Placebo Patients 
Extension Study Week 2  
MGL-3196 Concentration 
Extension Study 
Extension Study 
Predose 
4 h post dose 
Week 2 SHBG 
Week 4 Action  
>35 ng/ml 
>1350 ng/ml 
>125% CFB* 
Downtitrate to 40 mg 
Patients not meeting criteria for 40, 80, 100 or 120 mg  
Downtitrate to 60 mg 
<15 ng/ml 
< 600 ng/ml 
No rule 
Remain on 80 mg or 
increase (see next rows) 
<5 ng/ml 
≤ 350 ng/ml 
No rule 
Increase to 100 mg 
<2 ng/ml 
≤ 150 ng/ml 
No rule 
Increase to 120 mg 
*Change From Baseline, where baseline is Extension Study Day 1 
 
Extension Study Dosing Action for Former Main Study MGL-3196 Treated Patients 
Any Main Study patient assigned to MGL-3196 and continuing in the Extension Study will 
continue on the same dose when starting Extension Study. For patients on 60 or 40 mg, they will 
continue on the dose unchanged. For patients taking 80 or 100 mg there may be an increase in dose 
if criteria as described in the table below are met. 
Current dose 
Main Study Week 2 PK (AUC, 
combined MGL-3196 plus M1 
on 80 mg dose) 
Main Study 
Predose  
at Week 2  
Action in  
Extension Study 
40-60 mg 
 
 
No change 
80 mg 
< 3500 ng*hr/ml 
< 5 ng/ml 
Increase to 100 mg/day 
100 mg 
≤ 2500 ng*hr/ml 
< 5 ng/ml 
Increase to 120 mg 
120 mg 
 
 
No change 
 

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9 
SAFETY ASSESSMENTS 
9.1 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical investigation patient 
administered a pharmaceutical product, which does not necessarily have a causal relationship with 
this treatment. An adverse event can therefore be any unfavorable and/or unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an investigational medicinal product, whether or not related to the investigational medicinal 
product. All adverse events, including observed or volunteered problems, complaints, or 
symptoms, are to be recorded on the appropriate eCRF. 
Adverse events, which include clinical laboratory test variables, will be monitored and 
documented from the time of informed consent until study participation is complete. Patients 
should be instructed to report any adverse event that they experience to the Investigator. Beginning 
at the Screening Visit, investigators should make an assessment for adverse events at each visit 
and record the event on the appropriate adverse event eCRF. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the Investigator and recorded on the eCRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the Investigator, it should be recorded as a separate adverse event on the eCRF.  
Additionally, the condition that led to a medical or surgical procedure (eg, surgery, endoscopy, 
tooth extraction, or transfusion) should be recorded as an adverse event, not the procedure.  
Any medical condition already present at screening should not be reported as an adverse event 
unless the medical condition or signs or symptoms present at baseline change in severity or 
seriousness at any time during the study. In this case, it should be reported as an adverse event. 
Clinically significant abnormal laboratory or other examination (eg, ECG) findings that are 
detected during the study or are present at screening and significantly worsen during the study 
should be reported as adverse events. The Investigator will exercise his or her medical and 
scientific judgment in deciding whether an abnormal laboratory finding or other abnormal 
assessment is clinically significant. Clinically significant abnormal laboratory values occurring 
during the clinical study will be followed until repeat tests return to normal, stabilize, or are no 
longer clinically significant. Any abnormal test that is determined to be an error does not require 
reporting as an adverse event. 
9.1.1 
Adverse (Drug) Reaction 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered an adverse drug reaction. “Responses” to a medicinal product means that a causal 
relationship between a medicinal product and an adverse event is at least a reasonable possibility, 
ie, the relationship cannot be ruled out. 
9.1.2 
Unexpected Adverse Drug Reaction 
An Unexpected Adverse Drug Reaction is defined as an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information.  

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9.1.3 
Assessment of Adverse Events by the Investigator 
The Investigator will assess the severity (intensity) of each adverse event as mild, moderate, or 
severe, and will also categorize each adverse event as to its potential relationship to study drug 
using the categories of yes/no. 
9.1.3.1 
Assessment of severity: 
Mild – An event that is easily tolerated and generally not interfering with normal daily activities. 
Moderate – An event that is sufficiently discomforting to interfere with normal daily activities. 
Severe – An event that is incapacitating with inability to work or perform normal daily activities.   
9.1.3.2 
Causality assessment: 
The relationship of an adverse event to the administration of the study drug is to be assessed 
according to the following definitions: 
No (unrelated, not related, no relation) – The time course between the administration of study drug 
and the occurrence or worsening of the adverse event rules out a causal relationship and another 
cause (concomitant drugs, therapies, complications, etc.) is suspected. 
Yes (related) – The time course between the administration of study drug and the occurrence or 
worsening of the adverse event is consistent with a causal relationship and no other cause 
(concomitant drugs, therapies, complications, etc.) can be identified. 
The definition implies a reasonable possibility of a causal relationship between the event and the 
study drug. This means that there are facts (evidence) or arguments to suggest a causal relationship. 
The following factors should also be considered: 
• The temporal sequence from study drug administration- 
o The event should occur after the study drug is given. The length of time from study drug 
exposure to event should be evaluated in the clinical context of the event. 
• Underlying, concomitant, intercurrent diseases- 
o Each report should be evaluated in the context of the natural history and course of the 
disease being treated and any other disease the patient may have. 
• Concomitant drugs- 
o The other drugs the patient is taking or the treatment the patient receives should be 
examined to determine whether any of them might be recognized to cause the event in 
question. 
• Known response pattern for this class of study drug- 
o Clinical and/or preclinical data may indicate whether a particular response is likely to be a 
class effect. 
• Exposure to physical and/or mental stresses- 
o The exposure to stress might induce adverse changes in the recipient and provide a logical 
and better explanation for the event. 

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• The pharmacology and pharmacokinetics of the study drug- 
o The known pharmacologic properties (absorption, distribution, metabolism, and excretion) 
of the study drug should be considered. 
9.2 
Serious Adverse Events 
An adverse event or adverse reaction is considered serious if, in the view of either the Investigator 
or Sponsor, it results in any of the following outcomes: 
• Death; 
• A life-threatening adverse event; 
o Note: An adverse event or adverse reaction is considered “life-threatening” if, in the view 
of either the Investigator or Sponsor, its occurrence places the patient at immediate risk of 
death. It does not include an event that, had it occurred in a more severe form, might have 
caused death; 
• Requires hospitalization or prolongation of existing hospitalizations; 
o Note: Any hospital admission with at least 1 overnight stay will be considered an inpatient 
hospitalization. An emergency room visit without hospital admission will not be recorded 
as a SAE under this criterion, nor will hospitalization for a procedure scheduled or planned 
before signing of informed consent. However, unexpected complications and/or 
prolongation of hospitalization that occur during elective surgery should be recorded as 
adverse events and assessed for seriousness. Admission to the hospital for social or 
situational reasons (ie, no place to stay, live too far away to come for hospital visits) will 
not be considered inpatient hospitalizations;  
• A persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions; 
• A congenital anomaly/birth defect; or 
• An important medical event. 
o NOTE: Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical intervention 
to prevent one of the outcomes listed above. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalizations, or the 
development of drug dependency. 
9.3 
Serious Adverse Event Reporting − Procedures for Investigators 
9.3.1.1 
Initial reports 
All SAEs occurring from the time of informed consent until 30 days following the last 
administration of study drug must be reported to 
 within 24 hours of the 
knowledge of the occurrence (this refers to any adverse event that meets any of the aforementioned 
serious criteria). All SAEs that the Investigator considers related to study drug occurring after the 
30-day follow-up period must be reported to the Sponsor. 

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9.6 
Informed Consent 
All patients will be informed of the nature and purpose of the study. Patients will sign informed 
consent at the Screening Visit (Week -6 to 0), prior to any study procedures being performed.  
For patients participating in the extension phase of the study, an informed consent for the Extension 
Study must be signed prior to any Extension Study-related procedures being performed. 
9.7 
Demographic Information 
Demographic information including day, month, and year of birth; race; ethnicity; and gender will 
be collected at the Screening Visit (Week -6 to 0). 
9.8 
Clinical Laboratory Evaluations 
All standard blood and urine tests will be performed by a central laboratory. For the purposes of 
this study, fasting will be defined as nothing by mouth except water for 10 hours. If the patient is 
not fasting, the Investigator will reschedule the visit as soon as possible but no later than 3 days. 
Laboratory certification (including expiration date) and normal reference ranges for all laboratories 
used during the study will be on file with 
 prior to study initiation. For a complete list of 
laboratory assessments that will be performed, see Appendix C. For blood sampling procedures, 
including information on blood volume, collection tubes, sample processing, storage, and 
shipping, see the Laboratory Manual for this study.  
The Investigator must review and sign all laboratory test reports. The Investigator will be notified 
if laboratory values are outside of normal range and notified of alert values. In this case, the 
Investigator will be required to conduct clinically appropriate follow-up procedures.  
The following analytes will be measured at the Screening Visit (Week -6 to 0), Baseline Visit 
(Day 1), Main Study Weeks 2, 4, 8, 12, 16, 20, 24, 30, 36 and 38, and the Early Termination Visit, 
and Extension Study Day 1, Extension Study Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, and 38, and 
the Extension Study Early Termination Visit:  
• Chemistry – ALP, ALT, amylase, AST, blood urea nitrogen, calcium, carbon dioxide, chloride, 
creatine kinase, creatinine, direct bilirubin, eGFR (derived from creatinine), 
 
lactate dehydrogenase, lipase, magnesium, phosphate, potassium, serum albumin, sodium, 
total bilirubin, total protein, and uric acid; and 
• Hematology – hemoglobin, hematocrit, red blood cell count, white blood cell count, platelets, 
mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin 
concentration, red blood cell morphology, % differentials, and absolute differentials.  
The following urinalysis analytes will be measured at the Screening Visit (Week -6 to 0), 
Baseline Visit (Day 1), Main Study Weeks 2, 4, 8, 12, 16, 20, 24, 30, and 36, and the Early 
Termination Visit, and Extension Study Day 1, Extension Study Weeks 2, 4, 8, 12, 16, 20, 24, 28, 
32, 36, and 38, and the Extension Study Early Termination Visit: pH, specific gravity, protein, 
glucose, ketones, bilirubin, blood, nitrate, urobilinogen, and leukocyte esterase.  
Hepatitis B, HepC, and HIV will be measured at the Screening Visit (Week -6 to 0).  
Total testosterone, LH, FSH, and estradiol will be measured at the Baseline Visit (Day 1), Main 
Study Weeks 12, 36, and 38 (Follow-Up Visit), and the Early Termination Visit, and Extension 
Study Day 1, Weeks 12, 36, and 38 (Follow-Up Visit). Free testosterone to be calculated from 

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total testosterone, SHBG, and serum albumin for the Baseline Visit (Day 1), Week 12, Week 36, 
the Follow-Up Visit (Week 38), and the Early Termination Visit.  
Sex hormone binding globulin will be measured at the Baseline Visit (Day 1), Main Study Weeks 
2, 4, 8, 12, 16, 20, 24, 30, and 36, the Follow-Up Visit (Week 38), and the Early Termination Visit, 
and Extension Study Day 1, Extension Study Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, and 38, and 
the Extension Study Early Termination Visit.  
Alkaline phosphatase isoenzymes will be measured at the Baseline Visit (Day 1), Main Study 
Weeks 12, 36, and 38 (Follow-Up Visit), and the Early Termination Visit, and Extension Study 
Day 1, Weeks 12, 36, and 38 (Follow-Up Visit). 
CKMB and troponin I will be measured at the Baseline Visit (Day 1), Main Study Weeks 2, 4, 8, 
12, 16, 20, 24, 30, 36, the Follow-Up Visit (Week 38), and the Early Termination Visit, and 
Extension Study Day 1, Extension Study Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, and 38, and the 
Extension Study Early Termination Visit.  
Bile acids will be measured at Baseline Visit (Day 1), Main Study Weeks 2, 12, and 36, and the 
Early Termination Visit, and Extension Study Day 1, Extension Study Weeks 2, 12, and 36, and 
the Extension Study Early Termination Visit.  
Urine pregnancy tests will be administered for women of child bearing potential only at the 
Baseline Visit (Day 1), Main Study Weeks 2, 4, 8, 12, 16, 20, 24, 30, and 36, and the Early 
Termination Visit, and Extension Study Day 1, Extension Study Weeks 2, 4, 8, 12, 16, 20, 24, 28, 
32, and 36 and the Extension Study Early Termination Visit. Serum pregnancy tests will be 
administered at the Screening Visit (Week -6 to 0) for women of child bearing potential only.  
Thyroid axis hormones (T4, FT4, total T3, free T3 [FT3], and TSH) will be measured at the 
Screening Visit (Week -6 to 0), the Baseline Visit (Day 1), Weeks 2, 4, 8, 12, 16, 20, 24, 30, and 
36, the Follow-Up Visit (Week 38), and the Early Termination Visit, and Extension Study Day 1, 
Extension Study Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, and 36 and the Extension Study Early 
Termination Visit. Anti-thyroid peroxidase antibodies will be measured at the Baseline Visit (Day 
1).  Thyroxine-binding globulin will be measured at the Baseline Visit (Day 1), Weeks 2, 4, 8, 12, 
16, 20, 24, 30, and 36, the Follow Up Visit (Week 38), and the Early Termination Visit, and 
Extension Study Day 1, Extension Study Weeks, 2, 4, 8, 12, 16, 20, 24, 28, 32, and 36 and the 
Extension Study Early Termination Visit if necessary. Reverse T3 will be measured at the Baseline 
Visit (Day 1), Week 12, Week 36 and the Early Termination Visit, and Extension Study Day 1, 
Extension Study Weeks 2, 12, and 36, and the Extension Study Early Termination Visit. 
A fasting metabolic panel (
) will be measured at the 
Screening Visit (Weeks -6 to 0), the Baseline Visit (Day 1), Week 12, Week 36, and the Early 
Termination Visit, and Extension Study Day 1, Extension Study Weeks 12 and 36, and the 
Extension Study Early Termination Visit if necessary. 
 will be 
measured at the Baseline Visit (Day 1), Week 12, Week 36, and the Early Termination Visit, and 
Extension Study Day 1, Extension Study Weeks 12 and 36, and the Extension Study Early 
Termination Visit. 
Fasting lipid parameters (triglyceride, total cholesterol, LDL-C (direct and calculated), HDL-C, 
and non-HDL-C) will be collected at the Screening Visit (Weeks -6 to 0), the Baseline Visit (Day 
1), Main Study Weeks 2, 4, 8, 12, 16, 20, 24, 30, and 36, the Follow-Up Visit (Week 38), and the 
Early Termination Visit, and Extension Study Day 1, Extension Study Weeks, 2, 4, 8, 12, 16, 20, 

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24, 28, 32, and 36 and the Extension Study Early Termination Visit. ApoB, Apo A1 and Lp(a) 
particles will be collected at the Baseline Visit (Day 1), Main Study Weeks 2, 4, 8, 12, 16, 20, 24, 
30, and 36, the Follow-Up Visit (Week 38), and the Early Termination Visit, and Extension Study 
Day 1, Extension Study Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, and 36 and the Extension Study Early 
Termination Visit.  
Cytokeratin-18, FIB-4, ELF, fibrinogen, haptoglobin, alpha-2 macroglobulin, N-terminal pro b-
type natriuretic peptide, apolipoprotein C-III, and ferritin will be measured at the Baseline Visit 
(Day 1), Week 12, Week 36, and the Early Termination Visit, and Extension Study Day 1, 
Extension Study Weeks 12 and 36, and the Extension Study Early Termination Visit.  
High-sensitivity C-reactive protein will be measured at the Baseline Visit (Day 1), Weeks 4, 12, 
24, and 36, and the Early Termination Visit, and Extension Study Day 1, Extension Study Weeks 
4, 12, 24, and 36, and the Extension Study Early Termination Visit.  
Bone biomarkers Type 1 procollagen N-terminal propeptide and CTX will be measured at the 
Baseline Visit (Day 1), Main Study Weeks 12 and 36, and the Early Termination Visit, and 
Extension Study Day 1, Extension Study Weeks 12 and 36, and the Extension Study Early 
Termination Visit.  
Pre-dose PK samples will be drawn at baseline (Day 1), Main Study Weeks 2, 8, 16, 24, and 36, 
and the Early Termination Visit, and Extension Study Day 1, Extension Study Weeks 2, 4, 8, 16, 
24, and 36, and the Extension Study Early Termination Visit. In addition, postdose PK samples 
will be collected at Main Study Week 2 as described in 6.4.2 and the Extension Study Week 2 as 
described in 6.7.2. 
Coagulation markers (APTT, PT, and INR) will be measured at the Screening Visit (Week -6 to 0), 
the Baseline Visit (Day 1), Weeks 2, 4, 8, 12, 16, 20, 24, 30, and 36, at the Follow-Up Visit 
(Week 38), and at the Early Termination Visit, and Extension Study Day 1, Extension Study 
Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, and 36 and the Extension Study Early Termination Visit.  
Genomic samples will be drawn at the Baseline Visit (Day 1). 
9.9 
Vital Signs and Anthropometrics 
Vital signs and anthropometrics (weight, BMI, waist circumference, waist-hip ratio, temperature, 
pulse [resting], respiratory rate, and seated blood pressure [resting]) will be measured at the 
Screening Visit (Week -6 to 0), the Baseline Visit (Day 1), Main Study Weeks 2, 4, 8, 12, 16, 20, 
24, 30, and 36, and the Early Termination Visit, and Extension Study Day 1, Extension Study 
Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, and 36 and the Extension Study Early Termination Visit.  
Blood pressure will be measured using a standardized process:  
• Patient will sit for 5 minutes with feet flat on the floor and measurement arm supported so that 
the midpoint of the manometer cuff is at heart level; 
• Site staff will use of a mercury sphygmomanometer or automatic blood pressure device with 
an appropriately sized cuff with the bladder centered over the brachial artery;  
• Site staff will record the arm used for measurement and use the same arm throughout the study; 
and 
• Site staff will measure and record the blood pressure.  

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Blood pressure will be recorded to the nearest 2 mmHg mark on the manometer or to the nearest 
whole number on the automatic device. A blood pressure reading will be repeated 1 to 2 minutes 
later, and the second reading will also be recorded to the nearest 2 mmHg mark.  
9.10 
Electrocardiograms 
Twelve-lead ECGs with rhythm strip will be performed at the Screening Visit (Week -6 to 0), the 
Baseline Visit (Day 1), Main Study Weeks 2, 4, 8, 12, 16, 20, 24, 30, and 36, and the Early 
Termination Visit, and Extension Study Day 1, Extension Study Weeks 2, 4, 8, 12, 16, 20, 24, 28, 
32, and 36 and the Extension Study Early Termination Visit. Twelve-lead ECGs will be performed 
in triplicate in a consecutive manner after the patient has been resting in the supine position for at 
least 10 minutes. The ECG will include 12 standard leads and will be recorded at a paper speed of 
25 mm/sec. The following ECG parameters will be recorded:  
• PR interval,  
• QRS interval,  
• Heart rate,  
• RR interval,  
• QT interval,  
• QTcB interval, and 
• QTcF interval.  
All ECGs must be evaluated by a qualified reader for the presence of abnormalities.  
9.11 
Physical Examinations 
A complete physical examination will include documentation of general appearance, skin, and 
specific head and neck, heart, lung, abdomen, extremities, and neuromuscular assessments. A 
complete physical examination will be performed at the Screening Visit (Week -6 to 0), and a 
symptom-directed physical examination will be completed at the Baseline Visit (Day 1), Main 
Study Weeks 2, 4, 8, 12, 16, 20, 24, 30, and 36, and the Early Termination Visit, and Extension 
Study Day 1, Extension Study Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, and 36 and the Extension 
Study Early Termination Visit. 
9.12 
Diet and Lifestyle Counseling 
Patients will be counseled on maintaining a consistent diet, exercise regimen, and lifestyle at the 
Screening Visit (Week -6 to 0), Baseline Visit (Day 1), and Main Study Weeks 2, 4, 8, 12, 16, 20, 
24, 30, and 36, and Extension Study Day 1 and Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, and 36.   
9.13 
Health-Related Assessment-Quality of Life 
Patients will undergo a HR-QoL SF-36 assessment at the Baseline Visit (Day 1), Weeks 4, 12, 24, 
and 36, and the Early Termination Visit, and Extension Study Day 1, Extension Study Weeks 4, 
12, 24, and 36 and the Extension Study Early Termination Visit. 

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9.14 
Proton Density Fat Fraction Magnetic Resonance Imaging 
Patients will undergo MRI-PDFF at the Screening Visit (Week -6 to 0), Main Study Weeks 12 and 
36, and the Early Termination Visit, and Extension Study Weeks 12 and 36 and the Extension 
Study Early Termination Visit. The Screening Visit MRI-PDFF will be used as baseline and should 
be obtained as close to randomization as possible. The MRI-PDFFs will be read by a central reader.  
9.15 
Liver Biopsy 
Patients will undergo liver biopsy at the Screening Visit (Week -6 to 0) only in the event that the 
patient does not have available liver biopsy within 180 days of randomization. If a historical biopsy 
is to be used, patients must have had no change in metabolic status (diabetes, lipid metabolism, 
and/or >5% weight gain or loss) or change in diabetes medications. If a historical biopsy is not 
available, patients must have confirmation of ≥10% liver fat content on MRI-PDFF prior to 
undergoing liver biopsy. However, if, in the opinion of the patient’s physician, the patient would 
benefit from and be advised to obtain a liver biopsy, the patient may undergo liver biopsy prior to 
MRI-PDFF. All patients will undergo liver biopsy at Week 36. Patients may undergo liver biopsy 
at the Early Termination Visit based on the discretion of the Investigator. Liver biopsies will be 
read by 1 central reader. Reading will include assessment of fibrosis stage, portal inflammation, 
and NAS.   
9.16 
Dual-Energy X-Ray Absorptiometry 
Patients will undergo DXA scan to assess bone mineral density at the Baseline Visit (Day 1), Main 
Study Week 36, and the Early Termination Visit, and Extension Study Week 36 and the Extension 
Study Early Termination Visit.  
9.17 
Drug Induced Liver Injury Monitoring 
Close clinical monitoring must be applied to the following:  
• Any patient who had normal baseline ALT, AST, and total bilirubin values and then 
experienced a newly treatment-emergent ALT and/or AST value >3 × ULN OR total bilirubin 
value >2 × ULN; or 
• Any patient who had elevated ALT, AST, or total bilirubin values at baseline and then 
experienced a 2-fold increase above the baseline ALT and/or AST values AND/OR a 1.5-fold 
increase above the baseline total bilirubin values.  
The patient must return to the study site within 48 to 72 hours for a confirmatory evaluation and 
central laboratory testing. Repeat laboratory analyses must include the following chemistries: 
ALP, ALT, AST, total and direct bilirubin, INR and lactate dehydrogenase. At the same time repeat 
samples are drawn, a PK sample must be taken.  
Close monitoring of study patients includes: 
• Repeating liver enzyme and serum bilirubin tests at least once a week if abnormalities stabilize 
and the patient is asymptomatic; 
• Obtaining a more detailed history of symptoms and prior or concomitant diseases; 

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• Obtaining a history of concomitant drug use (including non-prescription medications and 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and special 
diets; 
• Ruling out acute viral hepatitis Types A, B, C, D, and E; autoimmune or alcoholic hepatitis; 
hypoxic/ischemic hepatopathy; and biliary tract disease; 
• Obtaining a history of exposure to environmental chemical agents; 
• Considering gastroenterology or hepatology consultation; and 
• Reporting to the Sponsor and Medical Monitor within 48 hours.  
If close monitoring is not possible, study drug should be discontinued. If a patient lives in a remote 
area, they can be tested locally and the results communicated to the investigator site promptly. 
Study drug must be discontinued if any of the following criteria are met: 
• For patients with ALT and/or AST values ≤1.5 × ULN at baseline: 
o Post-baseline ALT or AST value is >5 × ULN, or 
o Post-baseline ALT or AST value is >3 × ULN and total bilirubin is >2 × ULN or INR is 
>1.5; 
• For patients with ALT and/or AST values >1.5 × ULN at baseline: 
o Post-baseline ALT or AST value is >3 × the baseline value and at least 5 × ULN, or 
o Post-baseline ALT or AST value is >2 × the baseline value and is accompanied by a 
concomitant total bilirubin increase to >2 × the baseline value or the INR concomitantly 
increases by >0.2. 
Study drug will be discontinued for any patient with the appearance of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) and 1 of the 
following:  
• Had normal baseline ALT and AST values and then experienced a >3 × ULN post-baseline 
increase; or 
• Had elevated ALT and/or AST levels at baseline and then experienced a 2-fold post-baseline 
increase. 
Study drug may be resumed once the toxicity returns to below the values prompting 
discontinuation. If total bilirubin, ALT, or AST elevation recurs following rechallenge with study 
drug, then study drug must be permanently discontinued and the patient managed according to 
local practice.  
If acute viral hepatitis is diagnosed while the patient is on the study, study drug must be 
discontinued immediately and the necessary Early Termination Visit assessments will be 
performed (see Section 6.6).  
9.18 
Cardiovascular Monitoring 
Patients will be closely monitored for signs of cardiac toxicity including assessments of CV AEs 
and symptoms.   

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If any of the following abnormalities are identified, an additional clinical investigation may be 
appropriate: 
• Onset of new (i.e., not present at baseline or documented in the medical history) and 
clinically significant arrhythmia which is persistent (ie, confirmed on repeat assessment 
on a second visit), including but not limited to: 
o Sinus tachycardia (defined for the study as a HR ≥ 100 beat/min and at least a 20 
bpm increase from baseline) 
o Frequent ventricular premature contractions or atrial fibrillation 
• Systolic hypertension (defined for the study as a SBP >160 mmHg and at least a 20 
mmHg increase from baseline) 
• Increase in troponin I vs. baseline and above the ULN. 
 
Except in cases requiring immediate action for subject protection, the Investigator should consult 
with the Medical Monitor on how to best further determine rate/rhythm or blood pressure changes, 
in light of the known day to day variability in these physiological variables. The additional 
investigation may include the patient return to the study site within 72 hours for a confirmatory 
evaluation and repeat assessment. In this case, Sponsor and Medical Monitor should be notified 
within 48 h of the event. At the same time repeat lab samples are drawn, a PK sample may also be 
collected as deemed appropriate by Investigator and medical monitor.  
Confirmatory evaluations may include: 
• Obtaining a more detailed history of symptoms and prior or concomitant diseases; 
• Obtaining a history of concomitant drug use (including non-prescription medications and 
herbal and dietary supplement preparations), alcohol use, recreational drug use, changes in 
activity, and special diets; 
• Ruling out acute cardiovascular conditions, such as acute coronary syndrome, myocarditis, or 
acute aortic syndrome. 
• Repeating ECG, troponin and CK-MB tests on at least one further occasion if abnormalities 
stabilize and the patient is asymptomatic; 
• Considering requesting a cardiology consultation 
• If immediate dose reduction or dose discontinuation is not required for concerns of subject 
safety, then at the Investigator's discretion more complete documentation may be obtained via, 
e.g. Holter monitoring or 24h Ambulatory Blood Pressure Monitoring before deciding to 
discontinue the subject.   
 
If close monitoring is not possible, study drug should be discontinued temporarily, pending further 
evaluation by the Investigator in collaboration with the Medical Monitor and Sponsor. If a patient 
lives in a remote area, they can be tested locally and the results communicated to the investigator 
site promptly. 

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Study drug must be temporarily discontinued if the above abnormalities are confirmed.  Frequency 
of subsequent repeat assessments will be determined by Sponsor and Medical Monitor.   
Study drug may be resumed once abnormal results return to the normal range or to the patient’s 
baseline values.   
Study drug must be permanently discontinued if any of the following criteria are met: 
1. A definite new cardiovascular diagnosis is confirmed that is considered to be probably 
related to study drug. 
2. Abnormalities in symptoms, ECG, or laboratory biomarkers recur following re-
introduction of study drug. 
3. Abnormalities in symptoms, ECG, or laboratory biomarkers do not return to normal or 
baseline values. 
 
The required Early Termination Visit assessments will be performed (see Section 6.6). 
 
 

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10 
STATISTICS 
10.1 
Analysis Populations 
The Intent-to-Treat (ITT) Population will include all patients who are randomized in the study and 
receive at least 1 dose of study drug. The ITT Population will be used for all efficacy analyses.  
The Per Protocol Population will include all ITT patients who finish the Week 12 visit with valid 
MRI-PDFF measurements and do not have any major protocol deviations. Patients who are 
<80% compliant over the course of the initial 12-week Treatment Period will not be included in 
the Per Protocol Population. 
The Safety Population will include all patients who are randomized in the study and receive at 
least 1 dose of study drug and will be used for all safety analyses. 
Demographics, disposition, and study populations will be summarized descriptively. 
10.2 
Statistical Methods 
10.2.1 
Analysis of Efficacy 
10.2.1.1 
Primary efficacy analysis 
The primary efficacy variable will be the percent change in MRI-PDFF from baseline to Week 12. 
Summary statistics (number of patients, mean, standard deviation, median, minimum, and 
maximum) at all visits and change from baseline will be provided. The primary efficacy analysis 
will be analyzed with an analysis of covariance (ANCOVA) model with treatment as a factor. For 
any patients in the ITT Population with a missing primary efficacy parameter, the control 
(placebo)-based pattern mixture model will be used. Based on PK obtained in healthy volunteers 
dosed for up to two weeks on doses of MGL-3196 from 20-200 mg per day, a significant fraction 
of patients randomized to an 80 mg dose may have their dose reduced to 60 mg after PK assessment 
at Week 2. The multiplicity (MGL-3196 60 mg versus placebo and MGL-3196 80 mg versus 
placebo) will be controlled by Dunnett’s Test. The primary efficacy analysis will be performed 
based on the ITT Population and repeated based on the Per Protocol Population.  
10.2.1.2 
Secondary efficacy analysis 
For the continuous secondary efficacy variables, the same ANCOVA model will be used. 
Normality will be tested for the model residuals. For certain efficacy variables (such as hsCRP and 
triglycerides), logarithm transformation may be performed prior to fitting the ANCOVA model. 
For the categorical secondary efficacy variables, Fisher’s exact test will be used to compare the 
odds ratio between MGL-3196 doses versus placebo. 
10.2.1.3 
Other efficacy analysis 
The same efficacy analyses used for the secondary efficacy variables will be used for the 
tertiary/exploratory efficacy variables.  
10.2.1.4 
Subgroup analysis 
Subgroup analysis of the primary efficacy variable and/or selected secondary/other efficacy 
variables may be performed, such as gender (male/female), BMI (≥30 kg/m2 or <30 kg/m2), and 
age group (≥median or <median). 

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10.2.2 
Analysis of Safety 
The safety endpoints for this study include: adverse events, safety laboratory assessments, vital 
signs, 12-lead ECGs, concomitant medications, and clinical assessments. 
The adverse events will be coded using the latest version of the Medical Dictionary for Regulatory 
Activities (MedDRA). Treatment-emergent adverse events (TEAEs) will be defined as adverse 
events that are new or worsening after the first dose of study drug. A general summary of patients 
with TEAEs and SAEs will be tabulated with numbers and percentages of patients, and repeated 
for severity and relationship to study drug per treatment group. The number of adverse events 
leading to withdrawal and SAEs leading to death will also be summarized. The incidence of 
TEAEs will be summarized by body system and treatment group. 
The safety laboratory data will be summarized by visit and by treatment group, along with changes 
from the baseline. The values that are <LLN or >ULN of the reference range will be flagged. Those 
values or changes in values that are identified as being clinically significant will be flagged. 
Laboratory abnormalities of special interest will be summarized.   
10.2.3 
Interim Analysis 
Interim analysis is not designed for this study. However, an analysis will be performed once all 
patients reach Week 12 of the Treatment Period. The analysis will assess the efficacy of 
MGL-3196 on percent change in liver fat by MRI-PDFF.  
10.2.4 
Data Safety Monitoring Board 
A Data Safety Monitoring Board (DSMB) will oversee the study to ensure patient safety and to 
advise if any dosing alterations are recommended. The DSMB will review safety including thyroid 
hormone effects, liver-related events (ie, clinically meaningful elevations in liver enzymes ALT, 
AST, and bilirubin), cardiovascular assessment (ie, changes in ECG, cardiac biomarkers, cardiac 
AEs, cardiac symptoms, arrhythmias, etc.), SAEs for trends in causality, and other efficacy (lipid 
parameters) and safety data as needed. The DSMB will perform regularly scheduled reviews the 
first scheduled for when 25 patients have received 6 weeks of treatment. Additional regularly timed 
meetings will be held and ad hoc meetings may also occur if determined by Madrigal and the 
DSMB.  
10.2.5 
 Sample Size Determination 
Approximately 117 patients in total will be randomized to 80 mg (2/3) or placebo (1/3) treatments. 
After PK assessment, a significant fraction of patients’ combined AUC (MGL-3196 plus MGL-
3196-M1) may exceed 5500 ng*hr/ml resulting in a dose reduction to 60 mg. In order to power 
the study appropriately for an efficacious dose (which may be ≥80mg), randomization may 
continue until approximately 36 patients have continued at Week 4 on the 80 mg dose. It is 
estimated that the treatment difference of percent change in hepatic fat fraction from baseline to 
Week 12 between any dose of MGL-3196 and the placebo group is about -30%. With a common 
standard deviation for the percent change in hepatic fat fraction at 35%, 36 patients per group 
completing the Week 12 visit will provide 90% power with a 2-sample t-test. The significance 
level is set as 0.025 for the consideration of multiplicity in comparisons of 2 daily dosing regimens 

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of MGL-3196 versus the placebo group. The enrollment size is designed to allow for 10% drop 
out before the Week 12 visit, and as such, patients who drop out of the study will not be replaced. 
With the sample size of 39 patients per treatment, the power for selected secondary efficacy 
endpoints was calculated. The baseline hepatic fat fraction is expected to be approximately 15% 
to 17%, thus the change from baseline to Week 12 in hepatic fat fraction is approximately -5.5% 
when comparing to placebo. With common standard deviation of change in hepatic fat fraction as 
6%, 36 completed patients will provide 94% power for the study when evaluating the treatment 
effect in change of hepatic fat fraction. 
In addition, the sample size is expected to provide meaningful liver biopsy-related data.  
 

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11 
DATA MANAGEMENT AND RECORD KEEPING 
11.1 
Data Management 
11.1.1 
Data Handling 
Data will be recorded at the site on eCRFs and reviewed by the clinical research associate (CRA) 
during monitoring visits. The CRAs will verify data recorded in the EDC system with source 
documents. All corrections or changes made to any study data must be appropriately tracked in an 
audit trail in the EDC system. An eCRF will be considered complete when all missing, incorrect, 
and/or inconsistent data has been accounted for. 
11.1.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory requirements. 
11.1.3 
Data Entry 
Data must be recorded using the EDC system as the study is in progress. All site personnel must 
log into the system using their secure user name and password in order to enter, review, or correct 
study data. These procedures must comply with Title 21 of the Code of Federal Regulations 
(21 CFR Part 11) and other appropriate international regulations. All passwords will be strictly 
confidential. 
11.1.4 
Medical Information Coding 
For medical information, the following thesauri will be used: 
• Latest version of MedDRA for adverse events and medical history, and 
• World Health Organization Drug Dictionary for prior and concomitant medications. 
11.1.5 
Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, will 
be referred to the investigative site for resolution through data queries. 
The eCRFs must be reviewed and electronically signed by the Investigator. 
11.2 
Record Keeping 
Records of patients, source documents, monitoring visit logs, eCRFs, inventory of study product, 
regulatory documents, and other Sponsor correspondence pertaining to the study must be kept in 
the appropriate study files at the site. Source data is defined as all information in original records 
and certified copies of original records of clinical findings, observations, or other activities in a 
clinical study necessary for the evaluation and reconstruction of the clinical study. Source data are 
contained in source documents (original records or certified copies). These records will be retained 
in a secure file for the period as set forth in the Clinical Study Agreement. Prior to transfer or 
destruction of these records, the Sponsor must be notified in writing and be given the opportunity 
to further store such records.  

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12 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL 
12.1 
Ethical Conduct of the Study 
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve human patients. Compliance with this 
standard provides public assurance that the rights, safety, and well being of study patients are 
protected, consistent with the principles that have their origin in the Declaration of Helsinki, and 
that the clinical study data are credible. 
12.2 
Institutional Review Board 
The IRB will review all appropriate study documentation in order to safeguard the rights, safety, 
and well-being of patients. The study will only be conducted at sites where IRB approval has been 
obtained. The protocol, Investigator’s Brochure, informed consent form (ICF), advertisements (if 
applicable), written information given to the patients, safety updates, annual progress reports, and 
any revisions to these documents will be provided to the IRB by the Investigator. 
Federal regulations and ICH require that approval be obtained from an IRB prior to participation 
of patients in research studies. Prior to study onset, the protocol, any protocol amendments, ICFs, 
advertisements to be used for patient recruitment, and any other written information regarding this 
study to be provided to a patient or patient’s legal guardian must be approved by the IRB. 
No drug will be released to the site for dosing until written IRB authorization has been received 
by the Sponsor. 
12.3 
Informed Consent 
The ICF and any changes to the ICF made during the course of the study must be agreed to by the 
Sponsor or designee and the IRB prior to its use and must be in compliance with all ICH GCP, 
local regulatory requirements, and legal requirements.   
The Investigator must ensure that each study patient is fully informed about the nature and 
objectives of the study and possible risks associated with participation and must ensure that the 
patient has been informed of his/her rights to privacy. The Investigator will obtain written informed 
consent from each patient before any study-specific activity is performed and should document in 
the source documentation that consent was obtained prior to enrollment in the study. The original 
signed copy of the ICF must be maintained by the Investigator and is patient to inspection by a 
representative of the Sponsor, their representatives, auditors, the IRB and/or regulatory agencies. 
A copy of the signed ICF will be given to the patient. 
12.4 
Study Monitoring Requirements 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with 
the protocol, Declaration of Helsinki, ICH GCP, Directive 2001/20/EC, and applicable regulatory 
requirements, and that valid data are entered into the eCRFs. 
To achieve this objective, the monitor’s duties are to aid the Investigator and, at the same time, the 
Sponsor in the maintenance of complete, legible, well organized, and easily retrievable data. 
Before the enrollment of any patient in this study, the Sponsor or their designee will review with 
the Investigator and site personnel the following documents: protocol, Investigator’s Brochure, 

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eCRFs and procedures for their completion, informed consent process, and the procedure for 
reporting SAEs. 
The Investigator will permit the Sponsor or their designee to monitor the study as frequently as 
deemed necessary to determine that data recording and protocol adherence are satisfactory. During 
the monitoring visits, information recorded on the eCRFs will be verified against source 
documents and requests for clarification or correction may be made. After the eCRF data is entered 
by the site, the CRA will review the data for safety information, completeness, accuracy, and 
logical consistency. Computer programs that identify data inconsistencies may be used to help 
monitor the clinical study. If necessary, requests for clarification or correction will be sent to 
Investigators. The Investigator and his/her staff will be expected to cooperate with the monitor and 
provide any missing information, whenever possible. 
All monitoring activities will be reported and archived. In addition, monitoring visits will be 
documented at the investigational site by signature and date on the study-specific monitoring log. 
12.5 
Disclosure of Data 
Data generated by this study must be available for inspection by the FDA, the Sponsor or their 
designee, applicable foreign health authorities, and the IRB, as appropriate. Patients or their legal 
representatives may request their medical information be given to their personal physician or other 
appropriate medical personnel responsible for their welfare. 
Patient medical information obtained during the study is confidential and disclosure to third parties 
other than those noted above is prohibited. 
12.6 
Retention of Records 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
will keep records, including the identity of all participating patients (sufficient information to link 
records, eg, CRFs and hospital records), all original signed ICFs, copies of all CRFs, SAE forms, 
source documents, and detailed records of treatment disposition. The records should be retained 
by the Investigator according to specifications in the ICH guidelines, local regulations, or as 
specified in the Clinical Study Agreement, whichever is longer. The Investigator must obtain 
written permission from the Sponsor before disposing of any records, even if retention 
requirements have been met. 
If the Investigator relocates, retires, or for any reason withdraws from the study, the Sponsor should 
be prospectively notified. The study records must be transferred to an acceptable designee, such 
as another Investigator, another institution, or to the Sponsor.   
12.7 
Publication Policy 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting. Each Investigator is obligated to keep data 
pertaining to the study confidential. The Investigator must consult with the Sponsor before any 
study data are submitted for publication. The Sponsor reserves the right to deny publication rights 
until mutual agreement on the content, format, interpretation of data in the manuscript, and journal 
selected for publication are achieved. 

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12.8 
Financial Disclosure 
Investigators are required to provide financial disclosure information to the Sponsor to permit the 
Sponsor to fulfill its obligations under 21 CFR §54. In addition, Investigators must commit to 
promptly updating this information if any relevant changes occur during the study and for a period 
of 1 year after the completion of the study.  

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13.2.5 
Pharmacokinetic Samples 
 
 
 
 
 
 
 

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14 
REFERENCES 
1. Waters DD, Brotons C, Chiang CW, et al. Lipid Treatment Assessment Project. Lipid 
treatment assessment project 2: a multinational survey to evaluate the proportion of patients 
achieving low-density lipoprotein cholesterol goals. Circulation. 2009 July 7;120(1):28-34. 
2. Joy TR and Hegele RA. Narrative review: statin-related myopathy. Ann Intern Med. 
2009 Jun 15;150(12):858-868. 
3. DeFronzo RA and Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for 
NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. 
Diabetes Care. 1991 Mar;14(3):173-194.  
4. Mooradian AD. Dyslipidemia in type 2 diabetes mellitus. Nat Clin Pract Endocrinol Metab. 
2009 Mar;5(3):150-159. 
5. Toledo FG, Sniderman AD and Kelley DE. Influence of hepatic steatosis (fatty liver) on 
severity and composition of dyslipidemia in type 2 diabetes. Diabetes Care. 2006 Aug;29(8): 
1845-1850. 
6. LaBreque d et al. Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis World 
Gastroenterology Organization Global Guidelines 
http://www.worldgastroenterology.org/NAFLD-NASH.html, 2012. 
7. Baxter JD and Webb P. Thyroid hormone mimetics: potential applications in atherosclerosis, 
obesity and type 2 diabetes. Nat Rev Drug Discov. 2009 Apr:8(4):308-320. 
8. Grover GJ, Egan DM, Sleph PG, Beehler BC, Chiellini G, Nguyen NH, Baxter JD and Scanlan 
TS. Effects of the thyroid hormone receptor agonist GC-1 on metabolic rate and cholesterol in 
rats and primates: selective actions relative to 3,5,3'-triiodo-L-thyronine. Endocrinology. 2004 
April;145(4):1656-1661. 
9. Grover GJ, Mellstrom K, Ye L, Malm J, Li YL, Bladh LG, Sleph PG, Smith MA, George R, 
Vennstrom B, Mookhtiar K, Horvath R, Speelman J, Egan D and Baxter JD. Selective thyroid 
hormone receptor-beta activation: a strategy for reduction of weight, cholesterol, and 
lipoprotein (a) with reduced cardiovascular liability. Proc Natl Acad Sci U S A. 2003 Aug 19; 
100(17):10067-10072.  
10. Johansson L, Rudling M, Scanlan TS, Lundasen T, Webb P, Baxter J, Angelin B and Parini P. 
Selective thyroid receptor modulation by GC-1 reduces serum lipids and stimulates steps of 
reverse cholesterol transport in euthyroid mice. Proc Natl Acad Sci U S A. 2005 July 
19;102(29):10297-10302. 
11. Morkin E, Pennock GD, Spooner PH, Bahl JJ and Goldman S.Clinical and experimental 
studies on the use of 3,5-diiodothyropropionic acid, a thyroid hormone analogue, in heart 
failure. Thyroid. 2002;12(6):527-533.  
12. Gogakos AI, Duncan Bassett JH and Williams GR. Thyroid and bone. Arch Biochem Biophys. 
2010 Nov 1;503(1):129-136.  
13. Klein I and Danzi S. Thyroid disease and the heart. Circulation. 2007 Oct 
9;116(15):1725-1735.  

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Protocol Amendment 6, 26 December 2017 
119 
14. Erion MD, Cable EE, Ito BR, Jiang H, Fujitaki JM, Finn PD, Zhang BH, Hou J, Boyer SH, 
van Poelje PD and D. L. Linemeyer DL. Targeting thyroid hormone receptor-beta agonists to 
the liver reduces cholesterol and triglycerides and improves the therapeutic index. Proc Natl 
Acad Sci U S A. 2007 Sept 25;104(39):15490-15495.  
15. Dong BJ. How medications affect thyroid function. West J Med. 2000 Feb;172(2):102-106. 
16. Bengsston, P. “Karo Bio terminates the Eprotirome Program” Karo Bio February 14, 2012 
http://www.karobio.com/investormedia/pressreleaser/pressrelease?pid=639535. 
17. Sjouke B, Langslet G, Ceska R, Nicholls SJ, Nissen SE, Ohlander M, Ladenson, PW, Olsson 
AG, Hovingh GK, and Kastelein JJ. Eprotirome in patients with familial 
hypercholesterolaemia (the AKKA trial): a randomised, double-blind, placebo-controlled 
phase 3 study. Lancet Diabetes Endocrinol. 2014 Jun;2(6):455-463.  
18. Kelly MJ, Pietranico-Cole S, Larigan JD, Haynes NE, Reynolds CH, Scott N, Vermeulen J, 
Dvorozniak M, Conde-Knape K, Huang KS, So SS, Thakkar K, Qian Y, Banner B, Mennona 
F, Danzi S, Klein I, Taub R and Tilley J. Discovery of 2-[3,5-Dichloro-4-(5-isopropyl-6-oxo-
1,6-dihydropyridazin-3-yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazine-6-
carbonitrile (MGL-3196), a Highly Selective Thyroid Hormone Receptor beta Agonist in 
Clinical Trials for the Treatment of Dyslipidemia. J. Med. Chem. 2014;57(10):3912-3923.  
19. Taub R, Chiang E, Chabot-Blanchet M, Kelly MJ, Reeves RA, Guertin MC, and Tardif JC. 
Lipid lowering in healthy volunteers treated with multiple doses of MGL-3196, a liver-targeted 
thyroid hormone receptor-beta agonist. Atherosclerosis. 2013 Oct;230(2):373-380. 
20. Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, Cooper DS, Kim BW, 
Peeters RP, Rosenthal MS, Sawka AM; American Thyroid Association Task Force on Thyroid 
Hormone Replacement. Guidelines for the treatment of hypothyroidism: prepared by the 
american thyroid association task force on thyroid hormone replacement. Thyroid. 2014 
Dec;24(12):1670-751. doi: 10.1089/thy.2014.0028 
 

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120 
APPENDIX A:  SCHEDULE OF PROCEDURES - MAIN STUDY 
Continues on following page 
Study Week 
Screening 
Period 
Treatment Period 
Up to -6 
Weeks 
Baseline 
Week 
2 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 
30  
Week 
36 
 
Follow-Up 
Week 38 
Early 
Term [1] 
 Study Day Up to -42 
1 
14 
28 
56 
84 
112 
140 
168 
210 
252 
266 
n/a 
Determination of eligibility  
X [2] 
X 
 
 
 
 
 
 
 
 
 
 
 
Review of medical history 
[3] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Obtain informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG [4] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Complete/symptom-directed 
physical examination [5] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
HepB, HepC, and HIV 
screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization [6] 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Study drug dispensing and 
accountability [7] 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Vital signs/anthropometrics 
[8] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Hematology profile 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting chemistry profile [9] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Total and free testosterone, 
LH, FSH, estradiol [10] 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
X 
SHBG 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CK-MB, troponin I 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Bile acids 
 
X 
X 
 
 
X 
 
 
 
 
X 
 
X 
ALP isoenzymes 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
X 
Urinalysis  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Pregnancy test [11] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Thyroid axis hormones [12] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-05 
Confidential & Proprietary 
Protocol Amendment 6, 26 December 2017 
 
121 
 
APPENDIX A:  SCHEDULE OF PROCEDURES - MAIN STUDY (CONTINUED) 
Footnotes on following page 
 
 
Study Week 
Screening 
Period 
Treatment Period 
Up to -6 
Weeks 
Baseline 
 Day 1 
Week 
2 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 
30  
Week 
36 
 
Follow-Up 
Week 38 
Early 
Term [1] 
 Study Day Up to -42 
1 
14 
28 
56 
84 
112 
140 
168 
210 
252 
266 
n/a 
Diet and lifestyle counseling 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Health-related assessment 
(HR-QoL SF-36) 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
MRI-PDFF 
X 
X[13] 
 
 
 
X 
 
 
 
 
X[13] 
 
X 
Liver biopsy [14] 
X [15] 
 
 
 
 
 
 
 
 
 
X 
 
X 
Fasting metabolic panel [16] 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
Fasting lipid parameters 
[17] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CK-18, FIB-4, and ELF 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
Pre-dose PK sampling [18]  
 
X 
X[19] 
X 
X 
 
X 
 
X 
 
X 
 
X 
hsCRP 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Other biomarkers [20] 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
Bone biomarkers [21] 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
Coagulation markers [22] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DXA 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Genomics sample 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Review alcohol 
consumption 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Review concomitant 
medications 
-----------------------------------------------------------------continuous-------------------------------------------------------------------- 
 
Review adverse events 
-----------------------------------------------------------------continuous-------------------------------------------------------------------- 
 
 
 

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Clinical Study Protocol MGL-3196-05 
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Protocol Amendment 6, 26 December 2017 
 
123 
APPENDIX B: SCHEDULE OF PROCEDURES - EXTENSION STUDY 
Continues on following page 
 
 
 
 
 
Extension Study 
 
Main Study 
Week 38 / Ext. 
Study Day 1 [1] 
Week 
2 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 
28 
Week 
32 
Week 
36 
Follow-
Up 
Week 38 
Early 
Term [3] 
Extension Study Day 
1 
14 
28 
56 
84 
112 
140 
168 
196 
224 
252 
266 
n/a 
Determination of 
eligibility  
X[2] 
 
 
 
 
 
 
 
 
 
 
 
 
Obtain informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG [4] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Complete/symptom-
directed physical 
examination [5] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Study drug dispensing and 
accountability [6] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Vital signs /  
anthropometrics [7] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Hematology profile 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting chemistry profile 
[8] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Total and free testosterone, 
LH, FSH, estradiol [9] 
X 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
SHBG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CK-MB, troponin I 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Bile acids 
X 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
ALP isoenzymes 
X 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Urinalysis  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Pregnancy test [10] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Thyroid axis hormones 
[11] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Madrigal Pharmaceuticals, Inc. 
Clinical Study Protocol MGL-3196-05 
Confidential & Proprietary 
Protocol Amendment 6, 26 December 2017 
 
124 
 
APPENDIX B:  SCHEDULE OF PROCEDURES - EXTENSION STUDY (CONTINUED) 
Footnotes on following page 
 
 
 
 
Extension Study 
 
Main Study 
Week 38 / Ext. 
Study Day 1 
[2] 
Week 
2 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 
28 
Week 
32 
Week 
36 
Follow-
Up 
Week 38 
Early 
Term [3] 
Extension Study Day 
1 
14 
28 
56 
84 
112 
140 
168 
196 
224 
252 
266 
n/a 
Diet and lifestyle 
counseling 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Health-related assessment 
(HR-QoL SF-36) 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
X 
MRI-PDFF 
 
 
 
 
X 
 
 
 
 
 
X[12] 
 
X 
Fibroscan 
 
 
 
 
 
 
 
 
 
 
X 
 
 
DXA 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Fasting metabolic  
panel [13] 
X 
 
 
 
X 
 
 
 
 
 
X 
 
X 
Fasting lipid parameters 
[14] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CK-18, FIB-4, and ELF 
X 
 
 
 
X 
 
 
 
 
 
X 
 
X 
Pre-dose PK sampling 
[15]  
X 
X[16] 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
hsCRP 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
X 
Other biomarkers [17] 
X 
 
 
 
X 
 
 
 
 
 
X 
 
X 
Bone biomarkers [18] 
X 
 
 
 
X 
 
 
 
 
 
X 
 
X 
Coagulation markers [19] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review alcohol 
consumption 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Review concomitant 
medications 
-----------------------------------------------------------continuous-------------------------------------------------------------- 
Review adverse events 
-----------------------------------------------------------continuous-------------------------------------------------------------- 
 
 

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Protocol Amendment 6, 26 December 2017 
 
125 
APPENDIX B: SCHEDULE OF PROCEDURES – EXTENSION STUDY (CONTINUED) 
 
1. 
The Extension Study Day 1 visit should occur within 60 days inclusive of the Main Study Week 36 Visit and may occur concurrently with the Main Study Week 38 Follow-up Visit. The 
Extension Study Informed Consent Form must be signed prior to any Extension Study-related procedures. 
2. 
See Inclusion Criteria #9 for details regarding patient eligibility to participate in the extension phase of the study. 
3. 
The exact Extensions Study Early Termination procedures to be completed will depend on the guidance and discretion of the Investigators, Medical Monitors, and Sponsor and will 
include factors such as why and when the patient terminated early.  
4. 
See Section 9.10 for instructions on performing 12-lead ECG.  
5. 
Complete physical examination to be completed at screening only.  
6. 
Treatments include MGL-3196 40 to 120 mg. Each patient will receive study drug bottles labeled as A and B. Patients will take 1 capsule from bottle A and 1 capsule from bottle B once-
daily in the morning. No study drug will be dispensed at Extension Study Week 2, Week 36, or Early Termination. Study drug accountability will not be assessed at Day 1.  
7. 
Includes weight, BMI, waist circumference, waist-hip ratio, temperature, pulse, respiratory rate, and seated blood pressure. Pulse and blood pressure will be taken at rest.  
8. 
Samples to be collected under fasting conditions (no food or drink other than water for 10 hours prior to visit). For a list of analytes to be collected, see Appendix C. If a patient requires 
close clinical monitoring, the patient may be asked to return to the study site for additional visits or laboratory assessments (see Section 9.17).  
9. 
Free testosterone to be calculated from total testosterone, SHBG, and serum albumin at the Extension Study Day 1, Week 12, Week 36, and the Early Termination Visit.  
10. Urine pregnancy test for women of child bearing potential.  
11. Includes T4, FT4, total T3, FT3, TBG, and TSH. Anti-TPO antibodies to be measured at Baseline Visit (Day 1) only. Reverse T3 at the Day 1, Week 12, Week 36, and the Early Termination Visit 
only. 
12. Extension Study Week 36 MRI-PDFF should be obtained while on treatment within 10 days prior to the visit. 
13. Samples to be collected under fasting conditions (no food or drink other than water for 10 hours prior to visit). Includes 
 
 at Extension Study Day 1, Week 12, Week 36, and the Early Termination Visit only. 
14. Samples to be collected under fasting conditions (no food or drink other than water for 10 hours prior to visit). Includes triglyceride, total cholesterol, LDL-C (direct and calculated), 
HDL-C, non-HDL-C, ApoB, Apo AI, and Lp(a) particles.  
15. Patients will be instructed not to take study drug prior to PK sampling.  
16. Patients will be instructed to fast overnight prior to predose PK sampling. A PK sample will also be collected at 4 hours postdose. Patients may have a low fat meal 1 hour postdose 
following any other assessments requiring fasting (eg, chemistry, hematology, SHBG, thyroid axis hormones, and fasting lipid parameters). All other study assessments will be obtained as 
usual.  
17. Samples to be collected include fibrinogen, haptoglobin, alpha-2 macroglobulin, N-terminal pro b-type natriuretic peptide, apolipoprotein C-III, and ferritin. 
18. Serum sample for Type 1 procollagen N-terminal propeptide and CTX.  
19. Includes activated partial prothrombin time, prothrombin time, and international normalized ratio.  
 

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APPENDIX C:  CLINICAL LABORATORY ANALYTES 
Chemistry:  
• Alkaline phosphatase  
• Alkaline phosphatase isoenzymes 
• Alanine aminotransferase 
• Amylase 
• Aspartate aminotransferase 
• Blood urea nitrogen 
• Calcium 
• Carbon dioxide 
• Chloride 
• Creatine kinase 
• Creatinine 
• Direct bilirubin 
• Estimated glomerular filtration rate (derived from creatinine) 
• Gamma-glutamyl transpeptidase  
• Glucose 
• Lactate dehydrogenase 
• Lipase 
• Magnesium 
• Phosphate 
• Potassium 
• Serum albumin 
• Sodium 
• Total bilirubin 
• Total protein 
• Uric acid 
Hematology: 
• Hemoglobin 
• Hematocrit 
• Red blood cell count 
• White blood cell count 
• Platelets 
• Mean corpuscular volume 
• Mean corpuscular hemoglobin 
• Mean corpuscular hemoglobin concentration 
• Differentials % 
• Differentials absolute 
• Red blood cell morphology 
 
 

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Urinalysis: 
• pH 
• Specific gravity 
• Protein 
• Glucose 
• Ketones 
• Bilirubin 
• Blood 
• Nitrate 
• Urobilinogen 
• Leukocyte esterase 
Coagulation: 
• Activated partial prothrombin time 
• Prothrombin time 
• International normalized ratio 
Viral assessments: 
• Hepatitis B surface antigen (qualitative) 
• Hepatitis C virus antibody 
• Hepatitis C virus ribonucleic acid (qualitative) (only if HCV Ab positive) 
• Human immunodeficiency virus 1 and 2 antibody differentiation 
Sex hormones: 
• Estradiol 
• Free (calculated) testosterone 
• Follicle stimulating hormone 
• Luteinizing hormone 
• Sex hormone binding globulin 
• Total testosterone 
Thyroid axis hormones:  
• Anti-thyroid peroxidase 
• Free triiodothyronine 
• Free thyroxine 
• Thyroxine 
• Thyroxine-binding globulin 
• Total triiodothyronine 
• Thyroid stimulating hormone 
• Reverse T3 

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Metabolic panel:  
• Adipose tissue insulin resistance 
• Adiponectin 
• Glucose 
• Hemoglobin A1c 
• Homeostatic model assessment insulin resistance (calculated) 
• Insulin 
• Non-esterified fatty acid 
Lipid panel: 
• Apolipoprotein B 
• High-density lipoprotein cholesterol 
• Low-density lipoprotein cholesterol (direct and calculated) 
• Lipoprotein(a) particles 
• Non-high-density lipoprotein cholesterol 
• Total cholesterol 
• Triglycerides 
• Apolipoprotein A1 
Bone biomarkers: 
• C-terminal telopeptide 
• Type 1 procollagen N-terminal propeptide 
Other markers: 
• Cytokeratin-18 
• Enhanced liver function 
• Fibrosis-4 
• High sensitivity C-reactive protein 
• Creatine kinase MB 
• Troponin I 
• Bile acids 
• Fibrinogen 
• Haptoglobin 
• Alpha-2 macroglobulin 
• N-terminal pro b-type natriuretic peptide 
• Apolipoprotein C-III 
• Ferritin 
 
Other assessments: 
• Urine pregnancy test (for women of child bearing potential only) 
• Pharmacokinetic sample 
• Genomic sample 
• See Section 9.17 for possible labs and assessments for drug induced liver injury monitoring